Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, ...including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological ...mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Movements through or use of offshore wind farms by seabirds while commuting or foraging may increase the potential for collision with turbine blades. Collision risk models provide a method for ...estimating potential impacts of wind farms on seabird populations, but are sensitive to input parameters, including avoidance rates (ARs). Refining understanding of avoidance through the use of high-resolution empirical movement data has the potential to inform assessments of the collision impacts of offshore wind farms on seabird populations. We assessed the movements of GPS-tagged lesser black-backed gulls
Larus fuscus
from a breeding colony in northwest England to estimate the species’ AR and avoidance/attraction index (AAI) to nearby offshore wind farms. To investigate both macro- (0-4 km) and meso-scale (0-200 m) responses to wind turbines, we used calculations of AR and AAI based on simulated vs. observed tracks. We found that birds exhibited an AR of -0.15 (95% CI: -0.44 to 0.06), indicating a degree of attraction within 4 km of the wind farms. However, AAI values varied with distance from wind farm boundaries, with a degree of avoidance displayed between 3 and 4 km, which weakened as distance bands approach wind farm boundaries. Meso-scale avoidance/attraction was assessed with regard to the nearest individual turbine, and flight height relative to the rotor height range (RHR) of the nearest turbine. We found attraction increased below the RHR at distances <70 m, while avoidance increased within the RHR at distances approaching the turbine. We explore how high-resolution tracking data can be used to improve our knowledge of
L. fuscus
avoidance/attraction behaviour to established wind farms, and so inform assessments of collision impacts.
By early October, 2009, there had been more than 340 000 reported cases of H1N1 infection in 191 countries, with more than 4100 deaths.1 WHO initially projected that up to 2 billion people could ...become infected with the virus over the next 2 years.2 Although vaccination programmes and other factors should reduce this number, plausible estimates of the number of infected individuals who might benefit from admission to intensive care range from 200 000 to 10 million. Beyond antiviral agents, anecdotal reports and data from animal studies suggest that illness severity can be attenuated by readily available agents, such as corticosteroids and statins, that can modulate the host's inflammatory response.9 None of these drugs has been adequately studied for efficacy.
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identifed as high-affinity, selective 5-HT2A receptor antagonists. Bioavailability lacking in the parent, ...1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.
A novel protein (p34) was observed in polyacrylamide gel fluorographs of gestation day 13 embryonic mouse brain following retinoic acid dosing of dams. Another p34 polypeptide with identical gel ...migratory characteristics was seen in the hypothalamus of old caloric restricted rats after "food deprivation stress". Western blotting, employing an ultramicro trans-blot cell developed in our laboratory, detected identical immunochemical determinants between these proteins, verifying their homology. Peptide mapping and Western blotting further validated the uniqueness of p34 compared with other stress proteins including heme oxygenase.
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