bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization in humans ofin vitroleucocyte maximal telomerase activity capacity and association with stress
Authors: de Punder Karin , Heim Christine , Przesdzing Ingo , Wadhwa Pathik D. , Entringer Sonja 
Published: January 2018

The goal of this study was to develop and validate a measure ofmaximal telomerase activity capacity(mTAC) for use in human studies of telomere biology, and to determine its association with measures of stress and stress responsivity. The study was conducted in a population of 28 healthy young women and men who were assessed serially across two separate days, at multiple time points, and in response to a standardized laboratory stressor. Venous blood was collected at each of these multiple assessments, and anin vitromitogen challenge (phytohaemagglutinin supplemented with interleukin-2) was used to stimulate telomerase activity in leucocytes. After first establishing the optimal post-stimulation time course to characterize mTAC, we determined the within-subject stability and the between-subject variability of mTAC. The major findings of our study are as follows: (i) the optimal time point to quantify human leucocyte mTAC appears to be at 72 h after mitogen stimulation; (ii) mTAC exhibits substantial within-subject stability (correlations were in the range ofr0.68–0.82) and between-subject variability, with a high intra-class coefficient (0.70), indicating greater between-subject relative to within-subject variability; (iii) mTAC is not influenced by situational factors including time of day, cortisol, acute stress exposure and immune cell distribution in the pre-stimulation blood sample; and (iv) a significant proportion of the between-subject variability in mTAC is associated with measures of stress and stress responsivity (mTAC is lower in subjects reporting higher levels of perceived (chronic) stress and exhibiting higher psychophysiological stress reactivity). Based collectively on these findings, it appears that mTAC, as proposed and operationalized, empirically meets the key criteria to represent a potentially useful individual difference measure of telomerase activity capacity of human leucocytes.This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
The rate of telomere loss is related to maximum lifespan in birds
Authors: Tricola Gianna M. , Simons Mirre J. P. , Atema Els , Boughton Raoul K. , Brown J. L. , Dearborn Donald C. , Divoky G. , Eimes John A. , Huntington Charles E. , Kitaysky Alexander S. , Juola Frans A. , Lank David B. , Litwa Hannah P. , Mulder Ellis G. A. , Nisbet Ian C. T. , Okanoya Kazuo , Safran Rebecca J. , Schoech Stephan J. , Schreiber Elizabeth A. , Thompson Paul M. , Verhulst Simon , Wheelwright Nathaniel T. , Winkler David W. , Young Rebecca , Vleck Carol M. , Haussmann Mark F. 
Published: January 2018

Telomeres are highly conserved regions of DNA that protect the ends of linear chromosomes. The loss of telomeres can signal an irreversible change to a cell's state, including cellular senescence. Senescent cells no longer divide and can damage nearby healthy cells, thus potentially placing them at the crossroads of cancer and ageing. While the epidemiology, cellular and molecular biology of telomeres are well studied, a newer field exploring telomere biology in the context of ecology and evolution is just emerging. With work to date focusing on how telomere shortening relates to individual mortality, less is known about how telomeres relate to ageing rates across species. Here, we investigated telomere length in cross-sectional samples from 19 bird species to determine how rates of telomere loss relate to interspecific variation in maximum lifespan. We found that bird species with longer lifespans lose fewer telomeric repeats each year compared with species with shorter lifespans. In addition, phylogenetic analysis revealed that the rate of telomere loss is evolutionarily conserved within bird families. This suggests that the physiological causes of telomere shortening, or the ability to maintain telomeres, are features that may be responsible for, or co-evolved with, different lifespans observed across species.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
All's well that ends well: why large species have short telomeres
Authors: Risques Rosa Ana , Promislow Daniel E. L. 
Published: January 2018

Among mammal species, almost all life-history traits are strongly size dependent. This size dependence even occurs at a molecular level. For example, both telomere length and telomerase expression show a size-dependent threshold. With some exceptions, species smaller than approximately 2 kg express telomerase, while species larger than that do not. Among species greater than approximately 5 kg, telomeres tend to be short—less than 25 kb—while among smaller species, some species have short and some have long telomeres. Here, we present a model to explore the role of body size-dependent trade-offs in shaping this threshold. We assume that selection favours short telomeres as a mechanism to protect against cancer. At the same time, selection favours long telomeres as a protective mechanism against DNA damage and replicative senescence. The relative importance of these two selective forces will depend on underlying intrinsic mortality and risk of cancer, both of which are size-dependent. Results from this model suggest that a cost–benefit model for the evolution of telomere length could explain phylogenetic patterns observed within the Class Mammalia. In addition, the model suggests a general conceptual framework to think about the role that body size plays in the evolution of tumour suppressor mechanisms.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
Ectothermic telomeres: it's time they came in from the cold
Authors: Olsson Mats , Wapstra Erik , Friesen Christopher 
Published: January 2018

We review the evolutionary ecology and genetics of telomeres in taxa that cannot elevate their body temperature to a preferred level through metabolism but do so by basking or seeking out a warm environment. This group of organisms contains all living things on earth, apart from birds and mammals. One reason for our interest in this synthetic group is the argument that high, stable body temperature increases the risk of malignant tumours if long, telomerase-restored telomeres make cells ‘live forever’. If this holds true, ectotherms should have significantly lower cancer frequencies. We discuss to what degree there is support for this ‘anti-cancer’ hypothesis in the current literature. Importantly, we suggest that ectothermic taxa, with variation in somatic telomerase expression across tissue and taxa, may hold the key to understanding ongoing selection and evolution of telomerase dynamics in the wild. We further review endotherm-specific effects of growth on telomeres, effects of autotomy (‘tail dropping’) on telomere attrition, and costs of maintaining sexual displays measured in telomere attrition. Finally, we cover plant ectotherm telomeres and life histories in a separate ‘mini review’.This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
Heritability of telomere variation: it is all about the environment!
Authors: Dugdale Hannah L. , Richardson David S. 
Published: January 2018

Individual differences in telomere length have been linked to survival and senescence. Understanding the heritability of telomere length can provide important insight into individual differences and facilitate our understanding of the evolution of telomeres. However, to gain accurate and meaningful estimates of telomere heritability it is vital that the impact of the environment, and how this may vary, is understood and accounted for. The aim of this review is to raise awareness of this important, but much under-appreciated point. We outline the factors known to impact telomere length and discuss the fact that telomere length is a trait that changes with age. We highlight statistical methods that can separate genetic from environmental effects and control for confounding variables. We then review how well previous studies in vertebrate populations including humans have taken these factors into account. We argue that studies to date either use methodological techniques that confound environmental and genetic effects, or use appropriate methods but lack sufficient power to fully separate these components. We discuss potential solutions. We conclude that we need larger studies, which also span longer time periods, to account for changing environmental effects, if we are to determine meaningful estimates of the genetic component of telomere length.This article is part of the theme issue ‘Understanding diversity in telomere dynamics'.
Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis
Authors: Halama Anna , Kulinski Michal , Dib Shaima S. , Zaghlool Shaza B. , Siveen Kodappully S. , Iskandarani Ahmad , Satheesh Noothan J. , Bhagwat Aditya M. , Uddin Shahab , Kastenmüeller Gabi , Elemento Olivier , Gross Steven S. , Suhre Karsten 
Published: January 2018

SummarySuppressing glutaminolysis does not always induce cancer cell death in glutamine-dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis. We conducted metabolic profiling in the triple-negative breast cancer cell line MB-MDA-231, treated with different dosages of glutaminase inhibitor C.968 at multiple time points. We found that multiple molecules involved in lipid catabolism responded directly to glutamate deficiency as a presumed compensation for energy deficit. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. We therefore simultaneously inhibited glutaminolysis and autophagy, which induced cancer cell death. Our study emphasizes the potential of non-targeted metabolomics to characterize and identify metabolic escape mechanisms contributing to cancer cell survival under treatment. Our findings add to the increasing evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.
Metabolic co-dependence drives the evolutionary ancientHydra-Chlorellasymbiosis
Authors: Hamada Mayuko , Schröder Katja , Bathia Jay , Kürn Ulrich , Fraune Sebastian , Khalturina Mariia , Khalturin Konstantin , Shinzato Chuya , Satoh Nori , Bosch Thomas C.G. 
Published: January 2018

AbstractMany multicellular organisms rely on symbiotic associations for support of metabolic activity, protection, or energy. Understanding the mechanisms involved in controlling such interactions remains a major challenge. In an unbiased approach we identified key players that control the symbiosis betweenHydra viridissimaand its photobiontChlorellasp. A99. We discovered significant upregulation ofHydragenes encoding a phosphate transporter and glutamine synthetase suggesting regulated nutrition supply between host and symbionts. Interestingly, supplementing the medium with glutamine temporarily supports in vitro growth of the otherwise obligate symbioticChlorella, indicating loss of autonomy and dependence on the host. Genome sequencing ofChlorellaA99 revealed a large number of amino acid transporters and a degenerated nitrate assimilation pathway, presumably as consequence of the adaptation to the host environment. Our observations portray ancient symbiotic interactions as a codependent partnership in which exchange of nutrients appears to be the primary driving force.
Inherited BRCA1 epimutation as a novel cause of breast and ovarian cancer
Authors: Evans D. Gareth R. , van Veen Elke M. , Byers Helen J. , Wallace Andrew J. , Ellingford Jamie M. , Beaman Glenda , Santoyo-Lopez Javier , Aitman Timothy J. , Eccles Diana M. , Lalloo Fiona I. , Smith Miriam J. , Newman William G. 
Published: January 2018

AbstractBackgroundPathogenic variants in BRCA1 or BRCA2 are identified in ~20% of families with multiple individuals with early-onset breast/ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1/2 have not explained the missing heritability. For the first time, we report transgenerational epigenetic silencing of BRCA1 due to promoter hypermethylation in two families with breast/ovarian cancer.MethodsBRCA1 promoter methylation of ten CpG dinucleotides in breast/ovarian cancer families without germline BRCA1/2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants.FindingsBRCA1 promoter hypermethylation was identified in two of 49 families with multiple women affected with grade 3 breast/high grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa and hair follicles. Methylation levels were ~50%, consistent with the silencing of one allele and confirmed by clonal bisulfite sequencing. RNA sequencing revealed allelic loss of BRCA1 expression in both families and this segregated with a novel heterozygous variant c.-107A>T in the BRCA1 5’UTR.InterpretationOur results indicate a novel mechanism for familial breast/ovarian cancer, caused by epigenetic silencing of the BRCA1 promoter, segregating with an in cis 5’UTR variant in two independent families. We propose that methylation analyses are indicated in all families affected by early onset breast/ovarian cancer without a BRCA1/2 pathogenic variant.FundingFunded by Prevent Breast Cancer (GA 12-006 and GA 15-002) and the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).
Epigenetic Drift of H3K27me3 in Aging Links Glycolysis to Healthy Longevity
Authors: Ma Zaijun , Wang Hui , Cai Yuping , Wang Han , Niu Kongyan , Wu Xiaofen , Ma Huanhuan , Yang Yun , Tong Wenhua , Liu Feng , Liu Zhandong , Zhang Yaoyang , Liu Rui , Zhu Zheng-Jiang , Liu Nan 
Published: January 2018

ABSTRACTEpigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging is unclear. H3K27me3, a highly conserved histone modification signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using Drosophila, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. Moreover, we show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis by gene mutation diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 defines a new aging mechanism and that stimulation of glycolysis promotes metabolic health and longevity.
Noise-resistant developmental reproducibility in vertebrate somite formation
Authors: Naoki Honda , Akiyama Ryutaro , Ishii Shin , Bessho Yasumasa , Matsui Takaaki 
Published: January 2018

AbstractThe reproducibility of embryonic development is remarkable, although molecular processes are intrinsically stochastic at the single-cell level. How the multi-cellular system resists the inevitable noise to acquire developmental reproducibility constitutes a fundamental question in developmental biology. Toward this end, we focused on vertebrate somitogenesis as a representative system, because somites are repeatedly reproduced within a single embryo whereas such reproducibility is lost in segmentation clock gene-deficient embryos. However, the effect of noise on developmental reproducibility has not been fully investigated, because of the technical difficulty in manipulating the noise intensity in experiments. In this study, we developed a computational model of ERK-mediated somitogenesis, in which bistable ERK activity is regulated by an FGF gradient, cell-cell communication, and the segmentation clock, subject to the intrinsic noise. The model simulation generated our previousin vivoobservation that the ERK activity was distributed in a step-like gradient in the presomitic mesoderm, and its boundary was posteriorly shifted by the clock in a stepwise manner, leading to regular somite formation. Here we showed that this somite regularity was robustly maintained against the noise. Removing the clock from the model predicted that the stepwise shift of the ERK activity occurs at irregular timing with irregular distance owing to the noise, resulting in somite size variation. Through theoretical analysis, we presented a mechanism by which the clock reduces the inherent somite irregularity observed in clock-deficient embryos. Therefore, this study indicates a novel role of the segmentation clock in noise-resistant developmental reproducibility.
Control of non-homeostatic feeding in sated mice using associative learning of contextual food cues
Authors: Stern Sarah A. , Doerig Katherine R. , Azevedo Estefania P. , Stoffel Elina , Friedman Jeffrey M. 
Published: January 2018

ABSTRACTFeeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in ∼1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption.
Early diverging insect pathogenic fungi of the order Entomophthorales possess diverse and unique subtilisin-like serine proteases
Authors: Arnesen Jonathan A. , Malagocka Joanna , Gryganskyi Andrii , Grigoriev Igor V. , Voigt Kerstin , Stajich Jason E. , De Fine Licht Henrik H. 
Published: January 2018

AbstractInsect-pathogenic fungi use subtilisin-like serine proteases (SLSPs) to degrade chitin-associated proteins in the insect procuticle. Most insect-pathogenic fungi in the order Hypocreales (Ascomycota) are generalist species with a broad host-range, and most species possess a high number of SLSPs. The other major clade of insect-pathogenic fungi is part of the subphylum Entomophthoromycotina (Zoopagomycota, formerly Zygomycota) which consists of high host-specificity insect-pathogenic fungi that naturally only infect a single or very few host species. The extent to which insect-pathogenic fungi in the order Entomophthorales rely on SLSPs is unknown. Here we take advantage of recently available transcriptomic and genomic datasets from four genera within Entomophthoromycotina: the saprobic or opportunistic pathogens Basidiobolus meristosporus, Conidiobolus coronatus, C. thromboides, C. incongruus, and the host-specific insect pathogens Entomphthora muscae and Pandora formicae, specific pathogens of house flies (Muscae domestica) and wood ants (Formica polyctena), respectively. We use phylogenetics and protein domain analysis to show that the obligate biotrophic fungi E. muscae, P. formicae and the saprobic human pathogen C. incongruus all contain “classical” fungal SLSPs and a unique group of SLSPs that loosely resembles bacillopeptidase F-like SLSPs. This novel group of SLSPs is found in the genomes of obligate insect pathogens and a generalist saprobic opportunistic pathogen why they are unlikely to be responsible for the host specificity of Entomophthorales. However, this class represent a unique group of SLSPs so far only observed among Bacteria, Oomycetes and early diverging fungi such as Cryptomycota, Microsporidia, and Entomophthoromycotina and missing in the sister fungal lineages of Kickxellomycotina or the fungal phyla Mucoromyocta, Ascomycota and Basidiomycota fungi suggesting interesting gene loss patterns.
A pupillary index of susceptibility to decision biases
Authors: Eldar Eran , Felso Valkyrie , Cohen Jonathan D. , Niv Yael 
Published: January 2018

AbstractUnder what conditions do humans systematically deviate from rational decision making? Here we show that pupillary indices of low neural gain are associated with strong and consistent biases across six different extensively-studied decision making tasks, whereas indices of high gain are associated with weak or absent biases. Lower susceptibility to biases, however, comes at the cost of indecisiveness, or alternatively, prolonged deliberation time. We explain the association between low gain and strong biases as reflecting a broader information integration process that gives greater weight to weak biasing influences. The findings underscore the role of pupil-linked brain states in the generation of decision making biases.Significance“Framing effects” are demonstrations that people’s decisions can be biased by the way a decision problem is presented, and consequently, people can make decisions that violate the principles of rationality. Using a set of classic decision-making tasks, we show that pupil dilation, previously linked to levels of the neuromodulator norepinephrine and to a tradeoff between narrowly focused and broadly integrative modes of information processing, distinguishes between people who are consistently biased and people who are relatively immune to these effects. Our findings suggest that norepinephrine may drive these individual differences, and that a narrowly focused mode of information processing confers relative immunity to these decision making biases, whereas the integration of a wider range of information results in greater susceptibility.