bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benchmarking network propagation methods for disease gene identification
Authors: Picart-Armada Sergio , Barrett Steven J. , Willé David R. , Perera-Lluna Alexandre , Gutteridge Alex , Dessailly Benoit H. 
Published: October 2018

AbstractBackgroundIn-silico identification of potential disease genes has become an essential aspect of drug target discovery. Recent studies suggest that one powerful way to identify successful targets is through the use of genetic and genomic information. Given a known disease gene, leveraging intermolecular connections via networks and pathways seems a natural way to identify other genes and proteins that are involved in similar biological processes, and that can therefore be analysed as additional targets.ResultsHere, we systematically tested the ability of 12 varied network-based algorithms to identify target genes and cross-validated these using gene-disease data from Open Targets on 22 common diseases. We considered two biological networks, six performance metrics and compared two types of input gene-disease association scores. We also compared several cross-validation schemes and showed that different choices had a remarkable impact on the performance estimates. When seeding biological networks with known drug targets, we found that machine learning and diffusion-based methods are able to find novel targets, showing around 2-4 true hits in the top 20 suggestions. Seeding the networks with genes associated to disease by genetics resulted in poorer performance, below 1 true hit on average. We also observed that the use of a larger network, although noisier, improved overall performance.ConclusionsWe conclude that machine learning and diffusion-based prioritisers are suited for drug discovery in practice and improve over simpler neighbour-voting methods. We also demonstrate the large effect of several factors on prediction performance, especially the validation strategy, input biological network, and definition of seed disease genes.
Factors influencing leaf- and root-associated communities of bacteria and fungi across 33 plant orders in a grassland
Authors: Toju Hirokazu , Kurokawa Hiroko , Kenta Tanaka 
Published: October 2018

AbstractIn terrestrial ecosystems, plants interact with diverse taxonomic groups of bacteria and fungi in the phyllosphere and rhizosphere. Although recent studies based on high-throughput DNA sequencing have drastically increased our understanding of plant-associated microbiomes, we still have limited knowledge of how plant species in a species-rich community differ in their leaf and root microbiome compositions. In a cool-temperate semi-natural grassland in Japan, we compared leaf- and root-associated microbiomes across 138 plant species belonging to 33 plant orders. Based on the whole-microbiome inventory data, we analyzed how sampling season as well as the taxonomy, nativeness (native or alien), lifeform (herbaceous or woody), and mycorrhizal type of host plants could contribute to variation in microbiome compositions among co-occurring plant species. The data also allowed us to explore prokaryote and fungal lineages showing preferences for specific host characteristics. The list of microbial taxa showing significant host preferences involved those potentially having some impacts on survival, growth, or environmental resistance of host plants. Overall, this study provides a platform for understanding how plant and microbial communities are linked with each other at the ecosystem level.
Growth-factor like gene regulation is separable from survival and maturation in antibody secreting cells
Authors: Stephenson Sophie , Care Matthew A , Fan Im , Zougman Alexandre , Westhead David R , Doody Gina M , Tooze Reuben M 
Published: October 2018

AbstractRecurrent mutational activation of the MAP kinase pathway in plasma cell myeloma implicates growth factor-like signaling responses in the biology of antibody secreting cells (ASCs). Physiological ASCs survive in niche microenvironments, but how niche signals are propagated and integrated is poorly understood. Here we dissect such a response in human ASCs using an in vitro model. Applying time course expression data and parsimonious gene correlation networking analysis (PGCNA), we map expression changes that occur during the maturation of proliferating plasmablast to quiescent plasma cell under survival conditions including the potential niche signal TGFB3. This analysis demonstrates a convergent pattern of differentiation, linking UPR/ER stress to secretory optimization, co-ordinated with cell cycle exit. TGFB3 supports ASC survival while having a limited effect on gene expression including up-regulation of CXCR4. This is associated with a significant shift in response to SDF1 in ASCs with amplified ERK1/2 activation, growth factor-like immediate early gene regulation and EGR1 protein expression. Similarly, ASCs responding to survival conditions initially induce partially overlapping sets of immediate early genes, without sustaining the response. Thus, in human ASCs growth factor-like gene regulation is transiently imposed by niche signals but is not sustained during subsequent survival and maturation.
Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening
Authors: Arenaz Callao María Pilar , González del Río Rubén , Quintana Ainhoa Lucía , Thompson Charles J. , Mendoza-Losana Alfonso , Ramón-García Santiago 
Published: October 2018

ABSTRACTThe potential use of clinically approved beta-lactams for Buruli ulcer (BU) treatment was investigated with representative classes analyzed in vitro for activity against Mycobacterium ulcerans. Beta-lactams tested were effective alone and displayed a strong synergistic profile in combination with antibiotics currently used to treat BU, i.e. rifampicin and clarithromycin; this activity was further potentiated in the presence of the beta-lactamase inhibitor clavulanate. In addition, quadruple combinations of rifampicin, clarithromycin, clavulanate and beta-lactams resulted in multiplicative reductions in their minimal inhibitory concentration (MIC) values. The MIC of amoxicillin against a panel of clinical isolates decreased more than 200-fold within this quadruple combination. Amoxicillin/clavulanate formulations are readily available with clinical pedigree, low toxicity, and orally and pediatric available; thus, supporting its potential inclusion as a new anti-BU drug in current combination therapies.
Muller’s ratchet as a mechanism of frailty and multimorbidity
Authors: Govindaraju Diddahally R. , Innan Hideki 
Published: October 2018

Mutation accumulation has been proposed as a cause of senescence. In this process, both constitutional and recurrent mutations accumulate gradually and differentially among differentiating cells, tissues and organs, in relation to stage and age, analogous to Muller’s ratchet in asexually reproducing organisms. Latent and cascading deleterious effects of mutations might initiate steady “accumulation of deficits” in cells, leading to cellular senescence, and functional decline of tissues and organs, and ultimately manifest as frailties and disease. We investigated a few of these aspects in cell populations through modeling and simulation using the Moran birth-death process, under varied scenarios of mutation accumulation. Our results agree with the principle of Muller’s ratchet. The ratchet speed in a given tissue depends on the population size of cells, mutation rate, and selection coefficient. Additionally, deleterious mutations seem to rapidly accumulate particularly early in the life-course, during which the rate of cell division is high, thereby exerting a greater effect on cellular senescence. The speed of the ratchet afterward varies greatly between cells nested in tissues and tissues within organs due to heterogeneity in the life span and turnover rate of specific cell types. Importantly, the ratchet accelerates with age, resulting in a synergistic fitness decay in cell populations. We extend Fisher’s average excess concept and rank order scale to interpret differential phenotypic effects of mutation load in a given tissue. We conclude that classical evolutionary genetic models could explain partially, the origins of frailty, subclinical conditions, morbidity and health consequences of senescence.SignificanceFrailty is defined as physiological and functional decline of organs and organ systems, due to deficit accumulation from stochastic damages within the organism with advanced age. Equivalently, with age, both constitutional and somatic mutations accumulate gradually and differentially among cells, cell lineages, tissues, and organs. Since most mutations are deleterious, accumulation of random and recurrent mutations could create a “load,” on the genome and contextually express in the epigenome and phenotype spaces. Here we extend Muller’s ratchet principle to explain frailty and multi-morbidity using the Moran model and simulations. Our results agree with the Muller’s ratchet principle. We emphasize the need for considering cumulative effects of the entire spectrum of mutations for explaining the origin of frailty, sub-clinical conditions, and morbidity.
Computational noise in reward-guided learning drives behavioral variability in volatile environments
Authors: Findling Charles , Skvortsova Vasilisa , Dromnelle Rémi , Palminteri Stefano , Wyart Valentin 
Published: October 2018

AbstractWhen learning the value of actions in volatile environments, humans often make seemingly irrational decisions which fail to maximize expected value. We reasoned that these ‘non-greedy’ decisions, instead of reflecting information seeking during choice, may be caused by computational noise in the learning of action values. Here, using reinforcement learning (RL) models of behavior and multimodal neurophysiological data, we show that the majority of non-greedy decisions stems from this learning noise. The trial-to-trial variability of sequential learning steps and their impact on behavior could be predicted both by BOLD responses to obtained rewards in the dorsal anterior cingulate cortex (dACC) and by phasic pupillary dilation – suggestive of neuromodulatory fluctuations driven by the locus coeruleus-norepinephrine (LC-NE) system. Together, these findings indicate that most of behavioral variability, rather than reflecting human exploration, is due to the limited computational precision of reward-guided learning.
Comparative analysis of active sites in P-loop nucleoside triphosphatases suggests an ancestral activation mechanism
Authors: Shalaeva Daria N. , Cherepanov Dmitry A. , Galperin Michael Y. , Mulkidjanian Armen Y. 
Published: October 2018

AbstractP-loop nucleoside triphosphatases (NTPases) share common Walker A (P-loop) and Walker B sequence motifs and depend on activating moieties (Arg or Lys fingers or a K+ion). In search for a common catalytic mechanism, we combined structure comparisons of active sites in major classes of P-loop NTPases with molecular dynamics (MD) simulations of the Ras GTPase, a well-studied oncoprotein. Comparative structure analysis showed that positively charged activating moieties interact with gamma-phosphate groups of NTP substrates in all major classes of P-loop NTPases. In MD simulations, interaction of the activating Arg finger with the Mg-GTP-Ras complex led to the rotation of the gamma-phosphate group by 40 degrees enabling its interaction with the backbone amide group of Gly13. In all analyzed structures, the residue that corresponds to Gly13 of Ras was in a position to stabilize gamma-phosphate after its rotation, suggesting a common ancestral activation mechanism within the entire superfamily.
SMAP: exploiting high-throughput sequencing data of patient derived xenografts
Authors: Blum Yuna , de Reyniès Aurélien , Dusetti Nelson , Iovanna Juan , Marisa Laetitia , Nicolle Rémy 
Published: October 2018

AbstractBackgroundPatient-derived xenograft is the model of reference in oncology fordrug response analyses. Xenografts samples have the specificity to be composedof cells from both the graft and the host species. Sequencing analysis ofxenograft samples therefore requires specific processing methods to properlyreconstruct genomic profiles of both the host and graft compartments.ResultsWe propose a novel xenograft sequencing process pipeline termedSMAP for Simultaneous mapping. SMAP integrates the distinction of host andgraft sequencing reads to the mapping process by simultaneously aligning to bothgenome references. We show that SMAP increases accuracy of species-assignmentwhile reducing the number of discarded ambiguous reads compared to otherexisting methods. Moreover, SMAP includes a module called SMAP-fuz toimprove the detection of chimeric transcript fusion in xenograft RNAseq data. Finally, we apply SMAP on a real dataset and show the relevance of pathway andcell population analysis of the tumoral and stromal compartments.ConclusionsIn high-throughput sequencing analysis of xenografts, our resultsshow that: i. the use of ad hoc sequence processing methods is essential, ii. highsequence homology does not introduce a significant bias when proper methodsare used and iii. the detection of fusion transcripts can be improved using ourapproach. SMAP is available on GitHub: cit-bioinfo.github.io/SMAP.
OsJAZ9 overexpression improves potassium deficiency tolerance in rice by modulating jasmonic acid levels and signaling
Authors: Singh Ajit Pal , Pandey Bipin K. , Mehra Poonam , Chandan Ravindra Kumar , Jha Gopaljee , Giri Jitender 
Published: October 2018

AbstractPotassium (K) which makes around 2-10% of plants total dry biomass, when become deficient, makes the plants highly susceptible to both abiotic and biotic stresses. Recent evidences suggest overlapping transcriptional responses to K deficiency and Jasmonate (JA) treatment in plants. However, a link between these responses was missing. Notably, K deficiency and JA application produce similar phenotypic and transcriptional responses. Here, we used molecular, physiological and morphological studies to analyze the role of OsJAZ9 in JA homeostasis, K deficiency and sheath blight resistance. We raised OsJAZ9 overexpression, knockdown, translational reporter and C-terminal deleted translational reporter lines in rice to establish the role of JA signaling in K ion homeostasis and OsJAZ9 as a critical component of JA signaling for K deficiency response. OsJAZ9 overexpression and knockdown provide K deficiency tolerance and sensitivity, respectively, by modulating various K transporters and root system architecture. Furthermore, RNA Seq and JA profiling revealed an elevation of JA responsive genes and JA levels in OsJAZ9 OE lines under K deficiency. Our data provide clear evidence on the crucial role of JAZ repressor, OsJAZ9 in improving K deficiency tolerance in rice by altering JA levels and signaling.
Targeted RNA NextGenSeq profiling in oncology using single molecule molecular inversion probes
Authors: Lenting Krissie , van den Heuvel Corina N.A.M. , van Ewijk Anne , Tindall Elizabeth , Wei Ge , Kusters Benno , te Dorsthorst Maarten , ter Laan Mark , Huynen Martijn A. , Leenders William P. 
Published: October 2018

AbstractHundreds of biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals, leading to futile overtreatment. To acquire a comprehensive insight in aberrant actionable biological pathways in individual cancers we applied a cost-effective targeted RNA next generation sequencing (NGS) technique. The test allows NGS-based measurement of transcript levels and splice variants of hundreds of genes with established roles in the biological behavior in many cancer types. We here present proof of concept that the technique generates a correct molecular diagnosis and a prognosis for glioma patients. The test not only confirmed known brain cancer-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that are associated with other cancer types. Targeted RNA-NGS is therefore a highly attractive method to guide precision therapy for the individual patient based on pathway analysis.
In vitro characterization of human articular chondrocytes and chondroprogenitors derived from normal and osteoarthritic knee joints
Authors: Vinod Elizabeth , Kachroo Upasana , Sathishkumar Solomon , Boopalan P.R.J.V.C 
Published: October 2018

AbstractObjectiveCell based therapy optimization is constantly underway since regeneration of genuine hyaline cartilage is under par. Although single source derivation of chondrocytes and chondroprogenitors is advantageous, lack of a characteristic differentiating marker obscures clear identification of either cell type which is essential to create a biological profile and is also required to assess cell type superiority for cartilage repair. This study was the first attempt where characterization was performed on the two cell populations derived from the same human articular cartilage samples.DesignCells obtained from normal/osteoarthritic knee joints were expanded in culture (up to passage 10). Characterization studies was performed using flow cytometry, gene expression was studied using RT-PCR, growth kinetics and tri-lineage differentiation was also studied to construct a better biological profile of chondroprogenitors as well as chondrocytes.Results and conclusionsOur results suggest that sorting based on CD34(-), CD166(+) and CD146(+), instead of isolation using fibronectin adhesion assay (based on CD49e+/CD29+), would yield a population of cells primarily composed of chondroprogenitors which when derived from normal as opposed to osteoarthritic cartilage, could provide translatable results in terms of enhanced chondrogenesis and reduced hypertrophy; both indispensable for the field of cartilage regeneration.
The origin of fungi-culture in termites was associated with a shift to a mycolytic gut bacteria community
Authors: Hu Haofu , Rodrigues da Costa Rafael , Pilgaard Bo , Schiøtt Morten , Lange Lene , Poulsen Michael 
Published: October 2018

AbstractTermites forage on a range of substrates, and it has been suggested that diet shapes the composition and function of termite gut bacterial communities. Through comparative analyses of gut metagenomes in nine termite species with distinct diets, we characterise bacterial community compositions and identify biomass-degrading enzymes and the bacterial taxa that encode them. We find that fungus-growing termite guts are enriched in fungal cell wall-degrading and proteolytic enzymes, while wood-feeding termite gut communities are enriched for plant cell wall-degrading enzymes. Interestingly, wood-feeding termite gut bacteria code for abundant chitinolytic enzymes, suggesting that fungal biomass within the decaying wood likely contributes to gut bacteria or termite host nutrition. Across diets, the dominant biomass-degrading enzymes are predominantly coded for by the most abundant bacterial taxa, suggesting tight links between diet and gut community composition, with the most marked shift being the communities coding for the mycolytic capacity of the fungus-growing termite gut.
Integrating brain methylome with GWAS for psychiatric risk gene discovery
Authors: Han Shizhong , Lin Ying , Wang Minghui , Goes Fernando S. , Tan Kai , Zandi Peter , Hyde Thomas , Weinberger Daniel R. , Potash James B. , Kleinman Joel E. , Jaffe Andrew E. 
Published: October 2018

AbstractDNA methylation (DNAm) is heritable and plays a role in brain development and function through transcriptional regulation. Aberrant DNAm in human brain has been linked to psychiatric disorders, potentially as mediators of common genetic risk variants. In this study, we hypothesize that common risk variants for psychiatric disorders may act through affecting DNAm level in human brain. We first aimed to investigate the heritability pattern of DNAm levels in the human prefrontal cortex. Secondly, through imputation-driven methylome-wide association study (MWAS), we aimed to identify CpG sites whose methylation levels are genetically associated and that show methylation-trait associations in the prefrontal cortex of patients with schizophrenia or bipolar disorder. Our heritability analysis showed that, of ~370,000 CpG sites measured with the Illumina HumanMethylation450 microarray, 17% were heritable (p < 0.05), with a mean heritability of 0.22. Heritable CpG sites were enriched in intergenic regions, CpG shore, and regulatory regions in prefrontal cortex. Our MWAS approach identified known and potentially novel risk genes harboring CpG sites of methylation-trait associations for schizophrenia or bipolar disorder, which were not detectable using three alternative strategies (blood-based methylome reference, transcriptome-wide association study, and two gene-based association tests). Gene set enrichment analysis for genes with methylation-trait association evidence revealed pathways clearly related to neuronal functions, but also highlighted additional biological mechanisms that may underlie psychiatric disorders, such as microRNA-related regulation. In conclusion, our results showed the power of integrating brain methylation data with GWAS for psychiatric risk gene discovery, with potential applications in brain-related disorders or traits.
Electrochemical Evaluation of Ion Substituted-Hydroxyapatite on HeLa Cells Plasma Membrane Potential
Authors: Asimeng Bernard Owusu , Tiburu Elvis Kwason , Kuafmann Elsie Effah , Peamka Lily , Hayford Claude Fiifi , Essien-Baidoo Samuel , Dzikunu Obed Korshie , Anani Prince Atsu 
Published: October 2018

AbstractThis study reports the electrochemical activities of a novel ion substituted-Hydroxyapatite material in contact with HeLa cells. The work was performed to evaluate the inhibitory effects of various concentrations of the material on the ion transfer mechanisms in HeLa cells. The materials (n=2: HAp1 and HAp3) were prepared at different stirring times fromAchatina achatinasnail shells and phosphate-containing solution. The structure of the materials and the trace elements concentration were evaluated using x-ray diffractometry and infrared spectrometry as well as atomic absorption spectroscopy. Electrochemical studies conducted on the cells, after 30 min of exposure to the materials, demonstrated differential responses as elucidated by cyclic voltammetry. The voltammograms revealed HAp1 to be non-redox whereas HAp3 was redox active. Minimal concentrations of HAp1 showed high anodic peak current when compared to the HeLa cells alone, indicating a hyperpolarization of the cells. The peak current gradually reduced as the concentration of HAp1 was increased, and then a sudden rise suggesting inhibition of the cell action potential. HAp3 showed a wavy pattern of the anodic peak current when the material concentration was varied. Peak currents of 0.92 and 0.57 nA were recorded for HAp1 and HAp3, respectively at the highest concentration of 5μL. The results suggest that different inhibitory mechanisms are at play on the voltage-gated ion channels of the cells, indicating the possibility of using the materials to achieve different cancer proliferation inhibition.