Asymmetric base-pair opening drives helicase unwinding dynamics

The opening of a Watson-Crick double helix is required for crucial cellular processes, including replication, repair, and transcription. It has long been assumed that RNA or DNA base pairs are broken by the concerted symmetric movement of complementary nucleobases. By analyzing thousands of base-pair opening and closing events from molecular simulations, here, we uncover a systematic stepwise process driven by the asymmetric flipping-out probability of paired nucleobases. We demonstrate experimentally that such asymmetry strongly biases the unwinding efficiency of DNA helicases toward substrates that bear highly dynamic nucleobases, such as pyrimidines, on the displaced strand. Duplex substrates with identical thermodynamic stability are thus shown to be more easily unwound from one side than the other, in a quantifiable and predictable manner. Our results indicate a possible layer of gene regulation coded in the direction-dependent unwindability of the double helix

Vector-like Singlet Quarks: a Roadmap

We review the theory and phenomenology of isosinglet vector-like quarks (VLQs). In recent years, interest in VLQs has been increasing, due to their contributions to new physics effects that can be tested in experiments at LHC and High-Luminosity LHC. The similarities of models with isosinglet VLQs and the seesaw framework in the leptonic sector are pointed out. The existence of VLQs leads to flavour-changing neutral currents at tree level and deviations from unitarity of the CKM matrix, introducing rich phenomenological implications. These new effects are naturally suppressed by the masses of the new quarks, that are constrained to be above the electroweak scale. In addition, striking new effects can be achieved with the inclusion of an extra complex scalar singlet. Such a minimal extension of the SM can give rise to new sources of CP violation with profound theoretical implications, allowing for a solution to the strong CP problem and a possible explanation for the baryon asymmetry of the Universe. We list and explain strong motivations to consider this class of models. We also briefly review how models with VLQs can be matched to the SM effective field theory (SMEFT). A detailed analysis of flavour observables that can be affected by the presence of VLQs is presented. Current bounds from collider searches of VLQs are summarized. We point out that the discovery of VLQs can be within the reach of present or future colliders being planned.Comment: 109 pages, 7 figures, 7 tables. Work intended as a review. Comments, suggestions and missing references are welcome

PCNA stimulates catalysis by structure-specific nucleases using two distinct mechanisms: substrate targeting and catalytic step

The sliding clamp Proliferating Cell Nuclear Antigen (PCNA) functions as a recruiter and organizer of a wide variety of DNA modifying enzymes including nucleases, helicases, polymerases and glycosylases. The 5′-flap endonuclease Fen-1 is essential for Okazaki fragment processing in eukaryotes and archaea, and is targeted to the replication fork by PCNA. Crenarchaeal XPF, a 3′-flap endonuclease, is also stimulated by PCNA in vitro. Using a novel continuous fluorimetric assay, we demonstrate that PCNA activates these two nucleases by fundamentally different mechanisms. PCNA stimulates Fen-1 by increasing the enzyme's binding affinity for substrates, as suggested previously. However, PCNA activates XPF by increasing the catalytic rate constant by four orders of magnitude without affecting the KM. PCNA may function as a platform upon which XPF exerts force to distort DNA substrates, destabilizing the substrate and/or stabilizing the transition state structure. This suggests that PCNA can function directly in supporting catalysis as an essential cofactor in some circumstances, a new role for a protein that is generally assumed to perform a passive targeting and organizing function in molecular biology. This could provide a mechanism for the exquisite control of nuclease activity targeted to specific circumstances, such as replication forks or damaged DNA with pre-loaded PCNA

Physical activity and health related quality of life

Copyright @ 2012 Anokye et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.BACKGROUND: Research on the relationship between Health Related Quality of Life (HRQoL) and physical activity (PA), to date, have rarely investigated how this relationship differ across objective and subjective measures of PA. The aim of this paper is to explore the relationship between HRQoL and PA, and examine how this relationship differs across objective and subjective measures of PA, within the context of a large representative national survey from England. METHODS: Using a sample of 5,537 adults (40–60 years) from a representative national survey in England (Health Survey for England 2008), Tobit regressions with upper censoring was employed to model the association between HRQoL and objective, and subjective measures of PA controlling for potential confounders. We tested the robustness of this relationship across specific types of PA. HRQoL was assessed using the summary measure of health state utility value derived from the EuroQol-5 Dimensions (EQ-5D) whilst PA was assessed via subjective measure (questionnaire) and objective measure (accelerometer- actigraph model GT1M). The actigraph was worn (at the waist) for 7 days (during waking hours) by a randomly selected sub-sample of the HSE 2008 respondents (4,507 adults – 16 plus years), with a valid day constituting 10 hours. Analysis was conducted in 2010. RESULTS: Findings suggest that higher levels of PA are associated with better HRQoL (regression coefficient: 0.026 to 0.072). This relationship is consistent across different measures and types of PA although differences in the magnitude of HRQoL benefit associated with objective and subjective (regression coefficient: 0.047) measures of PA are noticeable, with the former measure being associated with a relatively better HRQoL (regression coefficient: 0.072). CONCLUSION: Higher levels of PA are associated with better HRQoL. Using an objective measure of PA compared with subjective shows a relatively better HRQoL.This project was funded by the NIHR Health Technology Assessment programme (project number 08/72/01)

Social support, simpatía, and hypertension prevalence in Hispanics/Latinos: Findings from the HCHS/SOL Sociocultural Ancillary Study.

There is a significant burden of hypertension in the United States, which extends to the large and growing Hispanic/Latino population. Previous literature suggests that psychosocial factors are related to hypertension in Hispanics/Latinos. However, cultural factors unique to this population have been largely understudied in this context. The purpose of the current investigation was to examine the association of hypertension prevalence with social support and simpatía, a Hispanic/Latino cultural value emphasizing social harmony. Cross-sectional data from 5,313 adult Hispanics/Latinos, age 18 to 75 years, representing multiple heritage groups were collected as part of the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. Contrary to predictions, higher social support was related to higher odds of hypertension prevalence across models (OR = 1.11, 95% CI: 1.02, 1.22). In the final main effects logistic regression model, higher simpatía was related to lower odds of hypertension (OR = .83, 95% CI: .77, .90). Sex modified the link between simpatía and hypertension, with significant effects for men but not women. A 1 SD increase in simpatía was associated with 36% lower odds of hypertension in Hispanic/Latino men. The findings suggest that social support was inversely related with hypertension prevalence and that simpatía may be a protective cultural characteristic in relation to hypertension in the Hispanic/Latino population, but only in men. These results contribute to a growing discourse about the role of Hispanic/Latino cultural values in cardiovascular health

Self-Reported Cancer Prevalence among Hispanics in the US: Results from the Hispanic Community Health Study/Study of Latinos

Cancer has surpassed heart disease as the leading cause of death among Hispanics in the U.S., yet data on cancer prevalence and risk factors in Hispanics in regard to ancestry remain scarce. This study sought to describe (a) the prevalence of cancer among Hispanics from four major U.S. metropolitan areas, (b) cancer prevalence across Hispanic ancestry, and (c) identify correlates of self-reported cancer prevalence. Participants were 16,415 individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), who self-identified as Cuban, Dominican, Mexican, Puerto Rican, Central or South American. All data were collected at a single time point during the HCHS/SOL baseline clinic visit. The overall self-reported prevalence rate of cancer for the population was 4%. The rates varied by Hispanic ancestry group, with individuals of Cuban and Puerto Rican ancestry reporting the highest cancer prevalence. For the entire population, older age (OR = 1.47, p < .001, 95% CI, 1.26–1.71) and having health insurance (OR = 1.93, p < .001, 95% CI, 1.42–2.62) were all significantly associated with greater prevalence, whereas male sex was associated with lower prevalence (OR = 0.56, p < .01, 95% CI, .40-.79). Associations between study covariates and cancer prevalence also varied by Hispanic ancestry. Findings underscore the importance of sociodemographic factors and health insurance in relation to cancer prevalence for Hispanics and highlight variations in cancer prevalence across Hispanic ancestry groups. Characterizing differences in cancer prevalence rates and their correlates is critical to the development and implementation of effective prevention strategies across distinct Hispanic ancestry groups

Genome-wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos

Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18–74) in the Hispanic Community Health Study/Study of Latinos. Using a shorted Spielberger Trait Anxiety measure, we analyzed: (1) a total trait anxiety score based on summing responses to all ten items; and (2) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V. We first calculated the heritability due to common variants (h2SNP) and then conducted a genome-wide association study (GWAS) of GAD symptoms. Replication was attempted in three independent Hispanic cohorts (Multi-Ethnic Study of Atherosclerosis, Women’s Health Initiative, Army STARRS). The GAD symptoms score showed evidence of modest heritability (7.2%; p=0.03), while the total trait anxiety score did not (4.97%; p=0.20). One genotyped SNP (rs78602344) intronic to Thrombospondin 2 (THBS2) was nominally associated (p=4.18×10−8) in the primary analysis adjusting for psychiatric medication use and significantly associated with the GAD symptoms score in the analysis excluding medication users (p=4.18×10−8). However, meta-analysis of the replication samples did not support this association. Although GWAS revealed a genome-wide significant locus in this sample, we were unable to replicate this finding. Evidence for heritability was also only detected for GAD symptoms, and not the trait anxiety measure, suggesting differential genetic influences within the domain of trait anxiety

Neighborhood environment and metabolic risk in Hispanics/Latinos from the Hispanic community health study/study of Latinos

Introduction This study examines the associations of neighborhood environments with BMI, HbA1c, and diabetes across 6 years in Hispanic/Latino adults. Methods Participants from the Hispanic Community Health Study/Study of Latinos San Diego site (n=3,851, mean age=39.4 years, 53.3% women, 94.0% Mexican heritage) underwent assessment of metabolic risk factors and diabetes status (categorized as normoglycemia, prediabetes, and diabetes) at baseline (2008–2011) and approximately 6 years later (2014–2017). In the Study of Latinos Community and Surrounding Areas Study ancillary study (2015–2020), participant baseline addresses were geocoded, and neighborhoods were defined using 800-meter circular buffers. Neighborhood variables representing socioeconomic deprivation, residential stability, social disorder, walkability, and greenness were created using Census and other public databases. Analyses were conducted in 2020–2021. Results Complex survey regression analyses revealed that greater neighborhood socioeconomic deprivation was associated with higher BMI (β=0.14, p<0.001) and HbA1c (β=0.08, p<0.01) levels and a higher odds of worse diabetes status (i.e., having prediabetes versus normoglycemia and having diabetes versus prediabetes; OR=1.25, 95% CI=1.06, 1.47) at baseline. Greater baseline neighborhood deprivation also was related to increasing BMI (β=0.05, p<0.01) and worsening diabetes (OR=1.27, 95% CI=1.10, 1.46) statuses, whereas social disorder was related to increasing BMI levels (β=0.05, p<0.05) at Visit 2. There were no associations of expected protective factors of walkability, greenness, or residential stability. Conclusions Neighborhood deprivation and disorder were related to worse metabolic health in San Diego Hispanic/Latino adults of mostly Mexican heritage. Multilevel interventions emphasizing individual and structural determinants may be most effective in improving metabolic health among Hispanic/Latino individuals