Summary Background Tuberculosis incidence in the UK has risen in the past decade. Disease control depends on epidemiological data, which can be difficult to obtain. Whole-genome sequencing can detect ...microevolution within Mycobacterium tuberculosis strains. We aimed to estimate the genetic diversity of related M tuberculosis strains in the UK Midlands and to investigate how this measurement might be used to investigate community outbreaks. Methods In a retrospective observational study, we used Illumina technology to sequence M tuberculosis genomes from an archive of frozen cultures. We characterised isolates into four groups: cross-sectional, longitudinal, household, and community. We measured pairwise nucleotide differences within hosts and between hosts in household outbreaks and estimated the rate of change in DNA sequences. We used the findings to interpret network diagrams constructed from 11 community clusters derived from mycobacterial interspersed repetitive-unit–variable-number tandem-repeat data. Findings We sequenced 390 separate isolates from 254 patients, including representatives from all five major lineages of M tuberculosis . The estimated rate of change in DNA sequences was 0·5 single nucleotide polymorphisms (SNPs) per genome per year (95% CI 0·3–0·7) in longitudinal isolates from 30 individuals and 25 families. Divergence is rarely higher than five SNPs in 3 years. 109 (96%) of 114 paired isolates from individuals and households differed by five or fewer SNPs. More than five SNPs separated isolates from none of 69 epidemiologically linked patients, two (15%) of 13 possibly linked patients, and 13 (17%) of 75 epidemiologically unlinked patients (three-way comparison exact p<0·0001). Genetic trees and clinical and epidemiological data suggest that super-spreaders were present in two community clusters. Interpretation Whole-genome sequencing can delineate outbreaks of tuberculosis and allows inference about direction of transmission between cases. The technique could identify super-spreaders and predict the existence of undiagnosed cases, potentially leading to early treatment of infectious patients and their contacts. Funding Medical Research Council, Wellcome Trust, National Institute for Health Research, and the Health Protection Agency.
Research supports abnormal inhibitory visual motion processing in adults with remitted and current depression, but all studies to date have used paradigms with simple grating stimuli. Global motion ...processing, where multiple motion signals must be integrated, has not been explored in depression, nor have inhibitory processes within that domain. Depressed participants (n = 46) and healthy controls (n = 28) completed a direction discrimination task featuring a random dot pattern stimulus. Various signal (rightward or leftward dots) to noise (dots with randomly assigned directions) ratios modulated task difficulty. Metrics of global center surround suppression and facilitation were calculated. Accuracy in the baseline condition (i.e., no surrounding annulus) was not significantly different between depressed and healthy participants. Global center surround suppression and facilitation were not significantly different between healthy and depressed participants overall. When limiting the sample to unmedicated individuals, depressed participants (n = 27) showed a reduced global center surround suppression effect compared to controls, and there was no difference in global center surround facilitation. While global motion processing is intact in depression, abnormal center surround suppression effects in depression do extend to global motion stimuli. These alterations may be mitigated by the psychotropic medications taken by some subjects in our depressed sample. Future studies should explore the mechanisms underlying these effects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn ...graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes.
Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA.
To reduce uncertainties about the metabolism and excretion of ...BPA in humans following oral administration.
We exposed six men and eight women to 100μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates.
Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711nM (390ng/ml) was observed at Tmax of 1.1±0.50h. Unconjugated d6-BPA appeared in serum within 5–20min of dosing with a mean Cmax of 6.5nM (1.5ng/ml) observed at Tmax of 1.3±0.52h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48h in some subjects at concentrations near the LOD (0.001–0.002ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4±2.0h and 6.2±2.6h, respectively. Recovery of total administered d6-BPA in urine was 84–109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h.
Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h.
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•Findings are consistent with data from animal and other human studies.•Maximum total serum levels are 3.9ng/ml for each μg ingested per kg.•Maximum unconjugated serum levels are 0.015ng/ml for each μg ingested per kg.•Unconjugated BPA in blood following oral administration is <1% of the total.•Most subjects excreted >90% as conjugated metabolites within 24h.
Human activities are increasing wildfires and livestock activity in arid ecosystems with potential implications for the spread of invasive grasses. The objective of this study was to test whether ...fire history and cattle activity alter soil resource gradients, thereby affecting patterns of
Bromus rubens
L. (red brome) invasion. Six paired burned and unburned transect lines (1-km long) were established in the northeast Mojave Desert along the boundaries of four independent wildfire scars. At 100-m transect increment points, we measured the distance to the two nearest cowpats, and two random points and measured the density, height, biomass, and seed production of red brome, soil moisture and inorganic nitrogen (N). Cattle activity was 29% greater along burned transects compared to unburned transects (
P
< 0.05). Red brome height, density, and seed production were 11–34% greater along burned transects than unburned transects (
P
< 0.05). Red brome height, biomass, density, and seed production were twofold to tenfold greater next to cowpats compared to random points (
P
< 0.05). Soils along burned transects and beneath cowpats had greater soil inorganic N (
P
< 0.05), which was positively correlated with red brome density, height, biomass, and seed production (
R
2
= 0.60–0.85,
P
< 0.0001). Transgenerational effects were evident as seeds from red brome next to cowpats had 27% higher germination than seeds collected from random points. Positive responses of red brome to increased inorganic N related to fire and cattle activity may contribute fine fuel infill that drives invasive grass-fire cycles in deserts.
Engineering cellular phenotypes often requires the regulation of many genes. When using CRISPR interference, coexpressing many single-guide RNAs (sgRNAs) triggers genetic instability and phenotype ...loss, due to the presence of repetitive DNA sequences. We stably coexpressed 22 sgRNAs within nonrepetitive extra-long sgRNA arrays (ELSAs) to simultaneously repress up to 13 genes by up to 3,500-fold. We applied biophysical modeling, biochemical characterization and machine learning to develop toolboxes of nonrepetitive genetic parts, including 28 sgRNA handles that bind Cas9. We designed ELSAs by combining nonrepetitive genetic parts according to algorithmic rules quantifying DNA synthesis complexity, sgRNA expression, sgRNA targeting and genetic stability. Using ELSAs, we created three highly selective phenotypes in Escherichia coli, including redirecting metabolism to increase succinic acid production by 150-fold, knocking down amino acid biosynthesis to create a multi-auxotrophic strain and repressing stress responses to reduce persister cell formation by 21-fold. ELSAs enable simultaneous and stable regulation of many genes for metabolic engineering and synthetic biology applications.
We present new arcminute-resolution maps of the Cosmic Microwave Background temperature and polarization anisotropy from the Atacama Cosmology Telescope, using data taken from 2013{2016 at 98 and 150 ...GHz. The maps cover more than 17,000 deg(^2), the deepest 600 deg(^2) with noise levels below 10µK-arcmin. We use the power spectrum derived from almost 6,000 deg(^2) of these maps to constrain cosmology. The ACT data enable a measurement of the angular scale of features in both the divergence-like polarization and the temperature anisotropy, tracing both the velocity and density at last-scattering. From these one can derive the distance to the last-scattering surface and thus infer the local expansion
rate, H0. By combining ACT data with large-scale information from WMAP we measure H0 = 67:6±1:1 km/s/Mpc, at 68% confidence, in excellent agreement with the independently measured Planck satellite estimate (from ACT alone we find H0 = 67:9± 1:5 km/s/Mpc). The ΛCDM model provides a good fit to the ACT data, and we find no evidence for deviations: both the spatial curvature, and the departure from the standard lensing signal in the
spectrum, are zero to within 1σ; the number of relativistic species, the primordial Helium fraction, and the running of the spectral index are consistent with ΛCDM predictions to within 1.5{2.2σ. We compare ACT, WMAP, and Planck at the parameter level and find good consistency; we investigate how the constraints on the correlated spectral index and baryon density parameters readjust when adding CMB large-scale information that ACT does not measure. The DR4 products presented here will be publicly released on the NASA Legacy Archive for Microwave Background Data Analysis.
We present the temperature and polarization angular power spectra of the CMB measured by the Atacama Cosmology Telescope (ACT) from 5400 deg
2
of the 2013–2016 survey, which covers >15000 deg
2
at 98 ...and 150 GHz. For this analysis we adopt a blinding strategy to help avoid confirmation bias and, related to this, show numerous checks for systematic error done before unblinding. Using the likelihood for the cosmological analysis we constrain secondary sources of anisotropy and foreground emission, and derive a “CMB-only” spectrum that extends to ℓ=4000. At large angular scales, foreground emission at 150 GHz is ∼1% of TT and EE within our selected regions and consistent with that found by
Planck
. Using the same likelihood, we obtain the cosmological parameters for ΛCDM for the ACT data alone with a prior on the optical depth of τ=0.065±0.015. ΛCDM is a good fit. The best-fit model has a reduced χ
2
of 1.07 (PTE=0.07) with
H
0
=67.9±1.5 km/s/Mpc. We show that the lensing BB signal is consistent with ΛCDM and limit the celestial EB polarization angle to ψ
P
=−0.07
̂
±0.09
̂
. We directly cross correlate ACT with
Planck
and observe generally good agreement but with some discrepancies in TE. All data on which this analysis is based will be publicly released.
Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers.
We sought to evaluate Diversity Outbred (DO) mice as a tool for ...exposure threshold assessment and to identify genetic factors that influence benzene-induced genotoxicity.
We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). The study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis.
We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. This estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identified a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity.
The genetically diverse DO mice provided a reproducible response to benzene exposure. The DO mice display interindividual variation in toxicity response and, as such, may more accurately reflect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. The identification of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Tetrahedrite, a promising thermoelectric material composed of earth-abundant elements, has been fabricated utilizing the rapid and low energy modified polyol process. Synthesis has been demonstrated ...for undoped and zinc-doped tetrahedrite samples on the gram scale requiring only 1 h at 220 °C. This method is capable of incorporating dopants and producing particles in the 50–200 nm size regime. For determination of bulk thermoelectric properties, powders produced by this solution-phase method were densified into pellets by spark plasma sintering. Thermopower, electrical resistivity, and thermal conductivity were obtained for temperatures ranging from 323 to 723 K. Maximum ZT values at 723 K were found to be 0.66 and 1.09 for the undoped and zinc-doped tetrahedrite samples, respectively. These values are comparable to or greater than those obtained using time and energy intensive conventional solid-state methods. Consolidated pellets fabricated using nanomaterial produced by this solution-phase method were found to have decreased thermal conductivity, increased electrical resistivity, and increased thermopower. Exceptionally low total thermal conductivity values were found (below 0.7 W m–1 K–1 for undoped tetrahedrite and 0.5 W m–1 K–1 for zinc-doped tetrahedrite), with both having lattice thermal conductivities below 0.4 W m–1 K–1. This study explores how nanostructuring and doping of tetrahedrite via a solution-phase polyol process impacts thermoelectric performance.
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