Structural pathway of regulated substrate transfer and threading through an Hsp100 disaggregase

Refolding aggregated proteins is essential in combating cellular proteotoxic stress. Together with Hsp70, Hsp100 chaperones, including Escherichia coli ClpB, form a powerful disaggregation machine that threads aggregated polypeptides through the central pore of tandem adenosine triphosphatase (ATPase) rings. To visualize protein disaggregation, we determined cryo–electron microscopy structures of inactive and substrate-bound ClpB in the presence of adenosine 5′-O-(3-thiotriphosphate), revealing closed AAA+ rings with a pronounced seam. In the substrate-free state, a marked gradient of resolution, likely corresponding to mobility, spans across the AAA+ rings with a dynamic hotspot at the seam. On the seam side, the coiled-coil regulatory domains are locked in a horizontal, inactive orientation. On the opposite side, the regulatory domains are accessible for Hsp70 binding, substrate targeting, and activation. In the presence of the model substrate casein, the polypeptide threads through the entire pore channel and increased nucleotide occupancy correlates with higher ATPase activity. Substrate-induced domain displacements indicate a pathway of regulated substrate transfer from Hsp70 to the ClpB pore, inside which a spiral of loops contacts the substrate. The seam pore loops undergo marked displacements, along with ordering of the regulatory domains. These asymmetric movements suggest a mechanism for ATPase activation and substrate threading during disaggregation

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Systematic review and meta-Analysis of the clinical characteristics and outcomes of spontanous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an uncommon, non-iatrogenic, non-atherosclerotic cause of acute coronary syndrome. A lack of large prospective cohort studies and randomised controlled trials means that important questions about clinical characteristics and outcomes of patients with SCAD are yet to be fully answered. Method: A literature search of PUBMED, EMBASE and SCOPUS was undertaken up to and including the 23rd January 2020. Studies reporting any cohort of 10 or more SCAD patients presenting with acute coronary syndrome, with appropriate clinical follow-up data were included in the analysis. Incidences of major adverse cardiovascular events (MACE), myocardial infarction and SCAD recurrence were meta-analysed using Poisson regression. Results: 19 studies, totalling p = 2,172 patients, were included in the analysis. There was significant heterogeneity across the studies in all baseline characteristics and clinical outcomes. Prevalence of traditional cardiovascular risk factors was low; however, hypertension had a prevalence of 45% (95% CI; [35-54]) and fibromuscular dysplasia (FMD) was present in 68% (95% CI; [61-74]). Across all cohorts, the incidence of MACE in patients with SCAD was 7.80 per 100 person years (n = 19, p = 2172, 95% CI; [4.50-13.54]) and SCAD recurrence was 5.49 per 100 person years (n = 13, p = 1408, 95% CI; [3.75-8.02]). Conclusions: This meta-analysis confirms that SCAD is not an inconsequential cause of acute coronary syndrome and heralds the need for further prospective research to identify predictors of recurrent events and therapies to prevent them.Kyle B. Franke, Nitesh Nerlekar, Henry Marshall, Peter J. Psalti

Current state-of-play in spontaneous coronary artery dissection

For over 80 years, spontaneous coronary artery dissection (SCAD) has been recognised as a cause of myocardial infarction. SCAD is described as a non-iatrogenic, non-atherosclerotic coronary artery dissection, resulting in formation of a false lumen or intramural haematoma in the coronary artery wall that compresses the true lumen, often compromising myocardial blood flow. In early literature, the incidence of SCAD in acute coronary syndrome (ACS) was underestimated. Recent advances in awareness and widespread early angiographic investigation in ACS has led to important shifts in our understanding of the prevalence, predisposing causes, natural history, aetiology, clinical and angiographic features, management, and prognosis of SCAD. It is now well understood that SCAD predominantly affects women and is responsible for around 20% of ACS presentations in females below the age of 60. Despite this, SCAD is still often overlooked and misdiagnosed as atherosclerotic disease. Misdiagnosis is multifactorial; with contributing factors including a low clinical index of suspicion, particularly in young females, a lack of clinician familiarity with angiographic variants, and limitations of angiography. Although increasing evidence suggests that optimal management is distinct from atherosclerotic coronary artery disease, many questions remain unanswered regarding the pathogenesis and optimal treatment of SCAD, heralding prospective research to answer these questions. This review aims to give a current clinical perspective on SCAD and highlight the importance of familiarity and vigilance with this condition when diagnosing and treating ACS.Kyle B. Franke, Dennis T. L. Wong, Angus Baumann, Stephen J. Nicholls, Rajiv Gulati, Peter J. Psalti

Tandem lesions associate with angiographic progression of coronary artery stenoses

Available online 3 May 2024Background: Although the clinical factors associated with progression of coronary artery disease have been well studied, the angiographic predictors are less defined. Objectives: Our objective was to study the clinical and angiographic factors that associate with progression of coronary artery stenoses. Methods: We conducted a retrospective analysis of consecutive patients undergoing multiple, clinically indicated invasive coronary angiograms with an interval greater than 6 months, between January 2013 and December 2016. Lesion segments were analysed using Quantitative Coronary Angiography (QCA) if a stenosis ≥ 20 % was identified on either angiogram. Stenosis progression was defined as an increase ≥ 10 % in stenosis severity, with progressor groups analysed on both patient and lesion levels. Mixed-effects regression analyses were performed to evaluate factors associated with progression of individual stenoses. Results: 199 patients were included with 881 lesions analysed. 108 (54.3 %) patients and 186 (21.1 %) stenoses were classified as progressors. The median age was 65 years (IQR 56–73) and the median interval between angiograms was 2.1 years (IQR 1.2–3.0). On a patient level, age, number of lesions and presence of multivessel disease at baseline were each associated with progressor status. On a lesion level, presence of a stenosis downstream (OR 3.07, 95 % CI 2.04–4.63, p < 0.001) and circumflex artery stenosis location (OR 1.81, 95 % CI 1.21–2.7, p = 0.004) were associated with progressor status. Other lesion characteristics did not significantly impact progressor status or change in stenosis severity. Conclusion: Coronary lesions which have a downstream stenosis may be at increased risk of stenosis progression. Further research into the mechanistic basis of this finding is required, along with its implications for plaque vulnerability and clinical outcomes.Kyle B. Franke, Nicholas J. Montarello, Adam J. Nelson, Jessica A. Marathe, Dennis T.L. Wong, Rosanna Tavella, Margaret Arstall, Christopher Zeitz, Matthew I. Worthley, John F. Beltrame, Peter J. Psalti

Conjunctive Therapy of Cisplatin With the OCT2 Inhibitor Cimetidine: Influence on Antitumor Efficacy and Systemic Clearance

The organic cation transporter 2 (OCT2) regulates uptake of cisplatin in proximal tubules and inhibition of OCT2 protects against severe cisplatin-induced nephrotoxicity. However, it remains uncertain whether potent OCT2 inhibitors such as cimetidine can influence the antitumor properties and/or disposition of cisplatin. Using an array of preclinical assays, we found that cimetidine had no effect on the uptake and cytotoxicity of cisplatin in ovarian cancer cells with high OCT2 mRNA levels (IGROV-1). Moreover, the antitumor efficacy of cisplatin in mice bearing luciferase-tagged IGROV-1 xenografts was unaffected by cimetidine (P = 0.39). Data obtained in 18 patients receiving cisplatin (100 mg/m(2)) in a randomized crossover fashion with or without cimetidine (800 mg×2) revealed that cimetidine did not alter exposure to unbound cisplatin, a marker of antitumor efficacy (4.37 vs 4.38 μg×h/mL; P = 0.86). These results support the future clinical exploration of OCT2 inhibitors as specific modifiers of cisplatin-induced nephrotoxicity

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness