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

Control and Characterization of Individual Grains and Grain Boundaries in Graphene Grown by Chemical Vapor Deposition

The strong interest in graphene has motivated the scalable production of high quality graphene and graphene devices. Since large-scale graphene films synthesized to date are typically polycrystalline, it is important to characterize and control grain boundaries, generally believed to degrade graphene quality. Here we study single-crystal graphene grains synthesized by ambient CVD on polycrystalline Cu, and show how individual boundaries between coalescing grains affect graphene's electronic properties. The graphene grains show no definite epitaxial relationship with the Cu substrate, and can cross Cu grain boundaries. The edges of these grains are found to be predominantly parallel to zigzag directions. We show that grain boundaries give a significant Raman "D" peak, impede electrical transport, and induce prominent weak localization indicative of intervalley scattering in graphene. Finally, we demonstrate an approach using pre-patterned growth seeds to control graphene nucleation, opening a route towards scalable fabrication of single-crystal graphene devices without grain boundaries.Comment: New version with additional data. Accepted by Nature Material

Production of phi mesons at mid-rapidity in sqrt(s_NN) = 200 GeV Au+Au collisions at RHIC

We present the first results of meson production in the K^+K^- decay channel from Au+Au collisions at sqrt(s_NN) = 200 GeV as measured at mid-rapidity by the PHENIX detector at RHIC. Precision resonance centroid and width values are extracted as a function of collision centrality. No significant variation from the PDG accepted values is observed. The transverse mass spectra are fitted with a linear exponential function for which the derived inverse slope parameter is seen to be constant as a function of centrality. These data are also fitted by a hydrodynamic model with the result that the freeze-out temperature and the expansion velocity values are consistent with the values previously derived from fitting single hadron inclusive data. As a function of transverse momentum the collisions scaled peripheral.to.central yield ratio RCP for the is comparable to that of pions rather than that of protons. This result lends support to theoretical models which distinguish between baryons and mesons instead of particle mass for explaining the anomalous proton yield.Comment: 326 authors, 24 pages text, 23 figures, 6 tables, RevTeX 4. To be submitted to Physical Review C as a regular article. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Activating Transcription Factor 4 Confers a Multidrug Resistance Phenotype to Gastric Cancer Cells through Transactivation of SIRT1 Expression

BACKGROUND: Multidrug resistance (MDR) in gastric cancer remains a major challenge to clinical treatment. Activating transcription factor 4 (ATF4) is a stress response gene involved in homeostasis and cellular protection. However, the expression and function of ATF4 in gastric cancer MDR remains unknown. In this study, we investigate whether ATF4 play a role in gastric cancer MDR and its potential mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that ATF4 overexpression confered the MDR phenotype to gastric cancer cells, while knockdown of ATF4 in the MDR variants induced re-sensitization. In this study we also showed that the NAD(+)-dependent histone deacetylase SIRT1 was required for ATF4-induced MDR effect in gastric cancer cells. We demonstrated that ATF4 facilitated MDR in gastric cancer cells through direct binding to the SIRT1 promoter, resulting in SIRT1 up-regulation. Significantly, inhibition of SIRT1 by small interfering RNA (siRNA) or a specific inhibitor (EX-527) reintroduced therapeutic sensitivity. Also, an increased Bcl-2/Bax ratio and MDR1 expression level were found in ATF4-overexpressing cells. CONCLUSIONS/SIGNIFICANCE: We showed that ATF4 had a key role in the regulation of MDR in gastric cancer cells in response to chemotherapy and these findings suggest that targeting ATF4 could relieve therapeutic resistance in gastric cancer

A Nationwide Population-Based Cohort Study: Will Anxiety Disorders Increase Subsequent Cancer Risk?

BACKGROUND: The aim of this study was to evaluate a possible association between malignancy and anxiety disorders (AD) in Taiwan. METHODS: We employed data from the National Health Insurance system of Taiwan. The AD cohort contained 24,066 patients with each patient randomly frequency matched according to age and sex with 4 individuals from the general population without AD. Cox's proportional hazard regression analysis was conducted to estimate the influence of AD on the risk of cancer. RESULTS: Among patients with AD, the overall risk of developing cancer was only 1% higher than among subjects without AD, and the difference was not significant (hazard ratio [HR] = 1.01, 95% confidence interval [95% CI] = 0.95-1.07). With regard to individual types of cancer, the risk of developing prostate cancer among male patients with AD was significantly higher (HR = 1.32, 95% CI = 1.02-1.71). On the other hand, the risk of cervical cancer among female patients with AD was marginally significantly lower than among female subjects without AD (HR = 0.72, 95% CI = 0.51-1.03). LIMITATIONS: One major limitation is the lack of information regarding the life style or behavior of patients in the NHI database, such as smoking and alcohol consumption. CONCLUSIONS: Despite the failure to identify a relationship between AD and the overall risk of cancer, we found that Taiwanese patients with AD had a higher risk of developing prostate cancer and a lower risk of developing cervical cancer

Effects of cereal breakfasts on postprandial glucose, appetite regulation and voluntary energy intake at a subsequent standardized lunch; focusing on rye products

<p>Abstract</p> <p>Background</p> <p>Rye products have been demonstrated to lower the acute insulin demand, induce a low and prolonged blood glucose response (high Glycemic Profile, GP) and reduce subclinical inflammation. These products may therefore contribute to a lowered risk of obesity, type 2 diabetes and cardio vascular disease. The objective of the present paper was to evaluate the mechanism for a reduced postprandial insulin demand with rye products, and to explore possible appetite regulating properties.</p> <p>Methods</p> <p>10 healthy subjects were served breakfast meals (50 g of available starch) with endosperm- or whole grain rye breads, with and without lactic acid, boiled whole grain rye- (RK) or wheat (WK) kernels, or white wheat bread reference (WWB) in random order in a cross-over design. Plasma concentrations of glucose, ghrelin, serum insulin, free fatty acids, adiponectin, breath hydrogen excretion (H₂), and subjective satiety was evaluated during the postprandial phase. 270 min after the breakfast, an ad lib lunch buffet was served and the voluntary energy intake (EI) was registered.</p> <p>Results</p> <p>All rye products and WK induced lower insulinemic indices (II) than WWB. A lower incremental insulin peak following breakfast correlated with a lower EI at lunch (r = 0.38). A low II was related to improved satiety in the early postprandial phase (fullness AUC 0-60 min, r = -0.36). RK induced a higher GP compared to WWB and WK. A higher GP was related to a lowered <it>desire to eat </it>before lunch (AUC 210-270) and to a lower concentration of ghrelin in the late postprandial phase after breakfast (270 min), r = -0.29 and -0.29), which in turn was related to a lower voluntary EI (r = 0.43 and 0.33). The RK breakfast improved satiety in the early postprandial phase (0-60 min) compared to WWB, and induced a lower EI at lunch (-16%). A high content of indigestible carbohydrates in the breakfast products was related to improved satiety (0-60 min, r = 0.68 for fullness), and a higher breath H₂in the late postprandial phase (120-270 and 270-390 min, r = 0.46 and 0.70). High H₂(AUC 120-270 min) also correlated with lower EI (r = -0.34).</p> <p>Conclusions</p> <p>Rye products, rich in indigestible carbohydrates, induce colonic fermentation already post the breakfast meal, and lowers acute insulin responses. A high excretion of breath H2 also correlated with a higher GP. Especially, rye kernels induced a high GP which was associated with a 16% lowering of energy intake at a subsequent lunch meal. The bulking effect of rye fiber, colonically derived fermentation metabolites, a high GP and a low insulin response possibly all contributes to the benefits on glucose- and appetite regulation seen in an acute and semi-acute perspective.</p

Quality of Reporting and Study Design of CKD Cohort Studies Assessing Mortality in the Elderly Before and After STROBE:A Systematic Review

BACKGROUND:The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement was published in October 2007 to improve quality of reporting of observational studies. The aim of this review was to assess the impact of the STROBE statement on observational study reporting and study design quality in the nephrology literature. STUDY DESIGN:Systematic literature review. SETTING & POPULATION:European and North American, Pre-dialysis Chronic Kidney Disease (CKD) cohort studies. SELECTION CRITERIA FOR STUDIES:Studies assessing the association between CKD and mortality in the elderly (>65 years) published from 1st January 2002 to 31st December 2013 were included, following systematic searching of MEDLINE & EMBASE. PREDICTOR:Time period before and after the publication of the STROBE statement. OUTCOME:Quality of study reporting using the STROBE statement and quality of study design using the Newcastle Ottawa Scale (NOS), Scottish Intercollegiate Guidelines Network (SIGN) and Critical Appraisal Skills Programme (CASP) tools. RESULTS:37 papers (11 Pre & 26 Post STROBE) were identified from 3621 potential articles. Only four of the 22 STROBE items and their sub-criteria (objectives reporting, choice of quantitative groups and description of and carrying out sensitivity analysis) showed improvements, with the majority of items showing little change between the period before and after publication of the STROBE statement. Pre- and post-period analysis revealed a Manuscript STROBE score increase (median score 77.8% (Inter-quartile range [IQR], 64.7-82.0) vs 83% (IQR, 78.4-84.9, p = 0.05). There was no change in quality of study design with identical median scores in the two periods for NOS (Manuscript NOS score 88.9), SIGN (Manuscript SIGN score 83.3) and CASP (Manuscript CASP score 91.7) tools. LIMITATIONS:Only 37 Studies from Europe and North America were included from one medical specialty. Assessment of study design largely reliant on good reporting. CONCLUSIONS:This study highlights continuing deficiencies in the reporting of STROBE items and their sub-criteria in cohort studies in nephrology. There was weak evidence of improvement in the overall reporting quality, with no improvement in methodological quality of CKD cohort studies between the period before and after publication of the STROBE statement

Epilepsy and Psychiatric Comorbidities: Drug Selection.

Purpose of review The pharmacological treatment of patients with epilepsy and psychiatric comorbidities may sometimes represent a therapeutic challenge. This review is focused on the pharmacological management of patients with epilepsy and psychiatric problems in terms of rationalization of the antiepileptic drug (AED) treatment and the pharmacological management of the most clinically relevant psychiatric comorbidities, namely mood and anxiety disorders, psychoses, and attention deficit hyperactivity disorder (ADHD). Recent findings Up to 8% of patients with drug-resistant epilepsy develop treatment-emergent psychiatric adverse events of AED regardless of the mechanism of action of the drug and this is usually related to an underlying predisposition given by the previous psychiatric history and the involvement of mesolimbic structures. Careful history taking, periodic screening for mood and anxiety disorders, low starting doses, and slow titration schedules can reduce the possibility of AED-related problems. A pragmatic checklist for the pharmacological management of patients with epilepsy and psychiatric disorders is presented. Summary patients should be informed of potential behavioral effects of AEDs but no drugs should be excluded a priori. Any psychiatric comorbidity should be addressed in the appropriate setting and full remission and recovery should always represent the first goal of any therapeutic intervention. Neurologists should be aware of the side effects of major psychotropic drug classes in order to fully counsel their patients and other health professionals involved

corona Is Required for Higher-Order Assembly of Transverse Filaments into Full-Length Synaptonemal Complex in Drosophila Oocytes

The synaptonemal complex (SC) is an intricate structure that forms between homologous chromosomes early during the meiotic prophase, where it mediates homolog pairing interactions and promotes the formation of genetic exchanges. In Drosophila melanogaster, C(3)G protein forms the transverse filaments (TFs) of the SC. The N termini of C(3)G homodimers localize to the Central Element (CE) of the SC, while the C-termini of C(3)G connect the TFs to the chromosomes via associations with the axial elements/lateral elements (AEs/LEs) of the SC. Here, we show that the Drosophila protein Corona (CONA) co-localizes with C(3)G in a mutually dependent fashion and is required for the polymerization of C(3)G into mature thread-like structures, in the context both of paired homologous chromosomes and of C(3)G polycomplexes that lack AEs/LEs. Although AEs assemble in cona oocytes, they exhibit defects that are characteristic of c(3)G mutant oocytes, including failure of AE alignment and synapsis. These results demonstrate that CONA, which does not contain a coiled coil domain, is required for the stable ‘zippering’ of TFs to form the central region of the Drosophila SC. We speculate that CONA's role in SC formation may be similar to that of the mammalian CE proteins SYCE2 and TEX12. However, the observation that AE alignment and pairing occurs in Tex12 and Syce2 mutant meiocytes but not in cona oocytes suggests that the SC plays a more critical role in the stable association of homologs in Drosophila than it does in mammalian cells