Insulin plays roles in lipid uptake, lipolysis, and lipogenesis, in addition to controlling blood glucose levels. Excessive circulating insulin is associated with adipose tissue expansion and ...obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance. Recently, evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models has been presented. Our experiments, and others in this field, question the current dogma that hyperinsulinemia is a response to obesity and/or insulin resistance. In this review, we discuss preclinical evidence in the context of the broader literature and speculate on the possibility of clinical translation of alternative approaches for treating obesity.
Insulin acts on multiple tissues to stimulate the synthesis and storage of carbohydrates, lipids, and proteins.
Hypersecretion of insulin is a physiological contributor to diet-induced obesity in animal models.
Obesity can be treated in adult mice following an acute reduction in insulin secretion.
The results of clinical studies are mixed, and additional, more specific manipulations are needed to translate the preclinical knowledge for humans.
70-year legacy of the Framingham Heart Study Andersson, Charlotte; Johnson, Andrew D; Benjamin, Emelia J ...
Nature reviews cardiology,
11/2019, Letnik:
16, Številka:
11
Journal Article
Recenzirano
The Framingham Heart Study (FHS) was established in 1948 to improve understanding of the epidemiology of coronary heart disease (CHD) in the USA. In 1961, seminal work identified major risk factors ...for CHD (high blood pressure, high cholesterol levels and evidence on the electrocardiogram of left ventricular hypertrophy), which later formed the basis for multivariable 10-year and 30-year risk-prediction algorithms. The FHS cohorts now comprise three generations of participants (n ≈ 15,000) and two minority cohorts. The FHS cohorts are densely phenotyped, with recurring follow-up examinations and surveillance for cardiovascular and non-cardiovascular end points. Assessment of subclinical disease and physiological profiling of these cohorts (with the use of echocardiography, ambulatory electrocardiographic monitoring, exercise stress testing, cardiac CT, heart and brain MRI, serial vascular tonometry and accelerometry) have been performed repeatedly. Over the past decade, the FHS cohorts have undergone deep 'omics' profiling (including whole-genome sequencing, DNA methylation analysis, transcriptomics, high-throughput proteomics and metabolomics, and microbiome studies). The FHS is a rich, longitudinal, transgenerational and deeply phenotyped cohort study with a sustained focus on state-of-the-art epidemiological methods and technological advances to facilitate scientific discoveries.
ABSTRACT At radio wavelengths, scattering in the interstellar medium distorts the appearance of astronomical sources. Averaged over a scattering ensemble, the result is a blurred image of the source. ...However, Narayan & Goodman and Goodman & Narayan showed that for an incomplete average, scattering introduces refractive substructure in the image of a point source that is both persistent and wideband. We show that this substructure is quenched but not smoothed by an extended source. As a result, when the scatter-broadening is comparable to or exceeds the unscattered source size, the scattering can introduce spurious compact features into images. In addition, we derive efficient strategies to numerically compute realistic scattered images, and we present characteristic examples from simulations. Our results show that refractive substructure is an important consideration for ongoing missions at the highest angular resolutions, and we discuss specific implications for RadioAstron and the Event Horizon Telescope.
Members of the genus Acidithiobacillus, now ranked within the class Acidithiobacillia, are model bacteria for the study of chemolithotrophic energy conversion under extreme conditions. Knowledge of ...the genomic and taxonomic diversity of Acidithiobacillia is still limited. Here, we present a systematic analysis of nearly 100 genomes from the class sampled from a wide range of habitats. Some of these genomes are new and others have been reclassified on the basis of advanced genomic analysis, thus defining 19 Acidithiobacillia lineages ranking at different taxonomic levels. This work provides the most comprehensive classification and pangenomic analysis of this deep-branching class of Proteobacteria to date. The phylogenomic framework obtained illuminates not only the evolutionary past of this lineage, but also the molecular evolution of relevant aerobic respiratory proteins, namely the cytochrome bo
ubiquinol oxidases.
Abstract
While many prokaryotic species are known to use hydrogen as an electron donor to support their growth, this trait has only previously been reported for two acidophilic bacteria, ...Hydrogenobaculum acidophilum (in the presence of reduced sulfur) and Acidithiobacillus (At.) ferrooxidans. To test the hypothesis that hydrogen may be utilized more widely by acidophilic bacteria, 38 strains of acidophilic bacteria, including representatives of 20 designated and four proposed species, were screened for their abilities to grow via the dissimilatory oxidation of hydrogen. Growth was demonstrated in several species of acidophiles that also use other inorganic electron donors (ferrous iron and sulfur) but in none of the obligately heterotrophic species tested. Strains of At. ferrooxidans, At. ferridurans and At. caldus, grew chemolithotrophically on hydrogen, though those of At. thiooxidans and At. ferrivorans did not. Growth was also observed with Sulfobacillus acidophilus, Sb. benefaciens and Sb. thermosulfidooxidans, though not with other iron-oxidizing Firmicutes. Similarly, Acidimicrobium ferrooxidans grew on hydrogen, closely related acidophilic actinobacteria did not. Growth yields of At. ferrooxidans and At. ferridurans grown aerobically on hydrogen (c. 1010 cells mL−1) were far greater than typically obtained using other electron donors. Several species also grew anaerobically by coupling hydrogen oxidation to the reduction of ferric iron.
The NLR family pyrin domain‐containing 3 (NLRP3) inflammasome plays an important role in liver fibrosis (LF) development. However, the mechanisms involved in NLRP3‐induced fibrosis are unclear. Our ...aim was to test the hypothesis that the NLRP3 inflammasome in hepatic stellate cells (HSCs) can directly regulate their activation and contribute to LF. Primary HSCs isolated from wild‐type (WT), Nlrp3–/–, or Nlrp3L351PneoR knock‐in crossed to inducible (estrogen receptor Cre‐CreT) mice were incubated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP), or 4OH‐tamoxifen, respectively. HSC‐specific Nlrp3L351P knock‐in mice were generated by crossing transgenic mice expressing lecithin retinol acyltransferase (Lrat)‐driven Cre and maintained on standard rodent chow for 6 months. Mice were then sacrificed; liver tissue and serum were harvested. Nlrp3 inflammasome activation along with HSC phenotype and fibrosis were assessed by RT‐PCR, western blotting, fluorescence‐activated cell sorting (FACS), enzyme‐linked immunosorbent assay, immunofluorescence (IF), and immunohistochemistry (IHC). Stimulated WT HSCs displayed increased levels of NLRP3 inflammasome‐induced reactive oxygen species (ROS) production and cathepsin B activity, accompanied by an up‐regulation of mRNA and protein levels of fibrotic makers, an effect abrogated in Nlrp3–/– HSCs. Nlrp3L351P CreT HSCs also showed elevated mRNA and protein expression of fibrotic markers 24 hours after inflammasome activation induced with 4‐hydroxytamoxifen (4OHT). Protein and mRNA expression levels of fibrotic markers were also found to be increased in isolated HSCs and whole liver tissue from Nlrp3L351P Lrat Cre mice compared to WT. Liver sections from 24‐week‐old NlrpL351P Lrat Cre mice showed fibrotic changes with increased alpha smooth muscle actin (αSMA) and desmin‐positive cells and collagen deposition, independent of inflammatory infiltrates; these changes were also observed after LPS challenge in 8‐week‐old NlrpL351P Lrat Cre mice. Conclusion: Our results highlight a direct role for the NLRP3 inflammasome in the activation of HSCs directly triggering LF.
Gravitational interactions between the Large Magellanic Cloud (LMC) and the stellar and dark matter halo of the Milky Way are expected to give rise to disequilibrium phenomena in the outer Milky Way
.... A local wake is predicted to trail the orbit of the LMC, and a large-scale overdensity is predicted to exist across a large area of the northern Galactic hemisphere. Here we report the detection of both the local wake and northern overdensity (hereafter the 'collective response') in a map of the Galaxy based on 1,301 stars at Galactocentric distances between 60 and 100 kiloparsecs. The location of the wake is in good agreement with an N-body simulation that includes the dynamical effect of the LMC on the Milky Way halo. The density contrast of the wake and collective response are stronger in the data than in the simulation. The detection of a strong local wake is independent evidence that the Magellanic clouds are on their first orbit around the Milky Way. The wake traces the path of the LMC, which will provide insight into the orbit of the LMC, which in turn is a sensitive probe of the mass of the LMC and the Milky Way. These data demonstrate that the outer halo is not in dynamical equilibrium, as is often assumed. The morphology and strength of the wake could be used to test the nature of dark matter and gravity.
Twelve strains of iron-oxidizing acidithiobacilli isolated from acidic sites throughout the world, including some previously shown by multi-locus sequence analyses and DNA–DNA hybridization to ...comprise a distinct species, were characterized in terms of their physiologies. The bacteria were shown to be obligately chemolithotrophic, acidophilic and mesophilic, and grew in both oxic and anoxic environments, using ferrous iron, reduced sulfur or hydrogen as electron donors and oxygen or ferric iron as electron acceptors. Some of the strains grew at lower pH than those reported for the two recognized iron-oxidizing Acidithiobacillus species, Acidithiobacillus ferrooxidans and Acidithiobacillus ferrivorans. Tolerance of transition metals and aluminium, and also specific rates of iron oxidation and reduction, were more similar to those of A. ferrooxidans (to which the strains are more closely related) than to A. ferrivorans. The name Acidithiobacillus ferridurans sp. nov. is proposed to accommodate the 12 strains, with the type strain being JCM 18981T ( = ATCC 33020T).
We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains >6.2 million SNP-phenotype association from among 1390 GWAS studies. We ...re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs).
To create a high-quality resource to facilitate further use and interpretation of human GWAS results in order to address important scientific questions.
GWAS have grown exponentially, with increases in sample sizes and markers tested, and continuing bias toward European ancestry samples. GRASP contains >100 000 phenotypes, roughly: eQTLs (71.5%), metabolite QTLs (21.2%), methylation QTLs (4.4%) and diseases, biomarkers and other traits (2.8%). cis-eQTLs, meQTLs, mQTLs and MHC region SNPs are highly enriched among significant results. After removing these categories, GRASP still contains a greater proportion of studies and results than comparable GWAS catalogs. Cardiovascular disease and related risk factors pre-dominate remaining GWAS results, followed by immunological, neurological and cancer traits. Significant results in GWAS display a highly gene-centric tendency. Sex chromosome X (OR = 0.180.16-0.20) and Y (OR = 0.0030.001-0.01) genes are depleted for GWAS results. Gene length is correlated with GWAS results at nominal significance (P ≤ 0.05) levels. We show this gene-length correlation decays at increasingly more stringent P-value thresholds. Potential pleotropic genes and SNPs enriched for multi-phenotype association in GWAS are identified. However, we note possible population stratification at some of these loci. Finally, via re-annotation we identify compelling functional hypotheses at GWAS loci, in some cases unrealized in studies to date.
Pooling summary-level GWAS results and re-annotating with bioinformatics predictions and molecular features provides a good platform for new insights.
The GRASP database is available at http://apps.nhlbi.nih.gov/grasp.
Galaxy observations are influenced by many physical parameters: stellar masses, star formation rates (SFRs), star formation histories (SFHs), metallicities, dust, black hole activity, and more. As a ...result, inferring accurate physical parameters requires high-dimensional models that capture or marginalize over this complexity. Here we reassess inferences of galaxy stellar masses and SFRs using the 14-parameter physical model Prospector- built in the Prospector Bayesian inference framework. We fit the photometry of 58,461 galaxies from the 3D-HST catalogs at 0.5 < z < 2.5. The resulting stellar masses are ∼0.1-0.3 dex larger than the fiducial masses while remaining consistent with dynamical constraints. This change is primarily due to the systematically older SFHs inferred with Prospector. The SFRs are ∼0.1-1+ dex lower than UV+IR SFRs, with the largest offsets caused by emission from "old" (t > 100 Myr) stars. These new inferences lower the observed cosmic SFR density by ∼0.2 dex and increase the observed stellar mass growth by ∼0.1 dex, finally bringing these two quantities into agreement and implying an older, more quiescent universe than found by previous studies at these redshifts. We corroborate these results by showing that the Prospector- SFHs are both more physically realistic and much better predictors of the evolution of the stellar mass function. Finally, we highlight examples of observational data that can break degeneracies in the current model; these observations can be incorporated into priors in future models to produce new and more accurate physical parameters.
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