The continuous increase of nitrous oxide (N ₂O) abundance in the atmosphere is a global concern. Multiple pathways of N ₂O production occur in soil, but their significance and dependence on oxygen (O ...₂) availability and nitrogen (N) fertilizer source are poorly understood. We examined N ₂O and nitric oxide (NO) production under 21%, 3%, 1%, 0.5%, and 0% (vol/vol) O ₂ concentrations following urea or ammonium sulfate (NH ₄) ₂SO ₄ additions in loam, clay loam, and sandy loam soils that also contained ample nitrate. The contribution of the ammonia (NH ₃) oxidation pathways (nitrifier nitrification, nitrifier denitrification, and nitrification-coupled denitrification) and heterotrophic denitrification (HD) to N ₂O production was determined in 36-h incubations in microcosms by ¹⁵N- ¹⁸O isotope and NH ₃ oxidation inhibition (by 0.01% acetylene) methods. Nitrous oxide and NO production via NH ₃ oxidation pathways increased as O ₂ concentrations decreased from 21% to 0.5%. At low (0.5% and 3%) O ₂ concentrations, nitrifier denitrification contributed between 34% and 66%, and HD between 34% and 50% of total N ₂O production. Heterotrophic denitrification was responsible for all N ₂O production at 0% O ₂. Nitrifier denitrification was the main source of N ₂O production from ammonical fertilizer under low O ₂ concentrations with urea producing more N ₂O than (NH ₄) ₂SO ₄ additions. These findings challenge established thought attributing N ₂O emissions from soils with high water content to HD due to presumably low O ₂ availability. Our results imply that management practices that increase soil aeration, e.g., reducing compaction and enhancing soil structure, together with careful selection of fertilizer sources and/or nitrification inhibitors, could decrease N ₂O production in agricultural soils.
We consider what can be learnt about the processes of gas accretion and depletion from the kinematic misalignment between the cold/warm gas and stars in local early-type galaxies. Using simple ...analytic arguments and a toy model of the processes involved, we show that the lack of objects with counter-rotating gas reservoirs strongly constrains the relaxation, depletion and accretion time-scales of gas in early-type galaxies. Standard values of the accretion rate, star-formation efficiency and relaxation rate are not simultaneously consistent with the observed distribution of kinematic misalignments. To reproduce that distribution, both fast gas depletion (t
dep ≲ 108 yr; e.g. more efficient star formation) and fast gas destruction (e.g. by active galactic nucleus feedback) can be invoked, but both also require a high rate of gas-rich mergers (>1 Gyr−1). Alternatively, the relaxation of misaligned material could happen over very long time-scales (≃100 dynamical times or ≈1–5 Gyr). We explore the various physical processes that could lead to fast gas depletion and/or slow gas relaxation, and discuss the prospects of using kinematic misalignments to probe gas-rich accretion processes in the era of large integral-field spectroscopic surveys.
Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used ...whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
The UKMYC5 plate is a 96-well microtiter plate designed by the CRyPTIC Consortium (Comprehensive Resistance Prediction for Tuberculosis: an International Consortium) to enable the measurement of MICs ...of 14 different antituberculosis (anti-TB) compounds for >30,000 clinical
isolates. Unlike the MYCOTB plate, on which the UKMYC5 plate is based, the UKMYC5 plate includes two new (bedaquiline and delamanid) and two repurposed (clofazimine and linezolid) compounds. UKMYC5 plates were tested by seven laboratories on four continents by use of a panel of 19 external quality assessment (EQA) strains, including H37Rv. To assess the optimal combination of reading method and incubation time, MICs were measured from each plate by two readers, using three methods (mirrored box, microscope, and Vizion digital viewing system), after 7, 10, 14, and 21 days of incubation. In addition, all EQA strains were subjected to whole-genome sequencing and phenotypically characterized by the 7H10/7H11 agar proportion method (APM) and by use of MGIT960 mycobacterial growth indicator tubes. We concluded that the UKMYC5 plate is optimally read using the Vizion system after 14 days of incubation, achieving an interreader agreement of 97.9% and intra- and interlaboratory reproducibility rates of 95.6% and 93.1%, respectively. The mirrored box had a similar reproducibility. Strains classified as resistant by APM, MGIT960, or the presence of mutations known to confer resistance consistently showed elevated MICs compared to those for strains classified as susceptible. Finally, the UKMYC5 plate records intermediate MICs for one strain for which the APM measured MICs close to the applied critical concentration, providing early evidence that the UKMYC5 plate can quantitatively measure the magnitude of resistance to anti-TB compounds that is due to specific genetic variation.
Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently
and the ...main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.
AbstractObjectivesTo determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, ...and the cumulative incidence for recurrent VTE up to 10 years.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019).Study selectionRandomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment.Data extraction and synthesisTwo investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of initial VTE were investigated as potential sources of between study heterogeneity.Results18 studies involving 7515 patients were included in the analysis. The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3-5, and 3.1 events/year (1.7 to 4.9) in years 6-10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%).ConclusionsIn patients with a first episode of unprovoked VTE who completed at least three months of anticoagulant treatment, the risk of recurrent VTE was 10% in the first year after treatment, 16% at two years, 25% at five years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death. These estimates should inform clinical practice guidelines, enhance confidence in counselling patients of their prognosis, and help guide decision making about long term management of unprovoked VTE.Systematic review registrationPROSPERO CRD42017056309.
In this study involving nearly 3400 patients with venous thromboembolism, both prophylactic and therapeutic doses of rivaroxaban were superior to aspirin in reducing the risk of recurrent ...thromboembolism with a similar risk of bleeding.
Venous thromboembolism, which includes deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular death after myocardial infarction and stroke.
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The mainstay of treatment is anticoagulation,
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and in patients without active cancer, guidelines suggest the use of direct oral anticoagulant agents such as rivaroxaban over vitamin K antagonists such as warfarin.
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Anticoagulation therapy is administered for 3 months or longer, depending on the balance between the risk of recurrent venous thromboembolism and the risk of bleeding.
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In patients without reversible risk factors, the risk of recurrent venous thromboembolism is as much as 10% in the first . . .
Genomes of the Mouse Collaborative Cross Srivastava, Anuj; Morgan, Andrew P; Najarian, Maya L ...
Genetics (Austin),
06/2017, Letnik:
206, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic ...stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 30× coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of new genetic variants introduced by mutation and drift in the CC genomes. We estimate that new SNP mutations are accumulating in each CC strain at a rate of 2.4 ± 0.4 per gigabase per generation. The fixation of new mutations by genetic drift has introduced thousands of new variants into the CC strains. The majority of these mutations are novel compared to currently sequenced laboratory stocks and wild mice, and some are predicted to alter gene function. Approximately one-third of the CC inbred strains have acquired large deletions (>10 kb) many of which overlap known coding genes and functional elements. The sequence of these mice is a critical resource to CC users, increases threefold the number of mouse inbred strain genomes available publicly, and provides insight into the effect of mutation and drift on common resources.
Several studies have reported reprogramming of fibroblasts into induced cardiomyocytes; however, reprogramming into proliferative induced cardiac progenitor cells (iCPCs) remains to be accomplished. ...Here we report that a combination of 11 or 5 cardiac factors along with canonical Wnt and JAK/STAT signaling reprogrammed adult mouse cardiac, lung, and tail tip fibroblasts into iCPCs. The iCPCs were cardiac mesoderm-restricted progenitors that could be expanded extensively while maintaining multipotency to differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells in vitro. Moreover, iCPCs injected into the cardiac crescent of mouse embryos differentiated into cardiomyocytes. iCPCs transplanted into the post-myocardial infarction mouse heart improved survival and differentiated into cardiomyocytes, smooth muscle cells, and endothelial cells. Lineage reprogramming of adult somatic cells into iCPCs provides a scalable cell source for drug discovery, disease modeling, and cardiac regenerative therapy.
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•Cardiac factors reprogram fibroblasts into induced cardiac progenitors cells (iCPCs)•Wnt and JAK/STAT signaling enables robust expansion of iCPCs•iCPCs differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells•Injected iCPCs generate myocardium in the embryonic and adult post-MI mouse heart
Lalit et al. report that a combination of cardiac factors and signaling molecules reprogram adult mouse fibroblasts into expandable induced cardiac progenitor cells (iCPCs). iCPCs are multipotent and can differentiate into cardiomyocytes, smooth muscle, and endothelial cells. Moreover, iCPCs generate myocardium when injected into the embryonic and adult post-MI mouse heart.
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