bluuebunny/crossref_metadata_2025_split huggingface dataset:
A boosted unbiased molecular dynamics method for predicting ligands binding mechanisms: Probing the binding pathway of dasatinib to Src-kinase
Authors: Sohraby Farzin , Moghadam Mostafa Javaheri , Aliyar Masoud , Aryapour Hassan 
Published: May 2019

AbstractSmall molecules such as metabolites and drugs play essential roles in biological processes and pharmaceutical industry. Knowing their interactions with biomacromolecular targets demands a deep understanding of binding mechanisms. Dozens of papers have suggested that discovering of the binding event by means of conventional unbiased molecular dynamics (MD) simulation urges considerable amount of computational resources, therefore, only one who holds a cluster or a supercomputer can afford such extensive simulations. Thus, many researchers who do not own such resources are reluctant to take the benefits of running unbiased molecular dynamics simulation, in full atomistic details, when studying a ligand binding pathway. Many researchers are impelled to be content with biased molecular dynamics simulations which seek its validation due to its intrinsic preconceived framework. In this work, we have presented a workable stratagem to encourage everyone to perform unbiased (unguided) molecular dynamics simulations, in this case a protein-ligand binding process, by typical desktop computers and so achieve valuable results in nanosecond time scale. Here, we have described a dynamical binding’s process of an anticancer drug, the dasatinib, to the c-Src kinase in full atomistic details for the first time, without applying any biasing force or potential which may lead the drug to artificial interactions with the protein. We have attained multiple independent binding events which occurred in the nano-second timescales, surprisingly as little as ∼30 ns. Both the protonated and deprotonated forms of the dasatinib reached the crystallographic binding mode without having any major intermediate state during induction.
Copulas and their potential for ecology
Authors: Ghosh Shyamolina , Sheppard Lawrence W. , Holder Mark T. , Loecke Terrance D. , Reid Philip C. , Bever James D. , Reuman Daniel C. 
Published: May 2019

AbstractAll branches of ecology study relationships among and between environmental and biological variables. However, standard approaches to studying such relationships, based on correlation and regression, provide only a small slice of the complex information contained in the relationships. Other statistical approaches exist that provide a complete description of relationships between variables, based on the concept of the copula; they are applied in finance, neuroscience and other fields, but rarely in ecology. We here explore the concepts that underpin copulas and examine the potential for those concepts to improve our understanding of ecology. We find that informative copula structure in dependencies between variables is common across all the environmental, species-trait, phenological, population, community, and ecosystem functioning datasets we considered. Many datasets exhibited asymmetric tail associations, whereby two variables were more strongly related in their left compared to right tails, or vice versa. We describe mechanisms by which observed copula structure and asymmetric tail associations can arise in ecological data, including a Moran-like effect whereby dependence structures between environmental variables are inherited by ecological variables; and asymmetric or nonlinear influences of environments on ecological variables, such as under Liebig’s law of the minimum. We also describe consequences of copula structure for ecological phenomena, including impacts on extinction risk, Taylor’s law, and the stability through time of ecosystem services. By documenting the importance of a complete description of dependence between variables, advancing conceptual frameworks, and demonstrating a powerful approach, we aim to encourage widespread use of copulas in ecology, which we believe can benefit the discipline.
PhenoGeneRanker: A Tool for Gene Prioritization Using Complete Multiplex Heterogeneous Networks
Authors: Dursun Cagatay , Shimoyama Naoki , Shimoyama Mary , Schläppi Michael , Bozdag Serdar 
Published: May 2019

ABSTRACTUncovering genotype-phenotype relationships is a fundamental challenge in genomics. Gene prioritization is an important step for this endeavor to make a short manageable list from a list of thousands of genes coming from high-throughput studies. Network propagation methods are promising and state of the art methods for gene prioritization based on the premise that functionally-related genes tend to be close to each other in the biological networks.In this study, we present PhenoGeneRanker, an improved version of a recently developed network propagation method called Random Walk with Restart on Multiplex Heterogeneous Networks (RWR-MH). PhenoGeneRanker allows multi-layer gene and disease networks. It also calculates empirical p-values of gene ranking using random stratified sampling of genes based on their connectivity degree in the network.We ran PhenoGeneRanker using multi-omics datasets of rice to effectively prioritize the cold tolerance-related genes. We observed that top genes selected by PhenoGeneRanker were enriched in cold tolerance-related Gene Ontology (GO) terms whereas bottom ranked genes were enriched in general GO terms only. We also observed that top-ranked genes exhibited significant p-values suggesting that their rankings were independent of their degree in the network.CCS CONCEPTS• Bioinformatics • Biological networks • System biology • Computational genomicsAvailability and implementationThe source code is available on GitHub at https://github.com/bozdaglab/PhenoGeneRanker under Creative Commons Attribution 4.0 licenseContactcdursun@mcw.edu or serdar.bozdag@marquette.edu
Diverse strategies link growth rate and competitive ability in phytoplankton responses to changes in CO2 levels
Authors: Collins Sinead , Schaum C. Elisa 
Published: May 2019

AbstractAquatic microbial primary producers exist in genetically variable populations, but are often studied as single lineages. However, the properties of lineages grown alone often fail to predict the composition of microbial assemblages. We demonstrate that different lineages of a marine picoplankter have unique growth strategies, and that they modulate their lineage growth rate in the presence of other lineages. This explains why growth rates of lineages in isolation do not reliably predict the lineage composition of assemblages. The diversity of growth strategies observed are consistent with lineage-specific energy-allocation that depends on social milieu. Since lineage growth is only one of many traits determining fitness in natural assemblages, we propose that in all but the poorest quality environments where allocating maximum energy to growth is the only viable strategy, we should expect intraspecific variation in growth strategies, with more strategies possible in ameliorated environments, such as high CO2 for many marine picoplankton. This emphasizes the importance of understanding and accounting for basic organismal biology in our models of aquatic primary producers.Data archivingShould this manuscript be accepted, data will be archived at Pangea, and the DOI be included at the end of the article
The Adaptor Protein Nck1, but not Nck2, Mediates Shear Stress-Induced Endothelial Permeability
Authors: Alfaidi Mabruka , Bhattarai Umesh , Cockerham Elizabeth D , Orr A.W. 
Published: May 2019

AbstractAlteration in hemodynamic shear stress at atheroprone sites promotes endothelial paracellular pore formation and permeability. Previously, we have reported that a peptide inhibitor to Nck prevented shear stress-induced p21 activated kinase (PAK) activation and endothelial permeability. However, the specificity of this peptide is unclear, and the role of individual Nck isoforms remain unknown. Here, we show that genetic deletion of Nck1/2 adaptor proteins significantly ameliorates shear stress induced permeability, and selective isoform depletion suggests distinct signaling mechanisms. Only Nck1 deletion significantly reduces flow-induced paracellular pore formation and permeability, whereas Nck2 depletion has no significant effects. Additionally, Nck1 reexpression, but not Nck2, restores shear stress-induced permeability in Nck1/2 knockout cells, confirming the non-compensating roles. In vivo, using the partial carotid ligation model of disturbed flow, Nck1 knockout prevented the increase in vascular permeability, as assessed by both Evans blue extravasation and leakage of plasma fibrinogen into the vessel wall. Domain swap experiments mixing SH2 (phosphotyrosine binding) and SH3 (proline rich binding) domains between Nck1 and Nck2 showed a dispensable role for SH2 domains but a critical role for the Nck1 SH3 domains in rescuing shear stress-induced endothelial permeability. Consistent with this, both Nck1 and Nck2 bind to PECAM-1 (SH2 dependent) in response to shear stress, but only Nck1 ablation interferes with shear stress-induced PAK2 activation (SH3 dependent). This work provides the first evidence that Nck1 and Nck2 play distinct roles in flow-induced vascular permeability.New and NoteworthyThe present study shows a specific role for Nck1 in endothelial permeability in response to shear stress. Using in vitro and in vivo models, we demonstrate improvement in endothelial barrier integrity in cells subjected to disturbed flow only following Nck1 but not Nck2 deletion. Selective Nck1 inhibition may limit endothelial permeability at sites of disturbed flow to reduce atherosclerosis without affecting angiogenesis, which requires both Nck1 and Nck2 inhibition.
Introgression of Austrian fire-bellied toads (Bombina bombina) into northern German populations confirmed by complete mitochondrial genomes and transcriptome-wide Single Nucleotide Polymorphisms (SNPs)
Authors: De Cahsan Binia , Westbury Michael V , Paraskevopoulou Sofia , Drews Hauke , Ott Moritz , Gollmann Günter , Tiedemann Ralph 
Published: May 2019

AbstractThe fire-bellied toad (Bombina bombina) is a small amphibian species inhabiting the lowlands of Central and Eastern Europe. Continual population fragmentation has caused a decrease in genetic diversity and gene flow in margin populations in Northern Germany. Previous research using mitochondrial control region data uncovered a translocation of allochthonous toads from Austria into a single northern German population, Högsdorf. Microsatellite and MHC data also confirmed this introgression, but were limited in revealing the true extent of this translocation for all investigated populations. Here, we utilize complete mitochondrial genomes and nuclear data, in the form of transcriptomes, to unravel the full extent of admixture from this translocation. The increased number of loci enabled us to uncover signs of introgression in four out of the five northern populations investigated. Moreover, as hybrids between B. bombina and its sister species, B. variegata, have been reported in Austria, we also investigated whether B. variegata alleles were translocated into the northern gene pool. We found evidence for hybridization between Austrian B. bombina and B. variegata, as well as traces of B. variegata alleles in one of the five German populations included in this study. These findings present the first reported case of introgressed relict B. variegata alleles from the Southern lineage being detected in Northern Germany.
Direct Pathway Neurons in Mouse Dorsolateral Striatum In Vivo Receive Stronger Synaptic Input than Indirect Pathway Neurons
Authors: Filipović Marko , Ketzef Maya , Reig Ramon , Aertsen Ad , Silberberg Gilad , Kumar Arvind 
Published: May 2019

AbstractStriatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1 or D2 type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modelling of the striatal network has predicted that under healthy conditions dMSNs should receive more excitatory input than iMSNs. To test this prediction, we analyzed in vivo whole-cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized towards the spike threshold significantly faster than iMSNs did. Together, these finding corroborate the theoretical prediction that direct-pathway MSNs receive stronger input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question how a lack of dopamine may lead to behavior deficits associated with Parkinson’s disease.Significance statementThe direct and indirect pathways of the basal ganglia originate from the D1 and D2 type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs), respectively. To understand the role of the striatum in brain function and dysfunction it is important to characterize the differences in synaptic inputs to the two MSN types. Theoretical results predicted that dMSNs should receive stronger excitatory input than iMSNs. Here, we studied membrane potential fluctuation statistics of MSNs recorded in vivo in anaesthetized mice and found that dMSNs, indeed, received stronger synaptic input than iMSNs. We corroborated this finding by spike-triggered membrane potential analysis, showing that dMSNs spiking required more synaptic input than iMSNs spiking did, as had been predicted by computational models.
Higher prevalence of homologous recombination-deficiency in lung squamous carcinoma from African Americans
Authors: Sinha Sanju , Mitchell Khadijah A. , Zingone Adriana , Bowman Elise , Sinha Neelam , Schäffer Alejandro A. , Lee Joo Sang , Ruppin Eytan , Ryan Bríd M. 
Published: May 2019

AbstractTo improve our understanding of the longstanding disparities in incidence and mortality across multiple cancer types among minority populations, we performed a systematic comparative analysis of molecular features in tumors from African American (AA) and European American (EA) ancestry. Our pan-cancer analysis on the cancer genome atlas (TCGA) and a more focused analysis of genome-wide somatic copy number profiles integrated with tumor-normal RNA sequencing in a racially balanced cohort of 222 non-small cell lung cancers (NSCLC) reveals more aggressive genomic characteristics of AA tumors. In general, we find AA tumors exhibit higher genomic instability (GI), homologous recombination-deficiency (HRD) levels, and more aggressive molecular features such as chromothripsis across many cancer types, including lung squamous carcinoma (LUSC). GI and HRD levels are strongly correlated across AA tumors, indicating that HRD plays an important role in GI in these patients. The prevalence of germline HRD is higher in AA tumors, suggesting that the somatic differences observed have genetic ancestry origins. Finally, we identify AA-specific copy number-based arm, focal and gene level recurrent features in lung cancer, including a higher frequency of PTEN deletion and KRAS amplification and a lower frequency of CDKN2A deletion. These results highlight the importance of including minority and under-represented populations in genomics research and may have therapeutic implications.
Dissecting the eQTL micro-architecture inCaenorhabditis elegans
Authors: Sterken Mark G. , Bevers Roel P. J. , Volkers Rita. J. M. , Riksen Joost A. G. , Kammenga Jan E. , Snoek L. Basten 
Published: May 2019

AbstractThe study of expression quantitative trait loci (eQTL) using natural variation in inbred populations has yielded detailed information about the transcriptional regulation of complex traits. Studies on eQTL using recombinant inbred lines (RILs) led to insights on local and distant regulatory loci of transcript abundance. However, determining the underlying causal polymorphic genes or variants is difficult, but ultimately essential for the understanding of regulatory networks of complex traits. This requires insight into whether associated loci are single eQTL or a combination of closely linked eQTL, and how this QTL micro-architecture depends on the environment. We addressed these questions by mapping eQTL in N2 x CB4856C. elegansRIL populations across three different environments (control, heat-stress, and recovery). To test for independent replication of the RIL eQTL, we used introgression lines (ILs). Both populations indicate that the overall heritability, number, and position of eQTL differed among environments. Across environments we were able to replicate 70% of the local- and 40% of the distant-eQTL using the ILs. Simulation models revealed that additive effects explain up to 60-93% of RIL/IL heritability across environments. Closely linked eQTL explained up to 40% of RIL/IL heritability in the control environment whereas only 7% in the heat-stress and recovery environments. In conclusion, we show that reproducibility of eQTL was higher for local vs. distant eQTL and that the environment affects the eQTL micro-architecture.
Fate mapping via Ms4a3 expression history traces monocyte-derived cells
Authors: Liu Zhaoyuan , Gu Yaqi , Chakarov Svetoslav , Bleriot Camille , Chen Xin , Shin Amanda , Huang Weijie , Dress Regine J. , Dutertre Charles-Antoine , Schlitzer Andreas , Chen Jinmiao , Wang Honglin , Liu Zhiduo , Su Bing , Ginhoux Florent 
Published: May 2019

SUMMARYMost tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone-marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes and their functions compared to embryonic RTM remains unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation and disease is highly debated. Here, we identified Ms4a3 as a specific marker expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3TdT reporter and Ms4a3Cre-RosaTdT fate mapper models to follow monocytes and their progenies. Our Ms4a3Cre-RosaTdT model traced efficiently blood monocytes (97%) and granulocytes (100%), but no lymphocytes or tissue dendritic cells. Using this model, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition.
Numerical Investigation of Drug Transport from Blood Vessels to Tumor Tissue Using a Tumor-Vasculature-on-a-Chip
Authors: Li Wei , Wang Hao-Fei , Li Zhi-Yong , Wang Tong , Zhao Chun-Xia 
Published: May 2019

AbstractThe delivery of adequate concentration of anticancer drugs to tumor site is critical to achieve effective therapeutic treatment, but it is challenging to experimentally observe drug transport and investigate the spatial distribution of the drug in tumor microenvironment. In this study, we investigated the drug transport from a blood vessel to tumor tissue, and explored the effect of tumor size, tumor numbers and positioning on drug concentration distribution using a numerical method in combination with a microfluidic Tumor-Vasculature-on-a-Chip (TVOC) model. The TVOC model is composed of a vessel channel, a tumor channel sandwiched with a porous membrane. A species transport model based on computational fluid dynamics was adapted to investigate drug transport. The numerical simulation was firstly validated using experimental data, and then used to analyse the spatial-temporal structure of the flow, and to investigate the effect of tumor size and positioning on drug transport and drug concentration heterogeneity. We found the drug concentration surrounding the tumor is highly heterogeneous, with the most downstream point the most difficult for drugs to transport and the nearest point to the blood vessel the easiest. Moreover, tumor size and positioning contribute significantly to this drug concentration heterogeneity on tumor surface, which is dramatically augmented in large and downstream-positioned tumors. These studies established the relationship between solid tumor size/positioning and drug concentration heterogeneity in the tumor microenvironment, which could help to understand heterogenous drug distribution in tumor microenvironment.
Risk of complications among diabetics self-reporting oral health status in Canada: A population-based cohort study
Authors: Parbhakar Kamini Kaura , Rosella Laura C. , Singhal Sonica , Quiñonez Carlos R. 
Published: May 2019

AbstractBackgroundPeriodontitis has persistently been associated with diabetes and poor health outcomes. While clear associations have been identified for the diabetes–oral health link, less is known about the implications of poor oral health on incident complications of diabetes. This study sought to investigate the risk of diabetes complications associated with self-reported “poor to fair” and “good to excellent” oral health status among diabetics living in Ontario, Canada.MethodsThis cohort study was undertaken of diabetics from the Canadian Community Health Survey (2003 and 2007-8). Self-reported oral health was linked to electronic health records at the Institute for Clinical Evaluative Sciences. Participants under the age of 40, missing self-reported oral health and those who could not be identified in linked databases were excluded (N=5,183). A series of Cox Proportional hazard models were constructed to determine the risk of diabetes complications. Participants who did not experience any diabetes complication were censored at time of death or at the study termination date (March 31, 2016). Models were adjusted for age and sex, followed by social characteristics and behavioural factors.ResultsDiabetes complications differed by self-reported oral health. For those reporting “poor to fair” oral health, the hazard of a diabetes complication was 30% greater (HR 1.29 95%CI 1.03, 1.61) than those reporting “good to excellent” oral health.ConclusionsOur findings indicate that oral health status is associated with increased risk for complications among diabetics, after adjusting for a wide range of confounders. Examining oral health and the risk for diabetes complications from a broader perspective including socio-behavioural and biological pathways is principal for informing policies and interventions that aim to mitigate the burdens of poor systemic health.
Degradations of tannin and saponin during co-composting of shell and seed cake of Camellia oleifera Abel
Authors: Zhang Jinping , Ying Yue , Yao Xiaohua 
Published: May 2019

AbstractThe degradation processes were studied in this paper of tannin and saponin during the co-composting of the shell and seed cake ofCamellia oleiferaAbel. Four treatments were designed with the dry weight of the seed cake accounting for 1/3(A1), 1/4(A2), 1/5(A3), and 1/10(A4) of the shell. The proportion of the seed cake is positively correlated with the duration of thermophilic phase, highest temperature and degradation rate of tannin and saponin whose maximum were in A1, but negatively correlated with C/N ratio and tannin content which were least in A1 of the final products. The content of saponin were all about 2% finally. The final content of saponin and tannin decreased 68.92-75.22% and 34.57-59.52%. The organic matters, total nutrient (N, P2O5and K2O) increased with the rising proportion of the seed cake. Overall, the addition of the seed cake promoted the stability, fertilizer efficiency and safety of the co-compost product.