accelerating discoveries, saving lives · s tsri prof sv reed, w, p s n t t researcher l s a aai...

A Newsletter for Philanthropists Published Quarterly by The Scripps Research Institute

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Scientists Demonstrate Long-Sought Drug Candidate Can Halt Tumor Growth

Researchers Identify Gene that Plays a Surprising Role in Combating Aging

Team Finds New Calorie-Burning Switch in Brown Fat

Professor Steven Reed: Cells and Stress

Accelerating Discoveries, Saving Lives

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RESEARCH UPDATES


Team Successfully Targets Common Mutation in ALS, Frontotemporal Dementia

Surprising Diversity of Antibody Family Provides Clues for HIV Vaccine Design

Researchers Link Alcohol-Dependence Gene to Neurotransmitter



Researchers Find Genetic Mutations Linked to Salivary Gland Tumors

TSRI Chemists Modify Antibiotic to Vanquish Resistant Bacteria

GIVING

A Gift that Makes a Difference to Medical Research

PROFILES

Donor Julie Hill: Shedding Light on the People of the World—and the Value of Medical Research

60 Seconds with TSRI Professor Steven Reed

APPOINTMENTS, AWARDS, HONORS

Peter Schultz Named Top Translational Researcher

Linda Sherman Assumes AAI Presidency

Team Awarded $4.4 Million to Investigate 10-Minute DNA Sequencing Technology

Karsten Sauer and Stephanie Rigaud Receive Immunology Award

Stephanie Sillivan Receives Early-Career Award

BACK COVER

TSRI Screening Center Helps Advance Drug Candidate to Clinical Trials

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10-11

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IN THIS ISSUE

publisher: david blinder, senior vice president for external affairseditors and contributing writers: elliot wolf and mika onoillustration credit: cami abel photographers: john dole, james mcentee

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Scripps Research Institute Scientists Demonstrate Long-Sought Drug Candidate Can Halt Tumor Growth

It’s a trick any cat burglar knows: to open a locked door, slide a credit card past the latch.

Scientists at The Scripps Research Institute (TSRI) tried a similar strategy when they attempted to disrupt the function of MYC, a cancer regulator thought to be “undruggable.” The researchers found that a credit card-like molecule they developed somehow moves in and disrupts the critical interactions between MYC and its binding partner.

The research, published in the journal Proceedings of the National Academy of Sciences, also shows the drug candidate can stop tumor growth in animal models.

“We finally hit a home run with this—maybe a grand slam,” said Kim Janda, co-author of the new study and Ely R. Callaway, Jr. Professor of Chemistry, director of the Worm Institute for Research and Medicine, and Skaggs Scholar and member of the Skaggs Institute for Chemical Biology at TSRI.

Team Successfully Targets Common Mutation in Lou Gehrig’s Disease, Frontotemporal Dementia

An international team led by scientists from TSRI’s Florida campus (Scripps Florida) and the Mayo Clinic have for the first time successfully designed a therapeutic strategy targeting a specific genetic mutation that causes a common form of amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, as well a type of frontotemporal dementia (FTD).

The scientists developed small-molecule drug candidates and showed they interfere with the synthesis of an abnormal protein that plays a key role in causing both diseases. The team also developed biomarkers that can test the efficacy of this and other therapies.

The study, led by Professor Matthew Disney of TSRI and Professor of Neuroscience Leonard Petrucelli of the Mayo Clinic, was published in the journal Neuron.

“Our small molecules target a genetic defect that is by far the most major cause of familial ALS, and if you have this defect you are assured of getting ALS or FTD,” Disney said. “Our findings show for the first time that targeting this mutation with a small-molecule drug candidate can inhibit toxic protein translation—and establishes that it could be possible to treat a large number of these patients, but this is just the start of these studies and additional investigations need to be done.”

Currently, ALS is usually fatal two to five years after diagnosis, and there is no effective treatment for FTD, a neurodegenerative disease that destroys neurons in the frontal lobes of the brain.

RESEARCH UPDATES


Team Successfully Targets Common Mutation in ALS, Frontotemporal Dementia







GIVING


PROFILES

Donor Julie Hill: Shedding Light on the People of the World—and the Value of Medical Research

60 Seconds with TSRI Professor Steven Reed

APPOINTMENTS, AWARDS, HONORS






BACK COVER

TSRI Screening Center Helps Advance Drug Candidate to Clinical Trials

RESEARCH UPDATES


TSRI scientists have described how a single family of antibodies that broadly neutralizes different strains of HIV has evolved remarkably diverse structures to attack a vulnerable

site on the virus. The findings provide clues for the design of a future HIV vaccine.

“In a sense, this antibody family takes more than one shot on goal in order to hit divergent forms of HIV,” said Ian A. Wilson, the Hansen

Professor of Structural Biology, chair of the Department of Integrative Structural and Computational Biology and member of the Skaggs Institute for Chemical Biology at TSRI.

“The findings give us new options for vaccine design,” added TSRI Professor Dennis R. Burton, who directs the Interna-tional AIDS Vaccine Initiative’s (IAVI) Neutralizing Antibody Consortium and the National Institutes of Health-sponsored Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI.

The new research, reported in the journal Cell, is part of a broad effort to “retro design” an effective HIV vaccine, based on an understanding of rare, natural antibodies that effectively hit HIV’s most vulnerable sites.


TSRI scientists have solved the mystery of why a specific signaling pathway can be associated with alcohol dependence.

This signaling pathway is regulated by a gene, called neuro-fibromatosis type 1 (Nf1), which TSRI scientists found is linked with excessive drinking in mice. The new research shows Nf1 regulates gamma-aminobutyric acid (GABA), a

neurotransmitter that lowers anxiety and increases feelings of relaxation.

“This novel and seminal study provides insights into the cellular mechanisms of alcohol dependence,” said TSRI Associate Professor Marisa Roberto, a co-author of the paper. “Importantly, the study also offers a correlation between rodent and human data.”

In addition to showing that Nf1 is key to the regulation of the GABA, the research, which was published recently in the journal Biological Psychiatry, shows that variations in the human version of the Nf1 gene are linked to alcohol-dependence risk and severity in patients.

Pietro Paolo Sanna, associate professor at TSRI and the study’s senior author, was optimistic about the long-term clinical implications of the work. “A better understanding of the molecular processes involved in the transition to alcohol dependence will foster novel strategies for prevention and therapy,” he said.


It is something of an eternal question: Can we slow or even reverse the aging process? Even though genetic manipulations can, in fact, alter some cellular dynamics, little is known about the mechanisms of the aging process in living organisms.

Now scientists from Scripps Florida have found in animal models that a single gene plays a surprising role in aging that can be detected early on in development, a discovery that could point toward the possibility of one day using therapeutics, even some commonly used ones, to manipulate the aging process itself.

“We believe that a previously uncharacterized developmental gene known as Spns1 may mediate the aging process,” said Shuji Kishi, a TSRI assistant professor who led the study, published recently by the journal PLOS Genetics. “Even a partial loss of Spns1 function can speed aging.”

Using various genetic approaches to disturb Spns1 during the embryonic and/or larval stages of zebrafish—which have emerged as a powerful system to study diseases associated with development and aging—the scientists were able to produce some models with a shortened life span, others that lived long lives.

The findings provide clues for the design of a future HIV vaccine.

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Throughout the year, you have read in Scripps Discovers about our research programs that tackle many dreaded diseases including cancer, diabetes, Alzheimer’s, Ebola and more. Now is your opportunity to help accelerate our research efforts with a year-end charitable gift to The Scripps Research Institute (TSRI). Simply visit our website at www.supportscrippsresearch.org and click on the Donate Now button.

If you’d like to learn more about other types of gifts to benefit TSRI, visit our planned giving website, Discover the Benefits of Giving Wisely at www.plannedgiving.scripps.edu. There you will find a resource of ideas and information on how to support our world-class research through estate and charitable planning, including tips for calculating your charitable gifts tax deduction and

inspirational stories about people like you who have supported TSRI with charitable planning.

Of course, if you would like to contact us directly, we would be happy to help you maximize your charitable opportunities and reach your financial goals. For more information, please contact Geoff Graham, director of planned giving and estates, at (858) 784-9365 or [email protected]. In Florida, contact Irv Geffen, director of major gifts and planned giving, at (561) 228-2017 or [email protected].

When considering charitable gifts, you are urged to seek the advice of your own financial and legal advisor(s) about your specific situation.

GIVING


Biologists at The Scripps Research Institute (TSRI) have identified a signaling pathway that switches on a powerful calorie-burning process in brown fat cells.

The study, which was reported recently in the Proceedings of the National Academy of Sciences, sheds light on a process known as “brown fat thermogenesis,” which is of great interest to medical researchers because it naturally stimulates weight loss and may also protect against diabetes.

“This finding offers new possibilities for the therapeutic activation of brown fat thermogenesis,” said team leader Anastasia Kralli, associate professor in TSRI’s Departments of Chemical Physiology and Cell Biology.


Research conducted at Scripps Florida has discovered links between a set of genes known to promote tumor growth and mucoepidermoid carcinoma, an oral cancer that affects the salivary glands. The discovery could help physicians develop new treatments that target the cancer’s underlying genetic causes.

The research, recently published by the Proceedings of the National Academy of Sciences, shows that a pair of proteins joined together by a genetic mutation—known as CRTC1/

MAML2 (C1/M2)—work with MYC, a protein commonly associated with other cancers, to promote the oral cancer’s growth and spread.

“This research provides new insights into the molecular mechanisms of these malignances and points to a new direction for potential therapies,” says TSRI biologist Michael Conkright, who led the study.


TSRI scientists have devised a new antibiotic based on vancomy-cin that is powerfully effective against vancomycin-resistant strains of MRSA and other disease-causing bacteria.

The new vancomycin analog appears to have not one but two distinct mechanisms of anti-microbial action, against which bacteria probably cannot evolve resistance quickly.

“This is the prototype of analogues that, once introduced, will still be in clinical use a generation or maybe even two generations from now,” said Dale L. Boger, the Richard and Alice Cramer Professor of Chemistry at TSRI.

The report by Boger and members of his laboratory was published recently by the Journal of the American Chemical Society


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Julie Hill is a happily footloose world traveler and author with a restless love of adventure, but she has faced challenging times as well.

An Alexandrian Greek, Julie met her late husband, Arthur, an Australian, when both were in graduate school in America. It was a golden marriage of 43 years, she says. Work opportunities brought them to faraway places with names that began to enter international consciousness only decades later—Thailand, the Philippines, Western Samoa and Afghanistan. Arthur represented the Ford Foundation and later on the United Nations Develop-ment Program, while Julie entered the corporate world of AT&T.

In 1986, Arthur had been diagnosed with a rare blood cancer known as hairy cell leukemia. He was treated with alpha interferon, but his immune system was compromised, and he lost so much weight he appeared skeletal. He was not expected to live. He read an article in The New York Times about TSRI’s development of 2-CdA (now marketed as Leustatin®) for the disease. He came to La Jolla and became patient #66 in 2-CdA clinical trials. A week later, his physician, Dr. Alan Saven at Scripps Health, told him that “there was no more circulating hairy cell leukemia.” He remained disease-free for almost 12 years until he passed away from other causes.

“Sometimes it’s difficult to be a believer, but I’m a true believer in TSRI,” said Julie, “I’m convinced of the value of its research—it saved my husband’s life. I’m also impressed with the inspiring enthusiasm of the young scientists I met at TSRI.”

In the ensuing years after Arthur’s treatment, he and Julie became major donors to TSRI. She remains a contributor and has created a bequest to benefit TSRI in hopes that her support will result in an endowed chair for cancer research for a young scientist, leading to development of more treatments like 2-CdA.

Julie has spent the past four decades exploring the planet and writing about it. Fluent in five languages, she authored the book Promises to Keep in 2003, after her husband’s death, followed a few years later by her second book, The Silk Road Revisited: Markets, Merchants, and Minarets. This year, she published her third book, Privileged Witness: Journeys of Rediscovery, where she takes us in hand on her journeys around 20 countries, from Asia to Africa. Although she has met many foreign dignitaries, what’s really rewarding for her is the interaction with the common people, be they tribesmen, children, or just ordinary folks trying to make a living and carve a better life for their children.

julie hill world traveler and author

DONOR PROFILEJulie Hill: Shedding Light on the

People of the World—and the Value of Medical Research

“I’m impressed with the inspiring enthusiasm of the young

scientists I met at TSRI.”

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“I’m a true believer in TSRI. I’m convinced of the value of its research—

it saved my husband’s life.”

julie hill

“In my travels I have discerned a similarity among people who bear the same universal aspirations: all want their children to lead a better life and have a better future than theirs; they all cry, laugh, eat, worry and die,” said Julie. “We share so much, but still have to work at under-standing one another. When I travel to India, I meet kids on the road.

What do I ask beyond “What is your name?” So I have learned the names of India’s leading cricket players—the better to open a conversation with those boys who loiter on the temple steps.”

In the nine months of the year that she’s home, Julie mentors graduate students at the UCSD Graduate School of International Relations and Pacific Studies. She enjoys sharing her wisdom with these students of various nationalities. “They have become my extended family,” she said.

Julie is scheduled to speak at a lunch with a group of TSRI graduate students, offering thoughtful insights based on her international experience on leadership, women in the work-place, negotiation tactics and inter-industry transferable skills.

By investing in young “up-and-coming” scientists, Julie Hill is both providing a meaningful tribute to her late husband, Arthur, and playing a critical role as a true partner in medical research.

When Arthur Hill developed hairy cell leukemia, he was treated with 2-CdA—a drug developed at Scripps that cleared all signs of his disease.

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“It’s exciting that my whole career is now culminating in doing something

useful for society.”

SCIENTIST PROFILE60 Seconds with: TSRI Professor Steven Reed

Tell us about your research and the diseases it impacts.We work on many diverse projects. One area of particular interest to us is how certain proteins determine whether cells will survive stress. Many diseases, such as diabetes and a host of neurodegenerative diseases, are due to stress-related cell death. We have discovered a promising pathway that we think can keep cells alive and force them to function. This discovery could result in many devastating diseases being mitigated and in some cases, cured.

Parkinson’s disease is devastating and unfortunately there is no cure or even an effective treatment because the disease is not really understood. A number of years ago, we made a significant discovery that could lead to a new therapeutic strategy for Parkinson’s disease, Huntington’s disease, ALS, and other neurodegenerative diseases. We focused on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson’s disease. Precisely how the loss of this enzyme leads to the deaths of neurons had been unclear. But we showed that parkin’s loss sharply reduces the level of another protein that normally helps protect neurons from stress and therefore keeps them alive. We have therefore focused on pharmacological ways of keeping levels of this protein high.

One application, in addition to neurological diseases such as Parkinson’s disease, is stroke, where a portion of the brain is starved of both nutrients and oxygen. Since nerve cells can’t live long under these conditions and because they can’t be regenerated, intellectual and motor deficits typically occur after a stroke. There is currently nothing on the market that can save these cells when under so-called ischemic conditions, but we’re working towards a potential drug that could keep neurons alive and thereby greatly reduce brain damage. Our work has evolved from basic research on cell cultures to developing lead compounds that we’re now testing in animal models. Hopefully, these will be successful and we can fast track these treatments to clinical trials for stroke and other diseases.

We also work on cancer and have discovered a basic mechanism that can enable developing cancer cells to sustain abnormal growth. This work will hopefully lead to the targeting of this mechanism with drugs and diagnostic techniques. We were able to illuminate the roles of two nearly identical proteins that were known to be overexpressed in many cancers, but no one understood why. It now appears that the proteins’ overexpression enables cancerous growth by nullifying a natural defense against uncontrolled cell division. We have discovered, however, that this makes those specific cancer cells extremely vulnerable to a specific novel chemotherapeutic strategy.

How did you get involved in science?Ever since I was five years old, I’ve been a science nerd—nothing else appealed to me as much as the idea of becoming a scientist. Well, except I wanted to be a rock star for a while but that didn’t pan out.

What motivates you and what do you hope to accomplish?I’ve always wanted to know what makes things tick and to try to under-stand living things at a very fundamental level. In science, my career

professor steven reed

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started by focusing on the basic mechanisms that control cell division. This eventually led me to the research of diseases, especially cancer, since it is a disease of cell division. Our work on stroke and neurodegenerative diseases is a spin-off of our work in cancer, where we had identified an interesting protein. Actually my wife, Sanna, who works with me, took the research in a different direction and found that it had other functions relevant to survival of cells in the brain. Today, my primary interest is in using basic biological knowledge to develop new therapeutic approaches and ultimately drugs to cure diseases. It’s exciting that my whole career is now culminating in doing something useful for society beyond the theoretical. This certainly wasn’t a given when I started out.

Why did you come to TSRI and what do you like about it?I came here in 1986 because I had the freedom to do what I wanted here—I was able to spend more time and energy on my research than elsewhere. I like the idea of being able to do what interests me without many competing obligations. I have no regrets. It’s been a great run for me at TSRI. I’ve also been able to train many great graduate students and postdoctoral fellows who have gone on to do wonderful things—I’m still good friends with many of them. San Diego is a great place to do research. It has such a vibrant research community—it’s one of the most intensive high-quality research zones in the world.

Do you have a need for private philanthropy for your research?Philanthropy helps accelerate discoveries in disease research—research is getting more and more expensive with the cutting-edge technologies that are now available to us. National Institutes of Health funding is extremely hard to come by these days. The NIH is funding a much smaller percentage of grants than before. As a result, we have a number of projects to test compounds in animal models that have not yet been funded. These projects could move forward with philanthropy, and as a result, might be propelled rapidly into clinical trials. So, the financial impact of philanthropy can be real with the NIH funding vacuum, which is not liable to change anytime soon. Therefore, supporting TSRI is likely to have a big impact on basic science and the therapeutics that will treat and cure human diseases.

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Peter Schultz, Scripps Family Chair Professor and member of the Skaggs Institute for Chemical Biology at TSRI, was ranked the top translational researcher in 2013, according to a study in the August 2014 issue of Nature Biotechnology.

The ranking is based on total patents awarded to faculty members at their current affiliations who were among corresponding authors on 200 papers highlighted in 2013 in the publication SciBX.

Schultz tops the study’s list of 20 scientists with 93 U.S. and European patents. Schultz’s translational research activities at TSRI are centered on regenerative medicine, cancer, autoimmune and orphan/neglected diseases, previously in collaboration with the Genomics Institute of the Novartis Research Foundation and more recently with the California Institute for Biomedical Research, where he serves as director.


TSRI Professor Linda Sherman has assumed the presidency of the American Association of Immunologists (AAI), a 101-year-old international organization of scientists dedicated to advancing the knowledge of immunology and its related disciplines.

An active AAI member for more than 30 years, Sherman began her one-year term July 1. The 7,600-member professional organization fosters the exchange of information and ideas among investigators and addresses the potential integration of immunologic principles into clinical practice. AAI also publishes the Journal of Immunology.

Sherman’s TSRI lab studies autoimmunity and tumor immunity, in particular examining how expression of proteins in normal tissues or tumor cells alters recognition and responsiveness by T lymphocytes to antigens of these proteins.


TSRI scientists have been awarded a four-year $4.4 million grant from the National Human Genome Research Institute to advance DNA sequencing technologies.

“If we can inexpensively, rapidly and accurately sequence the whole genome, cancer treatments could be different and monitoring someone during the course of treatment would be different,” said Professor M. Reza Ghadiri, who is principal investigator of the grant.

Ghadiri will develop “lab on a chip” technology, technically known as protein nanopore arrays, working toward techniques that could be used by physicians for DNA sequencing to better tailor care to the individual patient.

APPOINTMENTS, AWARDS ,

and HONORS

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In nanopore-based DNA sequencing, single strands of DNA pass through microscopic holes while the holes “read” the bases in the DNA sequence by detecting changes in electrical conductance. Current technology takes at least one week to sequence an entire genome, but Ghadiri hopes that by creating an array with thousands—or even millions of nanopores—the DNA-sequencing process could be completed in 10 minutes. Ghadiri said developing a more efficient process would also help lower the cost of sequencing and make it more practical for patients and their doctors.


TSRI Associate Professor Karsten Sauer and Stephanie Rigaud, research associate in the Sauer lab, have received a Careers Immunology Fellowship award from the American Association of Immunologists (AAI), a 101-year-old international organization of scientists dedicated to advancing the knowledge of immunology and its related disciplines.

The supported project studies signal transduction mechanisms that ensure the generation of a pathogen-reactive but self-tolerant T cell repertoire. Defects in these mechanisms cause immune deficiencies and autoimmune diseases such as rheumatoid arthritis or type 1 diabetes. By elucidating the underlying mechanisms, the Sauer lab hopes to ultimately develop improved therapies for these serious and unpreventable diseases.


Stephanie Sillivan, research associate in the Miller lab, has received a Young Investigator Award from the Brain & Behavior Research Founda-tion (formerly NARSAD), a nonprofit organization that promotes scientific research targeted at understanding the causes of, and improving treatments for, mental illness.

The two-year NARSAD grant supports promising young scientists conduct-ing neurobiological research, enabling early-career researchers to garner pilot data for innovative ideas prior to achieving proof-of-concept for their work.

Sillivan’s research is directed at understanding the mechanisms that support long-term memories, in particular traumatic or pathogenic memories that persevere over an extended period of time. This work has broad implications for neuropsychiatric disorders with a memory compo-nent, such as post-traumatic stress disorder, Alzheimer’s disease and substance use disorder.

The Molecular Screening Center at TSRI’s California campus has played an essential role in advancing to clinical trials a new compound to treat multiple myeloma, the second-most common form of cancer of the blood.

The compound, CB-5083, is produced by Cleave Biosciences, a biotechnology company headquartered in Burlingame, California. CB-5083 is a first-in-class, oral inhibitor of p97, a critical enzyme that controls various aspects of protein homeostasis.

Under the auspices of a National Institutes of Health (NIH) Molecular Libraries Screen Centers Network grant, spear- headed by TSRI Professor Hugh Rosen and in collaboration

with Professor Raymond Deshaies of the California Institute of Technology, TSRI scientists screened an NIH network library of small molecules (nearly 220,000 at that time) searching for potential p97 inhibitors. They narrowed the field to the top 50 candidates—cutting years off the research process.

The CB-5083 Phase I clinical trial will evaluate the

compound’s safety and efficacy in multiple myeloma

patients with relapsed/refractory or refractory disease who

have not responded to other forms of therapy. According to

the National Cancer Institute, an estimated 70,000 people

are living with multiple myeloma in the U.S., and approxi-

mately 24,050 new cases will be diagnosed this year.

TSRI SCREENING CENTER HELPS ADVANCE DRUG CANDIDATE TO CLINICAL TRIALS

Geoff C. Graham (858) 784-9365 or (800) 788.4931 [email protected]

Alex Bruner (561) 228-2013 [email protected]

FL: 130 Scripps Way, 4B2 Jupiter, FL 33458

CA: 10550 North Torrey Pines Road, TPC-2La Jolla, CA 92037

To learn more about supporting TSRI’s cutting-edge research, please contact:

www.supportscrippsresearch.org

The Scripps Research Institute is a 501(c)(3) not-for-profit organization, Tax ID# 33-0435954. A copy of the official registration (#CH17266) and financial information may be obtained from the Division of Consumer Services by calling toll-free (800-435-7352) within the State of Florida. Registration does not imply endorsement, approval, or recommendation by the State.

“At TSRI, the unique advantages we have in terms of scientific environment, colleagues and

facilities means our impact on human health can be disproportionately large.”

—hugh rosen

accelerating discoveries, saving lives · s tsri prof sv reed, w, p s n t t researcher l s a aai...

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