Identification of noncoding drivers from thousands of somatic alterations in a typical tumor is a difficult and unsolved problem. We report a computational framework, FunSeq2, to annotate and prioritize these mutations. The framework combines an adjustable data context integrating large-scale genomics and cancer resources with a streamlined variant-prioritization pipeline. The pipeline has a weighted scoring system combining: inter- and intra-species conservation; loss- and gain-of-function events for transcription-factor binding; enhancer-gene linkages and network centrality; and per-element recurrence across samples. We further highlight putative drivers with information specific to a particular sample, such as differential expression. FunSeq2 is available from funseq2.gersteinlab.org.

/pdf/funseq2-a-framework-for-prioritizing-noncoding-regulatory-1o0sphscmz.pdf

FunSeq2: a framework for prioritizing noncoding regulatory variants in cancer.

European Resuscitation Council Guidelines 2021: Systems saving lives.

Several studies have compared various features of heritable disease genes with other so called non-disease genes, but they have yielded some conflicting results. A potential problem in those studies is that the non-disease genes contained a large number of essential genes – genes which are indispensable for humans to survive and reproduce. Since a functional disruption of an essential gene has fatal consequences, it's more reasonable to regard essential genes as extremely severe "disease" genes. Here we perform a comparative study on the features of human essential, disease, and other genes. In the absence of a set of well defined human essential genes, we consider a set of 1,789 ubiquitously expressed human genes (UEHGs), also known as housekeeping genes, as an approximation. We demonstrate that UEHGs are very likely to contain a large proportion of essential genes. We show that the UEHGs, disease genes and other genes are different in their evolutionary conservation rates, DNA coding lengths, gene functions, etc. Our findings systematically confirm that disease genes have an intermediate essentiality which is less than housekeeping genes but greater than other human genes. The human genome may contain thousands of essential genes having features which differ significantly from disease and other genes. We propose to classify them as a unique group for comparisons of disease genes with non-disease genes. This new way of classification and comparison enables us to have a clearer understanding of disease genes.

/pdf/further-understanding-human-disease-genes-by-comparing-with-2av32e8she.pdf

Further understanding human disease genes by comparing with housekeeping genes and other genes

Recently, it was proposed that alternative splicing may act as a mechanism for opening accelerated paths of evolution, by reducing negative selection pressure, but there has been little evidence so far that this mechanism could produce adaptive benefit. Here, we use metrics of very different types of selection pressures [e.g., against amino acid mutations (Ka/Ks), against mutations at synonymous sites (Ks), and for protein reading-frame preservation] to address this question by genomewide analyses of human, chimpanzee, mouse, and rat. These data show that alternative splicing relaxes Ka/Ks selection pressure up to 7-fold, but intriguingly this effect is accompanied by a strong increase in selection pressure against synonymous mutations, which propagates into the adjacent intron, and correlates strongly with the alternative splicing level observed for each exon. These effects are highly local to the alternatively spliced exon. Comparisons of these four genomes consistently show an increase in the density of amino acid mutations (Ka) in alternatively spliced exons and a decrease in the density of synonymous mutations (Ks). This selection pressure against synonymous mutations in alternatively spliced exons was accompanied in all four genomes by a striking increase in selection pressure for protein reading-frame preservation, and both increased markedly with increasing evolutionary age. Restricting our analysis to a subset of exons with strong evidence for biologically functional alternative splicing produced identical results. Thus alternative splicing apparently can create evolutionary “hotspots” within a protein sequence, and these events have evidently been selected for during mammalian evolution.

/pdf/evidence-of-functional-selection-pressure-for-alternative-3se4ubryvy.pdf

Evidence of functional selection pressure for alternative splicing events that accelerate evolution of protein subsequences.

For this 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, the Education, Implementation, and Teams Task Force applied the population, intervention, comparator, outcome, study design, time frame format and performed 15 systematic reviews, applying the Grading of Recommendations, Assessment, Development, and Evaluation guidance. Furthermore, 4 scoping reviews and 7 evidence updates assessed any new evidence to determine if a change in any existing treatment recommendation was required. The topics covered included training for the treatment of opioid overdose; basic life support, including automated external defibrillator training; measuring implementation and performance in communities, and cardiac arrest centers; advanced life support training, including team and leadership training and rapid response teams; measuring cardiopulmonary resuscitation performance, feedback devices, and debriefing; and the use of social media to improve cardiopulmonary resuscitation application.

Education, Implementation, and Teams: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

Oncogenes and tumor suppressor genes (hereafter referred to as "cancer genes") result in cancer when they experience substitutions that prevent or distort their normal function. We examined evolutionary pressures acting on cancer genes and other classes of disease-related genes and compared our results to analyses of genes without known association to disease. We compared synonymous and nonsynonymous substitution rates in 3,035 human genes-approximately 10% of the genome-measuring the intensity of purifying selection on 311 human disease genes, including 122 cancer-related genes. Although the genes examined are similar to nondisease genes in product, expression, function, and pathway affiliation, we found intriguing differences in the selective pressures experienced by cancer genes relative to other (noncancer) disease-related and non-disease-related genes. We found a statistically significant increase in the intensity of purifying selection exerted on cancer genes (the average ratio of nonsynonymous to synonymous substitutions, omega, was 0.079) relative to all other disease-related genes groups (omega = 0.101) and non-disease-related genes (omega = 0.100). This difference indicates a striking increase in selection against nonsynonymous substitutions in oncogenes and tumor suppressor genes. This finding provides insight into the etiology of cancer and the differences between genes involved in cancer and those implicated in other human diseases. Specifically, we found a significant overlap between human oncogenes and tumor suppressor genes and "essential genes," human homologs of mouse lethal genes identified by knockout experiments. This insight may improve our ability to identify cancer-related genes and enhances our understanding of the nature of these genes.

Evolutionary dynamics of oncogenes and tumor suppressor genes: higher intensities of purifying selection than other genes.

Does an individualized feedback mechanism improve quality of out-of-hospital CPR?

OBJECTIVES : To determine the prevalence of cocaine use and associated risk factors in African Americans volunteering as research subjects for a hypertension study. METHODS : African Americans recruited from Milwaukee's inner city received $25 for completing a blood pressure screening protocol with the potential to participate in an additional protocol for $200, contingent on a negative drug test for cocaine. This study is based on the characteristics of the participants who completed the drug screen for cocaine. The significance of differences in the frequencies of categorical variables between users and nonusers was determined by χ analysis or Fisher exact test. RESULTS : Of 389 drug-tested participants, 35% tested positive for cocaine. Cocaine positive volunteers were slightly older (P = 0.02), had a lower body mass index (P = 0.001), a smaller waist circumference (P = 0.005), and lower serum cholesterol levels (P = 0.04). Those testing positive were more likely to be tobacco smokers (P < 0.0001), unemployed (P = 0.001), and alcohol users (P < 0.0001), but less likely to use prescription medications (P = 0.01). Income and education did not differ between cocaine positive and negative subjects. Individuals employed full-time were less likely to test positive than the unemployed, whereas part-time employees were intermediate (P = 0.0003). Although those testing positive were slightly less likely to have a living mother (P = 0.07), there was no association with living fathers.Cigarette smokers were almost five times more likely to test positive for cocaine than nonsmokers (OR 4.88, 95% CI 2.73-8.71). Additional predictors of positive tests were alcohol consumption (OR 1.90, 95% CI 1.18-3.19), a reported history of substance abuse (OR 1.83, 95% CI 1.05-3.19), and a family history that included one or more deceased siblings (OR 1.82, 95% CI 1.03-3.21). CONCLUSIONS : A high prevalence of substance use was detected among inner city African Americans offered financial incentives for participating in a general medical research protocol. This information may be relevant for designing future clinical trials and drug use intervention programs.

Benjamin W Weston

Papers

Evolutionary dynamics of oncogenes and tumor suppressor genes: higher intensities of purifying selection than other genes.

Does an individualized feedback mechanism improve quality of out-of-hospital CPR?

Cocaine use in inner city african american research volunteers.

Saving Lives with Tourniquets: A Review of Penetrating Injury Medical Examiner Cases

Self-Assessment Feedback Form Improves Quality of Out-of-Hospital CPR.