Principal Component Analysis Approach for Determination Of

Principal Component Analysis Approach for Determination of Stroke Protein Biomarkers and Modified Atmospheric Pressure Chemical Ionization Source Development for Volatile Analyses

A dissertation submitted to the Graduate School Of the University of Cincinnati

In partial fulfillment of the Requirements for the degree of

DOCTORATE OF PHILOSOPHY

In the Department of Chemistry Of the College of Arts and Sciences

March 2017

Keaton S. Nahan

B.S., Forensic Science, Chestnut Hill College, Philadelphia, PA, May 2011

Committee Co-Chairs: Dr. Julio A. Landero Figueroa and Dr. Peng Zhang

Abstract

Proteins play a role in neurological health and disorders. About 25% of proteins contain metals and these proteins are known as metalloproteins. Both blood plasma proteins and metalloproteins play an active role in stroke. These proteins may be quantified with approaches as simple as multiplexed assay to that of quantitative protein mass spectrometry (proteomics).

Identification of present bound metals is more elusive. Inductively coupled plasma mass spectrometry (ICP-MS) is capable of both quantitation as well as speciation of metalloproteins when coupled with chromatography. Determination of metalloproteins, for use as a stroke determination tool, was performed by bottom up proteomics. Multivariate analysis was used to simplify the determination of important stroke biomarkers that were identified or quantified by quantitative multiplexed assays and tandem mass spectrometry, respectively.

While ICP-MS was used as a means for determination of metal containing species, atmospheric pressure chemical ionization mass spectrometry (APCI-MS) is used for quantitation of volatile species. Typical means of APCI-MS are coupled with chromatography for separations prior to quantitation or directly performed by flow injection. Alternatively, gas chromatography mass spectrometry (GC-MS) also is capable of separating volatile molecules at low levels by using solid phase microextraction (SPME) fibers. In order to improve APCI-MS, it was proposed to modify an APCI source to incorporate a conductive SPME source that was capable of low solvent analysis for detection of volatile species. While commercial SPME fibers are produced from a variety of polymers, this modified APCI source was produced from multiwalled carbon nanotubes (MWCNT’s) to ensure flexibility, improved surface area, and conductivity.

iii

Acknowledgments I dedicate my dissertation to the late Dr. Joseph “Doc” Caruso. When I began at the University of Cincinnati, I had my own difficulties, but Doc took me into the research group anyways. He always made me feel like a part of the group and that he was the head of the research group family. If I ever had a lousy day, Doc always knew the perfect joke to tell. Some of my favorite moments with Doc were fixing things around the lab with him. He showed me how to plumb a water circulator, adhere polymer pipes, and what a passionate chemist looks like. He was as intelligent as he was warm-hearted. The parties that Doc and Judy Caruso held at their home were always a blast. Their family and our research group shared laughs as much as we enjoyed the sound of Doc playing the accordion. Doc and Judy made me and the rest of the group feel like family. I will never forget what Doc gave me and I will continue to become the greatest chemist I can become.

I would like to thank Dr. Julio Landero for mentoring me in everything from fixing instruments to the theory of instrumentation. He was able to convey many topics at a level I could understand in order to succeed in my projects. Most of all, I want to thank him for taking the heavy responsibility of the research group after Doc’s passing. While many were worried about what was going to happen next, Dr. Landero made it clear that he would be there to support us until we finished. As my advisor, he spent a substantial amount of time helping me with my manuscripts as well as preparing me for the future. When I needed a reality check, he gave me his blunt opinion and it was always appreciated to keep me on track for graduation.

I want to thank my committee Dr. Ridgway, Dr. Zhang, and Dr. Stan. You have aided me in my research decisions, improved my critical thinking, and turned me into a level headed chemist.

During my first year in teaching, I was the teaching assistant in general chemistry lab for Dr.

Anne Vonderheide. After working with Dr. Vonderheide my first year, I had received an

iv opportunity to work on a mass spectrometer in the analytical laboratory with her. At that moment, I had gained a deep insight into using the mass spectrometer and understanding its intricacies. After discussing an experiment with Dr. Vonderheide, I was allowed to modify the mass spectrometer to my heart’s content, which led me to another project that was inspired by my interest in instrumentation. I can’t thank her enough for allowing me to work mass spectrometric instrumentation as well as her aid in helping me gains funds for my 6th year. Dr. V has been an excellent mentor.

Dr. Vonderheide also introduced me to Dr. Vesselin Shanov and Dr. Noe Alvarez who have provided me with the nanomaterials essential for my project as well as aided me in improving the ionization source apparatus. Their help has been essential in making this project successful.

I would like to thank Dr. Anna Gudmundsdottir for providing funds from the department to finish my education during my 6th year of graduate school.

I want to thank Dr. Stephan Macha and Dr. Larry Sallans for allowing me to ask them numerous questions about mass spectrometry as well as letting me borrow seemingly miscellaneous tools.

They were quick to give me in-depth answers and suggestions.

During my time at UC, I was lucky to have been in such a great research group. I want to thank

Amberlie Clutterbuck, Anna Donnell, Skyler Smith, Jiawei Gong, Phanichand Kodali, Karnakar

Chitta, Cory Stiner, and Megan Stanton for being great peers to work with. I want to highlight

Anna Donnell for being a great peer mentor for my growth as a mass spectrometrist, chemist, and teacher. Also, I am happy to have made friends with visiting scholars: Oliver Hochmoller,

Aline Olivieri, Tina Wigger, and Dr. Maria Hespanhol.

Over the years at UC, I made many friends including Travis Pollard, Gus Powers, Brett Bolton,

Vianessa Ng, Rob Ross, Xiaoyu Cao, Jennifer Vernia, Daoli Zhao, Xuefei Guo, Tingting Wang, and Li Duan. I cherish the laughs, discussions, and parties we shared. I want to especially thank

Rob and Xiaoyu for reintroducing me to Wenwen.

Most of all, I want to thank my beautiful wife, Wenwen Yang. Ever since we started dating in

2013, she has stood by, supported me, and motivated me to achieve greater success. I will

vi always remember December 30, 2015 as the happiest day of my life. She is my other half and I can’t imagine making it out of graduate school without her. Even when I had to do my research on a broken foot, she would help me in whatever way she could. She always drove me to the easiest entrances to get in with crutches and told me when I was pushing myself too hard.

Wenwen is my constant source of inspiration. We are in for a great future together, dear, and I will lead the way.

vii

Table of Contents Page Table of Figures...... xi Table of Tables...... xii

1. Chapter 1:Introduction...... 1

1.1. Preface

1.2. Sample Preparation

1.2.1. Acid Sample Dissolution

1.3. Instrumentation

1.3.1. Molecular Mass Spectrometry

1.3.1.1. Ionization

1.3.1.1.1. Chemical Ionization

1.3.1.1.2. Electrospray Ionization

1.3.1.1.3. Atmospheric Pressure Chemical Ionization

1.3.1.1.4. Desorption Electrospray Ionization

1.3.1.1.5. Direct Probe Atmospheric Pressure Chemical Ionization

1.3.1.1.6. Atmospheric Solids Analysis Probe

1.3.1.1.7. Desorption Atmospheric Pressure Chemical Ionization

1.3.1.2. Sample Introduction

1.3.1.2.1. Infusion and Flow Injection Analysis

1.3.1.2.2. Solid Phase Microextraction

1.3.1.2.2.1. Carbon Nanotube Solid Phase Microextraction Fibers

1.3.1.2.3. Liquid Chromatography

1.3.1.2.3.1. Affinity Chromatography

1.3.1.2.3.2. Reverse Phase Chromatography

viii

1.3.2. Inductively Coupled Plasma Mass Spectrometry

1.3.2.1. Ionization, Nebulization, and Transport

1.3.2.2. Interferences in Atomic Mass Spectroscopy

1.3.2.3. Detection

1.3.2.4. Speciation

1.4. Statistics

1.4.1. Univariate Statistics

1.4.2. Multivariate Statistics

1.4.2.1. Data Pretreatment

1.4.2.2. Principal Component Analysis

1.5. Applications

1.5.1. Applications of Metallomics and Disease

1.5.2. Applications of Volatile Organic Molecule Determination

1.5.2.1. Chemical Warfare Agents

1.5.2.2. Mars

2. Chapter 2. The Metalloprotein and Metal Profile of Human Blood Plasma as a

Diagnostic Fingerprint for Stroke Determination...... 30

2.1. Abstract

2.2. Introduction

2.3. Methods

2.3.1. Blood Plasma Acquisition

2.3.2. Reagents

2.3.3. Apparatus

2.3.4. Procedure

2.3.4.1. Trace Metal Analysis

2.3.4.2. Immunodepletion and SEC-ICP-MS/MS

2.3.5. Metalloprotein Identification by LC-MS/MS

2.3.6. Statistical Analyses

2.3.6.1. Software

2.3.6.2. Data Pretreatment

2.4. Results and Discussion

2.4.1. ICP-MS/MS

2.4.2. SEC-ICP-MS/MS Metalloprotein Analyses

2.4.3. Multivariate Analysis

2.4.4. Metalloprotein Identifications

2.5. Conclusion

2.6. References

3. Chapter 3: Prediction of Stroke Type by Multivariate Analysis: Pentraxin-3 and

Transferrin as Blood Plasma Biomarkers...... 60

3.1. Abstract

3.2. Introduction

3.3. Methods

3.3.1. Sample Collection

3.3.2. Plasma Protein Analysis

3.3.3. Statistical Analysis

3.4. Results

3.5. Discussion

3.6. Conclusions

3.7. References

4. Chapter 4: Nano-Carbon Fiber Ionization Mass Spectrometry: A Fundamental Study of

a Multi-Walled Carbon Nanotube Functionalized Corona Discharge Pin for Polycyclic

Aromatic Hydrocarbons Analysis...... 79

4.1. Abstract

4.2. Introduction

4.3. Methods

4.3.1. Reagent

4.3.2. Mass Spectrometer

4.3.3. Nanomaterials Characterization

4.3.4. Functionalized Corona Discharge Pin

4.3.5. Untested Corona Discharge Pin Insert and Seat

4.4. Results and Discussion

4.5. Conclusions

4.6. References

5. Chapter 5. Conclusions and Work...... 96

6. Appendix...... 98

Page Table of Figures

1.1 Fields of study in Metallomics 3

1.2 Diagram of Collision Cell and Quadrupole Mass Analyzer in He Collision Mode 11

1.3 Diagram of Triple Quadrupole including Quadrupole Mass Filter 1(Q1), Collision/Reaction Cell, and Quadrupole Mass Filter 2 (Q2) 12

2.1 Simplified Stroke Scheme of Determination 41

2.2 Boxplot plot analysis of SEC-ICP-MS/MS Concentrations 46

2.3 Score and Loading plots of the Principal Component Analysis 49

2.4 Linear Discriminant Analysis for Prediction of Stroke Type 50

3.1 PCA model for Classification of Stroke Type 70

3.2 LDA Model for Stroke Type Determination 71

3.3 LDA predictive model for Determination of Race and Stroke Cases 72

4.1 Raman microscopy of Multi-Walled Carbon Nanotubes 83

4.2 Microscopy and Imaging of Modified Corona Discharge Pin 85

4.3 Experimental Design for Corona Discharge Experiments 86

4.4 Instrument Apparatus 86

4.5 Signal optimization of 100 ppm PAH mix 87

4.6 Thermal Desorption of 15 ppm phenanthrene Comparison 88

4.7 Limits of Detection and Linearity of Calibration Curves of PAH’s 89

4.8 Flow injection of 100 ppm Naphthalene in 100% Toluene 89

4.9 Solvent Effects on Extraction of 100 ppm Fluorene 90

xii

Table of Tables Page

2.1 Stroke Group Demographics 33

2.2 Trace metal analysis of plasma from Stroke Cases and Controls 42

2.3 Pearson Correlation Coefficient Matrix Analysis of Trace Metal Analysis 44

2.4 Descriptive statistics of SEC-ICP-MS/MS of Stroke Victim Blood Plasma 45

2.5 Pearson Correlation Coefficient Matrix Analysis of SEC-ICP-MS/MS 47 Concentration

2.6 Pearson Correlation Coefficient Matrix Between SEC-ICP-MS/MS and Trace 48 Metal Analysis

2.7 Metalloprotein Identifications 52

3.1 Descriptive Analysis of Protein Concentrations by Stroke Group 66

3.2 Descriptive Statistics by Race, Gender, and Comorbidity 68

3.3 Descriptive Analysis of Protein Concentrations by Stroke and Race 69

Appendix 98

xiii

Chapter 1

Introduction

1. Introduction

1.1 Preface

Analytical chemistry has honed on the focus of quantification and interpretation in an ever more evolving world. On one end of the spectrum, analytical techniques have approached a plethora of problems from detecting trace levels of toxic compounds such as chemical warfare agents to interpreting complex biological systems.

Instrumentation has been the vehicle for analytical chemistry, and at the head, is mass spectrometry. Mass spectrometry has been critical in qualitative as well as quantitative research. J.J. Thomson, the grandfather of mass spectrometry, discovered the cathode ray as a fundamental subatomic particle later known as the electron1. Thomson’s pupil and fellow Nobel Prize winner, F.W. Aston, discovered a multitude of non- radioactive isotopes and went on to develop the first high-resolution mass spectrometer2.

The importance of isotopes, as well as the natural isotopic abundance for elements, is particularly of interest in the field of atomic spectroscopy. Atomic spectroscopy is the study of atomic species and these species include metals as well as metalloids. Metals and metalloids play an important role in the body. For example, phosphorus composes phosphodiester bonds in DNA and sulfur plays a role in the disulfide bonds that provides proteins their secondary structure. In regards to metalloproteins, iron in blood binds to the heme porphyrin rings in the myoglobin units of hemoglobin.

Metallomics is described as an understanding of metal species in respect to biology. Metal containing molecules are known as metallomes3. Metallomics includes assessment of trace metals in the environment to understanding the toxicity of metals in body to how metals play a role in protein activity. Research in metallomics, as shown in Figure 1.1, extends to the roles of metallomes and their role in health. A metallomics approach may lead to the identification of important metals and metal-containing bio-molecules such as metalloproteins for disease diagnostic, or disease advance indicator. The importance of metal-containing species ranges from their influence in cancer treatment, as cisplatin, to prediction of disease onset.

Fluctuations of metal concentrations in body can lead to a variety of ailments such as fatigue induced by iron deficiency based anemia as well as low calcium and its effect on the bones of women.

While atomic spectroscopy focuses on atomic species, molecular mass spectrometers have been used to identify as well as quantify proteins to determination of trace levels of small molecules including chemical polychlorinated biphenyls (PCB’s) and polycyclic aromatic hydrocarbons (PAH’s). By coupling chromatography with mass spectrometry, the separation of these species becomes possible. Alternatively, direct measurement of these compounds may be possible without separations. Determinations of unknowns may be complicated by usage of low resolution mass spectrometers, but the utilization of tandem mass spectrometry improves the ability to identify unknowns. Many compact mass spectrometers utilize ionization sources that can function without extensive separations, high gas consumption, and usage of mobile phase. These features make it possible for use in portable mass spectrometers for in field analysis. The ideal ionization source for volatile compounds would include low gas consumption, small sample volume, and capability of simultaneous preconcentration.

Figure 1.1. Fields of study in Metallomics3

1.2 Sample Preparation for Trace Metal Analysis

1.2.1 Acid Sample Dissolution

Acid sample dissolution is used for simplification of sample matrices as preparation for trace metal quantification. Samples range from bodily fluids to polymers. The most common means of simplifying a matrix is by performing an acid dissolution. Dry bath acid digestions are commonly performed with an oxidizing acid such as nitric acid for the breakdown of biological matrices to nitrogen dioxide, nitrogen monoxide, and carbon dioxide. The remaining sample will primarily consist of inorganic components like metal ions or insoluble silicate. Samples may be lyophilized prior to dissolution and hydrogen peroxide can be added as an additional oxidizer. A standard method for dry bath acid digestion is US EPA 3050B. In comparison, acid digestion by microwave is also an option that is automated and is capable of breaking down more complex matrices such as petroleum with combustion. Digestion efficiency and reproducibility are improved with microwave heating in closed or semi-closed vessels at higher pressures that increase the temperature and the oxidizing power of the nitric acid. Standard methods for microwave acid digestion would include US EPA 3015A and US EPA 3051A.

1.3 Instrumentation

1.3.1 Molecular Mass Spectrometry

1.3.1.1 Ionization

Molecular mass spectrometry aims at ionization of molecules without fragmentation, whereas atomic mass spectrometry utilizes a hard ionization source that produces charged atomic species.

1.3.1.1.1 Chemical ionization

Chemical ionization is a soft ionization mode that produces the protonated molecular ion in the gas phase4, primarily for low molecular weight, volatile compounds. Chemical ionization occurs when the reagent gas is ionized by electron ionization produced by the removal of an electron, which result from a high-energy beam of electrons generated by a filament4. The protonated molecular ion is formed by proton transfer from the ionized reagent gas to the analyte when the analyte has a higher proton affinity in comparison with the ionized reagent gas.

1.3.1.1.2 Electrospray

Soft ionization sources produce ions with the least amount of fragmentation. These soft ionization sources include field ionization5-6, matrix assisted laser desorption ionization (MALDI) 7, and electrospray8. Electrospray ionization (ESI), was pioneering by Nobel Laureate; John Fenn, PhD8. Electrospray enabled the analysis of non-volatile, large thermally labile molecules beyond the mass range of the mass spectrometer by incorporating multiply-charged ions. While MALDI was able to ionize non-volatile, thermally labile large molecules, the ionization mechanism promoted formation of primarily singly-charged ions and that would primarily be incorporated with the large mass range of a time of flight mass spectrometer (TOF). Electrospray ionization is performed by applying a 3-5 kV needle voltage with solvent flow and nitrogen sheath gas flow.

Drying gas is applied to improve desolvation of the droplets. Each charged droplet contains numerous charges and, as the droplets are shrink, the numerous charged analytes overcome surface tension to cause a columbic explosion, which produces smaller droplets. This process occurs until the droplets are small enough such that ions may be desorbed from the droplets8. Electrospray is beneficial for proteins, peptides, and more considering that these analytes are produced with multiple charges. For improvement of positive electrospray signal, solutions are acidified with formic acid whereas when sample pH is increased, signal is improved for negative electrospray mode9.

1.3.1.1.3 Atmospheric Pressure Chemical Ionization

While electrospray ionization is performed for polar, thermally labile molecules, atmospheric pressure chemical ionization (APCI)10 is capable of analyzing non-polar, non-thermally labile compounds. While electrospray ionization is capable of ionizing large molecules, APCI is limited to small molecules and does not produce multiply charged ions. A disadvantage of APCI is its limit to non-thermally labile molecules, such as proteins, considering that temperature is applied to vaporize sample prior to ionization. There are extensive studies on the corona discharge generated in APCI10-12. In comparison, APCI is robust to high ionic strength and efficient at high flow rates.

The ionization process is highly dependent on proton transfer by gas phase basicity13 and ionization by charge exchange. When analytes are infused at rates 0.2 mL/min-2 mL/min, the solution is pneumatically sprayed with

nitrogen sheath gas flow. The APCI source is surrounded by a probe typically heated from 300-650°C to vaporize the aerosol. Desolvated analytes are ionized by the resulting corona discharge. The corona discharge is an electrical discharge produced ionized nitrogen gas with an established discharge current of 1-10 uA.

Protonation of analytes occurs by proton exchange from gas phase acidic hydronium ion clusters13 to the analytes after charge transfer from ionized nitrogen gas11-12. Solvent choice has been shown to play an important role in regards to ionization efficiency of analytes in APCI. For example, the usage of benzene as a charge transfer agent12 to an analyte of lower ionization potential. In regards to protonation, the protonated molecular ion is generated when the solvent has a lower proton affinity compared with the analyte. In comparison with electrospray, APCI is a mass dependent analysis14 compared with the concentration dependent electrospray ionization15.

1.3.1.1.4 Desorption Electrospray Ionization

Desorption electrospray ionization (DESI) was the first ambient ionization source pioneered16. This source produces an electrospray with a particular solvent and desorbs analytes from the surface. Analytes desorbed from the surface thereby undergo coulombic explosion, desolvation, and detection. Mass spectra match that of electrospray experiments, but do not require drying gas and can be conducted outside of a benchtop mass spectrometer. While handheld spectometers for IR and Raman existed, the DESI source created the boom on ambient ionization sources17-19 for use in portable mass spectrometers. Sampling and ionization of analytes can by DESI can be performed for analysis of pesticides on fruits in the field20 as well as image brain metabolites in real time16.

1.3.1.1.5 Direct Probe Atmospheric Pressure Chemical Ionization

As a complement to APCI, the direct probe atmospheric pressure chemical ionization (DP-APCI)21 source incorporates a metal needle for direct sampling rather than online chromatography. The needle is exposed to ambient conditions. The needle is plunged into solution then is pressed into the needle seat where it is heated with nitrogen gas and a discharge current is applied. This discharge current generates a corona discharge to ionize the analyte by means described by APCI.

1.3.1.1.6 Atmospheric Solids Analysis Probe

As an alternative to DP-APCI, atmospheric solid analysis probe (ASAP) is capable of analyzing both liquids and solids22. A capillary is placed into the liquid or solid. This capillary with sample is then placed in the system. The capillary is then bombarded with hot nitrogen gas and vaporized sample is then ionized by proton transfer or charge exchange resulting from the corona discharge pin.

1.3.1.1.7 Desorption Atmospheric Pressure Chemical Ionization

Rather than including a given solvent, the desorption atmospheric pressure chemical (DAPCI) source23 ionizes samples by direct contact with the corona discharge. The corona discharge can be produced from nitrogen, but is commonly produced in air. Desorption of ions occurs upon contact with solid or liquid samples.

1.3.1.2 Sample Introduction

1.3.1.2.1 Infusion and Flow Injection Analysis

Sample infusion by syringe pump is a separation-less means of sending the sample flow directly to the mass spectrometer with a suitable flow rate. In comparison, flow injection analysis (FIA) is a direction injection by an

HPLC system without a column24. FIA is beneficial over typical analysis due to small solvent consumption25 as well as a means for determination of lower limits of detection26.

1.3.1.2.2 Solid Phase Microextraction

While samples may be introduced to chromatography separations by an aliquot from a syringe, samples may also be introduced by a solid phase microextraction (SPME) fiber. Furthermore, SPME fibers can extract by both sample immersion as well as by headspace sampling27. Headspace sampling by SPME has been shown to have ppt limits of detection27. The selectivity of extraction varies on the SPME polymer coating28. Analytes are adsorped onto the surface or sorped into SPME coating by bulk partitioning29. Sorption occurs by an equilibrium process measured, by the equilibrium partition coefficient, in regards to a specific stationary phase and solvent. This equilibrium process can be affected by work or heat directed on the SPME fiber and solution shaking the solution to improve contact with the SPME fiber30.

1.3.1.2.2.1 Carbon Nanotube Solid Phase Microextraction Fibers

While polymer coatings are most common, literature has found that the use of carbon nanotubes improves detection of analytes31 in comparison with traditional PDMS fibers32. For example, PANI SPME fibers coated with multi-walled carbon nanotubes (MWCNTs) have been shown to improve the extraction of palmitic acid and oleic acid in chloroform by the at levels between 6 and 12 times higher, respectively, than that of typical PANI

SPME fibers33. Simplified methods have been applied to generate carbon nanotube functionalized metal fibers by sol gel methods. Improvements to analysis were also highlighted32. The benefit of nanomaterials is suggested to be due to the increased surface area per mass.

1.3.1.2.3 Liquid Chromatography

1.3.1.2.3.1 Affinity Chromatography

Affinity chromatography uses lectins, antigens, or antibodies as a means of separation or purification of biological samples34. For example, the human serum albumin (HSA) and immunoglobulin gamma (IgG) multiple affinity reaction system (MARS) column utilizes a stationary phase functionalized with anti-HSA and anti-IgG antibodies. These antibodies bind HSA/IgG, under the proper pH and ionic strength, and allow low abundance proteins to be isolated. By changing the pH and ionic strength, the bound HSA/IgG are released and leave the now open antibodies ready for the next sample34. Affinity chromatography is a means of sample preparation for purification and further analyses.

1.3.1.2.3.2 Reverse Phase Chromatography

Reverse phase chromatography separates analytes based on hydrophobicity. In particular, reverse phase columns are filled with a nonpolar stationary phase such as C18, a silica gel functionalized with an octadecyl carbon chain, with a polar solvent. Reverse phase separations may be conducted on analytes that are soluble or somewhat soluble in water35 and has been shown to be ideal for separation of range from peptides, proteins, to small molecules. Reverse phase chromatography is ideal as a means for separations in tandem

with electrospray mass spectrometry for biomolecules due to solvent compatibility, concentration dependence, low salt concentrations and low flow rates36.

1.3.2 Inductively Coupled Plasma Mass Spectrometry

1.3.2.1 Ionization, Nebulization, and Transport

Inductively coupled plasma tandem mass spectrometry (ICP-MS) is a robust and high throughput technique for quantification of metals in blood plasma and metals bound to proteins. ICP-MS is the most developed instrumentation to assess metals, nonmetals, and metalloids37 due to its robust performance at the ppt (parts-per-trillion) level, associated imaging,38-39 seamless coupling with chromatography,40 and low interferences. While inductively coupled plasma optical emission spectroscopy (ICP-OES) is capable to ppm- ppb quantification, ICP-MS is capable of sub-ppt limits of detection with comparatively low spectral overlap.

Quantification of metals in samples is commonly conducted as a whole or speciated, by element prior to ICP-

MS.

For total metal quantification, samples are introduced into the ICP-MS by laser ablation, pneumatic nebulization, ultrasonic nebulization, and electrothermal vaporization. Nebulization methods are used for liquid phase samples whereas solids and liquids laser ablation. Pneumatic nebulization of sample occurs by peristatic pump sample uptake to the pneumatic nebulizer. Liquid sample is met with argon makeup gas that creates a fine aerosol. This aerosol is then transported to the Peltier cooled-Scott type double pass or cyclonic spray chamber. Large droplets condense onto the cooled double pass spray chamber, whereas the smallest droplets proceed to the plasma. The Scott type double pass spray chamber yields lower oxide values compared with a cyclonic spray chamber, but is known for higher degrees of carry over in comparison.

Analytes are desolvated from the aerosol, atomized, and ionized in the 10,000 K argon plasma. The argon plasma is inductively formed by an RF generator which excites the argon atoms and releases electrons. These high energy electrons then cause a cascade effect to remove electrons from analytes by electron ionization.

Further, ions may also undergo ionization by excited argon atoms removing electrons from a metal analyte

otherwise known as Penning ionization. This ionization process that induces atomization and ionization is regarded as a hard ionization source rather than a soft ionization.

1.3.2.2 Interferences in Atomic Mass Spectroscopy

Ionized elemental species are transported from ambient pressure to vacuum by a sampler and skimmer. These ions are further focused by ion lenses. In an ICP coupled with a single quadrupole mass analyzer (ICP-MS/MS), the ions focused from the ion lenses first enter the collision/reaction cell prior to separation of ions by as a function of mass-to-charge ratio (m/z) by the first quadrupole mass filter (Q1). If

40 35 + 75 + Ar Cl and As enter the collision/reaction cell without a collision gas, then they are unable to be separated by the quadrupole mass analyzer due to low resolution as well as low mass accuracy. This results in false signal. By performing the analysis in He collision gas mode, the ions are bombarded by He and the kinetic energy of 40Ar35Cl+ will decrease substantially due to its comparably larger collisional cross-section in comparison with 75As+. While 75As+ has a reduced kinetic energy due to He collisions, it has sufficient energy to make across the voltage gap between the octopole and quadrupole, which results in more accurate quantification. In regards to the quadrupole mass analyzer, the m/z separation is caused by changes in the

Mathieu stability diagram. While the mass filter has a constant applied RF voltage to maintain a narrow range of ions, the DC voltage is ramped to the remove ions. The analyte ions are sent, by m/z, to the detector after separation by m/z. This mechanism is reported in Figure 1.2.

Q1 Collision Cell

40 35 + Ar Cl 75 + As

Figure 1.2. Diagram of Collision Cell and Quadrupole Mass Analyzer in He Collision Mode

In an ICP coupled with a triple quadrupole mass analyzer (ICP-MS/MS), the ions focused from the ion lenses are separated by the first quadrupole mass filter (Q1) by m/z. In collision mode, analyte ions are bombarded with helium gas and interferences (such as ArCl+ for As+) may be removed by kinetic energy discrimination as evidenced above. Alternatively, ions may be reacted with oxidative or reductive gases to eliminate interferences or produce ions that have been shifted by m/z. After ions exit the octopole, the ions are again separated by m/z by the second quadrupole mass filter (Q2). In no collision gas mode, 78Se+ has passed

Q1 as well as Q1, but the signal has been bolstered by unremoved polyatomic (40Ar38Ar+) and doubly charged interferences (156Gd++). Oxygen may be used as a reaction gas to generate elemental oxides if the reactions as either exothermic or mildly endothermic. In the case of the endothermic reaction between oxide formation of

Se, 78Se16O+ is produced whereas 40Ar38Ar+ and 156Gd++ are unchanged. When Q2 is set to isolate 94 m/z, then

Se, as 78Se16O+, is detected without 40Ar38Ar+ or 156Gd++ background. This process is shown in the Figure 1.3 below.

Q1 Q2 Collision Cell

38 40 + Ar Ar 78 + Se 78 16 + Se O 41 37 + K Cl 156 ++ Gd 156 ++ Dy 39 39 + K K

Figure 1.3. Diagram of Triple Quadrupole including Quadrupole 1(Q1), Collision/Reaction Cell, and

Quadrupole 2 (Q2)

High-resolution mass analyzers have been used to resolve analyte signal from interferences.

Collision/reaction cell technology has been developed to take deal with the low mass resolution of a quadrupole mass filter and take advantage of the uncapped ion capacity. Alternatively, double focusing magnetic sectors are able to separate many analyte signals from isobaric interferences due to the high resolution mass analyzer . Magnetic sectors are commonly used for radionuclide quantification. When coupling

ICP with a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer (FTICR-MS), most analyte signals can be resolved from isobaric interferences due to ultra-high mass resolution, but have limited quantitative properties due to low ion capacity traps.

1.3.2.3 Detection

For ion detection, an electron multiplier is used. This discrete dynode electron multiplier detects over 9 orders of magnitude and can be used in both pulse and analog mode. Pulse mode acts as directly as an ion counts whereby the positively charged ion hits the detector and releases electrons causing an electron cascade. The analog mode occurs by reduction of detector voltages41.

1.3.3 Speciation

As previously mentioned, the type of metal species is important in regards to health as well as environmental safety. In order to quantify metal containing species, chromatography has been known to yield impressive results in regards to chemical warfare agents by hyphenated gas chromatography to separation of selenoamino acids by ion pairing reverse phase chromatography. Chromatographic considerations must be taken when choosing a particular separation for an analyte of interest.

Reverse phase chromatography have been shown to denature metalloproteins prior to separation resulting in complications when matching metal signal with that of proteins. Immobilized metal affinity chromatography

(IMAC) and size exclusion chromatography (SEC) are known to separate metalloproteins in their native state.

Considering that metalloproteins can undergo demetallation and unfold under denaturing conditions, 42 coupling ICP-MS/MS with SEC 43 is an effective technique to detect metalloproteins in their native structure.44-

46 This is in contrast to denaturing gel techniques such as SDS-PAGE and desalt prior to bottom up proteomics by electrospray tandem mass spectrometry (ESI-MS/MS).46 By offline fractionating samples prior to proteomics, more protein identifications are possible due to limits on the ion capacity of trap based mass spectrometers as well as improvements to peak capacity.

1.4 Statistics

1.4.1 Univariate Statistics

Descriptive statistics are a fundamental part of data analysis. Descriptive statistics is capable of explaining data in a simple manner. The spread of the data is commonly explained by the standard deviation or the median absolute deviation, while the mean and median are generally used as a way to discriminate from one

group to another. In particular, the student’s t-test can be used to determine whether two groups are statistically different, at a given confidence level, based on their average. Analysis of the variance (ANOVA) is commonly used as an expansion of the student’s t-test to determine statistical differences for more than two groups. Alternatively, the biomedical research field commonly applies the Mann-Whitney U test for determination of statistical differences between two groups by their median at a given confidence. The Mann-

Whitney U test is used over ANOVA if the distribution values are skewed or not normally distributed, but do not result in high power analysis values. Power analysis assesses the degree of false negatives or Type 2 error and results with greater than 0.8 power, or less than 20% false negative error, are considered ideal for most applications. When comparing ANOVA and the Mann-Whitney U test, ANOVA is more susceptible to outliers compared with the Mann Whitney U test. Outliers can be observed in types of statistics including box-plots and removed by statistical tests including the Dixon’s q-test. Dixon’s q-test is limited to single outliers as well as normally distributed data. Comparatively, the extreme studentized deviate test (ESD) is used for multiple outlier removal for normally distributed data. Alternatively, some have taken to using the MAD as a means of robust detection of outliers for non-normally distributed data sets47.

1.4.2 Multivariate Statistics

1.4.2.1 Data Pretreatment

While data may be interpreted without pretreatment, influence of variables may be influenced by magnitude of values than changes in variance. For proper interpretation of the data, the data must be transformed or scaled to make values proportional. Autoscaling and standard deviation scaling are common means of scaling in the field of metabolomics48. If values are normally distributed, scaling by standard deviation may be ideal48 whereas scaling by median absolute deviation (MAD) has been shown to be less sensitive to outliers47, 49-52.

1.4.2.2 Principal Component Analysis

Principal component analysis (PCA) is a multivariate technique for dimension reduction53. Each principal component is a linear combination of the variables where the first principal component is has the highest percentage of explained variance53. The number of principal components (PC’s) is user defined, but the

optimum number of PC’s is governed by having a number of PC’s that has the most explained variance with the lowest number of PC’s. This is described in the residual variance plot. The loading plot describes the influences of the variables on a particular PC. A loading plot can be described in two or three dimensions to improve the interpretation. Variables farther from the origin have more influence, whereas those close to the origin have little or no influence on that particular PC. While correlations can be assessed by a typical loading plot, a 2D correlation plot can further simplify the interpretation of the correlations in the loadings plot by placing low influence variables within the 50% circle whereas important variables outside this circle. If two variables are outside the 50% confidence circle and on opposite sides of the axis, these variables are negatively correlated whereas those closer together are positively correlated. To isolate the most influential variables, orthogonal rotations are used. In particular, the varimax rotation aligns the variables with the most extensive variation along the extremes of the PC’s54.

1.5 Applications

1.5.1 Applications of Metallomics and Disease

Metals and metalloproteins play a role in neurological health and disorders. Neurological disorders can be affected by the misfolded and/or aggregated metalloproteins.55-56 For example, beta-amyloid is a zinc binding metalloprotein, and abnormal zinc homeostasis plays a role in the protein aggregation of beta-amyloid in

Alzheimer’s-associated neuropathogenesis.56 The defective ceruloplasmin, generated by improper gene coding, lacks copper cluster sites.57 This disease, aceruloplasminemia, causes a 5-10 fold increase in brain iron.58 Chelators, such as deferoxamine, have been used to excrete excess iron and have improved patients’ neurological symptoms.57 High levels of inflammatory-sensitive plasma proteins, such as ceruloplasmin, are elevated in ICH.59-60

Stroke was the fifth leading cause of death worldwide in 2012, resulting in 6.7 million deaths.61 The two primary types of stroke are acute ischemic stroke (AIS), caused impeded blood flow to the brain by blood clot or blood vessel occlusion, and hemorrhagic stroke, caused by bleeding into the brain from a ruptured blood

vessel. Hemorrhagic stroke is further classified into intracerebral hemorrhage (ICH), bleeding into the brain tissue itself, and subarachnoid hemorrhage, bleeding into a space surrounding the brain.

AIS is the most common type of stroke, accounting for about 87% of strokes, ICH results in approximately 10%, and subarachnoid hemorrhage comprises 3% of strokes.62 While ICH is less common than

AIS, it often results in greater morbidity and mortality and accounts for 50% of stroke mortality.63 Select patients presenting with AIS between up to 4.5 hours from symptom onset can be treated with tPA

(recombinant tissue plasminogen activator), a thrombolytic medication that can help to break apart the blood clot causing the stroke, thereby potentially restoring blood flow to that region of the brain.64-65 A more recent treatment option for certain AIS patients, particularly those that have a blood clot in a larger artery of the brain, is endovascular therapy. This can be performed in addition to tPA or as a stand-alone therapy, and it involves a procedure in which a specialized physician use a catheter, with radiographic imaging guidance, to enter the arteries of the brain and remove the blood clot.66 There is currently no clinically proven treatment for ICH, other than surgery, but potential therapies are being investigated.

Metalloproteomic analysis by ESI-MS/MS67 is most sensitive for low abundance metalloproteins when pretreated for removal of abundant proteins such as HSA and IgG.44, 68-70 Post-immunodepletion detection of tissue leakage metalloproteins, with a normal range from 102 to106 pg/mL, 71 is possible by ESI-MS/MS and bolstered by the 1014 dynamic range of ICP-MS/MS.72 Multidimensional separations of peptide mixtures by nano-ESI-MS/MS, induced by analyte protein proteolysis, improves ionization by reduction of ion discrimination, requires small sample volumes, and ensure more sensitive MS detection.73

The current diagnostic and treatment paradigm for stroke requires transportation of the patient to a hospital or other medical facility with the capability to perform emergent brain imaging, most commonly in the form of CT scan. This scan can require substantial time for transportation to the hospital, performing the scan, and review of results, but it is essential to identify whether the patient with stroke symptoms has an area of hemorrhage in the brain, which, if present, would most likely result in a diagnosis of ICH. This brain bleeding would also be a complication to treating the patient as an ischemic stroke with the thrombolytic medication tPA,

since a clot busting medication like tPA is very likely to worsen the brain bleeding and result in patient harm or even death.

In part because AIS patients often have a normal CT scan of the brain in the initial hours following stroke onset, they can be misdiagnosed in up to a third of cases.74 This misdiagnosis rate can increase to two thirds when the patient has atypical symptoms for a stroke.75 Overall, there is a major need for a blood test that can assist in the initial diagnosis of stroke patients. Blood biomarkers that could reliably identify stroke, including differentiation of ischemic from hemorrhagic stroke, could improve the speed of stroke diagnosis, help avoid misdiagnoses, increase the currently low tPA treatment rates for ischemic stroke 76 and overall help achieve the best possible stroke outcomes. Insight into determination of stroke biomarkers is featured in

Chapters 2 and 3.

1.5.2 Applications of Volatile Organic Molecule Determination

1.5.2.1 Chemical Warfare Agents

Ionization sources such as DAPCI are of particular interest due to their simplicity of use as well as their applicability for samples of solids as well as liquids23. Ambient Ion sources have been used to detect chemical warfare agents such as hexamethylene triperoxide diamine and HDMP at trace levels23. While polar ionization sources have been utilized, this particular application has called for the use of DAPCI. The DAPCI source requires low solvent, ambient air, and is capable of ionization of volatile compounds. In the foreseeable future, portable mass spectrometers may be used for identification as well as quantification of chemical warfare agents as safety precautions at large events or possibly expanded for use in public transportation.

1.5.2.2 Mars

Multitudes of compounds are possible by APCI as well as APCI based techniques. In the past, space expeditions have used mass spectrometry to measure hydrogen deuterium ratios on Venus77 to studying organic molecules in the soil as well as the atmosphere by the The Viking Mars Lander78. Currently, NASA

aims to apply laser desorption ionization (LDI) for the MOMA project for detection of carbon containing compounds in solids and liquids whereas gas chromatography coupled with electron ionization is already incorporated in the Mars Rover, Curiosity. Alternatively, these experiments have even taken solid samples, derivatized and conducted GC-MS detection79. Experiments extend from measurement of gas compositions in the atmosphere as well as those performed on Martian soil aim to determine levels of polycyclic aromatic hydrocarbons (PAH’s)79. Signs of PAH’s from Martian soil have been of interest since evidence of uncontaminated PAH levels from extraterrestrial Martian comets from across the world was found80. Detection and characterization of carbon containing compounds is difficult due to trace level concentrations81 as well as pyrolysis of samples prior to ionization81-82. Current desorption based ionization sources have already been used to detect PAH’s, but have not been extending to space exploration. For example, DAPCI has been used for the determination of PAH concentrations, but has not been applied in space23. For further information, refer to Chapter 4.

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McAdam, A. C.; Miller, K. E.; Ming, D. W.; Morris, R. V.; Navarro-Gonzalez, R.; Niles, P. B.; Owen, T.; Pepin,

R. O.; Squyres, S.; Steele, A.; Stern, J. C.; Summons, R. E.; Sumner, D. Y.; Sutter, B.; Szopa, C.; Teinturier, S.;

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Chapter 2

The Metalloprotein and Metal Profile of Human Blood Plasma as a Diagnostic Fingerprint for Stroke Determination

2.1 Abstract

Stroke, a major cause of disability and mortality, affects someone in the United States every 40 seconds. Stroke biomarkers, including those that could be used as a blood test for diagnosis of stroke, have been particularly elusive. We performed a double blind study to identify human plasma biomarkers for the diagnosis of stroke, including acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH). We utilized a three-track approach based on the total metal profile, the metal cofactor levels among metalloproteins, and the identification of stroke-related metalloproteins. The study included 14 case-control pairs of AIS and 23 case-control pairs of

ICH. Controls were matched to cases based on gender, ethnicity, and age (+/- 5 years). AIS cases were statistically higher from their respective controls for protein bound co-factors Se and

Cd, while unique correlations of metal cofactor concentrations among metalloproteins were identified between Pb-W, Sr-W, Pb-V, and Cu-V. ICH cases were statistically higher from their respective controls for Se and Co cofactors, whereas Cd and Pb were statistically lower. Unique correlations between metal cofactors for ICH cases were identified between Pb-W, Sr-W, Pb-V, and Cu-V. Stroke-related metalloproteins were identified, including calpain-15, protein-activated inward rectifier potassium channel 1, tau-tubulin kinase 1, and voltage-dependent L-type calcium channel subunit beta-3. Linear discriminant analysis (LDA) was able to predict stroke onset (93%) as well as differentiate accurately predict the group (85%). Additionally, this study found utmost importance in vanadium (V) and tungsten (W) correlations for both bound and total metal concentrations, suggestive of binding to transferrin. Future work in stroke patients will seek to quantify varying selenoproteins, including selenoprotein P and glutathione peroxidase, assess important selenoproteins by dimension reduction (PCA) of biased or uncorrelated proteins, and further explore the role of trace metal fluctuations with transferrin.

2.2 Introduction

In the United States, one person dies from a stroke every 4 minutes.1 Acute ischemic stroke (AIS) is caused by a blood clot that blocks blood flow to an area of the brain and intracerebral hemorrhagic stroke (ICH) occurs when there is bleeding in the brain parenchyma.

AIS is the most common type of stroke.1 Select patients with AIS may be treated within 4.5 hours of symptom onset with tPA (recombinant tissue plasminogen activator), a medication to break apart blood clots causing stroke, 2-3 but there is currently no noninvasive treatment for

ICH.

Blood biomarkers that could identify stroke, including differentiation of AIS from ICH, may improve the speed of stroke diagnosis, prevent misdiagnoses, and increase the low tPA treatment rates for AIS. 4 High levels of inflammatory-sensitive plasma proteins, such as ceruloplasmin, are elevated in ICH.5-6 Ceruloplasmin, when generated by improper gene coding, lacks copper binding sites.7 This genetic disorder causes aceruloplasminemia, which increases brain iron 5-10 fold.8 Chelators are used to excrete excess iron and improve a patients’ neurological symptoms.7

Inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) is a robust and high throughput technique for quantification of metals in blood plasma and metals bound to proteins. Metal binding proteins or metalloproteins can undergo demetallation and unfold under denaturing conditions 9, but coupling ICP-MS/MS with size exclusion chromatography (SEC) 10 is an effective technique to detect metalloproteins in their native structure.11-13 This is complemented by bottom up proteomics by electrospray tandem mass spectrometry (ESI-

MS/MS) for metalloprotein identification.13

The experimental schema was developed to identify plasma biomarkers for stroke diagnosis 14 specifically for distinguishing AIS and ICH from their matched controls as well as

AIS from ICH. This approach for human blood plasma analyses included unifying trace metal quantification, metal cofactor fluctuations, and the identification of metalloproteins.

2.3 Methods

2.3.1 Blood Plasma Acquisition

Stroke Type AIS Control AIS ICH Control ICH Average Age (years) 63.0 65.7 63.0 63.3 % Race (African American) 7.1 7.1 52.2 52.2 % Gender (Female) 42.9 42.9 60.9 60.9 % Past or Current Smoker 35.7 50.0 52.2 56.5 % History of Hypertension 28.6 64.3 52.2 73.9 %History of Diabetes 28.6 50.0 8.7 34.8 %History of Previous 0.0 0.0 0.0 4.3 Hemorrhagic Stroke % History of Previous 14.3 21.4 0.0 8.7 Ischemic Stroke % History of Other 14.3 0.0 0.0 0.0 Blood Diseases % History of Chronic obstructive 7.1 14.3 8.7 21.7 Pulmonary Disease Asthma % History of Resolved 14.3 21.4 26.1 17.4 Cancer Malignancy % History of Atrial Fibrillation 7.1 7.1 13.0 4.0 % History of Intracranial 0.0 0.0 0.0 4.3 Artery Stenosis %History of Other 0.0 7.0 0.0 13.0 Heart Arrhythmia %History of Carotid 0.0 0.0 0.0 0.0 Artery Stenosis % History of Coronary 0.0 0.0 0.0 4.3 Heart Disease

Table 2.1: Demographics of acute ischemic stroke (AIS), intracerebral hemorrhagic (ICH) stroke, as well as respective acute ischemic stroke (AIS control) and intracerebral hemorrhagic (ICH) stroke controls.

In order to properly assess biomarkers, without intrinsic bias, the study was conducted in a double-blind fashion. Stroke patients were enrolled within 12 hours of symptom onset between

August 2013 and May 2014 at the University of Cincinnati Medical Center. Potential cases were identified by the University of Cincinnati Stroke Team followed by screening performed by hospital-based research assistants in the emergency department and inpatient units. Inclusion criteria were as follows: age ≥18 years, acute ischemic stroke or primary spontaneous ICH with no radiographic features suggestive of aneurysmal subarachnoid hemorrhage, traumatic contusion, vascular malformation, tumor, or venous sinus thrombosis. Exclusion criteria included: recent history (<2 weeks) of myocardial infarction, stroke, surgery, or hospitalization, known active malignant cancer, lymphoma, or leukemia, history of a chronic inflammatory disorder, current treatment with anticoagulants, congenital or heritable disorder of coagulation, and liver disease or cirrhosis. The patient or their legally authorized representative provided signed, informed consent, and were then asked about medical history related to stroke risk factors including history of smoking, diabetes, hypertension, coronary artery disease, atrial fibrillation, and prior stroke. Venipuncture was performed for collection of a venous blood specimen. Controls were matched based on age (+/- five years), race, and gender and were recruited from hospital staff and well visitors to the hospital. Each sample was given an arbitrary number. Demographic information is presented in Table 2.1. Blood plasma samples were stored at -80 °C until use.

2.3.2 Reagents

Nitric acid and trace metal grade nitric acid (70 %w/w) were purchased (Fisher Scientific,

Pittsburgh, PA, USA). Solutions were prepared from 18 MΩ double deionized (DDI) water that was deionized by passing distilled water twice through a NanoPure treatment system

(Barnstead, Boston, MA, USA). Calibration curves and internal standards were produced with

Claritas (SPEX Certiiprep) multi-element standard and single element solutions. Finally, the following were purchased: Mobile Phase A and B for multiple affinity chromatography (Agilent

Technologies; Santa Clara, CA, USA), ammonium acetate, LC-MS Grade Water, LC-MS 34

Optima formic acid, HPLC-grade acetonitrile, and HPLC-grade methanol (Fisher Scientific,

Pittsburgh, PA, USA), and gel filtration standard (Bio-Rad Laboratories, Inc. Hercules, CA,

USA).

2.3.3 Apparatus

Human plasma was immunodepleted of HSA/IgG by use of a 4.6 x 50 mm Agilent Multiple

Affinity Removal (MAR) column coupled to an inline filter (Sigma Aldrich; St. Louis, MO, USA) with an Agilent 1100 HPLC. The plasma was filtered in 0.45 µm cellulose 0.5 mL spin filters

(Amicon; Billerica, Massachusetts, USA). The Agilent 1100 HPLC included an inline membrane degasser, binary pump, autosampler, autosampler thermostat, column oven, and 5 µl semi- micro flow cell diode array detector (DAD). The sample was injected by an external PEEK, metal-free six-port Rheodyne valve (IDEX; Oak Harbor, WA, USA) with 400 µL loop. After

MARS chromatography, samples were concentrated with 4 mL (Amicon; Billerica,

Massachusetts, USA) 5 kDa MWCO spin filters. For centrifugation, a Thermo Scientific™

Sorvall™ LYNX™ Superspeed Centrifuge (Fisher Scientific; Pittsburgh, PA, USA) was used.

An Agilent 8800 ICP-MS/MS (Agilent Technologies, Santa Clara, CA, USA), utilizing an

RF generated inductively coupled plasma with a triple quadrupole mass analyzer and octopole reaction cell system (ORS) was used for ICP-MS/MS and metalloprotein separations by SEC-

ICP-MS/MS. For SEC-ICP-MS/MS, size exclusion chromatography (SEC) was performed with an Agilent 1100 HPLC coupled with a 10 µm particle size TSKgel G3000SW (TOSOH

Biosciences, King of Prussia, PA, USA) 7.6 mm X 300 mm column with 250 Å pore size.

Detection was conducted with diode array detector (DAD) in tandem with ICP-MS/MS.

Lyophilization of collected fractions from SEC-HPLC-DAD analysis was performed with a

Millrock Lyophilizer (Millrock Technology, Inc. Kingston, NY, USA)

Metalloprotein identifications were conducted with an Agilent 6300 XCT Ultra coupled with the Agilent Chip Cube System, as well as a 1200 Agilent LC. The Agilent 1200 LC included 35

inline vacuum degassers, binary nano pump, binary capillary pump, autosampler, and autosampler thermostat. Agilent 1200 LC directly flowed to the Chip system with the nanospray source located in the Agilent large capacity (II) chip. The large capacity (II) chip contains a 150 mm x 75 µm, 5 µm particle size and 300 Å pore size C-18 analytical column, as well as a 160 nL peptide C-18 enrichment column.

2.3.4 Procedure

2.3.4.1 Trace Metal Analysis

Human plasma samples were weighed, lyophilized, and acid digested by hot block acid digestion prior to ICP-MS/MS detection. A 100 µL aliquot of plasma was lyophilized in a borosilicate culture tube to dryness and then 150 µL of Trace Metal Grade Nitric Acid (70% w/w) and 20 µL of 500 ng mL-1 internal standard (45Sc, 72Ge, 89Y, 115In and 209Bi) were added.

Samples were heated to 90°C for 1 h and then followed by 80°C for 12 h. Next, samples were heated to 120°C for 2 h, 50 µL of H2O2 (35% w/w), and followed by 120°C heating for 1 h.

Lastly, samples were diluted to 3 mL by mass. Calibration curves were generated using the

Claritas (SPEX Certiiprep) multi-element standard solution (5% w/w nitric acid).

The samples and the gel filtration standard were introduced to the ICP-MS/MS in three

78 78 + tune gas configurations. The Se concentration was analyzed in H2 to eliminate ArAr

15 background . The instrumental operating parameters for the H2 gas configuration were as follows: RF Power 1600 W, 8.0 mm sample depth, carrier gas flow rate 1.05 L min-1, make-up

-1 -1 gas flow rate 0.14 L min , nickel sampling and skimmer cones, 3.7 mL min of H2 and 0.1 rps peristaltic pump flow. Concentration of 6Li was quantified by an unpressurised collision cell configuration. The instrumental operating parameters for the no collision gas configuration were as follows: RF Power 1500 W, carriers gas flow rate 1.05 L min-1, 8.0 sample depth, make-up gas flow rate 0.14 L min-1, nickel sampling and skimmer cones, and 0.1 rps peristaltic pump flow. Remaining analytes were analyzed in He collision gas configuration to utilize kinetic 36

energy discrimination for polyatomic interference elimination. The instrumental operating parameters for the He collision gas configuration were as follows: RF Power 1550 W, 8.0 mm sample depth, carrier gas flow rate 1.05 L min-1, make-up gas flow rate 0.14 L min-1, nickel sampling and skimmer cones, 3.0 He mL min-1 and 0.1 rps peristaltic pump flow. Parameters were optimized to for CeO+ ≤1.0% and Ce++ <1.5%.

2.3.4.2 Immunodepletion and SEC-ICP-MS/MS

In order to remove the two most abundant proteins, the Agilent Technologies Multiple

Affinity Removal System (MARS) was employed by use of HSA/IgG Multiple Affinity Removal column. By removing HSA and IgG, it becomes possible to identify low abundance proteins by ion trap mass spectrometry (ITMS) and to remove substantial cations sequestered by HSA16. A volume of 200 µL was diluted 4 times in Mobile Phase A to 800 µL and filtered by 0.45 µm spin filters at 10,000 x g for 10 minutes. A 400 µL injection of diluted blood plasma was made per run, and two injections were made per sample. The low protein abundance (immunodepleted) fraction was taken between 2 and 5 minutes and kept at 4°C until centrifugation. In order to pre- concentrate samples, the immunodepleted fractions were centrifuged in 4 mL 5 kDa MWCO filters at 4°C at 6,000 x g for 1 hr. Samples were then diluted to 300 µL and the sample was split for two separate analyses.

A 50 µL aliquot of immunodepleted fraction was injected by SEC-ICP-MS/MS. The

-1 isocratic separation was performed at 0.7 mL min for 30 min using 50 mM ammonium acetate

(pH 7.4) with 0.5% methanol as the mobile phase. The size exclusion column was calibrated beforehand with a mixture containing thyroglobulin (Mr = 670 kDa), γ-globulin (Mr = 150 kDa), bovine serum albumin (Mr = 66 kDa), ovalbumin (Mr = 44 kDa), trypsin inhibitor (Mr = 22 kDa), myoglobin (Mr = 17 kDa), and vitamin B12 (Mr = 1.35 kDa). Linearity of the separation was found to be r = 0.990 for log MW vs volume. Protein recovery was measured to be 98% for

BSA. 37

In order to obtain reliable results and interference free the SEC-ICP-MS/MS analysis was conducted only in He collision gas mode. The instrumental operating parameters for the He collision gas configuration were as follows: RF Power 1550 W, 8.0 mm sample depth, carrier gas flow rate 0.98 L min-1, make-up gas flow rate 0.14 L min-1, nickel sampling and skimmer cones, 3.0 He mL min-1 and 0.5 rps peristaltic pump flow. Integrations were over 0.1 s for 1 point. Parameters were optimized to have CeO+ ≤1.0% and Ce++ <1.5%. From the SEC-ICP-

MS/MS analyte signal, chromatograms were integrated with Origin v. 8.5. Concentrations (ng of metal per mL of diluted immunodepleted blood plasma) of blood plasma samples were determined by generating elemental calibration curves (ng of metal per g solution) by the integration of ICP-MS/MS signal of gel filtration standard from time resolved analysis. These calibration curve values were based on the trace metal analysis of the gel filtration standard.

2.3.5 Metalloprotein Identification by LC-MS/MS:

The remaining 250 µL of diluted, immunodepleted plasma was separated and fractionated offline without ICP-MS/MS based on metal signal from SEC-LC-ICP-MS/MS.

Samples were then lyophilized to approximately 500 µL and then concentrated in a 10 kDa

MWCO spin filter at 14,000 x g for 10 min. A 500 µL aliquot of LC-MS grade water was added and centrifuged again under the same parameters. A 10 µL aliquot was taken for trypsin proteolysis, while the remainder of the sample was kept frozen at -20ºC.

Trypsin proteolysis was performed by heating 10 uL of concentrated proteins, 15.5 uL of

50 mM ammonium bicarbonate, and 1.5 µL of 50 mM DTT at 95 ºC for 5 min for disulfide bond reduction. Samples were then centrifuged for 1 min at 10,000 x g. The thiol groups were alkylated by addition of 1.5 mM iodoacetamide and kept in the dark for 20 minutes. A 3 µL aliquot of 100 µg/mL trypsin was heated at 37ºC overnight. Then, 1 µL of formic acid LC-MS grade was added to end the reaction and centrifuged at 10,000 x g for 1 min. To remove excess trypsin as well as undigested protein, the sample was passed to a 10 kDa MWCO spin filter and 38

centrifuged for 10 min at 14,000 x g. Samples were then diluted to 20 µL and run on the nanoLC-Chip-ESI-ITMS. Separation was conducted with both a nanoLC as well as capillary LC.

Mobile phase A consisted of 0.1% MS-Grade formic acid in LC-MS grade water, while mobile phase B was composed of 90% acetonitrile, 0.1 MS-Grade formic acid, and diluted with LC-MS grade water. The nanoLC gradient went from 3.0% B at 1 minutes, 12% B at 5 min, 45% B at 35 min, 90% B at 40 min, 100% B at 45 min, 100% B at 45-50 min, 3% B at 55 min, and 3% at 70 min. Flowrate was set to 0.3 uL min-1 from 0-50 min and 0.5 uL min-1 from 50-68 min. The capillary LC gradient went from 3% B at 25 min, 80% B at 35 min, 100% B at 45 min, 3% B at

-1 50-55 min, 3% B at 55, and 3% B at 70 minutes. Flowrate was maintained at 4 uL min .

LC-MS/MS was conducted by nanoLC-Chip-ESI-ITMS utilizing a large capacity, 300 Å large pore size C18 (80 nL C18 enrichment and 75 um x 150 mm analytical columns) chip with nanospray ionization source. A sample of the LC-MS/MS method for separation of tryptic digests of peptides is shown in the supplementary information. Metalloproteomics was conducted by bottoms up proteomics by LC-MS/MS by Triple TOF 6500 as well as Agilent 6300

XCT Ultra ITMS. Raw files were converted to MASCOT generic files and searched by MASCOT

(Matrix Science Inc., Boston, MA, USA) LC-MS/MS ion search. For mgf files generated from

Triple TOF analysis, the search parameters included enzyme (trypsin), missed enzymatic cleavages (3), database (Human_EST), taxonomy (Homo sapiens), peptide charge (1+,2+,3+), fixed peptide modification (Carbamidomethyl), peptide mass tolerance (0.15 Da), peptide fragment mass (0.1 Da), and instrument (ESI-QUAD-TOF)17. For mgf files generated from

Agilent 6300 XCT Ultra ITMS analysis, the search parameters included enzyme (trypsin), missed enzymatic cleavages (3), database (Human_EST), taxonomy (Homo sapiens), peptide

charge (1+,2+,3+), fixed peptide modification (Carbamidomethyl), peptide mass tolerance (2.0

Da), peptide fragment mass (0.8 Da), and instrument (ESI-QIT).

2.3.6 Statistical Analyses

2.3.6.1 Software

For means comparison and one-way ANOVA, Origin v. 8.5 (OriginLab Corporation,

Northampton, MA) was used. Pearson correlation coefficient (r) matrices were generated per stroke type with Statistica v. 10.0 (Dell Statistica; Tulsa, OK, USA). r-values labeled in red were shown to be statistically significant correlations. Values marked by underlining are those that have sufficient or greater power (Power ≥ 0.8). Distinctions were drawn between correlations for weak (0.0 < r < 0.5), moderate (0.5 ≤ r < 0.8), and strong (0.8 ≤ r ≤ 0.1). Score plots and loadings were generated by principal component analysis (PCA) of blood plasma by stroke group utilizing The Unscrambler X (v.10.2). Discrimination plots were generated by LDA in The

Unscrambler X (v.10.2). Power analysis for correlation coefficients was calculated by open source software, R, with power analysis package.

2.3.6.2 Data Pretreatment

Bound metal concentrations generated from SEC-ICP-MS/MS were pretreated prior to descriptive statistics. Values were normalized by the sample with the highest DAD peak area integration at 280 nm. Further normalization was performed utilizing the Fe concentration.

Normalization by Fe concentration was performed by setting the highest value as 1 divided by bound Fe concentration, then setting that value as 1. This factor, for each sample, was then multiplied by the DAD normalized data. For principal component analysis (PCA), each value was transformed by taking the square root of each of the previously mentioned values to decrease the spread of the data. Each variable was then vast scaled. For linear discriminant analysis (LDA), the values were square root transformed and outliers were removed by extreme studentized deviation outlier test prior to analysis. 40

2.4 Results and Discussion

Principal Component Analysis Funnel

Metal Co-Factor Analysis Total Metal Analysis

Metalloprotein ID

Metalloprotein Biomarkers

Fig.2.1: Simplified Experimental Design

The basis of this investigation, as evidenced by Fig.1, involved the determination of stroke metalloprotein biomarkers in blood plasma by using PCA as a funnel for trace metal values, bound metal cofactor fluctuations, and identified metalloproteins. Values for ICP-MS/MS determined fluctuations of total metals in blood plasma by stroke group, whereas Pearson correlation coefficient matrix assessed correlations of total metals by group to influx of metals.

Values for SEC-ICP-MS/MS found differences in bound metal cofactor concentrations in blood plasma metalloproteins by stroke group, whereas Pearson correlation coefficient matrix assessed correlations between bound metal cofactors by group. While a multitude of metalloproteins were identified by LC-MS/MS, PCA of SEC-ICP-MS/MS data was used as a means to determine important differences in bound metal cofactor concentrations in blood plasma metalloproteins as a means for selecting biologically relevant metalloproteins for stroke onset.

2.4.1 ICP-MS/MS

Plasma samples were analyzed by acid digestion and ICP-MS/MS to determine trace metal levels. In comparison with their respective controls, the AIS cases had higher As (22%),

Co (44%), Fe (31%), Li (30%), and Sr (25%), but lower U (17%) concentration. The ICH cases had lower Ag (22%), Al (20%), As (34%), Co (48%), Ni (30%), U (32%), and Zn (20%) but higher Fe (36%) and Sr (21%) concentration compared with their matched controls. When comparing the AIS and ICH groups, larger differences were found. The ICH cases had higher

Ag (28%), Co (29%), and Fe (21%) concentrations, while the AIS group had higher Al (28%), As

(39%), Li (24%), Ni (25%), U (31%) and W (21%). Total metal analysis did not conclude statistical differences between stroke groups, which was in contrast to the results from our previous studies14, 18.

AIS AIS Control ICH ICH Control Element Mean SEM Mean SEM Mean SEM Mean SEM Ag 0.71 0.16 0.98 0.24 1.27 0.54 1.99 0.50 Al 338 63 274 50 188 40 283 54 As 1.30 0.29 0.84 0.27 0.58 0.15 1.17 0.30 Ba 135.6 11.1 119.7 12.3 148.2 24.2 177.6 25.9 Co 0.29 0.07 0.11 0.07 0.54 0.19 1.53 1.06 Cu† 1.77 0.15 1.42 0.13 1.46 0.13 1.76 0.12 Fe† 1.67 0.36 0.89 0.12 2.56 0.66 1.21 0.20 Li 4.83 1.24 2.62 0.45 2.99 0.44 3.52 0.95 Mn 3.53 0.70 4.11 1.35 3.51 0.77 4.75 1.24 Mo 1.61 0.10 1.43 0.19 1.79 0.20 1.79 0.20 Ni 8.39 3.42 8.94 5.26 5.06 2.41 9.48 4.04 Se 212 18 193 21 188 14 208 9 Sr 48.1 12.4 29.0 3.3 58.6 18.9 38.6 2.8 U* 19.9 4.4 28.2 12.7 10.6 2.0 20.5 4.5 V 0.95 0.08 0.84 0.09 0.96 0.12 1.14 0.15 W 0.29 0.04 0.26 0.07 0.19 0.02 0.24 0.03 Zn† 1.06 0.16 0.85 0.10 0.75 0.07 1.13 0.15

Table 2.2: Trace metal analysis of plasma from stroke cases and controls. The mean and standard error of the mean (SEM) are described in units of ng/g. Elements designated with “†” are in units of ug/g and those designated with “*” are denoted in pg/g.

A Pearson Correlation Coefficient Matrix analysis was conducted using the ICP-MS/MS results and numerous strong, statistically significant correlations were found (defined as r =

XXX, P<0.05.) (Figure 1). For the AIS case, Cu-Al (r = 0.86) and Al-Zn (r = 0.80) were found to have strong, statistically significant correlations. Compared with the AIS cases, the analysis of the AIS controls found several strong correlations including Se-Zn (r = 0.83), Ba-V (r = 0.90), Sr-

V (r = 0.83), Cu-Se (r = 0.84), Co-Ni (r = 0.83), Ba-Fe (r = 0.80). For ICH cases, there was a moderate correlation with statistical significance for Cu-Se (r = 0.74). In comparison, the ICH

control group had a strong statistically significant correlation for Fe-Mn (r = 0.87).

Group Ag Al As Ba Co Cu Fe Li Mn Mo Ni Se Sr U V W Zn AIS Ag 1.00 0.12 -0.08 0.19 0.18 0.13 0.01 0.37 -0.09 0.01 0.22 -0.06 -0.18 -0.02 0.04 -0.20 0.23 Al 1.00 0.20 0.24 -0.01 0.86 0.12 0.39 0.50 0.26 0.31 0.41 0.09 0.21 0.52 -0.42 0.80 As 1.00 -0.26 0.08 -0.06 0.22 0.06 0.43 -0.06 -0.18 0.06 -0.06 -0.05 0.07 -0.20 0.16 Ba 1.00 0.21 0.52 0.18 0.40 0.07 0.79 0.08 0.65 0.66 0.36 0.74 0.12 0.37 Co 1.00 0.01 0.35 0.08 0.51 0.35 0.01 0.17 0.30 0.55 0.31 0.36 0.38 Cu 1.00 0.07 0.41 0.43 0.50 0.31 0.57 0.32 0.22 0.61 -0.34 0.77 Fe 1.00 0.03 0.38 0.47 -0.19 0.35 0.04 -0.10 0.31 -0.13 0.26 Li 1.00 -0.03 0.52 0.78 0.12 0.11 0.03 0.57 -0.14 0.21 Mn 1.00 0.22 -0.16 0.26 0.26 0.45 0.44 0.12 0.69 Mo 1.00 0.22 0.69 0.62 0.25 0.74 0.19 0.28 Ni 1.00 -0.16 -0.17 0.06 0.19 -0.07 0.13 Se 1.00 0.74 0.03 0.61 -0.09 0.45 Sr 1.00 0.30 0.53 0.34 0.25 U 1.00 0.24 0.56 0.37 V 1.00 0.00 0.51 W 1.00 -0.28 Zn 1.00 AIS Control Ag 1.00 0.30 0.37 0.19 0.43 -0.08 0.30 0.48 0.37 0.10 0.66 0.00 -0.02 -0.18 0.06 -0.28 0.03 Al 1.00 0.30 0.46 0.45 0.55 0.12 0.65 0.68 0.36 0.46 0.37 0.07 0.37 0.37 0.08 0.21 As 1.00 -0.25 0.17 -0.03 -0.06 0.27 0.10 0.19 0.51 -0.22 -0.26 -0.15 -0.21 -0.19 -0.28 Ba 1.00 0.36 0.73 0.80 0.48 0.55 0.54 0.19 0.63 0.74 0.35 0.90 0.41 0.44 Co 1.00 -0.09 0.30 0.80 0.68 -0.09 0.83 -0.33 0.23 0.50 0.39 -0.13 -0.36 Cu 1.00 0.45 0.23 0.29 0.59 -0.16 0.84 0.61 0.30 0.67 0.32 0.61 Fe 1.00 0.31 0.47 0.60 0.34 0.36 0.71 0.16 0.79 0.37 0.16 Li 1.00 0.51 0.16 0.76 0.10 0.42 0.31 0.53 0.11 0.05 Mn 1.00 0.21 0.58 -0.02 0.19 0.58 0.43 -0.08 -0.11 Mo 1.00 0.06 0.64 0.33 0.12 0.65 0.70 0.53 Ni 1.00 -0.30 0.06 0.09 0.21 -0.11 -0.42 Se 1.00 0.47 -0.04 0.58 0.53 0.83 Sr 1.00 0.36 0.83 0.29 0.32 U 1.00 0.50 0.01 0.07 V 1.00 0.58 0.45 W 1.00 0.52 Zn 1.00 ICH Ag 1.00 -0.15 -0.12 0.32 0.05 -0.02 -0.08 0.19 0.06 0.01 -0.16 0.08 -0.14 0.10 -0.20 0.04 0.05 Al 1.00 0.01 0.09 -0.15 0.60 0.10 0.07 0.13 0.03 0.06 0.39 0.05 0.42 0.36 0.24 0.50 As 1.00 -0.12 0.22 0.17 -0.20 0.09 0.37 0.59 0.08 0.10 -0.13 -0.22 0.15 0.02 -0.18 Ba 1.00 0.20 -0.03 -0.12 0.65 -0.05 0.26 -0.04 0.28 0.16 0.09 0.13 0.04 0.33 Co 1.00 -0.26 -0.12 0.62 0.22 0.66 0.21 -0.06 -0.03 -0.05 0.12 -0.37 0.13 Cu 1.00 0.14 -0.09 -0.05 0.03 0.01 0.74 0.11 0.08 0.49 0.36 0.50 Fe 1.00 -0.12 0.08 -0.04 0.32 0.26 -0.19 0.43 0.15 0.09 0.63 Li 1.00 -0.06 0.61 0.00 0.19 0.01 -0.16 -0.03 -0.48 0.25 Mn 1.00 0.13 0.40 0.16 -0.11 0.46 0.40 0.18 0.13 Mo 1.00 0.29 0.12 0.09 -0.28 0.20 -0.23 0.15 Ni 1.00 0.17 0.06 0.43 0.30 0.23 0.21 Se 1.00 -0.10 0.14 0.68 0.41 0.64 Sr 1.00 -0.04 0.07 0.10 0.14 U 1.00 0.20 0.44 0.51 V 1.00 0.48 0.51 W 1.00 0.27 Zn 1.00 ICH Control Ag 1.00 0.16 -0.15 -0.15 0.35 0.00 -.0898 0.04 -0.07 0.37 0.32 0.19 -0.16 0.23 -0.12 -0.09 -0.06 Al 1.00 0.34 0.14 -0.24 -0.14 -.1929 0.22 -0.09 0.16 0.67 0.55 0.26 0.08 -0.16 -0.17 0.64 As 1.00 0.01 -0.19 -0.20 -.1747 -0.04 -0.12 -0.07 0.15 0.03 0.06 -0.03 -0.08 -0.20 0.02 Ba 1.00 -0.11 -0.07 -.1094 0.49 -0.17 0.26 0.00 -0.08 0.40 0.03 -0.01 0.16 -0.03 Co 1.00 -0.29 .2018 -0.07 0.09 -0.06 0.03 -0.17 0.05 0.55 -0.06 -0.02 -0.14 Cu 1.00 -.2609 0.19 -0.33 0.24 -0.35 0.27 0.00 -0.29 0.10 -0.18 0.14 Fe 1.00 -0.23 0.87 -0.06 0.01 -0.17 -0.39 -0.05 0.01 0.03 -0.15 Li 1.00 -0.21 0.15 0.30 -0.04 0.49 -0.10 -0.10 0.02 0.20 Mn 1.00 -0.13 0.00 -0.20 -0.38 -0.02 0.03 0.09 -0.18 Mo 1.00 0.02 0.10 -0.19 0.05 -0.01 -0.06 0.14 Ni 1.00 0.08 0.11 0.15 -0.22 0.02 0.65 Se 1.00 0.17 -0.01 0.28 -0.16 0.23 Sr 1.00 0.06 0.18 -0.15 0.21 U 1.00 0.04 0.64 -0.08 V 1.00 0.15 -0.03 W 1.00 -0.27 Zn 1.00

Table 2.3: Pearson Correlation Coefficient matrix analyses of ICP-MS/MS data of total metal analysis by stroke. Correlations highlighted in red are considered statistically significant. Those in bold have a power analysis value greater or equal to 0.8, while those with r ≥ 0.8 were underlined.

2.4.2 SEC-ICP-MS/MS Metalloprotein Analyses

AIS AIS Control ICH ICH Control Elements Mean SEM Mean SEM Mean SEM Mean SEM Ag* 54.8 9.3 128.7 75.5 44.5 17.8 57.3 18.0 As 0.21 0.03 0.13 0.03 0.23 0.02 0.23 0.05 Cd* 12.5 2.0 30.1 6.0 11.1 1.6 25.6 4.2 Co 9.32 1.03 8.42 1.19 12.52 1.93 17.17 2.52 Cu 9.32 2.20 12.71 4.26 7.49 1.19 20.14 4.48 Mn 1.12 0.31 1.27 0.38 1.22 0.23 1.80 0.42 Ni 3.57 0.70 2.12 0.52 2.04 0.27 3.54 0.56 Pb 0.17 0.03 0.34 0.06 0.07 0.01 0.28 0.05 Se 9.20 1.05 4.20 0.57 9.71 1.26 5.99 0.74 Sr 1.53 0.46 2.21 0.84 1.27 0.18 2.67 0.68 V 1.07 0.50 1.68 0.70 0.87 0.20 3.21 1.12 W* 14.9 3.9 19.6 6.2 11.2 1.9 30.2 9.8

Table 2.4: Descriptive statistics of SEC-ICP-MS/MS analyses performed using plasma from AIS and ICH cases. Mean and standard error of the mean (SEM) values are defined in ng/g whereas elements denoted with “*” are defined in pg/g. Values were normalized to integrations of SEC-HPLC-DAD signal at 280 nm and Fe concentration-1. Integrations of 78Se and 75As were only normalized to integrations of SEC-HPLC-DAD signal at 280 nm. Fe concentration was excluded from this table due to in vitro hemolysis.

SEC-ICP-MS/MS analyses (Table 2.3) were performed after immunodepletion of HSA and IgG. The AIS group had higher concentrations of As (65%) and Se (119%), but lower Cd

(58%), Co (11%), Pb (50%), V (37%), and W (24%) compared with the respective control. The

ICH group had higher concentrations of Se (62%) relative to the control, while it had lower concentrations of Cd (57%), Co (27%), Cu (63%), Mn (32%), Ni (42%), Pb (75%), Sr (52%), V

(73%), and W (63%). When comparing both stroke types, the AIS cases had higher concentrations of Cd (13%), Cu (24%), Ni (75%), Pb (138%), Sr (21%), V (23%), and W (34%) relative to ICH case concentrations.

Elements that displayed statistically significant differences and had acceptable power value (Power ≥ 0.8) are shown in Figure 2. In the AIS group, statistically significant differences were found compared to AIS and ICH controls. The AIS case group had higher Se (9.20 ng/mL) than its respective control (4.20 ng/mL). The AIS case also had lower Cd (12.5 pg/mL) than its 45

respective control (30.1 pg/mL). The ICH case group was statistically lower for Cd (11.1 pg/mL) and Pb (0.07 ng/mL) compared with both control groups. The ICH case group was also statistically higher for Se (9.71 ng/mL) compared with both control groups.

a. * b. * *

c. d. * * *

Fig.2.2 (a-d): Boxplot plot analysis of normalized SEC-ICP-MS/MS. Units are denoted in ng of element per mL of diluted immunodepleted blood plasma (ng/mL). Boxplots represent the bottom 25% quartile, median (middle line), mean (□), top 75% quartile (top line), and the extremes in the plot represent the range of the values. Statistically different relationships (*) were determined with 95% confidence by one-way ANOVA and found to have sufficient or better power values (Power ≥ 0.8) after Bonferroni correction.

Compared with the total metal profile, the Pearson Correlation Coefficient matrix analysis for the

SEC-ICP-MS/MS data found numerous statistically significant correlations that had sufficient or better power values. Upon inspection, differences between the stroke groups became apparent, such as the AIS pattern including Pb-W, Pb-V, Sr-W, Cu-V, and Sr-V correlations. In regards to 46

unique identifiers, the ICH case group included strong correlations such as Co-Mn, As-Se, Pb-

Se, Cd-V, and Cd-W. Controls were discriminated from case groups with the following strong correlations: Ag-W, Ni-Sr, Cd-Ni, and As-Mn. All four groups shared the strong positive V-W correlation.

Ag (ppb) As (ppb) Cd (ppb) Co (ppb) Cu (ppb) Mn (ppb) Ni (ppb) Pb (ppb) Se (ppb) Sr (ppb) V (ppb) W (ppb) AIS Ag (ppb) 1.00 0.11 -0.09 -0.10 0.03 -0.14 0.50 0.14 0.26 -0.12 -0.07 -0.02 As (ppb) 1.00 0.88 0.63 0.72 0.76 0.38 0.15 -0.01 0.51 0.39 0.16 Cd (ppb) 1.00 0.73 0.73 0.93 0.31 0.21 -0.16 0.65 0.45 0.22 Co (ppb) 1.00 0.80 0.61 0.19 0.54 -0.44 0.76 0.78 0.63 Cu (ppb) 1.00 0.58 0.09 0.73 -0.08 0.93 0.89 0.77 Mn (ppb) 1.00 0.30 0.02 -0.02 0.56 0.30 0.05 Ni (ppb) 1.00 -0.11 0.05 -0.12 -0.13 -0.17 Pb (ppb) 1.00 -0.31 0.78 0.88 0.95 Se (ppb) 1.00 -0.13 -0.26 -0.26 Sr (ppb) 1.00 0.91 0.83 V (ppb) 1.00 0.95 W (ppb) 1.00 AIS Control Ag (ppb) 1.00 -0.07 0.20 0.89 0.91 -0.07 0.45 0.95 0.60 0.72 0.57 0.71 As (ppb) 1.00 0.74 0.32 0.18 0.81 0.53 -0.10 -0.04 0.42 0.42 0.24 Cd (ppb) 1.00 0.46 0.39 0.92 0.80 0.10 0.40 0.57 0.45 0.25 Co (ppb) 1.00 0.97 0.25 0.73 0.85 0.57 0.93 0.64 0.69 Cu (ppb) 1.00 0.17 0.74 0.87 0.69 0.94 0.50 0.59 Mn (ppb) 1.00 0.69 -0.15 0.23 0.42 0.36 0.14 Ni (ppb) 1.00 0.39 0.67 0.89 0.33 0.24 Pb (ppb) 1.00 0.50 0.69 0.54 0.67 Se (ppb) 1.00 0.65 -0.04 0.01 Sr (ppb) 1.00 0.46 0.47 V (ppb) 1.00 0.96 W (ppb) 1.00 ICH Ag (ppb) 1.00 0.16 -0.16 0.53 0.60 0.53 -0.04 0.57 0.31 0.39 0.12 -0.22 As (ppb) 1.00 0.12 -0.04 0.23 0.20 -0.13 0.59 0.81 0.39 0.20 0.15 Cd (ppb) 1.00 0.59 0.46 0.47 0.68 -0.20 -0.21 0.47 0.81 0.85 Co (ppb) 1.00 0.64 0.83 0.57 -0.01 -0.27 0.61 0.78 0.45 Cu (ppb) 1.00 0.58 0.27 0.44 0.20 0.75 0.50 0.35 Mn (ppb) 1.00 0.44 0.10 0.01 0.76 0.58 0.24 Ni (ppb) 1.00 -0.07 -0.23 0.31 0.45 0.49 Pb (ppb) 1.00 0.84 0.19 -0.20 -0.26 Se (ppb) 1.00 0.20 -0.25 -0.25 Sr (ppb) 1.00 0.55 0.29 V (ppb) 1.00 0.80 W (ppb) 1.00 ICH Control Ag (ppb) 1.00 0.50 0.27 0.64 0.63 0.38 0.29 0.49 -0.10 0.46 0.85 0.88 As (ppb) 1.00 0.84 0.71 0.59 0.89 0.82 0.47 0.11 0.87 0.56 0.65 Cd (ppb) 1.00 0.65 0.63 0.91 0.94 0.40 0.45 0.87 0.33 0.48 Co (ppb) 1.00 0.66 0.64 0.72 0.34 -0.04 0.67 0.74 0.78 Cu (ppb) 1.00 0.77 0.67 0.25 0.22 0.75 0.67 0.79 Mn (ppb) 1.00 0.92 0.29 0.33 0.93 0.46 0.60 Ni (ppb) 1.00 0.20 0.35 0.84 0.40 0.50 Pb (ppb) 1.00 0.24 0.48 0.32 0.52 Se (ppb) 1.00 0.29 -0.12 -0.05 Sr (ppb) 1.00 0.49 0.71 V (ppb) 1.00 0.88 W (ppb) 1.00

Table 2.5: Pearson Correlation Coefficient matrix analyses of normalized SEC-ICP-MS/MS analysis of plasma post-immunodepletion. Correlations with r > 0.8 were strong correlations 47

whereas those with 0.5 < r < 0.8 are considered moderate correlations. Correlations highlighted in red are considered statistically significant, those in bold have a power analysis value greater or equal to 0.8, and those with r > 0.8 were underlined.

Table 2.6: Pearson Correlation Coefficient matrix analyses of normalized SEC-ICP-MS/MS(a) analysis of plasma post-immunodepletion to total metal concentrations analyzed from ICP- MS/MS(b). Correlations with r ≥ 0.8 were strong correlations where as those with 0.5 ≤ r < 0.8 are considered moderate correlations. Correlations highlighted in red are considered statistically significant and those in bold have a power analysis value greater or equal to 0.8, while those with r > 0.8 were underlined.

When comparing the total metal concentrations to those from the SEC-ICP-MS/MS values, predominantly moderate correlations were found between total metal concentrations with 48

fluctuations of metals among metalloproteins (Supplementary Table S1). In the AIS group, there was a moderate correlation between total Fe concentration with bound W (r = 0.75) as well as total Sr concentration with bound Ag (r = 0.71). Correlations with protein bound As were found to be a moderate, negative correlation with V(r = -0.77) and strong negative with Ba (r = -0.84) in regard to the AIS control group. The ICH group was found to have total Ag moderately correlated with bound Ag (r = 0.78) as well as Pb (r= 0.74), and bound Cd was moderately correlated with total Ba (r = 0.76) and Cu (r = 0.73).

2.4.3 Multivariate Analysis

a. b.

Figure 2.3 (a-b): 2D score and loading plots of the principal component analysis (PCA) model identified from normalized SEC-ICP-MS/MS values. Each axis denotes a principal component (PC2-PC3). The 2D score plots of the PCA model conveys PC2 and PC3 on the upper left figure (a) whereas the loading plot of PC2 and PC3 are conveyed on the right (b). Figure 2.3a shows that only the AIS cases could be separated from the AIS controls.

Each principal component (PC) is a vector that is influenced by one or more factors and, in this context, the SEC-ICP-MS/MS data was utilized to identify multivariate model findings that described the changing metalloproteome. A 2D score plot was generated for two of the three

PC’s, but was not capable of separating all four stroke types. While mean centering is a common method of data pretreatment in metabolomics, prior to PCA,19 vast scaling has been shown to be ideal for biomarker identification19. Principal component 2, as evidenced by the 49

loadings plot, was strongly influenced by Se cofactor fluctuations among proteins. Principal component 3 was strongly influenced by a negative correlation between Co and Cd.

While PCA was capable of separation of the AIS cases compared with the controls, linear discriminant analysis (LDA) was used for classification of stroke type. Both LDA classifications were based on W, Mn, Cu, As, Pb, Se, Cd, and Co co-factor concentrations. The

LDA model determined that predicting between a stroke and stroke control had an accuracy of

93.44% (Fig. 2.4a), whereas the determination between stroke type had an achieved accuracy of 85.25% (Fig. 2.4b).

a. b.

Figure 2.4 (a-b): LDA discrimination plots by for prediction of occurrence of stroke (a) compared with a discrimination plot for prediction of stroke type (b)

2.4.4 Metalloprotein Identifications

Numerous unique metalloproteins were identified between the two stroke groups. Metalloprotein groups were consolidated by removing replicate proteins between the cases and the controls.

High abundant blood plasma proteins and immunoglobulins were removed. Low abundance metalloproteins were identified (Table 2.4). All identified proteins are provided in the

Supplementary Information (Appendix 1).

Metalloproteins identified from stroke patients included possible markers for damage to brain tissue. Multiple metalloproteins were identified in the AIS group including calpain-15, titin

(Isoform 3), and tropomyosin alpha-4 chain. Calapain-15 (CAPN15) is an exclusive brain metalloprotein that acts as a neutral protease activated by calcium ion, plays a role in calcium- delayed deregulation causing neuronal cell death,20 and may cause microtubular proteolysis in the ischemic brain.21 Tropomyosin alpha-4 chain identification may suggest high concentrations in platelets because of hypertension22. Metalloproteomics yielded the identifications of multiple metalloproteins for the ICH cases including bestrophin-3, G protein-activated inward rectifier potassium channel 1 (GIRK-1), tau-tubulin kinase 1 (TTBK1), and voltage-dependent L-type calcium channel subunit beta-3 (CAB3). GIRK-1 is a major component of brain neurons and its dysfunction has been shown to cause numerous disorders such as epilepsy and Parkinson’s disease23. CAB3 is a known calcium ion channel responsible for influx of calcium ions and is found primarily in the brain 24.

Table 2.7: Metalloproteomics above were a combination of data from LC-MS/MS from Sciex

Triple TOF and nanoLC-Chip-ITMS. Unique metalloproteins are presented from the (AIS) and

ICH groups. Metalloproteins designated with “*” are primarily expressed in the brain.

Group Metal Entry Name Protein Description Protein Score Peptide Sequence AIS Victim Zn* A0A0G2JNC7_HUMAN Baculoviral IAP repeat-containing protein 1 35 NLAEKEDNVK Zn CNDP1_HUMAN Beta-Ala-His dipeptidase 108 MMAVAADTLQR Zn* CAN15_HUMAN Calpain-15 40 RLSLPR Ca CAN2_HUMAN Calpain-2 catalytic subunit 48 KALEEAGFK Zn,Co E5RK37_HUMAN Carbonic anhydrase 2 84 AEKGISMLRK Mn CRNS1_HUMAN Carnosine synthase 1 (Isoform 3) 35 GSPEGAEAR Ca A0A0C4DFP6_HUMAN Cartilage acidic protein 1 47 DVAAEAGVSK Zn ZRAB3_HUMAN DNA annealing helicase and endonuclease ZRANB3 61 IDGSVSSSER Fe, Zn A0A087WX51_HUMAN DNA polymerase epsilon catalytic subunit A 37 IISFSR Ca DUOX1_HUMAN Dual oxidase 1 (Isoform 2) 39 VGIILSR Zn* BRE1A_HUMAN E3 ubiquitin-protein ligase BRE1A 37 VESSRR Zn RN220_HUMAN E3 ubiquitin-protein ligase RNF220 (Isoform 2) 42 ATTLLEGGFR Ca Q580Q6_HUMAN EGF-containing fibulin-like extracellular matrix protein 1 40 NPADPQRIPSNPSHR Ca FBLN3_HUMAN EGF-containing fibulin-like extracellular matrix protein 1 (Isoform 2) 54 ADQVCINLR Zn A0A0C4DGF0_HUMAN Endoplasmic reticulum metallopeptidase 1 38 MLEVLR Ca* H0YAH6_HUMAN Epithelial discoidin domain-containing receptor 1 39 INNRPGPR Mg, Mn, Zn* FAN1_HUMAN Fanconi-associated nuclease 1 36 RPALEAR Zn LIMA1_HUMAN LIM domain and actin-binding protein 1 (Isoform 4) 39 TVSPPIR Zn LONF3_HUMAN LON peptidase N-terminal domain and RING finger protein 3 (Isoform 2) 35 QVEAALLK Mg E7ERD7_HUMAN Long-chain-fatty-acid--CoA ligase 6 42 QTQEILR Fe, Zn KDM7A_HUMAN Lysine-specific demethylase 7A (Isoform 2) 47 TFIKELR Mg H3BPX2_HUMAN Obscurin 52 FIEDVK Ca A0A0A0MSC8_HUMAN Slit homolog 3 protein 46 KINLSNNK Ca SYTL2_HUMAN Synaptotagmin-like protein 2 (Isoform 8) 42 QRSDPYVK Mg,Ca TITIN_HUMAN Titin (Isoform 2) 46 TPILKK Mg, Ca* TITIN_HUMAN Titin (Isoform 3) 46 VIDITR Zn SP3_HUMAN Transcription factor Sp3 45 MTAPEKPVK Ca* K7EP68_HUMAN Tropomyosin alpha-4 chain 57 LVILEGELE ICH Victim Ca* BEST3_HUMAN Bestrophin-3 (Isoform 1) 36 LLLTGVQKR Ca I3L1J2_HUMAN Cadherin-5 44 YTFVVPEDTR Zn CAH3_HUMAN Carbonic anhydrase 3 40 VVFDDTYDR Ca COL11_HUMAN Collectin-11 (Isoform 10) 42 VFIGINDLEK Ca H0YE30_HUMAN Copine-7 37 VFVPFR Zn ZRAB3_HUMAN DNA annealing helicase and endonuclease ZRANB3 (Isoform 3) 37 IDGSVSSSER Mg,Mn,Ca H7BZ82_HUMAN DNA topoisomerase 2-beta 36 YETVQDILK Zn DMRTA_HUMAN Doublesex- and mab-3-related transcription factor A1 37 VGISPLR Ca EFC13_HUMAN EF-hand calcium-binding domain-containing protein 13 38 SDISSIPK Cu,Zn SODE_HUMAN Extracellular superoxide dismutase [Cu-Zn] 103 QAREHSERKK Ca A0A087WYV8_HUMAN Fibrillin-2 37 EGWIGNGIK Zn GPTC8_HUMAN G patch domain-containing protein 8 43 ALEDLR K* KCNJ3_HUMAN G protein-activated inward rectifier potassium channel 1 45 EDFPKK Ca ITA8_HUMAN Integrin alpha-8 40 MSPGASRGPR Ca F8WBG2_HUMAN Integrin beta-5 37 VPDGGLTR Zn LONF3_HUMAN LON peptidase N-terminal domain and RING finger protein 3 (Isoform 3) 45 QVEAALLK Fe, Cu B8ZZX6_HUMAN Metalloreductase STEAP3 35 VPDEAPK Mn, Co, Cd, Ni, V, Pb F8VRL7_HUMAN Natural resistance-associated macrophage protein 2 37 ISIPEEEAR Mg OBSCN_HUMAN Obscurin (Isoform 2) 35 FIEDVK Ca,Mg F5GWN5_HUMAN Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta 39 TGLEEVK Mn, Mg H0YJZ9_HUMAN Poly(A) polymerase alpha 36 KNVAVVALGR Zn J3QQW9_HUMAN Polycomb protein SUZ12 39 LYSLLK K* HCN3_HUMAN Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 36 ILSLLR Zn F5H579_HUMAN Probable cysteine--tRNA ligase, mitochondrial 42 EGAVLEAGGAR Mn, Mg* TTBK1_HUMAN Tau-tubulin kinase 1 37 VATISPR Mg TITIN_HUMAN Titin (Isoform 12) 44 TPILKK Zn* ZEP2_HUMAN Transcription factor HIVEP2 37 RDLSPR Zn F2Z2M2_HUMAN Tripartite motif-containing protein 14 42 AGDAAADEPR Ca* H0YHK1_HUMAN Voltage-dependent L-type calcium channel subunit beta-3 43 QQLERAK Zn* A0A0C4DGZ1_HUMAN Zinc finger CCCH domain-containing protein 8 47 QKNKNLK

While unique tissue leakage or damage biomarkers are ideal, the aim was to use both unique identifiers as well as select metalloprotein groups identified from the PCA model to determine appropriate metalloprotein biomarkers for stroke discrimination. Further, LDA was used as a means to predict stroke onset based on metal-cofactor concentrations. Considering 52

the Se influence on the PCA, as well as the statistical differences found between the groups for

Se, selenoproteins such as glutathione peroxidase, and selenoprotein P, are of interest and have a role in inflammation. Hypertensive patients have increased iron storage protein, ferritin,

25-26, while iron transport by transferrin may be inhibited.27-28 Transferrin, a metal transportation protein 28, binds numerous metals with a preference for iron, and binds to Apolipoprotein A-1.

Additionally, vanadium, as vanadate, as well as Mn may be displaced by iron from transferrin. 29

Arsenic inhibits numerous selenoproteins including glutathione peroxidase and glutathione transferase 30. The importance of arsenic may be in relation to cobalamin independent methionine synthase inhibition. Inorganic arsenic is known to bind methionine synthase, and, in this case, may bind to cobalamin independent methionine synthase31, thus inhibiting conversion of seleno-homocysteine to selenomethionine31.The Se signal is negatively correlated with Co signal in PC2 due to an alternative pathway of conversion, by cobalamin dependent methionine synthase, to selenoprotein P31. While these are just a few examples, many metals played an important role in prediction of stroke onset as well as prediction of the type of stroke.

Metalloproteins with Zn finger domains may have fluctuations between binding Co or Cd, considering the role of the negative correlation between Cd and Co as well as their influence on the LDA model32.

2.5 Conclusion

We successfully conducted a three-prong approach for the identification of stroke biomarkers in human plasma, including the analysis of metals, metals bound to proteins, and metalloproteins. Pearson correlation coefficient matrix of the total metal concentrations found unique identifiers for the AIS case that included Cu-Al (r = 0.86) and Al-Zn (r = 0.80). ICH cases had a moderate correlation for Cu-Se (r = 0.74) and did not include the Fe-Mn (r = 0.87) apparent in the ICH control group.

Pearson correlation coefficient analysis of SEC-ICP-MS/MS data found consistently strong correlations between W and V. Additionally, the AIS case group had unique identifiers including Pb-V (r=0.88) and Pb-W (r=0.95). The ICH case group was found to have unique identifiers including As-Se (r=0.81), Pb-Se (r=0.84), and Cd-V (r=0.81). From the descriptive analysis of the SEC-ICP-MS/MS, statistical differences were found between each stroke case group and its respective control in regard to bound Cd, Pb, as well as Se. The PCA analysis found that Co, Cd, As and Se fluctuations play an important role in stroke at the metalloprotein level. This further supports the importance of selenoproteins and their inhibition by arsenic species 30. Selenoproteins also play an important role as antioxidants33. While it is known that

90% of selenoproteins include glutathione peroxidases or selenoprotein P33, low blood Se concentrations have been associated with increased cardiovascular disease deaths caused by poor glutathione peroxidase 4 (GPX4) activity in the prevention of low density lipoprotein oxidation33. Considering that V and W correlations were critically important for bound metal concentrations in all four stroke groups, this may be suggestive that there is a proportional influx of these metals and that these metals are likely transported by transferrin considering that it has two metal binding sites that have affinity for numerous transition metals. 34

Unique biomarkers proposed include tissue leakage metalloproteins such as calpain-15, titin (Isoform 3), and tropomyosin alpha-4 chain. Additionally, metalloproteins, such as selenoprotein P or glutathione peroxidase, were identified in all stroke type groups. Future work will seek to quantify varying selenoproteins, including selenoprotein P and glutathione peroxidase, as well as identified tissue leakage metalloproteins by multiplexed assays and activity assay. Further, future work aims to improve the accuracy of the LDA model for stroke determination as well as explore the biological influence from the accompanied variables.

Lastly, in order to explore the effect of stroke type on trace metal transportation by transferrin,

we aim to offline fractionate transferrin from blood plasma samples and assess the changes in the metal being transported by SEC-ICP-MS/MS.

2.6 References

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S. R.; de Ferranti, S.; Despres, J. P.; Fullerton, H. J.; Howard, V. J.; Huffman, M. D.; Isasi, C. R.;

Jimenez, M. C.; Judd, S. E.; Kissela, B. M.; Lichtman, J. H.; Lisabeth, L. D.; Liu, S.; Mackey, R.

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11. Groessl, M.; Terenghi, M.; Casini, A.; Elviri, L.; Lobinski, R.; Dyson, P. J., Reactivity of anticancer metallodrugs with serum proteins: new insights from size exclusion chromatography-

ICP-MS and ESI-MS. J Anal At Spectrom 2010, 25 (3), 305-313.

12. Garcia Sar, D.; Montes-Bayon, M.; Aguado Ortiz, L.; Blanco-Gonzalez, E.; Sierra, L. M.;

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14. Kodali, P.; Jurkevica, A.; Landero, J.; Kuhlmann, C.; Caruso, J.; Adeoye, O., Multiple liquid chromatography separations and nanoESI-ion trap detection of plasma proteins in search of stroke biomarkers: A pilot study. Journal of separation science 2012, 35 (17), 2153-61.

15. Bishop, D. P.; Hare, D. J.; Fryer, F.; Taudte, R. V.; Cardoso, B. R.; Cole, N.; Doble, P. A.,

Determination of selenium in serum in the presence of gadolinium with ICP-QQQ-MS. The Analyst

2015, 140 (8), 2842-6.

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Ascenzi, P., The extraordinary ligand binding properties of human serum albumin. IUBMB life

2005, 57 (12), 787-96.

17. Shilov, I. V.; Seymour, S. L.; Patel, A. A.; Loboda, A.; Tang, W. H.; Keating, S. P.; Hunter,

C. L.; Nuwaysir, L. M.; Schaeffer, D. A., The Paragon Algorithm, a next generation search engine that uses sequence temperature values and feature probabilities to identify peptides from tandem mass spectra. Mol Cell Proteomics 2007, 6 (9), 1638-55.

18. Kodali, P.; Chitta, K. R.; Landero Figueroa, J. A.; Caruso, J. A.; Adeoye, O., Detection of metals and metalloproteins in the plasma of stroke patients by mass spectrometry methods.

Metallomics : integrated biometal science 2012, 4 (10), 1077-87.

19. van den Berg, R. A.; Hoefsloot, H. C.; Westerhuis, J. A.; Smilde, A. K.; van der Werf, M.

J., Centering, scaling, and transformations: improving the biological information content of metabolomics data. BMC genomics 2006, 7, 142.

20. Brustovetsky, T.; Bolshakov, A.; Brustovetsky, N., Calpain activation and Na+/Ca2+ exchanger degradation occur downstream of calcium deregulation in hippocampal neurons exposed to excitotoxic glutamate. Journal of neuroscience research 2010, 88 (6), 1317-28. 57

21. Pettigrew, L. C.; Holtz, M. L.; Craddock, S. D.; Minger, S. L.; Hall, N.; Geddes, J. W.,

Microtubular proteolysis in focal cerebral ischemia. Journal of cerebral blood flow and metabolism

: official journal of the International Society of Cerebral Blood Flow and Metabolism 1996, 16 (6),

1189-202.

22. Crabos, M.; Yamakado, T.; Heizmann, C. W.; Cerletti, N.; Buhler, F. R.; Erne, P., The calcium binding protein tropomyosin in human platelets and cardiac tissue: elevation in hypertensive cardiac hypertrophy. European journal of clinical investigation 1991, 21 (5), 472-8.

23. Luscher, C.; Slesinger, P. A., Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nature reviews. Neuroscience 2010, 11 (5),

301-15.

24. Hullin, R.; Singer-Lahat, D.; Freichel, M.; Biel, M.; Dascal, N.; Hofmann, F.; Flockerzi, V.,

Calcium channel beta subunit heterogeneity: functional expression of cloned cDNA from heart, aorta and brain. The EMBO journal 1992, 11 (3), 885-90.

25. Choi, B.; Yeum, K. J.; Park, S. J.; Kim, K. N.; Joo, N. S., Elevated serum ferritin and mercury concentrations are associated with hypertension; analysis of the fourth and fifth Korea national health and nutrition examination survey (KNHANES IV-2, 3, 2008-2009 and V-1, 2010).

Environmental toxicology 2015, 30 (1), 101-8.

26. Ryoo, J. H.; Kim, S. Y.; Oh, C. M.; Park, S. K.; Kim, E.; Park, S. J.; In Yu, J.; Kim, M. G.;

Choi, Y. S.; Ko, T. S., The incidental relationship between serum ferritin levels and hypertension.

International journal of cardiology 2015, 183, 258-62.

27. Nagaoka, M. H.; Akiyama, H.; Maitani, T., Binding patterns of vanadium to transferrin in healthy human serum studied with HPLC/high resolution ICP-MS. The Analyst 2004, 129 (1), 51-

28. Vincent, J. B.; Love, S., The binding and transport of alternative metals by transferrin.

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29. Harris, W. R.; Carrano, C. J., Binding of vanadate to human serum transferrin. J Inorg

Biochem 1984, 22 (3), 201-18.

30. Shen, S.; Li, X. F.; Cullen, W. R.; Weinfeld, M.; Le, X. C., Arsenic binding to proteins.

Chemical reviews 2013, 113 (10), 7769-92.

31. Zhou, Z. S.; Smith, A. E.; Matthews, R. G., L-Selenohomocysteine: one-step synthesis from L-selenomethionine and kinetic analysis as substrate for methionine synthases. Bioorganic

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Chapter 3

Prediction of Stroke Type by Multivariate Analysis: Pentraxin-3 and Transferrin as Blood Plasma Biomarkers

3.1 Abstract

Previous work reported paraoxonase-1 (PON1) and apolipoprotein (Apo) A-1 as biomarkers for ischemic stroke diagnosis. We aimed to assess the validity of these markers and identify viable protein biomarkers for acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) diagnosis. Plasma samples (n = 74) were collected from patients with AIS cases, AIS controls, ICH cases, and ICH controls. Plasma concentrations of proteins were quantified by multiplexed immunoassay, and multivariate analysis was applied to determine proteins capable of stroke classification. Omentin-1, metalloproteinase-7 (MMP-7), apolipoprotein A-I (Apo-AI) and Apo-AII were found to classify stroke type. Pentraxin-3 (PTX3) and transferrin (Tf) were found to be unbiased to diabetes and hypertension.

PTX3 concentration was higher in AIS cases (Median = 0.8 mg/mL, P=0.0062) than AIS controls

(Median = 0.5 mg/mL), while ICH cases were higher (Median = 1.0 mg/mL, P=0.0053) than ICH controls (Median = 0.6 mg/mL). AIS cases were lower in Tf (Median = 232.0 mg/mL, P=0.0047) compared with the respective control (Median = 272.5 mg/mL), while ICH cases were lower in Tf

(Median = 244.0 mg/mL, P=0.0296) compared with ICH controls (Median = 272.0 mg/mL). When comparing AIS and ICH cases, AIS and ICH cases were classified with 97.30% accuracy with linear discriminant analysis.

3.2 Introduction

Stroke is a leading cause of disability and mortality1 and resulted in an estimated 6.7 million deaths worldwide in 2012.2 The two types of stroke include acute ischemic stroke (AIS), caused by a lack of blood supply to an area of the brain, and hemorrhagic stroke, caused by bleeding into the brain from a ruptured blood vessel. Hemorrhagic stroke is further classified into intracerebral hemorrhage (ICH), bleeding into the brain tissue, and subarachnoid hemorrhage, bleeding into a space surrounding the brain. AIS accounts for about 87% of all strokes while ICH results in approximately 10%.1 There is currently no blood test available to assist in the diagnosis of stroke, and overall there is a lack of much needed biomarkers to provide information regarding stroke pathophysiology and diagnosis. Identifying such clinically useful biomarkers, particularly in plasma that is already routinely collected from patients in the clinical setting, has the potential to revolutionize the current diagnostic and treatment paradigm for stroke, enhance the understanding of stroke pathophysiology, and improve stroke patient outcomes.

When seeking insight into the biological responses caused by stroke, proteins yield a plethora of information due to their roles in signaling,3 inflammation,4 and ion transport.5-6 Proteins can be induced by a number of stimuli including inflammation7 and apoptosis.8 Cytokines are small proteins that have roles in influencing cell interaction, including anti-inflammatory as well as pro-inflammatory effects.9

Pro-inflammation processes are known to induce production of pentraxin-3 (PTX3)10. Elevated levels of

PTX3 have been shown to be correlated with atherosclerosis 10-11 as well as acute ischemic stroke10.

Injections of interleukin 6 (IL-6), a cytokine, have been shown to lower transferrin (Tf) and transthyretin

(TTR) levels within 48 to 96 hours.12 Elevated levels of Tf have been reported in acute ischemic stroke cases13 and has been shown to commonly reflect decreased levels of ferritin14.

A previous study, from which the same data was utilized for the currently reported research, found that apolipoprotein A-1 (Apo A-1) and paraoxonase-1 (Pon-1) concentrations were potential biomarkers for

AIS. The median Apo A-1 concentration was lower in AIS cases (140 mg/dL) compared to their respective matched controls (175 mg/dL) and the ICH cases (180 mg/dL).15 AIS cases had a lower

62 median concentration of Pon-1 (250,500 mg/dL) compared to AIS controls (345,500 mg/dL) and ICH cases (366,000 mg/dL).15 The AIS cases had a high prevalence of hypertension (64% of patients), second only to the ICH cases (73.9%) and the AIS cases also had the highest percentage of diabetic patients (50%) (Table 1). The current study approaches this data for a validation analysis of the statistical differences and to evaluate bias resulting from varying prevalence of hypertension and diabetes.

Our approach utilizes principal component analysis (PCA) as an unsupervised multivariate statistics technique for variable (dimension) reduction and group classification.16-17 When many observations are collected for numerous variables, PCA generates principal components (PCs) by a linear combination of the variables. This enables dimension reduction for visual interpretation16 that provides an alternative perspective of the raw data. The first PC describes the largest variance among the data, followed by the next PC with the second most explained variance.18 This alternative perspective of the observations is then presented as a scatterplot of one, two, or three PCs in the score plot. Classification of observations can be performed by the clustering of observations that occurs in the score plots of two or more PCs.16 To interpret the cause of the clustering, as well as the variation, the loadings plot consists of two or more PCs, where each PC is a linear combination of the variables with varying influence.19

Variables that are more distant from the origin have stronger influence on a respective PC and thus the overall PCA model. In correlation loading diagrams, variables that are close to the origin are uncorrelated, those closer together are positively correlated, and variables farther apart are negatively correlated.

By using the classification and dimension reduction of PCA, biological findings can be inferred. Other groups have utilized PCA to describe the relationships between peptide sequences and biological properties20 and to discover important clinical metabolites.17 PCA has been reported as ideal for clinical protein analysis due to its ability to explore grouping and to shrink large data sets into more manageable sizes, especially for multiplexed arrays21.

3.3 Methods

3.3.1 Sample Collection

Stroke patients were enrolled and plasma samples obtained within 12 hours of symptom onset between

August 2013 and May 2014 at an urban, tertiary care center. Potential cases were identified from pages to the institution’s stroke team and screening of the emergency department and inpatient units by hospital-based Research Assistants. Inclusion criteria were as follows: age ≥18 years, acute ischemic stroke or primary spontaneous ICH with no radiographic features suggestive of aneurysmal subarachnoid hemorrhage, traumatic contusion, vascular malformation, tumor, or venous sinus thrombosis. Exclusion criteria included: recent history (<2 weeks) of myocardial infarction, stroke, surgery, or hospitalization, known active malignant cancer, lymphoma, or leukemia, history of a chronic inflammatory disorder, current treatment with anticoagulants, congenital or heritable disorder of coagulation, and liver disease or cirrhosis. The patient or their legally authorized representative provided signed, informed consent, and were then asked about medical history related to stroke risk factors including history of smoking, diabetes, hypertension, coronary artery disease, atrial fibrillation, and prior stroke. Venipuncture was performed for collection of a venous blood specimen. Controls were matched based on age (+/- five years), race, and gender, and were recruited from hospital staff and well visitors to the hospital. Each sample was given an arbitrary number. Demographic information is presented in Table 2.1. Blood plasma samples were stored at -80°C until use.

3.3.2 Plasma Protein Analysis

The plasma levels were determined using commercially available multiplex assays for the following proteins: apolipoprotein(Apo) A-I, Apo A-II, Apo C-I, Apo C-III, Apo H, brain derived neurotrophic factor, factor VII, gastric inhibitory polypeptide (GIP), high-density lipoprotein cholesterol (HDL-C), intercellular adhesion molecule 1, Interleukin (IL) -1 beta, IL-1 receptor antagonist (IL-1ra), IL-12 subunit p40, leptin receptor, matrix metalloproteinase (MMP)-3, MMP-7, MMP-9, MMP-10, omentin-1, paraoxonase-

1(PON1), pentraxin 3 (PTX3), serotransferrin (Tf), serum amyloid alpha (SAA), stem cell factor, transthyretin (TTR), and vascular endothelial growth factor (VEGF).

3.3.3 Statistical Analysis

Descriptive statistics and box plot analysis were performed using Origin v. 8.5. Descriptive analysis was performed on AIS and ICH cases compared with their respective controls. Prior to determination of statistic differences, Kruskal–Wallis ANOVA was performed on all analytes to determine whether statistically significant (p<0.05) differences were apparent among the stroke groups. Descriptive analysis of stroke groups by race were performed to assess ethnic differences: African American (AA)

ICH cases (AA ICH cases), AA ICH controls, white ICH cases, white ICH controls , white AIS cases, and white AIS controls. For this descriptive analysis, sample size was insufficient (n=1) to assess AA

AIS cases or AA AIS controls. Statistically significant difference were assessed by the Mann-Whitney

U-test using Statistica 9.0 at 95% confidence.

The Unscrambler v. 10.2 was used for PCA. Analyte concentrations were transformed in The

Unscrambler software by performing the log transformation 17 of all values to decrease the skew of the data. This was followed by autoscaling the data set. Scaling and transformation were performed in The

Unscrambler. PCA was performed with the NIPALS algorithm using three PCs, and outliers were removed based on the default setting of the outlier detection and residual plots. Interpretation of loadings and score plots as used in the current study have been described previously.16

In order to determine whether the stroke group separation was biased based on comorbid disease status, the PCA model highlighted points in the score plots by ethnicity, hypertension, and diabetes.

Linear discriminant analysis (LDA) used for determination of stroke type. Analytes for LDA included age, Apo A-I, Apo A-II, GIP, HDL-C, MMP-7, MMP-9, omentin-1, PON1, PTX3, Tf, and TTR. The LDA models were generated with untransformed data and quadratic method in The Unscrambler.

3.4 Results

3.4.1 Descriptive Statistics

Stroke Group AIS Case AIS Control ICH Case ICH Control Analyte N total 14 14 23 23 Mean 242.9 322.2 293.3 332.2 Standard Deviation 47.0 62.2 54.0 65.3 Apo-AII (mg/mL) Median 242.0 303.5 298.0 352.0 P Value 0.0005 0.0358 Mean 0.4 1.0 0.4 1.2 Standard Deviation 0.5 0.9 0.4 1.0 GIP (mg/mL) Median 0.2 0.6 0.3 0.7 P Value 0.0291 0.0037 Mean 41.1 50.8 48.3 54.3 Standard Deviation 8.3 9.7 12.4 17.5 HDL-C (mg/dL) Median 41.1 52.1 45.2 51.7 P Value 0.0123 0.1410 Mean 8.4 6.0 19.2 6.3 Standard Deviation 4.8 2.5 26.1 2.9 MMP7 (mg/mL) Median 6.3 5.5 9.5 5.1 P Value 0.3577 0.0028 Mean 449.9 295.4 493.2 317.4 Standard Deviation 242.1 105.8 299.5 206.3 MMP9 (mg/mL) Median 411.0 257.0 407.0 267.0 P Value 0.0769 0.0389 Mean 133.0 100.2 174.3 160.7 Standard Deviation 40.7 37.5 77.8 89.1 Omentin (mg/mL) Median 120.5 93.5 143.0 132.0 P Value 0.0273 0.3854 Mean 1.0 0.7 1.2 0.7 Standard Deviation 0.7 0.9 0.8 0.4 PTX3 (mg/mL) Median 0.8 0.5 1.0 0.6 P Value 0.0062 0.0053 Mean 234.5 278.1 240.1 268.3 Standard Deviation 43.6 40.8 26.5 53.4 Tf (mg/mL) Median 232.0 272.5 244.0 272.0 P Value 0.0047 0.0296 Mean 27.5 34.5 29.3 32.9 Standard Deviation 7.6 7.3 9.6 7.9 TTR (mg/mL) Median 29.0 34.5 28.0 33.0 P Value 0.0081 0.0925

Table 3.1. Descriptive statistics of analytes found to be statistically different by Mann-Whitney

U-test at 95% confidence. P values lower than 0.05 are highlighted in red.

Prior to Mann Whitney U-test, the Kruskal Wallis ANOVA was used as a means to reduce the data to analytes with statistically significant differences. The Mann Whitney U-test was solely performed between stroke case group with the respective control due to unmatched race and gender demographics as well as differences in matched comorbity. Stroke cases were able to be separated from respective controls for Tf, PTX3, Apo-AII, and GIP (Table 3.1). Levels of Apo-AII were lower in

AIS cases (Median = 242.0 mg/mL, P=0.0005) than AIS controls (Median = 303.5 mg/mL) and levels were lower in ICH cases(Median = 298.0 mg/mL, P=0.0358) than ICH controls (Median = 352.0 mg/mL). Levels of GIP were lower in AIS cases (Median = 0.2 mg/mL, P=0.0291) than AIS controls

(Median = 0.6 mg/mL), while ICH cases (Median = 0.3 mg/mL, P=0.0037) than ICH controls (Median =

0.7 mg/mL). Further, PTX3 concentration was higher in AIS cases (Median = 0.8 mg/mL, P=0.0062) than AIS controls (Median = 0.5 mg/mL), while ICH cases (Median = 1.0 mg/mL, P=0.0053) than ICH controls (Median = 0.6 mg/mL). AIS cases were lower in Tf (Median = 232.0 mg/mL, P=0.0047) compared with the respective control (Median = 272.5 mg/mL), while ICH cases were lower in Tf

(Median = 244.0 mg/mL, P=0.0296) compared with ICH controls (Median = 272.0 mg/mL).

For determination of influence of demographic behavior, descriptive statistics was performed on the samples by gender, comorbidity, and race (Table 3.2). White patients were found to have statistically lower GIP (Median = 0.3 mg/mL, P=0.0413) than African American patients (Median = 0.5 mg/mL), while white patients had statistically lower PON1 (Median = 2795.3 mg/mL, P=0.00003) than African

American patients (Median = 3812.9 mg/mL). Female patients were found to have statistically lower

TTR (Median = 27.5 mg/mL, P=0.0002) than male patients (Median = 34.5 mg/mL). Further, hypertensive patients were found to have statistically lower HDL-C (Median = 45.0 mg/dL, P=0.0488) than non-hypertensive patients (Median = 51.8 mg/dL), while hypertensive patients were found to have statistically higher MMP-7 (Median = 8.2 mg/mL, P=0.0032) than non-hypertensive patients (Median =

5.4 mg/mL). Diabetic patients had statistically lower Apo-AI (Median = 1.6 mg/mL, P=0.0023), Apo-AII

(Median = 256.0 mg/mL, P=0.0318), and HDL-C (Median = 40.0 mg/dL, P=0.0001) compared with non- diabetic patients. Further, diabetic patients were found to have statistically higher MMP-7 (Median = 9.3 mg/mL, P=0.0162) and MMP-9 (Median = 407.0 mg/mL, P=0.0386) than non-diabetic patients.

Table valuesless0.05 than were highlighted in red. Statisticaldifferences were assessed by Mann U Whitney

Omentin(mg/mL)

Apo-AII(mg/mL)

MMP-9(mg/mL)

MMP-7(mg/mL)

Apo-AI(mg/mL)

HDL-C(mg/dL)

PON1(mg/mL)

PTX3(mg/mL) TTR(mg/mL)

GIP(mg/mL)

Tf(mg/mL)

African-American

White

African-American

White

African-American

White

African-American

White

African-American

White

African-American

White

African-American

White

African-American

White

African-American

White

African-American

White

African-American

White

Descriptivestatistics by race, gender, andcomorbidity.

Race

Ntotal

3812.9

2795.3

Mean

Race

259.4

252.8

168.0

136.9

392.2

392.7

317.2

292.2

32.0

30.5

14.0

51.1

48.5

0.8

1.0

8.9

0.9

0.6

1.8

1.7

Median

4015.0

2790.0

254.5

249.5

147.0

120.5

275.0

320.0

318.0

285.5

30.0

31.5

50.6

46.6

0.6

0.7

6.9

6.2

0.5

0.3

1.8

1.6

1068.1

1039.0

285.9

221.0

44.3

45.4

88.4

65.0

21.1

11.9

12.2

14.8

59.9

65.6

9.6

7.8

0.5

0.8

0.9

0.7

0.3

0.4

PValue

0.9066

0.5305

0.6099

0.0000

0.1460

0.5344

0.4354

0.2118

0.0413

0.1108

0.0927

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Gender

Ntotal

2904.4

3365.0

Mean

260.1

250.7

148.2

148.3

391.7

394.0

305.4

297.9

34.9

27.8

13.4

46.1

52.0

1.0

0.9

7.4

0.8

0.7

1.7

1.8

Gender

test. P test.

Median

3025.0

3290.0

254.0

252.5

136.0

127.0

291.0

294.5

293.0

294.0

34.5

27.5

46.7

49.8

0.7

5.9

6.7

0.3

0.4

1.7

1.8

1270.9

986.1

229.4

259.2

47.4

42.8

71.4

77.5

20.7

16.3

64.7

67.0

9.2

6.3

0.8

0.7

4.7

9.2

0.9

0.7

0.2

0.4

PValue

0.0002

0.4740

0.4705

0.0992

0.9395

0.8580

0.1194

0.1183

0.6604

0.5875

0.0950

Yes

Hypertensive

Ntotal

Hypertension

3015.8

3227.9

Mean

257.6

253.6

146.8

149.0

369.9

405.4

303.1

300.4

29.7

31.9

13.1

51.9

47.9

0.9

1.0

6.0

0.7

0.8

1.8

1.7

Median

2915.0

3570.0

257.5

250.0

108.0

134.0

270.0

298.5

300.0

290.5

31.0

30.5

51.8

45.0

0.7

5.4

8.2

0.3

0.4

1.7

1218.5

991.7

210.9

261.9

43.7

45.9

80.8

71.3

18.9

10.8

15.1

56.9

70.4

8.0

8.8

0.7

3.4

0.8

0.3

0.4

PValue

0.6421

0.6424

0.5075

0.2949

0.5751

0.7044

0.0032

0.0488

0.0937

0.6628

0.5612

Yes

Diabetes

Ntotal

3281.1

2831.1

Mean

254.4

256.5

149.2

145.9

348.1

506.2

312.6

272.9

Diabetes

31.2

30.9

18.2

52.8

40.5

0.9

7.6

0.8

0.6

1.8

1.5

Median

3370.0

2720.0

255.0

249.0

127.0

139.0

273.0

407.0

305.0

256.0

32.0

30.0

51.9

40.0

0.7

6.0

9.3

0.4

1.8

1.6

1019.7

1378.8

199.6

309.0

45.7

43.9

79.4

61.0

26.6

14.2

67.6

51.4

9.0

7.5

0.7

6.4

7.2

0.9

0.6

0.4

0.2

PValue

0.9140

0.9761

0.7506

0.1812

0.6315

0.0162

0.0001

0.8856

0.0318

0.0023 0.0386

Stroke Groups by Ethnicity AA ICH Case AA ICH Control W AIS Case W AIS Control W ICH Case W ICH Control

N total 12 12 13 13 10 10 Analyte Mean 1.8 1.8 1.5 1.8 1.7 2.0 Standard Deviation 0.2 0.3 0.2 0.3 0.2 0.6 APO-AI (mg/mL) Median 1.8 1.9 1.4 1.7 1.7 1.9 P Value 0.9073 0.0059 0.2709 Mean 311.8 318.4 242.7 313.2 280.2 341.3 Standard Deviation 51.8 59.9 48.9 54.2 48.0 71.1 APO-AII (mg/ml) Median 316.5 326.5 239.0 302.0 291.0 363.5 P Value 0.7072 0.0012 0.0539 Mean 0.6 1.2 0.4 0.9 0.2 0.9 Standard Deviation 0.5 1.0 0.5 0.8 0.1 1.0 GIP (mg/ml) Median 0.4 0.7 0.2 0.4 0.3 0.6 P Value 0.1408 0.0577 0.0283 Mean 51.5 50.3 40.7 50.1 45.4 59.9 Standard Deviation 14.6 10.8 8.5 9.8 9.2 23.3 HDL-C (mg/dl) Median 45.4 51.3 38.0 52.1 44.6 52.7 P Value 0.7508 0.0183 0.1405 Mean 22.7 5.8 7.7 6.1 16.4 6.8 Standard Deviation 29.0 3.1 4.3 2.6 24.2 2.9 MMP7 (mg/ml) Median 10.9 5.1 6.0 5.8 8.7 5.8 P Value 0.0038 0.5898 0.1728 Mean 437.0 318.2 410.4 304.8 593.2 283.4 Standard Deviation 270.6 264.9 199.4 103.8 320.3 69.2 MMP9 (mg/ml) Median 400.5 268.5 395.0 259.0 658.5 256.5 P Value 0.1059 0.1998 0.0451 Mean 207.3 134.3 127.9 102.5 138.5 191.7 Standard Deviation 86.2 80.5 37.5 38.0 51.7 97.4 Omentin (mg/ml) Median 179.0 107.5 119.0 94.0 134.0 177.0 P Value 0.0282 0.0767 0.2413 Mean 3976.7 3586.3 2325.1 3211.3 2616.0 3045.0 Standard Deviation 737.9 1387.3 1104.9 1135.2 788.3 869.4 PON1 (mg/ml) Median 4190.0 3780.0 2450.0 3380.0 2420.0 2960.0 P Value 0.5444 0.0225 0.3073 Mean 1.0 0.7 1.0 0.8 1.5 0.7 Standard Deviation 0.5 0.4 0.6 0.9 0.9 0.3 PTX3 (mg/ml) Median 0.8 0.5 0.7 0.5 1.0 0.7 P Value 0.1057 0.0158 0.0341 Mean 240.9 268.9 233.2 270.7 243.1 264.9 Standard Deviation 26.5 45.5 45.1 31.1 25.9 65.8 Tf (mg/ml) Median 247.5 271.0 231.0 270.0 240.0 285.0 P Value 0.0734 0.0089 0.4725 Mean 32.2 33.1 27.2 35.8 26.7 31.9 Standard Deviation 10.6 8.9 7.8 5.7 7.9 6.8 TTR (mg/ml) Median 30.0 32.5 28.0 35.0 27.0 33.0 P Value 0.6434 0.0024 0.1502 Table 3.3. Descriptive statistics including mean, standard deviation, and median. Statistical differences were assessed at 95% confidence with the Mann-Whitney U-test between case groups and respective controls.

Considering the statistical differences determined by demographic, stroke groups were divided into six groups (AA ICH cases, AA ICH controls, W AIS cases, W AIS controls, W ICH cases, W ICH controls) to determine differences between stroke groups and race (Table 3.3). Levels of PTX3 were higher in W

AIS cases (Median = 0.7 mg/mL, P=0.0158) than W AIS controls (Median = 0.5 mg/mL) and levels of

PTX3 were higher in W ICH cases (Median = 1.0 mg/mL, P=0.0341) than W ICH controls (Median = 0.7 mg/mL). These trends were not consistent with African American patients. Levels of omentin were found to be higher in AA ICH cases (Median = 179.0 mg/mL, P=0.0282) than AA ICH controls (Median

= 107.5 mg/mL) and levels of MMP-7 were higher in AA ICH cases (Median = 10.9 mg/mL, P=0.0038)

than AA ICH controls (Median = 5.1 mg/mL).

3.4.2 Multivariate Analysis

A. B. .

C. D.

Figure 3.1 (A-D). PCA model for classification of stroke type including score plot (A) and loading plot

(B) of PC1-PC2. Score plots highlighted onset of diabetes (C) as well as hypertension (D)

Subjects were classified based on Apo-AI, Apo-AII, Omentin, and MMP-7 (Figure 3.1B). Control

groups were separated from case groups by principal component 2 (PC2) influenced by higher Apo-AI

and Apo-AII values. ICH cases were separated from AIS cases by ICH cases having higher Apo-AI,

Apo-AI (PC1), omentin (PC2), and MMP7(PC2). As evidenced by diabetes (Figure 3.1C) and

hypertension (Figure 3.1D) score plots, the model was found not to be biased by the aforementioned

comorbity. A. B.

C. D.

Figure 3.2 (A-D). LDA predictive model for determination of stroke type (A), diabetes onset (B),

hypertension onset(C), and gender (D).

Prediction of stroke type (Figure 3.2A) was predicted by LDA at 95.95% accuracy. Further, the same

analytes determined diabetes affliction with 89.19% accuracy (Figure 3.2B), hypertension affliction with

94.59% (Figure 3.2C), gender by 90.54% accuracy (Figure 3.2D), and race by 91.67% (Figure 3.3A).

When comparing AIS and ICH cases, AIS and ICH cases were classified with 97.30% accuracy (Figure

3.3B)

A. B.

Figure 3.3 (A-B) LDA predictive model for determination of race (A) and differentiation between stroke

case groups (B)

3.5 Discussion

We found that Apo A-1 and PON1, previously reported as potential biomarkers for AIS diagnosis,15

were affected by race and diabetes status based on descriptive analysis. Our previous work15 included

controls that were matched based on age, race, and sex, but did not match for medical comorbidities

such as hypertension diabetes. This bias was highlighted by the statistical differences associated with

race as well as diabetes affliction.

A PCA model determined omentin, Apo-AI, Apo-AII, and MMP-7 to separate stroke cases from one

another as well as from the controls without influence from diabetes or hypertension. This reduced bias

was highlighted by lack of separation in the score plots between hypertensive patients and non-

hypertensive groups (Figure 3.1 D) as well as diabetic groups from non-diabetic groups (Figure 3.1C).

This developed model may be used for classification of stroke type with reduced bias. Though bias

reduction is possible, this analysis is limited by small sample sizes and surveyed variable that are

important to include in the model such as other demographic factors and disease diagnoses.

While omentin, Apo-AI, Apo-AII, and MMP-7 were found to be able to classify stroke groups, descriptive

analysis found that direct measurement of differences will be biased. Diabetic patients were found to

have statistically higher MMP-7 (Median = 9.3 mg/mL, P=0.0162) than non-diabetic patients. Further,

72 diabetic patients had statistically lower Apo-AI (Median = 1.6 mg/mL, P=0.0023) and Apo-AII (Median =

256.0 mg/mL, P=0.0318) compared with non-diabetic patients. While omentin was not biased by comorbidity affliction, omentin levels varied by stroke groups separated by race. Omentin-1 was statistically higher in AA ICH cases (median 179.0 mg/mL) compared with AA ICH controls (median

107.5 mg/mL, P= 0.0282).These findings were consistent with the EPIC-Potsdom cohort study,22 whereas the findings in the W ICH cases (median 134.0 mg/mL) and controls (median 177.0 mg/mL,

P= 0.2413) for omentin-1, in our study, are the opposite.

For determination of stroke from controls, Tf and PTX3 values were not skewed by race, gender, diabetes, and hypertension. Further, PTX3 concentration was higher in AIS cases (Median = 0.8 mg/mL, P=0.0062) than AIS controls (Median = 0.5 mg/mL), while ICH cases (Median = 1.0 mg/mL,

P=0.0053) than ICH controls (Median = 0.6 mg/mL). One role of PTX3 has been reported in the literature in regards to development of atherosclerosis11 and elevated levels of PTX3 have been proposed as a potential AIS biomarker10. AIS cases were lower in Tf (Median = 232.0 mg/mL,

P=0.0047) compared with the respective control (Median = 272.5 mg/mL), while ICH cases were lower in Tf (Median = 244.0 mg/mL, P=0.0296) compared with ICH controls (Median = 272.0 mg/mL). Lower

Tf levels have been evidenced previously in acute stroke compared with controls13. Iron transport has been shown to be the primary function of Tf23 as well as other trace elements23-25. Lower Tf levels may be in relation to the negative correlation with ferritin levels14 and low levels of Tf have been associated with stroke onset13. Elevated levels of ferritin has also been associated with hypertension onset26.

Lastly, stroke type could be classified by LDA at 95.95% accuracy (Figure 3.2A), while AIS and ICH cases were classified with 97.30% accuracy (Figure 3.3B). Considering these values, it is of concern due to the fact that diabetes (89.19% accuracy (Figure 3.5B)), hypertension (94.59% accuracy (Figure

3.2C)), gender (90.54% accuracy (Figure 3.2D)), and race (91.67% accuracy (Figure 3.3A)) could also be classified with the sample analytes. Increasing sample size and demographic matching may improve the accuracy of stroke type determination as well as determine if the LDA has overfit the data to the model.

3.6 Conclusions

Statistical analysis was utilized for simplicity to determine bias in previous work, determine unbiased analytes, and classify stroke groups. The Mann Whitney U-test exposed proteins that are biased by important comorbidities including hypertension and diabetes as well as race and gender. This PCA model determined omentin, Apo-AI, Apo-AII, and MMP-7 as important proteins for stroke classification.

Our study determined statistical differences in omentin levels between AA ICH cases and AA ICH controls. Considering that PTX3 and Tf were unbiased to comorbities, they may play an important role in stroke pathophysiology. Future work aims to collect a larger sample population and to improve the socioeconomic and physiological variables that are included in the analysis.

3.7 References

1. Mozaffarian, D.; Benjamin, E. J.; Go, A. S.; Arnett, D. K.; Blaha, M. J.; Cushman, M.; Das, S. R.; de Ferranti, S.; Despres, J. P.; Fullerton, H. J.; Howard, V. J.; Huffman, M. D.; Isasi, C. R.; Jimenez, M. C.; Judd, S. E.; Kissela, B. M.; Lichtman, J. H.; Lisabeth, L. D.; Liu, S.; Mackey, R. H.; Magid, D. J.; McGuire, D. K.; Mohler, E. R., 3rd; Moy, C. S.; Muntner, P.; Mussolino, M. E.; Nasir, K.; Neumar, R. W.; Nichol, G.; Palaniappan, L.; Pandey, D. K.; Reeves, M. J.; Rodriguez, C. J.; Rosamond, W.; Sorlie, P. D.; Stein, J.; Towfighi, A.; Turan, T. N.; Virani, S. S.; Woo, D.; Yeh, R. W.; Turner, M. B., Executive Summary: Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016, 133 (4), 447-54. 2. Mendis, S.; Davis, S.; Norrving, B., Organizational update: the world health organization global status report on noncommunicable diseases 2014; one more landmark step in the combat against stroke and vascular disease. Stroke; a journal of cerebral circulation 2015, 46 (5), e121-2. 3. Baxter, S. S.; Dibble, C. F.; Byrd, W. C.; Carlson, J.; Mack, C. R.; Saldarriaga, I.; Bencharit, S., Role of cytoskeletal proteins in cerebral cavernous malformation signaling pathways: a proteomic analysis. Molecular bioSystems 2014, 10 (7), 1881-9. 4. Dinarello, C. A., Anti-inflammatory Agents: Present and Future. Cell 2010, 140 (6), 935-50. 5. Hibino, H.; Inanobe, A.; Furutani, K.; Murakami, S.; Findlay, I.; Kurachi, Y., Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiological reviews 2010, 90 (1), 291-366. 6. Kramer, H. J.; Glanzer, K.; Sorger, M., The role of endogenous inhibition of Na-K-ATPase in human hypertension--sodium pump activity as a determinant of peripheral vascular resistance. Clinical and experimental hypertension. Part A, Theory and practice 1985, 7 (5-6), 769-82. 7. Tilg, H.; Moschen, A. R., Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature reviews. Immunology 2006, 6 (10), 772-83. 8. McIlwain, D. R.; Berger, T.; Mak, T. W., Caspase functions in cell death and disease. Cold Spring Harbor perspectives in biology 2013, 5 (4), a008656. 9. Zhang, J. M.; An, J., Cytokines, inflammation, and pain. International anesthesiology clinics 2007, 45 (2), 27-37. 10. Ryu, W. S.; Kim, C. K.; Kim, B. J.; Kim, C.; Lee, S. H.; Yoon, B. W., Pentraxin 3: a novel and independent prognostic marker in ischemic stroke. Atherosclerosis 2012, 220 (2), 581-6. 11. Rolph, M. S.; Zimmer, S.; Bottazzi, B.; Garlanda, C.; Mantovani, A.; Hansson, G. K., Production of the long pentraxin PTX3 in advanced atherosclerotic plaques. Arteriosclerosis, thrombosis, and vascular biology 2002, 22 (5), e10-4. 12. Banks, R. E.; Forbes, M. A.; Storr, M.; Higginson, J.; Thompson, D.; Raynes, J.; Illingworth, J. M.; Perren, T. J.; Selby, P. J.; Whicher, J. T., The acute phase protein response in patients receiving subcutaneous IL-6. Clinical and experimental immunology 1995, 102 (1), 217-23. 13. Altamura, C.; Squitti, R.; Pasqualetti, P.; Gaudino, C.; Palazzo, P.; Tibuzzi, F.; Lupoi, D.; Cortesi, M.; Rossini, P. M.; Vernieri, F., Ceruloplasmin/Transferrin system is related to clinical status in acute stroke. Stroke; a journal of cerebral circulation 2009, 40 (4), 1282-8. 14. Adams, P. C.; Barton, J. C., A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. Journal of hepatology 2011, 55 (2), 453-458. 15. Walsh, K. B.; Hart, K.; Roll, S.; Sperling, M.; Unruh, D.; Davidson, W. S.; Lindsell, C. J.; Adeoye, O., Apolipoprotein A-I and Paraoxonase-1 Are Potential Blood Biomarkers for Ischemic Stroke Diagnosis. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2016, 25 (6), 1360-5. 16. Bro, R.; Smilde, A. K., Principal component analysis. Anal Methods-Uk 2014, 6 (9), 2812-2831.

17. van den Berg, R. A.; Hoefsloot, H. C.; Westerhuis, J. A.; Smilde, A. K.; van der Werf, M. J., Centering, scaling, and transformations: improving the biological information content of metabolomics data. BMC genomics 2006, 7, 142. 18. Hotelling, H., Analysis of a complex of statistical variables into principal components. Warwick & York: Baltimore, 1933; p 48 p. 19. Wold, S.; Esbensen, K.; Geladi, P., Principal Component Analysis. Chemometr Intell Lab 1987, 2 (1-3), 37-52. 20. Wold, S.; Jonsson, J.; Sjostrom, M.; Sandberg, M.; Rannar, S., DNA and Peptide Sequences and Chemical Processes Multivariately Modeled by Principal Component Analysis and Partial Least-Squares Projections to Latent Structures. Analytica chimica acta 1993, 277 (2), 239-253. 21. Eriksson, L.; Antti, H.; Gottfries, J.; Holmes, E.; Johansson, E.; Lindgren, F.; Long, I.; Lundstedt, T.; Trygg, J.; Wold, S., Using chemometrics for navigating in the large data sets of genomics, proteomics, and metabonomics (gpm). Analytical and bioanalytical chemistry 2004, 380 (3), 419-429. 22. Menzel, J.; di Giuseppe, R.; Biemann, R.; Wittenbecher, C.; Aleksandrova, K.; Pischon, T.; Fritsche, A.; Schulze, M. B.; Boeing, H.; Isermann, B.; Weikert, C., Omentin-1 and risk of myocardial infarction and stroke: Results from the EPIC-Potsdam cohort study. Atherosclerosis 2016, 251, 415-421. 23. Vincent, J. B.; Love, S., The binding and transport of alternative metals by transferrin. Biochimica et biophysica acta 2012, 1820 (3), 362-78. 24. Harris, W. R.; Carrano, C. J., Binding of vanadate to human serum transferrin. J Inorg Biochem 1984, 22 (3), 201-18. 25. Nagaoka, M. H.; Akiyama, H.; Maitani, T., Binding patterns of vanadium to transferrin in healthy human serum studied with HPLC/high resolution ICP-MS. The Analyst 2004, 129 (1), 51-4. 26. Choi, B.; Yeum, K. J.; Park, S. J.; Kim, K. N.; Joo, N. S., Elevated serum ferritin and mercury concentrations are associated with hypertension; analysis of the fourth and fifth Korea national health and nutrition examination survey (KNHANES IV-2, 3, 2008-2009 and V-1, 2010). Environmental toxicology 2015, 30 (1), 101-8.

Chapter 4

Nano-Carbon Fiber Ionization Mass Spectrometry: A Fundamental Study of a Multi- Walled Carbon Nanotube Functionalized Corona Discharge Pin for Polycyclic Aromatic Hydrocarbons Analysis

4.1 Abstract

Mass spectrometry continues to tackle many complicated tasks while also continuing to simplify instrumentation as well as sampling. The desorption electrospray ionization (DESI) source was the first ambient ionization source to simplify analysis of analytes without extensive gas requirements and chromatography. Electrospray techniques have low efficiency for ionization of nonpolar analytes and some have resorted to techniques such as direct analysis in real time

(DART) or desorption atmospheric pressure chemical ionization (DAPCI) for their analysis. The nanoCFI source is capable of solid phase microextraction (SPME) as well as ionization and sampling similar to that of direct probe atmospheric pressure chemical ionization (DP-APCI).

Conductivity as well as adsorption were maintained by utilizing a corona pin functionalized with a multi-walled carbon nanotube (MWCNT) thread rather than a PDMS fiber. Linearity of analysis ranged from 0.357-0.985 dependent on the analyte. Poor linearity was attributed to source adhesive contaminants. Further, changes in extraction efficiency as well as ionization were determined by adjusting the solvents from toluene to benzyl alcohol. Results have determined that extraction and ionization can be performed by the nanoCFI source qualitatively, but linearity as well as LOD’s are hindered by adhesive contaminants. Future work aims to produce the source without a silver based adhesive as well as improve the dimensions of the MWCNT

4.2 Introduction

Mass spectrometry has been used for a variety of fields including trace detection of chemical warfare agents to gas compositions in space. Recent space expeditions aim at determination of organic compounds in Martian soil1. In particular, polycyclic aromatic hydrocarbons (PAH’s) have been of interest since PAH’s2 were quantified from meteorites originating from Mars3. In the past, volatile compounds were thermally desorbed, separated by gas chromatography, and ionized by electron ionization4. The ongoing mission to Mars aims to employ a laser desorption ionization source with a linear ion trap for trace detection of organic compounds5.

In the past, mass spectrometry was predominantly performed in the laboratory until the advent of desorption electrospray (DESI)6. The DESI ionization source ideal for ideals ability to be used outside the mass spectrometer for preparation-less analysis of samples at ambient conditions. Further, DESI has been used for imaging metabolites6 as well as detection of drugs analytes from solid-phase microextraction fibers(SPME)6. Solid-phase microextraction is an equilibrium process by which analytes undergo absorption or adsorption onto the surface of the fiber as a means of preconcentration as well as isolation from the sample matrix7. SPME has been shown to produce limits of detection in the ppt range8. Considering the mechanism of ionization by desorbed droplets, DESI has primary utility for polar molecules. Direct analysis in real time (DART) and desorption atmospheric pressure chemical ionization (DAPCI)9 have been used for the determination of nonpolar chemical compounds including chemical warfare agents10 as well as PAH’s11.

Carbon nanotubes (CNT’s) have shown promise with SPME12 as well as direct involvement in ionization including CNT functionalized paper spray13-14 as well as carbon fiber ionization (CFI)15. CFI as well as DAPCI abide by a similar mechanism of ionization deriving

81 from atmospheric pressure chemical ionization (APCI)16. By modifying a CFI source with

MWCNT, this source would be capable of single fiber SPME experiments, low gas consumption, as well as low preparation sampling. Considering that CFI occurs by corona discharge and there are known discharges utilizing carbon dioxide17, this would be practical extractive ionization source for a Martian atmosphere consisting primarily of carbon dioxide17-18. Considering that many NASA experiments consolidated into a small space, the usage of our MWCNT nanoCFI source may be used in DAPCI as well as DCI mass spectrometry experiments, but capable of coupling with other analytical techniques. These techniques include cyclic voltammetry19, anodic stripping voltammetry20, biochemical sensors21, as well as use as an extractive scaffold for

DAPPI22 or thermal desorption SPME for online GC-MS. The usage of a MWCNT fiber is ideal not only as a stand-alone technique, but as the centerpiece for a suite of analytical techniques in a small space.

The aim of this work was to develop the methodology of this source by utilizing PAH’s as a standard to assess limits of detection, linearity, and solvent effects on extraction as well as ionization.

4.3 Methods

4.3.1 Reagents

HPLC-Grade acetonitrile, formic acid, toluene, dichloromethane (MeCl) and water were purchased from Fisher Scientific (Waltham, MA,USA). ACS grade benzyl alcohol was also purchased from Fisher Scientific. ACS-grade fluorene and naphthalene were purchased from

Fisher Scientific. The State of Pennsylvania Polynuclear Aromatic Hydrocarbons Extractables

Mix standard was purchased from Fisher Scientific. This standard included 2000 ppm benz(a)anthracene, benzo(a)pyrene, fluorene, naphthalene, and phenanthrene in MeCl.

4.3.2 Mass Spectrometer

The mass spectrometer was a Thermo MSQ equipped with a single quadrupole mass filter. The

Thermo MSQ was run in both selected ion monitoring (SIM) as well as full scan between 100-

300 m/z in positive ion mode. Both protonated molecular ion as well as molecular ion peaks were monitored within 0.5 m/z. Data was collected over a 5 minute period, where integrations were performed for 3 mins. The corona discharge current and temperature was left off for the first minute of the run, turned on after the first minute and kept on until the 4th minute, and the run was ended after 5 minutes. Peak areas were subtracted from blank integrations.

4.3.3 Nanomaterials Characterization

The MWCNT were formed into a fiber from an MWCNT array. The MWCNT arrays were produced by carbon vapor deposition23 at the University of Cincinnati Nanoworld team.

Characterization of the nanomaterials were performed by optical microscopy as well as Raman microscopy. Raman spectra, as confirmed by the D and G bands in Figure 4.1, were consistent with the literature values23.

Figure 4.1. Raman microscopy of Multi-Walled Carbon Nanotubes

4.3.4 Functionalized Corona Discharge Pin

Functionalized corona discharge pins were produced by adhering a ~5 mm length of MWCNT to the corona pin with silver epoxy. The functionalized corona pin was cured at 60°C for 1 hr to establish a connection between the pin and the MWCNT thread. Validation of connection was established by appearance of the corona discharge when compared with a standard corona discharge.

4.3.5 Untested Corona Discharge Pin Insert and Seat

Corona discharge pin seat was machined from stainless steel to be consistent with standard corona discharge pin. Carbon nanotube inserts were made by pulling CNT thread through a 2 mm OD, 150 mm long borosilicate capillary. The threaded capillary was then pulled by a capillary puller and as a result the capillary was pulled to two separate pointed capillaries that encapsulated the CNT thread. The separate capillaries had their CNT thread cut between both halves of the capillary. Capillary was cut with a ceramic knife from the flat opening to a total of

~2 mm in length and the CNT thread was cut from the tip of the pulled capillary to a length of 5 mm. The open flat end was filled with silver paste and cured at

60°C for 1 hr to establish a connection between the seat and the CNT thread. Validation of connection was established by appearance of the corona discharge when compared with a standard corona discharge.

4.4 Results and Discussion

Figure 4.2 (a-d). Microscopy images of used a standard corona discharge pin (a) and used functionalized corona pin (b). The corona discharge emitted from the modified corona discharge pin (d) and standard corona discharge pin (c) at 10 µA with nitrogen sheath gas flow open to the air at ambient temperature

Prior to analysis, the modified corona discharge pin was compared with a standard corona pin.

The fine point on the corona discharge pin and the modified corona discharge pin are shown in

Figure 4.2 (a-b). In order to ensure that the ionization mechanism was consistent with APCI, the modified corona discharge pin was compared with the standard pin in order to ensure the ionization process was not consistent with field desorption or CNT functionalized paper spray.

The corona discharge was visually observed at 10 uA with both the standard discharge pin as well as functionalized pin with nitrogen gas flow when the mass spectrometer was left open in

Figure 4.2(c-d).

Figure 4.3. Experimental Design

The experimental design was streamlined in regards to extraction, apparatus, and data analysis

(Figure 4.3). Immersion extractions were performed for 10 minute periods then immediately placed inside the mass spectrometer (Figure 4.4). In order to ensure that a probe electrospray based process was not occurring, a prior one minute with only nitrogen gas flow was used for desolvation. After the first minute, the heater and corona discharge current were turned on enable thermal desorption as well as ionize by corona discharge.

Figure 4.4. Instrument Apparatus

In between analyses, the source was immersed in solvent matching the solvent composition of the analysis. Most runs were rinses in MeCl for 1 min, whereas those analyzed in toluene or benzyl alcohol composition were rinsed in the respective solvents for 1 min. A Considering the respectively lower proton affinity of MeCl, the protonated molecular ion peaks were targeted for

determination. In order to assess the optimum conditions for analysis, a 100 ppm PAH solution

was used for determination of optimum signal. The PAH solution included phenanthrene,

naphthalene, benzo(a)pyrene, benz(a)anthracene, and fluorene. The cone voltage was

optimized, in Figure 4.5a, at 10 uA corona current and a heater temperature of 350°C for

determination of optimum signal for all 5 protonated molecular ion peaks with minimal in source

fragmentation. Further, the analysis was performed by ramping the corona discharge current to

optimize the conditions for ionization as well as solvent (Figure 4.5b).

Figure A Figure B

10V B Corona Current = 5 uA

20V Corona Current = 10 uA

30V

Corona Current = 20 uA

40V

Corona Current = 50 uA

50V

Figure 4.5 (a-b). Signal optimization of 100 ppm PAH mix in 100% MeCl by varying the cone

voltage (10-50V) (b), at a corona current at 10 µA and 350°C, as well as (b) corona discharge

current (5-50 uA) at a 40V cone voltage after 10 minute extractions and 3 min integration time .

After parameter optimization, the system was compared by directly immersing both a standard corona discharge pin as well as the modified corona pin into the 15 ppm phenanthrene solution for 10 min. The immersed modified corona pin showed a signal signature consistent with thermal desorption (Figure 4.6).

Figure 4.6. Comparison between thermal desorption of 15 ppm phenanthrene ([M+H]+=179 m/z) in MeCl from the standard corona discharge pin (black) and modified discharge pin (red) after 10 min extraction period

In order to assess the linearity as well as limits of detection, standards from 10-100 ppm of the PAH mixture was tested by immersion for 5 minute intervals at the optimized parameters.

Linearity of calibration curves ranged from 0.357-0.985 (R2) (Figure 4.7). Naphthalene had the poorest linearity likely due to known difficulties in ionization as well as due to 2- piperazinoethylamine ([M]+=129 m/z). Ion suppression may have also played a part in poor linearity considering that diethylenetriamine was in the silver paste adhesive and its respective protonated dimer ([2M+H]+=207 m/z) was clear in many spectra.

Analyte Nominal Mass (m/z) R2 LODA (ppm) Naphthalene [M+H]+ = 129 0.357 155 Fluorene [M+H]+ = 167 0.980 8 Phenanthrene [M+H]+ = 179 0.629 90 Benz(a)anthracene [M+H]+ = 229 0.985 17 Benzo(a)pyrene [M+H]+ = 253 0.985 17 A Limit of detection (LOD) determined as LOD= 3.3*Sy/slope Figure 4.7. Limits of detection and linearity of calibration curves of PAH’s in 100% MeCl2 generated by 10 minute extractions and 3 minute integrations at 40V cone voltage, 350C, and 10 µA corona current. Integration values were blank subtracted.

Previous literature has determined that toluene increases the sensitivity of APCI experiments especially those involving hydrocarbons and PAH’s. Flow injection of 100 ppm naphthalene in toluene was performed and compared with a 10 min immersion (Figure 4.8).

This experiment was used to show that the molecular ion peak was produced as a result of charge transfer rather than the proton exchange occurring by the use of MeCl.

Figure 4.8. Flow injection of 100 ppm naphthalene in 100% toluene (top) and modified corona discharge pin analysis of a 10 min immersion (bottom) in the 100 ppm naphthalene solution at 10 uA and 40V cone voltage

A B

Figure 4.9. Extraction time compared with signal (a) of 100 ppm fluorene in 100% toluene and the effect of increasing concentration of benzyl alcohol to toluene (b) during a two minute extraction. This was performed with a 40V cone voltage, 350C, and 10 µA corona discharge current with 3 min integration time

In order to assess optimal extraction times, the modified corona pin was immersed into

100 ppm fluorene solutions (Figure 4.9a) in toluene considering that fluorene provided a linearity

above 0.9 as well as its comparably lower LOD Figure 4.9. This experiment concluded that

signal was increasing over time suggesting time dependent extraction. While toluene has been

shown to be ideal for APCI detection of PAH’s as well as hydrocarbons24-25, different solvents

may change the extraction efficiency. In particular, the Hansen parameters are experimental

values that provide insight to swelling as well as solubility. In order to improve the surface area

of the MWCNT, solvent compositions were changed in order to assess improvements to sample

extraction. Considering that benzyl alcohol has a higher swelling26-27 efficiency in comparison

with toluene, a plot of composition to signal was performed (Figure 4.9b). A ~3-fold increase in

signal was reported when changing the solvent from 100% toluene to 50% benzyl alcohol in

Figure 4.9b. This may be due to increased surface area providing improved adsorption as well

as absorption.

4.5 Conclusions

While this source was capable of qualitative results, quantitation by the nanoCFI source remains

elusive due to contaminants from the adhesive. Despite the limitations, it was apparent that

90 solvent choice was not only important for ionization but also for improved extraction. Future work aims at producing a nanoCFI source with reproducible MWCNT dimensions, such length as well as diameter, without the use of silver paste for determination of PAH’s in a carbon dioxide environment.

4.6 References

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Chapter 5

Conclusion and Future Work

5. Conclusion and Future Work

As evidenced by the previous chapters, proteins play a role in neurological health especially stroke. Unique tissue leakage biomarkers were proposed, which included metalloproteins such as calpain-15, titin (Isoform 3), and tropomyosin alpha-4 chain. Considering that selenoproteins were identified in all groups, such as selenoprotein P or glutathione peroxidase, future work aims to quantification of selenoproteins by identified tissue leakage metalloproteins by multiplexed assays and activity assay. Considering that Cd and Co showed statistical differences, this may be related with their binding to zinc finger domain containing proteins such as calpain-15. Targeting identified metalloproteins, containing Cd, Co, and Se, for quantification by mass spectrometry would be the ideal means of validation. To improve the accuracy of the

LDA, as well as the clustering in the PCA models, a larger samples size must be collected in order to have a sufficient sample size for both a training as well as test set.

While ICP-MS was used as a means for determination of metal containing species, the nanoCFI source was capable of qualitative to semi-quantitative analyses. The total extraction will likely be affected by the sufficiently lower total volume in comparison with a typical SPME fiber. To improve the total area, an array may be possible to replace a single fiber but would increase in price for manufacture and may more likely resemble a paper spray ionization source. Comparatively, the source requires sufficiently less solvent than a typical LC-MS and gas consumption can be removed by an ambient gas such as air or carbon dioxide. In regards to the results, the quantitation was particularly difficult due to adhesive contaminant background.

By removing silver paste, ion suppression of analyte signal will likely decrease as well as the contaminant background. Despite the limitations, it was apparent that solvent choice was not only important for ionization but also for improved extraction. Future work aims at producing a nanoCFI source with reproducible MWCNT dimensions, such length as well as diameter. More solvents should be explored to reveal the optimum balance of ionization and extraction.

Appendix

Appendix: Total Proteins Identified by Bottom Up Proteomics by Triple TOF MS

Stroke Group Protein Acquisition Protein Description Protein Score

ICH Victim tr|B0AZS6|B0AZS6_HUMAN 14-3-3 protein zeta/delta OS=Homo sapiens GN=YWHAZ PE=1 SV=1 60

ICH Victim sp|Q9Y676|RT18B_HUMAN 28S ribosomal protein S18b, mitochondrial OS=Homo sapiens GN=MRPS18B PE=1 SV=1 36 AIS Victim sp|Q16880|CGT_HUMAN 2-hydroxyacylsphingosine 1-beta-galactosyltransferase OS=Homo sapiens GN=UGT8 PE=2 SV=2 37 ICH Control sp|Q16880|CGT_HUMAN 2-hydroxyacylsphingosine 1-beta-galactosyltransferase OS=Homo sapiens GN=UGT8 PE=2 SV=2 37

ICH Victim sp|Q16880|CGT_HUMAN 2-hydroxyacylsphingosine 1-beta-galactosyltransferase OS=Homo sapiens GN=UGT8 PE=2 SV=2 40

AIS Victim tr|H3BUY0|H3BUY0_HUMAN 39S ribosomal protein L21, mitochondrial OS=Homo sapiens GN=MRPL21 PE=1 SV=1 39 ICH Victim tr|H3BUY0|H3BUY0_HUMAN 39S ribosomal protein L21, mitochondrial OS=Homo sapiens GN=MRPL21 PE=1 SV=1 38 ICH Control sp|P08253|MMP2_HUMAN 72 kDa type IV collagenase OS=Homo sapiens GN=MMP2 PE=1 SV=2 80 ICH Victim sp|Q8IZT6|ASPM_HUMAN Abnormal spindle-like microcephaly-associated protein OS=Homo sapiens GN=ASPM PE=1 SV=2 39

AIS Control tr|A6NL76|A6NL76_HUMAN Actin, alpha skeletal muscle OS=Homo sapiens GN=ACTA1 PE=1 SV=3 106 AIS Victim tr|A6NL76|A6NL76_HUMAN Actin, alpha skeletal muscle OS=Homo sapiens GN=ACTA1 PE=1 SV=3 37 AIS Victim sp|P62736|ACTA_HUMAN Actin, aortic smooth muscle OS=Homo sapiens GN=ACTA2 PE=1 SV=1 53 AIS Control tr|C9JTX5|C9JTX5_HUMAN Actin, cytoplasmic 1 (Fragment) OS=Homo sapiens GN=ACTB PE=1 SV=1 96

AIS Victim sp|P60709|ACTB_HUMAN Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 111 ICH Control sp|P60709|ACTB_HUMAN Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 61 ICH Victim sp|P60709|ACTB_HUMAN Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 38 ICH Control tr|I3L3I0|I3L3I0_HUMAN Actin, cytoplasmic 2 (Fragment) OS=Homo sapiens GN=ACTG1 PE=1 SV=1 38

ICH Victim tr|I3L3I0|I3L3I0_HUMAN Actin, cytoplasmic 2 (Fragment) OS=Homo sapiens GN=ACTG1 PE=1 SV=1 50 ICH Control tr|H0Y512|H0Y512_HUMAN Adipocyte plasma membrane-associated protein (Fragment) OS=Homo sapiens GN=APMAP PE=1 SV=1 39 AIS Control sp|Q15848|ADIPO_HUMAN Adiponectin OS=Homo sapiens GN=ADIPOQ PE=1 SV=1 50 AIS Victim sp|Q15848|ADIPO_HUMAN Adiponectin OS=Homo sapiens GN=ADIPOQ PE=1 SV=1 70

ICH Control sp|Q15848|ADIPO_HUMAN Adiponectin OS=Homo sapiens GN=ADIPOQ PE=1 SV=1 60 ICH Victim sp|Q15848|ADIPO_HUMAN Adiponectin OS=Homo sapiens GN=ADIPOQ PE=1 SV=1 131 ICH Control tr|A6NC48|A6NC48_HUMAN ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2 OS=Homo sapiens GN=BST1 PE=1 SV=1 36 AIS Control sp|P43652|AFAM_HUMAN Afamin OS=Homo sapiens GN=AFM PE=1 SV=1 144

AIS Victim sp|P43652|AFAM_HUMAN Afamin OS=Homo sapiens GN=AFM PE=1 SV=1 90 ICH Control sp|P43652|AFAM_HUMAN Afamin OS=Homo sapiens GN=AFM PE=1 SV=1 172 ICH Victim sp|P43652|AFAM_HUMAN Afamin OS=Homo sapiens GN=AFM PE=1 SV=1 159 AIS Control tr|B8ZZ81|B8ZZ81_HUMAN Alkyldihydroxyacetonephosphate synthase, peroxisomal OS=Homo sapiens GN=AGPS PE=1 SV=1 46

ICH Control tr|A0A087WZ31|A0A087WZ31_HUMAN alpha-1,2-Mannosidase OS=Homo sapiens GN=MAN1C1 PE=1 SV=1 45 ICH Victim tr|A0A087WZ31|A0A087WZ31_HUMAN alpha-1,2-Mannosidase OS=Homo sapiens GN=MAN1C1 PE=1 SV=1 38 AIS Control sp|P02763|A1AG1_HUMAN Alpha-1-acid glycoprotein 1 OS=Homo sapiens GN=ORM1 PE=1 SV=1 264 AIS Victim sp|P02763|A1AG1_HUMAN Alpha-1-acid glycoprotein 1 OS=Homo sapiens GN=ORM1 PE=1 SV=1 425

ICH Control sp|P02763|A1AG1_HUMAN Alpha-1-acid glycoprotein 1 OS=Homo sapiens GN=ORM1 PE=1 SV=1 330 ICH Victim sp|P02763|A1AG1_HUMAN Alpha-1-acid glycoprotein 1 OS=Homo sapiens GN=ORM1 PE=1 SV=1 278 AIS Control sp|P19652|A1AG2_HUMAN Alpha-1-acid glycoprotein 2 OS=Homo sapiens GN=ORM2 PE=1 SV=2 245 AIS Victim sp|P19652|A1AG2_HUMAN Alpha-1-acid glycoprotein 2 OS=Homo sapiens GN=ORM2 PE=1 SV=2 44

ICH Victim sp|P19652|A1AG2_HUMAN Alpha-1-acid glycoprotein 2 OS=Homo sapiens GN=ORM2 PE=1 SV=2 72 AIS Control tr|A0A087WY93|A0A087WY93_HUMAN Alpha-1-antichymotrypsin (Fragment) OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 41 AIS Victim tr|A0A087WY93|A0A087WY93_HUMAN Alpha-1-antichymotrypsin (Fragment) OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 138 ICH Control tr|A0A087WY93|A0A087WY93_HUMAN Alpha-1-antichymotrypsin (Fragment) OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 45

ICH Victim tr|A0A087WY93|A0A087WY93_HUMAN Alpha-1-antichymotrypsin (Fragment) OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 134 AIS Victim tr|G3V595|G3V595_HUMAN Alpha-1-antichymotrypsin (Fragment) OS=Homo sapiens GN=SERPINA3 PE=1 SV=3 38 ICH Control tr|G3V595|G3V595_HUMAN Alpha-1-antichymotrypsin (Fragment) OS=Homo sapiens GN=SERPINA3 PE=1 SV=3 174 ICH Victim tr|G3V595|G3V595_HUMAN Alpha-1-antichymotrypsin (Fragment) OS=Homo sapiens GN=SERPINA3 PE=1 SV=3 57

AIS Control tr|G3V3A0|G3V3A0_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 56 AIS Victim tr|G3V3A0|G3V3A0_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 74 ICH Control tr|G3V3A0|G3V3A0_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 60

ICH Victim tr|G3V3A0|G3V3A0_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=1 197 AIS Control sp|P01011|AACT_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=2 140 AIS Victim sp|P01011|AACT_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=2 442 ICH Control sp|P01011|AACT_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=2 168

ICH Victim sp|P01011|AACT_HUMAN Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 PE=1 SV=2 322 ICH Control tr|G3V2B9|G3V2B9_HUMAN Alpha-1-antitrypsin (Fragment) OS=Homo sapiens GN=SERPINA1 PE=1 SV=1 160 ICH Victim tr|G3V2B9|G3V2B9_HUMAN Alpha-1-antitrypsin (Fragment) OS=Homo sapiens GN=SERPINA1 PE=1 SV=1 668 AIS Control sp|P01009|A1AT_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=1 SV=3 389

AIS Victim sp|P01009|A1AT_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=1 SV=3 219 ICH Control sp|P01009|A1AT_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=1 SV=3 476 ICH Victim sp|P01009|A1AT_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=1 SV=3 1137 AIS Control tr|A0A024R6I7|A0A024R6I7_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=3 SV=1 564

AIS Victim tr|A0A024R6I7|A0A024R6I7_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=3 SV=1 110 ICH Control tr|A0A024R6I7|A0A024R6I7_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=3 SV=1 1042 ICH Victim tr|A0A024R6I7|A0A024R6I7_HUMAN Alpha-1-antitrypsin OS=Homo sapiens GN=SERPINA1 PE=3 SV=1 258

AIS Victim tr|M0R009|M0R009_HUMAN Alpha-1B-glycoprotein (Fragment) OS=Homo sapiens GN=A1BG PE=1 SV=5 47

AIS Control sp|P04217|A1BG_HUMAN Alpha-1B-glycoprotein OS=Homo sapiens GN=A1BG PE=1 SV=4 660 AIS Victim sp|P04217|A1BG_HUMAN Alpha-1B-glycoprotein OS=Homo sapiens GN=A1BG PE=1 SV=4 374 ICH Control sp|P04217|A1BG_HUMAN Alpha-1B-glycoprotein OS=Homo sapiens GN=A1BG PE=1 SV=4 454 ICH Victim sp|P04217|A1BG_HUMAN Alpha-1B-glycoprotein OS=Homo sapiens GN=A1BG PE=1 SV=4 70

AIS Control tr|C9JPV4|C9JPV4_HUMAN Alpha-2-antiplasmin (Fragment) OS=Homo sapiens GN=SERPINF2 PE=1 SV=1 49 ICH Victim tr|C9JPV4|C9JPV4_HUMAN Alpha-2-antiplasmin (Fragment) OS=Homo sapiens GN=SERPINF2 PE=1 SV=1 52 AIS Control sp|P08697|A2AP_HUMAN Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 PE=1 SV=3 78 AIS Victim sp|P08697|A2AP_HUMAN Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 PE=1 SV=3 186

ICH Control sp|P08697|A2AP_HUMAN Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 PE=1 SV=3 144 ICH Victim sp|P08697|A2AP_HUMAN Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 PE=1 SV=3 260 AIS Victim tr|A0A0G2JPA8|A0A0G2JPA8_HUMAN Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 PE=4 SV=1 113 ICH Control tr|A0A0G2JPA8|A0A0G2JPA8_HUMAN Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 PE=4 SV=1 271

ICH Victim tr|A0A0G2JPA8|A0A0G2JPA8_HUMAN Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 PE=4 SV=1 400 AIS Control tr|C9JV77|C9JV77_HUMAN Alpha-2-HS-glycoprotein OS=Homo sapiens GN=AHSG PE=1 SV=1 62 AIS Victim sp|P02765|FETUA_HUMAN Alpha-2-HS-glycoprotein OS=Homo sapiens GN=AHSG PE=1 SV=1 492

ICH Control sp|P02765|FETUA_HUMAN Alpha-2-HS-glycoprotein OS=Homo sapiens GN=AHSG PE=1 SV=1 262

ICH Victim sp|P02765|FETUA_HUMAN Alpha-2-HS-glycoprotein OS=Homo sapiens GN=AHSG PE=1 SV=1 400 AIS Victim tr|H0YFH1|H0YFH1_HUMAN Alpha-2-macroglobulin (Fragment) OS=Homo sapiens GN=A2M PE=1 SV=1 76 ICH Control tr|H0YFH1|H0YFH1_HUMAN Alpha-2-macroglobulin (Fragment) OS=Homo sapiens GN=A2M PE=1 SV=1 163 ICH Victim tr|F8W7L3|F8W7L3_HUMAN Alpha-2-macroglobulin (Fragment) OS=Homo sapiens GN=A2M PE=1 SV=1 176

AIS Control sp|P01023|A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 6013 AIS Victim sp|P01023|A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 139 ICH Control sp|P01023|A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 1102 ICH Victim sp|P01023|A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 2949

AIS Victim sp|P30533|AMRP_HUMAN Alpha-2-macroglobulin receptor-associated protein OS=Homo sapiens GN=LRPAP1 PE=1 SV=1 40 AIS Control sp|O43707|ACTN4_HUMAN Alpha-actinin-4 OS=Homo sapiens GN=ACTN4 PE=1 SV=2 38 ICH Victim sp|P04745|AMY1_HUMAN Alpha-amylase 1 OS=Homo sapiens GN=AMY1A PE=1 SV=2 184 AIS Control sp|P15144|AMPN_HUMAN Aminopeptidase N OS=Homo sapiens GN=ANPEP PE=1 SV=4 49

AIS Victim sp|P15144|AMPN_HUMAN Aminopeptidase N OS=Homo sapiens GN=ANPEP PE=1 SV=4 69 ICH Control sp|P15144|AMPN_HUMAN Aminopeptidase N OS=Homo sapiens GN=ANPEP PE=1 SV=4 45 ICH Victim sp|P15144|AMPN_HUMAN Aminopeptidase N OS=Homo sapiens GN=ANPEP PE=1 SV=4 69

AIS Control sp|P01019|ANGT_HUMAN Angiotensinogen OS=Homo sapiens GN=AGT PE=1 SV=1 114

AIS Victim sp|P01019|ANGT_HUMAN Angiotensinogen OS=Homo sapiens GN=AGT PE=1 SV=1 166 ICH Control sp|P01019|ANGT_HUMAN Angiotensinogen OS=Homo sapiens GN=AGT PE=1 SV=1 162 ICH Victim sp|P01019|ANGT_HUMAN Angiotensinogen OS=Homo sapiens GN=AGT PE=1 SV=1 121 ICH Control tr|H3BM45|H3BM45_HUMAN Ankyrin repeat and fibronectin type-III domain-containing protein 1 OS=Homo sapiens GN=ANKFN1 PE=1 SV=2 36

AIS Control sp|Q8NFD2|ANKK1_HUMAN Ankyrin repeat and protein kinase domain-containing protein 1 OS=Homo sapiens GN=ANKK1 PE=2 SV=1 36 AIS Victim sp|Q8NFD2|ANKK1_HUMAN Ankyrin repeat and protein kinase domain-containing protein 1 OS=Homo sapiens GN=ANKK1 PE=2 SV=1 37 ICH Victim sp|Q8NFD2|ANKK1_HUMAN Ankyrin repeat and protein kinase domain-containing protein 1 OS=Homo sapiens GN=ANKK1 PE=2 SV=1 33 AIS Control sp|P01008|ANT3_HUMAN Antithrombin-III OS=Homo sapiens GN=SERPINC1 PE=1 SV=1 830

AIS Victim tr|Q8TCE1|Q8TCE1_HUMAN Antithrombin-III OS=Homo sapiens GN=SERPINC1 PE=1 SV=1 62 ICH Control sp|P01008|ANT3_HUMAN Antithrombin-III OS=Homo sapiens GN=SERPINC1 PE=1 SV=1 96

100

ICH Victim sp|P01008|ANT3_HUMAN Antithrombin-III OS=Homo sapiens GN=SERPINC1 PE=1 SV=1 385 AIS Victim sp|Q63HQ0|AP1AR_HUMAN AP-1 complex-associated regulatory protein OS=Homo sapiens GN=AP1AR PE=1 SV=1 39 AIS Control tr|Q6P163|Q6P163_HUMAN APOC2 protein OS=Homo sapiens GN=APOC2 PE=1 SV=1 132 AIS Victim tr|Q6P163|Q6P163_HUMAN APOC2 protein OS=Homo sapiens GN=APOC2 PE=1 SV=1 50

ICH Control tr|Q6P163|Q6P163_HUMAN APOC2 protein OS=Homo sapiens GN=APOC2 PE=1 SV=1 132 ICH Victim tr|Q6P163|Q6P163_HUMAN APOC2 protein OS=Homo sapiens GN=APOC2 PE=1 SV=1 86 AIS Control sp|P02647|APOA1_HUMAN Apolipoprotein A-I OS=Homo sapiens GN=APOA1 PE=1 SV=1 1065 AIS Victim tr|F8W696|F8W696_HUMAN Apolipoprotein A-I OS=Homo sapiens GN=APOA1 PE=1 SV=1 59

ICH Control sp|P02647|APOA1_HUMAN Apolipoprotein A-I OS=Homo sapiens GN=APOA1 PE=1 SV=1 389 ICH Victim sp|P02647|APOA1_HUMAN Apolipoprotein A-I OS=Homo sapiens GN=APOA1 PE=1 SV=1 2043 ICH Control tr|V9GYC1|V9GYC1_HUMAN Apolipoprotein A-II (Fragment) OS=Homo sapiens GN=APOA2 PE=1 SV=1 57 ICH Victim tr|V9GYC1|V9GYC1_HUMAN Apolipoprotein A-II (Fragment) OS=Homo sapiens GN=APOA2 PE=1 SV=1 131

ICH Victim tr|V9GYE3|V9GYE3_HUMAN Apolipoprotein A-II OS=Homo sapiens GN=APOA2 PE=1 SV=1 662

AIS Control sp|P06727|APOA4_HUMAN Apolipoprotein A-IV OS=Homo sapiens GN=APOA4 PE=1 SV=3 196 ICH Control sp|P06727|APOA4_HUMAN Apolipoprotein A-IV OS=Homo sapiens GN=APOA4 PE=1 SV=3 60 ICH Victim sp|P06727|APOA4_HUMAN Apolipoprotein A-IV OS=Homo sapiens GN=APOA4 PE=1 SV=3 306 AIS Control tr|A0A087WTM7|A0A087WTM7_HUMAN Apolipoprotein B-100 OS=Homo sapiens GN=APOB PE=1 SV=1 1326

AIS Victim tr|A0A087WTM7|A0A087WTM7_HUMAN Apolipoprotein B-100 OS=Homo sapiens GN=APOB PE=1 SV=1 155 ICH Control tr|A0A087WTM7|A0A087WTM7_HUMAN Apolipoprotein B-100 OS=Homo sapiens GN=APOB PE=1 SV=1 318 ICH Victim tr|A0A087WTM7|A0A087WTM7_HUMAN Apolipoprotein B-100 OS=Homo sapiens GN=APOB PE=1 SV=1 37 AIS Victim sp|P04114|APOB_HUMAN Apolipoprotein B-100 OS=Homo sapiens GN=APOB PE=1 SV=2 121

AIS Victim tr|B0YIW2|B0YIW2_HUMAN Apolipoprotein C-III OS=Homo sapiens GN=APOC3 PE=1 SV=1 139

ICH Control tr|B0YIW2|B0YIW2_HUMAN Apolipoprotein C-III OS=Homo sapiens GN=APOC3 PE=1 SV=1 108 ICH Victim tr|B0YIW2|B0YIW2_HUMAN Apolipoprotein C-III OS=Homo sapiens GN=APOC3 PE=1 SV=1 77 AIS Control tr|C9JF17|C9JF17_HUMAN Apolipoprotein D (Fragment) OS=Homo sapiens GN=APOD PE=1 SV=1 149 AIS Victim tr|C9JF17|C9JF17_HUMAN Apolipoprotein D (Fragment) OS=Homo sapiens GN=APOD PE=1 SV=1 138

ICH Control tr|C9JF17|C9JF17_HUMAN Apolipoprotein D (Fragment) OS=Homo sapiens GN=APOD PE=1 SV=1 93 ICH Victim tr|C9JF17|C9JF17_HUMAN Apolipoprotein D (Fragment) OS=Homo sapiens GN=APOD PE=1 SV=1 116 AIS Control sp|P05090|APOD_HUMAN Apolipoprotein D OS=Homo sapiens GN=APOD PE=1 SV=1 49 AIS Control tr|E9PEV4|E9PEV4_HUMAN Apolipoprotein E (Fragment) OS=Homo sapiens GN=APOE PE=1 SV=1 139

ICH Control tr|E9PEV4|E9PEV4_HUMAN Apolipoprotein E (Fragment) OS=Homo sapiens GN=APOE PE=1 SV=1 87 ICH Victim tr|E9PEV4|E9PEV4_HUMAN Apolipoprotein E (Fragment) OS=Homo sapiens GN=APOE PE=1 SV=1 541 AIS Control tr|H0Y7L5|H0Y7L5_HUMAN Apolipoprotein E (Fragment) OS=Homo sapiens GN=APOE PE=1 SV=2 121 AIS Victim tr|H0Y7L5|H0Y7L5_HUMAN Apolipoprotein E (Fragment) OS=Homo sapiens GN=APOE PE=1 SV=2 157

ICH Control tr|H0Y7L5|H0Y7L5_HUMAN Apolipoprotein E (Fragment) OS=Homo sapiens GN=APOE PE=1 SV=2 114 ICH Victim tr|H0Y7L5|H0Y7L5_HUMAN Apolipoprotein E (Fragment) OS=Homo sapiens GN=APOE PE=1 SV=2 289 AIS Control sp|P02649|APOE_HUMAN Apolipoprotein E OS=Homo sapiens GN=APOE PE=1 SV=1 153

AIS Victim sp|P02649|APOE_HUMAN Apolipoprotein E OS=Homo sapiens GN=APOE PE=1 SV=1 257

ICH Control sp|P02649|APOE_HUMAN Apolipoprotein E OS=Homo sapiens GN=APOE PE=1 SV=1 145 ICH Victim sp|P02649|APOE_HUMAN Apolipoprotein E OS=Homo sapiens GN=APOE PE=1 SV=1 69 AIS Control sp|Q13790|APOF_HUMAN Apolipoprotein F OS=Homo sapiens GN=APOF PE=1 SV=2 65 AIS Victim sp|Q13790|APOF_HUMAN Apolipoprotein F OS=Homo sapiens GN=APOF PE=1 SV=2 52

ICH Control tr|Q5SRP5|Q5SRP5_HUMAN Apolipoprotein M OS=Homo sapiens GN=APOM PE=1 SV=1 41 ICH Victim tr|Q5SRP5|Q5SRP5_HUMAN Apolipoprotein M OS=Homo sapiens GN=APOM PE=1 SV=1 115

101

AIS Victim sp|P08519|APOA_HUMAN Apolipoprotein(a) OS=Homo sapiens GN=LPA PE=1 SV=1 355 ICH Control sp|P08519|APOA_HUMAN Apolipoprotein(a) OS=Homo sapiens GN=LPA PE=1 SV=1 230 ICH Victim sp|P08519|APOA_HUMAN Apolipoprotein(a) OS=Homo sapiens GN=LPA PE=1 SV=1 82 ICH Control sp|O95831|AIFM1_HUMAN Apoptosis-inducing factor 1, mitochondrial OS=Homo sapiens GN=AIFM1 PE=1 SV=1 54

ICH Control tr|H0Y5R1|H0Y5R1_HUMAN Aryl hydrocarbon receptor nuclear translocator-like protein 2 (Fragment) OS=Homo sapiens GN=ARNTL2 PE=1 SV=1 43 ICH Control tr|H0YH81|H0YH81_HUMAN ATP synthase subunit beta (Fragment) OS=Homo sapiens GN=ATP5B PE=1 SV=1 84 AIS Control tr|H0Y3H2|H0Y3H2_HUMAN ATP-binding cassette sub-family A member 3 OS=Homo sapiens GN=ABCA3 PE=1 SV=1 37 AIS Victim tr|A0A087WW65|A0A087WW65_HUMAN ATP-binding cassette sub-family B member 7, mitochondrial OS=Homo sapiens GN=ABCB7 PE=1 SV=1 35

AIS Victim tr|G3V529|G3V529_HUMAN ATP-dependent RNA helicase DDX24 OS=Homo sapiens GN=DDX24 PE=1 SV=1 46 ICH Victim tr|A0A087WXU8|A0A087WXU8_HUMAN ATP-dependent RNA helicase DDX24 OS=Homo sapiens GN=DDX24 PE=1 SV=1 44 AIS Victim sp|O75882|ATRN_HUMAN Attractin OS=Homo sapiens GN=ATRN PE=1 SV=2 162

ICH Control sp|O75882|ATRN_HUMAN Attractin OS=Homo sapiens GN=ATRN PE=1 SV=2 52

ICH Victim sp|O75882|ATRN_HUMAN Attractin OS=Homo sapiens GN=ATRN PE=1 SV=2 76 AIS Victim tr|A0A0G2JNC7|A0A0G2JNC7_HUMAN Baculoviral IAP repeat-containing protein 1 OS=Homo sapiens GN=NAIP PE=4 SV=1 35 ICH Control tr|A0A0G2JNC7|A0A0G2JNC7_HUMAN Baculoviral IAP repeat-containing protein 1 OS=Homo sapiens GN=NAIP PE=4 SV=1 39 ICH Victim tr|A0A0G2JNC7|A0A0G2JNC7_HUMAN Baculoviral IAP repeat-containing protein 1 OS=Homo sapiens GN=NAIP PE=4 SV=1 36

AIS Control tr|J3QRN2|J3QRN2_HUMAN Beta-2-glycoprotein 1 (Fragment) OS=Homo sapiens GN=APOH PE=1 SV=1 350 AIS Victim tr|J3KS17|J3KS17_HUMAN Beta-2-glycoprotein 1 (Fragment) OS=Homo sapiens GN=APOH PE=1 SV=1 267 ICH Victim tr|J3QRN2|J3QRN2_HUMAN Beta-2-glycoprotein 1 (Fragment) OS=Homo sapiens GN=APOH PE=1 SV=1 70 AIS Control sp|P02749|APOH_HUMAN Beta-2-glycoprotein 1 OS=Homo sapiens GN=APOH PE=1 SV=3 43

AIS Victim sp|P02749|APOH_HUMAN Beta-2-glycoprotein 1 OS=Homo sapiens GN=APOH PE=1 SV=3 60 ICH Control sp|P02749|APOH_HUMAN Beta-2-glycoprotein 1 OS=Homo sapiens GN=APOH PE=1 SV=3 101 ICH Victim sp|P02749|APOH_HUMAN Beta-2-glycoprotein 1 OS=Homo sapiens GN=APOH PE=1 SV=3 222 AIS Control tr|H0YL18|H0YL18_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=B2M PE=1 SV=1 57

AIS Victim tr|H0YL18|H0YL18_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=B2M PE=1 SV=1 54 ICH Control tr|H0YL18|H0YL18_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=B2M PE=1 SV=1 242 ICH Victim tr|H0YL18|H0YL18_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=B2M PE=1 SV=1 45

AIS Control tr|A0A087X1V9|A0A087X1V9_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=IGKC PE=1 SV=2 1063

AIS Victim tr|A0A087X1V9|A0A087X1V9_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=IGKC PE=1 SV=2 196 ICH Control tr|A0A087X1V9|A0A087X1V9_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=IGKC PE=1 SV=2 1414 ICH Victim tr|A0A087X1V9|A0A087X1V9_HUMAN Beta-2-microglobulin OS=Homo sapiens GN=IGKC PE=1 SV=2 388 ICH Victim sp|Q562R1|ACTBL_HUMAN Beta-actin-like protein 2 OS=Homo sapiens GN=ACTBL2 PE=1 SV=2 92

AIS Control tr|J3KRP0|J3KRP0_HUMAN Beta-Ala-His dipeptidase OS=Homo sapiens GN=CNDP1 PE=1 SV=2 35 AIS Victim tr|J3KRP0|J3KRP0_HUMAN Beta-Ala-His dipeptidase OS=Homo sapiens GN=CNDP1 PE=1 SV=2 81 ICH Control tr|J3KRP0|J3KRP0_HUMAN Beta-Ala-His dipeptidase OS=Homo sapiens GN=CNDP1 PE=1 SV=2 49 AIS Victim sp|Q96KN2|CNDP1_HUMAN Beta-Ala-His dipeptidase OS=Homo sapiens GN=CNDP1 PE=1 SV=4 108

ICH Control sp|Q96KN2|CNDP1_HUMAN Beta-Ala-His dipeptidase OS=Homo sapiens GN=CNDP1 PE=1 SV=4 182 ICH Victim sp|Q96KN2|CNDP1_HUMAN Beta-Ala-His dipeptidase OS=Homo sapiens GN=CNDP1 PE=1 SV=4 172 AIS Victim sp|Q9Y6D5|BIG2_HUMAN Brefeldin A-inhibited guanine nucleotide-exchange protein 2 OS=Homo sapiens GN=ARFGEF2 PE=1 SV=3 39 ICH Control sp|Q9Y6D5|BIG2_HUMAN Brefeldin A-inhibited guanine nucleotide-exchange protein 2 OS=Homo sapiens GN=ARFGEF2 PE=1 SV=3 42

ICH Victim sp|Q9Y6D5|BIG2_HUMAN Brefeldin A-inhibited guanine nucleotide-exchange protein 2 OS=Homo sapiens GN=ARFGEF2 PE=1 SV=3 39 ICH Victim tr|H0Y8F9|H0Y8F9_HUMAN Bromodomain-containing protein 8 (Fragment) OS=Homo sapiens GN=BRD8 PE=1 SV=1 39 AIS Victim tr|Q8N6L6|Q8N6L6_HUMAN C2 protein OS=Homo sapiens GN=C2 PE=1 SV=1 189

ICH Control tr|Q8N6L6|Q8N6L6_HUMAN C2 protein OS=Homo sapiens GN=C2 PE=1 SV=1 95

ICH Victim tr|Q8N6L6|Q8N6L6_HUMAN C2 protein OS=Homo sapiens GN=C2 PE=1 SV=1 170 AIS Control sp|P04003|C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 501 AIS Victim sp|P04003|C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 127 ICH Control sp|P04003|C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 322

ICH Victim sp|P04003|C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 234 ICH Victim tr|Q5VVQ7|Q5VVQ7_HUMAN C4b-binding protein beta chain (Fragment) OS=Homo sapiens GN=C4BPB PE=1 SV=1 38 AIS Victim tr|A0A087X0X6|A0A087X0X6_HUMAN Cadherin-13 OS=Homo sapiens GN=CDH13 PE=1 SV=1 61 ICH Control tr|A0A087X0X6|A0A087X0X6_HUMAN Cadherin-13 OS=Homo sapiens GN=CDH13 PE=1 SV=1 81

ICH Victim tr|A0A087X0X6|A0A087X0X6_HUMAN Cadherin-13 OS=Homo sapiens GN=CDH13 PE=1 SV=1 41 AIS Control tr|A0A0A0MTR1|A0A0A0MTR1_HUMAN Cadherin-13 OS=Homo sapiens GN=CDH13 PE=1 SV=2 36

102

ICH Victim tr|I3L1J2|I3L1J2_HUMAN Cadherin-5 OS=Homo sapiens GN=CDH5 PE=1 SV=1 44 ICH Control tr|H0YJR7|H0YJR7_HUMAN Calmodulin-binding transcription activator 1 (Fragment) OS=Homo sapiens GN=CAMTA1 PE=4 SV=1 37 ICH Control tr|I3L3W6|I3L3W6_HUMAN Calmodulin-binding transcription activator 2 OS=Homo sapiens GN=CAMTA2 PE=1 SV=1 52 AIS Victim sp|O75808|CAN15_HUMAN Calpain-15 OS=Homo sapiens GN=CAPN15 PE=1 SV=1 40

ICH Control sp|O75808|CAN15_HUMAN Calpain-15 OS=Homo sapiens GN=CAPN15 PE=1 SV=1 34 AIS Victim sp|P17655|CAN2_HUMAN Calpain-2 catalytic subunit OS=Homo sapiens GN=CAPN2 PE=1 SV=6 48 AIS Control sp|Q9NS84|CHST7_HUMAN Carbohydrate sulfotransferase 7 OS=Homo sapiens GN=CHST7 PE=1 SV=2 37 AIS Control tr|H0YBE2|H0YBE2_HUMAN Carbonic anhydrase 1 (Fragment) OS=Homo sapiens GN=CA1 PE=1 SV=1 69

AIS Victim tr|H0YBE2|H0YBE2_HUMAN Carbonic anhydrase 1 (Fragment) OS=Homo sapiens GN=CA1 PE=1 SV=1 52 ICH Control tr|H0YBE2|H0YBE2_HUMAN Carbonic anhydrase 1 (Fragment) OS=Homo sapiens GN=CA1 PE=1 SV=1 64 ICH Victim tr|H0YBE2|H0YBE2_HUMAN Carbonic anhydrase 1 (Fragment) OS=Homo sapiens GN=CA1 PE=1 SV=1 38 AIS Victim tr|E5RK37|E5RK37_HUMAN Carbonic anhydrase 2 OS=Homo sapiens GN=CA2 PE=1 SV=1 84

ICH Victim sp|P07451|CAH3_HUMAN Carbonic anhydrase 3 OS=Homo sapiens GN=CA3 PE=1 SV=3 40 AIS Control tr|F8WF14|F8WF14_HUMAN Carboxylic ester hydrolase OS=Homo sapiens GN=BCHE PE=1 SV=1 96 AIS Victim tr|F8WF14|F8WF14_HUMAN Carboxylic ester hydrolase OS=Homo sapiens GN=BCHE PE=1 SV=1 41

ICH Control tr|F8WF14|F8WF14_HUMAN Carboxylic ester hydrolase OS=Homo sapiens GN=BCHE PE=1 SV=1 35

ICH Victim tr|F8WF14|F8WF14_HUMAN Carboxylic ester hydrolase OS=Homo sapiens GN=BCHE PE=1 SV=1 108 AIS Control tr|A0A087WSY5|A0A087WSY5_HUMAN Carboxypeptidase B2 OS=Homo sapiens GN=CPB2 PE=1 SV=1 35 AIS Victim tr|A0A087WSY5|A0A087WSY5_HUMAN Carboxypeptidase B2 OS=Homo sapiens GN=CPB2 PE=1 SV=1 42 ICH Control tr|A0A087WSY5|A0A087WSY5_HUMAN Carboxypeptidase B2 OS=Homo sapiens GN=CPB2 PE=1 SV=1 69

ICH Victim tr|A0A087WSY5|A0A087WSY5_HUMAN Carboxypeptidase B2 OS=Homo sapiens GN=CPB2 PE=1 SV=1 184 AIS Victim tr|B1AP58|B1AP58_HUMAN Carboxypeptidase N catalytic chain (Fragment) OS=Homo sapiens GN=CPN1 PE=1 SV=1 41 ICH Victim tr|B1AP58|B1AP58_HUMAN Carboxypeptidase N catalytic chain (Fragment) OS=Homo sapiens GN=CPN1 PE=1 SV=1 41 AIS Control sp|P15169|CBPN_HUMAN Carboxypeptidase N catalytic chain OS=Homo sapiens GN=CPN1 PE=1 SV=1 139

AIS Victim sp|P15169|CBPN_HUMAN Carboxypeptidase N catalytic chain OS=Homo sapiens GN=CPN1 PE=1 SV=1 85 ICH Control sp|P15169|CBPN_HUMAN Carboxypeptidase N catalytic chain OS=Homo sapiens GN=CPN1 PE=1 SV=1 62 ICH Victim sp|P15169|CBPN_HUMAN Carboxypeptidase N catalytic chain OS=Homo sapiens GN=CPN1 PE=1 SV=1 56 AIS Control sp|P22792|CPN2_HUMAN Carboxypeptidase N subunit 2 OS=Homo sapiens GN=CPN2 PE=1 SV=3 247

AIS Victim sp|P22792|CPN2_HUMAN Carboxypeptidase N subunit 2 OS=Homo sapiens GN=CPN2 PE=1 SV=3 50 ICH Control sp|P22792|CPN2_HUMAN Carboxypeptidase N subunit 2 OS=Homo sapiens GN=CPN2 PE=1 SV=3 40 ICH Victim sp|P22792|CPN2_HUMAN Carboxypeptidase N subunit 2 OS=Homo sapiens GN=CPN2 PE=1 SV=3 60

AIS Victim tr|A0A0C4DFP6|A0A0C4DFP6_HUMAN Cartilage acidic protein 1 OS=Homo sapiens GN=CRTAC1 PE=1 SV=1 47

ICH Control tr|A0A0C4DFP6|A0A0C4DFP6_HUMAN Cartilage acidic protein 1 OS=Homo sapiens GN=CRTAC1 PE=1 SV=1 59 ICH Victim tr|A0A0C4DFP6|A0A0C4DFP6_HUMAN Cartilage acidic protein 1 OS=Homo sapiens GN=CRTAC1 PE=1 SV=1 65 AIS Control tr|G3XAP6|G3XAP6_HUMAN Cartilage oligomeric matrix protein OS=Homo sapiens GN=COMP PE=1 SV=1 51 ICH Control tr|G3XAP6|G3XAP6_HUMAN Cartilage oligomeric matrix protein OS=Homo sapiens GN=COMP PE=1 SV=1 97

ICH Victim tr|G3XAP6|G3XAP6_HUMAN Cartilage oligomeric matrix protein OS=Homo sapiens GN=COMP PE=1 SV=1 66 AIS Control tr|A0A087WTW5|A0A087WTW5_HUMAN CASP8-associated protein 2 OS=Homo sapiens GN=CASP8AP2 PE=1 SV=1 42 AIS Victim tr|A0A087WTW5|A0A087WTW5_HUMAN CASP8-associated protein 2 OS=Homo sapiens GN=CASP8AP2 PE=1 SV=1 39 ICH Victim tr|G3XAM7|G3XAM7_HUMAN Catenin (Cadherin-associated protein), alpha 1, 102kDa, isoform CRA_a OS=Homo sapiens GN=CTNNA1 PE=1 SV=1 38

AIS Control tr|H0Y2P0|H0Y2P0_HUMAN CD44 antigen (Fragment) OS=Homo sapiens GN=CD44 PE=1 SV=1 93 AIS Victim tr|H0YDX6|H0YDX6_HUMAN CD44 antigen (Fragment) OS=Homo sapiens GN=CD44 PE=1 SV=1 65 ICH Control tr|H0Y2P0|H0Y2P0_HUMAN CD44 antigen (Fragment) OS=Homo sapiens GN=CD44 PE=1 SV=1 40 ICH Victim tr|H0Y5E4|H0Y5E4_HUMAN CD44 antigen (Fragment) OS=Homo sapiens GN=CD44 PE=1 SV=1 83

AIS Victim tr|H0YD17|H0YD17_HUMAN CD44 antigen (Fragment) OS=Homo sapiens GN=CD44 PE=1 SV=5 44 AIS Victim tr|H0YD13|H0YD13_HUMAN CD44 antigen OS=Homo sapiens GN=CD44 PE=1 SV=2 62 ICH Victim tr|H0YD13|H0YD13_HUMAN CD44 antigen OS=Homo sapiens GN=CD44 PE=1 SV=2 58

AIS Control sp|O43866|CD5L_HUMAN CD5 antigen-like OS=Homo sapiens GN=CD5L PE=1 SV=1 317

AIS Victim sp|O43866|CD5L_HUMAN CD5 antigen-like OS=Homo sapiens GN=CD5L PE=1 SV=1 131 ICH Control sp|O43866|CD5L_HUMAN CD5 antigen-like OS=Homo sapiens GN=CD5L PE=1 SV=1 234 ICH Victim sp|O43866|CD5L_HUMAN CD5 antigen-like OS=Homo sapiens GN=CD5L PE=1 SV=1 94 ICH Victim sp|B2RD01|CENP1_HUMAN CENPB DNA-binding domain-containing protein 1 OS=Homo sapiens GN=CENPBD1 PE=2 SV=1 34

ICH Control sp|P49454|CENPF_HUMAN Centromere protein F OS=Homo sapiens GN=CENPF PE=1 SV=2 46 ICH Victim sp|P49454|CENPF_HUMAN Centromere protein F OS=Homo sapiens GN=CENPF PE=1 SV=2 57 AIS Victim tr|A0A0A0MSX2|A0A0A0MSX2_HUMAN Centrosomal protein C10orf90 (Fragment) OS=Homo sapiens GN=C10orf90 PE=4 SV=1 45 ICH Control tr|A0A0A0MSX2|A0A0A0MSX2_HUMAN Centrosomal protein C10orf90 (Fragment) OS=Homo sapiens GN=C10orf90 PE=4 SV=1 36

AIS Control tr|Q5T025|Q5T025_HUMAN Centrosomal protein C10orf90 OS=Homo sapiens GN=C10orf90 PE=4 SV=2 42 ICH Victim sp|Q5VT06|CE350_HUMAN Centrosome-associated protein 350 OS=Homo sapiens GN=CEP350 PE=1 SV=1 38

103

AIS Control tr|H7C5R1|H7C5R1_HUMAN Ceruloplasmin (Fragment) OS=Homo sapiens GN=CP PE=1 SV=1 1567 ICH Control tr|H7C5R1|H7C5R1_HUMAN Ceruloplasmin (Fragment) OS=Homo sapiens GN=CP PE=1 SV=1 99 ICH Victim tr|H7C5R1|H7C5R1_HUMAN Ceruloplasmin (Fragment) OS=Homo sapiens GN=CP PE=1 SV=1 2456 AIS Control tr|D6RE86|D6RE86_HUMAN Ceruloplasmin (Fragment) OS=Homo sapiens GN=CP PE=1 SV=5 156

AIS Victim tr|D6RE86|D6RE86_HUMAN Ceruloplasmin (Fragment) OS=Homo sapiens GN=CP PE=1 SV=5 237 ICH Control tr|D6RE86|D6RE86_HUMAN Ceruloplasmin (Fragment) OS=Homo sapiens GN=CP PE=1 SV=5 109 ICH Victim tr|D6RE86|D6RE86_HUMAN Ceruloplasmin (Fragment) OS=Homo sapiens GN=CP PE=1 SV=5 112 AIS Control sp|P00450|CERU_HUMAN Ceruloplasmin OS=Homo sapiens GN=CP PE=1 SV=1 1362

ICH Victim sp|Q8NHY5|HUS1B_HUMAN Checkpoint protein HUS1B OS=Homo sapiens GN=HUS1B PE=1 SV=2 38

ICH Control tr|H3BRJ9|H3BRJ9_HUMAN Cholesteryl ester transfer protein OS=Homo sapiens GN=CETP PE=1 SV=1 41 ICH Victim tr|H3BRJ9|H3BRJ9_HUMAN Cholesteryl ester transfer protein OS=Homo sapiens GN=CETP PE=1 SV=1 71 ICH Control sp|P06276|CHLE_HUMAN Cholinesterase OS=Homo sapiens GN=BCHE PE=1 SV=1 94 AIS Victim tr|G5E968|G5E968_HUMAN Chromogranin A (Parathyroid secretory protein 1), isoform CRA_b OS=Homo sapiens GN=CHGA PE=1 SV=1 37

ICH Victim tr|G5E968|G5E968_HUMAN Chromogranin A (Parathyroid secretory protein 1), isoform CRA_b OS=Homo sapiens GN=CHGA PE=1 SV=1 36 ICH Control tr|H0Y4A8|H0Y4A8_HUMAN Cingulin (Fragment) OS=Homo sapiens GN=CGN PE=1 SV=1 40 ICH Victim tr|J3KSQ2|J3KSQ2_HUMAN Clathrin heavy chain 1 (Fragment) OS=Homo sapiens GN=CLTC PE=1 SV=1 37 ICH Control tr|A0A087WVQ6|A0A087WVQ6_HUMAN Clathrin heavy chain OS=Homo sapiens GN=CLTC PE=1 SV=1 38

ICH Control tr|A0A0A0MQS2|A0A0A0MQS2_HUMAN CLK4-associating serine/arginine-rich protein OS=Homo sapiens GN=CLASRP PE=1 SV=1 40 AIS Victim tr|E5RGB0|E5RGB0_HUMAN Clusterin (Fragment) OS=Homo sapiens GN=CLU PE=1 SV=1 46 ICH Control tr|H0YAS8|H0YAS8_HUMAN Clusterin (Fragment) OS=Homo sapiens GN=CLU PE=1 SV=1 118 ICH Victim tr|E5RJZ5|E5RJZ5_HUMAN Clusterin (Fragment) OS=Homo sapiens GN=CLU PE=1 SV=1 126

AIS Control tr|E5RH61|E5RH61_HUMAN Clusterin (Fragment) OS=Homo sapiens GN=CLU PE=1 SV=5 139 AIS Victim tr|E5RH61|E5RH61_HUMAN Clusterin (Fragment) OS=Homo sapiens GN=CLU PE=1 SV=5 174 AIS Control sp|P00740|FA9_HUMAN Coagulation factor IX OS=Homo sapiens GN=F9 PE=1 SV=2 87

AIS Victim sp|P00740|FA9_HUMAN Coagulation factor IX OS=Homo sapiens GN=F9 PE=1 SV=2 51

ICH Control tr|A0A0A0MRJ7|A0A0A0MRJ7_HUMAN Coagulation factor V OS=Homo sapiens GN=F5 PE=1 SV=1 128 ICH Victim tr|A0A0A0MRJ7|A0A0A0MRJ7_HUMAN Coagulation factor V OS=Homo sapiens GN=F5 PE=1 SV=1 63 AIS Control tr|Q5JVE8|Q5JVE8_HUMAN Coagulation factor X OS=Homo sapiens GN=F10 PE=1 SV=1 49 ICH Control tr|B7ZBK1|B7ZBK1_HUMAN Coagulation factor X OS=Homo sapiens GN=F10 PE=1 SV=1 63

ICH Victim sp|P00742|FA10_HUMAN Coagulation factor X OS=Homo sapiens GN=F10 PE=1 SV=2 42 ICH Victim tr|H0Y596|H0Y596_HUMAN Coagulation factor XI (Fragment) OS=Homo sapiens GN=F11 PE=1 SV=1 37 AIS Victim tr|D6RB32|D6RB32_HUMAN Coagulation factor XI OS=Homo sapiens GN=F11 PE=1 SV=1 56

ICH Victim sp|P03951|FA11_HUMAN Coagulation factor XI OS=Homo sapiens GN=F11 PE=1 SV=1 68

AIS Control sp|P00748|FA12_HUMAN Coagulation factor XII OS=Homo sapiens GN=F12 PE=1 SV=3 160 AIS Victim sp|P00748|FA12_HUMAN Coagulation factor XII OS=Homo sapiens GN=F12 PE=1 SV=3 452 ICH Control sp|P00748|FA12_HUMAN Coagulation factor XII OS=Homo sapiens GN=F12 PE=1 SV=3 428 ICH Victim sp|P00748|FA12_HUMAN Coagulation factor XII OS=Homo sapiens GN=F12 PE=1 SV=3 72

AIS Victim tr|H0Y796|H0Y796_HUMAN Coagulation factor XIII A chain (Fragment) OS=Homo sapiens GN=F13A1 PE=1 SV=1 54 ICH Control tr|H0Y796|H0Y796_HUMAN Coagulation factor XIII A chain (Fragment) OS=Homo sapiens GN=F13A1 PE=1 SV=1 48 ICH Victim tr|H0Y796|H0Y796_HUMAN Coagulation factor XIII A chain (Fragment) OS=Homo sapiens GN=F13A1 PE=1 SV=1 115 ICH Control tr|A6PVK5|A6PVK5_HUMAN Coagulation factor XIII A chain (Fragment) OS=Homo sapiens GN=F13A1 PE=1 SV=6 51

AIS Control sp|P00488|F13A_HUMAN Coagulation factor XIII A chain OS=Homo sapiens GN=F13A1 PE=1 SV=4 89 AIS Victim sp|P00488|F13A_HUMAN Coagulation factor XIII A chain OS=Homo sapiens GN=F13A1 PE=1 SV=4 178

104

ICH Control sp|P00488|F13A_HUMAN Coagulation factor XIII A chain OS=Homo sapiens GN=F13A1 PE=1 SV=4 61 ICH Victim sp|P00488|F13A_HUMAN Coagulation factor XIII A chain OS=Homo sapiens GN=F13A1 PE=1 SV=4 130 AIS Control sp|P05160|F13B_HUMAN Coagulation factor XIII B chain OS=Homo sapiens GN=F13B PE=1 SV=3 113 AIS Victim sp|P05160|F13B_HUMAN Coagulation factor XIII B chain OS=Homo sapiens GN=F13B PE=1 SV=3 36

ICH Control sp|P05160|F13B_HUMAN Coagulation factor XIII B chain OS=Homo sapiens GN=F13B PE=1 SV=3 56 ICH Victim sp|P05160|F13B_HUMAN Coagulation factor XIII B chain OS=Homo sapiens GN=F13B PE=1 SV=3 39 AIS Control sp|P35606|COPB2_HUMAN Coatomer subunit beta~ OS=Homo sapiens GN=COPB2 PE=1 SV=2 37 AIS Victim sp|Q9P0B6|CC167_HUMAN Coiled-coil domain-containing protein 167 OS=Homo sapiens GN=CCDC167 PE=1 SV=2 35

AIS Control sp|P0C7W6|CC172_HUMAN Coiled-coil domain-containing protein 172 OS=Homo sapiens GN=CCDC172 PE=1 SV=1 40 AIS Victim sp|P0C7W6|CC172_HUMAN Coiled-coil domain-containing protein 172 OS=Homo sapiens GN=CCDC172 PE=1 SV=1 37 ICH Control sp|P0C7W6|CC172_HUMAN Coiled-coil domain-containing protein 172 OS=Homo sapiens GN=CCDC172 PE=1 SV=1 42 ICH Victim sp|P0C7W6|CC172_HUMAN Coiled-coil domain-containing protein 172 OS=Homo sapiens GN=CCDC172 PE=1 SV=1 46

ICH Victim sp|Q6PII3|CC174_HUMAN Coiled-coil domain-containing protein 174 OS=Homo sapiens GN=CCDC174 PE=2 SV=3 42 ICH Control sp|Q5VVM6|CCD30_HUMAN Coiled-coil domain-containing protein 30 OS=Homo sapiens GN=CCDC30 PE=2 SV=1 37 ICH Control tr|D6RB86|D6RB86_HUMAN Coiled-coil domain-containing protein 30 OS=Homo sapiens GN=CCDC30 PE=4 SV=1 37

AIS Control sp|Q96HJ3|CCD34_HUMAN Coiled-coil domain-containing protein 34 OS=Homo sapiens GN=CCDC34 PE=2 SV=2 40

AIS Victim sp|Q8IWA6|CCD60_HUMAN Coiled-coil domain-containing protein 60 OS=Homo sapiens GN=CCDC60 PE=1 SV=2 40 AIS Control sp|P02452|CO1A1_HUMAN Collagen alpha-1(I) chain OS=Homo sapiens GN=COL1A1 PE=1 SV=5 126 AIS Victim tr|E9PAL5|E9PAL5_HUMAN Collagen alpha-5(VI) chain OS=Homo sapiens GN=COL6A5 PE=1 SV=3 36 ICH Victim sp|Q9Y6Z7|COL10_HUMAN Collectin-10 OS=Homo sapiens GN=COLEC10 PE=2 SV=2 42

AIS Control tr|X6RLJ0|X6RLJ0_HUMAN Complement C1q subcomponent subunit A (Fragment) OS=Homo sapiens GN=C1QA PE=1 SV=4 59 AIS Victim tr|X6RLJ0|X6RLJ0_HUMAN Complement C1q subcomponent subunit A (Fragment) OS=Homo sapiens GN=C1QA PE=1 SV=4 39 ICH Control tr|X6RLJ0|X6RLJ0_HUMAN Complement C1q subcomponent subunit A (Fragment) OS=Homo sapiens GN=C1QA PE=1 SV=4 78 ICH Victim tr|X6RLJ0|X6RLJ0_HUMAN Complement C1q subcomponent subunit A (Fragment) OS=Homo sapiens GN=C1QA PE=1 SV=4 56

AIS Control sp|P02745|C1QA_HUMAN Complement C1q subcomponent subunit A OS=Homo sapiens GN=C1QA PE=1 SV=2 54 AIS Victim sp|P02745|C1QA_HUMAN Complement C1q subcomponent subunit A OS=Homo sapiens GN=C1QA PE=1 SV=2 60 ICH Control sp|P02745|C1QA_HUMAN Complement C1q subcomponent subunit A OS=Homo sapiens GN=C1QA PE=1 SV=2 43 ICH Victim sp|P02745|C1QA_HUMAN Complement C1q subcomponent subunit A OS=Homo sapiens GN=C1QA PE=1 SV=2 100

AIS Control tr|A0A0A0MSV6|A0A0A0MSV6_HUMAN Complement C1q subcomponent subunit B (Fragment) OS=Homo sapiens GN=C1QB PE=1 SV=3 128 AIS Victim tr|A0A0A0MSV6|A0A0A0MSV6_HUMAN Complement C1q subcomponent subunit B (Fragment) OS=Homo sapiens GN=C1QB PE=1 SV=3 73 ICH Control tr|A0A0A0MSV6|A0A0A0MSV6_HUMAN Complement C1q subcomponent subunit B (Fragment) OS=Homo sapiens GN=C1QB PE=1 SV=3 124

ICH Victim tr|A0A0A0MSV6|A0A0A0MSV6_HUMAN Complement C1q subcomponent subunit B (Fragment) OS=Homo sapiens GN=C1QB PE=1 SV=3 35

AIS Control sp|P02747|C1QC_HUMAN Complement C1q subcomponent subunit C OS=Homo sapiens GN=C1QC PE=1 SV=3 87 AIS Victim sp|P02747|C1QC_HUMAN Complement C1q subcomponent subunit C OS=Homo sapiens GN=C1QC PE=1 SV=3 49 ICH Control sp|P02747|C1QC_HUMAN Complement C1q subcomponent subunit C OS=Homo sapiens GN=C1QC PE=1 SV=3 129 ICH Victim sp|P02747|C1QC_HUMAN Complement C1q subcomponent subunit C OS=Homo sapiens GN=C1QC PE=1 SV=3 50

AIS Control tr|B4DPQ0|B4DPQ0_HUMAN Complement C1r subcomponent OS=Homo sapiens GN=C1R PE=1 SV=1 150 AIS Victim tr|B4DPQ0|B4DPQ0_HUMAN Complement C1r subcomponent OS=Homo sapiens GN=C1R PE=1 SV=1 220 ICH Control tr|B4DPQ0|B4DPQ0_HUMAN Complement C1r subcomponent OS=Homo sapiens GN=C1R PE=1 SV=1 236 ICH Victim tr|B4DPQ0|B4DPQ0_HUMAN Complement C1r subcomponent OS=Homo sapiens GN=C1R PE=1 SV=1 80

AIS Victim tr|F5H2D0|F5H2D0_HUMAN Complement C1r subcomponent OS=Homo sapiens GN=C1R PE=1 SV=3 36 ICH Control tr|F5H2D0|F5H2D0_HUMAN Complement C1r subcomponent OS=Homo sapiens GN=C1R PE=1 SV=3 1064 AIS Victim tr|H0YFL7|H0YFL7_HUMAN Complement C1r subcomponent-like protein (Fragment) OS=Homo sapiens GN=C1RL PE=1 SV=1 117 ICH Control tr|H0YFL7|H0YFL7_HUMAN Complement C1r subcomponent-like protein (Fragment) OS=Homo sapiens GN=C1RL PE=1 SV=1 83

ICH Victim tr|H0YFL7|H0YFL7_HUMAN Complement C1r subcomponent-like protein (Fragment) OS=Homo sapiens GN=C1RL PE=1 SV=1 180 ICH Control tr|F5GWF3|F5GWF3_HUMAN Complement C1r subcomponent-like protein OS=Homo sapiens GN=C1RL PE=1 SV=1 48 ICH Victim tr|F5GWF3|F5GWF3_HUMAN Complement C1r subcomponent-like protein OS=Homo sapiens GN=C1RL PE=1 SV=1 52

AIS Control sp|Q9NZP8|C1RL_HUMAN Complement C1r subcomponent-like protein OS=Homo sapiens GN=C1RL PE=1 SV=2 82

AIS Victim sp|Q9NZP8|C1RL_HUMAN Complement C1r subcomponent-like protein OS=Homo sapiens GN=C1RL PE=1 SV=2 64 ICH Victim sp|Q9NZP8|C1RL_HUMAN Complement C1r subcomponent-like protein OS=Homo sapiens GN=C1RL PE=1 SV=2 48 AIS Victim tr|H0Y5D1|H0Y5D1_HUMAN Complement C1s subcomponent (Fragment) OS=Homo sapiens GN=C1S PE=1 SV=1 44 ICH Control tr|C9IZP8|C9IZP8_HUMAN Complement C1s subcomponent (Fragment) OS=Homo sapiens GN=C1S PE=1 SV=1 70

ICH Victim tr|H0Y5D1|H0Y5D1_HUMAN Complement C1s subcomponent (Fragment) OS=Homo sapiens GN=C1S PE=1 SV=1 48 AIS Control tr|A0A087X232|A0A087X232_HUMAN Complement C1s subcomponent OS=Homo sapiens GN=C1S PE=1 SV=1 184 AIS Victim tr|A0A087X232|A0A087X232_HUMAN Complement C1s subcomponent OS=Homo sapiens GN=C1S PE=1 SV=1 188 ICH Control tr|A0A087X232|A0A087X232_HUMAN Complement C1s subcomponent OS=Homo sapiens GN=C1S PE=1 SV=1 46

ICH Victim tr|A0A087X232|A0A087X232_HUMAN Complement C1s subcomponent OS=Homo sapiens GN=C1S PE=1 SV=1 184 ICH Control tr|H0Y868|H0Y868_HUMAN Complement C2 (Fragment) OS=Homo sapiens GN=C2 PE=1 SV=1 131

105

AIS Control tr|A0A0G2JJM0|A0A0G2JJM0_HUMAN Complement C2 (Fragment) OS=Homo sapiens GN=C2 PE=4 SV=1 44 AIS Victim tr|A0A0G2JHM4|A0A0G2JHM4_HUMAN Complement C2 (Fragment) OS=Homo sapiens GN=C2 PE=4 SV=1 189 ICH Control tr|A0A0G2JHM4|A0A0G2JHM4_HUMAN Complement C2 (Fragment) OS=Homo sapiens GN=C2 PE=4 SV=1 75 ICH Victim tr|A0A0G2JHM4|A0A0G2JHM4_HUMAN Complement C2 (Fragment) OS=Homo sapiens GN=C2 PE=4 SV=1 155

ICH Victim tr|M0QXZ3|M0QXZ3_HUMAN Complement C3 (Fragment) OS=Homo sapiens GN=C3 PE=1 SV=1 273

AIS Control sp|P01024|CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 2856 AIS Victim sp|P01024|CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 58 ICH Control sp|P01024|CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 561 ICH Victim sp|P01024|CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 1283

AIS Control sp|P0C0L4|CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=2 4197 AIS Victim sp|P0C0L4|CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=2 1367 ICH Control sp|P0C0L4|CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=2 194 ICH Victim sp|P0C0L4|CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=2 724

ICH Control sp|P0C0L5|CO4B_HUMAN Complement C4-B OS=Homo sapiens GN=C4B PE=1 SV=2 1731 ICH Victim sp|P0C0L5|CO4B_HUMAN Complement C4-B OS=Homo sapiens GN=C4B PE=1 SV=2 116 AIS Victim sp|P01031|CO5_HUMAN Complement C5 OS=Homo sapiens GN=C5 PE=1 SV=4 1474

ICH Victim sp|P01031|CO5_HUMAN Complement C5 OS=Homo sapiens GN=C5 PE=1 SV=4 2101

AIS Control sp|P13671|CO6_HUMAN Complement component C6 OS=Homo sapiens GN=C6 PE=1 SV=3 71 AIS Victim sp|P13671|CO6_HUMAN Complement component C6 OS=Homo sapiens GN=C6 PE=1 SV=3 250 ICH Control sp|P13671|CO6_HUMAN Complement component C6 OS=Homo sapiens GN=C6 PE=1 SV=3 126 ICH Victim sp|P13671|CO6_HUMAN Complement component C6 OS=Homo sapiens GN=C6 PE=1 SV=3 180

AIS Control sp|P10643|CO7_HUMAN Complement component C7 OS=Homo sapiens GN=C7 PE=1 SV=2 190 AIS Victim sp|P10643|CO7_HUMAN Complement component C7 OS=Homo sapiens GN=C7 PE=1 SV=2 82 ICH Control sp|P10643|CO7_HUMAN Complement component C7 OS=Homo sapiens GN=C7 PE=1 SV=2 99 ICH Victim sp|P10643|CO7_HUMAN Complement component C7 OS=Homo sapiens GN=C7 PE=1 SV=2 258

AIS Control sp|P07357|CO8A_HUMAN Complement component C8 alpha chain OS=Homo sapiens GN=C8A PE=1 SV=2 94 AIS Victim sp|P07357|CO8A_HUMAN Complement component C8 alpha chain OS=Homo sapiens GN=C8A PE=1 SV=2 183 ICH Control sp|P07357|CO8A_HUMAN Complement component C8 alpha chain OS=Homo sapiens GN=C8A PE=1 SV=2 83 ICH Victim sp|P07357|CO8A_HUMAN Complement component C8 alpha chain OS=Homo sapiens GN=C8A PE=1 SV=2 64

AIS Control tr|F5GY80|F5GY80_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=1 77 AIS Victim tr|F5GY80|F5GY80_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=1 96 ICH Control tr|F5GY80|F5GY80_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=1 421

ICH Victim tr|F5GY80|F5GY80_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=1 41

AIS Control sp|P07358|CO8B_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=3 188 AIS Victim sp|P07358|CO8B_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=3 87 ICH Control sp|P07358|CO8B_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=3 267 ICH Victim sp|P07358|CO8B_HUMAN Complement component C8 beta chain OS=Homo sapiens GN=C8B PE=1 SV=3 40

AIS Control tr|Q5SQ08|Q5SQ08_HUMAN Complement component C8 gamma chain (Fragment) OS=Homo sapiens GN=C8G PE=1 SV=1 80 ICH Control tr|Q5SQ08|Q5SQ08_HUMAN Complement component C8 gamma chain (Fragment) OS=Homo sapiens GN=C8G PE=1 SV=1 139 ICH Victim tr|Q5SQ08|Q5SQ08_HUMAN Complement component C8 gamma chain (Fragment) OS=Homo sapiens GN=C8G PE=1 SV=1 37 AIS Control sp|P07360|CO8G_HUMAN Complement component C8 gamma chain OS=Homo sapiens GN=C8G PE=1 SV=3 184

AIS Victim sp|P07360|CO8G_HUMAN Complement component C8 gamma chain OS=Homo sapiens GN=C8G PE=1 SV=3 80 ICH Control sp|P07360|CO8G_HUMAN Complement component C8 gamma chain OS=Homo sapiens GN=C8G PE=1 SV=3 321

106

ICH Victim sp|P07360|CO8G_HUMAN Complement component C8 gamma chain OS=Homo sapiens GN=C8G PE=1 SV=3 248 AIS Control sp|P02748|CO9_HUMAN Complement component C9 OS=Homo sapiens GN=C9 PE=1 SV=2 56 AIS Victim sp|P02748|CO9_HUMAN Complement component C9 OS=Homo sapiens GN=C9 PE=1 SV=2 367 ICH Control sp|P02748|CO9_HUMAN Complement component C9 OS=Homo sapiens GN=C9 PE=1 SV=2 298

ICH Victim sp|P02748|CO9_HUMAN Complement component C9 OS=Homo sapiens GN=C9 PE=1 SV=2 165 AIS Victim tr|H7C5H1|H7C5H1_HUMAN Complement factor B (Fragment) OS=Homo sapiens GN=CFB PE=1 SV=1 543 ICH Control tr|H7C5H1|H7C5H1_HUMAN Complement factor B (Fragment) OS=Homo sapiens GN=CFB PE=1 SV=1 341 ICH Victim tr|H7C5H1|H7C5H1_HUMAN Complement factor B (Fragment) OS=Homo sapiens GN=CFB PE=1 SV=1 288

ICH Control tr|H7C526|H7C526_HUMAN Complement factor B (Fragment) OS=Homo sapiens GN=CFB PE=4 SV=1 118 ICH Victim tr|H7C526|H7C526_HUMAN Complement factor B (Fragment) OS=Homo sapiens GN=CFB PE=4 SV=1 48 AIS Control sp|P00751|CFAB_HUMAN Complement factor B OS=Homo sapiens GN=CFB PE=1 SV=2 525 AIS Victim tr|K7ERG9|K7ERG9_HUMAN Complement factor D OS=Homo sapiens GN=CFD PE=1 SV=1 77

AIS Control tr|A0A0D9SG88|A0A0D9SG88_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=1 1043 AIS Victim tr|A0A0D9SG88|A0A0D9SG88_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=1 2612 ICH Control tr|A0A0D9SG88|A0A0D9SG88_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=1 1158

AIS Control sp|P08603|CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 2153

AIS Victim sp|P08603|CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 49 ICH Control sp|P08603|CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 692 ICH Victim sp|P08603|CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 900 AIS Control tr|B1AKG0|B1AKG0_HUMAN Complement factor H-related protein 1 OS=Homo sapiens GN=CFHR1 PE=1 SV=1 148

AIS Victim tr|B1AKG0|B1AKG0_HUMAN Complement factor H-related protein 1 OS=Homo sapiens GN=CFHR1 PE=1 SV=1 390 ICH Control tr|B1AKG0|B1AKG0_HUMAN Complement factor H-related protein 1 OS=Homo sapiens GN=CFHR1 PE=1 SV=1 90 ICH Victim tr|B1AKG0|B1AKG0_HUMAN Complement factor H-related protein 1 OS=Homo sapiens GN=CFHR1 PE=1 SV=1 150 AIS Victim sp|Q03591|FHR1_HUMAN Complement factor H-related protein 1 OS=Homo sapiens GN=CFHR1 PE=1 SV=2 44

ICH Control sp|Q03591|FHR1_HUMAN Complement factor H-related protein 1 OS=Homo sapiens GN=CFHR1 PE=1 SV=2 53 ICH Victim sp|Q03591|FHR1_HUMAN Complement factor H-related protein 1 OS=Homo sapiens GN=CFHR1 PE=1 SV=2 348 AIS Control tr|V9GYE7|V9GYE7_HUMAN Complement factor H-related protein 2 OS=Homo sapiens GN=CFHR2 PE=1 SV=1 47 AIS Victim tr|V9GYE7|V9GYE7_HUMAN Complement factor H-related protein 2 OS=Homo sapiens GN=CFHR2 PE=1 SV=1 163

ICH Control tr|V9GYE7|V9GYE7_HUMAN Complement factor H-related protein 2 OS=Homo sapiens GN=CFHR2 PE=1 SV=1 80 ICH Victim tr|V9GYE7|V9GYE7_HUMAN Complement factor H-related protein 2 OS=Homo sapiens GN=CFHR2 PE=1 SV=1 71 AIS Control tr|A0A0C4DH21|A0A0C4DH21_HUMAN Complement factor H-related protein 4 OS=Homo sapiens GN=CFHR4 PE=1 SV=1 45

ICH Control tr|A0A0C4DH21|A0A0C4DH21_HUMAN Complement factor H-related protein 4 OS=Homo sapiens GN=CFHR4 PE=1 SV=1 49

AIS Control sp|Q9BXR6|FHR5_HUMAN Complement factor H-related protein 5 OS=Homo sapiens GN=CFHR5 PE=1 SV=1 68 AIS Victim sp|Q9BXR6|FHR5_HUMAN Complement factor H-related protein 5 OS=Homo sapiens GN=CFHR5 PE=1 SV=1 135 ICH Control sp|Q9BXR6|FHR5_HUMAN Complement factor H-related protein 5 OS=Homo sapiens GN=CFHR5 PE=1 SV=1 58 ICH Victim sp|Q9BXR6|FHR5_HUMAN Complement factor H-related protein 5 OS=Homo sapiens GN=CFHR5 PE=1 SV=1 93

AIS Control tr|H0YE30|H0YE30_HUMAN Copine-7 (Fragment) OS=Homo sapiens GN=CPNE7 PE=4 SV=2 33 ICH Victim tr|H0YE30|H0YE30_HUMAN Copine-7 (Fragment) OS=Homo sapiens GN=CPNE7 PE=4 SV=2 37 AIS Victim tr|Q5TCZ7|Q5TCZ7_HUMAN Copper homeostasis protein cutC homolog (Fragment) OS=Homo sapiens GN=CUTC PE=1 SV=1 40 ICH Victim tr|Q5TCZ7|Q5TCZ7_HUMAN Copper homeostasis protein cutC homolog (Fragment) OS=Homo sapiens GN=CUTC PE=1 SV=1 40

AIS Control sp|P08185|CBG_HUMAN Corticosteroid-binding globulin OS=Homo sapiens GN=SERPINA6 PE=1 SV=1 97 AIS Victim sp|P08185|CBG_HUMAN Corticosteroid-binding globulin OS=Homo sapiens GN=SERPINA6 PE=1 SV=1 73 ICH Control sp|P08185|CBG_HUMAN Corticosteroid-binding globulin OS=Homo sapiens GN=SERPINA6 PE=1 SV=1 71

ICH Victim sp|P08185|CBG_HUMAN Corticosteroid-binding globulin OS=Homo sapiens GN=SERPINA6 PE=1 SV=1 68

ICH Victim sp|P06732|KCRM_HUMAN Creatine kinase M-type OS=Homo sapiens GN=CKM PE=1 SV=2 36 AIS Control sp|Q7L576|CYFP1_HUMAN Cytoplasmic FMR1-interacting protein 1 OS=Homo sapiens GN=CYFIP1 PE=1 SV=1 36 AIS Victim tr|H0YCN4|H0YCN4_HUMAN DCN1-like protein (Fragment) OS=Homo sapiens GN=DCUN1D5 PE=1 SV=1 42 ICH Victim sp|Q9NXF7|DCA16_HUMAN DDB1- and CUL4-associated factor 16 OS=Homo sapiens GN=DCAF16 PE=1 SV=1 38

AIS Victim sp|P07585|PGS2_HUMAN Decorin OS=Homo sapiens GN=DCN PE=1 SV=1 35 ICH Control tr|H0YAW2|H0YAW2_HUMAN DENN domain-containing protein 3 (Fragment) OS=Homo sapiens GN=DENND3 PE=1 SV=1 37

107

ICH Control sp|P81605|DCD_HUMAN Dermcidin OS=Homo sapiens GN=DCD PE=1 SV=2 55 ICH Victim sp|Q02413|DSG1_HUMAN Desmoglein-1 OS=Homo sapiens GN=DSG1 PE=1 SV=2 64 ICH Control sp|Q96JH7|VCIP1_HUMAN Deubiquitinating protein VCIP135 OS=Homo sapiens GN=VCPIP1 PE=1 SV=2 37 AIS Victim sp|Q5FWF4|ZRAB3_HUMAN DNA annealing helicase and endonuclease ZRANB3 OS=Homo sapiens GN=ZRANB3 PE=1 SV=2 61

ICH Control sp|Q5FWF4|ZRAB3_HUMAN DNA annealing helicase and endonuclease ZRANB3 OS=Homo sapiens GN=ZRANB3 PE=1 SV=2 48 AIS Victim tr|A0A087WX51|A0A087WX51_HUMAN DNA polymerase epsilon catalytic subunit A (Fragment) OS=Homo sapiens GN=POLE PE=1 SV=1 37 AIS Control tr|E7EUB5|E7EUB5_HUMAN DNA repair protein-complementing XP-C cells (Fragment) OS=Homo sapiens GN=XPC PE=1 SV=1 37 ICH Victim tr|H7BZ82|H7BZ82_HUMAN DNA topoisomerase 2-beta (Fragment) OS=Homo sapiens GN=TOP2B PE=1 SV=1 36

ICH Control sp|P09172|DOPO_HUMAN Dopamine beta-hydroxylase OS=Homo sapiens GN=DBH PE=1 SV=3 70 ICH Victim sp|P09172|DOPO_HUMAN Dopamine beta-hydroxylase OS=Homo sapiens GN=DBH PE=1 SV=3 61 ICH Victim tr|H7C298|H7C298_HUMAN Doublecortin domain-containing protein 1 (Fragment) OS=Homo sapiens GN=DCDC1 PE=4 SV=1 42 AIS Victim tr|M0R2J8|M0R2J8_HUMAN Doublecortin domain-containing protein 1 OS=Homo sapiens GN=DCDC1 PE=4 SV=1 38

ICH Victim sp|Q5VZB9|DMRTA_HUMAN Doublesex- and mab-3-related transcription factor A1 OS=Homo sapiens GN=DMRTA1 PE=2 SV=1 37 AIS Control tr|A0A087WYC6|A0A087WYC6_HUMAN Dynein heavy chain 11, axonemal OS=Homo sapiens GN=DNAH11 PE=4 SV=1 37 ICH Victim sp|Q6ZR08|DYH12_HUMAN Dynein heavy chain 12, axonemal OS=Homo sapiens GN=DNAH12 PE=2 SV=2 42

ICH Control tr|E9PG32|E9PG32_HUMAN Dynein heavy chain 12, axonemal OS=Homo sapiens GN=DNAH12 PE=4 SV=2 111

AIS Control sp|Q9C0G6|DYH6_HUMAN Dynein heavy chain 6, axonemal OS=Homo sapiens GN=DNAH6 PE=2 SV=3 38 AIS Control tr|C9J196|C9J196_HUMAN Dystroglycan (Fragment) OS=Homo sapiens GN=DAG1 PE=1 SV=1 49 ICH Victim tr|K7ES11|K7ES11_HUMAN E2/E3 hybrid ubiquitin-protein ligase UBE2O (Fragment) OS=Homo sapiens GN=UBE2O PE=1 SV=1 42 AIS Victim sp|Q5VTR2|BRE1A_HUMAN E3 ubiquitin-protein ligase BRE1A OS=Homo sapiens GN=RNF20 PE=1 SV=2 37

AIS Control tr|A0A087WU39|A0A087WU39_HUMAN E3 ubiquitin-protein ligase parkin OS=Homo sapiens GN=PARK2 PE=1 SV=1 43 ICH Control tr|A0A087WU39|A0A087WU39_HUMAN E3 ubiquitin-protein ligase parkin OS=Homo sapiens GN=PARK2 PE=1 SV=1 45 ICH Victim tr|A0A087WU39|A0A087WU39_HUMAN E3 ubiquitin-protein ligase parkin OS=Homo sapiens GN=PARK2 PE=1 SV=1 41 AIS Control tr|Q5TDE7|Q5TDE7_HUMAN E3 ubiquitin-protein ligase RNF220 (Fragment) OS=Homo sapiens GN=RNF220 PE=1 SV=1 39

ICH Victim sp|Q5VTB9|RN220_HUMAN E3 ubiquitin-protein ligase RNF220 OS=Homo sapiens GN=RNF220 PE=1 SV=1 39 ICH Control tr|H0Y612|H0Y612_HUMAN E3 ubiquitin-protein ligase TRIM33 (Fragment) OS=Homo sapiens GN=TRIM33 PE=1 SV=1 58 AIS Control tr|E7EN20|E7EN20_HUMAN E3 ubiquitin-protein ligase TRIM33 OS=Homo sapiens GN=TRIM33 PE=1 SV=2 42 AIS Victim tr|E7EN20|E7EN20_HUMAN E3 ubiquitin-protein ligase TRIM33 OS=Homo sapiens GN=TRIM33 PE=1 SV=2 47

ICH Control tr|E7EN20|E7EN20_HUMAN E3 ubiquitin-protein ligase TRIM33 OS=Homo sapiens GN=TRIM33 PE=1 SV=2 40 ICH Victim tr|E7EN20|E7EN20_HUMAN E3 ubiquitin-protein ligase TRIM33 OS=Homo sapiens GN=TRIM33 PE=1 SV=2 59 AIS Control sp|Q8IY85|EFC13_HUMAN EF-hand calcium-binding domain-containing protein 13 OS=Homo sapiens GN=EFCAB13 PE=2 SV=2 38

ICH Victim sp|Q8IY85|EFC13_HUMAN EF-hand calcium-binding domain-containing protein 13 OS=Homo sapiens GN=EFCAB13 PE=2 SV=2 38

AIS Victim tr|Q580Q6|Q580Q6_HUMAN EGF-containing fibulin-like extracellular matrix protein 1 (Fragment) OS=Homo sapiens GN=EFEMP1 PE=1 SV=1 40 ICH Control sp|Q8IUD2|RB6I2_HUMAN ELKS/Rab6-interacting/CAST family member 1 OS=Homo sapiens GN=ERC1 PE=1 SV=1 40 ICH Victim tr|A0A0C4DGE7|A0A0C4DGE7_HUMAN Ellis van Creveld syndrome 2 (Limbin), isoform CRA_c OS=Homo sapiens GN=EVC2 PE=1 SV=1 37 ICH Control sp|P49411|EFTU_HUMAN Elongation factor Tu, mitochondrial OS=Homo sapiens GN=TUFM PE=1 SV=2 46

AIS Victim tr|A0A0C4DGF0|A0A0C4DGF0_HUMAN Endoplasmic reticulum metallopeptidase 1 OS=Homo sapiens GN=ERMP1 PE=1 SV=1 38 ICH Victim sp|Q8IYW4|ENTD1_HUMAN ENTH domain-containing protein 1 OS=Homo sapiens GN=ENTHD1 PE=2 SV=1 38 ICH Victim sp|Q99645|EPYC_HUMAN Epiphycan OS=Homo sapiens GN=EPYC PE=2 SV=3 43 AIS Victim tr|H0YAH6|H0YAH6_HUMAN Epithelial discoidin domain-containing receptor 1 (Fragment) OS=Homo sapiens GN=DDR1 PE=1 SV=1 39

ICH Control tr|H0YAH6|H0YAH6_HUMAN Epithelial discoidin domain-containing receptor 1 (Fragment) OS=Homo sapiens GN=DDR1 PE=1 SV=1 38 AIS Control tr|E7EUU4|E7EUU4_HUMAN Eukaryotic translation initiation factor 4 gamma 1 OS=Homo sapiens GN=EIF4G1 PE=1 SV=1 37 AIS Control sp|P08294|SODE_HUMAN Extracellular superoxide dismutase [Cu-Zn] OS=Homo sapiens GN=SOD3 PE=1 SV=2 192

ICH Victim sp|P08294|SODE_HUMAN Extracellular superoxide dismutase [Cu-Zn] OS=Homo sapiens GN=SOD3 PE=1 SV=2 103

AIS Victim sp|Q9Y2M0|FAN1_HUMAN Fanconi-associated nuclease 1 OS=Homo sapiens GN=FAN1 PE=1 SV=4 36 AIS Victim tr|M0R0I5|M0R0I5_HUMAN Far upstream element-binding protein 2 (Fragment) OS=Homo sapiens GN=KHSRP PE=1 SV=1 43 ICH Control tr|M0R0I5|M0R0I5_HUMAN Far upstream element-binding protein 2 (Fragment) OS=Homo sapiens GN=KHSRP PE=1 SV=1 41 ICH Victim tr|A0A087WTP3|A0A087WTP3_HUMAN Far upstream element-binding protein 2 OS=Homo sapiens GN=KHSRP PE=1 SV=1 40

ICH Control tr|H0YAE2|H0YAE2_HUMAN F-BAR domain only protein 2 (Fragment) OS=Homo sapiens GN=FCHO2 PE=1 SV=6 46 ICH Control tr|H7C3M7|H7C3M7_HUMAN FERM, RhoGEF and pleckstrin domain-containing protein 2 (Fragment) OS=Homo sapiens GN=FARP2 PE=1 SV=2 37 ICH Victim sp|P02792|FRIL_HUMAN Ferritin light chain OS=Homo sapiens GN=FTL PE=1 SV=2 122 AIS Control tr|F8WAW1|F8WAW1_HUMAN Fetuin-B OS=Homo sapiens GN=FETUB PE=1 SV=1 59

AIS Victim sp|Q9UGM5|FETUB_HUMAN Fetuin-B OS=Homo sapiens GN=FETUB PE=1 SV=2 301 ICH Control sp|Q9UGM5|FETUB_HUMAN Fetuin-B OS=Homo sapiens GN=FETUB PE=1 SV=2 262

108

AIS Victim tr|A0A087WUA0|A0A087WUA0_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=1 36 ICH Control tr|A0A087WUA0|A0A087WUA0_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=1 3838 ICH Victim tr|A0A087WUA0|A0A087WUA0_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=1 1219 AIS Control sp|P02671|FIBA_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 1555

AIS Victim sp|P02675|FIBB_HUMAN Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 39 ICH Control sp|P02675|FIBB_HUMAN Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 1112 ICH Victim sp|P02675|FIBB_HUMAN Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 1720

AIS Control tr|C9JPQ9|C9JPQ9_HUMAN Fibrinogen gamma chain (Fragment) OS=Homo sapiens GN=FGG PE=1 SV=1 461

AIS Victim tr|C9JPQ9|C9JPQ9_HUMAN Fibrinogen gamma chain (Fragment) OS=Homo sapiens GN=FGG PE=1 SV=1 838 ICH Control tr|C9JPQ9|C9JPQ9_HUMAN Fibrinogen gamma chain (Fragment) OS=Homo sapiens GN=FGG PE=1 SV=1 582 ICH Victim tr|C9JPQ9|C9JPQ9_HUMAN Fibrinogen gamma chain (Fragment) OS=Homo sapiens GN=FGG PE=1 SV=1 847 AIS Control tr|C9JC84|C9JC84_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=1 1438

AIS Victim tr|C9JC84|C9JC84_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=1 61 ICH Control tr|C9JC84|C9JC84_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=1 1496 ICH Victim tr|C9JC84|C9JC84_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=1 120 ICH Victim sp|P08F94|PKHD1_HUMAN Fibrocystin OS=Homo sapiens GN=PKHD1 PE=1 SV=1 40

AIS Victim tr|H0Y4K8|H0Y4K8_HUMAN Fibronectin (Fragment) OS=Homo sapiens GN=FN1 PE=1 SV=1 753 ICH Victim sp|Q8NA03|FSIP1_HUMAN Fibrous sheath-interacting protein 1 OS=Homo sapiens GN=FSIP1 PE=2 SV=1 44 AIS Victim tr|B1AHM9|B1AHM9_HUMAN Fibulin-1 (Fragment) OS=Homo sapiens GN=FBLN1 PE=1 SV=1 85 ICH Control tr|B1AHM7|B1AHM7_HUMAN Fibulin-1 (Fragment) OS=Homo sapiens GN=FBLN1 PE=1 SV=1 40

ICH Control tr|B1AHL2|B1AHL2_HUMAN Fibulin-1 OS=Homo sapiens GN=FBLN1 PE=1 SV=1 165

ICH Control sp|P09958|FURIN_HUMAN Furin OS=Homo sapiens GN=FURIN PE=1 SV=2 36 AIS Control tr|A0A0A0MRK1|A0A0A0MRK1_HUMAN G patch domain-containing protein 4 OS=Homo sapiens GN=GPATCH4 PE=1 SV=1 42 ICH Victim sp|Q9UKJ3|GPTC8_HUMAN G patch domain-containing protein 8 OS=Homo sapiens GN=GPATCH8 PE=1 SV=2 43 AIS Control sp|P48549|KCNJ3_HUMAN G protein-activated inward rectifier potassium channel 1 OS=Homo sapiens GN=KCNJ3 PE=1 SV=1 51

AIS Victim sp|P48549|KCNJ3_HUMAN G protein-activated inward rectifier potassium channel 1 OS=Homo sapiens GN=KCNJ3 PE=1 SV=1 37 ICH Victim sp|P48549|KCNJ3_HUMAN G protein-activated inward rectifier potassium channel 1 OS=Homo sapiens GN=KCNJ3 PE=1 SV=1 45 AIS Control sp|Q08380|LG3BP_HUMAN Galectin-3-binding protein OS=Homo sapiens GN=LGALS3BP PE=1 SV=1 249

AIS Victim sp|Q08380|LG3BP_HUMAN Galectin-3-binding protein OS=Homo sapiens GN=LGALS3BP PE=1 SV=1 52

ICH Control sp|Q08380|LG3BP_HUMAN Galectin-3-binding protein OS=Homo sapiens GN=LGALS3BP PE=1 SV=1 188 ICH Victim sp|Q08380|LG3BP_HUMAN Galectin-3-binding protein OS=Homo sapiens GN=LGALS3BP PE=1 SV=1 526 AIS Control tr|A0A0A0MS51|A0A0A0MS51_HUMAN Gelsolin OS=Homo sapiens GN=GSN PE=1 SV=1 426 AIS Victim tr|A0A0A0MS51|A0A0A0MS51_HUMAN Gelsolin OS=Homo sapiens GN=GSN PE=1 SV=1 117

ICH Control tr|A0A087X1J7|A0A087X1J7_HUMAN Glutathione peroxidase OS=Homo sapiens GN=GPX3 PE=1 SV=1 181 ICH Victim tr|A0A087X1J7|A0A087X1J7_HUMAN Glutathione peroxidase OS=Homo sapiens GN=GPX3 PE=1 SV=1 36

109

AIS Victim sp|O14556|G3PT_HUMAN Glyceraldehyde-3-phosphate dehydrogenase, testis-specific OS=Homo sapiens GN=GAPDHS PE=1 SV=2 62 ICH Control sp|O14556|G3PT_HUMAN Glyceraldehyde-3-phosphate dehydrogenase, testis-specific OS=Homo sapiens GN=GAPDHS PE=1 SV=2 42 ICH Victim sp|O14556|G3PT_HUMAN Glyceraldehyde-3-phosphate dehydrogenase, testis-specific OS=Homo sapiens GN=GAPDHS PE=1 SV=2 60 AIS Control tr|A0A0C4DGZ8|A0A0C4DGZ8_HUMAN Glycoprotein Ib (Platelet), alpha polypeptide OS=Homo sapiens GN=GP1BA PE=1 SV=1 36

AIS Victim tr|A0A0C4DGZ8|A0A0C4DGZ8_HUMAN Glycoprotein Ib (Platelet), alpha polypeptide OS=Homo sapiens GN=GP1BA PE=1 SV=1 48 ICH Control tr|A0A0C4DGZ8|A0A0C4DGZ8_HUMAN Glycoprotein Ib (Platelet), alpha polypeptide OS=Homo sapiens GN=GP1BA PE=1 SV=1 50 ICH Victim tr|A0A0C4DGZ8|A0A0C4DGZ8_HUMAN Glycoprotein Ib (Platelet), alpha polypeptide OS=Homo sapiens GN=GP1BA PE=1 SV=1 46 ICH Control tr|A0A087WYX5|A0A087WYX5_HUMAN Golgi SNAP receptor complex member 1 OS=Homo sapiens GN=GOSR1 PE=1 SV=1 41

AIS Victim tr|H0Y6I0|H0Y6I0_HUMAN Golgin subfamily A member 4 (Fragment) OS=Homo sapiens GN=GOLGA4 PE=1 SV=1 36 AIS Victim sp|Q8IWJ2|GCC2_HUMAN GRIP and coiled-coil domain-containing protein 2 OS=Homo sapiens GN=GCC2 PE=1 SV=4 39 ICH Control sp|Q9NY12|GAR1_HUMAN H/ACA ribonucleoprotein complex subunit 1 OS=Homo sapiens GN=GAR1 PE=1 SV=1 37 ICH Victim sp|Q9NY12|GAR1_HUMAN H/ACA ribonucleoprotein complex subunit 1 OS=Homo sapiens GN=GAR1 PE=1 SV=1 47

ICH Victim tr|J3KSV1|J3KSV1_HUMAN Haptoglobin (Fragment) OS=Homo sapiens GN=HP PE=1 SV=1 470

AIS Control tr|J3KTC3|J3KTC3_HUMAN Haptoglobin-related protein OS=Homo sapiens GN=HPR PE=1 SV=1 369 AIS Victim tr|J3KTC3|J3KTC3_HUMAN Haptoglobin-related protein OS=Homo sapiens GN=HPR PE=1 SV=1 169 ICH Control tr|J3KTC3|J3KTC3_HUMAN Haptoglobin-related protein OS=Homo sapiens GN=HPR PE=1 SV=1 254 ICH Victim tr|J3KTC3|J3KTC3_HUMAN Haptoglobin-related protein OS=Homo sapiens GN=HPR PE=1 SV=1 49

AIS Victim sp|P00739|HPTR_HUMAN Haptoglobin-related protein OS=Homo sapiens GN=HPR PE=2 SV=2 4238 ICH Control sp|P00739|HPTR_HUMAN Haptoglobin-related protein OS=Homo sapiens GN=HPR PE=2 SV=2 4784 AIS Victim tr|G3V1N2|G3V1N2_HUMAN HCG1745306, isoform CRA_a OS=Homo sapiens GN=HBA2 PE=1 SV=1 178 ICH Victim tr|G3V1N2|G3V1N2_HUMAN HCG1745306, isoform CRA_a OS=Homo sapiens GN=HBA2 PE=1 SV=1 466

AIS Victim tr|A0A0B4J2G9|A0A0B4J2G9_HUMAN HCG1789329, isoform CRA_a OS=Homo sapiens GN=hCG_1789329 PE=3 SV=1 39 AIS Control tr|Q5TEH5|Q5TEH5_HUMAN HCG2029799, isoform CRA_b OS=Homo sapiens GN=PLG PE=1 SV=1 39 AIS Victim tr|Q5TEH5|Q5TEH5_HUMAN HCG2029799, isoform CRA_b OS=Homo sapiens GN=PLG PE=1 SV=1 118

ICH Control tr|Q5TEH5|Q5TEH5_HUMAN HCG2029799, isoform CRA_b OS=Homo sapiens GN=PLG PE=1 SV=1 96

ICH Victim tr|Q5TEH5|Q5TEH5_HUMAN HCG2029799, isoform CRA_b OS=Homo sapiens GN=PLG PE=1 SV=1 79 AIS Control tr|A0A075B6K4|A0A075B6K4_HUMAN HCG2043238 (Fragment) OS=Homo sapiens GN=IGLV3-10 PE=1 SV=1 52 ICH Control tr|A0A075B6K4|A0A075B6K4_HUMAN HCG2043238 (Fragment) OS=Homo sapiens GN=IGLV3-10 PE=1 SV=1 39 ICH Victim sp|P08238|HS90B_HUMAN Heat shock protein HSP 90-beta OS=Homo sapiens GN=HSP90AB1 PE=1 SV=4 39

ICH Victim sp|P25092|GUC2C_HUMAN Heat-stable enterotoxin receptor OS=Homo sapiens GN=GUCY2C PE=1 SV=2 43 AIS Victim sp|P69905|HBA_HUMAN Hemoglobin subunit alpha OS=Homo sapiens GN=HBA1 PE=1 SV=2 42 ICH Victim sp|P69905|HBA_HUMAN Hemoglobin subunit alpha OS=Homo sapiens GN=HBA1 PE=1 SV=2 52 AIS Victim tr|E9PEW8|E9PEW8_HUMAN Hemoglobin subunit delta (Fragment) OS=Homo sapiens GN=HBD PE=1 SV=1 238

ICH Control tr|E9PEW8|E9PEW8_HUMAN Hemoglobin subunit delta (Fragment) OS=Homo sapiens GN=HBD PE=1 SV=1 318 ICH Victim tr|E9PEW8|E9PEW8_HUMAN Hemoglobin subunit delta (Fragment) OS=Homo sapiens GN=HBD PE=1 SV=1 331 AIS Control tr|E9PFT6|E9PFT6_HUMAN Hemoglobin subunit delta OS=Homo sapiens GN=HBD PE=1 SV=1 45 AIS Control sp|P02042|HBD_HUMAN Hemoglobin subunit delta OS=Homo sapiens GN=HBD PE=1 SV=2 192

AIS Victim sp|P02042|HBD_HUMAN Hemoglobin subunit delta OS=Homo sapiens GN=HBD PE=1 SV=2 141 ICH Control sp|P02042|HBD_HUMAN Hemoglobin subunit delta OS=Homo sapiens GN=HBD PE=1 SV=2 212 ICH Victim sp|P02042|HBD_HUMAN Hemoglobin subunit delta OS=Homo sapiens GN=HBD PE=1 SV=2 464

AIS Control tr|A8MUF7|A8MUF7_HUMAN Hemoglobin subunit epsilon (Fragment) OS=Homo sapiens GN=HBE1 PE=1 SV=1 132

ICH Control tr|A8MUF7|A8MUF7_HUMAN Hemoglobin subunit epsilon (Fragment) OS=Homo sapiens GN=HBE1 PE=1 SV=1 73 AIS Victim sp|P02100|HBE_HUMAN Hemoglobin subunit epsilon OS=Homo sapiens GN=HBE1 PE=1 SV=2 160 ICH Control sp|P02100|HBE_HUMAN Hemoglobin subunit epsilon OS=Homo sapiens GN=HBE1 PE=1 SV=2 76 AIS Control sp|P69891|HBG1_HUMAN Hemoglobin subunit gamma-1 OS=Homo sapiens GN=HBG1 PE=1 SV=2 45

AIS Victim sp|P69891|HBG1_HUMAN Hemoglobin subunit gamma-1 OS=Homo sapiens GN=HBG1 PE=1 SV=2 160 ICH Victim sp|P69891|HBG1_HUMAN Hemoglobin subunit gamma-1 OS=Homo sapiens GN=HBG1 PE=1 SV=2 95 AIS Control tr|E9PBW4|E9PBW4_HUMAN Hemoglobin subunit gamma-2 OS=Homo sapiens GN=HBG2 PE=1 SV=1 36 AIS Victim tr|E9PBW4|E9PBW4_HUMAN Hemoglobin subunit gamma-2 OS=Homo sapiens GN=HBG2 PE=1 SV=1 68

ICH Control tr|E9PBW4|E9PBW4_HUMAN Hemoglobin subunit gamma-2 OS=Homo sapiens GN=HBG2 PE=1 SV=1 81 ICH Victim tr|E9PBW4|E9PBW4_HUMAN Hemoglobin subunit gamma-2 OS=Homo sapiens GN=HBG2 PE=1 SV=1 48

110

ICH Victim sp|P02008|HBAZ_HUMAN Hemoglobin subunit zeta OS=Homo sapiens GN=HBZ PE=1 SV=2 41 AIS Control sp|P02790|HEMO_HUMAN Hemopexin OS=Homo sapiens GN=HPX PE=1 SV=2 128 AIS Victim sp|P02790|HEMO_HUMAN Hemopexin OS=Homo sapiens GN=HPX PE=1 SV=2 1087 ICH Control sp|P02790|HEMO_HUMAN Hemopexin OS=Homo sapiens GN=HPX PE=1 SV=2 415

ICH Victim sp|P02790|HEMO_HUMAN Hemopexin OS=Homo sapiens GN=HPX PE=1 SV=2 996 AIS Control sp|P05546|HEP2_HUMAN Heparin cofactor 2 OS=Homo sapiens GN=SERPIND1 PE=1 SV=3 115 AIS Victim sp|P05546|HEP2_HUMAN Heparin cofactor 2 OS=Homo sapiens GN=SERPIND1 PE=1 SV=3 153 ICH Control sp|P05546|HEP2_HUMAN Heparin cofactor 2 OS=Homo sapiens GN=SERPIND1 PE=1 SV=3 59

ICH Victim sp|P05546|HEP2_HUMAN Heparin cofactor 2 OS=Homo sapiens GN=SERPIND1 PE=1 SV=3 80 AIS Control tr|D6RAR4|D6RAR4_HUMAN Hepatocyte growth factor activator OS=Homo sapiens GN=HGFAC PE=1 SV=1 70 AIS Victim tr|D6RAR4|D6RAR4_HUMAN Hepatocyte growth factor activator OS=Homo sapiens GN=HGFAC PE=1 SV=1 88 ICH Control tr|D6RAR4|D6RAR4_HUMAN Hepatocyte growth factor activator OS=Homo sapiens GN=HGFAC PE=1 SV=1 41

ICH Victim tr|D6RAR4|D6RAR4_HUMAN Hepatocyte growth factor activator OS=Homo sapiens GN=HGFAC PE=1 SV=1 107 AIS Control tr|G3XAK1|G3XAK1_HUMAN Hepatocyte growth factor-like protein OS=Homo sapiens GN=MST1 PE=1 SV=1 58 AIS Victim tr|G3XAK1|G3XAK1_HUMAN Hepatocyte growth factor-like protein OS=Homo sapiens GN=MST1 PE=1 SV=1 109

ICH Control tr|G3XAK1|G3XAK1_HUMAN Hepatocyte growth factor-like protein OS=Homo sapiens GN=MST1 PE=1 SV=1 101

ICH Victim tr|G3XAK1|G3XAK1_HUMAN Hepatocyte growth factor-like protein OS=Homo sapiens GN=MST1 PE=1 SV=1 50 AIS Victim sp|O95568|MET18_HUMAN Histidine protein methyltransferase 1 homolog OS=Homo sapiens GN=METTL18 PE=1 SV=1 49 ICH Control sp|O95568|MET18_HUMAN Histidine protein methyltransferase 1 homolog OS=Homo sapiens GN=METTL18 PE=1 SV=1 36 ICH Victim sp|O95568|MET18_HUMAN Histidine protein methyltransferase 1 homolog OS=Homo sapiens GN=METTL18 PE=1 SV=1 66

AIS Control sp|P04196|HRG_HUMAN Histidine-rich glycoprotein OS=Homo sapiens GN=HRG PE=1 SV=1 140 AIS Victim sp|P04196|HRG_HUMAN Histidine-rich glycoprotein OS=Homo sapiens GN=HRG PE=1 SV=1 699 ICH Control sp|P04196|HRG_HUMAN Histidine-rich glycoprotein OS=Homo sapiens GN=HRG PE=1 SV=1 61 ICH Victim sp|P04196|HRG_HUMAN Histidine-rich glycoprotein OS=Homo sapiens GN=HRG PE=1 SV=1 283

ICH Control sp|P57053|H2BFS_HUMAN Histone H2B type F-S OS=Homo sapiens GN=H2BFS PE=1 SV=2 108 ICH Control sp|P62805|H4_HUMAN Histone H4 OS=Homo sapiens GN=HIST1H4A PE=1 SV=2 94 ICH Victim sp|P05534|1A24_HUMAN HLA class I histocompatibility antigen, A-24 alpha chain OS=Homo sapiens GN=HLA-A PE=1 SV=2 41 ICH Victim tr|A0A0G2JNF2|A0A0G2JNF2_HUMAN HLA class I histocompatibility antigen, alpha chain F OS=Homo sapiens GN=HLA-F PE=4 SV=1 43

ICH Victim tr|A0A0G2JPQ3|A0A0G2JPQ3_HUMAN HLA class I histocompatibility antigen, alpha chain G OS=Homo sapiens GN=HLA-G PE=4 SV=1 43 ICH Victim sp|P10319|1B58_HUMAN HLA class I histocompatibility antigen, B-58 alpha chain OS=Homo sapiens GN=HLA-B PE=1 SV=1 43 AIS Control tr|H0YHX3|H0YHX3_HUMAN Homeobox protein Hox-A4 (Fragment) OS=Homo sapiens GN=HOXA4 PE=3 SV=1 54

AIS Victim tr|H0YHX3|H0YHX3_HUMAN Homeobox protein Hox-A4 (Fragment) OS=Homo sapiens GN=HOXA4 PE=3 SV=1 43

ICH Control tr|H0YHX3|H0YHX3_HUMAN Homeobox protein Hox-A4 (Fragment) OS=Homo sapiens GN=HOXA4 PE=3 SV=1 44 AIS Victim sp|Q00056|HXA4_HUMAN Homeobox protein Hox-A4 OS=Homo sapiens GN=HOXA4 PE=2 SV=3 42 ICH Victim sp|P09017|HXC4_HUMAN Homeobox protein Hox-C4 OS=Homo sapiens GN=HOXC4 PE=1 SV=2 44 ICH Victim sp|Q9GZZ0|HXD1_HUMAN Homeobox protein Hox-D1 OS=Homo sapiens GN=HOXD1 PE=2 SV=1 42

ICH Control sp|P09016|HXD4_HUMAN Homeobox protein Hox-D4 OS=Homo sapiens GN=HOXD4 PE=2 SV=3 43 AIS Victim tr|Q9BS19|Q9BS19_HUMAN HPX protein OS=Homo sapiens GN=HPX PE=1 SV=1 75 AIS Control sp|P01876|IGHA1_HUMAN Ig alpha-1 chain C region OS=Homo sapiens GN=IGHA1 PE=1 SV=2 1402 AIS Victim sp|P01876|IGHA1_HUMAN Ig alpha-1 chain C region OS=Homo sapiens GN=IGHA1 PE=1 SV=2 112

ICH Control sp|P01876|IGHA1_HUMAN Ig alpha-1 chain C region OS=Homo sapiens GN=IGHA1 PE=1 SV=2 459 ICH Victim sp|P01876|IGHA1_HUMAN Ig alpha-1 chain C region OS=Homo sapiens GN=IGHA1 PE=1 SV=2 1313 AIS Victim tr|A0A075B6N7|A0A075B6N7_HUMAN Ig alpha-2 chain C region (Fragment) OS=Homo sapiens GN=IGHA2 PE=1 SV=1 52 ICH Victim tr|A0A075B6N7|A0A075B6N7_HUMAN Ig alpha-2 chain C region (Fragment) OS=Homo sapiens GN=IGHA2 PE=1 SV=1 352

AIS Victim tr|A0A0A0MS09|A0A0A0MS09_HUMAN Ig delta chain C region (Fragment) OS=Homo sapiens GN=IGHD PE=1 SV=1 37 ICH Control tr|A0A0A0MS09|A0A0A0MS09_HUMAN Ig delta chain C region (Fragment) OS=Homo sapiens GN=IGHD PE=1 SV=1 93 ICH Victim tr|A0A0A0MS09|A0A0A0MS09_HUMAN Ig delta chain C region (Fragment) OS=Homo sapiens GN=IGHD PE=1 SV=1 141

AIS Victim tr|A0A087WUS7|A0A087WUS7_HUMAN Ig delta chain C region OS=Homo sapiens GN=IGHD PE=1 SV=1 98

ICH Control tr|A0A087WUS7|A0A087WUS7_HUMAN Ig delta chain C region OS=Homo sapiens GN=IGHD PE=1 SV=1 58 ICH Victim tr|A0A087WUS7|A0A087WUS7_HUMAN Ig delta chain C region OS=Homo sapiens GN=IGHD PE=1 SV=1 93 AIS Control tr|A0A0A0MS08|A0A0A0MS08_HUMAN Ig gamma-1 chain C region (Fragment) OS=Homo sapiens GN=IGHG1 PE=1 SV=1 130 ICH Control tr|A0A0A0MS08|A0A0A0MS08_HUMAN Ig gamma-1 chain C region (Fragment) OS=Homo sapiens GN=IGHG1 PE=1 SV=1 158

AIS Control tr|A0A087WYC5|A0A087WYC5_HUMAN Ig gamma-1 chain C region OS=Homo sapiens GN=IGHG1 PE=1 SV=1 175 AIS Victim tr|A0A087WV47|A0A087WV47_HUMAN Ig gamma-1 chain C region OS=Homo sapiens GN=IGHG1 PE=1 SV=1 63 ICH Control tr|A0A087WYC5|A0A087WYC5_HUMAN Ig gamma-1 chain C region OS=Homo sapiens GN=IGHG1 PE=1 SV=1 69 ICH Victim tr|A0A087WV47|A0A087WV47_HUMAN Ig gamma-1 chain C region OS=Homo sapiens GN=IGHG1 PE=1 SV=1 145

AIS Control tr|A0A075B6N8|A0A075B6N8_HUMAN Ig gamma-3 chain C region (Fragment) OS=Homo sapiens GN=IGHG3 PE=1 SV=1 308 AIS Victim tr|A0A075B6N8|A0A075B6N8_HUMAN Ig gamma-3 chain C region (Fragment) OS=Homo sapiens GN=IGHG3 PE=1 SV=1 207

111

ICH Victim tr|A0A075B6N8|A0A075B6N8_HUMAN Ig gamma-3 chain C region (Fragment) OS=Homo sapiens GN=IGHG3 PE=1 SV=1 386 AIS Control tr|A0A087WXL8|A0A087WXL8_HUMAN Ig gamma-3 chain C region OS=Homo sapiens GN=IGHG3 PE=1 SV=1 480 AIS Victim tr|A0A087WXL8|A0A087WXL8_HUMAN Ig gamma-3 chain C region OS=Homo sapiens GN=IGHG3 PE=1 SV=1 65 ICH Control tr|A0A087WXL8|A0A087WXL8_HUMAN Ig gamma-3 chain C region OS=Homo sapiens GN=IGHG3 PE=1 SV=1 1641

ICH Victim tr|A0A087WXL8|A0A087WXL8_HUMAN Ig gamma-3 chain C region OS=Homo sapiens GN=IGHG3 PE=1 SV=1 675 ICH Victim sp|P01602|KV110_HUMAN Ig heavy chain V-I region 5 (Fragment) OS=Homo sapiens GN=IGKV1-5 PE=4 SV=2 36 AIS Control sp|P23083|HV103_HUMAN Ig heavy chain V-I region V35 OS=Homo sapiens PE=1 SV=1 50 AIS Victim sp|P23083|HV103_HUMAN Ig heavy chain V-I region V35 OS=Homo sapiens PE=1 SV=1 71

ICH Control sp|P23083|HV103_HUMAN Ig heavy chain V-I region V35 OS=Homo sapiens PE=1 SV=1 64 ICH Victim sp|P23083|HV103_HUMAN Ig heavy chain V-I region V35 OS=Homo sapiens PE=1 SV=1 52 AIS Control sp|P06331|HV209_HUMAN Ig heavy chain V-II region ARH-77 OS=Homo sapiens PE=4 SV=1 44 AIS Victim sp|P06331|HV209_HUMAN Ig heavy chain V-II region ARH-77 OS=Homo sapiens PE=4 SV=1 44

ICH Control sp|P06331|HV209_HUMAN Ig heavy chain V-II region ARH-77 OS=Homo sapiens PE=4 SV=1 127 ICH Victim sp|P06331|HV209_HUMAN Ig heavy chain V-II region ARH-77 OS=Homo sapiens PE=4 SV=1 222 ICH Victim sp|P01825|HV207_HUMAN Ig heavy chain V-II region NEWM OS=Homo sapiens PE=1 SV=1 111

ICH Control sp|P04438|HV208_HUMAN Ig heavy chain V-II region SESS OS=Homo sapiens PE=2 SV=1 43

AIS Control sp|P01824|HV206_HUMAN Ig heavy chain V-II region WAH OS=Homo sapiens PE=1 SV=1 55 AIS Victim sp|P01824|HV206_HUMAN Ig heavy chain V-II region WAH OS=Homo sapiens PE=1 SV=1 104 ICH Control sp|P01824|HV206_HUMAN Ig heavy chain V-II region WAH OS=Homo sapiens PE=1 SV=1 66 ICH Victim sp|P01824|HV206_HUMAN Ig heavy chain V-II region WAH OS=Homo sapiens PE=1 SV=1 66

AIS Control sp|P01766|HV305_HUMAN Ig heavy chain V-III region BRO OS=Homo sapiens PE=1 SV=1 182 AIS Victim sp|P01766|HV305_HUMAN Ig heavy chain V-III region BRO OS=Homo sapiens PE=1 SV=1 62 ICH Control sp|P01766|HV305_HUMAN Ig heavy chain V-III region BRO OS=Homo sapiens PE=1 SV=1 202 ICH Victim sp|P01766|HV305_HUMAN Ig heavy chain V-III region BRO OS=Homo sapiens PE=1 SV=1 88

ICH Control sp|P01767|HV306_HUMAN Ig heavy chain V-III region BUT OS=Homo sapiens PE=1 SV=1 75 AIS Control sp|P01768|HV307_HUMAN Ig heavy chain V-III region CAM OS=Homo sapiens PE=1 SV=1 82 AIS Victim sp|P01768|HV307_HUMAN Ig heavy chain V-III region CAM OS=Homo sapiens PE=1 SV=1 40 ICH Control sp|P01768|HV307_HUMAN Ig heavy chain V-III region CAM OS=Homo sapiens PE=1 SV=1 72

ICH Victim sp|P01768|HV307_HUMAN Ig heavy chain V-III region CAM OS=Homo sapiens PE=1 SV=1 79 ICH Control sp|P01781|HV320_HUMAN Ig heavy chain V-III region GAL OS=Homo sapiens PE=1 SV=1 35 AIS Control sp|P01771|HV310_HUMAN Ig heavy chain V-III region HIL OS=Homo sapiens PE=1 SV=1 37

AIS Victim sp|P01771|HV310_HUMAN Ig heavy chain V-III region HIL OS=Homo sapiens PE=1 SV=1 37

ICH Control sp|P01771|HV310_HUMAN Ig heavy chain V-III region HIL OS=Homo sapiens PE=1 SV=1 42 ICH Victim sp|P01771|HV310_HUMAN Ig heavy chain V-III region HIL OS=Homo sapiens PE=1 SV=1 51 ICH Control sp|P01780|HV319_HUMAN Ig heavy chain V-III region JON OS=Homo sapiens PE=1 SV=1 44 ICH Victim sp|P01780|HV319_HUMAN Ig heavy chain V-III region JON OS=Homo sapiens PE=1 SV=1 38

ICH Victim sp|P01774|HV313_HUMAN Ig heavy chain V-III region POM OS=Homo sapiens PE=1 SV=1 92 AIS Control sp|P01777|HV316_HUMAN Ig heavy chain V-III region TEI OS=Homo sapiens PE=1 SV=1 144 AIS Victim sp|P01777|HV316_HUMAN Ig heavy chain V-III region TEI OS=Homo sapiens PE=1 SV=1 62 ICH Control sp|P01777|HV316_HUMAN Ig heavy chain V-III region TEI OS=Homo sapiens PE=1 SV=1 159

ICH Victim sp|P01777|HV316_HUMAN Ig heavy chain V-III region TEI OS=Homo sapiens PE=1 SV=1 228 AIS Control sp|P01765|HV304_HUMAN Ig heavy chain V-III region TIL OS=Homo sapiens PE=1 SV=1 146 AIS Victim sp|P01765|HV304_HUMAN Ig heavy chain V-III region TIL OS=Homo sapiens PE=1 SV=1 166 ICH Control sp|P01765|HV304_HUMAN Ig heavy chain V-III region TIL OS=Homo sapiens PE=1 SV=1 159

ICH Victim sp|P01765|HV304_HUMAN Ig heavy chain V-III region TIL OS=Homo sapiens PE=1 SV=1 115 AIS Victim sp|P01779|HV318_HUMAN Ig heavy chain V-III region TUR OS=Homo sapiens PE=1 SV=1 133 ICH Control sp|P01779|HV318_HUMAN Ig heavy chain V-III region TUR OS=Homo sapiens PE=1 SV=1 136

ICH Victim sp|P01779|HV318_HUMAN Ig heavy chain V-III region TUR OS=Homo sapiens PE=1 SV=1 92

AIS Control sp|P01763|HV302_HUMAN Ig heavy chain V-III region WEA OS=Homo sapiens PE=1 SV=1 59 AIS Victim sp|P01763|HV302_HUMAN Ig heavy chain V-III region WEA OS=Homo sapiens PE=1 SV=1 86 ICH Control sp|P01763|HV302_HUMAN Ig heavy chain V-III region WEA OS=Homo sapiens PE=1 SV=1 70 ICH Victim sp|P01763|HV302_HUMAN Ig heavy chain V-III region WEA OS=Homo sapiens PE=1 SV=1 93

AIS Control tr|A0A075B6H6|A0A075B6H6_HUMAN Ig kappa chain C region (Fragment) OS=Homo sapiens GN=IGKC PE=1 SV=1 859 AIS Victim tr|A0A075B6H6|A0A075B6H6_HUMAN Ig kappa chain C region (Fragment) OS=Homo sapiens GN=IGKC PE=1 SV=1 3541 ICH Control tr|A0A075B6H6|A0A075B6H6_HUMAN Ig kappa chain C region (Fragment) OS=Homo sapiens GN=IGKC PE=1 SV=1 1131 ICH Victim tr|A0A075B6H6|A0A075B6H6_HUMAN Ig kappa chain C region (Fragment) OS=Homo sapiens GN=IGKC PE=1 SV=1 69

AIS Control tr|A0A087WTX5|A0A087WTX5_HUMAN Ig kappa chain C region OS=Homo sapiens GN=IGKC PE=1 SV=1 1069 AIS Victim tr|A0A087WTX5|A0A087WTX5_HUMAN Ig kappa chain C region OS=Homo sapiens GN=IGKC PE=1 SV=1 297

112

ICH Control tr|A0A087WTX5|A0A087WTX5_HUMAN Ig kappa chain C region OS=Homo sapiens GN=IGKC PE=1 SV=1 190 ICH Victim tr|A0A087WTX5|A0A087WTX5_HUMAN Ig kappa chain C region OS=Homo sapiens GN=IGKC PE=1 SV=1 394 AIS Control sp|P01593|KV101_HUMAN Ig kappa chain V-I region AG OS=Homo sapiens PE=1 SV=1 150 AIS Victim sp|P01593|KV101_HUMAN Ig kappa chain V-I region AG OS=Homo sapiens PE=1 SV=1 397

ICH Control sp|P01593|KV101_HUMAN Ig kappa chain V-I region AG OS=Homo sapiens PE=1 SV=1 196 ICH Victim sp|P01593|KV101_HUMAN Ig kappa chain V-I region AG OS=Homo sapiens PE=1 SV=1 169 AIS Victim sp|P01594|KV102_HUMAN Ig kappa chain V-I region AU OS=Homo sapiens PE=1 SV=1 105 ICH Control sp|P01594|KV102_HUMAN Ig kappa chain V-I region AU OS=Homo sapiens PE=1 SV=1 80

ICH Victim sp|P01594|KV102_HUMAN Ig kappa chain V-I region AU OS=Homo sapiens PE=1 SV=1 230 ICH Control sp|P04430|KV122_HUMAN Ig kappa chain V-I region BAN OS=Homo sapiens PE=1 SV=1 40 AIS Control sp|P01596|KV104_HUMAN Ig kappa chain V-I region CAR OS=Homo sapiens PE=1 SV=1 127 AIS Victim sp|P01596|KV104_HUMAN Ig kappa chain V-I region CAR OS=Homo sapiens PE=1 SV=1 55

ICH Control sp|P01596|KV104_HUMAN Ig kappa chain V-I region CAR OS=Homo sapiens PE=1 SV=1 241 ICH Victim sp|P01596|KV104_HUMAN Ig kappa chain V-I region CAR OS=Homo sapiens PE=1 SV=1 104 AIS Control sp|P01597|KV105_HUMAN Ig kappa chain V-I region DEE OS=Homo sapiens PE=1 SV=1 123

AIS Victim sp|P01597|KV105_HUMAN Ig kappa chain V-I region DEE OS=Homo sapiens PE=1 SV=1 201

ICH Control sp|P01597|KV105_HUMAN Ig kappa chain V-I region DEE OS=Homo sapiens PE=1 SV=1 70 ICH Victim sp|P01597|KV105_HUMAN Ig kappa chain V-I region DEE OS=Homo sapiens PE=1 SV=1 100 AIS Control sp|P01598|KV106_HUMAN Ig kappa chain V-I region EU OS=Homo sapiens PE=1 SV=1 35 AIS Victim sp|P01598|KV106_HUMAN Ig kappa chain V-I region EU OS=Homo sapiens PE=1 SV=1 66

ICH Control sp|P01598|KV106_HUMAN Ig kappa chain V-I region EU OS=Homo sapiens PE=1 SV=1 97 ICH Victim sp|P01598|KV106_HUMAN Ig kappa chain V-I region EU OS=Homo sapiens PE=1 SV=1 68 AIS Victim sp|P01599|KV107_HUMAN Ig kappa chain V-I region Gal OS=Homo sapiens PE=1 SV=1 361 ICH Control sp|P01599|KV107_HUMAN Ig kappa chain V-I region Gal OS=Homo sapiens PE=1 SV=1 327

ICH Victim sp|P01599|KV107_HUMAN Ig kappa chain V-I region Gal OS=Homo sapiens PE=1 SV=1 100 AIS Victim sp|P01600|KV108_HUMAN Ig kappa chain V-I region Hau OS=Homo sapiens PE=1 SV=1 201 ICH Control sp|P01600|KV108_HUMAN Ig kappa chain V-I region Hau OS=Homo sapiens PE=1 SV=1 106 AIS Control sp|P01604|KV112_HUMAN Ig kappa chain V-I region Kue OS=Homo sapiens PE=1 SV=1 55

AIS Victim sp|P01604|KV112_HUMAN Ig kappa chain V-I region Kue OS=Homo sapiens PE=1 SV=1 61 ICH Control sp|P01604|KV112_HUMAN Ig kappa chain V-I region Kue OS=Homo sapiens PE=1 SV=1 77 ICH Victim sp|P01604|KV112_HUMAN Ig kappa chain V-I region Kue OS=Homo sapiens PE=1 SV=1 40

ICH Control sp|P01605|KV113_HUMAN Ig kappa chain V-I region Lay OS=Homo sapiens PE=1 SV=1 43

ICH Control sp|P01612|KV120_HUMAN Ig kappa chain V-I region Mev OS=Homo sapiens PE=1 SV=1 111 AIS Victim sp|P01613|KV121_HUMAN Ig kappa chain V-I region Ni OS=Homo sapiens PE=1 SV=1 148 ICH Control sp|P01613|KV121_HUMAN Ig kappa chain V-I region Ni OS=Homo sapiens PE=1 SV=1 44 ICH Victim sp|P01613|KV121_HUMAN Ig kappa chain V-I region Ni OS=Homo sapiens PE=1 SV=1 118

AIS Victim sp|P01606|KV114_HUMAN Ig kappa chain V-I region OU OS=Homo sapiens PE=1 SV=1 189 ICH Control sp|P01606|KV114_HUMAN Ig kappa chain V-I region OU OS=Homo sapiens PE=1 SV=1 47 ICH Victim sp|P01606|KV114_HUMAN Ig kappa chain V-I region OU OS=Homo sapiens PE=1 SV=1 100 AIS Victim sp|P01607|KV115_HUMAN Ig kappa chain V-I region Rei OS=Homo sapiens PE=1 SV=1 201

ICH Control sp|P01607|KV115_HUMAN Ig kappa chain V-I region Rei OS=Homo sapiens PE=1 SV=1 80 ICH Victim sp|P01607|KV115_HUMAN Ig kappa chain V-I region Rei OS=Homo sapiens PE=1 SV=1 230 AIS Control sp|P01608|KV116_HUMAN Ig kappa chain V-I region Roy OS=Homo sapiens PE=1 SV=1 123 ICH Control sp|P01608|KV116_HUMAN Ig kappa chain V-I region Roy OS=Homo sapiens PE=1 SV=1 78

ICH Victim sp|P01608|KV116_HUMAN Ig kappa chain V-I region Roy OS=Homo sapiens PE=1 SV=1 141 AIS Victim sp|P01609|KV117_HUMAN Ig kappa chain V-I region Scw OS=Homo sapiens PE=1 SV=1 389 ICH Control sp|P01609|KV117_HUMAN Ig kappa chain V-I region Scw OS=Homo sapiens PE=1 SV=1 210

ICH Victim sp|P01609|KV117_HUMAN Ig kappa chain V-I region Scw OS=Homo sapiens PE=1 SV=1 164

ICH Victim sp|P80362|KV125_HUMAN Ig kappa chain V-I region WAT OS=Homo sapiens PE=1 SV=1 219 AIS Control sp|P01610|KV118_HUMAN Ig kappa chain V-I region WEA OS=Homo sapiens PE=1 SV=1 129 AIS Victim sp|P01610|KV118_HUMAN Ig kappa chain V-I region WEA OS=Homo sapiens PE=1 SV=1 228 ICH Control sp|P01610|KV118_HUMAN Ig kappa chain V-I region WEA OS=Homo sapiens PE=1 SV=1 210

ICH Victim sp|P01610|KV118_HUMAN Ig kappa chain V-I region WEA OS=Homo sapiens PE=1 SV=1 50 ICH Control sp|P01611|KV119_HUMAN Ig kappa chain V-I region Wes OS=Homo sapiens PE=1 SV=1 40 AIS Control sp|P01614|KV201_HUMAN Ig kappa chain V-II region Cum OS=Homo sapiens PE=1 SV=1 75 AIS Control sp|P01619|KV301_HUMAN Ig kappa chain V-III region B6 OS=Homo sapiens PE=1 SV=1 105

AIS Victim sp|P01619|KV301_HUMAN Ig kappa chain V-III region B6 OS=Homo sapiens PE=1 SV=1 45 ICH Control sp|P01619|KV301_HUMAN Ig kappa chain V-III region B6 OS=Homo sapiens PE=1 SV=1 186

113

ICH Victim sp|P01619|KV301_HUMAN Ig kappa chain V-III region B6 OS=Homo sapiens PE=1 SV=1 203 AIS Victim sp|P04207|KV308_HUMAN Ig kappa chain V-III region CLL OS=Homo sapiens PE=4 SV=2 38 ICH Control sp|P04207|KV308_HUMAN Ig kappa chain V-III region CLL OS=Homo sapiens PE=4 SV=2 66 ICH Victim sp|P04207|KV308_HUMAN Ig kappa chain V-III region CLL OS=Homo sapiens PE=4 SV=2 95

AIS Control sp|P04206|KV307_HUMAN Ig kappa chain V-III region GOL OS=Homo sapiens PE=1 SV=1 239 ICH Control sp|P04206|KV307_HUMAN Ig kappa chain V-III region GOL OS=Homo sapiens PE=1 SV=1 603 ICH Victim sp|P18135|KV312_HUMAN Ig kappa chain V-III region HAH OS=Homo sapiens PE=2 SV=1 257 AIS Control sp|P01621|KV303_HUMAN Ig kappa chain V-III region NG9 (Fragment) OS=Homo sapiens PE=2 SV=1 43

AIS Victim sp|P01621|KV303_HUMAN Ig kappa chain V-III region NG9 (Fragment) OS=Homo sapiens PE=2 SV=1 45 ICH Control sp|P01621|KV303_HUMAN Ig kappa chain V-III region NG9 (Fragment) OS=Homo sapiens PE=2 SV=1 61 ICH Victim sp|P01621|KV303_HUMAN Ig kappa chain V-III region NG9 (Fragment) OS=Homo sapiens PE=2 SV=1 38 AIS Control sp|P01620|KV302_HUMAN Ig kappa chain V-III region SIE OS=Homo sapiens PE=1 SV=1 292

AIS Victim sp|P01620|KV302_HUMAN Ig kappa chain V-III region SIE OS=Homo sapiens PE=1 SV=1 318 ICH Control sp|P01620|KV302_HUMAN Ig kappa chain V-III region SIE OS=Homo sapiens PE=1 SV=1 91 ICH Victim sp|P01620|KV302_HUMAN Ig kappa chain V-III region SIE OS=Homo sapiens PE=1 SV=1 119

AIS Control sp|P01622|KV304_HUMAN Ig kappa chain V-III region Ti OS=Homo sapiens PE=1 SV=1 56

AIS Victim sp|P01622|KV304_HUMAN Ig kappa chain V-III region Ti OS=Homo sapiens PE=1 SV=1 71 ICH Control sp|P01622|KV304_HUMAN Ig kappa chain V-III region Ti OS=Homo sapiens PE=1 SV=1 603 ICH Victim sp|P01622|KV304_HUMAN Ig kappa chain V-III region Ti OS=Homo sapiens PE=1 SV=1 113 AIS Control sp|P01623|KV305_HUMAN Ig kappa chain V-III region WOL OS=Homo sapiens PE=1 SV=1 70

ICH Control sp|P01623|KV305_HUMAN Ig kappa chain V-III region WOL OS=Homo sapiens PE=1 SV=1 255 ICH Control sp|P06312|KV401_HUMAN Ig kappa chain V-IV region (Fragment) OS=Homo sapiens GN=IGKV4-1 PE=4 SV=1 56 AIS Control sp|P01625|KV402_HUMAN Ig kappa chain V-IV region Len OS=Homo sapiens PE=1 SV=2 153 AIS Victim sp|P01625|KV402_HUMAN Ig kappa chain V-IV region Len OS=Homo sapiens PE=1 SV=2 159

ICH Control sp|P01625|KV402_HUMAN Ig kappa chain V-IV region Len OS=Homo sapiens PE=1 SV=2 135 ICH Victim sp|P01625|KV402_HUMAN Ig kappa chain V-IV region Len OS=Homo sapiens PE=1 SV=2 37 AIS Victim sp|P01700|LV102_HUMAN Ig lambda chain V-I region HA OS=Homo sapiens PE=1 SV=1 42 ICH Control sp|P01700|LV102_HUMAN Ig lambda chain V-I region HA OS=Homo sapiens PE=1 SV=1 50

ICH Control sp|P01701|LV103_HUMAN Ig lambda chain V-I region NEW OS=Homo sapiens PE=1 SV=1 47 ICH Victim sp|P01703|LV105_HUMAN Ig lambda chain V-I region NEWM OS=Homo sapiens PE=1 SV=1 56 AIS Control sp|P04208|LV106_HUMAN Ig lambda chain V-I region WAH OS=Homo sapiens PE=1 SV=1 40

ICH Control sp|P04208|LV106_HUMAN Ig lambda chain V-I region WAH OS=Homo sapiens PE=1 SV=1 61

ICH Victim sp|P04208|LV106_HUMAN Ig lambda chain V-I region WAH OS=Homo sapiens PE=1 SV=1 62 AIS Victim sp|P01707|LV204_HUMAN Ig lambda chain V-II region TRO OS=Homo sapiens PE=1 SV=1 41 AIS Control sp|P80748|LV302_HUMAN Ig lambda chain V-III region LOI OS=Homo sapiens PE=1 SV=1 174 ICH Control sp|P80748|LV302_HUMAN Ig lambda chain V-III region LOI OS=Homo sapiens PE=1 SV=1 195

ICH Victim sp|P80748|LV302_HUMAN Ig lambda chain V-III region LOI OS=Homo sapiens PE=1 SV=1 130 AIS Victim sp|P01714|LV301_HUMAN Ig lambda chain V-III region SH OS=Homo sapiens PE=1 SV=1 42 ICH Control sp|P01714|LV301_HUMAN Ig lambda chain V-III region SH OS=Homo sapiens PE=1 SV=1 60 ICH Victim sp|P01714|LV301_HUMAN Ig lambda chain V-III region SH OS=Homo sapiens PE=1 SV=1 45

AIS Control sp|P01717|LV403_HUMAN Ig lambda chain V-IV region Hil OS=Homo sapiens PE=1 SV=1 110 AIS Victim sp|P01717|LV403_HUMAN Ig lambda chain V-IV region Hil OS=Homo sapiens PE=1 SV=1 97 ICH Control sp|P01717|LV403_HUMAN Ig lambda chain V-IV region Hil OS=Homo sapiens PE=1 SV=1 103 ICH Victim sp|P01717|LV403_HUMAN Ig lambda chain V-IV region Hil OS=Homo sapiens PE=1 SV=1 62

AIS Victim sp|P06889|LV405_HUMAN Ig lambda chain V-IV region MOL OS=Homo sapiens PE=1 SV=1 52 AIS Control sp|P01719|LV501_HUMAN Ig lambda chain V-V region DEL OS=Homo sapiens PE=1 SV=1 53 ICH Control sp|P01719|LV501_HUMAN Ig lambda chain V-V region DEL OS=Homo sapiens PE=1 SV=1 44

ICH Victim sp|P01719|LV501_HUMAN Ig lambda chain V-V region DEL OS=Homo sapiens PE=1 SV=1 136

ICH Victim tr|A0A075B6K8|A0A075B6K8_HUMAN Ig lambda-1 chain C regions (Fragment) OS=Homo sapiens GN=IGLC1 PE=4 SV=1 583 AIS Victim sp|P0CG04|LAC1_HUMAN Ig lambda-1 chain C regions OS=Homo sapiens GN=IGLC1 PE=1 SV=1 856 ICH Control sp|P0CG04|LAC1_HUMAN Ig lambda-1 chain C regions OS=Homo sapiens GN=IGLC1 PE=1 SV=1 553 ICH Control tr|A0A075B6K9|A0A075B6K9_HUMAN Ig lambda-2 chain C regions (Fragment) OS=Homo sapiens GN=IGLC2 PE=4 SV=1 993

ICH Victim tr|A0A075B6K9|A0A075B6K9_HUMAN Ig lambda-2 chain C regions (Fragment) OS=Homo sapiens GN=IGLC2 PE=4 SV=1 883 AIS Control sp|P0CG05|LAC2_HUMAN Ig lambda-2 chain C regions OS=Homo sapiens GN=IGLC2 PE=1 SV=1 729 AIS Victim sp|P0CG05|LAC2_HUMAN Ig lambda-2 chain C regions OS=Homo sapiens GN=IGLC2 PE=1 SV=1 291 ICH Control sp|P0CG05|LAC2_HUMAN Ig lambda-2 chain C regions OS=Homo sapiens GN=IGLC2 PE=1 SV=1 283

ICH Victim sp|P0CG05|LAC2_HUMAN Ig lambda-2 chain C regions OS=Homo sapiens GN=IGLC2 PE=1 SV=1 556 AIS Victim tr|A0A075B6L0|A0A075B6L0_HUMAN Ig lambda-3 chain C regions (Fragment) OS=Homo sapiens GN=IGLC3 PE=1 SV=2 138

114

ICH Control sp|P0CG06|LAC3_HUMAN Ig lambda-3 chain C regions OS=Homo sapiens GN=IGLC3 PE=1 SV=1 735 AIS Control sp|P0CF74|LAC6_HUMAN Ig lambda-6 chain C region OS=Homo sapiens GN=IGLC6 PE=4 SV=1 848 ICH Victim sp|P0CF74|LAC6_HUMAN Ig lambda-6 chain C region OS=Homo sapiens GN=IGLC6 PE=4 SV=1 847 AIS Victim tr|A0A075B6L1|A0A075B6L1_HUMAN Ig lambda-7 chain C region (Fragment) OS=Homo sapiens GN=IGLC7 PE=1 SV=2 534

AIS Control sp|A0M8Q6|LAC7_HUMAN Ig lambda-7 chain C region OS=Homo sapiens GN=IGLC7 PE=4 SV=2 562 AIS Victim sp|A0M8Q6|LAC7_HUMAN Ig lambda-7 chain C region OS=Homo sapiens GN=IGLC7 PE=4 SV=2 129 ICH Control sp|A0M8Q6|LAC7_HUMAN Ig lambda-7 chain C region OS=Homo sapiens GN=IGLC7 PE=4 SV=2 532 ICH Victim sp|A0M8Q6|LAC7_HUMAN Ig lambda-7 chain C region OS=Homo sapiens GN=IGLC7 PE=4 SV=2 189

ICH Control tr|A0A075B6N9|A0A075B6N9_HUMAN Ig mu chain C region (Fragment) OS=Homo sapiens GN=IGHM PE=1 SV=2 151 ICH Victim tr|A0A075B6N9|A0A075B6N9_HUMAN Ig mu chain C region (Fragment) OS=Homo sapiens GN=IGHM PE=1 SV=2 227 AIS Control tr|A0A087X2C0|A0A087X2C0_HUMAN Ig mu chain C region OS=Homo sapiens GN=IGHM PE=1 SV=1 1318 AIS Victim tr|A0A087X2C0|A0A087X2C0_HUMAN Ig mu chain C region OS=Homo sapiens GN=IGHM PE=1 SV=1 626

ICH Victim tr|A0A087X2C0|A0A087X2C0_HUMAN Ig mu chain C region OS=Homo sapiens GN=IGHM PE=1 SV=1 622 AIS Control sp|P04220|MUCB_HUMAN Ig mu heavy chain disease protein OS=Homo sapiens PE=1 SV=1 1085 AIS Victim sp|P04220|MUCB_HUMAN Ig mu heavy chain disease protein OS=Homo sapiens PE=1 SV=1 331

ICH Control sp|P04220|MUCB_HUMAN Ig mu heavy chain disease protein OS=Homo sapiens PE=1 SV=1 99

ICH Victim sp|P04220|MUCB_HUMAN Ig mu heavy chain disease protein OS=Homo sapiens PE=1 SV=1 336 AIS Control tr|A0A087WXI2|A0A087WXI2_HUMAN IgGFc-binding protein OS=Homo sapiens GN=FCGBP PE=1 SV=1 41 AIS Victim tr|A0A087WXI2|A0A087WXI2_HUMAN IgGFc-binding protein OS=Homo sapiens GN=FCGBP PE=1 SV=1 176 ICH Control tr|A0A087WXI2|A0A087WXI2_HUMAN IgGFc-binding protein OS=Homo sapiens GN=FCGBP PE=1 SV=1 64

ICH Victim sp|P01591|IGJ_HUMAN Immunoglobulin J chain OS=Homo sapiens GN=IGJ PE=1 SV=4 193 ICH Victim sp|P15814|IGLL1_HUMAN Immunoglobulin lambda-like polypeptide 1 OS=Homo sapiens GN=IGLL1 PE=1 SV=1 38 AIS Control tr|A0A087WWC9|A0A087WWC9_HUMAN Immunoglobulin lambda-like polypeptide 5 OS=Homo sapiens GN=IGLL5 PE=1 SV=1 572 AIS Victim tr|A0A087WU42|A0A087WU42_HUMAN Immunoglobulin lambda-like polypeptide 5 OS=Homo sapiens GN=IGLL5 PE=1 SV=1 123

ICH Control tr|A0A087WWC9|A0A087WWC9_HUMAN Immunoglobulin lambda-like polypeptide 5 OS=Homo sapiens GN=IGLL5 PE=1 SV=1 99 ICH Victim tr|A0A087WU42|A0A087WU42_HUMAN Immunoglobulin lambda-like polypeptide 5 OS=Homo sapiens GN=IGLL5 PE=1 SV=1 179 ICH Control sp|B9A064|IGLL5_HUMAN Immunoglobulin lambda-like polypeptide 5 OS=Homo sapiens GN=IGLL5 PE=2 SV=2 323

ICH Victim tr|A0A087WZV0|A0A087WZV0_HUMAN Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 2 OS=Homo sapiens GN=PPIP5K2 PE=1 SV=1 39

AIS Control sp|P35568|IRS1_HUMAN Insulin receptor substrate 1 OS=Homo sapiens GN=IRS1 PE=1 SV=1 45 ICH Victim sp|P35568|IRS1_HUMAN Insulin receptor substrate 1 OS=Homo sapiens GN=IRS1 PE=1 SV=1 42 AIS Control tr|A6XND0|A6XND0_HUMAN Insulin-like growth factor binding protein 3 OS=Homo sapiens GN=IGFBP3 PE=1 SV=1 105 AIS Victim tr|A6XND0|A6XND0_HUMAN Insulin-like growth factor binding protein 3 OS=Homo sapiens GN=IGFBP3 PE=1 SV=1 55

ICH Control tr|A6XND0|A6XND0_HUMAN Insulin-like growth factor binding protein 3 OS=Homo sapiens GN=IGFBP3 PE=1 SV=1 58 AIS Victim tr|B3KWK7|B3KWK7_HUMAN Insulin-like growth factor binding protein 3, isoform CRA_b OS=Homo sapiens GN=IGFBP3 PE=1 SV=1 46 ICH Control tr|C9J6H2|C9J6H2_HUMAN Insulin-like growth factor-binding protein 1 OS=Homo sapiens GN=IGFBP1 PE=1 SV=1 57 ICH Control sp|P18065|IBP2_HUMAN Insulin-like growth factor-binding protein 2 OS=Homo sapiens GN=IGFBP2 PE=1 SV=2 51

AIS Control tr|H0Y485|H0Y485_HUMAN Insulin-like growth factor-binding protein 3 (Fragment) OS=Homo sapiens GN=IGFBP3 PE=1 SV=1 45 ICH Control tr|H0Y5K2|H0Y5K2_HUMAN Insulin-like growth factor-binding protein 3 (Fragment) OS=Homo sapiens GN=IGFBP3 PE=1 SV=1 48 ICH Victim tr|H0Y485|H0Y485_HUMAN Insulin-like growth factor-binding protein 3 (Fragment) OS=Homo sapiens GN=IGFBP3 PE=1 SV=1 36 ICH Control sp|P22692|IBP4_HUMAN Insulin-like growth factor-binding protein 4 OS=Homo sapiens GN=IGFBP4 PE=1 SV=2 43

ICH Control tr|F8VYK9|F8VYK9_HUMAN Insulin-like growth factor-binding protein 6 OS=Homo sapiens GN=IGFBP6 PE=1 SV=1 43 ICH Victim tr|H0Y509|H0Y509_HUMAN Integral membrane protein GPR137B (Fragment) OS=Homo sapiens GN=GPR137B PE=1 SV=1 37 ICH Victim sp|P53708|ITA8_HUMAN Integrin alpha-8 OS=Homo sapiens GN=ITGA8 PE=1 SV=3 40

ICH Victim tr|F8WBG2|F8WBG2_HUMAN Integrin beta-5 OS=Homo sapiens GN=ITGB5 PE=4 SV=2 37

AIS Control tr|H7C5I0|H7C5I0_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 (Fragment) OS=Homo sapiens GN=ITIH1 PE=1 SV=1 78 AIS Victim tr|H7C5I0|H7C5I0_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 (Fragment) OS=Homo sapiens GN=ITIH1 PE=1 SV=1 298 ICH Control tr|H7C5I0|H7C5I0_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 (Fragment) OS=Homo sapiens GN=ITIH1 PE=1 SV=1 62 ICH Victim tr|H7C5I0|H7C5I0_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 (Fragment) OS=Homo sapiens GN=ITIH1 PE=1 SV=1 210

AIS Control tr|F8WAS2|F8WAS2_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=1 481 AIS Victim tr|F8WAS2|F8WAS2_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=1 842 ICH Control tr|F8WAS2|F8WAS2_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=1 283 ICH Victim tr|F8WAS2|F8WAS2_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=1 71

AIS Control sp|P19827|ITIH1_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=3 911 AIS Victim sp|P19827|ITIH1_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=3 372

115

ICH Control sp|P19827|ITIH1_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=3 267 ICH Victim sp|P19827|ITIH1_HUMAN Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 PE=1 SV=3 391 AIS Control tr|Q5T985|Q5T985_HUMAN Inter-alpha-trypsin inhibitor heavy chain H2 OS=Homo sapiens GN=ITIH2 PE=1 SV=1 874 AIS Victim tr|Q5T985|Q5T985_HUMAN Inter-alpha-trypsin inhibitor heavy chain H2 OS=Homo sapiens GN=ITIH2 PE=1 SV=1 737

ICH Control tr|A0A087WTE1|A0A087WTE1_HUMAN Inter-alpha-trypsin inhibitor heavy chain H2 OS=Homo sapiens GN=ITIH2 PE=1 SV=1 215 ICH Victim tr|Q5T985|Q5T985_HUMAN Inter-alpha-trypsin inhibitor heavy chain H2 OS=Homo sapiens GN=ITIH2 PE=1 SV=1 618 ICH Control sp|P19823|ITIH2_HUMAN Inter-alpha-trypsin inhibitor heavy chain H2 OS=Homo sapiens GN=ITIH2 PE=1 SV=2 1166 AIS Control tr|A0A087WW43|A0A087WW43_HUMAN Inter-alpha-trypsin inhibitor heavy chain H3 OS=Homo sapiens GN=ITIH3 PE=1 SV=1 213

AIS Victim tr|A0A087WW43|A0A087WW43_HUMAN Inter-alpha-trypsin inhibitor heavy chain H3 OS=Homo sapiens GN=ITIH3 PE=1 SV=1 58 ICH Control tr|A0A087WW43|A0A087WW43_HUMAN Inter-alpha-trypsin inhibitor heavy chain H3 OS=Homo sapiens GN=ITIH3 PE=1 SV=1 264 ICH Victim tr|A0A087WW43|A0A087WW43_HUMAN Inter-alpha-trypsin inhibitor heavy chain H3 OS=Homo sapiens GN=ITIH3 PE=1 SV=1 92 AIS Control tr|H7C0L5|H7C0L5_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 (Fragment) OS=Homo sapiens GN=ITIH4 PE=1 SV=1 191

AIS Victim tr|H7C0L5|H7C0L5_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 (Fragment) OS=Homo sapiens GN=ITIH4 PE=1 SV=1 391 ICH Control tr|H7C0L5|H7C0L5_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 (Fragment) OS=Homo sapiens GN=ITIH4 PE=1 SV=1 185 ICH Victim tr|H7C0L5|H7C0L5_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 (Fragment) OS=Homo sapiens GN=ITIH4 PE=1 SV=1 178

AIS Control sp|Q14624|ITIH4_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 OS=Homo sapiens GN=ITIH4 PE=1 SV=4 314

AIS Victim sp|Q14624|ITIH4_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 OS=Homo sapiens GN=ITIH4 PE=1 SV=4 368 ICH Control sp|Q14624|ITIH4_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 OS=Homo sapiens GN=ITIH4 PE=1 SV=4 712 ICH Victim sp|Q14624|ITIH4_HUMAN Inter-alpha-trypsin inhibitor heavy chain H4 OS=Homo sapiens GN=ITIH4 PE=1 SV=4 1187 AIS Victim tr|E7ESS4|E7ESS4_HUMAN Intercellular adhesion molecule 1 OS=Homo sapiens GN=ICAM1 PE=1 SV=1 82

ICH Control tr|E7ESS4|E7ESS4_HUMAN Intercellular adhesion molecule 1 OS=Homo sapiens GN=ICAM1 PE=1 SV=1 56 ICH Victim tr|E7ESS4|E7ESS4_HUMAN Intercellular adhesion molecule 1 OS=Homo sapiens GN=ICAM1 PE=1 SV=1 43 ICH Control sp|P05362|ICAM1_HUMAN Intercellular adhesion molecule 1 OS=Homo sapiens GN=ICAM1 PE=1 SV=2 117 AIS Control tr|F8WDH6|F8WDH6_HUMAN Interferon regulatory factor 5 OS=Homo sapiens GN=IRF5 PE=1 SV=1 38

AIS Victim tr|F8WDH6|F8WDH6_HUMAN Interferon regulatory factor 5 OS=Homo sapiens GN=IRF5 PE=1 SV=1 38 ICH Victim tr|F8WDH6|F8WDH6_HUMAN Interferon regulatory factor 5 OS=Homo sapiens GN=IRF5 PE=1 SV=1 37 AIS Victim tr|H0YAI8|H0YAI8_HUMAN Intraflagellar transport protein 172 homolog (Fragment) OS=Homo sapiens GN=IFT172 PE=1 SV=1 37 ICH Victim sp|Q86XH1|IQCA1_HUMAN IQ and AAA domain-containing protein 1 OS=Homo sapiens GN=IQCA1 PE=2 SV=1 47

AIS Victim tr|A0A087WX19|A0A087WX19_HUMAN IQ domain-containing protein E OS=Homo sapiens GN=IQCE PE=1 SV=1 39 AIS Victim tr|H0YL72|H0YL72_HUMAN Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial OS=Homo sapiens GN=IDH3A PE=1 SV=1 38 ICH Control tr|H0YL72|H0YL72_HUMAN Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial OS=Homo sapiens GN=IDH3A PE=1 SV=1 58

ICH Victim tr|H0YL72|H0YL72_HUMAN Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial OS=Homo sapiens GN=IDH3A PE=1 SV=1 37

AIS Control sp|Q8N1M1-1|BEST3_HUMAN Isoform 1 of Bestrophin-3 OS=Homo sapiens GN=BEST3 35 AIS Victim sp|Q8N1M1-1|BEST3_HUMAN Isoform 1 of Bestrophin-3 OS=Homo sapiens GN=BEST3 35

ICH Victim sp|Q8N1M1-1|BEST3_HUMAN Isoform 1 of Bestrophin-3 OS=Homo sapiens GN=BEST3 36

AIS Victim sp|Q9HBX8-1|LGR6_HUMAN Isoform 1 of Leucine-rich repeat-containing G-protein coupled receptor 6 OS=Homo sapiens GN=LGR6 35 ICH Victim sp|Q8IUR5-1|TMTC1_HUMAN Isoform 1 of Transmembrane and TPR repeat-containing protein 1 OS=Homo sapiens GN=TMTC1 39 ICH Victim sp|Q9BWP8-10|COL11_HUMAN Isoform 10 of Collectin-11 OS=Homo sapiens GN=COLEC11 42 AIS Control sp|P02751-10|FINC_HUMAN Isoform 10 of Fibronectin OS=Homo sapiens GN=FN1 57

AIS Victim sp|P02751-10|FINC_HUMAN Isoform 10 of Fibronectin OS=Homo sapiens GN=FN1 77 ICH Control sp|P02751-10|FINC_HUMAN Isoform 10 of Fibronectin OS=Homo sapiens GN=FN1 508 ICH Victim sp|P02751-10|FINC_HUMAN Isoform 10 of Fibronectin OS=Homo sapiens GN=FN1 1263 AIS Victim sp|P02751-11|FINC_HUMAN Isoform 11 of Fibronectin OS=Homo sapiens GN=FN1 198

ICH Control sp|P02751-11|FINC_HUMAN Isoform 11 of Fibronectin OS=Homo sapiens GN=FN1 108 ICH Control sp|P02751-12|FINC_HUMAN Isoform 12 of Fibronectin OS=Homo sapiens GN=FN1 307 ICH Victim sp|Q8WZ42-12|TITIN_HUMAN Isoform 12 of Titin OS=Homo sapiens GN=TTN 44 AIS Control sp|P02751-14|FINC_HUMAN Isoform 14 of Fibronectin OS=Homo sapiens GN=FN1 2222

ICH Control sp|P02751-14|FINC_HUMAN Isoform 14 of Fibronectin OS=Homo sapiens GN=FN1 2008 AIS Victim sp|P02751-17|FINC_HUMAN Isoform 17 of Fibronectin OS=Homo sapiens GN=FN1 2214 AIS Control sp|P04217-2|A1BG_HUMAN Isoform 2 of Alpha-1B-glycoprotein OS=Homo sapiens GN=A1BG 318 AIS Victim sp|P04217-2|A1BG_HUMAN Isoform 2 of Alpha-1B-glycoprotein OS=Homo sapiens GN=A1BG 2056

ICH Victim sp|P04217-2|A1BG_HUMAN Isoform 2 of Alpha-1B-glycoprotein OS=Homo sapiens GN=A1BG 190 AIS Victim sp|P08697-2|A2AP_HUMAN Isoform 2 of Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 535 ICH Control sp|P08697-2|A2AP_HUMAN Isoform 2 of Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 104 AIS Control sp|Q8N7J2-2|AMER2_HUMAN Isoform 2 of APC membrane recruitment protein 2 OS=Homo sapiens GN=AMER2 38

AIS Victim sp|Q8N7J2-2|AMER2_HUMAN Isoform 2 of APC membrane recruitment protein 2 OS=Homo sapiens GN=AMER2 44 ICH Control sp|Q8N7J2-2|AMER2_HUMAN Isoform 2 of APC membrane recruitment protein 2 OS=Homo sapiens GN=AMER2 55 ICH Victim sp|Q8N7J2-2|AMER2_HUMAN Isoform 2 of APC membrane recruitment protein 2 OS=Homo sapiens GN=AMER2 38

116

AIS Control sp|O14791-2|APOL1_HUMAN Isoform 2 of Apolipoprotein L1 OS=Homo sapiens GN=APOL1 112 AIS Victim sp|O14791-2|APOL1_HUMAN Isoform 2 of Apolipoprotein L1 OS=Homo sapiens GN=APOL1 94 ICH Control sp|O14791-2|APOL1_HUMAN Isoform 2 of Apolipoprotein L1 OS=Homo sapiens GN=APOL1 152 AIS Victim sp|O95445-2|APOM_HUMAN Isoform 2 of Apolipoprotein M OS=Homo sapiens GN=APOM 39

ICH Victim sp|O95445-2|APOM_HUMAN Isoform 2 of Apolipoprotein M OS=Homo sapiens GN=APOM 91 AIS Control sp|O43150-2|ASAP2_HUMAN Isoform 2 of Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 OS=Homo sapiens GN=ASAP2 40 ICH Control sp|O43150-2|ASAP2_HUMAN Isoform 2 of Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 OS=Homo sapiens GN=ASAP2 39 ICH Victim sp|O43150-2|ASAP2_HUMAN Isoform 2 of Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 OS=Homo sapiens GN=ASAP2 39

ICH Control sp|P25705-2|ATPA_HUMAN Isoform 2 of ATP synthase subunit alpha, mitochondrial OS=Homo sapiens GN=ATP5A1 71 AIS Victim sp|P45844-2|ABCG1_HUMAN Isoform 2 of ATP-binding cassette sub-family G member 1 OS=Homo sapiens GN=ABCG1 40 ICH Control sp|P45844-2|ABCG1_HUMAN Isoform 2 of ATP-binding cassette sub-family G member 1 OS=Homo sapiens GN=ABCG1 34 ICH Victim sp|P45844-2|ABCG1_HUMAN Isoform 2 of ATP-binding cassette sub-family G member 1 OS=Homo sapiens GN=ABCG1 39

AIS Control sp|O75882-2|ATRN_HUMAN Isoform 2 of Attractin OS=Homo sapiens GN=ATRN 339 AIS Victim sp|O75882-2|ATRN_HUMAN Isoform 2 of Attractin OS=Homo sapiens GN=ATRN 455 ICH Control sp|O75882-2|ATRN_HUMAN Isoform 2 of Attractin OS=Homo sapiens GN=ATRN 110

ICH Victim sp|O75882-2|ATRN_HUMAN Isoform 2 of Attractin OS=Homo sapiens GN=ATRN 86

AIS Victim sp|O95803-2|NDST3_HUMAN Isoform 2 of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 OS=Homo sapiens GN=NDST3 37 ICH Control sp|O95803-2|NDST3_HUMAN Isoform 2 of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 OS=Homo sapiens GN=NDST3 35 ICH Victim sp|O95803-2|NDST3_HUMAN Isoform 2 of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 OS=Homo sapiens GN=NDST3 37 AIS Control sp|P43251-2|BTD_HUMAN Isoform 2 of Biotinidase OS=Homo sapiens GN=BTD 79

AIS Control sp|P20851-2|C4BPB_HUMAN Isoform 2 of C4b-binding protein beta chain OS=Homo sapiens GN=C4BPB 49 AIS Victim sp|P20851-2|C4BPB_HUMAN Isoform 2 of C4b-binding protein beta chain OS=Homo sapiens GN=C4BPB 101 ICH Control sp|P20851-2|C4BPB_HUMAN Isoform 2 of C4b-binding protein beta chain OS=Homo sapiens GN=C4BPB 125 ICH Victim sp|P20851-2|C4BPB_HUMAN Isoform 2 of C4b-binding protein beta chain OS=Homo sapiens GN=C4BPB 38

ICH Control sp|Q9Y6Y1-2|CMTA1_HUMAN Isoform 2 of Calmodulin-binding transcription activator 1 OS=Homo sapiens GN=CAMTA1 37 ICH Control sp|P17655-2|CAN2_HUMAN Isoform 2 of Calpain-2 catalytic subunit OS=Homo sapiens GN=CAPN2 48 ICH Victim sp|P17655-2|CAN2_HUMAN Isoform 2 of Calpain-2 catalytic subunit OS=Homo sapiens GN=CAPN2 36

AIS Victim sp|P30622-1|CLIP1_HUMAN Isoform 2 of CAP-Gly domain-containing linker protein 1 OS=Homo sapiens GN=CLIP1 37

ICH Victim sp|P30622-1|CLIP1_HUMAN Isoform 2 of CAP-Gly domain-containing linker protein 1 OS=Homo sapiens GN=CLIP1 37 AIS Victim sp|O60671-2|RAD1_HUMAN Isoform 2 of Cell cycle checkpoint protein RAD1 OS=Homo sapiens GN=RAD1 38 ICH Victim sp|P43121-2|MUC18_HUMAN Isoform 2 of Cell surface glycoprotein MUC18 OS=Homo sapiens GN=MCAM 37 AIS Victim sp|Q02224-2|CENPE_HUMAN Isoform 2 of Centromere-associated protein E OS=Homo sapiens GN=CENPE 40

ICH Victim sp|Q9BY43-2|CHM4A_HUMAN Isoform 2 of Charged multivesicular body protein 4a OS=Homo sapiens GN=CHMP4A 39 ICH Control sp|P11597-2|CETP_HUMAN Isoform 2 of Cholesteryl ester transfer protein OS=Homo sapiens GN=CETP 160 AIS Control sp|P10909-2|CLUS_HUMAN Isoform 2 of Clusterin OS=Homo sapiens GN=CLU 736 AIS Victim sp|P10909-2|CLUS_HUMAN Isoform 2 of Clusterin OS=Homo sapiens GN=CLU 297

ICH Control sp|P10909-2|CLUS_HUMAN Isoform 2 of Clusterin OS=Homo sapiens GN=CLU 683 ICH Victim sp|P10909-2|CLUS_HUMAN Isoform 2 of Clusterin OS=Homo sapiens GN=CLU 296 AIS Control sp|P00740-2|FA9_HUMAN Isoform 2 of Coagulation factor IX OS=Homo sapiens GN=F9 108 AIS Victim sp|P00740-2|FA9_HUMAN Isoform 2 of Coagulation factor IX OS=Homo sapiens GN=F9 62

ICH Control sp|P00740-2|FA9_HUMAN Isoform 2 of Coagulation factor IX OS=Homo sapiens GN=F9 93 ICH Victim sp|P00740-2|FA9_HUMAN Isoform 2 of Coagulation factor IX OS=Homo sapiens GN=F9 240 AIS Control sp|P03951-2|FA11_HUMAN Isoform 2 of Coagulation factor XI OS=Homo sapiens GN=F11 113

AIS Victim sp|P03951-2|FA11_HUMAN Isoform 2 of Coagulation factor XI OS=Homo sapiens GN=F11 38

ICH Control sp|P03951-2|FA11_HUMAN Isoform 2 of Coagulation factor XI OS=Homo sapiens GN=F11 70 ICH Victim sp|P03951-2|FA11_HUMAN Isoform 2 of Coagulation factor XI OS=Homo sapiens GN=F11 90 AIS Victim sp|P35606-2|COPB2_HUMAN Isoform 2 of Coatomer subunit beta~ OS=Homo sapiens GN=COPB2 37 ICH Control sp|P35606-2|COPB2_HUMAN Isoform 2 of Coatomer subunit beta~ OS=Homo sapiens GN=COPB2 54

ICH Victim sp|P35606-2|COPB2_HUMAN Isoform 2 of Coatomer subunit beta~ OS=Homo sapiens GN=COPB2 38 ICH Control sp|Q4G0X9-2|CCD40_HUMAN Isoform 2 of Coiled-coil domain-containing protein 40 OS=Homo sapiens GN=CCDC40 40 ICH Control sp|Q8NCU4-2|K1407_HUMAN Isoform 2 of Coiled-coil domain-containing protein KIAA1407 OS=Homo sapiens GN=KIAA1407 47 ICH Victim sp|A8TX70-2|CO6A5_HUMAN Isoform 2 of Collagen alpha-5(VI) chain OS=Homo sapiens GN=COL6A5 40

AIS Control sp|P0C0L4-2|CO4A_HUMAN Isoform 2 of Complement C4-A OS=Homo sapiens GN=C4A 1481 AIS Victim sp|P0C0L4-2|CO4A_HUMAN Isoform 2 of Complement C4-A OS=Homo sapiens GN=C4A 102

117

ICH Victim sp|P0C0L4-2|CO4A_HUMAN Isoform 2 of Complement C4-A OS=Homo sapiens GN=C4A 57 AIS Victim sp|P00751-2|CFAB_HUMAN Isoform 2 of Complement factor B OS=Homo sapiens GN=CFB 216 ICH Control sp|P00751-2|CFAB_HUMAN Isoform 2 of Complement factor B OS=Homo sapiens GN=CFB 1119 AIS Control sp|Q02985-2|FHR3_HUMAN Isoform 2 of Complement factor H-related protein 3 OS=Homo sapiens GN=CFHR3 42

AIS Victim sp|Q02985-2|FHR3_HUMAN Isoform 2 of Complement factor H-related protein 3 OS=Homo sapiens GN=CFHR3 37 ICH Victim sp|Q02985-2|FHR3_HUMAN Isoform 2 of Complement factor H-related protein 3 OS=Homo sapiens GN=CFHR3 52 AIS Victim sp|Q92496-2|FHR4_HUMAN Isoform 2 of Complement factor H-related protein 4 OS=Homo sapiens GN=CFHR4 54 ICH Victim sp|Q92496-2|FHR4_HUMAN Isoform 2 of Complement factor H-related protein 4 OS=Homo sapiens GN=CFHR4 39

AIS Control sp|P81605-2|DCD_HUMAN Isoform 2 of Dermcidin OS=Homo sapiens GN=DCD 52 AIS Victim sp|P81605-2|DCD_HUMAN Isoform 2 of Dermcidin OS=Homo sapiens GN=DCD 43 ICH Control sp|P81605-2|DCD_HUMAN Isoform 2 of Dermcidin OS=Homo sapiens GN=DCD 64 ICH Victim sp|P81605-2|DCD_HUMAN Isoform 2 of Dermcidin OS=Homo sapiens GN=DCD 51

AIS Victim sp|Q9NRD9-2|DUOX1_HUMAN Isoform 2 of Dual oxidase 1 OS=Homo sapiens GN=DUOX1 39 ICH Victim sp|P33981-2|TTK_HUMAN Isoform 2 of Dual specificity protein kinase TTK OS=Homo sapiens GN=TTK 39 AIS Victim sp|Q9P225-2|DYH2_HUMAN Isoform 2 of Dynein heavy chain 2, axonemal OS=Homo sapiens GN=DNAH2 37

ICH Victim sp|Q9P225-2|DYH2_HUMAN Isoform 2 of Dynein heavy chain 2, axonemal OS=Homo sapiens GN=DNAH2 36

AIS Victim sp|Q5VTB9-3|RN220_HUMAN Isoform 2 of E3 ubiquitin-protein ligase RNF220 OS=Homo sapiens GN=RNF220 42 ICH Control sp|Q5VTB9-3|RN220_HUMAN Isoform 2 of E3 ubiquitin-protein ligase RNF220 OS=Homo sapiens GN=RNF220 37 ICH Victim sp|Q5VTB9-3|RN220_HUMAN Isoform 2 of E3 ubiquitin-protein ligase RNF220 OS=Homo sapiens GN=RNF220 50 AIS Control sp|Q6Q0C0-2|TRAF7_HUMAN Isoform 2 of E3 ubiquitin-protein ligase TRAF7 OS=Homo sapiens GN=TRAF7 39

ICH Victim sp|O60447-2|EVI5_HUMAN Isoform 2 of Ecotropic viral integration site 5 protein homolog OS=Homo sapiens GN=EVI5 38 AIS Control sp|Q8IY85-2|EFC13_HUMAN Isoform 2 of EF-hand calcium-binding domain-containing protein 13 OS=Homo sapiens GN=EFCAB13 39 AIS Victim sp|Q8IY85-2|EFC13_HUMAN Isoform 2 of EF-hand calcium-binding domain-containing protein 13 OS=Homo sapiens GN=EFCAB13 37 ICH Control sp|Q8IY85-2|EFC13_HUMAN Isoform 2 of EF-hand calcium-binding domain-containing protein 13 OS=Homo sapiens GN=EFCAB13 39

ICH Victim sp|Q8IY85-2|EFC13_HUMAN Isoform 2 of EF-hand calcium-binding domain-containing protein 13 OS=Homo sapiens GN=EFCAB13 41 AIS Victim sp|Q12805-2|FBLN3_HUMAN Isoform 2 of EGF-containing fibulin-like extracellular matrix protein 1 OS=Homo sapiens GN=EFEMP1 54 ICH Control sp|Q12805-2|FBLN3_HUMAN Isoform 2 of EGF-containing fibulin-like extracellular matrix protein 1 OS=Homo sapiens GN=EFEMP1 40 ICH Victim sp|Q12805-2|FBLN3_HUMAN Isoform 2 of EGF-containing fibulin-like extracellular matrix protein 1 OS=Homo sapiens GN=EFEMP1 39

AIS Victim sp|Q9NVH0-2|EXD2_HUMAN Isoform 2 of Exonuclease 3~-5~ domain-containing protein 2 OS=Homo sapiens GN=EXD2 35 AIS Victim sp|Q16610-2|ECM1_HUMAN Isoform 2 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 86 ICH Control sp|Q16610-2|ECM1_HUMAN Isoform 2 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 60

ICH Victim sp|Q16610-2|ECM1_HUMAN Isoform 2 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 129

AIS Control sp|Q0JRZ9-2|FCHO2_HUMAN Isoform 2 of F-BAR domain only protein 2 OS=Homo sapiens GN=FCHO2 39 AIS Victim sp|Q0JRZ9-2|FCHO2_HUMAN Isoform 2 of F-BAR domain only protein 2 OS=Homo sapiens GN=FCHO2 42 ICH Victim sp|Q0JRZ9-2|FCHO2_HUMAN Isoform 2 of F-BAR domain only protein 2 OS=Homo sapiens GN=FCHO2 43 AIS Control sp|Q9UGM5-2|FETUB_HUMAN Isoform 2 of Fetuin-B OS=Homo sapiens GN=FETUB 271

AIS Victim sp|P02671-2|FIBA_HUMAN Isoform 2 of Fibrinogen alpha chain OS=Homo sapiens GN=FGA 171 ICH Victim sp|P02671-2|FIBA_HUMAN Isoform 2 of Fibrinogen alpha chain OS=Homo sapiens GN=FGA 1440 ICH Control sp|P02751-2|FINC_HUMAN Isoform 2 of Fibronectin OS=Homo sapiens GN=FN1 240 AIS Control sp|O75636-2|FCN3_HUMAN Isoform 2 of Ficolin-3 OS=Homo sapiens GN=FCN3 111

AIS Victim sp|O75636-2|FCN3_HUMAN Isoform 2 of Ficolin-3 OS=Homo sapiens GN=FCN3 46 ICH Control sp|O75636-2|FCN3_HUMAN Isoform 2 of Ficolin-3 OS=Homo sapiens GN=FCN3 127 ICH Victim sp|O75636-2|FCN3_HUMAN Isoform 2 of Ficolin-3 OS=Homo sapiens GN=FCN3 225

ICH Victim sp|P06396-2|GELS_HUMAN Isoform 2 of Gelsolin OS=Homo sapiens GN=GSN 206

ICH Victim sp|Q9H0J4-2|QRIC2_HUMAN Isoform 2 of Glutamine-rich protein 2 OS=Homo sapiens GN=QRICH2 44 AIS Control sp|Q8NBJ4-2|GOLM1_HUMAN Isoform 2 of Golgi membrane protein 1 OS=Homo sapiens GN=GOLM1 35 ICH Victim sp|Q75T13-2|PGAP1_HUMAN Isoform 2 of GPI inositol-deacylase OS=Homo sapiens GN=PGAP1 37 AIS Control sp|Q9NY12-2|GAR1_HUMAN Isoform 2 of H/ACA ribonucleoprotein complex subunit 1 OS=Homo sapiens GN=GAR1 61

ICH Control sp|Q9NY12-2|GAR1_HUMAN Isoform 2 of H/ACA ribonucleoprotein complex subunit 1 OS=Homo sapiens GN=GAR1 37 ICH Victim sp|Q9NY12-2|GAR1_HUMAN Isoform 2 of H/ACA ribonucleoprotein complex subunit 1 OS=Homo sapiens GN=GAR1 42 AIS Control sp|P00738-2|HPT_HUMAN Isoform 2 of Haptoglobin OS=Homo sapiens GN=HP 3490 AIS Victim sp|P00738-2|HPT_HUMAN Isoform 2 of Haptoglobin OS=Homo sapiens GN=HP 124

ICH Control sp|P00738-2|HPT_HUMAN Isoform 2 of Haptoglobin OS=Homo sapiens GN=HP 2578 AIS Control sp|P00739-2|HPTR_HUMAN Isoform 2 of Haptoglobin-related protein OS=Homo sapiens GN=HPR 1694

118

AIS Victim sp|P00739-2|HPTR_HUMAN Isoform 2 of Haptoglobin-related protein OS=Homo sapiens GN=HPR 1456 ICH Control sp|P00739-2|HPTR_HUMAN Isoform 2 of Haptoglobin-related protein OS=Homo sapiens GN=HPR 703 ICH Victim sp|P00739-2|HPTR_HUMAN Isoform 2 of Haptoglobin-related protein OS=Homo sapiens GN=HPR 303 ICH Victim sp|Q68CZ6-2|HAUS3_HUMAN Isoform 2 of HAUS augmin-like complex subunit 3 OS=Homo sapiens GN=HAUS3 42

ICH Victim sp|Q9NR48-2|ASH1L_HUMAN Isoform 2 of Histone-lysine N-methyltransferase ASH1L OS=Homo sapiens GN=ASH1L 34 ICH Control sp|Q9BZ95-2|NSD3_HUMAN Isoform 2 of Histone-lysine N-methyltransferase NSD3 OS=Homo sapiens GN=WHSC1L1 39 AIS Control sp|Q14520-2|HABP2_HUMAN Isoform 2 of Hyaluronan-binding protein 2 OS=Homo sapiens GN=HABP2 60 AIS Victim sp|Q14520-2|HABP2_HUMAN Isoform 2 of Hyaluronan-binding protein 2 OS=Homo sapiens GN=HABP2 39

ICH Control sp|Q14520-2|HABP2_HUMAN Isoform 2 of Hyaluronan-binding protein 2 OS=Homo sapiens GN=HABP2 59 ICH Victim sp|Q14520-2|HABP2_HUMAN Isoform 2 of Hyaluronan-binding protein 2 OS=Homo sapiens GN=HABP2 75 ICH Victim sp|P01880-2|IGHD_HUMAN Isoform 2 of Ig delta chain C region OS=Homo sapiens GN=IGHD 698 ICH Control sp|P05019-2|IGF1_HUMAN Isoform 2 of Insulin-like growth factor I OS=Homo sapiens GN=IGF1 56

AIS Control sp|P01344-2|IGF2_HUMAN Isoform 2 of Insulin-like growth factor II OS=Homo sapiens GN=IGF2 97 AIS Victim sp|P01344-2|IGF2_HUMAN Isoform 2 of Insulin-like growth factor II OS=Homo sapiens GN=IGF2 51 ICH Control sp|P01344-2|IGF2_HUMAN Isoform 2 of Insulin-like growth factor II OS=Homo sapiens GN=IGF2 48

ICH Victim sp|P01344-2|IGF2_HUMAN Isoform 2 of Insulin-like growth factor II OS=Homo sapiens GN=IGF2 42

AIS Victim sp|P22692-2|IBP4_HUMAN Isoform 2 of Insulin-like growth factor-binding protein 4 OS=Homo sapiens GN=IGFBP4 39 ICH Control sp|P22692-2|IBP4_HUMAN Isoform 2 of Insulin-like growth factor-binding protein 4 OS=Homo sapiens GN=IGFBP4 40 ICH Victim sp|P22692-2|IBP4_HUMAN Isoform 2 of Insulin-like growth factor-binding protein 4 OS=Homo sapiens GN=IGFBP4 41 AIS Control sp|P35858-2|ALS_HUMAN Isoform 2 of Insulin-like growth factor-binding protein complex acid labile subunit OS=Homo sapiens GN=IGFALS 288

AIS Victim sp|P35858-2|ALS_HUMAN Isoform 2 of Insulin-like growth factor-binding protein complex acid labile subunit OS=Homo sapiens GN=IGFALS 92 ICH Control sp|P35858-2|ALS_HUMAN Isoform 2 of Insulin-like growth factor-binding protein complex acid labile subunit OS=Homo sapiens GN=IGFALS 252 ICH Victim sp|P35858-2|ALS_HUMAN Isoform 2 of Insulin-like growth factor-binding protein complex acid labile subunit OS=Homo sapiens GN=IGFALS 597 ICH Victim sp|P19827-2|ITIH1_HUMAN Isoform 2 of Inter-alpha-trypsin inhibitor heavy chain H1 OS=Homo sapiens GN=ITIH1 48

AIS Control sp|Q06033-2|ITIH3_HUMAN Isoform 2 of Inter-alpha-trypsin inhibitor heavy chain H3 OS=Homo sapiens GN=ITIH3 55 ICH Victim sp|Q06033-2|ITIH3_HUMAN Isoform 2 of Inter-alpha-trypsin inhibitor heavy chain H3 OS=Homo sapiens GN=ITIH3 83 AIS Control sp|P50213-2|IDH3A_HUMAN Isoform 2 of Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial OS=Homo sapiens GN=IDH3A 51 AIS Victim sp|P50213-2|IDH3A_HUMAN Isoform 2 of Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial OS=Homo sapiens GN=IDH3A 84

ICH Victim sp|P50213-2|IDH3A_HUMAN Isoform 2 of Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial OS=Homo sapiens GN=IDH3A 81 AIS Control sp|Q96L93-2|KI16B_HUMAN Isoform 2 of Kinesin-like protein KIF16B OS=Homo sapiens GN=KIF16B 38 AIS Victim sp|O75037-2|KI21B_HUMAN Isoform 2 of Kinesin-like protein KIF21B OS=Homo sapiens GN=KIF21B 39

AIS Control sp|Q659C4-2|LAR1B_HUMAN Isoform 2 of La-related protein 1B OS=Homo sapiens GN=LARP1B 36

AIS Victim sp|Q659C4-2|LAR1B_HUMAN Isoform 2 of La-related protein 1B OS=Homo sapiens GN=LARP1B 38 ICH Control sp|Q659C4-2|LAR1B_HUMAN Isoform 2 of La-related protein 1B OS=Homo sapiens GN=LARP1B 41 ICH Victim sp|Q659C4-2|LAR1B_HUMAN Isoform 2 of La-related protein 1B OS=Homo sapiens GN=LARP1B 37 ICH Victim sp|Q96JA1-2|LRIG1_HUMAN Isoform 2 of Leucine-rich repeats and immunoglobulin-like domains protein 1 OS=Homo sapiens GN=LRIG1 41

AIS Victim sp|Q496Y0-2|LONF3_HUMAN Isoform 2 of LON peptidase N-terminal domain and RING finger protein 3 OS=Homo sapiens GN=LONRF3 35 AIS Control sp|P14151-2|LYAM1_HUMAN Isoform 2 of L-selectin OS=Homo sapiens GN=SELL 65 AIS Victim sp|P14151-2|LYAM1_HUMAN Isoform 2 of L-selectin OS=Homo sapiens GN=SELL 39 ICH Control sp|P14151-2|LYAM1_HUMAN Isoform 2 of L-selectin OS=Homo sapiens GN=SELL 50

ICH Victim sp|P14151-2|LYAM1_HUMAN Isoform 2 of L-selectin OS=Homo sapiens GN=SELL 47 AIS Victim sp|Q6ZMT4-2|KDM7A_HUMAN Isoform 2 of Lysine-specific demethylase 7A OS=Homo sapiens GN=KDM7A 47 ICH Control sp|Q5TGP6-2|MROH9_HUMAN Isoform 2 of Maestro heat-like repeat-containing protein family member 9 OS=Homo sapiens GN=MROH9 40 AIS Control sp|P48740-2|MASP1_HUMAN Isoform 2 of Mannan-binding lectin serine protease 1 OS=Homo sapiens GN=MASP1 63

AIS Victim sp|P48740-2|MASP1_HUMAN Isoform 2 of Mannan-binding lectin serine protease 1 OS=Homo sapiens GN=MASP1 60 ICH Control sp|P48740-2|MASP1_HUMAN Isoform 2 of Mannan-binding lectin serine protease 1 OS=Homo sapiens GN=MASP1 79 ICH Victim sp|P48740-2|MASP1_HUMAN Isoform 2 of Mannan-binding lectin serine protease 1 OS=Homo sapiens GN=MASP1 36

AIS Victim sp|O00187-2|MASP2_HUMAN Isoform 2 of Mannan-binding lectin serine protease 2 OS=Homo sapiens GN=MASP2 51

ICH Control sp|O00187-2|MASP2_HUMAN Isoform 2 of Mannan-binding lectin serine protease 2 OS=Homo sapiens GN=MASP2 50 ICH Victim sp|O00187-2|MASP2_HUMAN Isoform 2 of Mannan-binding lectin serine protease 2 OS=Homo sapiens GN=MASP2 95 AIS Control sp|Q9BY79-2|MFRP_HUMAN Isoform 2 of Membrane frizzled-related protein OS=Homo sapiens GN=MFRP 37 AIS Victim sp|Q9BY79-2|MFRP_HUMAN Isoform 2 of Membrane frizzled-related protein OS=Homo sapiens GN=MFRP 46

AIS Control sp|Q9ULD2-2|MTUS1_HUMAN Isoform 2 of Microtubule-associated tumor suppressor 1 OS=Homo sapiens GN=MTUS1 36 AIS Victim sp|Q9ULD2-2|MTUS1_HUMAN Isoform 2 of Microtubule-associated tumor suppressor 1 OS=Homo sapiens GN=MTUS1 40 ICH Victim sp|Q99683-2|M3K5_HUMAN Isoform 2 of Mitogen-activated protein kinase kinase kinase 5 OS=Homo sapiens GN=MAP3K5 44 AIS Victim sp|Q9UNW1-2|MINP1_HUMAN Isoform 2 of Multiple inositol polyphosphate phosphatase 1 OS=Homo sapiens GN=MINPP1 41

ICH Control sp|P35749-2|MYH11_HUMAN Isoform 2 of Myosin-11 OS=Homo sapiens GN=MYH11 43 ICH Victim sp|P35749-2|MYH11_HUMAN Isoform 2 of Myosin-11 OS=Homo sapiens GN=MYH11 41

119

AIS Control sp|Q96PD5-2|PGRP2_HUMAN Isoform 2 of N-acetylmuramoyl-L-alanine amidase OS=Homo sapiens GN=PGLYRP2 66 AIS Victim sp|Q96PD5-2|PGRP2_HUMAN Isoform 2 of N-acetylmuramoyl-L-alanine amidase OS=Homo sapiens GN=PGLYRP2 156 ICH Control sp|Q96PD5-2|PGRP2_HUMAN Isoform 2 of N-acetylmuramoyl-L-alanine amidase OS=Homo sapiens GN=PGLYRP2 170 ICH Victim sp|Q96PD5-2|PGRP2_HUMAN Isoform 2 of N-acetylmuramoyl-L-alanine amidase OS=Homo sapiens GN=PGLYRP2 71

AIS Victim sp|P55160-2|NCKPL_HUMAN Isoform 2 of Nck-associated protein 1-like OS=Homo sapiens GN=NCKAP1L 40 ICH Control sp|P55160-2|NCKPL_HUMAN Isoform 2 of Nck-associated protein 1-like OS=Homo sapiens GN=NCKAP1L 40 AIS Control sp|O00533-2|NCHL1_HUMAN Isoform 2 of Neural cell adhesion molecule L1-like protein OS=Homo sapiens GN=CHL1 63 ICH Victim sp|O00533-2|NCHL1_HUMAN Isoform 2 of Neural cell adhesion molecule L1-like protein OS=Homo sapiens GN=CHL1 129

ICH Control sp|P12036-2|NFH_HUMAN Isoform 2 of Neurofilament heavy polypeptide OS=Homo sapiens GN=NEFH 39 AIS Victim sp|Q9Y6Q9-2|NCOA3_HUMAN Isoform 2 of Nuclear receptor coactivator 3 OS=Homo sapiens GN=NCOA3 35 ICH Victim sp|Q5VST9-2|OBSCN_HUMAN Isoform 2 of Obscurin OS=Homo sapiens GN=OBSCN 35 AIS Victim sp|Q5BJF6-2|ODFP2_HUMAN Isoform 2 of Outer dense fiber protein 2 OS=Homo sapiens GN=ODF2 39

ICH Victim sp|Q6UXB8-2|PI16_HUMAN Isoform 2 of Peptidase inhibitor 16 OS=Homo sapiens GN=PI16 52

AIS Control sp|Q92835-2|SHIP1_HUMAN Isoform 2 of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 OS=Homo sapiens GN=INPP5D 43 ICH Control sp|Q92835-2|SHIP1_HUMAN Isoform 2 of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 OS=Homo sapiens GN=INPP5D 35 ICH Victim sp|Q6VY07-2|PACS1_HUMAN Isoform 2 of Phosphofurin acidic cluster sorting protein 1 OS=Homo sapiens GN=PACS1 42 AIS Control sp|P36871-2|PGM1_HUMAN Isoform 2 of Phosphoglucomutase-1 OS=Homo sapiens GN=PGM1 37

AIS Victim sp|P55058-2|PLTP_HUMAN Isoform 2 of Phospholipid transfer protein OS=Homo sapiens GN=PLTP 132 ICH Control sp|P55058-2|PLTP_HUMAN Isoform 2 of Phospholipid transfer protein OS=Homo sapiens GN=PLTP 95 ICH Victim sp|P55058-2|PLTP_HUMAN Isoform 2 of Phospholipid transfer protein OS=Homo sapiens GN=PLTP 48 AIS Victim sp|P05155-2|IC1_HUMAN Isoform 2 of Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 540

ICH Control sp|P05155-2|IC1_HUMAN Isoform 2 of Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 1432 ICH Victim sp|P05155-2|IC1_HUMAN Isoform 2 of Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 969 ICH Control sp|P56696-2|KCNQ4_HUMAN Isoform 2 of Potassium voltage-gated channel subfamily KQT member 4 OS=Homo sapiens GN=KCNQ4 37 AIS Victim sp|P20742-2|PZP_HUMAN Isoform 2 of Pregnancy zone protein OS=Homo sapiens GN=PZP 116

ICH Control sp|P20742-2|PZP_HUMAN Isoform 2 of Pregnancy zone protein OS=Homo sapiens GN=PZP 38 ICH Victim sp|P20742-2|PZP_HUMAN Isoform 2 of Pregnancy zone protein OS=Homo sapiens GN=PZP 38 ICH Control sp|Q9Y255-2|PRLD1_HUMAN Isoform 2 of PRELI domain-containing protein 1, mitochondrial OS=Homo sapiens GN=PRELID1 36

ICH Victim sp|Q9HCQ7-2|NPVF_HUMAN Isoform 2 of Pro-FMRFamide-related neuropeptide VF OS=Homo sapiens GN=NPVF 39

AIS Victim sp|Q9H6K5-2|PRR36_HUMAN Isoform 2 of Proline-rich protein 36 OS=Homo sapiens GN=PRR36 39 AIS Victim sp|O94964-2|SOGA1_HUMAN Isoform 2 of Protein SOGA1 OS=Homo sapiens GN=SOGA1 39 ICH Control sp|Q9BVV6-2|TALD3_HUMAN Isoform 2 of Protein TALPID3 OS=Homo sapiens GN=KIAA0586 38 AIS Control sp|Q2TV78-2|MST1L_HUMAN Isoform 2 of Putative macrophage stimulating 1-like protein OS=Homo sapiens GN=MST1L 63

ICH Control sp|Q2TV78-2|MST1L_HUMAN Isoform 2 of Putative macrophage stimulating 1-like protein OS=Homo sapiens GN=MST1L 52 ICH Victim sp|Q2TV78-2|MST1L_HUMAN Isoform 2 of Putative macrophage stimulating 1-like protein OS=Homo sapiens GN=MST1L 65 ICH Control sp|Q9P2R3-2|ANFY1_HUMAN Isoform 2 of Rabankyrin-5 OS=Homo sapiens GN=ANKFY1 40 AIS Victim sp|Q5VT52-2|RPRD2_HUMAN Isoform 2 of Regulation of nuclear pre-mRNA domain-containing protein 2 OS=Homo sapiens GN=RPRD2 42

ICH Victim sp|Q5VT52-2|RPRD2_HUMAN Isoform 2 of Regulation of nuclear pre-mRNA domain-containing protein 2 OS=Homo sapiens GN=RPRD2 42 ICH Victim sp|Q9BZI7-2|REN3B_HUMAN Isoform 2 of Regulator of nonsense transcripts 3B OS=Homo sapiens GN=UPF3B 37 AIS Victim sp|O76054-4|S14L2_HUMAN Isoform 2 of SEC14-like protein 2 OS=Homo sapiens GN=SEC14L2 46 ICH Victim sp|O76054-4|S14L2_HUMAN Isoform 2 of SEC14-like protein 2 OS=Homo sapiens GN=SEC14L2 37

AIS Control sp|Q8IYB3-2|SRRM1_HUMAN Isoform 2 of Serine/arginine repetitive matrix protein 1 OS=Homo sapiens GN=SRRM1 37 ICH Victim sp|P36952-2|SPB5_HUMAN Isoform 2 of Serpin B5 OS=Homo sapiens GN=SERPINB5 38 ICH Victim sp|P04278-2|SHBG_HUMAN Isoform 2 of Sex hormone-binding globulin OS=Homo sapiens GN=SHBG 117

ICH Control sp|Q9UI33-2|SCNBA_HUMAN Isoform 2 of Sodium channel protein type 11 subunit alpha OS=Homo sapiens GN=SCN11A 37

ICH Control sp|Q07890-2|SOS2_HUMAN Isoform 2 of Son of sevenless homolog 2 OS=Homo sapiens GN=SOS2 35 AIS Victim sp|Q14247-2|SRC8_HUMAN Isoform 2 of Src substrate cortactin OS=Homo sapiens GN=CTTN 35 ICH Victim sp|Q8NDV3-2|SMC1B_HUMAN Isoform 2 of Structural maintenance of chromosomes protein 1B OS=Homo sapiens GN=SMC1B 37 ICH Victim sp|O00391-2|QSOX1_HUMAN Isoform 2 of Sulfhydryl oxidase 1 OS=Homo sapiens GN=QSOX1 81

AIS Victim sp|Q9BYX2-2|TBD2A_HUMAN Isoform 2 of TBC1 domain family member 2A OS=Homo sapiens GN=TBC1D2 39 ICH Control sp|Q9BYX2-2|TBD2A_HUMAN Isoform 2 of TBC1 domain family member 2A OS=Homo sapiens GN=TBC1D2 37 ICH Control sp|Q9NXF1-2|TEX10_HUMAN Isoform 2 of Testis-expressed sequence 10 protein OS=Homo sapiens GN=TEX10 48 AIS Control sp|P07996-2|TSP1_HUMAN Isoform 2 of Thrombospondin-1 OS=Homo sapiens GN=THBS1 37

AIS Victim sp|P07996-2|TSP1_HUMAN Isoform 2 of Thrombospondin-1 OS=Homo sapiens GN=THBS1 96 ICH Victim sp|P07996-2|TSP1_HUMAN Isoform 2 of Thrombospondin-1 OS=Homo sapiens GN=THBS1 103

120

AIS Victim sp|Q8WZ42-2|TITIN_HUMAN Isoform 2 of Titin OS=Homo sapiens GN=TTN 46 ICH Victim sp|Q92481-2|AP2B_HUMAN Isoform 2 of Transcription factor AP-2-beta OS=Homo sapiens GN=TFAP2B 35 ICH Victim sp|Q96MC5-2|CP045_HUMAN Isoform 2 of Uncharacterized protein C16orf45 OS=Homo sapiens GN=C16orf45 38 AIS Victim sp|Q9GZN8-2|CT027_HUMAN Isoform 2 of UPF0687 protein C20orf27 OS=Homo sapiens GN=C20orf27 37

AIS Control sp|P22891-2|PROZ_HUMAN Isoform 2 of Vitamin K-dependent protein Z OS=Homo sapiens GN=PROZ 53 ICH Control sp|P22891-2|PROZ_HUMAN Isoform 2 of Vitamin K-dependent protein Z OS=Homo sapiens GN=PROZ 78 ICH Control sp|Q9Y4E6-2|WDR7_HUMAN Isoform 2 of WD repeat-containing protein 7 OS=Homo sapiens GN=WDR7 37 ICH Control sp|Q6ZQQ6-2|WDR87_HUMAN Isoform 2 of WD repeat-containing protein 87 OS=Homo sapiens GN=WDR87 39

ICH Victim sp|O14791-3|APOL1_HUMAN Isoform 3 of Apolipoprotein L1 OS=Homo sapiens GN=APOL1 121 ICH Control sp|O75882-3|ATRN_HUMAN Isoform 3 of Attractin OS=Homo sapiens GN=ATRN 127 ICH Victim sp|O75882-3|ATRN_HUMAN Isoform 3 of Attractin OS=Homo sapiens GN=ATRN 59 ICH Control sp|Q9HB09-3|B2L12_HUMAN Isoform 3 of Bcl-2-like protein 12 OS=Homo sapiens GN=BCL2L12 40

AIS Victim sp|A5YM72-3|CRNS1_HUMAN Isoform 3 of Carnosine synthase 1 OS=Homo sapiens GN=CARNS1 35 AIS Victim sp|P16070-3|CD44_HUMAN Isoform 3 of CD44 antigen OS=Homo sapiens GN=CD44 62 AIS Control sp|Q02224-3|CENPE_HUMAN Isoform 3 of Centromere-associated protein E OS=Homo sapiens GN=CENPE 44

ICH Control sp|Q02224-3|CENPE_HUMAN Isoform 3 of Centromere-associated protein E OS=Homo sapiens GN=CENPE 44

ICH Victim sp|Q02224-3|CENPE_HUMAN Isoform 3 of Centromere-associated protein E OS=Homo sapiens GN=CENPE 44 AIS Control sp|P10909-3|CLUS_HUMAN Isoform 3 of Clusterin OS=Homo sapiens GN=CLU 44 ICH Control sp|P10909-3|CLUS_HUMAN Isoform 3 of Clusterin OS=Homo sapiens GN=CLU 598 ICH Victim sp|P10909-3|CLUS_HUMAN Isoform 3 of Clusterin OS=Homo sapiens GN=CLU 371

ICH Victim sp|Q5FWF4-3|ZRAB3_HUMAN Isoform 3 of DNA annealing helicase and endonuclease ZRANB3 OS=Homo sapiens GN=ZRANB3 37 AIS Control sp|P55060-3|XPO2_HUMAN Isoform 3 of Exportin-2 OS=Homo sapiens GN=CSE1L 51 AIS Victim sp|P55060-3|XPO2_HUMAN Isoform 3 of Exportin-2 OS=Homo sapiens GN=CSE1L 37 ICH Victim sp|P55060-3|XPO2_HUMAN Isoform 3 of Exportin-2 OS=Homo sapiens GN=CSE1L 45

AIS Control sp|Q16610-3|ECM1_HUMAN Isoform 3 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 61 AIS Victim sp|Q16610-3|ECM1_HUMAN Isoform 3 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 43 ICH Victim sp|Q16610-3|ECM1_HUMAN Isoform 3 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 42 AIS Control sp|Q0JRZ9-3|FCHO2_HUMAN Isoform 3 of F-BAR domain only protein 2 OS=Homo sapiens GN=FCHO2 40

ICH Control sp|Q0JRZ9-3|FCHO2_HUMAN Isoform 3 of F-BAR domain only protein 2 OS=Homo sapiens GN=FCHO2 46 ICH Control sp|Q13439-3|GOGA4_HUMAN Isoform 3 of Golgin subfamily A member 4 OS=Homo sapiens GN=GOLGA4 36 ICH Control sp|P01042-3|KNG1_HUMAN Isoform 3 of Kininogen-1 OS=Homo sapiens GN=KNG1 426

ICH Victim sp|P00338-3|LDHA_HUMAN Isoform 3 of L-lactate dehydrogenase A chain OS=Homo sapiens GN=LDHA 103

ICH Victim sp|Q496Y0-3|LONF3_HUMAN Isoform 3 of LON peptidase N-terminal domain and RING finger protein 3 OS=Homo sapiens GN=LONRF3 45 AIS Control sp|Q5VST9-3|OBSCN_HUMAN Isoform 3 of Obscurin OS=Homo sapiens GN=OBSCN 44 ICH Control sp|Q5VST9-3|OBSCN_HUMAN Isoform 3 of Obscurin OS=Homo sapiens GN=OBSCN 45 ICH Control sp|Q8TCU6-3|PREX1_HUMAN Isoform 3 of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein OS=Homo sapiens GN=PREX1 35

AIS Victim sp|P05155-3|IC1_HUMAN Isoform 3 of Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 854 ICH Control sp|P05155-3|IC1_HUMAN Isoform 3 of Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 958 ICH Victim sp|Q9Y570-3|PPME1_HUMAN Isoform 3 of Protein phosphatase methylesterase 1 OS=Homo sapiens GN=PPME1 36 ICH Victim sp|Q9BVV6-3|TALD3_HUMAN Isoform 3 of Protein TALPID3 OS=Homo sapiens GN=KIAA0586 38

ICH Control sp|P49798-3|RGS4_HUMAN Isoform 3 of Regulator of G-protein signaling 4 OS=Homo sapiens GN=RGS4 35 AIS Victim sp|Q8WZ42-3|TITIN_HUMAN Isoform 3 of Titin OS=Homo sapiens GN=TTN 46 AIS Victim sp|Q7Z392-3|TPC11_HUMAN Isoform 3 of Trafficking protein particle complex subunit 11 OS=Homo sapiens GN=TRAPPC11 41 ICH Control sp|Q96HZ4-3|HES6_HUMAN Isoform 3 of Transcription cofactor HES-6 OS=Homo sapiens GN=HES6 35

ICH Victim sp|Q96HZ4-3|HES6_HUMAN Isoform 3 of Transcription cofactor HES-6 OS=Homo sapiens GN=HES6 34 AIS Victim sp|P07951-3|TPM2_HUMAN Isoform 3 of Tropomyosin beta chain OS=Homo sapiens GN=TPM2 57 ICH Victim sp|Q8WVN8-3|UB2Q2_HUMAN Isoform 3 of Ubiquitin-conjugating enzyme E2 Q2 OS=Homo sapiens GN=UBE2Q2 42

AIS Control sp|P02774-3|VTDB_HUMAN Isoform 3 of Vitamin D-binding protein OS=Homo sapiens GN=GC 925

AIS Victim sp|P02774-3|VTDB_HUMAN Isoform 3 of Vitamin D-binding protein OS=Homo sapiens GN=GC 669 ICH Control sp|P02774-3|VTDB_HUMAN Isoform 3 of Vitamin D-binding protein OS=Homo sapiens GN=GC 663 ICH Victim sp|P02774-3|VTDB_HUMAN Isoform 3 of Vitamin D-binding protein OS=Homo sapiens GN=GC 891 AIS Victim sp|P10909-4|CLUS_HUMAN Isoform 4 of Clusterin OS=Homo sapiens GN=CLU 1783

ICH Victim sp|P10909-4|CLUS_HUMAN Isoform 4 of Clusterin OS=Homo sapiens GN=CLU 429 AIS Control sp|Q16610-4|ECM1_HUMAN Isoform 4 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 101 AIS Victim sp|Q16610-4|ECM1_HUMAN Isoform 4 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 198 ICH Control sp|Q16610-4|ECM1_HUMAN Isoform 4 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 134

ICH Victim sp|Q16610-4|ECM1_HUMAN Isoform 4 of Extracellular matrix protein 1 OS=Homo sapiens GN=ECM1 96 ICH Control sp|P06396-4|GELS_HUMAN Isoform 4 of Gelsolin OS=Homo sapiens GN=GSN 437

121

ICH Victim sp|P06396-4|GELS_HUMAN Isoform 4 of Gelsolin OS=Homo sapiens GN=GSN 911 ICH Control sp|Q9NPH3-5|IL1AP_HUMAN Isoform 4 of Interleukin-1 receptor accessory protein OS=Homo sapiens GN=IL1RAP 49 AIS Victim sp|Q9UHB6-4|LIMA1_HUMAN Isoform 4 of LIM domain and actin-binding protein 1 OS=Homo sapiens GN=LIMA1 39 ICH Control sp|P20929-4|NEBU_HUMAN Isoform 4 of Nebulin OS=Homo sapiens GN=NEB 48

ICH Victim sp|Q0ZGT2-4|NEXN_HUMAN Isoform 4 of Nexilin OS=Homo sapiens GN=NEXN 35 ICH Victim sp|P55058-4|PLTP_HUMAN Isoform 4 of Phospholipid transfer protein OS=Homo sapiens GN=PLTP 79 AIS Victim sp|Q15020-4|SART3_HUMAN Isoform 4 of Squamous cell carcinoma antigen recognized by T-cells 3 OS=Homo sapiens GN=SART3 39 ICH Control sp|Q8NB59-4|SYT14_HUMAN Isoform 4 of Synaptotagmin-14 OS=Homo sapiens GN=SYT14 33

ICH Victim sp|P22105-3|TENX_HUMAN Isoform 4 of Tenascin-X OS=Homo sapiens GN=TNXB 56 AIS Victim sp|P06753-4|TPM3_HUMAN Isoform 4 of Tropomyosin alpha-3 chain OS=Homo sapiens GN=TPM3 57 AIS Control sp|Q5VIR6-4|VPS53_HUMAN Isoform 4 of Vacuolar protein sorting-associated protein 53 homolog OS=Homo sapiens GN=VPS53 37 AIS Victim sp|Q9C0C7-5|AMRA1_HUMAN Isoform 5 of Activating molecule in BECN1-regulated autophagy protein 1 OS=Homo sapiens GN=AMBRA1 38

ICH Victim sp|Q9C0C7-5|AMRA1_HUMAN Isoform 5 of Activating molecule in BECN1-regulated autophagy protein 1 OS=Homo sapiens GN=AMBRA1 37 ICH Control sp|P0C869-6|PA24B_HUMAN Isoform 5 of Cytosolic phospholipase A2 beta OS=Homo sapiens GN=PLA2G4B 40 AIS Victim sp|Q9ULD2-6|MTUS1_HUMAN Isoform 6 of Microtubule-associated tumor suppressor 1 OS=Homo sapiens GN=MTUS1 40

ICH Victim sp|P02751-7|FINC_HUMAN Isoform 7 of Fibronectin OS=Homo sapiens GN=FN1 4918

ICH Control sp|Q9ULD2-7|MTUS1_HUMAN Isoform 7 of Microtubule-associated tumor suppressor 1 OS=Homo sapiens GN=MTUS1 36 AIS Victim sp|Q9HCH5-11|SYTL2_HUMAN Isoform 8 of Synaptotagmin-like protein 2 OS=Homo sapiens GN=SYTL2 42 ICH Control sp|Q659C4-9|LAR1B_HUMAN Isoform 9 of La-related protein 1B OS=Homo sapiens GN=LARP1B 60 ICH Control sp|P53367-2|ARFP1_HUMAN Isoform A of Arfaptin-1 OS=Homo sapiens GN=ARFIP1 39

AIS Victim sp|Q92954-2|PRG4_HUMAN Isoform B of Proteoglycan 4 OS=Homo sapiens GN=PRG4 65 ICH Control sp|Q92954-2|PRG4_HUMAN Isoform B of Proteoglycan 4 OS=Homo sapiens GN=PRG4 70 ICH Victim sp|Q92954-2|PRG4_HUMAN Isoform B of Proteoglycan 4 OS=Homo sapiens GN=PRG4 49 AIS Victim sp|Q14978-2|NOLC1_HUMAN Isoform Beta of Nucleolar and coiled-body phosphoprotein 1 OS=Homo sapiens GN=NOLC1 37

ICH Victim sp|Q14978-2|NOLC1_HUMAN Isoform Beta of Nucleolar and coiled-body phosphoprotein 1 OS=Homo sapiens GN=NOLC1 39 AIS Victim sp|Q92954-3|PRG4_HUMAN Isoform C of Proteoglycan 4 OS=Homo sapiens GN=PRG4 200 ICH Control sp|Q92954-3|PRG4_HUMAN Isoform C of Proteoglycan 4 OS=Homo sapiens GN=PRG4 38

AIS Victim sp|Q92954-5|PRG4_HUMAN Isoform E of Proteoglycan 4 OS=Homo sapiens GN=PRG4 65

AIS Control sp|Q92954-6|PRG4_HUMAN Isoform F of Proteoglycan 4 OS=Homo sapiens GN=PRG4 111 ICH Control sp|Q92954-6|PRG4_HUMAN Isoform F of Proteoglycan 4 OS=Homo sapiens GN=PRG4 142 ICH Victim sp|Q92954-6|PRG4_HUMAN Isoform F of Proteoglycan 4 OS=Homo sapiens GN=PRG4 190 AIS Control sp|P02679-2|FIBG_HUMAN Isoform Gamma-A of Fibrinogen gamma chain OS=Homo sapiens GN=FGG 1841

AIS Victim sp|P02679-2|FIBG_HUMAN Isoform Gamma-A of Fibrinogen gamma chain OS=Homo sapiens GN=FGG 5833 ICH Control sp|P02679-2|FIBG_HUMAN Isoform Gamma-A of Fibrinogen gamma chain OS=Homo sapiens GN=FGG 778 ICH Victim sp|P02679-2|FIBG_HUMAN Isoform Gamma-A of Fibrinogen gamma chain OS=Homo sapiens GN=FGG 1601 AIS Control sp|P13473-2|LAMP2_HUMAN Isoform LAMP-2B of Lysosome-associated membrane glycoprotein 2 OS=Homo sapiens GN=LAMP2 39

ICH Control sp|P13473-2|LAMP2_HUMAN Isoform LAMP-2B of Lysosome-associated membrane glycoprotein 2 OS=Homo sapiens GN=LAMP2 52 ICH Victim sp|P13473-2|LAMP2_HUMAN Isoform LAMP-2B of Lysosome-associated membrane glycoprotein 2 OS=Homo sapiens GN=LAMP2 36 AIS Control sp|P01042-2|KNG1_HUMAN Isoform LMW of Kininogen-1 OS=Homo sapiens GN=KNG1 303 AIS Victim sp|P01042-2|KNG1_HUMAN Isoform LMW of Kininogen-1 OS=Homo sapiens GN=KNG1 857

ICH Control sp|P01042-2|KNG1_HUMAN Isoform LMW of Kininogen-1 OS=Homo sapiens GN=KNG1 66 ICH Victim sp|P01042-2|KNG1_HUMAN Isoform LMW of Kininogen-1 OS=Homo sapiens GN=KNG1 215 AIS Victim sp|P36980-2|FHR2_HUMAN Isoform Short of Complement factor H-related protein 2 OS=Homo sapiens GN=CFHR2 38

ICH Control sp|P36980-2|FHR2_HUMAN Isoform Short of Complement factor H-related protein 2 OS=Homo sapiens GN=CFHR2 162

AIS Control tr|M0QXA9|M0QXA9_HUMAN Izumo sperm-egg fusion protein 2 (Fragment) OS=Homo sapiens GN=IZUMO2 PE=4 SV=1 44 AIS Victim tr|M0QXA9|M0QXA9_HUMAN Izumo sperm-egg fusion protein 2 (Fragment) OS=Homo sapiens GN=IZUMO2 PE=4 SV=1 54 ICH Control tr|M0R2L8|M0R2L8_HUMAN Izumo sperm-egg fusion protein 2 (Fragment) OS=Homo sapiens GN=IZUMO2 PE=4 SV=1 38 ICH Victim tr|M0QXA9|M0QXA9_HUMAN Izumo sperm-egg fusion protein 2 (Fragment) OS=Homo sapiens GN=IZUMO2 PE=4 SV=1 43

AIS Control tr|H0Y343|H0Y343_HUMAN Jouberin (Fragment) OS=Homo sapiens GN=AHI1 PE=1 SV=1 39 AIS Control sp|P29622|KAIN_HUMAN Kallistatin OS=Homo sapiens GN=SERPINA4 PE=1 SV=3 87

122

AIS Victim tr|A0A087X0P0|A0A087X0P0_HUMAN Kinesin-like protein OS=Homo sapiens GN=CENPE PE=1 SV=1 48 ICH Control tr|A0A087X0P0|A0A087X0P0_HUMAN Kinesin-like protein OS=Homo sapiens GN=CENPE PE=1 SV=1 43 ICH Victim tr|A0A087X0P0|A0A087X0P0_HUMAN Kinesin-like protein OS=Homo sapiens GN=CENPE PE=1 SV=1 44 ICH Victim tr|J3KNA1|J3KNA1_HUMAN Kinesin-like protein OS=Homo sapiens GN=KIF5A PE=1 SV=1 52

AIS Control sp|P01042|KNG1_HUMAN Kininogen-1 OS=Homo sapiens GN=KNG1 PE=1 SV=2 1635 AIS Victim sp|P01042|KNG1_HUMAN Kininogen-1 OS=Homo sapiens GN=KNG1 PE=1 SV=2 84 ICH Control sp|P01042|KNG1_HUMAN Kininogen-1 OS=Homo sapiens GN=KNG1 PE=1 SV=2 1050 ICH Victim sp|P01042|KNG1_HUMAN Kininogen-1 OS=Homo sapiens GN=KNG1 PE=1 SV=2 571

AIS Control tr|H0Y9K3|H0Y9K3_HUMAN La-related protein 1B (Fragment) OS=Homo sapiens GN=LARP1B PE=1 SV=1 36

ICH Victim tr|D6RJB0|D6RJB0_HUMAN La-related protein 1B (Fragment) OS=Homo sapiens GN=LARP1B PE=1 SV=5 38 AIS Victim tr|D6R9W6|D6R9W6_HUMAN La-related protein 1B OS=Homo sapiens GN=LARP1B PE=1 SV=1 41 ICH Control tr|J3KP02|J3KP02_HUMAN Leucine-, glutamate- and lysine-rich protein 1 OS=Homo sapiens GN=LEKR1 PE=4 SV=1 41 AIS Control sp|P02750|A2GL_HUMAN Leucine-rich alpha-2-glycoprotein OS=Homo sapiens GN=LRG1 PE=1 SV=2 104

AIS Victim sp|P02750|A2GL_HUMAN Leucine-rich alpha-2-glycoprotein OS=Homo sapiens GN=LRG1 PE=1 SV=2 126 ICH Control sp|P02750|A2GL_HUMAN Leucine-rich alpha-2-glycoprotein OS=Homo sapiens GN=LRG1 PE=1 SV=2 146 ICH Victim sp|P02750|A2GL_HUMAN Leucine-rich alpha-2-glycoprotein OS=Homo sapiens GN=LRG1 PE=1 SV=2 107 ICH Victim sp|Q96AG4|LRC59_HUMAN Leucine-rich repeat-containing protein 59 OS=Homo sapiens GN=LRRC59 PE=1 SV=1 36

AIS Victim sp|Q7Z2Q7|LRR70_HUMAN Leucine-rich repeat-containing protein 70 OS=Homo sapiens GN=LRRC70 PE=2 SV=1 35 ICH Control tr|F8VQE1|F8VQE1_HUMAN LIM domain and actin-binding protein 1 OS=Homo sapiens GN=LIMA1 PE=1 SV=1 40 ICH Victim tr|F8VQE1|F8VQE1_HUMAN LIM domain and actin-binding protein 1 OS=Homo sapiens GN=LIMA1 PE=1 SV=1 37 AIS Victim sp|Q9UN81|LORF1_HUMAN LINE-1 retrotransposable element ORF1 protein OS=Homo sapiens GN=L1RE1 PE=1 SV=1 37

AIS Control sp|O00370|LORF2_HUMAN LINE-1 retrotransposable element ORF2 protein OS=Homo sapiens PE=1 SV=1 36 AIS Control sp|P18428|LBP_HUMAN Lipopolysaccharide-binding protein OS=Homo sapiens GN=LBP PE=1 SV=3 57 AIS Victim sp|P18428|LBP_HUMAN Lipopolysaccharide-binding protein OS=Homo sapiens GN=LBP PE=1 SV=3 315

ICH Control sp|P18428|LBP_HUMAN Lipopolysaccharide-binding protein OS=Homo sapiens GN=LBP PE=1 SV=3 117

ICH Victim sp|P18428|LBP_HUMAN Lipopolysaccharide-binding protein OS=Homo sapiens GN=LBP PE=1 SV=3 100 ICH Victim sp|P07195|LDHB_HUMAN L-lactate dehydrogenase B chain OS=Homo sapiens GN=LDHB PE=1 SV=2 73 ICH Victim tr|F5H245|F5H245_HUMAN L-lactate dehydrogenase OS=Homo sapiens GN=LDHC PE=1 SV=1 72 ICH Victim tr|H0Y7Q8|H0Y7Q8_HUMAN LON peptidase N-terminal domain and RING finger protein 3 (Fragment) OS=Homo sapiens GN=LONRF3 PE=1 SV=1 43

AIS Control sp|Q496Y0|LONF3_HUMAN LON peptidase N-terminal domain and RING finger protein 3 OS=Homo sapiens GN=LONRF3 PE=1 SV=1 39 AIS Victim sp|Q496Y0|LONF3_HUMAN LON peptidase N-terminal domain and RING finger protein 3 OS=Homo sapiens GN=LONRF3 PE=1 SV=1 37 ICH Control sp|Q496Y0|LONF3_HUMAN LON peptidase N-terminal domain and RING finger protein 3 OS=Homo sapiens GN=LONRF3 PE=1 SV=1 36 AIS Victim tr|E7ERD7|E7ERD7_HUMAN Long-chain-fatty-acid--CoA ligase 6 OS=Homo sapiens GN=ACSL6 PE=1 SV=1 42

AIS Control tr|H0YMC3|H0YMC3_HUMAN Long-chain-fatty-acid--CoA ligase ACSBG1 (Fragment) OS=Homo sapiens GN=ACSBG1 PE=1 SV=1 37 AIS Control tr|H0Y755|H0Y755_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-A (Fragment) OS=Homo sapiens GN=FCGR3A PE=1 SV=1 42 AIS Victim tr|H0Y755|H0Y755_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-A (Fragment) OS=Homo sapiens GN=FCGR3A PE=1 SV=1 63 ICH Control tr|H0Y755|H0Y755_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-A (Fragment) OS=Homo sapiens GN=FCGR3A PE=1 SV=1 70

ICH Victim tr|H0Y755|H0Y755_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-A (Fragment) OS=Homo sapiens GN=FCGR3A PE=1 SV=1 65 AIS Control tr|A0A087WU90|A0A087WU90_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-B OS=Homo sapiens GN=FCGR3B PE=1 SV=1 52 ICH Control tr|A0A087WZR4|A0A087WZR4_HUMAN Low affinity immunoglobulin gamma Fc region receptor III-B OS=Homo sapiens GN=FCGR3B PE=1 SV=1 104

AIS Control sp|P14151|LYAM1_HUMAN L-selectin OS=Homo sapiens GN=SELL PE=1 SV=2 50

AIS Victim sp|P14151|LYAM1_HUMAN L-selectin OS=Homo sapiens GN=SELL PE=1 SV=2 47 AIS Control sp|P51884|LUM_HUMAN Lumican OS=Homo sapiens GN=LUM PE=1 SV=2 37 AIS Victim sp|P51884|LUM_HUMAN Lumican OS=Homo sapiens GN=LUM PE=1 SV=2 44 ICH Control sp|P51884|LUM_HUMAN Lumican OS=Homo sapiens GN=LUM PE=1 SV=2 74

ICH Victim sp|P51884|LUM_HUMAN Lumican OS=Homo sapiens GN=LUM PE=1 SV=2 39 ICH Victim sp|Q9Y5Y7|LYVE1_HUMAN Lymphatic vessel endothelial hyaluronic acid receptor 1 OS=Homo sapiens GN=LYVE1 PE=1 SV=2 39 ICH Control tr|H0YAR1|H0YAR1_HUMAN Lysyl oxidase homolog 2 (Fragment) OS=Homo sapiens GN=LOXL2 PE=1 SV=1 38 ICH Victim tr|H0YAR1|H0YAR1_HUMAN Lysyl oxidase homolog 2 (Fragment) OS=Homo sapiens GN=LOXL2 PE=1 SV=1 36

ICH Victim tr|E9PEK4|E9PEK4_HUMAN Macrophage colony-stimulating factor 1 receptor OS=Homo sapiens GN=CSF1R PE=1 SV=1 35 AIS Control tr|A0A087WU53|A0A087WU53_HUMAN Magnesium transporter protein 1 OS=Homo sapiens GN=MAGT1 PE=1 SV=1 57

123

ICH Control tr|A0A087WU53|A0A087WU53_HUMAN Magnesium transporter protein 1 OS=Homo sapiens GN=MAGT1 PE=1 SV=1 49 ICH Control tr|F8W876|F8W876_HUMAN Mannan-binding lectin serine protease 1 OS=Homo sapiens GN=MASP1 PE=1 SV=1 45 ICH Control sp|P48740|MASP1_HUMAN Mannan-binding lectin serine protease 1 OS=Homo sapiens GN=MASP1 PE=1 SV=3 35 ICH Victim sp|P48740|MASP1_HUMAN Mannan-binding lectin serine protease 1 OS=Homo sapiens GN=MASP1 PE=1 SV=3 202

ICH Victim sp|O00187|MASP2_HUMAN Mannan-binding lectin serine protease 2 OS=Homo sapiens GN=MASP2 PE=1 SV=4 42 ICH Control sp|P11226|MBL2_HUMAN Mannose-binding protein C OS=Homo sapiens GN=MBL2 PE=1 SV=2 55 ICH Victim sp|P11226|MBL2_HUMAN Mannose-binding protein C OS=Homo sapiens GN=MBL2 PE=1 SV=2 46 AIS Victim sp|Q9NVC6|MED17_HUMAN Mediator of RNA polymerase II transcription subunit 17 OS=Homo sapiens GN=MED17 PE=1 SV=2 37

ICH Control tr|H7C052|H7C052_HUMAN Melanophilin (Fragment) OS=Homo sapiens GN=MLPH PE=1 SV=1 39 ICH Victim tr|B8ZZX6|B8ZZX6_HUMAN Metalloreductase STEAP3 OS=Homo sapiens GN=STEAP3 PE=1 SV=1 35 AIS Victim tr|K7EIE8|K7EIE8_HUMAN Methyl-CpG binding domain protein 3, isoform CRA_b OS=Homo sapiens GN=MBD3 PE=1 SV=1 37 AIS Victim sp|Q9BRT3|MIEN1_HUMAN Migration and invasion enhancer 1 OS=Homo sapiens GN=MIEN1 PE=1 SV=1 36

AIS Control tr|J3QSG2|J3QSG2_HUMAN Mitochondrial Rho GTPase 1 (Fragment) OS=Homo sapiens GN=RHOT1 PE=4 SV=1 67 AIS Victim tr|J3QSG2|J3QSG2_HUMAN Mitochondrial Rho GTPase 1 (Fragment) OS=Homo sapiens GN=RHOT1 PE=4 SV=1 69 ICH Control tr|J3QSG2|J3QSG2_HUMAN Mitochondrial Rho GTPase 1 (Fragment) OS=Homo sapiens GN=RHOT1 PE=4 SV=1 46

ICH Victim tr|J3QSG2|J3QSG2_HUMAN Mitochondrial Rho GTPase 1 (Fragment) OS=Homo sapiens GN=RHOT1 PE=4 SV=1 54

ICH Control sp|Q99683|M3K5_HUMAN Mitogen-activated protein kinase kinase kinase 5 OS=Homo sapiens GN=MAP3K5 PE=1 SV=1 38 AIS Control tr|D6RFL4|D6RFL4_HUMAN Monocyte differentiation antigen CD14 (Fragment) OS=Homo sapiens GN=CD14 PE=1 SV=1 55 AIS Victim tr|D6RFL4|D6RFL4_HUMAN Monocyte differentiation antigen CD14 (Fragment) OS=Homo sapiens GN=CD14 PE=1 SV=1 123 ICH Victim tr|D6RFL4|D6RFL4_HUMAN Monocyte differentiation antigen CD14 (Fragment) OS=Homo sapiens GN=CD14 PE=1 SV=1 56

ICH Control sp|P08571|CD14_HUMAN Monocyte differentiation antigen CD14 OS=Homo sapiens GN=CD14 PE=1 SV=2 60 ICH Victim sp|P08571|CD14_HUMAN Monocyte differentiation antigen CD14 OS=Homo sapiens GN=CD14 PE=1 SV=2 40 AIS Control tr|A0A0G2JRI9|A0A0G2JRI9_HUMAN Mucin-20 OS=Homo sapiens GN=MUC20 PE=4 SV=1 38 AIS Victim sp|Q96PD5|PGRP2_HUMAN N-acetylmuramoyl-L-alanine amidase OS=Homo sapiens GN=PGLYRP2 PE=1 SV=1 316

ICH Victim sp|Q96PD5|PGRP2_HUMAN N-acetylmuramoyl-L-alanine amidase OS=Homo sapiens GN=PGLYRP2 PE=1 SV=1 481 ICH Victim tr|F8VRL7|F8VRL7_HUMAN Natural resistance-associated macrophage protein 2 OS=Homo sapiens GN=SLC11A2 PE=4 SV=1 37 ICH Victim tr|F8W050|F8W050_HUMAN Nck-associated protein 1-like OS=Homo sapiens GN=NCKAP1L PE=1 SV=1 45 ICH Control sp|P48681|NEST_HUMAN Nestin OS=Homo sapiens GN=NES PE=1 SV=2 36

ICH Control sp|O00533|NCHL1_HUMAN Neural cell adhesion molecule L1-like protein OS=Homo sapiens GN=CHL1 PE=1 SV=4 55 ICH Control tr|H7C2R2|H7C2R2_HUMAN Neurochondrin (Fragment) OS=Homo sapiens GN=NCDN PE=1 SV=1 40 ICH Victim tr|F6X2W2|F6X2W2_HUMAN Neuronal growth regulator 1 OS=Homo sapiens GN=NEGR1 PE=1 SV=1 40

ICH Control sp|P59665|DEF1_HUMAN Neutrophil defensin 1 OS=Homo sapiens GN=DEFA1 PE=1 SV=1 60

AIS Victim tr|H7C0A1|H7C0A1_HUMAN N-glycosylase/DNA lyase (Fragment) OS=Homo sapiens GN=OGG1 PE=1 SV=1 47 ICH Control tr|A0A087WY61|A0A087WY61_HUMAN Nuclear mitotic apparatus protein 1 OS=Homo sapiens GN=NUMA1 PE=1 SV=1 35 ICH Victim tr|H0YDF4|H0YDF4_HUMAN Nuclear pore complex protein Nup98-Nup96 (Fragment) OS=Homo sapiens GN=NUP98 PE=1 SV=1 39 AIS Control tr|A0A0A0MRM9|A0A0A0MRM9_HUMAN Nucleolar and coiled-body phosphoprotein 1 (Fragment) OS=Homo sapiens GN=NOLC1 PE=1 SV=1 53

AIS Victim tr|A0A0A0MRM9|A0A0A0MRM9_HUMAN Nucleolar and coiled-body phosphoprotein 1 (Fragment) OS=Homo sapiens GN=NOLC1 PE=1 SV=1 63 ICH Control tr|A0A0A0MRM9|A0A0A0MRM9_HUMAN Nucleolar and coiled-body phosphoprotein 1 (Fragment) OS=Homo sapiens GN=NOLC1 PE=1 SV=1 64 ICH Victim tr|A0A0A0MRM9|A0A0A0MRM9_HUMAN Nucleolar and coiled-body phosphoprotein 1 (Fragment) OS=Homo sapiens GN=NOLC1 PE=1 SV=1 39 AIS Victim tr|H3BPX2|H3BPX2_HUMAN Obscurin OS=Homo sapiens GN=OBSCN PE=1 SV=2 52

AIS Victim sp|Q99453|PHX2B_HUMAN Paired mesoderm homeobox protein 2B OS=Homo sapiens GN=PHOX2B PE=1 SV=2 39 ICH Control sp|P04746|AMYP_HUMAN Pancreatic alpha-amylase OS=Homo sapiens GN=AMY2A PE=1 SV=2 47 AIS Control sp|O95497|VNN1_HUMAN Pantetheinase OS=Homo sapiens GN=VNN1 PE=1 SV=2 40 ICH Control sp|O95497|VNN1_HUMAN Pantetheinase OS=Homo sapiens GN=VNN1 PE=1 SV=2 39

AIS Control tr|D6RJH8|D6RJH8_HUMAN Pentatricopeptide repeat-containing protein 2, mitochondrial OS=Homo sapiens GN=PTCD2 PE=4 SV=1 49 AIS Victim tr|A0A0A0MRQ5|A0A0A0MRQ5_HUMAN Peroxiredoxin-1 OS=Homo sapiens GN=PRDX1 PE=1 SV=1 50 AIS Victim sp|P32119|PRDX2_HUMAN Peroxiredoxin-2 OS=Homo sapiens GN=PRDX2 PE=1 SV=5 63

ICH Victim sp|P32119|PRDX2_HUMAN Peroxiredoxin-2 OS=Homo sapiens GN=PRDX2 PE=1 SV=5 72

ICH Control tr|H7C3V6|H7C3V6_HUMAN Peroxisomal membrane protein 11B (Fragment) OS=Homo sapiens GN=PEX11B PE=1 SV=1 69 AIS Control tr|A0A0C4DG33|A0A0C4DG33_HUMAN Peroxisome biogenesis factor 1 OS=Homo sapiens GN=PEX1 PE=1 SV=1 39 AIS Victim tr|A0A0C4DG33|A0A0C4DG33_HUMAN Peroxisome biogenesis factor 1 OS=Homo sapiens GN=PEX1 PE=1 SV=1 42 ICH Control tr|A0A0C4DG33|A0A0C4DG33_HUMAN Peroxisome biogenesis factor 1 OS=Homo sapiens GN=PEX1 PE=1 SV=1 45

ICH Victim tr|A0A0C4DG33|A0A0C4DG33_HUMAN Peroxisome biogenesis factor 1 OS=Homo sapiens GN=PEX1 PE=1 SV=1 36 AIS Control sp|O75420|PERQ1_HUMAN PERQ amino acid-rich with GYF domain-containing protein 1 OS=Homo sapiens GN=GIGYF1 PE=1 SV=2 39 AIS Victim sp|O75420|PERQ1_HUMAN PERQ amino acid-rich with GYF domain-containing protein 1 OS=Homo sapiens GN=GIGYF1 PE=1 SV=2 48 ICH Control sp|O75420|PERQ1_HUMAN PERQ amino acid-rich with GYF domain-containing protein 1 OS=Homo sapiens GN=GIGYF1 PE=1 SV=2 43

ICH Victim sp|O75420|PERQ1_HUMAN PERQ amino acid-rich with GYF domain-containing protein 1 OS=Homo sapiens GN=GIGYF1 PE=1 SV=2 44 ICH Control tr|A0A087WUI3|A0A087WUI3_HUMAN PHD finger protein 7 OS=Homo sapiens GN=PHF7 PE=4 SV=1 42

124

ICH Control tr|J3QKT0|J3QKT0_HUMAN Phosphatidylcholine-sterol acyltransferase (Fragment) OS=Homo sapiens GN=LCAT PE=1 SV=1 75 ICH Victim tr|J3QKT0|J3QKT0_HUMAN Phosphatidylcholine-sterol acyltransferase (Fragment) OS=Homo sapiens GN=LCAT PE=1 SV=1 88 AIS Control sp|P04180|LCAT_HUMAN Phosphatidylcholine-sterol acyltransferase OS=Homo sapiens GN=LCAT PE=1 SV=1 37 AIS Victim sp|P04180|LCAT_HUMAN Phosphatidylcholine-sterol acyltransferase OS=Homo sapiens GN=LCAT PE=1 SV=1 37

ICH Control sp|P04180|LCAT_HUMAN Phosphatidylcholine-sterol acyltransferase OS=Homo sapiens GN=LCAT PE=1 SV=1 125 ICH Victim sp|P04180|LCAT_HUMAN Phosphatidylcholine-sterol acyltransferase OS=Homo sapiens GN=LCAT PE=1 SV=1 129 AIS Control sp|Q8TCU6|PREX1_HUMAN Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein OS=Homo sapiens GN=PREX1 PE=1 SV=3 39 AIS Victim tr|H0Y871|H0Y871_HUMAN Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (Fragment) OS=Homo sapiens GN=PIK3CB PE=1 SV=1 43

ICH Control sp|P48736|PK3CG_HUMAN Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform OS=Homo sapiens GN=PIK3CG PE=1 SV=3 42 AIS Control tr|F5GWN5|F5GWN5_HUMAN Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta OS=Homo sapiens GN=PIK3C2B PE=1 SV=1 37 AIS Victim tr|F5GWN5|F5GWN5_HUMAN Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta OS=Homo sapiens GN=PIK3C2B PE=1 SV=1 38 ICH Victim tr|F5GWN5|F5GWN5_HUMAN Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta OS=Homo sapiens GN=PIK3C2B PE=1 SV=1 39

AIS Control sp|P80108|PHLD_HUMAN Phosphatidylinositol-glycan-specific phospholipase D OS=Homo sapiens GN=GPLD1 PE=1 SV=3 83 AIS Victim sp|P80108|PHLD_HUMAN Phosphatidylinositol-glycan-specific phospholipase D OS=Homo sapiens GN=GPLD1 PE=1 SV=3 159 ICH Control sp|P80108|PHLD_HUMAN Phosphatidylinositol-glycan-specific phospholipase D OS=Homo sapiens GN=GPLD1 PE=1 SV=3 66

ICH Victim sp|P80108|PHLD_HUMAN Phosphatidylinositol-glycan-specific phospholipase D OS=Homo sapiens GN=GPLD1 PE=1 SV=3 37

ICH Control tr|I3L4N7|I3L4N7_HUMAN Pigment epithelium-derived factor (Fragment) OS=Homo sapiens GN=SERPINF1 PE=1 SV=1 221 ICH Victim tr|I3L4N7|I3L4N7_HUMAN Pigment epithelium-derived factor (Fragment) OS=Homo sapiens GN=SERPINF1 PE=1 SV=1 144 AIS Control tr|I3L1U4|I3L1U4_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=1 41 AIS Victim tr|I3L1U4|I3L1U4_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=1 62

ICH Control tr|I3L1U4|I3L1U4_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=1 35 ICH Victim tr|I3L1U4|I3L1U4_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=1 44 AIS Control sp|P36955|PEDF_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=4 120 AIS Victim sp|P36955|PEDF_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=4 173

ICH Control sp|P36955|PEDF_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=4 687 ICH Victim sp|P36955|PEDF_HUMAN Pigment epithelium-derived factor OS=Homo sapiens GN=SERPINF1 PE=1 SV=4 80 AIS Control tr|H0YAC1|H0YAC1_HUMAN Plasma kallikrein (Fragment) OS=Homo sapiens GN=KLKB1 PE=1 SV=1 362 AIS Victim tr|H0YAC1|H0YAC1_HUMAN Plasma kallikrein (Fragment) OS=Homo sapiens GN=KLKB1 PE=1 SV=1 286

ICH Control tr|H0YAC1|H0YAC1_HUMAN Plasma kallikrein (Fragment) OS=Homo sapiens GN=KLKB1 PE=1 SV=1 126 ICH Victim tr|H0YAC1|H0YAC1_HUMAN Plasma kallikrein (Fragment) OS=Homo sapiens GN=KLKB1 PE=1 SV=1 170 AIS Control sp|P03952|KLKB1_HUMAN Plasma kallikrein OS=Homo sapiens GN=KLKB1 PE=1 SV=1 317

AIS Victim sp|P03952|KLKB1_HUMAN Plasma kallikrein OS=Homo sapiens GN=KLKB1 PE=1 SV=1 259

ICH Control sp|P03952|KLKB1_HUMAN Plasma kallikrein OS=Homo sapiens GN=KLKB1 PE=1 SV=1 182 AIS Control tr|H0YCA1|H0YCA1_HUMAN Plasma protease C1 inhibitor (Fragment) OS=Homo sapiens GN=SERPING1 PE=1 SV=1 68 AIS Victim tr|H0YCA1|H0YCA1_HUMAN Plasma protease C1 inhibitor (Fragment) OS=Homo sapiens GN=SERPING1 PE=1 SV=1 101 ICH Victim tr|H0YCA1|H0YCA1_HUMAN Plasma protease C1 inhibitor (Fragment) OS=Homo sapiens GN=SERPING1 PE=1 SV=1 153

AIS Control tr|E9PGN7|E9PGN7_HUMAN Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 PE=1 SV=1 72 AIS Victim tr|E9PGN7|E9PGN7_HUMAN Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 PE=1 SV=1 306 ICH Control tr|E9PGN7|E9PGN7_HUMAN Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 PE=1 SV=1 52 ICH Victim tr|E9PGN7|E9PGN7_HUMAN Plasma protease C1 inhibitor OS=Homo sapiens GN=SERPING1 PE=1 SV=1 61

AIS Victim sp|P05154|IPSP_HUMAN Plasma serine protease inhibitor OS=Homo sapiens GN=SERPINA5 PE=1 SV=3 208 ICH Victim sp|P05154|IPSP_HUMAN Plasma serine protease inhibitor OS=Homo sapiens GN=SERPINA5 PE=1 SV=3 58 ICH Victim tr|A6PVI2|A6PVI2_HUMAN Plasminogen (Fragment) OS=Homo sapiens GN=PLG PE=1 SV=1 133 AIS Control sp|P00747|PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 541

AIS Victim sp|P00747|PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 73 ICH Control sp|P00747|PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 134 ICH Victim sp|P00747|PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 234

AIS Control sp|Q02325|PLGB_HUMAN Plasminogen-like protein B OS=Homo sapiens GN=PLGLB1 PE=3 SV=1 59

AIS Control sp|P02775|CXCL7_HUMAN Platelet basic protein OS=Homo sapiens GN=PPBP PE=1 SV=3 107 AIS Victim sp|P02775|CXCL7_HUMAN Platelet basic protein OS=Homo sapiens GN=PPBP PE=1 SV=3 39 ICH Control sp|P02775|CXCL7_HUMAN Platelet basic protein OS=Homo sapiens GN=PPBP PE=1 SV=3 95 ICH Victim sp|P02775|CXCL7_HUMAN Platelet basic protein OS=Homo sapiens GN=PPBP PE=1 SV=3 55

AIS Victim sp|P02776|PLF4_HUMAN Platelet factor 4 OS=Homo sapiens GN=PF4 PE=1 SV=2 38 ICH Control sp|P02776|PLF4_HUMAN Platelet factor 4 OS=Homo sapiens GN=PF4 PE=1 SV=2 46

125

ICH Victim tr|H0YJZ9|H0YJZ9_HUMAN Poly(A) polymerase alpha (Fragment) OS=Homo sapiens GN=PAPOLA PE=4 SV=1 36 ICH Victim tr|J3QQW9|J3QQW9_HUMAN Polycomb protein SUZ12 OS=Homo sapiens GN=SUZ12 PE=1 SV=1 39 AIS Victim sp|Q9P1Z3|HCN3_HUMAN Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 OS=Homo sapiens GN=HCN3 PE=2 SV=2 37 ICH Victim sp|Q9P1Z3|HCN3_HUMAN Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 OS=Homo sapiens GN=HCN3 PE=2 SV=2 36

ICH Control sp|Q6S8J3|POTEE_HUMAN POTE ankyrin domain family member E OS=Homo sapiens GN=POTEE PE=1 SV=3 48 ICH Victim sp|Q6S8J3|POTEE_HUMAN POTE ankyrin domain family member E OS=Homo sapiens GN=POTEE PE=1 SV=3 75 AIS Control sp|A5A3E0|POTEF_HUMAN POTE ankyrin domain family member F OS=Homo sapiens GN=POTEF PE=1 SV=2 134 AIS Victim sp|A5A3E0|POTEF_HUMAN POTE ankyrin domain family member F OS=Homo sapiens GN=POTEF PE=1 SV=2 68

ICH Control sp|A5A3E0|POTEF_HUMAN POTE ankyrin domain family member F OS=Homo sapiens GN=POTEF PE=1 SV=2 61 ICH Victim sp|A5A3E0|POTEF_HUMAN POTE ankyrin domain family member F OS=Homo sapiens GN=POTEF PE=1 SV=2 106 ICH Victim sp|P0CG38|POTEI_HUMAN POTE ankyrin domain family member I OS=Homo sapiens GN=POTEI PE=3 SV=1 41

AIS Victim sp|P20742|PZP_HUMAN Pregnancy zone protein OS=Homo sapiens GN=PZP PE=1 SV=4 5103

AIS Victim sp|Q96GQ7|DDX27_HUMAN Probable ATP-dependent RNA helicase DDX27 OS=Homo sapiens GN=DDX27 PE=1 SV=2 40 ICH Control tr|D6RA70|D6RA70_HUMAN Probable ATP-dependent RNA helicase YTHDC2 OS=Homo sapiens GN=YTHDC2 PE=1 SV=1 40 ICH Victim tr|F5H579|F5H579_HUMAN Probable cysteine--tRNA ligase, mitochondrial (Fragment) OS=Homo sapiens GN=CARS2 PE=1 SV=1 42 ICH Control sp|Q15113|PCOC1_HUMAN Procollagen C-endopeptidase enhancer 1 OS=Homo sapiens GN=PCOLCE PE=1 SV=2 36

ICH Victim sp|Q15113|PCOC1_HUMAN Procollagen C-endopeptidase enhancer 1 OS=Homo sapiens GN=PCOLCE PE=1 SV=2 44 ICH Control sp|P07737|PROF1_HUMAN Profilin-1 OS=Homo sapiens GN=PFN1 PE=1 SV=2 99 AIS Victim tr|A0A087WUI6|A0A087WUI6_HUMAN Progesterone-induced-blocking factor 1 OS=Homo sapiens GN=PIBF1 PE=1 SV=1 41 ICH Victim tr|A0A087WUI6|A0A087WUI6_HUMAN Progesterone-induced-blocking factor 1 OS=Homo sapiens GN=PIBF1 PE=1 SV=1 39

ICH Victim sp|Q12796|PNRC1_HUMAN Proline-rich nuclear receptor coactivator 1 OS=Homo sapiens GN=PNRC1 PE=1 SV=1 41 ICH Victim tr|J3QKY4|J3QKY4_HUMAN Proline-rich protein 11 (Fragment) OS=Homo sapiens GN=PRR11 PE=1 SV=1 36 AIS Victim tr|C9J7V5|C9J7V5_HUMAN Properdin (Fragment) OS=Homo sapiens GN=CFP PE=1 SV=1 123 ICH Control tr|C9J7V5|C9J7V5_HUMAN Properdin (Fragment) OS=Homo sapiens GN=CFP PE=1 SV=1 100

ICH Control tr|E9PAQ1|E9PAQ1_HUMAN Properdin OS=Homo sapiens GN=CFP PE=1 SV=1 63

AIS Victim sp|Q3B8N5|PROX2_HUMAN Prospero homeobox protein 2 OS=Homo sapiens GN=PROX2 PE=2 SV=3 42 AIS Control sp|P41222|PTGDS_HUMAN Prostaglandin-H2 D-isomerase OS=Homo sapiens GN=PTGDS PE=1 SV=1 68 AIS Victim sp|P41222|PTGDS_HUMAN Prostaglandin-H2 D-isomerase OS=Homo sapiens GN=PTGDS PE=1 SV=1 37 AIS Control sp|P02760|AMBP_HUMAN Protein AMBP OS=Homo sapiens GN=AMBP PE=1 SV=1 473

AIS Victim sp|P02760|AMBP_HUMAN Protein AMBP OS=Homo sapiens GN=AMBP PE=1 SV=1 251 ICH Control sp|P02760|AMBP_HUMAN Protein AMBP OS=Homo sapiens GN=AMBP PE=1 SV=1 73 ICH Victim sp|P02760|AMBP_HUMAN Protein AMBP OS=Homo sapiens GN=AMBP PE=1 SV=1 241 AIS Control tr|K7ER74|K7ER74_HUMAN Protein APOC4-APOC2 OS=Homo sapiens GN=APOC4-APOC2 PE=4 SV=1 101

AIS Victim tr|K7ER74|K7ER74_HUMAN Protein APOC4-APOC2 OS=Homo sapiens GN=APOC4-APOC2 PE=4 SV=1 78 ICH Control tr|K7ER74|K7ER74_HUMAN Protein APOC4-APOC2 OS=Homo sapiens GN=APOC4-APOC2 PE=4 SV=1 125 ICH Victim tr|K7ER74|K7ER74_HUMAN Protein APOC4-APOC2 OS=Homo sapiens GN=APOC4-APOC2 PE=4 SV=1 254

ICH Victim tr|A0A087X211|A0A087X211_HUMAN Protein CIP2A OS=Homo sapiens GN=KIAA1524 PE=1 SV=1 36

ICH Control sp|Q96M60|F227B_HUMAN Protein FAM227B OS=Homo sapiens GN=FAM227B PE=2 SV=2 38 ICH Victim sp|Q96M60|F227B_HUMAN Protein FAM227B OS=Homo sapiens GN=FAM227B PE=2 SV=2 37 AIS Control tr|A0A0C4DH31|A0A0C4DH31_HUMAN Protein IGHV1-18 (Fragment) OS=Homo sapiens GN=IGHV1-18 PE=1 SV=1 59 ICH Control tr|A0A0C4DH31|A0A0C4DH31_HUMAN Protein IGHV1-18 (Fragment) OS=Homo sapiens GN=IGHV1-18 PE=1 SV=1 130

ICH Victim tr|A0A0C4DH31|A0A0C4DH31_HUMAN Protein IGHV1-18 (Fragment) OS=Homo sapiens GN=IGHV1-18 PE=1 SV=1 35 ICH Control tr|A0A0B4J1V4|A0A0B4J1V4_HUMAN Protein IGHV1-46 (Fragment) OS=Homo sapiens GN=IGHV1-46 PE=4 SV=1 107 ICH Victim tr|A0A0B4J1V4|A0A0B4J1V4_HUMAN Protein IGHV1-46 (Fragment) OS=Homo sapiens GN=IGHV1-46 PE=4 SV=1 56 ICH Control tr|A0A0B4J1V5|A0A0B4J1V5_HUMAN Protein IGHV1-69 (Fragment) OS=Homo sapiens GN=IGHV1-69 PE=1 SV=1 50

ICH Victim tr|A0A0B4J1V5|A0A0B4J1V5_HUMAN Protein IGHV1-69 (Fragment) OS=Homo sapiens GN=IGHV1-69 PE=1 SV=1 54 AIS Victim tr|A0A075B7D0|A0A075B7D0_HUMAN Protein IGHV1OR15-1 (Fragment) OS=Homo sapiens GN=IGHV1OR15-1 PE=4 SV=1 70

126

ICH Control tr|A0A075B7D0|A0A075B7D0_HUMAN Protein IGHV1OR15-1 (Fragment) OS=Homo sapiens GN=IGHV1OR15-1 PE=4 SV=1 37 ICH Victim tr|A0A075B7D0|A0A075B7D0_HUMAN Protein IGHV1OR15-1 (Fragment) OS=Homo sapiens GN=IGHV1OR15-1 PE=4 SV=1 38 ICH Control tr|A0A0B4J1V2|A0A0B4J1V2_HUMAN Protein IGHV2-26 (Fragment) OS=Homo sapiens GN=IGHV2-26 PE=1 SV=1 41 AIS Control tr|A0A0B4J2B7|A0A0B4J2B7_HUMAN Protein IGHV3-30 (Fragment) OS=Homo sapiens GN=IGHV3-30 PE=1 SV=1 86

ICH Control tr|A0A0B4J2B7|A0A0B4J2B7_HUMAN Protein IGHV3-30 (Fragment) OS=Homo sapiens GN=IGHV3-30 PE=1 SV=1 41 ICH Victim tr|A0A0B4J2B7|A0A0B4J2B7_HUMAN Protein IGHV3-30 (Fragment) OS=Homo sapiens GN=IGHV3-30 PE=1 SV=1 57 AIS Control tr|A0A0B4J1V3|A0A0B4J1V3_HUMAN Protein IGHV3-33 (Fragment) OS=Homo sapiens GN=IGHV3-33 PE=1 SV=1 50 AIS Victim tr|A0A0C4DH35|A0A0C4DH35_HUMAN Protein IGHV3-35 (Fragment) OS=Homo sapiens GN=IGHV3-35 PE=1 SV=1 45

ICH Control tr|A0A0C4DH35|A0A0C4DH35_HUMAN Protein IGHV3-35 (Fragment) OS=Homo sapiens GN=IGHV3-35 PE=1 SV=1 63 ICH Victim tr|A0A0C4DH35|A0A0C4DH35_HUMAN Protein IGHV3-35 (Fragment) OS=Homo sapiens GN=IGHV3-35 PE=1 SV=1 49 ICH Control tr|A0A0C4DH36|A0A0C4DH36_HUMAN Protein IGHV3-38 (Fragment) OS=Homo sapiens GN=IGHV3-38 PE=1 SV=1 60 ICH Victim tr|A0A0C4DH36|A0A0C4DH36_HUMAN Protein IGHV3-38 (Fragment) OS=Homo sapiens GN=IGHV3-38 PE=1 SV=1 43

ICH Control tr|A0A087WU91|A0A087WU91_HUMAN Protein IGHV3-49 OS=Homo sapiens GN=IGHV3-49 PE=1 SV=1 40 ICH Victim tr|A0A087WU91|A0A087WU91_HUMAN Protein IGHV3-49 OS=Homo sapiens GN=IGHV3-49 PE=1 SV=1 37 AIS Victim tr|A0A087WSX4|A0A087WSX4_HUMAN Protein IGHV3-53 (Fragment) OS=Homo sapiens GN=IGHV3-53 PE=1 SV=1 63

AIS Victim tr|A0A075B6Q5|A0A075B6Q5_HUMAN Protein IGHV3-64 (Fragment) OS=Homo sapiens GN=IGHV3-64 PE=1 SV=1 42

AIS Control tr|A0A087WW89|A0A087WW89_HUMAN Protein IGHV3-72 OS=Homo sapiens GN=IGHV3-72 PE=1 SV=1 144 AIS Victim tr|A0A087WW89|A0A087WW89_HUMAN Protein IGHV3-72 OS=Homo sapiens GN=IGHV3-72 PE=1 SV=1 35 ICH Control tr|A0A087WW89|A0A087WW89_HUMAN Protein IGHV3-72 OS=Homo sapiens GN=IGHV3-72 PE=1 SV=1 162 ICH Victim tr|A0A087WW89|A0A087WW89_HUMAN Protein IGHV3-72 OS=Homo sapiens GN=IGHV3-72 PE=1 SV=1 58

AIS Control tr|A0A0B4J1X5|A0A0B4J1X5_HUMAN Protein IGHV3-74 (Fragment) OS=Homo sapiens GN=IGHV3-74 PE=1 SV=1 82 AIS Victim tr|A0A0B4J1X5|A0A0B4J1X5_HUMAN Protein IGHV3-74 (Fragment) OS=Homo sapiens GN=IGHV3-74 PE=1 SV=1 60 ICH Control tr|A0A0B4J1X5|A0A0B4J1X5_HUMAN Protein IGHV3-74 (Fragment) OS=Homo sapiens GN=IGHV3-74 PE=1 SV=1 60 ICH Victim tr|A0A0B4J1X5|A0A0B4J1X5_HUMAN Protein IGHV3-74 (Fragment) OS=Homo sapiens GN=IGHV3-74 PE=1 SV=1 87

ICH Control tr|A0A075B7D8|A0A075B7D8_HUMAN Protein IGHV3OR15-7 (Fragment) OS=Homo sapiens GN=IGHV3OR15-7 PE=1 SV=1 45 AIS Control tr|A0A075B7B8|A0A075B7B8_HUMAN Protein IGHV3OR16-12 (Fragment) OS=Homo sapiens GN=IGHV3OR16-12 PE=1 SV=1 106 AIS Victim tr|A0A075B7B8|A0A075B7B8_HUMAN Protein IGHV3OR16-12 (Fragment) OS=Homo sapiens GN=IGHV3OR16-12 PE=1 SV=1 86 ICH Control tr|A0A075B7B8|A0A075B7B8_HUMAN Protein IGHV3OR16-12 (Fragment) OS=Homo sapiens GN=IGHV3OR16-12 PE=1 SV=1 39

ICH Victim tr|A0A075B7B8|A0A075B7B8_HUMAN Protein IGHV3OR16-12 (Fragment) OS=Homo sapiens GN=IGHV3OR16-12 PE=1 SV=1 78 AIS Control tr|A0A075B7E8|A0A075B7E8_HUMAN Protein IGHV3OR16-13 (Fragment) OS=Homo sapiens GN=IGHV3OR16-13 PE=4 SV=1 46 ICH Control tr|A0A075B7E8|A0A075B7E8_HUMAN Protein IGHV3OR16-13 (Fragment) OS=Homo sapiens GN=IGHV3OR16-13 PE=4 SV=1 46

AIS Control tr|A0A0B4J2B5|A0A0B4J2B5_HUMAN Protein IGHV3OR16-9 (Fragment) OS=Homo sapiens GN=IGHV3OR16-9 PE=1 SV=1 179

AIS Victim tr|A0A0B4J2B5|A0A0B4J2B5_HUMAN Protein IGHV3OR16-9 (Fragment) OS=Homo sapiens GN=IGHV3OR16-9 PE=1 SV=1 50 ICH Control tr|A0A0B4J2B5|A0A0B4J2B5_HUMAN Protein IGHV3OR16-9 (Fragment) OS=Homo sapiens GN=IGHV3OR16-9 PE=1 SV=1 185 ICH Victim tr|A0A0B4J2B5|A0A0B4J2B5_HUMAN Protein IGHV3OR16-9 (Fragment) OS=Homo sapiens GN=IGHV3OR16-9 PE=1 SV=1 88 AIS Victim tr|A0A0C4DH34|A0A0C4DH34_HUMAN Protein IGHV4-28 (Fragment) OS=Homo sapiens GN=IGHV4-28 PE=1 SV=1 135

ICH Control tr|A0A0C4DH34|A0A0C4DH34_HUMAN Protein IGHV4-28 (Fragment) OS=Homo sapiens GN=IGHV4-28 PE=1 SV=1 37 ICH Victim tr|A0A0C4DH34|A0A0C4DH34_HUMAN Protein IGHV4-28 (Fragment) OS=Homo sapiens GN=IGHV4-28 PE=1 SV=1 52 ICH Control tr|A0A087WSY4|A0A087WSY4_HUMAN Protein IGHV4-31 (Fragment) OS=Homo sapiens GN=IGHV4-31 PE=4 SV=1 66 AIS Control tr|A0A0A0MS12|A0A0A0MS12_HUMAN Protein IGHV4-34 (Fragment) OS=Homo sapiens GN=IGHV4-34 PE=1 SV=1 54

AIS Victim tr|A0A0A0MS12|A0A0A0MS12_HUMAN Protein IGHV4-34 (Fragment) OS=Homo sapiens GN=IGHV4-34 PE=1 SV=1 346 ICH Control tr|A0A0A0MS12|A0A0A0MS12_HUMAN Protein IGHV4-34 (Fragment) OS=Homo sapiens GN=IGHV4-34 PE=1 SV=1 325 ICH Victim tr|A0A0A0MS12|A0A0A0MS12_HUMAN Protein IGHV4-34 (Fragment) OS=Homo sapiens GN=IGHV4-34 PE=1 SV=1 42 AIS Victim tr|A0A075B6R2|A0A075B6R2_HUMAN Protein IGHV4-4 (Fragment) OS=Homo sapiens GN=IGHV4-4 PE=4 SV=2 60

ICH Control tr|A0A075B6R2|A0A075B6R2_HUMAN Protein IGHV4-4 (Fragment) OS=Homo sapiens GN=IGHV4-4 PE=4 SV=2 292 ICH Victim tr|A0A075B6R2|A0A075B6R2_HUMAN Protein IGHV4-4 (Fragment) OS=Homo sapiens GN=IGHV4-4 PE=4 SV=2 65 AIS Control tr|A0A0C4DH38|A0A0C4DH38_HUMAN Protein IGHV5-51 (Fragment) OS=Homo sapiens GN=IGHV5-51 PE=1 SV=1 90

AIS Victim tr|A0A0C4DH38|A0A0C4DH38_HUMAN Protein IGHV5-51 (Fragment) OS=Homo sapiens GN=IGHV5-51 PE=1 SV=1 56

ICH Control tr|A0A0C4DH38|A0A0C4DH38_HUMAN Protein IGHV5-51 (Fragment) OS=Homo sapiens GN=IGHV5-51 PE=1 SV=1 102 ICH Victim tr|A0A0C4DH38|A0A0C4DH38_HUMAN Protein IGHV5-51 (Fragment) OS=Homo sapiens GN=IGHV5-51 PE=1 SV=1 35 AIS Victim tr|A0A0B4J1Z4|A0A0B4J1Z4_HUMAN Protein IGKV1-17 (Fragment) OS=Homo sapiens GN=IGKV1-17 PE=1 SV=1 79 ICH Control tr|A0A0B4J1Z4|A0A0B4J1Z4_HUMAN Protein IGKV1-17 (Fragment) OS=Homo sapiens GN=IGKV1-17 PE=1 SV=1 50

ICH Victim tr|A0A0B4J1Z4|A0A0B4J1Z4_HUMAN Protein IGKV1-17 (Fragment) OS=Homo sapiens GN=IGKV1-17 PE=1 SV=1 65 AIS Control tr|A0A087WZH9|A0A087WZH9_HUMAN Protein IGKV1-33 OS=Homo sapiens GN=IGKV1D-33 PE=4 SV=1 150 ICH Control tr|A0A087WZH9|A0A087WZH9_HUMAN Protein IGKV1-33 OS=Homo sapiens GN=IGKV1D-33 PE=4 SV=1 196 AIS Control tr|A0A0B4J2D9|A0A0B4J2D9_HUMAN Protein IGKV1D-13 (Fragment) OS=Homo sapiens GN=IGKV1D-13 PE=1 SV=1 91

AIS Victim tr|A0A075B6P5|A0A075B6P5_HUMAN Protein IGKV2-28 (Fragment) OS=Homo sapiens GN=IGKV2D-28 PE=1 SV=1 47 ICH Control tr|A0A075B6P5|A0A075B6P5_HUMAN Protein IGKV2-28 (Fragment) OS=Homo sapiens GN=IGKV2D-28 PE=1 SV=1 74

127

ICH Victim tr|A0A075B6P5|A0A075B6P5_HUMAN Protein IGKV2-28 (Fragment) OS=Homo sapiens GN=IGKV2D-28 PE=1 SV=1 67 AIS Control tr|A0A075B6S3|A0A075B6S3_HUMAN Protein IGKV2-30 (Fragment) OS=Homo sapiens GN=IGKV2-30 PE=4 SV=1 94 AIS Victim tr|A0A075B6S3|A0A075B6S3_HUMAN Protein IGKV2-30 (Fragment) OS=Homo sapiens GN=IGKV2-30 PE=4 SV=1 98 ICH Control tr|A0A075B6S3|A0A075B6S3_HUMAN Protein IGKV2-30 (Fragment) OS=Homo sapiens GN=IGKV2-30 PE=4 SV=1 81

ICH Control tr|A0A075B6R9|A0A075B6R9_HUMAN Protein IGKV2D-24 (Fragment) OS=Homo sapiens GN=IGKV2D-24 PE=4 SV=1 68 ICH Victim tr|A0A075B6R9|A0A075B6R9_HUMAN Protein IGKV2D-24 (Fragment) OS=Homo sapiens GN=IGKV2D-24 PE=4 SV=1 57 AIS Control tr|A0A0A0MTQ6|A0A0A0MTQ6_HUMAN Protein IGKV2D-28 OS=Homo sapiens GN=IGKV2D-28 PE=1 SV=1 50 ICH Control tr|A0A0A0MTQ6|A0A0A0MTQ6_HUMAN Protein IGKV2D-28 OS=Homo sapiens GN=IGKV2D-28 PE=1 SV=1 96

AIS Victim tr|A0A075B6S2|A0A075B6S2_HUMAN Protein IGKV2D-29 (Fragment) OS=Homo sapiens GN=IGKV2D-29 PE=1 SV=1 70 ICH Control tr|A0A075B6S2|A0A075B6S2_HUMAN Protein IGKV2D-29 (Fragment) OS=Homo sapiens GN=IGKV2D-29 PE=1 SV=1 114 ICH Victim tr|A0A075B6S2|A0A075B6S2_HUMAN Protein IGKV2D-29 (Fragment) OS=Homo sapiens GN=IGKV2D-29 PE=1 SV=1 102 ICH Control tr|A0A075B6S6|A0A075B6S6_HUMAN Protein IGKV2D-30 (Fragment) OS=Homo sapiens GN=IGKV2D-30 PE=1 SV=1 104

AIS Control tr|A0A087WZW8|A0A087WZW8_HUMAN Protein IGKV3-11 OS=Homo sapiens GN=IGKV3-11 PE=4 SV=1 128 AIS Victim tr|A0A087WZW8|A0A087WZW8_HUMAN Protein IGKV3-11 OS=Homo sapiens GN=IGKV3-11 PE=4 SV=1 360 ICH Control tr|A0A087WZW8|A0A087WZW8_HUMAN Protein IGKV3-11 OS=Homo sapiens GN=IGKV3-11 PE=4 SV=1 190

ICH Victim tr|A0A087WZW8|A0A087WZW8_HUMAN Protein IGKV3-11 OS=Homo sapiens GN=IGKV3-11 PE=4 SV=1 401

ICH Victim tr|A0A0B4J1Z6|A0A0B4J1Z6_HUMAN Protein IGKV3-20 (Fragment) OS=Homo sapiens GN=IGKV3-20 PE=4 SV=1 167 AIS Control tr|A0A075B6H7|A0A075B6H7_HUMAN Protein IGKV3-7 (Fragment) OS=Homo sapiens GN=IGKV3-7 PE=4 SV=1 39 AIS Victim tr|A0A075B6H7|A0A075B6H7_HUMAN Protein IGKV3-7 (Fragment) OS=Homo sapiens GN=IGKV3-7 PE=4 SV=1 45 ICH Victim tr|A0A075B6H7|A0A075B6H7_HUMAN Protein IGKV3-7 (Fragment) OS=Homo sapiens GN=IGKV3-7 PE=4 SV=1 41

AIS Victim tr|A0A087WSY6|A0A087WSY6_HUMAN Protein IGKV3D-15 (Fragment) OS=Homo sapiens GN=IGKV3D-15 PE=1 SV=3 38 ICH Control tr|A0A087WSY6|A0A087WSY6_HUMAN Protein IGKV3D-15 (Fragment) OS=Homo sapiens GN=IGKV3D-15 PE=1 SV=3 36 AIS Control tr|A0A0C4DH25|A0A0C4DH25_HUMAN Protein IGKV3D-20 (Fragment) OS=Homo sapiens GN=IGKV3D-20 PE=1 SV=1 39 AIS Victim tr|A0A0C4DH25|A0A0C4DH25_HUMAN Protein IGKV3D-20 (Fragment) OS=Homo sapiens GN=IGKV3D-20 PE=1 SV=1 225

ICH Control tr|A0A0C4DH25|A0A0C4DH25_HUMAN Protein IGKV3D-20 (Fragment) OS=Homo sapiens GN=IGKV3D-20 PE=1 SV=1 36 ICH Victim tr|A0A0C4DH25|A0A0C4DH25_HUMAN Protein IGKV3D-20 (Fragment) OS=Homo sapiens GN=IGKV3D-20 PE=1 SV=1 117 ICH Control tr|A0A0A0MT36|A0A0A0MT36_HUMAN Protein IGKV6D-21 (Fragment) OS=Homo sapiens GN=IGKV6D-21 PE=4 SV=1 64 ICH Victim tr|A0A0A0MT36|A0A0A0MT36_HUMAN Protein IGKV6D-21 (Fragment) OS=Homo sapiens GN=IGKV6D-21 PE=4 SV=1 70

AIS Control tr|A0A075B6I8|A0A075B6I8_HUMAN Protein IGLV1-47 (Fragment) OS=Homo sapiens GN=IGLV1-47 PE=1 SV=1 51 AIS Victim tr|A0A075B6I8|A0A075B6I8_HUMAN Protein IGLV1-47 (Fragment) OS=Homo sapiens GN=IGLV1-47 PE=1 SV=1 74 AIS Control tr|A0A075B6I5|A0A075B6I5_HUMAN Protein IGLV1-51 (Fragment) OS=Homo sapiens GN=IGLV1-51 PE=1 SV=1 39

ICH Control tr|A0A075B6I5|A0A075B6I5_HUMAN Protein IGLV1-51 (Fragment) OS=Homo sapiens GN=IGLV1-51 PE=1 SV=1 80

ICH Victim tr|A0A075B6I5|A0A075B6I5_HUMAN Protein IGLV1-51 (Fragment) OS=Homo sapiens GN=IGLV1-51 PE=1 SV=1 40 ICH Control tr|A0A075B6K3|A0A075B6K3_HUMAN Protein IGLV2-11 (Fragment) OS=Homo sapiens GN=IGLV2-11 PE=1 SV=1 42 ICH Victim tr|A0A075B6K3|A0A075B6K3_HUMAN Protein IGLV2-11 (Fragment) OS=Homo sapiens GN=IGLV2-11 PE=1 SV=1 46 AIS Control tr|A0A075B6K1|A0A075B6K1_HUMAN Protein IGLV2-14 (Fragment) OS=Homo sapiens GN=IGLV2-14 PE=1 SV=1 48

AIS Victim tr|A0A075B6K1|A0A075B6K1_HUMAN Protein IGLV2-14 (Fragment) OS=Homo sapiens GN=IGLV2-14 PE=1 SV=1 37 ICH Victim tr|A0A075B6K1|A0A075B6K1_HUMAN Protein IGLV2-14 (Fragment) OS=Homo sapiens GN=IGLV2-14 PE=1 SV=1 50 AIS Control tr|A0A075B6J8|A0A075B6J8_HUMAN Protein IGLV3-19 (Fragment) OS=Homo sapiens GN=IGLV3-19 PE=1 SV=1 77 AIS Victim tr|A0A075B6J8|A0A075B6J8_HUMAN Protein IGLV3-19 (Fragment) OS=Homo sapiens GN=IGLV3-19 PE=1 SV=1 52

ICH Control tr|A0A075B6J8|A0A075B6J8_HUMAN Protein IGLV3-19 (Fragment) OS=Homo sapiens GN=IGLV3-19 PE=1 SV=1 46 AIS Control tr|A0A075B6J7|A0A075B6J7_HUMAN Protein IGLV3-21 (Fragment) OS=Homo sapiens GN=IGLV3-21 PE=1 SV=1 284 AIS Victim tr|A0A075B6J7|A0A075B6J7_HUMAN Protein IGLV3-21 (Fragment) OS=Homo sapiens GN=IGLV3-21 PE=1 SV=1 104 ICH Control tr|A0A075B6J7|A0A075B6J7_HUMAN Protein IGLV3-21 (Fragment) OS=Homo sapiens GN=IGLV3-21 PE=1 SV=1 309

ICH Victim tr|A0A075B6J7|A0A075B6J7_HUMAN Protein IGLV3-21 (Fragment) OS=Homo sapiens GN=IGLV3-21 PE=1 SV=1 105 AIS Control tr|A0A075B6J4|A0A075B6J4_HUMAN Protein IGLV3-25 (Fragment) OS=Homo sapiens GN=IGLV3-25 PE=1 SV=2 52 AIS Victim tr|A0A075B6J4|A0A075B6J4_HUMAN Protein IGLV3-25 (Fragment) OS=Homo sapiens GN=IGLV3-25 PE=1 SV=2 50

ICH Victim tr|A0A075B6J4|A0A075B6J4_HUMAN Protein IGLV3-25 (Fragment) OS=Homo sapiens GN=IGLV3-25 PE=1 SV=2 68

AIS Victim tr|A0A075B6J3|A0A075B6J3_HUMAN Protein IGLV3-27 (Fragment) OS=Homo sapiens GN=IGLV3-27 PE=1 SV=1 69 ICH Victim tr|A0A075B6J3|A0A075B6J3_HUMAN Protein IGLV3-27 (Fragment) OS=Homo sapiens GN=IGLV3-27 PE=1 SV=1 37 AIS Victim tr|A0A075B6I2|A0A075B6I2_HUMAN Protein IGLV6-57 OS=Homo sapiens GN=IGLV6-57 PE=1 SV=2 41 ICH Control tr|A0A075B6I2|A0A075B6I2_HUMAN Protein IGLV6-57 OS=Homo sapiens GN=IGLV6-57 PE=1 SV=2 46

AIS Control tr|A0A075B6I9|A0A075B6I9_HUMAN Protein IGLV7-46 (Fragment) OS=Homo sapiens GN=IGLV7-46 PE=1 SV=4 48 AIS Victim tr|A0A075B6I9|A0A075B6I9_HUMAN Protein IGLV7-46 (Fragment) OS=Homo sapiens GN=IGLV7-46 PE=1 SV=4 42 ICH Control tr|A0A075B6I9|A0A075B6I9_HUMAN Protein IGLV7-46 (Fragment) OS=Homo sapiens GN=IGLV7-46 PE=1 SV=4 43 ICH Victim tr|A0A075B6I9|A0A075B6I9_HUMAN Protein IGLV7-46 (Fragment) OS=Homo sapiens GN=IGLV7-46 PE=1 SV=4 86

AIS Control tr|A0A075B6I0|A0A075B6I0_HUMAN Protein IGLV8-61 (Fragment) OS=Homo sapiens GN=IGLV8-61 PE=1 SV=4 48 AIS Victim tr|A0A075B6I0|A0A075B6I0_HUMAN Protein IGLV8-61 (Fragment) OS=Homo sapiens GN=IGLV8-61 PE=1 SV=4 50

128

ICH Control tr|A0A075B6I0|A0A075B6I0_HUMAN Protein IGLV8-61 (Fragment) OS=Homo sapiens GN=IGLV8-61 PE=1 SV=4 40 AIS Control tr|A0A0B4J1Y8|A0A0B4J1Y8_HUMAN Protein IGLV9-49 OS=Homo sapiens GN=IGLV9-49 PE=1 SV=1 36 ICH Control tr|A0A0B4J1Y8|A0A0B4J1Y8_HUMAN Protein IGLV9-49 OS=Homo sapiens GN=IGLV9-49 PE=1 SV=1 45 ICH Victim tr|A0A0B4J1Y8|A0A0B4J1Y8_HUMAN Protein IGLV9-49 OS=Homo sapiens GN=IGLV9-49 PE=1 SV=1 57

AIS Control tr|C9JA05|C9JA05_HUMAN Protein JCHAIN (Fragment) OS=Homo sapiens GN=JCHAIN PE=1 SV=1 48 AIS Victim tr|D6RHJ6|D6RHJ6_HUMAN Protein JCHAIN (Fragment) OS=Homo sapiens GN=JCHAIN PE=1 SV=1 103 ICH Control tr|D6RHJ6|D6RHJ6_HUMAN Protein JCHAIN (Fragment) OS=Homo sapiens GN=JCHAIN PE=1 SV=1 86 ICH Victim tr|D6RHJ6|D6RHJ6_HUMAN Protein JCHAIN (Fragment) OS=Homo sapiens GN=JCHAIN PE=1 SV=1 101

AIS Control tr|D6RD17|D6RD17_HUMAN Protein JCHAIN (Fragment) OS=Homo sapiens GN=JCHAIN PE=1 SV=5 194 AIS Victim tr|D6RD17|D6RD17_HUMAN Protein JCHAIN (Fragment) OS=Homo sapiens GN=JCHAIN PE=1 SV=5 101 ICH Control tr|D6RD17|D6RD17_HUMAN Protein JCHAIN (Fragment) OS=Homo sapiens GN=JCHAIN PE=1 SV=5 161 AIS Control tr|H0YFG4|H0YFG4_HUMAN Protein NLRC5 (Fragment) OS=Homo sapiens GN=NLRC5 PE=1 SV=1 38

AIS Control tr|G5E9F8|G5E9F8_HUMAN Protein S (Alpha), isoform CRA_b OS=Homo sapiens GN=PROS1 PE=1 SV=1 272

AIS Victim tr|G5E9F8|G5E9F8_HUMAN Protein S (Alpha), isoform CRA_b OS=Homo sapiens GN=PROS1 PE=1 SV=1 205 ICH Control tr|G5E9F8|G5E9F8_HUMAN Protein S (Alpha), isoform CRA_b OS=Homo sapiens GN=PROS1 PE=1 SV=1 65 ICH Victim tr|G5E9F8|G5E9F8_HUMAN Protein S (Alpha), isoform CRA_b OS=Homo sapiens GN=PROS1 PE=1 SV=1 80 AIS Victim sp|P05109|S10A8_HUMAN Protein S100-A8 OS=Homo sapiens GN=S100A8 PE=1 SV=1 52

AIS Victim tr|A0A096LPE2|A0A096LPE2_HUMAN Protein SAA2-SAA4 OS=Homo sapiens GN=SAA2-SAA4 PE=4 SV=1 64 ICH Control tr|A0A096LPE2|A0A096LPE2_HUMAN Protein SAA2-SAA4 OS=Homo sapiens GN=SAA2-SAA4 PE=4 SV=1 76 ICH Victim tr|A0A096LPE2|A0A096LPE2_HUMAN Protein SAA2-SAA4 OS=Homo sapiens GN=SAA2-SAA4 PE=4 SV=1 48 ICH Victim sp|Q8TF72|SHRM3_HUMAN Protein Shroom3 OS=Homo sapiens GN=SHROOM3 PE=1 SV=2 57

AIS Control tr|A0A075B6Z2|A0A075B6Z2_HUMAN Protein TRAJ56 (Fragment) OS=Homo sapiens GN=TRAJ56 PE=4 SV=1 51 AIS Victim tr|A0A075B6Z2|A0A075B6Z2_HUMAN Protein TRAJ56 (Fragment) OS=Homo sapiens GN=TRAJ56 PE=4 SV=1 44 ICH Control tr|A0A075B6Z2|A0A075B6Z2_HUMAN Protein TRAJ56 (Fragment) OS=Homo sapiens GN=TRAJ56 PE=4 SV=1 52

ICH Victim tr|A0A075B6Z2|A0A075B6Z2_HUMAN Protein TRAJ56 (Fragment) OS=Homo sapiens GN=TRAJ56 PE=4 SV=1 36

AIS Control tr|G3V2W1|G3V2W1_HUMAN Protein Z-dependent protease inhibitor OS=Homo sapiens GN=SERPINA10 PE=1 SV=1 41 AIS Victim tr|G3V2W1|G3V2W1_HUMAN Protein Z-dependent protease inhibitor OS=Homo sapiens GN=SERPINA10 PE=1 SV=1 99 ICH Control tr|G3V2W1|G3V2W1_HUMAN Protein Z-dependent protease inhibitor OS=Homo sapiens GN=SERPINA10 PE=1 SV=1 349 ICH Victim tr|G3V2W1|G3V2W1_HUMAN Protein Z-dependent protease inhibitor OS=Homo sapiens GN=SERPINA10 PE=1 SV=1 58

AIS Control tr|A0A0G2JPK4|A0A0G2JPK4_HUMAN Putative alpha-1-antitrypsin-related protein OS=Homo sapiens GN=SERPINA2 PE=4 SV=1 52

ICH Victim tr|A0A0G2JPK4|A0A0G2JPK4_HUMAN Putative alpha-1-antitrypsin-related protein OS=Homo sapiens GN=SERPINA2 PE=4 SV=1 38 AIS Control sp|Q9BYX7|ACTBM_HUMAN Putative beta-actin-like protein 3 OS=Homo sapiens GN=POTEKP PE=5 SV=1 134 AIS Victim sp|Q9BYX7|ACTBM_HUMAN Putative beta-actin-like protein 3 OS=Homo sapiens GN=POTEKP PE=5 SV=1 68 ICH Victim sp|Q9BYX7|ACTBM_HUMAN Putative beta-actin-like protein 3 OS=Homo sapiens GN=POTEKP PE=5 SV=1 106

ICH Control sp|Q2TV78|MST1L_HUMAN Putative macrophage stimulating 1-like protein OS=Homo sapiens GN=MST1L PE=2 SV=2 37 AIS Control sp|Q14964|RB39A_HUMAN Ras-related protein Rab-39A OS=Homo sapiens GN=RAB39A PE=1 SV=2 36 ICH Control tr|H0Y750|H0Y750_HUMAN Renin receptor (Fragment) OS=Homo sapiens GN=ATP6AP2 PE=4 SV=1 37 AIS Victim tr|H3BTN3|H3BTN3_HUMAN Retinaldehyde-binding protein 1 OS=Homo sapiens GN=RLBP1 PE=1 SV=1 36

AIS Control tr|Q5VY30|Q5VY30_HUMAN Retinol binding protein 4, plasma, isoform CRA_b OS=Homo sapiens GN=RBP4 PE=1 SV=2 86 AIS Victim tr|Q5VY30|Q5VY30_HUMAN Retinol binding protein 4, plasma, isoform CRA_b OS=Homo sapiens GN=RBP4 PE=1 SV=2 89

129

ICH Control tr|Q5VY30|Q5VY30_HUMAN Retinol binding protein 4, plasma, isoform CRA_b OS=Homo sapiens GN=RBP4 PE=1 SV=2 141 AIS Control tr|A0A0C4DGV7|A0A0C4DGV7_HUMAN Retinol-binding protein 4 OS=Homo sapiens GN=RBP4 PE=1 SV=1 365 AIS Victim tr|A0A0C4DGV7|A0A0C4DGV7_HUMAN Retinol-binding protein 4 OS=Homo sapiens GN=RBP4 PE=1 SV=1 59 ICH Control tr|A0A0C4DGV7|A0A0C4DGV7_HUMAN Retinol-binding protein 4 OS=Homo sapiens GN=RBP4 PE=1 SV=1 48

ICH Victim tr|A0A0C4DGV7|A0A0C4DGV7_HUMAN Retinol-binding protein 4 OS=Homo sapiens GN=RBP4 PE=1 SV=1 225 AIS Victim sp|P02753|RET4_HUMAN Retinol-binding protein 4 OS=Homo sapiens GN=RBP4 PE=1 SV=3 222 ICH Control sp|P02753|RET4_HUMAN Retinol-binding protein 4 OS=Homo sapiens GN=RBP4 PE=1 SV=3 512 ICH Victim sp|P02753|RET4_HUMAN Retinol-binding protein 4 OS=Homo sapiens GN=RBP4 PE=1 SV=3 47

ICH Control sp|P82980|RET5_HUMAN Retinol-binding protein 5 OS=Homo sapiens GN=RBP5 PE=1 SV=3 48 AIS Control tr|A0A0A0MSK6|A0A0A0MSK6_HUMAN Rho GTPase-activating protein 5 OS=Homo sapiens GN=ARHGAP5 PE=1 SV=1 36 AIS Victim tr|A0A0A0MR66|A0A0A0MR66_HUMAN RNA binding motif protein 10, isoform CRA_d OS=Homo sapiens GN=RBM10 PE=1 SV=1 37 ICH Victim tr|A0A0A0MR66|A0A0A0MR66_HUMAN RNA binding motif protein 10, isoform CRA_d OS=Homo sapiens GN=RBM10 PE=1 SV=1 35

ICH Control tr|C9J6K0|C9J6K0_HUMAN Secreted phosphoprotein 24 (Fragment) OS=Homo sapiens GN=SPP2 PE=1 SV=1 69

AIS Victim sp|Q13103|SPP24_HUMAN Secreted phosphoprotein 24 OS=Homo sapiens GN=SPP2 PE=1 SV=1 45 AIS Control tr|D6REX5|D6REX5_HUMAN Selenoprotein P (Fragment) OS=Homo sapiens GN=SEPP1 PE=1 SV=1 128 AIS Victim tr|D6REX5|D6REX5_HUMAN Selenoprotein P (Fragment) OS=Homo sapiens GN=SEPP1 PE=1 SV=1 82 ICH Control tr|D6REX5|D6REX5_HUMAN Selenoprotein P (Fragment) OS=Homo sapiens GN=SEPP1 PE=1 SV=1 150

ICH Victim tr|D6REX5|D6REX5_HUMAN Selenoprotein P (Fragment) OS=Homo sapiens GN=SEPP1 PE=1 SV=1 57 AIS Control tr|G3V4W5|G3V4W5_HUMAN Serine hydroxymethyltransferase, mitochondrial (Fragment) OS=Homo sapiens GN=SHMT2 PE=1 SV=1 35 ICH Control tr|G3V4W5|G3V4W5_HUMAN Serine hydroxymethyltransferase, mitochondrial (Fragment) OS=Homo sapiens GN=SHMT2 PE=1 SV=1 40 AIS Control tr|H0YJV2|H0YJV2_HUMAN Serine palmitoyltransferase 2 (Fragment) OS=Homo sapiens GN=SPTLC2 PE=1 SV=1 45

ICH Victim sp|O15270|SPTC2_HUMAN Serine palmitoyltransferase 2 OS=Homo sapiens GN=SPTLC2 PE=1 SV=1 50 AIS Victim sp|Q9NUV7|SPTC3_HUMAN Serine palmitoyltransferase 3 OS=Homo sapiens GN=SPTLC3 PE=1 SV=3 50 ICH Control sp|Q9NUV7|SPTC3_HUMAN Serine palmitoyltransferase 3 OS=Homo sapiens GN=SPTLC3 PE=1 SV=3 40 AIS Victim tr|E9PCT1|E9PCT1_HUMAN Serine/arginine repetitive matrix protein 1 OS=Homo sapiens GN=SRRM1 PE=1 SV=3 35

AIS Victim sp|Q9C098|DCLK3_HUMAN Serine/threonine-protein kinase DCLK3 OS=Homo sapiens GN=DCLK3 PE=2 SV=2 50 AIS Victim sp|O96013|PAK4_HUMAN Serine/threonine-protein kinase PAK 4 OS=Homo sapiens GN=PAK4 PE=1 SV=1 41 ICH Control sp|O75460|ERN1_HUMAN Serine/threonine-protein kinase/endoribonuclease IRE1 OS=Homo sapiens GN=ERN1 PE=1 SV=2 35

ICH Victim sp|O75460|ERN1_HUMAN Serine/threonine-protein kinase/endoribonuclease IRE1 OS=Homo sapiens GN=ERN1 PE=1 SV=2 35

ICH Victim tr|Q5T5C7|Q5T5C7_HUMAN Serine--tRNA ligase, cytoplasmic OS=Homo sapiens GN=SARS PE=1 SV=1 36 AIS Control tr|H7C5E8|H7C5E8_HUMAN Serotransferrin (Fragment) OS=Homo sapiens GN=TF PE=1 SV=1 1332 AIS Victim tr|H7C5E8|H7C5E8_HUMAN Serotransferrin (Fragment) OS=Homo sapiens GN=TF PE=1 SV=1 144 ICH Control tr|H7C5E8|H7C5E8_HUMAN Serotransferrin (Fragment) OS=Homo sapiens GN=TF PE=1 SV=1 937

ICH Victim tr|H7C5E8|H7C5E8_HUMAN Serotransferrin (Fragment) OS=Homo sapiens GN=TF PE=1 SV=1 156 AIS Control tr|C9JB55|C9JB55_HUMAN Serotransferrin (Fragment) OS=Homo sapiens GN=TF PE=1 SV=5 215 ICH Control tr|C9JB55|C9JB55_HUMAN Serotransferrin (Fragment) OS=Homo sapiens GN=TF PE=1 SV=5 915 ICH Victim tr|C9JB55|C9JB55_HUMAN Serotransferrin (Fragment) OS=Homo sapiens GN=TF PE=1 SV=5 842

ICH Victim tr|A0A0C4DGB6|A0A0C4DGB6_HUMAN Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=1 104

AIS Victim tr|G3V1D9|G3V1D9_HUMAN Serum amyloid A protein OS=Homo sapiens GN=SAA2 PE=3 SV=1 44 ICH Control tr|G3V1D9|G3V1D9_HUMAN Serum amyloid A protein OS=Homo sapiens GN=SAA2 PE=3 SV=1 73 AIS Victim tr|A0A087X0E2|A0A087X0E2_HUMAN Serum amyloid A protein OS=Homo sapiens GN=SAA2-SAA4 PE=3 SV=1 62 ICH Control tr|A0A087X0E2|A0A087X0E2_HUMAN Serum amyloid A protein OS=Homo sapiens GN=SAA2-SAA4 PE=3 SV=1 51

AIS Victim sp|P0DJI8|SAA1_HUMAN Serum amyloid A-1 protein OS=Homo sapiens GN=SAA1 PE=1 SV=1 133 ICH Control sp|P0DJI8|SAA1_HUMAN Serum amyloid A-1 protein OS=Homo sapiens GN=SAA1 PE=1 SV=1 427 ICH Victim sp|P0DJI8|SAA1_HUMAN Serum amyloid A-1 protein OS=Homo sapiens GN=SAA1 PE=1 SV=1 45 AIS Victim sp|P0DJI9|SAA2_HUMAN Serum amyloid A-2 protein OS=Homo sapiens GN=SAA2 PE=1 SV=1 108

ICH Control sp|P0DJI9|SAA2_HUMAN Serum amyloid A-2 protein OS=Homo sapiens GN=SAA2 PE=1 SV=1 287 ICH Victim sp|P0DJI9|SAA2_HUMAN Serum amyloid A-2 protein OS=Homo sapiens GN=SAA2 PE=1 SV=1 45

130

ICH Victim sp|P35542|SAA4_HUMAN Serum amyloid A-4 protein OS=Homo sapiens GN=SAA4 PE=1 SV=2 40 AIS Control sp|P02743|SAMP_HUMAN Serum amyloid P-component OS=Homo sapiens GN=APCS PE=1 SV=2 365 AIS Victim sp|P02743|SAMP_HUMAN Serum amyloid P-component OS=Homo sapiens GN=APCS PE=1 SV=2 259 ICH Control sp|P02743|SAMP_HUMAN Serum amyloid P-component OS=Homo sapiens GN=APCS PE=1 SV=2 152

ICH Victim sp|P02743|SAMP_HUMAN Serum amyloid P-component OS=Homo sapiens GN=APCS PE=1 SV=2 232 AIS Control sp|P27169|PON1_HUMAN Serum paraoxonase/arylesterase 1 OS=Homo sapiens GN=PON1 PE=1 SV=3 237 AIS Victim sp|P27169|PON1_HUMAN Serum paraoxonase/arylesterase 1 OS=Homo sapiens GN=PON1 PE=1 SV=3 86 ICH Control sp|P27169|PON1_HUMAN Serum paraoxonase/arylesterase 1 OS=Homo sapiens GN=PON1 PE=1 SV=3 45

ICH Victim sp|P27169|PON1_HUMAN Serum paraoxonase/arylesterase 1 OS=Homo sapiens GN=PON1 PE=1 SV=3 110 AIS Control tr|F8WD41|F8WD41_HUMAN Serum paraoxonase/lactonase 3 OS=Homo sapiens GN=PON3 PE=1 SV=1 43 AIS Victim tr|F8WD41|F8WD41_HUMAN Serum paraoxonase/lactonase 3 OS=Homo sapiens GN=PON3 PE=1 SV=1 42 AIS Control sp|Q15166|PON3_HUMAN Serum paraoxonase/lactonase 3 OS=Homo sapiens GN=PON3 PE=1 SV=3 56

AIS Victim sp|Q15166|PON3_HUMAN Serum paraoxonase/lactonase 3 OS=Homo sapiens GN=PON3 PE=1 SV=3 40 ICH Control sp|Q15166|PON3_HUMAN Serum paraoxonase/lactonase 3 OS=Homo sapiens GN=PON3 PE=1 SV=3 47 ICH Victim sp|Q15166|PON3_HUMAN Serum paraoxonase/lactonase 3 OS=Homo sapiens GN=PON3 PE=1 SV=3 40

AIS Victim tr|A0A0C4DGN2|A0A0C4DGN2_HUMAN Sex hormone-binding globulin (Fragment) OS=Homo sapiens GN=SHBG PE=1 SV=1 59

ICH Victim tr|A0A0C4DGN2|A0A0C4DGN2_HUMAN Sex hormone-binding globulin (Fragment) OS=Homo sapiens GN=SHBG PE=1 SV=1 67 AIS Victim tr|I3L145|I3L145_HUMAN Sex hormone-binding globulin OS=Homo sapiens GN=SHBG PE=1 SV=1 42 ICH Control tr|I3L145|I3L145_HUMAN Sex hormone-binding globulin OS=Homo sapiens GN=SHBG PE=1 SV=1 199 ICH Victim tr|I3L2X4|I3L2X4_HUMAN Sex hormone-binding globulin OS=Homo sapiens GN=SHBG PE=1 SV=1 56

ICH Victim tr|R4GN84|R4GN84_HUMAN SH2B adapter protein 3 (Fragment) OS=Homo sapiens GN=SH2B3 PE=1 SV=5 36 ICH Victim sp|A6NMB1|SIG16_HUMAN Sialic acid-binding Ig-like lectin 16 OS=Homo sapiens GN=SIGLEC16 PE=2 SV=3 38 AIS Victim tr|A0A0A0MSC8|A0A0A0MSC8_HUMAN Slit homolog 3 protein OS=Homo sapiens GN=SLIT3 PE=1 SV=1 46 AIS Victim tr|E9PPJ3|E9PPJ3_HUMAN Smoothelin-like protein 1 OS=Homo sapiens GN=SMTNL1 PE=1 SV=1 38

AIS Control tr|A0A0G2JNW7|A0A0G2JNW7_HUMAN Solute carrier family 12 member 7 OS=Homo sapiens GN=SLC12A7 PE=4 SV=1 45 AIS Victim tr|A0A0G2JNW7|A0A0G2JNW7_HUMAN Solute carrier family 12 member 7 OS=Homo sapiens GN=SLC12A7 PE=4 SV=1 39 ICH Control tr|A0A0G2JNW7|A0A0G2JNW7_HUMAN Solute carrier family 12 member 7 OS=Homo sapiens GN=SLC12A7 PE=4 SV=1 40 ICH Victim tr|A0A0G2JNW7|A0A0G2JNW7_HUMAN Solute carrier family 12 member 7 OS=Homo sapiens GN=SLC12A7 PE=4 SV=1 38

ICH Control sp|Q9NY15|STAB1_HUMAN Stabilin-1 OS=Homo sapiens GN=STAB1 PE=1 SV=3 44

ICH Victim sp|Q9NY15|STAB1_HUMAN Stabilin-1 OS=Homo sapiens GN=STAB1 PE=1 SV=3 38 ICH Victim tr|H3BRG5|H3BRG5_HUMAN StAR-related lipid transfer protein 13 (Fragment) OS=Homo sapiens GN=STARD13 PE=1 SV=5 42 ICH Control tr|H7C3J6|H7C3J6_HUMAN Sterile alpha motif domain-containing protein 11 (Fragment) OS=Homo sapiens GN=SAMD11 PE=1 SV=1 43 AIS Victim sp|Q8NDV3|SMC1B_HUMAN Structural maintenance of chromosomes protein 1B OS=Homo sapiens GN=SMC1B PE=2 SV=2 39

ICH Victim sp|Q9UQE7|SMC3_HUMAN Structural maintenance of chromosomes protein 3 OS=Homo sapiens GN=SMC3 PE=1 SV=2 40 AIS Victim tr|A8MXT8|A8MXT8_HUMAN Sulfhydryl oxidase 1 OS=Homo sapiens GN=QSOX1 PE=1 SV=2 56 AIS Victim sp|O00391|QSOX1_HUMAN Sulfhydryl oxidase 1 OS=Homo sapiens GN=QSOX1 PE=1 SV=3 61 ICH Control sp|O00391|QSOX1_HUMAN Sulfhydryl oxidase 1 OS=Homo sapiens GN=QSOX1 PE=1 SV=3 125

AIS Victim sp|Q5TCY1|TTBK1_HUMAN Tau-tubulin kinase 1 OS=Homo sapiens GN=TTBK1 PE=1 SV=2 38

ICH Control sp|P05452|TETN_HUMAN Tetranectin OS=Homo sapiens GN=CLEC3B PE=1 SV=3 159 ICH Victim sp|P05452|TETN_HUMAN Tetranectin OS=Homo sapiens GN=CLEC3B PE=1 SV=3 84

131

AIS Victim sp|Q6PGP7|TTC37_HUMAN Tetratricopeptide repeat protein 37 OS=Homo sapiens GN=TTC37 PE=1 SV=1 37 AIS Victim sp|Q9NYJ8|TAB2_HUMAN TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 OS=Homo sapiens GN=TAB2 PE=1 SV=1 42 ICH Victim sp|Q9NYJ8|TAB2_HUMAN TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 OS=Homo sapiens GN=TAB2 PE=1 SV=1 42 ICH Control sp|P62328|TYB4_HUMAN Thymosin beta-4 OS=Homo sapiens GN=TMSB4X PE=1 SV=2 36

ICH Control tr|A0A0A0MTJ0|A0A0A0MTJ0_HUMAN Thyrotropin receptor OS=Homo sapiens GN=TSHR PE=1 SV=1 40 AIS Control sp|P05543|THBG_HUMAN Thyroxine-binding globulin OS=Homo sapiens GN=SERPINA7 PE=1 SV=2 274 AIS Victim sp|P05543|THBG_HUMAN Thyroxine-binding globulin OS=Homo sapiens GN=SERPINA7 PE=1 SV=2 72 ICH Control sp|P05543|THBG_HUMAN Thyroxine-binding globulin OS=Homo sapiens GN=SERPINA7 PE=1 SV=2 44

ICH Victim sp|P05543|THBG_HUMAN Thyroxine-binding globulin OS=Homo sapiens GN=SERPINA7 PE=1 SV=2 64 AIS Control tr|C9J103|C9J103_HUMAN Tissue factor pathway inhibitor (Fragment) OS=Homo sapiens GN=TFPI PE=1 SV=1 40 ICH Victim tr|A0A0D9SFL5|A0A0D9SFL5_HUMAN Trafficking kinesin-binding protein 1 OS=Homo sapiens GN=TRAK1 PE=1 SV=1 41 ICH Control sp|Q9H3H9|TCAL2_HUMAN Transcription elongation factor A protein-like 2 OS=Homo sapiens GN=TCEAL2 PE=2 SV=1 37

AIS Control sp|P31629|ZEP2_HUMAN Transcription factor HIVEP2 OS=Homo sapiens GN=HIVEP2 PE=1 SV=2 38 AIS Victim sp|P31629|ZEP2_HUMAN Transcription factor HIVEP2 OS=Homo sapiens GN=HIVEP2 PE=1 SV=2 46 ICH Victim sp|P31629|ZEP2_HUMAN Transcription factor HIVEP2 OS=Homo sapiens GN=HIVEP2 PE=1 SV=2 37

AIS Victim sp|Q02447|SP3_HUMAN Transcription factor Sp3 OS=Homo sapiens GN=SP3 PE=1 SV=3 45

AIS Victim tr|G3V0E5|G3V0E5_HUMAN Transferrin receptor (P90, CD71), isoform CRA_c OS=Homo sapiens GN=TFRC PE=1 SV=1 38 ICH Control tr|G3V0E5|G3V0E5_HUMAN Transferrin receptor (P90, CD71), isoform CRA_c OS=Homo sapiens GN=TFRC PE=1 SV=1 39 ICH Victim tr|G3V0E5|G3V0E5_HUMAN Transferrin receptor (P90, CD71), isoform CRA_c OS=Homo sapiens GN=TFRC PE=1 SV=1 71 AIS Victim sp|P02786|TFR1_HUMAN Transferrin receptor protein 1 OS=Homo sapiens GN=TFRC PE=1 SV=2 42

AIS Victim tr|H0Y9D7|H0Y9D7_HUMAN Transforming growth factor-beta-induced protein ig-h3 (Fragment) OS=Homo sapiens GN=TGFBI PE=1 SV=1 83 ICH Victim tr|H0Y8L3|H0Y8L3_HUMAN Transforming growth factor-beta-induced protein ig-h3 (Fragment) OS=Homo sapiens GN=TGFBI PE=1 SV=1 106 AIS Victim sp|Q15582|BGH3_HUMAN Transforming growth factor-beta-induced protein ig-h3 OS=Homo sapiens GN=TGFBI PE=1 SV=1 34 AIS Control tr|A0A0B4J1R6|A0A0B4J1R6_HUMAN Transketolase OS=Homo sapiens GN=TKT PE=1 SV=1 41

AIS Control sp|Q8N614|TM156_HUMAN Transmembrane protein 156 OS=Homo sapiens GN=TMEM156 PE=2 SV=2 40 AIS Victim sp|Q8N614|TM156_HUMAN Transmembrane protein 156 OS=Homo sapiens GN=TMEM156 PE=2 SV=2 52 ICH Control sp|Q8N614|TM156_HUMAN Transmembrane protein 156 OS=Homo sapiens GN=TMEM156 PE=2 SV=2 40 ICH Victim sp|Q8N614|TM156_HUMAN Transmembrane protein 156 OS=Homo sapiens GN=TMEM156 PE=2 SV=2 44

ICH Victim tr|A0A087WT59|A0A087WT59_HUMAN Transthyretin OS=Homo sapiens GN=TTR PE=1 SV=1 415

ICH Victim tr|F2Z2M2|F2Z2M2_HUMAN Tripartite motif-containing protein 14 OS=Homo sapiens GN=TRIM14 PE=1 SV=1 42 AIS Control sp|Q9C029|TRIM7_HUMAN Tripartite motif-containing protein 7 OS=Homo sapiens GN=TRIM7 PE=1 SV=2 38 AIS Victim tr|K7EP68|K7EP68_HUMAN Tropomyosin alpha-4 chain (Fragment) OS=Homo sapiens GN=TPM4 PE=1 SV=1 57 AIS Control tr|G3V2F4|G3V2F4_HUMAN Tyrosyl-DNA phosphodiesterase 1 OS=Homo sapiens GN=TDP1 PE=1 SV=1 37

ICH Victim sp|Q8NCR0|B3GL2_HUMAN UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2 OS=Homo sapiens GN=B3GALNT2 PE=1 SV=1 37 AIS Victim tr|I3L4J1|I3L4J1_HUMAN Uncharacterized protein (Fragment) OS=Homo sapiens PE=1 SV=3 39 ICH Control tr|H0YJW9|H0YJW9_HUMAN Uncharacterized protein (Fragment) OS=Homo sapiens PE=1 SV=3 53 ICH Victim tr|A0A0C4DH43|A0A0C4DH43_HUMAN Uncharacterized protein (Fragment) OS=Homo sapiens PE=4 SV=1 43

ICH Victim tr|I3L072|I3L072_HUMAN Uncharacterized protein C17orf80 OS=Homo sapiens GN=C17orf80 PE=1 SV=1 37 ICH Control tr|A0A087WWL5|A0A087WWL5_HUMAN Uncharacterized protein C19orf68 OS=Homo sapiens GN=C19orf68 PE=1 SV=1 38 AIS Victim tr|H0Y452|H0Y452_HUMAN Uncharacterized protein C7orf43 (Fragment) OS=Homo sapiens GN=C7orf43 PE=1 SV=1 46 ICH Control tr|H0Y452|H0Y452_HUMAN Uncharacterized protein C7orf43 (Fragment) OS=Homo sapiens GN=C7orf43 PE=1 SV=1 42

ICH Victim tr|H0Y452|H0Y452_HUMAN Uncharacterized protein C7orf43 (Fragment) OS=Homo sapiens GN=C7orf43 PE=1 SV=1 38 AIS Control sp|C9J069|CI172_HUMAN Uncharacterized protein C9orf172 OS=Homo sapiens GN=C9orf172 PE=3 SV=1 39 AIS Victim sp|C9J069|CI172_HUMAN Uncharacterized protein C9orf172 OS=Homo sapiens GN=C9orf172 PE=3 SV=1 38

ICH Control sp|C9J069|CI172_HUMAN Uncharacterized protein C9orf172 OS=Homo sapiens GN=C9orf172 PE=3 SV=1 38

ICH Victim sp|C9J069|CI172_HUMAN Uncharacterized protein C9orf172 OS=Homo sapiens GN=C9orf172 PE=3 SV=1 38 AIS Victim tr|B1ARL5|B1ARL5_HUMAN Uncharacterized protein CXorf22 OS=Homo sapiens GN=CXorf22 PE=4 SV=3 36 ICH Control tr|I3L2A7|I3L2A7_HUMAN Uncharacterized protein KIAA0753 (Fragment) OS=Homo sapiens GN=KIAA0753 PE=4 SV=1 37 ICH Victim sp|Q2KHM9|K0753_HUMAN Uncharacterized protein KIAA0753 OS=Homo sapiens GN=KIAA0753 PE=1 SV=3 39

AIS Control tr|B4E1Z4|B4E1Z4_HUMAN Uncharacterized protein OS=Homo sapiens PE=1 SV=1 476 AIS Victim tr|B4E1Z4|B4E1Z4_HUMAN Uncharacterized protein OS=Homo sapiens PE=1 SV=1 630 ICH Control tr|B4E1Z4|B4E1Z4_HUMAN Uncharacterized protein OS=Homo sapiens PE=1 SV=1 228 ICH Victim tr|B4E1Z4|B4E1Z4_HUMAN Uncharacterized protein OS=Homo sapiens PE=1 SV=1 675

AIS Control tr|F5GYJ5|F5GYJ5_HUMAN Uncharacterized protein OS=Homo sapiens PE=3 SV=1 40 AIS Victim tr|F5GYJ5|F5GYJ5_HUMAN Uncharacterized protein OS=Homo sapiens PE=3 SV=1 38

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ICH Control tr|F5GYJ5|F5GYJ5_HUMAN Uncharacterized protein OS=Homo sapiens PE=3 SV=1 44 AIS Victim tr|A0A0G2JMB2|A0A0G2JMB2_HUMAN Uncharacterized protein OS=Homo sapiens PE=4 SV=1 3853 ICH Control tr|A0A0G2JN06|A0A0G2JN06_HUMAN Uncharacterized protein OS=Homo sapiens PE=4 SV=1 953 ICH Control tr|A0A087WY00|A0A087WY00_HUMAN Unconventional myosin-Va OS=Homo sapiens GN=MYO5A PE=1 SV=1 37

AIS Victim tr|D6RF35|D6RF35_HUMAN Vitamin D-binding protein OS=Homo sapiens GN=GC PE=1 SV=1 47

ICH Control tr|D6RF35|D6RF35_HUMAN Vitamin D-binding protein OS=Homo sapiens GN=GC PE=1 SV=1 711 AIS Control tr|E7END6|E7END6_HUMAN Vitamin K-dependent protein C OS=Homo sapiens GN=PROC PE=1 SV=1 62 AIS Victim tr|E7END6|E7END6_HUMAN Vitamin K-dependent protein C OS=Homo sapiens GN=PROC PE=1 SV=1 39 ICH Control tr|E7END6|E7END6_HUMAN Vitamin K-dependent protein C OS=Homo sapiens GN=PROC PE=1 SV=1 62

ICH Victim tr|E7END6|E7END6_HUMAN Vitamin K-dependent protein C OS=Homo sapiens GN=PROC PE=1 SV=1 75 ICH Control tr|H7BXT0|H7BXT0_HUMAN Vitamin K-dependent protein S (Fragment) OS=Homo sapiens GN=PROS1 PE=1 SV=1 70 AIS Control sp|P07225|PROS_HUMAN Vitamin K-dependent protein S OS=Homo sapiens GN=PROS1 PE=1 SV=1 267 AIS Victim sp|P07225|PROS_HUMAN Vitamin K-dependent protein S OS=Homo sapiens GN=PROS1 PE=1 SV=1 90

ICH Control sp|P07225|PROS_HUMAN Vitamin K-dependent protein S OS=Homo sapiens GN=PROS1 PE=1 SV=1 292 ICH Victim sp|P07225|PROS_HUMAN Vitamin K-dependent protein S OS=Homo sapiens GN=PROS1 PE=1 SV=1 123 AIS Control sp|P04004|VTNC_HUMAN Vitronectin OS=Homo sapiens GN=VTN PE=1 SV=1 258 AIS Victim sp|P04004|VTNC_HUMAN Vitronectin OS=Homo sapiens GN=VTN PE=1 SV=1 84

ICH Control sp|P04004|VTNC_HUMAN Vitronectin OS=Homo sapiens GN=VTN PE=1 SV=1 101 ICH Victim sp|P04004|VTNC_HUMAN Vitronectin OS=Homo sapiens GN=VTN PE=1 SV=1 90 ICH Victim tr|H0YHK1|H0YHK1_HUMAN Voltage-dependent L-type calcium channel subunit beta-3 (Fragment) OS=Homo sapiens GN=CACNB3 PE=1 SV=1 43

AIS Control sp|P04275|VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 71

AIS Victim sp|P04275|VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 162 ICH Control sp|P04275|VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 304 ICH Victim sp|P04275|VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 401 ICH Control tr|H3BMH3|H3BMH3_HUMAN WD repeat-containing protein 59 (Fragment) OS=Homo sapiens GN=WDR59 PE=1 SV=5 37

AIS Control sp|Q5T200|ZC3HD_HUMAN Zinc finger CCCH domain-containing protein 13 OS=Homo sapiens GN=ZC3H13 PE=1 SV=1 58 AIS Victim sp|Q5T200|ZC3HD_HUMAN Zinc finger CCCH domain-containing protein 13 OS=Homo sapiens GN=ZC3H13 PE=1 SV=1 46 ICH Control sp|Q5T200|ZC3HD_HUMAN Zinc finger CCCH domain-containing protein 13 OS=Homo sapiens GN=ZC3H13 PE=1 SV=1 43 ICH Victim sp|Q5T200|ZC3HD_HUMAN Zinc finger CCCH domain-containing protein 13 OS=Homo sapiens GN=ZC3H13 PE=1 SV=1 43

ICH Victim tr|A0A0C4DGZ1|A0A0C4DGZ1_HUMAN Zinc finger CCCH domain-containing protein 8 OS=Homo sapiens GN=ZC3H8 PE=1 SV=1 47 ICH Control sp|O43296|ZN264_HUMAN Zinc finger protein 264 OS=Homo sapiens GN=ZNF264 PE=1 SV=1 36 AIS Control tr|A0A087WVT1|A0A087WVT1_HUMAN Zinc finger protein 48 OS=Homo sapiens GN=ZNF48 PE=1 SV=1 39 AIS Victim tr|A0A087WVT1|A0A087WVT1_HUMAN Zinc finger protein 48 OS=Homo sapiens GN=ZNF48 PE=1 SV=1 37

ICH Control tr|A0A087WVT1|A0A087WVT1_HUMAN Zinc finger protein 48 OS=Homo sapiens GN=ZNF48 PE=1 SV=1 42 ICH Victim tr|A0A087WVT1|A0A087WVT1_HUMAN Zinc finger protein 48 OS=Homo sapiens GN=ZNF48 PE=1 SV=1 38 AIS Control tr|H7BZJ8|H7BZJ8_HUMAN Zinc-alpha-2-glycoprotein (Fragment) OS=Homo sapiens GN=AZGP1 PE=1 SV=1 162

AIS Victim tr|H7BZJ8|H7BZJ8_HUMAN Zinc-alpha-2-glycoprotein (Fragment) OS=Homo sapiens GN=AZGP1 PE=1 SV=1 42

ICH Control tr|H7BZJ8|H7BZJ8_HUMAN Zinc-alpha-2-glycoprotein (Fragment) OS=Homo sapiens GN=AZGP1 PE=1 SV=1 106 ICH Victim tr|H7BZJ8|H7BZJ8_HUMAN Zinc-alpha-2-glycoprotein (Fragment) OS=Homo sapiens GN=AZGP1 PE=1 SV=1 356 AIS Victim tr|C9JEV0|C9JEV0_HUMAN Zinc-alpha-2-glycoprotein OS=Homo sapiens GN=AZGP1 PE=1 SV=1 275 ICH Control tr|C9JEV0|C9JEV0_HUMAN Zinc-alpha-2-glycoprotein OS=Homo sapiens GN=AZGP1 PE=1 SV=1 213

ICH Victim tr|C9JEV0|C9JEV0_HUMAN Zinc-alpha-2-glycoprotein OS=Homo sapiens GN=AZGP1 PE=1 SV=1 36 AIS Control sp|P25311|ZA2G_HUMAN Zinc-alpha-2-glycoprotein OS=Homo sapiens GN=AZGP1 PE=1 SV=2 459 AIS Victim sp|P25311|ZA2G_HUMAN Zinc-alpha-2-glycoprotein OS=Homo sapiens GN=AZGP1 PE=1 SV=2 284 ICH Control sp|P25311|ZA2G_HUMAN Zinc-alpha-2-glycoprotein OS=Homo sapiens GN=AZGP1 PE=1 SV=2 283

ICH Victim sp|P25311|ZA2G_HUMAN Zinc-alpha-2-glycoprotein OS=Homo sapiens GN=AZGP1 PE=1 SV=2 240

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