In vertebrates, including humans, individuals harbor gut microbial communities whose species composition and relative proportions of dominant microbial groups are tremendously varied. Although external and stochastic factors clearly contribute to the individuality of the microbiota, the fundamental principles dictating how environmental factors and host genetic factors combine to shape this complex ecosystem are largely unknown and require systematic study. Here we examined factors that affect microbiota composition in a large (n = 645) mouse advanced intercross line originating from a cross between C57BL/6J and an ICR-derived outbred line (HR). Quantitative pyrosequencing of the microbiota defined a core measurable microbiota (CMM) of 64 conserved taxonomic groups that varied quantitatively across most animals in the population. Although some of this variation can be explained by litter and cohort effects, individual host genotype had a measurable contribution. Testing of the CMM abundances for cosegregation with 530 fully informative SNP markers identified 18 host quantitative trait loci (QTL) that show significant or suggestive genomewide linkage with relative abundances of specific microbial taxa. These QTL affect microbiota composition in three ways; some loci control individual microbial species, some control groups of related taxa, and some have putative pleiotropic effects on groups of distantly related organisms. These data provide clear evidence for the importance of host genetic control in shaping individual microbiome diversity in mammals, a key step toward understanding the factors that govern the assemblages of gut microbiota associated with complex diseases.16S rDNA | pyrosequencing | quantitative trait loci mapping | microbiome phenotyping | population
Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that β-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with β-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.
Vertebrates and invertebrates initiate a series of defence mechanisms following infection by Gram-negative bacteria by sensing the presence of lipopolysaccharide (LPS), a major component of the cell wall of the invading pathogen. In humans, monocytes and macrophages respond to LPS by inducing the expression of cytokines, cell-adhesion proteins, and enzymes involved in the production of small proinflammatory mediators. Under pathophysiological conditions, LPS exposure can lead to an often fatal syndrome known as septic shock. Sensitive responses of myeloid cells to LPS require a plasma protein called LPS-binding protein and the glycosylphosphatidylinositol-anchored membrane protein CD14. However, the mechanism by which the LPS signal is transduced across the plasma membrane remains unknown. Here we show that Toll-like receptor 2 (TLR2) is a signalling receptor that is activated by LPS in a response that depends on LPS-binding protein and is enhanced by CD14. A region in the intracellular domain of TLR2 with homology to a portion of the interleukin (IL)-1 receptor that is implicated in the activation of the IL-1-receptor-associated kinase is required for this response. Our results indicate that TLR2 is a direct mediator of signalling by LPS.
Severe malaria is caused by the apicomplexan parasite Plasmodium falciparum. Despite decades of research the unique biology of these parasites has made it challenging to establish high throughput genetic approaches for identification of therapeutic targets. Using transposon mutagenesis of P. falciparum in an approach that exploited its AT-rich genome we generated >38,000 mutants, saturating the genome and defining fitness costs for 95% of genes. Of 5,399 genes we found ~3,000 genes are essential for optimal growth of asexual blood-stages in vitro. Our study defines ∼1000 essential genes, including genes associated with drug resistance, vaccine candidates, and conserved proteins of unknown function. We validated this approach by testing proteasome pathways for individual mutants associated with artemisinin sensitivity.
The study analysed healthcare workers' (HCWs) knowledge, practices, and attitudes regarding coronavirus disease 2019 . A cross-sectional survey was conducted from February 4 th to February 8 th , 2020, involving a total of 1357 HCWs across 10 hospitals in Henan, China. Of those surveyed, 89% of HCWs had sufficient knowledge of COVID-19, more than 85% feared self-infection with the virus, and 89.7% followed correct practices regarding COVID-19. In addition to knowledge level, some risk factors including work experience and job category influenced HCWs' attitudes and practice concerning COVID-19. Measures must be taken to protect HCWs from risks linked to job category, work experience, working hours, educational attainment, and frontline HCWs.
A simple and facile method was developed to prepare fluorescent carbon nanocrystals (CNCs) with low cytotoxicity and no photobleaching, by electrooxidation of graphite in aqueous solution.
The potent sphingolipid metabolite sphingosine 1-phosphate is produced by phosphorylation of sphingosine catalyzed by sphingosine kinase (SphK) types 1 and 2. In contrast to pro-survival SphK1, the putative BH3-only protein SphK2 inhibits cell growth and enhances apoptosis. Here we show that SphK2 catalytic activity also contributes to its ability to induce apoptosis. Overexpressed SphK2 also increased cytosolic free calcium induced by serum starvation. Transfer of calcium to mitochondria was required for SphK2-induced apoptosis, as cell death and cytochrome c release was abrogated by inhibition of the mitochondrial Ca 2؉ transporter. Serum starvation increased the proportion of SphK2 in the endoplasmic reticulum and targeting SphK1 to the endoplasmic reticulum converted it from anti-apoptotic to pro-apoptotic. Overexpression of SphK2 increased incorporation of [ 3 H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide, whereas SphK1 decreased it. Electrospray ionizationmass spectrometry/mass spectrometry also revealed an opposite effect on ceramide mass levels. Importantly, specific down-regulation of SphK2 reduced conversion of sphingosine to ceramide in the recycling pathway and conversely, down-regulation of SphK1 increased it. Our results demonstrate that SphK1 and SphK2 have opposing roles in the regulation of ceramide biosynthesis and suggest that the location of sphingosine 1-phosphate production dictates its functions.The sphingolipid metabolite, sphingosine 1-phosphate (S1P), 3 a ligand for a family of five specific G protein-coupled receptors, and regulates many important cellular processes including growth, survival, differentiation, cytoskeleton rearrangements, motility, angiogenesis, and immunity (reviewed in Refs. 1-3). Although there is no doubt that S1P acts extracellularly, several studies suggest that this potent lipid, like its precursors sphingosine (4) and ceramide (N-acylsphingosine) (5-7), may also have intracellular functions important for calcium homeostasis (8), cell growth (9, 10), and suppression of apoptosis (11)(12)(13)(14).Like other lipid mediators, S1P levels are tightly regulated by the balance between synthesis, catalyzed by sphingosine kinase (SphK), irreversible cleavage by S1P lyase, and reversible dephosphorylation to sphingosine by specific S1P phosphatases. Two distinct SphK isoforms, SphK1 and SphK2, have been cloned and characterized (15,16). Diverse external stimuli, particularly growth and survival factors, stimulate SphK1 and intracellularly generated S1P has been implicated in their mitogenic and anti-apoptotic effects (10,13,(17)(18)(19)(20)(21)(22)(23)(24). Expression of SphK1 enhanced proliferation and growth in soft agar, promoted the G 1 -S transition, protected cells from apoptosis (10,14,17), and induced tumor formation in mice (17, 18). However, although SphK1 and intracellularly generated S1P can signal "inside-out" to regulate cytoskeletal rearrangements and cell movement, remarkably, cell growth stimulation...
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