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The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells (1,2). Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the [Notch.sup.+][Apc.sup.+/1638N] mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and β-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure invivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of β-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by β-catenin nuclear translocation after 15 days. As a consequence, increased expression of β-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic β-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity., To test the tumorous impact of early tumour growth pressure on non-tumorous epithelial tissues in vivo, apart from the mechanical stiffness characteristic of the microenvironment of late tumours (1-6) (see [...]

The northern pike Esox lucius is a freshwater fish with low genetic diversity but ecological success throughout the Northern Hemisphere. Here, we generate an annotated chromosome-level genome assembly of 941 Mbp in length with 25 chromosome-length scaffolds. We then genotype 47 northern pike from Alaska through New Jersey at a genome-wide scale and characterize a striking decrease in genetic diversity along the sampling range. Individuals west of the North American Continental Divide have substantially higher diversity than those to the east (e.g. Interior Alaska and St. Lawrence River have on average 181 and 64K heterozygous SNPs per individual, or a heterozygous SNP every 5.2 and 14.6 kbp, respectively). Individuals clustered within each population with strong support, with numerous private alleles observed within each population. Evidence for recent population expansion was observed for a Manitoba hatchery and the St. Lawrence population (Tajima's D = −1.07 and −1.30, respectively). Several chromosomes have large regions with elevated diversity, including LG24, which holds amhby , the ancestral sex determining gene. As expected amhby was largely male-specific in Alaska and the Yukon and absent southeast to these populations, but we document some amhby (−) males in Alaska and amhby (+) males in the Columbia River, providing evidence for a patchwork of presence of this system in the western region. These results support the theory that northern pike recolonized North America from refugia in Alaska and expanded following deglaciation from west to east, with probable founder effects resulting in loss of both neutral and functional diversity (e.g. amhby). [ABSTRACT FROM AUTHOR]

Background: The recently launched DNA methylation profiling platform, Illumina MethylationEPIC BeadChip Infinium microarray v2.0 (EPICv2), is highly correlated with measurements obtained from its predecessor MethylationEPIC BeadChip Infinium microarray v1.0 (EPICv1). However, the concordance between the two versions in the context of DNA methylation-based tools, including cell type deconvolution algorithms, epigenetic clocks, and inflammation and lifestyle biomarkers has not yet been investigated. To address this, we profiled DNA methylation on both EPIC versions using matched venous blood samples from individuals spanning early to late adulthood across four cohorts., Findings: Within each cohort, samples primarily clustered by the EPIC version they were measured on. High concordance between EPIC versions at the array level, but variable concordance at the individual probe level was noted. Significant differences between versions in estimates from DNA methylation-based tools were observed, irrespective of the normalization method, with some nuanced differences across cohorts and tools. Adjusting for EPIC version or calculating estimates separately for each version largely mitigated these version-specific discordances., Conclusions: Our work illustrates the importance of accounting for EPIC version differences in research scenarios, especially in meta-analyses and longitudinal studies, when samples profiled across different versions are harmonized. Alongside DNA methylation-based tools, our observations also have implications in interpretation of epigenome-wide association studies (EWAS) findings, when results obtained from one version are compared to another, particularly for probes that are poorly concordant between versions., Competing Interests: Competing interests D.W.B. is listed as an inventor of the Duke University and University of Otago invention DunedinPACE, which is licensed to TruDiagnostic. The other authors declare that they have no competing interests.

Introduction: Mental health conditions are a major contributor to productivity loss and are common after injury. This study quantifies postinjury productivity loss and its association with preinjury and postinjury mental health, injury, demographic, health, social and other factors., Methods: Multicentre, longitudinal study recruiting hospitalised employed individuals aged 16-69 years with unintentional injuries, followed up at 1, 2, 4 and 12 months. Participants completed questionnaires on injury, demographic factors, health (including mental health), social factors, other factors and on-the-job productivity upon return to work (RTW). ORs were estimated for above median productivity loss using random effects logistic regression., Results: 217 adults had made an RTW at 2, 4 or 12 months after injury: 29% at 2 months, 66% at 4 months and 83% at 12 months. Productivity loss reduced over time: 3.3% of working time at 2 months, 1.7% at 4 months, 1% at 12 months. Significantly higher productivity loss was associated with preinjury psychiatric conditions (OR 21.40, 95% CI 3.50 to 130.78) and post-traumatic stress avoidance symptoms at 1 month (OR for 1-unit increase in score 1.15, 95% CI 1.07 to 1.22). Significantly lower productivity loss was associated with male gender (OR 0.32, 95% CI 0.14 to 0.74), upper and lower limb injuries (vs other body regions, OR 0.15, 95% CI 0.03 to 0.81) and sports injuries (vs home, OR 0.18, 95% CI 0.04 to 0.78). Preinjury psychiatric conditions and gender remained significant in analysis of multiply imputed data., Conclusions: Unintentional injury results in substantial productivity loss. Females, those with preinjury psychiatric conditions and those with post-traumatic stress avoidance symptoms experience greater productivity loss and may require additional support to enable successful RTW., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

beta-catenin acts as a critical regulator of gastrointestinal homeostasis through its control of the Wnt signaling pathway, and genetic or epigenetic lesions which activate Wnt signaling are the primary feature of colon cancer. beta-catenin is also a key element of mechanotranscription pathways, leading to upregulation of master developmental gene expression during Drosophila gastrulation, or regulating mammalian bone development and maintenance. Here we investigate the impact of mechanical stimulation on the initiation of colon cancer. Myc and Twist1, two oncogenes regulated through beta-catenin, are expressed in response to transient compression in APC deficient (APC(1638N+)) colon tissue explants, but not in wild-type colon explants. Mechanical stimulation of APC(1638N+) tissue leads to the phosphorylation of beta-catenin at tyrosine 654, the site of interaction with E-cadherin, as well as to increased nuclear localization of beta-catenin. The mechanical activation of Myc and Twist1 expression in APC(1638N+) colon can be prevented by blocking beta-catenin phosphorylation using Src kinase inhibitors. Microenvironmental signals are known to cooperate with genetic lesions to promote the nuclear beta-catenin accumulation which drives colon cancer. Here we demonstrate that when APC is limiting, mechanical strain, such as that associated with intestinal transit or tumor growth, can be interpreted by cells of preneoplastic colon tissue as a signal to initiate a beta-catenin dependent transcriptional program characteristic of cancer.