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STONY BROOK UNIVERSITY

YOUNG INVESTIGATORS REVIEW

Demystifying Star Formation Dr. Jin Koda Explores Star Formation with Radio Astronomy p. 23

Volume 4 Spring 2014


Young Investigators Review Staff 2013-2014

Editor-in-Chief Julia Joseph B.S. Biochemistry, 2015

President Viven Solomon B.S. Biology, 2014

Associate Editors Matthew Alsaloum ’15 Sherry Bermeo ’15 Ashwin Kelkar ’16 Erin Thomas ’14

Vice President Surya Chalil ’15

Layout Editors Preston Kung ’15 Sherin Kuriakose ’14

Webmaster Evan Magaliff ’15

Photographer Yaruq Hassan ’14

Copy Editors Sahar Bilal ’14 Eman Kazi ’15 Advisors Dr. Robert Haltiwanger Dep’t. of Biochemistry and Cell Biology

Staff Writers Print

Online

Sonali Bahl ’15 Kelsie Cassell ’15 Megan Chang ’17 Brian Chin ’15 Jessica Desamero ’15 Plinio Guzman ’15 Ephraim Hallford ’14 Albany Jacobson Eckert ’16 Prithviraj Rajebhosale ’14 Zohair Saquib ’14 Justin Thomas ’15

Linnea Adams ’15 Shipra Arjun ’16 David John Davani ’16 Lisa Jakubczyk ’15 Sanjay Jonnavithula ’17 Joshua Kantharia ’14 Katherine Maiorisi ’17 Nujbat Meraji ’15 Hillary Steinberg ’15 Raazia Syedda ’15

Dr. John Peter Gergen Dep’t. of Undergraduate Biology

From left to right: (Front) Sherin, Viven, Julia, Erin, Surya, Sherry, and Sahar; (Back) Evan, Matthew, Preston, Ashwin, Eman, and Yaruq.


Letter from the Staff Dear Reader, Stony Brook University, one of the top-ranked public universities in the country and among the nation’s top 100 colleges, has historically been a leading research institution. Aside from being the birthplace of MRI technology and finding the causative agent of Lyme disease, it has also forged close ties with the world-renowned Cold Spring Harbor Laboratory and co-manages Brookhaven National Laboratory, imbuing a spirit of collaboration that has inspired numerous pioneering discoveries. Today, this tradition of excellence in research has hardly changed, as some of the most distinguished investigators, many of whom are recognized as leading scientists in their respective fields, continue to uncover the most elusive mysteries of the 21st century. Though often overlooked, undergraduate research plays a key role in significantly contributing to the progress of our institution’s research. The Truman, Churchill, and Goldwater scholars that have since graduated from Stony Brook can attest to the significance of the undergraduate research here—yet, these individuals are only some of the many bright minds that have went on to share their work at national conferences or publish their work in peer-reviewed publications. Despite the sizable number of undergraduates that actively engage in furthering the research goals of this institution, few avenues are available to students to share their work with their peers and professors, a crucial aspect for encouraging advancement and innovation in the process of scientific research. The Young Investigators Review was thus founded in 2008 with the primary aim of addressing this issue. Upon recognizing the journal’s unique position in having the ability to unite the science departments on campus, as well as bridge the gap between the faculty and the rest of the SBU community, the goals of the journal soon expanded. The journal became an interdisciplinary forum that not only served to provide an outlet for undergraduates interested in science-writing or sharing their original research, but also to increase public awareness of the cutting-edge research occurring on campus. The journal has successfully published three issues and hosted two symposiums since its duration from 2008-2011. With much anticipation and enthusiasm from the student body and faculty, YIR has been reestablished under new management and presents to you our first journal since its reinstitution. In the spirit of improvement and modernization, we have drastically changed the face of YIR, providing what we hope is a fresh look with a new layout and an original logo. We have also created a new online web presence that showcases its own set of unique articles. Yet, despite the many changes, the original goals of the journal will remain the same, encompassing a wide scope of topics in the form of original scholarly articles, reviews, interviews, science news, and more. In this edition of our journal, our staff and writers have worked diligently to present you with some of the most interesting and relevant science of today. These range from discussions of alternative sources of energy, such as multijunction solar cells and piezoelectricity, to the emerging technology of optogenetics. We have also included interviews of well-known professors, such as Dr. Marvin O’Neal and Dr. Lorna Role, as well as an in-depth discussion of the research of Dr. Jin Koda, who is featured as our cover story, in the hopes of inspiring undergraduate students to participate in the exciting research taking place on our campus. We are also proud to showcase two works of original research, in addition to including a “research news” section that highlights only some of the many research accomplishments of the 2013-2014 school year. We hope to solidify the foundation for the journal to ensure its success in the future. However, this can only be accomplished with the participation of energetic, bright, and ambitious undergraduate students that also share our vision to improve and expand YIR. We urge you to reach out to us and to learn more by visiting our website at www.sbyir.com Special thanks to Dr. Gergen and Dr. Haltiwanger, who have provided us with guidance, advice, and resources to make the reinstatement of YIR possible, to our donors, who have made this endeavor possible with their generous support, and to our writers, for their patience and dedication in working alongside us to realize our vision for YIR. We hope you enjoy reading!


Table of Contents Dr. Lorna Role on Science, Sculpting, and Success..............................................8 Megan Chang ’17

Revolutionizing Introductory Biology: An Interview with Dr. O’Neal.............11 Kelsie Cassell ’15

Harnessing the Power of Piezoelectricity.............................................................14 Plinio Guzman ’15 and Ya Wang, Ph.D.

The Secret to Happily Ever After: An Overview of Romantic Relationship Success Factors.................................................................................17 Brian Chin ’15

Peptides as a Novel Approach for Tumor Targeting...........................................20 Sonali Bahl ’15

Exploring Star Formation by Radio Astronomy Techniques with Dr. Jin Koda........................................................................................................23 Albany Jacobson Eckert ’16

Optogenetics as a Therapeutic Measure for Irregular Cardiac Functionality.............................................................................................26 Zohair Saquib ’14

Multijunction Solar Cells: Energy Recaptured and Converted........................29 Justin Thomas ’15

Treating Rheumatoid Arthritis: Advances and Obstacles..................................32 Ephraim Hallford ’14

Design and Testing of Amplification Frame for Piezoelectric Energy Harvester.............................................................................35 Plinio Guzman ’15

“Neuregulating” Transcription: Effects of Neuregulin 1 Type III Back-Signaling on the Expression of α7 Nicotinic Acetylcholine Receptors (α7nAChR)...............................................................................................................40 Prithviraj Rajebhosale ’14


RESEARCH NEWS Stony Brook Medicine is among the first in the nation to offer simultaneous PET/MRI As of October 2013, Stony Brook Medicine has become the first site in Long Island and tenth in North America to clinically offer simultaneous whole-body PET/ MRI scans. In this new Siemens Biograph mMR hybrid imaging system, molecular information from positron emission tomography (PET) is combined with soft-tissue contrasts from magnetic resonance imaging (MRI). This lowers the body’s exposure to radiation and further enhances the accuracy and precision of both images. Simultaneous PET/MRI aids doctors in giving patients finer clinical diagnoses. According to Mark Schweitzer, Chief of Diagnostic Imaging and Chair of the Department of Radiology, the dual capability of this machine allows patient exams to be faster and more inclusive, while the advanced imaging quality provided allows disease staging to be more accurate. This technology is also a significant advancement for ground-

breaking medical research. Stony Brook plans to use this device for a variety of future investigations, including studies on radioisotopes and new cancer treatment tracers, as well as on psychiatric diseases and their neurological causes. What makes this PET/MRI technology a notable research development is that it enables scientists to perform functional and structural studies at the molecular level. Because of this, many major diseases can be further understood. “With this acquisition, we look forward to being one of the preeminent molecular imaging facilities in the country.” said Ramin Parsey, Professor and Chair of the Department of Psychiatry and Behavioral Science, and Director of Positron Emission Tomography Research. References

“Stony Brook Medicine Among First Clinical Sites in US for simultaneous PET/MRI.” Stony Brook Newsroom. 16 October 2013. Stonybrook.edu. Web.

SBU Faculty Member Invents Mobility Device That Will Now Be Manufactured by Biodex Anurag Purwar, Associate Professor of Stony Brook University, works as a researcher in the Department of Mechanical Engineering. Dr. Purwar was faced with a proposition to create a device that would facilitate the movement of individuals and help his friend, Dr. Hari B. Pillai. Dr. Pillai suffers from post-polio syndrome and struggles to lift himself out of a chair in order to use his walker. “Today, in the United States, there are more than two million people over the age of 64 who find it difficult to rise from a chair without assistance,” explained Professor Purwar. “Biomechanically, sitting and standing involve complex movements that require muscle strength greater than other activities of daily life.” Consequently, he produced the state-of-the-art patented invention, Mobility Assist. In 2012, Purwar received a $50,000 award from the SUNY Technology Accelerator Fund to prototype the device, and was granted a $30,000 from the New York State Strategic Partnership for Industrial Resurgence program with the Center for Biotechnology and Biodex. It was announced in October 2013 that it will finally be manufactured by Biodex Medical Systems and made avail-

Professor Purwar’s device allows disabled people to get into standing position so that they can walk. https://www.asme.org/getmedia/6e02580a-9a04-4b3e-ac035a2a82d3d242/Making-a-Stand_02.jpg.aspx?width=340

able to patients in 2014. The device resembles and functions in the same way as a walker. However, it also incorporates support bars, a pelvic harness, and a linkage that is controlled by the user with a remote. These ingenious elements enable the user to imitate the natural standing motion of a human body. Mobility Assist has the potential to serve countless patients and residents once it becomes marketed to physical and occupational therapists, living facilities, hospitals, and nursing homes. References 1. Mobility Device Patented at SBU Will Now Be Manufactured at Biodex. 2013. Stony Brook Happenings. <http://sb.cc.stonybrook.edu/ happenings/featuredpost/mobility-devicepatent-biodex>. 2. SBU Mechanical Engineering Professor Invents Portable Mobility Assist Device. 2013. Stony Brook University Press. <http://commcgi.cc.stonybrook.edu/artman/publish/ index.shtml>.

SBU Scientists Enhance Cancer Drugs with New Targeting Techniques

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Mark Schweitzer, M.D., Chair of Radiology with Stony Brook Unversity’s PET/MRI machine.

Currently, working cancer drug treatments successfully attack cancer cells, but they also attack the healthy cells, causing recovery for patients to be difficult. Dr. Nobuhide Ueki, a research scientist in the Department of Molecular Genetics and Microbiology, and his team are working on a new ap-

proach to drug therapy that targets only the cancer cells. Their findings were published in Nature Communications in November 2013. His team first discovered two enzymes that were very highly active in the cancer cells they tested: histone deacetylase (HDAC) and cathepsin L (CTSL). They took a

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Stony Brook Researchers Receive $3.8 Million NIH Grant to Develop New Class of Painkillers

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Dr. Nobuhide Ueki and his team are researching techniques that only target cancer cells

commercial chemical tag substrate and attached it to cancer prodrugs, which are drugs used to help improve cell interaction selectivity before the primary drugs are administered. Removing the acetylated and unacetylated lysine groups of this substrate released the puromycin antibiotic upon cells. This protected normal cells, as only the two enzymes in the cancer cells were able to cleave this tag. Several in vitro proof-ofconcept studies and in vivo mice studies proved the efficacy of the prodrug. “This cancer-selective cleavage of the masking group is a

promising strategy for the next generation of anticancer drug development, and could be applied to many other cytotoxic agents,” said Dr. Ueki. Further studies include trying to modify the substrate to make it more efficient. Dr. Ueki also thinks that this compound, due to its supposed ability to attach to other drugs, could play a role in other various applications, such as acting as cancer cell markers in imaging. References “SBU Scientists Develop a New Cancer Targeting Technique to Improve Cancer Drugs.” Stony Brook Newsroom. 6 November 2013. Stonybrook.edu. Web.

The Institute for Chemical Biology & Drug Discovery (ICB&DD) at Stony Brook has become responsible for a project called “Targeting FABPS.” The research team is led by Dale Deutsch, Professor of Biochemistry and Cell Biology at Stony Brook University, and member of the ICB&DD. The project also includes an eclectic group of individuals from various Stony Brook University departments, the ICB&DD, and the Laufer Center for Quantitative and Physical Biology, and started with their discovery that fatty acid binding proteins (FABPs) could be intracellular transporters that transfer a neurotransmitter known as AEA (endocannabinoid anadamide) into the interior of the cell. Once AEA enters the cell, it is destroyed and triggers an increase in the amount of pain signals. In November 2013, a subsection of the National Institute of Health (NIH), the National Institute on Drug Abuse (NIDA), offered a five-year, $3.8 million grant to the research team after recognizing this discovery as a ground-breaking frontrunner for developing new drugs that can treat pain, inflammation, and potentially drug addiction.

Professor Deutsch stated, “The major goal of our drug discovery proposal is to develop drugs that inhibit these neurotransmitter transporters. We expect that by targeting FABPs with certain compounds made by the ICB&DD group, endocannbinoid levels will increase within the brain, essentially resulting in anti-pain and antiinflammatory effects.” It is a promising goal after their discovery of the FABP inhibitor alpha-truxilic acid. In the future, this type of drug could also have the added benefit of reducing symptoms of drug withdrawal. Furthermore, the drug would not have any negative side effects, since the research project attempts to increase neurotransmitter levels naturally. References

1. Berger, W. et al. 2012. Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs. PLoS One. 7(12):e50968. 2. Stony Brook Researchers Receive $3.8 Million NIH Grant to Develop Drugs for Pain, Inflammation. 2013. Stony Brook Newsroom. <http://stonybrookmedicine.edu/newsroom/ nida-grant>.

Stony Brook University is Chosen by NASA to Explore Space Virtually NASA has formed the Solar System Exploration Research Virtual Institute (SSERVI), which has carefully chosen nine research teams from seven states. The research teams will create a virtual setting where they can address issues related to space science and human space exploration. Topics include scientific questions about the moon, near-Earth asteroids, and the Martian moons Phobos and Deimos. In November 2013, Stony Brook University was laudably selected to be the leading institution for one of the research teams. The Stony Brook project is called “Remote, In Situ and Synchroton Studies for Science and Exploration” (RIS4E) and is led by Timothy

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Glotch, associate professor in the Department of Geosciences at Stony Brook. The RIS4E project will focus on four areas of research. The first area is interpreting the data transmitted to Earth from orbiters and landers. The second area, led by Dr.Jacob Bleacher of NASA’s Goddard Space Flight Center, simulates human space exploration. Researchers will travel to locations that mimic the volcanic terrains of outer space bodies. The third component involves the intertwining of geology and medicine. A team of geologists led by Martin Schoonen, a Stony Brook University professor and chair of the Environmental Science Department at Brookhaven

National Laboratory, will work with two Stony Brook Pharmacology professors, Bruce Demple and Styliani-Anna Tsirka, to understand how the dust that astronauts breathe on the planetary bodies could affect their health. Lastly, Stony Brook scientists will use the National Synchrotron Light Source II (NSLS-II), which will begin operating in 2015 and will be one of the brightest Xray light sources in the world. The $5.5 million NASA-funded research collaborative will enable opportunities for future space exploration and will provide vital information for the potential use of humans and robots in the exploration of our solar system.

Timothy Glotch is leading the RIS4E project at Stony Brook University https://www.bnl.gov/bnlweb/pubaf/pr/photos/2013/11/timothyglotch-hr.jpg

References 1. Stony Brook Interdisciplinary Team Plays Lead Role in NASA “Expedition” to Explore Space Virtually. 2013. Stony Brook University Press. <http://sb.cc.stonybrook.edu/news/ general/131106ExploreSpaceVirtually. php?=marquee2>. 2. Brown, D. Hoover, R. 2013. NASA Selects Research Teams for New Virtual Institute. NASA News Release. <http://www.nasa.gov/ press/2013/november/nasa-selects-researchteams-for-new-virtual-institute/#UyDtz_ldV1X>.


Research Group Unearths Clues to the Origin of Human Bipedalism Habitual terrestrial bipedalism is noted as being one of the earliest characteristics to develop in human history. It is a major evolutionary step that has provided human beings with the ability to walk upright on two legs, but questions regarding the origins of human bipedalism have been left largely unanswered. However, after analyzing the femur of a six-million-year-old Orrorin tugenensis, known as the “Millenium Man,” research published in December 2013 has revealed ground-breaking insights into the origin of human bipedalism. 3-D geometric morphometric analyses have provided further evidence that the Orrorin femur serves as a noteworthy “intermediate” between the fossil apes from 23 to 5 million years ago and the late human ancestors called hominins. This disputes the idea of living apes being our only ancestral models. This research was led by Dr. Sergio Almécija, a Research Instructor from the Department of Anatomical Sciences at Stony Brook University School of Medicine, and co-authored by Dr. William Jungers, Distinguished Teaching

Professor, and Chair of the Department of Anatomical Sciences at Stony Brook University School of Medicine. The study set a precedent by comparing Millenium Man’s femur to numerous hominin fossils, great apes, apes in the family Hylobatidae, and fossil apes from the Miocene period. The use of cutting-edge techniques provided an incredible morphometric analysis of more than 400 species. Dr. Almécija stated, “Our paper provides quantitative results of the Orrorin femur as a unique mosaic and stresses the need to incorporate fossil apes into future analyses and discussions dealing with the evolution of human bipedalism, an investigation that should stop considering chimpanzees as default living ‘starting point’ models.” References 1. Almécija, S. et al. 2013.The femur of Orrorin tugenensis exhibits morphometric affinities with both Miocene apes and later hominins. Nat. Commun. 4:2888. 2. Early Tree-Dwelling Human Ancestor was Similar to Ancient Apes but not Living Apes. 2013. Stony Brook Newsroom. <http://sb.cc.stonybrook.edu/news/ general/131204earlytreedwelling.php>. 3. Johnson, D. 2006. How Bipedalism Arose. Nova. <http://www.pbs.org/wgbh/nova/evolution/what-evidence-suggests.html>.

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Femurs of the Orrorin tugenensis provide clues for studying human bipedalism.

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An angioplasty procedure done with a stent.

Angioplasty May Not Always Be the Answer in Heart Disease The most common treatment for stable coronary artery disease (CAD) today is angioplasty, a procedure that opens blocked coronary arteries in the heart. However, a survey conducted by cardiologists at Stony Brook University School of Medicine in December 2013 has shown that patients with CAD who are neither enduring a heart attack nor have an abnormal stress test may not benefit from angioplasty, as opposed to drug therapy alone. The study is published in the first edition of JAMA Internal Medicine online. David L. Brown, M.D., and Kathleen Stergiopoulos, M.D., Ph.D., professors in the Division of Cardiovascular Medicine of the Department of Medicine at Stony Brook University School of Medicine, organized the meta-analysis in conjunction with colleagues globally. The study joined clinical trials data from 1970 to 2012 of two groups of patients: those who received percutaneous coronary intervention (PCI), commonly referred to as angioplasty, in conjunction with drug therapy, and those who received drug therapy alone. All of the clinical trials included in the study reported death and nonfatal myocardial infarction. At least

50 percent of the patients, in both the “angioplasty alone” group and “drug therapy alone” group, needed to use statins to lower cholesterol. In addition, at least 50 percent of the patients who received PCI needed to have a stent inserted. This was to ensure the study reflected the nature of current cardiovascular treatments. The study contained five clinical trials consisting of a total of 4,074 patients with myocardial ischemia. In patients with controlled CAD and documented myocardial ischemia, PCI with drug therapy did not lead to a decrease in death, nonfatal myocardia ischemia, unplanned revascularization, or angina, as compared to drug therapy alone. This disagrees with current medical thinking and questions whether angioplasty should not be considered the first option for patients with stable CAD and ischemia. References 1. Brown. (2013, Dec 6). Angioplasty May Not Be Better than Drug Therapy in Stable Disease. Retrieved from http://stonybrookmedicine.edu/newsroom/david-brown 2. Stergiopoulos K, Boden WE, Hartigan P, et al. Percutaneous Coronary Intervention Outcomes in Patients With Stable. Obstructive Coronary Artery Disease and Myocardial Ischemia: A Collaborative Metaanalysis of Contemporary Randomized Clinical Trials. JAMA Intern Med.2014;174(2):232-240.

Editors’ Note: The research being featured here is only some of the many noteworthy accomplishments recognized at Stony Brook University in the past (2013-2014) school year. For others, visit www.stonybrook.edu/happenings. Research News was compiled by Surya Chalil, Jessica Desamero, and Erin Thomas.

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Courtesy of Lorna Role

readers that goals can be achieved with curiosity, passion, and drive. How did you decide to pursue a career in research? I majored in Applied Math and minored in Architectural History [as an undergraduate] because I had no clue what I wanted to do with my life. By the time I was a senior, I still had no idea what I wanted to do. I had done a thesis on gothic architecture and a thesis on Laplace’s theorem and applications to cardiac mechanics; I was all over the place! I ended up applying to schools of architecture, medical schools, and Ph.D. programs, and I decided that whatever I got into first, I would go there. So I think that if I hadn’t gone into medical research, I would have gone into architecture or some form of art. Though I decided to pursue research, I still paint and sculpt; art is still a big part of my life.

Dr. Lorna Role on Science, Sculpting, and Success By Megan Chang ’17 Earning both her B.A. in Applied Mathematics and her Ph.D. in Physiology from Harvard University, her full professor title at Columbia University, and more awards and honors than can be accounted for, it is safe to say that Dr. Lorna Role is accomplished beyond the norm. She has been a member of Stony Brook’s Department of Neurobiology and Behavior for six years and currently serves as a professor, as well as its Chair. In those six years, Role has done astounding research in her field, focusing mainly on central cholinergic circuits, which are neural circuits related to the acetylcholine transmitter. These cholinergic circuits play a significant role in the modulation of synaptic excitability and have been associated with multiple neurological diseases, including schizophrenia, depression, and Alzheimer’s. Dr. Role’s lab has studied the function of cholinergic signaling in memory and learning, and is currently studying the role that products of neuregulin-1, a novel class of signaling molecules, may have in maintaining cholinergic circuits. Dr. Role has earned multiple esteemed titles, such as Fellow of the American College of Neuropsychopharmacology (ACNP) in 2009, and many prestigious awards, like the NIH Pioneer Award in 2010. Despite her remarkable success as an accomplished scientist, Dr. Lorna Role remains downto-earth, hard-working, and continues to strive to help others reach their aspirations. She sat down with the Stony Brook Young Investigators Review to tell her story and to remind

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Why did you decide to pursue research, as opposed to medicine? Research was completely the right decision for me because I knew I wanted to be involved in that process of finding new things. It’s really thrilling when you discover something; I have always been captivated by that. I was initially in a M.D./Ph.D. program, and medical training does give one a broader context for research; if you get an education in both, then you’re in the truly ideal situation because you have better perspective. You know what it takes to understand how something works and then you also know which diseases are in desperate need of an intervention—both perspectives are great to have! Ultimately though, I think one’s heart goes in one direction or the other. How were you drawn to neurobiology? That was definitely a post-hoc decision. I was in a Ph.D. program in physiology and interested in cardiovascular mechanics. I was very lucky; I was at Harvard and taught by Hubel and Weisel, who both received the Nobel Prize [in Physiology and Medicine]. There were a number of people who were remarkable teachers and inspirational researchers, so I got pulled into neurobiology. It’s a blast! I really believe the [brain] is the final frontier. The most amazing thing was watching my kids grow up and do things like acquire language. It’s so interesting how different it is in every individual. Out of all the places you could have gone, why did you choose Stony Brook? You have different stages of your career in terms of what you want to put your energy into. I had been at these fancy private schools my whole life. I’m a 60s kid, so my inner hippie finally decided to express itself. Also, I had been at a medical school all my life, so I thought I would enjoy being at a university where there were departments of art and music, or other things than what they call “preclinical sciences.” I never dreamed it would be as incredibly invigorating as it is—it’s such a different environment for teaching and interacting with students. I was really interested in so many different things and I missed that after 25 years of teaching at medical school. Aside from that, the biggest thing that attracted me was the people who were here.


Much of your research focuses on the molecule acetylcholine. What is it exactly? There are many transmitter systems in the brain that all act together to shape something complex, such as personality and memory. Acetylcholine is an important modulatory transmitter in these processes. It doesn’t necessarily excite or inhibit the neurons in the brain directly, but rather, fine-tunes them all the time. A lot of the nuanced activity of neurons is actually influenced by these kinds of modulatory transmitters. Acetylcholine is the last one that people are figuring out. Acetylcholine plays a significant role in Alzheimer’s disease, which is the most prevalent neurodegenerative disease today [2]. It has been said that there may never be a true form of treatment for the disease—is this still the case? There is no cure; that’s for sure. Alzheimer’s usually results in death within eight years of diagnosis, but there is a lot of hope in terms of the research. The diagnosis has come very late in the process, so we have not been able to recognize earlier signs. By the time most people are diagnosed with Alzheimer’s, they have already had the disease for ten to fifteen years. The time between onset and diagnosis can be improved by getting earlier biomarkers and understanding more about the processes that go on. Another area that’s really important is quality of life. What is particularly devastating about Alzheimer’s is that it often robs the individual of critical aspects of their personality. It takes away their memories and the things that they’ve experienced. When that goes, it erodes fundamental aspects of people’s personalities, their interactions with others, and their ability to understand and enjoy their environment. We’re looking for mechanisms that could enhance cognitive functions so that they have a little bit more control because that’s really devastating, not just to the individuals who have it, but to the family. Almost no one exists that hasn’t been touched by Alzheimer’s in one way or another. What is a normal day like for you? Well, it starts with me waking up at 4 A.M. That’s “me” time, when I can think, write, and prepare for what I have to do that day. Then I’ll head over to my lab, but only for a bit because when you’ve been the head of a lab for a long time, the researchers don’t want you to touch anything anymore. I’ll come over to a student or postdoc’s workspace and say, “How’s it going?” and they’ll often usher me away. In the afternoon, I’m here in the Chair’s office. As a Chair, you really serve your faculty—that’s your first line of duty. Your science no longer comes first; it’s the science and the careers of those in your department. I’ll try to guide the junior professors in terms of balancing the demands, because there are a lot of things that an academic scientist does in particular. You get asked to review grants and papers for journals. At the university level, you serve on committees where you’re involved in hiring individuals at different levels. You have departmental service, university service, service in your field, meetings, have to be sure you’re publishing and getting all your grants—and oh yeah, have some kids in the middle! I’ve been able to do all those things. I know what it’s like to handle that juggle, so it’s nice to help people along in their careers and make it easier on them.

Dr. Role’s research focuses on cholinergic circuits, which are neural circuits that play a significant role in the modulation of synaptic excitability. http://3.bp.blogspot.com/-yWcV2pnwsqg/TdeFdN5v_RI/AAAAAAAADV8/U2IaGY2xH10/s1600/single_neuron_BlueBrain.jpg

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At Stony Brook University, the students ask anything off the top of their heads! It’s really refreshing. I teach science, but I think they teach me more science than I teach them. What is most enjoyable about your job? The students, definitely. The students are fun because they’re always willing to ask questions. While teaching at Columbia medical school, I got a lot of, “What questions are going to be on the exam? What do I need to do to get my A?” At Stony Brook University, the students ask anything off the top of their heads! It’s really refreshing. I teach science, but I think they teach me more science than I teach them. What hobbies do you have? My very favorite thing to do [besides being with my girls] was running. I was a really serious long distance runner until I [messed] up my knee. I love sports, and I also love the cold, so winter sports are definitely huge. Otherwise, it’s art. I really enjoy sculpting. I think that if I hadn’t gone into medical research, I would have gone into architecture or some form of art. I love it because it’s actually similar to research. You look at a rock or a piece of metal and you have to see what it forms itself into. You may guide it a bit, but it evolves. I like when you see something and it finds its way out.

Despite the connotations associated with smoking, for schizophrenics, smoking can actually be beneficial.

Out of all your accomplishments, which one do you consider your greatest? I am most proud of my daughters, without question. One is a clinical psychologist and the other is finishing medical school to be a psychiatrist, so they’re [both] studying the brain! They’re really neat, but I don’t think I had much to do with that—I just watched them become awesome. In regards to science, I’d say it’s a toss-up. The one that’s been the most fun was getting the Pioneer Award because it’s a huge amount of money: half a million dollars per year for five years. It’s given to people for crazy ideas, and if there’s anything I can do, it’s have a crazy idea! I think the most surprising one was when I got the Distinguished Investigator Award from NARSAD. I had never done anything related to schizophrenia, but I was looking for regulators of the [acetylcholine] receptors that bind nicotine

in the brain, and I found that the regulator was this gene that is a major schizophrenia susceptibility gene. If you’re missing one copy of this gene, called neuregulin, it messes up some of your cholinergic receptors. The real problem that schizophrenics have is that the sensory information comes in and it’s all equally vital. Most people know to ignore certain things, but for schizophrenics, everything is important. They cannot sort between necessary and not necessary. [For example], the noise of the air conditioners would be just as important as our voices or as a flashing light going off outside. Smoking apparently helps them focus and enables them to attend to the essential rather than the nonessential information coming into their brains. So schizophrenics are basically self-medicating when they smoke! That’s how I got the award for innovative research on schizophrenia. It was a real surprise. I never expected a gene that regulated nicotinic receptors would have anything to do with schizophrenia. I remember thinking, “Really? This isn’t even what I was researching!” That’s why you have to keep an open mind. It’s the stuff you don’t expect. The stuff that makes you go, “What? I don’t get that.” That’s the cool stuff. How would you advise a student who also wanted to go into neurobiological research? First, I’d tell them to read everything that they could get their hands on and see what parts of it they gravitate towards. And then I would tell them to find a doctor, lab, or hospital job and immerse themselves in it. Remember, there are a million different ways you could be a neuroscientist. Find out what people you want to be interacting with. You have to find your niche, and then you won’t mind working hard. You want to find where you love it because work really has to be something you love. I got that advice from my dad; he was right with that one. If you had the world’s undivided attention for ten minutes, what would you say? I would make a pitch for people to give science a chance. People think that science is for geeks, but it’s really not. I would really love to talk to people who don’t do science and help them see how much fun it is, how varied it is, and how creative it is. I would try to convey that science is a part of their lives and that they can enrich so much of their life by understanding it and not pushing it aside. It’s hard to communicate the beauty of science to people. Sometimes, there’s this wall and I think it’s partially the fault of the people who do science. We don’t make enough of an effort to convey how fun and interesting it is and the ways in which it relates to everybody. It isn’t just about knowing stuff, but understanding your own self and how you work. And it can be about anything, like why people smoke, why it’s so fun to go dancing, or even why Jello congeals. It can be literally anything! References 1. Role, Lorna. Personal interview. 30 Jan 2014. 2. Thies W., Blieler L., Alzheimer’s Association. 2013. 2013 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2(9):208-245.

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By Kelsie Cassell ’15 Each year, about two thousand Stony Brook University students enroll in the Introductory Biology labs, BIO 204, 205, and 207. The students in these courses have the opportunity to practice valuable biological lab techniques central to research, such as transformations, PCR, pipetting, and centrifugation. The director and designer of these courses is Dr. Marvin H. O’Neal III. Dr. O’Neal was raised in a small South Carolina town where he spent his time learning to fly and sail, but most of all, wanting to know how things worked. This interest led him to apply and be accepted into Georgia Tech’s Mechanical Engineering program. However, despite his strong interest in math and engineering, he soon discovered his passion for biology. Dr. O’Neal went on to obtain a Bachelor of Science degree in Biology from Wofford College, and a Master’s degree in Basic Health Sciences and doctoral degree in Physiology from Stony Brook University. During this time at Stony Brook, he studied the central control of breathing in Dr. Irene Solomon’s lab, and it was also during this time when his research was featured on the cover of Journal of Neurophysiology. Upon discovering his passion for teaching, Dr. O’Neal became the course director of Undergraduate Biology Labs in 2007, a role that he now fully embraces. His primary focus has shifted from conducting experiments to directing and improving introductory biology education, and he strives to find the most effective ways of educating undergraduate students. 3-D printing, which is currently being used in the second semester of undergraduate biology course sequence, BIO 207, is among the novel and creative teaching methods that Dr. O’Neal has introduced. Between overseeing the undergraduate biology instruction of two thousand SBU students and conducting his independent research, Dr. O’Neal managed to find time to talk to the Young Investigators Review, where he conveyed his passion for learning, his belief in the value of persistence, and his eagerness to engage students in gaining a deeper, fundamental understanding of biology. Did you enter college knowing that you wanted to study in biology? No, [I did not]. I knew I loved building things, designing things, and figuring out how things work. It’s what initially attracted me to engineering. But I went into engineering [without] really knowing that there was a Ph.D. that studied how living systems worked. I had no idea what a research scientist did on a daily basis. I came from a small town in South Carolina, and I thought Ph.D.’s wrote books and read. I didn’t know that you could have a laboratory where you investigated, pulled things apart, and put them back together. It wasn’t until my senior year of college, [when I seriously considered biology research], and it’s actually a funny story. I applied for a research position in [a professor’s] laboratory and he denied my application—but I showed up anyway. He [told me], “You know, you were not accepted, you can’t be here,” and I said, “I’ll just stand over in the corner. I won’t cost you any money. I just need to know what research is like.” [Then], he was like, “Okay, fine, stay.” So I watched for

Revolutionizing Introductory Biology: an Interview with Dr. Marvin O’Neal

a couple weeks until one of the students quit. And when that student quit, I stepped in their place. What did their research entail? [The research was about] glutamatergic neurotransmission in fish. It was the first time that I enjoyed biology. I was never good at taxonomy or labeling or naming things. I always enjoyed the application biology courses, like physiology, and when I took physiology I thought, “This is it. This is the ‘engineer’s biology.’” What kind of research did you get involved in when you first came to Stony Brook? At Stony Brook, I came in and knew what lab I wanted to work in. That was one of the reasons why I came here. I was accepted into Dr. Solomon’s lab, and I really enjoyed the research. She was studying the central control of breathing, and I liked the combination of neurophysiology, respiratory physiology and sympathetic control. What awards did you earn either here at Stony Brook or outside the school? One of the first awards that I received [when I was young] was a Duke Scholars award. It allowed seventh and eighth grade students [from] South Carolina to engage in academic activities at the University of South Carolina and Duke University. When Duke University, a North Carolina university, recognized a student in South Carolina, I realized for the first time that I [could] probably do well if I just focused in school. More recently, I think that the award that I am most proud of is [being named a] National Academy of Sciences Fellow. This award introduced me to about 300 educators in

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the United States who are all thinking like I am and are doing [the same things] at their institutions that I am doing here. That group has really pushed me to learn more, [and has] not allowed me to settle. How did you switch from research at Stony Brook to education? By TAing. Every Ph.D. student is required to do three things, and you have to do all three well: You have to take classes, teach, and do research. I really enjoyed teaching, and I wanted to do it more and more until finally my committee said, “Stop! If you keep doing this, you’re not going to finish your research.” So I had to take a year off from my teaching, focus entirely on my research, and finish my Ph.D. [After that], the first opportunity I had to teach, I took it. The Department of Pharmacology wanted me to teach the 400-level Pharmacology labs and I said “Absolutely.” So I taught Pharmacology labs for 3 years, [from] 2003-2006. [During] the spring semester that I received my Ph.D., I started this job and finished my dissertation. It was a stressful time.

Your previous research was in neurophysiology and respiratory rates. Are you still pursuing research in those areas? The short answer is yes. I am still interested in the question, [but] it occupies a very small amount of my time. I can’t have a large research lab and still teach 2,000 students a year. Most of my effort is in teaching and Biology Education Research (BER). This scholarly pursuit occupies the vast majority of my time. However, I still enjoy going into the lab. I do it one night a week. I get away from everything else that’s on my plate and go into the lab to run some experiments. Can you tell me more about your Biology Education Research? The intro biology labs that I took as an undergraduate caused me to run screaming, [so] I wanted to do something different with these labs, something that balanced lab work and gave insight into research and science. I didn’t want students to just come in and be told what to do. I want them to design an experiment that they wanted to run.

Dr. O’Neal is the course director of BIO 204, 205, and 207, which are taught at the Center of Molecular Medicine/Biology Laboratories.

http://www.stonybrook.edu/commcms/biology/images/new%20cmmbll%20photo%20042211%20JPG.jpg


We implemented the change in how labs are taught in 2007. We didn’t really know what was going to work at the start, and we’re just now getting to the point where we’re finding things that work well for the students, based on our assessment data. In the next five years, we’ll probably have five to ten publications. We’re right at the cusp where we’re understanding what works and what doesn’t for a student at Stony Brook. Students who take the undergraduate introductory biology lab sequence have the opportunity to participate in surveys throughout the semester. Do these student surveys contribute to the research here at the University? Every survey that a student takes is analyzed either by me, faculty [at SBU], or by a national group. So they are nationally recognized surveys that students take that allow me to figure out how Stony Brook students [compare] to the rest of the students [in the U.S.]. It allows me to respond to [our] students’ needs, and I [also] try to give some points in class to thank them for their time. Stony Brook University was one of the first universities to have access to 3-D printing and rapid prototyping. What first made you try to get a 3-D printer for the undergraduate biology labs? You’re not going to believe this. I was at an experimental biology meeting in 2007 presenting my work, and there was a place for venders there. As I was wandering around, I saw someone who had protein models. [At that point], I was about to take the position in Undergraduate Biology labs, and I [thought], “Wouldn’t it be cool if I could use these models to teach students?” His name was Tim Herman from the Milwaukee School of Engineering, and he told me about rapid prototyping and 3-D printing. I started collaborating with [him, and] I actually still work with [him]. Then I thought, “Well, what if the students had a printer here? They could design their own models and maybe they could learn even more.” [So] the next step was to put a printer in a lab and ask students to design a model to understand, and to use it to explain their work. I think we can say it does help students gain a deeper understanding of their subject in biology. Do you have any other interests that are not science related that you feel influence how you approach research? I sang in my college glee club, [which was actually] before glee club was popular. [So] I enjoy singing. I’m a private pilot, [and] I love to fly planes. I’m [also] a blue-water sailor, and I love to take a boat out for a few weeks and sail in the Caribbean. I can say that flying and sailing aided in my understanding of research. When flying, you have a checklist and it’s a huge demand on your ability to stay focused and make judgments. There’s always math, you’re always calculating your fuel, descent, [and distance to the] nearest airport. The rigor of thought and rules, [and the fact that] you have to read before you do it—it’s the same with research. The same [applies to] sailing, [since] the weather is constantly shifting. I love risks, and I love doing things no one else is doing. Failure doesn’t bother me. Failure is liberating. It’s from those

mistakes you learn. I remember one afternoon I was flying and I was going for my exam in a couple weeks and practicing figure eights and slow flight. I was focused entirely on what I was doing, and when I looked over, I saw that there was an A10 air force jet right next to me! I was so focused on my maneuvers that I didn’t realize I had drifted over Shaw Air Force Base. You get focused on something and you forget what you’re supposed to be looking at. Science is like that too—you can get too focused and need to take a step back. Do you have any recommendations to students at Stony Brook regarding their classes or research? Share your passion. There are a lot of students that I see who don’t utilize personal, human contact as much as they could. We’re all humans—even professors. If you want to work with someone, go meet them. Don’t be rude, but go introduce yourself. Every opportunity that I have received in my life has been from someone that I knew, who knew me or knew of my work, and that opened the door. Experience college, network and meet people. Don’t pigeon-hole yourself with classes. If you’re curious about something, college is the time to experiment and take a risk. References O’Neal, Marvin. Personal Interview. 3 Feb 2014.

A protein model printed with a 3-D printer similar to the one used in the Biology Laboratories.


Harnessing the Power of Piezoelectricity By Plinio Guzman â&#x20AC;&#x2122;15 and Ya Wang, Ph.D. The search for clean alternative energy sources has made its way into the spotlight of the scientific community largely due to the rising costs of power production, the creeping exhaustion of non-renewable energy sources, and the negative toll on global climate associated with it [1]. This looming energy crisis has forced the energy industry to shift its focus from developing means of exploiting natural resources to finding new methods of generating energy in ways that are sustainable and harmless to the environment. The use of ambient vibrations to harvest energy has gained noteworthy attention in the field of energy engineering in the past decades. Beginning in the late 1990s, researchers from the disciplines of mechanics, materials science, and electrical circuitry have been investigating the phenomenon of piezoelectricity to develop new ways to harness energy that is input into the environment as a byproduct of natural and human activity [2, 3]. This promising method aims to scavenge mechanical energy that would otherwise be dissipated into the environment and convert it into useful electric power. What is Piezoelectricity? Piezoelectricity means â&#x20AC;&#x153;pressure induced electricity.â&#x20AC;? The roots of the word come from the Greek word piezo or piezin, which means to press or forcibly squeeze, and the

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word electric or electron, which come from the Greek word for amber, an ancient source of electric charge [4]. Piezoelectricity was first studied in 1880 by French physicist brothers Pierre and Jaques Curie, but only drew the attention of the scientific community after World War I, during which Paul Langevin used piezoelectric transducers to develop sonar, an ultrasonic submarine detector. This technology later evolved into the popular echolocation devices used in modern cars to help the driver determine the distance between the vehicle and adjacent objects. Its success in the war led to a sudden interest to develop synthetic piezoelectric materials, which have now made their way into everyday lives [1]. Piezoelectricity from an Atomic Standpoint Piezoelectric materials are either natural or synthetic crystal structures that lack a center of symmetry. In a piezoelectric crystal, atoms are arranged in a crystalline array, which locks in a new, asymmetric pattern when under mechanical stress. This causes the disassociation of the centers of positive and negative charges, which results in the generation of dipoles within the structure. When these dipoles are aligned (which is sought when manufacturing synthetic piezoelectrics), an electric polarization occurs within, resulting in the appearance of an electric potential due to accumulating electric charge on its surface. When paired with the appropriate electric conditioning circuit, this can be used to generate electric power [5].


the surface creates an alternating voltage that can be rectified through an AC-DC converter and stored in a small battery or capacitor, ultimately serving as an energy generating device [10].

Figure 3 Piezoelectric film generates electricity as it is made to oscillate [11]. Figure 1 Piezoelectric crystal structures generate an electrical potential when and under mechanical stress [6].

It is important to note that the piezoelectric effect is a reversible interaction between the mechanical and electrical state of these materials, so a reversed effect also exists. A mechanical deformation of a piezomaterial can be achieved through the application of an electric field. Mechanical actuators, such as the ones found in audio speakers, exploit this phenomenon to convert electrical into mechanical power [7]. Manufacturing Piezoelectric Material Natural piezoelectric crystals, such as quartz and tourmaline, are limited in terms of the power they can produce (due in part to the nonalignment of their dipoles), but synthetic crystals that work at higher power ranges can be created out of polycrystalline ferroelectric ceramic materials [8]. The most common of these synthetic crystals are electro-active PZT ceramics, which were developed at the Tokyo Institute of Technology in the 1950s. Their name comes from their chemical composition; they are created by binding a finely powdered mixture of Lead (Pb), Zirconium (Zr), and Titanium (Ti), and heating them at specific times and temperatures in order to give them specified characteristics. PZT and other piezoceramics can be arranged into multilayer structures, which are known as multilayer piezoelectric stacks. The layer structure and composition of a stack determines its electrical and mechanical behavior. For example, thicker layers give a stack a higher voltage capacity compared to a similar stack of the same size with thinner layers.

Figure 2 Piezoelectric stacks can be given customized mechanical and electrical properties [9].

In addition to being able to give piezoelectric ceramics a wide array of electrical and mechanical properties, the capability to manufacture them in varied shapes and sizes gives engineers vast possibilities when designing energy harvesting devices. Another common design involves placing flexible piezoceramic film along surfaces. The dynamic strain on the piezoceramic layers that occurs due to the vibratory motion of

Self-Charging Structures The concept of applying flexible piezoelectric ceramics to surfaces can be used to create self-charging structures when coupled to thin-film battery layers [12]. These multifunctional structures have the potential to replace existing structures used in load-bearing applications, as they are able to generate electrical energy from dynamic loads and store it within themselves. A proposed use of self-charging structures is to embed them in wing spars of unmanned aerial vehicles (UAVâ&#x20AC;&#x2122;s), where they can be used to power small onboard electronic components. This reduces the dependence on batteries and lowers the overall weight, improving the flight capabilities of the UAV [13].

Figure 4 Self-charging wing spars [14].

Unmanned air vehicle uses self-charging wing spars to power onboard commands.


While piezoelectric technologies may not cure society’s dependence on fossil fuels in the foreseeable future... the possibilities of piezolectricity that can be brought about are only inhibited by our imagination.

Medical Applications The capability of piezoelectrics to generate electricity stands out in applications where a conventional power source has difficulties reaching an electronic device. The medical field has begun to adapt this technology into their devices, the most famous of these being pacemaker batteries [15]. More often than not, patients that require the use of pacemakers must submit themselves to recurring battery replacement surgeries once the power of the battery runs out. Heart surgery is an expensive and risky procedure which poses difficulties to patients and their families, but researchers are attempting to circumvent this by pushing the envelope with piezoelectric technology. By implanting nanoribbon piezoelectric elements on the heart or nearby organs, scientists hope to use the energy from the organ’s natural motion to recharge the battery of pacemakers and other implantable medical devices. Clinical trials of these devices have not been carried out yet, but the technology looks promising and may be in the market within the next decade [16].

Figure 5 The piezoelectricity powered pacemaker recharges its battery directly from the motion of the heart [16].

Energy from Roads One of the most remarkable aspects of this technology is its wide range of application. Energy companies have developed piezoelectric roadway systems, which scavenge energy from vibrations that vehicles generate on the pavement on which they travel [17]. These systems, which are embedded under a layer of asphalt or concrete, are able to provide electricity to remote sites along the highway, that would otherwise be ineffectively powered from a remote grid. Besides energy production, they can also act as sensors that provide statistical data to road authorities, such as velocities of individual vehicles and traffic densities at different times of the day.

Figure 6 Piezoelectric roadway systems harness energy from vehicular motion [18].

Future of piezoelectricity The capabilities of piezoelectrics have yet to equal that of other power generating techniques, such as solar panels and wind turbines. However, their low cost and weight, size

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versatility, and ability to operate in isolated environments enable them to be implemented in ways that no other technology has before. By minimizing the power requirements of small electronic components and maximizing the power output of piezoelectric devices, engineers are able to use this technology to create independent, localized power sources, reducing the need for batteries and reducing power required from the grid. While piezoelectric technologies may not cure society’s dependence on fossil fuels in the foreseeable future, they are a step towards reducing the global carbon footprint and making more sustainable cities in the future. It will take many creative approaches from innovative minds to implement piezoelectric energy methods into our society. The possibilities of piezoelectricity that can be brought about are only inhibited by our imagination. References 1. Anton, S.R. and Sodano, H.A. 2007. A Review of Power Harvesting Using Piezoelectric Materials (2003–2006). Smart Materials and Structures. 16:R1-R21. 2. Bilgen, O., Wang, Y., and Inman, D. J. 2011 Electromechanical comparison of cantilevered beams with multifunctional piezoceramic devices. Mechanical Systems and Signal Processing. 27:763-777. 3. Wang, Y., and Inman, D.J. 2013. Simultaneous Energy Harvesting and Gust Alleviation for a Multifunctional Wing Spar Using Reduced Energy Control via Piezoceramics. Journal of Composite Materials. 47 (1):125-146. 4. Harper, Douglas. “Piezoelectric.” Online Etymology Dictionary. 5. Lee, A.J., Wang, Y., Inman, D. J. 2014 Energy Harvesting of Piezoelectric Stack Actuator from a Shock Event. Journal of Vibration and Acoustics (In Press). 6. Katzir, S. 2012. Who knew piezoelectricity? Rutherford and Langevin on submarine detection and the invention of sonar. Notes Rec. R. Soc. 66 (2): 141–157. 7. Gautschi, G. 2002. Piezoelectric Sensorics: Force, Strain, Pressure, Acceleration and Acoustic Emission Sensors, Materials and Amplifiers. Springer. 8. Trolier-McKinstry, S. 2008. Chapter 3: Crystal Chemistry of Piezoelectric Materials. In A. Safari, E.K. Akdo˘gan. Piezoelectric and Acoustic Materials for Transducer Applications. New York: Springer. 9. Noliac. Plate Stacks. 2014. <http://www.noliac.com/Plate_stacks-59.asp&xgt>. 10. Erturk, A., and Inman, D. J. 2008. On Mechanical Modeling of Cantilevered Piezoelectric Vibration Energy Harvesters,” J. Intell. Mater. Syst. Struct. 19(11):1311–1325. 11. Sonitron Support. Piezo bending principle. 2011. <http://en.wikipedia.org/w/ index.php?title=Piezoelectricity&oldid=602082549>. 12. Thomas, J.P. and Qidwai, M.A. 2005. The design and application of multifunctional structure-battery materials systems. Journal of Minerals, Metals and Materials Society. 57:18–24. 13. Wang, Y. and Inman, D.J. 2013. Experimental Validation for a Multifunctional Wing Spar Design with Sensing, Harvesting and Gust Alleviation Capabilities. IEEE/ASME Transaction on Mechatronics. 18(4)1289-1299. 14. Inman, Daniel J. Piezoelectric Energy Harvesting. 2011. 1st ed. Southern Gate, Chichester, West Sussex, United Kingdom: John Wiley & Sons. 15. M. A. Karami and D. J. Inman. Powering pacemakers from heartbeat vibrations using linear and nonlinear energy harvesters. Appl. Phys. Lett. 100 (4): 042901–042904 16. Lee, Kevin. New Nanoribbon Implant Powers Pacemakers With Heartbeats. 2014. <http://inhabitat.com/wild-new-nanoribbon-implant-uses-heartbeats-topower-pacemakers>. 17. Garland, Rex. Piezoelectric Roads in California. 2013. <http://large.stanford. edu/courses/2012/ph240/garland1>. 18. Kloosterman, K. Innowattech Proves It Can Collect Energy From Highways and Byways. 2009. <http://www.greenprophet.com/2009/10/innowattechisrael-road-energy>.


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The Secret to Happily Ever After: an Overview of Romantic Relationship Success Factors

By Brian Chin ’15 Romantic relationships and the quest for love are among the most ubiquitous and impactful influences on contemporary life around the world [1,2]. A litany of recent studies have demonstrated the ostensible health benefits of being involved in a satisfying, loving relationship [3,4], as well as the possible detriments to health if involved in a lowquality relationship [5,6]. Given the dichotomous effects on health caused by relationship quality, research in the field has shifted its focus away from relationship formation and toward identification of three types of factors that make an existing relationship successful and satisfying: individual, interactive, and external. Introduction Romantic relationship research traces its origins back to the 1960s, when Ellen Berscheid and Elaine Hatfield pioneered its introduction to the psychological field [7]. In contrast with the preceding decades in which the research focused on relationship description, the field began to spawn a litany of theories and models of relationship over the next half century. However, the newly flourishing field would soon find itself at a point of contention over a key idea that would influence the research agenda going forward: Was romantic love characterized by intensity, engagement, and sexual interest, and its positive effects sustainable, or were relationships doomed to decay and dull over time? The earliest attempts at investigation provided conflicting results. One school of thought posited that it was necessary for romantic love to fade in order for a relation-

If romantic love was proven to be sustainable, then perhaps focus could turn away from strictly seeking to prevent negative relationships, and towards an attempt to identify factors that mediate success.

ship to succeed [8]. However, others argued that romantic love was sustainable and beneficial as long as its early obsessive component disappeared with time [9,10]. In other words, as long as the early constant preoccupation with a new significant other has disappeared, love could survive, unobtrusive to other pursuits. A definitive resolution to this conflict would create significant ramifications for both the research field and actual relationships. Amid popular press coverage of the downsides of love, such as high divorce rates, adultery, and abusive relationships, it is no wonder that researchers, counseling professionals, and laypeople alike possess mediocre expectations for romantic relationships [11]. However, if romantic love was proven to be sustainable, then perhaps focus could turn away from strictly seeking to prevent negative relationships, and towards an attempt to identify factors that mediate success. Recently, Stony Brook University’s Bianca Acevedo and Arthur Aron sought to address this issue conclusively. In a comprehensive analysis of long-term relationships, Acevedo and Aron demonstrated that not only was romantic love sustainable in a long-term relationship, but it was also closely associated with marital satisfaction, individual wellbeing, and self-esteem [11]. The paper’s most significant impact was its role in catalyzing the sweeping paradigm shift occurring in the field. Mediocre relationships no longer needed to be characterized as the norm for those involved in them or for those who studied them. Follow-up cross-cultural and psychophysiological research stemming from Acevedo & Aron’s study convincingly agreed that long lasting romantic love is indeed possible [11,12,13]. As a result, the research agenda has begun to demonstrate an interest in identifying factors that differentiate healthy and unhealthy relationships. Romantic Relationship Success Factors Individual One angle that researchers have taken is to look into the role of individual differences in relationship satisfaction. Generally speaking, psychologically healthy traits appear to bode well for relationships. High individual self-esteem is positively correlated with romantic love and negatively correlated with relationship obsessiveness [14]. Similarly, those with a secure attachment style, as reflected by interdependence, trust, commitment, and satisfaction, also tend to report higher levels of self-esteem and endorse feeling mutual support and development within a relationship [15]. Conversely, it appears that negative individual characteristics can also have deleterious effects on a romantic connection. For example, sensitivity to rejection has been noted to lead to greater emotional reactivity, increased hostility, and subsequently, higher rates of abandonment in a relationship [16].

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Interactive On the surface, it seems logical to conclude that there is a simple relationship at work, as two psychologically healthy partners may seem bound to have a successful union. However, while the role of individual differences is an important source worthy of investigation, recent research has also highlighted the importance of interactions within a couple. While intuitively one may think that one’s partner thinking exceptionally highly of them leads to both providing and receiving better treatment, it turns out that the opposite is actually true. Although prior work placed an emphasis on espousing the benefits of expressing positive regard for a significant other, it appears that too much praise can actually lead to negative outcomes [8,17]. When one partner senses that the other is over-idealizing them, they tend to be less willing to perform accommodating behaviors, or actions which help their partner without providing any personal benefit [18]. Conversely, when an individual feels underidealized by their significant other, they place an emphasis on performing “good” behaviors to compensate [19]. In other words, a partner who feels that their significant other holds them on a pedestal would be less likely to provide support during a time of need, whereas a couple who view one another in a realistic manner would be more eager to give help, even if that entailed a small personal cost. Even though feeling liked and admired by a romantic partner has a positive effect on relationship satisfaction, this only holds true if one feels that their partner genuinely understands and likes them for their true self [5,17]. The underlying mechanism at work may be the importance of feelSocial networking has often been depicted as negatively affecting relationships. However, research has shown that it is more complex than previously thought, as it is based heavily on individual factors.

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ing that a partner supports the growth of personal autonomy and a sense of identity, rather than undermining it [20]. Admiration that feels undeserved places the burden of unrealistic expectations upon an individual, causing anxiety that the absence of the praised trait will eventually be discovered [17,21]. However, cautious idealization has been shown to benefit romantic relationships by pushing both partners to achieve their goals [22]. Generally, relationships appear to benefit from healthy interactions, such as daily expressions of gratitude and spontaneous acts of kindness [23]. However, some actions that are psychologically unhealthy may be paradoxically beneficial to a romantic relationship. “Downward social comparison,” or the evaluation of one’s relationship against inferior ones, has been shown to be beneficial to relationship satisfaction by distorting the evaluation of one’s own partner to an unrealistically positive state [24]. That is, a poorly functioning couple that surrounds themselves with couples that interact in an even poorer fashion can cover up their own relationship inadequacy through comparison with their inferior counterparts. External Considering the delicate and complex effects that individual psychological health and interaction behaviors have on romantic relationships alone do not account entirely for relationship satisfaction. Externally based factors, such as social support and alcohol usage, have been noted to play a role in romantic relationship quality [6,25]. However, the advent of social networking has added another factor for relationship research to consider. Predictably, the effect of sohttp://sweetdb.files.wordpress.com/2012/12/et_facebookrelationships.jpg


cial networking on a relationship is heavily contingent upon individual based factors [26]. For example, social networking surveillance, usually categorized as negative in both layliterature and research, can actually have a positive effect, depending on the individual [26]. Conclusion Relationship research has come a long way from its origins in the work of Ellen Berscheid and Elaine Hatfield, and will no doubt continue to progress in the coming decades as well. More likely than not, the interaction between these three types of factors is ultimately what determines relationship satisfaction. However, in a study of normative versus distress marriages, romantic love, characterized by a deep emotional bond, mutual caring, attraction, trust, and closeness, was shown to be the biggest difference maker in determining satisfaction [27]. This backs up earlier research, and shows that there really is no substitute for true love [28]. Going forward, research needs to expand the type of relationships looked at in order to compare and contrast relationships that are presently studied. Dating, engaged, non-heterosexual, interracial, cross-cultural, long-distance, and nontraditionally-aged relationships have all only recently begun to be studied, despite their ostensible differences from married couples previously under investigation [6,29,30]. Over the past 50 years, the psychology of romantic relationships has evolved from a scantly considered topic to one on the forefront of the research agenda. It is clear from the previous decades spent investigating relationship formation, and the current research focused on the individual, interactive and external factors that underlie relationship success, that the psychological field can only benefit from continuing to integrate the ideas of human relationships into the study of human behavior [7]. References 1. Dion, K.L., & Dion, K.K. 1991. Psychological individualism and romantic love. Journal of Social Behavior and Personality, 6:17–33. 2. Dion, K.K. & Dion, K.L. 1993. Individualistic and collectivist perspectives on gender and the cultural context of love and intimacy, J. Soc. Issues, 49:5369. 3. Braithwaite, S.R., Delevi, R., & Fincham, F.D. 2010. Romantic relationships and the physical and mental health of college students, Personal Relationships, 17:1-12. 4. Kim, J., & Hatfield, E. 2004. Love types and subjective well-being: A crosscultural study. Social Behavior and Personality, 32(2):173-182. 5. Uysal, A., Lin, H.L., Knee, C.R., & Bush, A. 2012. The association between self-concealment from one’s partner and relationship well-being. Personality and Social Psychology Bulletin, 38:39-51. 6. Hall, J., Fals-Stewart, W., Fincham, F. 2008. Risky sexual behavior among married alcoholic men. Journal of Family Psychology, 22:287-292. 7. Reis, H.T., Aron, A.P., Clark, M.S., & Finkel, E.J. 2013. Ellen Berscheid, Elaine Hatfield, and the emergence of relationship science. Perspectives on Psychological Science, 8:558-572. 8. Fisher, H.E. 2006. The drive to love. In R. Sternberg & K. Weis (Eds.), The new psychology of love (pp. 87–115). New Haven: Yale University Press. 9. Tucker, P., & Aron, A. 1993. Passionate love and marital satisfaction at key transition points in the family cycle. Journal of Social and Clinical Psychology, 12:135–147. 10. Hatfield, E., Traupmann, J., & Sprecher, S. 1984. Older women’s perceptions of their intimate relationships. Journal of Social and Clinical Psychology, 2:108–124. 11. Acevedo, B.P. & Aron, A. 2009. Does a Long-Term Relationship Kill Romantic Love? Review of General Psychology, 13(1):59-65. 12. Xu, X., Aron, A., Brown, L., Cao, G., Feng, T., & Weng, X. 2011. Reward and motivation systems: A brain mapping study of early-stage intense romantic love in Chinese participants. Human Brain Mapping, 32(2), 249-257 13. Acevedo, B.P., Aron, A., Fisher, H.E. & Brown, L.L. 2012. Neural correlates of long-term intense romantic love. Soc Cogn Affect Neurosci, 7(2):145-159. 14. Campbell, L., Foster, C.A., & Finkel, E.J. 2002. Does self-love lead to love for others? A story of narcissistic game playing. Journal of Personality and Social Psychology, 83:340–354.

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15. Simpson, J.A. 1990. Influence of attachment styles on romantic relationships. Journal of Personality and Social Psychology, 59(5):971-980. 16. Romero-Canyas, R., Downey, G., Berenson, K., Ayduk, O., Kang, N.J. 2010. Rejection Sensitivity and the Rejection-Hostility Link in Romantic Relationships. Journal of Personality, 78(1):119-148. 17. Tomlinson, J.M., Aron, A., Carmichael, C.L., Reis, H.T., & Holmes, J.G. 2013. The costs of being put on a pedestal: Effects of feeling overidealized. Journal of Social and Personal Relationships, Online First. doi: 10.1177/0265407513498656 18. Finkel, E.J., & Campbell, W.K. 2001. Self-control and accommodation in close relationships: An interdependence analysis. Journal of Personality and Social Psychology, 81:263-277. 19. Murray, S.L., Holmes, J.G., Aloni, M., Pinkus, R.T., Derrick, J., & Leder, S. 2009. Commitment insurance: Compensating for the autonomy costs of interdependence in close relation- ships. Journal of Personality and Social Psychology, 97:256–278. 20. Patrick, H., Knee, C.R., Canevello, A., & Lonsbary, C. 2007. The role of need fulfillment in relationship functioning and well-being: A self-determination theory perspective. Journal of Personality and Social Psychology, 92:434–457. 21. Neff, L.A., & Karney, B.R. 2005. To know you is to love you: The implications of global adoration and specific accuracy for marital relationships. Journal of Personality and Social Psychology, 88:480–497. 22. Rusbult, C.E., Finkel, E.J., & Kumashiro, M. 2009. The Michelangelo phenomenon. Current Directions in Psychological Science, 18:305–309. 23. Algoe, S.B., Gable, S.L., & Maisel, N.C. 2010. It’s the little things: Everyday gratitude as a booster shot for romantic relationships. Personal Relationships, 17:217-233. 24. Rusbult, C.E., Van Lange, P.A.M., Wildschut, T., Yovetich, N.A., & Verette, J. 2000. Perceived superiority in close relationships: Why it exists and persists. Journal of Personality and Social Psychology, 79:521–545. 25. Newcomb, M.D., & Bentler, P.M. 1988. Impact of adolescent drug use and social support on problems of young adults: A longitudinal study. Journal of Abnormal Psychology, 97(1):64-75. 26. Utz, S., & Beukeboom, C.J. 2011. The role of social network sites in romantic relationships: Effects on jealousy and relationship happiness. Journal of Computer-Mediated Communication, 16:511-527. 27. Riehl-Emde, A., Thomas, V., & Willi, J. 2003. Love: An important dimension in marital research and therapy. Family Process, 42:253–267. 28. Aron, A., & Henkemeyer, L. 1995. Marital satisfaction and passionate love. Journal of Social and Personal Relationships, 12, 139–146. 29. Ball, M., & Hayes, S. 2010. Same-sex intimate partner violence: Exploring the parameters. In B. Scherer (Ed.), Queering paradigms. Oxford: Peter Lang. 30. Finkel, E.J., Eastwick, P.W., Karney, B.R., Reis, H.T., & Sprecher, S. 2012. Online dating: A critical analysis from the perspective of psychological science. Psychological Science in the Public Interest, 13:3-66.

Research shows the level of care, love, and trust in a relationship can determine its success.

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Peptides as a Novel Approach for Tumor Targeting http://mon-pharmacien.com/wp-content/uploads/2011/05/metastasizing_cancer-1864x1568.jpg http://mon-pharmacien.com/wp-content/uploads/2011/05/metastasizing_cancer-1864x1568.jpg

By Sonali Bahl â&#x20AC;&#x2122;15 What makes cancer so difficult to treat? Treatments must be researched, developed, and modified because some cancer cells are multidrug resistant, and drugs on the market are proving to be ineffective [1]. Research is being performed to develop an ideal treatment that overcomes resistance and is specific to tumor cells [2]. At present, a large drug dose cannot be used against the tumor lest normal cells be destroyed as well [3]. The purpose of the latest research is to find the most efficient method by which a higher concentration from the given dose of drug can be delivered to the tumor without collateral damage [4]. Targeting Receptors on Tumor Cells Key factors differentiate tumor tissue from normal tissue and can thus be manipulated. A tumor can grow and metastasize because of the conditions of its microenvironment. Blood vessels develop in the tumor to ensure that the cells survive hypoxia, a condition in which the tumor has minimal access to oxygen [1]. These blood vessels then support tumor growth, serving as a pathway for nutrients to reach the corresponding receptors on the tumor cells. Consequently, there is a higher expression of certain receptors, such as growth factor receptors, on cancer cells [4]. The receptors can be used as molecular markers for targeting and delivering the drug to either tumor cells or tumor vessels [5].

Figure 1 An example of a drug conjugate. The LHRH peptide and CPT, the cytotoxic drug, are connected by the PEG carrier molecule, a linker [2].

Research suggests that anti-cancer drugs are most effective when they enter the tumor [3], and one method that is used to penetrate the tumor is through the use of an endosome that contains a specific CendR peptide. Drug release can then occur when the endosome fuses with the plasma membrane [5]. While drugs can theoretically treat tumors alone, the drug is more likely to reach the tumor when a tumor-targeting group is employed [2]. The produced molecule, a drug conjugate, consists of the cytotoxic drug connected by a linker to a moiety (Figure 1). This moiety, which targets specific receptors, is often a peptide.

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Using Peptides to Target Receptors Peptides are one set of molecules involved in binding to receptors on tumor cells. Peptides are useful for targeting cancer cells and the endothelial cells that form the tumor vasculature. They are favored for their high stability during delivery and high affinity to the target receptors. Their low molecular weight also allows them to successfully enter the tumor tissue [4]. Besides being conjugated to a cytotoxic drug, the tumor-homing, or tumortargeting, peptide can also be conjugated to an imaging molecule to study the tumor in vivo [4]. Peptide targeting is important in cases in which the expression of Hsp27, a heat shock protein, is upregulated by tumor cells. Under such conditions, chemotherapy and radiotherapy are ineffective. The increased expression of Hsp27 counters apoptosis and allows tumors to continue to grow and metastasize. If Hsp27 expression is silenced, however, proliferation will continue but metastasis will not occur [7]. The process of targeting and internalizing the ligand-receptor complex (the ligand, in this case, being the peptide) allows for the desired effect of drug accumulation within the tumor since the drug is connected to the peptide [8]. Following accumulation, tumor cells can die by apoptosis [9]. Agonists and Antagonists A significant area of research regarding peptide tumortargeting is concerned with the types and efficiency of different peptides. Peptides can be characterized as agonists and antagonists. Agonists are radiolabeled for imaging and used primarily for the diagnosis and therapy of cancer. Agonists have been used commonly in research since they are known to be internalized by tumor cells following specific binding [8]. Their affinity depends on the extent to which coupling occurs between corticotropin-releasing factor (CRF) receptors and G proteins [10]. Antagonists, however, may be more effective than agonists because they are more stable in cellular environments, and they are radiolabeled. Though they bind to tumor cells, antagonists are different from agonists in that they are not internalized [8]. By using antagonists, cells have more binding sites, and unlike agonists, antagonistsâ&#x20AC;&#x2122; affinity to cell receptors is not dependent on coupling between CRF receptors and G proteins. In other words, antagonists will recognize uncoupled receptors [10]. This, in conjunction with the fact that they bind to a diverse set of receptors, increases the likelihood of binding to receptors on tumor cells. Once they reach the cells, the radiolabel of the antagonists accumulates for a longer period of time than for the agonists so that they can be better tracked during the study [8].


Somatostatin (sst) is one such protein that has been under study. Sst receptor antagonists have been proven to be more effective than agonists for tumors expressing certain sst receptors [8]. When the highly-expressed sst receptors on cancer cells were targeted by the antagonists, the growth hormone somatotropin was inhibited and the cancer cells did not receive the protein that allows them to proliferate for survival. The study of sst receptors indicated a viable route by which cancer cells could be targeted for drug delivery [6]. iRGD, a Tumor Penetrating Peptide Once peptides bind to cell receptors, the next step is to enter the tumor. Tumor penetrating peptides are vehicles for drugs to enter and accumulate [5]. â&#x20AC;&#x201A; iRGD is one tumor penetrating peptide that has been studied extensively [3]. The peptide has several components that define its function. The RGD (arginylglycylaspartic acid) motif recognizes integrin, a protein on the tumor cell surface, and allows binding. Another motif is defined for the C-end Rule (CendR) effect by which the drug is taken up by the tumor cell, a process known as endocytosis. In addition, one site on iRGD binds to a protease, a type of enzyme, which works to expose and prepare the CendR motif [5]. Drugs have various ways of entering tumor cells. Conjugation is a method that involves the attachment of the drug to the tumor penetrating peptide. Several issues arise, however. Conjugation requires a proper molecular design and reduces drug activity when the peptide and drug are coupled [3]. Moreover, since the number of cell receptors is limited, a sufficient amount of drug cannot reach the tumor [5]. One method under analysis for rectifying such issues is the separate administration of the iRGD peptide and cancer drug [3]. The CendR effect is defined by bulk transport: once the peptide is bound to the receptor, the drug is taken in by the tumor in large quantities, even if it is not attached to the peptide. Other targeting molecules, in comparison to the iRGD peptide are not as effective [5]. Conjugate Entry Mechanisms Diffusion Molecular Retention (DMR) Tumor Targeting Tumor targeting mechanisms must be tracked closely to ensure that they successfully deliver the drug to the tumor. In effective mechanisms, low doses of the drug are needed for minimal toxicity. The DMR tumor targeting mechanism is designed to overcome the delivery barriers that exist between vascular areas, or blood vessels, and the tumor itself. Its efficiency is measured by tumor surface fluorescence [11]. The DMR tumor targeting mechanism is effective under specific conditions. The RGD probe, a peptide, contains fluorochrome to observe diffusion. Polyethylene glycol (PEG)fluorochrome shielding prevents non-specific binding, which can be caused by the fluorochrome. The RGD probe should theoretically only bind to the integrin on the tumor cell. The probe must move slowly in vivo since PEG is both bulky and hydrophilic. As the probe moves from the interstitial space to the vascular areas, sufficient diffusion can occur [11]. The DMR method requires several steps from when the conjugate is first administered to when it reaches the tumor. The probe is inserted into the body by a peritumoral (PT) injection, which is preferred over an IV injection for specific

Peptides are useful for targeting cancer cells and the endothelial cells that form the tumor vasculature...they are favored for their high stability during delivery and high affinity to the target receptors. Their low molecular weight also allows them to successfully enter the tumor tissue. targeting (Figure 2). The probe diffuses within the tissue interstitium and is retained in the tumor where integrin, the molecular target, exists on the cell surface.

Figure 2 Note the â&#x20AC;&#x153;Probe:Target Complex,â&#x20AC;? in which the probe is the peptide and the target is the receptor on the tumor cell. With IV molecular targeting, the drug enters normal tissue in addition to tumor tissue. DMR targeting is more specific to the tumor tissue [11].

EPR Effect vs. CendR Penetration Effect The molecular interactions in the tumor microenvironment can result in the enhanced permeability and retention (EPR) and CendR penetration effects. EPR is a passive targeting method [2]. The extent of EPR depends on tumor-specific characteristics [5]. Tumor capillaries are permeable such that the designed drugs can pass through and reach the tumor tissue by EPR. Since lymphatic drainage is inadequate, the drug molecule is not able to be removed from the tumor site. Consequently, the drug is retained to accumulate [12]. In the CendR penetration effect, the drug is linked to a tumor-homing peptide, such as iRGD (Figure 3). The effect is receptor-mediated, and thus is more effective and has quicker results when compared to EPR [3]. The tumor targeting process is also more active and produces better results for apoptosis [2].

Figure 3 The process by which tumor penetrating peptides undergo the CendR penetration effect [5].

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http://milkgenomics.org/wp-content/uploads/2013/08/bigstock-antibodies-attaking-a-virus-1676932.jpg

A cancer cell is being recognized by monoclonal antibodies.

Using Imaging Techniques to Evaluate the Tumor Targeting Efficacy of Peptides In order to measure the progress and efficiency of the tumor targeting methods, researchers employ various imaging techniques. For example, radiography is used to view the movement of tumor cells due to metastasis [7], where radioactive labels, such as 111In, 90Y, and 177Lu, are attached to the tumor-homing peptide [8]. In addition, fluorescence imaging has also been used, where molecular imaging probes are applied for in vivo observations. In this method, greater fluorescence is observed wherever the tumor is present [14]. By fluorescence imaging, it has been shown that treatment is more effective when the tumor targeting peptide is used with the drug, proving the potential of peptides to be used as an effective cancer drug [3]. Conclusion With several treatments for cancer currently being studied, tumor conditions are a valuable tool for research. There is potential to effectively target tumor cells when their microenvironment defines and separates them from normal cells [9]. Peptides are unique for tumor-targeting in that they can be employed in the CendR pathway, a recent area of development. Further research is being performed to enhance drug delivery to tumors. As more findings result, the process will be developed to become more effective and efficient [5].

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References

1. Cheng, G.M.Y. & To, K.K.W. 2012. Adverse cell culture conditions mimicking the tumor microenvironment upregulate ABCG2 to mediate multidrug resistance and a more malignant phenotype. ISRN Oncol. 2012: 1-10. 2. Dharap, S.S., Wang, Y., Chandna, P., Khandare, J.J., Qiu, B., Gunaseelan, S., Sinko, P.J., Stein, S., Farmanfarmaian, A., Minko, T., Einhorn, L.H. 2005. Tumorspecific targeting of an anticancer drug delivery system by LHRH peptide. Proc Natl Acad Sci U S A 102(36): 12962-12967. 3. Sugahara, K.N., Teesalu, T., Karmali, P.P., Kotamraju, V.R., Agemy, L., Greenwald, D.R., Ruoslahti, E. 2010. Co-administration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328(5981): 1031-1035. 4. Li, Z.J. & Cho, C.H. 2012. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery. J Transl Med. 10(1): 1-9. 5. Teesalu, T., Sugahara, K.N., Ruoslahti, E. 2013. Tumor penetrating peptides. Front Oncol. 3: 1-18. 6. Jaracz, S., Chen, J., Kuznetsova, L.V., Ojima, I. 2005. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 13(17): 5043-5054. 7. Gibert, B., Eckel, B., Gonin, V., Goldschneider, D., Fombonne, J., Deux, B., Mehlen, P., Arrigo, A.P., ClĂŠzardin, P., Diaz-Latoud, C. 2012. Targeting heat shock protein 27 (HspB1) interferes with bone metastasis and tumour formation in vivo. Br J Cancer 107(1): 63-70. 8. Ginj, M., Zhang, H., Waser, B., Cescato, R., Wild, D., Wang, X., Erchegyi, J., Rivier, J., Mäcke, H.R., Reubi, J.C. 2006. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A 103(44): 16436-16441. 9. Laakkonen, P., Ă&#x2026;kerman, M.E., Biliran, H., Yang, M., Ferrer, F., Karpanen, T., Hoffman, R.M., Ruoslahti, E. 2004. Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells. Proc Natl Acad Sci U S A 101(25): 9381-9386. 10. Perrin, M.H., Sutton, S.W., Cervini, L.A., Rivier, J.E., Vale, W.W. 1999. Comparison of an agonist, urocortin, and an antagonist, astressin, as radioligands for characterization of corticotropin-releasing factor receptors. JPET 288(2): 729-734. 11. Guo, Y., Yuan, H., Cho, H., Kuruppu, D., Jokivarsi, K., Agarwal, A., Shah, K., Josephson, L. 2013. High efficiency diffusion molecular retention tumor targeting. PLoS ONE 8(3): 1-11. 12. Greish, K. 2007. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target. 15(7-8): 457-464.


Exploring Star Formation by Radio Astronomy Techniques with

Dr. Jin Koda

By Albany Jacobson Eckert ’16 How does a star form? As in a performance of the New York City ballet, an intricate dance emerges: from the depths of a dark, empty nebula, gas and dust swirl around each other, faster and faster until they collapse into each other. It is this collapsed mass that forms what will become a beacon of shining light for billions of year to come— a protostar. Every day, scientists like Dr. Jin Koda work with this elegant dance, relegating it into a mere two-dimensional representation of formulas and numbers on a computer screen. His research focuses on star formation in nebulas and the gases that make up galactic disks, and helps predict the mechanisms for the next star formation. Dr. Koda is currently an Assistant Professor at Stony Brook University, and has a B.A., M.S., and Ph.D. in Astronomy from the University of Tokyo. Grants awarded to Dr. Koda include the Hubble Space Telescope Grant, the National Science Foundation Grant, a NASA grant, and the Herschel Space Observatory Grant. Transition to Stony Brook University Dr. Koda was raised in Tokyo, Japan, where he “couldn’t see the stars.” Yet initially, Dr. Koda was not interested in seeing stars; when he first started studying at the University of Tokyo, he wanted to become a physicist. Later, Dr. Koda decided to shift his focus to astrophysics. As Dr. Koda explained, “I wanted to study something that showed the big picture of the universe, which astrophysics suited more than physics.” Stony Brook University appealed to Dr. Koda because the research here matched his academic interests. Dr. Koda’s

research focuses on star formation and gas dynamics. Currently, Dr. Koda is continuing the research of Dr. Phillip Solomon, who was a professor of Astronomy at Stony Brook from 1974 to 2008. Dr. Solomon revolutionized millimeterwavelength astronomy and also studied star formation via gas properties in galaxies [1]. Along with continuing Dr. Solomon’s research, Dr. Koda is also conducting research with the Stony Brook Extragalactic Group in detecting factors that affect star formation in neighboring galaxies. A Closer Look at Dr. Koda’s Research: How a Star is Born Current research has gathered a rough picture of star formation: when a molecular cloud becomes very cool and dense (around 10-20 Kelvin), it begins to collapse on itself and forms “cloud fragments,” which becomes a protostar. The protostar then emits a high-speed flow of particles, or stellar wind, and may form into a T-Tauri star, which is characterized by high stellar winds and many solar flares. Some T-Tauri stars can lose as much as half of their masses and eventually become main sequence stars (Figure 1). Main sequence stars, such as the sun, are 90% of stars in the universe [2]. Galaxies like the Milky Way have regions of gas and dust clouds that eventually form stars. Such regions are called nebulae, and the gas and dust that make up these nebulae are known as interstellar medium (ISM). Gas makes up around 99% of the ISM, with the remaining 1% being dust. Stars are made in the coolest, densest part of the ISM, known as molecular clouds. Large molecular clouds are known as Giant Molecular Clouds (GMCs) [3].

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design how to answer the question you have.” One way astronomers circumvent this problem and in Dr. Koda’s words, “design how to answer” such questions, is by utilizing radio astronomy techniques.

Figure 1 The process of star formation, which can take millions of years.

Comet Lovejoy, a long-period comet, as viewed from the International Space Station in 2001. Dr. Koda used the Subaru Telescope, one of the largest optical telescopes in the world, to track Comet Lovejoy.

Since GMCs are the birthplaces of stars, tracking the changes that take place in GMCs is crucial. Dr. Koda’s research focuses on the changing structure and composition of GMCs, and he has discovered that the environment where GMCs come from determine how they change. For example, in molecule-rich galaxies (meaning diatomic gases are prevalent), the largest GMCs break up and form smaller GMCs as they move along the spiral arms in galaxies. However, in atomrich galaxies (meaning gases composed of different atoms, like HI, are prevalent), GMCs have shorter lifetimes [4]. Knowing the background of a GMC environment can help predict where stars will be forming. Dr. Koda’s research on GMCs not only determines how stars are forming, but also where they are forming. According to Professor Koda, galaxies are like traffic. In areas of high star density, there is a “traffic jam,” which tends to occur near the center of galaxies, as in cities. It was previously thought that stars can only form in the arms of spiral galaxies, or to continue the analogy further, the “suburbs.” Recently, however, scientists have found evidence of intergalactic star formation in the “rural” areas, or in the space between galaxies [5]. What affects the rate at which stars form in GMCs? Working with a team of scientists, Dr. Koda found that as gas converges in an area in a spiral arm and combines with collisions with other molecular couds, the molecular clouds become larger and the rate of star formation increases. The gas accumulation then ultimately collapses on itself from the cloud becoming so massive [6]. Though research is revealing new discoveries about star formation, there are still questions about the factors that determine star formation. One of the most challenging parts of how to answer these questions, according to Dr. Koda, is the fact that astronomers cannot directly measure what they’re studying. “In astronomy, any measurement isn’t very precise because you cannot go [to space] and measure it. You have to

An Overview of Radio Astronomy Radio astronomy is the use of radio waves emitted from gas for detection. There are many types of radio telescopes that are specific for the size of the waves (Figure 2). For example, Dr. Koda uses millimeter-wave radio astronomy techniques in order to study GMCs. While radio astronomy uses radio waves in detecting celestial objects, optical astronomy uses only optical waves. Radio astronomy picked up momentum in the 1940s, when Jan Oort predicted that the hydrogen spectral lines, or energy levels that the electrons surrounding a hydrogen nucleus are excited to, would be useful for studying objects obscured by the dusty molecular clouds [7]. In 1951, H.I. Ewen and E.M. Purcell were the first ones to deduce the shape of the spiral Milky Way Galaxy using the spectral lines of a hydrogen atom [8]. Since then, radio astronomy has come a long way in terms of both discoveries and technological advances. One technology that both radio and optical astronomers use is telescopes. According to Dr. Koda, telescopes are 400 years old, yet they are constantly being modified, so in a sense, astronomers use both the latest technology and technology that has been developed for decades to make measurements on extrasolar bodies. While optical telescopes use eyepieces and mirrors, radio telescopes use antennae. The Combined Array for Research in Millimeter Astronomy (CARMA) that Professor Koda often uses is an example of a radio interferometer, composed of fifteen massive antennas working together to gather radio waves from distant galaxies. Each antenna retrieves its own signal and a correlator makes a composite image from the separate antennae by superimposing all the data. There are major radio and optical telescopes and observatories located all over the world. One of the largest optical telescopes is the Subaru Telescope in Hawaii. In December 2013, Dr. Koda was part of a team of researchers that tracked Comet Lovejoy using the technology at the observatory. The shift that changed the system of radio astronomy observation came in the 1960s and 1970s, when Dr. Phillip Solomon and his research team did the first survey of carbon monoxide gas emission in the Milky Way Galaxy [7]. This was a significant breakthrough because carbon monoxide emission could be utilized to detect star formation. Though hydrogen gas is the key to star formation, scientists had difficulty identifying it directly because it cannot transmit or absorb light in a http://www.fromquarkstoquasars.com/wp-content/uploads/2014/02/iss030e014350.jpg


g

way that could be picked up by telescopes. Instead, Solomon used levels of CO to extrapolate the amount of hydrogen gas present. Finding one molecule of carbon monoxide could mean that there were millions more hydrogen gas molecules in the vicinity [9], and thus, was an important advancement in detecting star formation. Today, Dr. Koda uses the techniques developed by Dr. Solomon to study gas behavior and evolution in GMCs. In his studies, he uses data from CO emission to extrapolate the locations and structures of GMCs [4].

Figure 2 There are many types of radio telescopes, which use various wavelengths of the electromagnetic spectrum [10].

Recent Advances in Radio Astronomy According to Professor Koda, the field of radio astronomy is growing quite rapidly, as there have been many groundbreaking discoveries due to its use. For instance, radio astronomy could be used to find extraterrestrial life. In 2007, researchers found evidence of radio emission of the “pre-biotic” molecules, methanimine and hydrogen cyanide, which are building blocks of amino acids found in DNA. The galaxy in which these molecules were found, Arp 220, is 250 million light years away from the Milky Way galaxy and has a relatively high rate of star formation. Since these molecules are found so far from Earth, they could be a sign pointing to the existence of life outside the solar system [12]. Research has also suggested that binary star systems may be potential hosts for extraterrestrial life, and they have thus been closely studied by the use of radio astronomy. Binary star systems are two stars orbiting around a point, which is the center of their mass. In the last few years, scientists using the Very Large Array telescope in New Mexico have discovered that binary stars form from a process called “disk fragmentation,” in which the gas and dust surrounding a protostar collapse onto themselves and form another star nearby. Their recent observations confirmed the fragmentation theory [13]. Another study by scientists working at the National Radio Astronomy Observatory has found what influences the size of a newly-formed star [14]. Smaller stars like the sun form fairly quickly in their molecular clouds, with little time to grow. Yet for some larger stars, the presence of deuterium, a heavier hydrogen isotope, can provide a force that will delay the collapse of a molecular cloud, which will result in a more massive star. Discoveries in the broader field of general astronomy have also affected our knowledge of radio astronomy techniques. One example is dark matter. Though dark matter is now known as the force that pulls galaxies apart and accounts for the faster rate of expansion in the universe [11], its importance was understated and poorly understood in the past. As Dr. Koda said, “Fifteen years ago, dark matter and dark energy had yet to be better understood. [Now], it’s a very important concept, so even the most basic textbooks have to be rewritten.”

The Future of Radio Astronomy Radio astronomy will become increasingly significant in studying the connection between galaxy collisions and star formations. When galaxies interact, the collision triggers a burst of star formation from gas, becoming dense and packed. Scientists are now observing collisions of galaxies, which may give insight to the Milky Way’s predicted collision with Andromeda in four billion years. From the Hubble Space Telescope’s images, it is theorized that the nearby Triangulum Galaxy will join the collision. Eventually, the three galaxies, which are currently spiral galaxies, will merge together to form a smooth elliptical galaxy [15]. Current observations and images of other galaxy collisions will help scientists draw conclusions about the blueprint of the upcoming three-galaxy collision. For example, the Atacama Large Millimeter/submillimeter Array telescope (ALMA), in its radio images of the Antennae Galaxies (which are two galaxies currently in collision 70 million light years away), provide a revelation about how stars form from galaxy interactions [16]. The radio images show the density of gas in the two galaxies and their relevance to star formation. As the field of radio astronomy is growing quickly, new breakthroughs will continue to further our knowledge of how stars form. Professor Koda remains optimistic that there will be new major discoveries as the field continues to advance. “Fifteen years ago, people said that galaxies formed by themselves,” Dr. Koda said. “In your lifetime, the view of the universe has changed. I’m hoping ten years from now, we can write one chapter in the textbooks about the formation process of stars in terms of gas behavior.” References

1. Scoville, Nick. 2009. Obituary: Philip Solomon, 1939-2008. Bulletin of the Astronomical Society, 41: 579. 2. Schombert, J. Star Formation. University of Oregon Department of Physics. <http://abyss.uoregon.edu/~js/ast122/lectures/lec13.html>. 3. Smith, H.E. Gene Smith’s Astronomy Tutorial: The Interstellar Medium. University of California, San Diego Center for Astrophysics & Space Sciences. <http:// casswww.ucsd.edu/archive/public/tutorial/ISM.html>. 4. Koda, J. 2013. Evolution of Giant Molecular Clouds in Nearby Galaxies. Ast Soc of the Pacific. 476: 49. 5. Donovan, J. Starbirth in Nearby Galaxies. <http://www.astro.sunysb.edu/ jdonovan/Research.html>. 6. Rebolledo, D., Wong, T., Leroy, A., Koda, J., and Donovan Meyer, J. 2012. Giant Molecular Clouds and Star Formation in the Non-Grand Design Spiral Galaxy NGC 6946. The Astrophysical Journal. Institute of Physics. 7. MIT Haystack Observatory. The History of Radio Astronomy. <http://www. haystack.edu/edu/undergrad/materials/tut4.html>. 8. National Radio Astronomy Observatory. Prediction of 21cm Line Radiation. <http://www.nrao.edu/whatisra/hist_oortvandehulst.shtml>. 9. The Interstellar Medium: Gas. <http://spiff.rit.edu/classes/phys230/lectures/ ism_gas/ism_gas.html>. 10. Cardiff University. Plank Mission. Millimeter Radioastronomy. <http:// planck.cf.ac.uk/files/gals.jpg>. 11. National Air and Space Administration. Dark Energy, Dark Matter. <http:// science.nasa.gov/astrophysics/focus-areas/what-is-dark-energy/>. 12. Salter, C.J., Ghosh, T., Catinella, B., Lebron, M., Lerner, M.S., Minchin, R., and Momjian, E. 2008. The Arecibo Arp 220 Spectral Census I: Discovery of the Pre-Biotic Molecule Methanimine and New Cm-wavelength Transitions of Other Molecules. The Astronomical Journal. 13. National Radio Astronomy Observatory. 2013. New Studies Give Strong Boost to Binary-Star Formation Theory. <https://public.nrao.edu/news/pressreleases/ new-study-boosts-binary-star-formation-theory>. 14. National Radio Astronomy Observatory. 2013. Starless cloud cores reveal why some stars are bigger than others. <https://public.nrao.edu/news/pressreleases/ starless-cores>. 15. National Air and Space Administration. NASA’s Hubble Shows Milky Way is Destined for Head-On Collision. 2012. <http://www.nasa.gov/mission_pages/ hubble/science/milky-way-collide.html>. 16. Atacama Large Millimeter/submillimeter Array. ALMA view of the Antennae Galaxies. <http://www.almaobservatory.org/en/visuals/images/the-almaobservatory/?g2_itemId=3454>. 17. Koda, Jin. Personal Interview. 30 Jan 2014.

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Optogenetics as a Therapeutic Measure for Irregular Cardiac Functionality By Zohair Saquib ’14 Lub-dub Lub-dub. That’s the sound of a healthy heartbeat. Your heart beats, on average, at least one beat per second. Every beat requires the collaboration of thousands of cells in a synchronous fashion. Twenty-four hours later, your heart has contracted about 100,000 times, pumping 2,000 gallons of blood. Looking at the big picture, for a person with an average life expectancy of 70, the heart will beat 2.5 billion times [1]. Shifting to the microscopic level, a small bundle of natural pacemaker cells at the Sinoatrial and Atrioventricular nodes act as supervisors, while the remaining cardiac cells follow the pacemaker cells (Figure 1). When this organization malfunctions, the cardiac cells contract in an asynchronous manner, unable to follow the Lub-dub rhythm. To mitigate this setback, man-made pacemakers were developed and implanted in the heart.

Irregular Heartbeat and Pacemaker Functionality The rhythm of the heart can be subject to malfunction, termed “arrhythmias,” in the medical community. Colloquial terms such as “fast heart rate” or “slow heart rate” are scientifically known as tachycardia and bradycardia, respectively. Being tachycardic and bradycardic typically is not life-threatening, but if an irregular heartbeat is prolonged, it can be a problem for the individual. The problem can often lead to heart attacks, heart failure, and in some extreme cases, death. Other examples of abnormal rhythms that are more lethal are atrial fibrillation and ventricular fibrillation. These rhythms are abnormal contractions of the atriums or the ventricles of the heart and often require a pacemaker or implanted defibrillator, which is used to shock the heart and restore normal heart contractions. Today, pacemakers are widely used all across the globe. In the United States alone, approximately 400,000 devices are implanted each year and more than three million patients live with implanted cardiac devices [3]. The pacemaker itself is a system inserted near the collarbone (Figure 2). One major part of the system is the pulse generator. This pulse generator, formed of metal, contains electric circuits and a battery. Another part of the system is the wires or leads, which connects the pacemaker to the heart. These leads allow the pacemaker to regulate cardiac contractions by shocking the heart with small bursts of electrical energy for regulatory purposes [3].

Figure 1 Depiction of the neural conducting system in the heart [2].

Through medical advancement, man-made pacemakers are becoming more user-friendly and efficient. One area of research, called optogenetics, focuses on replacing electrical energy with light energy through the insertion of lightsensitive proteins called opsins. Opsins are being studied in order to correct cardiac anomalies in a controlled and efficient manner. The employment of optogenetics to regulate cardiac function seems promising and much more beneficial to cardiac patients. By gathering scientific data from studies and the application of computer-based models in humans, researchers hope to facilitate the practical use of optogenetics for patients with cardiac abnormalities.

Despite the benefits attained from pacemaker use, there are risks involved during the implantation procedure and post-surgery...The employment of optogenetics to regulate cardiac function seems promising and much more beneficial to cardiac patients

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Figure 2 Depiction of a typical pacemaker [4].

Just like there are different types of arrhythmias, there are multiple types of pacemakers that were developed to correct the different kinds of irregular heartbeats. The procedure of inserting a pacemaker below the collarbone is called Cardiac Resynchronization Therapy (CRT). While a single chamber pacemaker has a generator that sends pulses to the right ventricle, a dual-chamber pacemaker has a generator that sends pulses to the right atrium and right ventricle to coordinate correct timing and contraction. Another kind of pacemaker is a biventricular device, which sends pulses to an atrium (either left or right) and both ventricles. Some pacemakers have additional functionality, such as acting as defibrillators. Devices


that act as pacemakers and defibrillators are called Implantable Cardioverter Defibrillators [5]. All these distinct types have one key purpose: to mitigate cardiac anomalies. Despite the benefits attained from pacemaker use, there are risks involved during the implantation procedure and post-surgery. For example, during surgery, “pneumothorax,” or lung collapse, can occur due to the buildup of air in the pleural space between the lung and the chest wall. Statistically, this problem can occur one to five times out of one hundred [6]. Other complications during surgery that can occur are heart attacks and strokes. After the surgery, complications can arise in the patients as well, such as the development of an infection at the implantation site of the pacemaker [7]. In addition, more major problems can occur with the device itself. Any kind of device problems, such as the leads breaking or moving out of place, requires another procedure for repair, and occurs one out of one hundred times [8].

Figure 3 Channelrhodopsin is a type of opsin that is gated by blue wavelength light activation and isomerization of the retinal-derived chromophore.

Optogenetic Physiology Optogenetics refers to the insertion of opsins into cells. Opsins are light-sensitive protein channels that become tiny portals within the target cells when exposed to light, permitting a flow of ions to pass through the cell membrane [9]. Specifically, there are two kinds of opsins: neuron “activators” and neuron “silencers.” Neuron “activators” are stimulated when a specific wavelength of light shines on the opsin-containing cell, resulting in positive ions entering a cell through a channel. These positive ions will depolarize the cell (meaning the cell becomes more positive) up to the threshold and generate an action potential. On the other hand, neuron “silencers” require a specific wavelength as well, but rather than positive ions, they allow negative ions to flow through the channel and enter the cell. Negative ions will hyperpolarize the cell (or will make the cell more negative), inhibiting generation of an action potential. Intuitively, these neuron “activators” and “silencers” are operating similar to on and off switches [10]. This property of opsins can lead to finetuning and further insight into neural functionality.

Optogenetics Utility and Benefits

Image of an opsin-containg neuron being stimulated by a specific wavelength of light, allowing it to serve as either a neuron “activator” or a neuron “silencer.” http://the-gist.org/wp-content/uploads/2014/01/39.-Doug-Young.jpg

Studies have been conducted to assess the practicality of optogenetics and whether the notion of regulating heartbeats with the use of opsins will come to fruition. One assay that was executed was on zebrafish. Without any kind of stimuli, the zebrafish heart contracted normally (Figure 4A). Opsins were then inserted into the heart and the investigators illuminated the entire heart with an orange light for three days post-fertilization. The orange light caused an immediate ces-

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Opsin-containing neuronal networks are being activated.

sation of the contractile heart (Figure 4B). Microscopically, the light activated the chloride pump, NpHR, which is a neural “silencer.” Thus, the light induced strong hyperpolarization and prevented depolarization and the generation of an action potential. The light was then turned off, and in the dark environment, the zebrafish heart began to contract immediately (Figure 4C). The responsiveness and lack of hesitation, in regards to the light turning on and off, illustrates the potency of the opsins [11]. The eventual goal of this research is to extend it to human patients. Currently, computer models are being utilized to provide a deeper understanding and visual aid for the implementation of this novel promising technology. The idea is to have an optrode deliver blue light to the heart using a fiber optic tip. The heart cells will have the opsins inserted along with the normal proteins present in the cell. The light energy, resulting from the shining of the blue light, will then cause the generation of an electric impulse. With numerous cardiac cells, this will result in a regulated, normal, and “healthy” heartbeat. If this proves successful, optogenetics may be used in the development of improved pacemakers and

A

B

C

Figure 4A Zebrafish heart contracting [11]. Figure 4B Zebrafish heart stopped in response to light stimulus [11]. Figure 4C Zebrafish heart contracted immediately after light is turned off [11].

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defibrillators sometime in the foreseeable future [11]. The support for the implementation of optogenetics to regulate cardiac function is derived from the benefits it can imbue for treatment. One unique property of optogenetics is its specificity. Compared to the usage of an electric field, which essentially requires shocking the entire heart muscle, optogenetics can be designed to be more cell-selective. The optical pacing can provide contactless stimulation, and with a higher degree of spatiotemporal resolution, the result is high cell selectivity [12]. Rather than using an electric field and unnecessarily stimulating cardiac cells that do not require stimulation, only specific cells will be stimulated with opsins. Other potential benefits include an extension of battery life for pacemakers, and patients experiencing lesser pain from a defibrillator shock [12]. The Director of the Computational Cardiology Lab at the Institute for Computational Medicine at John Hopkins University, Natalia Trayanova, Ph.D., gives a brief insight into the inefficiency with the current technology and the potential behind implementing optogenetics when she writes, “When we use a defibrillator, it’s like blasting open a door because we don’t have the key…We want to control this treatment in a more intelligent way. We think it’s possible to use light to reshape the behavior of the heart without blasting it” [9]. Implicitly, an extension in battery life means fewer procedures would be required to replace the battery, which would decrease complications compared to the current technology with electric pacemakers. Meanwhile, pain reduction will be an enticing positive for the patient in contrast to implanted defibrillators. In a society where good practices of medicine and a high standard of patient care are revered, optogenetics has the potential to deliver. As optogenetic therapy is continually being perfected and ameliorated, the efficient design and benefits seem to be its conduit to a clinical setting. Conversely, current technology for regulating cardiac function has its drawbacks, such as the inability to target only a specific part of the heart or the emphasis on health precautions post-surgery. For these reasons, optogenetics may revolutionize treatment for cardiac treatments, and perhaps, for other sub-specialties of medicine. References 1. Anyaegbunam, F. N.C. 2013. OnIntegration of ICT in National Healthcare Delivery System. IJERT. 10(2):739. 2. Reece, J.B., Urry, L.A., Cain, M.L., Wasserman, S.A., Minorsky, P.V., Jackson, R.B. 2011. Campbell Biology. Pearson. 9e. 3. Buch, E., Boyle, N.G., Belott, P. 2011. Pacemaker and Defibrillator Lead Extraction. AHA. 123: e378-e380. 4. Gandelman, G. 2010. Pacemaker. ADAM. 5. NIH. 2012. How Does a Pacemaker Work. 6. Res, J.C.J., Priester de J.A., van Lier, A.A., van Engelen, C.L.J.M., Bronzwaer, P.N.A., Tan, P-H., Visser, M. 2004. Pneumothorax Resulting from Subclavian Puncture: a Complication of Permanent Pacemaker Lead Implantation. Neth Heart J. 12(3): 101-105. 7. Baddour, L.M., Epstein, A.E., Erickson, C.C., Knight, B.P., Levison, M.E., Lockhart, P.B., Masoudi, F.A., Okum, E.J., Wilson, W.R., Beerman, L.B., Bolger, A.F., Estes, N.A. M. III, Gewitz, M., Newburger, J.W., Schron, E.B., Taubert, K.A. 2010. Update on cardiovascular implantable electronic device infections and their management. Circulation. 121(3): 458-477. 8. Swerdlow CD, et al. (2012). Pacemakers and implantable cardioverter-defibrillators. In RO Bonow et al., eds., Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 9th ed., vol. 1, pp. 745–770. Philadelphia: Saunders. 9. “Researchers Aim to Use Light-Not Electric Jolts-to Restore Healthy Heartbeats.” News from The Johns Hopkins University Researchers Aim to Use Light Not Electric Jolts to Restore Healthy Heartbeats. N.p., n.d. Web. 04 Dec. 2013. 10. Saey, T.H. 2010. Let There be Light: New Technology Illuminates Neuronal Conversations in the Brain. Science News. 177:18-21. 11. Arrenberg, A.B., Stainier, D.Y.R., Baier, H., Huisken, J. 2010. Optogenetic Control of Cardiac Function. Science. 330: 971-974. 12. Entcheva, E. 2013. Cardiac Optogenetics. Am J Physiol Heart Circ Physiol 304: H1179 –H1191.


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Multijunction Solar Cells: Energy Recaptured and Converted By Justin Thomas ’15 In a world with over seven billion people and continuously advancing technology, energy has become essential for daily life, powering our homes, cars, and phones. However, this extreme demand for energy has placed a severe strain on the environment. According to the U.S. Energy Information Administration, 37% of our energy demand is met by the burning of coal, while another 30% is from the burning of natural gas [1]. Research has shown the detrimental effects of burning these types of fuels, which produce greenhouse gases and pollutants. In addition, these fuel sources are finite, so the heavy demand will soon outweigh the supply. The implications of continuous dependence on current sources of energy would be devastating, and thus, it is important to search for a clean renewable energy source. Solar power is an eminent area of energy production because of its free availability, environmental friendliness, and promising growth potential. To say that the sun is the most reliable and energy dense object in the solar system would be an understatement. More than 1.5×10 22J (15000EJ) of solar energy reaches Earth every day, which is enough to supply the daily energy consumption of approximately  1.3EJ  by human activity [2]. Solar energy is clean and renewable, and does not produce any harmful byproducts, such as CO 2 and particulate pollutants. The benefits of relying on solar energy as our primary energy source would thus be revolutionary, and scientists are currently studying methods by which to do so. Presently, research have decades of experience in the design and implementation of silicon solar cells. However, current research is now focusing on improving the efficiency of multijunction solar cells. Silicon Solar Cells Silicon solar cells have been extensively studied due to the availability and low cost of silicon, as well as its relatively high efficiency-to-cost ratio. They are used in both commercial and personal applications to power buildings and houses. Solar energy can also be commercialized by

the construction of solar farms, which are cells that are spread out over a large expanse [3]. Composed of silicon, a natural semiconductor, each wafer of the silicon cell is doped with boron or phosphorus to produce either p or n-type semiconductors, respectively. When a photon strikes the p-n junction, it creates an electron-hole pair. This electron then travels to the electrical contact and around the circuit, creating current flow [4]. Since these cells only have one p-n junction, the conversion efficiency is limited. The best lab examples of traditional cells have efficiencies of around 25%, while the maximum theoretical efficiency for silicon cells is about 33% [5]. In other words, only one-quarter of the electromagnetic energy that arrives at the solar cell is converted into electrical energy, and even in ideal conditions with little energy loss, only one-third of the energy would be able to be collected. Therefore, the current silicon solar cell needs to be modified in order to improve efficiency.

Figure 1 This schematic outlines electron-hole creation of a single junction solar cell and resulting charge flow [6].

Multijunction cells The limitation of the traditional silicon solar cell was its single junction. Multijunction cells solve this problem by adding more junctions, thus increasing the overall efficiency. Multijunction cells have crystalline layers, each of a different band gap 1 stacked on top of each other. This allows for a minimal loss of energy, as more wavelengths of light will be converted to energy. This higher efficiency results in a demonstrated performance in excess of 43%, with an 86% maximum theoretical efficiency for an infinite junction cell [7]. This maximum theoretical efficiency is 1. A band gap is the energy difference between the top of the valence band and the conduction band of either insulating or semiconducting material, and is one of th emost crucial aspects of solar energy technology. Solar technology takes advantage of the fact that electrons in a semiconductive material can be excited by both ultraviolet and visible light to produce energy.

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How They Work These cells perform similarly to the standard silicon solar cells. Light enters the cell and hits the p-n junction, creating an electron-hole pair. The electron then travels to the electrical contact and creates a current at every semiconductor junction. To help with electron transport, tunnel junctions made up of a low resistance semiconducting or conducting material are installed to allow electrons in the center of the cell to move into circulation as well. When the electron moves around the circuit, it refills the hole from where it came and thus completes the cycle. Cells made from different materials have their own characteristic band gaps that correspond to a certain wavelength of light. Essentially, the cell as a whole will respond to multiple light wavelengths, and some of the energy that would otherwise be lost to recombination can now be captured and converted [4].

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The Gemasolar Power Plant in Seville, Spain, which supplies enough energy to power 27,500 homes, demonstrates the potential of solar energy as a renewable energy source.

derived from the supposed ideal case of having both an infinite number of layers and minor loss of incoming photon energy. Structure Aside from their design, multijunction solar cells differ from traditional silicon cells by primarily being composed of GaAs (Gallium Arsenide) compounds. GaAs compounds are created by a complex process called Metalorganic vapour phase epitaxy (MOVPE). They are tuned to be excited by different wavelengths of light by doping them with other elements. These tunable compounds are ideal because once they are layered on top of each other and made into a cell, they are able to absorb and convert a wide range of available light wavelengths into electrical energy [8]. The cells are commonly composed of three layers. Each layer is tuned to absorb a different wavelength of light. Most often, GaInP (Gallium Indium Phosphide), GaAs (Gallium Arsenide), and Ge (Germanium). This is a great improvement from the considerably narrow range of the silicon cell. Multijunction solar cells also have aluminum electrical contacts at the top and bottom of the cell that connect the cell to the electrical circuit. Anti-reflective coating is put on the cell to increase light absorption and reduce loss of energy [9].

Figure 2 This basic 3 layer multijunction cell made is made with various types of GaAs and As compounds [10].

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Loss mechanisms Solar cells have a theoretical efficiency limit that is much higher than what is seen in reality. This is due to the loss of energy that happens by various mechanisms. Loss mechanisms in multijunction cells are primarily the same problems encountered in traditional solar cells, though the multiple layer cells experience the loss of energy to a lesser degree, resulting in a better efficiency. The ShockleyQueisser limit is the maximum theoretical efficiency limit that is possible for solar cells using p-n junction [5]. This limit is approximately 33% for a standard silicon solar cell. Since multijunction cells are composed of more than one layer, they do not obey this limit and thus have a maximum theoretical efficiency of around 86% [11]. The limit takes into account three primary considerations for energy loss: blackbody radiation, radiative recombination, and spectrum loss. Blackbody radiation is a prevalent energy loss mechanism [5]. When a photon is not converted into electrical energy and lost to the environment as heat, the temperature of the cells increases, which in turn increases the blackbody radiation of the cell. Radiative recombination is another loss mechanism, where an electron recombines with its hole and emits light. This is a required loss mechanism that is difficult to avoid. Since electron hole pairs can be created when a photon enters the cell, the opposite reaction must also be allowed to take place [12]. The final loss mechanism that is taken into account is known as spectrum loss. Spectrum loss occurs when light, with too little or too much energy, enters the cell and cannot create an electron-hole pair. For example, energy would be lost if blue light entered a junction that was tuned for red light. Spectrum losses account for the majority of losses in a cell [5]. Since multijunction cells have more layers tuned for different wavelengths, spectrum loss is drastically reduced and this allows for better energy retention and efficiency. However, since no solar cell can absorb all wavelengths of light, there will always be some energy loss. Applications Aside from being complex to manufacture, this method is also not easily scalable, thereby leading to


higher costs than their silicon counterparts. Because of this, multijunction solar cells have limited applications. Currently, they are being use in Mars rover missions, where their high efficacy and lightweight portability is crucial for the study of the Martian surface [13]. They are also used in satellite applications, in which the necessity for a lightweight and powerful cell outweighs the high cost. Although it is expensive to make these cells, this improvement is necessary to efficiently harness energy from the sun and prevent the devastating impact of society’s dependence on environmentally harmful energy sources. As time progresses it is almost certain that new, inexpensive and more efficient multijunction solar cells will emerge and become essential to future applications. Conclusion As our fossil fuel supply is diminishing and demand for energy is rapidly increasing, it is necessary to find alternative energy sources. The step towards solar energy has brought forward substantial advancement in energy production. Future research works toward further improvement this technology and increase its availability by introducing more inexpensive and efficient modifications to the existing model. This relatively simple improvement

in the engineering of the solar cell has led to higher efficiency and a promising future for the solar power industry. Multijunction solar cells can pave the way, not only towards the future of solar energy, but also towards energy production as a whole. References

1. 2013. What is U.S. Electricity generation by energy source? U.S Energy Information Administration. <http://www.eia.gov/tools/faqs/faq.cfm?id=427&t=3>. 2. 2006. International Energy Annual. Energy Information Administration. <http://www.eia.doe.gov/iea/overview.html>. 3. Shockley, W., Tamme, R., Taut, U., Streuber, C., and Kalfa, H. 1991. Energy storage development for solar thermal processes. Solar energy materials. 24(1): 386-396. 4. Sah, R. Y., Noyce, R. N., & Shockley, W. 1957. Carrier generation and recombination in pn junctions and p-n junction characteristics. Proceedings of the IRE. 45(9): 1228-1243. 5. Shockley, W., Queisser, H.J., 1961. Detailed Balance Limit of Efficiency of p-n Junction Solar Cells. Journal of Applied Physics. 32: 510-519 6. 2014. Photovoltaic Cells – Generating electricity. <http://www.imagesco.com/ articles/photovoltaic/photovoltaic-pg4.html>. 7. Zyga,L. Multijunction solar cell could exceed 50% efficiency goal. 2013. <http:// phys.org/news/2013-02-multijunction-solar-cell-efficiency-goal.html>. 8. Nell, M. E., & Barnett, A. M. 1987. The spectral p-n junction model for tandem solar-cell design. Electron Devices, IEEE Transactions on. 34(2): 257-266. 9. King, R. R., Law, D. C., Edmondson, K. M., Fetzer, C. M., Kinsey, G. S., Yoon, H, Sherif, R.A, and Karam, N. H. 2007. 40% efficient metamorphic GaInP/GaInAs/ Ge multijunction solar cells. Applied physics letters, 90(18), 183516-183516. 10. Leite, M.S. 2013. Towards an optimized all lattice-matched InAlAs/InGaAsP/InGaAs multijunction solar cell with efficiency >50%. Applied Physics Letters. 102. 11. De Vos.1980. Detailed balance limit of the efficiency of tandem solar cells. Journal of Physics D. Applied Physics 5(13):839-846. 12. Green, M. A. 1982. Solar cells: operating principles, technology, and system applications. Englewood Cliffs, NJ, Prentice-Hall, Inc., 1982. 288 p., 1. 13. Edmondson, K. M., Fetzer, C., Karam, N. H., Stella, P., Mardesich, N., & Mueller, R. 2007. Multijunction solar cells optimized for the Mars surface solar spectrum.

A Mars Rover utilizes solar panels with multijunction solar cells.

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Treating Rheumatoid Arthritis: Advances and Obstacles By Ephraim Hallford ’14 Advancements in medicine that incorporate biological strategies have increased drug effectiveness and improved disease outcomes. Rheumatoid arthritis (RA) is an inflammatory disease that destroys the joints of the hands and feet [1]. It affects roughly one percent of the population and its underlying causes remain diverse and multifactorial. For example, T cells, Major Histocompatibility Complex (MHC), T-reg cells, and numerous cytokines, such as tumor necrosis factor (TNF-α) and interleukins (IL-2, IL-6, IL-12, IL-17) have been implicated in RA’s progression [2]. Disease modifying anti-rheumatic drugs (DMARDS) are among several mainstream therapies to help ameliorate RA symptoms by interfering with intracellular signaling, immune cell activation, and immune cell recruitment [3]. In recent years, there have been advancements in treating RA by modulating the underlying physiology that is associated with the disease. Through their actions targeting IL-2, TNF-α and interfering with T cell activation, researchers have been able to improve disease prognosis and expand the library of drugs that physicians can use to treat RA [4]. In recent years, this has led to the development of novel DMARDs, such as Abatacept, VX702, and R788. An Overview of a Healthy Joint and Immune System Joints are structures composed of connective tissue and permit bones to move past one another. The synovial joint, such as the knee joint, is one of the most complex and interesting structures. In the interior of the synovial joint capsule (a structure encasing the joint with ligaments), the synovial membrane produces synovial fluid to lubricate ends of bone, which prevent abrasion and scarring when bones slide past one another [5].

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In healthy adults, white blood cells, such as macrophages, neutrophils and other lymphocytes, circulate in the bloodstream to fight infection caused by bacteria and viruses. They also release chemicals such as metalloproteases (which use metal ions to degrade protein), lysozymes, and other hydrolytic enzymes to degrade and protect against cellular invaders. B cells, which produce antibodies, and T cells, which aid in recognizing foreign antigens and regulate B cell activation and maturation, receive signals to replicate through their interaction with cytokines and are attracted by chemokines to travel to sites of infection. In order to recognize host cells, B and T cells, or more commonly termed Antigen Presenting Cells (APCs) attach via their MHC to CD4 on the surface of normal cells and other associated structures. Interleukins, cytokines like interferon and TNF-α, and chemokines are among a host of extracellular signals for the immune system to attack foreign invaders or virally infected cells. T-reg cells are involved in preventing autoimmune disorders by removing T cells that attack self-cells [6]. The Molecular Basis of Rheumatoid Arthritis Rheumatoid arthritis’ etiology is dependent upon several factors and mechanisms, such as autoimmunity, chronic inflammation, T regulatory cell tolerance, and articular and bone erosion. A strong genetic component exists in RA. Given that MHC’s structure is important for cell recognition via CD4, certain amino acid residues and alleles in Human Leukocyte Antigen DR regions in MHC have been strongly linked with RA’s severity. The nature of the DR region and its genotype has been associated with RA among many tested ethnicities [7]. Additionally, chronic inflammation in RA is normally associated with synovial membrane penetration by white blood cells, as well as cartilage, bone and articular erosion.


Neutrophil recruitment into synovial fluid by macrophages and cytokines lead to chronic inflammation. Subsequently, chronic inflammation precipitates release of metalloproteases by neutrophils and cytokines by macrophages, T cells, and B cells. The systemic inflammation brought upon by these cells lead to bone erosion and articular destruction of joint capsule. Not surprisingly, a recent discovery of linking osteoclast maturation with TNF-α (a cytokine involved in T cell and B cell proliferation, which is released in response to infection) and RANK (a receptor for nucleotide factor or NFkB) in synoviocytes has added to evidence suggesting that RA leads to prolonged destruction of bone by osteoclasts [8]. Scientists have sought mechanisms to slow bone degradation and articular destruction by dampening inflammation. Anti-cytokine treatment, by blocking cellular signaling cascades that mediate cytokine release, has shown to be effective in several invasive RA cases through interfering with T cell activation, macrophage chemotaxis and angiogenesis. TNF-α therapy is just one example of how immune response severity may be modulated by blocking cytokine activity. Since sustained cytokine release is essential to sustain an immune response due to their involvement in activation of lymphocytes, therapies that interfere and/or block genetic expression of cytokines or cytokines directly have been shown to be promising strategies to treat RA. However, not all therapies employing TNF-α therapies have been successful. To overcome these obstacles, kinase inhibitors have been suggested to be a target to alter genetic transcription and to lessen autoimmune sensitivity and severity, since they are upstream of many factors that affect inflammation and growth. Drugs which interfere with B cell and T cell maturation/activation have thus also been developed by scientists, given that B cells and T cells sustain continued inflammation in synovial and articular structures [8]. Therapies such as Abatacept, a fusion protein which interferes with T cell activation, and R788, a kinase inhibitor which dampens kinase cascades and modulates cytokine release, are prime examples of the advancements researchers have made in developing new medications to treat challenging diseases. DMARDS Disease modifying anti-rheumatic drugs (DMARDs) are the mainstream therapy for rheumatic diseases. Methotextrate is a commonly used immunosuppressant to treat RA, but its efficacy and safety concerns remain a large obstacle for healthcare practitioners, since a large fraction of patients remain unresponsive to its effects [9]. Fortunately, the discovery and development of novel therapies has aided in treatment goals and has improved disease outcomes. TNF-α inhibitors, such as Infliximab, hold a promising lead in treating methotextrateresistant form of RA [10]. However, in cases where TNF-α treatment is difficult, such as in instances where negative side effects make treatment unmanageable or when a patient is unresponsive to the therapy, novel kinase inhibitors like VX-702, R788, and Atacicept have been effective complementary drug regimes in clinical trials. Inhibition of T cell activation with Abatacept (CTL4-4Ig) used concurrently with other therapies has been seen to improve RA prognosis. Another novel fusion protein, Atacicept, reduced serum autoantibodies, B cells and T cells counts and thus reduced inflammatory-mediated ero-

sion of cartilage and bone. By binding BLyS and APRIL (cytokines which sustain B cell activation), Atacicept serves as an example of the many biological DMARDs that interfere with extracellular signaling pathways to modulate disease behavior [11]. Abatacept CLTA-4 is a surface receptor constitutively expressed on T regulatory surface that binds the TCR (T cell Receptor) co-receptor, CD28. In T cells, CD28 is a necessary co-stimulating receptor that must be activated in order for T cells to mature. It maintains peripheral tolerance by CTL4 binding to rogue T cells and eliminates them so as to reduce the risk of autoimmunity. CTL4 prevents T cell activation by binding with its CD28 [13]. Abatacept was designed as a fusion protein of CDL4 and Fc region of Ig antibody in order to prevent the activation of T lymphocytes and limit inflammation in the synovium [14]. For example, by targeting CD80 and CD86 (B7), necessary co-stimulatory ligands for T cell activation via their coengagement CD28 with MHC-I receptor, Abatacept has led to a reduction of T cell mediated pathogenesis [15]. Additionally, this therapy has been associated with decreased T-reg count but increased T-regulatory efficiency in RA. Therefore, it was suggested that CD28 signaling could be involved in T-regulatory cell maintenance [16]. In RA, this is especially relevant, since by T cell regulation, the prognosis of disease could be affected based on level of inflammation in joints caused by those cell’s activity. Abatacept administration has been shown to be an effective alternative for physicians when conservative TNF-α treatment fails. A double blind placebo conducted by Stanford University (in association with Bristol-Meyer Squibb) confirmed in 2012 that over a period of five years, Abatacept remained effective and safe when compared with conservative therapies [17]. Kinase Inhibitors Kinases are among the first messengers in inflammatory signaling and therefore, have been chosen as potential therapeutic targets to decrease inflammation and prevent joint destruction in late-term RA patients by preventing transcription of pro-inflammatory cytokines. Syk (tyrosine kinases which contribute to growth signaling) inhibitors have been suggested to be novel targets. Additionally, MAP kinases have been suggested as well, due to their ubiquity as the primary second messengers that amplify the signaling cascade in inflammatory signaling pathways [18]. Kinases are optimal targets because they affect a wide variety of cytokines, including interleukins, interferons and TNF-α. One example of these molecules, IL-17 (a cytokine involved in B cell proliferation), has been shown to be implicated in RA by aiding in angiogenesis in inflamed synovial tissue [19]. MAP kinase inhibition may affect angiogenesis, since it has been shown that IL-17 is involved in PI3k activation, given that PI3 is a kinase involved in growth and is upstream in the

...the discovery and development of novel therapies has aided in treatment goals and has improved disease outcomes.

33


MAP kinase signaling pathway. It is interesting that PI3k has been shown to play a more important role in inflammation than previously thought, and has been suggested for a target for RA treatment, especially since its delta isoform is highly expressed in RA synovial tissue [20]. VX-702 and R788 VX-702 was developed by Vertex Pharmaceuticals to target p38 MAPK in order to downregulate the expression of IL-6 and IL-8, which are both potent pro-inflammatory cytokines that increase the speed and degree of macrophage, fibroblast, T cell, and B cell recruitment and activation upon chemical and physiological stress. It additionally has been shown to downregulate TNF-α and INF-γ, which are both potent pro-inflammatory signals that increase proliferation and activation of B and T cells [21]. Phase I clinical trials show therapeutic potential, given that it prevented collagen-induced RA and osteoclast formation in the synovium [22]. Phase II randomized double-blind, placebo trials indicated that an increase in VX-702 suppresses the immune system without a significant benefit to lessen RA prognosis [23]. Despite the promising finding in initial trial, Phase II of VX-702 results highlight the obstacles that researchers face when developing new drug therapies However, R788 in Phase II trials fared much better, showing overall improvement in ACR scores (values assessing relative improvement in health and joint function) when compared against groups taking placebos [24]. Overall, the effects that a kinase inhibitor can have on altering prognosis of RA indicate the diverse role cytokines play in inflammation, growth signaling and bone maintenance. Implications and Insight The general causes of RA remain unknown. In recent years, a resurgence of the immune complex theory (which posits that those who suffer from RA possess an antibody that can bind to itself and thereby, recruit immune cells to cause inflammation in joints) has led to widespread debate. For the first part of the last fifty years, it was proposed that immune complexes accumulated in synovial fluid. The incidence of RF factor in patients who suffered from RA led researchers to believe inflammation was a consequence of the presence of RF in their blood, which had bound to itself, was deposited in synovial fluid and joints, and recruited immune cells to fight what was perceived as an infection [25]. On the other side of the debate, researchers had found several antibodies in synovial fluid, which led researchers to believe RA was largely auto-antibody mediated. The action of R788, VX-702, TNF-α, and Abatacept therapies could have duplicitous function and may be acting upon both of the underlying mechanisms. Since the action of most therapies are immunosuppressive and still rely on more symptomatic management, the theories explaining the disease need to be further expanded. Future research should use developed technologies such VX-702, despite its lower efficacy and increased toxicity, because it may shed light on the pathology of immunodeficiency and autoimmunity. Conclusion Rheumatoid arthritis remains an elusive disease. Its exact etiology remains uncertain, even though it is known to

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be an autoimmune disease affecting joints, articular tissue, MHC, cytokines and T cell mediation. Although much progress has been made in its treatment, there are still significant risks associated with the therapies available to patients who suffer from the disease. The large gaps in our understanding of RA’s mechanism still remain a large obstacle, although there is a large body of evidence to suggest it is a multi-layered and intricately complex disease that involves autoantibodies, T cells, cytokines and genetic susceptibilities. Future research should be geared towards expanding our knowledge of genetic susceptibility and ways to individualize care on a patientto-patient basis by assessing the severity and progression of disease. Clinicians should employ a larger library of drugs to combat inflammation and to reduce articular destruction and bone erosion by osteoclasts, hydrolytic enzymes and metalloproteases. Just one example of these drugs is Abatacept that has been shown to improve prognosis of patients by interfering with T cell activation. Incorporating these drugs in a strategy by physicians would enhance the quality of care and lead to better outcomes for patients who suffer from rheumatoid arthritis. References 1. Firestien GS. 2003. Evolving Concepts of Rhematoid Arthritis. Nature. 423:356-361. 2. Feldman M, Brennen F N, Maini RN, Role of Cytokines in Rheumatoid Arthritis. Immunology. 14:397-440. 3. Quan L, Thiele GM, Tian J, Wang D. 2008. The development of novel therapies for rheumatoid arthritis. Expert Opinion on Therapuetic Patents. 7:723-738. 4. Kim S, Yelin E, Tonner C, Solomon D. 2013. Changes in the Use of disease-modifying drugs for Rheumatoid Arthritis in the United States during 1983-2009. Arthritis care and Research. 65(8):1529-1533. 5. Ralphs. JR, Benjamin M. 1994. The Joint Capsulel. J Anat. 184(3):503:509. 6. William Paul E. Fundamental Immunology. Philadelphia. Lippincott Williams and Wilkins. Print. 7. Weyand, C. M., Hicok, K. C., Conn, D. L. & Goronzy, J. J. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann. Intern. Med. 117, 801–803 (1992). 8. Firestein G. 2003. Evolving Concepts in Rheumatoid Arthritis. Nature. . 423:356-361. 9. Tian HT, Cronstein BN. 2007. Understanding Mechanism of Action of Methotrexate. Bulletin of NYU hospital of Join Diseases. 65(3):168-173. 10. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C. 2004. Compromised function of Regulatory T cells in Rhematoid Arthritis and reversal by AntiTNFa therapy Journal of Experimental Medicine. 200 (3): 277-285. 11. Vollenhoven RF. Kinnman N, Vincent E. Wax S. Bathon J. 2011. Atacicept in Patients with Inadequate Response to Methotrexate. Arthritis and Rheumatism. 63(7):1782-1792. 12. Shevac E. 2008. Regulating Suppression. Science. 332: 202-203. 13. Alvarez-Quiroga Crisol, Abud-Mendoza C, Doniz-Padilla L, Juarez-Reyes A, MonsiviasUrenda, Baranda L, Gonzalez-Amaro. 2011. CTLA-4-Ig Therapy Diminishes Frequency but enhances the function of Treg Cells in Patients with Rhematoid Arthritis. J Clin Immunol. 31. 588-595. 14. Pieper J, Herrah J, Raghavan S, Muhammad K, Vollenhoven R, Malmstrom V. 2013. CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody positive rheumatoid arthritis patients. BMC Immunology 14:34. 15. Alvarez-Quiroga Crisol, Abud-Mendoza C, Doniz-Padilla L, Juarez-Reyes A, MonsiviasUrenda, Baranda L, Gonzalez-Amaro. 2011. CTLA-4-Ig Therapy Diminishes Frequency but enhances the function of Treg Cells in Patients with Rhematoid Arthritis. J Clin Immunol. 31. 588-595. 17. Genovese MC1, Schiff M, Luggen M, Le Bars M, Aranda R, Elegbe A, Dougados M. 2012. Longterm safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy. J Rheumatol. 39(8):1546-54 18. Bonilla-Hernan N, Miranda-Caru ME, Martin-Mola E. 2011. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. Rheumatology. 50(9):1542-1550. 19. Pickens S, Volin M, Mandelin A, Kolls J, Pope R, Shahrara S. 2010. IL-17 contributes to angiogenesis in Rhematoid Arthtritis. J Immunol. 184:3233-3241. 20. Bartok B, Boyle D, Lui Y, Ren P, Ball S, Bugbee WD, Rommel C, Firestein GS. 2012. PI3 Kinase delta is a key regulator in the function of Rhematoid Arthritis. The American Journal of Pathology. 180(5):1906-1916. 21. Ding C. 2006. Drug Evulation: VX-702, a MAP kinase inhibitor for rheumatoid arthritis and acute coronary syndrome. Current Opinion in Investigational Drugs 7 (11):1010-1025. 22. Damjanov N, Kauffman R, Spencer-Green G. 2009. Efficacy, Pharmacodynamics and Safety of VX-702, a novel p38 MAPK Inhibitor, in Rheumatoid Arthritis. Arthritis and Rheumatism. 60(5): 1232-1241. 23. Ding C. 2006. Drug Evaulation: VX-702, a MAP kinase inhibitor for rheumatoid arthritis and acute coronary syndrome. Current Opinion in Investigational Drugs 7 (11):1010-1025. 24. Weinblatt M, Kavanaugh A, Genovese M, Jones D A, Musser TK, Grossbard EB, Magilavy. Effects of Fostamatinib (R788), an Oral Spleen Tyrosine Kinase inhibitor on Health-related Quality of life on Patients with Active Rheuamtoid Arthritis: Analysis of patient-reported outcomes from Randomized, double-blind, Placebo-controlled trial. The Journal of Rheumatology. 40(4)369-378. 25. Zvaifler NJ 1973. The Immunopathology of joint inflammation in rheumatoid arthritis. Adv. Immunology. 16(0):265-336.


Design and Testing of Amplification Frame for Piezoelectric Energy Harvester Plinio Guzman1, Wusi Chen1, Ya Wang1,2, and Lei Zuo1,3 1 2 3

Department of Mechanical Engineering, State University of New York, Stony Brook, NY Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA

ABSTRACT This paper presents the design, modeling and experimental analysis of an amplification frame for a piezoelectric stack to be used in a floor tile energy harvesting device. The proposed energy harvester captures the kinetic energy that a footstep carries as it strikes the ground and converts it into usable DC power. The device can be used in urban areas that are heavily trafficked by pedestrians in order to provide a localized, alternative power supply, ultimately reducing the power requirements from the grid. The system was modeled using Single Degree Of Freedom (SDOF) and Finite Element Method (FEM), and to predict output voltage. Experimental results show a strong correlation with theoretical models and validate their accuracy. As a proof of concept, the energy harvesting performance of the amplified piezoelectric stack was also compared to that of the piezoelectric stack without the use of the frame. A considerable increase in performance proves the design of the amplification frame to be successful. 1 INTRODUCTION Scavenging energy from ambient vibrations has gained popularity in recent years due in part to the growing concern for clean energy generation [1]. Particular emphasis has been placed on the use of piezoelectricity to convert mechanical to electrical energy [2-4]. One such method, which is the subject of study of this paper, uses a piezoelectric ceramic multilayer stack operating in the d33 mode in order to generate energy from an impact force [5]. The proposed floor tile energy harvester can be placed on the ground as a regular floor tile would be, but has the ability to capture the kinetic energy carried in a footstep and convert that energy into electric power. This device can act as a localized energy source, which can be used to power nearby electronic devices. Ultimately, the energy harvesting system includes a power conditioning unit and a super capacitor in order to store the generated electric power, as shown in Figure 1.

the top of the frame to a compressive force on the piezoelectric stack, as shown in Figure 2. An additional advantage of the design is that the links on the frame operate only in tension when a force is applied, which eliminates the concern for buckling. A computer generated model of the amplification frame appears in Figure 3.

Figure 2 Diagram of amplification stack.

Figure 1 Floor tile energy harvesting system.

This paper presents the design, modeling, and testing of an amplified piezoelectric stack. Two modeling approaches, Single Degree Of Freedom (SDOF) and Finite Element Method (FEM), are used to model the system and predict the voltage and power output of the device. Experimental testing is used to validate the accuracy of these models. 2 DESIGN Piezoelectric stacks generate relatively low amounts of energy under direct loading due to their high stiffness. This issue is assessed using a frame which is designed to sustain, amplify, and transmit a load onto a piezoelectric stack in a controlled manner. Piezoceramics are able to bear relatively large compressive stresses, but tend to be weak when under tension, which is why the frame has an auxetic shape that compresses the stack when it receives a load. Its simple kinematic design allows for an indirect transmission of an impact force from

Figure 3 Computer generated model of amplification frame.

The frame ensures that the input load is always applied indirectly onto the stack in a predictable manner and in an axial direction. Guaranteeing that strain occurs axially in the active direction of the stack prevents shear (piezoceramics tend to be brittle) and maximizes energy conversion by having the mechanical deformation occur in the direction of the generated electric field. The flexible frame also acts as a shock absorber, which can prevent against sudden extreme loads that might damage the stack. Furthermore, using a customized frame allows the stack to be used in a variety of applications, as it acts as an interface with the environment. This also opens the possibility of using multiple frames in conjunction with an energy harvesting system.

35


2.1 Stress Analysis Energy storage within the frame at the moment of impact reduces the energy transfer efficiency. Of all the parts of the frame, the links are the most prone to store energy due to their relatively higher flexibility. Thicker links allow for less bending and for reduced energy storage, and thus make for a stiffer overall frame. The links used in this particular design have a thickness of 0.762 mm and are oriented at 6˚ from the horizontal. A Von Mises stress analysis of the frame under a load of 30 N (6.7 lbf) appears in Figure 4. The ideal version of the mechanism has rigid links connected with a pivot, resulting in no potential energy within the frame. In this case, no potential energy is stored within the frame and the amplification ratio becomes a function of the geometrical shape only. However, this is not the case. Variations in the frame design are considered throughout the project, and experimental and theoretical comparisons are done with the intent of optimizing the design.



(1) ∑ F

F1x = F2 x

= 0

å M 1 = 0 F2 x L sin θ −

(2)

Rearranging equations (1) and (2),

F1x =

(3)

F footstep 2

F1x

Finput 2

L cos θ = 0

can be expressed as

cotq

The free body diagram of the block on the left end of the piezoelectric stack is shown in Figure 6. Due to its relatively low displacement, it is assumed to be in the state of dynamic equilibrium.

Figure 6 Free body diagram of the left block.

and F1′y are the reaction forces of F1x and F1 y , respectively. is the reaction force from the left end of the piezoelectric stack. The dynamic equation of the block can be expressed as

′ FPZT

F1x′



Figure 4 Von Mises stress analysis frame under a load of 30 N (6.7 lbf) deformation of the frame is exaggerated for illustrative purposes.

(

∑F = 0 : ( F1x '+ F1x '− FPZT ) i + F1′y − F1′y (4) FPZT’ can be determined from Eqn. 4.

0 )j=

F= 2= F1x ' Fstep cot θ PZT '

3 MATHEMATICAL MODELING Theoretical models for predicting the energy output of the system are derived through the methods of SDOF and FEM. Two electromechanical equations of motion are derived from the -33 mode constitutive equations, each one describing the physical and the electrical system. The derived SDOF and FEM state space equations are simulated with MATLAB and are solved using the input force signal obtained during the experiment.

3.1 Kinematic Analysis of Input Force A force analysis of the frame is performed in order to determine the relationship between the force input on the frame and the force transferred onto the stack. A free body diagram of the upper left link of the frame appears in figure 5.

As shown in Figure 6, the input force on the piezoelectric stack is the sum of the forces applied to both ends, and is expressed as

Figure 5 Free body diagram of upper left link.

In the free body diagram (Figure 5) the two ends of the link are labeled 1 and 2. θ is the angle of the link to the horizontal. L is the length of the link. F footstep is the force applied on the top of the harvester by a would-be footstep. Due to the symmetric configuration, F footstep /2 is applied at point 2. F1x and F1 y are forces in the horizontal and vertical direction at joint point 1, F2 x is the force in the horizontal direction at point 2. The dynamic equations of the link can be expressed according to Newton’s Law.

The free body diagram of the piezoelectric stack is shown in Figure 7. The piezoelectric stack is assumed to be in a state of equilibrium.

Figure 7 Free body diagram of the PZT stack.

= Finput 2= FPZT 2 F footstep cot θ

. The calculated force received by the piezoelectric stack is used to predict the voltage and power output of the system through the derived electromechanical governing piezoelectric equations. The force signal obtained during the experiment is input as a variable in this function in order to model the system’s behavior throughout the duration of the impact. 3.2 Mathematical Modeling of the Constitutive Piezoelectricity Equations The electromechanical governing piezoelectric equations combine the effect of the electrical behavior of the stack D=εE where D is the electric charge density displacement, is the permittivity, and E is the strength of the electric field, and Hooke’s Law S=sT

36


where S is the mechanical strain, s is the elastic compliance constant and T is the stress. Combined, they constitute the coupled constitutive equations, which for a piezoelectric stack operating under the d33 mode result in the form S3=sE33 T3+d33E3 D3=d33 T3+εT33E3 In order to predict the voltage output of the system, the constitutive equations are analyzed through both FEM and SDOD in state space form. Derivations of each analysis are omitted from the paper for simplicity. Both models are simulated with MATLAB using the force signal obtained during the experiment. The predicted results appear alongside those obtained experimentally in the results section.

The piezoelectric stack is placed in the frame, as shown in Figure 9. It is preloaded using the frame’s flexibility so as to minimize energy storage within the frame and ensure full contact. Its two external electrodes are connected in parallel with an Elenco Electronics RS-500 resistor substitution box and a National Instruments NI USB-6212 BNC Data Acquisition (DAQ) board in order to measure output voltage. The resistance on the RS-500 resistor substitution box is adjusted in order to match the source and load impedances in order to optimize the power output [5].

4 EXPERIMENTAL VALIDATION 4.1 Manufacturing of Amplification Frame The Amplification Frame is made of Impact-Resistant A516 Carbon Steel. It was manufactured through a Wire Electrical Discharge Machining process at Stony Brook University. The finished frames appear in Figure 8.

Figure 9 Stack in amplification frame.

Figure 8 Steel amplification frame.

4.2 Experimental Setup The piezoelectric stack used in this study is a P 25/10 stack type actuator manufactured by piezosystems jena. Its physical, electrical and electromechanical properties appear in Table 1.

Property

Symbol

P-113-00

Cross-sectional area (m )

A

7.85e-5

Length (m)

L

42e-3

Length of the piezo stack (m)

Lactive

27e-3

Stack mass (kg)

mstack

2.64e-2

Density (kg/m )

ρ

8000

Layer thickness (m)

h

100e-6

Number of layers

n

250

C

2.6e-6

2

3

Capacitance (F)

E 33 T 33

Elastic constant (m /N)

s

18.1e-12

Dielectric constant (F/m)

ε d 33

4.82e-8

2

Piezoelectric constant (m/V) Stiffness (N/μm)

Similarly, a PCB Piezotronics 086C03 impact hammer is connected to the DAQ board with the intention of providing a measurable impact force. The setup allows for the top of the frame to be struck with the hammer and for the output voltage and power of the piezoelectric stack to be recorded and analyzed in a computer. The voltage output of the stack is obtained through a resistive load and acquired by the DAQ board. In the same manner, the applied force is measured by the hammer’s force sensor as a voltage signal, which is processed through the signal conditioner and acquired by the DAQ board. The actual force is determined by dividing the output voltage by a factor of 2.25 mV/N as indicated by the hammer’s manufacturer [10]. A photographic and schematic representation of the test setup appears in Figures 10 and 11, respectively.

635e-12 28

Figure 10 Photograph of a test setup.

Table 1 Properties of P 25/10 stack type actuator.

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Figure 13 Force input signal. Figure 11 Schematic Representation of test setup.

4.3 Experimental Procedure The experiment consists of striking the top of the amplification frame or stack with a vertical motion using the impact hammer, as shown in Figure 12. The setup allows the voltage output of the piezoelectric stack to be related to the force applied with the hammer. Raw data of each test run is recorded with LabVIEW at a sample rate of 1 kHz for a duration of 1 second. The performance of the amplified piezoelectric stack is compared to both theoretical models and to the performance of the piezoelectric stack without an amplification frame. In order to maximize power output, the source impedance is matched to the load impedance by using a resistive load of 1500 â&#x201E;Ś in both the experimental setup and in the theoretical calculations.

Figure 14 Voltage output of FEM, SDOF, and experimental cases.

Figure 15 Power output of FEM, SDOF, and experimental cases.

a

b

Figure 12a Striking with amplification frame. Figure 12b Striking without aplification frame.

4.3 Experimental Validation of Theoretical Models The force signal obtained from the experimental trial, which appears in Figure 13, was used to model the SDOF and FEM systems. The peak magnitude of the signal is 36.73817 N. The voltage and power outputs for each case appear in Figures 14 and 15, respectively. A strong correlation between the experimental results and both model predictions can be observed both numerically and graphically. The peak voltage and power outputs of each case appear in Table 2.

Magnitude

Percent Error

Vexp (V)

9.5309

VFEM (V)

9.6081

4.07%

VSDOF (V)

9.9998

0.80%

Pexp (W)

0.0606

PFEM (W)

0.0615

1.48

PSDOF (W)

0.0667

10%

Table 2 Peak voltage and power outputs.

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4.4 Proof of Concept As proof of concept, the energy harvesting performance of the piezoelectric stack is studied experimentally with and without the use of the amplification frame. In the first case, a peak input force of 37.46296 N was applied onto the frame, and in the second case, a force of 36.73817 N was applied directly onto the stack. The force signals, voltage output, and power output for each case appear in Figures 16, 17 and 18, respectively. It is determined both graphically and numerically that the voltage and power output of the piezoelectric stack is considerably greater when the amplification frame was used.

Figure 16 Force input signal.


9. duToit, N. E., Wardle, B. L., and Kim, S., 2005, “Design Considerations for MEMS-Scale Piezoelectric Mechanical Vibration Energy Harvesters,” in Symposium on Ferroelectricity and Piezoelectricity, Cancun, Mexico. 10. Pcb piezotronics model 086c03. . (2014, January 25). Retrieved from http://www.pcb.com/Products.aspx?m=086C03 11. M. A. Karami and D. J. Inman, “Powering pacemakers from heartbeat vibrations using linear and nonlinear energy harvesters,”Appl. Phys. Lett., vol. 100, no. 4, pp. 042901-1–042901-4, Jan. 12. M. Umeda, K. Nakamura, S. Ueha, Energy storage characteristics of a piezo-generator using impact induced vibration, Japanese. Journal of Applied Physics 36(Pt. 1, No. 5B) (1997) 3146–3151. 13. H.A. Sodano, G. Park, D.J. Inman, Generation and storage of electricity from power harvesting devices, Journal of Intelligent Material Systems and Structures 16 (1) (2005) 67–75. 14. Lee, A.J., Wang, Y., Inman, D. J., 2014, “Energy Harvesting of Piezoelectric Stack Actuator from a Shock Event,” Journal of Vibration and Acoustics, Vol. 136, pp.011016-1-011016-7.

Figure 17 Voltage output of piezoelectric stack with and without amplification frame.

Figure 18 Power output of piezoelectric stack with and without amplification frame.

5 DISCUSSION The energy harvesting performance of an amplified piezoelectric stack submitted to an impulse force was analyzed experimentally and through SDOF and FEM modeling. The SDOF and FEM peak voltage outputs vary from the experimentally obtained peak voltage output by 0.80% and 4.07%, respectively. The SDOF and FEM peak power outputs differ from the experimentally determined peak power output by 10.00% and 1.48%. This strong correlation validates the accuracy of the theoretical models of the system, but suggests that room for improvement still exists. As a proof of concept, the energy harvesting capabilities of the piezoelectric stack were investigated with and without the use of an amplification frame. Data analysis shows a great improvement in performance when the amplification frame is used, proving the design of the frame to be successful. The frame will be incorporated into a floor-tile energy harvesting system, which will be produced at the Multi-Functional and Adaptive Structures Lab at Stony Brook University. 6 REFERENCES

1. Wang, Y., and Inman, D.J., 2012, “A Survey of Control Strategies for Simultaneous Vibration Suppression and Energy Harvesting,” Journal of Intelligent Material Systems and Structures, Vol.23, No.18, pp. 2021 - 2037. 2. Bilgen, O., Wang, Y., and Inman, D. J., 2011, “Electromechanical comparison of cantilevered beams with multifunctional piezoceramic devices,” Mechanical Systems and Signal Processing,Vol.27, pp. 763-777. 3. Wang, Y., and Inman, D.J., 2013, “Simultaneous Energy Harvesting and Gust Alleviation for a Multifunctional Wing Spar Using Reduced Energy Control via Piezoceramics,” Journal of Composite Materials, Vol. 47, No. 1, pp.125-146. 4. Wang, Y. and Inman, D.J. 2013, “Experimental Validation for a Multifunctional Wing Spar Design with Sensing, Harvesting and Gust Alleviation Capabilities,” IEEE/ASME Transaction on Mechatronics, Vol. 18, No. 4, pp.1289-1299. 5. Lee, A.J., Wang, Y., Inman, D. J., 2014, “Energy Harvesting of Piezoelectric Stack Actuator from a Shock Event,” Journal of Vibration and Acoustics, Vol. 136, pp.011016-1-011016-7. 6. Feenstra, J., Granstrom, J., and Sodano, H., 2008, “Energy Harvesting Through a Backpack Employing a Mechanically Amplified Piezoelectric Stack,” Mech. Syst. Signal Proc., Vol. 22, No.3, pp. 721–734. 7. Erturk, A., and Inman, D. J., 2008, “On Mechanical Modeling of Cantilevered Piezoelectric Vibration Energy Harvesters,” J. Intell. Mater. Syst. Struct., vol. 19(11), pp. 1311–1325. 8. F. IEEE Ultrasonics, and Frequency Control Society, 1988, “IEEE Standard on Piezoelectricity,” ANSI/IEEE Standard.

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“Neuregulating” Transcription Effects of Neuregulin 1 Type III Back-Signaling on the Expression of α7 Nicotinic Acetylcholine Receptors (α 7nAChR) P M Rajebhosale1, L W Role2,3,4, and D A Talmage 2,5 Undergraduate Program in Pharmacology, Stony Brook University, NY 11794 Center for Nervous System Disorders Research, Stony Brook University, NY11794 3 Department of Neurobiology & Behavior, Stony Brook University, NY 11794 4 Neurosciences Institute, Stony Brook University, NY 11794 5 Department of Pharmacology, Stony Brook University, NY 11794 1

2

ABSTRACT The NRG1 gene has been implicated in schizophrenia. Mice that are heterozygous for one mutated allele of the NRG1 gene show PPI deficits that are improved upon chronic nicotine administration. Patients suffering from schizophrenia also are heavy smokers. In the PNS, Nrg1 isoforms have been shown to upregulate the expression of certain types of nicotinic acetylcholine receptors. In this study, using a neural stem cell model (N2a mouse neuroblastoma cell line), we explore whether Nrg1 typeIII affects transcription of the α7 nicotinic acetylcholine receptor gene and the mechanism employed by the Nrg1typeIII Intra-cellular Domain (ICD) to regulate gene transcription. Neuro-2A, neuroblastoma cells do not endogenously express α7nAChR or Nrg1typeIII. Upon stimulating N2a cells that express Nrg1typeIII (stable transfection) with soluble ErbB4 receptors, we found increase in expression of α7nAChRs by immunocytochemistry. Expression of α7nAChRs was not detected by immunocytochemistry or presence of α7nAChR mRNA upon induced “differentiation” without ErbB4 stimulation. Thus, the N2a model might serve as a good preliminary model to study mechanistic aspects of Nrg1typeIII ICD mediated back signaling, eventually helping to elucidate the functions of Nrg1typeIII in the CNS and its role in affective disorders such as schizophrenia. INTRODUCTION The Neuregulin1 (NRG1) gene has been implicated as a susceptibility gene for schizophrenia. Polymorphisms and mutations in the gene have been linked with susceptibility to schizophrenia in various populations around the globe [1][2][3][4][5]. NRG1 hypomorphic mice display deficits in Pre-Pulse Inhibition (PPI) [6]. Sensorimotor gating deficits such as PPI are considered to be an endophenotype for schizophrenia and have been used to study the disorder in animal models. Similar sensory gating deficits are associated with the gene encoding for the alpha7 subunit of the nicotinic acetylcholine receptor (α7nAChR), which has also been linked to schizophrenia and other affective disorders [7]. 70-80% of patients suffering with schizophrenia are cigarette smokers, a statistic that is much higher than the normal population. Smoking alleviates sensory gating deficits in these patients and makes the cholinergic system a point of interest in studying schizoaffective disorders [8]. In addition to genetic linkages of NRG1 and CHRNA7 (α7nAChR gene) to schizophrenia and related phenotypes, recent studies have indicated that the typeIII isoform of the protein neuregulin1 (Nrg1) regulates targeting of α7nAChRs to axonal surfaces in the basolateral amygdala (BLA) and in sensory and ventral hippocampal (v.Hipp) neurons [9][10]. The NRG1 gene produces six major types of isoforms via alternative splicing and exon usage. Types I, II, IV, and V are known as Ig Neuregulins and are structurally distinct from Type III Nrg1. Ig Neuregulins are single-pass integral membrane proteins consisting of an extracellular N-terminus, comprising an Immunoglobulin (Ig) domain and an extracellular growth factor (EGF)-like domain, followed by a transmembrane (Tm) domain, and an intracellular C-terminus. Type III Nrg1 is unique in its structure because both its N and C termini are intracellular, with the EGF-like domain tethered between the two on the extracellular side. In addition to this, the type III isoform also has a cysteine-rich domain (CRD), which has resulted in the alternative naming of type III Nrg1 as CRD-Nrg1 (Refer to Figure 1) [5]. Besides

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structural differences, the Ig-Nrg1s are also processed differently from CRD-Nrg1. Proteolytic cleavage of Ig-Nrg1s on the Ig and Tm sides of the EGF-like domain liberates it for paracrine signaling via erbB receptors. Proteolytic cleavage of type III Nrg1 generates a tethered N terminal fragment with the EGF-like domain, which can bind erbB4 dimers on cells in close proximity [5]. Interestingly, following this event, the intracellular domain (ICD) is also cleaved and is translocated to the nucleus where it modulates transcriptional activity [11]. Thus, the typeIII molecule acts as both a ligand and a receptor for erbB4 dimers, participating in bi-directional signaling. Similar release of the ICD is also observed upon depolarization of the plasma membrane [11]. The mechanistic details of the back-signaling pathway are still largely uncovered. However, studies have shown that there are two main modes of back-signaling, one mediated by phosphatidylinositol 3-kinase (PI3K) and the other via the intracellular domain (ICD) migrating to the nucleus [9]. The PI3K mediated back-signaling pathway has been associated with surface trafficking of α7nAChRs in sensory neurons [9]. There has been some evidence from human post-mortem studies linking schizophrenia associated Single Nucleotide Polymorphisms (SNPs) in NRG1 and CHRNA7 transcript levels in the brain [12]. Thus, Nrg1 might not only affect the levels of functional α7nAChR by regulating the surface expression profile of neurons, but might also regulate the expression of the gene encoding for them. Although there is evidence for the involvement of PI3K mediated back signaling in α7nAChR trafficking, there has been no direct evidence for demonstrating that that ICD-mediated back signaling is involved in the upregulation of the CHRNA7 gene. In this study, we aim to understand the involvement of typeIII Nrg1 in the transcriptional control of the CHRNA7 gene. In order to study this, we used the Neuro-2A, neuroblastoma cell line (N2a). N2a cells do not endogenously express NRG1 and hence provide us with a “vanilla background” to study mechanistic aspects of typeIII Nrg1 signaling. N2a cells can be maintained in culture with relative ease and


differentiated into neuronal phenotypes. N2a cells expressing type III Nrg1 with an YFP reporter and a Flag-tag fused with the ICD were obtained from Dr. Kevin Czaplinski. The parental N2a cell line and N2a cells expressing Nrg1 (Nrg-YFP) were characterized for any differences in growth kinetics, differentiation, and gene expression. The N2a (NrgYFP) cells were also characterized for ICD-mediated back signaling in response to sErbB4 and depolarization by KCl. The parental N2a cells and N2a (Nrg-YFP) cells were stimulated with sErbB4 and probed for expression of α7nAChRs by immunofluorescence. Our results demonstrate that typeIII Nrg1 back-signaling initiated via ErbB4 binding increases total expression of α7nAChRs measured by Bungarotoxin binding and is in the process of being confirmed using other techniques. A

B

SuperScript III reverse transcriptase (Invitrogen) to make cDNA. Immunofluorescence Cells were fixed with 4% PFA for twenty minutes at RT, permeabilized with 0.5% Igepal (where indicated) for five minutes at RT, blocked with 10% NDS/NGS, and incubated with primary antibodies overnight at 4°C. The following primary antibodies were used: antiFlag (1:500; Santa Cruz Biotechnologies Inc.), and Pan-axonal neurofilament maker (1:1000; Covance Inc.). For α Bungarotoxin staining, cells were incubated in Bgtx conjugated with A594 (1:1000; Invitrogen) overnight at 4°C. Cells were washed and incubated in secondary antibodies conjugated to Alexa 488 (1:1000; Invitrogen), Alexa 594 (1:1000; Invitrogen), for one hour at RT. RESULTS AND DISCUSSION Type III Nrg1 expression in N2a cells does not affect growth and differentiation properties

C

Figure 2 Nrg1 typeIII expression in N2a cells does not affect growth kinetics. The growth curves

indicate a population doubling time of approximately 17 hours for the N2a cells and 17.28 hours for the N2a (Nrg-YFP) cells.

Figure 1 Nrg1 structure and processing. A.) Ig Nrg1 and CRD-Nrg1 generalized structure

depicting the prominent functional domains. B & C.) Nrg 1 processing: Ig Nrg1s are processed by ADAM10/17 and BACE1 resulting in the generation of a soluble N-terminal fragment (NTF), which can bind erbB receptors. CRD-Nrg1 is processed similarly by cell-surface metalloproteases. However, it generates a membrane tethered NTF which can bind to erbB4:B4 in close proximity. The ICD of CRD-Nrg1 is also cleaved (possibly by gamma-secretase).

MATERIALS AND METHODS Cell culture and Differentiation N2a parental line and the N2a (Nrg1-ICD-YFP) line were maintained in Dulbecco’s Minimal Essential Medium (DMEM), supplemented with 10% Fetal Bovine Serum (FBS) and 1:1000 Gentamycin at 37°C in a 5% CO 2 incubator. Differentiation was induced by serum starvation and/or retinoic acid treatment. For differentiation, cells were plated onto Poly-D-lysine/Laminin coated coverslips at a density of 20,00050,000 cells/well in a 12 well plate in DMEM supplemented with 10% FBS and 1:1000 Gentamycin. 24 hours later, the media was changed to DMEM with 1%FBS and 1:1000 Gentamycin. 24 hours following, the media was changed to DMEM containing 0.1% FBS 1:1000 Gentamycin and cells were maintained at this stage until sufficient neuritogenesis was observed. Alternatively, 0.1μM all-trans Retinoic Acid was added to the differentiation media.

In order to study mechanistic aspects of Nrg1 signaling, it was essential to establish a model system. In this investigation, we used the N2a cell line as a model to study back signaling via the Nrg1 typeIII ICD. Characterization of the N2a cell line for Nrg1 typeIII signaling was a preliminary goal for our study. Bao et al. indicated that back signaling via the ICD of typeIII Nrg1 affected transcription of genes related to cell cycle and apoptosis regulation [11]. We wanted to ensure that ectopic expression of NRG1 in N2a cells did not affect growth kinetics of the cell line. The results indicate that expression of Nrg1 typeIII in N2a cells does not cause any significant changes in the population doubling times (Figure 2).

sErbB4 and KCl treatment Cells were stimulated by sErbB4 at a final concentration of ~300 ng/mL in DMEM with 0.1%FBS and 1:1000 Gentamycin at 37°C in a 5% CO 2 incubator. Cells were depolarized using KCl at a final concentration of 50mM in DMEM at 37°C in a 5% CO 2 incubator for 5-7 minutes followed by 2 washes in DMEM and incubation in DMEM with 0.1%FBS and 1:1000 Gentamycin at 37°C in a 5% CO 2 incubator. RNA extraction and RT-PCR Total RNA was extracted using TRIzol® Reagent (Invitrogen). 1μg of total RNA was reverse transcribed by oligo DT-primers using

Figure 3 Differentiation of N2a cells by serum starvation. Differential interference contrast im-

age of differentiated A) N2a cells and B) N2a cells expressing Nrg1 typeIII. Figures C and D indicate the expression of neurofilaments (red).

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Differentiation of N2a cells by serum starvation resulted in a predominantly axonal phenotype indicated by a pan-axonal neurofilament marker (Figure 3C and 3D). Expression of Nrg1 typeIII did not seem to interfere with the differentiation in N2a cells. Analysis of differentiation as measured by the length and number of processes did not show any significant differences between the two cell lines. Further characterization of the differentiated cells in terms of neural markers, their neurotransmitter and receptor expression profiles has is yet to be carried out.

like cells, they should have expressed α7nAChRs. Whether they express other forms of nicotinic acetylcholine receptors is not known. Detection of α7nAChRs with αBungarotoxin-594 in N2a (Nrg1-ICDYFP) upon stimulation with sErbB4

Stimulation of typeIII Nrg1 by sErbB4 treatment or KCl results in the translocation of the ICD into the nucleus in N2a cells

Figure 6 Expression of α7nAChRs was detected by αBgTx-594 labelling. A) Differentiated N2a (Nrg-YFP) cells. B & C) Differentiated N2a(Nrg-YFP) cells stimulated with serbB4:B4 overnight. Presence of αBgTx-594 (red) puncta can be noted. D) Differentiated N2a cells. E) Differentiated N2a cells stimulated with serbB4 overnight.

Figure 4 Stimulation of N2a (Nrg-YFP) cells by serbB4:B4 and depolarization by application

of 50mM KCl. A) Undifferentiated N2a (Nrg-YFP) cells. B) Undifferentiated N2a (Nrg-YFP) cells stimulated with serbB4:B4 for 20min. C) Differentiated N2a (Nrg-YFP) cells. D) Differentiated N2a (Nrg-YFP) cells stimulated with serbB4:B4 for 20min. E) Differentiated N2a (Nrg-YFP) cells depolarized with KCl for 5min.

Stimulation of N2a cells expressing Nrg1 typeIII results in the migration of the intra-cellular domain into the nucleus detected by ICD puncta in the nucleus. ICD staining prior to stimulation (Figure 4A and 4C) is mainly peripheral. Back signaling via the ICD is functional in N2a cells and is responsive to both serbB4:B4 binding as well as depolarization of the cell membrane by the application of 50mM KCl. Poststimulation, ICD staining is diffuse and shows concentration in a ER/ Golgi like area outside the nucleus and puncta that colocalize with the nuclear stain (Figures 4B, 4D and 4E). N2a cells do not express α7nAChRs upon differentiation regardless of Nrg1 expression

A.

B.

Figure 5 Parental N2a and N2a (Nrg-YFP) cells were differentiated by serum starvation. Total

RNA was collected and converted to cDNA. Gene specific PCR for CHRNA7 and TBP was performed to probe for the relative expression of α7nAChR. Whole Brain cDNA and α7nAChR knockout neuronal cDNA were used as positive and negative controls respectively. Amplified products were resolved on an agarose gel and visualized using ethidium bromide A) Whole brain cDNA lane shows the expected product of ~214bp for CHRNA7 transcripts. N2a cells do not express α7nAChRs upon differentiation or expression of Nrg1 typeIII. B) Presence of TBP (119bp) amplified product in all samples.

N2a cells do not express α7nAChRs. Differentiation of N2a cells via serum starvation did not induce CHRNA7 expression. Nrg1 typeIII expression did not seem to change this phenotype in N2a cells either (Figure 5). N2a cells are neuroblastoma cells derived from the neural crest [13]. Neural crest stem cells have one of their fates as peripheral neurons. Thus, if the N2a cells differentiated into sympathetic neuron-

42

Stimulation via serbB4:B4 results in the visualization of α7nAChRs in N2a cells expressing Nrg1 typeIII, as detected by αBgTx-594 binding (Figure 6). The αBgTx stain shows colocalization with the ICD/Nrg1typeIII in an ER/Golgi-like area outside the nucleus. The presence of α7nAChRs by αBgTx was not detected in N2a, cells thereby implying that the effect is possibly due to Nrg1-typeIII back signaling. Depolarization by KCl also elicits back signaling, but whether it leads to similar observation of increased expression of α7nAChR is ambiguous. CONCLUSION The main finding of our study was that typeIII Nrg1 might regulate expression of the CHRNA7 gene. TypeIII Nrg1 has been referred to as a neuronal acetylcholine receptor-inducing agent (nARIA) [5]. Previous studies have shown that the type III isoform of Nrg1 regulates the surface expression of α7nAChRs, thereby affecting the levels of functional α7 receptors. Our results suggest that Nrg1typeIII might also have a transcriptional control over α7nAChR expression. Lower CHRNA7 transcript and α7nAChR levels in the brains of patients suffering with schizophrenia correlate with the presence of NRG1 risk alleles [12]. Nrg1 TypeIII participates in bi-driectional signaling with its binding partner erbB4. Stimulation of erbB4 by CRD-Nrg1 has been shown to increase expression of CHRNA7 in sympathetic neurons [14]. Therefore, the decreased transcript levels could be a result of aberrant forward signaling, however, our results point towards back signaling also being a possible contributing factor. We are currently in the process of confirming this result using other techniques such as RT-PCR and Immunoblotting. Previous analysis of the ICD has displayed no obvious DNA binding domains [11]. Thus, if the ICD does indeed participate in the upregulation of CHRNA7, how it does so is not known. Current experiments are aimed at examining whether the ICD interacts with the CHRNA7 promoter region. Results from the study might help us understand mechanistic aspects of Nrg1 typeIII mediated transcriptional control and possibly give us an insight into how Nrg1 contributes to susceptibility to schizoaffective disorders.


References

1. Alaerts, M., S. Ceulemans, D. Forero, L. N. Moens, S. De Zutter, L. Heyrman, A.-S. Lenaerts, K.-F. Norrback, P. De Rijk, L.-G. Nilsson, D. Goossens, R. Adolfsson, and J. Del-Favero. “Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population.” Archives of General Psychiatry 66.8 (2009): 828-37. Print. 2. Stefansson, H., H. Petursson, E. Sigurdsson, V. Steinthorsdottir, S. Bjornsdottir, T. Sigmundsson, S. Ghosh, J. Brynjolfsson, S. Gunnarsdottir, and O. Ivarsson. “Neuregulin 1 and Susceptibility to Schizophrenia.” The American Journal of Human Genetics 71.4 (2002): 877-92. Print. 3. Kukshal, Prachi, Triptish Bhatia, A.m. Bhagwat, Raquel E. Gur, Ruben C. Gur, Smita N. Deshpande, Vishwajit L. Nimgaonkar, and B.k. Thelma. “Association Study of Neuregulin-1 Gene Polymorphisms in a North Indian Schizophrenia Sample.”Schizophrenia Research 144.1-3 (2013): 24-30. Print. 4. Huertas-Vazquez, Adriana, Carmen Teodorescu, Kyndaron Reinier, Audrey Uy-Evanado, Harpriya Chugh, Katherine Jerger, Jo Ayala, Karen Gunson, Jonathan Jui, Christopher NewtonCheh, Christine M. Albert, and Sumeet S. Chugh. “A Common Missense Variant in the Neuregulin 1 Gene Is Associated with Both Schizophrenia and Sudden Cardiac Death.” Heart Rhythm 10.7 (2013): 994-98. Print. 5. Harrison, Paul J., and Amanda J. Law. “Neuregulin 1 and Schizophrenia: Genetics, Gene Expression, and Neurobiology.” Biological Psychiatry 60.2 (2006): 132-40. Print. 6. Chen, Y.-J. J., M. A. Johnson, M. D. Lieberman, R. E. Goodchild, S. Schobel, N. Lewandowski, G. Rosoklija, R.-C. Liu, J. A. Gingrich, S. Small, H. Moore, A. J. Dwork, D. A. Talmage, and L. W. Role. “Type III Neuregulin-1 Is Required for Normal Sensorimotor Gating, Memory-Related Behaviors, and Corticostriatal Circuit Components.” Journal of Neuroscience 28.27 (2008): 6872-883. Print. 7. Martin, Laura F., Sherry Leonard, Mei-Hua Hall, Jason R. Tregellas, Robert Freedman, and Ann Olincy. “Sensory Gating and Alpha-7 Nicotinic Receptor Gene Allelic Variants in Schizoaffective Disorder, Bipolar Type.” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 144B.5 (2007): 611-14. Print. 8. Simosky, J.k., K.e. Stevens, and R. Freedman. “Nicotinic Agonists and Psychosis.”Current Drug Targets-CNS & Neurological Disorders 1.2 (2002): 149-62. Print. 9. Hancock, M. L., S. E. Canetta, L. W. Role, and D. A. Talmage. “Presynaptic Type III Neuregulin1ErbB Signaling Targets 7 Nicotinic Acetylcholine Receptors to Axons.” The Journal of General Physiology 131.6 (2008): I4. Print. 10. Zhong, C., C. Du, M. Hancock, M. Mertz, D. A. Talmage, and L. W. Role. “Presynaptic Type III Neuregulin 1 Is Required for Sustained Enhancement of Hippocampal Transmission by Nicotine and for Axonal Targeting of 7 Nicotinic Acetylcholine Receptors.” Journal of Neuroscience 28.37 (2008): 9111-116. Print. 11. Bao, J., D. Wolpowitz, L. W. Role, and D. A. Talmage. “Back Signaling by the Nrg-1 Intracellular Domain.” The Journal of Cell Biology 161.6 (2003): 1133-141. Print. 12. Mathew, S. V., A. J. Law, B. K. Lipska, M. I. Davila-Garcia, E. D. Zamora, S. N. Mitkus, R. Vakkalanka, R. E. Straub, D. R. Weinberger, J. E. Kleinman, and T. M. Hyde. “A7 Nicotinic Acetylcholine Receptor MRNA Expression and Binding in Postmortem Human Brain Are Associated with Genetic Variation in Neuregulin 1.” Human Molecular Genetics 16 (2007): 2921-932. Web. 13. Tremblay, Roger G., Marianna Sikorska, Jagdeep K. Sandhu, Patricia Lanthier, Maria RibeccoLutkiewicz, and Mahmud Bani-Yaghoub. “Differentiation of Mouse Neuro 2A Cells into Dopamine Neurons.” Journal of Neuroscience Methods 186.1 (2010): 60-67. Print. 14. Yang, Xia, Yuhung Kuo, Piroska Devay, Congrong Yu, and Lorna Role. “A Cysteine-Rich Isoform of Neuregulin Controls the Level of Expression of Neuronal Nicotinic Receptor Channels during Synaptogenesis.” Neuron 20.2 (1998): 255-70. Print.

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Young Investigator's Review Spring 2014 Issue  

2014.04.28 version

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