bluuebunny/crossref_metadata_2025_split huggingface dataset:
ProxECAT: Proxy External Controls Association Test. A new case-control gene region association test using allele frequencies from public controls
Authors: Hendricks AE , Billups S , Pike HNC , Farooqi IS , Zeggini E , Santorico SA , Barroso I , Dupuis J 
Published: February 2018

AbstractA primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous number of sequenced genomes, individual studies of complex traits are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) could be used as controls in these studies. Fully utilizing these and other existing sequencing resources has the potential to increase power and could be especially useful in studies where resources to sequence additional samples are limited. However, to date, these large, publicly available genetic resources remain underutilized, or even misused, in large part due to the lack of statistical methods that can appropriately use this summary level data. We present a new method to incorporate external controls in case-control analysis called ProxECAT (Proxy External Controls Association Test). ProxECAT estimates enrichment of rare variants within a gene region using internally sequenced cases and external controls. We evaluated ProxECAT in simulations and empirical analyses of obesity cases using both low-depth of coverage (7x) whole-genome sequenced controls and ExAC as controls. We find that ProxECAT maintains the expected type I error rate with increased power as the number of external controls increases. With an accompanying R package, ProxECAT enables the use of publicly available allele frequencies as external controls in case-control analysis.
Emergence of evolutionary stable communities through eco-evolutionary tunneling
Authors: Kotil Seyfullah Enes , Vetsigian Kalin 
Published: February 2018

AbstractEcological and evolutionary dynamics of communities are inexorably intertwined. The ecological state determines the fate of newly arising mutants, and mutations that increase in frequency can reshape the ecological dynamics. Evolutionary game theory and its extensions within adaptive dynamics (AD) have been the mathematical frameworks for understanding this interplay, leading to notions such as Evolutionary Stable States (ESS) in which no mutations are favored, and evolutionary branching points near which the population diversifies. A central assumption behind these theoretical treatments has been that mutations are rare so that the ecological dynamics has time to equilibrate after every mutation. A fundamental question is whether qualitatively new phenomena can arise when mutations are frequent. Here we describe an adaptive diversification process that robustly leads to complex ESS, despite the fact that such communities are unreachable through a step-by-step evolutionary process. Rather, the system as a whole tunnels between collective states over a short time scale. The tunneling rate is a sharply increasing function of the rate with which mutations arise in the population. This makes the emergence of ESS communities virtually impossible in small populations, but generic in large ones. Moreover, communities emerging through this process can spatially spread as single replication units that outcompete other communities. Overall, this work provides a qualitatively new mechanism for adaptive diversification and shows that complex structures can generically evolve even when no step-by-step evolutionary path exists.
Lung Cancer Explorer (LCE): an open web portal to explore gene expression and clinical associations in lung cancer
Authors: Cai Ling , Lin ShinYi , Zhou Yunyun , Yang Lin , Ci Bo , Zhou Qinbo , Luo Danni , Yao Bo , Tang Hao , Allen Jeffrey , Huffman Kenneth , Gazdar Adi , Heymach John , Wistuba Ignacio , Xiao Guanghua , Minna John , Xie Yang 
Published: February 2018

AbstractWe constructed a lung cancer-specific database housing expression data and clinical data from over 6,700 patients in 56 studies. Expression data from 23 “whole-genome” based platforms were carefully processed and quality controlled, whereas clinical data were standardized and rigorously curated. Empowered by this lung cancer database, we created an open access web resource – the Lung Cancer Explorer (LCE), which enables researchers and clinicians to explore these data and perform analyses. Users can perform meta-analyses on LCE to gain a quick overview of the results on tumor vs normal differential gene expression and expression-survival association. Individual dataset-based survival analysis, comparative analysis, and correlation analysis are also provided with flexible options to allow for customized analyses from the user.
Predicting Evolutionarily Stable Strategies from Functional Responses of Sonoran Desert Annuals to Precipitation
Authors: Cuello William S. , Gremer Jennifer R. , Trimmer Pete C. , Sih Andrew , Schreiber Sebastian J. 
Published: February 2018

AbstractFor many decades, researchers have studied how plants use bet-hedging strategies to insure against unpredictable, unfavorable conditions. We improve upon earlier analyses by explicitly accounting for how variable precipitation affects annual plant species’ bet-hedging strategies. We consider how the survival rates of dormant seeds (in a ‘seed bank’) interact with precipitation responses to influence optimal germination strategies. Specifically, we incorporate how response to resource availability (i.e. the amount of offspring (seeds) generated per plant in response to variation in desert rainfall) influences the evolution of germination fractions. Using data from 10 Sonoran Desert annual plants, we develop models that explicitly include these responses to model fitness as a function of precipitation. For each of the species, we identify the predicted evolutionarily stable strategies (ESS) for the fraction of seeds germinating each year and then compare our estimated ESS values to the observed germination fractions. We also explore the relative importance of seed survival and precipitation responses in shaping germination strategies by regressing ESS values and observed germination fractions against these traits. We find that germination fractions are lower for species with higher seed survival, with lower reproductive success in dry years, and with better yield responses in wet years. These results illuminate the evolution of bethedging strategies in an iconic system, and provide a framework for predicting how current and future environmental conditions may reshape those strategies.
Fierce selection and interference in B-cell repertoire response to chronic HIV-1
Authors: Nourmohammad Armita , Otwinowski Jakub , Łuksza Marta , Mora Thierry , Walczak Aleksandra M 
Published: February 2018

AbstractDuring chronic infection, HIV-1 engages in a rapid coevolutionary arms race with the host’s adaptive immune system. While it is clear that HIV exerts strong selection on the adaptive immune system, the characteristics of the somatic evolution that shape the immune response are still unknown. Traditional population genetics methods fail to distinguish chronic immune response from healthy repertoire evolution. Here, we infer the evolutionary modes of B-cell repertoires and identify complex dynamics with a constant production of better B-cell receptor mutants that compete, maintaining large clonal diversity and potentially slowing down adaptation. A substantial fraction of mutations that rise to high frequencies in pathogen engaging CDRs of B-cell receptors (BCRs) are beneficial, in contrast to many such changes in structurally relevant frameworks that are deleterious and circulate by hitchhiking. We identify a pattern where BCRs in patients who experience larger viral expansions undergo stronger selection with a rapid turnover of beneficial mutations due to clonal interference in their CDR3 regions. Using population genetics modeling, we show that the extinction of these beneficial mutations can be attributed to the rise of competing beneficial alleles and clonal interference. The picture is of a dynamic repertoire, where better clones may be outcompeted by new mutants before they fix.
Efficient differentiation of vascular endothelial cells from dermal-derived mesenchymal stem cells induced by endothelial cell lines conditioned medium
Authors: Zhou Ling , Niu Xuping , Liang Jiannan , Li Junqin , Li Jiao , Cheng Yueai , Meng Yanfeng , Wang Qiang , Yang Xiaoli , Wang Gang , Shi Yu , Dang Erle , Zhang Kaiming 
Published: February 2018

AbstractObjectiveTo directionally-differentiate dermis-derived mesenchymal stem cells (DMSCs) into vascular endothelial cells (VECs) in vitro, providing an experimental basis for studies on the pathogenesis and treatment of vascular diseases.MethodsAfter separation by adherent culture, VEC line supernatant, vascular endothelial growth factor (VEGF), bone morphogenetic protein-4 and hypoxia were used for the differentiation of VECs from DMSCs. The cell type was authenticated by flow cytometry, matrigel angiogenesis assay in vitro, and immunofluorescent staining during differentiation. The VEGF concentration was investigated by enzyme-linked immunosorbent assay.ResultsAfter 28 days of differentiation, the cell surface marker CD31 was significantly positive (80%-90%) by flow cytometry in the VEC line-conditioned culture, which was significantly higher than in the other groups. Differentiated DMSCs had the ability to ingest Dil-ac-LDL and vascularize in the conditioned culture, but not in the other groups. In the VEC line supernatant, the concentration of VEGF was very low. The VEGF concentration changed along with the differentiation into VECs in the medium of the conditioned culture group.ConclusionVEC line supernatant can induce the differentiation of DMSCs into VECs, possibly through the pathway except VEGF.
Regulation of midgut cell proliferation impacts Aedes aegypti susceptibility to dengue virus
Authors: Taracena Mabel L. , Bottino-Rojas Vanessa , Talyuli Octavio A.C. , Walter-Nuno Ana Beatriz , Oliveira José Henrique M. , Angleró-Rodriguez Yesseinia I. , Wells Michael B. , Dimopoulos George , Oliveira Pedro L. , Paiva-Silva Gabriela O. 
Published: February 2018

AbstractAedes aegypti is the vector of some of the most important vector-borne diseases like Dengue, Chikungunya, Zika and Yellow fever, affecting millions of people worldwide. The cellular processes that follow a blood meal in the mosquito midgut are directly associated with pathogen transmission. We studied the homeostatic response of the midgut against oxidative stress, as well as bacterial and dengue virus (DENV) infections, focusing on the proliferative ability of the intestinal stem cells (ISC). Inhibition of the peritrophic matrix (PM) formation led to an increase in ROS production by the epithelial cells in response to contact with the resident microbiota, suggesting that maintenance of low levels of ROS in the intestinal lumen is key to keep ISCs division in balance. We show that dengue virus infection induces midgut cell division in both DENV susceptible (Rockefeller) and refractory (Orlando) mosquito strains. However, the susceptible strain delays the activation of the regeneration process compared with the refractory strain. Impairment of the Delta/Notch signaling, by silencing the Notch ligand Delta using RNAi, significantly increased the susceptibility of the refractory strains to DENV infection of the midgut. We propose that this cell replenishment is essential to control viral infection in the mosquito. Our study demonstrates that the intestinal epithelium of the blood fed mosquito is able to respond and defend against different challenges, including virus infection. In addition, we provide unprecedented evidence that the activation of a cellular regenerative program in the midgut is important for the determination of the mosquito vectorial competence.
Mitochondrial ATP synthase dimers spontaneously self-associate driven by a long-ranged membrane-induced force
Authors: Anselmi Claudio , Davies Karen M. , Faraldo-Gómez José D. 
Published: February 2018

AbstractATP synthases populate the inner membranes of mitochondria, where they produce the majority of the ATP required by the cell. Cryo-electron tomograms of these membranes from yeast to vertebrates have consistently revealed a very precise organization of these enzymes. Rather than being scattered throughout the membrane, the ATP synthases form dimers, and these dimers are organized into rows that extend for hundreds of nanometers. These rows are only observed in the membrane invaginations known as cristae, specifically along their sharply curved edges. Although the presence of these macromolecular structures has been irrefutably linked to the proper development of cristae morphology, it has been unclear what drives the formation of the rows and why they are specifically localized in the cristae. We present the result of a quantitative molecular-simulation analysis that strongly suggests that the ATP synthase dimers organize into rows spontaneously, driven by a long-ranged attractive force that results from relief in the overall elastic strain of the membrane. This strain is caused by the V-like shape of the dimers, unique among membrane-protein complexes, which induces a strong deformation in the surrounding membrane. The process of row formation is therefore not a result of protein-protein interactions, or of a specific lipid composition of the membrane. We further hypothesize that once assembled, the ATP synthase dimer rows prime the inner mitochondrial membrane to develop folds and invaginations, by causing macroscopic membrane ridges that ultimately become the cristae edges. In this view, mitochondrial ATP synthases would contribute to the generation of a morphology that maximizes the surface area of the inner membrane, and thus ATP production. Finally, we outline the key experiments that would be required to verify or refute this hypothesis.
VideoTagger: User-Friendly Software for Annotating Video Experiments of Any Duration
Authors: Rennert Peter , Aodha Oisin Mac , Piper Matthew , Brostow Gabriel 
Published: February 2018

AbstractBackgroundScientific insight is often sought by recording and analyzing large quantities of video. While easy access to cameras has increased the quantity of collected videos, the rate at which they can be analyzed remains a major limitation. Often, bench scientists struggle with the most basic problem that there is currently no user-friendly, flexible, and open source software tool with which to watch and annotate these videos.ResultsWe have created the VideoTagger tool to address these and many of the other associated challenges of video analysis. VideoTagger allows non-programming users to efficiently explore, annotate, and visualize large quantities of video data, within their existing experimental protocols. Further, it is built to accept programmed plugins written in Python, to enable seamless integration with other sophisticated computer-aided analyses.We tested VideoTagger ourselves, and have a growing base of users in other scientific disciplines. Capitalising on the unique features of VideoTagger to play back infinite lengths of video footage at various speeds, we annotated 39h of a Drosophila melanogaster lifespan video, at approximately 10-15x faster than real-time. We then used these labels to train a machine-learning plugin, which we used to annotate an additional 538h of footage automatically. In this way, we found that flies fall over spontaneously with increasing frequency as they age, and also spend longer durations struggling to right themselves. Ageing in flies is typically defined by length of life. We propose that this new mobility measure of ageing could help the discovery of mechanisms in biogerontology, refining our definition of what healthy ageing means in this extremely small, but widely used, invertebrate.ConclusionsWe show how VideoTagger is sufficiently flexible for studying lengthy and/or numerous video experiments, thus directly improving scientists’ productivity across varied domains.
The tumor suppressor FBW7 and the vitamin D receptor are mutual cofactors
Authors: Salehi-Tabar Reyhaneh , Memari Babak , Wong Hilary , Rochel Natacha , White John H. 
Published: February 2018

ABSTRACTThe E3 ligase FBW7 targets drivers of cell cycle progression such as c-MYC for proteasomal degradation. It is frequently mutated in cancer, and is a tumor suppressor. Extensive epidemiological data links vitamin D deficiency to increased incidence of several cancers, although the underlying cancer-preventive mechanisms are poorly understood. Here, we show that hormonal 1,25-dihydroxyvitamin D3 (1,25D) rapidly stimulates the interaction of the VDR with FBW7, and that of FBW7 with c-MYC. In contrast, it blocks the association of FBW7 with c-MYC antagonist MXD1. 1,25D also enhances the association of FBW7, proteasome subunits, and ubiquitin with DNA-bound c-MYC, consistent with induced degradation of c-MYC on DNA. In addition to c-MYC, 1,25D accelerates the turnover of other FBW7 target proteins. Intriguingly, FBW7 is essential for optimalVDRgene expression. It is also recruited to VDR targets genes, and its depletion attenuates 1,25D-stimulated VDR DNA binding, transactivation, and cell cycle arrest. Thus, the VDR and FBW7 are mutual cofactors, which provides a molecular basis for the cancer-preventive actions of vitamin D through accelerated turnover of FBW7 target proteins.
HDGF supports anti-apoptosis and pro-fibrosis in pancreatic stellate cells of pancreatic cancer
Authors: Chen Yi-Ting , Wang Tso-Wen , Chang Tsung-Hao , Hsu Teng-Po , Chi Jhih-Ying , Hsiao Yu-Wei , Li Chien-Feng , Wang Ju-Ming 
Published: February 2018

ABSTRACTPancreatic cancer is refractory and characterized by extensively surrounding- and intra-tumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Activation of PSCs plays a pivotal role for developing fibrotic reactions to affect themselves or pancreatic cancer cells (PCCs). In the current study, we demonstrated that hepatoma-derived growth factor (HDGF) was secreted from transforming growth factor-β1 (TGF-β1)-treated PSCs. We found that HDGF contributed to anti-apoptosis of PSCs and led to synthesis and depositions of extracellular matrix proteins for stabilizing PSCs/PCCs tumor foci. CCAAT/enhancer binding protein δ (CEBPD) responds to TGF-β1 through a reciprocal loop regulation and further activated hypoxia inducible factor-1α (HIF-1α) contributed to up-regulation ofHDGFgene. It agrees with the observation that severe stromal growth positively correlated with stromal HDGF and CEBPD in pancreatic cancer specimens. Collectively, the identification of TGF-β1-activated CEBPD/HIF-1α/HDGF axis provides new insights for the novel discoveries of HDGF in anti-apoptosis and pro-fibrosis of PSCs and outgrowth of pancreatic cancer cells.
MACPET: Model-based Analysis for ChIA-PET
Authors: Vardaxis Ioannis , Drabløs Finn , Rye Morten B. , Lindqvist Bo Henry 
Published: February 2018

AbstractWe present Model-based Analysis for ChIA-PET (MACPET) which analyzes paired-end read sequences provided by ChIA-PET for finding binding sites of a protein of interest. MACPET uses information from both tags of each PET and searches for binding sites in a two-dimensional space, while taking into account different noise levels in different genomic regions. MACPET shows favorable results compared to MACS in terms of motif occurrence, spatial resolution and false discovery rate. Significant binding sites discovered by MACPET are involved in a higher number of significant 3D interactions than those discovered by MACS. MACPET is freely available on Bioconductor.
A catalog of microbial genes from the bovine rumen unveils a specialized and diverse biomass-degrading environment
Authors: Li Junhua , Zhong Huanzi , Ramayo-Caldas Yuliaxis , Terrapon Nicolas , Lombard Vincent , Potocki-Veronese Gabrielle , Estellé Jordi , Popova Milka , Yang Ziyi , Zhang Hui , Li Fang , Tang Shanmei , Chen Weineng , Chen Bing , Li Jiyang , Guo Jing , Martin Cécile , Maguin Emmanuelle , Xu Xun , Yang Huanming , Wang Jian , Madsen Lise , Kristiansen Karsten , Henrissat Bernard , Ehrlich Stanislav D. , Morgavi Diego P. 
Published: February 2018

AbstractBackgroundThe rumen microbiota provides essential services to its host and, through its role in ruminant production, contributes to human nutrition and food security. A thorough knowledge of the genetic potential of rumen microbes will provide opportunities for improving the sustainability of ruminant production systems. The availability of gene reference catalogs from gut microbiomes has advanced the understanding of the role of the microbiota in health and disease in humans and other mammals. In this work, we established a catalog of reference prokaryote genes from the bovine rumen.ResultsUsing deep metagenome sequencing we identified 13,825,880 non-redundant prokaryote genes from the bovine rumen. Compared to human, pig and mouse gut metagenome catalogs, the rumen is larger and richer in functions and microbial species associated with the degradation of plant cell wall material and production of methane. Genes encoding enzymes catalyzing the breakdown of plant polysaccharides showed a particularly high richness that is otherwise impossible to infer from available genomes or shallow metagenomics sequencing. The catalog expands by several folds the dataset of carbohydrate-degrading enzymes described in the rumen. Using an independent dataset from a group of 77 cattle fed 4 common dietary regimes, we found that only <0.1% of genes were shared by all animals, which contrast with a large overlap for functions, i.e. 63% for KEGG functions. Different diets induced differences in the relative abundance rather than the presence or absence of genes explaining the great adaptability of cattle to rapidly adjust to dietary changes.ConclusionsThese data bring new insights into functions, carbohydrate-degrading enzymes and microbes of the rumen that is complementing the available information on microbial genomes. The catalog is a significant biological resource enabling deeper understanding of phenotypes and biological processes and will be expanded as new data is made available.