bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating Heritability and Genetic Correlation in Case Control Studies Directly and with Summary Statistics
Authors: Weissbrod Omer , Flint Jonathan , Rosset Saharon 
Published: February 2018

AbstractMethods that estimate heritability and genetic correlations from genome-wide association studies have proven to be powerful tools for investigating the genetic architecture of common diseases and exposing unexpected relationships between disorders. Many relevant studies employ a case-control design, yet most methods are primarily geared towards analyzing quantitative traits. Here we investigate the validity of three common methods for estimating genetic heritability and genetic correlation. We find that the Phenotype-Correlation-Genotype-Correlation (PCGC) approach is the only method that can estimate both quantities accurately in the presence of important non-genetic risk factors, such as age and sex. We extend PCGC to work with summary statistics that take the case-control sampling into account, and demonstrate that our new method, PCGC-s, accurately estimates both heritability and genetic correlations and can be applied to large data sets without requiring individual-level genotypic or phenotypic information. Finally, we use PCGC-S to estimate the genetic correlation between schizophrenia and bipolar disorder, and demonstrate that previous estimates are biased due to incorrect handling of sex as a strong risk factor. PCGC-s is available athttps://github.com/omerwe/PCGCs.
Fission yeast cells overproducing HSET/KIFC1 provides a useful tool for identification and evaluation of human kinesin-14 inhibitors
Authors: Yukawa Masashi , Yamauchi Tomoaki , Kimura Ken-ichi , Toda Takashi 
Published: February 2018

ABSTRACTMany cancer cells contain more than two centrosomes, yet these cancer cells can form bipolar spindles and appear to proliferate normally, instead of committing lethal mitoses with multipolar spindles. It is shown that extra centrosomes are clustered into two pseudo-bipolar spindle poles, thereby escaping from multipolarity. Human kinesin-14 (HSET or KIFC1), a minus end-directed motor, plays a crucial role in centrosome clustering and as such, HSET is essential for cell viability only in cancer cells with supernumerary centrosomes, but not in non-transformed cells. Accordingly, HSET is deemed to be an efficient chemotherapeutic target to selectively kill cancer cells. Recently, three HSET inhibitors (AZ82, CW069 and SR31527) have been reported, but their specificity, efficacy and off-target cytotoxicity have not been evaluated rigorously. Here we show that these inhibitors on their own are cytotoxic to fission yeast, suggesting that they have other targets in vivo except for kinesin-14. Nonetheless, intriguingly, AZ82 can neutralize overproduced HSET and partially rescue its lethality. This methodology of protein overproduction in fission yeast provides a convenient, functional assay system by which to screen for not only selective human kinesin-14 inhibitors but also those against other molecules of interest.
Biological and clinical insights from genetics of insomnia symptoms
Authors: Lane Jacqueline M , Jones Samuel , Dashti Hassan S , Wood Andrew R , Aragam Krishna , van Hees Vincent T. , Brumpton Ben , Winsvold Bendik , Wang Heming , Bowden Jack , Song Yanwei , Patel Krunal , Anderson Simon G , Beaumont Robin , Bechtold David A , Cade Brian , Kathiresan Sek , Little Max A , Luik Annemarie I , Loudon Andrew S , Purcell Shaun , Richmond Rebecca C , Scheer Frank AJL , Tyrrell Jessica , Winkelman John ,   HUNT All In Sleep, Strand Linn B , Nielsen Jonas B. , Willer Cristen J. , Redline Susan , Spiegelhalder Kai , Kyle Simon D , Ray David W , Zwart John-Anker , Hveem Kristian , Frayling Timothy M , Lawlor Deborah , Rutter Martin K , Weedon Michael N , Saxena Richa 
Published: February 2018

ABSTRACTInsomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n=453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in Partners Biobank (n=2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis, phototransduction and muscle development pathways and of genes expressed in multiple brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being.One Sentence SummaryWe identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.
Thermoelectric Heat Exchange and Growth Regulation in a Continuous Yeast Culture
Authors: Latorre-Pérez Adriel , Vilanova Cristina , Alcaina José J , Porcar Manuel 
Published: February 2018

AbstractWe have designed a thermoelectric heat exchanger (TEHE) for microbial fermentations, able to control the temperature of a microbial continuous culture, and produce electric power. The system proved able to stably maintain both the temperature and the optical density of the culture during the exponential, highly productive phase.
Evaluation of redundancy analysis to identify signatures of local adaptation
Authors: Capblancq Thibaut , Luu Keurcien , Blum Michael G.B. , Bazin Eric 
Published: February 2018

ABSTRACTOrdination is a common tool in ecology that aims at representing complex biological information in a reduced space. In landscape genetics, ordination methods such as principal component analysis (PCA) have been used to detect adaptive variation based on genomic data. Taking advantage of environmental data in addition to genotype data, redundancy analysis (RDA) is another ordination approach that is useful to detect adaptive variation. This paper aims at proposing a test statistic based on RDA to search for loci under selection. We compare redundancy analysis to pcadapt, which is a nonconstrained ordination method, and to a latent factor mixed model (LFMM), which is a univariate genotype-environment association method. Individual-based simulations identify evolutionary scenarios where RDA genome scans have a greater statistical power than genome scans based on PCA. By constraining the analysis with environmental variables, RDA performs better than PCA in identifying adaptive variation when selection gradients are weakly correlated with population structure. Additionally, we show that if RDA and LFMM have a similar power to identify genetic markers associated with environmental variables, the RDA-based procedure has the advantage to identify the main selective gradients as a combination of environmental variables. To give a concrete illustration of RDA in population genomics, we apply this method to the detection of outliers and selective gradients on an SNP data set of Populus trichocarpa (Geraldes et al., 2013). The RDA-based approach identifies the main selective gradient contrasting southern and coastal populations to northern and continental populations in the northwestern American coast.
Disentangling eco-evolutionary effects on trait fixation
Authors: Czuppon Peter , Gokhale Chaitanya S. 
Published: February 2018

AbstractIn population genetics, fixation of traits in a demographically changing population under frequency-independent selection has been extensively analysed. In evolutionary game theory, models of fixation have typically focused on fixed population sizes and frequency-dependent selection. A combination of demographic fluctuations with frequency-dependent interactions such as Lotka-Volterra dynamics has received comparatively little attention. We consider a stochastic, competitive Lotka-Volterra model with higher order interactions between two traits. The emerging individual based model allows for stochastic fluctuations in the frequencies of the two traits and the total population size. We calculate the fixation probability of a trait under differing competition coefficients. This fixation probability resembles qualitatively the deterministic evolutionary dynamics. Furthermore, we partially disentangle the selection effects into their ecological and evolutionary components. We find that changing the evolutionary selection strength also changes the population dynamics and vice versa. Thus, a clean separation of the ecological and evolutionary effects is not possible. The entangled eco-evolutionary processes thus cannot be ignored when determining fixation properties in a co-evolutionary system.
Blue light advances bud burst in branches of three temperate deciduous tree species under short-day conditions
Authors: Brelsford Craig C. , Robson T Matthew 
Published: February 2018

AbstractDuring spring, utilising multiple cues allow temperate tree species to coordinate their bud burst and leaf out, at the right moment to capitalise on favourable conditions for photosynthesis. Whilst the effect of blue light (400-500nm) has been shown to increase percentage bud burst of axillary shoots ofRosasp, the effects of blue light on spring-time bud burst of temperate deciduous tree species has not previously been reported. We tested the hypotheses that blue light would advance spring bud burst in temperate tree species, and that late-successional species would respond more than early-successional species, who’s bud burst is primarily determined by temperature. The bud development ofAlnus glutinosa, Betula pendula, andQuercus roburbranches, cut from dormant trees, was monitored under two light treatments of equal photosynthetically active radiation (PAR, 400-700 nm) and temperature, either with or without blue light, under controlled environmental conditions. In the presence of blue light, the mean time required to reach 50% bud burst was reduced by 3.3 days inBetula pendula,6 days inAlnus glutinosa,and 6.3 days inQuercus robur. This result highlights the potential of the blue region of the solar spectrum to be used as an extra cue that could help plants to regulate their spring phenology, alongside photoperiod and temperature. Understanding how plants combine photoreceptor-mediated cues with other environmental cues such as temperature to control phenology is essential if we are to accurately predict how tree species might respond to climate change.Key MessageAn LED spectrum containing blue light advanced bud burst in branches ofBetula pendula, Alnus glutinosaandQuercus roburcompared with a spectrum without blue light in a controlled environment.
The divergence history of European blue mussel species reconstructed from Approximate Bayesian Computation: the effects of sequencing techniques and sampling strategies
Authors: Fraïsse Christelle , Roux Camille , Gagnaire Pierre-Alexandre , Romiguier Jonathan , Faivre Nicolas , Welch John J. , Bierne Nicolas 
Published: February 2018

AbstractGenome-scale diversity data are increasingly available in a variety of biological systems, and can be used to reconstruct the past evolutionary history of species divergence. However, extracting the full demographic information from these data is not trivial, and requires inferential methods that account for the diversity of coalescent histories throughout the genome. Here, we evaluate the potential and limitations of one such approach. We reexamine a well-known system of mussel sister species, using the joint site frequency spectrum (jSFS) of synonymous mutations computed either from exome capture or RNA-seq, in an Approximate Bayesian Computation (ABC) framework. We first assess the best sampling strategy (number of: individuals, loci, and bins in the jSFS), and show that model selection is robust to variation in the number of individuals and loci. In contrast, different binning choices when summarizing the joint site frequency spectrum, strongly affect the results: including classes of low and high frequency shared polymorphisms can more effectively reveal recent migration events. We then take advantage of the flexibility of ABC to compare more realistic models of speciation, including variation in migration rates through time (i.e. periodic connectivity) and across genes (i.e. genome-wide heterogeneity in migration rates). We show that these models were consistently selected as the most probable, suggesting that mussels have experienced a complex history of gene flow during divergence and that the species boundary is semi-permeable. Our work provides a comprehensive evaluation of ABC demographic inference in mussels based on the coding site frequency spectrum, and supplies guidelines for employing different sequencing techniques and sampling strategies. We emphasize, perhaps surprisingly, that inferences are less limited by the volume of data, than by the way in which they are analyzed.
Sensory neurons sprouting is dependent on osteoclast-derived extracellular vesicles involving the activation of epidermal growth factor receptors
Authors: Neto Estrela , Leitão Luís , Mateus José , Sousa Daniela M. , Conceição Francisco , Alves Cecília J. , Oreffo Richard O. C. , West Jonathan , Aguiar Paulo , Lamghari Meriem 
Published: February 2018

AbstractThe patterning of peripheral innervation is accomplished through the tissue expression, in specific space and timeframe, of attractive or repulsive axonal guidance cues. At the bone microenvironment, neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, vascular endothelial growth factor, netrin-1 and others were described to regulate the nerve ingrowth towards the bone compartment, by acting directly on receptors expressed at the nerve terminals. Interestingly, besides the gradient of soluble factors, neurons were described to be responsive to extracellular vesicles (EV) derived from myelinating cells and mesenchymal stem cells.Here we provide evidence on a new mechanism by which peripheral innervation can be coordinated. We show that sensory nerves outgrowth and electric signal propagation are dependent on the EV secreted by osteoclasts, the bone resorbing cells. Furthermore, we demonstrate that the axonal sprouting is achieved through the activation of epidermal-growth factor receptor (EGFR) family signaling pathway. We proved that the EV-depleted osteoclast secretome leads to a significant decrease of neurons firing rate and axonal sprouting, concomitant with a decrease of EGFR/ErbB2 activation levels. Excitingly, the proteomic analysis of the osteoclast-derived EV cargo shows a high correlation with synaptic components reinforcing the role on sensory neurons/osteoclast crosstalk.Our findings that osteoclast-derived EV hold effect in axonal outgrowth, contributing actively to the dynamics of the sensory neurons sprouting and electrophysiology, is a step toward unraveling target mechanisms to control electrical signal propagation and nerve fibers sprouting and consequently open new avenues for the development of innovative therapies to control bone pain.Significance StatementSensory nerve fibers sprouting in bone pathologies is highly associated with pain. Thus, understanding the mechanisms behind sensory nerves ingrowth, sprouting and electrical activity, within the bone compartment, is essential for improving the strategies to overcome pain in bone disorders. We provide a new mechanism on the sensory nerves sprouting, indicating that the effect is dependent on the extracellular vesicles (EV) released by osteoclasts, through the epidermal growth factor receptor family targeting, by integrin independent pathways. We show different electrophysiology patterns being triggered in the presence of osteoclasts secretome and the abolishment of sensory neurons firing rate in EV-depleted conditions. Overall, our results elucidate novel mechanisms on the peripheral nerves sprouting, essential for pursuing new targets for bone pain therapies.
Inhibitor of apoptosis proteins determine glioblastoma stem-like cells fate depending on oxygen level
Authors: Soubéran Aurélie , Cappaï Jessica , Chocry Mathieu , Nuccio Christopher , Raujol Julie , Colin Carole , Lafitte Daniel , Kovacic Hervé , Quillien Véronique , Baeza-Kallee Nathalie , Rougon Geneviève , Figarella-Branger Dominique , Tchoghandjian Aurélie 
Published: February 2018

AbstractIn glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and non-apoptotic processes. Here we used GDC-0152, a small molecule IAP inhibitor, to explore how IAPs participate in glioblastoma stem-like cell maintenance and fate under both hypoxic and normoxic environments. In hypoxia, IAPs inhibition triggered stem-like cells apoptosis and decreased proliferation in four human glioblastoma cell lines, whereas in normoxia it induced a loss of stemness and differentiation. In addition, we characterized a 3D glioblastoma spheroid model. By using MALDI images we validated that GDC-0152 penetrates in the entire sphere. TOF-SIMS analyses revealed an oxygen gradient correlated with spatial cellular heterogeneity with proliferative and apoptotic cells located close to the hypoxic core and GFAP+cells at the periphery. Notably, Serine-Threonine Kinases activation analysis revealed that oxygen level affects signaling pathways activated by GDC-0152. In hypoxia, IAPs inhibition activated ATR whereas in normoxia it activated NF-κB. Our data brings new mechanistic insights revealing the dual role of IAPs inhibitors like GDC-0152 that are relevant to their therapeutic application in tumors like glioblastomas.
Long-range Notch-mediated tissue patterning requires actomyosin contractility
Authors: Hunter Ginger L , He Li , Perrimon Norbert , Charras Guillaume , Giniger Edward , Baum Buzz 
Published: February 2018

AbstractDynamic, actin-based protrusions function in cell-cell signaling in a variety of systems. In the dorsal thorax of the developing fly, basal protrusions enable non-neighboring epithelial cells to touch, extending the range over which Notch-mediated lateral inhibition can occur during bristle patterning. Given that actin-based cell protrusions can exert mechanical forces on their environment and Notch receptor activation is mechanically sensitive, how might cytoskeletal contractility contribute to Notch signaling? We identify a pool of basal non-muscle myosin II (myosin II) that regulates protrusion dynamics, promotes Notch signaling, and is required in signal sending and receiving cells for Notch-dependent patterning. We show that interactions between protrusions are extensive and subject to actomyosin contractility. The effects of reducing myosin II activity are more pronounced for protrusion-mediated signaling than for signaling at lateral cell contacts. Together, these results reveal a role for actomyosin contractility in Notch activation, signaling, and patterning in a developmental context.
The national alert-response strategy against cholera in Haiti: a four-year assessment of its implementation
Authors: Rebaudet Stanislas , Bulit Gregory , Gaudart Jean , Michel Edwige , Gazin Pierre , Evers Claudia , Beaulieu Samuel , Abedi Aaron Aruna , Osei Lindsay , Barrais Robert , Pierre Katilla , Moore Sandra , Boncy Jacques , Adrien Paul , Beigbeder Edouard , Guillaume Florence Duperval , Piarroux Renaud 
Published: February 2018

AbstractBackgroundA massive cholera epidemic struck Haiti on October 2010. As part of the national cholera elimination plan, the Haitian government, UNICEF and other international partners launched a nationwide alert-response strategy from July 2013. This strategy established a coordinated methodology to rapidly target cholera-affected communities with WaSH (water sanitation and hygiene) response interventions conducted by field mobile teams. An innovative red-orange-green alert system was established, based on routine surveillance data, to weekly monitor the epidemic.Methodology/Principal findingsWe used cholera consolidated surveillance databases, alert records and details of 31,306 response interventions notified by WaSH mobile teams to describe and assess the implementation of this approach between July 2013 and June 2017. Response to red and orange alerts was heterogeneous across the country, but significantly improved throughout the study period so that 75% of red and orange alerts were responded within the same epidemiological week during the 1st semester of 2017. Numbers of persons educated about cholera, houses decontaminated by chlorine spraying, households which received water chlorination tablets and water sources that were chlorinated during the same week as cholera alerts significantly increased. Alerts appeared to be an interesting and simple indicator to monitor the dynamic of the epidemic and assess the implementation of response activities.Conclusions/SignificanceThe implementation of a nationwide alert-response strategy against cholera in Haiti was feasible albeit with certain obstacles. Its cost was less than USD 8 million per year. Continuing this strategy seems essential to eventually defeat cholera in Haiti while ambitious long-term water and sanitation projects are conducted in vulnerable areas. It constitutes a core element of the current national plan for cholera elimination of the Haitian Government.
Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons
Authors: Venkatesh Ishwariya , Mehra Vatsal , Wang Zimei , Califf Ben , Blackmore Murray G. 
Published: February 2018

ABSTRACTAxon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age-dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome-wide maps of chromatin accessibility. When applied to the developing cortex, this pipeline detected overall closure of chromatin in sub-networks of genes associated with axon growth. We next analyzed mature CNS neurons that were supplied with various pro-regenerative transcription factors. Unlike prior results with SOX11 and KLF7, here we found that neither JUN nor an activated form of STAT3 promoted substantial corticospinal tract regeneration. Correspondingly, chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7. Finally, we used the pipeline to predict pioneer factors that could potentially relieve chromatin constraints at growth-associated loci. Overall this integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments.