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Structurally Sound  In the June 4 issue of Structure, Drs. Vern Schramm, Steven Almo and Antti Haapalainen report their use of crystallography – a method used to determine molecular structures by examining them in crystalline form – to identify novel inhibitors of a key enzyme of the bacteria Salmonella enterica.  This enzyme, called MTAN (MTA/SAH nucleosidase), is responsible for metabolism of the amino acid methionine and is only expressed by bacteria, making it an ideal target for developing antibiotics.  Drs. Schramm and Almo analyzed the crystal structure of MTAN and used this structural information to develop rational design of inhibitors that bind to the enzyme very strongly, identifying new possible antibiotics against S. enterica as well as a method that can be used to develop inhibitors of other bacterial targets. Dr. Schramm is professor and chair of biochemistry and the Ruth Merns Chair in Biochemistry; Dr. Almo is professor of biochemistry and holds the Wollowick Family Foundation Chair in Multiple Sclerosis and Immunology; Dr. Haapalainen is a postdoctoral fellow in the Schramm lab.

Wednesday, July 31, 2013
 

PREP-ing for the Future  Dr. Myles Akabas has been awarded a $1.4 million grant over four years from the National Institute of General Medical Sciences. The grant will support the establishment of a Post-Baccalaureate Research Education Program (PREP) at Einstein. The racial and ethnic diversity of the American population is not reflected in the biomedical workforce or faculty at research universities and medical schools; PREP provides underrepresented minority college graduates with a year-long intensive research experience that will allow them to be competitive applicants to rigorous Ph.D. and M.D.-Ph.D. programs. PREP will combine didactic and experiential learning components, community outreach through visits to local Bronx high schools and mentorship at all levels. Dr. Akabas is director of the Medical Scientist Training Program (MSTP) at Einstein, as well as professor in the departments of physiology and biophysics, neuroscience and medicine. PREP is co-directed by Drs. Victoria Freedman, associate dean of graduate studies, and Genevieve Neal-Perry, associate dean for diversity mentoring.

Wednesday, July 31, 2013
 

Focus on Cataracts  The National Eye Institute has awarded Dr. Ales Cvekl a $2.2 million renewal grant, over four years, for his investigations into the formation of ocular lens through studies of its major protein component, the aA-crystallin. Because loss of expression of aA-crystallin leads to cataract formation, the researchers aim to determine the molecular mechanisms that regulate the protein’s expression. Lens cataract is a major cause of blindness worldwide. Age-related cataracts generally develop after 40 years of age; increasing life expectancy is expected to increase the prevalence of cataracts. Current treatment of cataract requires surgery to replace the opaque lens with an artificial lens. In this project, the researchers hope to identify strategies that might delay the onset of cataracts, ultimately decreasing the number of surgeries needed as well as vision care costs. Dr. Cvekl is professor and vice chair for research of ophthalmology & visual science and professor of genetics. He also is the Max Berger Chair in Ophthalmology.

Wednesday, July 31, 2013
 

The Mighty Macrophage  In the April 2013 issue of Nature, Dr. Jeffrey Pollard published a scientific review on the role of macrophages in development, homeostasis (the maintenance of balance within a system), and disease, which was featured on the cover as their “Cell for All Seasons.”  Macrophages are immune cells that have primarily been thought to be controllers of infection; by engulfing invading microbes and orchestrating immune responses. Dr. Pollard’s review focuses on emerging evidence – from his lab and others – that, in addition to their immune functions, these cells play important roles in development and homeostasis. Furthermore, most of these cells do not arise from bone marrow, where other immune cells typically do, but rather from yolk-sac progenitors during embryo development. This new information about these important cells could facilitate development of therapeutic interventions to treat obesity, cancer, and degenerative diseases.  Dr. Pollard is professor of developmental and molecular biology and of obstetrics & gynecology and women’s health.  He is also director of the Center for Study of Reproductive Biology and Women’s Health; and the Louis Goldstein Swan Chair in Women’s Cancer Research.

Wednesday, July 31, 2013
 

Regulating Human Immune Response­­  Dr. Xingxing Zang, Dr. Matthew Scharff,  and colleagues published a study in the June 11, 2013 issue of Proceedings of the National Academy of Sciences USA, describing a new pathway that inhibits human T cell functions. T cells are key part of the immune system and the discovery may aid the development of new therapies for treating cancer, autoimmune disorders, infection and transplant rejection; it also may aid the design of better vaccines. The researchers identified a protein, HHLA2, as the newest  member of the B7 family of proteins; B7 proteins bind to receptors on the surface of T cells and either inhibit or activate the T cell response. The researchers demonstrated that exposing human T cells to HHLA2 inhibited proliferation and protein production, suggesting that this pathway may be a potent regulator of human immune responses. Dr. Zang is associate professor of microbiology & immunology, and Dr. Scharff is distinguished professor of cell biology.  Einstein has filed for patent protection on this technology. It's available for licensing.

Wednesday, July 31, 2013
 

Improving Screening  Dr. Howard Strickler has received a $2.4 million grant over four years from the National Cancer Institute to identify molecular methods for improving cervical cancer screening in HIV-positive women. These women a have an increased incidence of cervical pre-cancer and cancer and, at each doctor visit, nearly one-third of them experience abnormal Pap tests (the screening tool used to detect these conditions). Because many abnormal Pap tests are false positive, leading to unnecessary follow-up procedures that are costly and unpleasant to undergo, Dr. Strickler’s study will assess whether new molecular screening methods can provide more accurate results among this patient population. Improving accuracy of cervical cancer screening tests through the use of these molecular assays, either alone or in combination with Pap tests, could possibly improve clinical care for women with HIV, while reducing the burden on patients and the health care system. In addition, a related study by Dr. Strickler and colleagues published last year in the Journal of the American Medical Association was picked recently by the Epidemiology & Genomics Research Program of the NCI as a “Research Highlight.” Dr. Strickler is a Harold and Muriel Block Chair in Epidemiology & Population Health, as well as professor of epidemiology & population health.

Wednesday, July 31, 2013
 

The “TB Terminator”  Dr. William Jacobs has received a grant totaling $2.4 million over four years from the National Institute of Allergy and Infectious Diseases. The grant will support his research aimed at developing new treatments for individuals infected with drug-resistant tuberculosis (TB).  Each year, TB accounts for roughly 2 million deaths worldwide. The emergence of drug-resistant strains of TB has created an urgent need for faster-acting antibiotics that have fewer side effects than therapies currently used.  Dr. Jacobs and colleagues will screen compounds for their ability to inhibit biofilm formation of Mycobacterium tuberculosis, the bacteria that causes TB, representing a novel and promising approach for treatment.  Dr. Jacobs is professor of microbiology & immunology and of genetics at Einstein, as well as Howard Hughes Medical Institute Investigator. He was recently inducted into the National Academy of Sciences.         

Wednesday, July 31, 2013
 

Exploring HAAF pathways  Dr. Ilan Gabriely has been awarded $1.8 million over five years from the National Institute of Diabetes and Digestive Kidney Diseases. The grant will allow him to continue his investigations into the mechanisms responsible for autonomic failure after repeated episodes of hypoglycemia (low blood glucose levels). Patients with type 1 diabetes are susceptible to develop this condition due to defects in hypoglycemia counterregulation. Previously, Dr. Gabriely’s team demonstrated that hypoglycemia-associated autonomic failure (HAAF) could be prevented in healthy volunteers and in individuals with type 1 diabetes, by blocking their opioid receptors with naloxone. The researchers hope to determine whether a common mechanism exists between the opioid receptor pathway and the adrenergic pathway, in instances when HAAF occurs. Additionally, they will conduct a clinical trial examining the efficacy of chronic opioid receptor blockade, in preventing HAAF in patients with Type 1 diabetes. Dr. Gabriely is associate professor of medicine.

Wednesday, July 31, 2013
 

Detecting the Elusive ‘Ylide’  Ylides, molecules containing two opposing charges on adjacent atoms, have been proposed as intermediates in biochemical reactions, but until now there was little evidence supporting this theory. In a study appearing in Nature’s May 15 online edition, Drs. Jungwook Kim and Steven Almo, and colleagues describe a ylide intermediate — formed from the biomolecule SAM (S-adenosylmethionine) — during biosynthesis of the newly identified metabolite Cx-SAM. The group subsequently demonstrated that Cx-SAM is used to generate the modified nucleotide5-oxyacetyl uridine (cmo5U) on bacterial tRNAs, which is required for efficient processing of the genetic code. While determining the X-ray crystal structure of an enzyme required for the biosynthesis of cmo5U, the researchers discovered Cx-SAM — a SAM molecule with a carboxylate (CO2-) group attached, in the enzyme’s active site. They theorized that this metabolite was generated from SAM via a series of biochemical reactions involving the formation of a ylide, and then tested several compounds that led to their discovery that prephenate (an aromatic amino acid precursor) generated Cx-SAM, thereby providing compelling evidence for the existence of the ylide intermediate. Dr. Kim is an associate of biochemistry and Dr. Almo is professor of biochemistry and of physiology & biophysics. Dr. Almo holds the Wollowick Family Foundation Chair in Multiple Sclerosis and Immunology.

Wednesday, July 31, 2013
 

B7x-cellent — In the March 1, 2013 issue of the Journal of Immunology, Drs. Xingxing Zang, Yael Abadi, and Hyungjun Jeon report a role for the immune regulatory molecule B7x in promoting the spread of cancer (metastasis). B7x inhibits the immune response and increased levels on tumors in cancer patients has been associated with poor clinical outcomes and death. Using a mouse model of metastatic breast cancer, the researchers found that removal of B7x signaling enhanced the anti-tumor immune response, which resulted in a decrease in tumors and enhanced survival. Cancer is the leading cause of death worldwide and targeted treatments for metastasis are critical to improving survival. The findings suggest that blocking B7x could offer a therapy that harnesses the power of the immune response to treat metastatic cancers. In related news, the journal OncoImmunology has invited Dr. Zang to write an “Auto-Commentary” on this work, and the Department of Defense’s Prostate Cancer Research Program has selected Dr. Zang's cancer immunology research to be highlighted in its program materials that communicate buzz-worthy research to Congress and other stakeholders. Dr. Zang is assistant professor of microbiology and immunology. Dr. Jeon is a research fellow in the Zang lab, and Dr. Abadi is a Ph.D. student who successfully defended her thesis recently.

Wednesday, May 01, 2013
 
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