Explore the vast range of titles available.

Background The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery. Methods We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery. Results A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance ( PHLPP2 , rs78064607, p  = 3.77 × 10 − 8 ) and 139 (adjusted for all other outcomes) SNPs showed promising association with p  < 1 × 10 − 5 from the GWAS. Conclusions We identified several potential loci, in particular PHLPP2 , BBS9 , RyR2 , DUSP4 and HSPA8 , associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery. Trial registration The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.

The adaptor ASC is required for caspase-1 activation via the NLRP3 and AIM2 inflammasomes. Mitsuyama and colleagues show that signaling dependent on the kinases Syk and Jnk controls ASC speck formation through ASC phosphorylation. The inflammasome adaptor ASC contributes to innate immunity through the activation of caspase-1. Here we found that signaling pathways dependent on the kinases Syk and Jnk were required for the activation of caspase-1 via the ASC-dependent inflammasomes NLRP3 and AIM2. Inhibition of Syk or Jnk abolished the formation of ASC specks without affecting the interaction of ASC with NLRP3. ASC was phosphorylated during inflammasome activation in a Syk- and Jnk-dependent manner, which suggested that Syk and Jnk are upstream of ASC phosphorylation. Moreover, phosphorylation of Tyr144 in mouse ASC was critical for speck formation and caspase-1 activation. Our results suggest that phosphorylation of ASC controls inflammasome activity through the formation of ASC specks.

YAP and TAZ are the major downstream effectors of the Hippo pathway. This Progress article summarizes the latest findings regarding the biological functions of YAP and TAZ, and their role in connecting the Hippo pathway with other relevant pathways in cancer. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the major downstream effectors of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration and tumorigenesis. In this Progress article, we summarize the current understanding of the biological functions of YAP and TAZ, and how the regulation of these two proteins can be disrupted in cancer. We also highlight recent findings on their expanding role in cancer progression and describe the potential of these targets for therapeutic intervention.

Impaired turnover of the autophagy substrate p62 leads to liver injury. p62 inhibits the ubiquitin ligase Keap1, leading to stabilization of the transcription factor Nrf2. High levels of p62 in autophagy deficient animals leads to unusually high expression of Nrf2 targets genes and results in liver injury. Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.

Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration 1 – 4 . Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process 5 – 8 , and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity 9 , 10 . However, the mechanisms by which the activation of SARM1 is stringently controlled are unclear. Here we report the cryo-electron microscopy structures of full-length SARM1 proteins. We show that NAD + is an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1. This binding of NAD + to the ARM domain facilitated the inhibition of the TIR-domain NADase through the domain interface. Disruption of the NAD + -binding site or the ARM–TIR interaction caused constitutive activation of SARM1 and thereby led to axonal degeneration. These findings suggest that NAD + mediates self-inhibition of this central pro-neurodegenerative protein. NAD + is shown to be a ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1, and it is suggested that this binding of NAD + mediates self-inhibition of SARM1.

Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer’s disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6 , TSPAN14 , NCK2 and SPRED2 . Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1 , APH1B , PTK2B , PILRA and CASS4 . Genome-wide meta-analysis, fine-mapping and integrative prioritization using expression quantitative trait loci, protein interaction networks and tissue-specific expression implicate new candidate susceptibility genes for Alzheimer’s disease.

Single-cell sequencing methods have emerged as powerful tools for identification of heterogeneous cell types within defined brain regions. Application of single-cell techniques to study the transcriptome of activated neurons can offer insight into molecular dynamics associated with differential neuronal responses to a given experience. Through evaluation of common whole-cell and single-nuclei RNA-sequencing (snRNA-seq) methods, here we show that snRNA-seq faithfully recapitulates transcriptional patterns associated with experience-driven induction of activity, including immediate early genes (IEGs) such as Fos , Arc and Egr1 . SnRNA-seq of mouse dentate granule cells reveals large-scale changes in the activated neuronal transcriptome after brief novel environment exposure, including induction of MAPK pathway genes. In addition, we observe a continuum of activation states, revealing a pseudotemporal pattern of activation from gene expression alone. In summary, snRNA-seq of activated neurons enables the examination of gene expression beyond IEGs, allowing for novel insights into neuronal activation patterns in vivo. The molecular dynamics associated with neuronal activation patterns in vivo are unclear. Lacar et al . perform single-nuclei RNA-sequencing of hippocampal neurons from mice exposed to a novel environment, and identify large-scale transcriptome changes in individual neurons associated with the experience.

We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain—reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P -values for multiple correlated tests, and used a Bonferroni-corrected α-level of 5 × 10 −4 to determine system-wide significance. Four single-nucleotide polymorphisms (rs12021667, rs12027267, rs6702335, rs12039988; r 2 >0.98) in erythrocyte membrane protein band 4.1 ( EPB41 ) had a significant male-specific marginal association with smoking abstinence (odds ratio (OR)=0.5; 95% confidence interval (CI): 0.3–0.6) at end of treatment (adjusted P <6 × 10 −5 ). rs806365 in cannabinoid receptor 1 ( CNR1 ) had a significant male-specific gene–treatment interaction at 6-month follow-up (adjusted P =3.9 × 10 −5 ); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR=0.04; 95% CI: 0.01–0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.

The α-adducin ( ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.

The ability to split one cell into two is fundamental to all life, and many bacteria can accomplish this feat several times per hour with high accuracy. Most bacteria call on an ancient homologue of tubulin, called FtsZ, to localize and organize the cell division machinery, the divisome, into a ring-like structure at the cell midpoint. The divisome includes numerous other proteins, often including an actin homologue (FtsA), that interact with each other at the cytoplasmic membrane. Once assembled, the protein complexes that comprise the dynamic divisome coordinate membrane constriction with synthesis of a division septum, but only after overcoming checkpoints mediated by specialized protein–protein interactions. In this Review, we summarize the most recent evidence showing how the divisome proteins of Escherichia coli assemble at the cell midpoint, interact with each other and regulate activation of septum synthesis. We also briefly discuss the potential of divisome proteins as novel antibiotic targets.In this Review, Margolin and Cameron explore how the divisome of Escherichia coli is assembled and activated to modulate the division process, and discuss how the divisome machinery can be targeted for therapeutic purposes.