Sudden cardiac death athletes: a systematic review

Previous events evidence that sudden cardiac death (SCD) in athletes is still a reality and it keeps challenging cardiologists. Considering the importance of SCD in athletes and the requisite for an update of this matter, we endeavored to describe SCD in athletes. The Medline (via PubMed) and SciELO databases were searched using the subject keywords "sudden death, athletes and mortality". The incidence of SCD is expected at one case for each 200,000 young athletes per year. Overall it is resulted of complex dealings of factors such as arrhythmogenic substrate, regulator and triggers factors. In great part of deaths caused by heart disease in athletes younger than 35 years old investigations evidence cardiac congenital abnormalities. Athletes above 35 years old possibly die due to impairments of coronary heart disease, frequently caused by atherosclerosis. Myocardial ischemia and myocardial infarction are responsible for the most cases of SCD above this age (80%). Pre-participatory athletes' evaluation helps to recognize situations that may put the athlete's life in risk including cardiovascular diseases. In summary, cardiologic examinations of athletes' pre-competition routine is an important way to minimize the risk of SCD

Posterior Association Networks and Functional Modules Inferred from Rich Phenotypes of Gene Perturbations

Combinatorial gene perturbations provide rich information for a systematic exploration of genetic interactions. Despite successful applications to bacteria and yeast, the scalability of this approach remains a major challenge for higher organisms such as humans. Here, we report a novel experimental and computational framework to efficiently address this challenge by limiting the ‘search space’ for important genetic interactions. We propose to integrate rich phenotypes of multiple single gene perturbations to robustly predict functional modules, which can subsequently be subjected to further experimental investigations such as combinatorial gene silencing. We present posterior association networks (PANs) to predict functional interactions between genes estimated using a Bayesian mixture modelling approach. The major advantage of this approach over conventional hypothesis tests is that prior knowledge can be incorporated to enhance predictive power. We demonstrate in a simulation study and on biological data, that integrating complementary information greatly improves prediction accuracy. To search for significant modules, we perform hierarchical clustering with multiscale bootstrap resampling. We demonstrate the power of the proposed methodologies in applications to Ewing's sarcoma and human adult stem cells using publicly available and custom generated data, respectively. In the former application, we identify a gene module including many confirmed and highly promising therapeutic targets. Genes in the module are also significantly overrepresented in signalling pathways that are known to be critical for proliferation of Ewing's sarcoma cells. In the latter application, we predict a functional network of chromatin factors controlling epidermal stem cell fate. Further examinations using ChIP-seq, ChIP-qPCR and RT-qPCR reveal that the basis of their genetic interactions may arise from transcriptional cross regulation. A Bioconductor package implementing PAN is freely available online at http://bioconductor.org/packages/release/bioc/html/PANR.html

Identifying Determinants of Cullin Binding Specificity Among the Three Functionally Different Drosophila melanogaster Roc Proteins via Domain Swapping

BACKGROUND: Cullin-dependent E3 ubiquitin ligases (CDL) are key regulators of protein destruction that participate in a wide range of cell biological processes. The Roc subunit of CDL contains an evolutionarily conserved RING domain that binds ubiquitin charged E2 and is essential for ubiquitylation. Drosophila melanogaster contains three highly related Roc proteins: Roc1a and Roc2, which are conserved in vertebrates, and Roc1b, which is specific to Drosophila. Our previous genetic data analyzing Roc1a and Roc1b mutants suggested that Roc proteins are functionally distinct, but the molecular basis for this distinction is not known. METHODOLOGY/PRINCIPAL FINDINGS: Using co-immunoprecipitation studies we show that Drosophila Roc proteins bind specific Cullins: Roc1a binds Cul1-4, Roc1b binds Cul3, and Roc2 binds Cul5. Through domain swapping experiments, we demonstrate that Cullin binding specificity is strongly influenced by the Roc NH(2)-terminal domain, which forms an inter-molecular beta sheet with the Cullin. Substitution of the Roc1a RING domain with that of Roc1b results in a protein with similar Cullin binding properties to Roc1a that is active as an E3 ligase but cannot complement Roc1a mutant lethality, indicating that the identity of the RING domain can be an important determinant of CDL function. In contrast, the converse chimeric protein with a substitution of the Roc1b RING domain with that of Roc1a can rescue the male sterility of Roc1b mutants, but only when expressed from the endogenous Roc1b promoter. We also identified mutations of Roc2 and Cul5 and show that they cause no overt developmental phenotype, consistent with our finding that Roc2 and Cul5 proteins are exclusive binding partners, which others have observed in human cells as well. CONCLUSIONS: The Drosophila Roc proteins are highly similar, but have diverged during evolution to bind a distinct set of Cullins and to utilize RING domains that have overlapping, but not identical, function in vivo

A redox state-dictated signalling pathway deciphers the malignant cell specificity of CD40-mediated apoptosis

CD40, a member of the tumour necrosis factor receptor (TNFR) superfamily, has the capacity to cause extensive apoptosis in carcinoma cells, while sparing normal epithelial cells. Yet, apoptosis is only achieved by membrane-presented CD40 ligand (mCD40L), as soluble receptor agonists are but weakly pro-apoptotic. Here, for the first time we have identified the precise signalling cascade underpinning mCD40L-mediated death as involving sequential TRAF3 stabilisation, ASK1 phosphorylation, MKK4 (but not MKK7) activation and JNK/AP-1 induction, leading to a Bak- and Bax-dependent mitochondrial apoptosis pathway. TRAF3 is central in the activation of the NADPH oxidase (Nox)-2 component p40phox and the elevation of reactive oxygen species (ROS) is essential in apoptosis. Strikingly, CD40 activation resulted in down-regulation of Thioredoxin (Trx)-1 to permit ASK1 activation and apoptosis. Although soluble receptor agonist alone could not induce death, combinatorial treatment incorporating soluble CD40 agonist and pharmacological inhibition of Trx-1 was functionally equivalent to the signal triggered by mCD40L. Finally, we demonstrate using normal, ‘para-malignant’ and tumour-derived cells that progression to malignant transformation is associated with increase in oxidative stress in epithelial cells, which coincides with increased susceptibility to CD40 killing, while in normal cells CD40 signalling is cytoprotective. Our studies have revealed the molecular nature of the tumour specificity of CD40 signalling and explained the differences in pro-apoptotic potential between soluble and membrane-bound CD40 agonists. Equally importantly, by exploiting a unique epithelial culture system that allowed us to monitor alterations in the redox-state of epithelial cells at different stages of malignant transformation, our study reveals how pro-apoptotic signals can elevate ROS past a previously hypothesised ‘lethal pro-apoptotic threshold’ to induce death; an observation that is both of fundamental importance and carries implications for cancer therap

Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway

Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a CD40 risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the CD40 risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of CD40 coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, P = 1.4×10(−9)). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(−9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA–approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in complex traits such as RA

Turning gold into lead: Dampening appraisals reduce happiness and pleasantness and increase sadness during anticipation and recall of pleasant activities in the laboratory

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Two studies examined whether use of dampening appraisals (e.g., thinking “this is too good to last”) or amplifying appraisals (e.g., thinking “I deserve this”) modulated affective experience when remembering (Study One) and anticipating (Study Two) positive events. Both studies used a mixed within-between participants design, with participants completing an uninstructed positive recall/anticipation task before being randomized to either control, dampening, or amplifying instructions during a second positive recall/anticipation task. During memory recall (Study One), instructed dampening increased dampening appraisals and led to a reduction in happiness and pleasantness and an increase in sadness, significantly differing from the control and amplifying conditions. While the amplifying condition significantly increased amplifying appraisals, it did not alter affective experience (relative to the control condition). During anticipation (Study Two), identical findings emerged for the dampening manipulation. The amplifying manipulation did not significantly increase amplifying appraisals, precluding conclusions being drawn about the impact of amplifying in this study. These results suggest that dampening appraisals contribute to altered affective experience when imagining and recalling positive activities and may account for why attempts to do so can have paradoxically negative effects in clinical populations. Moreover, the studies preliminarily validate a novel scale measuring state appraisal of positive experiences.The authors declare no conflict of interest. The authors received no funding from an external source. Barnaby Dunn conceived of the original idea for the studies, co-designed the studies, supervised data collection, co-analysed the data, and wrote the manuscript. Leigh Anne Burr and Harrie Bunker-Smith co-designed Study One, collected data for Study One, co-analysed the data and assisted with writing the manuscript. Daniel Dadgostar and Anna Hunt co-designed and collected data for Study One. Lucy Dalglish, Sophie Smith, Ellie Attree co-designed and collected data for Study Two. Nikita Bos co-analysed and collected data for Study Two and co-wrote the manuscript. Grace Jell co-supervised Study Two and commented on the manuscript. James Martyn designed the study and collected data used in the validation of the state RPA in the Supplementary Materials. Aliza Werner-Seidler co-conceived of the original idea for the studies and provided comments on the manuscript. Thanks to Sophie Dunn for proofreading this manuscript