bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of long-range aromatic clique and community in protein stability
Authors: Mahanta P , Bhardwaj A , Reddy VS , Ramakumar S 
Published: May 2018

AbstractAromatic interactions make an important contribution to protein structure, function, folding and have attracted intense study. Earlier studies on a recombinant xylanase from Bacillus sp. NG-27 (RBSX), which has the ubiquitous (beta/alpha)8-triosephosphate isomerase barrel fold showed that three aromatic residues to alanine substitutions, in the N-terminal and C-terminal regions, significantly decreased the stability of the enzyme. Of these mutations, F4A mutation decreased the stability of the enzyme by ∼4 degree C, whereas W6A mutation and Y343A mutation remarkably decreased the stability of the enzyme by ∼10 degree C. On the other hand, the F4W mutation did not affect the thermal stability of RBSX. We provide here a network perspective of aromatic-aromatic interactions in terms of aromatic clique community and long-range association. Our study reveals that disruption of long-range k-clique aromatic interaction cluster holding the N- and C-terminal regions are associated with the decreased stability of the enzyme. The present work reiterates as well as expands on those findings concerning the role of interactions between the N- and C-terminus in protein stability. Furthermore, comparative analyses of crystal structures of homologous pairs of proteins from thermophilic and mesophilic organisms emphasize the prevalence of long-range k-clique communities of aromatic interaction that may be playing an important role and highlights an additional source of stability in thermophilic proteins. The design principle based on clustering of long-range aromatic residues in the form of aromatic-clique and clique community may be effectively applied to enhance the stability of enzymes for biotechnological applications.DatabaseThe coordinates o fF4A, F4W, W6A, and Y343A are deposited in the PDB database under the accession numbers 5EFF, 5E58, 5EFD, and 5EBA respectively.AbbreviationsBSX, xylanase from Bacilllus sp. NG-27; RBSX, recombinant BSX xylanase; TIM, Triosephosphate isomerase; GH10, Glycosyl hydrolase family 10; 3D, three-dimensional; r.m.s.d, root mean square deviation; RSA, relative solvent accessible surface area; Tm, melting temperature; CD, Circular Dichroism; BHX, GH10 xylanase from Bacillus halodurans; BFX, GH10 xylanase from Bacillus firmus; TmxB, GH10 xylanase from Thermotoga maritima
Isolation and antibiotic profile ofVibriospp. in final effluents of two wastewater treatment plants in the Eastern Cape of South Africa
Authors: Osuolale Olayinka , Okoh Anthony 
Published: May 2018

ABSTRACTBackgroundPoorly or partially treated wastewater disposed of can contaminate water and even properly treated sewage can have its problems. The highlight of this danger is wastewater treatment plants serving as reservoir for proliferation of antibiotic resistant organisms. We have reported the state of two wastewater treatment in the Eastern Cape of South Africa which discharge poorly and partially treated effluents. Our aims to identify Vibrio spp. and their antibiotic profiles in treated final effluent discharge from wastewater treatment plant.MethodsCulture based approach using the TCBS agar for isolationVibriospp., presumptive isolates were purified and confirmed using PCR. The confirmed isolated were also genotyped to identify the species present. The antibiotic profiling of the confirmed isolates was using the CLSI recommended first line antibiotics for Vibrio.ResultsOut of the 786 presumptive isolates, 374 were confirmed asVibriospp. None of the Vibrio spp. pathotypes were present in the confirmed isolates. Randomized isolates of 100 Vibrio spp. were selected, > 90 % of the isolates were susceptible to Ciprofloxacin, and > 50 – 80 % for Ampicillin, Chloramphenicol, Tetracycline, Cefotaxime, and Trimethoprim-sulfamethoxazole respectively.ConclusionsWe are able to isolate Vibrio spp. from treated effluents but none of their pathotypes were present. The antibiotic agents considered for primary testing which are ciprofloxacin was the most effective of the antibiotic drugs, followed by cefotaxime, tetracycline with less susceptibility. Contamination from discharged effluents from wastewater treatment can lead to spread of spread of disease in this environment. The WWTPs studied are sources of pollution to surface water with environmental and public health.
Optimization of Experiment Design for Mass Spectrometric Isotopic Labeling Kinetics
Authors: Lathwal Shefali , Raaisa Raaisa , Alves Tiago C. , Kibbey Richard G. , Jha Abhishek K. , Mason Graeme F. 
Published: May 2018

AbstractDetermination of metabolic fluxes by measurement of time-dependent sampling of isotopic enrichments during the administration of labeled substrates provides rich information. Because such experiments are resource-intensive and frequently push the limits of sensitivity of the measurement techniques, optimization of experiment design can improve feasibility with respect to financial and labor costs, time to completion, and increase precision and accuracy of the results. Here we used a previously published set of data acquired in cultured insulinoma cells to evaluate contributions to the sensitivity and variability of the rate of citrate synthase (CS). Specifically, we calculated changes in uncertainty in CS if sample times were dropped or new ones were added, and we observed that some sampling times can be dropped with little effect, while improvements can be made with a strategic choice of when to add samples. We measured the contributions of data sampled at different times on the sensitivity of CS, finding that CS had greater sensitivity at early time points. We tested the concept that if two estimated parameters are correlated significantly, then refining one might constrain the other. In this case, the rate of Beta-oxs was found to be correlated with CS, and narrower variability in Beta-ox did indeed improve the sensitivity of CS. The tests described here might be applied at the initial design stage and then after a pilot phase to improve sensitivities of targeted fluxes and the reduction of materials, time, labor, and other experimental resources. The correlation analyses can be used to consider what orthogonal measurements might be beneficial for further improvement of measurements. While this study used a specific example of a set of time-dependent kinetic isotopic measurements, the results illustrate some generalizable behaviors that can be tested in other experimental systems.
Temporal alignment and latent Gaussian process factor inference in population spike trains
Authors: Duncker Lea , Sahani Maneesh 
Published: May 2018

AbstractWe introduce a novel scalable approach to identifying common latent structure in neural population spike-trains, which allows for variability both in the trajectory and in the rate of progression of the underlying computation. Our approach is based on shared latent Gaussian processes (GPs) which are combined linearly, as in the Gaussian Process Factor Analysis (GPFA) algorithm. We extend GPFA to handle unbinned spike-train data by incorporating a continuous time point-process likelihood model, achieving scalability with a sparse variational approximation. Shared variability is separated into terms that express condition dependence, as well as trial-to-trial variation in trajectories. Finally, we introduce a nested GP formulation to capture variability in the rate of evolution along the trajectory. We show that the new method learns to recover latent trajectories in synthetic data, and can accurately identify the trial-to-trial timing of movement-related parameters from motor cortical data without any supervision.
Explainable machine learning prediction of synergistic drug combinations for precision cancer medicine
Authors: Janizek Joseph D. , Celik Safiye , Lee Su-In 
Published: May 2018

AbstractAlthough combination therapy has been a mainstay of cancer treatment for decades, it remains challenging, both to identify novel effective combinations of drugs and to determine the optimal combination for a particular patient’s tumor. While there have been several recent efforts to test drug combinationsin vitro, examining the immense space of possible combinations is far from being feasible. Thus, it is crucial to develop datadriven techniques to computationally identify the optimal drug combination for a patient. We introduce TreeCombo, an extreme gradient boosted tree-based approach to predict synergy of novel drug combinations, using chemical and physical properties of drugs and gene expression levels of cell lines as features. We find that TreeCombo significantly outperforms three other state-of-theart approaches, including the recently developed DeepSynergy, which uses the same set of features to predict synergy using deep neural networks. Moreover, we found that the predictions from our approach were interpretable, with genes having well-established links to cancer serving as important features for prediction of drug synergy.
Host protein CD63 enhances viral RNA replication by interacting with human astrovirus nonstructural protein nsP1a/4
Authors: zhao wei , liu Nian , Tao Xiao Li , Zheng Chun hong , Li Xiang yu , Yu Man , Li Yong gang 
Published: May 2018

ABSTRACTHuman astrovirus nonstructural protein nsP1a/4, located at the C-terminal end of nsP1a, is thought to be involved in the regulation of RNA replication and capsid maturation;however, its rolesviral growth and virulence are not well understood. We investigated the intracellular host proteins that interact with nsP1a and explored the potential roles of the interaction in the pathogenesis of human astrovirus infection. We screened 14 independent proteins with a cDNA library derived from Caco-2 cells using a yeast two-hybrid technique. Deletion analysis revealed that interaction between the nsP1a/4 domain and the large extracellular loop (LEL) domain of the human protein CD63 is necessary for astrovirus replication. The interaction was confirmed by glutathione-S-transferase (GST) pull-down assays and co-immunoprecipitation assays. Confocal microscopy showed that nsP1a/4 and CD63 co-localized in the cytoplasm of infected cells. Over expression of CD63 promoted viral RNA synthesis, whereas knockdown of CD63 markedly decreased viral RNA levels. Those results suggest that CD63 plays a critical role in human astrovirus RNA replication. The interaction between CD63 and nsP1a/4 provides a channel to further understand the roles of interactions between host and virus proteins in astrovirus infection and release.IMPORTANCEHuman astroviruses cause gastroenteritis in young children and immunocompromised patients. In this study, we provide evidence that nsP1a/4, a nonstructural protein located at the C-terminal end of the human astrovirus nsP1a polyprotein, interacts with the host protein CD63. Over expression of CD63 promoted viral RNA replication, whereas knockdown of CD63 decreased virus RNA replication, indicating that CD63 plays a critical role in the human astrovirus life cycle.
Using molecular ecological network analysis to explore the effects of chemotherapy on intestinal microbial communities of colorectal cancer patients
Authors: Cong Jing , Zhu Jingjuan , Zhang Chuantao , Li Tianjun , Liu Kewei , Liu Dong , Zhou Na , Jiang Man , Hou Helei , Zhang Xiaochun 
Published: May 2018

AbstractIntestinal microbiota is now widely known to be key roles in the nutrition uptake, metabolism, and the regulation of human immune responses. However, we do not know how changes the intestinal microbiota in response to the chemotherapy. In this study, we used network-based analytical approaches to explore the effects of five stages of chemotherapy on the intestinal microbiota of colorectal cancer patients. The results showed that chemotherapy greatly reduced the alpha diversity and changed the specie-specie interaction networks of intestinal microbiota, proved by the network size, network connectivity and modularity. The OTU167 and OTU8 from the genus Fusobacterium and Bacteroides were identified as keystone taxa by molecular ecological networks in the first two stages of chemotherapy, and were significantly correlated with tumor makers (P < 0.05). Five stages of chemotherapy did not make the intestinal micro-ecosystem regain a steady state, because of the lower alpha diversity and more complicated ecological networks compared to the healthy individuals. Furthermore, combing the changes of ecological networks with the tumor markers, the intestinal microbiota was closely linked with clinical chemotherapeutic effects.ImportanceA deeply understanding of the role of intestinal microbiota contributes to help us find path forward for improving the prognosis of colorectal cancer patients. In addition, diet or probiotics interventions will be a possible attempt to improve the clinical chemotherapeutic effects for colorectal cancer patients.
Global mycorrhizal plant distribution linked to terrestrial carbon stocks
Authors: Soudzilovskaia Nadejda A. , van Bodegom Peter M. , Terrer César , van’t Zelfde Maarten , McCallum Ian , McCormack M. Luke , Fisher Joshua B. , Brundrett Mark , de Sá Nuno César , Tedersoo Leho 
Published: May 2018

AbstractVegetation impacts on ecosystem functioning are mediated by mycorrhiza, a plant-fungal association formed by most plant species. Ecosystems dominated by distinct mycorrhizal types differ strongly in their biogeochemistry. Quantitative analyses of mycorrhizal impacts on ecosystem functioning are hindered by the absence of information on mycorrhizal distribution. We present the first global high-resolution maps of vegetation biomass distribution among main types of mycorrhizal associations. Arbuscular, ecto-, ericoid and non-mycorrhizal vegetation store 241±15, 100±17, 7±1.8 and 29 ± 5.5 GT carbon in aboveground biomass, respectively. Soil carbon stocks in both topsoil and subsoil are positively related to the biomass fraction of ectomycorrhizal plants in the community, though the strength of this relationship varies across biomes. We show that human-induced transformations of Earth’s ecosystems have reduced ectomycorrhizal vegetation, with potential knock-on effects on terrestrial carbon stocks. Our work provides a benchmark for spatially explicit global quantitative assessments of mycorrhizal impacts on ecosystem functioning and biogeochemical cycles.One Sentence SummaryFirst maps of the global distribution of mycorrhizal plants reveal global losses of ectomycorrhizal vegetation, and quantitative links between mycorrhizal vegetation patterns and terrestrial carbon stocks.
Activation of the TRKB receptor mediates the panicolytic-like effect of NOS inhibitor aminoguanidine
Authors: Ribeiro DE , Casarotto PC , Spiacci A , Fernandes GG , Pinheiro LC , Tanus-Santos JE , Zangrossi H , Guimarães FS , Joca SRL , Biojone C 
Published: May 2018

AbstractNitric oxide (NO) triggers escape reactions in the dorsal periaqueductal gray matter (dPAG), a core structure mediating panic-associated responses, and decreases the release of BDNFin vitro. BDNF mediates the panicolytic effect induced by antidepressant drugs and produces these effectsper sewhen injected into the dPAG. Based on these findings, we hypothesize that nitric oxide synthase (NOS) inhibitors would have panicolytic properties associated with increased BDNF signaling in the dPAG. We observed that the repeated (7 days), but not acute (1day), systemic administration of the NOS inhibitor aminoguanidine (AMG; 15 mg/kg/day) increased the latency to escape from the open arm of the elevated T-maze (ETM) and inhibited the number of jumps in hypoxia-induced escape reaction in rats, suggesting a panicolytic-like effect. Repeated, but not acute, AMG administration (15mg/kg) also decreased nitrite levels and increased TRKB phosphorylation at residues Y706/7 in the dPAG. Notwithstanding the lack of AMG effect on total BDNF levels in that structure, the microinjection of the TRK antagonist K252a into the dPAG blocked the anti-escape effect of this drug in the ETM. Taken together our data suggest that the inhibition of NO production by AMG increased the levels of pTRKB, which is required for the panicolytic-like effect observed.
Prioritizing Small Molecule as Candidates for Drug Repositioning using Machine Learning
Authors: Shameer Khader , Johnson Kipp W. , Glicksberg Benjamin S. , Hodos Rachel , Readhead Ben , Tomlinson Max S. , Dudley Joel T. 
Published: May 2018

ABSTRACTDrug repositioning, i.e. identifying new uses for existing drugs and research compounds, is a cost-effective drug discovery strategy that is continuing to grow in popularity. Prioritizing and identifying drugs capable of being repositioned may improve the productivity and success rate of the drug discovery cycle, especially if the drug has already proven to be safe in humans. In previous work, we have shown that drugs that have been successfully repositioned have different chemical properties than those that have not. Hence, there is an opportunity to use machine learning to prioritize drug-like molecules as candidates for future repositioning studies. We have developed a feature engineering and machine learning that leverages data from publicly available drug discovery resources: RepurposeDB and DrugBank. ChemVec is the chemoinformatics-based feature engineering strategy designed to compile molecular features representing the chemical space of all drug molecules in the study. ChemVec was trained through a variety of supervised classification algorithms (Naïve Bayes, Random Forest, Support Vector Machines and an ensemble model combining the three algorithms). Models were created using various combinations of datasets as Connectivity Map based model, DrugBank Approved compounds based model, and DrugBank full set of compounds; of which RandomForest trained using Connectivity Map based data performed the best (AUC=0.674). Briefly, our study represents a novel approach to evaluate a small molecule for drug repositioning opportunity and may further improve discovery of pleiotropic drugs, or those to treat multiple indications.
Ethylene signaling regulates natural variation in the abundance of antifungal acetylated diferuloylsucroses andFusarium graminearumresistance in maize seedling roots
Authors: Zhou Shaoqun , Zhang Ying K. , Kremling Karl A. , Ding Yezhang , Bennett John S. , Bae Justin S. , Kim Dean K. , Kolomiets Michael V. , Schmelz Eric A. , Schroeder Frank C. , Buckler Edward S. , Jander Georg 
Published: May 2018

SummaryThe production and regulation of defensive specialized metabolites plays a central role in pathogen resistance in maize (Zea mays) and other plants. Therefore, identification of genes involved in plant specialized metabolism can contribute to improved disease resistance.We used comparative metabolomics to identify previously unknown antifungal metabolites in maize seedling roots, and investigated the genetic and physiological mechanisms underlying their natural variation using quantitative trait locus (QTL) mapping and comparative transcriptomics approaches.Two maize metabolites, smilaside A (3,6-diferuloyl-3′,6′-diacetylsucrose) and smiglaside C (3,6-diferuloyl-2′,3′,6′-triacetylsucrose), that may contribute to maize resistance againstFusarium graminearumand other fungal pathogens were identified. Elevated expression of an ethylene receptor gene,ETHYLENE INSENSITIVE 2(ZmEIN2), co-segregated with decreased smilaside A/smiglaside C ratio. Pharmacological and genetic manipulation of ethylene availability and sensitivityin vivoindicated that, whereas ethylene was required for the production of both metabolites, the smilaside A/smiglaside C ratio was negatively regulated by ethylene sensitivity. This ratio, rather than the absolute abundance of these two metabolites, was important for maize seedling root defense againstF. graminearum.Ethylene signaling regulates the relative abundance of the twoF. graminearum-resistance-related metabolites and affects resistance againstF. graminearumin maize seedling roots.
Disease and climate effects on individuals jointly drive post-reintroduction population dynamics of an endangered amphibian
Authors: Joseph Maxwell B. , Knapp Roland A. 
Published: May 2018

AbstractThe emergence of novel pathogens often has dramatic negative effects on previously unexposed host populations. Subsequent disease can drive populations and even species to extinction. After establishment in populations, pathogens can continue to affect host dynamics, influencing the success or failure of species recovery efforts. However, quantifying the effect of pathogens on host populations in the wild is challenging because individual hosts and their pathogens are difficult to observe. Here we use long-term mark-recapture data to describe the dynamics of reintroduced populations of an endangered amphibian (Rana sierrae) and evaluate the success of these recovery efforts in the presence of a recently-emerged pathogen, the amphibian chytrid fungusBatrachochytrium dendrobatidis. We find that highB. dendrobatidisinfection intensities are associated with increases in detectability, reductions in survival, and more infected adults. We also find evidence for intensity-dependent survival, with heavily infected individuals suffering higher mortality. These results highlight the need in disease ecology for probabilistic approaches that account for uncertainty in infection intensity using imperfect observational data. Such approaches can advance the understanding of disease impacts on host population dynamics, and in the current study will improve the effectiveness of species conservation actions.
Cryo-EM structure of the circumsporozoite protein of Plasmodium falciparum with a vaccine-elicited antibody reveals maturation of inter-antibody contacts
Authors: Oyen David , Torres Jonathan L. , Cottrell Christopher A. , Richter King C. , Wilson Ian A. , Ward Andrew B. 
Published: May 2018

AbstractThe circumsporozoite protein (CSP) on the surface of Plasmodium falciparum sporozoites is important for parasite development, motility, and host hepatocyte invasion. However, intrinsic disorder of the NANP repeat sequence in the central region of CSP has hindered its structural and functional characterization. Here, the cryo-EM structure at ∼3.4 Å resolution of a recombinant shortened CSP construct (rsCSP) with the variable domains (Fabs) of a highly protective monoclonal antibody reveals an extended spiral conformation of the central NANP repeat region surrounded by antibodies. This unusual structure appears to be stabilized and/or induced by interaction with an antibody where contacts between adjacent Fabs are somatically mutated and enhance the interaction. Such maturation in non-antigen contact residues may be an effective mechanism for antibodies to target tandem repeat sequences and provide novel insights into malaria vaccine design.SummaryAn unusual spiral conformation is formed for the NANP repeat region in Plasmodium falciparum circumsporozoite protein (CSP) in complex with antibodies generated by the RTS,S vaccine and is stabilized by affinity-matured inter-Fab interactions.
Dynamics of the Previte-Hoffman food web model with small immigrations
Authors: Hassan Sk. Sarif 
Published: May 2018

AbstractThe ecological dynamics of prey-predator systems are extensively studied over a century.Previte and Hoffmanintroduced a three species(predator-prey with an omnivore) model in 2013. We demonstrate the asymptotic stability of the Previte and Hoffman modified model adding with small immigration into the prey or predator or omnivore population. A comparison of dynamics is also drawn with immigration and without immigration. It is worth noting that the qualitative dynamics is unchanged among the immigration system over the classical Previte-Hoffman system.