Widespread sex differences in gene expression and splicing in the adult human brain

There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures

A new hammer to crack an old nut : interspecific competitive resource capture by plants is regulated by nutrient supply, not climate

Peer reviewedPublisher PD

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Bedside Sublingual Video Imaging of Microcirculation in Assessing Bacterial Infection in Cirrhosis

Bacterial infections are common in cirrhosis and can lead to life-threatening complications. Sidestream dark-field (SDF) imaging has recently emerged as a noninvasive tool for capturing real-time video images of sublingual microcirculation in critically ill patients with sepsis. The objective of this study was to assess the utility of SDF in determining underlying infection in patients with cirrhosis. Sublingual microcirculation was compared among patients with compensated cirrhosis (Group A, n = 13), cirrhosis without sepsis (Group B, n = 18), cirrhosis with sepsis (Group C, n = 14), and sepsis only (Group D, n = 10). The blood flow was semi-quantitatively evaluated in four equal quadrants in small (10–25 mm); medium (26–50 mm); and large (51–100 mm) sublingual capillaries. The blood flow was described as no flow (0), intermittent flow (1), sluggish flow (2), and continuous flow (3). The overall flow score or microvascular flow index (MFI) was measured for quantitative assessment of microcirculation and predicting power for concurrent infection in cirrhosis. Marked impairment was observed at all levels of microvasculature in Groups B and C when compared with Group A. This effect was restricted to small vessels only when Group B was compared with Group C. MFI < 1.5 was found to have highest sensitivity (100%) and specificity (100%) for infection in decompensated cirrhosis. SDF imaging of sublingual microcirculation can be a useful bedside diagnostic tool to assess bacterial infection in cirrhosis

Human papillomavirus-mediated carcinogenesis and HPV-associated oral and oropharyngeal squamous cell carcinoma. Part 1: Human papillomavirus-mediated carcinogenesis

High-risk human papillomavirus (HPV) E6 and E7 oncoproteins are essential factors for HPV-induced carcinogenesis, and for the maintenance of the consequent neoplastic growth. Cellular transformation is achieved by complex interaction of these oncogenes with several cellular factors of cell cycle regulation including p53, Rb, cyclin-CDK complexes, p21 and p27. Both persistent infection with high-risk HPV genotypes and immune dysregulation are associated with increased risk of HPV-induced squamous cell carcinoma

Signs of positive selection of somatic mutations in human cancers detected by EST sequence analysis

BACKGROUND: Carcinogenesis typically involves multiple somatic mutations in caretaker (DNA repair) and gatekeeper (tumor suppressors and oncogenes) genes. Analysis of mutation spectra of the tumor suppressor that is most commonly mutated in human cancers, p53, unexpectedly suggested that somatic evolution of the p53 gene during tumorigenesis is dominated by positive selection for gain of function. This conclusion is supported by accumulating experimental evidence of evolution of new functions of p53 in tumors. These findings prompted a genome-wide analysis of possible positive selection during tumor evolution. METHODS: A comprehensive analysis of probable somatic mutations in the sequences of Expressed Sequence Tags (ESTs) from malignant tumors and normal tissues was performed in order to access the prevalence of positive selection in cancer evolution. For each EST, the numbers of synonymous and non-synonymous substitutions were calculated. In order to identify genes with a signature of positive selection in cancers, these numbers were compared to: i) expected numbers and ii) the numbers for the respective genes in the ESTs from normal tissues. RESULTS: We identified 112 genes with a signature of positive selection in cancers, i.e., a significantly elevated ratio of non-synonymous to synonymous substitutions, in tumors as compared to 37 such genes in an approximately equal-sized EST collection from normal tissues. A substantial fraction of the tumor-specific positive-selection candidates have experimentally demonstrated or strongly predicted links to cancer. CONCLUSION: The results of EST analysis should be interpreted with extreme caution given the noise introduced by sequencing errors and undetected polymorphisms. Furthermore, an inherent limitation of EST analysis is that multiple mutations amenable to statistical analysis can be detected only in relatively highly expressed genes. Nevertheless, the present results suggest that positive selection might affect a substantial number of genes during tumorigenic somatic evolution

Rapid appraisal of barriers to the diagnosis and management of patients with dementia in primary care: a systematic review

<p>Abstract</p> <p>Background</p> <p>The diagnosis of dementia in primary care is perceived as a problem across countries and systems, resulting in delayed recognition and adverse outcomes for patients and their carers. Improving its early detection is an area identified for development in the English National Dementia Strategy 2009; there are thought to be multiple benefits to the patient, family, and resources by doing this. The aim of this review was to carry out a rapid appraisal in order to inform the implementation of this policy.</p> <p>Method</p> <p>Publications in English up to August 2009 relating to barriers to the recognition of dementia, were identified by a broad search strategy, using electronic databases MEDLINE, EMBASE, and psycINFO. Exclusion criteria included non-English language, studies about pharmacological interventions or screening instruments, and settings without primary care.</p> <p>Results</p> <p>Eleven empirical studies were found: 3 quantitative, 6 qualitative, and 2 with mixed methodologies. The main themes from the qualitative studies were found to be lack of support, time constraints, financial constraints, stigma, diagnostic uncertainty, and disclosing the diagnosis. Quantitative studies yielded diverse results about knowledge, service support, time constraints, and confidence. The factors identified in qualitative and quantitative studies were grouped into 3 categories: patient factors, GP factors and system characteristics.</p> <p>Conclusion</p> <p>Much can still be done in the way of service development and provision, GP training and education, and the eradication of stigma attached to dementia, to improve the early detection and management of dementia. Implementation of dementia strategies should include attention to all three categories of barriers. Further research should focus on their interaction, using different methods from studies to date.</p

Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>The effects of gonadotrophin-releasing hormone agonist (GnRH-a) administered in the luteal phase remains controversial. This meta-analysis aimed to evaluate the effect of the administration of a single-dose of GnRH-a in the luteal phase on ICSI clinical outcomes.</p> <p>Methods</p> <p>The research strategy included the online search of databases. Only randomized studies were included. The outcomes analyzed were implantation rate, clinical pregnancy rate (CPR) per transfer and ongoing pregnancy rate. The fixed effects model was used for odds ratio. In all trials, a single dose of GnRH-a was administered at day 5/6 after ICSI procedures.</p> <p>Results</p> <p>All cycles presented statistically significantly higher rates of implantation (P < 0.0001), CPR per transfer (P = 0.006) and ongoing pregnancy (P = 0.02) in the group that received luteal-phase GnRH-a administration than in the control group (without luteal-phase-GnRH-a administration). When meta-analysis was carried out only in trials that had used long GnRH-a ovarian stimulation protocol, CPR per transfer (P = 0.06) and ongoing pregnancy (P = 0.23) rates were not significantly different between the groups, but implantation rate was significant higher (P = 0.02) in the group that received luteal-phase-GnRH-a administration. On the other hand, the results from trials that had used GnRH antagonist multi-dose ovarian stimulation protocol showed statistically significantly higher implantation (P = 0.0002), CPR per transfer (P = 0.04) and ongoing pregnancy rate (P = 0.04) in the luteal-phase-GnRH-a administration group. The majority of the results presented heterogeneity.</p> <p>Conclusions</p> <p>These findings demonstrate that the luteal-phase single-dose GnRH-a administration can increase implantation rate in all cycles and CPR per transfer and ongoing pregnancy rate in cycles with GnRH antagonist ovarian stimulation protocol. Nevertheless, by considering the heterogeneity between the trials, it seems premature to recommend the use of GnRH-a in the luteal phase. Additional randomized controlled trials are necessary before evidence-based recommendations can be provided.</p

The Complete Spectrum of Yeast Chromosome Instability Genes Identifies Candidate CIN Cancer Genes and Functional Roles for ASTRA Complex Components

Chromosome instability (CIN) is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ∼2,000 reduction-of-function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2) complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease