Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells

Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer

Modality-Independent Effects of Phonological Neighborhood Structure on Initial L2 Sign Language Learning

The goal of the present study was to characterize how neighborhood structure in sign language influences lexical sign acquisition in order to extend our understanding of how the lexicon influences lexical acquisition in both sign and spoken languages. A referent-matching lexical sign learning paradigm was administered to a group of 29 hearing sign language learners in order to create a sign lexicon. The lexicon was constructed based on exposures to signs that resided in either sparse or dense handshape and location neighborhoods. The results of the current study indicated that during the creation of the lexicon signs that resided in sparse neighborhoods were learned better than signs that resided in dense neighborhoods. This pattern of results is similar to what is seen in child first language acquisition of spoken language. Therefore, despite differences in child first language and adult second language acquisition, these results contribute to a growing body of literature that implicates the phonological features that structure of the lexicon is influential in initial stages of lexical acquisition for both spoken and sign languages. This is the first study that uses an innovated lexicon-construction methodology to explore interactions between phonology and the lexicon in L2 acquisition of sign language

Agroecosystem energy transitions in the old and new worlds: trajectories and determinants at the regional scale

Energy efficiency in biomass production is a major challenge for a future transition to sustainable food and energy provision. This study uses methodologically consistent data on agroecosystem energy flows and different metrics of energetic efficiency from seven regional case studies in North America (USA and Canada) and Europe (Spain and Austria) to investigate energy transitions in Western agroecosystems from the late nineteenth to the late twentieth centuries. We quantify indicators such as external final energy return on investment (EFEROI, i.e., final produce per unit of external energy input), internal final EROI (IFEROI, final produce per unit of biomass reused locally), and final EROI (FEROI, final produce per unit of total inputs consumed). The transition is characterized by increasing final produce accompanied by increasing external energy inputs and stable local biomass reused. External inputs did not replace internal biomass reinvestments, but added to them. The results were declining EFEROI, stable or increasing IFEROI, and diverging trends in FEROI. The factors shaping agroecosystem energy profiles changed in the course of the transition: Under advanced organic and frontier agriculture of the late nineteenth and early twentieth centuries, population density and biogeographic conditions explained both agroecosystem productivity and energy inputs. In industrialized agroecosystems, biogeographic conditions and specific socio-economic factors influenced trends towards increased agroecosystem specialization. The share of livestock products in a region's final produce was the most important factor determining energy returns on investment

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

RUNX1 is a driver of renal cell carcinoma correlating with clinical outcome

The recurring association of specific genetic lesions with particular types of cancer is a fascinating, and largely unexplained area of cancer biology. This is particularly true of clear cell renal cell carcinoma (ccRCC) where although key mutations such as loss of VHL is an almost ubiquitous finding, there remains a conspicuous lack of targetable genetic drivers. In this study, we have identified a previously unknown pro-tumorigenic role for the RUNX genes in this disease setting. Analysis of patient tumor biopsies together with loss of function studies in preclinical models established the importance of RUNX1 and RUNX2 in ccRCC. Patients with high RUNX1 (and RUNX2) expression exhibited significantly poorer clinical survival compared to patients with low expression. This was functionally relevant as deletion of RUNX1 in ccRCC cell lines reduced tumor cell growth and viability in vitro and in vivo. Transcriptional profiling of RUNX1-CRISPR-deleted cells revealed a gene signature dominated by extracellular matrix remodelling, notably affecting STMN3, SERPINH1, and EPHRIN signaling. Finally, RUNX1 deletion in a genetic mouse model of kidney cancer improved overall survival and reduced tumor cell proliferation. In summary, these data attest to the validity of targeting a RUNX1-transcriptional program in ccRCC. [Abstract copyright: Copyright ©2020, American Association for Cancer Research.

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18