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Found 34611 matches. Displaying 31-40
Zeevi D, Korem T, Godneva A, Bar N, Kurilshikov A, Lotan-Pompan M, Weinberger A, Fu JY, Wijmenga C, Zhernakova A, Segal E
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Structural variation in the gut microbiome associates with host health

NATURE 2019 APR 4; 568(7750):43-48
Differences in the presence of even a few genes between otherwise identical bacterial strains may result in critical phenotypic differences. Here we systematically identify microbial genomic structural variants (SVs) and find them to be prevalent in the human gut microbiome across phyla and to replicate in different cohorts. SVs are enriched for CRISPR-associated and antibiotic-producing functions and depleted from housekeeping genes, suggesting that they have a role in microbial adaptation. We find multiple associations between SVs and host disease risk factors, many of which replicate in an independent cohort. Exploring genes that are clustered in the same SV, we uncover several possible mechanistic links between the microbiome and its host, including a region in Anaerostipes hadrus that encodes a composite inositol catabolism-butyrate biosynthesis pathway, the presence of which is associated with lower host metabolic disease risk. Overall, our results uncover a nascent layer of variability in the microbiome that is associated with microbial adaptation and host health.
He H, Guttman-Yassky E
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JAK Inhibitors for Atopic Dermatitis: An Update

AMERICAN JOURNAL OF CLINICAL DERMATOLOGY 2019 APR; 20(2):181-192
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. AD is driven by barrier dysfunction and abnormal immune activation of Thelper (Th) 2, Th22, and varying degrees of Th1 and Th17 among various subtypes. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and spleen tyrosine kinase (SYK) pathways are involved in signaling of several AD-related cytokines, such as IFN-gamma, IL-4, IL-13, IL-31, IL-33, IL-23, IL-22, and IL-17, mediating downstream inflammation and barrier alterations. While AD is primarily Th2-driven, the clinical and molecular heterogeneity of AD endotypes highlights the unmet need for effective therapeutic options that target more than one immune axis and are safe for long-term use. The JAK inhibitors, which target different combinations of kinases, have overlapping but distinct mechanisms of action and safety profiles. Several topical and oral JAK inhibitors have been shown to decrease AD severity and symptoms. A review of the JAK and SYK inhibitors that are currently undergoing evaluation for efficacy and safety in the treatment of AD summarizes available data on a promising area of therapeutics and further elucidates the complex molecular interactions that drive AD.
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.
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.
Caskey M, Klein F, Nussenzweig MC
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Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic

NATURE MEDICINE 2019 APR; 25(4):547-553
Combination anti-retroviral therapy (ART) has revolutionized the treatment and prevention of HIV-1 infection. Taken daily, ART prevents and suppresses the infection. However, ART interruption almost invariably leads to rebound viremia in infected individuals due to a long-lived latent reservoir of integrated proviruses. Therefore, ART must be administered on a life-long basis. Here we review recent preclinical and clinical studies suggesting that immunotherapy may be an alternative or an adjuvant to ART because, in addition to preventing new infections, anti-HIV-1 antibodies clear the virus, directly kill infected cells and produce immune complexes that can enhance host immunity to the virus.
Lacy KD, Shoemaker D, Ross KG
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Joint Evolution of Asexuality and Queen Number in an Ant

CURRENT BIOLOGY 2019 APR 22; 29(8):1394-1400.e4
Ants exhibit a striking diversity of reproductive systems, varying in traits such as the number of reproductives per colony [1], the mode of daughter production (sexual or asexual) [2], and the mode of caste determination (genetic or environmental) [3]. Species employing mixed reproductive systems present a unique opportunity to explore the causes and consequences of alternative breeding strategies. Mixed reproductive systems in ants include social polymorphism in colony queen number, whereby single-queen (monogyne) and multiple-queen (polygyne) colonies co-occur within species [4-7], and facultative asexuality, in which female offspring may be produced sexually or asexually within colonies [8-13 ]. Here, we document a remarkable confluence of multiple mixed reproductive systems in the tropical fire ant, Solenopsis geminate, in a population with three important features: (1) polygyne colonies produce workers sexually but queens asexually, whereas monogyne colonies produce both castes sexually; (2) polygyne queens mate with monogyne males to produce workers, but monogyne queens do not mate with polygyne males; and (3) different asexual/polygyne lineages evidently were founded separately by genetically distinct founder queens, which appear to have originated from the same neighboring monogyne population. Multiple asexual/polygyne genomes are transmitted undiluted in this system, but sterile workers produced with sperm from a sexually-reproducing/monogyne population are necessary for the persistence of these lineages. The intersection of social polymorphism, facultative asexuality, and genetic caste determination marks this population of S. geminata as an embodiment of the diversity of ant reproductive systems and suggests previously unknown connections between these phenomena.
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.
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.
Silva HM, Bafica A, Rodrigues-Luiz GF, Chi J, Santos PDA, Reis BS, van Konijnenburg DPH, Crane A, Arifa RDN, Martin P, Mendes DAGB, Mansur DS, Torres CJ, Cadwell K, Cohen P, Mucida D, Lafaille JJ
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Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges

JOURNAL OF EXPERIMENTAL MEDICINE 2019 APR; 216(4):786-806
Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c(+)CD64(+ )double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.
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.