bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust Inference of Kinase Activity Using Functional Networks
Authors: Yılmaz Serhan , Ayati Marzieh , Schlatzer Daniela , Çiçek A. Ercüment , Chance Mark R. , Koyutürk Mehmet 
Published: May 2020

AbstractMass spectrometry enables high-throughput screening of phospho-proteins across a broad range of biological contexts. When complemented by computational algorithms, phospho-proteomic data allows the inference of kinase activity, facilitating the identification of dysregulated kinases in various diseases including cancer, Alzheimer’s disease and Parkinson’s disease. To enhance the reliability of kinase activity inference, we present a network-based framework, RoKAI, that integrates various sources of functional information to capture coordinated changes in signaling. Through computational experiments, we show that phosphorylation of sites in the functional neighborhood of a kinase are significantly predictive of its activity. The incorporation of this knowledge in RoKAI consistently enhances the accuracy of kinase activity inference methods while making them more robust to missing annotations and quantifications. This enables the identification of understudied kinases and will likely lead to the development of novel kinase inhibitors for targeted therapy of many diseases. RoKAI is available as web-based tool athttp://rokai.io.
A novel DNA binding mode, conformational change and intramolecular signaling in MutS upon mismatch recognition in replication DNA structures
Authors: Busseti Milagros Inés Ibáñez , Margara Lucía Malvina , Castell Sofía Daiana , Fernández Marisa Mariel , Malchiodi Emilio Luis , Montich Guillermo Gabriel , Miguel Virginia , Argaraña Carlos Enrique , Monti Mariela Roxana 
Published: May 2020

ABSTRACTMutS initiates mismatch repair by recognizing mismatches in newly replicated DNA. Specific interactions between MutS and mismatches within double-stranded DNA promote ADP-ATP exchange and a conformational change into a sliding clamp. Here, we demonstrated that MutS fromPseudomonas aeruginosaassociates with primed DNA replication substrates. The predicted structure of this MutS-DNA complex revealed a new DNA binding site, in which Asn 279 and Arg 272 appeared to directly interact with the 3’-OH terminus of primed DNA. Mutation of these residues resulted in a noticeable defect in the interaction of MutS with replication DNA substrates. Remarkably, MutS interaction with a mismatch within primed DNA induced a compaction of the protein structure and impaired the formation of an ATP-bound sliding clamp. Our findings reveal a novel DNA binding mode, conformational change and intramolecular signaling for MutS recognition of mismatches within DNA replication structures.
The complete genome sequence of theStaphylococcusbacteriophage Metroid
Authors: Crane Adele , Abaidoo Joy , Beltran Gabriella , Fry Danielle , Furey Colleen , Green Noe , Johal Ravneet , La Rosa Bruno , Jimenez Catalina Lopez , Luong Linh , Maag Garett , Porche Jade , Reyes Lauren , Robinson Aspen , Sabbara Samantha , Herrera Lucia Soto , Negrete Angelica Urquidez , Wilson Pauline , Geiler-Samerotte Kerry , Pfeifer Susanne P. 
Published: May 2020

AbstractPhages infecting bacteria of the genusStaphylococcusplay an important role in their host’s ecology and evolution. On one hand, horizontal gene transfer from phage can encourage the rapid adaptation of pathogenicStaphylococcusenabling them to escape host immunity or access novel environments. On the other hand, lytic phages are promising agents for the treatment of bacterial infections, especially those resistant to antibiotics. As part of an ongoing effort to gain novel insights into bacteriophage diversity, we characterized the complete genome of theStaphylococcusbacteriophage Metroid, a cluster C phage with a genome size of 151kb, encompassing 254 predicted protein-coding genes as well as 4 tRNAs. A comparative genomic analysis highlights strong similarities – including a conservation of the lysis cassette – with otherStaphylococcuscluster C1 bacteriophages, several of which were previously characterized for therapeutic applications.
Close encounters of the three morphs: does color affect aggression in a polymorphic lizard?
Authors: Scali Stefano , Mangiacotti Marco , Sacchi Roberto , Coladonato Alan Jioele , Falaschi Mattia , Saviano Luca , Rampoldi Marina Giulia , Crozi Matteo , Perotti Cesare , Zucca Francesco , Gozzo Elisabetta , Luca Zuffi Marco Alberto 
Published: May 2020

AbstractColor polymorphism is genetically controlled and the process generating and maintaining morphs can affect speciation and/or extinction rates. Competition and aggression among morphs can contribute to polymorphism maintenance and color badges are useful signals in intraspecific communication, because they convey information about alternative strategies and avoid unnecessary conflicts. This could lead to an uneven spatial distribution of morphs in a population, because the local frequency of each morph establishes the intensity of the competition in that neighborhood, and then the fitness of each male. We used a polymorphic lizard,Podarcis muralis, to assess if aggression varies among morphs under two contrasting hypotheses: a heteromorphic vs. a homomorphic aggression. We used laboratory mirror tests after lizard color manipulation and we verified the results consistency with the analysis of the spatial distribution of morphs in a wild population. Both the experiments confirmed that aggression is morph-specific and notably homomorphic. The adoption of behavioral alternative strategies that minimize risks and costs of unwanted conflicts could facilitate the stable coexistence of the phenotypes and reduce the resource competition. A bias in aggression to like-coloured males would advantage rarer morph, which would suffer less harassment by common morphs and obtain a fitness advantage. This process would be negatively-frequency-dependent and would stabilize polymorphism in the populations, possibly leading to sympatric speciation.
Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Authors: Vuong Wayne , Khan Muhammad Bashir , Fischer Conrad , Arutyunova Elena , Lamer Tess , Shields Justin , Saffran Holly A. , McKay Ryan T. , van Belkum Marco J. , Joyce Michael , Young Howard S. , Tyrrell D. Lorne , Vederas John C. , Lemieux M. Joanne 
Published: May 2020

AbstractThe COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (Mpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog GC373, are effective inhibitors of the Mprofrom both SARS-CoV and SARS-CoV-2 with IC50values in the nanomolar range. Crystal structures of the SARS-CoV and SARS-CoV-2 Mprowith these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 in cell culture, with EC50values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.
Pathogen Reduction of SARS-CoV-2 Virus in Plasma and Whole Blood using Riboflavin and UV Light
Authors: Ragan Izabela , Hartson Lindsay , Pidcoke Heather , Bowen Richard , Goodrich Raymond P. 
Published: May 2020

ABSTRACTBACKGROUNDSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has recently been identified as the causative agent for Coronavirus Disease 2019 (COVID-19). The ability of this agent to be transmitted by blood transfusion has not been documented, although viral RNA has been detected in serum. Exposure to treatment with riboflavin and ultraviolet light (R + UV) reduces blood-borne pathogens while maintaining blood product quality. Here, we report on the efficacy of R + UV in reducing SARS-CoV-2 infectivity when tested in human plasma and whole blood products.STUDY DESIGN AND METHODSSARS-CoV-2 (isolate USA-WA1/2020) was used to inoculate plasma and whole blood units that then underwent treatment with riboflavin and UV light (Mirasol Pathogen Reduction Technology System, Terumo BCT, Lakewood, CO). The infectious titers of SARS-CoV-2 in the samples before and after R + UV treatment were determined by plaque assay on Vero cells. Each plasma pool (n=9) underwent R + UV treatment performed in triplicate using individual units of plasma and then repeated using individual whole blood donations (n=3).RESULTSRiboflavin and UV light reduced the infectious titer of SARS-CoV-2 below the limit of detection for plasma products at 60-100% of the recommended energy dose. At the UV light dose recommended by the manufacturer, the mean log reductions in the viral titers were ≥ 4.79 ± 0.15 Logs in plasma and 3.30 ± 0.26 in whole blood units.CONCLUSIONRiboflavin and UV light effectively reduced the titer of SARS-CoV-2 to the limit of detection in human plasma and by 3.30 ± 0.26 on average in whole blood. Two clades of SARS-CoV-2 have been described and questions remain about whether exposure to one strain confers strong immunity to the other. Pathogen-reduced blood products may be a safer option for critically ill patients with COVID-19, particularly those in high-risk categories.
Community succession of the grapevine fungal microbiome in the annual growth cycle
Authors: Liu Di , Howell Kate 
Published: May 2020

SummaryMicrobial ecology is an integral component of wine production. From the vineyard to the winery, microbial activity influences grapevine health and productivity, conversion of sugar to ethanol during fermentation, wine aroma production, wine quality and distinctiveness. Fungi in the vineyard ecosystem are not well described. Here, we characterised the spatial and temporal dynamics of fungal communities associated with the grapevine (grapes, flowers, leaves, and roots) and soils over an annual growth cycle in two vineyards to investigate the influences of grape habitat, plant developmental stage (flowering, fruit set, veraison, and harvest), vineyards, and climatic conditions. Fungi were influenced by both the grapevine habitat and plant development stage. The core microbiome was prioritised over space and time, and the identified core members drove seasonal community succession. The development stage of veraison, where the grapes undergo a dramatic change in metabolism and start accumulating sugar, displayed a distinct shift in fungal communities. Co-occurrence networks showed strong correlations between the plant microbiome, the soil microbiome, and weather indices. Our study describes the complex ecological dynamics that occur in microbial assemblages over a growing season and highlight the importance of core community succession in vineyards. In addition to enriching our understanding of how plants and microbes interact, these findings may provide insights to craft wine regional distinctiveness and cope with global climate change.
Host adaptations in thefixLJpathway of theBurkholderia cepaciacomplex increase virulence
Authors: Schaefers Matthew M. , Wang Benjamin X. , Boisvert Nicole M. , Martini Sarah J. , Bonney Sarah L. , Marshall Christopher W. , Laub Michael T. , Cooper Vaughn S. , Priebe Gregory P. 
Published: May 2020

AbstractTheBurkholderia cepaciacomplex (BCC) is composed of multiple species, includingB. multivoransandB. dolosa,that are significant pathogens for people with cystic fibrosis (CF) and are extensively resistant to many antibiotics. ThefixLgene of thefixLJ2-component system (TCS) in these BCC species shows evidence of positive selection for nonsynonymous mutations during chronic lung infection in CF. Previous work showed that theB. dolosa fixLJsystem regulates 11% of the genome and modulates biofilm formation, motility, persistence within macrophages, and virulence in a murine pneumonia model. Here, we assess the impacts of clinically observed FixL evolved variants infixLJpathway-mediated phenotypes inB. dolosaandB. multivorans.BCC carrying the ancestralfixLsequence are less pathogenic than constructs carrying evolved variants in both a macrophage infection model and a murine pneumonia model.In vitrophospho-transfer experiments demonstrate that the evolvedB. dolosaFixL variants are able to reducefixLJpathway activity by either having lower levels of kinase activity or increased phosphatase activity. Notably, the ancestralfixLgenotype has increased ability to survive within the soil compared to isogenic constructs with evolvedfixLgenotypes, demonstrating that increased virulence comes at an expense. Modulation of the FixLJ system has profound effects on many BCC phenotypes including full pathogenicity, and this modulation is critical for BCC adaptation to the host.
Design of 18 nm Doxorubicin-loaded 3-helix Micelles: Cellular Uptake and Cytotoxicity in Patient-derived GBM6 Cells
Authors: Jung Benson T. , Jung Katherine , Lim Marc , Li Michael , Santos Raquel , Ozawa Tomoko , Xu Ting 
Published: May 2020

AbstractThe fate of nanocarrier materials at the cellular level constitutes a critical checkpoint in the development of effective nanomedicines, determining whether tissue level accumulation results in therapeutic benefit. The cytotoxicity and cell internalization of ~18 nm 3-helix micelle (3HM) loaded with doxorubicin (DOX) was analyzed in patient-derived glioblastoma (GBM) cellsin vitro. The inhibitory concentration (IC50) of 3HM-DOX increased to 6.2 µg/mL from < 0.5 µg/mL for free DOX in patient derived GBM6 cells, 15.0 µg/mL from 6.5 µg/mL in U87MG cells, and 21.5 µg/mL from ~0.5 µg/mL in LN229 cells. Modeling analysis of previous 3HM biodistribution results predict these cytotoxic concentrations are achievable with intravenous injection in rodent GBM models. 3HM-DOX formulations were internalized intact and underwent intracellular trafficking distinct from free DOX. 3HM was quantified to have an internalization half-life of 12.6 h in GBM6 cells, significantly longer than comparable reported liposome and polymer systems. 3HM was found to traffic through active endocytic processes, with clathrin-mediated endocytosis being the most involved of the pathways studied. Inhibition studies suggest substantial involvement of low density lipoprotein receptor (LDLR) in initiating 3HM uptake. Since 3HM surface is polyethylene glycol (PEG)-ylated with no targeting functionalities, protein corona involvement in 3HM recognition is expected. The present work develops insights of the cytotoxicity, pharmacodynamics and cellular interactions of 3HM and 3HM-DOX relevant for ongoing pre-clinical studies. This work also contributes to efforts to develop predictive mathematical models tracking accumulation and biodistribution kinetics at a systemic level.Graphical Abstract
Pre-TCR signaling intensity shapes the TCRβ repertoire
Authors: Bovolenta Elena R. , García-Cuesta Eva M. , Ponomarenko Julia , Mellado Mario , Castro Mario , Abia David , van Santen Hisse M. 
Published: May 2020

AbstractSignaling via pre-TCR is essential for initial T cell differentiation. How the signal is triggered and whether its alteration impacts on lymphocyte repertoires is nevertheless debated. We show that a mutation in the transmembrane domain of the CD3ζ chain impairs murine thymocyte development at the double negative (DN) stage coinciding with reduced levels of steady-state pre-TCR signaling. Single particle tracking and TIRF microscopy on mouse primary DN3/DN4 thymocytes shows that wild-type pre-TCR form particles with a broad range of fluorescent intensities whereas mutant complexes are less intensely labeled and move faster, suggesting reduced pre-TCR nanoclustering. Notably, the mutant early-pre-TCR-selected-DP population shows less TCRβ repertoire diversity. We thus propose that the pre-TCR forms stable nanoclusters, the size of which determines signaling efficacy. This signaling does not merely promote maturation of any thymocyte expressing a rearranged TCRβ chain, but shapes the repertoire of DP thymocytes that can audition for positive and negative selection.
Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach
Authors: Wang Yafei , Brodin Erik , Nishii Kenichiro , Frieboes Hermann B. , Mumenthaler Shannon , Sparks Jessica L. , Macklin Paul 
Published: May 2020

ABSTRACTColorectal cancer (CRC) and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect tumor cell behavior in primary and metastatic tumors, the role of these properties in driving or inhibiting metastatic inception remains poorly understood, as are the longer-term multicellular dynamics. This study adopts a multi-model approach to study the dynamics of tumor-parenchyma biomechanical interactions during metastatic seeding and growth. We employ a detailed poroviscoelastic (PVE) model of a liver lobule to study how micrometastases disrupt flow and pressure on short time scales. Results from short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for a minimal agent-based model of metastatic growth in centimeter-scale tissue over months-long time scales. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling. These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors could “reawaken” after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach yields insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, and advances the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer.
Crystal Structure of the Werner’s Syndrome Helicase
Authors: Newman Joseph A. , Gavard Angeline E. , Lieb Simone , Ravichandran Madhwesh C. , Hauer Katja , Werni Patrick , Geist Leonhard , Böttcher Jark , Engen John. R. , Rumpel Klaus , Samwer Matthias , Petronczki Mark , Gileadi Opher 
Published: May 2020

AbstractWerner syndrome helicase (WRN) plays important roles in multiple pathways of DNA repair and the maintenance of genome integrity. Recently, loss of WRN was identified as a strong synthetic lethal interaction for microsatellite instable (MSI) cancers making WRN a promising drug target. Yet, structural information for the helicase domain is lacking, which prevents structure-based design of drug molecules. In this study, we show that ATP binding and hydrolysis in the helicase domain are required for genome integrity and viability of MSI cancer cells. We then determined the crystal structure of an ADP bound form of the WRN helicase core at 2.2 Å resolution. The structure features an atypical mode of nucleotide binding with extensive contacts formed by motif VI, which in turn defines the relative positioning of the two RecA like domains. The structure features a novel additional β-hairpin in the second RecA and an unusual helical hairpin in the Zn2+ binding domain, and modelling DNA substrates based on existing RecQ DNA complexes suggests roles for these features in the binding of alternative DNA structures. We have further analysed possible interfaces formed from the interactions between the HRDC domain and the helicase core by NMR. Together, this study will facilitate the structure-based design of inhibitors against WRN helicase.
Pain and breathlessness: Salient, somatosensory and similar, but not the same
Authors: Harrison Olivia K. , Hayen Anja , Wager Tor D. , Pattinson Kyle T. S. 
Published: May 2020

AbstractQuantifying pain currently relies upon subjective self-report. Alongside the inherent variability embedded within these metrics, added complications include the influence of ambiguous or prolonged noxious inputs, or in situations when communication may be compromised. As such, there is continued interest in the development of brain biomarkers of pain, such as in the form of neural ‘signatures’ of brain activity. However, issues pertaining to pain-related specificity remain, and by understanding the current limits of these signatures we can both progress their development and investigate the potentially generalizable properties of pain to other salient and/or somatomotor tasks. Here, we utilized two independent datasets to test one of the established Neural Pain Signatures (the NPS (Wager et al. 2013)). In Study 1, brain activity was measured using functional magnetic resonance imaging (fMRI) in 40 healthy subjects during experimentally induced breathlessness, conditioned anticipation of breathlessness and a simple finger opposition task. In Study 2, brain activity was again measured during anticipation and breathlessness in 19 healthy subjects, as well as a modulation with the opioid remifentanil. We were able to identify significant NPS-related brain activity during anticipation and perception of breathlessness, as well as during finger opposition using the global NPS. Furthermore, localised NPS responses were found in early somatomotor regions, bilateral insula and dorsal anterior cingulate for breathlessness and finger opposition. In contrast, no conditions were able to activate the local signature in the dorsal posterior insula - thought to be critical for pain perception. These results provide properties of the present boundaries of the NPS, and offer insight into the overlap between breathlessness and somatomotor conditions with pain.