The authors present an ecological framework to understand the efficacy of fecal microbiota transplantation (FMT) in treating conditions associated with a disrupted gut microbiota, using the recurrent Clostridioides difficile infection as a prototype disease. This framework predicts several key factors that determine the efficacy of FMT. Moreover, it offers an efficient algorithm for the rational design of personalized probiotic cocktails to decolonize pathogens.
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The authors modeled the network of factors that control gene expression and observed that these factors act differently between men and women. By analyzing gene regulatory networks in twenty-nine tissues, they found sex differences in the network structure, and showed that differential targeting of genes by sex occurs in most tissues. Exploring sex differences is crucial not only for understanding biological sex differences, but also for guiding the best therapeutic strategies in men and women.
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Alzheimer’s disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out…
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Despite the growing burden and high morbidity and mortality associated with non-alcoholic fatty liver disease (NAFLD), treatments are limited to risk factor modification including lifestyle intervention and management of co-morbid metabolic disease. Using a murine model of NAFLD, BMP signaling was found to be essential for the development of hepatic steatosis, independent of plasma cholesterol levels or glucose tolerance.
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The typical measurement for evaluating drugs doesn’t distinguish between responses that are due to inhibition of cell growth versus those that are due to activation of cell death. The authors developed a new drug evaluation metric that reports in a quantitative way the relative contribution of growth inhibition vs. cell death for a given drug response. Using this method, they evaluated a panel of common anti-cancer drugs finding an unexpected range of diverse types of response.
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The authors demonstrate that agents that raise cGMP and activate the cGMP-dependent protein kinase (PKG), including the widely-used phosphodiesterase 5 inhibitors sildenafil (Viagra) and tadalafil (Cialis), stimulate proteasome activities and protein breakdown by the ubiquitin proteasome system, without affecting autophagy. Like cAMP, cGMP enhances the degradation of misfolded and regulatory proteins, but cGMP also stimulates the breakdown of the bulk of cell proteins, which is unaffected by cAMP.
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The authors reveal how a well described anti-cancer barrier, “the replication stress response,” is overcome in cancer. They uncover that a key feature of the replication stress response is the induction of toxic single-stranded DNA gaps, and that fundamental to cancer development is suppression of these gaps. They also identify that cancer cells mitigate oncogene-induced gaps to sustain cell growth by aberrantly activating translesion synthesis.
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Approximately 20–30% of human lung adenocarcinomas (LUADs) harbor mutations in Kelch-like ECH-associated protein 1 (KEAP1) that hyperactivate the nuclear factor, erythroid 2-like 2 (NFE2L2) antioxidant program. We previously showed that Kras-driven Keap1-mutant LUAD is highly aggressive and dependent on glutaminolysis. Here we performed a druggable genome CRISPR screen and uncovered a Keap1-mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), as well…
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Outbreaks of filoviruses, such as those caused by the Ebola (EBOV) and Marburg (MARV) virus, are difficult to detect and control. The initial clinical symptoms of these diseases are nonspecific and can mimic other endemic pathogens. This makes confident diagnosis based on clinical symptoms alone impossible. Molecular diagnostics for these diseases that rely on the detection of viral RNA in…
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Genomic imprinting and X-chromosome inactivation (XCI) are classic epigenetic phenomena that involve transcriptional silencing of one parental allele. Germline-derived differential DNA methylation is the best-studied epigenetic mark that initiates imprinting, but evidence indicates that other mechanisms exist. Recent studies have revealed that maternal trimethylation of H3 on lysine 27 (H3K27me3) mediates autosomal maternal allele-specific gene silencing and has an important role…
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