652 research outputs found
Cellular basis of neuroepithelial bending during mouse spinal neural tube closure
Bending of the neural plate at paired dorsolateral hinge points (DLHPs) is required for neural tube closure in the spinal region of the mouse embryo. As a step towards understanding the morphogenetic mechanism of DLHP development, we examined variations in neural plate cellular architecture and proliferation during closure. Neuroepithelial cells within the median hinge point (MHP) contain nuclei that are mainly basally located and undergo relatively slow proliferation, with a 7h cell cycle length. In contrast, cells in the dorsolateral neuroepithelium, including the DLHP, exhibit nuclei distributed throughout the apico-basal axis and undergo rapid proliferation, with a 4h cell cycle length. As the neural folds elevate, cell numbers increase to a greater extent in the dorsolateral neural plate that contacts the surface ectoderm, compared with the more ventromedial neural plate where cells contact paraxial mesoderm and notochord. This marked increase in dorsolateral cell number cannot be accounted for solely on the basis of enhanced cell proliferation in this region. We hypothesised that neuroepithelial cells may translocate in a ventral-to-dorsal direction as DLHP formation occurs, and this was confirmed by vital cell labelling in cultured embryos. The translocation of cells into the neural fold, together with its more rapid cell proliferation, leads to an increase in cell density dorsolaterally compared with the more ventromedial neural plate. These findings suggest a model in which DLHP formation may proceed through 'buckling' of the neuroepithelium at a dorso-ventral boundary marked by a change in cell-packing density
Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes
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Long-term outcome in biopsy-proven acute interstitial nephritis treated with steroids
BACKGROUND: There are no prospective randomized controlled trials describing the outcome of acute interstitial nephritis (AIN) treated with steroids, and retrospective studies are limited.
METHODS: We identified adult patients with a diagnosis of AIN without glomerular pathology over a 14-year period. Treated patients all received oral prednisolone and three also recieved IV methylprednisolone. Data were collected retrospectively on estimated glomerular filtration rate (eGFR), change in eGFR from time of biopsy, dependence on renal replacement therapy (RRT) and mortality, and outcomes were analysed according to the treatment prescribed.
RESULTS: A total of 187 eligible patients with AIN were identified and 158 were treated with steroids. There was no difference in median eGFR or dependence on RRT at the time of biopsy. Steroid-treated patients had significantly higher eGFR at all time points post-biopsy up to 24 months, when median eGFR was 43âmL/min in the steroid-treated group and 24âmL/min in the untreated group (P â= â0.01). Fewer patients in the steroid-treated group were dialysis dependent by 6 months (3.2% versus 20.6%, P â= â0.0022) and 24 months (5.1% versus 24.1%, P â= â0.0019).
CONCLUSIONS: This large retrospective study suggests a benefit of steroids in treatment of AIN with greater improvement in eGFR and fewer patients progressing to end-stage renal disease
Mechanochemical basis of protein degradation by a double-ring AAA+ machine
Molecular machines containing double or single AAA+ rings power energy-dependent protein degradation and other critical cellular processes, including disaggregation and remodeling of macromolecular complexes. How the mechanical activities of double-ring and single-ring AAA+ enzymes differ is unknown. Using single-molecule optical trapping, we determine how the double-ring âClpA enzyme from Escherichia coli, in complex with the âClpP peptidase, mechanically degrades proteins. We demonstrate that âClpA unfolds some protein substrates substantially faster than does the single-ring âClpX enzyme, which also degrades substrates in collaboration with âClpP. We find that âClpA is a slower polypeptide translocase and that it moves in physical steps that are smaller and more regular than steps taken by âClpX. These direct measurements of protein unfolding and translocation define the core mechanochemical behavior of a double-ring AAA+ machine and provide insight into the degradation of proteins that unfold via metastable intermediates.Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (Grant AI-16892
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Investigation of recast and crack formation in laser trepanning drilling of CMSX-4 angled holes
This paper presents an experimental investigation on the influences of laser trepanning drilling process parameters on the recast layer thickness and surface crack formation in CMSX-4 nickel-based superalloy angled holes. The effects of peak power, pulse frequency and the trepanning speed as input parameters were investigated in details by varying the laser drilling conditions using Taguchi orthogonal array-based design of experiment approach. Analysis of variance identifies the significant parameters affecting the output responses. It is found that the output responses are affected mainly by the peak power and trepanning speed. The experimental results reveal that the recast layer thickness increases with the increase of peak power and trepanning speed whereas the crack number density decreases with the increase of peak power only. Pulse frequency has no significant effect on both output responses within the range of values investigated. The knowledge gained in this parametric study could be used to improve the metallurgical characteristics of laser-drilled nickel-based acute angled holes
Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015
SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factorsâthe summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6â58·8) of global deaths and 41·2% (39·8â42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation
Burden of waterpipe smoking and chewing tobacco use among women of reproductive age group using data from the 2012-13 Pakistan Demographic and Health Survey
Background:
Despite the general decline in cigarette smoking, use of alternative forms of tobacco has increased particularly in developing countries. Waterpipe (WP) and Chewing Tobacco (CT) are two such alternative forms, finding their way into many populations. However, the burden of these alternative forms of tobacco and their socio demographic determinants are still unclear. We assessed the prevalence of WP and CT use among women of reproductive age group in Pakistan.
Methods:
Data from the most recent Pakistan Demographic and Health Survey 2012â13 (nâ=â13,558) was used for this analysis. Information obtained from ever married women, aged between 15 and 49 years were analyzed using two separate data subgroups; exclusive WP smokers (total nâ=â12,995) and exclusive CT users (total nâ=â12,771). Univariate and Multivariate logistic regression analyses were conducted and results were reported as crude and adjusted Odds Ratio with 95 % confidence intervals.
Results:
Prevalence of WP smoking and CT were 4 % and 2 %, respectively. After multivariate adjustments, ever married women who were: older than 35 years (OR; 4.68 95 % CI, 2.62â8.37), were poorest (ORâ=â4.03, 95 % CI 2.08â7.81), and had no education (ORâ=â9.19, 95 % CI 5.10â16.54), were more likely to be WP smokers. Similarly, ever married women who were: older than 35 years (ORâ=â3.19, 95 % CI 1.69â6.00), had no education (ORâ=â4.94, 95 % CI 2.62â9.33), were poor (ORâ=â1.64, 95 % CI 1.07â2.48) and had visited health facility in last 12 months (ORâ=â1.81, 95 % CI 1.22â2.70) were more likely to be CT users as well.
Conclusion:
Older women with lower socio-economic profile were more likely to use WP and CT. Focused policies aiming towards reducing the burden of alternate forms of tobacco use among women is urgently needed to control the tobacco epidemic in the country
Observation of associated near-side and away-side long-range correlations in âsNN=5.02ââTeV proton-lead collisions with the ATLAS detector
Two-particle correlations in relative azimuthal angle (ÎÏ) and pseudorapidity (Îη) are measured in âsNN=5.02ââTeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1ââÎŒb-1 of data as a function of transverse momentum (pT) and the transverse energy (ÎŁETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Îη|<5) ânear-sideâ (ÎÏâŒ0) correlation that grows rapidly with increasing ÎŁETPb. A long-range âaway-sideâ (ÎÏâŒÏ) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ÎŁETPb, is found to match the near-side correlation in magnitude, shape (in Îη and ÎÏ) and ÎŁETPb dependence. The resultant ÎÏ correlation is approximately symmetric about Ï/2, and is consistent with a dominant cosâĄ2ÎÏ modulation for all ÎŁETPb ranges and particle pT
Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at âs = 7 TeV with the ATLAS detector
This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of âs = 7 TeV;{\rm Te}{\rm V}4.6\;{\rm f}{{{\rm b}}^{-1}}{{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}|\eta |\lt 1.9{{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques
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