Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to ...common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimer's disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues—especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10−7). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology.
Folate, a cofactor for the supply of one‐carbon groups, is required by epigenetic processes to regulate cell lineage determination during development. The intake of folic acid (FA), the synthetic ...form of folate, has increased significantly over the past decade, but the effects of high periconceptional FA intake on cell lineage determination in the early embryo remains unknown. Here, we investigated the effect of maternal high FA (HFA) intake on blastocyst development and expression of key regulatory genes. C57BL/6 adult female mice were fed either Control diet (1 mg FA) for 4 weeks before conception and during the preimplantation period (Con‐Con); Control diet for 4 weeks preconception, followed by HFA (5 mg FA) diet during preimplantation (Con‐HFA); or HFA diet for 4 weeks preconception and during preimplantation (HFA‐HFA). At E3.5, blastocyst cell number, protein, and mRNA expression were measured. In HFA‐HFA blastocysts, trophectoderm cell numbers and expression of CDX2, Oct‐4, and Nanog were reduced compared with Con‐Con blastocysts; Con‐HFA blastocysts showed lower CDX2 and Oct‐4 expression than Con‐Con blastocysts. These findings suggest periconceptional HFA intake induces changes in key regulators of embryo morphogenesis with potential implications for subsequent development.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We recently developed an approach for recording from muscle spindles in the intrinsic muscles of the foot in freestanding humans by inserting a tungsten microelectrode into the posterior tibial nerve ...behind the medial malleolus of the ankle. Here we characterize the behavior of muscle spindles in the small muscles of the foot in 1) seated subjects with the leg horizontal and the foot naturally plantarflexed and 2) standing subjects. In the first study, recordings were made from 26 muscle spindle afferents located within flexor digiti minimi brevis ( n = 4), abductor digiti minimi ( n = 3), quadratus plantae ( n = 3), plantar interossei ( n = 4), flexor digitorum brevis ( n = 3), dorsal interossei ( n = 2), and lumbricals ( n = 2), with one each supplying abductor hallucis, adductor hallucis, and flexor hallucis brevis. The identity of another two muscle afferents was unknown. The majority of the units were silent at rest, only seven (27%) being spontaneously active. Because of the anatomic constraints of the foot, some spindles supplying muscles acting on the toes responded to movements of one or more digits. In the second study, 12 muscle spindle afferents were examined during standing. The ongoing discharge of eight spindle afferents covaried with changes in the center of pressure during postural sway. We conclude that the majority of spindle endings in the small muscles of the foot are silent at rest, which may allow them to encode changes in conformation of the foot when it is loaded during standing. Moreover, these muscle spindle afferents can provide useful proprioceptive information during standing and postural sway. NEW & NOTEWORTHY We have characterized the firing properties of muscle spindles in the intrinsic muscles of the human foot for the first time. The majority of the spindle endings are silent in seated subjects, and most fire tonically during standing, their discharge covarying with center of pressure during postural sway. We conclude that spindle endings in the intrinsic muscles of the foot provide useful proprioceptive information during free standing.
Global climate change and increases in sea levels will affect coastal marine communities. The conservation of these ecologically important areas will be a challenge because of their wide geographic ...distribution, ecological diversity and species richness. To address this problem, we need to better understand how the genetic variation of the species in these communities is distributed within local populations, among populations and between distant regions. In this study we apply genotyping by sequencing (GBS) and examine 955 SNPs to determine Sailfin molly (Poecilia latipinna) genetic diversity among three geographically close mangrove salt marsh flats in the Florida Keys compared to populations in southern and northern Florida. The questions we are asking are whether there is sufficient genetic variation among isolated estuarine fish within populations and whether there are significant divergences among populations. Additionally, we want to know if GBS approaches agree with previous studies using more traditional molecular approaches. We are able to identify large genetic diversity within each saltmarsh community (π ≈ 36%). Additionally, among the Florida Key populations and the mainland or between southern and northern Florida regions, there are significant differences in allele frequencies seen in population structure and evolutionary relationships among individuals. Surprisingly, even though the cumulative FST value using all 955 SNPs within the three Florida Key populations is small, there are 29 loci with significant FST values, and 11 of these were outliers suggestive of adaptive divergence. These data suggest that among the salt marsh flats surveyed here, there is significant genetic diversity within each population and small but significant differences among populations. Much of the genetic variation within and among populations found here with GBS is very similar to previous studies using allozymes and microsatellites. However, the meaningful difference between GBS and these previous measures of genetic diversity is the number of loci examined, which allows more precise delineations of population structure as well as facilitates identifying loci with excessive FST values that could indicate adaptive divergence.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The posterior tibial nerve, located behind the medial malleolus of the ankle, supplies the intrinsic muscles of the foot and most of the skin of the sole. We describe a novel approach for recording ...from this nerve via a percutaneously inserted tungsten microelectrode and provide examples of recordings from presumed muscle spindle endings recorded in freely standing human subjects. The fact that the angular excursions of the ankle joint are small as the foot is loaded during the transition from the seated position to standing means that one can obtain stable recordings of neural traffic in unloaded, loaded, and freely standing conditions. We conclude that this novel approach will allow studies that will increase our understanding of the roles of muscle and cutaneous afferents in the foot in the control of upright posture. NEW & NOTEWORTHY We have performed the first microneurographic studies from the posterior tibial nerve at the ankle. Stability of the recording site allows one to record from muscle spindles in the intrinsic muscles of the foot as well as from cutaneous mechanoreceptors in the sole of the foot during the transition from seated to standing. This novel approach opens up new opportunities for studying the roles of muscle and cutaneous afferents in the foot in the control of upright stance.
Introduction
Excess mortality monitoring is not dependent on completeness or consistency of coding of causes of death and captures deaths caused directly and indirectly by COVID-19. It takes account ...of existing inequalities in the baseline rates and shows the additional impact of COVID-19. We report weekly on excess mortality by age, gender, geographical area, deprivation, and ethnicity.
Methods
A quasi-Poisson model was fitted to deaths data for 2015-2019 to estimate expected mortality in population sub-groups each week during the COVID-19 pandemic. This was compared with observed mortality reported each week. Information on deaths registered was obtained from death certificates. Ethnicity was obtained from hospital records linked to deaths data.
Results
Early in the pandemic, excess deaths exceeded official reported COVID-19 deaths every week. Throughout the pandemic there were stark inequalities in excess death rates. Based on data from 21 March 2020 to 9 April 2021, people living in the most deprived areas in England experienced more excess (1.21 times; 95% CI 1.21-1.22) compared with people living in the least deprived areas (1.17; 1.16-1.18). Black (1.56; 1.53-1.58) and Asian groups (1.55; 1.53-1.56) experienced more excess than the White group (1.16; 1.16-1.17). There was wide variation between English regions.
Conclusions
Reporting overall excess mortality early in the pandemic is important to inform policy makers and public about the true scale of the death toll when coding is inconsistent and developing. This approach has highlighted the large increases in already established inequalities in mortality. It provides rapid surveillance of developing disparities for national and local decision makers. It has been used to inform policy around reducing disparities and to revise messaging to encourage hospital attendance for non- COVID-19 health problems.
Key messages
Excess deaths from all causes is a robust measure of overall impact, unaffected by coding consistency.
COVID-19 has dramatically worsened established inequalities between ethnic groups and deprivation groups.
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NUK, OILJ, UL, UM, UPUK, VSZLJ
Abstract
When monitoring marine recreational fishers at sub-bio-regional scales—for example those who are accessing a Marine Park—on-site sampling is often required. This poses various logistical ...challenges, such as the efficient timing of intercept interviews. Here, we examine these challenges, combining trail cameras, closed-circuit television (CCTV), weather stations, and interviews at boat ramps that bracket an offshore Marine Park. Trail camera results were similar to those from a CCTV system co-located at one of the boat ramps. Fishers’ boat launches peaked early, but return times varied considerably by ramp and weather. Both the numbers of launches and trip durations were strongly responsive to good weather, particularly at ramps used for offshore fishing. Weather was a more important factor to predict the likelihood of intercept interview opportunities than holiday period, which may reflect changing dynamics in work culture and improvements in weather prediction. Interviewed fishers reported preferences to individual ramps over the fishing season and nearly all trips to the Marine Park were reported by fishers accessing just one ramp. The strong relationships between fishing, weather, and ramp, observed by the trail camera and correlated with the weather station data, may allow for the efficient targeting of intercept interviews and potentially the modelling of fishing effort.
Nuclear receptor binding to coactivator proteins is an obligate first step in the regulation of gene transcription. Nuclear receptors preferentially bind to an LXXLL peptide motif which is highly ...conserved throughout the 300 or so natural coactivator proteins. This knowledge has shaped current understanding of this fundamental protein–protein interaction, and continues to inspire the search for new drug therapies. However, sequence specificity beyond the LXXLL motif and the molecular functioning of flanking residues still requires urgent addressing. Here, ribosome display has been used to reassess the estrogen receptor for new and enlarged peptide recognition motifs, leading to the discovery of a potent and highly evolved PXLXXLLXXP binding consensus. Molecular modeling and X-ray crystallography studies have provided the molecular insights on the role of the flanking prolines in priming the length of the α-helix and enabling optimal interactions of the α-helix dipole and its surrounding amino acids with the surface charge clamp and the receptor activation function 2. These findings represent new structural parameters for modulating the nuclear receptor–coactivator interaction based on linear sequences of proteinogenic amino acids and for the design of chemically modified inhibitors.
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IJS, KILJ, NUK, PNG, UL, UM
Alcohol consumption, smoking, and excess weight independently increase the risk of morbidity/mortality. Less is known about how they interact. This research aims to quantify the independent and joint ...associations of these exposures across health outcomes and identify whether these associations are synergistic.
The protocol for this systematic review and meta-analysis was pre-registered (PROSPERO CRD42021231443).
Medline and Embase were searched between 1 January 2010 and 9 February 2022. Eligible peer-reviewed observational studies had to include adult participants from Organisation for Co-Operation and Development countries and report independent and joint associations between at least two eligible exposures (alcohol, smoking, and excess weight) and an ICD-10 outcome (or equivalent). For all estimates, we calculated the synergy index (SI) to identify whether joint associations were synergistic. Meta-analyses were conducted for outcomes with sufficiently homogenous data.
The search returned 26,290 studies, of which 98 were included. Based on 138,130 participants, the combined effect (SI) of alcohol and smoking on head and neck cancer death/disease was 3.78 times greater than the additive effect of each exposure (95% confidence interval CI = 2.61, 5.48). Based on 2,603,939 participants, the combined effect of alcohol and excess weight on liver disease/death was 1.55 times greater than the additive effect of each exposure (95% CI = 1.33, 1.82).
Synergistic associations suggest the true population-level risk may be underestimated. In the absence of bias, individuals with multiple risks would experience a greater absolute risk reduction from an intervention that targets a single exposure than individuals with a single risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Modern radio interferometers such as the LOw Frequency ARray (LOFAR) are capable of producing data at hundreds of gigabits to terabits per second. This high data rate makes the analysis of radio data ...cumbersome and computationally expensive. While high performance computing facilities exist for large national and international facilities, that may not be the case for instruments operated by a single institution or a small consortium. Data rates for next generation radio telescopes are set to eclipse those currently in operation, hence local processing of data will become all the more important. Here, we introduce the REAL-time Transient Acquisition backend (REALTA), a computing backend at the Irish LOFAR station (I-LOFAR) which facilitates the recording of data in near real-time and post-processing. We also present first searches and scientific results of a number of radio phenomena observed by I-LOFAR and REALTA, including pulsars, fast radio bursts, rotating radio transients, the search for extraterrestrial intelligence, Jupiter, and the Sun.
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FMFMET, NUK, UL, UM, UPUK