Explore the vast range of titles available.

CRISPR-Cas systems are one of the most widespread phage resistance mechanisms in prokaryotes. Our lab recently identified the first examples of phage-borne anti-CRISPR genes that encode protein inhibitors of the type I-F CRISPR-Cas system of Pseudomonas aeruginosa . A key question arising from this work was whether there are other types of anti-CRISPR genes. In the current work, we address this question by demonstrating that some of the same phages carrying type I-F anti-CRISPR genes also possess genes that mediate inhibition of the type I-E CRISPR-Cas system of P. aeruginosa . We have discovered four distinct families of these type I-E anti-CRISPR genes. These genes do not inhibit the type I-F CRISPR-Cas system of P. aeruginosa or the type I-E system of Escherichia coli . Type I-E and I-F anti-CRISPR genes are located at the same position in the genomes of a large group of related P. aeruginosa phages, yet they are found in a variety of combinations and arrangements. We have also identified functional anti-CRISPR genes within nonprophage Pseudomonas genomic regions that are likely mobile genetic elements. This work emphasizes the potential importance of anti-CRISPR genes in phage evolution and lateral gene transfer and supports the hypothesis that more undiscovered families of anti-CRISPR genes exist. Finally, we provide the first demonstration that the type I-E CRISPR-Cas system of P. aeruginosa is naturally active without genetic manipulation, which contrasts with E. coli and other previously characterized I-E systems. IMPORTANCE The CRISPR-Cas system is an adaptive immune system possessed by the majority of prokaryotic organisms to combat potentially harmful foreign genetic elements. This study reports the discovery of bacteriophage-encoded anti-CRISPR genes that mediate inhibition of a well-studied subtype of CRISPR-Cas system. The four families of anti-CRISPR genes described here, which comprise only the second group of anti-CRISPR genes to be identified, encode small proteins that bear no sequence similarity to previously studied phage or bacterial proteins. Anti-CRISPR genes represent a newly discovered and intriguing facet of the ongoing evolutionary competition between phages and their bacterial hosts. The CRISPR-Cas system is an adaptive immune system possessed by the majority of prokaryotic organisms to combat potentially harmful foreign genetic elements. This study reports the discovery of bacteriophage-encoded anti-CRISPR genes that mediate inhibition of a well-studied subtype of CRISPR-Cas system. The four families of anti-CRISPR genes described here, which comprise only the second group of anti-CRISPR genes to be identified, encode small proteins that bear no sequence similarity to previously studied phage or bacterial proteins. Anti-CRISPR genes represent a newly discovered and intriguing facet of the ongoing evolutionary competition between phages and their bacterial hosts.

Physician-scientists have been a driving force in biomedical research and have made broad contributions in both the private and public sectors. In the past four decades, however, the proportion of U.S. physicians engaged in research has dropped.

Expression levels of human genes vary extensively among individuals. This variation facilitates analyses of expression levels as quantitative phenotypes in genetic studies where the entire genome can be scanned for regulators without prior knowledge of the regulatory mechanisms, thus enabling the identification of unknown regulatory relationships. Here, we carried out such genetic analyses with a large sample size and identified cis- and trans-acting polymorphic regulators for about 1,000 human genes. We validated the cis-acting regulators by demonstrating differential allelic expression with sequencing of transcriptomes (RNA-Seq) and the trans-regulators by gene knockdown, metabolic assays, and chromosome conformation capture analysis. The majority of the regulators act in trans to the target (regulated) genes. Most of these trans-regulators were not known to play a role in gene expression regulation. The identification of these regulators enabled the characterization of polymorphic regulation of human gene expression at a resolution that was unattainable in the past.

Abstract Study Objectives No study has yet examined the prevalence of frequent nightmares in representative youth populations in Asia and how they may contribute to future mental health risks. We aimed to fill this gap using data from a large-scale household-based youth sample in Hong Kong. Methods Participants were consecutively recruited from a large-scale epidemiological youth mental health study in Hong Kong (n = 3132). A subset of participants were invited for a follow-up assessment after 1 year (n = 1154 in the final analyses). Frequent nightmares (≥1/week during the past month) were assessed using an item from the Pittsburgh Sleep Quality Index. Univariate analyses and multivariable logistic regression models were applied to examine the contribution of frequent nightmares at baseline to moderate-to-severe depressive and anxiety symptoms, post-traumatic stress disorder symptoms, and 30-day major depressive episode (MDE) or generalized anxiety disorder (GAD), both at baseline and follow-up. The long-term functional implications of frequent nightmares were also examined. Results The prevalence of frequent nightmares was 16.3%. Females were more likely to experience frequent nightmares (20.4%) compared to males (12.1%), p < 0.001. Baseline frequent nightmares were significantly associated with all four mental health outcomes at 1 year. Notably, their prospective associations with depressive and anxiety symptoms and 30-day MDE/GAD remained significant even after adjusting for external stressors, resilience, and sociodemographic characteristics. Frequent nightmares were also significantly associated with both current and 1-year functional impairments. Conclusions Frequent nightmares have significant long-term implications on mental health and functioning. Identifying young adults with frequent nightmares can improve early risk detection and intervention in the population. Graphical Abstract Graphical Abstract

Direct RNA sequencing would enhance understanding of individual variations in gene expression, facilitate the determination of precise steps in RNA processing and reveal which processes are pathogenic when dysregulated. Currently, most structural analyses of RNA are performed with polymers of the four canonical nucleotides (A, C, G and U) without any modifications. Because relatively little is known about how the different modified nucleotides pair with one another or the four canonical ribonucleotides, the prediction of RNA structure remains rudimentary. [...]the modifications are identified separately rather than together in the same experiment, and sequence context is not captured. [...]this approach makes de novo mapping of previously known and unknown modifications at new positions in RNA challenging at best.

The number of recombination events per meiosis varies extensively among individuals. This recombination phenotype differs between female and male, and also among individuals of each gender. In this study, we used high-density SNP genotypes of over 2,300 individuals and their offspring in two datasets to characterize recombination landscape and to map the genetic variants that contribute to variation in recombination phenotypes. We found six genetic loci that are associated with recombination phenotypes. Two of these (RNF212 and an inversion on chromosome 17q21.31) were previously reported in the Icelandic population, and this is the first replication in any other population. Of the four newly identified loci (KIAA1462, PDZK1, UGCG, NUB1), results from expression studies provide support for their roles in meiosis. Each of the variants that we identified explains only a small fraction of the individual variation in recombination. Notably, we found different sequence variants associated with female and male recombination phenotypes, suggesting that they are regulated by different genes. Characterization of genetic variants that influence natural variation in meiotic recombination will lead to a better understanding of normal meiotic events as well as of non-disjunction, the primary cause of pregnancy loss.

Key Points Expression levels of genes are heritable traits. Genetic determinants of individual variation in human gene expression can be mapped by linkage and association analyses. Cis - and trans -acting DNA variants influence expression levels of genes. Genetics of gene expression (GOGE) studies have identified cis -acting regulatory variants of many genes; however, few trans -acting variants have yet been identified. In humans, ∼30–50% of cis -acting variants identified in immortalized B cells have the same effects in other cell types, such as adipose tissue and blood. Differences in genotype frequencies of regulatory alleles contribute to population differences in gene expression. By combining results from GOGE studies with correlation analysis, one can construct directed gene co-expression networks that provide information on causal rather than just correlative relationships. The results also extend regulatory relationships from pairs to groups of genes. GOGE studies in cells exposed to cellular, medical or environmental perturbations will uncover additional regulators of human gene expression. Uncovering the genetic determinants of individual variation in gene expression in humans can improve our understanding of gene regulation and help to identify disease risk alleles. Further advances might be achieved by testing under different conditions, by using larger sample sizes or through network analysis. There is extensive natural variation in human gene expression. As quantitative phenotypes, expression levels of genes are heritable. Genetic linkage and association mapping have identified cis - and trans -acting DNA variants that influence expression levels of human genes. New insights into human gene regulation are emerging from genetic analyses of gene expression in cells at rest and following exposure to stimuli. The integration of these genetic mapping results with data from co-expression networks is leading to a better understanding of how expression levels of individual genes are regulated and how genes interact with each other. These findings are important for basic understanding of gene regulation and of diseases that result from disruption of normal gene regulation.

I know it's a little late in the day for it, but I want to start with breakfast. It was a Sunday in May 1990, final exam week of my first year in medical school. I was thoroughly tired of exams. Filling out another answer sheet with a number 2 pencil was the last thing I wanted to do. So I was thrilled to see the flyer on my desk for a breakfast seminar. Free breakfast and a lecture by Dr. Robert Mahley. I went for the breakfast, but was nourished more by Dr. Mahley's project, a population study of lipid metabolism in Turkey. In those days, they knew, as I did not, that I was a future physician-scientist at risk. I might have become discouraged, or distracted, and quit research. But today, as a Council member, and this year, as President of the ASCI, I have spent considerable time thinking about the existential risks of physician-scientists.

Using data from global run-on and sequencing (GRO-seq) or related methods, the dREG software identifies a new class of transcriptional regulatory elements with strong evidence for directing active transcription. Modifications to the global run-on and sequencing (GRO-seq) protocol that enrich for 5′-capped RNAs can be used to reveal active transcriptional regulatory elements (TREs) with high accuracy. Here, we introduce discriminative regulatory-element detection from GRO-seq (dREG), a sensitive machine learning method that uses support vector regression to identify active TREs from GRO-seq data without requiring cap-based enrichment ( https://github.com/Danko-Lab/dREG/ ). This approach allows TREs to be assayed together with gene expression levels and other transcriptional features in a single experiment. Predicted TREs are more enriched for several marks of transcriptional activation—including expression quantitative trait loci, disease-associated polymorphisms, acetylated histone 3 lysine 27 (H3K27ac) and transcription factor binding—than those identified by alternative functional assays. Using dREG, we surveyed TREs in eight human cell types and provide new insights into global patterns of TRE function.

Radiation-induced changes in gene expression We are regularly are exposed to radiation from environmental sources, and in medical procedures. To deal with radiation-induced damage, cells mount complex responses that rely on changes in gene expression. It has long been known that individuals vary in their sensitivity to radiation, and this variability is also seen at the gene expression level. Using radiation-induced changes in gene expression as quantitative traits, Smirnov et al . performed genetic linkage and association studies to map their regulators. The results provide new insights into the architecture of gene expression regulation in response to stress and have implications for basic and clinical understanding of how human cells respond to radiation. Humans are exposed to cell-damaging radiation from environmental and medical sources, causing cells to mount complex responses that rely on modifying gene expression. The regulators responsible for this are now mapped through genetic linkage and association studies, using radiation-induced changes in gene expression as quantitative traits and providing new insight into the architecture of gene expression regulation in response to stress. Humans are exposed to radiation through the environment and in medical settings. To deal with radiation-induced damage, cells mount complex responses that rely on changes in gene expression. These gene expression responses differ greatly between individuals 1 and contribute to individual differences in response to radiation 2 . Here we identify regulators that influence expression levels of radiation-responsive genes. We treated radiation-induced changes in gene expression as quantitative phenotypes 3 , 4 , and conducted genetic linkage and association studies to map their regulators. For more than 1,200 of these phenotypes there was significant evidence of linkage to specific chromosomal regions. Nearly all of the regulators act in trans to influence the expression of their target genes; there are very few cis -acting regulators. Some of the trans -acting regulators are transcription factors, but others are genes that were not known to have a regulatory function in radiation response. These results have implications for our basic and clinical understanding of how human cells respond to radiation.