bluuebunny/crossref_metadata_2025_split huggingface dataset:
G-quadruplex dynamics contribute to epigenetic regulation of mitochondrial function
Authors: Falabella M. , Kolesar J. E. , Xiang I. M. , Wang T. , Horne W. , Wallace C. , Sun L. , Taguchi Y. V. , Wang C. , Turek-Herman J. , St. Croix C. M. , Sondheimer N. , Yatsunyk L. A. , Johnson F. B. , Kaufman B. A. 
Published: July 2018

AbstractSingle-stranded DNA or RNA sequences rich in guanine (G) can adopt non-canonical structures known as G-quadruplexes (G4). Predicted G4-forming sequences in the mitochondrial genome are enriched on the heavy-strand and have been associated with formation of deletion breakpoints that cause mitochondrial disorders. However, the functional roles of G4 structures in regulating mitochondrial respiration in non-cancerous cells remain unclear. Here, we demonstrate that RHPS4, previously thought to be a nuclear G4-ligand, localizes primarily to mitochondria in live cells by mechanisms involving mitochondrial membrane potential. We find that RHPS4 exposure causes an acute inhibition of mitochondrial transcript elongation, leading to respiratory complex depletion. At higher ligand doses, RHPS4 causes mitochondrial DNA (mtDNA) replication pausing and genome depletion. Using these different levels of RHPS4 exposure, we describe discrete nuclear gene expression responses associated with mitochondrial transcription inhibition or with mtDNA depletion. Importantly, a mtDNA variant with increased anti-parallel G4-forming characteristic shows a stronger respiratory defect in response to RHPS4, supporting the conclusion that mitochondrial sensitivity to RHPS4 is G4-structure mediated. Thus, we demonstrate a direct role for G4 perturbation in mitochondrial genome replication, transcription processivity, and respiratory function in normal cells and describe the first molecule that differentially recognizes G4 structures in mtDNA.
Concordance of Genetic Variation that Increases Risk for Tourette Syndrome and that Influences its Underlying Neurocircuitry
Authors: Mufford Mary , Cheung Josh , Jahanshad Neda , van der Merwe Celia , Ding Linda , Groenewold Nynke , Koen Nastassja , Chimusa Emile R. , Dalvie Shareefa , Ramesar Raj ,   Psychiatric Genomics Consortium - Tourette Syndrome working group, Knowles James A. , Lochner Christine , Hibar Derrek P. , Paschou Peristera , van den Heuvel Odile A. , Medland Sarah E. , Scharf Jeremiah M. , Mathews Carol A. , Thompson Paul M. , Stein Dan J. 
Published: July 2018

ABSTRACTBACKGROUNDThere have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variations that increase risk for TS - and its main symptom dimensions - influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS.METHODSWe obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4,644 cases and 8,695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP Effect Concordance Analysis (SECA) was used to examine genetic pleiotropy - the same SNP affecting two traits - and concordance - the agreement in SNP effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage Disequilibrium Score Regression (LDSR) was used as validation of SECA.RESULTSSECA revealed significant pleiotropy between TS and putaminal (p=2×10−4) and caudal (p=4×10−4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p=1×10−3). LDSR lent additional support for the association between TS and thalamic volume (p=5.85×10−2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamic volume (p=1×10−3), as well as concordance between symmetry behaviour and greater putaminal volume (p=7×10−4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p<8×10−7) when conditioning on intracranial (rs2708146,q=0.046; and rs72853320,q=0.035 and hippocampal (rs1922786,q=0.001 volumes respectively.CONCLUSIONThese data indicate concordance for genetic variations involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.
Neuropsychological Test Performance of Cognitively Healthy Centenarians: Normative data from the Dutch 100-plus Study
Authors: Beker Nina , Sikkes Sietske A.M. , Hulsman Marc , Schmand Ben , Scheltens Philip , Holstege Henne 
Published: July 2018

ABSTRACTBackgroundThe population who reaches the extreme age of 100 years is growing. At this age, dementia incidence is high and cognitive functioning is variable and influenced by sensory impairments. Appropriate cognitive testing requires normative data generated specifically for this group. Currently, these are lacking. We set out to generate norms for neuropsychological tests in cognitively healthy centenarians while taking sensory impairments into account.MethodsWe included 235 centenarians (71.5% female) from the 100-plus Study, who self-reported to be cognitively healthy, which was confirmed by an informant and a trained researcher. Normative data were generated for 15 tests that evaluate global cognition, pre-morbid intelligence, attention, language, memory, executive and visuo-spatial functions by multiple linear regressions and/or percentiles. Centenarians with vision and/or hearing impairments were excluded for tests that required these faculties.ResultsSubjects scored on average 25.6±3.1 (range 17-30, interquartile-range 24-28) points on the MMSE. Vision problems and fatigue often complicated the ability to complete tests, and these problems explained 41% and 22% of the missing test scores respectively, whereas hearing problems (4%) and task incomprehension (6%) only rarely did. Sex and age showed a limited association with test performance, whereas educational level was associated with performance on the majority of the tests.ConclusionsNormative data for the centenarian population is provided, while taking age-related sensory impairments into consideration. Results indicate that, next to vision impairments, fatigue and education level should be taken into account when assessing cognitive functioning in centenarians.
Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure
Authors: Commowick Olivier , Istace Audrey , Kain Michaël , Laurent Baptiste , Leray Florent , Simon Mathieu , Pop Sorina Camarasu , Girard Pascal , Améli Roxana , Ferré Jean-Christophe , Kerbrat Anne , Tourdias Thomas , Cervenansky Frédéric , Glatard Tristan , Beaumont Jérémy , Doyle Senan , Forbes Florence , Knight Jesse , Khademi April , Mahbod Amirreza , Wang Chunliang , McKinley Richard , Wagner Franca , Muschelli John , Sweeney Elizabeth , Roura Eloy , Lladó Xavier , Santos Michel M. , Santos Wellington P. , Silva-Filho Abel G. , Tomas-Fernandez Xavier , Urien Hélène , Bloch Isabelle , Valverde Sergi , Cabezas Mariano , Vera-Olmos Francisco Javier , Malpica Norberto , Guttmann Charles , Vukusic Sandra , Edan Gilles , Dojat Michel , Styner Martin , Warfield Simon K. , Cotton François , Barillot Christian 
Published: July 2018

AbstractWe present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-the-art algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, …), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores.
Mendelian Randomization Analysis Using Mixture Models (MRMix) for Genetic Effect-Size-Distribution Leads to Robust Estimation of Causal Effects
Authors: Qi Guanghao , Chatterjee Nilanjan 
Published: July 2018

AbstractWe propose a novel method for robust estimation of causal effects in two-sample Mendelian randomization analysis using potentially large number of genetic instruments. We consider a “working model” for bi-variate effect-size distribution across pairs of traits in the form of normal-mixtures which assumes existence of a fraction of the genetic markers that are valid instruments, i.e. they have only direct effect on one trait, while other markers can have potentially correlated, direct and indirect effects, or have no effects at all. We show that model motivates a simple method for estimating causal effect (θ) through a procedure for maximizing the probability concentration of the residuals,, at the “null” component of a two-component normal-mixture model. Simulation studies showed that MRMix provides nearly unbiased or/and substantially more robust estimates of causal effects compared to alternative methods under various scenarios. Further, the studies showed that MRMix is sensitive to direction and can achieve much higher efficiency (up to 3–4 fold) relative to other comparably robust estimators. We applied the proposed methods for conducting MR analysis using largest publicly available datasets across a number of risk-factors and health outcomes. Notable findings included identification of causal effects of genetically determined BMI and ageat-menarche, which have relationship among themselves, on the risk of breast cancer; detrimental effect of HDL on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI, but no causal effect of years of education, on the risk of major depressive disorder.
A Mathematical Model of the Effect of Natural Selection on Adaptation Forms that Implemented by disruptive coloration of Taurotragus oryx
Authors: Bespalov Yu. G. , Nosov K. V. , Kabalyants P. S. 
Published: July 2018

In the study, results of mathematical modelling of the influence of natural selection on performance of various forms of animal adaptation to habitat conditions are presented. For a formalized description of the subject of study, we used a new class of mathematical models— discrete models of dynamical systems. Sets of strategies of protective coloration of antelopes Taurotragus oryx are the subject of a formalized description. Various combinations of brightness of green and red components of gray-brown non-uniform protective coloration of different parts of the silhouette of these animals were considered as such strategies. The sets based on the material of digital pictures of the two groups of Taurotragus oryx were compared. The first group includes antelopes Taurotragus oryx from Serengeti National Park (Tanzania) exposed to natural selection. The second group includes Taurotragus oryx, actually domesticated in Askania-Nova reserve (Ukraine), for which natural selection is not active. The sets of above mention strategies-combinations, modelled for the two groups, were compared by the numbers of unique combinations of values of brightness of red and green colours, as well as combinations with closest values of these brightness. The adaptive role of combinations with different values of red and green colours was identified with the role of idioadaptations. The adaptive role of combinations with equal values of red and green colours was identified with a more wide performance of aromorphoses. In this connection, the notions “quasi-idioadaptation” and “quasi-aromorphosis” were introduced in the paper.It is assumed that both quasi-aromorphoses and quasi-idiadaptations, in certain conditions, contribute to the destruction of an integral visual perception of the silhouette of an animal against a many-coloured background of vegetation. At that, assumed that an adaptation function of a quasi-aromorphosis can be implemented in a wider range of colorimetric parameters of a plant background. The results of modelling indicate that the coloration of Taurotragus oryx from Serengeti is characterized by a larger set of quasi-adaptations than coloration of Taurotragus oryx from Askania-Nova. In the coloration of the latter, there is no quasi-aromorphosis with maximum values of brightness of both red and green components. But there exists a quasi-aromorphosis in the coloration of Taurotragus oryx from Serengeti. Such results of mathematical modelling correspond to prevailing ideas about the influence of natural selection on the character of adaptive reactions of living beings.
Transcriptome analysis of Pv11 cells infers the mechanism of desiccation tolerance and recovery
Authors: Yamada Takahiro G , Suetsugu Yoshitaka , Deviatiiarov Ruslan , Gusev Oleg , Cornette Richard , Nesmelov Alexander , Hiroi Noriko , Kikawada Takahiro , Funahashi Akira 
Published: July 2018

ABSTRACTThe larvae of the African midge, Polypedilum vanderplanki, can enter an ametabolic state called anhydrobiosis to conquer fatal desiccation stress. The Pv11 cell line, derived from embryos of the midge, shows desiccation tolerance by pretreatment with trehalose before desiccation; they can resume proliferation after rehydration. To address the underlying molecular mechanisms, we desiccated Pv11 cells after pretreatment with the medium containing trehalose and induced proliferation by rehydration. We collected the cells at each before and after desiccation and rehydration step and performed CAGE-seq of mRNA of those cells. By analysing differentially expressed genes (DEGs) among the results of CAGE-seq, we detected 384 DEGs after trehalose treatment and 14 DEGs after rehydration. Hierarchical clustering of the identified DEGs indicated that rehydration returns their expression pattern to that in the control culture state. DEGs involved in various stress responses, detoxification of harmful chemicals, and regulation of oxidoreduction were upregulated by trehalose treatment. DEGs for rehydration supported that DNA repair is one of the potential mechanisms involves recovery. This study provided initial insight into the molecular mechanisms underlying the extreme desiccation tolerance of Pv11 cells with a potential for proliferation following rehydration.
Apparent thinning of visual cortex during childhood is associated with myelination, not pruning
Authors: Natu Vaidehi S. , Gomez Jesse , Barnett Michael , Jeska Brianna , Kirilina Evgeniya , Jaeger Carsten , Zhen Zonglei , Cox Siobhan , Weiner Kevin S. , Weiskopf Nikolaus , Grill-Spector Kalanit 
Published: July 2018

AbstractMicrostructural mechanisms underlying apparent cortical thinning during childhood development are unknown. Using functional, quantitative, and diffusion magnetic resonance imaging in children and adults, we tested if tissue growth (lower T1 relaxation time and mean diffusivity (MD)) or pruning (higher T1 and MD) underlies cortical thinning in ventral temporal cortex (VTC). After age 5, T1 and MD decreased in mid and deep cortex of functionally-defined regions in lateral VTC, and in their adjacent white matter. T1 and MD decreases were (i) consistent with tissue growth related to myelin proliferation, which we verified with adult postmortem histology and (ii) correlated with apparent cortical thinning. Thus, contrary to prevailing theories, cortical tissue does not thin during childhood, it becomes more myelinated, shifting the gray-white matter boundary deeper into cortex. As tissue growth is prominent in regions with protracted functional development, our data suggest an intriguing hypothesis that functional development and myelination are interlinked.
Intergenerational paternal effect of adult density inDrosophila melanogaster
Authors: Dasgupta Purbasha , Sarkar Saubhik , Das Akankshya A. , Verma Tanya , Nandy Bodhisatta 
Published: July 2018

AbstractNotwithstanding recent evidences, paternal environment is thought to be a potential but unlikely source of fitness variation that can affect trait evolution. Here we studied intergenerational effects of males’ exposure to varying adult density inDrosophila melanogasterlaboratory populations.We held sires at normal (N), medium (M) and high (H) adult densities for two days before allowing them to mate with virgin females. This treatment did not introduce selection through differential mortality. Further, we randomly paired males and females and allowed a single round of mating between the sires and the dams. We then collected eggs from the dams and measured the egg size. Finally, we investigated the effect of the paternal treatment on juvenile and adult (male) fitness components.We found a significant treatment effect on juvenile competitive ability where the progeny sired by the H-males had higher competitive ability. Since we did not find the treatment to affect egg size, this effect is unlikely to be mediated through variation in female provisioning.Male fitness components were also found to have a significant treatment effect: M-sons had lower dry weight at eclosion, higher mating latency and lower competitive mating success.While being the first study to show both adaptive and non-adaptive effect of the paternal density inDrosophila, our results highlight the importance of considering paternal environment as important source of fitness variation.
KS-Burden: Assessing distributional differences of rare variants in dichotomous traits
Authors: Porsch Robert M. , Mak Timothy , Tang Clara , Sham Pak C. 
Published: July 2018

AbstractA number of rare variant tests have been developed to explore the effect of low frequency genetic variations on complex phenotypes. However, an often neglected aspect in these tests is the position of genetic variations. Here we are proposing a way to assess the differences in spatial organization of rare variants by assessing their distributional differences between affected and unaffected subjects. To do so, we have formulated an adaptation of the well know Kolmogorov-Smirnov (KS) test, combining both KS and a simple gene burden approach, called KS-Burden.The performance of our test was evaluated under a comprehensive simulations framework using real data and various scenarios. Our results show that the KS-Burden test is able to outperform the commonly used SKAT-O test, as well as others, in the presents of clusters of causal variants within a genomic region. Furthermore, our test is able to maintain competitive statistical power in scenarios unfavorable to its original assumptions. Hence, the KS-Burden test is a valuable alternative to existing tests and provides better statistical power in the presents of causal clusters within a gene.
Comparative analysis of anther development in natural populations indicate premature degradation of sporogenous tissue as a cause of male sterility inGaultheria fragrantissima
Authors: Langstang Wympher , Kharshiing Eros , Venugopal Nagulan 
Published: July 2018

AbstractGaultheria fragrantissimaWall. (Ericaceae) is a gynodioecious species having both hermaphrodite and male sterile plants. In this study, we present a comparative analysis of the different stages of anther development in naturally occuring hermaphrodite and male sterile populations ofG. fragrantissimafound in Meghalaya, India. While hermaphrodite flowers had well developed anther lobes, the male sterile flowers formed a white unorganized mass of tissues with a tuft of hairy outgrowth at the tip of the stamens. Histological analyses of progressive anther development in both the lines indicate an abnormal development of the sporogenous tissue in the developing anthers in the male steril line. While anther development in the hermaphrodite line was of the dicotyledonous type, the anthers of male sterile line showed progressive degradation of the sporogenous tissues and wall layers. Pollen development was also disrupted in male sterile line resulting in distorted pollen due to the irregular projection of exine wall. Our results suggest that premature degradation of the sporogenous tissues during anther development determines male sterility inG. fragrantissima.
N-terminal BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands
Authors: Day Matthew , Rappas Mathieu , Ptasińska Katie , Boos Dominik , Oliver Antony W. , Pearl Laurence H. 
Published: July 2018

AbstractTOPBP1 and its fission yeast homologue Rad4, are critical players in a range of DNA replication, repair and damage signalling processes. They are composed of multiple BRCT domains, some of which have the capacity to bind phosphorylated motifs in other proteins. They thus act as multi-point adaptors bringing proteins together into functional combinations, dependent on post-translational modifications downstream of cell cycle and DNA damage signals. We have now structurally and/or biochemically characterised a sufficient number of high-affinity complexes for the conserved N-terminal region of TOPBP1 and Rad4 in complex with diverse phospho-ligands – which include human RAD9 and Treslin, as well as S.pombe Crb2 and Sld3 – to define the key determinants of BRCT domain specificity. We use this information to identify and characterise previously unknown phosphorylation-dependent TOPBP1/Rad4-binding motifs in human RHNO1 and the fission yeast homologue of MDC1, Mdb1. These results provide important insights into how multiple BRCT domains within TOPBP1/Rad4 achieve selective and combinatorial binding of their multiple partner proteins.