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Mediation analysis is used to gain insight into the mechanisms of exposure-outcome effects by dividing this effect into a direct and an indirect effect. One of the problems of mediation analysis is that in many situations, the standard error of the indirect effect is much lower than the standard errors of the total and direct effect. Because this problem is ignored in the epidemiological literature, the purpose of this paper was to illustrate this problem and to provide an advice regarding the statistical testing of indirect effects in mediation analysis. To illustrate the problem of the estimation of the standard error of the indirect effect two real life datasets and several simulations are used. The paper shows that the problem of estimating the standard error of the indirect effect was most pronounced when the relationship between exposure and mediator and the relationship between mediator and outcome were equally strong. Furthermore, the magnitude of the estimation problem is different for different strengths of the mediation effect. The indirect effect in mediation analysis should not be tested for statistical significance but the importance of mediation should be evaluated by its clinical relevance.

Because missing data are present in almost every study, it is important to handle missing data properly. First of all, the missing data mechanism should be considered. Missing data can be either completely at random (MCAR), at random (MAR), or not at random (MNAR). When missing data are MCAR, a complete case analysis can be valid. Also when missing data are MAR, in some situations a complete case analysis leads to valid results. However, in most situations, missing data imputation should be used. Regarding imputation methods, it is highly advised to use multiple imputations because multiple imputations lead to valid estimates including the uncertainty about the imputed values. When missing data are MNAR, also multiple imputations do not lead to valid results. A complication hereby is that it not possible to distinguish whether missing data are MAR or MNAR. Finally, it should be realized that preventing to have missing data is always better than the treatment of missing data.

Histone acetylation regulates chromatin structure and gene expression and is removed by histone deacetylases (HDACs). HDACs are commonly found in various protein complexes to confer distinct cellular functions, but how the multi-subunit complexes influence deacetylase activities and site-selectivities in chromatin is poorly understood. Previously we reported the results of studies on the HDAC1 containing CoREST complex and acetylated nucleosome substrates which revealed a notable preference for deacetylation of histone H3 acetyl-Lys9 vs. acetyl-Lys14 (Wu et al, 2018). Here we analyze the enzymatic properties of five class I HDAC complexes: CoREST, NuRD, Sin3B, MiDAC and SMRT with site-specific acetylated nucleosome substrates. Our results demonstrate that these HDAC complexes show a wide variety of deacetylase rates in a site-selective manner. A Gly13 in the histone H3 tail is responsible for a sharp reduction in deacetylase activity of the CoREST complex for H3K14ac. These studies provide a framework for connecting enzymatic and biological functions of specific HDAC complexes.

Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases, which are broadly expected to lead to the identification of new drug targets and opportunities for treatment. Drug development, however, remains hampered by the time taken and costs expended to achieve regulatory approval, leading many clinicians and researchers to consider alternative paths to more immediate clinical outcomes. In this Review, we explore approaches that leverage common variant genetics to identify opportunities for repurposing existing drugs, also known as drug repositioning. These approaches include the identification of compounds by linking individual loci to genes and pathways that can be pharmacologically modulated, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization, and polygenic scoring.Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases. The authors review approaches that leverage GWAS to identify opportunities for repurposing existing drugs, including single-loci mapping to drug targets, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization and polygenic scoring.

The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities. The complex regulates the higher-order structure of chromatin, and has important roles in the regulation of gene expression, DNA damage repair and cell differentiation. HDACs 1 and 2 are recruited by the MTA1 corepressor to form the catalytic core of the complex. The histone chaperone protein RBBP4, has previously been shown to bind to the carboxy-terminal tail of MTA1. We show that MTA1 recruits a second copy of RBBP4. The crystal structure reveals an extensive interface between MTA1 and RBBP4. An EM structure, supported by SAXS and crosslinking, reveals the architecture of the dimeric HDAC1:MTA1:RBBP4 assembly which forms the core of the NuRD complex. We find evidence that in this complex RBBP4 mediates interaction with histone H3 tails, but not histone H4, suggesting a mechanism for recruitment of the NuRD complex to chromatin. The correct regulation of our genes is essential for life. Genes are actively switched on or off through the action of assemblies of proteins that act together as molecular machines. Some of these machines alter the way that DNA is packaged inside cells. Packaged DNA – called chromatin – consists of DNA wrapped around proteins called histones, which together form structures called nucleosomes. Changing how tightly nucleosomes are packed together can alter whether a gene is active: tighter packing makes it harder to access the genes in that stretch of DNA and therefore inactivates them. In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. Understanding how protein complexes are assembled tells us a lot about how they work. Millard et al. have therefore used a number of structural techniques to investigate the three-dimensional architecture of the three core proteins in the NuRD complex. The resulting structures have revealed how the HDAC1, MTA1 and RBBP4 proteins interact to influence how the complex is recruited to nucleosomes. The next step will be to assemble all the remaining proteins of the NuRD complex to understand its architecture as a whole.

In this randomized trial involving 13,885 patients with symptomatic peripheral artery disease (PAD), ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates with ticagrelor and clopidogrel. Peripheral artery disease is considered to be a clinical manifestation of systemic atherosclerosis affecting the vascular territories supplying the lower limbs. Most patients presenting with peripheral artery disease do not have a clinical history of cardiac or cerebral ischemic events, yet these patients are at high risk for myocardial infarction, ischemic stroke, and cardiovascular death. 1 Concomitant clinical evidence of coronary or cerebrovascular disease only magnifies this risk. 2 Therapies to reduce the ischemic risk associated with atherosclerosis have focused on patients with acute coronary syndromes and stable coronary artery disease. Antithrombotic drugs, mainly antiplatelet therapies and statins, are the cornerstone of . . .

The core CoREST complex (LHC) contains histone deacetylase HDAC1 and histone demethylase LSD1 held together by the scaffold protein CoREST. Here, we analyze the purified LHC with modified peptide and reconstituted semisynthetic mononucleosome substrates. LHC demethylase activity toward methyl-Lys4 in histone H3 is strongly inhibited by H3 Lys14 acetylation, and this appears to be an intrinsic property of the LSD1 subunit. Moreover, the deacetylase selectivity of LHC unexpectedly shows a marked preference for H3 acetyl-Lys9 versus acetyl-Lys14 in nucleosome substrates but this selectivity is lost with isolated acetyl-Lys H3 protein. This diminished activity of LHC to Lys-14 deacetylation in nucleosomes is not merely due to steric accessibility based on the pattern of sensitivity of the LHC enzymatic complex to hydroxamic acid-mediated inhibition. Overall, these studies have revealed how a single Lys modification can confer a composite of resistance in chromatin to a key epigenetic enzyme complex involved in gene silencing.

Nanometer-scale properties of the extracellular matrix influence many biological processes, including cell motility. While much information is available for single-cell migration, to date, no knowledge exists on how the nanoscale presentation of extracellular matrix receptors influences collective cell migration. In wound healing, basal keratinocytes collectively migrate on a fibronectin-rich provisional basement membrane to re-epithelialize the injured skin. Among other receptors, the fibronectin receptor integrin α5β1 plays a pivotal role in this process. Using a highly specific integrin α5β1 peptidomimetic combined with nanopatterned hydrogels, we show that keratinocyte sheets regulate their migration ability at an optimal integrin α5β1 nanospacing. This efficiency relies on the effective propagation of stresses within the cell monolayer independent of substrate stiffness. For the first time, this work highlights the importance of extracellular matrix receptor nanoscale organization required for efficient tissue regeneration.

Additive manufacturing (AM), also known as three-dimensional printing (3DP), has been widely applied to various fields and industries, including automotive, healthcare, and rapid prototyping. This study evaluates the effects of 3DP on textile properties. The usability of a textile and its durability are determined by its strength, washability, colorfastness to light, and abrasion resistance, among other traits, which may be impacted by the application of 3DP on the fabric’s surface. This study examines the application of photosensitive acrylic resin on two fabric substrates: 100% cotton and 100% polyester white woven fabrics made of yarns with staple fibers. A simple alphanumeric text was translated into braille and the braille dots were 3D printed onto both fabrics. The color of the printed photosensitive acrylic resin was black, and it was an equal mixture of VeroCyanV, VeroYellowV, and VeroMagentaV. The 3D-printed design was the same on both fabrics and was composed of braille dots with a domed top. Both of the 3DP fabrics passed the colorfastness to washing test with no transfer or color change, but 3D prints on both fabrics showed significant color change during the colorfastness to light test. The tensile strength tests indicated an overall reduction in strength and elongation when the fabrics had 3DP on their surface. An abrasion resistance test revealed that the resin had a stronger adhesion to the cotton than to the polyester, but both resins were removed from the fabric with the abrader. These findings suggest that while 3DP on textiles offers unique possibilities for customization and design, mechanical properties and color stability trade-offs need to be considered. Further evaluation of textiles and 3D prints of textiles and their performance in areas such as colorfastness and durability are warranted to harness the full potential of this technology in the fashion and textile industry.

ObjectiveThis randomised controlled trial evaluated the efficacy of the Tailored Injury Prevention in Adapted Sports (TIPAS) intervention on sports-related health problems in athletes participating in adaptive sports with physical impairments.MethodsWe randomly assigned 60 athletes participating in adaptive sports with physical impairments to an intervention group and 47 to a control group. The intervention group received direct, automated, predetermined preventive and management measures tailored to their weekly reported health problems, physical impairments and sports. The primary outcome was injury and illness prevalence over 40 weeks. Secondary outcomes were incidence, weekly cumulative severity score, weekly time loss, and total burden. A multinomial mixed methods analysis was performed to identify an intervention effect over time.ResultsThe athletes (53 women, 54 men; age±45 years) reported 449 health problems (162 illnesses, 287 injuries) during the study period. The overall prevalence of health problems was 44% in the intervention group and 46% in the control group. Over time, no significant main intervention effect was found (illnesses OR: 1.02; 95% CI: 0.52 to 1.99; and injuries OR: 1.01; 95% CI: 0.55 to 1.86). However, a significant positive time×group interaction effect (p<0.001) indicated a reduction in injury prevalence in the intervention group over time, though not for illnesses. The rates versus severity analysis showed a significantly lower illness severity in the intervention group relative to the control group.ConclusionThe TIPAS intervention provides a non-significant decrease in the overall prevalence of sport-related injuries and illnesses and may reduce the severity of sport-related illnesses throughout a Dutch sports season. This tailored online preventive strategy provides an accessible programme to consider in adapted sports suited to athletes’ physical impairments, sports participation and current health status.Trial registration number: ICTRP register: NL-OMON24078