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BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (P

Background: Resistance training is hardly recommended for postmenopausal women to counteract negative effects of hormonal changes. However, some concern exists about the marked hemodynamic responses caused by high-load resistance exercises. In this regard, studies on young, healthy, physically active individuals suggest that set configuration can modulate acute cardiovascular, metabolic, and cardiac autonomic responses caused by resistance training sessions, but this has not yet been explored in postmenopausal women. Methods: A sample of 60 physically active postmenopausal women (30 normotensive, 30 hypertensive) will participate in this crossover study. After a medical exam, ergometry, familiarization session, and two testing sessions, participants will complete three experimental sessions and one control session in a randomized order. Each experimental session includes 36 repetitions of four exercises (horizontal leg press, bench press, prone leg curl, and lat pull-down) differing in set configuration: 9 sets of 4 repetitions (i.e., 33% intensity of effort) with 45 s of inter-set recovery, 6 sets of 6 repetitions (50% intensity of effort) with 72 s, and 4 sets of 9 repetitions (75% intensity of effort) with 120 s; with 4 min rest between exercises. Before and immediately after each session, arterial stiffness, hemodynamic variables, cardiac autonomic modulation, baroreflex sensitivity, sympathetic vasomotor tone, and resting oxygen uptake will be evaluated. Furthermore, perceived effort, mechanical performance (e.g., power, velocity), heart rate, and lactatemia will be collected throughout sessions. The impact of set configuration on these variables will be analyzed, along with comparisons between normotensive and hypertensive women. Discussion: Cardiovascular responses to resistance exercise have been scarcely studied in females, particularly postmenopausal women. The results of this study will provide information about the modulating role of set structure on metabolic and cardiovascular responses of normotensive and hypertensive postmenopausal women to resistance training. Clinical trial registration: NCT05544357 on 7 December 2022. [ABSTRACT FROM AUTHOR]

This paper contributes to current debates on the technologies and practices of prehistoric artists using the rock art site of el Carche (Jalance, Spain) as a case study. The site preserves both Levantine and Schematic paintings, yet poorly understood from an analytical point of view. In the past, it has even been argued how little differentiation there is between these two post-Paleolithic traditions in terms of paint composition. Our aim with this paper was to identify pigments, paint recipes and technologies and decipher the order of the superimpositions, both between Levantine motifs of different styles, and between these and the Schematic ones. To do so, we adopted a multi-stage and multi-technical analytical strategy, trying to find a balance between sound scientific investigation and impact on the art, considering the irreplaceable nature of this World Heritage rock art. As such, our approach begins with in situ non-invasive investigations using portable EDXRF, to then collect micro-samples for non-destructive analyses by means of Optical Microscopy, Scanning Electron Microscopy coupled with Energy Dispersive X-Ray Spectroscopy (SEM-EDX), micro-Raman Spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR). One of the key highlights of these paper is the identification of up to four different paint compositions, produced with various hematite-based raw materials and different processing techniques. This variability had not been previously documented. Interestingly though, no direct correlations appear to exist between styles or sub-styles and recipes. Some of these paint mixtures were even shared by both traditions. These results are discussed in cultural terms, challenging previous interpretations suggesting a similar pigment composition between Levantine and Schematic art. Microstratigraphic analysis of the cross-sections only partially clarified the overlapping sequence unveiling the complexity of these analysis. They also revealed several degradation layers and external crusts related to rock alteration processes and biological formations. Their role in rock art conservation is also discussed.

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (PConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

The south of Iberia conserves an important group of Palaeolithic rock art sites. The graphisms have been mostly attributed to the Solutrean and Magdalenian periods, while the possibility that older remains exist has provoked extensive debate. This circumstance has been linked to both the cited periods, until recently, due to the transition from the Middle to Upper Palaeolithic in the extreme southwest of Europe as well as the non-existence of some of the early periods of Palaeolithic art documented in northern Iberia. This study presents the results of interdisciplinary research conducted in Las Ventanas Cave. These results enabled us to identify a new Palaeolithic rock art site. The technical, stylistic and temporal traits point to certain similarities with the range of exterior deep engravings in Cantabrian Palaeolithic rock art. Ventanas appears to corroborate the age attributed to those kinds of graphic expression and points to the early arrival of the Upper Palaeolithic in the south of Iberia. Importantly, the results provide information on the pre-Solutrean date attributed to trilinear hind figures. These findings challenge the supposed Neanderthal survival idea at one of the main late Middle Palaeolithic southern Iberian sites (Carigüela) and, due to the parallels between them and an engraving attributed to this period in Gibraltar, it raises the possibility of interaction between modern humans and Neanderthals in the extreme southwest of Europe.

[This corrects the article DOI: 10.1371/journal.pone.0204651.].

Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel). Using this gene panel, we were able to identify disease-causing variants in 17 out of 87 (19.5%) analyzed patients, all found in known epilepsy-associated genes (KCNQ2, CDKL5, STXBP1, SCN1A, PCDH19, POLG, SLC2A1, ARX, ALG13, CHD2, SYNGAP1, and GRIN1). Twelve of 18 variants arose de novo and 6 were novel. The highest yield was found in patients with onset in the first years of life, especially in patients classified as having early-onset epileptic encephalopathy. Knowledge of the underlying genetic cause provides essential information on prognosis and could be used to avoid unnecessary studies, which may result in a greater diagnostic cost-effectiveness.

Geographic patterns in total mortality and in mortality by cause of death are widely known to exist in many countries. However, the geographic pattern of inequalities in mortality within these countries is unknown. This study shows mathematically and graphically the geographic pattern of mortality inequalities by education in Spain.Data are from a nation-wide prospective study covering all persons living in Spain's 50 provinces in 2001. Individuals were classified in a cohort of subjects with low education and in another cohort of subjects with high education. Age- and sex-adjusted mortality rate from all causes and from leading causes of death in each cohort and mortality rate ratios in the low versus high education cohort were estimated by geographic coordinates and province.Latitude but not longitude was related to mortality. In subjects with low education, latitude had a U-shaped relation to mortality. In those with high education, mortality from all causes, and from cardiovascular, respiratory and digestive diseases decreased with increasing latitude, whereas cancer mortality increased. The mortality-rate ratio for all-cause death was 1.27 in the southern latitudes, 1.14 in the intermediate latitudes, and 1.20 in the northern latitudes. The mortality rate ratios for the leading causes of death were also higher in the lower and upper latitudes than in the intermediate latitudes. The geographic pattern of the mortality rate ratios is similar to that of the mortality rate in the low-education cohort: the highest magnitude is observed in the southern provinces, intermediate magnitudes in the provinces of the north and those of the Mediterranean east coast, and the lowest magnitude in the central provinces and those in the south of the Western Pyrenees.Mortality inequalities by education in Spain are higher in the south and north of the country and lower in the large region making up the central plateau. This geographic pattern is similar to that observed in mortality in the low-education cohort.

Many fungi form complex three-dimensional fruiting bodies, within which the meiotic machinery for sexual spore production has been considered to be largely conserved over evolutionary time. Indeed, much of what we know about meiosis in plant and animal taxa has been deeply informed by studies of meiosis in Saccharomyces and Neurospora. Nevertheless, the genetic basis of fruiting body development and its regulation in relation to meiosis in fungi is barely known, even within the best studied multicellular fungal model Neurospora crassa. We characterized morphological development and genome-wide transcriptomics in the closely related species Neurospora crassa, Neurospora tetrasperma, and Neurospora discreta, across eight stages of sexual development. Despite diverse life histories within the genus, all three species produce vase-shaped perithecia. Transcriptome sequencing provided gene expression levels of orthologous genes among all three species. Expression of key meiosis genes and sporulation genes corresponded to known phenotypic and developmental differences among these Neurospora species during sexual development. We assembled a list of genes putatively relevant to the recent evolution of fruiting body development by sorting genes whose relative expression across developmental stages increased more in N. crassa relative to the other species. Then, in N. crassa, we characterized the phenotypes of fruiting bodies arising from crosses of homozygous knockout strains of the top genes. Eight N. crassa genes were found to be critical for the successful formation of perithecia. The absence of these genes in these crosses resulted in either no perithecium formation or in arrested development at an early stage. Our results provide insight into the genetic basis of Neurospora sexual reproduction, which is also of great importance with regard to other multicellular ascomycetes, including perithecium-forming pathogens, such as Claviceps purpurea, Ophiostoma ulmi, and Glomerella graminicola.

BACKGROUND: Schizotypal traits in adolescents from the general population represent the behavioral expression of liability for psychotic disorders. Schizotypy assessment in this sector of population has advanced considerably in the last few years; however, it is necessary to incorporate recent advances in psychological and educational measurement. OBJECTIVE: The main goal of this study was to develop a Computerized Adaptive Test (CAT) to evaluate schizotypy through "The Oviedo Questionnaire for Schizotypy Assessment" (ESQUIZO-Q), in non-clinical adolescents. METHODS: The final sample consisted of 3,056 participants, 1,469 males, with a mean age of 15.9 years (SD=1.2). RESULTS: The results indicated that the ESQUIZO-Q scores presented adequate psychometric properties under both Classical Test Theory and Item Response Theory. The Information Function estimated using the Gradual Response Model indicated that the item pool effectively assesses schizotypy at the high end of the latent trait. The correlation between the CAT total scores and the paper-and-pencil test was 0.92. The mean number of presented items in the CAT with the standard error fixed at ≤ 0.30 was of 34 items. CONCLUSION: The CAT showed adequate psychometric properties for schizotypy assessment in the general adolescent population. The ESQUIZO-Q adaptive version could be used as a screening method for the detection of adolescents at risk for psychosis in both educational and mental health settings.

BACKGROUND: Ancestral reconstructions of mammalian genomes have revealed that evolutionary breakpoint regions are clustered in regions that are more prone to break and reorganize. What is still unclear to evolutionary biologists is whether these regions are physically unstable due solely to sequence composition and/or genome organization, or do they represent genomic areas where the selection against breakpoints is minimal. METHODOLOGY AND PRINCIPAL FINDINGS: Here we present a comprehensive study of the distribution of tandem repeats in great apes. We analyzed the distribution of tandem repeats in relation to the localization of evolutionary breakpoint regions in the human, chimpanzee, orangutan and macaque genomes. We observed an accumulation of tandem repeats in the genomic regions implicated in chromosomal reorganizations. In the case of the human genome our analyses revealed that evolutionary breakpoint regions contained more base pairs implicated in tandem repeats compared to synteny blocks, being the AAAT motif the most frequently involved in evolutionary regions. We found that those AAAT repeats located in evolutionary regions were preferentially associated with Alu elements. SIGNIFICANCE: Our observations provide evidence for the role of tandem repeats in shaping mammalian genome architecture. We hypothesize that an accumulation of specific tandem repeats in evolutionary regions can promote genome instability by altering the state of the chromatin conformation or by promoting the insertion of transposable elements.

BackgroundColorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect.Methodology/principal findingsWe examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene.ConclusionsThese results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.

Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel). Using this gene panel, we were able to identify disease-causing variants in 17 out of 87 (19.5%) analyzed patients, all found in known epilepsy-associated genes (KCNQ2, CDKL5, STXBP1, SCN1A, PCDH19, POLG, SLC2A1, ARX, ALG13, CHD2, SYNGAP1, and GRIN1). Twelve of 18 variants arose de novo and 6 were novel. The highest yield was found in patients with onset in the first years of life, especially in patients classified as having early-onset epileptic encephalopathy. Knowledge of the underlying genetic cause provides essential information on prognosis and could be used to avoid unnecessary studies, which may result in a greater diagnostic cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect. Methodology/Principal Findings: We examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene. Conclusions: These results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC. [ABSTRACT FROM AUTHOR]