bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tankyrase inhibition sensitizes cells to CDK4 blockade
Authors: Foronda Miguel , Tarumoto Yusuke , Schatoff Emma M. , Leach Benjamin I. , Diaz Bianca J , Goswami Sukanya , Shusterman Michael , Vakoc Christopher R. , Dow Lukas E 
Published: June 2019

AbstractTankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the β-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition. We show that the loss of CDK4, but not CDK6, synergizes with TNKS1/2 blockade to drive G1 cell cycle arrest and senescence. Through precise modelling of cancer-associated mutations using cytidine base editors, we show that this therapeutic approach is absolutely dependent on suppression of canonical WNT signaling by TNKS inhibitors and is effective in cells from multiple epithelial cancer types. Together, our results suggest that combined WNT and CDK4 inhibition might provide a potential therapeutic strategy for difficult-to-treat epithelial tumors.
The causal role of circulating vitamin D concentrations in human complex traits and diseases: a large-scale Mendelian randomization study
Authors: Jiang Xia , Ge Tian , Chen Chia-Yen 
Published: June 2019

AbstractVitamin D has been associated with a variety of human complex traits and diseases in observational studies, but a causal relationship remains unclear. To examine a putative causal effect of vitamin D across phenotypic domains and disease categories, we conducted Mendelian randomization (MR) analyses using genetic instruments associated with circulating 25-hydroxyvitamin D [25(OH)D] concentrations. We leveraged genome-wide significant 25(OH)D-associated SNPs (N=138) from a meta-analysis combining a vitamin D GWAS conducted in 401,460 white British UK Biobank (UKBB) participants and an independent vitamin D GWAS including 42,274 samples of European ancestry, and examined 190 large-scale health-related GWAS spanning a broad spectrum of complex traits, diseases and biomarkers. We applied multiple MR methods to estimate the causal effect of vitamin D while testing and controlling for potential biases from horizontal pleiotropy. Consistent with previous findings, genetically predicted increased 25(OH)D levels significantly decreased the risk of multiple sclerosis (OR=0.824; 95%CI=0.689-0.986). The protective effect estimate was consistent across different MR methods and four different multiple sclerosis GWAS with varying sample sizes and genotyping platforms. On the contrary, we found limited evidence in support of a causal effect of 25(OH)D on anthropometric traits, obesity, cognitive function, sleep behavior, breast and prostate cancer, and autoimmune, cardiovascular, metabolic, neurological and psychiatric traits and diseases, and blood biomarkers. Our results may inform ongoing and future randomized clinical trials of vitamin D supplementation.
Mixture Network Regularization of Generalized Linear Model With Application in Genomics Data
Authors: Li Kaiqiao , Li Jialiang , Wang Xuefeng , Kuan Pei Fen 
Published: June 2019

AbstractHigh dimensional genomics data in biomedical sciences is an invaluable resource for constructing statistical prediction models. With the increasing knowledge of gene networks and pathways, such information can be utilized in the statistical models to improve prediction accuracy and enhance model interpretability. However, in certain scenarios the network structure may only be partially known or subject to inaccuracy. Thus, the performance of statistical models incorporating such network structure may be compromised. In this paper, we propose a weighted sparse network learning method by optimally combining a data driven network with sparsity property to prior known or partially known network to address this issue. We show that our proposed model attains the oracle property and achieves a parsimonious structure in high dimensional setting for different types of outcomes including continuous, binary and survival data. Simulations studies show that our proposed model is robust and outperforms existing methods. Case study on melanoma gene expression further demonstrates that our proposed model achieves good operating characteristics in identifying informative genes and predicting survival risk. An R package glmaag implementing our method is available on the Comprehensive R Archive Network (CRAN).
Mapping gene regulatory networks of primary CD4+T cells using single-cell genomics and genome engineering
Authors: Gate Rachel E. , Kim Min Cheol , Lu Andrew , Lee David , Shifrut Eric , Subramaniam Meena , Marson Alexander , Ye Chun J. 
Published: June 2019

AbstractGene regulatory programs controlling the activation and polarization of CD4+T cells are incompletely mapped and the interindividual variability in these programs remain unknown. We sequenced the transcriptomes of ~160k CD4+T cells from 9 donors following pooled CRISPR perturbation targeting 140 regulators. We identified 134 regulators that affect T cell functionalization, includingIRF2as a positive regulator of Th2polarization. Leveraging correlation patterns between cells, we mapped 194 pairs of interacting regulators, including known (e.g.BATFandJUN) and novel interactions (e.g.ETS1andSTAT6). Finally, we identified 80 natural genetic variants with effects on gene expression, 48 of which are modified by a perturbation. In CD4+T cells, CRISPR perturbations can influencein vitropolarization and modify the effects oftransandcisregulatory elements on gene expression.
Generalizing movement patterns following shoulder fixation
Authors: Maeda Rodrigo S. , Zdybal Julia M. , Gribble Paul L. , Pruszynski J. Andrew 
Published: June 2019

AbstractA common goal of motor learning is generalizing newly learned movement patterns beyond the training context. Here we tested whether learning a new physical property of the arm during self-initiated reaching generalizes to new arm configurations. One hundred human participants performed a single-joint elbow reaching task and/or countered mechanical perturbations that created pure elbow motion. Participants did so with the shoulder joint either free to rotate or locked by the robotic manipulandum. With the shoulder free, we found activation of shoulder extensor muscles for pure elbow extension trials, as required to counter the interaction torques that arise at the shoulder due to forearm rotation. After locking the shoulder joint, we found a substantial reduction in shoulder muscle activity that developed slowly over many trials. This reduction is appropriate because locking the shoulder joint cancels the interaction torques that arise at the shoulder to do forearm rotation and thus removes the need to activate shoulder muscles. In our first three experiments, we tested whether this reduction generalizes when reaching is self-initiated in (1) a different initial shoulder orientation, (2) a different initial elbow orientation and (3) for a different reach distance/speed. We found reliable generalization across initial shoulder orientation and reach distance/speed but not for initial elbow orientation. In our fourth experiment, we tested whether generalization is also transferred to feedback control by applying mechanical perturbations and observing reflex responses in a distinct shoulder orientation. We found robust transfer to feedback control.New & NoteworthyHere we show that learning to reduce shoulder muscles activity following shoulder fixation generalizes to other movement conditions but does not generalize globally, indicating that the nervous system does not implement such learning by modifying a general internal model of arm dynamics.DisclosuresThe authors declare no conflict of interest.
Epitope - based peptide vaccine against glycoprotein G of Nipah henipavirus using immunoinformatics approaches
Authors: Mohammed Arwa A. , Shantier Shaza W. , Mustafa Mujahed I. , Osman Hind K. , Elmansi Hashim E. , Osman Isam-Aldin A. , Mohammed Rawan A. , Abdelrhman Fatima A. , Elnnewery Mihad E. , Yousif Einas M. , M.Mustafa Marwa , Elfadol Nafisa M. , Abdalla Alaa I. , Mahmoud Eiman , Eltay Ahmed A. , Ahmed yassir A. , Hassan Mohamed A. 
Published: June 2019

AbstractBackgroundNipah virus (NiV) is a member of the genus Henipavirus of the family Paramyxoviridae, characterized by high pathogenicity and endemic in South Asia, first emerged in Malaysia in 1998. The case-fatality varies from 40% to 70% depending on the severity of the disease and on the availability of adequate healthcare facilities. At present no antiviral drugs are available for NiV disease and the treatment is just supportive. Clinical presentation ranges from asymptomatic infection to fatal encephalitis. Bats are the main reservoir for this virus, which can cause disease in humans and animals. The last investigated NiV outbreak has occurred in May 2018 in Kerala.ObjectiveThis study aims to predict effective epitope-based vaccine against glycoprotein G of Nipah henipavirus using immunoinformatics approaches.Methods and MaterialsGlycoprotein G of Nipah henipavirus sequence was retrieved from NCBI. Different prediction tools were used to analyze the nominee’s epitopes in BepiPred-2.0: Sequential B-Cell Epitope Predictor for B-cell, T-cell MHC class II & I. Then the proposed peptides were docked using Autodock 4.0 software program.Results and ConclusionsPeptide TVYHCSAVY shows a very strong binding affinity to MHC I alleles while FLIDRINWI shows a very strong binding affinity to MHC II and MHC I alleles. This indicates a strong potential to formulate a new vaccine, especially with the peptide FLIDRINWI that is likely to be the first proposed epitope-based vaccine against glycoprotein G of Nipah henipavirus. This study recommends an in-vivo assessment for the most promising peptides especially FLIDRINWI.
Inorganic salts and compatible solutes help mesophilic bacteria inhabit the high temperature waters of a Trans-Himalayan sulfur-borax spring
Authors: Mondal Nibendu , Roy Chayan , Peketi Aditya , Alam Masrure , Mapder Tarunendu , Mandal Subhrangshu , Fernandes Svetlana , Bhattacharya Sabyasachi , Rameez Moidu Jameela , Haldar Prabir Kumar , Volvoikar Samida Prabhakar , Nandi Nilanjana , Bhattacharya Tannisha , Mazumdar Aninda , Chakraborty Ranadhir , Ghosh Wriddhiman 
Published: June 2019

AbstractWhile geographically-/geologically-distinct hot springs harbor different levels of microbial diversity, some of them encompass several such taxa which have no strain reported for laboratory growth at >45°C. We, therefore, hypothesized that native geomicrobial factors could be potent determinants of the microbial habitability of hot spring environments. To test this hypothesis, aquatic microbial communities were revealed metataxonomically, and considered in the context of spring-water chemistry, along the 85-14°C hydrothermal gradient of a sulfur-boron spring namedLotus Pondlocated at 4,436 m, within the Puga geothermal area of the Indian Trans-Himalayan region of Ladakh. Water samples were studied from four distinct sites alongLotus Pond’s spring-water transit from the vent to an adjacent river calledRulang. Insinuations obtained from geomicrobiological data were tested via pure-culture growth experiments in habitat-inspired media. Microbial diversities were found to be high at all the sample-sites; majority of the genera identified at the 70-85°C sites were found to have no report of laboratory growth at >45°C; concurrently, these sample-sites had high concentrations of the kosmotropic solutes boron, lithium, sodium, sulfide, thiosulfate and sulfate, which are known to biophysically stabilize macromolecules. Based on the universal thermodynamic status of these solutes, we conjectured that they may be instrumental in helping mesophiles withstand highin situtemperatures. Corroboratively, growth experiments with a mesophilic, 80°C-isolate,ParacoccusSMMA_5 showed that at 50°C and 70°C, depending on the incubation-time, lithium/boron/sulfate/sodium/glycine-betaine either increases the number of colony-forming units present in the culture or arrests decline of the same. Incubations at 70°C, followed by fluorescein diacetate staining and flow cytometry, showed that these solutes keep more cells under viable condition than in ready-to-divide state. We concluded that kosmotropes and compatible solutes help mesophiles overcome the chaotropic effects of heat by augmenting such indigenous, entropy-minimizing biophysical mechanisms that apparently trade-off cell division for cell viability.
Dolosigranulum pigrum cooperation and competition in human nasal microbiota
Authors: Brugger Silvio D. , Eslami Sara M. , Pettigrew Melinda M. , Escapa Isabel F. , Henke Matthew T. , Kong Yong , Lemon Katherine P. 
Published: June 2019

AbstractBackgroundMultiple epidemiological studies identify Dolosigranulum pigrum as a candidate beneficial bacterium based on its positive association with health, including negative associations with nasal/nasopharyngeal colonization by the pathogenic species Staphylococcus aureus and Streptococcus pneumoniae.ResultsUsing a multipronged approach to gain new insights into D. pigrum function, we observed phenotypic interactions and predictions of genomic capacity that support a role for microbe-microbe interactions involving D. pigrum in shaping the composition of human nasal microbiota. We identified in vivo community-level and in vitro phenotypic cooperation by specific nasal Corynebacterium species. Also, D. pigrum inhibited S. aureus growth in vitro. Whereas, robust inhibition of S. pneumoniae required both D. pigrum and a nasal Corynebacterium together, and not either alone. D. pigrum L-lactic-acid production was insufficient to account for these inhibitions. Genomic analysis of 11 strains revealed that D. pigrum has a small genome (average 1.86 Mb) and multiple predicted auxotrophies consistent with D. pigrum relying on its human host and cocolonizing bacteria for key nutrients. Further, the accessory genome of D. pigrum encoded a diverse repertoire of biosynthetic gene clusters, some of which may have a role in microbe-microbe interactions.ConclusionsThese new insights into D. pigrum’s functions advance the field from compositional analysis to genomic and phenotypic experimentation on a potentially beneficial bacterial resident of the human upper respiratory tract and lay the foundation for future animal and clinical experiments.
Functional connectome linking child-parent relationships with psychological problems in adolescence
Authors: Itahashi Takashi , Okada Naohiro , Ando Shuntaro , Yamasaki Syudo , Koshiyama Daisuke , Morita Kentaro , Yahata Noriaki , Koike Shinsuke , Nishida Atsushi , Kasai Kiyoto , Hashimoto Ryu-ichiro 
Published: June 2019

AbstractPaternal- and maternal-child relationships are associated with partly distinct psychobehavioral problems, which often manifest differently between boys and girls. In order to understand neural mechanisms underlying complicated mappings between child-parent relationship and adolescents’ problems, we used a dataset of early adolescents (N=93) and separately estimated the effects of paternal- and maternal-child relationships on resting-state functional connectivity and problems in boys and girls. General linear models identified the effects of paternal- and maternal-child relationships in different sets of functional connectivity, which we termed functional brain connectomes associated with paternal- and maternal-child relationship (FBCp and FBCm), respectively. Subsequent connectome-based models using these FBCs significantly predicted aggressive behaviors only for boys and internalizing problems selectively only girls. Lastly, a causal discovery method identified causal paths from daughter-mother relationship to FBCm, and then to daughter’s internalizing problems. These observations highlight sex-dependent mechanisms linking child-parent relationship, brain, and psychobehavioral problems in early adolescence.
Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension
Authors: Gilinsky Michael A. , Polityko Yulia K. , Markel Arkady L. , Latysheva Tatyana V. , Samson Abraham O. , Polis Baruh , Naumenko Sergey E. 
Published: June 2019

AbstractGrowing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, to superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis.Recent preclinical investigations point to arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with non-proteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed.We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolites levels were amplified in normotonic but not in hypertensive rats following the treatment.The data indicate that L-norvaline is a potential antihypertensive agent, and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon the BP regulation.
Reproducible microbial community dynamics of two drinking water systems treating similar source waters
Authors: Potgieter Sarah C , Dai Zihan , Havenga Minette , Vosloo Solize , Sigudu Makhosazana , Pinto Ameet J , Venter Stefanus N 
Published: June 2019

AbstractUnderstanding whether the spatial-temporal dynamics of the drinking water microbiome are reproducible in full-scale drinking water systems is an important step towards devising engineering strategies to manipulate it. Yet, direct comparisons across full-scale drinking water systems are challenging because multiple factors, from source water to treatment process choice and configuration, can be unique to each system. This study compared the spatial-temporal dynamics of the drinking water microbiome in two drinking water treatment plants (DWTPs) with identical sequence of treatment strategies treating source waters from the same river system and with treated drinking water distributed in same large-scale (but independent) distribution system (DWDS) with similar disinfectant residual regiment. Dissimilarities in source water communities were tempered by the pre-disinfection treatments, resulting in highly similar post-filtration microbial communities between the two systems. However, high community turnover due to disinfection resulted in highly dissimilar microbial communities in the finished water between the two systems. Interestingly however, the microbial communities in the two systems increased in similarity during transit through the DWDS despite presence of a disinfectant residual. Overall our study finds that the drinking water microbiome demonstrated reproducible spatial and temporal dynamics within both independent but nearly identical DWTPs and their corresponding DWDSs.Graphical abstract
Intensity warping for multisite MRI harmonization
Authors: Wrobel J , Martin ML , Bakshi R , Calabresi PA , Elliot M , Raolf D , Gur RC , Gur RE , Henry RG , Nair G , Oh J , Papinutto N , Pelletier D , Reich DS , Rooney W , Satterthwaite TD , Stern W , Prabhakaran K , Sicotte N , Shinohara RT , Goldsmith J ,   on behalf of the NAIMS Cooperative
Published: June 2019

AbstractIn multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These “scanner effects” can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We assess scanner effects in two brain magnetic resonance imaging (MRI) studies where subjects were measured on multiple scanners within a short time frame, so that one could assume any differences between images were due to technical rather than biological effects. We propose mica (multisite image harmonization by CDF alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite trials so these can be reduced as a preprocessing step. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by warping intensity distributions. We further studied the ability to predict intensity harmonization results for a scan taken on an existing subject at a new site using cross-validation.
Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion
Authors: Brewer M. Kathryn , Uittenbogaard Annette , Austin Grant , McCarthy John J. , Segvich Dyann M. , DePaoli-Roach Anna , Roach Peter J. , Hodges Bradley L. , Zeller Jill , Pauly James R. , McKnight Tracy , Armstrong Dustin , Gentry Matthew S. 
Published: June 2019

AbstractLafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no effective therapy or cure. LD is caused by recessive mutations in theEPM2AorEPM2Bgenes that encode the glycogen phosphatase laforin and an E3 ubiquitin ligase malin, respectively. A hallmark of LD is the intracellular accumulation of abnormal and insoluble α-linked polysaccharide deposits known as Lafora bodies (LBs) in several tissues, including most regions of the brain. In mouse models of LD, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Since multiple groups have confirmed that neurodegeneration and epilepsy result from LB accumulation, a major focus in the field has shifted toward the development of therapies that reduce glycogen synthesis or target LBs for degradation with the goal of treating LD. Herein, we identify the optimal enzymes for degrading LBs, and we develop a novel therapeutic agent by fusing human pancreatic α-amylase to a cellpenetrating antibody fragment. This antibody-enzyme fusion (VAL-0417) degrades LBsin vitro, shows robust cellular uptake, and significantly reduces the LB loadin vivoinEpm2a-/- mice. VAL-0417 is a promising therapeutic for the treatment of LD and a putative precision therapy for an intractable epilepsy. Antibody-enzyme fusions represent a new class of antibody-based drugs that could be utilized to treat glycogen storage disorders and other diseases.One Sentence SummaryAn antibody-enzyme fusion delivering an amylase degrades the toxic polyglucosan bodies that cause Lafora disease, a fatal childhood epilepsy.