bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting ion channel TRPM7 promotes thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation
Authors: Mendu Suresh K. , Schappe Michael S. , Moser Emily K. , Krupa Julia K. , Rogers Jason S. , Stipes Eric J. , Parker Clare A. , Braciale Thomas J. , Desai Bimal N. 
Published: May 2018

In BriefGenetic deletion of Trpm7 in T-cells or pharmacological inhibition of TRPM7 channel promotes the development of fully functional Treg cells by increasing IL-2Rα and STAT5-dependent FOXP3 expression in the developing thymocytes. The study identifies the ion channel TRPM7 as a putative drug target to increase Treg numbers in vivo and induce immunotolerance.HIGHLIGHTSIon channel TRPM7 controls Treg developmentThe deletion of Trpm7 in the T-cell lineage increases fully functional Treg cells in the peripheryTRPM7 negatively regulates Foxp3 expression by restraining IL-2-dependent STAT5 activationInhibition of TRPM7 channel by FTY720 promotes the development of functional Treg cellsSUMMARYThe thymic development of regulatory T cells (Treg), the crucial suppressors of the effector T cells (Teff), is governed by the transcription factor FOXP3. Despite the clinical significance of Treg cells, there is a dearth of druggable molecular targets capable of increasing Treg numbers in vivo. We report a surprising discovery that TRPM7 restrains Treg development by negatively regulating STAT5-dependent Foxp3 expression. The deletion of Trpm7 potentiates the thymic development of Treg cells, leads to a significantly higher frequency of functional Treg cells in the periphery and renders the mice highly resistant to T cell-dependent hepatitis. The deletion of Trpm7 or the inhibition of TRPM7 channel activity by the FDA-approved prodrug FTY720, increases IL-2 sensitivity through a feed forward positive feedback loop involving high IL-2Rα expression and STAT5 activation. Enhanced IL-2 signaling increases the expression of Foxp3 in thymocytes and promotes the development of Treg cells. Thus, TRPM7 emerges as the first ion channel that can be drugged to increase Treg numbers, revealing a novel pharmacological path toward the induction of immune tolerance.
Tau local structure shields amyloid motif and controls aggregation propensity
Authors: Chen Dailu , Drombosky Kenneth W. , Hou Zhiqiang , Sari Levent , Kashmer Omar M. , Ryder Bryan D. , Perez Valerie A. , Woodard DaNae R. , Lin Milo M. , Diamond Marc I. , Joachimiak Lukasz A. 
Published: May 2018

ABSTRACTTauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within tau’s repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306VQIVYK311. Using cross-linking mass spectrometry, intramolecular FRET, recombinant protein and synthetic peptide systems, in silico modeling, and cell models, we conclude that the aggregation prone 306VQIVYK311 motif forms metastable compact structures with the upstream sequence that modulates aggregation propensity. Disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis.
Assessing sustainability in North America’s ecosystems using criticality and information theory
Authors: Ramírez-Carrillo Elvia , López-Corona Oliver , Toledo-Roy Juan C. , Lovett Jon C. , de León-González Fernando , Osorio-Olvera Luis , Equihua Julian , Robredo Everardo , Frank Alejandro , Dirzo Rodolfo , Perez-Cirera Vanessa 
Published: May 2018

AbstractSustainability is a key concept in economic and policy debates. Nevertheless, it is usually treated only in a qualitative way and has eluded quantitative analysis. Here, we propose a sustainability index based on the premise that sustainable systems do not lose or gain Fisher Information over time. We test this approach using time series data from the AmeriFlux network that measures ecosystem respiration, water and energy fluxes in order to elucidate two key sustainability features: ecosystem health and stability. A novel definition of ecosystem health is developed based on the concept of criticality, which implies that if a system’s fluctuations are scale invariant then the system is in a balance between robustness and adaptability. We define ecosystem stability by taking an information theory approach that measures its entropy and Fisher information. Analysis of the Ameriflux consortium big data set of ecosystem respiration time series is contrasted with land condition data. In general we find a good agreement between the sustainability index and land condition data. However, we acknowledge that the results are a preliminary test of the approach and further verification will require a multi-signal analysis. For example, high values of the sustainability index for some croplands are counter-intuitive and we interpret these results as ecosystems maintained in artificial health due to continuous human-induced inflows of matter and energy in the form of soil nutrients and control of competition, pests and disease.
Solving scaffolding problem with repeats
Authors: Mandric Igor , Zelikovsky Alex 
Published: May 2018

AbstractOne of the most important steps in genome assembly is scaffolding. Increasing the length of sequencing reads allows assembling short genomes but assembly of long repeat-rich genomes remains one of the most interesting and challenging problems in bioinformatics. There is a high demand in developing computational approaches for repeat aware scaffolding. In this paper, we propose a novel repeat-aware scaffolder BATISCAF based on the optimization formulation for filtering out repeated and short contigs. Our experiments with five benchmarking datasets show that the proposed tool BATISCAF outperforms state-of-the-art tools. BATISCAF is freely available on GitHub: https://github.com/mandricigor/batiscaf.
REVA: a rank-based multi-dimensional measure of correlation
Authors: Afsari Bahman , Favorov Alexander , Fertig Elana J. , Cope Leslie 
Published: May 2018

AbstractThe neighbors principle implicit in any machine learning algorithm says that samples with similar labels should be close to one another in feature space as well. For example, while tumors are heterogeneous, tumors that have similar genomics profiles can also be expected to have similar responses to a specific therapy. Simple correlation coefficients provide an effective way to determine whether this principle holds when features and labels are both scalar, but not when either is multivariate. A new class of generalized correlation coefficients based on inter-point distances addresses this need and is called “distance correlation”. There is only one rank-based distance correlation test available to date, and it is asymmetric in the samples, requiring that one sample be distinguished as a fixed point of reference. Therefore, we introduce a novel, nonparametric statistic, REVA, inspired by the Kendall rank correlation coefficient. We use U-statistic theory to derive the asymptotic distribution of the new correlation coefficient, developing additional large and finite sample properties along the way. To establish the admissibility of the REVA statistic, and explore the utility and limitations of our model, we compared it to the most widely used distance based correlation coefficient in a range of simulated conditions, demonstrating that REVA does not depend on an assumption of linearity, and is robust to high levels of noise, high dimensions, and the presence of outliers. We also present an application to real data, applying REVA to determine whether cancer cells with similar genetic profiles also respond similarly to a targeted therapeutic.Author summarySometimes a simple question arises: how does the distance between two samples in multivariate space compare to another scalar value associated with each sample. Here, we propose theory for a nonparametric test to statistically test this association. This test is independent of the scale of the scalar data, and thus generalizable to any comparison of samples with both high-dimensional data and a scalar. We apply the resulting statistic, REVA, to problems in cancer biology motivated by the model that cancer cells with more similar gene expression profiles to one another can be expected to have a more similar response to therapy.
General Functional Connectivity: shared features of resting-state and task fMRI drive reliable and heritable individual differences in functional brain networks
Authors: Elliott Maxwell L. , Knodt Annchen R. , Cooke Megan , Kim M. Justin , Melzer Tracy R. , Keenan Ross , Ireland David , Ramrakha Sandhya , Poulton Richie , Caspi Avshalom , Moffitt Terrie E. , Hariri Ahmad R. 
Published: May 2018

AbstractIntrinsic connectivity, measured using resting-state fMRI, has emerged as a fundamental tool in the study of the human brain. However, due to practical limitations, many studies do not collect enough resting-state data to generate reliable measures of intrinsic connectivity necessary for studying individual differences. Here we present general functional connectivity (GFC) as a method for leveraging shared features across resting-state and task fMRI and demonstrate in the Human Connectome Project and the Dunedin Study that GFC offers better test-retest reliability than intrinsic connectivity estimated from the same amount of resting-state data alone. Furthermore, at equivalent scan lengths, GFC displays higher heritability on average than resting-state functional connectivity. We also show that predictions of cognitive ability from GFC generalize across datasets, performing as well or better than resting-state or task data alone. Collectively, our work suggests that GFC can improve the reliability of intrinsic connectivity estimates in existing datasets and, subsequently, the opportunity to identify meaningful correlates of individual differences in behavior. Given that task and resting-state data are often collected together, many researchers can immediately derive more reliable measures of intrinsic connectivity through the adoption of GFC rather than solely using resting-state data. Moreover, by better capturing heritable variation in intrinsic connectivity, GFC represents a novel endophenotype with broad applications in clinical neuroscience and biomarker discovery.
Learning Nonlinear Brain Dynamics: van der Pol Meets LSTM
Authors: Abrevaya Germán , Aravkin Aleksandr , Cecchi Guillermo , Rish Irina , Polosecki Pablo , Zheng Peng , Dawson Silvina Ponce 
Published: May 2018

AbstractMany real-world data sets, especially in biology, are produced by highly multivariate and nonlinear complex dynamical systems. In this paper, we focus on brain imaging data, including both calcium imaging and functional MRI data. Standard vector-autoregressive models are limited by their linearity assumptions, while nonlinear general-purpose, large-scale temporal models, such as LSTM networks, typically require large amounts of training data, not always readily available in biological applications; furthermore, such models have limited interpretability. We introduce here a novel approach for learning a nonlinear differential equation model aimed at capturing brain dynamics. Specifically, we propose a variable-projection optimization approach to estimate the parameters of the multivariate (coupled) van der Pol oscillator, and demonstrate that such a model can accurately represent nonlinear dynamics of the brain data. Furthermore, in order to improve the predictive accuracy when forecasting future brain-activity time series, we use this analytical model as an unlimited source of simulated data for pretraining LSTM; such model-specific data augmentation approach consistently improves LSTM performance on both calcium and fMRI imaging data.
Condensin controls cellular RNA levels through the accurate segregation of chromosomes instead of directly regulating transcription
Authors: Hocquet Clémence , Robellet Xavier , Modolo Laurent , Sun Xi-Ming , Burny Claire , Cuylen-Haering Sara , Toselli Esther , Clauder-Münster Sandra , Steinmetz Lars M. , Haering Christian H. , Marguerat Samuel , Bernard Pascal 
Published: May 2018

AbstractCondensins are genome organisers that shape chromosomes and promote their accurate transmission. Several studies have also implicated condensins in gene expression, although the mechanisms have remained enigmatic. Here, we report on the role of condensin in gene expression in fission and budding yeasts. In contrast to previous studies, we provide compelling evidence that condensin plays no direct role in the maintenance of the transcriptome, neither during interphase nor during mitosis. We further show that the changes in gene expression in post-mitotic fission yeast cells that result from condensin inactivation are largely a consequence of chromosome missegregation during anaphase, which notably depletes the RNA-exosome from daughter cells. Crucially, preventing karyotype abnormalities in daughter cells restores a normal transcriptome despite condensin inactivation. Thus, chromosome instability, rather than a direct role of condensin in the transcription process, changes gene expression. This knowledge challenges the concept of gene regulation by canonical condensin complexes.
Transparent Titanium Dioxide Nanotubes: Processing, Characterization, and Application in Establishing Cellular Response Mechanisms
Authors: Meyerink Jevin G. , Kota Divya , Wood Scott T. , Crawford Grant A. 
Published: May 2018

AbstractThe therapeutic applications of titanium dioxide nanotubes (TiO2 NTs) as osteogenic surface treatments for titanium (Ti)-based implants are largely due to the finely tunable physical characteristics of these nanostructures. As these characteristics change, so does the cellular response, yet the exact mechanisms for this relationship remains largely undefined. We present a novel TiO2 NT imaging platform that is suitable for use with live-cell imaging techniques, thereby enabling, for the first time, dynamic investigation of those mechanisms. In this work, fabrication methods for producing transparent TiO2 NTs with diameters of 56 ± 6 nm, 75 ± 7 nm, 92 ± 9 nm, and 116 ± 10 nm are described. To demonstrate the diagnostic potential of these TiO2 NT imaging platforms, the focal adhesion protein vinculin and actin cytoskeletal filaments were fluorescently tagged in osteoblasts and real-time, high-resolution fluorescent microscopy of live-cell interactions with TiO2 NT substrates were observed. The scope of such a platform is expected to extend far beyond the current proof-of-concept, with great potential for addressing the dynamic response of cells interacting with nanostructured substrates.
Age-specific differences in the dynamics of protective immunity to influenza
Authors: Ranjeva Sylvia , Subramanian Rahul , Fang Vicky J. , Leung Gabriel M. , Ip Dennis K. M. , Perera Ranawaka A. P. M. , Peiris J. S. Malik , Cowling Benjamin J. , Cobey Sarah 
Published: May 2018

AbstractInfluenza A viruses evolve rapidly to escape host immunity, such that individuals can be infected multiple times with the same subtype. The form and duration of protective immunity after each influenza infection are poorly understood. Here, we quantify the dynamics of protective immunity against influenza A virus infections by fitting individual-level mechanistic models to longitudinal serology from children and adults in a household cohort study. We find that most protection in children is explained by antibody titers measured by the hemagglutination inhibition (HI) assay. In contrast, in adults, HI antibody titers explain a smaller fraction of protection. Protection against circulating strains wanes to approximately 50% of peak levels 3.5-7 years after infection in both age groups, and wanes faster against influenza A(H3N2) than A(H1N1)pdm09. Protection against H3N2 lasts longer in adults than in children. Our results suggest that the focus of influenza antibody responses changes over time from the highly mutable hemagglutinin head to other epitopes, consistent with the immunological theory of original antigenic sin, and that this change of focus might affect protection. Additionally, we estimate that imprinting, or primary infection with a subtype of one phylogenetic group, has little to no effect on the risk of non-medically attended influenza infections in adults. We also find no evidence of long-term cross-protection between subtypes. This work underscores the need for longitudinal data on multiple components of the immune response to better understand the development of immunity and differences in susceptibility within populations.
Construction of high-density genetic maps and detection of QTLs associated with Huanglongbing infection in citrus
Authors: Huang Ming , Roose Mikeal L. , Yu Qibin , Du Dongliang , Zhang Yi , Deng zhanao , Irey Michael , Stover Ed , Gmitter Fredrick G. 
Published: May 2018

AbstractNo true resistance to Huanglongbing (HLB), a citrus disease associated with infection ofCandidatusLiberibacter asiaticus (CLas), is found within commercial citrus cultivars, though trifoliate orange (Poncirus trifoliata) has been described as resistant or tolerant. Through genotyping an intergeneric F1population by Genotyping-by-Sequencing, high-density SNP-based genetic maps were constructed separately for trifoliate orange and sweet orange (Citrus sinensis). Both genetic maps exhibited high synteny and high coverage of citrus genome. After exposure to intense HLB pressure for two years, Ct value of qPCR forCLas detection in leaves throughout ten time points during the next three years was above 35 in trifoliate oranges, under 28 in sweet oranges, and ranged from 24 to 38 and exhibited obvious segregation among progenies. Phenotypic data of percentage of healthy trees showed high correlation with the Ct value. By mapping the two traits at all time points, a total of nine clusters of QTLs were detected, of which five, respectively located on LG-t7 and LG-t8 of trifoliate orange map and LG-s3, LG-s5 and LG-s9 of sweet orange map, collectively explained a major part of the phenotypic variation. This study provides a starting point for citrus breeding to support long-term control of this devastating disease.Highlight1). Constructed the first high-density genetic map for trifoliate orange (Poncirus trifoliata)2). The first report on identification of QTLs related to Huanglongbing in citrus.AbbreviationsACPAsian citrus psyllidCLasCandidatusLiberibacter asiaticuscMcentiMorgansCtCycle thresholdHLBHuanglongbingIMInterval mappingKWKruskal-WallisLGLinkage groupLODLogarithm of oddsQTLQuantitative trait locusRADRestriction site associated DNArMQMrestricted multiple QTL mappingSNPSingle nucleotide polymorphism.
GenVectors: an integrative analytical tool for spatial genetics
Authors: Duarte Leandro , Lima Jacqueline Souza , Maestri Renan , Debastiani Vanderlei , Collevatti Rosane Garcia 
Published: May 2018

AbstractMetapopulations are sets of local populations connected by dispersal. While genetic turnover informs about the number of alleles shared by (meta)populations, a set of populations that do not share alleles with a second set may still show low genetic divergence to it. Recent secondary contact driven by anthropogenic habitat fragmentation and/or current climate change, for instance, may erase the historical track of genetic turnover. On the other hand, genetic turnover among sets of populations is expected to be related to the degree of genetic divergence among them if metapopulations become isolated from others due to vicariance or ancient dispersal. Yet, current analytical tools do not permit direct inference about alternative processes underlying spatial, environmental and/or biogeographic correlates of genetic turnover among populations. We introduce GenVectors, a new R package that offers flexible analytical tools that allow evaluating biogeographic or environmental correlates of genetic turnover among sets of local populations based on fuzzy set theory. Analyses implemented in GenVectors allow exploring the distribution of haplotypes or SNPs across sets of local populations. Moreover, GenVectors provides tools to analyze environmental or biogeographic correlates of haplotype or SNP turnover among sets of local populations by applying appropriate null models, which enable to discriminate history-driven genetic turnover (vicariance, ancient dispersal) from non-historical ones (recent secondary contact). Finally, we demonstrate the application of GenVectors in two empirical datasets, one based on single-locus marker (haplotypes) and other based on multi-loci marker (SNPs).
High-resolution genetic and phenotypic analysis of KIR2DL1 alleles and their association with pre-eclampsia
Authors: Huhn Oisin , Chazara Olympe , Ivarsson Martin , Retiere Christelle , Venkatesan Tim , Ghadially Hormas , Moffett Ashley , Sharkey Andrew , Colucci Francesco 
Published: May 2018

ABSTRACTKiller-cell immunoglobulin-like receptor (KIR) genes are inherited as haplotypes, expressed by NK cells and linked to outcomes of infectious diseases and pregnancy. Understanding how genotype relates to phenotype is difficult because of the extensive diversity of the KIR family. Indeed, high-resolution KIR genotyping and phenotyping in single NK cells in the context of disease association is lacking. Here, we describe a new method to separate NK cells expressing allotypes of the KIR2DL1 gene carried by the KIR A haplotype (KIR2DL1A) from those expressing KIR2DL1 alleles carried by the KIR B haplotype (KIR2DL1B). We find that in KIR AB heterozygous individuals, different KIR2DL1 allotypes can be detected both in peripheral blood and in uterine single NK cells. Using this new method, we demonstrate that both blood and uterine NK cells co-dominantly express KIR2DL1A and KIR2DL1B allotypes, but with a predominance of KIR2DL1A variants, which associate with enhanced NK cell function. In a case-control study of pre-eclampsia, we show that KIR2DL1A, not KIR2DL1B, associates with increased disease risk. This method will facilitate our understanding of how individual KIR2DL1 allelic variants affect NK cell function and contribute to disease risk.