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Growing the actual genotypic array of TXNL4A variants in Burn-McKeown syndrome.
Several modifiable factors leading to poor asthma control have been described. We aimed to determine the proportion of patients with inadequate treatment, adherence to it, or critical mistakes with inhaler technique, and their impact on asthma control. We conducted a cross-sectional multicenter observational study including asthma patients referred from primary to specialist care for the first time. Data collected were adequate prescription according to guidelines, treatment adherence, and disease control. Of the 1682 patients (age 45 ± 17 years, 64.6% men), 35.9% showed inadequate prescription, 76.8% low adherence, and 17% critical mistakes with inhaler technique, with significantly less critical mistakes among Easyhaler users versus other dry powder inhaler users (10.3 versus 18.4%; p  less then  0.05). Factors related to bad asthma control were inadequate prescription (OR 3.65), non-adherence to treatment (OR 1.8), and inhaler misuse (OR 3.03). A higher number of risk factors were associated with a higher probability of having badly controlled asthma.Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.Resolving the distribution of specific proteins at the nanoscale in the ultrastructural context of the cell is a major challenge in fluorescence microscopy. We report the discovery of a new principle for an optical contrast equivalent to electron microscopy (EM) which reveals the ultrastructural context of the cells with a conventional confocal microscope. By decrowding the intracellular space through 13 to 21-fold physical expansion while simultaneously retaining the proteins, bulk (pan) labeling of the proteome resolves local protein densities and reveals the cellular nanoarchitecture by standard light microscopy.Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.Creating micro/nanostructures on fibers is beneficial for extending the application range of fiber-based devices. To achieve this using thermal fiber drawing is particularly important for the mass production of longitudinally uniform fibers up to tens of kilometers. However, the current thermal fiber drawing technique can only fabricate one-directional micro/nano-grooves longitudinally due to structure elongation and polymer reflow. Here, we develop a direct imprinting thermal drawing (DITD) technique to achieve arbitrarily designed surface patterns on entire fiber surfaces with high resolution in all directions. Such a thermal imprinting process is simulated and confirmed experimentally. learn more Key process parameters are further examined, showing a process feature size as small as tens of nanometers. Furthermore, nanopatterns are fabricated on fibers as plasmonic metasurfaces, and double-sided patterned fibers are produced to construct self-powered wearable touch sensing fabric, revealing the bright future of the DITD technology in multifunctional fiber-based devices, wearable electronics, and smart textiles.Polygenic scores (PGS) have been widely used to predict disease risk using variants identified from genome-wide association studies (GWAS). To date, most GWAS have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European ancestry populations. Here, we derive a theoretical model of the relative accuracy (RA) of PGS across ancestries. We show through extensive simulations that the RA of PGS based on genome-wide significant SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of causal SNP effects and heritability. We find that LD and MAF differences between ancestries can explain between 70 and 80% of the loss of RA of European-based PGS in African ancestry for traits like body mass index and type 2 diabetes. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWAS are mostly shared across continents.An amendment to this paper has been published and can be accessed via a link at the top of the paper.It is becoming widely appreciated that human perceptual decision making is suboptimal but the nature and origins of this suboptimality remain poorly understood. Most past research has employed tasks with two stimulus categories, but such designs cannot fully capture the limitations inherent in naturalistic perceptual decisions where choices are rarely between only two alternatives. We conduct four experiments with tasks involving multiple alternatives and use computational modeling to determine the decision-level representation on which the perceptual decisions are based. The results from all four experiments point to the existence of robust suboptimality such that most of the information in the sensory representation is lost during the transformation to a decision-level representation. These results reveal severe limits in the quality of decision-level representations for multiple alternatives and have strong implications about perceptual decision making in naturalistic settings.
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