Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ...'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.
•Screening of >60 major and trace elements in >40 wastewater treatment facilities.•Calculation of per-person influent loads and (basin-scale) effluent discharge loads.•Higher trace element removal ...efficiencies generally found with tertiary treatment.•Qualitative geospatial analysis of sewersheds for trace element source attribution.
The growing use of trace elements in industrialized societies is driving an increase in the occurrence of trace elements in anthropogenic waste streams globally. Yet, the large-scale sources of many trace elements to wastewater and their elimination during treatment remain poorly understood and potential environmental impacts on freshwater systems therefore unclear. We screened 42 wastewater treatment facilities in the North American Great Lakes basin and deployed a black-box approach to calculate representative estimates for average per-capita trace element loads and basin-scale effluent discharge rates, as well as trace element removal efficiencies across different treatment technologies. Our results show different removal of specific groups of trace elements during wastewater treatment: average removal efficiencies were 25% for alkali metals, 50% for alkaline earth metals, 74% for transition metals, and 85% for rare earth elements. Higher elimination of the majority of trace elements was generally achieved by more advanced, tertiary treatment types. Elemental loads generally followed natural abundance patterns, but anomalous loading rates were observed for various trace elements across the sampled facilities. By examining geospatial attributes of the sampled sewersheds, trends in select trace element loads were qualitatively tied to possible point sources and diffuse sources. Overall, these results illustrate the potential of wastewater surveillance to inform environmental management of emerging trace element contaminants.
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Optical coherence tomography angiography (OCTA) is a noninvasive method of 3D imaging of the retinal and choroidal circulations. However, vascular depth discrimination is limited by superficial ...vessels projecting flow signal artifact onto deeper layers. The projection-resolved (PR) OCTA algorithm improves depth resolution by removing projection artifact while retaining in-situ flow signal from real blood vessels in deeper layers. This novel technology allowed us to study the normal retinal vasculature in vivo with better depth resolution than previously possible. Our investigation in normal human volunteers revealed the presence of 2 to 4 distinct vascular plexuses in the retina, depending on location relative to the optic disc and fovea. The vascular pattern in these retinal plexuses and interconnecting layers are consistent with previous histologic studies. Based on these data, we propose an improved system of nomenclature and segmentation boundaries for detailed 3-dimensional retinal vascular anatomy by OCTA. This could serve as a basis for future investigation of both normal retinal anatomy, as well as vascular malformations, nonperfusion, and neovascularization.
We present the results of a PDF fit to differential top quark production within the MMHT framework. We in particular consider ATLAS data in the lepton + jet and dilepton channels and CMS data in the ...lepton + jet channel, at 8 TeV. While the fit quality to the ATLAS dilepton data is good, for the CMS case we see some issues in achieving a good fit quality for certain distributions. However, we focus on the ATLAS lepton + jet data, for which correlations of the statistical and systematic errors are provided across the four relevant distributions for PDF determination, namely
p
T
t
,
M
tt
,
y
t
and
y
tt
. We find severe difficulties in fitting these distributions simultaneously, with particular sensitivity to the precise degree of correlation taken between the dominant two-point MC uncertainties in the data. We investigate the effect of some reasonable decorrelation of these uncertainties, finding the impact on the fit quality to be significant and the resultant gluon not negligible. This is in particular found to be larger than the effect of including NNLO QCD and NLO EW corrections in the top quark pair production cross section on the fit, motivating a closer understanding of the physics underlying these errors sources and in particular the uncertainty on the degree of correlation in them.
We have developed an efficient simulation tool 'GOLLUM' for the computation of electrical, spin and thermal transport characteristics of complex nanostructures. The new multi-scale, multi-terminal ...tool addresses a number of new challenges and functionalities that have emerged in nanoscale-scale transport over the past few years. To illustrate the flexibility and functionality of GOLLUM, we present a range of demonstrator calculations encompassing charge, spin and thermal transport, corrections to density functional theory such as local density approximation +U (LDA+U) and spectral adjustments, transport in the presence of non-collinear magnetism, the quantum Hall effect, Kondo and Coulomb blockade effects, finite-voltage transport, multi-terminal transport, quantum pumps, superconducting nanostructures, environmental effects, and pulling curves and conductance histograms for mechanically-controlled break-junction experiments.
Imprecise measurement of physical activity variables might attenuate estimates of the beneficial effects of activity on health-related outcomes. We aimed to compare the cardiometabolic risk factor ...dose-response relationships for physical activity and sedentary behaviour between accelerometer- and questionnaire-based activity measures.
Physical activity and sedentary behaviour were assessed in 317 adults by 7-day accelerometry and International Physical Activity Questionnaire (IPAQ). Fasting blood was taken to determine insulin, glucose, triglyceride and total, LDL and HDL cholesterol concentrations and homeostasis model-estimated insulin resistance (HOMA(IR)). Waist circumference, BMI, body fat percentage and blood pressure were also measured.
For both accelerometer-derived sedentary time (<100 counts.min(-1)) and IPAQ-reported sitting time significant positive (negative for HDL cholesterol) relationships were observed with all measured risk factors--i.e. increased sedentary behaviour was associated with increased risk (all p ≤ 0.01). However, for HOMA(IR) and insulin the regression coefficients were >50% lower for the IPAQ-reported compared to the accelerometer-derived measure (p<0.0001 for both interactions). The relationships for moderate-to-vigorous physical activity (MVPA) and risk factors were less strong than those observed for sedentary behaviours, but significant negative relationships were observed for both accelerometer and IPAQ MVPA measures with glucose, and insulin and HOMA(IR) values (all p<0.05). For accelerometer-derived MVPA only, additional negative relationships were seen with triglyceride, total cholesterol and LDL cholesterol concentrations, BMI, waist circumference and percentage body fat, and a positive relationship was evident with HDL cholesterol (p = 0.0002). Regression coefficients for HOMA(IR), insulin and triglyceride were 43-50% lower for the IPAQ-reported compared to the accelerometer-derived MVPA measure (all p≤0.01).
Using the IPAQ to determine sitting time and MVPA reveals some, but not all, relationships between these activity measures and metabolic and vascular disease risk factors. Using this self-report method to quantify activity can therefore underestimate the strength of some relationships with risk factors.
KCNMA1 -linked channelopathy Bailey, Cole S; Moldenhauer, Hans J; Park, Su Mi ...
The Journal of general physiology,
10/2019, Letnik:
151, Številka:
10
Journal Article
Recenzirano
Odprti dostop
encodes the pore-forming α subunit of the "Big K
" (BK) large conductance calcium and voltage-activated K
channel. BK channels are widely distributed across tissues, including both excitable and ...nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (
) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare
mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as "
-linked channelopathy." These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human
mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with
mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different
alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of
mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with
-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between
-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.
Asymmetric polystyrene−polylactide (PS-PLA) bottlebrush block copolymers have been shown to self-assemble into a cylindrical morphology with large domain spacings. PLA cylinders can be selectively ...etched out of the shear-aligned polymer monoliths to generate nanoporous materials with an average cylindrical pore diameter of 55 nm. The remaining bottlebrush backbone provides a functional, hydrophilic coating inside the nanopores. This methodology significantly expands the range of pore sizes attainable in block copolymer based nanoporous materials.
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