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Found 35038 matches. Displaying 91-100
Liberatore RA, Mastrocola EJ, Cassella E, Schmidt F, Willen JR, Voronin D, Zang TM, Hatziioannou T, Bieniasz PD
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Rhabdo-immunodeficiency virus, a murine model of acute HIV-1 infection

ELIFE 2019 OCT 23; 8(?):? Article e49875
Numerous challenges have impeded HIV-1 vaccine development. Among these is the lack of a convenient small animal model in which to study antibody elicitation and efficacy. We describe a chimeric Rhabdo-Immunodeficiency virus (RhIV) murine model that recapitulates key features of HIV-1 entry, tropism and antibody sensitivity. RhIVs are based on vesicular stomatitis viruses (VSV), but viral entry is mediated by HIV-1 Env proteins from diverse HIV-1 strains. RhIV infection of transgenic mice expressing human CD4 and CCR5, exclusively on mouse CD4+ cells, at levels mimicking those on human CD4+ T-cells, resulted in acute, resolving viremia and CD4+ T-cell depletion. RhIV infection elicited protective immunity, and antibodies to HIV-1 Env that were primarily non-neutralizing and had modest protective efficacy following passive transfer. The RhIV model enables the convenient in vivo study of HIV-1 Env-receptor interactions, antiviral activity of antibodies and humoral responses against HIV-1 Env, in a genetically manipulatable host.
Fins JJ
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Mosaic Decisionmaking and Severe Brain Injury: Adding Another Piece to

CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS 2019 OCT; 28(4):737-743 Article PII S0963180119000677
Jarvis ED
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Evolution of vocal learning and spoken language

SCIENCE 2019 OCT 4; 366(6461):50-54
Although language, and therefore spoken language or speech, is often considered unique to humans, the past several decades have seen a surge in nonhuman animal studies that inform us about human spoken language. Here, I present a modern, evolution-based synthesis of these studies, from behavioral to molecular levels of analyses. Among the key concepts drawn are that components of spoken language are continuous between species, and that the vocal learning component is the most specialized and rarest and evolved by brain pathway duplication from an ancient motor learning pathway. These concepts have important implications for understanding brain mechanisms and disorders of spoken language.
Ganesh K
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A rectal cancer organoid platform to study individual responses to

NATURE MEDICINE 2019 OCT; 25(10):1607-1614
Rectal cancer (RC) is a challenging disease to treat that requires
Zhang D, Tang ZY, Huang H, Zhou GL, Cui C, Weng YJ, Liu WC, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He MM, Zheng YG, Shuman HA, Dai LZ, Ren B, Roeder RG, Becker L, Zhao YM
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Metabolic regulation of gene expression by histone lactylation

NATURE 2019 OCT 24; 574(7779):575-580
The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases(1,2). Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous 'lactate clock' in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.
Del Duca E
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Major Differences in Expression of Inflammatory Pathways in Skin from

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2019 OCT; 139(10):2228-2232
Haremaki T, Metzger JJ, Rito T, Ozair MZ, Etoc F, Brivanlou AH
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Self-organizing neuruloids model developmental aspects of Huntington's disease in the ectodermal compartment

NATURE BIOTECHNOLOGY 2019 OCT; 37(10):1198-1208
Harnessing the potential of human embryonic stem cells to mimic normal and aberrant development with standardized models is a pressing challenge. Here we use micropattern technology to recapitulate early human neurulation in large numbers of nearly identical structures called neuruloids. Dual-SMAD inhibition followed by bone morphogenic protein 4 stimulation induced self-organization of neuruloids harboring neural progenitors, neural crest, sensory placode and epidermis. Single-cell transcriptomics unveiled the precise identities and timing of fate specification. Investigation of the molecular mechanism of neuruloid self-organization revealed a pulse of pSMAD1 at the edge that induced epidermis, whose juxtaposition to central neural fates specifies neural crest and placodes, modulated by fibroblast growth factor and Wnt. Neuruloids provide a unique opportunity to study the developmental aspects of human diseases. Using isogenic Huntington's disease human embryonic stem cells and deep neural network analysis, we show how specific phenotypic signatures arise in our model of early human development as a consequence of mutant huntingtin protein, outlining an approach for phenotypic drug screening.
Riessland M
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Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic

CELL STEM CELL 2019 OCT 3; 25(4):514-530.e8
Cellular senescence is a mechanism used by mitotic cells to prevent
Fins JJ
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Disorders of Consciousness, Past, Present, and Future

CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS 2019 OCT; 28(4):603-615 Article PII S0963180119000719
This paper, presented as the 2019 Cambridge Quarterly Neuroethics
Duncan A, Heyer MP, Ishikawa M, Caligiuri SPB, Liu XA, Chen ZX, Di Bonaventura MVM, Elayouby KS, Ables JL, Howe WM, Bali P, Fillinger C, Williams M, O'Connor RM, Wang ZC, Lu Q, Kamenecka TM, Ma'ayan A, O'Neill HC, Ibanez-Tallon I, Geurts AM, Kenny PJ
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Habenular TCF7L2 links nicotine addiction to diabetes

NATURE 2019 OCT 17; 574(7778):372-377
Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes- like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.