bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reflections on telomere dynamics and ageing-related diseases in humans
Authors: Aviv Abraham , Shay Jerry W. 
Published: January 2018

Epidemiological studies have principally relied on measurements of telomere length (TL) in leucocytes, which reflects TL in other somatic cells. Leucocyte TL (LTL) displays vast variation across individuals—a phenomenon already observed in newborns. It is highly heritable, longer in females than males and in individuals of African ancestry than European ancestry. LTL is also longer in offspring conceived by older men. The traditional view regards LTL as a passive biomarker of human ageing. However, new evidence suggests that a dynamic interplay between selective evolutionary forces and TL might result in trade-offs for specific health outcomes. From a biological perspective, an active role of TL in ageing-related human diseases could occur because short telomeres increase the risk of a category of diseases related to restricted cell proliferation and tissue degeneration, including cardiovascular disease, whereas long telomeres increase the risk of another category of diseases related to increased proliferative growth, including major cancers. To understand the role of telomere biology in ageing-related diseases, it is essential to expand telomere research to newborns and children and seek further insight into the underlying causes of the variation in TL due to ancestry and geographical location.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
Experimental manipulation of telomere length: does it reveal a corner-stone role for telomerase in the natural variability of individual fitness?
Authors: Criscuolo F. , Smith S. , Zahn S. , Heidinger B. J. , Haussmann M. F. 
Published: January 2018

Telomeres, the non-coding ends of linear chromosomes, are thought to be an important mechanism of individual variability in performance. Research suggests that longer telomeres are indicative of better health and increased fitness; however, many of these data are correlational and whether these effects are causal are poorly understood. Experimental tests are emerging in medical and laboratory-based studies, but these types of experiments are rare in natural populations, which precludes conclusions at an evolutionary level. At the crossroads between telomere length and fitness is telomerase, an enzyme that can lengthen telomeres. Experimental modulation of telomerase activity is a powerful tool to manipulate telomere length, and to look at the covariation of telomerase, telomeres and individual life-history traits. Here, we review studies that manipulate telomerase activity in laboratory conditions and emphasize the associated physiological and fitness consequences. We then discuss how telomerase's impact on ageing may go beyond telomere maintenance. Based on this overview, we then propose several research avenues for future studies to explore how individual variability in health, reproduction and survival may have coevolved with different patterns of telomerase activity and expression. Such knowledge is of prime importance to fully understand the role that telomere dynamics play in the evolution of animal ageing.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
The relationship between telomere length and mortality risk in non-model vertebrate systems: a meta-analysis
Authors: Wilbourn Rachael V. , Moatt Joshua P. , Froy Hannah , Walling Craig A. , Nussey Daniel H. , Boonekamp Jelle J. 
Published: January 2018

Telomere length (TL) has become a biomarker of increasing interest within ecology and evolutionary biology, and has been found to predict subsequent survival in some recent avian studies but not others. Here, we undertake the first formal meta-analysis to test whether there is an overall association between TL and subsequent mortality risk in vertebrates other than humans and model laboratory rodents. We identified 27 suitable studies and obtained standardized estimates of the hazard ratio associated with TL from each. We performed a meta-analysis on these estimates and found an overall significant negative association implying that short telomeres are associated with increased mortality risk, which was robust to evident publication bias. While we found that heterogeneity in the hazard ratios was not explained by sex, follow-up period, maximum lifespan or the age group of the study animals, the TL–mortality risk association was stronger in studies using qPCR compared to terminal restriction fragment methodologies. Our results provide support for a consistent association between short telomeres and increased mortality risk in birds, but also highlight the need for more research into non-avian vertebrates and the reasons why different telomere measurement methods may yield different results.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
The role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing
Authors: Young Andrew J. 
Published: January 2018

Evolutionary biology and biomedicine have seen a surge of recent interest in the possibility that telomeres play a role in life-history trade-offs and ageing. Here, I evaluate alternative hypotheses for the role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing, and highlight outstanding challenges. First, while recent findings underscore the possibility of a proximate causal role for telomeres in current–future trade-offs and ageing, it is currently unclear (i) whether telomeres ever play a causal role in either and (ii) whether any causal role for telomeres arises via shortening or length-independent mechanisms. Second, I consider why, if telomeres do play a proximate causal role, selection has not decoupled such a telomere-mediated trade-off between current and future performance. Evidence suggests that evolutionary constraints have not rendered such decoupling impossible. Instead, a causal role for telomeres would more plausibly reflect an adaptive strategy, born of telomere maintenance costs and/or a function for telomere attrition (e.g. in countering cancer), the relative importance of which is currently unclear. Finally, I consider the potential for telomere biology to clarify the constraints at play in life-history evolution, and to explain the form of the current–future trade-offs and ageing trajectories that we observe today.This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
The fetal programming of telomere biology hypothesis: an update
Authors: Entringer Sonja , de Punder Karin , Buss Claudia , Wadhwa Pathik D. 
Published: January 2018

Research on mechanisms underlying fetal programming of health and disease risk has focused primarily on processes that are specific to cell types, organs or phenotypes of interest. However, the observation that developmental conditions concomitantly influence a diverse set of phenotypes, the majority of which are implicated in age-related disorders, raises the possibility that such developmental conditions may additionally exert effects via a common underlying mechanism that involves cellular/molecular ageing–related processes. In this context, we submit that telomere biology represents a process of particular interest in humans because, firstly, this system represents among the most salient antecedent cellular phenotypes for common age-related disorders; secondly, its initial (newborn) setting appears to be particularly important for its long-term effects; and thirdly, its initial setting appears to be plastic and under developmental regulation. We propose that the effects of suboptimal intrauterine conditions on the initial setting of telomere length and telomerase expression/activity capacity may be mediated by the programming actions of stress-related maternal–placental–fetal oxidative, immune, endocrine and metabolic pathways in a manner that may ultimately accelerate cellular dysfunction, ageing and disease susceptibility over the lifespan. This perspectives paper provides an overview of each of the elements underlying this hypothesis, with an emphasis on recent developments, findings and future directions.This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
The mitochondrial genome, paternal age and telomere length in humans
Authors: Aviv Abraham 
Published: January 2018

Telomere length (TL) in humans is highly heritable and undergoes progressive age-dependent shortening in somatic cells. By contrast, sperm donated by older men display comparatively long telomeres, presumably because in the male germline, telomeres become longer with age. This puzzling phenomenon might explain why TL in the offspring correlates positively with paternal age. The present communication proposes that mitochondrial DNA polymorphisms and heteroplasmy cause variation in the production of reactive oxygen species, which, in turn, mediate age-dependent selection of germ stem cells with long telomeres and hence sperm with long telomeres. These long telomeres are then inherited by the offspring. The effect of paternal age on the offspring TL might be an evolutionarily driven mechanism that helps regulate TL across the human population.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
GWAS on family history of Alzheimer’s disease
Authors: E. Marioni Riccardo , Harris Sarah E. , McRae Allan F. , Zhang Qian , Hagenaars Saskia P. , David Hill W. , Davies Gail , Ritchie Craig W. , Gale Catharine , Starr John M. , Goate Alison M. , Porteous David J. , Yang Jian , Evans Kathryn L. , Deary Ian J. , Wray Naomi R. , Visscher Peter M. 
Published: January 2018

AbstractAlzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. Using self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of over 300,000 participants from UK Biobank (32,222 maternal cases, 16,613 paternal cases) and meta-analysing with published consortium data (n=74,046 with 25,580 cases across the discovery and replication analyses), six new AD-associated loci (P<5x10−8) are identified. Three contain genes relevant for AD and neurodegeneration: ADAM10, ADAMTS4, and ACE. Suggestive loci include drug targets such as VKORC1 (warfarin dose) and BZRAP1 (benzodiazepine receptor). We report evidence that association of SNPs and AD at the PVR gene is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, given that many are existing drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.
Integration and analysis of CPTAC proteomics data in the context of cancer genomics in the cBioPortal
Authors: Wu Pamela , Heins Zachary J , Muller James T , Abeshouse Adam A , Sun Yichao , Schultz Nikolaus , Fenyö David , Gao Jianjiong 
Published: January 2018

SummaryThe Clinical Proteomic Tumor Analysis Consortium (CPTAC) has produced extensive mass spectrometry based proteomics data for selected breast, colon and ovarian tumors from The Cancer Genome Atlas (TCGA). We have incorporated the CPTAC proteomics data into the cBioPotal to support easy exploration and integrative analysis of these proteomic datasets in the context of the clinical and genomics data from the same tumors. cBioPortal is an open source platform for exploring, visualizing, and analyzing multi-dimensional cancer genomics and clinical data. The public instance of the cBioPortal (http://cbioportal.org/) hosts more than 100 cancer genomics studies including all of the data from TCGA. Its biologist-friendly interface provides many rich analysis features, including a graphical summary of gene-level data across multiple platforms, correlation analysis between genes or other data types, survival analysis, and network visualization. Here, we present the integration of the CPTAC mass spectrometry based proteomics data into the cBioPortal, consisting of 77 breast, 95 colorectal, and 174 ovarian tumors that already have been profiled by TCGA for mutations, copy number alterations, gene expression, and DNA methylation. As a result, the CPTAC data can now be easily explored and analyzed in the cBioPortal in the context of clinical and genomics data. By integrating CPTAC data into cBioPortal, limitations of TCGA proteomics array data can be overcome while also providing a user-friendly web interface, a web API and an R client to query the mass spectrometry data together with genomic, epigenomic, and clinical data.
Correlation Detection with and without the Theories of Conditionals: A model update of Hattori & Oaksford (2007)
Authors: Takahashi Tatsuji , Oyo Kuratomo , Tamatsukuri Akihiro , Higuchi Kohki 
Published: January 2018

AbstractWe view observational causal induction as a statistical independence test under rarity assumption. This paper complements the two-stage theory of causal induction proposed by Hattori and Oaksford (2007) with a computational analysis. We show that their dual-factor heuristic (DFH) model has a rational account as the square root of the index of (non-)independence under extreme rarity assumption, contrary to the criticism that the DFH model is non-normative (e.g., Lu et al., 2008). We introduce a model that considers the proportion of assumed-to-be rare instances (pARIs), which is the probability of biconditionals (according to several theories of compound conditionals) and can be seen as a simplified version of the DFH model. While being a single conditional probability, pARIs approximates the non-independence measure, the square of DFH. In reproducing the meta-analysis in Hattori and Oaksford (2007), we confirm that pARIs and DFH have the same level of descriptive adequacy, and that the two models have the highest fit among more than 40 models. Then, we critically examine the computer simulations which were central to the rational analysis in Hattori and Oaksford (2007). We point out two problems in their simluations: samples in some of the simulations being restricted to generative ones, and in-definite values of models because of the small samples. In the light of especially the latter problem of definability, pARIs shows higher applicability.
Combining high-throughput micro-CT-RGB phenotyping and genome-wide association study to dissect the genetic architecture of tiller growth in rice
Authors: Wu Di , Guo Zilong , Ye Junli , Liu Jianxiao , Chen Guoxing , Zheng Jingshan , Yan Dongmei , Yang Xiaoquan , Xiong Xiong , Liu Qian , Niu Zhiyou , Xiong Lizhong , Yang Wanneng 
Published: January 2018

AbstractTraditional phenotyping of rice tillers is time consuming and labor intensive and lags behind the rapid development of rice functional genomics. Thus, dynamic phenotyping of rice tiller traits at a high spatial resolution and high-throughput for large-scale rice accessions is urgently needed. In this study, we developed a high-throughput micro-CT-RGB (HCR) imaging system to non-destructively extract 730 traits from 234 rice accessions at 9 time points. We used these traits to predict the grain yield in the early growth stage, and 30% of the grain yield variance was explained by 2 tiller traits in the early growth stage. A total of 402 significantly associated loci were identified by GWAS, and dynamic and static genetic components were found across the nine time points. A major locus associated with tiller angle was detected at nine time points, which contained a major gene TAC1. Significant variants associated with tiller angle were enriched in the 3'-UTR of TAC1. Three haplotypes for the gene were found and tiller angles of rice accessions containing haplotype H3 were much smaller. Further, we found two loci contained associations with both vigor-related HCR traits and yield. The superior alleles would be beneficial for breeding of high yield and dense planting.HighlightCombining high-throughput micro-CT-RGB phenotyping facility and genome-wide association study to dissect the genetic architecture of rice tiller development by using the indica subpopulation.
Simulations of higher-order protein assemblies using a fuzzy framework
Authors: Tüű-Szabó B. , Kóczy L. , Fuxreiter M. 
Published: January 2018

AbstractSpatiotemporal regulation of the biochemical information is often linked to supramolecular organizations proteins and nucleic acids, which generate membraneless cellular organelles. Owing to difficulties in high-resolution structural studies, the driving forces of assembling these low-complexity polymers have yet to be elucidated. Polymer physics approaches captured the experimentally demonstrated critical role of binding element multivalency and highlighted the importance of linker solvation. Here we present a simulation method based on a fuzzy mathematical framework. This approach is suitable to handle the heterogeneity of interactions pattern generated by redundant binding motifs and the resulted multiplicity of conformational states. Using a hypothetical polymer, fuzzy simulations recapitulate the experimental observations on valency-dependence and are more efficient than the one-to-one binding model. Systematic studies on binding element affinity and linker dynamics demonstrate that these two factors present alternative scenarios to promote polymerization: stronger binding result in more ordered states, whereas increasing dynamics contributes to heterogeneity and a more favorable entropy of the assembly. We propose that the fuzzy framework could be employed to characterize/predict mutations leading to pathological aggregates.
Systems pathology analysis identifies neurodegenerative nature of age-related retinal diseases
Authors: Öhman Tiina , Tamene Fitsum , Göös Helka , Loukovaara Sirpa , Varjosalo Markku 
Published: January 2018

AbstractAging is a phenomenon associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. The iERM is characterized by fibrous tissue developing on the surface of the macula, leading to biomechanical and biochemical macular damage. MH is a small breakage in the macula associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry based label-free quantitative proteomics analysis of the vitreous proteomes from patients with iERM (n=26) and MH (n=21) to identify the key proteins as well as the multiple interconnected biochemical pathways contributing to the development of these diseases. We identified a total of 1014 unique proteins, of which many were linked to inflammation and complement cascade, revealing the inflammational processes in retinal diseases. Additionally, we detected a profound difference in proteomes of the iEMR and MH compared to the non-proliferative diabetic retinopathy. A large number of neuronal proteins were present at higher levels in iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins and signalling molecules. This points toward the important role of neurodegeneration component in the pathogenesis of age-related vitreoretinal diseases. Despite of marked similarities, several unique vitreous proteins were identified in both iERM and MH conditions, providing a candidate targets for diagnostic and new therapeutic approaches. Identification of previously reported and novel proteins in human vitreous humor from patient with iERM and MH provide renewed understanding of the pathogenesis of age-related vitreoretinal diseases.
Evolution of sexually-transferred steroids inAnophelesmosquitoes
Authors: Pondeville Emilie , Puchot Nicolas , Lang Michael , Cherrier Floriane , Schaffner Francis , Dauphin-Villemant Chantal , Bischoff Emmanuel , Bourgouin Catherine 
Published: January 2018

AbstractHuman malaria, which remains a major public health problem, is transmitted by a subset ofAnophelesmosquitoes belonging to only three out of eight subgenera:Anopheles, CelliaandNyssorhynchus. Unlike almost every other insect species, it was shown that males of someAnophelesspecies produce and transfer steroid hormones to females during copulation and that this transfer mediates reproductive changes. Steroids are consequently seen as a potential target for malaria vector control. Here, we analysed the evolution of sexually-transferred steroids and their effects on female reproductive traits acrossAnophelesby using a set of 16 mosquito species (5Anopheles, 8Cellia, and 3Nyssorhynchus), including malaria vector and non-vector species. We show that male steroid production and transfer are specific to theCelliasubgenus and that there is no correlation between mating-induced effects in females and sexually-transferred steroids. In the light of our results, male steroid production, transfer and post-mating effects in females do not correlate with their ability to transmit human malaria, which overturns the suggestion from previous studies and suggests that manipulation of steroid-response pathways in the field should be considered with caution in order to benefit malaria vector control strategies.
FANCM-family branchpoint translocases remove co-transcriptional R-loops
Authors: Hodson Charlotte , O’Rourke Julienne J , Twest Sylvie van , Murphy Vincent J , Dunn Elyse , Deans Andrew J 
Published: January 2018

AbstractCo-transcriptional R-loops arise from physiological or aberrant stalling of RNA polymerase, leading to formation of stable DNA:RNA hybrids. Unresolved R-loops can promote genome instability. Here, we show that the Fanconi anemia- and breast cancer-associated FANCM protein can directly unwind DNA-RNA hybrids from co-transcriptional R-loopsin vitro. FANCM processively unwinds both short and long R-loops, irrespective of sequence, topology or coating by replication protein A. R-loops can also be unwound in the same assay by the yeast and bacterial orthologs of FANCM, Mph1 and RecG, indicating an evolutionary conserved function. Consistent with this biochemical activity of FANCM, we show that FANCM deficient cells are sensitive to drugs that stabilize R-loop formation.Our work reveals a mechanistic basis for R-loop metabolism that is critical for genome stability.