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Solving a Key Enzyme's Structure

Solving a Key Enzyme's Structure—The enzyme cytochrome c oxidase (CcO) plays a key role in enabling the mitochondria in cells to generate energy: It propels protons across the inner mitochondrial membrane so that molecules of ATP can be synthesized. But how CcO performs that function isn’t known. To help answer that question, the National Institute of General Medical Sciences has awarded Denis Rousseau, Ph.D. and Syun-Ru Yeh, Ph.D., a four-year, $2 million grant to determine CcO’s crystal structure. To do so, serial femtosecond crystallography with an X-ray free electron laser will be used, which should for the first time reveal the structure of the enzyme’s catalytic intermediates under near-physiological conditions. The findings could lead to therapies for some of the 40 or so diseases caused by defective mitochondrial function. Drs. Rousseau and Yeh are professors of physiology & biophysics at Einstein and Dr. Rousseau is chair of the department.

Thursday, December 14, 2017
Clues to Alphavirus Exit Strategy

Clues to Alphavirus Exit Strategy—Chikungunya is a mosquito-borne alphavirus that infects millions of people worldwide each year. Understanding how alphaviruses enter and exit the host cells could lead to treatments and vaccines. In a study published November 7 in mBio, Einstein researchers describe a mechanism required for membrane budding, the process by which the virus creates new infectious particles near the membranes of infected cells. They found that a region of the virus’s membrane proteins called the E2 D-loop plays a major role in the interaction of the membrane proteins, E1 and E2. The contact between the E2 D-loop and E1 drives the formation of the membrane structure required for alphavirus budding. The study’s senior author is Margaret Kielian, Ph.D., who holds the Samuel H. Golding Chair in Microbiology and is a professor of cell biology at Einstein; the first author is M.D./Ph.D. student Emily Byrd.

Tuesday, December 12, 2017
Understanding blood-forming stem cells

Understanding blood-forming stem cells—Hematopoietic stem cells (HSCs) not only renew themselves by dividing but also differentiate to form all of the body’s blood cells. But the mechanisms that keep HSC division and differentiation in balance remain unclear. Keisuke Ito, M.D., Ph.D., has received a five-year, $2.9 million grant to find the factors that determine the fate of HSCs. After transplanting HSCs into a mouse model, Dr. Ito and his colleagues will isolate and analyze individual HSCs to determine which fate they have chosen—division or differentiation—and what cellular factors caused them to make that choice. Findings from this study could, for example, allow scientists to manipulate HSCs so that they differentiate into blood for use in transfusions. Dr. Ito is associate professor of cell biology and of medicine and director of scientific resources at the Gottesman Institute for Stem Cell and Regenerative Medicine Research. (1R01DK115577)

Thursday, December 07, 2017
Reducing Opioid Use Disorder

Reducing Opioid Use Disorder—Eighty percent of people who have opioid use disorder (OUD) don’t get treated. Syringe exchange programs (SEPS) are a great way to reach many of these people, who receive sterile syringes and other health services at those sites. Aaron Fox, M.D., M.S., has received a $3.5 million, five-year NIH grant to conduct a 24-week clinical trial to evaluate the possible benefits of offering OUD treatment at SEPs. Two hundred fifty out-of-treatment opioid users who use SEPs will be randomized into two groups. People in the experimental group will receive on-site buprenorphine maintenance treatment (shown to reduce opioid use and overdose and HIV risk behaviors) and then will be referred to a community health center (CHC) for continued care. People in the control group won’t receive buprenorphine maintenance treatment at SEPS but will be referred directly to a CHC for buprenorphine treatment. The researchers will evaluate whether receiving OUD treatment at SEPS encourages people to remain in treatment and reduces HIV-risk behavior. Dr. Fox is associate professor of medicine at Einstein and attending physician at Montefiore. (1R01DA044878)

Thursday, December 07, 2017
Studying Roundworms to Treat Alzheimer's

Studying Roundworms to Treat Alzheimer's—Humans are not the only organisms faced with age-related declines in thinking ability and memory. The same problems afflict the roundworm C. elegans. The NIH has awarded Einstein scientists a five-year, $3.7 million grant to seek new Alzheimer’s treatments by combining roundworm and human research. Using tools for studying memory in worms and identifying gene expression changes in worm neurons, the researchers will identify genes that change with age and are risk factors for Alzheimer’s. They’ll combine those results with findings from human genome-wide association studies, which indicate that changes in gene regulation are responsible for cases of heightened genetic risk for Alzheimer’s. This approach will identify gene regulatory networks shared by humans and worms and may provide new targets for Alzheimer’s drugs. The Einstein principal investigator is Yousin Suh, Ph.D., professor in the departments of genetics, of ophthalmology & visual sciences, and of medicine at Einstein. (1RF1AG057341)

Thursday, November 30, 2017
Epigenetic Markers in Pancreatic Cancer

Epigenetic Markers in Pancreatic Cancer—Cancers sometimes start when external influences cause changes in DNA. These so-called epigenetic modifications can alter gene expression—silencing a gene or over-activating it, for example. In a study published on the cover of the November issue of Genome Research, Amit Verma, M.B.B.S., reported that pancreatic cancers have unique epigenetic modifications in a regulatory portion of DNA known as Hydroxymethylcytosine (5-hmC). He and his team found that 5-hmC was abnormally distributed at locations in the genome that regulate the expression of several genes associated with cancer, such as the gene BRD4. Dr. Verma is professor of oncology and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. The study’s first author is Sanchari Bhattacharyya, Ph.D., a research associate in the department of medicine.

Thursday, November 30, 2017
How the brain drives adaptive behavior

How the brain drives adaptive behavior—When we react to sensory stimuli, our brains tap into a network of neurons that drives behavior. But little is understood about that network’s architecture, the contributions of its individual cells nor how the network changes with learning. Jose Luis Peña, M.D., Ph.D., has been awarded a five-year $3-million NIH BRAIN Initiative grant to investigate how neural networks become fine-tuned to their environment and adapt through exposure to life experiences. The research will involve barn owls, which are keenly attuned to relying on sound for locating prey. Dr. Pena and colleagues from Seattle University, University of California in Davis and San Diego will use high-throughput electrophysiology, electron microscopy, behavior and theory to determine how sound drives the owl's orienting behavior. Dr. Peña is a professor in the Dominick P. Purpura Department of Neuroscience. (1R01NS104911-01)

Tuesday, November 28, 2017
Eating Twice a Day Keeps Fat Away

Eating Twice a Day Keeps Fat Away—In a study published online on October 26 in Cell Metabolism, Einstein researchers found that feeding mice just twice a day decreases fat tissue and enhances muscle mass. By contrast, mice allowed to consume the same number of daily calories whenever they wanted did not obtain those benefits. The researchers found the fasting period created by twice-daily feeding activated the cellular cleansing process known as autophagy in liver, fat, brain, and muscle tissues in young and old mice. This lowered glucose and lipid levels without the muscle loss that usually accompanies calorie restriction. The findings suggest that twice-a-day feeding without restricting calories could help prevent obesity and type 2 diabetes as well as the metabolic decline that occurs when autophagy becomes less efficient in old age. Senior author Rajat Singh, M.D., M.B.B.S., is associate professor of medicine and of molecular pharmacology at Einstein.

Monday, November 27, 2017
The Cerebellum -Addiction Connection

The Cerebellum -Addiction Connection—Evidence suggests that dysregulation of the cerebellum—a part of the brain well known for motor coordination—contributes to mental health disorders including schizophrenia, autism and addiction. Yet the cerebellum’s impact on cognitive function remains largely unexplored. Kamran Khodakhah, Ph.D., has received a five-year, $3.6 million grant from the National Institute on Drug Abuse to expand on his earlier research linking the cerebellum to the ventral tegmental area (VTA), a brain region involved in addiction and other reward-seeking behaviors. He and his colleagues will use anatomical and physiological approaches to find the neural pathways by which the cerebellum can affect the VTA as well as two other regions associated with addiction: the prefrontal cortex and the nucleus accumbens. Dr. Khodakhah is professor and chair of the Dominick P. Purpura Department of Neuroscience and the Florence and Irving Rubinstein Chair in Neuroscience. (1R01DA044761-01A1)

Tuesday, November 21, 2017
Supporting People with Intellectual and Developmental Disabilities

Supporting People with Intellectual and Developmental Disabilities—Einstein has received a five year, $2.75 million grant from the Department of Health and Human Services for the University Center for Excellence in Developmental Disabilities (UCEDD), based at the Rose F. Kennedy Children’s Evaluation and Rehabilitation Center (RFK CERC). The UCEDD promotes an integrated, “disability-informed” approach to caring for children and adults with developmental disabilities. It also advocates on behalf of individuals with developmental disabilities and trains leaders in the field. The project director is Theodore Kastner, M.D., M.S., the Ruth L. Gottesman Chair in Developmental Pediatrics, professor and chief of the division of developmental medicine in the department of pediatrics. The project co-director is Karen Bonuck, Ph.D., professor of family and social medicine. (90DDUC0035-01-00)

Monday, November 20, 2017
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