Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Recreational sea fishing in Europe in a global contextParticipation rates, fishing effort, expenditure, and implications for monitoring and assessment

Marine recreational fishing (MRF) is a high-participation activity with large economic value and social benefits globally, and it impacts on some fish stocks. Although reporting MRF catches is a European Union legislative requirement, estimates are only available for some countries. Here, data on numbers of fishers, participation rates, days fished, expenditures, and catches of two widely targeted species were synthesized to provide European estimates of MRF and placed in the global context. Uncertainty assessment was not possible due to incomplete knowledge of error distributions; instead, a semi-quantitative bias assessment was made. There were an estimated 8.7 million European recreational sea fishers corresponding to a participation rate of 1.6%. An estimated 77.6 million days were fished, and expenditure was Euro5.9 billion annually. There were higher participation, numbers of fishers, days fished and expenditure in the Atlantic than the Mediterranean, but the Mediterranean estimates were generally less robust. Comparisons with other regions showed that European MRF participation rates and expenditure were in the mid-range, with higher participation in Oceania and the United States, higher expenditure in the United States, and lower participation and expenditure in South America and Africa. For both northern European sea bass (Dicentrarchus labrax, Moronidae) and western Baltic cod (Gadus morhua, Gadidae) stocks, MRF represented 27% of the total removals. This study highlights the importance of MRF and the need for bespoke, regular and statistically sound data collection to underpin European fisheries management. Solutions are proposed for future MRF data collection in Europe and other regions to support sustainable fisheries management.Institut Francais de Recherche pour l'Exploitation de la Mer; French Ministry of Fisheries Management; Greek National Data Collection Programme; European Commission, Data Collection Framework; Department for Environment, Food and Rural Affairs [MF1221, MF1230, MI001]; Norges Forskningsrad [267808]; State Department of Agriculture, Food Security and Fisheries Mecklenburg-Western Pomerania; Interreg IVa 2 Seas; Dutch Ministry of Economic Affairs; European Fishery Fund; Government of Galicia [ED481B2014/034-0

A survey for variable young stars with small telescopes – VIII. Properties of 1687 Gaia selected members in 21 nearby clusters

The Hunting Outbursting Young Stars (HOYS) project performs long-term, optical, multi-filter, high cadence monitoring of 25 nearby young clusters and star forming regions. Utilising Gaia DR3 data we have identified about 17000 potential young stellar members in 45 coherent astrometric groups in these fields. Twenty one of them are clear young groups or clusters of stars within one kiloparsec and they contain 9143 Gaia selected potential members. The cluster distances, proper motions and membership numbers are determined. We analyse long term (≈ 7 yr) V, R, and I-band light curves from HOYS for 1687 of the potential cluster members. One quarter of the stars are variable in all three optical filters, and two thirds of these have light curves that are symmetric around the mean. Light curves affected by obscuration from circumstellar materials are more common than those affected by accretion bursts, by a factor of 2 – 4. The variability fraction in the clusters ranges from 10 to almost 100 percent, and correlates positively with the fraction of stars with detectable inner disks, indicating that a lot of variability is driven by the disk. About one in six variables shows detectable periodicity, mostly caused by magnetic spots. Two thirds of the periodic variables with disk excess emission are slow rotators, and amongst the stars without disk excess two thirds are fast rotators – in agreement with rotation being slowed down by the presence of a disk

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes

A survey for variable young stars with small telescopes: VIII — Properties of 1687 Gaia selected members in 21 nearby clusters

The Hunting Outbursting Young Stars (HOYS) project performs long-term, optical, multi- filter, high cadence monitoring of 25 nearby young clusters and star forming regions. Utilising Gaia DR3 data we have identified about 17000 potential young stellar members in 45 coherent astrometric groups in these fields. Twenty one of them are clear young groups or clusters of stars within one kiloparsec and they contain 9143 Gaia selected potential members. The cluster distances, proper motions and membership numbers are determined. We analyse long term ( 7 yr) V, R, and I-band light curves from HOYS for 1687 of the potential cluster members. One quarter of the stars are variable in all three optical filters, and two thirds of these have light curves that are symmetric around the mean. Light curves affected by obscuration from circumstellar materials are more common than those affected by accretion bursts, by a factor of 2 – 4. The variability fraction in the clusters ranges from 10 to almost 100 percent, and correlates positively with the fraction of stars with detectable inner disks, indicating that a lot of variability is driven by the disk. About one in six variables shows detectable periodicity, mostly caused by magnetic spots. Two thirds of the periodic variables with disk excess emission are slow rotators, and amongst the stars without disk excess two thirds are fast rotators – in agreement with rotation being slowed down by the presence of a disk

Ancient mitochondrial DNA provides high-resolution time scale of the peopling of the Americas

The exact timing, route, and process of the initial peopling of the Americas remains uncertain despite much research. Archaeological evidence indicates the presence of humans as far as southern Chile by 14.6 thousand years ago (ka), shortly after the Pleistocene ice sheets blocking access from eastern Beringia began to retreat. Genetic estimates of the timing and route of entry have been constrained by the lack of suitable calibration points and low genetic diversity of Native Americans. We sequenced 92 whole mitochondrial genomes from pre-Columbian South American skeletons dating from 8.6 to 0.5 ka, allowing a detailed, temporally calibrated reconstruction of the peopling of the Americas in a Bayesian coalescent analysis. The data suggest that a small population entered the Americas via a coastal route around 16.0 ka, following previous isolation in eastern Beringia for ~2.4 to 9 thousand years after separation from eastern Siberian populations. Following a rapid movement throughout the Americas, limited gene flow in South America resulted in a marked phylogeographic structure of populations, which persisted through time. All of the ancient mitochondrial lineages detected in this study were absent from modern data sets, suggesting a high extinction rate. To investigate this further, we applied a novel principal components multiple logistic regression test to Bayesian serial coalescent simulations. The analysis supported a scenario in which European colonization caused a substantial loss of pre-Columbian lineages

Identification of heavy-flavour jets with the CMS detector in pp collisions at 13 TeV

Many measurements and searches for physics beyond the standard model at the LHC rely on the efficient identification of heavy-flavour jets, i.e. jets originating from bottom or charm quarks. In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented. Heavy-flavour jet identification algorithms have been improved compared to those used previously at centre-of-mass energies of 7 and 8 TeV. For jets with transverse momenta in the range expected in simulated $\mathrm{t}\overline{\mathrm{t}}$ events, these new developments result in an efficiency of 68% for the correct identification of a b jet for a probability of 1% of misidentifying a light-flavour jet. The improvement in relative efficiency at this misidentification probability is about 15%, compared to previous CMS algorithms. In addition, for the first time algorithms have been developed to identify jets containing two b hadrons in Lorentz-boosted event topologies, as well as to tag c jets. The large data sample recorded in 2016 at a centre-of-mass energy of 13 TeV has also allowed the development of new methods to measure the efficiency and misidentification probability of heavy-flavour jet identification algorithms. The heavy-flavour jet identification efficiency is measured with a precision of a few per cent at moderate jet transverse momenta (between 30 and 300 GeV) and about 5% at the highest jet transverse momenta (between 500 and 1000 GeV)