bluuebunny/crossref_metadata_2025_split huggingface dataset:
Listeria monocytogenes GlmR is an accessory uridyltransferase essential for cytosolic survival and virulence
Authors: Pensinger Daniel A. , Gutierrez Kimberly V. , Smith Hans B. , Vincent William J.B. , Stevenson David S. , Black Katherine A. , Perez-Medina Krizia M. , Dillard Joseph P. , Rhee Kyu Y. , Amador-Noguez Daniel , Huynh TuAnh N , Sauer John-Demian 
Published: October 2021

AbstractThe cytosol of eukaryotic host cells is an intrinsically hostile environment for bacteria. Understanding how cytosolic pathogens adapt to and survive in the cytosol is critical to developing novel therapeutic interventions for these pathogens. The cytosolic pathogen Listeria monocytogenes requires glmR (previously known as yvcK), a gene of unknown function, for resistance to cell wall stress, cytosolic survival, inflammasome avoidance and ultimately virulence in vivo. A genetic suppressor screen revealed that blocking utilization of UDP-GlcNAc by a non-essential wall teichoic acid decoration pathway restored resistance to cell wall stress and partially restored virulence of ΔglmR mutants. In parallel, metabolomics revealed that ΔglmR mutants are impaired in the production of UDP-GlcNAc, an essential peptidoglycan and wall teichoic acid (WTA) precursor. We next demonstrated that purified GlmR can directly catalyze the synthesis of UDP-GlcNAc from GlcNAc-1P and UTP, suggesting that it is an accessory uridyltransferase. Biochemical analysis of GlmR orthologues suggest that uridyltransferase activity is conserved. Finally, mutational analysis resulting in a GlmR mutant with impaired catalytic activity demonstrated that uridyltransferase activity was essential to facilitate cell wall stress responses and virulence in vivo. Taken together these studies indicate that GlmR is an evolutionary conserved accessory uridyltransferase required for cytosolic survival and virulence of L. monocytogenes.ImportanceBacterial pathogens must adapt to their host environment in order to cause disease. The cytosolic bacterial pathogen Listeria monocytogenes requires a highly conserved protein of unknown function, GlmR (previously known as YvcK) to survive in the host cytosol. GlmR is important for resistance to some cell wall stresses and is essential for virulence. The ΔglmR mutant is deficient in production of an essential cell wall metabolite, UDP-GlcNAc, and suppressors which increase metabolite levels also restore virulence. Purified GlmR can directly catalyze the synthesis of UDP-GlcNAc and this enzymatic activity is conserved in pathogens from Firmicutes and Actinobacteria phyla. These results highlight the importance accessory cell wall metabolism enzymes in responding to cell wall stress in a variety of bacterial pathogens.
Designing an evidence-based Bayesian network for estimating the risk versus benefits of AstraZeneca COVID-19 vaccine
Authors: Mayfield Helen J. , Lau Colleen L. , Sinclair Jane E. , Brown Samuel J. , Baird Andrew , Litt John , Vuorinen Aapeli , Short Kirsty R. , Waller Michael , Mengersen Kerrie 
Published: October 2021

AbstractUncertainty surrounding the risk of developing and dying from Thrombosis and Thromobocytopenia Syndrome (TTS) associated with the AstraZeneca (AZ) COVID-19 vaccine may contribute to vaccine hesitancy. A model is urgently needed to combine and effectively communicate the existing evidence on the risks versus benefits of the AZ vaccine. We developed a Bayesian network to consolidate the existing evidence on risks and benefits of the AZ vaccine, and parameterised the model using data from a range of empirical studies, government reports, and expert advisory groups. Expert judgement was used to interpret the available evidence and determine the structure of the model, relevant variables, data to be included, and how these data were used to inform the model.The model can be used as a decision support tool to generate scenarios based on age, sex, virus variant and community transmission rates, making it a useful for individuals, clinicians, and researchers to assess the chances of different health outcomes. Model outputs include the risk of dying from TTS following the AZ COVID-19 vaccine, the risk of dying from COVID-19 or COVID-19-associated atypical severe blood clots under different scenarios. Although the model is focused on Australia, it can be easily adaptable to international settings by re-parameterising it with local data. This paper provides detailed description of the model-building methodology, which can used to expand the scope of the model to include other COVID-19 vaccines, booster doses, comorbidities and other health outcomes (e.g., long COVID) to ensure the model remains relevant in the face of constantly changing discussion on risks versus benefits of COVID-19 vaccination.
Personalized survival probabilities for SARS-CoV-2 positive patients by explainable machine learning
Authors: Zucco Adrian G. , Agius Rudi , Svanberg Rebecka , Moestrup Kasper S. , Marandi Ramtin Z. , MacPherson Cameron Ross , Lundgren Jens , Ostrowski Sisse R. , Niemann Carsten U. 
Published: October 2021

ABSTRACTInterpretable risk assessment of SARS-CoV-2 positive patients can aid clinicians to implement precision medicine. Here we trained a machine learning model to predict mortality within 12 weeks of a first positive SARS-CoV-2 test. By leveraging data on 33,928 confirmed SARS-CoV-2 cases in eastern Denmark, we considered 2,723 variables extracted from electronic health records (EHR) including demographics, diagnoses, medications, laboratory test results and vital parameters. A discrete-time framework for survival modelling enabled us to predict personalized survival curves and explain individual risk factors. Performances of weighted concordance index 0.95 and precision-recall area under the curve 0.71 were measured on the test set. Age, sex, number of medications, previous hospitalizations and lymphocyte counts were identified as top mortality risk factors. Our explainable survival model developed on EHR data also revealed temporal dynamics of the 22 selected risk factors. Upon further validation, this model may allow direct reporting of personalized survival probabilities in routine care.
Neural population dynamics underlying evidence accumulation in multiple rat brain regions
Authors: DePasquale Brian , Brody Carlos D. , Pillow Jonathan W. 
Published: October 2021

AbstractAccumulating evidence to make decisions is a core cognitive function. Previous studies have tended to estimate accumulation using either neural or behavioral data alone. Here we develop a unified framework for modeling stimulus-driven behavior and multi-neuron activity simultaneously. We applied our method to choices and neural recordings from three rat brain regions — the posterior parietal cortex (PPC), the frontal orienting fields (FOF), and the anterior-dorsal striatum (ADS) — while subjects performed a pulse-based accumulation task. Each region was best described by a distinct accumulation model, which all differed from the model that best described the animal’s choices. FOF activity was consistent with an accumulator where early evidence was favored while the ADS reflected near perfect accumulation. Neural responses within an accumulation framework unveiled a distinct association between each brain region and choice. Choices were better predicted from all regions using a comprehensive, accumulation-based framework and different brain regions were found to differentially reflect choice-related accumulation signals: FOF and ADS both reflected choice but ADS showed more instances of decision vacillation. Previous studies relating neural data to behaviorally-inferred accumulation dynamics have implicitly assumed that individual brain regions reflect the whole-animal level accumulator. Our results suggest that different brain regions represent accumulated evidence in dramatically different ways and that accumulation at the whole-animal level may be constructed from a variety of neural-level accumulators.Impact StatementA computational framework for combining neural and behavioral data to infer latent dynamics underlying decision-making reveals distinct accumulation dynamics in different brain regions in the rat.
Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis
Authors: Broadhead MJ , Bonthron C , Waddington J , Smith WV , Lopez MF , Burley S , Valli J , Zhu F , Komiyama NH , Smith C , Grant SGN , Miles GB 
Published: October 2021

AbstractAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.
Regulation Mechanisms of the Dual ATPase in KaiC
Authors: Furuike Yoshihiko , Mukaiyama Atsushi , Koda Shinichi , Simon Damien , Ouyang Dongyan , Ito-Miwa Kumiko , Saito Shinji , Yamashita Eiki , Nishiwaki-Ohkawa Taeko , Terauchi Kazuki , Kondo Takao , Akiyama Shuji 
Published: October 2021

AbstractKaiC is a dual ATPase, with one active site in its N-terminal domain and another in its C-terminal domain, that drives the circadian clock system of cyanobacteria through sophisticated coordination of the two sites. To elucidate the coordination mechanism, we studied the contribution of the dual ATPase activities in the ring-shaped KaiC hexamer and these structural bases for activation and inactivation. At the N-terminal active site, a lytic water molecule is sequestered between the N-terminal domains, and its reactivity to ATP is controlled by the quaternary structure of the N-terminal ring. The C-terminal ATPase activity is regulated mostly by water-incorporating voids between the C-terminal domains, and the size of these voids is sensitive to phosphoryl modification of S431. The N-terminal ATPase activity inversely correlates with the affinity of KaiC for KaiB, a clock protein constitutes the circadian oscillator together with KaiC and KaiA, and the complete dissociation of KaiB from KaiC requires KaiA-assisted activation of the dual ATPase. Delicate interactions between the N-terminal and C-terminal rings make it possible for the components of the dual ATPase to work together, thereby driving the assembly and disassembly cycle of KaiA and KaiB.Significance StatementKaiC, a core clock protein in the cyanobacterial circadian clock system, hydrolyzes ATP at two distinct sites in a slow but ordered manner to measure the circadian time scale. We used biochemical and structural biology techniques to characterize the properties and interplay of dual ATPase active sites. Our results show that the N-terminal and C-terminal ATPases communicate with each other through an interface between the N-terminal and C-terminal domains in KaiC. The dual ATPase sites are regulated rhythmically in a concerted or opposing manner dependent on the phase of the circadian clock system, controlling the affinities of KaiC for other clock proteins, KaiA and KaiB.
Reversing anterior insular cortex neuronal hypoexcitability attenuates compulsive behavior in juvenile rats
Authors: Jadhav Kshitij S. , Bernheim Aurélien P. , Aeschlimann Léa , Kirschmann Guylène , Decosterd Isabelle , Hoffman Alexander F. , Lupica Carl R. , Boutrel Benjamin 
Published: October 2021

AbstractDevelopment of self-regulatory competencies during adolescence is partially dependent on normative brain maturation. Here we report that juvenile rats as compared to adults exhibit impulsive and compulsive-like behavioral traits, the latter being associated with lower expression of mRNA levels of the immediate early gene zif268 in the anterior insula (AI). This observation suggests that deficits in AI function in juvenile rats could explain their immature pattern of interoceptive cue integration in rational decision-making and compulsive phenotype. In support of this, here we report hypoexcitability of juvenile layer-V pyramidal neurons in the AI, concomitant with reduced glutamatergic synaptic input to these cells. Chemogenetic activation of the AI attenuated the compulsive trait suggesting that delayed maturation of the AI results in suboptimal integration of sensory and cognitive information in adolescents and this contributes to inflexible behaviors in specific conditions of reward availability.
GATA4 regionalizes intestinal metabolism and barrier function to prevent immunopathology
Authors: Earley Zachary M. , Lisicka Wioletta , Sifakis Joseph J. , Aguirre-Gamboa Raúl , Kowalczyk Anita , Barlow Jacob T. , Shaw Dustin G. , Discepolo Valentina , Tan Ineke L. , Gona Saideep , Ernest Jordan D. , Matzinger Polly , Barreiro Luis B. , Morgun Andriy , Bendelac Albert , Ismagilov Rustem F. , Shulzhenko Natalia , Riesenfeld Samantha J. , Jabri Bana 
Published: October 2021

SummaryDifferent regions of the gastrointestinal tract have distinct digestive and absorptive functions, which may be locally disrupted by infection or autoimmune disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. Here, we used mouse models, transcriptomics, and immune profiling to show that regional epithelial expression of the transcription factor GATA4 prevented adherent bacterial colonization and inflammation in the proximal small intestine by regulating retinol metabolism and luminal IgA. Loss of epithelial GATA4 expression increased mortality in mice infected with Citrobacter rodentium. In active celiac patients with villous atrophy, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. This study reveals broad impacts of GATA4-regulated intestinal regionalization and highlights an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.One-sentence summaryEpithelial GATA4 regulates intestinal regionalization of bacterial colonization, metabolic pathways, and tissue immunity.
Effect of eribulin on angiogenesis and endothelial adhesion molecules
Authors: Abbona Andrea , Falletta Antonella , Paccagnella Matteo , Astigiano Simonetta , Martini Stefania , Denaro Nerina , Ruatta Fiorella , Barbieri Ottavia , Merlano Marco , Garrone Ornella 
Published: October 2021

AbstractTumor vasculature is an important component of the tumor microenvironment and deeply affect anticancer immune response. Eribulin is a non taxane inhibitor of the mitotic spindle. However, off-target effect interfering with the tumor vasculature have been reported. The mechanisms responsible of this effect is not clear.We designed an in vitro study to investigate the effect of eribulin on neo-angiogenesis and on the adhesion molecules ICAM-1 and VCAM-1, with or without TGF-β. We also investigated the effects of paclitaxel and vinorelbine in the same experimental conditions.Eribulin was able to up-regulate the epithelial markers VE-cadherin and CD-31 in the HUVEC and tube formation in HUVEC cultured in Matrigel. The drug effectively arrested tube formation even in presence of TGF-β. Eribulin counteracted the TGF-β induced change in cell shape from the endothelial cobblestone-like morphology to an elongated spindle-shaped morphology that is characteristic of EndMT.We also observed that eribulin is able to upregulate ICAM-1 and to counteract its downregulation induced by TGF-β.In this study, eribulin was able to inhibit the vasculature remodeling and the downregulation of ICAM-1 induced by TGF-β. These effects might have important therapeutic consequence if the drug will be administered with immunotherapy.
Absolute quantitation of serum antibody reactivity using the Richards growth model for antigen microspot titration
Authors: Papp Krisztián , Kovács Ágnes , Orosz Anita , Hérincs Zoltán , Randek Judit , Liliom Károly , Pfeil Tamás , Prechl József 
Published: October 2021

AbstractIn spite of its pivotal role in the characterization of humoral immunity, there is no accepted method for the absolute quantitation of antigen specific serum antibodies. We devised a novel method to quantify polyclonal antibody reactivity, which exploits protein microspot assays and employs a novel analytical approach. Microarrays with a density series of disease specific antigen were treated with different serum dilutions and developed for IgG and IgA binding. By fitting binding data of both dilution series to a product of two generalized logistic functions, we obtained estimates of antibody reactivity of two immunoglobulin classes simultaneously. These estimates are the antigen concentrations required for reaching the inflection point of thermodynamic activity coefficient of antibodies and the limiting activity coefficient of antigen. By providing universal chemical units, this approach may improve standardization of serological testing, the quality control of antibodies and the quantitative mapping of antibody-antigen interaction space.
FITTING OF HYPERELASTIC CONSTITUTIVE MODELS IN DIFFERENT SHEEP HEART REGIONS BASED ON BIAXIAL MECHANICAL PROPERTIES
Authors: Nemavhola Fulufhelo , Pandelani Thanyani , Ngwangwa Harry 
Published: October 2021

AbstractHeart failure remains one of the leading causes of death especially among people over the age of 60 years worldwide. To develop effective therapy and suitable replacement materials for the heart muscle it is necessary to understand its biomechanical behaviour under load. This paper investigates the passive mechanical response of the sheep myocardia excised from three different regions of the heart. Due to the relatively higher cost and huge ethical demands in acquisition and testing of real animal heart models, this paper evaluates the fitting performances of five different constitutive models on the myocardial tissue responses. Ten sheep were sacrificed, and their hearts excised and transported within 3h to the testing biomechanical laboratory. The upper sections of the hearts above the short axes were carefully dissected out. Tissues were dissected from the mid-sections of the left ventricle, mid-wall and right ventricle for each heart. The epicardia and endocardia were then carefully sliced off each tissue to leave the myocardia. Stress-strain curves were calculated, filtered and resampled. The results show that Choi-Vito model was found to provide the best fit to the LV, the polynomial (Anisotropic) model to RV, the Four-Fiber Family model to RV, Holzapfel (2000) to RV, Holzapfel (2005) to RV and the Fung model to LV.
Detecting ice artefacts in processed macromolecular diffraction data with machine learning
Authors: Nolte Kristopher , Gao Yunyun , Stäb Sabrina , Kollmansberger Philip , Thorn Andrea 
Published: October 2021

AbstractContamination with diffraction from ice crystals can negatively affect, or even impede macromolecular structure determination and therefore, detecting the resulting artefacts in diffraction data is crucial. However, once the data have been processed, it can be very difficult to automatically recognize this problem. To address this, a set of convolutional neural networks named Helcaraxe has been developed which can detect ice diffraction artefacts in processed diffraction data from macromolecular crystals. The networks outperform previous algorithms and will be available as part of the AUSPEX webserver and CCP4-distributed software.SynopsisA program utilizing artificial learning and convolutional neural networks, named Helcaraxe, has been developed which can detect ice crystal artefacts in processed macromolecular diffraction data with unprecedented accuracy.
Plasticity in stomatal behavior across a gradient of water supply is consistent among field-grown maize inbred lines with varying stomatal patterning
Authors: Ding Risheng , Xie Jiayang , Mayfield-Jones Dustin , Zhang Yanqun , Kang Shaozhong , Leakey Andrew D.B. 
Published: October 2021

AbstractStomata regulate leaf CO2 assimilation (A) and water loss. The Ball–Berry and Medlyn models predict stomatal conductance (gs) with a slope parameter (m or g1) that reflects sensitivity of gs to A, atmospheric CO2 and humidity, and is inversely related to water use efficiency (WUE). This study addressed knowledge gaps about what the values of m and g1 are in C4 crops under field conditions, as well as how they vary among genotypes and with drought stress. m and g1 were unexpectedly consistent in four inbred maize genotypes across a gradient of water supply. This was despite genotypic variation in stomatal patterning, A and gs. m and g1 were strongly correlated with soil water content, moderately correlated with pre-dawn leaf water potential (Ψpd), and weakly correlated with midday leaf water potential (Ψmd). This implied that m and g1 respond to long-term water supply more than short-term drought stress. The conserved nature of m and g1 across anatomically diverse genotypes and water supplies suggests there is flexibility in structure-function relationships underpinning WUE. This evidence can guide simulation of maize gs across a range of water supply in the primary maize growing region and inform efforts to improve WUE.Summary statementParameter values for models simulating stomatal conductance were unexpectedly consistent for anatomically and physiologically diverse genotypes of the model C4 crop maize when they were grown across a range of water supplies in the field.
RACK1 associates with RNA-binding proteins Vigilin and SERBP1 to control dengue virus replication
Authors: Brugier Alexis , Hafirrassou Mohamed-Lamine , Pourcelot Marie , Baldaccini Morgane , Couture Laurine , Kril Vasiliya , Kümmerer Beate M. , Gallois-Montbrun Sarah , Bonnet-Madin Lucie , Pfeffer Sébastien , Vidalain Pierre -Olivier , Delaugerre Constance , Meertens Laurent , Amara Ali 
Published: October 2021

AbstractDengue virus (DENV), a re-emerging virus transmitted byAedesmosquitoes, causes severe pathogenesis in humans. No effective treatment is available against this virus. We recently identified the scaffold protein RACK1 as a component of the DENV replication complex, a macromolecular complex essential for viral genome amplification. Here, we show that RACK1 is important for DENV infection. RACK1 mediates DENV replication through binding to the 40S ribosomal subunit. Mass spectrometry analysis of RACK1 partners coupled to a loss-of-function screen identified the RNA binding proteins Vigilin and SERBP1 as DENV host dependency factors. Vigilin and SERBP1 interact with DENV viral RNA (vRNA), forming a ternary complex with RACK1 to mediate viral replication. Overall, our results indicate that RACK1 recruits Vigilin and SERBP1, linking the DENV vRNA to the translation machinery for optimal translation and replication.