bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced dopamine signaling impacts pyramidal neuron excitability in mouse motor cortex
Authors: Swanson Olivia K. , Semaan Rosa , Maffei Arianna 
Published: February 2020

AbstractDopaminergic modulation is essential for the control of voluntary movement, however the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined if chronic depletion of dopaminergic input to the entire motor circuit, through a mouse model of Parkinson’s Disease, was sufficient to shift M1 neuron excitability. We show that D1 and D2 receptor (D1R, D2R) antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission.In contrast, chronic depletion of dopamine to the motor circuit with 6-hydroxydopamine (6OHDA) induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mechanisms engaged are distinct depending on the duration and location of the manipulation. Our study highlights dopamine’s broad influence on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function.Significance statementDopaminergic signaling is crucial for the control of voluntary movement, and loss of dopaminergic transmission in the motor circuit is thought to underlie motor symptoms in those with Parkinson’s Disease (PD). Studies in animal models of PD highlight changes in M1 activity following dopamine depletion, however the mechanisms underlying this phenomenon remain poorly understood. Here we show that diminished dopamine signaling significantly alters the excitability and input/output function of M1 pyramidal neurons. The effects differed depending on the mode and location – local versus across the motor pathway – of the dopamine manipulation. Our results demonstrate how loss of dopamine can engage complex mechanisms to alter M1 neurons activity.
Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model
Authors: Donnard Elisa , Shu Huan , Garber Manuel 
Published: February 2020

AbstractDespite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative. We applied single cell RNA sequencing to profile a FXS mouse model. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.
Characterising the mechanism of action of an ancient antimicrobial, honey, using modern transcriptomics
Authors: Bouzo Daniel , Cokcetin Nural N. , Li Liping , Ballerin Giulia , Bottomley Amy L. , Lazenby James , Whitchurch Cynthia B. , Paulsen Ian T. , Hassan Karl A. , Harry Elizabeth J. 
Published: February 2020

AbstractManuka honey has broad-spectrum antimicrobial activity and unlike traditional antibiotics, resistance to its killing effects has not been reported. However, its mechanism of action remains unclear. Here we investigated the mechanism of action of manuka honey and its key antibacterial components using a transcriptomic approach in a model organism,Pseudomonas aeruginosa.We show that no single component of honey can account for its total antimicrobial action, and that honey affects the expression of genes in the SOS response, oxidative damage and quorum sensing. Manuka honey uniquely affects genes involved in the explosive cell lysis process and in maintaining the electron transport chain, causing protons to leak across membranes and collapsing the proton motive force; and induces membrane depolarisation and permeabilisation inP. aeruginosa. These data indicate that the activity of manuka honey comes from multiple mechanisms of action that do not engender bacterial resistance.ImportanceThe threat of antimicrobial resistance to human health has prompted interest in complex, natural products with antimicrobial activity. Honey has been an effective topical wound treatment throughout history, predominantly due to its broad-spectrum antimicrobial activity. Unlike traditional antibiotics, honey-resistant bacteria have not been reported, however, honey remains underutilised in the clinic in part due to a lack of understanding of its mechanism of action. Here we demonstrate that honey affects multiple processes in bacteria, and this is not explained by its major antibacterial components. Honey also uniquely affects bacterial membranes and this can be exploited for combination therapy with antibiotics that are otherwise ineffective on their own. We argue that honey should be included as part of the current array of wound treatments due to its effective antibacterial activity that does not promote resistance in bacteria.
Understanding the present status and forecasting of COVID―19 in Wuhan
Authors: Tomie Toshihisa 
Published: February 2020

AbstractThe present status of COVID―19 is analyzed and the end of the disease is forecasted. The peak of the epidemic is different in three regions, Wuhan, Hubei province except Wuhan, and mainland China except Hubei. In two regions except Wuhan, the peak of the epidemic passed ten days ago. If the trend until February 11 does not change, the disease may end by the end of February. In Wuhan, the epidemic reached a peak but the reported number of newly infected patients fluctuates largely. We need to know the reason for the big fluctuation to forecast the end of the disease.
Evaluating quality improvement at scale: routine reporting for executive board governance in a UK National Health Service organisation
Authors: Chua Kia-Chong , Henderson Claire , Grey Barbara , Holland Michael , Sevdalis Nick 
Published: February 2020

ABSTRACTPurposeQuality improvement (QI) in healthcare is a cultural transformation process that requires long-term commitment from the executive board. As such, an overview of QI applications and their impact needs to be made routinely visible. We explored how routine reporting could be developed for QI governance.DesignWe developed a retrospective evaluation of QI projects in an NHS healthcare organisation. The evaluation was conducted as an online survey so that the data accrual process resembled routine reporting to help identify implementation challenges. A purposive sample of QI projects was identified to maximise contrast between projects that were or were not successful as determined by the resident QI team. To hone strategic focus in what should be reported, we also compared factors that might affect project outcomes.FindingsOut of 52 QI projects, 10 led to a change in routine practice (‘adoption’). Details of project outcomes were limited. Project team outcomes, indicative of capacity building, were not systematically documented. Service user involvement, quality of measurement plan, fidelity of plan-do-study-act (PDSA) cycles had a major impact on adoption. We discussed how routine visibility of these factors may aid QI governance.OriginalityDesigning a routine reporting framework is an iterative process involving continual dialogue with frontline staff and improvement specialists to navigate data accrual demands. We demonstrated how a retrospective evaluation, as in this study, can yield empirical insights to support dialogue around QI governance, thereby honing the implementation science of QI in a healthcare organisation.
LanD-like Flavoprotein-Catalyzed Aminovinyl-Cysteine Formation through Oxidative Decarboxylation and Cyclization of a Peptide at the C-Terminus
Authors: Liu Jingyu , Qiu Yanping , Fu Tao , Li Miao , Li Yuqing , Yang Qian , Tang Zhijun , Tang Haoyu , Li Guangyu , Pan Lifeng , Liu Wen 
Published: February 2020

ABSTRACTAminovinyl-cysteine residues arise from processing the C-terminall-Cys and an internall-Ser/l-Thr orl-Cys of a peptide. Formation of these nonproteinogenic amino acids, which occur in a macrocyclic ring of diverse ribosomally synthesized lanthipeptides and non-lanthipeptides, remains poorly understood. Here, we report that LanD-like flavoproteins in the biosynthesis of distinct non-lanthipeptides share an unexpected dual activity for aminovinyl-cysteine formation. Each flavoprotein catalyzes oxidative decarboxylation of the C-terminall-Cys and couples the resulting enethiol nucleophile with the internal residue to afford a thioether linkage for peptide cyclization. The cyclization step, which largely depends on proximity effect by positioning the enethiol intermediate with a bent conformation at the active site, can be substrate-dependent, proceeding inefficiently through nucleophilic substitution for an unmodified peptide or efficiently through Michael addition for a dehydrated/dethiolated peptide. Uncovering this unusual flavin-dependent paradigm for thioether residue formation advances the understanding in the biosynthesis of aminovinyl-cysteine-containing RiPPs and renews interest in flavoproteins, particularly those involved in non-redox transformations. LanD-like flavoproteins activity, which is flexible in peptide substrate and amenable for evolution by engineering, can be combined with different post-translational modifications for structural diversity, thereby holding promise for peptide macrocyclization/functionalization in drug development by chemoenzymatic or synthetic biology approaches.
Identification of potential candidates for drug designing againstKlebsiella Pneumoniaeamong hypothetical proteins of DNA Adenine Methyltransferase through subtractive genomics approach
Authors: Omeershffudin Umairah Natasya Mohd , Kumar Suresh 
Published: February 2020

ABSTRACTKlebsiella Pneumoniaeis a gram-negative bacterium that is known for causing infection in nosocomial settings. As reported by WHO, this bacterial pathogen is classified as an urgent threat our most concern is that these bacterial pathogens acquired genetic traits that make them resistant towards antibiotics. The last class of antibiotics; carbapenems are not able to combat these bacterial pathogens allowing them to clonally expand their antibiotic-resistant strain. Most antibiotics target the essential pathways of the bacteria cell however these targets are no longer susceptible to the antibiotic. Hence in our study, we focus onKlebsiella Pneumoniaebacterial strains that contain DNA Adenine Methyltransferase domain which suggests a new potential site for a drug target. DNA methylation is seen to regulate the attenuation of bacterial virulence. In this study, all hypothetical proteins ofKlebsiella Pneumoniaecontaining N6 DNA Adenine Methyltransferase domain were analysed for a potential drug target. About 32 hypothetical proteins were retrieved from Uniprot. 19 proteins were selected through a step-wise subtractive genomics approach like a selection of non-homologus proteins against the human host, selection of bacterial proteins contains an essential gene, broad-spectrum analysis, druggability analysis, Non-homology analysis against gut microbiota. Through drug target prioritization like sub-cellular analysis, drug property analysis, anti-target non-homology analysis, virulence factor analysis and protein-protein interaction analysis one drug target protein (Uniprot ID: A0A2U0NNR3) was prioritized. Identified drug target docked with potential inhibitors like are mahanine (PubChem ID: 375151), curcumin (PubChem ID: 969516), EGCG (PubChem ID: 65064), nanaomycin A (PubChem ID: 40586), parthenolide (PubChem ID: 7251185), quercetin (PubChem ID: 5280343) and trimethylaurintricarboxylic acid. Based on the moelcular docking analysis, mahanine has the highest binding affinity. In order to identify novel natural inhibitor based on mahanine fingerprint search is performed against NPASS (Natural Product Activity and Species Source databases) and Koenimbine was identified as a novel natural inhibitor based on virtual screening.
Jointing analysis of scATAC-seq datasets using epiConv
Authors: Lin Li , Zhang Liye 
Published: February 2020

AbstractTechnical improvement in ATAC-seq makes it possible to profile the chromatin states of single cells at high throughput, but currently no method is available to integrate datasets from multiple sources (different batches of same protocol or multiple experimental protocols). Here we present an algorithm to perform joint analyses on scATAC-seq datasets from multiple sources. In addition to batch correction, we also demonstrate that epiConv is capable of aligning co-assay data (simultaneous profiling of transcriptome and chromatin) onto high-quality ATAC-seq reference or integrating cells in different biological conditions (malignantvs. normal), which increases the statistical power of downstream analyses and reveals hidden hierarchy of malignant cells.
Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor
Authors: Debaker Clément S. , Djemai Boucif , Ciobanu Luisa , Tsurugizawa Tomokazu , Le Bihan Denis 
Published: February 2020

AbstractThe Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its dysfunction might lead to several brain pathologies, including the Alzheimer’s disease. A key component of the GS and brain tissue water circulation is the astrocyte which is regulated by acquaporin4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo and non-invasively.
Exploring spatiotemporal changes in ecosystem service values and hotspots in Southwest of China, Mekong Region
Authors: Zhang Zhuoya , Yang Junjie , Yang Xin , Xie Fuming 
Published: February 2020

AbstractXishuangbanna in the southwestern border of China is located in the upper reaches of the Mekong River between the Indo-China Peninsula and the East Asian continent. It is the largest tropical rain forest and monsoon forest in China. They have an irreplaceable ecological service function and are an important barrier to maintaining the ecological security of the Mekong River transboundary basin of the Lancang River. Based on three sets of remote sensing data (1996, 2003, 2010 and 2016), this study has made an exploration on spatio-temporal changes of Xishuangbanna, and also made an assessment on different ecosystem values of six types of ecosystem in Xishuangbanna based on related theories of ecological economics. Results showed that the values of Xishuangbanna ecosystem services in 1996, 2003, 2010, and 2016 were 70.4014billion yuan, 70.2115 billion yuan, 68.5129 billion yuan and 63.6098 billion yuan, respectively. The total value shows a continuous decreasing trend, reflecting the continuous decline in the ability of the Xishuangbanna ecosystem to provide services to humans. If divided by ecosystem types, forest and rubber were two types that have the greatest proportion of service values. In the perspective of service types, soil formation and protection account for the largest proportion, followed by gas regulation and biodiversity protection. Studying Xishuangbanna’s ecosystem service values is helpful to explore the sustainable development of resources and economy.HighlightThis paper used coefficient of sensitivity to determine the dependence of ESV on the change of ecosystem value coefficient over time.The total amount of ESV shows a continuous downward trend, indicating that the ecological environment of Xishuangbanna is still severe.The temporal-spatial change of ESV was analyzed for two decades.
Drug-adapted cancer cell lines reveal drug-induced heterogeneity and enable the identification of biomarker candidates for the acquired resistance setting
Authors: Michaelis Martin , Wass Mark N. , Reddin Ian , Voges Yvonne , Rothweiler Florian , Hehlgans Stephanie , Cinatl Jaroslav , Mernberger Marco , Nist Andrea , Stiewe Thorsten , Rödel Franz , Cinatl Jindrich 
Published: February 2020

AbstractSurvivin is a drug target and the survivin suppressant YM155 a drug candidate for high-risk neuroblastoma. Findings from one YM155-adapted subline of the neuroblastoma cell line UKF-NB-3 had suggested that increased ABCB1 (mediates YM155 efflux) levels, decreased SLC35F2 (mediates YM155 uptake) levels, decreased survivin levels, andTP53mutations indicate YM155 resistance. Here, the investigation of ten additional YM155-adapted UKF-NB-3 sublines only confirmed the roles of ABCB1 and SLC35F2. However, cellular ABCB1 and SLC35F2 levels did not indicate YM155 sensitivity in YM155-naïve cells, as indicated by drug response data derived from the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) databases. Moreover, the resistant sublines were characterised by a remarkable heterogeneity. Only seven sublines developed on-target resistance as indicated by resistance to RNAi-mediated survivin depletion. The sublines also varied in their response to other anti-cancer drugs. In conclusion, cancer cell populations of limited intrinsic heterogeneity can develop various resistance phenotypes in response to treatment. Therefore, individualised therapies will require monitoring of cancer cell evolution in response to treatment. Moreover, biomarkers can indicate resistance formation in the acquired resistance setting, even when they are not predictive in the intrinsic resistance setting.
MSH1 is required for maintenance of the low mutation rates in plant mitochondrial and plastid genomes
Authors: Wu Zhiqiang , Waneka Gus , Broz Amanda K. , King Connor R. , Sloan Daniel B. 
Published: February 2020

ABSTRACTMitochondrial and plastid genomes in land plants exhibit some of the slowest rates of sequence evolution observed in any eukaryotic genome, suggesting an exceptional ability to prevent or correct mutations. However, the mechanisms responsible for this extreme fidelity remain unclear. We tested seven candidate genes involved in cytoplasmic DNA replication, recombination, and repair (POLIA, POLIB, MSH1, RECA3, UNG, FPG, and OGG1) for effects on mutation rates in the model angiosperm Arabidopsis thaliana by applying a highly accurate DNA sequencing technique (duplex sequencing) that can detect newly arisen mitochondrial and plastid mutations still at low heteroplasmic frequencies. We find that disrupting MSH1 (but not the other candidate genes) leads to massive increases in the frequency of point mutations and small indels and changes to the mutation spectrum in mitochondrial and plastid DNA. We also used droplet digital PCR to show transmission of de novo heteroplasmies across generations in msh1 mutants, confirming a contribution to heritable mutation rates. This dual-targeted gene is part of an enigmatic lineage within the mutS mismatch repair family that we find is also present outside of green plants in multiple eukaryotic groups (stramenopiles, alveolates, haptophytes, and cryptomonads), as well as certain bacteria and viruses. MSH1 has previously been shown to limit ectopic recombination in plant cytoplasmic genomes. Our results point to a broader role in recognition and correction of errors in plant mitochondrial and plastid DNA sequence, leading to greatly suppressed mutation rates perhaps via initiation of double-stranded breaks and repair pathways based on faithful homologous recombination.
A Total-Evidence Dated Phylogeny of Echinoids and the Evolution of Body Size across Adaptive Landscape
Authors: Koch Nicolás Mongiardino , Thompson Jeffrey R. 
Published: February 2020

AbstractSeveral unique properties of echinoids (sea urchins) make them useful for exploring macroevolutionary dynamics, including their remarkable fossil record that can be incorporated into explicit phylogenetic hypotheses. However, this potential cannot be exploited without a robust resolution of the echinoid tree of life. We revisit the phylogeny of crown group Echinoidea using both the largest phylogenomic dataset compiled for the clade, as well as a large-scale morphological matrix with a dense fossil sampling. We also gather a new compendium of both tip and node age constraints, allowing us to combine phylogenomic, morphological and stratigraphic data using a total-evidence dating approach. For this, we develop a novel method for subsampling phylogenomic datasets that selects loci with high phylogenetic signal, low systematic biases and enhanced clock-like behavior. Our approach restructure much of the higher-level phylogeny of echinoids, and demonstrates that combining different data sources increases topological accuracy. We are able to resolve multiple alleged conflicts between molecular and morphological datasets, such as the position of Echinothurioida and Echinoneoida, as well as unravelling the relationships between sand dollars and their closest relatives. We then use this topology to trace the evolutionary history of echinoid body size through more than 270 million years, revealing a complex pattern of convergent evolution to stable peaks in macroevolutionary adaptive landscape. Our efforts show how combining phylogenomic and paleontological evidence offers new ways of exploring evolutionary forces operating across deep timescales.
Second messenger control of mRNA translation by dynamic ribosome modification
Authors: Grenga Lucia , Little Richard Howard , Chandra Govind , Woodcock Stuart Daniel , Saalbach Gerhard , Morris Richard James , Malone Jacob George 
Published: February 2020

SummaryControl of mRNA translation is a crucial regulatory mechanism used by bacteria to respond to their environment. In the soil bacteriumPseudomonas fluorescens, RimK modifies the C-terminus of ribosomal protein RpsF to influence important aspects of rhizosphere colonisation through proteome remodelling. In this study, we show that RimK activity is itself under complex, multifactorial control by the co-transcribed phosphodiesterase trigger enzyme (RimA) and a polyglutamate-specific protease (RimB). Furthermore, biochemical experimentation and mathematical modelling reveal a role for the nucleotide second messenger cyclic-di-GMP in coordinating these activities. Active ribosome regulation by RimK occurs by two main routes: indirectly, through changes in the abundance of the global translational regulator Hfq and directly, with translation of surface attachment factors, amino acid transporters and key secreted molecules linked specifically to RpsF modification. Our findings show that post-translational ribosomal modification functions as a rapid-response mechanism that tunes global gene translation in response to environmental signals.