The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Does it matter that people don't expect to 'see' me in this role?

This paper aims to present the preliminary findings from an ongoing research investigating the business ownership experience of women owner-managers of small UK construction firms. The theoretical lens for this research is the social identity approach. Social identity posits that individuals have multiple identities that originate from their individual self-perceptions and social categories. The identification of self-perceptions allows different understandings of the diverse ways that women owner-managers experience the construction industry. Using narrative inquiry and semi-structured interviews with three women owner-managers, the preliminary findings suggest that women owner-managers are pursuing business ownership in construction even though in some cases industry members do not expect to see women in these roles. The self-perceptions identified from the participants regarding their experience in the industry could be interpreted as positive. The findings further reveal their commitment as business owners to long-term career goals. The exploratory findings of the experience of women owner-managers in construction might assist to counter the fact that they seemingly remain without a voice in the literature

Women owner-managers of small construction firms: a complementary perspective

Studies on women in construction tend to focus on women in professional roles and building trades. Current literature has a bias towards the assumption that barriers affecting women hinder the efforts to address the gender imbalance in the industry. These barriers have been linked to the vertical and horizontal segregation that the industry exhibits. Although there is a growing number of small construction firms that are owned-managed by women, there is a scarcity of research on the experience of these owner-managers. Thus, exploring women's experience in senior management positions within their organisations offers a complementary perspective to the ongoing discussion of the gender balance in construction. This paper aims to examine how the experience of women in construction has been reviewed to date and to present the need to gain a more situated understanding of the experience of women owner-managers, especially those within small construction firms, which comprise 98% of UK construction businesses. This paper will contribute to a contextualised understanding of why the study of women's individual experience in small construction firms continues to be relevant in construction gender research

Transcriptomic effects of tributyltin (TBT) in zebrafish eleutheroembryos. A functional benchmark dose analysis

Exposure to the antifouling tributyltin (TBT) has been related to imposex in mollusks and to obesogenicity, adipogenesis and masculinization in fish. To understand the underlying molecular mechanisms, we evaluated dose-response effects of TBT (1.7-56 nM) in zebrafish eleutheroembryos transcriptome exposed from 2 to 5 days post-fertilization. RNA-sequencing analysis identified 3238 differentially expressed transcripts in eleutheroembryos exposed to TBT. Benchmark dose analyses (BMD) showed that the point of departure (PoD) for transcriptomic effects (9.28 nM) was similar to the metabolomic PoD (11.5 nM) and about one order of magnitude lower than the morphometric PoD (67.9 nM) or the median lethal concentration (LC50: 93.6 nM). Functional analysis of BMD transcriptomic data identified steroid metabolism and cholesterol and vitamin D3 biosynthesis as the most sensitive pathways to TBT (<50% PoD). Conversely, transcripts related to general stress and DNA damage became affected only at doses above the PoD. Therefore, our results indicate that transcriptomes can act as early molecular indicators of pollutant exposure, and illustrates their usefulness for the mechanistic identification of the initial toxic events. As the estimated molecular PoDs are close to environmental levels, we concluded that TBT may represent a substantial risk in some natural environments.This work was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/ 2007-2013)/ERC Grant Agreement n. 320737. Some part of this study was also supported by a grant from the Spanish Ministry of Economy and Competitiveness (CTQ2014-56777-R). AEC acknowledges the funding from ISCIII (Spanish Ministry of Economy and Competitiveness, grant number PT17/0009/0019), co-financed by the European Fund for Regional Development (FEDER). RM was supported by a FPU predoctoral fellow from the Spanish Ministry of Education, Culture and Sport (ref. FPU15/03332).Peer reviewe

Unravelling the mechanisms of PFOS toxicity by combining morphological and transcriptomic analyses in zebrafish embryos

Exposure to PFOS (perfluorooctanesulfonate) has been related to toxic effects on lipid metabolism, immunological response, and different endocrine systems. We present here a transcriptomic analysis of zebrafish embryos exposed to different concentrations of PFOS (0.03–1.0 mg/L) from 48 to 120 hpf. No major survival or morphological alterations (swimming bladder inflation, kyphosis, eye separation and size…) were observed below the 1.0 mg/L mark. Conversely, we observed significant increase in transcripts related to lipid transport and metabolism even at the lowest used concentration. In addition, we observed a general decrease on transcripts related to natural immunity and defense again infections, which adds to the recent concerns about PFOS as immunotoxicant, particularly in humans. Derived PoD (Point of Departure) values for transcriptional changes (0.011 mg/L) were about 200-fold lower than the corresponding PoD values for morphometric effects (2.53 mg/L), and close to levels observed in human blood serum or bird eggs. Our data suggest that currently applicable tolerable levels of PFOS in commercial goods should be re-evaluated, taking into account its potential effects on lipid metabolism and the immune system.This work was supported by European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 320737, and by the Spanish Ministry of Economy and Competitiveness (CTM2014-51985-R). AEC acknowledges the funding from ISCIII (Spanish Ministry of Economy and Competitiveness, grant number PT17/0009/0019), co-financed by the European Fund for Regional Development (FEDER). LNM was supported by a Beatriu de Pinos Postdoctoral Fellowship (2013BP-B-00088) funded by the Secretary for Universities and Research of the Department of Economy and Knowledge of the Government of Catalonia and the Cofund programme of the Marie Curie Actions of the 7th R&D Framework Programme of the European Union. RML was supported by an FPU Fellowship (FPU15/03332) from the Spanish Ministry of Education, Culture and Sport.Peer reviewe

Na+ controls hypoxic signalling by the mitochondrial respiratory chain

All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism

Mortality after surgery in Europe: a 7 day cohort study

Background: Clinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe.Methods: We did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ² and Fisher’s exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p&lt;0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries.Findings: We included 46 539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9–3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0–3·0] for Iceland to 21·5% [16·9–26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19 1·05; p=0·06] for Finland to 6·92 [2·37–20·27; p=0·0004] for Poland).Interpretation: The mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.Funding: European Society of Intensive Care Medicine, European Society of Anaesthesiology