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Sugar Modification Essential for Notch Signaling

Sugar Modification Essential for Notch Signaling—Normal development of mammals and other multicellular organisms depend on Notch—a large cell-surface receptor that enables cells to communicate with each other. In a paper published online on April 11 in eLife, researchers led by Pamela Stanley, Ph.D., and Tetsuya Okajima, M.D., Ph.D., of Nagoya University, looked at how glycan modifications of Notch affect its cell-signaling ability. The researchers showed that, in the development of the retina, Notch-regulated signaling depends on the presence of the sugar O-GlcNAc on certain epidermal growth factor-like (EGF) repeats of the extracellular domain of Notch1. Cell-based assays showed that Delta Notch ligands (molecules that bind to and activate receptors) recognize O-GlcNAc on Notch1. The deletion of O-GlcNAc leads to a decrease in signaling that causes defects in perinatal retinal development. Dr. Stanley is professor of cell biology and the Horace W. Goldsmith Foundation Chair.

Wednesday, April 26, 2017
 
Tracing the Origin of Breast Tissue

Tracing the Origin of Breast Tissue—Researchers had long assumed that two of the main types of human mammary tissue--estrogen-receptor positive and estrogen-receptor negative cells—develop from a single type of stem cell. Now, Wenjun Guo, Ph.D., and his group have collaborated with Maja Oktay, M.D., Ph.D., to show that these two cell types are derived from and maintained by two distinct stem cell populations. Their study published online on March 21 in Cell Reports, used genetic techniques to monitor cells over multiple generations in a mouse model of mammary development. These findings have important clinical applications, since breast cancers are classified and treated based on whether they are estrogen-receptor positive or negative. Dr. Guo is assistant professor of cell biology. Dr. Oktay is associate professor of pathology and of anatomy and structural biology.

Monday, April 10, 2017
 
Suppressing Leukemia Progression

Suppressing Leukemia Progression—Myeloproliferative neoplasms (MPNs) are poorly understood malignant diseases caused by overproduction of white cells, red cells or platelets. Some types of MPN can develop into acute leukemia. In a paper published online on February 23 in the Journal of Experimental Medicine involving a newly developed mouse model of MPN, Ulrich Steidl, M.D., Ph.D., and colleagues describe a novel tumor suppressor role for the gene NOL3 in MPN. NOL3 had previously been shown to be an oncogene in other tissue types. The researchers also found that the NOL3 gene is deleted and its levels are lower in a subset of patients with MPNs. This major finding regarding the biology of MPNs means that NOL3 should be considered important for preventing disease progression in a subset of patients, as opposed to being a driver of disease. This insight may help researchers develop new approaches for targeted therapies for MPNs and leukemia. Dr. Steidl is professor of cell biology and of medicine, and is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research.

Friday, April 07, 2017
 
Studying How Nerve Cells Connect

Studying How Nerve Cells Connect—The National Institute of Mental Health has awarded Scott W. Emmons, Ph.D., a five-year, $2 million grant to investigate the synaptic connections that allow signals to travel from neuron to neuron throughout the brain. The researchers will conduct their studies on the nematode worm Caenorhabditis elegans, which depends on genes similar to those that lay down the neuronal architecture in human brains. Through a combination of genetic, molecular and biochemical studies, the research should shed light on the function of these genes and the factors that make accurate nerve connectivity possible. Dr. Emmons is professor of genetics and of neuroscience and holds the Siegfried Ullmann Chair in Molecular Genetics. (1R01MH112689-01)

Thursday, March 23, 2017
 
New Target For Dystonia Therapy

New Target For Dystonia Therapy—Dystonia—when someone’s muscles contract uncontrollably—is the third most common movement disorder (after Parkinson’s and essential tremor), affecting about 250,000 Americans. Research and treatment for the most common inherited form of dystonia, called DYT1, has focused mainly on the basal ganglia region of the brain. But new animal research by Einstein scientists implicates a different part of the brainthe cerebellumas the site of the problem. The study, published in the February 15 online issue of eLife, was led by Kamran Khodakhah, Ph.D., professor and chair of the Dominick P. Purpura Department of Neuroscience and the Harold and Muriel Block Chair in Neuroscience. He and his colleagues made their discovery after generating the first mouse model of DYT1 to exhibit the overt symptoms of dystonia seen in patients. Previous research in Dr. Khodakhah’s lab has shown that severing the link between the cerebellum and the basal ganglia might be an effective way to treat cerebellar-induced dystonias.

Monday, March 20, 2017
 
Putting the Brakes on Cancer

Putting the Brakes on Cancer—Stimulation of the PD-1 (Programmed Cell Death-1) receptor on the surface of T cells puts the brakes on T cells’ immune response. Tumors manage to avoid T-cell attack by using their cell-surface proteins PD-L1 and PD-L2 to activate PD-1. Einstein researchers led by Steven C. Almo, Ph.D., and Chandan Guha, M.B.B.S, Ph.D., developed a PD-1 receptor variant that binds strongly to PD-L1 and PD-L2 tumor proteins, rendering them unable to bind PD-1 receptors on T cells. As described in the February 6 issue of EBioMedicine, using the PD-1 receptor variant combined with radiation therapy in a mouse model of lung cancer caused decreases in both tumor burden and tumor recurrence. Radiation therapy fragments tumor cells, releasing tumor proteins that stimulate the immune system much as a vaccine would. Dr. Almo is professor and chair of biochemistry, professor of physiology & biophysics, and Wollowick Family Foundation Chair in Multiple Sclerosis and Immunology. Dr. Guha is professor and vice chair of radiation oncology.

Friday, March 17, 2017
 
Focusing on RNA-protein Interactions

Focusing on RNA-protein Interactions—Gene expression relies on interactions between messenger RNA molecules and RNA-binding proteins.  Insufficient resolution means that today’s microscopes tend to “see” molecular interactions that actually don’t occur. In a paper published on February 21 in the journal Proceedings of the National Academy of Sciences, Robert Singer, Ph.D., along with Carolina Eliscovich, Ph.D., and Shailesh Shenoy, B.S., describe their high-resolution methodology for detecting whether two molecules are physically interacting or are close to each other merely due to chance. Surprisingly, the methodology showed that certain proteins thought to bind mRNAs actually don’t. The new methodology could reveal dysfunctional RNA-protein interactions that can cause genetic disorders including neurodevelopmental and neurodegenerative diseases and cancer. Dr. Singer is professor and co-chair of anatomy & structural biology, as well as co-director of the Gruss-Lipper Biophotonics Center and of the Integrated Imaging Program. He also is professor in the Dominick P. Purpura Department of Neuroscience and of cell biology and the Harold and Muriel Block Chair in anatomy & structural biology.

Monday, March 06, 2017
 
Mixed Results from Testosterone Treatment

Mixed Results from Testosterone Treatment—For older men with low testosterone levels, supplementary testosterone can have both positive and negative health effects. The findings, published on February 21 in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine, come from clinical trials carried out at Einstein and 11 other centers around the country. The Einstein senior principal investigator was Jill P. Crandall, M.D., professor of clinical medicine and attending physician, endocrinology at Montefiore. Researchers at the Perlman School of Medicine at the University of Pennsylvania oversaw the trials, which involved 788 men with low testosterone, age 65 and over, who were randomized into two groups: one used a testosterone gel daily for one year and the other used a daily placebo gel. The four papers published report on four different health effects from testosterone treatment:

Bone: improved bone density and estimated bone strength. (JAMA Internal Medicine)

Anemia: improved red blood cell count in men with some types of anemia. (JAMA Internal Medicine)

Cognition: did not improve memory or any other measure of cognition. (JAMA)

Cardiovascular: more coronary artery plaque buildup in testosterone-treated men (as assessed by CT angiography), although the number of major adverse cardiovascular events (such as heart attacks or strokes) was similar in both groups. (JAMA)

Other results from this trial, published in February 2016 in the New England Journal of Medicine, showed that testosterone treatment resulted in modest improvements in sexual function, walking ability and mood.

Friday, March 03, 2017
 
Investigating Enzymes

Investigating Enzymes—Sulfotransferases (SULT) are enzymes that regulate the activities of hundreds of metabolites, including the activity of many drugs.  Dr. Leyh and his group have discovered that SULTS are regulated by allosteres — small-molecule metabolites that bind to SULTS at pockets distinct from their catalytic sites. These findings have increased understanding of the molecular basis of SULT function and may lead to ways of designing allosteres that can control SULT function. Such man-made allosteres could potentially help in treating diseases including addiction, depression, Parkinson’s disease, HIV infection and obesity. To that end, the National Institute of General Medical Sciences has awarded Thomas S. Leyh, Ph.D., a four-year, $1.5 million grant to characterize SULT-allostere binding structures. Dr. Leyh is professor of microbiology & immunology. (1R01GM121849-01)

Thursday, March 02, 2017
 
Probing Autophagy

Probing Autophagy—Cells use several kinds of autophagy—a process for breaking down and recycling proteins and other cellular components. Defects in autophagy can lead to liver and kidney diseases as well as neurodegenerative diseases including Alzheimer’s. One type of autophagy, called endosomal microautophagy (eMI), has been characterized in mammalian cell culture, but lacked a genetic system in an easily managed model organism. The National Institute of General Medical Sciences has awarded Andreas Jenny, Ph.D., a four-year, $1.8 million grant that his group will use to characterize eMI in fruit flies. Dr. Jenny and colleagues previously established a system in fruit flies for monitoring eMI and the proteins that it selectively degrades. They plan to use their system to identify components that regulate eMI in fruit flies. Dr. Jenny is associate professor of developmental and molecular biology and of genetics. (1R01GM119160-01A1)

Wednesday, February 22, 2017
 
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