345 research outputs found
Mining Virulence Genes Using Metagenomics
When a bacterial genome is compared to the metagenome of an environment it inhabits, most genes recruit at high sequence identity. In free-living bacteria (for instance marine bacteria compared against the ocean metagenome) certain genomic regions are totally absent in recruitment plots, representing therefore genes unique to individual bacterial isolates. We show that these Metagenomic Islands (MIs) are also visible in bacteria living in human hosts when their genomes are compared to sequences from the human microbiome, despite the compartmentalized structure of human-related environments such as the gut. From an applied point of view, MIs of human pathogens (e.g. those identified in enterohaemorragic Escherichia coli against the gut metagenome or in pathogenic Neisseria meningitidis against the oral metagenome) include virulence genes that appear to be absent in related strains or species present in the microbiome of healthy individuals. We propose that this strategy (i.e. recruitment analysis of pathogenic bacteria against the metagenome of healthy subjects) can be used to detect pathogenicity regions in species where the genes involved in virulence are poorly characterized. Using this approach, we detect well-known pathogenicity islands and identify new potential virulence genes in several human pathogens
Enhanced Long-Path Electrical Conduction in ZnO Nanowire Array Devices Grown via Defect-Driven Nucleation
Vertical arrays of nanostructures have been widely used as major components in some of the most ground-breaking modern research-based devices, and ZnO nanowires have received particular attention because of their favorable electronic properties. Using a local multiprobe technique to measure the properties of individual ZnO nanowires in vertical arrays, we show for the first time that for metal-catalyzed ZnO nanowire growth the electrical contribution of individual wires to a device is highly dependent on the fate of the catalyst nanoparticle during growth. To overcome the limitations of metal-catalyzed growth, nanowires grown from a defect-driven nucleation process are shown to provide high-quality device structures with excellent long-path electrical conduction
Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas
Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN
Differential gene expression in mouse primary hepatocytes exposed to the peroxisome proliferator-activated receptor α agonists
BACKGROUND: Fibrates are a unique hypolipidemic drugs that lower plasma triglyceride and cholesterol levels through their action as peroxisome proliferator-activated receptor alpha (PPARα) agonists. The activation of PPARα leads to a cascade of events that result in the pharmacological (hypolipidemic) and adverse (carcinogenic) effects in rodent liver. RESULTS: To understand the molecular mechanisms responsible for the pleiotropic effects of PPARα agonists, we treated mouse primary hepatocytes with three PPARα agonists (bezafibrate, fenofibrate, and WY-14,643) at multiple concentrations (0, 10, 30, and 100 ΌM) for 24 hours. When primary hepatocytes were exposed to these agents, transactivation of PPARα was elevated as measured by luciferase assay. Global gene expression profiles in response to PPARα agonists were obtained by microarray analysis. Among differentially expressed genes (DEGs), there were 4, 8, and 21 genes commonly regulated by bezafibrate, fenofibrate, and WY-14,643 treatments across 3 doses, respectively, in a dose-dependent manner. Treatments with 100 ΌM of bezafibrate, fenofibrate, and WY-14,643 resulted in 151, 149, and 145 genes altered, respectively. Among them, 121 genes were commonly regulated by at least two drugs. Many genes are involved in fatty acid metabolism including oxidative reaction. Some of the gene changes were associated with production of reactive oxygen species, cell proliferation of peroxisomes, and hepatic disorders. In addition, 11 genes related to the development of liver cancer were observed. CONCLUSION: Our results suggest that treatment of PPARα agonists results in the production of oxidative stress and increased peroxisome proliferation, thus providing a better understanding of mechanisms underlying PPARα agonist-induced hepatic disorders and hepatocarcinomas
A Spectroscopic Road Map for Cosmic Frontier: DESI, DESI-II, Stage-5
In this white paper, we present an experimental road map for spectroscopic
experiments beyond DESI. DESI will be a transformative cosmological survey in
the 2020s, mapping 40 million galaxies and quasars and capturing a significant
fraction of the available linear modes up to z=1.2. DESI-II will pilot
observations of galaxies both at much higher densities and extending to higher
redshifts. A Stage-5 experiment would build out those high-density and
high-redshift observations, mapping hundreds of millions of stars and galaxies
in three dimensions, to address the problems of inflation, dark energy, light
relativistic species, and dark matter. These spectroscopic data will also
complement the next generation of weak lensing, line intensity mapping and CMB
experiments and allow them to reach their full potential.Comment: Contribution to Snowmass 202
Probing of Exosites Leads to Novel Inhibitor Scaffolds of HCV NS3/4A Proteinase
Hepatitis C is a treatment-resistant disease affecting millions of people worldwide. The hepatitis C virus (HCV) genome is a single-stranded RNA molecule. After infection of the host cell, viral RNA is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. Cleavage of the polyprotein involves the viral NS3/4A proteinase, a proven drug target. HCV mutates as it replicates and, as a result, multiple emerging quasispecies become rapidly resistant to anti-virals, including NS3/4A inhibitors.To circumvent drug resistance and complement the existing anti-virals, NS3/4A inhibitors, which are additional and distinct from the FDA-approved telaprevir and boceprevir α-ketoamide inhibitors, are required. To test potential new avenues for inhibitor development, we have probed several distinct exosites of NS3/4A which are either outside of or partially overlapping with the active site groove of the proteinase. For this purpose, we employed virtual ligand screening using the 275,000 compound library of the Developmental Therapeutics Program (NCI/NIH) and the X-ray crystal structure of NS3/4A as a ligand source and a target, respectively. As a result, we identified several novel, previously uncharacterized, nanomolar range inhibitory scaffolds, which suppressed of the NS3/4A activity in vitro and replication of a sub-genomic HCV RNA replicon with a luciferase reporter in human hepatocarcinoma cells. The binding sites of these novel inhibitors do not significantly overlap with those of α-ketoamides. As a result, the most common resistant mutations, including V36M, R155K, A156T, D168A and V170A, did not considerably diminish the inhibitory potency of certain novel inhibitor scaffolds we identified.Overall, the further optimization of both the in silico strategy and software platform we developed and lead compounds we identified may lead to advances in novel anti-virals
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Astro2020 APC White Paper: The MegaMapper: a z > 2 spectroscopic instrument for the study of Inflation and Dark Energy
MegaMapper is a proposed ground-based experiment to measure Inflation
parameters and Dark Energy from galaxy redshifts at
First observation of a doubly charged tetraquark and its neutral partner
A combined amplitude analysis is performed for the decays and , which are
related by isospin symmetry. The analysis is based on data collected by the
LHCb detector in proton-proton collisions at center-of-mass energies of 7, 8
and 13. The full data sample corresponds to an integrated
luminosity of 9. Two new resonant states with masses of
and widths of
are observed, which decay to and
respectively. The former state indicates the first observation of
a doubly charged open-charm tetraquark state with minimal quark content
, and the latter state is a neutral tetraquark composed of
quarks. Both states are found to have spin-parity ,
and their resonant parameters are consistent with each other, which suggests
that they belong to an isospin triplet.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-026.html (LHCb
public pages
Amplitude analysis of and decays
Resonant contributions in and
decays are determined with an amplitude
analysis, which is performed both separately and simultaneously, where in the
latter case isospin symmetry between the decays is assumed. The analysis is
based on data collected by the LHCb detector in proton-proton collisions at
center-of-mass energies of 7, 8 and 13 . The full data sample
corresponds to an integrated luminosity of 9 . A doubly charged
spin-0 open-charm tetraquark candidate together with a neutral partner, both
with masses near , are observed in the decay channel.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-027.html (LHCb
public pages
Search for the doubly heavy baryon decaying to
A first search for the
decay is performed by the LHCb experiment with a data sample of proton-proton
collisions, corresponding to an integrated luminosity of
recorded at centre-of-mass energies of 7, 8, and . Two peaking structures are seen with a local (global) significance of
and standard deviations at masses of
and , respectively. Upper limits are set on the baryon
production cross-section times the branching fraction relative to that of the
decay at centre-of-mass energies of 8 and
, in the and in the
rapidity and transverse-momentum ranges from 2.0 to 4.5 and 0 to
, respectively. Upper limits are presented
as a function of the mass and lifetime.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-005.html (LHCb
public pages
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