Abstract
We investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against ...SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observe a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 do not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals do not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus can be detected in lungs of vaccinated animals. Histopathological evaluation shows extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs.
The extent that both positive and negative selection vary across different portions of plant genomes remains poorly understood. Here, we sequence whole genomes of 13 Capsella grandiflora individuals ...and quantify the amount of selection across the genome. Using an estimate of the distribution of fitness effects, we show that selection is strong in coding regions, but weak in most noncoding regions, with the exception of 5' and 3' untranslated regions (UTRs). However, estimates of selection on noncoding regions conserved across the Brassicaceae family show strong signals of selection. Additionally, we see reductions in neutral diversity around functional substitutions in both coding and conserved noncoding regions, indicating recent selective sweeps at these sites. Finally, using expression data from leaf tissue we show that genes that are more highly expressed experience stronger negative selection but comparable levels of positive selection to lowly expressed genes. Overall, we observe widespread positive and negative selection in coding and regulatory regions, but our results also suggest that both positive and negative selection on plant noncoding sequence are considerably rarer than in animal genomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Significance Plants have undergone repeated rounds of whole-genome duplication, followed by gene degeneration and loss. Using whole-genome resequencing, we examined the origins of the recent ...tetraploid Capsella bursa-pastoris and the earliest stages of genome evolution after polyploidization. We conclude the species had a hybrid origin from two distinct Capsella lineages within the past 100,000–300,000 y. Our analyses suggest the absence of rapid gene loss but provide evidence that the species has large numbers of inactivating mutations, many of which were inherited from the parental species. Our results suggest that genome evolution following polyploidy is determined not only by genome redundancy but also by demography, the mating system, and the evolutionary history of the parental species.
Whole-genome duplication (WGD) events have occurred repeatedly during flowering plant evolution, and there is growing evidence for predictable patterns of gene retention and loss following polyploidization. Despite these important insights, the rate and processes governing the earliest stages of diploidization remain poorly understood, and the relative importance of genetic drift, positive selection, and relaxed purifying selection in the process of gene degeneration and loss is unclear. Here, we conduct whole-genome resequencing in Capsella bursa-pastoris , a recently formed tetraploid with one of the most widespread species distributions of any angiosperm. Whole-genome data provide strong support for recent hybrid origins of the tetraploid species within the past 100,000–300,000 y from two diploid progenitors in the Capsella genus. Major-effect inactivating mutations are frequent, but many were inherited from the parental species and show no evidence of being fixed by positive selection. Despite a lack of large-scale gene loss, we observe a decrease in the efficacy of natural selection genome-wide due to the combined effects of demography, selfing, and genome redundancy from WGD. Our results suggest that the earliest stages of diploidization are associated with quantitative genome-wide decreases in the strength and efficacy of selection rather than rapid gene loss, and that nonfunctionalization can receive a “head start” through a legacy of deleterious variants and differential expression originating in parental diploid populations.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF ...>40% after a worsening heart failure (WHF) event is unknown.
PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event.
PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro–B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP.
In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95).
Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The associations between intake of or circulating fatty acids and risk of colorectal cancer (CRC) are unclear. We examined prospectively the associations between dietary or biomarker fatty acids and ...CRC. For 41,514 men and women, aged 40–69 years, baseline (1990–94) dietary intakes of fatty acids were estimated using a food frequency questionnaire and plasma phospholipid (PPL) fatty acids were measured for 4,205 participants including 395 CRC cases, according to a case‐cohort design. Hazard ratios were computed using Cox regression adjusting for education, alcohol intake, smoking status, physical activity and total energy intake; and stratified for gender, ethnicity and family history of cancer, with age as the time scale. We assessed the heterogeneity of associations with colon and rectal cancers. PPL saturated fatty acids (SFAs) were positively associated with CRC risk, while total n‐3 polyunsaturated fatty acids (PUFA) and long chain marine n‐3 PUFAs showed inverse associations, significant only for 22:5 n‐3. No significant associations were observed for dietary fatty acid intakes but positive associations with CRC of borderline significance were seen for both dietary and PPL linoleic acid. Positive associations with dietary palmitic acid (16:0), MUFAs and n‐6 PUFAs were seen for rectal but not colon cancers. PPL 22:6 n‐3 was inversely associated with rectal cancer. Limiting intakes of SFAs and MUFAs could be assisted by following existing guidelines to limit red and processed meats which are important sources in the Australian diet. Our observations regarding linoleic acid should be examined further.
What's new?
While there is considerable evidence that diet is associated with colorectal cancer (CRC) risk, the associations for specific fatty acids remain unclear. Here, the authors prospectively examine associations between dietary intake estimates or plasma phospholipids (PPL) estimates of fatty acids and incident CRC. PPL saturated fat (SF) is positively associated with incident CRC and dietary SF with rectal cancer, while long chain n‐3 fats are inversely associated with both. Following guidelines to limit red and processed meat would help reduce saturated fatty acids intake; the adverse association with linoleic acid, found in margarines and vegetable oils, requires further confirmation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To determine the risk of emergent dialysis and short-term mortality following intravenous iodinated contrast material exposure.
This single-center retrospective study was HIPAA compliant and ...institutional review board approved. All contrast material-enhanced (contrast group) and unenhanced (noncontrast group) abdominal, pelvic, and thoracic computed tomography scans from 2000-2010 were identified. Patients in the contrast and noncontrast groups were compared following propensity score-based 1:1 matching to reduce intergroup selection bias. Patients with preexisting diabetes mellitus, congestive heart failure, or chronic or acute renal failure were identified as high-risk patient subgroups for nephrotoxicity. The effects of contrast material exposure on the rate of acute kidney injury ( AKI acute kidney injury ) (serum creatinine level ≥ 0.5 mg/dL 44.2 μmol/L above baseline within 24-72 hours of exposure) and dialysis or death within 30 days of exposure were determined by using odds ratios ( OR odds ratio s) and covariate-adjusted Cox proportional hazards models. Results were validated with a bootstrapped sensitivity analysis.
The 1:1 matching on the basis of the propensity score yielded a cohort of 21 346 patients (10 673 in the contrast group, 10 673 in the noncontrast group). Within this cohort, the risks of AKI acute kidney injury ( OR odds ratio , 0.94; 95% confidence interval CI confidence interval : 0.83, 1.07; P = .38), emergent dialysis ( OR odds ratio , 0.96; 95% CI confidence interval : 0.54, 1.60; P = .89), and 30-day mortality (hazard ratio HR hazard ratio , 0.97; 95% CI confidence interval : 0.87, 1.06; P = .45) were not significantly different between the contrast group and the noncontrast group. Although patients who developed AKI acute kidney injury had higher rates of dialysis and mortality, contrast material exposure was not an independent risk factor for either outcome for dialysis ( OR odds ratio , 0.89; 95% CI confidence interval : 0.40, 2.01; P = .78) or for mortality ( HR hazard ratio , 1.03; 95% CI confidence interval : 0.82, 1.32; P = .63), even among patients with compromised renal function or predisposing comorbidities.
Intravenous contrast material administration was not associated with excess risk of AKI acute kidney injury , dialysis, or death, even among patients with comorbidities reported to predispose them to nephrotoxicity.
To determine the causal association and effect of intravenous iodinated contrast material exposure on the incidence of acute kidney injury (AKI), also known as contrast material-induced nephropathy ...(CIN).
This retrospective study was approved by an institutional review board and was HIPAA compliant. Informed consent was waived. All contrast material-enhanced (contrast group) and unenhanced (noncontrast group) abdominal, pelvic, and thoracic CT scans from 2000 to 2010 were identified at a single facility. Scan recipients were sorted into low- (<1.5 mg/dL), medium- (1.5-2.0 mg/dL), and high-risk (>2.0 mg/dL) subgroups of presumed risk for CIN by using baseline serum creatinine (SCr) level. The incidence of AKI (SCr ≥ 0.5 mg/dL above baseline) was compared between contrast and noncontrast groups after propensity score adjustment by stratification, 1:1 matching, inverse weighting, and weighting by the odds methods to reduce intergroup selection bias. Counterfactual analysis was used to evaluate the causal relation between contrast material exposure and AKI by evaluating patients who underwent contrast-enhanced and unenhanced CT scans during the study period with the McNemar test.
A total of 157,140 scans among 53,439 unique patients associated with 1,510,001 SCr values were identified. AKI risk was not significantly different between contrast and noncontrast groups in any risk subgroup after propensity score adjustment by using reported risk factors of CIN (low risk: odds ratio OR, 0.93; 95% confidence interval CI: 0.76, 1.13; P = .47; medium risk: odds ratio, 0.97; 95% CI: 0.81, 1.16; P = .76; high risk: OR, 0.91; 95% CI: 0.66, 1.24; P = .58). Counterfactual analysis revealed no significant difference in AKI incidence between enhanced and unenhanced CT scans in the same patient (McNemar test: χ(2) = 0.63, P = .43) (OR = 0.92; 95% CI: 0.75, 1.13; P = .46).
Following adjustment for presumed risk factors, the incidence of CIN was not significantly different from contrast material-independent AKI. These two phenomena were clinically indistinguishable with established SCr-defined criteria, suggesting that intravenous iodinated contrast media may not be the causative agent in diminished renal function after contrast material administration.
http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12121823/-/DC1.
Plant-defense responses are triggered by perception of conserved microbe-associated molecular patterns (MAMPs), for example, flagellin or peptidoglycan. However, it remained unknown whether plants ...can detect conserved molecular patterns derived from plant-parasitic animals, including nematodes. Here we show that several genera of plant-parasitic nematodes produce small molecules called ascarosides, an evolutionarily conserved family of nematode pheromones. Picomolar to micromolar concentrations of ascr#18, the major ascaroside in plant-parasitic nematodes, induce hallmark defense responses including the expression of genes associated with MAMP-triggered immunity, activation of mitogen-activated protein kinases, as well as salicylic acid- and jasmonic acid-mediated defense signalling pathways. Ascr#18 perception increases resistance in Arabidopsis, tomato, potato and barley to viral, bacterial, oomycete, fungal and nematode infections. These results indicate that plants recognize ascarosides as a conserved molecular signature of nematodes. Using small-molecule signals such as ascarosides to activate plant immune responses has potential utility to improve economic and environmental sustainability of agriculture.
The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe ...alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-β mediated degradation of β-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises β-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells.
Purpose To compare the rates of acute kidney injury (AKI), emergent dialysis, and short-term mortality between patients who underwent intravenous administration of the iso-osmolar contrast material ...(IOCM) iodixanol 320 and patients who underwent a noncontrast computed tomography (CT) examination. Materials and Methods Study design and implementation were overseen by an institutional review board and conformed to HIPAA guidelines on patient data integrity. All patients who underwent an iodixanol-enhanced (IOCM group) or a noncontrast (noncontrast group) CT examination from January 2003 to December 2014 were identified. Patients were subdivided into subgroups of those with stage 1-2 chronic kidney disease (CKD) (estimated glomerular filtration rate eGFR, ≥ 60 mL/min/1.73 m
), those with stage 3 CKD (eGFR, 30-59 mL/min/1.73 m
), and those with stage 4-5 CKD (eGFR < 30 mL/min/1.73 m
) and separately underwent propensity score stratification and matching. Rates of AKI, emergent dialysis, and mortality were compared between IOCM and noncontrast groups. Additional analyses incorporating intravenous fluid administration, including additional CT studies at other sites within a single institution, and a paired analysis of patients who underwent both IOCM and noncontrast CT studies during the study time frame, were also performed. Results A total of 5758 patients (1538 with stage 1-2 CKD, 2899 with stage 3 CKD, and 1321 with stage 4-5 CKD) were included in the study. After propensity score adjustment, rates of AKI, dialysis, and mortality were not significantly higher in the IOCM group compared with the noncontrast group for all CKD subgroups (AKI odds ratios ORs, 0.74-0.91, P = .16-0.69; dialysis ORs, 0.74-2.00, P = .42-.76; mortality ORs, 0.98-1.24, P = .39-.88). Sensitivity analyses yielded similar results. Conclusion Among patients at the highest perceived risk of postcontrast AKI, intravenous administration of iodixanol for contrast material enhanced CT was not an independent risk factor for AKI, dialysis, or mortality.
RSNA, 2017 Online supplemental material is available for this article.
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