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Learning How Neural Networks Form

Learning How Neural Networks Form—In two recent papers involving the roundworm C. elegans, Hannes E. Buelow, Ph.D., and colleagues shed light on how neural networks are assembled during development. Dendrites are string-like extensions of neurons that sample the environment or connect with other neurons at junctions called synapses. Electrical impulses from a neuron’s dendrites are conveyed by the neuron’s other long projection—its axon—to the next neuron in the network. Sensory nerves often form elaborately branched dendritic trees, or “arbors,” so that they can collect information or sample the environment appropriately. Researchers have long known that an axon’s neuronal activity can shape the dendrites of neurons with which they are connected. In a study published on January 17 in Developmental Cell, Dr. Buelow and his team report that axons can also shape dendrites of certain C. elegans sensory neurons, known as PVD neurons, by acting as scaffolds; the researchers identified several conserved genes involved in this process. The second paper, which published January 29 in eLife, uncovers an additional mechanism involved in forming dendritic arbors. Dr. Buelow and colleagues describe how three different proteins interact within the extracellular matrix to help form the PVD dendrites and regulate the growth of dendritic branches. Psychiatric conditions such as autism spectrum disorders and schizophrenia may result from incorrectly interconnected neural networks. So defects in any one or more of these conserved genes, or in genes coding for the interacting proteins, may be a cause of those disorders. Dr. Buelow is professor of genetics and in the Dominick P. Purpura Department of Neuroscience at Einstein.

Wednesday, February 13, 2019
Recognizing Early-Stage TB

Recognizing Early-Stage TB—Tuberculosis is a leading cause of global mortality, responsible for around 1.6 million deaths each year. Some people who test negative based on sputum testing still have active pulmonary tuberculosis (PTB); diagnosing and treating them is vital for preventing the development of disease that can spread. Moreover, sputum culture-negative PTB is an early stage of the disease that can be treated with fewer drugs for a shorter time than sputum-culture positive PTB. To gauge the frequency of culture-negative PTB among adult PTB patients, Jacqueline Achkar, M.D., M.Sc., and colleagues analyzed data reported to the New York City Department of Health from 2011 through 2013 on 796 patients with active PTB. A significant number of patients—116, or 15 percent—were culture-negative. Compared with people with culture-positive PTB, culture-negative individuals tended to have fewer symptoms such as coughing and weight loss and had fewer abnormalities on radiographic imaging. Awareness of these findings could improve the detection and treatment of this early-disease state and reduce PTB transmission. Dr. Achkar is associate professor of medicine and of microbiology & immunology. The first author of the study, which published online on February 8 in JAMA Network Open, is Minh-Vu H. Nguyen, M.D., M.Sc., who was an Einstein medical student and a scholar of Einstein’s Master of Science Clinical Research Training Program (CRTP).

Friday, February 08, 2019
Inhibiting a Cell-Execution Protein

Inhibiting a Cell-Execution Protein—Apoptosis is a normal cellular process that enables damaged or defective cells to self-destruct—but uncontrolled apoptosis can be harmful.  For example, the death of heart-muscle tissue following heart attacks is largely due to apoptotic cell death. In a study published online on February 4 in Nature Chemical Biology, Evripidis Gavathiotis, Ph.D., describes previously unknown, small molecules that bind to and inhibit BAX, the protein that plays a key role in causing apoptosis. Dr. Gavathiotis and colleagues also identified a pocket within the BAX protein to which these novel inhibitors bind, thereby stabilizing BAX and preventing it from triggering apoptosis. In in vitro experiments, Dr. Gavathiotis and colleagues showed that the inhibitors protected mouse fibroblasts from apoptotic stimulation. Such BAX inhibitors could potentially be used as drugs to prevent cell death during heart attacks, strokes, neurodegenerative diseases, and chemotherapy or radiation treatment. Dr. Gavathiotis is an associate professor of biochemistry and of medicine at Einstein.

Thursday, February 07, 2019
First Imaging of Powerful Antiviral Proteins

First Imaging of Powerful Antiviral Proteins—Interferon-induced transmembrane proteins (IFITMs) are broadly active against deadly viruses, from flu to Ebola, and play an important role in defending humans from viral infections. But because IFITMs are tiny, researchers haven’t been able to easily observe how they work. Now, in a study published online on January 14 in Nature Chemical Biology, Jennifer Spence, Ph.D., and Kartik Chandran, Ph.D., used fluorescence microscopy to live-image IFITMs for the first time in cells while the proteins were fighting viruses. Drs. Spence and Chandran found that IFITMs 1, 2, and 3 worked together to prevent viruses from penetrating cellular membranes and entering the cytoplasm. Once viruses entered cells, IFITM3 fused with the virus-bearing compartments and helped carry them into the lysosomes, where they are digested. The results show that this imaging technique could be useful for future research into antiviral mechanisms. Dr. Chandran is professor of microbiology & immunology and the Harold and Muriel Block Faculty Scholar in Virology at Einstein. Dr. Spence is a research assistant professor of microbiology & immunology at Einstein.

Thursday, February 07, 2019
Insight into a Sex Development Disorder

Insight into a Sex Development Disorder—Disorders of sex development (DSDs) affect approximately one in every 2000 live births. One such DSD is 46,XY gonadal dysgenesis (46,XY DSDs), also known as Swyer syndrome. Harry Ostrer, M.D., and colleagues previously showed that mutations in the MAP3K1 gene are one of the most common causes of 46,XY DSDs. They found that MAP3K1 mutations give the expressed protein new functions that override the normal testes-determining pathway. In their new study, published online on January 4 in Human Molecular Genetics, they show how those mutations alter MAP3K1’s structure and function and describe a previously uncharacterized domain of the protein. Their research reveals two distinct mechanisms by which MAP3K1 mutations co-opt the normal male sex-determining pathway. These findings can offer people with 46,XY DSDs greater insight into their disorder. Dr. Ostrer is professor of pathology and of pediatrics at Einstein.

Wednesday, February 06, 2019
Investigating the Causes of Lung Disease

Investigating the Causes of Lung Disease—Lung disease results from complex molecular and cellular interactions that may involve genetic alterations occurring over time and environmental factors, such as cigarette smoking. The National Heart, Lung, and Blood Institute has awarded Simon D. Spivack, M.D., M.P.H., and Jan Vijg, Ph.D., a four-year, $2.6 million grant to study age- and tobacco-related molecular alterations that affect human lungs. By shedding light on how aging and smoking interact in the lung, the research could lead to better strategies for diagnosing, preventing, and treating lung cancer and other lung diseases. Dr. Spivack is professor of medicine, of epidemiology & population health, and of genetics at Einstein. Dr. Vijg is professor and chair of genetics, and the Lola and Saul Kramer Chair in Molecular Genetics at Einstein. (1U01HL145560-01)

Monday, February 04, 2019
Extending Plasma Cells' Lifespan

Extending Plasma Cells' Lifespan—Following infection or vaccination, long-lived antibody secreting cells (LLASCs) are chiefly responsible for producing the antibodies that combat infections. However, protein-based vaccines poorly induce LLASCs, and multiple boosters are often needed to generate sufficient numbers of antibodies. The National Heart, Lung, and Blood Institute has awarded David Fooksman, Ph.D., a five-year, $2.3 million grant to investigate how greater numbers of vaccine-induced antibodies can be produced. Dr. Fooksman recently found that, after vaccination, expression of the cell-surface receptor CD138 promotes potent antibody responses by giving antibody-producing LLASCs a survival advantage over new ASCs. He will explore ways to increase CD138 expression to enhance the survival of LLASs after vaccination. Dr. Fooksman is an assistant professor of pathology and of microbiology & immunology at Einstein. (3R01HL141491-01S1)

Friday, February 01, 2019
Insight into Autoimmunity-Fighting Cells

Insight into Autoimmunity-Fighting Cells—T regulatory (Treg) cells are essential for suppressing the body’s immune response. Understanding how Treg cells mature in the thymus gland could shed light on treating fatal autoimmune disorders like IPEX syndrome, which is caused by mutations in the Foxp3 gene. In a study published online on December 18 in Nature Communications, Gregoire Lauvau, Ph.D., and colleagues provide important information on how Treg cells mature and acquire their functional identity in mice. The interleukin-2 (IL-2) cytokine is known to trigger Treg cell development, followed by expression of the gene that encodes the Foxp3 transcription factor. The work reveals that IL-2 is also essential to control a genome organizing protein called SATB1 needed for Treg cells to develop and function normally prior to Foxp3 expression.  The findings suggest that earlier use of current low-dose IL-2 therapy could reprogram Treg cells and help them reach maturity before autoimmunity appears. Dr. Lauvau is professor of microbiology and immunology at Einstein.

Wednesday, January 30, 2019
Depression and Diabetes Management

Depression and Diabetes Management—People with both type 2 diabetes (T2D) and depression tend to neglect their medication regimen. In a study published online on December 7 in Journal of Diabetes and Its Complications, Jeffrey Gonzalez, Ph.D., and Claire Hoogendoorn, Ph.D., clarify this link among 376 low-income, racially diverse adults with poorly managed T2D. Those with self-reported depressive symptoms had a nearly three-fold increased risk for low medication adherence compared with non-depressed individuals. Surprisingly, compared to non-fatigued patients, those with fatigue unrelated to depression were 71 to 77 percent more likely to have low adherence. The findings suggest depression and unrelated fatigue increase the chance for inadequate disease management among low-income T2D patients. The study was supported by the Einstein–Mount Sinai Diabetes Research Center and the New York Regional Center for Diabetes Translation Research. Dr. Gonzalez is an associate professor of medicine and of epidemiology and population health at Einstein. Dr. Hoogendoorn is a research associate and adjunct assistant professor at Ferkauf Graduate School of Psychology.

Monday, January 28, 2019
Suffocating Persistent TB

Suffocating Persistent TB—Tuberculosis (TB) is one of the world’s leading causes of mortality, associated with 1.6 million deaths in 2017. Antibiotics help eliminate Mycobacterium tuberculosis (Mtb), the bacterial species that causes TB. But a subpopulation of Mtb resists antibiotic treatment, remaining dormant until all too often reviving to cause active disease. Michael Berney, Ph.D., received a five-year, $3.2 million grant from the National Institute of Allergy and Infectious Diseases to determine if respiration inhibitors can eliminate Mtb persisters—suffocating them by inhibiting two critical enzymes (cytochrome bc1:aa3 and cytochrome bd oxidase) in Mtb’s respiration pathway. He will study the role of these enzymes during TB pathogenesis and test combinations of existing and novel enzymatic inhibitors in vitro and in animal models of TB. Dr. Berney will also develop new inhibitors in collaboration with Dr. Kevin Pethe (Nanyang Technical University, Singapore) and Dr. Garrett Moraski (Montana State University).  The findings may enhance the effectiveness of current TB treatments and reduce fatalities. Dr. Berney is an assistant professor of microbiology & immunology at Einstein. (1R01AI139465-01A1)

Wednesday, January 16, 2019
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