99 research outputs found

    Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context

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    Minichromosome maintenance proteins (Mcm2-7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3'UTR of the Mcm2 gene (designated Mcm2Cre ) have decreased Mcm2 expression and invariably develop precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL), due to 100-1000‚ÄČkb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre-T LBL would develop non-T-cell malignancies, we used two approaches. Mice engrafted with Mcm2Cre/Cre Lin- Sca-1+ Kit+ hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6‚ÄČmonths of age. Placing the Mcm2Cre allele onto an athymic nu/nu background completely prevented pre-T LBL and extended survival of these mice three-fold (median 296.5 vs. 80.5‚ÄČdays). Ultimately, most Mcm2Cre/Cre ;nu/nu mice developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We identified recurrent deletions of 100-1000‚ÄČkb that involved genes known or suspected to be involved in BCP-ALL, including Pax5, Nf1, Ikzf3, and Bcor. Moreover, whole-exome sequencing identified recurrent mutations of genes known to be involved in BCP-ALL progression, such as Jak1/Jak3, Ptpn11, and Kras. These findings demonstrate that an Mcm2Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a "deletor" phenotype affecting known or suspected tumor suppressor genes

    Hearing impairment and cognitive energy: The Framework for Understanding Effortful Listening (FUEL)

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    The Fifth Eriksholm Workshop on ‚ÄúHearing Impairment and Cognitive Energy‚ÄĚ was convened to develop a consensus amongst interdisciplinary experts about what is known on the topic, gaps in knowledge, the use of terminology, priorities for future research and implications for practice. The general term cognitive energy was chosen to facilitate the broadest possible discussion of the topic. It goes back to Titchener (1908) who described the effects of attention on perception; he used the term psychic energy for the notion that limited mental resources can be flexibly allocated among perceptual and mental activities. The workshop focused on three main areas: 1) theories, models, concepts, definitions, and frameworks; 2) methods and measures; and 3) knowledge translation. We defined effort as the deliberate allocation of mental resources to overcome obstacles in goal pursuit when carrying out a task, with listening effort applying more specifically when tasks involve listening. We adapted Kahneman‚Äôs seminal (1973) Capacity Model of Attention to listening and proposed a heuristically useful Framework for Understanding Effortful Listening (FUEL). Our FUEL incorporates the well-known relationship between cognitive demand and the supply of cognitive capacity that is the foundation of cognitive theories of attention. Our FUEL also incorporates a motivation dimension based on complementary theories of motivational intensity, adaptive gain control and optimal performance, fatigue, and pleasure. Using a 3D illustration, we highlight how listening effort depends not only on hearing difficulties and task demands, but also on the listener‚Äôs motivation to expend mental effort in the challenging situations of everyday life

    Search for dark matter produced in association with bottom or top quarks in ‚ąös = 13 TeV pp collisions with the ATLAS detector

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    A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb‚ąí1 of proton‚Äďproton collision data recorded by the ATLAS experiment at ‚ąös = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

    Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study