P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

Association of accelerometer-derived sleep measures with lifetime psychiatric diagnoses : A cross-sectional study of 89,205 participants from the UK Biobank

Funding Information: The authors acknowledge Milos Milic for data curation assistance. MW and SJT acknowledge support from the Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC (RGPIN-2020-05834 and DGECR-2020-00048) and CIHR (NGN-171423). DF is supported by the Michael and Sonja Koerner Foundation New Scientist Program, Krembil Foundation, CAMH Discovery Fund, and the McLaughlin Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research was conducted under the auspices of UK Biobank application 61530, ?Multimodal subtyping of mental illness across the adult lifespan through integration of multi-scale whole-person phenotypes?. The authors acknowledge Milos Milic for data curation assistance. This research was conducted under the auspices of UK Biobank application 61530, ?Multimodal subtyping of mental illness across the adult lifespan through integration of multi-scale whole-person phenotypes.? Publisher Copyright: Copyright: © 2021 Wainberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background Sleep problems are both symptoms of and modifiable risk factors for many psychiatric disorders. Wrist-worn accelerometers enable objective measurement of sleep at scale. Here, we aimed to examine the association of accelerometer-derived sleep measures with psychiatric diagnoses and polygenic risk scores in a large community-based cohort. Methods and findings In this post hoc cross-sectional analysis of the UK Biobank cohort, 10 interpretable sleep measures—bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration—were derived from 7-day accelerometry recordings across 89,205 participants (aged 43 to 79, 56% female, 97% self-reported white) taken between 2013 and 2015. These measures were examined for association with lifetime inpatient diagnoses of major depressive disorder, anxiety disorders, bipolar disorder/mania, and schizophrenia spectrum disorders from any time before the date of accelerometry, as well as polygenic risk scores for major depression, bipolar disorder, and schizophrenia. Covariates consisted of age and season at the time of the accelerometry recording, sex, Townsend deprivation index (an indicator of socioeconomic status), and the top 10 genotype principal components. We found that sleep pattern differences were ubiquitous across diagnoses: each diagnosis was associated with a median of 8.5 of the 10 accelerometer-derived sleep measures, with measures of sleep quality (for instance, sleep efficiency) generally more affected than mere sleep duration. Effect sizes were generally small: for instance, the largest magnitude effect size across the 4 diagnoses was β = −0.11 (95% confidence interval −0.13 to −0.10, p = 3 × 10−56, FDR = 6 × 10−55) for the association between lifetime inpatient major depressive disorder diagnosis and sleep efficiency. Associations largely replicated across ancestries and sexes, and accelerometry-derived measures were concordant with self-reported sleep properties. Limitations include the use of accelerometer-based sleep measurement and the time lag between psychiatric diagnoses and accelerometry. Conclusions In this study, we observed that sleep pattern differences are a transdiagnostic feature of individuals with lifetime mental illness, suggesting that they should be considered regardless of diagnosis. Accelerometry provides a scalable way to objectively measure sleep properties in psychiatric clinical research and practice, even across tens of thousands of individuals.Peer reviewe

Artificial drainage of peatlands: hydrological and hydrochemical process and wetland restoration

Peatlands have been subject to artificial drainage for centuries. This drainage has been in response to agricultural demand, forestry, horticultural and energy properties of peat and alleviation of flood risk. However, the are several environmental problems associated with drainage of peatlands. This paper describes the nature of these problems and examines the evidence for changes in hydrological and hydrochemical processes associated with these changes. Traditional black-box water balance approaches demonstrate little about wetland dynamics and therefore the science of catchment response to peat drainage is poorly understood. It is crucial that a more process-based approach be adopted within peatland ecosystems. The environmental problems associated with peat drainage have led, in part, to a recent reversal in attitudes to peatlands and we have seen a move towards wetland restoration. However, a detailed understanding of hydrological, hydrochemical and ecological process-interactions will be fundamental if we are to adequately restore degraded peatlands, preserve those that are still intact and understand the impacts of such management actions at the catchment scale

Soil warming alters nitrogen cycling in a New England forest : implications for ecosystem function and structure

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Oecologia 168 (2012): 819-828, doi:10.1007/s00442-011-2133-7.Global climate change is expected to affect terrestrial ecosystems in a variety of ways. Some of the more well-studied effects include the biogeochemical feedbacks to the climate system that can either increase or decrease the atmospheric load of greenhouse gases such as carbon dioxide and nitrous oxide. Less well-studied are the effects of climate change on the linkages between soil and plant processes. Here, we report the effects of soil warming on these linkages observed in a large field manipulation of a deciduous forest in southern New England, USA, where soil was continuously warmed 5°C above ambient for 7 years. Over this period, we have observed significant changes to the nitrogen cycle that have the potential to affect tree species composition in the long term. Since the start of the experiment, we have documented a 45% average annual increase in net nitrogen mineralization and a three-fold increase in nitrification such that in years 5 through 7, 25% of the nitrogen mineralized is then nitrified. The warming-induced increase of available nitrogen resulted in increases in the foliar nitrogen content and the relative growth rate of trees in the warmed area. Acer rubrum (red maple) trees have responded the most after 7 years of warming, with the greatest increases in both foliar nitrogen content and relative growth rates. Our study suggests that considering species-specific responses to increases in nitrogen availability and changes in nitrogen form is important in predicting future forest composition and feedbacks to the climate system.This work was supported by the National Institute for Climate Change Research (DOE-DE-FCO2-06-ER64157), DOE BER (DE-SC0005421) and the Harvard Forest Long-Term Ecological Research program (NSF-DEB-0620443)

Quantum Tunneling in Nuclear Fusion

Recent theoretical advances in the study of heavy ion fusion reactions below the Coulomb barrier are reviewed. Particular emphasis is given to new ways of analyzing data, such as studying barrier distributions; new approaches to channel coupling, such as the path integral and Green function formalisms; and alternative methods to describe nuclear structure effects, such as those using the Interacting Boson Model. The roles of nucleon transfer, asymmetry effects, higher-order couplings, and shape-phase transitions are elucidated. The current status of the fusion of unstable nuclei and very massive systems are briefly discussed.Comment: To appear in the January 1998 issue of Reviews of Modern Physics. 13 Figures (postscript file for Figure 6 is not available; a hard copy can be requested from the authors). Full text and figures are also available at http://nucth.physics.wisc.edu/preprints

Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines

Staphylococcus aureus Bacteremia in Children of Rural Areas of The Gambia, 2008–2015

Staphylococcus aureus bacteremia is a substantial cause of childhood disease and death, but few studies have described its epidemiology in developing countries. Using a population-based surveillance system for pneumonia, sepsis, and meningitis, we estimated S. aureus bacteremia incidence and the case-fatality ratio in children <5 years of age in 2 regions in the eastern part of The Gambia during 2008–2015. Among 33,060 children with suspected pneumonia, sepsis, or meningitis, we performed blood culture for 27,851; of 1,130 patients with bacteremia, 198 (17.5%) were positive for S. aureus. S. aureus bacteremia incidence was 78 (95% CI 67–91) cases/100,000 person-years in children <5 years of age and 2,080 (95% CI 1,621–2,627) cases/100,000 person-years in neonates. Incidence did not change after introduction of the pneumococcal conjugate vaccine. The case-fatality ratio was 14.1% (95% CI 9.6%–19.8%). Interventions are needed to reduce the S. aureus bacteremia burden in The Gambia, particularly among neonates

STEP: the VST survey of the SMC and the Magellanic Bridge - I : Overview and first results

STEP (the SMC in Time: Evolution of a Prototype interacting late-type dwarf galaxy) is a Guaranteed Time Observation survey being performed at the VST (the ESO VLT Survey Telescope). STEP will image an area of 74 sq. deg. covering the main body of the Small Magellanic Cloud (32 sq. deg.), the Bridge that connects it to the Large Magellanic Cloud (30 sq. deg.) and a small part of the Magellanic Stream (2 sq. deg.). Our g, r, i, Hα photometry is able to resolve individual stars down to magnitudes well below the main-sequence turn-off of the oldest populations. In this first paper, we describe the observing strategy, the photometric techniques and the upcoming data products of the survey. We also present preliminary results for the first two fields for which data acquisition is completed, including some detailed analysis of the two stellar clusters IC 1624 and NGC 419.Peer reviewedFinal Accepted Versio

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty