bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reconstructing contact network structure and cross-immunity patterns from multiple infection histories
Authors: Christian Selinger , Samuel Alizon 
Published: July 2019

AbstractInteractions within a population shape the spread of infectious diseases but contact patterns between individuals are difficult to access. We hypothesised that key properties of these patterns can be inferred from multiple infection data in longitudinal follow-ups. We developed a simulator for epidemics with multiple infections on networks and analysed the resulting individual infection time series by introducing the concept of infection barcodes. We find that, depending on infection multiplicity and network sampling, infection barcode summary statistics can recover network properties such as degree distribution. Furthermore, we show that by mining infection barcodes for multiple infection patterns, one can detect immunological interference between pathogens (i.e. the fact that past infections in a host condition future probability of infection). The combination of individual-based simulations and barcode analysis of infection histories opens promising perspectives to infer and validate transmission networks and immunological interference for infectious diseases from longitudinal cohort data.Author summaryInfectious disease dynamics are constrained both by between-host contacts and pathogen interactions within a host. Furthermore, multiple parasites circulate such that hosts are infected (sometimes simultaneously) by a variety of strains or species. We hypothesise that multiple infection history can inform us about the networks on which parasites are transmitted, but also on within-host interactions such as immunological interference. We developed a simulator for multiple infections on networks. By combining intuitive novel metrics for multiple infection events and established tools from computational data analysis, we show that similarity in infection history between two hosts correlates with their proximity in the contact network. By analysing pathogens co-occurrence patterns within hosts, we also recover immunological interference at the population level. The demonstrated robustness of our results in terms of observability, network clustering, and pathogen diversity opens new perspectives to extract host contact and between-pathogen immunity information from longitudinal cohort data.
Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signalled to DNA damage by Ataxia Telangiectasia Mutated kinase
Authors: Suart Celeste E. , Perez Alma M. , Al-Ramahi Ismael , Maiuri Tamara , Botas Juan , Truant Ray 
Published: July 2019

ABSTRACTSpinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington’s Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.
Treatment with commonly used antiretroviral drugs induces a type I/III interferon signature in the gut in the absence of HIV infection
Authors: Hughes Sean M. , Levy Claire N. , Calienes Fernanda L. , Stekler Joanne D. , Pandey Urvashi , Vojtech Lucia , Berard Alicia R. , Birse Kenzie , Noël-Romas Laura , Richardson Brian , Golden Jackelyn B. , Cartwright Michael , Collier Ann C. , Stevens Claire E. , Curlin Marcel E. , Holtz Timothy H. , Mugo Nelly , Irungu Elizabeth , Katabira Elly , Muwonge Timothy , Lama Javier R. , Baeten Jared M. , Burgener Adam , Lingappa Jairam R. , McElrath M. Juliana , Mackelprang Romel , McGowan Ian , Cranston Ross D. , Cameron Mark J. , Hladik Florian 
Published: July 2019

AbstractTenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here we assessed the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induced type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r=0.91) and between the rectum and duodenum (r=0.81). Gene set testing also indicated stimulation of type I/III pathways in the ectocervix, as well as of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence staining confirmed IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN-I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.
Predicted genetic gains from introgressing chromosome segments from exotic germplasm into an elite soybean cultivar
Authors: Ru Sushan , Bernardo Rex 
Published: July 2019

AbstractBroadening the diversity of cultivated soybean [Glycine max(L.) Merrill] through introgression of exotic germplasm has been difficult. Our objectives were to 1) determine if introgressing specific chromosome segments (instead of quantitative trait locus alleles) from exotic soybean germplasm has potential for improving an elite cultivar, and 2) identify strategies to introgress and pyramid exotic chromosome segments into an elite cultivar. We estimated genomewide marker effects for yield and other traits in seven crosses between the elite line IA3023 and seven soybean plant introductions (PIs). We then predicted genetic gains from having ≤2 targeted recombinations per linkage group. When introgression was modeled for yield while controlling maturity in the seven PI × IA3023 populations, the predicted yield was 8 to 25% over the yield of IA3023. Correlated changes in maturity, seed traits, lodging, and plant height were generally small but were in the favorable direction. In contrast, selecting the best recombinant inbred (without targeted recombination) in each of the PI × IA3023 populations led to negative or minimal yield gains over IA3023. In one PI × IA3023 population, introgressing and pyramiding only two linkage groups from recombinant inbreds into IA3023 was predicted to achieve an 8% yield gain over IA3023 without sacrificing the performance of other traits. The probability of inheriting intact chromosomes was high enough to allow introgression and pyramiding of chromosome segments in 5-6 generations. Overall, our study suggested that introgressing specific chromosome segments is an effective way to introduce exotic soybean germplasm into an elite cultivar.Key messageTo improve an elite soybean line, introgress longer chromosome segments instead of QTL alleles from exotic germplasm.
SID-4/NCK-1 is important for dsRNA import in Caenorhabditis elegans
Authors: Bhatia Sonya , Hunter Craig P. 
Published: July 2019

AbstractRNA interference (RNAi) is sequence-specific gene silencing triggered by double-stranded (ds)RNA. When dsRNA is expressed or introduced into one cell and is transported to and initiates RNAi in other cells, it is called systemic RNAi. Systemic RNAi is very efficient in C. elegans and genetic screens for systemic RNAi defective (Sid) mutants have identified RNA transporters (SID-1, SID-2 and SID-5) and a signaling protein (SID-3). Here we report that SID-4 is nck-1, a C. elegans NCK-like adaptor protein. sid-4 null mutations cause a weak, dosesensitive, systemic RNAi defect and can be effectively rescued by SID-4 expression in target tissues only, implying a role in dsRNA import. SID-4 and SID-3 (ACK-1 kinase) homologs interact in mammals and insects, suggesting they may function in a common signaling pathway, however, a sid-3; sid-4 double mutants showed additive resistance to RNAi, suggesting that these proteins likely interact with other signaling pathways as well. A bioinformatic screen coupled to RNAi sensitivity tests identified 23 additional signaling components with weak RNAi defective phenotypes. These observations suggest that environmental conditions may modulate systemic RNAi efficacy, and indeed, sid-3 and sid-4 are required for growth temperature effects on systemic RNAi silencing efficiency.
Genetic risks of schizophrenia identified in a matched case-control study
Authors: Oishi Kengo , Niitsu Tomihisa , Kanahara Nobuhisa , Sato Yasunori , Iwayama Yoshimio , Toyota Tomoko , Hashimoto Tasuku , Sasaki Tsuyoshi , Takase Masayuki , Yoshikawa Takeo , Iyo Masaomi 
Published: July 2019

BackgroundGenetic association studies of schizophrenia may be confounded by the pathological heterogeneity and multifactorial nature of this disease. We demonstrated previously that combinations of the three functional single nucleotide polymorphisms (SNPs) rs10770141 of tyrosine hydroxylase (TH) gene, rs4680 of catechol-O-methyltransferase (COMT) gene, and rs1800497 of dopamine D2 receptor (DRD2) gene may be associated with schizophrenia onset, and we tested those associations herein. Methods: We conducted a secondary study of 2,542 individuals in age- and sex-matched case-control populations. The schizophrenia diagnosis was based on the DSM-IV. To reduce the influence of confounders (age and sex), we performed a propensity score matching analysis. Genotyping and associative analyses of rs10770141, rs4680, and rs1800497 with schizophrenia were performed. Results: We analyzed 1,271 schizophrenics (male/female: 574/698; age 47.4±13.9 years) and 1,271 matched controls (male/female: 603/669; age 46.5±13.4 years). The estimated odds ratios (ORs) were 1.245 (p<0.001) for rs4680, 1.727 (p<0.0001) for rs1800497, and 1.788 (p<0.0001) for rs10770141. Double SNP analyses revealed the ORs of 2.010 (p<0.0001) for the combination of rs4680*rs1800497, 1.871 (p<0.001) for rs1800497*rs10770141, and 1.428 (p=0.068) for rs4680*rs1800497. Among the individuals with any of the three double SNP risk combinations (which accounted for 35.8% of the involved patients), the estimated OR was 2.224 (p<0.0001). Conclusions: In this validation study, the combinations of functional polymorphisms related to dopaminergic genes were associated with the development of schizophrenia. Analyzing combinations of functional polymorphisms with the control of possible confounders may provide new insights for association research.
New interpretable machine learning method for single-cell data reveals correlates of clinical response to cancer immunotherapy
Authors: Greene Evan , Finak Greg , D’Amico Leonard A. , Bhardwaj Nina , Church Candice D. , Morishima Chihiro , Ramchurren Nirasha , Taube Janis M. , Nghiem Paul T. , Cheever Martin A. , Fling Steven P. , Gottardo Raphael 
Published: July 2019

AbstractHigh-dimensional single-cell cytometry is routinely used to characterize patient responses to cancer immunotherapy and other treatments. This has produced a wealth of datasets ripe for exploration but whose biological and technical heterogeneity make them difficult to analyze with current tools. We introduce a new interpretable machine learning method for single-cell mass and flow cytometry studies, FAUST, that robustly performs unbiased cell population discovery and annotation. FAUST processes data on a per-sample basis and returns biologically interpretable cell phenotypes that can be compared across studies, making it well-suited for the analysis and integration of complex datasets. We demonstrate how FAUST can be used for candidate biomarker discovery and validation by applying it to a flow cytometry dataset from a Merkel cell carcinoma anti-PD-1 trial and discover new CD4+ and CD8+ effector-memory T cell correlates of outcome co-expressing PD-1, HLA-DR, and CD28. We then use FAUST to validate these correlates in an independent CyTOF dataset from a published metastatic melanoma trial. Importantly, existing state-of-the-art computational discovery approaches as well as prior manual analysis did not detect these or any other statistically significant T cell sub-populations associated with anti-PD-1 treatment in either data set. We further validate our methodology by using FAUST to replicate the discovery of a previously reported myeloid correlate in a different published melanoma trial, and validate the correlate by identifying itde novoin two additional independent trials. FAUST’s phenotypic annotations can be used to perform cross-study data integration in the presence of heterogeneous data and diverse immunophenotyping staining panels, enabling hypothesis-driven inference about cell sub-population abundance through a multivariate modeling framework we callPhenotypic andFunctionalDifferentialAbundance (PFDA). We demonstrate this approach on data from myeloid and T cell panels across multiple trials. Together, these results establish FAUST as a powerful and versatile new approach for unbiased discovery in single-cell cytometry.
Liquid-liquid phase separation and fibrillization of tau are independent processes with overlapping conditions
Authors: Lin Yanxian , Fichou Yann , Zeng Zhikai , Hu Nicole Y. , Han Songi 
Published: July 2019

AbstractAmyloid aggregation of the microtubule binding protein tau is a hallmark of Alzheimer’s disease and many other neurodegenerative diseases. Recently, tau has been found to undergo liquid-liquid phase separation (LLPS) near physiological conditions. Although LLPS and aggregation have been shown to simultaneously occur under certain common conditions, it remains to be seen whether tau LLPS promotes aggregation, or if they are two independent processes. In this study, we address this question by combining multiple biochemical and biophysical assays in vitro. We investigated the impacts of LLPS on tau aggregation at three stages: conformation of tau, kinetics of aggregation and fibril quantity. We showed that none of these properties are influenced directly by LLPS, while amyloid aggregation propensity of tau can be altered without affecting its LLPS behavior. LLPS and amyloid aggregation of tau occur under overlapping conditions of enhanced intermolecular interactions and localization, but are two independent processes.
Predictors of arm non-use in chronic stroke: a preliminary investigation
Authors: Buxbaum Laurel J. , Varghese Rini , Stoll Harrison , Winstein Carolee J. 
Published: July 2019

AbstractBackgroundThe phenomenon of non-use after stroke is characterized by failure to use the contralesional arm despite adequate capacity. It has been suggested that non-use is a consequence of the greater effort and/or attention required to use the affected limb, but such accounts have not been tested, and we have poor understanding of the characteristics of individuals who exhibit non-use.ObjectiveWe aimed to provide preliminary evidence regarding the demographic, neuropsychological, and psychological factors that may influence non-use in chronic stroke.MethodsTwenty chronic stroke survivors (10 left and 10 right hemisphere stroke) with mild-to-moderate sensory-motor impairment on the upper extremity Fugl-Meyer (UEFM) were assessed with the Actual Amount of Use Test (AAUT), which measures the disparity between amount of use and quality of movement in “spontaneous” versus “forced” conditions. Participants were als assessed with measures of limb apraxia, spatial neglect, attention/arousal, and self-efficacy (confidence in arm movement). Using stepwise multiple regression, we determined whether demographic information and/or performance on these measures predicted AAUT non-use scores.ResultsScores on the UEFM as well as attention/arousal and self-efficacy predicted the degree of non-use. Attention/arousal predicted non-use above and beyond UEFM.ConclusionsGiven the complexity of the non-use phenomenon, it follows that a combination of impairment, attention/arousal, and perceived confidence predicted non-use behavior. That a measure of attention/arousal predicted non-use behavior above and beyond sensory-motor functioning highlights the importance of motivated engagement to drive use of the paretic limb. Larger-scale studies incorporating additional measures (e.g., mental health, lesion volume and white matter connectivity, pain, motivation) will be important for future investigations.
Bottleneck Size-Dependent Changes in the Genetic Diversity and Specific Growth Rate of a Rotavirus A Strain
Authors: Kadoya Syun-suke , Urayama Syun-ichi , Nunoura Takuro , Hirai Miho , Takaki Yoshihiro , Kitajima Masaaki , Nakagomi Toyoko , Nakagomi Osamu , Okabe Satoshi , Nishimura Osamu , Sano Daisuke 
Published: July 2019

ABSTRACTRNA viruses form a dynamic distribution of mutant swarm (termed “quasispecies”) due to the accumulation of mutations in the viral genome. The genetic diversity of a viral population is affected by several factors, including a bottleneck effect. Human-to-human transmission ex-emplifies a bottleneck effect in that only part of a viral population can reach the next susceptible hosts. In the present study, the rhesus rotavirus (RRV) strain of Rotavirus A was serially passaged five times at a multiplicity of infection (MOI) of 0.1 or 0.001 in duplicate (the 1st and 2nd lineages), and three phenotypes (infectious titer, cell binding ability and specific growth rate) were used to evaluate the impact of a bottleneck effect on the RRV population. The specific growth rate values of lineages passaged under the stronger bottleneck (MOI of 0.001) were higher after five passages. The nucleotide diversity also increased, which indicated that the mutant swarms of the lineages under the stronger bottleneck effect were expanded through the serial passages. The random distribution of synonymous and non-synonymous substitutions on rotaviral genome segments indicated that almost all mutations were selectively neutral. Simple simulations revealed that the presence of minor mutants could influence the specific growth rate of a population in a mutant frequency-dependent manner. These results indicate that a stronger bottleneck effect can create more sequence spaces for minor mutants originally existing in a hidden layer of mutant swarm.IMPORTANCEIn this study, we investigated a bottleneck effect on an RRV population, which may drastically impact a viral population structure. RRV populations were serially passaged under two levels of a bottleneck effect, which exemplified a human-to-human transmission. As a result, the genetic diversity and specific growth rate of RRV populations increased under the stronger bottleneck effect, which implied that a bottleneck could create a new sequence space in a population for minor mutants originally existing in a hidden layer of a mutant swarm of the double-stranded RNA virus. The results of this study suggest that the genetic drift caused by a bottleneck in a human-to-human transmission explains the random appearance of new genetic lineages causing viral outbreaks, which can be expected by the molecular epidemiology using next generation sequencing in which the viral genetic diversity within a viral population is investigated.
Antiviral and virucidal activities against herpes simplex viruses of umesu phenolics extracted from Japanese apricot
Authors: Nishide Mitsunori , Ikeda Keiko , Mimura Hisa , Yoshida Minoru , Mitani Takahiko , Hajime Koyama Augustine 
Published: July 2019

AbstractUmesu phenolics were obtained from the salt extracts of Japanese apricot (Nanko‐mume cultivar of Prunus mume Sieb. et Zucc.) as purified phenolics. The antiviral activities of umesu phenolics obtained were then examined against herpes simplex virus type 1 (HSV‐1) and type 2 (HSV‐2), enveloped DNA viruses. The phenolics inhibited the multiplication of these viruses when added to the culture media of the infected cells. This inhibition occurred at phenolic concentrations at which they showed no severe cytotoxicity. One‐step growth experiments showed that the eclipse period in the HSV‐1 multiplication process was extended in the presence of umesu phenolics and that the addition of phenolics after the completion of viral DNA replication did not affect their multiplication. More drastic effects were observed on virucidal activities against HSV‐1 and HSV‐2; the infectivity decreased to 0.0001 when infected cells were incubated with 3 mg/ml phenolics at 30°C for 5 min. These results demonstrate the antiviral and virucidal activities of umesu phenolics and suggest a potential pharmacological use for these phenolics as a sanitizing or preventive medicine against superficial HSV infections.
HprKXcc is a serine kinase that regulates virulence in the Gram‐negative phytopathogen Xanthomonas campestris
Authors: Li Rui‐Fang , Cui Ping , Wei Ping‐Zhen , Liu Xing‐Yan , Tang Ji‐Liang , Lu Guang‐Tao 
Published: July 2019

SummaryThe HprK serine kinase is a component of the phosphoenolpyruvate phosphotransferase system (PTS) of bacteria that generally regulates catabolite repression through phosphorylation/dephosphorylation of the PTS protein PtsH at a conserved serine residue. However, many bacteria do not encode a complete PTS or even have an HprK homologue. Xanthomonas campestris pv. campestris (Xcc) is a pathogen that cause black rot disease in crucifer plants and one of the few Gram‐negative bacteria that encodes a homologue of HprK protein (herein HprKXcc). To gain insight into the role of HprKXcc and other PTS‐related components in Xcc we individually mutated and phenotypically assessed the resulting strains. Deletion of hprK
Xcc demonstrated its requirement for virulence and other diverse cellular processes associated including extracellular enzyme activity, extracellular‐polysaccharide production and cell motility. Global transcriptome analyses revealed the HprKXcc had a broad regulatory role in Xcc. Additionally, through overexpression, double gene deletion and transcriptome analysis we demonstrated that hprK
Xcc shares an epistatic relationship with ptsH. Furthermore, we demonstrate that HprKXcc is a functional serine kinase, which has the ability to phosphorylate PtsH. Taken together, the data illustrates the previously unappreciated global regulatory role of HprKXcc and previously uncharacterized PTS components that control virulence in this pathogen.