We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 ...loci newly associated with PBC (at P<5×10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2>0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains ...unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10−33) seen for rs2395029G, a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 × 10−19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10−8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In this phase 3 trial, among children with later-onset spinal muscular atrophy, those who received nusinersen had improvement in motor-function scores and those who underwent a sham procedure did not.
More than three-quarters of the baryonic content of the Universe resides in a highly diffuse state that is difficult to detect, with only a small fraction directly observed in galaxies and galaxy ...clusters
. Censuses of the nearby Universe have used absorption line spectroscopy
to observe the 'invisible' baryons, but these measurements rely on large and uncertain corrections and are insensitive to most of the Universe's volume and probably most of its mass. In particular, quasar spectroscopy is sensitive either to the very small amounts of hydrogen that exist in the atomic state, or to highly ionized and enriched gas
in denser regions near galaxies
. Other techniques to observe these invisible baryons also have limitations; Sunyaev-Zel'dovich analyses
can provide evidence from gas within filamentary structures, and studies of X-ray emission are most sensitive to gas near galaxy clusters
. Here we report a measurement of the baryon content of the Universe using the dispersion of a sample of localized fast radio bursts; this technique determines the electron column density along each line of sight and accounts for every ionized baryon
. We augment the sample of reported arcsecond-localized
fast radio bursts with four new localizations in host galaxies that have measured redshifts of 0.291, 0.118, 0.378 and 0.522. This completes a sample sufficiently large to account for dispersion variations along the lines of sight and in the host-galaxy environments
, and we derive a cosmic baryon density of Formula: see text (95 per cent confidence; h
= H
/(70 km s
Mpc
) and H
is Hubble's constant). This independent measurement is consistent with values derived from the cosmic microwave background and from Big Bang nucleosynthesis
.
Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate ...functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We announce the discovery of a low-mass planet orbiting the super metal-rich K0V star HD 77338 as part of our ongoing Calan-Hertfordshire Extrasolar Planet Search. We measure a metallicity for the ...star of +0.35 + o- 0.06 dex, whereas another recent work finds +0.47 + or - 0.05 dex. We also highlight an emerging trend where metallicity and mass seem to correlate at very low masses, a discovery that would be in agreement with the core accretion model of planet formation. A Monte Carlo analysis shows that this low-mass planet desert is statistically significant with the current sample of 36 planets at the ~4.5sigma level. In addition, results from Kepler strengthen the claim for this paucity of the lowest-mass planets in super metal-rich systems. Finally, this discovery adds to the growing population of low-mass planets around low-mass and metal-rich stars and shows that very low mass planets can now be discovered with a relatively small number of data points using stable instrumentation.
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