The two most common histological subtypes of malignant germ cell tumour are distinguished by global microRNA profiles, associated with differential transcription factor expression.

BACKGROUND: We hypothesised that differences in microRNA expression profiles contribute to the contrasting natural history and clinical outcome of the two most common types of malignant germ cell tumour (GCT), yolk sac tumours (YSTs) and germinomas. RESULTS: By direct comparison, using microarray data for paediatric GCT samples and published qRT-PCR data for adult samples, we identified microRNAs significantly up-regulated in YSTs (n = 29 paediatric, 26 adult, 11 overlapping) or germinomas (n = 37 paediatric). By Taqman qRT-PCR we confirmed differential expression of 15 of 16 selected microRNAs and further validated six of these (miR-302b, miR-375, miR-200b, miR-200c, miR-122, miR-205) in an independent sample set. Interestingly, the miR-302 cluster, which is over-expressed in all malignant GCTs, showed further over-expression in YSTs versus germinomas, representing six of the top eight microRNAs over-expressed in paediatric YSTs and seven of the top 11 in adult YSTs. To explain this observation, we used mRNA expression profiles of paediatric and adult malignant GCTs to identify 10 transcription factors (TFs) consistently over-expressed in YSTs versus germinomas, followed by linear regression to confirm associations between TF and miR-302 cluster expression levels. Using the sequence motif analysis environment iMotifs, we identified predicted binding sites for four of the 10 TFs (GATA6, GATA3, TCF7L2 and MAF) in the miR-302 cluster promoter region. Finally, we showed that miR-302 family over-expression in YST is likely to be functionally significant, as mRNAs down-regulated in YSTs were enriched for 3' untranslated region sequences complementary to the common seed of miR-302a~miR-302d. Such mRNAs included mediators of key cancer-associated processes, including tumour suppressor genes, apoptosis regulators and TFs. CONCLUSIONS: Differential microRNA expression is likely to contribute to the relatively aggressive behaviour of YSTs and may enable future improvements in clinical diagnosis and/or treatment.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Evaluating the reactivation of herpesviruses and inflammation as cardiovascular and cerebrovascular risk factors in antiretroviral therapy initiators in an African HIV-infected population (RHICCA): a protocol for a longitudinal cohort study.

INTRODUCTION In Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive risk and may not completely suppress the risk associated with HIV infection. High-quality prospective studies are needed to determine if HIV-infected patients in Africa are at increased risk of CBD/CVD and to identify factors associated with this risk. This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent herpesvirus infections, lead to increased CBD/CVD risk in Malawian adults aged ≥35 years. METHODS AND ANALYSIS We will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected controls in Blantyre, Malawi. Patients and controls will be recruited from government ART clinics and the community, respectively, and will be frequency-matched by 5-year age band and sex. At baseline and follow-up visits, we will measure carotid intima-media thickness and pulse wave velocity as surrogate markers of vasculopathy, and will be used to estimate CBD/CVD risk. Our primary exposures of interest are cytomegalovirus and varicella zoster reactivation, changes in HIV plasma viral load, and markers of systemic inflammation and endothelial function. Multivariable regression models will be developed to assess the study's primary hypothesis. The occurrence of clinical CBD/CVD will be assessed as secondary study endpoints. ETHICS AND DISSEMINATION The University of Malawi College of Medicine and Liverpool School of Tropical Medicine research ethics committees approved this work. Our goal is to understand the pathogenesis of CBD/CVD among HIV cohorts on ART, in Sub-Saharan Africa, and provide data to inform future interventional clinical trials. This study runs between May 2017 and August 2020. Results of the main trial will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER ISRCTN42862937

A trade-off between plant and soil carbon storage under elevated CO2

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this record.Data availability: All the empirical data that support the main findings of this study have been deposited in Figshare: (https://figshare.com/account/home#/projects/74721) and GitHub (https://github.com/cesarterrer/SoilC_CO2). FACE-MDS data can be accessed at https://www.osti.gov/dataexplorer/biblio/dataset/1480327. CMIP5 data can be accessed at https://esgf-index1.ceda.ac.uk/search/cmip5-ceda/. TRENDY data can be requested at http://dgvm.ceh.ac.uk/index.html.Code availability: The R code used in the analysis presented in this paper is available in GitHub and can be accessed at https://github.com/cesarterrer/SoilC_CO2Terrestrial ecosystems remove about 30% of the CO2 emitted by human activities each year, yet the persistence of this carbon sink partly depends on how plant biomass and soil carbon stocks respond to future increases in atmospheric CO2. While plant biomass often increases in elevated CO2 (eCO2) experiments, soil carbon has been observed to increase, remain unchanged, or even decline. The mechanisms driving this variation across experiments remain poorly understood, creating uncertainty in climate projections. Here, we synthesized data from 108 eCO2 experiments and found that the effect of eCO2 on soil carbon stocks is best explained by a negative relationship with plant biomass: when plant biomass is strongly stimulated by eCO2, soil carbon accrual declines; conversely, when biomass is weakly stimulated, soil carbon accumulates. This trade-off appears related to plant nutrient acquisition, whereby enhanced biomass requires mining the soil for nutrients, which decreases soil carbon accrual. We found an increase in soil carbon stocks with eCO2 in grasslands (8±2%) and no increase in forests (0±2%), even though plant biomass in grassland responded less strongly (9±3%) than in forest (23±2%). Ecosystem models do not reproduce this trade-off, which implies that projections of soil carbon may need to be revised.Lawrence Livermore National Laboratory (LLNL).U.S. Department of Energy, Terrestrial Ecosystem Science ProgramNAS

Cost Analysis of Various Low Pathogenic Avian Influenza Surveillance Systems in the Dutch Egg Layer Sector

Background: As low pathogenic avian influenza viruses can mutate into high pathogenic viruses the Dutch poultry sector implemented a surveillance system for low pathogenic avian influenza (LPAI) based on blood samples. It has been suggested that egg yolk samples could be sampled instead of blood samples to survey egg layer farms. To support future decision making about AI surveillance economic criteria are important. Therefore a cost analysis is performed on systems that use either blood or eggs as sampled material. Methodology/Principal Findings: The effectiveness of surveillance using egg or blood samples was evaluated using scenario tree models. Then an economic model was developed that calculates the total costs for eight surveillance systems that have equal effectiveness. The model considers costs for sampling, sample preparation, sample transport, testing, communication of test results and for the confirmation test on false positive results. The surveillance systems varied in sampled material (eggs or blood), sampling location (farm or packing station) and location of sample preparation (laboratory or packing station). It is shown that a hypothetical system in which eggs are sampled at the packing station and samples prepared in a laboratory had the lowest total costs (i.e. J 273,393) a year. Compared to this a hypothetical system in which eggs are sampled at the farm and samples prepared at a laboratory, and the currently implemented system in which blood is sampled at the farm and samples prepared at a laboratory have 6 % and 39 % higher costs respectively

Differential Methylation of the HPV 16 Upstream Regulatory Region during Epithelial Differentiation and Neoplastic Transformation

High risk human papillomaviruses are squamous epitheliotropic viruses that may cause cervical and other cancers. HPV replication depends on squamous epithelial differentiation. Transformation of HPV-infected cells goes along with substantial alteration of the viral gene expression profile and preferentially occurs at transformation zones usually at the uterine cervix. Methylation of the viral genome may affect regulatory features that control transcription and replication of the viral genome. Therefore, we analyzed the methylation pattern of the HPV16 upstream regulatory region (URR) during squamous epithelial differentiation and neoplastic transformation and analyzed how shifts in the HPV URR methylome may affect viral gene expression and replication. HPV 16 positive biopsy sections encompassing all stages of an HPV infection (latent, permissive and transforming) were micro-dissected and DNA was isolated from cell fractions representing the basal, intermediate, and superficial cell layers, each, as well as from transformed p16INK4a-positive cells. We observed fundamental changes in the methylation profile of transcription factor binding sites in the HPV16 upstream regulatory region linked to the squamous epithelial differentiation stage. Squamous epithelial transformation indicated by p16INK4a overexpression was associated with methylation of the distal E2 binding site 1 leading to hyper-activation of the HPV 16 URR. Adjacent normal but HPV 16-infected epithelial areas retained hyper-methylated HPV DNA suggesting that these viral genomes were inactivated. These data suggest that distinct shifts of the HPV 16 methylome are linked to differentiation dependent transcription and replication control and may trigger neoplastic transformation

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Interaction between CRHR1 and BDNF Genes Increases the Risk of Recurrent Major Depressive Disorder in Chinese Population

BACKGROUND: An important etiological hypothesis about depression is stress has neurotoxic effects that damage the hippocampal cells. Corticotropin-releasing hormone (CRH) regulates brain-derived neurotrophic factor (BDNF) expression through influencing cAMP and Ca2+ signaling pathways during the course. The aim of this study is to examine the single and combined effects of CRH receptor 1 (CRHR1) and BDNF genes in recurrent major depressive disorder (MDD). METHODOLOGY/PRINCIPAL FINDING: The sample consists of 181 patients with recurrent MDD and 186 healthy controls. Whether genetic variations interaction between CRHR1 and BDNF genes might be associated with increased susceptibility to recurrent MDD was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). CRHR1 gene (rs1876828, rs242939 and rs242941) and BDNF gene (rs6265) were identified in the samples of patients diagnosed with recurrent MDD and matched controls. Allelic association between CRHR1 rs242939 and recurrent MDD was found in our sample (allelic: p = 0.018, genotypic: p = 0.022) with an Odds Ratio 0.454 (95% CI 0.266-0.775). A global test of these four haplotypes showed a significant difference between recurrent MDD group and control group (chi-2 = 13.117, df = 3, P = 0.016. Furthermore, BDNF and CRHR1 interactions were found in the significant 2-locus, gene-gene interaction models (p = 0.05) using a generalized multifactor dimensionality reduction (GMDR) method. CONCLUSION: Our results suggest that an interaction between CRHR1 and BDNF genes constitutes susceptibility to recurrent MDD