N-linked glycans attached to specific amino acids of the gp120 envelope trimer of a HIV virion can modulate the binding affinity of gp120 to CD4, influence coreceptor tropism, and play an important ...role in neutralising antibody responses. Because of the challenges associated with crystallising fully glycosylated proteins, most structural investigations have focused on describing the features of a non-glycosylated HIV-1 gp120 protein. Here, we use a computational approach to determine the influence of N-linked glycans on the dynamics of the HIV-1 gp120 protein and, in particular, the V3 loop. We compare the conformational dynamics of a non-glycosylated gp120 structure to that of two glycosylated gp120 structures, one with a single, and a second with five, covalently linked high-mannose glycans. Our findings provide a clear illustration of the significant effect that N-linked glycosylation has on the temporal and spatial properties of the underlying protein structure. We find that glycans surrounding the V3 loop modulate its dynamics, conferring to the loop a marked propensity towards a more narrow conformation relative to its non-glycosylated counterpart. The conformational effect on the V3 loop provides further support for the suggestion that N-linked glycosylation plays a role in determining HIV-1 coreceptor tropism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Survival rates after severe injury are improving, but complication rates and outcomes are variable.
Objective
This cohort study addressed the lack of longitudinal data on the steroid ...response to major trauma and during recovery.
Design
We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15).
Main outcome measures
We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models.
Findings
We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 interquartile range 24–31 years; median NISS 34 29–44). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis.
Conclusion
The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.
Airborne laser scanning (ALS; LiDAR) data are an increasingly common data source for forest inventories, and approaches integrating ALS data with field plot measurements have become operational in ...several jurisdictions. As technology continues to evolve, different LiDAR sensors can provide new opportunities to incorporate LiDAR data into forest inventory workflows. Single photon LiDAR (SPL) enables efficient, large area data acquisition and merits further investigation for forest inventory applications. Herein, we investigated the capacity of leaf-on SPL data, combined with 269 field plots, for estimating forest inventory attributes in the Great Lakes–St. Lawrence mixedwood forests of southern Ontario, Canada. Inventory attribute estimates were validated at the stand level using independent reference data acquired for 27 intensively sampled stands. Top height, Lorey’s height, gross total volume for merchantable stems, merchantable stem volume, basal area, quadratic mean diameter, and total aboveground biomass were estimated with a relative RMSE of 13.52%, 7.24%, 14.61%, 16.27%, 14.42%, 12.25%, and 11.72%, respectively. Relative bias was < 1% for all attributes except top height (10.34%), merchantable volume (3.37%), and basal area (1.68%). Accuracy and bias varied by forest type and stand-level validation was important for assessing model performance in different stand conditions. SPL data can be used to generate accurate, area-based forest inventories in mixedwood forests that have a multitude of tree species and complex forest management histories.
University students experience high rates of stress and mental illness; however, few studies have comprehensively examined the impact of academic and non-academic stressors on student mental health. ...Similarly, there has been little focus on the role of social groups in protecting against mental distress in this young adult group.
To identify the key social determinants of mental health symptoms in a student population.
Using an online survey, we administered measures of social connectedness and mental health symptoms alongside academic and non-academic stressors to a large sample of UK university students.
Loneliness was the strongest overall predictor of mental distress, while assessment stress was the most important academic predictor. Strong identification with university friendship groups was most protective against distress relative to other social identities, and the beneficial impact of identification on symptoms was mediated by reduced loneliness.
The study highlights the benefits of establishing strong social connections at university and the importance of minimising stress associated with assessment tasks.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Dementia is a major public health issue with rising prevalence rates, but many individuals remain undiagnosed. Accurate and timely diagnosis is key for the optimal targeting of interventions. A ...noninvasive, easily measurable peripheral biomarker would have greatest utility in population-wide diagnostic screening. Epigenetics, including DNA methylation, is implicated in dementia; however, it is unclear whether epigenetic changes can be detected in peripheral tissue. This study aimed to systematically review the evidence for an association between dementia and peripheral DNA methylation. Forty-eight studies that measured DNA methylation in peripheral blood were identified, and 67% reported significant associations with dementia. However, most studies were underpowered and limited by their case-control design. We emphasize the need for future longitudinal studies on large well-characterized populations, measuring epigenetic patterns in asymptomatic individuals. A biomarker detectable in the preclinical stages of the disease would have the greatest utility in future intervention and treatment trials.
•Forty-eight manuscripts investigating peripheral DNA methylation in dementia were included.•Most have been small cross-sectional studies, and findings have been mixed.•Longitudinal studies of individuals before dementia diagnosis are needed.•Preclinical biomarkers have the greatest clinical utility enabling early diagnosis.•Continual advances in epigenetic technologies will ensure new discoveries.
Identity-by-descent (IBD) segments are a useful tool for applications ranging from demographic inference to relationship classification, but most detection methods rely on phasing information and ...therefore require substantial computation time. As genetic datasets grow, methods for inferring IBD segments that scale well will be critical. We developed IBIS, an IBD detector that locates long regions of allele sharing between unphased individuals, and benchmarked it with Refined IBD, GERMLINE, and TRUFFLE on 3,000 simulated individuals. Phasing these with Beagle 5 takes 4.3 CPU days, followed by either Refined IBD or GERMLINE segment detection in 2.9 or 1.1 h, respectively. By comparison, IBIS finishes in 6.8 min or 7.8 min with IBD2 functionality enabled: speedups of 805–946× including phasing time. TRUFFLE takes 2.6 h, corresponding to IBIS speedups of 20.2–23.3×. IBIS is also accurate, inferring ≥7 cM IBD segments at quality comparable to Refined IBD and GERMLINE. With these segments, IBIS classifies first through third degree relatives in real Mexican American samples at rates meeting or exceeding other methods tested and identifies fourth through sixth degree pairs at rates within 0.0%–2.0% of the top method. While allele frequency-based approaches that do not detect segments can infer relationship degrees faster than IBIS, the fastest are biased in admixed samples, with KING inferring 30.8% fewer fifth degree Mexican American relatives correctly compared with IBIS. Finally, we ran IBIS on chromosome 2 of the UK Biobank dataset and estimate its runtime on the autosomes to be 3.3 days parallelized across 128 cores.
: media-1vid110.1542/5985300176001PEDS-VA_2018-2303
BACKGROUND: Teen mothers often present with depression, social complexity, and inadequate parenting skills. Many have rapid repeat pregnancy, which ...increases risk for poor outcomes. We conducted a randomized controlled trial of a parenting and life skills intervention for teen mothers aimed at impacting parenting and reproductive outcomes.
Teen mothers were recruited from a teen-tot clinic with integrated medical care and social services. Participants were randomly assigned 1:1 to receive (1) teen-tot services plus 5 interactive parenting and life skills modules adapted from the Nurturing and Ansell-Casey Life Skills curricula, delivered by a nurse and social worker over the infant's first 15 months or (2) teen-tot services alone. A computerized questionnaire was self-administered at intake, 12, 24, and 36 months. Outcomes included maternal self-esteem, parenting attitudes associated with child maltreatment risk, maternal depression, life skills, and repeat pregnancy over a 36-month follow-up. We used generalized linear mixed modeling and logistic regression to examine intervention effects.
Of 152 invited, 140 (92%) participated (intervention = 72; control = 68). At 36 months, maternal self-esteem was higher in the intervention group compared with controls (
= .011), with higher scores on preparedness for mothering role (
= .011), acceptance of infant (
= .008), and expected relationship with infant (
= .029). Repeat pregnancy by 36 months was significantly lower for intervention versus control participants.
A brief parenting and/or life skills intervention paired with medical care for teens and their children has positive effects on maternal self-esteem and repeat pregnancy over 36 months.
After a median follow-up of 4.7 years, there were 1.6 more deaths per 1000 person-years among healthy older adults who were randomly assigned to receive aspirin than among those who received placebo. ...Cancer-related death accounted for much of the excess mortality.
Aim
Investigate if childhood measures of sleep health are associated with epigenetic age acceleration in late adolescence.
Methods
Parent‐reported sleep trajectories from age 5 to 17, self‐reported ...sleep problems at age 17, and six measures of epigenetic age acceleration at age 17 were studied in 1192 young Australians from the Raine Study Gen2.
Results
There was no evidence for a relationship between the parent‐reported sleep trajectories and epigenetic age acceleration (p ≥ 0.17). There was a positive cross‐sectional relationship between self‐reported sleep problem score and intrinsic epigenetic age acceleration at age 17 (b = 0.14, p = 0.04), which was attenuated after controlling for depressive symptom score at the same age (b = 0.08, p = 0.34). Follow‐up analyses suggested this finding may represent greater overtiredness and intrinsic epigenetic age acceleration in adolescents with higher depressive symptoms.
Conclusion
There was no evidence for a relationship between self‐ or parent‐reported sleep health and epigenetic age acceleration in late adolescence after adjusting for depressive symptoms. Mental health should be considered as a potential confounding variable in future research on sleep and epigenetic age acceleration, particularly if subjective measures of sleep are used.
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