bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studying the drug treatment pattern based on the action of drug and multi-layer network model
Authors: Yu Liang , Shi Yayong , Zou Quan , Gao Lin 
Published: September 2019

AbstractObjectivesA drug can treat multiple diseases, indicating that the treatment of the drug has certain patterns. In this paper, we studied the treatment pattern of drugs from a new perspective based on theaction of drug andmulti-layer network model (STAM). Diseases affect the gene expression in related tissues and each disease corresponds to a tissue-specific protein-protein interaction (TSPPI) network. Therefore, a drug is associated with a multi-layer TSPPI network associated with diseases it treats. Single tissue-specific PPI network cannot consider all disease-related information, leading to find the potential treatment pattern of drugs difficultly. Research on multi-layer networks can effectively solve this disadvantage. Furthermore, proteins usually interact with other proteins in PPI to achieve specific functions, such as causing disease. Hence, studying the drug treatment patterns is equivalent to study common module structures in the multi-layer TSPPI network corresponding to drug-related diseases. Knowing the treatment patterns of the drug can help to understand the action mechanisms of the drug and to identify new indications of the drug.MethodsIn this paper, we were based on the action of drug and multi-layer network model to study the treatment patterns of drugs. We named our method as STAM. As a case of our proposed method STAM, we focused on a study to trichostatin A (TSA) and three diseases it treats: leukemia, breast cancer, and prostate cancer. Based on the therapeutic effects of TSA on various diseases, we constructed a tissue-specific protein-protein interaction (TSPPI) network and applied a multi-layer network module mining algorithm to obtain candidate drug-target modules. Then, using the genes affected by TSA and related to the three diseases, we employed Gene Ontology (GO), the modules’ significance, co-expression network and literatures to filter and analyze the identified drug-target modules. Finally, two modules (named as M17 and M18) were preserved as the potential treatment patterns of TSA.ResultsThe processed results based on the above framework STAM demonstrated that M17 and M18 had strong potential to be the treatment patterns of TSA. Through the analysis of the significance, composition and functions of the selected drug-target modules, we validated the feasibility and rationality of our proposed method STAM for identifying the drug treatment pattern.ConclusionThis paper studied the drug treatment pattern from a new perspective. The new method STAM used a multi-layer network model, which overcame the shortcomings of the single-layer network, and combined the action of drug. Research on drug treatment model provides new research ideas for disease treatment.
Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-Dolutegravir binding
Authors: Chitongo Rumbidzai , Obasa Adetayo Emmanuel , Mikasi Sello Given , Jacobs Graeme Brendon , Cloete Ruben 
Published: September 2019

AbstractResistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. Molecular modelling of HIV-1C IN was performed using the SWISS-MODEL webserver; with quality assessment performed using internal methods and external software tools. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Interaction analysis between neighbouring residues was done using PyMOL. Three randomly selected mutations were chosen for molecular dynamic simulation studies using Gromacs. Trajectory analysis included Root mean square deviation and fluctuation, Radius of gyration, Principal component analysis and Interaction analysis between Dolutegravir and protein residues. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the G140S mutant indicated a stabilizing effect and simulation analysis showed it to affect structural stability and flexibility of the protein structure. This was further supported by the drug being expelled from the G140S mutant active site, as indicated by interaction analysis. Our findings suggest the G140S mutant has a strong effect on the HIV-1C IN protein structure and Dolutegravir binding and should be validated using laboratory-based experiments. This approach can be applied to determine the effect of other mutations/variants on HIV-1C integrase drug binding.
Radiofrequency Remote Control of Thermolysin Activity
Authors: Collins Christian B. , Ackerson Christopher J. 
Published: September 2019

AbstractNearly all biological processes are regulated by enzymes, precise control over specific enzymes could create the potential for controlling cellular processes remotely. We have successfully shown that the thermophilic enzyme thermolysin can be remotely activated in 17.76 MHz radiofrequency (RF) fields when covalently attached to 6.1 nm gold coated magnetite nanoparticles. Without raising the bulk solution temperature, we observe enzyme activity as if the solution was 16 ± 2 °C warmer in RF fields, or an increase in enzymatic rate of 129 ± 8%. Kinetics studies show that the activity increase of the enzyme is consistent with the induced fit of a hot enzyme with cold substrate.
CRISPR/Cas13a signal amplification linked immunosorbent assay (CLISA)
Authors: Chen Qian , Tian Tian , Xiong Erhu , Wang Po , Zhou Xiaoming 
Published: September 2019

ABSTRACTThe enzyme-linked immunosorbent assay (ELISA) is a basic technique used in analytical and clinical investigations. However, conventional ELISA is still not sensitive enough to detect ultra-low concentrations of biomarkers for the early diagnosis of cancer, cardiovascular risk, neurological disorders, and infectious diseases. Herein we show a mechanism utilizing the CRISPR/Cas13a-based signal export amplification strategy, which double-amplifies the output signal by T7 RNA polymerase transcription and CRISPR/Cas13a collateral cleavage activity. This process is termed the CRISPR/Cas13a signal amplification linked immunosorbent assay (CLISA). The proposed method was validated by detecting an inflammatory factor, human interleukin-6 (human IL-6), and a tumor marker, human vascular endothelial growth factor (human VEGF), which achieved limit of detection (LOD) values of 45.81 fg/mL (2.29 fM) and 32.27 fg/m (0.81 fM), respectively, demonstrating that CLISA is at least 102-fold more sensitive than conventional ELISA.
The OpenPicoAmp-100k : an open-source high performance amplifier for single channel recording in planar lipid bilayers
Authors: Shlyonsky V , Gall D 
Published: September 2019

AbstractWe propose an upgraded version of our previously designed open-source lipid bilayer amplifier. This improved amplifier is now suitable both for the use in introductory courses in biophysics and neurosciences at the undergraduate level and for scientific research. Similar to its predecessor, the OpenPicoAmp-100k is designed using the common lithographic printed circuit board fabrication process and off-the-shelf electronic components. It consists of the high-speed headstage, followed by voltage-gain amplifier with built-in 6-order Bessel filter. The amplifier has a bandwidth of 100 kHz in the presence of 100 pF input membrane capacitance and is capable of measuring ion channel current with amplitudes from sub-pA and up to ±4 nA. At the full bandwidth and with a 1 GΩ transimpedance gain, the amplifier shows 12 pArms noise with an open input and 112 pArms noise in the presence of 100 pF input capacitance, while at the 5 kHz bandwidth (typical in single-channel experiments) noise amounts to 0.45 pArms and 2.11 pArms, respectively. Using an optocoupler circuit producing TTL-controlled current impulses and using 50% threshold analysis we show that at full bandwidth the amplifier has deadtimes of 3.5 µs and 5 µs at signal-to-noise ratios(SNR) of 9 and 1.7, respectively. Near 100% of true current impulses longer than 5 µs and 6.6 µs are detected at these two respective SNRs, while false event detection rate remains acceptably low. The wide bandwidth of the amplifier was confirmed in bilayer experiments with alamethicin, for which open ion channel current events shorter that 10 µs could be resolved.
Anisotropy links cell shapes to a solid-to-fluid transition during convergent extension
Authors: Wang Xun , Merkel Matthias , Sutter Leo B. , Erdemci-Tandogan Gonca , Manning M. Lisa , Kasza Karen E. 
Published: September 2019

AbstractWithin developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extendingDrosophilagermband epithelium, which displays planar polarized myosin II and experiences anisotropic forces from neighboring tissues, and we show that in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues two experimentally accessible metrics of cell patterns—the cell shape index and a cell alignment index—are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in theDrosophilagermband indicate a solid-to-fluid transition that corresponds to the onset of cell rearrangement and convergent extension in wild-type embryos and are also consistent with more solid-like behavior inbntmutant embryos. Thus, the onset of cell rearrangement in the germband can be predicted by a combination of cell shape and alignment. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue shape changes during rapid developmental events.
A highly prevalent and pervasive densovirus discovered among sea stars from the North American Atlantic Coast
Authors: Jackson Elliot W. , Pepe-Ranney Charles , Johnson Mitchell R. , Distel Daniel L. , Hewson Ian 
Published: September 2019

AbstractViral metagenomes prepared from tissues from Forbes’ sea star (Asterias forbesi) led to the discovery of a complete genome of a novel sea star densovirus (AfaDV). The genome organization of AfaDV and phylogenetic analysis place this virus among the Ambidensovirus genus in the subfamily Densoviridae, family Parvoviridae. AfaDV shares 78% nucleotide pairwise identity to the sea star associated densovirus (SSaDV), previously described as the putative causative agent of Sea Star Wasting Syndrome among sea stars from the Northwest Pacific. SSaDV was not found in specimens collected in this study, and the discovery of AfaDV might explain previous reports of SSaDV among sea stars from the Atlantic Coast. A qPCR assay was designed to assess tissue tropism, host specificity, and prevalence of AfaDV among wild populations of sea stars at five locations on the North American Atlantic Coast. AfaDV was detected in all three common sea star species (Asterias forbesi, Asterias rubens, and Henricia sp.) found in the region and was highly prevalent (80-100% of individuals tested, n=134), among populations collected at disparate sites 7 years apart. AfaDV was detected in the body wall, gonads, and pyloric caeca (digestive gland) of specimens but was not detected in their coelomic fluid. A significant difference in viral load was found between tissue types with the pyloric caeca having the highest viral load suggesting it is the primary site of viral replication in the animal. Further investigation of Asterias forbesi gonad tissue found germline cells (oocytes) to be virus positive suggesting a potential route of vertical transmission. Taken together, these observations show that the presence AfaDV is not an indicator of Sea Star Wasting Syndrome because AfaDV is a common constituent of these animals’ microbiome, regardless of health. These results broaden the understanding of echinoderm densoviruses outside the context of disease that suggest these viruses might form commensal or mutualistic relationships with their hosts.
Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics
Authors: Keyes Jeremiah , Ganesan Ambhighainath , Molinar-Inglis Olivia , Hamidzadeh Archer , Ling Megan , Trejo JoAnn , Levchenko Andre , Zhang Jin 
Published: September 2019

AbstractA variety of different signals induce specific responses through a common, ERK-dependent kinase cascade. It has been suggested that signaling specificity can be achieved through precise temporal regulation of ERK activity. Given the wide distrubtion of ERK susbtrates across different subcellular compartments, it is important to understand how ERK activity is temporally regulated at specific subcellular locations. To address this question, we have expanded the toolbox of FRET-based ERK biosensors by creating a series of improved biosensors targeted to various subcellular regions via sequence specific motifs to measure spatiotemporal changes in ERK enzymatic activity. Using these sensors, we showed that EGF induces sustained ERK activity near the plasma membrane in sharp contrast to the transient activity observed in the cytopolasm and nucleus. Furthermore, EGF-induced plasma membrane ERK activity involves Rap1, a noncanonical activator, and controls cell morphology and EGF-induced membrane protrusion dynamics. Our work strongly supports that spatial and temporal regulation of ERK activity is integrated to control signaling specificity from a single extracellular signal to multiple cellular processes.
Modelling the in vitro pre-infection dynamics of Colletotrichum spp. isolated from yellow passion fruit in function of environmental variables
Authors: Velame Karinna Vieira Chiacchio , Santos Filho Hermes Peixoto , de Almeida Lima Adelise , Bragança Carlos Augusto Dórea , Laranjeira Francisco Ferraz 
Published: September 2019

AbstractBrazil is the largest world producer of yellow passion fruit, but the mean yield (14.3t.ha-1) is less than half the potential of the crop. Part of this difference can be explained by plant health problems, including anthracnose caused by Colletotrichum spp. In regions with favorable climatic conditions, anthracnose can be a factor of significant yield reduction, but these regions have not yet been zoned. The objective of this study was to model the pre-infection dynamics of the fungus. The influence of temperature and photoperiod was studied on mycelia growth, sporulation and conidia germination. Mathematical models were fitted to the results and the optima for the environmental variables were estimated. The maximum mycelia growth was estimated to occur at 26.5°C. Between 24.5°C and 28.5°C the fungus grew from 95% to 100% of the estimated maximum. Temperatures below 13°C or above 34°C were harmful to mycelia growth. Temperatures over 26°C were the most favorable to sporulation while below 13°C sporulation was only 5% of the maximum. Optimum germination occurred between 25°C and 29°C with the ideal wetness period between 11h and 13h. These results can be used as a basis for zoning the risk of anthracnose occurrence in passion fruit producing regions.Significance and Impact of the StudyMany diseases affect the yellow passion fruit crop, limiting its yield; among them anthracnose, caused by Colletotrichum spp. The disease occurs in both field (leaf and stem symptoms) and post-harvest (fruits) conditions. Understanding the role environmental conditions play in the biological cycle of such diseases is essential for developing management strategies. By modelling mycelial growth, spore production and spore germination of Colletotrichum spp. as affected by temperature, photoperiod and wetness period, it was possible to characterize the pathogen’s pre-infectional dynamics. The results should be used as a first approximation to estimate the risk of anthracnose occurrence in pre- or post-harvest.
Systematic identification of functional SNPs interrupting 3’ UTR polyadenylation signals
Authors: Shulman Eldad David , Elkon Ran 
Published: September 2019

AbstractAlternative polyadenylation (APA) is emerging as a widespread regulatory layer as the majority of human protein-coding genes contain several polyadenylation (p(A)) sites in their 3’ UTRs. By generating isoforms with different 3’ UTR length, APA potentially affects mRNA stability, translation efficiency, nuclear export, and cellular localization. Polyadenylation sites are regulated by adjacent RNA cis-regulatory elements, the principals among them are the polyadenylation signal (PAS) AAUAAA and its main variant AUUAAA, typically located ~20- nt upstream of the p(A) site. Mutations in PAS and other auxiliary poly(A) cis-elements in the 3’ UTR of several genes have been shown to cause human Mendelian diseases, and to date, only a few common SNPs that regulate APA were associated with complex diseases. Here, we systematically searched for SNPs that affect gene expression and human traits by modulation of 3’ UTR APA. Focusing on the variants most likely to exert the strongest effect, we identified 2,305 SNPs that interrupt the canonical PAS or its main variant. Implementing pA-QTL tests using GTEx RNA-seq data, we identified 139 PAS SNPs significantly associated with the usage of their p(A) site. As expected, PAS-interrupting alleles were significantly linked with decreased cleavage at their p(A) site and the consequential 3’ UTR lengthening. As an indication for a functional effect of these PAS SNPs on gene expression, 65 of the pA-QTLs were also detected as eQTLs of the same gene in the same tissue. Furthermore, we observed that PAS-interrupting alleles linked with 3’ UTR lengthening were also strongly associated with decreased gene expression, pointing that shorter isoforms generated by APA are generally more stable than longer ones. Last, indicative of the impact of PAS SNPs on human phenotypes, 53 pA-QTLs overlapped GWAS SNPs that are significantly linked with human traits.
Formula alters preterm infant gut microbiota and increases its antibiotic resistance load
Authors: Pärnänen Katariina , Hultman Jenni , Satokari Reetta , Rautava Samuli , Lamendella Regina , Wright Justin , McLimans Christopher J. , Kelleher Shannon L. , Virta Marko 
Published: September 2019

SummaryInfants are at a high risk of acquiring infections caused by antibiotic resistant bacterial strains. Antibiotic resistance gene (ARG) load is typically higher in newborns than in adults, but it is unknown which factors besides antibiotic treatment affect the load. Our study demonstrates that inclusion of any formula in the newborn diet causes shifts in microbial community composition that result in higher ARG loads in formula-fed infants compared to infants not fed formula. The effect of formula was especially strong in premature newborns and newborns treated with antibiotics. Interestingly, antibiotics alone without formula did not have a detectable impact on the ARG load of the newborn gut. We also observed that formula-fed infants had enriched numbers of pathogenic species and were depleted in typical infant gut species such as Bifidobacterium bifidum. The results suggest infant feeding choices should include assessment of risks associated with elevated ARG abundance.
Effects of fiscal decentralization on carbon emissions in China
Authors: Yang Yuanhua , Tang Dengli , Zhang Peng 
Published: September 2019

PurposeFiscal fund is the key support of carbon emissions control for local governments. This paper aims to analyze the impact of fiscal decentralization on carbon emissions by spatial Durbin model (SDM), and verify the existence of “free-riding” phenomenon to reveal the behavior of local governments in carbon emissions control.Design/methodology/approachBased on the provincial data of carbon emissions from 2005 to 2016 in China, this paper uses spatial exploratory data analysis technology to analyze the spatial correlation characteristics and constructs SDM to test the impact of fiscal decentralization on carbon emissions.FindingsThe results show that carbon emissions exhibits significant spatial autocorrelation in China, and the increasing of fiscal decentralization in the region will increase carbon emissions in surrounding areas and on the whole. Then, by comparing the impact of fiscal decentralization on carbon emissions and industrial solid waste, it is found that “free-riding” phenomenon of carbon emissions control exists in China.Practical implicationsBased on the spatial cluster characteristics of China’s provincial carbon emissions, carbon emissions control regions can be divided into regions and different carbon emission control policies can be formulated for different cluster regions. Carbon emissions indicators should be included in the government performance appraisal policy, and carbon emissions producer survey should be increased in environmental policies to avoid “free-riding” behaviors of local government in carbon emissions control in China.Originality/valueThis paper contributes to fill this gap and fully considers the spatial spillover characteristics of carbon emissions by introducing spatial exploratory data analysis technology, constructs SDM to test the impact of fiscal decentralization on carbon emissions in the perspective of space econometrics, and tests the existence of “free-riding” phenomenon in carbon emissions control for local governments in China.