Hendrick Hudson High School

Science May 2018

Research

Sponsored by the Hendrick Hudson Community Educational Foundation (HHCEF)

“ You are limited only by your imagination”

1 Mr. Beau White

2 Hendrick Hudson High School

May 2018 Science Research

Margaret Quinn Gruber has worked on the effects of radiation on neurogenesis, an important topic not just about our future in space flight, but also addressing the neural degeneration happening in radiation thera- py treating brain cancers. Quinn will attend University of Pennsylvania in the fall.

Our Juniors competed this year as well. Thea Barbelet took First place for her poster in the Animal Science category on bee pollination at JSHS and got Second best overall grade. Buu-Hac Nguyen got First place for her poster in the Neurosci- ence 1 category at JSHS and got Third best overall grade. She also got the College Ad- mission Central Science Horizon Award at WESEF. Buu-Hac worked on charac- terizing the Dopamine transporter with nanobodies. Hailey Kissner competed at WESEF with her fabulous work on Dys- lexia.

Congratulations to a wonderful group of students. We would like to express our sincere and profound gratitude for the work of Dr. Matthias Quick, who Melody Munitz received two Regeneron STS badges, for has been mentoring several of our students over the years, Student Initiative and for her Research Report. She placed who has acted as judge, advised and helped our students Second in the Behavior category for WESEF and Second as present their research better. a speaker for JSHS, qualifying for the finals. Her work on Aphantasia defined new characteristics of this condition. In Our collaboration with the Pine Ridge Girls School in South addition to her accomplishments in Science Research, Mel- Dakota is continuing. We will be able to pair our Science ody is an outstanding actress and singer, who will join the Research classroom with the science class of Mr. Beau Pennsylvania State University, Schreyer Honors College, to White on a regular basis starting in the fall, thanks to the major in musical theater. She is the 2018 Salutatorian. generosity of Mr. James Mackin, who equipped both of our classrooms with webcams. This Science Research Program Peter Manthey placed Second in Tri-County Science Fair in collaboration is part of a developing and pilot program from computer science category. His project, modeling the devel- the Society for Science and the Public to help underserved opment of birds’ beaks, is very important in understanding communities build science research programs. the epigenetic modifications leading to specific beaks’ shapes. Peter is going to attend Colgate University in the fall. 3 An Epidemiological Study of Aphantasia by Melody Munitz (STS paper excerpt) (Senior) Abstract high-functioning as individ- frontoparietal and Aphantasia is a newly ac- uals and in society. One of posterior brain knowledged condition char- the most prominent results is processes (Barto- acterized by the inability that most aphantasiacs have lomeo, 2008), this to form mental images in vivid visual dreams, suggest- skill has numerous one’s mind’s eye. As it has ing that aphantasia affects practical implications, such cally quantifying visualiza- recently surfaced, there has conscious, but not uncon- as its assistance in learning, tion skills. This questionnaire been little research conduct- scious visualization. Anoth- glancing ability and creativ- describes several situations ed on it. I created a survey er important result lies in the ity, among other psychologi- and then asks the participant and distributed it to groups fact that most aphantasiacs cal processes. The formation to rate the vividness of their of self-declared aphantasi- experience diminished im- of mental imagery is also mental imagery on a scale acs via social media, and re- agery of their other senses, linked to memory, as sup- of 1-5. Using the VVIQ and ceived 395 responses. These not simply visual; i.e., they ported by Marks’ 1973 ex- other similar tools and ques- responses were compared to have difficulty conjuring au- periment in which male and tionnaires, Galton found that a control group of 150 sub- ditory or gustatory imagery. female subjects who claimed not everyone is equipped jects. This epidemiological This suggests that aphanta- to have varying visual imag- with comparable visual im- study of aphantasia is the sia is caused by a neurologi- ery capabilities were shown agery capabilities. While first of its kind to function cal mechanism broader than an image and then asked to most people fall somewhere on a large scale, providing those responsible for just vi- recall it. The results sug- on the high end of the spec- important information about sual imagery formation and gested that the subjects who trum, having good or even the nature of the condition recall. claimed to have higher visu- superb visual imagery skills, and its effects on those who Introduction al imagery capabilities were there is a small percentage of people that possess very have it. The results suggest Visualization, or being able more accurate in their recall that aphantasiacs find mental of the images they had seen, poor visualization abilities to conceive an image in one’s (Galton, 1880). In similar re- workarounds to compensate mind’s eye, is an impressive allowing for the conclusion for their lack of visualization that “images have an impor- search conducted by Faw in and impactful ability. Be- 2009, assessing such capa- skills that allow them to be lieved to be the product of tant role in memory” (Marks, 1973). In another experiment bilities of 2,500 participants, relating to the correlation it was found that 2.1-2.7% of between eye movements and them fell in this small group, visualization, there was “no claiming extremely poor or evidence that vivid visual- absent visual imagination izers showed more scanning (Faw, 2009). activity than a group of Ss Aside from Faw’s limited [patients] operationally de- work, this phenomenon has fined to be poor at visualiz- not received much scien- ing”, suggesting that visual tific exploitation. Recently, imagery is more than sim- however, Professor Adam ply eye movements (Marks, Zeman at the University of D.F., 1973). Exeter has begun conduct- Some of the first document- ing research on this topic. ed research regarding visual This condition now named imagery was conducted in ‘aphantasia’ (Zeman, 2015), 1880 by Sir Francis Galton, is hypothesized to be the re- esteemed English scientific sult of either of two different pioneer of the 19th century, types of neurogenic visual and was geared toward de- imagery impairments: i) vi- termining how different peo- sual memory disorders, or ple’s visual imagery skills ii) ‘imagery generation’ de- compare. To assess where privation (Farah, 1984). To each patient lay on the scale explore further features of of visualization, Galton de- aphantasia, Zeman and his veloped the Vividness of Vi- team distributed a shortened sual Imagery Questionnaire version of the VVIQ as well (VVIQ), which has since be- as a supplemental question- come a standard of scientifi- naire addressing additional

4 a good basis for further re- US: 58% Other). Of aphan- search (Zeman, 2015). tasiacs, 42% reported hav- I created a questionnaire and ing been in the academic top distributed it via the internet 10% in high school, compa- to self-proclaimed aphanta- rable to the 39% of the con- sia patients to gather addi- trol group that reported such, tional statistics of the con- showing that aphantasiacs dition. This study gathered don’t feel that aphantasia demographics of the tested has hindered their academic population, as well as infor- success. Most subjects ex- mation regarding the effects pressed that their visual im- of aphantasia on learning agery had been equally weak ability, glancing ability, fa- throughout their life, and did cial recognition ability, cre- not seem to be the result of ativity, career and memory. an accident or other change. This data will facilitate an Confirming Aphantasia: improved understanding of Since most aphantasiacs aphantasia within the sci- were self-identified (only 4% entific community, and act reported that their mind’s eye as a base for further studies weakness has been verified aimed at determining the by a healthcare profession- cause of the condition. al), it was important to verify Goal of Study/Hypothesis personal information to 21 versation with ‘normal’ visu- their standing as aphanta- participants who suspected alizers. Interestingly, despite Develop a survey to be ad- siacs. The first questions of that they had the condition, the 21 participants’ VVIQ ministered to self-proclaimed the survey asked subjects to 19 of whom were male. This scores being tremendously aphantasiacs to verify their undergo a series of visual- testing generated various re- lower than those of the 121 condition, as well as gage izations and record their ex- sults; 5/21 reported having control patients, many sub- additional information about perience. The experimental relatives who experience jects claimed to experience aphantasia that will facilitate group consistently reported similar symptoms, and most involuntary imagery at vari- further scientific investiga- low numerical responses, participants claimed having ous times. This first explor- tions. This will serve as the showing their diminished realized their visualizing atory study of aphantasia first in depth epidemiologi- mind’s eye and categorizing deficit during their teens or began to define and quantify cal study of this condition, them as aphantasiacs. The early twenties through con- the condition, and acted as providing useful information consistently high numeri- about the demographics of cal responses of the control the population of non-visu- group on the same questions alizers, as well as highlight- verified them as non-aphan- ing the effects of the condi- tasiacs, making them a vi- tion on various functions. able control population. When compared to a control Life Function of Aphantasi- group of normal visualizers, acs: it is expected that aphantasi- The collected data suggests acs will report distinctively that aphantasiac’s dimin- different functional experi- ished visualization abilities ences that can thereafter be affect various aspects of considered characteristics of their functionality, specifi- the condition. (...) cally their career, creativ- Results ity, memory, learning ability, Population Demographics: glancing ability, and facial recognition abilities. Normal There was a fairly even visualizers reported that their spread of ages tested, rang- visual imagery capabilities ing from 18-75, with the 25- had a very strong impact on 34 range being the most pop- these aspects of their life, ular. There was a relatively showing that visual imag- even split between male and ery is a skill that the normal female subjects (53% fe- population relies on heavily male: 47% male). Subjects for daily function. Thus, it were from the United States would be expected that those and other countries (42% 5 who do not possess the abil- creativity, or to being a cre- pact on memory, but not a than the rest of the popula- ity to visualize would expe- ative thinker (i.e. thinking in drastic one. Since memory tion, and though they are just rience a noticeable deficit, a creative manner). The lat- tends to be highly depen- as likely to be intelligent and and would note very high ter may be more prominent dent on mental images, and high-achieving, are relying impact of their lack of visu- among aphantasiacs, as their aphantasiacs are not report- on work-arounds to learn alization abilities in Figure possible compensation for ing an extremely weak mem- and memorize. 3. However, aphantasiacs their lack of visual imagery ory, they must be finding Since glancing ability, the reported mid-range impact, may mean they rely on other, means of compensation and ability to take in information suggesting that aphantasi- ‘creative’, methods of think- relying on other methods to at a glance, relies on taking acs do not find their condi- ing. remember and memorize. a mental snapshot for later tion debilitating, but rather, For memory, there was a Since visualization tends to recall and analysis, it would something they are finding spread of strengths reported play a large role in learn- be expected that aphantasi- ways to compensate for. by aphantasiacs, but very ing, it was relevant to as- acs would have weak glanc- Considering the reported few reported “excellent” sess how aphantasiacs learn. ing abilities. Indeed, most impact of visualization on memory (Figure 5). Most of While most control subjects aphantasiacs reported either creativity, it would be ex- the control group reported reported being visual learn- average, very poor, or mildly pected that aphantasiacs above-average memory, with ers, this was not the case below average glancing abil- would experience decreased very few reporting memory among aphantasiacs (Figure ities, with very few reporting creativity. However, most weaker than average. The 6). Rather, most aphantasiac above average or excellent aphantasiacs reported above- memory strength reported subjects reported being ei- (Figure 7). These results are average creativity, just as the by aphantasiacs is swayed ther “kinesthetic” or “read- significant when compared control group did (Figure 4). to the lower end of the scale, write” learners, with the to the control group’s re- Here, it is beneficial to con- whereas the results from the smallest percentage report- sponses of primarily average sider the varying definition control group are swayed to ing being visual learners. or above average, with the of ‘creativity’; these results the higher end, showing that This suggests that aphanta- smallest percentages report- may either speak to artistic aphantasia does have an im- siacs are learning differently ing mildly below average

6 or very poor. The aphanta- imagery is also affected by cause of the large number of their visual dreams occur siac responses skewed to the the condition. Subjects were participants in the study, the rarely, the aphantasiacs re- lower end of the spectrum, asked to rate the strength of 81.1% of aphantasiacs who sponses were spread across compared to the non-skewed their imagery when attempt- dream visually is statistically the options, showing that control group responses, ing to imagine, for example, significant when compared their visual dreams are less suggest that aphantasiacs do a song, the feeling of a cer- to the 94.6% percent of nor- consistent than those of the in fact struggle with glanc- tain fabric, the taste of their mal visualizers who dream normal-visualizer popula- ing ability. favorite food, and the scent visually (Figure 10). How- tion. As in Figure 10, the ever, we must look beyond statistical significance dis- Facial recall (Figure 8) re- of a candle. Compared to the the statistics to understand played in the data regarding quires one to capture a men- control subjects, the aphan- what this particular data set the strength of these dreams tal image of a face, and thus tasiacs reported consistently is truly saying. In actuality, can be misleading due to the it seemed likely that aphan- lower strength of imagery this 81.1% is much higher large population. While the tasiacs would have difficulty for sounds, textures, tastes, than expected, as based on strength of the dreams ex- recalling faces. Nearly 60% and smells, suggesting that their deficit in visualization, perienced by aphantasiacs of aphantasiacs reported Aphantasia is inhibiting not it seemed highly unlikely is lower than the strength of difficulty with this—a sig- only visual imagery, but also that aphantasiacs would dreams experienced by the nificantly higher percentage auditory, tactile, gustatory, dream visually at all. control group, the aphanta- compared to the approxi- and olfactory imagery (Fig- siac strength reported is still mately 15% of normal vi- ure 9). Though aphantasiacs are surprisingly high. Especially sualizers that reported diffi- Function of Dreaming: dreaming visually, they seem to be doing so less when compared to the mean culty recalling faces. Since visual dreaming re- frequently than the popula- strength of wakeful visual- Function of Other Sensory quires the playback of vi- tion of normal visualizers ization reported by aphanta- Imagery: sual images in the mind’s (Figure 11). Whereas over siacs as approximately 1.5 eye, it was under question if While aphantasia is defined half of the control popula- (see Figures 1 and 2), the aphantasiacs would be able by diminished visual imag- tion reports always having mean strength of visualiza- to dream visually. Surpris- ery, it was a point of inter- visual dreams, and only a tion while dreaming report- ingly, many of them can. Be- est to see if other sensory small percentage report that ed here as approximately 3.4

7 calls for further research to ex- plain what brain Dr. Adam Zeman, MD mechanism al- lows for involun- tary visualization while asleep, but not voluntary vi- sualization while awake. In provid- ing new and inter- esting results, this survey adhered to the goals of study and served as Professor of Cognitive the first in depth and Behavioral Neurology is significantly higher, and between what they can and epidemiological should be legitimately con- can’t compensate for seems study of aphanta- sidered. to fall logically, as glancing sia. Though this University of Exeter, Discussion ability and facial recall are survey should Medical School, Exeter, based almost entirely off of This questionnaire yielded not be considered UK. the formation and recall of a many unprecedented results sole proof for the mental image, whereas cre- that begin to characterize and drawn conclu- ativity and memory are sup- alization skills (Fulford et al explain aphantasia. While sions, it has helped to high- ported by other mechanisms. 2017). This result supports this condition does not seem light what areas of aphan- One of the most fascinating the hypothesis suggested by to act as a major deficit to the tasia should receive further results of this study was that my study that aphantasiacs success of those who have it, research. the vast majority of people are utilizing compensatory it certainly affects the way with decreased visual im- Conclusion brain processes different they function and learn (see agery also have weakened Research of aphantasia is than normal visualizers. Fur- Figure 3). Their relatively imagery of their other senses important as it appears to ther neuroimaging studies high strengths of creativ- (see Figure 9). This leads be a condition that is affect- should be conducted to help ity and memory suggest that one to believe that the neural ing a significant number of us understand why aphanta- they must be implementing deficit that causes aphantasia people, supported by Faw’s sia seems to affect imagery mental and lifestyle adjust- is not necessarily based spe- proposal that 2.1-2.7% of a of all the senses, as well as ments to compensate for the cifically in brain processes population are likely to have how aphantasiacs are able to effects of their diminished relating to visualization or extremely diminished or dream visually. If a large per- visualization abilities (see sight, but rather in a more entirely nonexistent visual centage of aphantasiacs are Figures 4 and 5). However, general process relating to imagery capabilities (Faw, dreaming in images, often there do seem to be some the recall of all modalities 2009), and recognizing the vivid ones, they must be able functions that aphantasi- of sensory imagery. Another high number of responses to create and store visual im- acs cannot compensate for surprising and interesting this study received in a short ages that are retrievable dur- so readily; they did report result was that most aphan- period of time. Overall, this ing dreaming, but not con- significantly weak glanc- tasiacs (81%) experience vi- study suggested that aphan- sciously during wakefulness. ing ability as well as dif- sual dreams, and peculiarly, tasiacs are finding ways to Additional brain imaging ficulty recalling faces (see very vivid ones. This result compensate for their visual studies may help to pinpoint Figures 7 and 8). This split imagery deficit, as they are the neural pathways that are high functioning and can prohibiting conscious visual even dream visually. The imagery recall, helping us to next step in aphantasia re- understand how visual imag- search is underway with ery is generated in the brain. the recent completion of an Such findings can relate to fMRI study observing the other fields by possibly aid- brain function of poor vi- ing in the development of sualizers. That study found therapies for patients with that those with low visual visual recall impairments, imagery capabilities utilize a (caused by stroke or brain more widespread set of brain injuries) or by expanding regions when attempting to the knowledge base of other visualize than those with av- conditions pertaining to vi- erage or above average visu- sual imagery such as synes- 8 thesia (a crossing of sensory References imaging research. Journal of Con- ments in the recall of modalities) or schizophrenia Bartolomeo, P. (2008). The neural sciousness Studies, 16, 45-68. pictures.” Perception & Psy- (where there may be visual correlates of visual mental imag- Fulford, J., et al., The neural cor- chophysics 14.3 hallucinations). In learning ery: an ongoing debate. Cortex, relates of visual imagery vividness Marks, D.F. (1973). Visual imagery 44, 107-108. e An fMRI study and about how visualization oc- differences in the recall of pictures. Farah, M.J. (1984). The neuro- literature review, Cortex (2017), British Journal of Psychology, 64: curs, we can expand our un- logical basis of mental imagery: https://doi.org/10.1016/j. 17–24. derstanding of the functions a componential analysis. Cogni- cortex.2017.09.014 Zeman, A., Dewar, M., & Della and processes carried out by tion, 18, 245-272. Galton, Francis (1880). Statistics of Sala, S. (2015). Lives without im- different structures of the Faw, B. (2009). Conflicting intu- mental imagery. Mind, 5, 301-318. agery: Congenital aphantasia. Cor- human brain. itions may be based on differing Marks, David F. (1973) “Visual tex, 73, 378-380. abilities - evidence from mental imagery differences and eye move- Using Bioinformatics to Model Cell Proliferation by Peter Manthey (STS Paper excerpt) (Senior)

Abstract ing to analyze and translate laborators receive sequences low the treat- Bioinformatics is the use of biological and genetic data, produced in laboratories ing doctor computer science, statistics, as well as healthcare infor- throughout the world from to reference mathematics, and engineer- mation. Although bioin- more than 100,000 distinct those sources 1 ing to analyze and interpret formatics has been around organisms.” for potential biological data. The ad- since the 1960s, it is now be- As a result, there has been an treatment. In 2003, research- vancements in this field are ing widely used. In the sim- increase in the application of ers from several universi- currently being used to pro- plest form, bioinformatics is bioinformatics tools to help ties in the United States duce simulations to analyze data that is collected from medical researchers not only leveraged CompuCell3D, a dynamic cell to cell inter- specific sources, run through analyze larger quantities of multi-model framework that actions providing scientist unique code and organized data in shorter period of time, simulates morphogenesis, to more in-depth data regard- by the associated biological but to also become more pre- simulate how limbs form in ing how different cells and macromolecules. cise in diagnosing and de- multicellular organisms dur- cell groups interact with one The amount of data being termining treatments. One ing the stages of embryonic 2 another, as well as allowing collected today throughout breakthrough is using DNA development. The program them to visualize the data. the world is enormous. One sequencing to break apart a was designed to help re- Here we leverage Compu- of the largest databases be- DNA strand which is made searchers better understand Cell3D to analyze genetic ing used for bioinformatics up of four nucleotide bases. the processes of morphogen- and epigenetic data regard- is the GenBank, which is By doing this, scientists can esis. The program simula- ing the formation of the beak part of the International Nu- determine varia- and facial development of cleotide Sequence Database tions for genetic bird embryos. This simula- Collaboration. As of Decem- diseases. Collect- tion will demonstrate how ber 2015, this database con- ing all of this data an abnormally curved beak tained over 203 billion nucle- and using bio- shape in chicken embryos otide bases in more than 189 informatics will can be achieved by altering million sequences, collected now allow doctors cell proliferation. Research- from daily exchanges of data to break down a ers have found that adminis- with the DNA DataBank of person’s entire tration of certain chemicals Japan (DDBJ), the European human genome in can modify the growth rate Molecular Biology Labora- one day and pro- of critical regions of the de- tory (EMBL), and GenBank vide personalized veloping bird’s beak and fa- at NCBI. treatment and cial region. In these simula- “This database is produced medication. One tions the goal is to produce and maintained by the Na- bioinformatics observable changes in the tional Center for Biotechnol- software tool cur- simulation’s output graphics ogy Information (NCBI) as rently being tested that reflect the key features part of the International Nu- will automate the that were observed in the cleotide Sequence Database interpretation of original research. Collaboration (INSDC). The the genome data Introduction National Center for Bio- by accessing any Bioinformatics is an emerg- technology Information is medical journal, ing discipline that uses com- a part of the National Insti- research and ar- puter technology, statistics, tutes of Health in the United ticles applicable mathematics, and engineer- States. GenBank and its col- to the data and al- 9 In late October toms present themselves in of 2015 several later stages of development. databases have In 2012, there were over were created to 200,000 documented cases provide doctors and 125,000 deaths world- with access to wide. Researchers have allergen lists, found that NSC 319726, a protein classifi- small-molecule anticancer, cations and se- could be used to effectively quence informa- treat ovarian cancer. This tion to be used study used bioinformatics to to determine analyze and map the interac- potential risk tions between differentially of allergenic expressed genes across a net- cross-reactivity. work. This allows research- Over 55% of the ers to find potential targets US population for NSC 319726. The result has tested posi- suggested that these genes tive for some and pathways may be candi- tion models the interactions In October of 2015, a group type of allergy. 8 Allergies date agents for NSC 319726. between the gene regulatory of scientists in Italy devel- are caused by a person’s This is because NSC 319726 network and genetic and oped a bioinformatics pro- immune system which mis- has been found to reduce lev- cellular mechanisms. This gram that is capable of iden- takes an allergen, a foreign els of RPS6KA6, a chemical new technology for model- tifying potential biomarkers body, as a threat and launch- that is found to be overex- ing morphogenesis could for diseases and disorders es and attacks to neutralize pressed in patients with can- help us to better understand know was SANIST. In this it. The researchers used bio- cer due to it influencing the defects that occur during study, researchers used informatics to predict which growth of cancer cells.10 limb development.2 In 2005 SANIST to identify a bio- proteins in parasitic worms One of the most important additional research was per- marker for prostate cancer would cause a reaction simi- formed presenting Compu- known as carnitine, an am- tools in the CompuCell3D lar to an allergic reaction in program is the chemical Cell3D, a three-dimension- monium compound involved humans. They were able to al, cell-centered, multiscale in fatty acid metabolism. The field tool. These tools allow 3 isolate in a parasitic worm researchers to simulate the framework. Today Com- research found that carnitine one of the most common puCell3D is being used to in was expressed at lower lev- morphogenesis of multicellu- proteins in pollen. This pro- lar organisms. The “French an open source environment els in the plasma of prostate tein was similar to a protein that allows for “virtual tissue cancer patients and conclud- flag” model displayed how only known previously in the cells placed into varying po- simulations of development, ed that SANIST was able to genomes of plants. Pollen is homeostasis, toxicity and accurately identify and sepa- sitions on the chemical field one of the most prevalent al- changed their parameters in- disease in tissues, organs rate individuals with pros- lergens. This bioinformatics and organisms, covering tate cancer from those with cluding target volume, shape, tool will allow scientists to orientation and diffusion due subcellular, multi-cell and benign conditions at a rapid predict proteins that cause continuum tissue scales.”4 rate.7 to the surrounding environ- allergies, and to design pro- ment. One prominent theory tein molecules for surrounding the develop- 9 Figure 2 – CompuCell3D Floating Windows Layout 15 treating them. ment of a curved bird beak is Right now, research that at a curtain point in the is occurring to find beaks development, the car- a more accurate de- tilage bar will pass through a tection for ovarian chemical field that weakens cancer in women. the strength of the bar. This Currently fifty per- chemical field is stronger cent of women who though at the bottom of the have been diagnosed bird’s beak than it is on the with ovarian cancer top of the beak causing it to do not survive more develop a hooked shape. than five years. The Recent research on the for- reason this cancer mation of body segments is so deadly is be- (somites) in vertebrate em- cause ovarian can- bryos also utilizes cell growth cer is very hard to with multiple parameters de- detect and symp- pendent of the age of the de- 10 aggregates”.13 development. This simula- Researchers compared tion will demonstrate how the embryological pro- an abnormally curved beak cesses that shapes the shape in chicken embryos limb bud, teeth and beaks can be achieved by altering to current theory of bone cell proliferation. Research- and cartilage develop- ers have found that admin- ment. Bioinformatics istration of valproic acid, a was used to determine drug used to treat epilepsy that the current theory in humans, changes the rela- only applies to limb de- tive rates of growth of the velopment. This research FNM and LN regions of the has been the foundation developing bird face (Fig- for a new therapy regard- ure 1). Researchers theorize ing the process of evolu- that this is most likely due to changes in the chemical Figure 3 – The CellDraw User Interface 16 tion in which an organ- ism’s genetic expression fields that control cell - divi veloping cells. This research limb development and any or phenotype, will often sion. Success will be deter- used bioinformatics to prove complications that may oc- change before there is an ac- mined if the simulation pro- it is possible to model cells cur in utero. tual change in the organism’s duces a change in the beak with multiple age dependent In 2012 in the Physico-Ge- genetic code of genotype. shape in the output graphics parameters in the Compu- netic Determinants in the This theory has more recent- that parallel those observed Cell3D program by using lo- Evolution of Development, ly been used to examine the during original study. cal cell interactions versus an scientists found embryos evolutionary changes that external segmentation clock. exhibit an assortment of ste- were first observed by - Dar Systems & Methodology The research concludes that win during his finch study in reotypes and patterns during I used CompuCell3D (Exhib- somites are self-organizing the Galapagos Islands. Re- development that have been it 1) to run the simulation and structures whose size and searchers were able to find present for millions of years. produces output graphics. shape is controlled by local This has led researchers to that by introducing different 11 CompuCell3D is a widely cell-cell interactions. external factors into the en- believe the origins of ani- used open-source simulation vironments of a developing Over the last ten years there mal development lay in the environment for multi-cell, bird embryo, all beak shapes has also been significant effects of external forces on single-cell-based modeling described by Darwin in his progress in the field of using how these animals develop. of tissues, organs and organ- studies could be achieved. 14 bioinformatics for epigenet- Dr. Stuart Newman believes isms. The program leverages ic research. In 2010, Bare “that the origins of animal the Cellular Potts Model to Bones Pattern Formation: A development lay in the mo- Purpose of Study model cell behavior. Within Core Regulatory Network bilization of physical organi- The purpose of this research the program CellDraw was in Varying Geometries Re- zational effects that resulted used to create the initial cell produces Major Features of when certain gene products is to use bioinformatics and the CompuCell3D software layout and Twedit++ to de- Vertebrate Limb Develop- of single-celled ancestors fine the cell properties and ment and Evolution used came to operate on the spa- to create a simulation of the developing facial region in behaviors, and edit the code. bioinformatics to “simulat- tial scale of multicellular The simulation and related ed the behavior of the core a bird embryo at Day 5 in chondrogenic mechanism of the developing limb in the presence of an FGF gradient using a novel computational environment that permits simulation of LALI systems in domains of varying shape and size.” 12 This research concluded when a gradient is present the limb it affects the behavior of the mesenchyme and can form limb-like skel- etal structures. Bioinformat- ics was applied to simulate in vitro and in vivo limb de- velopment. This will allow doctors to better understand 11 create a disturbance in the into Simulation 1, to make surrounding cell group, in- the simulation more accurate dicated by the green shaded and allow me to focus on us- cells, causing the cells to ing cell to cell group inter- break apart and eventually action to reposition existing drive the expansion of the cell groups. Simulation 3 outer most cell group, indi- represents the development cated by the brown shaded of normal beak growth that cells, as it stretches to con- includes the presence of an tain the internal cell groups. epithelium. This included The inner green cell in this a similar one directional simulation will have an in- growth pattern for the beak credibly high growth rate, used in Simulation 1, as well Figure 4 – Cell Simulation 1- Single Growth Rate ( Source: Dr. S. Newman) but will only grow to fill as an outer cell group with programs are run through regarding bird beak growth any unoccupied locations extremely strong inter-cellu- Python 27. I then utilized the in utero at a single growth in the medium that directly lar connections to act as an CMake program to compile rate (Figure 4). These simu- neighbor themselves. The epithelium. The epithelium the CompuCell3D source lations were successful be- final shape of this simula- of a bird’s beak is theorized to write scripts for more cause they only required the tion should resemble that of to play a key role in the de- advanced cellular func- modification of the single the initial shape of the simu- velopment of a bird beak tions. Then Windows Movie growth rate and inter-cell in- lation but should be much due to possible changes in Maker was used to edit the teractions of two cell groups larger in scale. Additionally, its elasticity. However, this output still graphics into an – the top beak and the bot- the blue central cell group simulation did not include a animated simulation. tom beak. should take up all spaces group of neutral cells to rep- The second attempt was to from its starting position resent the mesenchyme and use CompuCell3D to model to the tip of the outer most instead represented the area Creating the Baseline Sim- cell layer, without having the cartilage bar grew into ulations bird beak development of birds with a curved beak. I broken the outer most cell as on an empty space or me- The recreation of cell simu- narrowed my focus to look- group at any point during the dium indicated below. lations requires knowledge ing solely at the develop- simulation. Finally, the cell Simultaneously I shifted my several types of code. These ment of the top portion of green group should occupy approach to focus cell pro- codes include Python, C++, the beak because it is theo- any other spaces inside the liferation during an earlier Bash, as well as how to in- rized that the top and bottom outer brown cell group, and stage of bird beak develop- corporate these languages portion of a bird’s beak grow all spaces outside the outer ment. This allowed me cre- into the CompuCell3D pro- independent of each other. brown cell group should re- ate mesenchyme cell in a gram. To familiarize myself To accomplish this, I exam- main unoccupied. simpler environment so I with Python, Bash and C++ ined areas of beak growth During this process, I also could learn how to manipu- I used several online courses based on significant areas of attempted to produce simu- late their cell properties in and tutorials. concentrated cell prolifera- lations using the program my main simulation. The first simulation attempt tion. I was unable to get the EmbryoMaker on the Li- was to use CompuCell3D to nux operating system. The surrounding areas of prolif- Cell Proliferation Control recreate existing simulations eration to grow at a correct EmbryoMaker modeling rate to consistently framework is designed influence the posi- to better model epi- Figure 6 – Cell Simulation 3 – One Directional Figure 5 – Cell Simulation 2 – Top Bird Beak tioning of the carti- thelial cells in a three- Growth lage bar. dimensional space. In this simula- However, the program tion (See Figure was designed to work 5) a singular large on a smaller scale with central cell group, more complex cell to indicated by blue cell interactions, ver- shaded cells, sus working on large should expand out group of cells with in a singular direc- identical interactions tion and should ini- at the same time. tiate various inter- Based on the results cellular reactions received in Simulation as a result of its ex- 2, I returned to rein- pansion. Most im- corporate the group portantly it should of mesenchyme cells 12 the growth of tempts with each OS I aban- the specified doned the use of Linux. cell groups. The third and final approach This was was to bypass the issues by done by us- using a MAC operating sys- ing Windows tem to compile the Compu- to compile Cell3D source code because the Com- the Mac operating systems p u C e l l 3 D does not require the use of source code SWIG. To compile Compu- in CMake. Cell3D on the MAC oper- The first at- ating system the programs tempt was required include CMake and leveraging the CompuCell3D binaries. the Compu- As well as I downloaded Figure 7 – CMake Interface, Source: Building CompuCell3D on Windows using Visual Studio 2015 17 Cell3D tu- Celldraw.bat through an torial 17 to UNBUNTU Linux Virtual- incorporate Box so I could create custom SWIG into PIFF files to run on the Com- In the Control Simulation duce a similar, if not identi- the environ- puCell3D program. I am attempting to model cal, final shape to that of the mental variables so that the I am now in the process of two separate identical cell control, but should be able to program could be utilized working with the MAC to groups that grow at the same accomplish this task without while CMake compiled the write a custom module to in- constant rate to manipulate the presence of the red shad- CompuCell3D source code. terface with CompuCell3D to the shape of a singular outer ed cell group. This mean All attempts to download, produce varying cell growth cell group that has an ex- that this simulation will install and incorporate SWIG simulations. I am currently tremely slow constant rate need to create its final shape into the environmental vari- coding new modules that that allows it to fill unoccu- solely through the use of the ables on both Window and will allow me to manipulate pied shapes in the medium properties that are present Linux operating systems multiple growth parameters that appear when it interacts in the other cell groups. To were unsuccessful. to a greater specificity than with the other cell groups. make comparing these two Simultaneously attempts There will also be one final simulations easier, the color allowed in the basic tools to were made to leverage GIT CompuCell3D. cell group that should re- of the cell group will remain for Windows, which includes main unchanged throughout the same. precompiled dependencies the entirety of the simula- These simulations did not to be utilized by the Compu- Results tion and should only serve to work as anticipated. I was Cell3D program. Both GIT Although my final simula- impede the expansion of the unable to get the mesen- and SWIG needed to run si- tions are not complete the other cell groups. This can chyme cells to interact cor- multaneously to accomplish intent is to produce simu- be accomplished by creating rectly with other cell groups. the compiling of the source lations using bioinformat- a cell group with no growth At this point I attempted to code, therefore the use of ics and CompuCell3D that rate and extremely strong go back and incorporate neu- GIT for Windows was aban- successful replicate the cell cell-to-cell interactions, tral mesenchyme cells into doned. group formations that were such that this cell group the simulation that would observed on Day 5 in the fa- could not be influenced by The second approach was be overtaken by the grow- cial region of the developing the others. In this simulation compile the data using the ing cartilage bar. However, 18 bird embryo. This simula- the two separate identical Linux operating system. I was unable to accurately tion, once complete, will also cell groups are represented Linux is an open source op- simulate the behavior of the demonstrated how a certain by cells that are shaded blue, erating system that is avail- mesenchyme cells by using beak shape can be achieved while the other cell group is able in various distributions, a singular growth rate and solely through cell prolif- represented by the cells that three of which CompuCell3D varying cell to cell interac- eration without the use of re- are shaded green. Finally, supports. These distributions tions. Numerous attempts strictive chemical fields. the group of cells that is in- would be UBUNTU, RedHat were made to produce simu- tended to remain unchanged and CentOS. For UBUTU lations of cell groups to grow throughout the simulation is the binaries are provided Conclusion, Implications at different rate of growth, shaded red. through the CompuCell3D & Future Research but they were unsuccessful. site, while RedHat and Cen- The establishment of the The various approaches that tOS require you to compile bird embryonic development Cell Proliferation Experi- were attempted are detailed your own binaries. To com- simulation demonstrates that mental below. pile CompuCell3D on these it is possible for the facial 3 operating systems SWIG is The Experimental Simula- The first approach was to cre- cell region to develop as tion should be able to pro- ate custom module to affect required. After numerous at- 13 observed in prior research Hentschel, H. G. E., Alber, M. 14 Linde-Medina, M., solely through the use of cell S., et al. (2005). A framework for & Newman, S. A. three-dimensional simulation of (2014). Limb, tooth, proliferation. The success morphogenesis. Computational beak: Three modes Mentor: of this project shows that Biology and Bioinformatics, of development and bioinformatics can be used IEEE/ACM Transactions on, 2(4), evolutionary innova- Dr. Stuart A. Newman, to model sophisticated cell 273-288. tion of form. Journal of biosciences, 39(2), Ph.D. behavior during embryonic 4 (2015). Compucell3d.org - User- 211-223. development. This method exp.io. Retrieved January 24, could potentially be used 2016, from http://userexp.io/com- 15 (2015, May 15). to demonstrate and validate pucell3d.org.html. Screenshots - Com- puCell3D. Retrieved 5 Home - Autism Society. Re- other theories regarding the November 13, 2017, trieved January 10, 2016, from embryonic development of from http://www. http://www.autism-society.org/. birds and other animal sys- compucell3d.org/ tems including humans. It is 6 (2015). $9 million grant to estab- Screenshots lish open-access autism database worth investigating whether 16 CompuCell3D. ... Retrieved January 10, 2016, (2012). CellDraw or not this same method of from https://med.stanford.edu/ Manual and Tutorial bioinformatics modeling can news/all-news/2015/06/9-million- Version 1.5.1: User grant-to-establish-open-access- be applied to interpret more Manual. Biocom- autism-database.html. sophisticated epigenetic plexity Institute and Professor of Cell Biology data. Because simulations 7 Albini, A., Briga, D., Conti, M., Department of Phys- are not technically physical- Bruno, A., Farioli, D., Canali, S., ics, Indiana Univer- and Anatomy, New York ly observable data, all con- et al. (2015). SANIST: a rapid sity, 727 East 3rd Medical College, Valhalla, mass spectrometric SACI/ESI data Street, Bloomington clusion drawn from them are acquisition and elaboration plat- IN, 47405-7105, NY. essentially implication. form for verifying potential can- USA: Indiana Uni- Because of my interactions didate biomarkers. Rapid Commu- versity. nications in Mass Spectrometry, with the CompuCell3D re- 17 (2017). Building 29(19), 1703-1710. search team, the Compu- CompuCell3D on Windows us- 8 Cell3D website was modi- (2010). Allergy Statistics and Al- ing Visual Studio 2015. Retrieved lergy Facts - WebMD. Retrieved November 14, 2017, from http:// fied to include an area and January 10, 2016, from http:// www.compucell3d.org/SrcBin/ form where users like my- www.webmd.com/allergies/aller- CC3DWindowsCompile_vs2015 self can now go to for sup- gy-statistics. 18 (2017, July 19). SrcBin/Linux- port with issues they may be 9 Tyagi, N., Farnell, E. J., Fitzsim- Compile - CompuCell3D. Re- encountering. mons, C. M., Ryan, S., Tukahebwa, trieved November 13, 2017, from E., Maizels, R. M., et al. (2015). http://compucell3d.org/SrcBin/ Comparisons of Allergenic and LinuxCompile Following the completion of Metazoan Parasite Proteins: Al- my cell proliferation simula- lergy the Price of Immunity. PLoS tions, I plan turn my efforts Comput Biol, 11(10), e1004546. to the development of my 10 Xue, J., Yang, G., Ding, H., original simulation of using Wang, P., & Wang, C. (2015). Role bioinformatics and Compu- of NSC319726 in ovarian cancer based on the bioinformatics analy- Cell3D to model simulations ses. OncoTargets and therapy, 8, to help support the theory 3757. that external environmental 11 Susan Hester-Julio Belmonte-J. factors introduced in vitro Gens-Sherry Clendenon-James can have an impact on the Glazier (2011). A Multi-cell, development of a chicken Multi-scale Model of Vertebrate embryo. Segmentation and Somite Forma- tion. PLoS Comput Biol., 7(10), e1002155. References 12 1 Zhu, J., Zhang, Y., Alber, M. S., GenBank Home. Retrieved Janu- & Newman, S. A. (2010). Bare ary 10, 2016, from http://www. bones pattern formation: a core ncbi.nlm.nih.gov/genbank/. regulatory network in varying 2 Izaguirre, J. A., Chaturvedi, R., geometries reproduces major fea- Huang, C., Cickovski, T., Coffland, tures of vertebrate limb develop- J., Thomas, G., et al. (2004). Com- ment and evolution. PLoS One, puCell, a multi-model framework 5(5), e10892. for simulation of morphogenesis. 13 Newman, S. A. (2012). Physico- Bioinformatics, 20(7), 1129-1137. genetic determinants in the evo- 3 Cickovski, T. M., Huang, C., lution of development. Science, Chaturvedi, R., Glimm, T., 338(6104), 217-219. 14 The Impact of Thyroxine upon Neurogenesis after Galactic Cosmic Ra- diation Exposure by Margaret Quinn Gruber (WESEF paper excerpt) (Senior) Abstract search supported by the Na- risks other than GCRs on tem, which regulates emotions As long-term space mis- tional Aeronautics and Space missions. However, if they and memory (Yassa 2009). sions to planets such as Mars Administration. suffer neurological damage The dentate gyrus (DG) is a come closer to fruition, it is while in space, their ability specific section of the- hip to handle mechanical issues pocampus which is involved essential that astronauts are Review of Literature protected from galactic cos- and other problems will be in the process of “pattern sep- With rapid technological ad- mic radiation on these trips. compromised. Mice exposed aration:” the sorting of neural vancement allowing human- Galactic cosmic radiation to GCRs have been shown inputs so that memories may ity to explore space further (GCR) poses a risk to astro- to perform worse on novel be encoded in the CA3. than ever before, there is a nauts because they do not object recognition (NOR). It is especially important that pressing need for novel ways have the protection of Earth’s NOR tests memory retention the hippocampus is protected to protect astronauts from magnetosphere. GCR hin- and degree of hippocampal from GCRs due to its role in the extreme conditions of ders neurogenesi, the growth function by measuring a ro- adult neurogenesis. The sub- the final frontier. One such of new neurons in the den- dent’s ability to distinguish granular zone (SGZ) of the threat is galactic cosmic rays tate gyrus, a part of the brain between new and previously dentate gyrus (DG) is one (GCRs), which are caused responsible for sorting mem- introduced objects. Signifi- of two sections of the adult by solar flares and supernova ories and patterns. Impaired cant reductions in recogni- brain in which neurogenesis events outside of our solar neurogenesis results in cog- tion memory were observed occurs (Zhao 2008). Neural system. Earth’s magnetic nitive deficits and depres- in mice treated with 30 cen- stem cells are the first stage of field protects the planet from sion, so steps must be taken tigrays (cGy, grays=Joules/ neurogenesis, dividing repeat- GCRs, but on planets such to preserve neurogenesis in kilogram) 48Ti. Neurons of edly into clones of themselves as Mars which lack a mag- astronauts. Thyroid hormone the medial prefrontal cortex until they form neuronal pro- netosphere, astronauts are stimulates neurogenesis, and (mPFC) had significantly re- genitors. Neural progenitor left vulnerable to the health GCR leads to hypothyroid- duced dendritic complexity cells (NPCs) cannot renew risks posed by GCRs (NASA ism. Thyroxine, a thyroid fifteen weeks post-irradia- themselves as stem cells can, 2002). hormone, was administered tion, measured by number of but still have the potential to to mice in order to determine GCRs consist of atoms whose dendritic branches, branch differentiate into different if it may act as a protective electrons were removed as points, and dendritic lengths, types of neurons. In the SGZ, agent against GCR-induced the particles traveled at light indicating memory deficits NPCs most often form dentate impairment of neurogen- speed through the galaxy. The (Parihar 2016). These results granule cells (DGC). Running esis. Mice were irradiated particle makeup of a GCR is indicate that GCR exposure directly results in increased with 28Si. Doublecortin was eighty-five percent protons negatively impacts cognition proliferation of NPCs in the used to visualize immature (hydrogen), fourteen per- and memory, neurons in order to compare cent helium, and one percent so finding a rates of neurogenesis be- heavy charged nuclei (HZE) treatment ca- tween experimental groups. particles, which includes pable of limit- Mice which received thyrox- iron, silicon, carbon, alumi- ing or revers- ine and no radiation showed num, and other elements. ing the effects the highest number of im- Although HZE particles do of GCRs is all mature neurons. All groups not make up a large portion the more nec- which received radiation of GCR particles, their high essary to en- had significantly lower num- energy causes them to ionize sure the safety bers of new neurons than the atoms inside the body, caus- of astronauts control group, but there was ing breaks in DNA strands on long-term no significant difference be- which are extremely diffi- missions. tween irradiated mice who cult, if not impossible, for The hip- received thyroxine and those the body to repair (NASA pocampus is who did not. Our results sup- 2002; Schimmerling 2011). the section of port current literature show- Therefore, HZE particles the brain lo- ing the negative impact of pose a great risk to the health cated beneath GCR upon neurogenesis, but of astronauts even though the cerebral thyroxine does not rescue they are fewer in number cortex and is new neurons and neurogen- than other GCR particles. a part of the esis from GCR damage. Re- Astronauts face a myriad of limbic sys-

15 SGZ and improved cognition, radiation has also been shown esis at this level in the indicating that neurogenesis to cause significant damage to adult (Desouza 2005). Mentor: is correlated with increased DNA, as seen by an increase Thyroid hormones play Dr. Patric K. Stanton, cognition. In addition, neural in DNA damage response a significant role in hip- stimuli activate adult-born protein 53BP1 foci in the DG pocampal neurogenesis Ph.D. dentate granule cells at a (DeCarolis 2014). and cognition. Hypo- higher rate than mature gran- Cancer therapies utilizing ra- thyroidism is linked ule cells are activated. Models diation also negatively impact to higher levels of de- of neuron replacement in the adult hippocampal neurogen- pression and lowered DG imply that new DGCs do esis. Since cancer treatments amounts of new neu- not override previous memo- aim to prevent malignant roblasts in the DG. The ries, but allow for a greater cells from dividing, but lack number of proliferating number of memories to be the ability to discern between progenitor cells in the stored. Adult-born DGCs are healthy and unhealthy cells, SGZ is decreased by less selective in firing, involv- NPCs are also harmed by these 30% due to hypothy- ing them in the process of therapies. Radiation used for roidism; the reduction “pattern integration,” which the purposes of treating cancer in progenitor cells was Professor of Cell Biology is similar to pattern separation in the central nervous system ameliorated with thy- and Anatomy, but ensures that similarities increased apoptosis of neural roxine treatments (Re- New York Medical College, between memories are rec- stem cells and decreased pro- maud 2007). Valhalla, NY ognized by the brain. Pattern duction of new neurons by integration links memories 95% overall. Cognitive defi- Statement of Purpose encoded at close time points, cits resulting from radiation pothesis that thyroxine reduc- while memories encoded fur- therapy include a slowing of We aim to prevent damage to es harm to neurogenesis from ther apart in terms of time are information processing speed, the brains of astronauts due to GCR exposure. Radiation ex- separated. These models show memory impairments, and exposure to galactic cosmic posure in space takes place at that DGCS born in adult- difficulty with word retrieval radiation using thyroxine as a much slower rate than the hood play an important role (Pereira Dias 2014). a stimulating agent of neuro- radiation used in the experi- in memory formation (Deng genesis. ment, multiple exposures ver- The thyroid gland, located 2010). (...) sus one exposure, which may below the larynx, produces have impacted experiment GCR exposure has been hormones which regulate shown to have a negative results. Further experimenta- the body’s metabolism. Two Results, Discussion and impact upon neurogenesis. tion will include examining types of thyroid hormone, Conclusion neurogenesis at a time closer Irradiation with either five triiodothyronine (T3) and The control groups exposed to irradiation. “fractionated” 20 cGy doses thyroxine (T4) are produced to no radiation showed sig- or one “acute” 100 cGy dose from tyrosine and iodine. nificantly higher numbers of of 56Fe particle radiation Thyroid hormones bind to References immature neurons than exper- resulted in a respective 58% two types of thyroid nuclear Amaral, D., Scharfman, H., & Lave- imental mice exposed to ir- and 74% decrease in prolif- receptors (TRs), TRα and nex, P. (2008). The dentate gyrus: radiation, which is consistent Fundamental neuroanatomical or- erating neurons in the DG 24 TRβ, which affect how genes with current literature demon- ganization (dentate gyrus for dum- hours post-irradiation. Three are expressed depending on strating the negative impact mies). Progress in Brain Research, months after irradiation, the their ligand binding. When 3-22. https://doi.org/10.1016/S0079- of GCRs upon neurogenesis fractionated radiation group thyroid hormones bind to their 6213(07)63001-5 (Figures 2 and 3). Thyroxine had 36% fewer proliferating receptors, gene expression is Christie, L.-A., Acharya, M., Parihar, treatments did not significant- neurons than the sham group, activated. The presence of V., Nguyen, A., Martirosian, V., & Li- ly alter the number of imma- moli, C. (2012). Impaired cognitive while the acute radiation thyroid hormone receptors in ture neurons, and the thyrox- function and hippocampal neurogen- group had 46% fewer prolif- the hippocampus suggests an ine group which underwent esis following cancer chemotherapy. erating neurons than shams important regulation of neu- Clinical Cancer Research, 1954- 100 cGy of radiation showed (Rivera 2014). 56Fe particle rogen- 1965. https://doi.org/10.1158/1078- a lower 0432.CCR-11-2000 amount of DeCarolis, N. (2014). 56Fe particle new neu- exposure results in long-lasting in- rons than crease in a cellular index of ge- the vehi- nomic instability and transiently cle group. suppresses adult hippocampal neu- rogenesis in vivo. Life Sciences in Therefore, Space Research, 70-79. https://doi. this data org/10.1016/j.lssr.2014.06.004 does not Deng, W. (2011). New neurons and s u p p o r t new memories: How does adult hip- Figure 1: Coronal slice of a mouse brain (Left) The section encapsulated by the red box is the hippocampus (Richards). Detailed diagram of the mouse hippocampus (Right) (Deng 2010) the hy- pocampal neurogenesis affect learn-

16 Figure 2: These photos are of the subgranular zones of mice from each experimental group. The first row received saline injections, and the second row received thyrox- ine. The first column was not exposed to radiation, the second column was exposed to 50 cGy of radiation, and the third column was exposed to 100 cGy of radiation. ing and memory? Nature Review view of Psychology, 61, 111–C3. [Digital image]. Retrieved from srep34774 Neuroscience, 339-350. https://doi. http://doi.org/10.1146/annurev. http://www.spacetelescope.org/im- Parihar, V. K., Allen, B., Tran, K. K., org/10.1038/nrn2822 psych.093008.100359 ages/heic0607a/ Macaraeg, T. G., Chu, E. M., Kwok, Desouza LA1, Ladiwala U, Daniel Limbic system: Hippocampus. (n.d.). National Aeronautics and Space Ad- S. F., … Limoli, C. L. (2015). What SM, Agashe S, Vaidya RA, Vaidya Retrieved from Neuroscience Online ministration. Thyroid disease investi- happens to your brain on the way VA. Thyroid hormone regulates hip- of University of Texas Health web- gated among LSAH population. Lon- to Mars. Science Advances, 1(4), pocampal neurogenesis in the adult site: http://nba.uth.tmc.edu/neurosci- gitudinal Study of Astronaut Health e1400256. https://doi.org/10.1126/ rat brain. Mol Cell Neurosci. 2005 ence/s4/chapter05.html Newsletter. February 1998;7(1): 1 sciadv.1400256 Jul;29(3):414-26. Malik, S., Vinukonda, G., Vose, L. R., National Aeronautics and Space Pereira Dias, G., Hollywood, R., Encinas, J. (2008). Quiescent Diamond, D., Bhimavarapu, B., Hu, Administration. (2002, October). Bevilaqua, M. C. do N., da Silveira adult neural stem cells are excep- F., . . . Ballabh, P. (2013). Neurogen- Understanding space radiation. Re- da Luz, A. C. D., Hindges, R., Nardi, tionally sensitive to cosmic ra- esis continues into the third trimester trieved from https://spaceflight.nasa. A. E., & Thuret, S. (2014). Con- diation. Experimental Neurology, of pregnancy and is suppressed by gov/spacenews/factsheets/pdfs/ra- sequences of cancer treatments on 274-279.https://doi.org/10.1016/j. premature birth. The Journal of Neu- diation.pdf adult hippocampal neurogenesis: expneurol.2007.10.021 roscience. https://doi.org/10.1523/ National Aeronautics and Space Ad- implications for cognitive function JNEUROSCI.4445-12.2013 and depressive symptoms. Neuro- Erikson, P. (1998). Neurogenesis in ministration. (2011, February). The Oncology, 16(4), 476–492. http:// the adult human hippocampus. Na- Montero-Pedrazuela, A., Venero, C., space radiation environment: An doi.org/10.1093/neuonc/not321 ture Medicine, 4(11), 1313-1317. & Lavado-Autric, R. (2006). Modu- introduction (W. Schimmerling, Au- lation of adult hippocampal neuro- thor). Retrieved from https://three. Puymirat, J., Miehe, M., March- Gotz, M., & Huttner, W. (2005). The genesis by thyroid hormones: Impli- jsc.nasa.gov/concepts/SpaceRadia- and, R., Sarlieve, L., & Dussault, J. cell biology of neurogenesis. Nature cations in depressive-like behavior. tionEnviron.pdf (1991). Immunocytochemical local- Reviews, 6, 777-788. https://doi.org/ Molecular Psychiatry. ization of thyroid hormone receptors to.1038/nrm1739 National Aeronautics and Space National Aeronautics and Space Ad- Administration. (2013, May 30). in the adult rat brain. [Abstract]. Thy- Leuner, B., & Gould, E. (2010). ministration (2006). Large and small Sources of ionizing radiation in in- roid: Official Journal of the Ameri- Structural Plasticity and Hip- stars in harmonious coexistence terplanetary radiation [Photograph]. can Thyroid Association. https://doi. pocampal Function. Annual Re- Retrieved from org/10.1089/thy.1991.1.173 https://www. Richards, K. (n.d.). Coronal section Figure 3: The two furthest left columns received no radiation. The middle two columns received from mouse brain stained for neu- 50 cGy radiation. The two furthest right columns received 100 cGy radiation. The right four jpl.nasa.gov/spa- columns were significantly lower (p<0.05) than the control groups. ceimages/details. rons with NeuN DAB histochemistry php?id=PIA16938 [Photograph]. Retrieved from http:// melbournebraincentre.edu.au/con- Nature Clinical Prac- tent/coronal-section-mouse-brain tice Endocrinology & Metabolism 3, 249– Rivas, M., & Naranjo, J. R. (2007). 259 (2007) Thyroid hormones, learning and memory. Genes, Brain and Behavior. https://doi.https://doi.org/10.1111/j.1601-183- org/10.1038/ncpend- X.2007.00321.x met0424 Rivera, P., Shih, H.-Y., & LeBlanc, J. Parihar, V. K. (2016). (2014). Acute and fractionated expo- Cosmic radiation sure to high-LET 56Fe HZE-particle exposure and persis- radiation both result in similar long- tent cognitive dys- term deficits in adult hippocampal function. Scientific neurogenesis. 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Abstract Nb494 and Nb499. Further- ies are comprised The human dopamine trans- more, the results of this study of a heavy chain porter (hDAT) maintains do- portray how the addition of homodimer rather pamine homeostasis in the nanobodies affect alanine up- than of light chains central nervous system. Sub- take activity by LeuT. In this (Saerens et al., stances such as cocaine or study, I identified two nano- 2010). Studies have amphetamines inhibit hDAT, bodies that bind to LeuT and shown the antigen- causing an imbalanced dop- increase or decrease LeuT-me- binding portion of amine homeostasis that results diated alanine uptake activity. the heavy-chain in severe psychiatric condi- With the similarities of LeuT antibodies, which tions. To counteract the effect and the DAT, nanobodies can constitutes the com- of these illicit substances or later be directed against DAT plete nanobody, has other therapeutic substances to observe the effect on pro- a greater tendency that target hDAT, it would be tein activity. If the nanobody to interact with desirable to have available and DAT interaction alters the parts of the target molecular tools that aid in the function of the DAT, this may that are not easily regulation of hDAT’s activity. lead to the use of the DAT as recognized by con- One promising approach is a target for nanobody-based ventional antibod- the use of small proteins that, immunotherapy. ies because of their in theory, can inhibit or stim- smaller size, which allows access to ulate hDAT function. This Introduction study analyzes the effect of hard-to-reach areas Single-domain Antibodies nanobodies directed against of the target (Saer- (sdAb), also known as nano- a homolog of hDAT, LeuT, ens et al., 2010). protein that catalyzes the neu- bodies, are antibody frag- a bacterial amino acid trans- Although these nanobodies rotransmitter dopamine into ments that are derived from porter that serves as model are free from light chains, presynaptic neurons. camelids (Cortez-Retamozo the nanobodies remain fully system for hDAT. The per- To determine the potential use et al., 2004). Single-domain functional (Cortez-Retamozo formed methods focus on the of nanobodies in biosensing antibodies are used from cam- et al., 2004). They are stable, isolation of two nanobodies, and diagnostic assays, scien- elids because the antibod- highly soluble, distinctly spe- tists secured single-domain cific and have high - affin antibodies onto biosensor sur- Figure 1. This diagram illustrates the similar structure of DAT and LeuT. ity (Cortez-Retamozo et al., faces with the use of multiple 2004). immobilization strategies (Pia Through these favorable et al., 2015). The character- characteristics and their mi- ization of the interaction with nuscule size, scientists are the single-domain antibodies’ examining the potential uses specific target was done by of single-domain antibodies Surface Plasmon Resonance in biosensing applications (SPR) biosensors, which are as well as treating diseases used to monitor biomolecular through isolating, cloning, interactions due to their high and selecting nanobodies sensitivity and reproducibil- with specificity to the desired ity (Pia et al., 2015). Through antigens (Cortez-Retamozo the immobilization methods, et al., 2004). The results of scientists determined the ki- these studies exhibit the pos- netic binding constants of the sible use of nanobodies in immobilized nanobodies for the dopamine transporter, a their antigens on the different 18 surfaces. This data was com- revealed how the nano- smaller, which alters pared to traditional mono- body conjugate stopped the the biodistribution clonal antibodies with their growth of the tumor xeno- of the single-domain Mentor: kinetic binding constants graft that was placed in nude antibodies and im- Dr. Matthias Quick, and showed that the immo- mice (Cortez-Retamozo proves access to the bilized nanobodies were the et al., 2004). These results target. Other advan- Ph.D. most successful in capturing show that the minuscule size tages of nanobodies molecules (Pia et al., 2015). of single-domain antibod- against regular anti- Furthermore, the results of ies alters their biodistribu- bodies are the ability this study also revealed im- tion and distinctly improves to block certain pro- mobilized nanobodies with access to epitopes (Cortez- teins for biochemi- high affinities to their -anti Retamozo et al., 2004). The cal/crystallographic gens and high resistance to improved access to epitopes studies, can be screen numerous denaturing agents, further illustrates the likeli- for specifically de- such as temperature. These hood of using nanobodies in sired conformation, characteristics portray the the dopamine transporter be- and can be produced Associate Professor of possibility of using nanobod- cause of their smaller size, as from libraries in E. Neurobiology (in Psy- ies in the dopamine trans- compared to whole antibod- coli. Nanobodies also chiatry) porter because the nanobody ies, which has better access show high affinities is likely to identify the do- to the dopamine transporter. for their target and re- Department of Psychia- pamine transporter without Furthermore, a previous main stable under de- try and Center for Mo- becoming impaired. study shows the application naturing agents; with lecular Recognition, In addition, nanobodies have of specific whole antibodies these superior char- the ability to treat diseases, in the dopamine transporter acteristics, nanobod- Columbia University and such as cancer, by attaching (DAT) (Ciliax et al., 1995). ies portray potential College of Physicians to the tumor site and killing The antibodies were used for use on the dopamine and Surgeons. cancer cells (McMurphy et immunolocalization of trans- transporter. The use al., 2014). Previous studies porter protein in rat brain of nanobodies on the dopamine transporter exhibit similar to the DAT. The sec- have shown that nanobodies (Ciliax et al., 1995). This ond goal of the study is to specific to carcinoembryonic study showed how the anti- promising advancements in immunotherapy. research the advantages of antigen (CEA), a protein bodies targeting the N-termi- using nanobodies to charac- which appears in the blood nus and the C-terminus were The other part of the study terize the DAT. Additionally, of cancer patients, targeted specific to the expressed involves the similarities in to research if and where the a distinct non-overlapping cloned DAT, recognized structure of the DAT and nanobody binds to the DAT epitope on the CEA mol- the transporter protein and LeuT (Penmatsa et al., 2013). and if this interaction alters ecule (Cortez-Retamozo et were sensitive to the excess The DAT functions through the function of the DAT, al- al., 2004). An experiment homologous fusion protein cotransport, pumping do- lowing them to be used as im- (Ciliax et al., pamine out of the synaptic munotherapy agents. If nano- Figure 2. Coomassie-stained SDS-PAGE gel of the two puri- 1995). The cleft and into the neuron inte- bodies are engineered against fied nanobodies 494 and 499. The leftmost column provides results of this rior. This is important as do- LeuT, the nanobodies can lat- the standard while the dark blue lanes represent nanobodies study prove pamine plays a critical role in 494 and 499. er be characterized and tested how the gen- movement, reward, behavior, against the DAT. Additionally, eration of and more. The DAT allows if monoclonal antibodies can specific DAT the conclusion of dopamine be used for immunotherapy a n t i b o d i e s neurotransmission and there- by binding to the dopamine will allow fore maintains dopamine transporter then nanobodies further char- homeostasis in the central exhibit potential in the ad- acterization nervous system. The similar- vancement of immunotherapy of the cellu- ity in structure between the due to the nanobodies’ smaller lar as well as dopamine transporter and the size, widespread biodistribu- subcellular leucine transporter provides tion, and high stability. localization a reliable template to deter- of DAT pro- mine DAT structure-function (...) tein (Ciliax et predictions. al., 1995). Results Compared to Statement of Purpose The Coomassie-stained SDS- whole anti- PAGE gel of the two purified The first goal of this study bodies, nano- nanobodies 494 and 499 were is to direct the nanobodies bodies are subjected to size-exclusion against the LeuT, a model significantly chromatography. Thus, after 19 the protocol, the proteins are the leucine found in a highly pure form transporter. as I was able to purify the Thus, the two nanobodies to apparent nanobod- homogeneity. ies 494 and The time course of 3H-al- 499 have anine uptake was tested in the ability proteoliposomes that contain to affect the LeuT. Uptake was performed activity of in the absence or presence the trans- of Nb494 or Nb499. With porter. With Nb494, uptake of 3H-Ala the similari- was almost completely inhib- ties of the ited, whereas, in stark con- LeuT and trast, uptake in the presence the DAT, of Nb499 was about double nanobod- of that observed for LeuT in ies can later be directed Figure 3. This graph exhibits a time course of the uptake of liposomes, the two nanobodies 494 and 499, the absence of a Nb. and LeuT-WT. As shown, the uptake of the liposomes act as a control. LeuT-WT shows an uptake but then a g a i n s t plateaus at 10 nmo/mg LeuT. + Nb 499 reaches 20 nmo/mg LeuT and plateaus. Additionally, + Nb 494 DAT to ob- uptake looks similar to the control liposomes. Discussion serve the The image of the Coomassie- effect on E. (2013) Nature. 503(7474):85- stained SDS-PAGE gel of the protein activity. 90. doi: 10.1038/nature12533. nanobodies 494 and 499 ex- Epub 2013 Sep 15. X-ray structure hibits the proteins after being References of dopamine transporter elucidates antidepressant mechanism. subjected to size-exclusion Cortez-Retamozo et al, (2004), Can- chromatography. Thus, the cer Research, 4, n.a., 2853–2857, Yamashita A1, Singh SK, Kawate proteins are found in a highly Efficient Cancer Therapy with a T, Jin Y, Gouaux E. (2005) Nature. Nanobody-Based Conjugate. 437(7056):215-23. Epub 2005 Jul pure form. Referencing the 24. Crystal structure of a bacterial graph displaying the uptake Della Pia, E. A. & Martinez, K. homologue of Na+/Cl--dependent of alanine by LeuT-WT in L., (2015), PLOS ONE, 10, n.a., neurotransmitter transporters the presence and absence of 1-17. Single Domain Antibodies as a Powerful Tool for High Quality nanobodies 494 and 499, the Surface Plasmon Resonance Stud- presence of nanobody 499 ies. reaches 20 nmo/mg LeuT McMurphy et al, (2014), PLOS which portrays a double ala- ONE, 9, n.a., 1-8. The Anti-Tumor nine uptake. Additionally, Activity of a Neutralizing uptake by LeuT-WT with the Nanobody Targeting Leptin Re- presence of nanobody 494 ceptor in a Mouse Model of Mela- looks similar to the uptake noma. of the liposomes, the control; Saerens, D., (2010), World journal of biological chemistry, 1, n.a., this indicates the presence of 235-238. Isolation and optimiza- nanobody 494 inhibits up- tion of camelid single-domain an- take of alanine. Overall, the tibodies: Dirk Saerens’ work on graph exhibits how the ad- Nanobodies. dition of nanobodies affect Vaughan, R. A., & Foster, J. D. alanine uptake and increases (2013). Mechanisms of dopamine or decreases leucine activ- transporter regulation in normal and disease states. Trends in Phar- ity. Following, nanobodies macological Sciences, 34(9) directed against the LeuT af- Ciliax et al, (1995), The Journal of fect protein activity. The re- Neuroscience, 75(3): 1714-1723. sults exhibit how nanobody The Dopamine Transporter: Immu- 499 increases the uptake, ac- nochemical Characterization and tivating the transport protein Localization in Brain. more than the normal LeuT- Ablynx’s Nanobody [Digital im- WT. This raises the question age]. (2015, August 11). Retrieved Dec. & jan., 16, from of which section of the pro- http://seekingalpha.com/ tein transporter is enhanced. article/3429536-ablynx-unlike- Meanwhile, nanobody 494 any-other-biotech-company shuts down the activity of Penmatsa A1, Wang KH, Gouaux 20 Pollinator Landing Frequency after Floral Modification of Tagetes patu- la, French Marigolds by Thea Barbelet (WESEF Paper) (Junior)

Abstract markings decreased the num- nectar, which has Pollination has been occur- ber of pollinator visits. The a high sucrose ring for millions of years. results of this study may lead content and pro- Over time, different species of to a way to help stop invasive vided an even pollinators and angiosperms, plant species from being pol- more enticing or flowers, have adapted to linated, and therefore limit reward. As each increase the efficiency of the their spreading. insect visited a process. Through evolution, flower to feed, pollen stuck to angiosperms have developed Introduction different ways to draw polli- its body, and was nators in, have them pick up Fossil evidence dates the first then transferred pollen, and then transfer that existence of pollinators at to the next visited pollen to another flower, over nearly 100 million years ago flower, and with and over again. Specifically, (Peñalver et al., n.d.), and this new meth- some flowers began to show amber from Cretaceous New od of pollina- close range visual guides in Jersey holds a 96 million year tion, pollinators the form of ultraviolet mark- old member of the Apoidea were established ings to gain the attention of superfamily (Michener & (Goulson, 2014). Grimaldi, 1988). Flowers, or insects. These ultraviolet Since then, both angiosperms, are plants that markings look like dark rings pollinators and Fig 2: Shows a group of French marigolds reproduce using seeds. Before to the eyes of most pollinators, flowers have The flowers were temporarily marked with flags to angiosperms, before plants randomly select blossoms for treatment and in this study we evaluate greatly evolved, evolved to have petals around the relationship between the but the impor- their respective sex parts, they presence of these markings, tance of their attract only male orchid bees would instead release all of and the frequency of pollina- symbiotic relationship has with a specialized scent, and their pollen into the wind, and tor visits. Natural sunscreen is not diminished. In New York the structure of the orchid al- most of it would not reach the used to inhibit the reflectance specifically, frequent pollina- lows only these male orchid desired destination, which of close range visual guides tors include European honey bees to pollinate it (Schnepf, was the female sex parts of on Tagetes patula, or French bees, common eastern bumble Deichgräber, & Barthlott, plants of the same species. If marigolds, and the results bees, yellow-masked bees, 1983). pollen does not reach a plant showed that inhibiting these virescent sweat bees, pearl of the opposite Furthermore, pollinators have crescent butterflies, American sex, the plants will varying types and degrees of hoverflies, and long hoverflies not reproduce and vision. Most research focuses (Matteson, 2014). While Eu- the species may Mentor: ropean honey bees are eventually die out. Hillary Siener, MS the most effective pol- Clearly, this pro- linators, contributing Conservation Biology cess was futile, and $20 billion worth of eventually, evolu- crops to the American tion resulted in a economy and $200 more effective sys- billion worldwide tem. Plants devel- (Fairbrother, Purdy, oped white petals, Anderson, Fellk, & creating early an- Bellevue, n.d.), other giosperms, which pollinators serve more allowed insects to niche purposes and differentiate plants should not be over- from the rest of the looked. Some flowers landscape. Early have developed incen- pollinators would tives for specific pol- Director of Environmental seek out plants be- linators, referred to as cause pollen pro- Stewardship floral guides (Horth, vided a steady food Campbell, & Bray, source, but some 2014). For example, Teatown Lake Reservation angiosperms be- the bucket orchid will gan to also produce 21 can additionally see into the ultraviolet end of the spectrum, while humans can- not. Most likely not by coincidence, but due to years of ad- aptation, some flow- ers have ultraviolet markings, which are visible to bees in a variety of ways, but most commonly as a dark ring around the center of the flower (Orbán & Plowright, 2014). These markings are guides have a significant role research may stand to offer considered close range vi- in attracting pollinators, then solutions to current or future sual guides, and serve to their modification may affect problems. draw pollinators into the the frequency of pollinator Hypothesis visits, offering the ability to center of the flower, similar If the floral guides of the lessen the pollination of inva- to a bull’s eye. Close range French Marigolds are modi- sive plant species. Removal visual guides help flowers fied, then the frequency of of close range floral guides Fig 1: Rudbeckia hirta flower heads to be pollinated, and also re- pollinator visits will decrease, on ornamental, or maintained, under normal and ultraviolet light. The ward the visitor with nectar because pollinators rely on vi- ultraviolet light allows humans to see plants can keep them in gar- (Horth et al., 2014; Menzel sion to effectively find flow- flowers the same way honey bees do, dens and out of the rest of an with a thick reflecting floral guide ring & Shmida, 1993). ers. ecosystem, since they may no around the center of the floral head, act- Statement of Purpose Materials and Methods ing as a bull’s eye. (Horth et al., 2014) longer be pollinated. While In the present study, we ana- each pollinator species has French marigolds were select- on honey bees, which see on lyze the relationship between different characteristics, a ed for their strong ultraviolet the same spectrum as humans the presence of strong ultra- broad study can offer a basis close range visual guides. A (Hempel De Ibarra, Vorobyev, violet floral guides on Tagetes for further research on each bloom of French Marigolds & Menzel, 2014). Honeybees patula, or French marigolds, individual species, and also were commercially pur- can see all parts of the spec- and frequency of pollina- other plant species. Nonethe- chased, and each blossom was trum that humans can see, ex- tor visits to learn more about less, there is always more to inspected with an ultraviolet cept for red hues. Honey bees how insects see the world. If learn about pollinators and flashlight to ensure the - pres close range ultraviolet floral their respective flora, and any ence of ultraviolet markings.

After purchase, the flow- ers were divided into three groups: two study and one control. Each group con- tained ten blossoms, with 30 blossoms total. The flow- ers were taken to a fenced in wildflower garden with a small apiary containing a single European honey bee colony. They were then split into two groups, with 15 blossoms each. One group was placed flush against one row of wildflowers, while the other group was placed on the other side of the row. After random selection, five blossoms were left as con- trols. The next five blossoms were treated with natural 22 lotion sunscreen, which in- outcome on the hibited the reflectance of the results of both ultraviolet markings, mak- tests. The polli- ing them invisible. Five more nators accounted blossoms were treated with for included Eu- natural spray sunscreen, again ropean honey inhibiting the close range vi- bees, common sual guides. Both sunscreens eastern bumble were the same brand, and each bees, yellow- ingredient was checked to en- masked bees, sure that the visiting insects virescent sweat would not be harmed. Once bees, pearl cres- both groups were treated with cent butterflies, sunscreen, the frequency of American hov- pollinator visits was recorded erflies, and long for five minute intervals. Af- hoverflies, and the mentioned before, they can- son, T., Fellk, R., & Bellevue, W. (n.d.). Risks of Neonicotinoid In- ter each five minute period, group was diverse. not see red hues. Albeit, the color may have attracted more secticides to Honeybees. https://doi. the position of the two groups Discussion/ Conclusion org/10.1002/etc.2527 were swapped, and then af- pearl crescent butterflies, who In this experiment, we com- Frentiu, F. D., Bernard, G. D., Cue- ter ten minutes, the groups of can see the hue (Frentiu et al., vas, C. I., Sison-Mangus, M. P., Pru- pared the frequency of pol- flowers were moved farther 2007). dic, K. L., & Briscoe, A. D. (2007). linator visits after the inhibi- down the row of wildflowers. Adaptive evolution of color vision as tion of ultraviolet close range seen through the eyes of butterflies. This process was repeated. visual guides. Understanding Some additional problems Proceedings of the National Acad- Results pollination is vital for main- were encountered during the emy of Sciences of the United States The control group had a to- taining our ecosystem. Both study that may have led to of America, 104 Suppl 1(suppl 1), unsatisfactory results include: 8634–40. https://doi.org/10.1073/ tal of 78 pollinator landings. species of hoverfly were the pnas.0701447104 overall lack of time, season, The majority of landings were most frequent pollinators, Goulson, D. (2014). A Sting in the made by the American hover- despite their ineffectiveness weather, financial restrictions, Tale: My Adventures with Bumble- fly, with 44%, while the Euro- when pollinating. This may and only one accessible study bees. Picador. Retrieved from https:// pean honey bee only account- have been a result of the addi- site. Future studies may be us.macmillan.com/astinginthetaleda ed for 2.6% of the landings. tional scent of the sunscreen, proposed to further investigate vegoulson/9781250070975 The lotion treatment group which added the smell of the white coloring of the lo- Hempel De Ibarra, N., Vorobyev, • M, had a total of 24 landings. lavender and green tea to the tion sunscreen versus the clear & Menzel, • R. (2014). Mechanisms, spray sunscreen, varying eye functions and ecology of colour vi- The majority of landings were French marigolds, and hov- sion in the honeybee. J Comp Phys- again made by the American erflies have a great attraction structure of each pollinator, iol A, 200, 411–433. https://doi. hoverfly, with 62.5%. Lastly, to scent (Larson, Kevan, & and a wider set of both flora org/10.1007/s00359-014-0915-1 the spray treatment group had Inouye, 2001). The European and fauna subjects. Horth, L., Campbell, L., & Bray, 5 total landings, with the Long honey bees’ flower blindness, In conclusion, the hypothesis R. (2014). Wild bees preferentially hoverfly this time having 40% the fact that honey bees will was supported, but more thor- visit Rudbeckia flower heads with exaggerated ultraviolet absorbing of all landings. not visit a flower until it has ough testing may yield stron- floral guides. Biology Open, 3(3), Overall, the control group had been in their environment for ger and more reliable results. 221–30. https://doi.org/10.1242/ more visits than either of the some time, may have kept a The revised hypothesis states: bio.20146445 treatment groups. The Chi- greater number of honey bees if the natural color, scent, and Larson, B. M. H., Kevan, P. G., & square test was very signifi- from visiting the flowers, as ultraviolet markings of French Inouye, D. W. (2001). Flies and they were only present in the marigolds are modified, then flowers: taxonomic diversity of an- cant, refuting the null hypoth- thophiles and pollinators. The Cana- esis of an equal distribution of environment for a short period the frequency of pollinators dian Entomologist, 133(4), 439–465. pollinator visits in each group of time (Orbán & Plowright, will decrease, because sight https://doi.org/10.4039/Ent133439-4 2014). The orange-red color and smell direct pollinators to Japanese beetle visits were Matteson, K. (2014). A Pictorial of the French marigold may the flowers. omitted due to being a minor Guide to Some Common Bees of have also prevented more bees References the New York City Metropolitan pollinator, but had minimal from visiting the blossoms, as Fairbrother, A., Purdy, J., Ander- Area. New York City: Great Polli- nator Project. Retrieved from http:// Fig 4: Results of the post-hoc test show that the comparison between the control and spray groups was significant greatpollinatorproject.org/sites/all/ downloads/pdfs/Pictorial_Guide_to_ Common_NYC_Bees.pdf Menzel, R., & Shmida, A. (1993). The ecology of flower colours and the natural colour vision of insect pollinators: The Israeli flora as a study case. Biological Reviews of the Cambridge Philosophical Soc.,

23 68(1), 81–120. http://bio.huji.ac.il/ tiquity of social behavior. PNAS, 325–336. https://doi.org/10.1007/ Schnepf, E., Deichgräber, G., & Bar- upload/E084-C The Ecology of 85(17), 6424–6. http://www.ncbi. s00040-014-0366-2 thlott, W. (1983). On the fine structure Flower Colours and the Natural nlm.nih.gov/pubmed/16593976 Peñalver, E., Labandeira, C. C., Bar- of the liquid producing floral gland Colour Vision of Insect Pollinators. Orbán, L. L., & Plowright, C. M. S. rón, E., Delclòs, X., Nel, P., Nel, of the orchid, Coryanthes speciosa. pdf (2014). Getting to the start line: how A., … Soriano, C. (n.d.). Thrips Nordic Journal of Botany, 3(4), 479– Michener, C. D., & Grimaldi, D. A. bumblebees and honeybees are visu- pollination of Mesozoic gymno- 491. https://doi.org/10.1111/j.1756- (1988). The oldest fossil bee: Apoid ally guided towards their first floral sperms. https://doi.org/10.1073/ 1051.1983.tb01457.x history, evolutionary stasis, and an- contact. Insectes Sociaux, 61(4), pnas.1120499109

Examining Neural Structure of the Visual System Related to the Read- ing Ability of Young Children by Hailey Kissner (WESEF Paper) (Junior)

Abstract scores. Participants in this This study investigated study were 6-7 years old and brain structure as it relates to had to undergo an extensive reading and the dual deficit set of standardized read- model of dyslexia. In this ing, language, and cognitive research, differences associ- measures. An MRI scan was ated with brain structure and obtained for each subject and reading scores were found, analysis was performed on which could relate to dys- regions of the brain involv- lexia. Dyslexia is hypothe- ing the visual system includ- sized to have three subtypes ing the precuneus, fusiform including rapid automatic gyrus, entorhinal cortex, lat- naming (RAN), phonologi- eral occipital cortex, lingual cal awareness deficits, and gyrus, cuneus, pericalcarine double deficit consisting of cortex, the isthmus of the both RAN and phonologi- cingulate gyrus, and right cal awareness. Lower RAN and left thalamus were ana- and phonological awareness lyzed. There were signifi- scores have been shown as cant negative associations a strong indicator of poor between the thickness of the reading. Based on current right pericalcarine region research, MRI results have with letter word identifica- demonstrated atypical sur- tion (LW) and RAN. Also, face area, cortical thickness, there was a trending associa- and volume in multiple brain tion between the volume of regions which have been as- the left thalamus and RAN. sociated with lower reading Children with less thickness in the right peri- calcarine regions were found to have higher scores on the RAN and LW tests. the Diagnostic and Statisti- tremely successful despite However, larger cal Manual of Mental Dis- adversity. Visual processing scale studies are orders (DSM-5), “Dyslexia is one important component warranted to con- is an alternative term used of reading that is engaged in firm these findings. to refer to a pattern of learn- both reading and Rapid auto- ing difficulties characterized matic naming, also known as Introduction by problems with accurate RAN, so the following study One of the most or fluent word recognition, is looking at brain regions One of the most poor decoding, and poor and performance on these prevalent learning spelling abilities.” (p.67, assessments. Since reading disabilities is dys- DSM-5). Although dyslex- relies on the visual system to lexia, affecting 4 ics struggle with reading and process text, I am interested – 10 % of the pop- writing, the disability does in brain regions related to ulation (Pijpker, not impact the individual’s’ this aspect of reading. 2013). According overall intelligence. In fact, many dyslexics are ex- to the 5th edition of Literature Review 24 One leading hypothesis of repeating items including between the ventral visual located at the junction of the holds that children with dys- numbers, objects, letters, and stream and middle-inferior forebrain in the parietal lobe lexia are made up of three colors. Amid a RAN test, temporal) and is associated and has been associated with subtypes: rapid automatic the time taken to name the with speech, fluency, word emotion processing, learn- naming (RAN) deficit, pho- visual stimuli shown is re- recognition, phonological ing, and memory (Webb, nological awareness defi- corded and is thought to par- reading, silent reading, and 2017; Johns 2014; Desikan, cit, and double deficit (DD) allel the cognitive and neural naming. For example, the Segonne, 2006). consisting of both RAN and demands for proper reading. fusiform gyrus or visual word Other areas used in this phonological awareness. In readers, RAN has been form area is one such struc- study that are not specific to In order to investigate the shown as a strong indicator ture in the ventral circuit, this the dorsal or ventral systems, double-deficit hypothesis, of reading achievement (Oz- region stretches across the but have more basic sensory extensive research has been ernov, Gaab, 2016) . RAN is basal surface of the tempo- functions are the thalamus, conducted. For instance, re- known to be associated with ral and occipital lobes, it has cuneus, pericalcarine gyrus, searchers have tested adoles- brain regions including the been found to play an impor- and the entorhinal cortex. cents in areas relating to the left inferior frontal gyrus, tant role in word processing The thalamus, the dorsal part specified subtypes through left posterior middle frontal (McCandliss, Dehaene, Co- of the diencephalon which color naming, digit match- gyrus, bilateral inferior oc- hen, 2003). Also, the lingual is mainly interconnected ing, and math expression cipital areas, and was less gyrus, located in the occipi- with the cerebral neocortex, problems and found that dys- strongly correlated with the tal lobe is a part of the ven- is between the cerebral cor- lexics performed worse than left parietal and right frontal tral system and plays a role tex and the midbrain (Bear, the control group. Children areas (Pugh, 2001; Norton, in color perception, and is 2007). This region is re- presumed with the DD hy- 2014). Another strong pre- linked to processing vision, sponsible for relaying motor pothesis scored significantly dictor of reading ability is especially related to letters. and sensory information (in- lower in the reading and phonological awareness, a It is thought to be involved cluding visual signals) to the word decoding tasks (Träff, skill used to recognize and in the analysis of logical con- cerebral cortex. The cuneus, 2016). Additionally, dyslex- manipulate parts of a spoken ditions (i.e. logical order of located between the calcar- ics completed fewer math language such as words and events) and encoding visual ine fissure and the medial problems during the math syllables. This skill has been memories (Bogousslavsky, part of the parieto-occipital fluency and calculation tasks deemed an indicator of dys- Miklossy, 1987; Raschle, fissure in the occipital lobe, and had difficulty with sym- lexia. During a phonological Chang, 2011). Like the other is responsible for visual pro- bolic number comparisons. awareness test, individuals aforementioned parts of the cessing such as spatial fre- (Träff, 2016). Norton et al. must complete tasks related brain, the lateral occipital quency, orientation, and mo- (2014) assessed a group of to the sounds of words like cortex (located in the occipi- tion (Gray, 1918). Another poor readers and normal rhyming and decoding. Sev- tal lobe) also in the ventral general sensory region is the readers while completing eral studies have looked at system and has more general entorhinal cortex, located tests of phonological aware- phonological awareness and sensory functions, but it still in the temporal lobe serves ness and RAN (double-defi- its associated brain regions imposes important functions as the interface between the cit hypothesis) during brain like the superior tempo- such as the processing of hippocampus and the neo- imaging with functional ral gyrus, middle temporal tactile and visual informa- cortex (Joseph, 2000). Ad- MRI (fMRI). Individuals gyrus, superior frontal gyri, tion like object processing ditionally, this area is impor- with dyslexia showed a dis- and fusiform gyrus (Morken, (Margalit, Shah, 2016). In tant for processing impulses sociation between brain re- Helland, 2014; Kovelman, contrast, the dorsal circuit from eye and ear and plays gions that were sensitive to Norton, 2012). Similarly, the is located in the temporopa- a role in memory formation phonological awareness (left left inferior frontal gyrus and rietal areas of the brain and navigation. Lastly, the peri- inferior frontal and inferior the left middle frontal gyrus consists of the supramarginal calcarine cortex or Primary parietal regions) and RAN are both associated with RAN gyrus and the angular gyrus, Visual Cortex is responsible (right cerebellar lobule VI) and phonological awareness which are thought to be as- for receiving and processing (Norton, 2014). The authors (Kovelman, Norton, 2012). sociated with phonological impulses from optic nerves found that the DD group Other brain regions will be processing (Pugh, 2001). are located in the occipi- scored the lowest on the important for various aspects Specifically, the precuneus tal lobe (Visual Processing: reading ability tasks. There of reading since reading is a which is located in the dor- Cortical Pathways, n.d). The was little difference between complex task that requires sal circuit and is a part of aims of this study are to in- the reading ability according the support of many cogni- the front of the occipital vestigate brain regions that to the testing of the DD and tive processes. lobe was found to be associ- may support visual aspects single phonological deficit The brain has two systems ated with visual-spatial pro- of reading because deficits in individuals (Norton, 2014). associated with reading, the cessing (Trimble, Cavanna, visual processing contribute RAN is one reliable indica- ventral circuit, and the dor- 2006). The isthmus, the pos- to poor reading. Therefore a tor of literacy and is char- sal circuit. The ventral cir- terior portion of the cingu- selection of the specified ar- acterized as the capacity to cuit includes occipitotempo- late gyrus is also a part of the eas of the brain listed above quickly list an assortment ral regions (point of contact dorsal system, this region is will be analyzed (Margalit, 25 Shah, 2016). I hypothesize that MRI re- sults and associated behav- ioral data with lower reading scores will have less surface area and cortical thickness in the precuneus (Trimble, Cavanna, 2006). In contrast, people who performed bet- ter on the reading tasks most probably will have more surface area and cortical thickness in those specific regions. According to other learning tasks to dyslexics, resulted in impaired recog- reduced activation compared studies comparing normal there was a major deviation nition memory for tactile to the control, normal read- readers’ scores on visual between the performance of and recurring visual stimuli. ers (Demb, 1997). Specifi- dyslexic individuals and non- Since dyslexics have these cally, this lack of activation dyslexics, there- impairments, the cortical could account for a lacking fore, suggesting thickness and surface area amount of surface area and Mentor: dyslexics have a of the entorhinal cortex in cortical thickness in the peri- deficit with visual- lower reading scores may be calcarine cortex and may be Meaghan Perdue spatial processing smaller which would explain associated with the lower Ph.D. Student (Richlan, Kron- these symptoms (Schröder, reading scores. According bichler, Wimmer, Haak, 2015). The lateral oc- to a study, the isthmus of the 2013). This deficit cipital cortex is associated dyslexic brain is smaller than in dyslexia may with general visual process- in typical readers. Therefore, be linked to the ing. Since it has been dis- I think the surface area and reduced gray mat- covered that dyslexia has cortical thickness will be ter structure of the both an auditory and visual lower with the lower read- precuneus. The perception deficit (Margalit, ing scores (Paul, 2011). The fusiform gyrus or Shah, 2016), my hypothesis Thalamus, the dorsal part of visual word form is that this deficit may be the diencephalon which is area showed more linked to the reduced gray mainly interconnected with Developmental activation in nor- matter structure (surface area the cerebral neocortex be- Psychology mal readers while and cortical thickness) in the tween the cerebral cortex Neurobiology of Language reading compared lateral occipital cortex of the and is responsible for relay- to dyslexics who poorer readers. Studies have ing motor and sensory info University of Connecticut had a minimal in- shown differences in brain to the cerebral cortex. I think dication of activa- structure in the lingual gyrus, that the amount of volume tion in this area of therefore, I think that both in this region will be lower Under the direction of the brain (McCa- the surface area and cortical with the lower reading scores ndliss, Dehaene, thickness are lower with the in this region because it has Dr. Nicole Landi, Ph.D. Cohen, 2003). A lower reading scores (Rasch- been shown in neuroimaging lack of activa- le, Chang, 2011). Relating to dyslexia studies that thal- tion in this region the cuneus, a study compar- amic anomalies are present of a person with ing a dyslexic brain to “nor- (Fan, Davis, 2014). dyslexia’s brain mal” individuals, activation could be related occurred for the average Goals of Study to reduced surface readers in the cuneus while area and cortical reading, while there was no The following study seeks to thickness and may activation in the brain of the identify associations among look similar to an dyslexic readers. This lack brain structure of various re- gions in the visual system and Assistant Professor individual in this of activation may be related experiment with to reduced surface area and reading ability. The research Psychology lower scores on cortical thickness and may will determine if there are University of Connecticut reading tests. In correlate with lower reading structural associations with Yale Child Study Center one study, lesions scores (Olulade 2015). In the lower reading scores which and Haskins Laboratory located in the tem- pericalcarine cortex or Pri- could be related to dyslexia. Possibly, these results could Yale University poral lobe (area of mary Visual Cortex individ- entorhinal cortex) uals with dyslexia showed provide a neural marker for

26 kids with reading difficulties ine region and and aid in the diagnosis pro- LW (R(14) cess of dyslexia and related = -.585, p = issues. Additionally, this .017). could help identify aspects Result 3: Brain of brain structure associated Region areas with individual differences and Reading in reading. (...) Test correla- tion Hypothesis As for the cor- determined by experience. pruning may also be respon- I predict that lower reading tical surface area, no correla- In this case, it is assumed sible for the specified result scores will be associated tions were found for RAN or that in order to form a more of the letter word test. For with reduced surface area, LW in any brain region. effective pathway pruning instance, in order to create a cortical thickness and vol- cuts away connections in the more effective pathway prun- ume in a set of brain regions Discussion of Results and brain to make stronger ones. ing eliminates connections in in the visual network that Conclusion There was a trend towards the brain which may account may support reading. We ran a false discovery test statistical significance -be for why there were less thick- for multiple comparisons to tween the volume of the left ness and higher scores in the Results further prove our findings. thalamus and RAN scores. right pericalcarine. As pre- This suggests that in a more viously mentioned, trending Results 1. RAN and Brain However, it gave us a p value high powered study, the as- associations could prove to be Region correlations. threshold of .0008, therefore, There sociation of RAN with this significant in future studies. was a significant negative our results are not corrected for multiple comparisons brain region may be signifi- Also, trending associations association between thick- cant. So in the future, it is were found between region a ness of the right pericalcar- but they are significant at the standard threshold of .05. possible that we might find with more basic sensory func- ine region and RAN (R(14) that higher RAN scores are tions not located in the ventral = -.695, p = .003. Also, there There was a large negative associated with higher vol- or dorsal circuit, the thamus. was a trending positive as- association between thick- ume in the left thalamus. This sociation between the vol- ness of the right pericalcar- Possible limitations of this would support the idea that study may be that most chil- ume of the left thalamus ine region and RAN; what in dyslexia there are thalam- and RAN (R(14) = .472, p = this means is that individu- dren had high scores on the ic abnormalities and explain RAN and Letter Word tests .065). This suggests that on als with less thickness have speech deficit and RAN a larger scale the association higher scores on the RAN because the sample does not deficit in dyslexia since the have a lot of variability in their with this brain region might test. These findings could thalamus is responsible for be significant. be associated with synaptic mean scores (RAN:11.35, sending sensory information LW:119.71) as seen in Fig- Results 2. LW and Brain pruning, a process in which to the cerebral cortex. The ures 3 and 4. Region Correlations. There weaker synaptic connections significant negative associa- Additionally, the mental status was a significant negative are eliminated and stronger tion between thickness of the of the children during behav- association between thick- connections are preserved right pericalcarine region ioral testing was not reported; ness of the right pericalcar- and strengthened. In synap- and LW means that individu- therefore, the test results may tic pruning, the contacts that als with higher scores on the Figure 3 not be an accurate represen- are enhanced or pruned are LW test had less thickness tation of their performance. in the right pericalcarine Perhaps with a larger scale region. A study of sighted, population, a greater corre- impaired vision, and blind lation between the reading individuals brain structure tests and cortical thickness, further supports these find- surface area, and volume may ings because more thickness be found. 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Pathways (Section 2, Chapter 15)

A Study on Long Term Memory by Supriya Baskaran (Junior)

Long term memory (LTM) is liable sources that have con- Scientists have also conducted attention is a factor that af- information retained by the ducted studies and obtained studies to determine if indi- fects the encoding process in human brain for more than a results about variables af- viduals are able to recognize long term/explicit memory. couple of days up until death. fecting the encoding and re- explicit memories without After an engram for long term The formation and recollec- trieval processes, scientists awareness that they are do- memory is created through the tion of long term memory is needed the positron emission ing so (Craik, Rose, & Gopie, encoding process, the next step a complicated process that in- tomography (PET) scan to n.d.). They conducted an ex- in long term memory is the volves several steps including understand the neuroanatomi- periment where individuals consolidation process, which encoding, consolidation, stor- cal correlates of the encoding were had to recognize pictures is vital for long term memo- age and retrieval. The encod- process (Tulving et al., 1994). in a set time constraint, while ry. Consolidation is the pro- ing process takes place in the Tulving and his associated encoding was per- brain, and occurs when neu- conducted a study utilizing formed under full at- rons fire rapidly, due to your the PET scan to determine that tention, (FA), or di- senses perceiving an important there was correlation between vided attention, (DA) or traumatic event (Tulving, blood flow and memory en- (Craik et al., n.d.). Kapurt, Craik, Moscovitch, & coding. During the study they During this study Houlet, 1994).When neurons observed that while the brain they found that indi- are fired rapidly, the experi- was engaging in “deeper” en- viduals were able to ence becomes more intense coding activity there was a recognize more im- and you are more likely to re- prominent increase in blood ages while encoding member that particular event. flow to the left prefrontal re- was done under full This biological conceptualiza- gion, but no significant change attention however, tion of a memory is referred to on the right hemisphere of the when individuals as an engram (Ramirez, Tone- prefrontal region (Tulving et were forced to guess gawa, & Liu, 2013). al.,1994). This helped scien- about which images Episodic memory is a type of tists cement the idea that the they had seen, indi- explicit and long-term mem- prefrontal cortical regions are viduals performed ory, that allows humans to involved in episodic memory, better with divided recall personally experienced and that there is a prefrontal attention (Craik et events (Tulving et al., 1994). hemispheric asymmetry in the al., n.d.). Craik and Although there are several re- encoding and retrieval pro- his associates’ study cesses of memory. helped identify that 29 pus is the funda- different group of flies were Almost 75% percent of human mental portion of utilized. Using this method, disease causing genes have a Mentor: the brain involved the flies were taught to as- functional homolog in the fly Dr. Frances Hannan, in memory. New sociate an odor with shock and drosophila also have a rel- discoveries has using spaced training, and atively low cost and are easy proven that long then were tested 24 hours to work with (Pandey et al., term potentiation later to determine whether 2017). There are also a variety requires the post- the flies remembered to of genetic techniques that can synaptic Ca2+ en- avoid the odor paired with be used to create mutant flies try, activation of the shock (Ho et al., 2007). (Jeibmann & Paulus, 2009). glutamate recep- The researchers found that Studying human brains is also tors, and intracel- NF1 null mutants did not re- against ethics, which prevents lular messengers member while the wild type us from experimenting on hu- (Bear & Malenka, flies did; cementing the hy- man brains. 1994). AMPA re- pothesis that the NF1 gene Although there are many ceptors found in played a major role in long proposed drosophila models Ph.D. the brain conduct term memory retention (Ho to represent schizophrenia, most excitatory et al., 2007). The formation Overexpression of the DISC1 Assistant Professor of neurotransmis- and retrieval of long term gene is currently being stud- sions in the brain memory is a complicated ied to understand behavioral Cell Biology and Anatomy (Oku & Huganir, process that involves many New York Medical College issues at the molecular level 2013). NMDA (an different steps and proteins. (Pandey et al., 2017). The amino acid that Once a memory is formed Disrupted-in-schizophrenia 1, mimics the ac- the long-term potentiation of or the DISC1 gene, produces cess under which a memory tion of glutamate) that memory determines how the DISC1 protein. Through trace is stabilized after first long term potentiation oc- long the memory remains. its interaction with other pro- being acquired (Ramirez et curs through the trafficking of This form of synaptic plas- teins, it is involved with neu- al., 2013). Studies show that AMPA receptors (Oku et al., ticity is extremely important rite outgrowth and cortical long term memory consoli- 2013). Scientists conducted for long term memory and is development (Kamiya et al., dation is highly dependent an experiment to see the ef- studied extensively for this 2006). Researchers have in- on the hippocampal cortex fects of the amyloid β protein reason. Further research in troduced the human DISC1 (Moscovitch & Addresses, (A β) on long term potentia- the molecular biology of gene in the drosophila ner- 1998). The brain contains tion. They used rats in vivo memory seems as a prom- vous system to investigate millions of neurons, and and injected them with A β ising start to ending many genetic interactions of DISC1 each neuron contains thou- oligomer only, to determine memory related diseases. and psychiatric risk factor sands of synapses. All these that this protein can inhibit One memory related disease genes (Pandey et al., 2017). neurons and synapses are long term potentiation (Walsh that is being looked into They then looked at the larval connected together to form et al., 2002). more closely is Schizophre- neuromuscular junctions of a complicated network that Another protein that inhibits nia. This behavioral disorder Drosophila which have sev- can be utilized to store and the formation of long term is characterized by thoughts eral features in common with transport information. New memory is the NF-1 pro- or ideas that do not seem the vertebrate brain, to obtain studies have determined tein (neurofibromin), which possible in reality, difficulty results (Pandey et al., 2017). that the acquisition and con- is encoded in the NF1 gene with memory, and disorga- To investigate genes that in- solidation of memory are (Ho, Hannan, Guo, Hakker, nization in speech or behav- teract with DISC1, scientists dependent on synaptic plas- & Zhong, 2007). Research- ior. Although the cognitive expressed the DISC1 gene in ticity (Dudai, 2002). Syn- ers used NF1 null mutant and characteristics of schizo- a wild type background (Pan- aptic plasticity is the ability wild type Drosophila Melano- phrenia are well described, dey et al., 2017). They then of synapses to strengthen or gaster and the odor tests and the pathophysiology and the performed an immunological weaken over time, in correla- the Pavlovian conditioning etiology are yet to be fully staining of the glutamatergic tion to the amount of activity protocol to determine whether described. Researchers are synapses on neuromuscular they endure. this protein really had an ef- currently using various ani- junctions (NMJ) and measured fect on memory or not. They mal models to discover the total bouton area, number of Long term potentiation (LTP) set up a maze with one tube molecular implications of boutons, and the number of is the specific type of synap- with the odor of benzaldehyde schizophrenia. One common axonal branch points that are tic plasticity associated with (BA) and the other tube with animal used to examine the made on the muscle (Pandey long term memory (Oku & methyl cyclohexanol (MCH) molecular and cellular mech- et al., 2017). Boutons are also Huganir, 2013). LTP is being (Ho et al., 2007). The BA tube anisms of schizophrenia is the known as synaptic terminals. studied predominantly on was paired with a shock while Drosophila Melanogaster, or This is where axons come into in vitro slices of living hip- the MCH was not, and then the fruit fly (Lessing & Bon- contact with and communicate pocampus; as the hippocam- the odors were switched and a ini, 2009). This is because, with other neurons. More bou- 30 tons mean more messages hibitor and examining the Hakker, I., & Zhong, Y. (2007). oligomers of amyloid β protein can be transmitted between current density mediated by Distinct Functional Domains of potently inhibit hippocampal long- Neurofibromatosis Type 1 Regu- term potentiation in vivo. Nature, neurons fast. Scientists ob- GluN2A, the scientists were late Immediate versus Long-Term 416(6880), 535–539. https://doi. served a reduction in total also able to discover that Memory Formation. Journal of org/10.1038/416535a bouton area, but not number NMDAR response induced Neuroscience, 27(25), 6852– Yan, Z., Wei, J., Graziane, N. M., of axonal branch points nor by DISC1 knockdown is 6857. https://doi.org/10.1523/ Wang, H., Zhong, P., Wang, Q., … number of boutons in the mainly mediated through the JNEUROSCI.0933-07.2007 Brandon, N. J. (2014). Regulation DISC1 mutants (Pandey et use of GluN2A, a NMDAR Jeibmann, A., & Paulus, W. of N-methyl-D-aspartate receptors al., 2017). Researchers then subunit. (Yan et al., 2014). (2009). Drosophila melanogaster by disrupted-in-schizophrenia- 1. as a model organism of brain Biological Psychiatry. https://doi. expressed the DISC1 mu- When scientists then exam- diseases. International Journal of org/10.1016/j.biopsych.2013.06.009 tants in a heterozygous back- ined NMDAR subunits in Molecular Sciences. https://doi. ground of fly psychiatric risk DISC1 knockdown neurons, org/10.3390/ijms10020407 gene mutations, and com- they found that the total and Kamiya, A., Tomoda, T., Chang, pared their synaptic pheno- surface levels of GluN2A J., Takaki, M., Zhan, C., Morita, types to the DISC1 phenotype were elevated whereas the M., … Sawa, A. (2006). DISC1- NDEL1/NUDEL protein interac- in the wild type background levels of GluN1, and GluN2B tion, an essential component for (Pandey et al., 2017). Using were mostly unchanged (Yan neurite outgrowth, is modulated by this method scientists were et al., 2014). These findings genetic variations of DISC1. Hu- able to find that a mutation suggest that DISC1 decrease man Molecular Genetics. https:// of dnrx1 caused changes to leads to an increase in GluN1 doi.org/10.1093/hmg/ddl407 the DISC1 phenotype in the and GluN2A channels, which Lessing, D., & Bonini, N. M. NMJs (Pandey et al., 2017). then elevate NMDAR re- (2009). Maintaining the brain: Insight into human neurodegenera- Dnrx1, which is the Droso- sponses (Yan et al., 2014). tion from Drosophila melanogaster phila homolog of the human Since NMDA receptors play mutants. Nature Reviews Genetics. Neurexin gene, failed DISC1 a major role in controlling https://doi.org/10.1038/nrg2563 in causing a decrease in syn- synaptic plasticity and long- Moscovitch, M., & Addresses, L. aptic bouton area, and caused term memory, it’s interaction N. (1998). Consolidation and the reductions in the number of hippocampal complex revisited: in with the DISC1 gene reveals defense of the multiple-trace mod- axonal branch points (Pan- a possible explanation for el. Current Opinion in Neurobiol- dey et al., 2017). They then the memory loss associated ogy, 8, 297–300. http://biomednet. used RNA interference to de- with behavioral issues such com/elecref/0959438800800297 termine that reduction of the as Schizophrenia. DISC1 Oku, Y., & Huganir, R. L. (2013). dnrx1 activity led to changes impairs NMDAR function, AGAP3 and Arf6 Regulate Traf- of the DISC1 synaptic phe- and could thus be impairing ficking of AMPA Receptors and notypes at a molecular and Synaptic Plasticity. Journal of long term memory as well. Neuroscience, 33(31). http://www. morphological level (Pandey Better understanding of the jneurosci.org/content/33/31/12586 et al., 2017). These results molecular basis and the in- Pandey, H., Bourahmoune, K., show an interaction between teraction between DISC1, Honda, T., Honjo, K., Kurita, K., DISC1 and dnrx1 a molecule NMDA and other proteins Sato, T., … Furukubo-Tokunaga, that organizes trans synaptic can lead to faster cure for K. (2017). Genetic interaction of structures and functions. DISC1 and Neurexin in the devel- memory related diseases opment of fruit fly glutamatergic The DISC1 gene in associated such as Schizophrenia. synapses. Npj Schizophrenia. with a wide range of mental https://doi.org/10.1038/s41537- 017-0040-6 conditions, and since NMDA References Ramirez, S., Tonegawa, S., & receptor (NMDAR) dys- Bear, M. F., & Malenka, R. C. function has a lot in common Liu, X. (2013). Identification (1994). Synaptic plasticity: LTP and optogenetic manipulation of with the mental conditions and LTD. Current Opinion in memory engrams in the hip- of the DISC1 gene, scientists Neurobiology, 4(3), 389–399. pocampus. Frontiers in Behavioral examined whether NMDAR https://doi.org/10.1016/0959-4388- Neuroscience, 7, 226. https://doi. is a target of DISC1. Scien- (94)90101-5 org/10.3389/fnbeh.2013.00226 tists reduced DISC1 levels Craik, F. I. M., Rose, N. S., & Tulving, E., Kapurt, S., Craik, Gopie, N. (n.d.). Recognition F. I. M., Moscovitch, M., & with RNA interference and Without Awareness: Encoding examined how NMDA re- Houlet, S. (1994). Hemispheric and Retrieval Factors. https://doi. encoding/retrieval asymmetry in ceptors were affected. (Yan org/10.1037/xlm0000137 episodic memory: Positron emis- et al., 2014). They discov- Dudai, Y. (2002). Molecular sion tomography findings, 91, ered that DISC1 knockdown bases of long-term memories: A 2016–2020. http://www.pnas.org/ led to a significant increase question of persistence. Current content/91/6/2016.full.pdf Opinion in Neurobiology. https:// Walsh, D. M., Klyubin, I., Fade- in the NMDAR current den- doi.org/10.1016/S0959-4388- sity (Yan et al., 2014). By eva, J. V., Cullen, W. K., Anwyl, (02)00305-7 R., Wolfe, M. S., … Selkoe, D. introducing a GluN2B in- Ho, I. S., Hannan, F., Guo, H.-F., J. (2002). Naturally secreted 31 Implicit Racial Bias Affecting The Health Care System by Kimberly Mckoy (Junior)

More than 2,300 African American Infants die each year in the U.S before their first birthday (Carpenter 2017). It’s found that African Americans have 2.2 times the infant mortality rate than white mothers, and are more than six times more likely to lose their infants (Car- penter 2017). The Factors of income, socioeconomic status, and occupation has nothing to do with the in- fant mortality rate ; and it’s actually the factor of Racial Discrimination (Carpenter has Implicit Bias and some differences in medical treat- As a result, Black patients are 2017). Which increases the people have Explicit Bias. Ex- ment due to racial differences assigned less pain medica- rate of African American in- plicit bias is a intentional bias (Biernat M, Manis M 1994). tion compared to white pa- fant mortality rate. And this is that someone has to another Differences in medical treat- tients but are diagnosed more contributed through implicit group and that is derived from diseases (Sabin 2016). As an bias (Carpenter 2017). ment includes the increase in personal opinions based on the rate of infant mortality of example, a Arizona Mother Implicit bias is simply the un- cultural stereotypes. As well African American infants be- died from the amount of anes- conscious bias of someone to- this person is considered to be cause of racial discrimination. thesia that was given prior to wards another group. This bias prejudice. Evidently, explicit Evidently, Doctors with im- fetal surgery from the implicit is developed through cultural bias occurs among children plicit bias make treatment de- bias from the anesthesiolo- differences based on stereo- as young as three years old of cisions based on race instead gist, who believe that because types that our society portrays age, and as we get older we of the patient’s description of she wore dreads that she of different groups. Cultural start to hide it (Bigler, Liben pain (Cooper L.A, Roter DL, smoked marijuana (Martin stereotypes influence informa- and Baron, Banaji 2006). Im- Carson K.A, Beach MC, Sa- 2018). Doctors with implicit tion about an individual lead- plicit bias is not just entitled bin JA, Greenwald AG 2012). bias make treatment decisions ing them into an unintended to racism but also gender, Results 1 shows the examples based on race instead of the bias. It is found that everyone sexuality, religion and many of treatments that showed a patient’s description of pain more. Implicit bias implicit bias outcome, and 6 (Cooper LA, Roter DL, Car- affects everyone out 7 show that implicit bias son KA, Beach MC, Sabin JA, and everything that was present with treatments Greenwald AG, 2012). Which they do. It is shown from doctors. This implicit causes constant disparities in that as Humans bias of doctors happens under the healthcare system and the our brains have pressure, which increases the death of African American in- developed uncon- rate of African American in- fants. sciously in a way fant mortality rate (Carpenter The Hypothesis of my study that we have devel- 2017). Implicit bias of Doc- is if the OBGYNs, Pediatri- oped implicit bias. tors further contributes to the cians, and Fetal Surgeons of As we evolved relationship with their patient. different race have a large im- from tribes which Patients who get less health plicit bias then there will be gave us the abil- care are found to have less of disparities in the healthcare ity to distinguish a relationship with their doc- system causing the increase from other tribes tors. The lost of communica- in the infant mortality rate of or racial groups as tion has to deal with, racial Black infants; because care- a defense mecha- bias and difference in cultures givers are not aware of their nism (Johnston between the doctor and the own bias. Using this hypoth- 2017). Implicit patient (Meltzer 2017). And esis, the goal of my study is bias contributes to mostly doctors are more like- to lower the percentage of health care dispari- ly to not listen to their patients implicit bias, decreasing the ties by producing because of a poor relationship. mortality rate in the health- 32 differently. With the ple to be aware that everyone http://doi.org/10.2105/ given Vignettes this has implicit bias. And I want AJPH.2011.300558 Mentor: would test to see if To change society’s view of Devine, P. G. (1989). Stereotypes Dr. Anna Kaatz, physicians are more one another by making them and prejudice: Their automatic and controlled components. Jour- PhD, MPH, MA likely to treat a white aware of their own implicit nal of Personality and Social Psy- infant properly than bias and eliminating the dis- chology, 56(1), 5-18.http://dx.doi. a black infant. Phy- parities in health care system org/10.1037/0022-3514.56.1.5 sicians would also by race and ethnicity. Devine et al., 2012, P.G. Devine, P.S. take a demographic References Forscher, J.A. Austin, W.T.L. Cox survey that would Long-term reduction in implicit race Allport,G.W. (1993) The Nature of bias: a prejudice habit-breaking inter- help us see if there is Prejudice. Psychological Reports, vention. J. Exp. Soc. Psychol., 48 (6), any linking to their 72, 299-308 https://doi.org/10.2466/ 1267–1278 https://doi.org/10.1016/j. bias. And questions pr0.1993.72.1.299 jesp.2012.06.003 that deal with treat- Baron AS,Banaji MR. (2009) The de- Gaertner S.L. Gaertner, M.C. Rust, ing the patient any velopment of Implicit Attitudes: Evi- J.F. Dovidio, B.A. Bachman, P.A. dence of race evaluations from ages (1994) The contact hypothesis: the differently by their 6 and to and adulthood. Psychol Sci, relationship with the role of common ingroup identity 17(1)53-8. https://doi.org/10.1111/ on reducing intergroup bias. Small Director of Computation- father or, treatment j.1467-9280.2005.01664.x Group Res., 25 (2) ,224–249 https:// al Sciences based on the type of Biernat, M., & Manis, M. (1994). doi.org/10.1177/1046496494252005 insurance the patient Shifting standards and stereotype- Center for Women’s Johnston, I. (2017). Racism and sex- has. based judgments. Journal of Person- ism stem from optical illusion brain Health Research ality and Social Psychology, 66(1), Cognitive stress can that is part of the Human condi- 5-20.http://dx.doi.org/10.1037/0022- tion University of Wisconsin- lead a caregiver to 3514.66.1.5 Madison Martin N, (2017). Nothing protects have a large implicit Bigler RS, Liben LS.(2006) A de- Black Women from Dying in Preg- bias (Devine et al., velopmental intergroup theory of so- nancy and in Childbirth 2012). But a large cial stereotypes and prejudice. ADV care system. Using Vignettes, Child Dev Behav;34:39-89 Meltzer LJ, Steinmiller E, Simms these physicians will be given implicit bias can occur within S, Grossman M, Li Y.(2009) Staff Carpenter Z. (2017) What’s Killing pictures of pregnant women a caregiver if there is racial engagement during complex pediat- America’s Black Infants? The Na- ric medical care: the role of patient, of both races during prenatal, differences between them tion. and their patient (Schaa et family, and treatment variables. pregnancy, and surgery, and Chapman EN. (2013) Physicians Patient Educ Couns.Jan;74(1):77- as well of black babies and a al., 2015). Furthermore, Pro- and Implicit Bias: How Doctors 83. https://doi.org/10.1016/j. white babies; who are young- White bias physicians show May Unwillingly Perpetuate Health pec.2008.07.051 er than 1 . These Vignettes more support towards light Care Disparities. J Gen Intern Med Rossen et al.,B. Rossen, K. Johnsen, colored patients than to dark (11):1504-10 https://doi.org/10.1007/ A. Deladisma, S. Lind, B. Lok would describe certain sce- s11606-013-2441-1 narios of these individuals colored patients (Rossen et al., (2008) Virtual humans elicit skin- Cook, 1978, S. Cook. Interpersonal asking treatment questions on 2008). Evidently, physicians tone bias consistent with real-world and attitudinal outcomes in cooper- skin-tone biases, Lecture Notes in how they would treat them. with implicit bias tend to have ating interracial groups. J. Res. Dev. Computer Science, 5208 https://doi. Half of the physicians will different treatment outcomes Educ., 12 (1), 97–113 org/10.1007/978-3-540-85483-8_24 be given pictures of black pa- based on the racial differenc- Cooper LA, Roter DL, Carson KA, Schaa et al., 2015 K.L. Schaa, D.L. tients and a list of symptoms. es of patients (Allport, 1954; Beach MC, Sabin JA, Greenwald Roter, B.B. Biesecker, L.A. Cooper, The Other Half of physicians Cook, 1978 ; Gaertner et al., AG, et al. (2012) The associations L.H. Erby (2015) Genetic coun- 1994). If people are aware of of clinicians’ implicit attitudes about selors’ implicit racial attitudes and will be given pictures of race with medical visit communi- their implicit bias then they their relationship to communication. white patients listing the same cation and patient ratings of inter- Health Psychol, 34 (2), 111–119 symptoms and to see if they can consciously prevent it. In personal care. Am J Public Health. https://doi.org/10.1037/hea0000155 would treat the patients any my future studies, I want peo- 105(5):979-87

The Influence of Gut Microbiota on Behavior and Brain Functions by James Reilly (Sophomore)

In the world today, millions of study done in 2012 estimated ASD are three times more ASD, including social with- people suffer from neurologi- that 1 in 68 children aged eight likely to experience symp- drawal, irritability, and hyper- cal diseases and disabilities in the United States have been toms such as abdominal pain, activity (Chaidez, Hansen, & such as depression, anxiety, diagnosed with ASD (Chris- bloating, constipation, pain on Hertz-Picciotto, 2014). Other Autism Spectrum Disorder tensen et al., 2012). Along stooling, sensitivity to foods, neurological disorders report (ASD), and schizophrenia. with this, many people diag- and diarrhea than the controls. gastrointestinal issues that The prevalence of these such nosed with ASD suffer from The severity of these GI issues also correlate with symptom diseases in the United States an array of gastrointestinal correlated with the severity of severity, such as schizophre- is very alarming and sparks problems. One study shows many symptoms related to nia, Rett syndrome, cerebral many people’s interest. A that children diagnosed with 33 palsy, and major depression stress in adult specific patho- tassium salt from 3 weeks to of Clostridium species in the (Heijtz et al., 2011). These gen free Sprague-Dawley rats 6 weeks of age. This behavior gut. After analyzing the urine findings support the commu- (Liang et al., 2015). Also, the of the mice treated with 4EPS of 62 children diagnosed with nication between the gut and probiotic Lactobacillus rham- was similar to the observed ASD and the urine of 62 non- brain, known as the gut-brain nosus was able to modulate behavior in the offspring of ASD children, all 1.5-7 years axis. However, how the gut behavior in mice by reduc- mice injected with the viral of age, it was found that the and brain interact is still un- ing activity related to anxiety. mimic poly (I:C) during preg- urine of the children diagnosed known. This probiotic also decreased nancy in order to activate the with ASD had significantly In the past, studies have fur- the augmentation of plasma immune system. The offspring higher levels of the com- ther supported the gut-brain corticosterone levels in mice of these Maternal Immune pounds 3-(hydroxyphenyl)- axis by exposing the effect induced by stress (Cryan & Activation (MIA) mice ex- 3-hydroxypropionic acid that probiotics, live bacteria Dinan 2012). All of these find- hibit many behavioral symp- (HPHPA), 3-hydroxyphenyla- or bacterial products, have ings support communication toms relevant to ASD. These cetic acid (3HPA), and 3-hy- on, both, the brain and behav- between the gut and the brain results suggest that metabo- droxyhippuric acid (3HHA) ior. For example, the imple- along the gut-brain axis. The lites may cause or influence than in the controls. After the mentation of Bifidobacteria consistent demonstrations of symptoms associated with administration of oral vanco- treatment resulted in reduced probiotics altering brain and ASD and other neurodevel- mycin treatment to children levels of 3,4-dihydroxypheny- behavior provide insight on opmental disorders (Hsiao et with ASD, their urinary levels lacetic acid (DOPAC) and de- how our gut and brain inter- al., 2013). Additionally, many of HPHPA, 3HPA, and 3HHA creased levels of 5-hydroxyin- act. More importantly, the re- studies have demonstrated decreased dramatically, in- doleacetic acid (5-HIAA) in sults of these studies expose how metabolites have the abil- dicating that these metabo- the amygdaloid cortex and the the possible roles probiotic ity to alter the production of lites may be produced by the frontal cortex in rats, respec- administration may play in neurotransmitters. One study Clostridium species in the gut tively (Desbonnet et al., 2010). controlling and manipulating introduced metabolites pro- (Xiong, Liu, Wang, Zeng, & Another study expressed how the gut microbiota, the brain, duced by spore forming bac- Peng, 2016). The metabolite the introduction of live Lacto- and the interactions between teria, such as 4-aminobenzoic HPHPA is of notable inter- bacillus plantarum PS128 sig- them. acid (PABA), α-tocopherol, est due to its ability to inhibit nificantly increased the levels Bacterial metabolites are and tyramine, to germ-free dopamine beta hydroxylase, of serotonin and dopamine substances that act as inter- mice. After the metabolites a compound required during in the brain. The enhanced mediates and endpoints of were introduced, there was the process of converting do- locomotor activity observed biological processes, making an increase in the biosynthe- pamine into norepinephrine. in this study may have been metabolites essential to proper sis of 5-hydroxytryptamine The inhibition of dopamine caused by the increased trans- function of the body. Metabo- (5-HT, serotonin) in special- beta hydroxylase may be re- mission of dopamine after lites have have been shown to ized endocrine cells, called lated to excess amounts of the probiotic treatment (Li- enter the brain, which may be enterochromaffin cells, in the dopamine associated with ang et al., 2015). On top of one method of communica- gastrointestinal tract. It was schizophrenia and psychotic this, continuous L. helveticus tion between the gut and brain discovered that these same behavior (Shaw, 2010). The NS8 treatment resulted in the (Hsiao et al., 2013). For ex- metabolites increased the influence that bacterial me- reduction of biochemical, be- ample, propionic acid, a sto- expression of tryptophan hy- tabolites have on behavior and havioral, and cognitive abnor- machic metabolite produced droxylase 1 (TPH1), implying brain function suggests that malities induced by chronic by bacteria, has been shown to that the metabolites commu- these compounds may be the access the brain, both pas- nicate with enterochromaffin path of interaction between sively and actively, by cells, signaling the enhance- the gut and the brain. crossing the gut-blood ment of 5-HT biosynthesis Metabolites have been found barrier and the blood- (Yano et al., 2015). Even the to influence the brain directly. brain barrier (Thomas bacteria that produce these Propionic acid is one such et al., 2012; Conn et al., metabolites have been shown metabolite to do so. Upon en- 1983). The metabolite to influence neurotransmit- tering the brain by crossing 4-ethylphenyl sulfate ter production. The absence the blood brain-barrier, a bar- (4EPS) is one metabo- of the native microbiota that rier that tightly regulates the lite that has been shown produce these metabolites dis- movement of molecules be- to influence behavior. rupted the levels of serotonin tween the blood and the brain 4EPS is of particular in the hippocampus, suggest- (Daneman & Prat, 2015), interest due to the po- ing that the metabolites affect through the use of high affin- tential role it plays in related neural process (Clarke ity transporters, studies have behaviors relevant to et al., 2013). shown this metabolite affect- ASD. Anxiety-like be- Children with ASD have been ing an array of neurologi- havior was observed shown to have some abnor- cal functions, including the after naive mice were mal levels of metabolites release of neurotransmitters, treated with 4EPS po- mostly due to overpopulation mitochondrial functions, and 34 gene expression (Thomas et EM4 cells with a recombi- signaling. This could al., 2012; Conn et al., 1983; nant bacmid containing the be due to a change DeCastro et al., 2005; Mau- recombinant dopamine trans- in the expression of Mentor: rer et al., 2004). Propionic porter gene, an assessment of dDAT. A study done Dr. Matthias Quick, acid has been shown to alter the expression and function to discover the ef- the release of neurotransmit- of DAT as a result of expo- fects of dDAT ex- Ph.D. ters, including serotonin and sure to the metabolites pro- pression on behavior dopamine after entering the pionic acid, indoxyl sulfate, found that normal brain (El-Ansary, Bacha, & hippuric acid, and p-cresol dDAT expression is Kotb, 2012). These results was performed. By conduct- necessary for normal of the ability of propionic ing a bicinchoninic acid as- sleep patterns. A de- acid to cross the highly re- say, western blot, and uptake crease in expression strictive blood-brain barrier assay, it was revealed that of dDAT resulted in and affect neurotransmitter exposure to these metabolites a short sleep pattern, release exposes the possibili- resulted in altered expression while the overexpres- ty of neurotransmitter signal- of DAT. It was concluded sion of dDAT abol- Associate Professor of ing to be affected by metabo- that the exposure of p-cresol ished olfactory aver- Neurobiology (in Psy- lites. One study conducted to and propionic acid increased sive memory (Ueno chiatry) discover the effects of anti- the expression of DAT, while & Kume, 2014). biotic treatment on the brain indoxyl sulfate and hippuric These results show Department of Psychia- also measured the change in acid reduced the expression how altered expres- try and Center for Molec- expression of neural signal- of DAT (Chung, 2017). The sion of monoamine ular Recognition, ing-related molecules. After ability of metabolites to af- transporters results in antibiotic treatment, the me- fect the neurological pro- a subsequent behav- Columbia University and tabolites propionate, p-cre- cesses of neurotransmitter ioral alteration. College of Physicians syl, trimethylamine-N-oxide, release and reuptake sparks The findings of - me and Surgeons. and deoxycholic acid were the speculation whether or tabolites produced by recorded at dramatically al- not metabolites play a role in gut bacteria affecting ing Network, 11 Sites, United States, tered levels. This study test- the gut-brain axis. the expression of SLC6A3 2012. https://www.cdc.gov/mmwr/ ed the expression of different The expression of monoam- and SLC6A4 mRNA to- volumes/65/ss/ss6503a1.htm neurotransmitter transporters ine transporters plays a ma- gether with the discovery of Chung, J. (2017). Interaction of cir- after antibiotic treatment. jor role in the development behavioral changes due to culating gut microbiota-generated Neurotransmitter transport- of neurological disorders the overexpression and un- metabolites with the function and ex- ers bind to neurotransmit- and behavior. Impulsive ag- derexpression of monoamine pression of SLC6A3, the dopamine ters in the synapse between transporter. STS Submitted Paper gression and its related dis- transporters is very interest- 2017. neurons, terminating neu- orders and behaviors, such ing. If a study were to be done Clarke G, Grenham S, Scully P, rotransmission by releasing as depression, substance in order to test the effects of Fitzgerald P, Moloney RD, Sha- the binded neurotransmitter abuse, and suicidal behavior, metabolites on the behavior nahan F, Dinan TG, Cryan JF. The back into the presynaptic may be related to the altered of Drosophila melanogaster microbiome-gut-brain axis during cell (Rudnik, 2002). Among expression and function of along with an examination early life regulates the hippocam- the tested transporters in the pal serotonergic system in a sex- the serotonin and dopamine of the mRNA expression, the dependent manner. Mol Psychiatry. brain was SLC6A4, the se- transporters. Dysfunctional results would provide a bet- 2013;18:666–673. rotonin transporter. After the interactions between the se- ter understanding as to how Conn AR, Fell DI, Steele RD: Char- antibiotic treatment, the ex- rotonin and dopamine sys- bacterial metabolites of the acterization of alpha-keto acid trans- pression of SLC6A4 mRNA tems in the prefrontal cortex gut affect behavior and brain port across blood brain barrier in in the hypothalamus and may be related to impulsive function. rats. Am J Physiol 1983, 245:E253- E260. hippocampus was slightly aggression and the behaviors References Cryan JF, Dinan TG (2012) Mind- reduced when compared the relevant to it. More specifi- Chaidez, V., Hansen, R. L., & vehicle-treated mice. On the altering microorganisms: the im- cally, the hypoactivity of the Hertz-Picciotto, I. (2014). Gas- pact of the gut microbiota on brain other hand, the expression serotonin transporter coupled trointestinal problems in children and behaviour. Nat Rev Neurosci of mRNA was increased in with hyperactivity of the do- with autism, developmental delays, 13:701–712. the medial prefrontal cortex or typical development. https:// pamine transporter may be www.ncbi.nlm.nih.gov/pmc/ar- Daneman R, Prat A. (2015). The and greatly increased in the an underlying biochemical ticles/PMC3981895/ Blood–Brain Barrier. Cold Spring amygdala (Frohlich et al., Harb Perspect Biol.;7:a20412. cause of impulsive aggres- Christensen, D. L., Baio, J., Van 2016). A more recent study sion (Seo, Patrick & Ken- Naarden Braun, K., Bilder, D., DeCastro M, Nankova BB, Shah tested the function and ex- nealy, 2008). In Drosophila Charles, J.,Constantino, J. N., P, Patel P, Mally PV, Mishra R, La Gamma EF: Short chain fatty acids pression of SLC6A3, the do- melanogaster, a mutation Yeargin-Allsopp, M. (2012). Preva- lence and Characteristics of Autism regulate tyrosine hydroxylase gene pamine transporter (DAT), in the dopamine transporter expression through a cAMP depen- after exposure to metabolites. Spectrum Disorder Among Chil- (dDAT) gene is associated dren Aged 8 Years -Autism and De- dent signaling pathway. Brain Res After infecting HEK293- with an increase in dopamine velopmental Disabilities Monitor- Mol Brain Res 2005, 142:28–38. 35 Desbonnet L., Garrett L., Clarke org/10.1073/pnas.1010529108. motility through serotonin release smayer F, Liu S, MacFabe DF. G., Kiely B., Cryan J.F., Dinan Hsiao EY, McBride SW, Hsien S, from enterochromaffin cells. PNAS (2012). The enteric bacterial me- T.G. (2010). Effects of the pro- Sharon G, Hyde ER, McCue T, 106(9),3408–3413.http://doi. tabolite propionic acid alters brain biotic Bifidobacterium infantis Mazmanian SK. (2013) Micro- org/10.1073/pnas.0805 323106 and plasma phospholipid molecular in the maternal separation model biota modulate behavioral and Rudnick G, editor. (2002). Mech- species: further development of a of depressionNeuroscience.;(1 physiological abnormalities as- anisms of biogenic amine neu- rodent model of autism spectrum 70):1179–1188. doi: 10.1016/ sociated with neurodevelopmental rotransmitter transporters. 2 edn disorders. J Neuroinflammation. 9: neuroscience.2010.08.005. disorders. Cell.;155(7):1451–63. Humana Press Inc.; Totowa, New 153-10.1186/1742-2094-9 153. El-Ansary, A.K.; Ben Bacha, A.; doi:10.1016/j.cell.2013.11.024. Jersey. Ueno, T., & Kume, K. (2014). Func- Kotb, M. (2012). Etiology of au- Liang S., Wang T., Hu X., Luo J., Seo, D., Patrick, C., & Kennealy, P. tional characterization of dopamine tistic features: The persisting neu- Li W., Wu X., et al. (2015) Admin- (2008). Role of serotonin and do- transporter in vivo using Drosophila rotoxic effects of propionic acid. J. istration of Lactobacillus helveti- pamine system interactions in the melanogaster behavioral assays. Neuroinflamm. ( 9), 74. cus ns8 improves behavioral, cog- neurobiology of impulsive aggres- https://www.ncbi.nlm.nih.gov/pmc/ Frohlich EE, Farzi A, Mayerhofer nitive, and biochemical aberrations sion and its comorbidity with other articles/PMC4153294/ R, Reichmann F, Jacan A, Wagner caused by chronic restraint stress. clinical disorders. https://www.ncbi. Xiong, X., Liu, D., Wang, Y., Zeng, B, et al. (2016). Cognitive impair- Neuroscience 310: 561–577. nlm.nih.gov/pubmed/19802333 T., & Peng, Y. (2016). Urinary 3-(3- ment by antibiotic-induced gut Maurer MH, Canis M, Kuschinsky Shaw W. (2010) Increased urinary Hydroxyphenyl)-3-hydroxypropi- dysbiosis: analysis of gut micro- W, Duelli R. (2004). Correlation excretion of a 3-(3-hydroxyphenyl)- onic acid, 3-Hydroxyphenylacetic biota-brain communication. Brain between local monocarboxylate 3-hydroxypropionic acid (HPH- acid, and 3-Hydroxyhippuric acid Behav Immun.. doi:10.1016/j. transporter 1 (MCT1) and glucose PA), an abnormal phenylalanine are elevated in children with autism bbi.2016.02.020. transporter 1 (GLUT1) densities in metabolite of Clostridia spp. in spectrum disorders. https://www. Heijtz, R. D., Wang, S., Anuar, F., the adult rat brain. Neurosci Lett , the gastrointestinal tract, in urine ncbi.nlm.nih.gov/pubmed/27123458 Qian, Y., Björkholm, B., Samuels- 355:105–108. samples from patients with autism Yano JM, Yu K, Donaldson GP, et al. son, A., Pettersson, S. (2011). Nor- Nozawa, K., Kawabata-Shoda, E., and schizophrenia. Nutr Neurosci. (2015). Indigenous bacteria from the mal gut microbiota modulates brain Doihara, H., Kojima, R., Okada, 13(3):135-43. gut microbiota regulate host sero- development and behavior. 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Tumor Targeting Nanoparticles by Paul Williams (Sophomore)

The field of nanomedicine breaking up clusters of bac- phenomenon of the EPR, or the method nanoparticles uti- includes a very broad range teria to synthesize treatment, enhanced permeability and re- lize to heat to solid cancerous of studies that seem to for- usage for treatment of car- tention effect. When engineer- mass to such a high tempera- mulate new topics based off diovascular disease such as ing a nanoparticle, this phe- ture where it cannot thrive and of eachother. What they have atherosclerosis, to serve as an nomenon heavily influences function any longer leading to in common is that they work antioxidant to repair damage what the nanoparticle is com- its demise. Cellular apoptosis with nano sized structures in the bloodstream or rest of posed of, as well as simply the however a more natural ap- referred to as nanoparticles body, increase growth for es- tumor targeting process itself. proach, introduces cytotoxic typically ranging from 1-100 sential parts of the body, and Upon the synthesis process of or “toxic to living cells” agents nm in size to serve many even cleaning up parts of the the nanoparticle through the to the tumor which cause it to functions as well as topics of environment (Boysen, 2007). bloodstream, it will accumu- naturally commit suicide (Gi- study. Many of these studies Seemingly enough, relatively late and recognize that a cell anella et al., 2011). This may include but are not limited to, recently all of these uses came is cancerous or abnormally seem ideal that nanoparticles together to treat a disease growing through it settling in can just perform just simply affecting many millions gaps existing between cells in these functions, but they also of people all around the the tumor. This is a reliable aid in reversing the damage world, and also being one feedback system that makes due to the tumor along the of the largest causes of tumor targeting very reliable. way to the cancer site, or most death in the world, which Buildup of nanoparticles in likely at the site due to the is most commonly referred the tumor site is the main goal EPR Effect. When a cancer to as cancer. of treatment, leading to the cell is formed somewhere in Tumor targeting nanopar- destruction of the tumor (Gre- the body, it’s main function is ticles function to destroy ish, 2010). This can be done to grow and obtain more nu- these large cancerous clus- in several different ways, trients. This is done through ters as well as repair their which depend ultimately on the process of angiogenesis, damage that they have the structure and composi- which in part of its process done to healthy body cells. tion of the nanoparticle. Two secretes VEGF or Vascular The realization that these main methods that have been Endothelial Growth Factor nanoparticles are known studied and tested are through protein. Angiogenesis is for- to accumulate in tumor thermal ablation, and cellular mally defined as the formation sites is expressed in the apoptosis (Cormode et al., of new cells from pre-existing 2009). Thermal ablation is ones. The VEGF protein is se- 36 creted as the “signal protein” diagnose cancer much quick- to the whole body as possible. ing (DLS), and Transmission to stimulate the formation of er than most modern cancer The outer portion of the nano- Electron Microscopy (TEM). the new cells which ultimate- treatments (Zhu et al., 2014). particle, hydrophilic, and the The purpose of both of these ly are created to be sent to the The precision of nanoparticle interior or encapsulated drug mainly to get and idea of the tumor as nourishment for it tumor targeting treatment is hydrophobic, is specific to structure of the nanoparticles to grow and flourish. Under unmatched for repairing tissue these qualities in order to get to furthermore understand ideal circumstances, a tumor deep in the body, anywhere in them through the bloodstream how they will function and can thrive for years and even it, and for destruction of the which is also an aqueous en- perform with their task to tar- spread. Abnormal cell growth, tumor mass. Mostly beneficial vironment (Cormode et al., get the tumor. As for the in angiogenesis and the spread- in terms of cost, the synthesis 2009). Most of the outer and vivo analysis, the sole pur- ing of tumors is why cancer is and engineering of tumor tar- middle layers of the nanoparti- pose of imaging is to track so fatal, and often is not dedi- geting nanoparticles is much cles assist in destruction of the the nanoparticles progress, cated one location. The syn- cheaper than most treatments tumor mass through processes and make sure upon that it thesis of nanoparticles, and available today, due to them such as thermal ablation or actually makes it to the tumor creation of nanoemulsion plat- being designed with natural cellular apoptosis, and assist site. Some of these include, forms, work to neutralize the and cost efficient components in imaging guided therapy for Magnetic Resonance Imaging negative effects of the VEGF such as iron oxide. They per- the nanoparticle. At this time (MRI), Computed Tomogra- protein, and show a promis- form better at tumor targeting these studies are still experi- phy (CT), and Near-Infrared- ing future for cancer research. therapy than treatments most mental and have not been ex- Fluorescence imaging (NIRF). (Gianella et al., 2011). commonly used today (Zhu et panded or implemented on a With the assistance of these In Most cancer treatments avail- al., 2014). As aforementioned, larger scale. Vivo imaging techniques, it able currently for serious can- tumor targeting nanoparticles Within the past couple years, was noted that the nanoemul- cer diagnoses are relatively only work for the destruction an experiment was run to test sion platform responsible for ineffective, due to them often of cancerous tumor masses the effect of a nanoemulsion a large amount of shrinkage having more negative effects and not healthy body cells. All platform on an several experi- of the tumor mass, “this study than positive results. Treat- these factors, are why research mental cancer mouse models demonstrated that our nano- ment therapies such as chemo- of tumor targeting nanopar- along with imaging guided emulsions, when loaded with therapy, and radiation therapy, ticles have become so popular therapy. “The theranostic plat- PAV, iron oxide nanocrystals introduce very strong toxins within the past decade. form had oil-in-water nano- and Cy7, represent a flexible in high doses to the body, and Nanoparticles are man made, emulsions, with Iron Oxide and unique theranostic nano- most of the time the patient mainly engineered with natu- nanocrystals for the purpose of particle platform that can be suffers more bodily damage ral components. Materials MRI imaging, fluorescent dye applied for imaging guided from the traditional devices, such as iron oxide and quan- Cy7 for Near-Infrared-Fluo- therapy of cancer” (Gianella than from therapeutic agents tum dots serve as a natural rescence NIRF imaging, and et al., 2011). This is a very and even the cancer itself basis for the structure of them hydrophobic glucocorticoid large milestone in cancer (Zhu et al., 2014). The im- (Jarzyna, P. A., Skajaa, T et prednisolone acetate valerate treatment, especially that an- mune system is also heavily al,. 2009). They can also be (PAV) for therapeutic purpos- giogenesis was not prevalent affected by these treatments, referred to as a micelle that es” (Gianella et al., 2011). Fif- with the platform (Gianella et weakening it, and also making has a cytotoxic cancer drug ty-six mice were randomized al., 2011). This still however it more susceptible to many encapsulated in to deliver into seven groups and injected opens room for some future types of pathogens while on to the tumor (Jarzyna, P. A., with the tumors in various lo- studies, and improvement to treatment. Nanomedicine for Gianella, A., et al., 2011) . cations. “Nanoemulsions were incorporate other capabilities the purpose of tumor target- This is known as nanoparticle administered at a dose of 30 to this platform, or use the ing, works to exclude most drug-delivery and is a concept mg FeO/kg and 10 mg PAV/ fundamentals of this formula- harm from treatment, and that has been studied in much kg”, and so treatment began tion, and improve upon it. just focus on small doses. depth over the past decade, in conjunction with the imag- One specific type of nanopar- There are other key benefits and is a recurring concept ing techniques. The control ticles has attracted a great deal attributed to tumor targeting in most review and research groups were given the control of attention to the biomedical nanoparticles. Cancer has the papers. This is so due to the drug saline, and the experi- field due to it’s duality and highest probability of being fact that the body’s immune mental groups were treated multifunctionality. “Gold overcome when it is detected system doesn’t attack the with the nanoemulsion plat- nanoparticles (AuNPs) have early as possible. This is so nanoparticles as they circu- form. For the nanoparticles an a number of physical proper- because at the earliest stages late through the bloodstream, individual in vitro “outside of ties that make them appeal- of development of the tumor, and reacts to them as they are the body” and in vivo “inside ing for medical applications” it is the least nourished, and a normal body cell. With this the body” examinations were (Mieszawska et al., 2013). shows the most signs of be- fact known, cancer drugs can performed with the assistance They have ideal properties to ing an abnormally growing now be delivered directly to of various molecular imaging be utilized with the specific mass. Nanoparticles with the the tumor site, and treat it a techniques. Some of the main imaging methods aforemen- use of certain imaging tech- known and controlled dosage in vitro imaging methodities tioned and as adjuvants for niques as well, can detect and to make therapy as less toxic are Dynamic Light Scatter- radiotherapy. Gold nanopar- 37 ticles can be well utilized nanoparticles with hydro- imaging guided therapy in for Anticancer Nanomedicine Drug for therapy, diagnosis, and philic lipids on the outer conjunction with this nano- Targeting. In: Grobmyer S., Moud- gil B. (eds) Cancer Nanotechnol- imaging which are the three shell, with the structure of it particle formulation, de- ogy. Methods in Molecular Biology key attributes needed to tar- being of natural compounds struction of a tumorous mass (Methods and Protocols), vol 624. get a tumorous cancer mass. such as Aluminum-Oxide, may be possible, and can’t Humana Press. DOI: https://doi. Gold nanoparticles can be Iron-Oxide, Copper Oxide, harm the body in any way, org/10.1007/978-1-60761-609-2_3 applied to larger structures to or Aluminum Carbonate, and which is what mainly makes Jarzyna, P. A., Gianella, A., Ska- deliver more treatment to the be encapsulated with a cyto- it so beneficial, that even if it jaa, T., Knudsen, G., Deddens, L. cancerous site, and increase toxic cancer drug, favorably, fails, it won’t have a negative H., Cormode, D. P., Mulder, W. J. (2011). Multifunctional imaging the abilities of a nanoparticle bevacizumab. Bevacizumab effect on the body. However, nanoprobes. Wiley Interdiscip Rev itself. They are also consid- is ideal due to its function this model is based off of Nanomed Nanobiotechnol, 2(2), ered biocompatible and non- which is to inhibit the nega- previous studies, therefore it 138–150. DOI: 10.1002/wnan.72 toxic, and can be modified tive effects of the tumorous will likely represent an effec- Jarzyna, P. A., Skajaa, T., Gianella, easily (Mieszawska et al., clusters vascular external tive treatment for tumorous A., Cormode, D. P., Samber, D. D., 2013). Gold nanoparticles growth factor (VEGF), so masses, along with imaging Dickson, S. D., Mulder, W. J. (2009). have quite useful charac- that way further treatment guided therapy. Iron oxide core oil-in-water emul- teristics, and are well worth can be done to the cancer- sions as a multifunctional nanopar- ticle platform for tumor targeting being considered to being ous masses such as thermal References and imaging. Biomaterials, 30(36), applied to a nanoemulsion ablation, or cellular induced Boysen, E. (2007). Nanoparticle 6947–6954. DOI: 10.1016/j. platform in imaging guided apoptosis from the nanopar- Applications and Uses. biomaterials.2009.09.004 therapy for cancer treatment. ticle (Pavlidis et al., 2013). Cormode, D. P., Jarzyna, P. A., Mieszawska, A. J., Mulder, W. J., An effective treatment for VEGF can be reversed to Mulder, W. J.M., & Fayad, Z. A. Fayad, Z. A., & Cormode, D. P. (2013). Multifunctional gold nano- cancer isn’t as far as it may that way it can only be done (2009). Modified natural nanopar- ticles as contrast agents for medi- particles for diagnosis and therapy of seem. Due to some nano- with angiogenesis to restore disease. Mol Pharm,10(3), 831–847. the old body cells to new cal imaging. Adv Drug Deliv Rev, emulsion platforms created 62(3): 329–338. DOI: 10.1016/j. DOI: 10.1021/mp3005885 Pavlidis, already, as well as reviews healthy ones (Pavlidis et al., addr.2009.11.005 E. T., & Pavlidis, T. E. (2013). Role of bevacizumab in colorectal can- upon more effective nano- 2013). Gold nanoparticles Gianella, A., Fayad, Z., Mani, V., to be involved in the system cer growth and its adverse effects: particle components or nano- Jarzyna, P., Mulder, W., Storm, A review. World J Gastroenterol, 21 crystals, studies can just be would be essential with the G., et al. (2011). A Multifunctional 19(31), 5051–5060. DOI: 10.3748/ improved respectively upon diagnosis, therapy, and treat- Nanoemulsion Platform for Imag- wjg.v19.i31.5051 ment. They could potentially ing Guided Therapy Evaluated in the last in order to formu- Experimental Cancer. ACS Nano, Zhu, G., Mei, L., & Tan, W. (2014). late a treatment that can of- be the ones that hold the en- 5, 4422–4433. DOI: 10.1021/ Nanomedicine. https://www. ficially be used in modern capsulated drug and deliver nn103336a the-scientist.com/?articles.view/ articleNo/40598/title/Nanomedicine/ cancer therapy. A nanoemul- it to the tumorous masses Greish K. (2010) Enhanced Perme- sion platform comprised of (Pavlidis et al., 2013). With ability and Retention (EPR) Effect New Strategies to Fight Antibiotic Resistance by Aiden Breneman-Pennas (Sophomore)

The threat due to bacteria be- resistance to multiple anti- 3475 invasive pneumococ- ing refers to the fact that the coming resistant to Antibiot- biotics.” (Liñares, Ardanuy, cal isolates collected in 1998 process undergone by some ics is increasingly becoming Pallares, & Fenoll, 2010). were PNSP. Seven serotypes bacteria essentially produce relevant. This major threat Before these incidents, (6A, 6B, 9V, 14, 19A, 19F, a molecule that “poisoned” may lead to a new age of Streptococcus pneumoniae and 23F) accounted for 91% the cell. A quorum-sensing- epidemics and problems if was completely susceptible of all PNSP” (Whitney et al., regulated molecule is a mol- immediate steps to eradicate to penicillin and other anti- 2000). ecule that is produced when this problem are not imme- microbial treatments, and in Serotypes, like the ones men- a certain population density diately dealt with. “Over the the years preceding, drug re- tioned, are increasingly be- is reached. Altruism is when past three decades, antimi- sistance only amplified with coming dangerous because of a few weaker cells of, in this crobial resistance in Strepto- other serotypes of penicillin processes that make the bac- case, bacteria are killed off coccus pneumoniae has dras- as well as serotypes of other terial colony stronger. One of for the benefit of the colony. tically increased worldwide. antibiotic treatments (Liñares these processes undergone by “2-n-heptyl-4-hydroxyqui- Non-susceptibility to peni- et al., 2010). PNSP (Peni- bacteria is auto poisoning of noline-N-oxide (HQNO), cillin in S. pneumoniae was cillin Non-susceptibility in the respiratory chain by a quo- a Pseudomonas aeruginosa first discovered in Australia Streptococcus pneumoniae) rum-sensing-regulated mol- quorum-sensing-regulated in 1967, and later in New was also noted in occurence. ecule favoring bacteria that low-molecular-weight ex- Guinea (1947), South Africa “In the USA, the CDC’s Ac- have formed a biofilm matrix creted molecule, triggers au- (1977), and Spain (1979). tive Bacterial Core surveil- and antibiotic tolerance (Haz- tolysis by self-perturbing the Most of these strains showed lance reported that 24% of an et al., 2016). Auto-Poison- electron transfer reactions of 38 the cytochrome bc1 complex inside the PMN dissect the apoptosis or apoptotic like for long term application, [of the mitochondria][...], bacteria and kill it.(Meyle processes, including mito- HAMLET is a likely candi- causing bacterial cell autoly- et al., 2010). Other ways chondrial permeability (Ha- date towards non-antibiotic sis and DNA release” (Ha- that PMN cells kill immune kansson, Roche-Hakansson, solutions towards multi-drug zan et al., 2016). HQNO is threats is via release of cy- Mossberg, & Svanborg, resistant bacteria. released when a population totoxic entities into the me- 2011). The purpose of addi- Another one of these pos- density of 0.8-1.0 OD600 is dium, which causes bacterial tional studies of HAMLET sible candidates comes from achieved within a sample. cell death (Soehnlein, 2009). was to see whether apoptosis a natural killer of bacteria, Cell autolysis and DNA re- When a specimen of biofilm encompass uniform process silver. “Silver nanoparticles lease are signs of apoptosis positive Staphylococci was to kill prokaryotic cells and (Ag-NPs) have been known caused by HQNO. P. Aerugi- introduced, the PMN was eukaryotic cells. A previ- to have inhibitory and bacte- nosa cells without a bacte- able to consume the bacte- ous examination of the hu- ricidal effects” (Shahverdi, rial biofilm, and therefore by ria with biofilm. However, man milk protein showed the Fakhimi, Shahverdi, & Mina- extension, without any spe- after prolonged exposure, apoptotic abilities with eu- ian, 2007). Silver is an effec- cial antibiotic resistance are the PMN exhibited apoptotic karyotic cells. However, now tive natural killer of bacteria primarily the bacterial fatali- behaviors, including a con- it is known that prokaryotes due to its high specific area ties caused by HQNO. This densation of the nucleus and are also able to undergo apop- and high fraction of surface becomes a problem first be- DNA, causing death. Fur- tosis. This is crucial towards atoms. Production of the sil- cause that means that in this thermore, after 30 minutes, understanding the underly- ver nanoparticles was done by environment, the HQNO reg- 20%-30% death of PMNs ing mechanisms in bacteria, introducing Staphylococcus ulation promotes more cell to those who ingested bio- like the dangerous multidrug aureus and Escherichia coli to viability and then reproduc- film positive Staphylococci resistant biofilm matrix posi- silver nitrate solution. Adding tion of cells with a biofilm, cell. After 60-90 minutes, tive bacteria, and then how to the resulting silver nanoparti- and these biofilms can cause 80% death of PMN to those effectively kill them. HAM- cles to various antibiotics was major problems. Bacterial who ingested biofilm posi- LET primarily causes apop- recorded. The performance biofilm refers to the -struc tive Staphylococci. Conden- tosis by inducing mitochon- of penicillin G, amoxicillin, ture produced when bacterial sation in the PMNs nuclei drial permeability, killing the erythromycin, clindamycin cells bind together with ex- was also recorded, indicat- cell (Hakansson et al., 2011). and vancomycin were re- tracellular polymers that are ing apoptosis (Meyle et al., Similar human protein com- corded with highest perfor- secreted by bacterial cells. 2010).The PMN was able to plexes have also been stud- mance noticed with penicillin “Bacteria in biofilms can break down the bacterial bio- ied, such as MLA, or mul- G, amoxicillin and vancomy- resist antibiotic treatment, film with release of DNAse timeric alpha-lactalbumin, cin (Shahverdi et al., 2007). host immune responses, and 1, and shortly after ingestion for their similar apoptosis Silver nanoparticles have not biocide treatment”(Harmsen, of the biofilm, Elastase and inducing properties (Köhler been tested on bacteria with a Yang, Pamp, & Tolker-Niels- Lactoferrin were released, et al., 2001). These human biofilm matrix, which can be en, 2010). Elimination of seemingly for transportation milk protein complexes are a possible limitation. Silver cells outside the biofilm ma- of DNAse 1(Meyle et al., known not to attack body nanoparticles could be a great trix, via inhibition of bacterial 2010). Past trends indicate cells (Hakansson et mitochondrial reaction sites that the presence of bacterial al., 2011).Bacteria caused by HQNO,promoting biofilm matrix can cause a may never develop a more viable bacteria popu- larger intake of antibiotic re- resistance to HAM- lation, able to resist antibiot- sistant bacteria than the cell LET and other sim- ics, host immune response can handle(Liñares et al., ilar milk protein efforts and other attempts to 2010). complexes because kill the bacteria. This coupled There are a few innova- “The native, folded with new natural antibiotic tions that currently exist form of ALA, with resistance within individual that could possibly cause lactose synthase bacteria can make for a po- the reverse effect needed for activity, has no tu- tentially hard to eradicate the coming years. A human moricidal or bacte- population of bacteria. milk protein complex of al- ricidal effect, how- Viability of these biofilms pha lactalbumin and oleic ever” (Hakansson was tested with the primary acid called “HAMLET”, or et al., 2011). ALA immune response cells in human alpha-lactalbumin requires the pres- the blood, polymorphonu- made lethal to tumor cells, ence of oleic acid clear neutrophils (PMNs). has been researched for its to unfold into the PMNs kill their bacteria by applications towards tumor proper protein that a process called phagocy- cells, however, there trends can cause apop- tosis where they ingest the of eradication can be seen tosis in onologic bacteria through their cell for bacteria as well. This is cells and bacterial membrane and the proteins because HAMLET causes cells. Therefore, 39 asset towards treatments Svanborg, C. (2011). Apoptosis- son, A., Svanborg, C., Orrenius, S., 42F8-B882-13DC6B442D85 [pii] in the future. One possible like death in bacteria induced by & Zhivotovsky, B. (2001). A fold- Shahverdi, A. R., Fakhimi, A., Shah- HAMLET, a human milk lipid- ing variant of human α-lactalbumin verdi, H. R., & Minaian, S. (2007). use for these nanoparticles protein complex. PLoS ONE, 6(3). induces mitochondrial permeabil- could be to combine the hu- Synthesis and effect of silver nano- https://doi.org/10.1371/journal. ity transition in isolated mitochon- particles on the antibacterial activ- man milk protein complexes pone.0017717 dria. Eur. J. of Biochem., 268(1), ity of different antibiotics against mentioned before to create Harmsen, M., Yang, L., Pamp, S. 186–191. https://doi.org/10.1046/ Staphylococcus aureus and Escheri- a better antimicrobial envi- J., & Tolker-Nielsen, T. (2010). An j.1432-1327.2001.01870.x chia coli. Nanomedicine: Nano- ronment as well as possi- update on Pseudomonas aerugi- Liñares, J., Ardanuy, C., Pallares, technology, Bio., and Med., 3(2), bly provide ways to combat nosa biofilm formation, tolerance, R., & Fenoll, A. (2010). Changes in 168–171. https://doi.org/10.1016/j. and dispersal. FEMS Immunol- antimicrobial resistance, serotypes nano.2007.02.001 multidrug resistant bacterial ogy and Medical Microbiology. and genotypes in Streptococcus Soehnlein, O. (2009). Direct and al- biofilms. I propose to com- https://doi.org/10.1111/j.1574-695- pneumoniae over a 3-year period. ternative antimicrobial mechanisms bine these findings to create X.2010.00690.x Clin. Microbio. and Infect., 16(5), of neutrophil-derived granule pro- an additional antimicrobial Hazan, R., Que, Y. A., Maura, D., 402–410. https://doi.org/10.1111/ teins. J. of Mol. Medicine. https:// treatment, hopefully limiting Strobel, B., Majcherczyk, P. A., j.1469-0691.2010.03182.x doi.org/10.1007/s00109-009-0508-6 the use of antibiotics as much Hopper, L. R., … Rahme, L. G. Meyle, E., Stroh, P., Günther, F., Whitney, C. G., Farley, M. M., Ha- (2016). Auto Poisoning of the Re- Hoppy-Tichy, T., Wagner, C., & dler, J., Harrison, L. H., Lexau, C., as possible to avoid produc- spiratory Chain by a Quorum-Sens- Hänsch, G. M. (2010). Destruction ing more of these multidrug Reingold, A., Schuchat, A. (2000). In- ing-Regulated Molecule Favors of bacterial biofilms by polymor- creasing prevalence of multidrug-re- resistant bacteria, and avoid Biofilm Formation and Antibiotic phonuclear neutrophils: Relative sistant Streptococcus pneumoniae in possible public health crises. Tolerance. Current Biology, 26(2), contribution of phagocytosis, DNA the United States. The New England References 195–206. https://doi.org/10.1016/j. release, and degranulation. Int. J. of J. of Medicine, 343(26), 1917–1924. cub.2015.11.056 Artificial Organs, 33(9), 608–620. https://doi.org/10.1097/00019048- Hakansson, A. P., Roche-Ha- https://doi.org/BFBDAE8C-0582- kansson, H., Mossberg, A. K., & Köhler, C., Gogvadze, V., Håkans- 200105000-00025

Oligodendrocytes and Multiple Sclerosis in the Central Nervous Sys- tem by Adhithya Rajasekar (Sophomore)

The nervous system uses the cell body, through the the nerve fibers are unmy- just before and after birth, electrical impulses to axon, going across the elinated. In unmyelinated under a highly-regulated communicate with cells nodes of ranvier, out the nerves, impulses are con- program. Both oligoden- all over the body, which is axon terminals, and across ducted by the propaga- drocytes and their precur- necessary for the body to the synapse to another tion of the action potential sors are very susceptible to function. These electrical neuron where the process along the membrane of the injury by several mecha- impulses moves through repeats. These electrical axon. In myelinated nerves, nisms, including excitotox- neurons, starting at the impulses are facilitated by impulses are transmitted ic damage, oxidative stress dendrites, moving through the myelin sheath, which by an slightly different and inflammatory events covers the process, called saltatory (Barateiro et al. 2016). axon. conduction, in which the In order to make myelin, M y e l i n a t e d impulse jumps from one the glial tongue of an oli- nerve fibers node of ranvier to the next. godendrocyte surrounds occur predom- Impulses in myelinated the axon, forming a dou- inantly in the nerves are transmitted ble-membrane structure cranial and spi- hundreds of times faster which is called a mesaxon. nal nerves and and require much less en- There is an inner mesaxon compose the ergy than in unmyelinated and an outer mesaxon that white matter of nerves (Miller-Keane En- ends in a loop, or tongue, the brain and cyclopedia and Dictionary of glial cytoplasm. This spinal cord. of Medicine, Nursing, and glial tongue is continuous White matter Allied Health, Seventh with the plasma membrane refers to the ar- Edition). of the oligodendroglial cell eas of the ner- Oligodendrocytes pro- through slender processes. vous system duce this myelin in the One glial cell can myelinate that contain central nervous system. forty or more separate ax- myelinated ax- According to an article ons (Siegel GJ et al. 1999). ons, while gray by Barateiro et al, oligo- There are many disorders, matter refers dendrocytes arise from both in the central and pe- to areas in the oligodendrocyte progeni- ripheral nervous system, nervous sys- tor cells (OPCs) that pro- that destroy this myelin, tem in which liferate and differentiate and these disorders can

40 cause disastrous effects in specific T cells, and these cells initiate the local pro- leased and approved by the brain function. One such activated myelin-reactive inflammatory cascade. Food and Drug Administra- disorder in the central ner- T cells circulate through Eventually, a variety of tion (FDA): “fingolimod vous system in Multiple the body searching for effector mechanisms— marketed by Novartis as Sclerosis. An article by their specific antigens to including antibody-medi- Gilenya, dimethyl fumar- Khaled Mohamed Mo- become re-activated. Next ated cytotoxicity, oxygen ate (Tecfidera, Biogen Idec, hamed Koriem lists the occurs the migration of the and nitrogen radicals, pro- MA, USA), and terifluno- symptoms of Multiple proinflammatory T-cells inflammatory cytokines mide (Aubagio from Sanofi, Sclerosis including muscle across the blood-brain bar- and apoptosis-mediating Paris, France)” (Podbielska weakness, weak reflexes, rier (BBB). (Engelhardt molecules that damage et al. 2013). These drugs muscle spasm, difficulty 2006). oligodendrocytes, myelin mainly affect lymphocyte in movement, miss-coor- This is a complex multi- sheaths and occasionally, trafficking and/or differen- dination and unbalance step process that and oc- at this stage, axons—are tiation, though more needs with others. The mecha- curs via interactions be- induced (Becher 2006). to be done to clarify their nism underlying MS can tween adhesion molecules Finally comes the effec- mechanisms. These thera- be summarized into 2 rea- found on the surface of tor phase of the disease, pies aim to reduce the im- sons, “ (1) the immune lymphocytes and endothe- which is invasion of CNS mune response by targeting system destroying the my- lial cells. First, circulating parenchyma resulting in immunological pathways. elin sheath, and (2) failure T cells slow in the blood- damaging of oligodendro- They slow down the im- of the myelin-producing stream due to contact be- cytes, myelin sheath and mune response such that cells (oligodendrocytes) tween distinct adhesion axons. Despite this insight oligodendrocytes have time to produce new sheathes,” molecules on their surface into pathophysiology, the to catch up and remyelinate (Koriem, 2016). and on endothelial cells. cause of MS remains un- the damaged axons, but this MS is considered an auto- In the second step, homeo- clear and definitive treat- treatment method isn’t al- immune disease, which is static chemokines, such ment of this frequent and ways effective at prevent- when the body’s immune as CCL19 and CCL21 are chronic disease is still elu- ing the onset of disability. system attacks its own produced by cells and me- sive. (Engelhardt 2006). They can, however, often cells. The way in which diate T cell activation, a According to a review by leave the body susceptible this happens in MS in- step followed by third and Robin J.M. Franklin, dis- to infectious diseases. With volves T cells, which are fourth steps of firm adhe- ease progression is thought the immune system slowed, one type of white blood sion and final transmigra- to be compounded from foreign antigens have an cell in the immune system. tion of the lymphocytes. In two underlying processes: easier path into the body. They become sensitized to the fifth step, CD4+T cells myelin destruction (demy- A focus on remyelina- proteins in the CNS. It is accumulate within en- elination) with failure to tion may be a better path not known what causes T larged perivascular spaces remyelinate, and progres- of treatment. If a method cells in persons with MS where they can encounter sive axonal damage with of improving remyelina- to become activated, but their specific antigens pre- little capacity for recovery tion can be developed, it is postulated that both sented by the major his- (Franklin 2002). The cur- then patients can be treated genetic and environmental tocompatibility complex rent treatments for MS as without the decrease in im- factors are important, (Na- (MHC) class II or CD1 on listed in a review by Ma- mune capability. For that, tional Multiple Sclerosis the surface of APCs such ria Podbielska, Naren L. the specific mechanisms Society 2017). as perivascular dendritic Banik, Ewa Kurowska and of remyelination that are The immunopathological cells. This immune synap- Edward L. Hogan include, being blocked in MS need events involved in the on- tic contact reactivates the “ β-interferons, IFNβ-1α to be found. According to set of MS can be divided T cells. However, for com- (Avonex, Rebif) and IFN the study by Podbielska et into 5 steps. First is the ini- plete activation, differenti- β-1β (Betaseron); the syn- al, there are a multitude of tial T-cell priming, which ation and clonal expansion, thetic peptide glatiramer hypotheses as to why re- occurs within systemic im- a co-stimulating process acetate (Copaxone); the myelination fails in MS, mune compartments and involving additional mol- antineoplastic agent mi- which may reflect either is initiated by sensitiza- ecules is required. This toxantrone (Novantrone), changes in environmental tion with myelin antigens antigen-triggered activa- and; a very late antigen-4 inputs or intrinsic pathways including myelin lipids. tion enables T cells to tra- (VLA-4) blocker natali- regulating OPCs functions. Next is activation phase of verse the glia limitans and zumab (Tysabri)”. These Several factors are likely the periphery (thymus and migrate into CNS paren- are only partially effec- to impair the completion lymph nodes), Antigens chyma (Engelhardt 2006). tive. All of these drugs are of remyelination. Among presented by antigen pre- After this comes the am- administered by injection them are factors related to senting cells (APCs) with- plification of local inflam- and many MS patients a defect in OPCs activation in secondary lymphoid or- mation and activation of prefer oral treatment. and recruitment, or to local gans induce the activation APCs, such as microglia. There are three new oral inhibitors of remyelination. and expansion of myelin- the autoreactive CD4+T medications, already re- Theoretically remyelina- 41 tion can be blocked at any a treatment method can be protection in autoimmune Asian Pacific Journal of Tropical Biomedicine. Hainan Medical Uni- point in the remyelination created to combat that and demyelination. Remy- versity, 6(5), 429-40. https://doi. process: oligodendrocyte to keep the body’s natural elination and functional org/10.1016/j.apjtb.2016.03.009 survival, proliferation, mi- remyelination strong to recovery have also been Types of MS (n.d.). National Mul- gration, maturation, and/ combat the inflammatory reported following trans- tiple Sclerosis Society: https://www. or myelin sheath forma- effects of the disease. plantation of glial-restrict- nationalmssociety.org/What-is-MS/ Types-of-MS tion. In MS lesions late in Research has been done ed precursor cells (GRPs) Engelhardt, B. (2006). Molecular the course of disease, oli- on certain pathways that expressing a multi-neu- mechanisms involved in T cell mi- godendrocyte recruitment promote remyelination rotrophin of BDNF and gration across the blood-brain bar- is deficient and appears overall, such as Neurotro- NT-3 into the CNS of rier. Journal of Neural Transmis- to be the primary reason phins, Insulin Like growth rats subjected to spinal sion, 113(4), 477–85. https://doi. org/10.1007/s00702-005-0409-y for poor remyelination factors, the Gp130 family cord injury,” (Girard et Becher, B., Bechmann, I., & Greter, in late stage MS. In late of Neurotrophic Cytok- al. 2005). However, while M. (2006). Antigen presentation in stage MS, remyelination ines, the gene Interleukin- these studies provide evi- autoimmunity and CNS inflamma- appears limited by oligo- 11, and Neuregulin 1 type dence that neurotrophins tion: How T lymphocytes recognize dendrocyte density, which III, (Zhang et al. 2011). are effective at promoting the brain. J. of Molec. Med., 84(7), 532-43.https://doi.org/10.1007/ could be a product of im- There has also been re- regeneration of the injured s00109-006-0065-1 paired survival, prolifera- search done on certain spinal cord, the relative Franklin, R. J. M. (2002). Why does tion, and/or migration of inhibitors of myelination, contributions to these out- remyelination fail in multiple scle- oligodendrocytes. In le- such as Canonical Notch comes of effects on neu- rosis? Nature Rev. Neurosci., 3(9), sions containing more oli- Signaling, the Canonical rons versus glia remain to 705-14 https://doi.org/10.1038/ nrn917 godendrocytes, impaired Wingless Pathway, and be fully defined. I propose Podbielska, M., Banik, N., Kurows- oligodendrocyte matura- Bone Morphogenetic pro- that that we combine the ka, E., & Hogan, E. (2013). Myelin tion is a major problem teins (Zhang et al. 2011). two studies, and research Recovery in Multiple Sclerosis: The for efficient remyelination Out of these growth fac- further the full effect of Challenge of Remyelination. Brain of lesions. Beyond the oli- tors, Neurotrophins show transplanting neurotrophic Sci., 3(3), 1282–1324. https://doi.org/10.3390/brains- godendrocyte recruitment the greatest promise in factors into MS mice mod- ci3031282 and maturation, myelina- terms of increasing func- els, for if we can use this Jacques, F. H. (2015). Defin- tion also requires contact tional recovery and remy- to increase OPC differ- ing the clinical course of mul- between axons and oli- elination. Neurotrophins entiation, which seems to tiple sclerosis: The 2013 revisions. godendrocytes and cre- (NTs) comprise a fam- be the biggest factor pre- Neurol. Lippincott Williams and Wilkins. https://doi.org/10.1212/01. ation of multiple wraps ily of soluble mediators venting remyelination in wnl.0000462309.76486.c5 of oligodendrocyte pro- including nerve growth MS, then we can treat MS New diagnostic criteria for multiple cesses around the axon, factor (NGF), brain-de- without leaving the body sclerosis: guidelines for research culminating in the myelin rived neurotrophic factor susceptible to diseases. protocols. (n.d.). sheath. Another factor is (BDNF), neurotrophin-3 Bunge, R. P. (1968). Glial cells and that repeated demyelinat- (NT-3) and neurotrophin- References: the central myelin sheath. Physi- Myelin. (n.d.). In The free diction- ological Reviews, 48(1), 197 LP- ing insults, as observed 4/5. A study by Christelle ary. https://medical-dictionary.the- 251. http://physrev.physiology.org/ in the relapse-remitting Girard et al. found that freedictionary.com/myelin content/48/1/197.abstract form of MS, can exhaust “transplantation of fibro- Morrel, P., & Quarles, R. H. Miravalle, Schreiner, & Miravalle. the OPCs source so that blasts expressing either (1999). The myelin sheath. https:// (2012). Current and Emerging Ther- remyelination failure may BDNF or NT-3 has been www.ncbi.nlm.nih.gov/books/ apies for the Treatment of Multiple NBK27954/ Sclerosis: Focus on Cladribine. J. of be regionally defined due shown to enhance axonal Barateiro, A., Brites, D., & Fer- Central Nervous Sys. Dis., 4, 1-14 to exhaustion of distinct growth, OPC proliferation nandes, A. (2016). Oligodendro- https://doi.org/10.4137/JCNSD. progenitor pools (Podbiel- and myelination in adult cyte Development and Myelination S5128 ska et al 2013). While this rat spinal cords after in- in Neurodevelopment: Molecular Zhang, J., Kramer, E. G., Mahase, S., study lists possible aspects jury. Moreover, transplan- Mechanisms in Health and Dis- Dutta, D. J., Bonnamain, V., Argaw, ease. Cur. Pharma. Design, 22(6), A. T., & John, G. R. (2011). Target- of remyelination that could tation of BDNF or NT-3- 656–679. https://doi.org/10.2174/1 ing oligodendrocyte protection and be affected, it is unknown expressing Schwann cells 381612822666151204000636 remyelination in multiple sclerosis. whether it’s a combina- into demyelinated mouse Siegal, G. J., Agranoff, B. W., Al- Mount Sinai J. of Med., 78(2), 244– tion of these problems, or spinal cords leads to in- bers, W. R., Fisher, S. K., & Uhler, 257. https://doi.org/10.1002/msj.20244 just one major mistake is creased OPC proliferation M. D. (Eds.). (1999). Basic neuro- Girard, C., Bemelmans, A.-P., Du- chemistry: Molecular, cellular and four, N., Mallet, J., Bachelin, C., occuring in MS. It seems and differentiation, remy- medical aspects (6th ed.). https:// Nait-Oumesmar, B., Lachapelle, F. however, that the main elination and locomotor www.ncbi.nlm.nih.gov/books/ (2005). Grafts of brain-derived neu- problem is less OPC dif- recovery. Interestingly, NBK20385/ rotrophic factor and neurotrophin ferentiation into oligoden- studies in the MS model Who gets MS? Natl Multiple 3-transduced primate Schwann cells drocytes, which causes a experimental autoimmune Sclerosis Soc. https://www.na- lead to functional recovery of the de- tionalmssociety.org/What-is-MS/ myelinated mouse spinal cord. J. of lack of oligodendrocyte encephalomyelitis (EAE) Who-Gets-MS Neurosci. 25(35), 7924–33. https:// density. If the root cause of imply a functional role of Koriem, K. M. M. (2016). Multiple doi.org/10.1523/JNEUROSCI.4890- this problem is found, then BDNF in mediating axon sclerosis: New insights and trends. 04.2005 42 43 Acknowledgments This program would not be University and Staff. Thank you so much for your possible without: • Ms. Meaghan Perdue, constant support: Developmental Psychol- • Mr. Joseph Hochreiter, • Ms. Michele Glidden, Mentors and Scientists. ogy, Neurobiology of Superintendent Chief Program Officer Thank you to all of the sci- Language, University of • Dr. Margaret Ruller, • Ms. Caitlin Sullivan, entists who have taken our Connecticut Executive Director of Director of Outreach & high school students under • Dr. Anna Kaatz, Direc- Curriculum and Instruc- Equity tion. their wings and given them tor of Computational Sci- • Ms. Anna Rhymes, unprecedented possibilities ences, Center for Wom- • Mr. Enrique Catalan, Science News in High to access genuine scientific en’s Health Research, Assistant Superintendent Schools Program Man- research, to act as profes- University of Wisconsin- for Business. ager sionals and to express their Madison • Mr. James Mackin • Ms. June Kee, Science talents and creativity in their • Dr. Frances Hannan, Principal. projects. Education Programs Assistant Professor of • Mr. Anthony Giovinazzi Cell Biology and Anat- Assistant Principal. Members of the School In- • Dr. Matthias Quick, omy, New York Medical • Ms. Laura Neier, As- stitutional Review Board: Ph.D. Associate Pro- College fessor, Department of sistant Principal. Thank you for taking the • Ms. Hillary Siener, Psychiatry and Center for • Dr. Mathew Swerdloff, time to review the work of Conservation Biology, Molecular Recognition, Executive Director of students’ projects throughout Director of Environmen- Columbia University, Educational Support the year. tal Stewardship, Teatown College of Physicians Services. Lake Reservation and Surgeons. Dr. Quick • Mr. Thomas Confrey • Mr. James Mackin, • Ms. Michelle (Shelly) served on our Institu- and Ms. Stephanie Principal. A. Forster, Educational tional Review Board and McQuade, Science • Mr Anthony Giovanaz- Program Specialist, Cary guided science research Teachers, for their sup- zi, Assistant Principal Institute students through their port of the program in my projects throughout the • Ms. Ann-Marie Gal- absence. lagher, Science Teacher. years. Dr. Quick served Sponsors: • Ms. Beth Gruber, HH- • Mr. Thomas Confrey, a judge in all the ma- We want to thank the Hen- CEF. Science Teacher jor competitions of the drick Hudson Community • Ms. Valerie Oddo and region, hereby gaining Educational Foundation • Ms. Stephanie Mc- Ms. Jill Wheeler for important knowledge of (HHCEF) for its on-going Quade, Science Teacher their sustaining support. the competition process. funding of the science re- • Dr. Matthias Quick, • Dr. Adam Zeman, MD, search program. • Ms. Clare Carey for Associate Professor of Professor of Cognitive catering services Clinical Neurobiology and Behavioral Neurol- We would like to extend spe- • The custodial staff. ogy. University of Exeter, cial thanks to Mr. and Mrs. Pine Ridge Girls School Medical School, Exeter, Chung for their generous Science Research Col- Outreach Initiative: UK. donation. leagues: Our deepest gratitude to: • Dr. Stuart A. Newman, Parents: Ph.D. Professor of Cell • Mr. Michael Blueglass, • Ms. Victoria Shorr, Biology and Anatomy. This program would not be Yorktown High School Pine Ridge Girls School New York Medical Col- successful without the sup- • Mr. Angelo Piccirillo, Founder, for providing us lege, Valhalla, NY. port of the students’ families, Ossining High School with the opportunity to who sacrifice so much of • Dr. Patric K. Stanton, • Ms. Donna Light Dono- work with you their time to ensure that the Ph.D. Professor of Cell van, Croton-Harmon • Ms. Cindy Giago, Head students get the best possible Biology and Anatomy, High School. of the School New York Medical Col- experience when they work lege, Valhalla, NY. on site, in labs and during the • Mr. Leonard Behr • Mr. Beau White, Science Science Research in the Teacher. • Dr. Nicole Landi, As- school year. High School Program, • Ms. Mary McDonnell, sistant Professor Psy- University at Albany. chology, University of Thanks to Mr. and Mrs. for her generous donation Connecticut and Yale Kissner for volunteering as to the Pine Ridge Girls Child Study Center and judges. Society for Science and the School, on behalf of out- Haskins Laboratory, Yale Public officers: reach program, and her Administrators, Teachers unwavering support. 44 For more information on the Science Research Program, Contact Dr. Christine Rogers, Ph.D. [email protected]