Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis.

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells

MOESM1 of Absence makes the heart grow fonder: social compensation when failure to interact risks weakening a relationship

Supplementary material. (pdf

DNA methylation and general psychopathology in childhood: An epigenome-wide meta-analysis from the PACE consortium

This is the author accepted manuscriptData availability: Site-level meta-analytical results will be made publicly available upon acceptance for publication. For access to cohort-level data, requests can be sent directly to individual studies. Code availability: Analytical codes can be requested from authors.The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N=2,178 and N=2,190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p=8.58×10–8). We also identified a significant differentially methylated region (DMR) at school-age (p=1.63×10–8), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GP

Monte Carlo-based modeling of secondary particle tracks generated by intermediate- and low-energy protons in water

This chapter gives an overview of recent developments in the Monte Carlo-based modeling of the interaction of ionizing radiation with biologically relevant systems. Several track structure codes, such as Geant4 (GEometry ANd Tracking 4), Geant4-DNA, and LEPTS (Low-Energy Particle Track Simulation), are described. Main features, areas of application and current limitations of each tool are discussed. A special attention is focused on the energy range covered by primary and secondary charged particles and on the type of interactions included in the simulation. A recent development of LEPTS is presented, aimed at the simulation of full slowing-down of protons in water together with all molecular processes involving secondary particles. The utilized approach allows one to study radiation effects on the nanoscale in terms of the number and the type of induced molecular processes