Aneuploidy triggers a TFEB-mediated lysosomal stress response

Aneuploidy, defined as an alteration in chromosome number that is not a multiple of the haploid complement, severely affects cellular physiology. Changes in chromosome number lead to imbalances in cellular protein composition, thus disrupting cellular processes and causing proteins to misfold and aggregate. We recently reported that in mammalian cells protein aggregates are readily encapsulated within autophagosomes but are not degraded by lysosomes. This leads to a lysosomal stress response in which the transcription factor TFEB induces expression of factors needed for macroautophagy-mediated protein degradation. Our studies uncover lysosomal degradation defects as a feature of the aneuploid state, and a role for the transcription factor TFEB in the response thereto. Keywords: aneuploidy; autophagy; cancer; proteotoxicity; TFE

Gamete Formation Resets the Aging Clock in Yeast

Gametogenesis is a process whereby a germ cell differentiates into haploid gametes. We found that, in budding yeast, replicatively aged cells remove age-induced cellular damage during gametogenesis. Importantly, gametes of aged cells have the same replicative potential as those derived from young cells, indicating that life span resets during gametogenesis. Here, we explore the potential mechanisms responsible for gametogenesis-induced rejuvenation and discuss putative analogous mechanisms in higher eukaryotes.National Institutes of Health (U.S.) (grant GM62207

Gametogenesis Eliminates Age-Induced Cellular Damage and Resets Life Span in Yeast

Eukaryotic organisms age, yet detrimental age-associated traits are not passed on to progeny. How life span is reset from one generation to the next is not known. We show that in budding yeast resetting of life span occurs during gametogenesis. Gametes (spores) generated by aged cells show the same replicative potential as gametes generated by young cells. Age-associated damage is no longer detectable in mature gametes. Furthermore, transient induction of a transcription factor essential for later stages of gametogenesis extends the replicative life span of aged cells. Our results indicate that gamete formation brings about rejuvenation by eliminating age-induced cellular damage.National Institutes of Health (U.S.) (Grant GM62207

Short- and long-term effects of chromosome mis-segregation and aneuploidy

Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.National Institutes of Health (U.S.) (Grant GM56800

A System to Study Aneuploidy In Vivo

Aneuploidy, an imbalanced chromosome number, is associated with both cancer and developmental disorders such as Down syndrome (DS). To determine how aneuploidy affects cellular and organismal physiology, we have developed a system to evaluate aneuploid cell fitness in vivo. By transplanting hematopoietic stem cells (HSCs) into recipient mice after ablation of recipient hematopoiesis by lethal irradiation, we can directly compare the fitness of HSCs derived from a range of aneuploid mouse models with that of euploid HSCs. This experimental system can also be adapted to assess the interplay between aneuploidy and tumorigenesis. We hope that further characterization of aneuploid cells in vivo will provide insight both into the origins of hematopoietic phenotypes observed in DS individuals as well as the role of different types of aneuploid cells in the genesis of cancers of the blood.National Institutes of Health (U.S.) (Grant GM056800

Emergent Collectivity in Nuclei and Enhanced Proton-Neutron Interactions

Enhanced proton-neutron interactions occur in heavy nuclei along a trajectory of approximately equal numbers of valence protons and neutrons. This is also closely aligned with the trajectory of the saturation of quadrupole deformation. The origin of these enhanced p-n interactions is discussed in terms of spatial overlaps of proton and neutron wave functions that are orbit-dependent. It is suggested for the first time that nuclear collectivity is driven by synchronized filling of protons and neutrons with orbitals having parallel spins, identical orbital and total angular momenta projections, belonging to adjacent major shells and differing by one quantum of excitation along the z-axis. These results may lead to a new approach to symmetry-based theoretical calculations for heavy nuclei.Comment: 6 pages, 4 figure

Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes

Aneuploidy—the gain or loss of one or more whole chromosome—typically has an adverse impact on organismal fitness, manifest in conditions such as Down syndrome. A central question is whether aneuploid phenotypes are the consequence of copy number changes of a few especially harmful genes that may be present on the extra chromosome or are caused by copy number alterations of many genes that confer no observable phenotype when varied individually. We used the proliferation defect exhibited by budding yeast strains carrying single additional chromosomes (disomes) to distinguish between the “few critical genes” hypothesis and the “mass action of genes” hypothesis. Our results indicate that subtle changes in gene dosage across a chromosome can have significant phenotypic consequences. We conclude that phenotypic thresholds can be crossed by mass action of copy number changes that, on their own, are benign.National Institutes of Health (U.S.) (GM056800

Assessment of megabase-scale somatic copy number variation using single-cell sequencing

Megabase-scale copy number variants (CNVs) can have profound phenotypic consequences. Germline CNVs of this magnitude are associated with disease and experience negative selection. However, it is unknown whether organismal function requires that every cell maintain a balanced genome. It is possible that large somatic CNVs are tolerated or even positively selected. Single-cell sequencing is a useful tool for assessing somatic genomic heterogeneity, but its performance in CNV detection has not been rigorously tested. Here, we develop an approach that allows for reliable detection of megabase-scale CNVs in single somatic cells. We discover large CNVs in 8%–9% of cells across tissues and identify two recurrent CNVs. We conclude that large CNVs can be tolerated in subpopulations of cells, and particular CNVs are relatively prevalent within and across individuals.United States. National Institutes of Health (GM056800)Kathy and Curt Marble Cancer Research FundUnited States. National Institutes of Health (P30-CA14051)National Institute of General Medical Sciences (U.S.) (T32GM007753

Uncertainty in the measurement of indoor temperature and humidity in naturally ventilated dairy buildings as influenced by measurement technique and data variability

[EN] The microclimatic conditions in dairy buildings affect animal welfare and gaseous emissions. Measurements are highly variable due to the inhomogeneous distribution of heat and humidity sources (related to farm management) and the turbulent inflow (associated with meteorologic boundary conditions). The selection of the measurement strategy (number and position of the sensors) and the analysis methodology adds to the uncertainty of the applied measurement technique. To assess the suitability of different sensor positions, in situations where monitoring in the direct vicinity of the animals is not possible, we collected long-term data in two naturally ventilated dairy barns in Germany between March 2015 and April 2016 (horizontal and vertical profiles with 10 to 5 min temporal resolution). Uncertainties related to the measurement setup were assessed by comparing the device outputs under lab conditions after the on-farm experiments. We found out that the uncertainty in measurements of relative humidity is of particular importance when assessing heat stress risk and resulting economic losses in terms of temperature-humidity index. Measurements at a height of approximately 3 m-3.5 m turned out to be a good approximation for the microclimatic conditions in the animal occupied zone (including the air volume close to the emission active zone). However, further investigation along this cross-section is required to reduce uncertainties related to the inhomogeneous distribution of humidity. In addition, a regular sound cleaning (and if possible recalibration after few months) of the measurement devices is crucial to reduce the instrumentation uncertainty in long-term monitoring of relative humidity in dairy barns (C) 2017 The Authors. Published by Elsevier Ltd on behalf of IAgrE.The work was financially supported by the German Federal Ministry of Food and Agriculture (BMEL) through the Federal Office for Agriculture and Food (BLE), grant number 2814ERA02C.Hempel, S.; König, M.; Menz, C.; Janke, D.; Amon, B.; Banhazi, T.; Estellés, F.... (2018). Uncertainty in the measurement of indoor temperature and humidity in naturally ventilated dairy buildings as influenced by measurement technique and data variability. Biosystems Engineering. 166:58-75. https://doi.org/10.1016/j.biosystemseng.2017.11.004S587516