Compendium of TCDD-mediated transcriptomic response datasets in mammalian model systems

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent congener of the dioxin class of environmental contaminants. Exposure to TCDD causes a wide range of toxic outcomes, ranging from chloracne to acute lethality. The severity of toxicity is highly dependent on the aryl hydrocarbon receptor (AHR). Binding of TCDD to the AHR leads to changes in transcription of numerous genes. Studies evaluating the transcriptional changes brought on by TCDD may provide valuable insight into the role of the AHR in human health and disease. We therefore compiled a collection of transcriptomic datasets that can be used to aid the scientific community in better understanding the transcriptional effects of ligand-activated AHR.Peer reviewe

Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6

Functional blood vessel growth depends on generation of distinct but coordinated responses from endothelial cells. Bone morphogenetic proteins (BMP), part of the TGFβ superfamily, bind receptors to induce phosphorylation and nuclear translocation of SMAD transcription factors (R-SMAD1/5/8) and regulate vessel growth. However, SMAD1/5/8 signalling results in both pro- and anti-angiogenic outputs, highlighting a poor understanding of the complexities of BMP signalling in the vasculature. Here we show that BMP6 and BMP2 ligands are pro-angiogenic in vitro and in vivo, and that lateral vessel branching requires threshold levels of R-SMAD phosphorylation. Endothelial cell responsiveness to these pro-angiogenic BMP ligands is regulated by Notch status and Notch sets responsiveness by regulating a cell-intrinsic BMP inhibitor, SMAD6, which affects BMP responses upstream of target gene expression. Thus, we reveal a paradigm for Notch-dependent regulation of angiogenesis: Notch regulates SMAD6 expression to affect BMP responsiveness of endothelial cells and new vessel branch formation

Mouth Rinsing With Carbohydrate Solutions at the Postprandial State Fail to Improve Performance During Simulated Cycling Time Trials.

Mouth-rinsing with carbohydrate solutions during cycling time trials results in performance enhancements, however the majority of studies have utilised ∼6% carbohydrate solutions. Therefore, the purpose of this study was to compare the effectiveness of mouth-rinsing with 4%, 6%, and 8% carbohydrate (CHO) solutions on 1-h simulated cycling time trial performance. On four occasions, seven trained male cyclists completed at the postprandial period, a set amount of work as fast as possible in a randomised, counterbalanced order. The subjects mouth rinsed for 5-s, upon completion of each 12.5% of the trial, with 25 mL of a non-CHO placebo, 4%, 6%, and 8% CHO solutions. No additional fluids were consumed during the time trial. Heart rate (HR), ratings of perceived exertion (RPE), thirst (TH) and subjective feelings (SF) were recorded after each rinse. Further, blood samples were drawn every 25% of the trial to measure blood glucose (BG) and blood lactate (BG) concentrations, whilst whole body carbohydrate oxidation was monitored continuously. Time to completion was not significant between conditions with the placebo, 4%, 6%, and 8% conditions completing the trials in 62.0 ± 3.0, 62.8 ± 4.0, 63.4 ± 3.4, and 63 ±4.0 minutes respectively. There were no significant differences between conditions in any of the variables mentioned above however significant time effects were observed for HR, RPE, TH, and SF. Post-hoc analysis showed that TH and SF of subjects in the CHO conditions but not in the placebo were significantly increased by completion of the time trial. In conclusion, mouth-rinsing with CHO solutions did not impact 1-h cycling performance in the postprandial period and in the absence of fluid intake. Our findings suggest that there is scope for further research to explore the activation regions of the brain and whether they are receptive to CHO dose, before specific recommendations for athletic populations are established. Consequently mouth-rinsing as a practical strategy for coaches and athletes is questionable under specific conditions and should be carefully considered before its inclusion. The emphasis should be focused on appropriate dietary and fluid strategies during training and competition

Cross-species transcriptomic analysis elucidates constitutive aryl hydrocarbon receptor activity

Peer reviewe

Single cell transcriptome analysis reveals disease-defining T cell subsets in the tumor microenvironment of classic Hodgkin lymphoma

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. SIGNIFICANCE: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints

sFDvent: A global trait database for deep‐sea hydrothermal‐vent fauna

Motivation: Traits are increasingly being used to quantify global biodiversity patterns, with trait databases growing in size and number, across diverse taxa. Despite grow‐ ing interest in a trait‐based approach to the biodiversity of the deep sea, where the impacts of human activities (including seabed mining) accelerate, there is no single re‐ pository for species traits for deep‐sea chemosynthesis‐based ecosystems, including hydrothermal vents. Using an international, collaborative approach, we have compiled the first global‐scale trait database for deep‐sea hydrothermal‐vent fauna – sFD‐ vent (sDiv‐funded trait database for the Functional Diversity of vents). We formed a funded working group to select traits appropriate to: (a) capture the performance of vent species and their influence on ecosystem processes, and (b) compare trait‐based diversity in different ecosystems. Forty contributors, representing expertise across most known hydrothermal‐vent systems and taxa, scored species traits using online collaborative tools and shared workspaces. Here, we characterise the sFDvent da‐ tabase, describe our approach, and evaluate its scope. Finally, we compare the sFD‐ vent database to similar databases from shallow‐marine and terrestrial ecosystems to highlight how the sFDvent database can inform cross‐ecosystem comparisons. We also make the sFDvent database publicly available online by assigning a persistent, unique DOI. Main types of variable contained: Six hundred and forty‐six vent species names, associated location information (33 regions), and scores for 13 traits (in categories: community structure, generalist/specialist, geographic distribution, habitat use, life history, mobility, species associations, symbiont, and trophic structure). Contributor IDs, certainty scores, and references are also provided. Spatial location and grain: Global coverage (grain size: ocean basin), spanning eight ocean basins, including vents on 12 mid‐ocean ridges and 6 back‐arc spreading centres. Time period and grain: sFDvent includes information on deep‐sea vent species, and associated taxonomic updates, since they were first discovered in 1977. Time is not recorded. The database will be updated every 5 years. Major taxa and level of measurement: Deep‐sea hydrothermal‐vent fauna with spe‐ cies‐level identification present or in progress. Software format: .csv and MS Excel (.xlsx).This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders