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Found 34725 matches. Displaying 131-140
Katz M, Corson F, Keil W, Singhal A, Bae A, Lu Y, Liang YP, Shaham S
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Glutamate spillover in C. elegans triggers repetitive behavior through presynaptic activation of MGL-2/mGluR5

NATURE COMMUNICATIONS 2019 APR 23; 10(?):? Article 1882
Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gaq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.
Julg B, Dee L, Ananworanich J, Barouch DH, Bar K, Caskey M, Colby DJ, Dawson L, Dong KL, Dube K, Eron J, Frater J, Gandhi RT, Geleziunas R, Goulder P, Hanna GJ, Jefferys R, Johnston R, Kuritzkes D, Li JZ, Likhitwonnawut U, van Lunzen J, Martinez-Picado J, Miller V, Montaner LJ, Nixon DF, Palm D, Pantaleo G, Peay H, Persaud D, Salzwedel J, Salzwedel K, Schacker T, Sheikh V, Sogaard OS, Spudich S, Stephenson K, Sugarman J, Taylor J, Tebas P, Tiemessen CT, Tressler R, Weiss CD, Zheng L, Robb ML, Michael NL, Mellors JW, Deeks SG, Walker BD
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Recommendations for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting

LANCET HIV 2019 APR; 6(4):E259-E268
Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research.
Zhu XG, Puthenveedu SN, Shen YH, La K, Ozlu C, Wang T, Klompstra D, Gultekin Y, Chi JY, Fidelin J, Peng T, Molina H, Hang HC, Min W, Birsoy K
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CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4

MOLECULAR CELL 2019 APR 4; 74(1):45-58.e7
Cells require a constant supply of fatty acids to survive and proliferate. Fatty acids incorporate into membrane and storage glycerolipids through a series of endoplasmic reticulum (ER) enzymes, but how these enzymes are regulated is not well understood. Here, using a combination of CRISPR-based genetic screens and unbiased lipidomics, we identified calcineurin B homologous protein 1 (CHP1) as a major regulator of ER glycerolipid synthesis. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. Mechanistically, CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis. GPAT4 activity requires CHP1 to be N-myristoylated, forming a key molecular interface between the two proteins. Interestingly, upon CHP1 loss, the peroxisomal enzyme, GNPAT, partially compensates for the loss of ER lipid synthesis, enabling cell proliferation. Thus, our work identifies a conserved regulator of glycerolipid metabolism and reveals plasticity in lipid synthesis of proliferating cells.
Phillips RE, Yang YH, Smith RC, Thompson BM, Yamasaki T, Soto-Feliciano YM, Funato K, Liang YP, Garcia-Bermudez J, Wang XS, Garcia BA, Yamasaki K, McDonald JG, Birsoy K, Tabar V, Allis CD
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Target identification reveals lanosterol synthase as a vulnerability in glioma

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2019 APR 16; 116(16):7957-7962
Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain tumor for which novel therapeutic approaches are desperately needed. Previous studies have shown that the menin inhibitor MI-2 exhibits promising activity in preclinical DIPG and adult glioma models, although the mechanism underlying this activity is unknown. Here, using an integrated approach, we show that MI-2 exerts its antitumor activity in glioma largely independent of its ability to target menin. Instead, we demonstrate that MI-2 activity in glioma is mediated by disruption of cholesterol homeostasis, with suppression of cholesterol synthesis and generation of the endogenous liver X receptor ligand, 24,25-epoxycholesterol, resulting in cholesterol depletion and cell death. Notably, this mechanism is responsible for MI-2 activity in both DIPG and adult glioma cells. Metabolomic and biochemical analyses identify lanosterol synthase as the direct molecular target of MI-2, revealing this metabolic enzyme as a vulnerability in glioma and further implicating cholesterol homeostasis as an attractive pathway to target in this malignancy.
Caskey M
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Delivery of anti-HIV bNAbs by viral vectors

LANCET HIV 2019 APR; 6(4):E207-E208
Graham WV, He WQ, Marchiando AM, Zha JM, Singh G, Li HS, Biswas A, Ong MLDM, Jiang ZH, Choi WS, Zuccola H, Wang YT, Griffith J, Wu JS, Rosenberg HJ, Wang YM, Snapper SB, Ostrov D, Meredith SC, Miller LW, Turner JR
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Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis

NATURE MEDICINE 2019 APR; 25(4):690-700
Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.
Thomas JL, Lewis JB, Martinez I, Cunningham SD, Siddique M, Tobin JN, Ickovics JR
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Associations between intimate partner violence profiles and mental health among low-income, urban pregnant adolescents

BMC PREGNANCY AND CHILDBIRTH 2019 APR 26; 19(?):? Article 120
BackgroundIntimate partner violence (IPV) during pregnancy is associated with adverse maternal and child health outcomes, including poor mental health. Previous IPV research has largely focused on women's victimization experiences; however, evidence suggests young women may be more likely to engage in bilateral violence (report both victimization and perpetration) or perpetrate IPV (unilateral perpetration) during pregnancy than to report being victimized (unilateral victimization). This study examined prevalence of unilateral victimization, unilateral perpetration, and bilateral violence, and the association between these IPV profiles and mental health outcomes during pregnancy among young, low-income adolescents.MethodsSurvey data were collected from 930 adolescents (14-21years; 95.4% Black and Latina) from fourteen Community Health Centers and hospitals in New York City during second and third trimester of pregnancy. Multivariable regression models tested the association between IPV profiles and prenatal depression, anxiety, and distress, adjusting for known predictors of psychological morbidity.ResultsThirty-eight percent of adolescents experienced IPV during their third trimester of pregnancy. Of these, 13% were solely victims, 35% were solely perpetrators, and 52% were engaged in bilateral violence. All women with violent IPV profiles had significantly higher odds of having depression and anxiety compared to individuals reporting no IPV. Adolescents experiencing bilateral violence had nearly 4-fold higher odds of depression (OR=3.52, 95% CI: 2.43, 5.09) and a nearly 5-fold increased likelihood of anxiety (OR=4.98, 95% CI: 3.29, 7.55). Unilateral victims and unilateral perpetrators were also at risk for adverse mental health outcomes, with risk of depression and anxiety two- to three-fold higher, compared to pregnant adolescents who report no IPV. Prenatal distress was higher among adolescents who experienced bilateral violence (OR=2.84, 95% CI: 1.94, 4.16) and those who were unilateral victims (OR=2.21, 95% CI: 1.19, 4.12).ConclusionsAll violent IPV profiles were associated with adverse mental health outcomes among pregnant adolescents, with bilateral violence having the most detrimental associations. Comprehensive IPV screening for both victimization and perpetration experiences during pregnancy is warranted. Clinical and community prevention efforts should target pregnant adolescents and their partners to reduce their vulnerability to violence and its adverse consequences.
Pisa R, Cupido T, Kapoor TM
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Designing Allele-Specific Inhibitors of Spastin, a Microtubule-Severing AAA Protein

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2019 APR 10; 141(14):5602-5606
The bump hole approach is a powerful chemical biology strategy to specifically probe the functions of closely related proteins. However, for many protein families, such as the ATPases associated with diverse cellular activities (AAA), we lack structural data for inhibitor-protein complexes to design allele-specific chemical probes. Here we report the X-ray structure of a pyrazolylaminoquinazoline-based inhibitor bound to spastin, a microtubule-severing AAA protein, and characterize the residues involved in inhibitor binding. We show that an inhibitor analogue with a single-atom hydrogen-to-fluorine modification can selectively target a spastin allele with an engineered cysteine mutation in its active site. We also report an X-ray structure of the fluoro analogue bound to the spastin mutant. Furthermore, analyses of other mutant alleles suggest how the stereoelectronics of the fluorine cysteine interaction, rather than sterics alone, contribute to the inhibitor allele selectivity. This approach could be used to design allele-specific probes for studying cellular functions of spastin isoforms. Our data also suggest how tuning stereoelectronics can lead to specific inhibitor allele pairs for the AAA superfamily.
Zeng X, Hunt A, Jin SC, Duran D, Gaillard J, Kahle KT
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EphrinB2-EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease

TRENDS IN MOLECULAR MEDICINE 2019 APR; 25(4):265-286
Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.
Frank MO, Koyama T, Rhrissorrakrai K, Robine N, Utro F, Emde AK, Chen BJ, Arora K, Shah M, Geiger H, Felice V, Dikoglu E, Rahman S, Fang A, Vacic V, Bergmann EA, Vogel JLM, Reeves C, Khaira D, Calabro A, Kim D, Lamendola-Essel MF, Esteves C, Agius P, Stolte C, Boockvar J, Demopoulos A, Placantonakis DG, Golfinos JG, Brennan C, Bruce J, Lassman AB, Canoll P, Grommes C, Daras M, Diamond E, Omuro A, Pentsova E, Orange DE, Harvey SJ, Posner JB, Michelini VV, Jobanputra V, Zody MC, Kelly J, Parida L, Wrzeszczynski KO, Royyuru AK, Darnell RB
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Sequencing and curation strategies for identifying candidate glioblastoma treatments

BMC MEDICAL GENOMICS 2019 APR 25; 12(?):? Article 56
BackgroundPrompted by the revolution in high-throughput sequencing and its potential impact for treating cancer patients, we initiated a clinical research study to compare the ability of different sequencing assays and analysis methods to analyze glioblastoma tumors and generate real-time potential treatment options for physicians.MethodsA consortium of seven institutions in New York City enrolled 30 patients with glioblastoma and performed tumor whole genome sequencing (WGS) and RNA sequencing (RNA-seq; collectively WGS/RNA-seq); 20 of these patients were also analyzed with independent targeted panel sequencing. We also compared results of expert manual annotations with those from an automated annotation system, Watson Genomic Analysis (WGA), to assess the reliability and time required to identify potentially relevant pharmacologic interventions.ResultsWGS/RNAseq identified more potentially actionable clinical results than targeted panels in 90% of cases, with an average of 16-fold more unique potentially actionable variants identified per individual; 84 clinically actionable calls were made using WGS/RNA-seq that were not identified by panels. Expert annotation and WGA had good agreement on identifying variants [mean sensitivity=0.71, SD=0.18 and positive predictive value (PPV)=0.80, SD=0.20] and drug targets when the same variants were called (mean sensitivity=0.74, SD=0.34 and PPV=0.79, SD=0.23) across patients. Clinicians used the information to modify their treatment plan 10% of the time.ConclusionThese results present the first comprehensive comparison of technical and machine augmented analysis of targeted panel and WGS/RNA-seq to identify potential cancer treatments.