International Conference on Gram-Positive Pathogens
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Pin1 Inhibitors: Towards Understanding the Enzymatic
Pin1 Inhibitors: Towards Understanding the Enzymatic Mechanism Guoyan Xu Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University In the partial fulfillment of the requirement for the degree of Doctor of Philosophy In Chemistry Felicia A Etzkorn, Chair David G. I. Kingston Neal Castagnoli Paul R. Carlier Brian E. Hanson May 6, 2010 Blacksburg, Virginia Keywords: Pin1, anti-cancer drug target, transition-state analogues, ketoamides, ketones, reduced amides, PPIase assay, inhibition Pin1 Inhibitors: Towards Understanding the Enzymatic Mechanism Guoyan Xu Abstract An important role of Pin1 is to catalyze the cis-trans isomerization of pSer/Thr- Pro bonds; as such, it plays an important role in many cellular events through the effects of conformational change on the function of its biological substrates, including Cdc25, c- Jun, and p53. The expression of Pin1 correlates with cyclin D1 levels, which contributes to cancer cell transformation. Overexpression of Pin1 promotes tumor growth, while its inhibition causes tumor cell apoptosis. Because Pin1 is overexpressed in many human cancer tissues, including breast, prostate, and lung cancer tissues, it plays an important role in oncogenesis, making its study vital for the development of anti-cancer agents. Many inhibitors have been discovered for Pin1, including 1) several classes of designed inhibitors such as alkene isosteres, non-peptidic, small molecular Pin1 inhibitors, and indanyl ketones, and 2) several natural products such as juglone, pepticinnamin E analogues, PiB and its derivatives obtained from a library screen. These Pin1 inhibitors show promise in the development of novel diagnostic and therapeutic anticancer drugs due to their ability to block cell cycle progression. -
Anti-Inflammatory Role of Curcumin in LPS Treated A549 Cells at Global Proteome Level and on Mycobacterial Infection
Anti-inflammatory Role of Curcumin in LPS Treated A549 cells at Global Proteome level and on Mycobacterial infection. Suchita Singh1,+, Rakesh Arya2,3,+, Rhishikesh R Bargaje1, Mrinal Kumar Das2,4, Subia Akram2, Hossain Md. Faruquee2,5, Rajendra Kumar Behera3, Ranjan Kumar Nanda2,*, Anurag Agrawal1 1Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, New Delhi, 110025, India. 2Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India. 3School of Life Sciences, Sambalpur University, Jyoti Vihar, Sambalpur, Orissa, 768019, India. 4Department of Respiratory Sciences, #211, Maurice Shock Building, University of Leicester, LE1 9HN 5Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia- 7003, Bangladesh. +Contributed equally for this work. S-1 70 G1 S 60 G2/M 50 40 30 % of cells 20 10 0 CURI LPSI LPSCUR Figure S1: Effect of curcumin and/or LPS treatment on A549 cell viability A549 cells were treated with curcumin (10 µM) and/or LPS or 1 µg/ml for the indicated times and after fixation were stained with propidium iodide and Annexin V-FITC. The DNA contents were determined by flow cytometry to calculate percentage of cells present in each phase of the cell cycle (G1, S and G2/M) using Flowing analysis software. S-2 Figure S2: Total proteins identified in all the three experiments and their distribution betwee curcumin and/or LPS treated conditions. The proteins showing differential expressions (log2 fold change≥2) in these experiments were presented in the venn diagram and certain number of proteins are common in all three experiments. -
(12) Patent Application Publication (10) Pub. No.: US 2008/0261923 A1 Etzkorn Et Al
US 20080261923A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0261923 A1 Etzkorn et al. (43) Pub. Date: Oct. 23, 2008 54) ALKENE MIMICS Related U.S. Applicationpp Data (76) Inventors: Felicia A. Etzkorn, Blacksburg, VA (60) Provisional application No. 60/598.421, filed on Aug. (US); Xiaodong X. Wang, 4, 2004. Maricopa, AZ (US); Bulling Xu, Publication Classification Blacksburg, VA (US) (51) Int. Cl. Correspondence Address: A63/675 (2006.01) WHITHAM, CURTIS & CHRISTOFFERSON & C07F 9/06 (2006.01) COOK, PC A6IP35/00 (2006.01) 9 Lew e 11491 SUNSET HILLS ROAD, SUITE 340 A6II 3/662 (2006.01) RESTON, VA 20190 (US) (52) U.S. Cl. ............... 514/80; 546/22: 548/414: 546/23; 548/112:558/166; 514/89: 514/114 (22) PCT Filed: Jul. 29, 2005 Ac-Phe-Tyr-phosphoSer-CH=C-Pro-Arg-NHAND Fmoc-bis(pivaloylmethoxy)phosphoSer-CH=C-Pro-2- (86). PCT No.: PCT/USOS/26821 aminoethyl-(3-indole); and their Phospho-(D)-serine stereoi Somers are novel compounds. I refers to a pseudo amide. S371 (c)(1), Such novel compounds advantageously may be used as alk (2), (4) Date: Sep. 26, 2007 ene mimics. US 2008/0261923 A1 Oct. 23, 2008 ALKENE MIMICS 0005. The possibility of Pin1 activity led to interest and work on certain alkene mimics. (Wang, Supra); Wang, X. J., FIELD OF THE INVENTION Xu, B., Mullins, A. B., Neiler, F.K., and Etzkorn, F.A. (2004), Conformationally Locked Isostere of PhosphoSer-cis-Pro 0001. This invention relates to the design and synthesis of Inhibits Pin1 23-Fold Better than PhosphoSer-trans-Pro Isos compounds that are alkene mimics. -
Role of Protein Repair Enzymes in Oxidative Stress Survival And
Shome et al. Annals of Microbiology (2020) 70:55 Annals of Microbiology https://doi.org/10.1186/s13213-020-01597-2 REVIEW ARTICLE Open Access Role of protein repair enzymes in oxidative stress survival and virulence of Salmonella Arijit Shome1* , Ratanti Sarkhel1, Shekhar Apoorva1, Sonu Sukumaran Nair2, Tapan Kumar Singh Chauhan1, Sanjeev Kumar Bhure1 and Manish Mahawar1 Abstract Purpose: Proteins are the principal biomolecules in bacteria that are affected by the oxidants produced by the phagocytic cells. Most of the protein damage is irreparable though few unfolded proteins and covalently modified amino acids can be repaired by chaperones and repair enzymes respectively. This study reviews the three protein repair enzymes, protein L-isoaspartyl O-methyl transferase (PIMT), peptidyl proline cis-trans isomerase (PPIase), and methionine sulfoxide reductase (MSR). Methods: Published articles regarding protein repair enzymes were collected from Google Scholar and PubMed. The information obtained from the research articles was analyzed and categorized into general information about the enzyme, mechanism of action, and role played by the enzymes in bacteria. Special emphasis was given to the importance of these enzymes in Salmonella Typhimurium. Results: Protein repair is the direct and energetically preferred way of replenishing the cellular protein pool without translational synthesis. Under the oxidative stress mounted by the host during the infection, protein repair becomes very crucial for the survival of the bacterial pathogens. Only a few covalent modifications of amino acids are reversible by the protein repair enzymes, and they are highly specific in activity. Deletion mutants of these enzymes in different bacteria revealed their importance in the virulence and oxidative stress survival. -
Auction Database 0206 IN
Toy Train Auction Lot Descriptions June 14, 2014 2001 Lionel postwar 2460 and 6460 black Bucyrus Erie crane cars. The 2460 is C7-8 and the 6460 is C7. 2002 Lionel postwar two 6560 Bucyrus Erie crane cars, one with red cab and one with a gray cab. Also included is a 6660 boom car with a detached hook that is included. All cars are C6. 2003 Lionel postwar 2332 dark green Pennsylvania GG1 electric diesel with five stripes. The stripes and lettering are faded. The GG1 is C6. 2004 Lionel postwar 2560 crane car with cream cab, red roof and black boom, C6. 2005 Lionel postwar Five-Star Frontier Special outfit no. 2528WS including; 1872 General steam loco, 1872T W.& A.R.R. tender, 1877 horse car with six horses, 1876 baggage car and a 1875W illuminated passenger car with whistle. The ornamental whistle on the engine is broken and the piping detail on the hand rails is broken. Engine is C6. Rest of set is C7. 2006 Lionel postwar freight cars including; X2454 orange Pennsylvania boxcar with original cardboard insert, X2758 Tuscan Pennsylvania boxcar and a 2457 red Pennsylvania caboose. The X2454 is C5. The other two cars are C7. The 2478 is in a reproduction box. The other two cars are in OBs. The OBs show some wear. 2007 Lionel postwar 726RR Berkshire steam loco and a 2046W tender, circa 1952, C7. The tender is in a worn OB. 2008 Lionel postwar X6454 Tuscan Pennsylvania boxcar and a 6420 gray searchlight wrecking car with original cardboard insert both in OBs. -
2019 Building America Report
UNION PACIFIC 2019 Building America Report A report to communities on our social, environmental and economic sustainability progress. Our Company Economic Impact Delivering an Excellent Customer Experience Operating Safely Strengthening Our Communities Engaging Employees Protecting the Environment Appendix About the Report Union Pacific’s vision of Building America means we connect the nation’s businesses We used the Global Reporting Initiative’s global sustainability reporting standards as and communities to each other and the world by providing safe, reliable and efficient a framework to report our most material social responsibility issues. This publication supply chain solutions that support sustainable economic growth. In doing so, we strive focuses on initiatives and accomplishments from the 2019 calendar year and includes to serve our customers, enhance shareholder value, invest in our communities and 2019 data, unless otherwise noted. The impact of COVID-19 and our response provide promising careers, while operating in an ethical manner. occurred in 2020 and will be thoroughly detailed in the 2020 Building America Report. Information also is available at up.com. This report details progress in key areas supporting our environmental, social, and governance pillars: delivering an excellent customer experience, operating safely, strengthening communities, engaging employees and protecting the environment. We also summarize our 2019 financial performance. Table of Contents LETTER TO STAKEHOLDERS 3 DELIVERING AN EXCELLENT CUSTOMER EXPERIENCE -
Cyclophilins and Other Foldases: Cell Signaling Catalysts and Drug Targets
International Symposium on Cyclophilins and other Foldases: Cell Signaling Catalysts and Drug Targets Halle (Saale), Germany, September 19-21, 2013 CONFERENCE MATERIAL Cyclophilins and other Foldases CONFERENCE VENUE The symposium will be held at the Martin-Luther-University Halle-Wittenberg Lecture hall XXII Universitätsplatz 1 06108 Halle (Saale) Germany Conference office telephone: 0157-30056381 2 Cyclophilins and other Foldases CONFERENCE VENUE LOCATION 3 Cyclophilins and other Foldases ORGANIZING COMMITTEE Jochen Balbach (MLU Halle-Wittenberg) Gunter Fischer (MPI BPC Göttingen, BO Halle) Franz X. Schmid (University of Bayreuth) The conference is supported by SCYNEXIS Inc. Selcia Ltd. AstraZeneca Takeda Pharma Debiopharm Fonds der Chemischen Industrie The City of Halle 4 Cyclophilins and other Foldases WELCOME TO THE CONFERENCE We take great pleasure in setting aside our regular lab work and welcoming you all to the International Conference on Cyclophilins and other Foldases - Cell Signaling Catalysts and Drug Targets, which will be held at the Martin-Luther-University Halle- Wittenberg, Germany from September 19th to 22th, 2013. In the last few years, the scientific and biotechnological communities have become increasingly interested in the challenges involved in conformational regulation of bioactivities by endogenous factors such as foldases. This is reflected in the number of over 600 papers published during 2012 about the enzymes addressed in this conference. We are just beginning to understand how catalyzed conformational interconversions of peptide bonds may affect protein functioning under physiological and pathophysiological conditions. This conference is thought to provide an unique forum for researchers to present and exchange new data and to call attention on all aspects of foldase enzymes and their inhibitors. -
Transcriptomic Analysis of Cortical Versus Cancellous Bone in Response to Mechanical Loading and Estrogen Signaling
TRANSCRIPTOMIC ANALYSIS OF CORTICAL VERSUS CANCELLOUS BONE IN RESPONSE TO MECHANICAL LOADING AND ESTROGEN SIGNALING A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Natalie H Kelly January 2017 © 2017 Natalie H Kelly TRANSCRIPTOMIC ANALYSIS OF CORTICAL VERSUS CANCELLOUS BONE IN RESPONSE TO MECHANICAL LOADING AND ESTROGEN SIGNALING Natalie H Kelly, Ph. D. Cornell University 2017 Osteoporosis is a skeletal disease characterized by low bone mass that often results in fracture. Mechanical loading of the skeleton is a promising approach to maintain or recover bone mass. Mouse models of in vivo loading differentially increase bone mass in cortical and cancellous sites. The molecular mechanisms behind this anabolic response to mechanical loading need to be determined and compared between cortical and cancellous bone. This knowledge could enhance the development of drug therapies to increase bone formation in osteoporotic patients. After developing a method to isolate high-quality RNA from marrow- free mouse cortical and cancellous bone, differences in gene transcription were determined at baseline and at two time points following mechanical loading of wild-type mice. Cortical and cancellous bone exhibited different transcriptional profiles at baseline and in response to mechanical loading. Enhanced Wnt signaling dominated the response in cortical bone at both time points, but in cancellous bone only at the early time point. In cancellous bone at the later time point, many muscle-related genes were downregulated. Decreased bioavailable estrogen levels are a major cause of bone loss in postmenopausal women. -
Cyclophilin a Catalyzes Proline Isomerization by an Electrostatic Handle Mechanism
Cyclophilin A catalyzes proline isomerization by an electrostatic handle mechanism Carlo Camillonia, Aleksandr B. Sahakyana, Michael J. Hollidayb, Nancy G. Isernc, Fengli Zhangd, Elan Z. Eisenmesserb, and Michele Vendruscoloa,1 aDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; bDepartment of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; cWilliam R. Wiley Environmental Molecular Sciences Laboratory, High Field NMR Facility, Richland, WA 99532; and dNational High Magnetic Field Laboratory, Tallahassee, FL 32310 Edited by Arieh Warshel, University of Southern California, Los Angeles, CA, and approved June 3, 2014 (received for review March 5, 2014) Proline isomerization is a ubiquitous process that plays a key role residue in the substrate and induces the rotation of the electric in the folding of proteins and in the regulation of their functions. dipole corresponding to the carbonyl group of the residue pre- Different families of enzymes, known as “peptidyl-prolyl isomer- ceding the proline. In this sense, the carbonyl group represents ases” (PPIases), catalyze this reaction, which involves the intercon- a handle operated by an electrostatic field and helps overcome version between the cis and trans isomers of the N-terminal amide the isomerization barrier. bond of the amino acid proline. However, complete descriptions of We investigated the conformational properties of cyclophilin the mechanisms by which these enzymes function have remained A during the proline isomerization process by using NMR elusive. We show here that cyclophilin A, one of the most common spectroscopy, which can provide atomic-resolution descriptions PPIases, provides a catalytic environment that acts on the sub- of the motions of macromolecules in solution (24–32). -
2020 Building America Report a Report to Our Stakeholders on Union Pacific’S Environmental, Social and Governance Initiatives and Achievements
Steven Boyd Christian Deneumostier John Richard Jessica Marsa Aris Garcia Jr Berkeley, IL Omaha, NE System Gang Omaha, NE Menlo Park, CA Brittany Miller Matthew Havard Chuck Wullschleger Joe Downs Thomas Hottenrott Omaha, NE De Soto, MO System Gang Omaha, NE Dupo, IL Richard Estrada Joshy Madathil Jimmy Thompson Jenn Dellacqua Demarcus Thompson System Gang Omaha, NE Cheyenne, WY Omaha, NE Crystal Lake, IL Adrienne Jensen Jose Guzman Atosha Coleman Bryan Prince Yolanda Delgado Omaha, NE Omaha, NE Omaha, NE Fort Worth, TX Omaha, NE Henry Ward III Sharron Jourdan Booker Williams Marypat Dennis Jon Ruda Kansas City, MO Roseville, CA Fort Worth, TX Omaha, NE Omaha, NE 2020 Building America Report A report to our stakeholders on Union Pacific’s environmental, social and governance initiatives and achievements. 1 About the Report Union Pacific’s vision of Building America means we connect the nation’s businesses and communities to each other and the world by providing safe, reliable and efficient supply chain solutions. In doing so, we strive to serve our customers, enhance shareholder value, invest in our communities and provide promising careers, while operating in an ethical manner. Together, these actions allow Union Pacific to build a more sustainable future. This report details progress in our four areas of concentration related to environmental, social, and governance issues: investing in our workforce, driving sustainable solutions, championing environmental stewardship and strengthening our communities. This report also summarizes our 2020 financial performance and, new this year, includes a Facts and Figures section. We used the Global Reporting Initiative’s global sustainability reporting standards as a framework to report our most material social responsibility issues, and are reporting our GRI Standards Index data for the first time. -
Inhibition of the FKBP Family of Peptidyl Prolyl Isomerases Induces Abortive Translocation and Degradation of the Cellular Prion Protein
Inhibition of the FKBP Family of Peptidyl Prolyl Isomerases Induces Abortive Translocation and Degradation of the Cellular Prion Protein by Maxime Sawicki A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Biochemistry University of Toronto © Copyright by Maxime Sawicki 2015 Inhibition of the FKBP Family of Peptidyl Prolyl Isomerases Induces Abortive Translocation and Degradation of the Cellular Prion Protein Maxime Sawicki Master of Science Department of Biochemistry University of Toronto 2015 Abstract Prion disorders are a class of neurodegenerative diseases that feature a structural change of the prion protein from its cellular form (PrPC) into its scrapie form (PrPSc). As these disorders are currently incurable, there is a crucial need for novel therapeutic agents. Here, the FDA-approved immunosuppressive drug FK506 was shown to cause an attenuation in the endoplasmic reticulum (ER) translocation of PrPC by exacerbating an intrinsic inefficiency of PrP’s ER-targeting signal sequence, effectively causing the proteasomal degradation of PrPC. Furthermore, the depletion of FKBP10 also caused the degradation of PrPC but at a later stage following translocation into the ER. Additionally, novel FK506 analogues with reduced immunosuppressive properties were shown to be as efficacious as FK506 in downregulating PrPC. Finally, both FK506 treatment and FKBP10 depletion were shown to reduce the levels of PrPSc in chronically infected cell models. These findings offer a new insight into the development of treatments against prion disorders. ii Acknowledgments The completion of the present thesis would not have been possible without the help and support of a number of people. First and foremost, I would like to thank my supervisor, Dr David Williams, for his constant guidance and expertise that allowed me to successfully complete my degree, as well as my committee members, Dr John Glover and Dr Gerold Schmitt-Ulms, for their invaluable advice and suggestions over the course of this project. -
Network Evolution: the Origins, Development And
Network Evolution: The Origins, Development and Effectiveness of ’s Railway System Manitoba by Christopher G. L. McCombe A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfillment of the requirements of the degree of MASTER OF ARTS Department of Environment and Geography University of Manitoba Winnipeg, Manitoba © 2011 by Christopher McCombe Copyright ABSTRACT This thesis examines the changing characteristics of railway infrastructure development and associated issues in the province of Manitoba, Canada. The period under consideration dates from when the first tracks were laid in 1878 through to the completion of the Hudson Bay Railway in 1929. Setting the scene is a template for railway development in general, one that allows hypotheses to be drawn that are specific to Manitoba. In order to test those hypotheses it is necessary to first provide a comprehensive overview of the historical evolution of the railway network. Next, the tools for testing the hypotheses as to how that network emerged have to be reviewed. That review examines aspects of graph theory, identifying the methodology most appropriate for a spatial analysis of railway networks. With the fundamental assumption in mind that no railway system of any real complexity can be effectively understood without considering the process of its creation, this analysis attempts to draw conclusions about the relationship between the railway companies and the governments, people and geography that they were compelled to deal with. Given that objective, an emphasis is placed during hypothesis testing on a set of geographic forms developed by prominent geographer Donald Meinig, who set the precedent in the field of railway-network geography.