bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperglycemia increases the severity ofStaphylococcus aureusosteomyelitis and influences bacterial genes required for survival in bone
Authors: Butrico Casey E. , Klopfenstein Nathan B. , Green Erin R. , Johnson Joshua R. , Peck Sun H. , Ibberson Carolyn B. , Serezani C. Henrique , Cassat James E. 
Published: December 2022

ABSTRACTHyperglycemia, or elevated blood glucose, renders individuals more prone to developing severeStaphylococcus aureusinfections.S. aureusis the most common etiological agent of musculoskeletal infection, which is a common manifestation of disease in hyperglycemic patients. However, the mechanisms by whichS. aureuscauses severe musculoskeletal infection during hyperglycemia are incompletely characterized. To examine the influence of hyperglycemia onS. aureusvirulence during invasive infection, we used a murine model of osteomyelitis and induced hyperglycemia with streptozotocin. We discovered that hyperglycemic mice exhibited increased bacterial burdens in bone and enhanced dissemination compared to control mice. Furthermore, infected hyperglycemic mice sustained increased bone destruction relative to euglycemic controls, suggesting that hyperglycemia exacerbates infection-associated bone loss. To identify genes contributing toS. aureuspathogenesis during osteomyelitis in hyperglycemic animals relative to euglycemic controls, we used transposon sequencing (TnSeq). We identified 71 genes uniquely essential forS. aureussurvival in osteomyelitis in hyperglycemic mice and another 61 mutants with compromised fitness. Among the genes essential forS. aureussurvival in hyperglycemic mice was superoxide dismutase A (sodA), one of twoS. aureussuperoxide dismutases involved in detoxifying reactive oxygen species (ROS). We determined that asodAmutant exhibits attenuated growthin vitroin high glucose andin vivoduring osteomyelitis in hyperglycemic mice. SodA therefore serves an important role during growth in high glucose and promotesS. aureussurvival in bone. Collectively, these studies demonstrate that hyperglycemia increases the severity of osteomyelitis and identify genes contributing toS. aureussurvival during hyperglycemic infection.
Modeling and Simulation of CAR T cell Therapy in Chronic Lymphocytic Leukemia Patients
Authors: Nukala Ujwani , Messan Marisabel Rodriguez , Yogurtcu Osman N. , Sauna Zuben , Yang Hong 
Published: December 2022

AbstractAdvances in genetic engineering have made it possible to reprogram an individual’s immune cells to express receptors that recognize markers on tumor cell surfaces. The process of re-engineering T cell lymphocytes to express Chimeric Antigen Receptors (CARs) and reinfusing the CAR-modified T cells into patients to treat various cancers is being explored in clinical trials. While the majority of patients with some cancers (e.g., B cell acute lymphocytic leukemia) respond to CAR-T cell therapy, this success is not evidenced in all cancers. For example, only 26% of Chronic Lymphocytic Leukemia (CLL) patients respond to CAR T cell therapy. Understanding of the factors associated with an individual patient’s response is important for patient selection and could help develop more effective CAR T cell therapies. Here we present a mechanistic mathematical model to identify factors associated with responses to CAR T cell therapeutic interventions. The proposed model is a system of coupled ordinary differential equations designed based on known immunological principles and prevailing hypotheses on the mechanism of CAR T cell kinetics, Interleukin 6 (IL-6) secretion, and tumor killing in CAR T cell therapy. The model reportsin silicodisease outcomes using B cell concentration as a surrogate biomarker. Our results are consistent with thein vitroexperimental observations that CAR T cell fitness in terms of its tumor cell killing capacity and proliferation plays an important role in the patient response. We demonstrate the utility of mathematical modelling in understanding the factors that play an important role in patient response to CAR T cell therapy.
Mapping young people’s journeys through mental health services: a prospective longitudinal qualitative study protocol
Authors: Pilbeam Caitlin , Walsh Erin , Barnes Katelyn , Scholz Brett , Olsen Anna , Stone Louise 
Published: December 2022

AbstractMental ill health is a major health risk for young people. There is unmet need for mental health assessment and treatment across Australia despite significant investment in government-funded plans to cover mental health and youth-oriented services. Understandings of mental health care for young people are impeded by a lack of longitudinal research. Without this research, it is difficult to understand how services do or do not support the recovery of young people over time.This project will analyse the healthcare journeys of young people aged 16-25 years experiencing their first significant episode of mental ill health, over 12 months in the Australian Capital Territory. The study team will recruit up to 25 diverse young people and their general practitioners (GPs), and conduct four qualitative semi-structured interviews over 12 months with each participant. GP interviews will explore their role in the mental health care and care coordination for the young person. Interviews with young people will explore experiences and perceptions of navigating the health system, and the supports and resources they engaged with during the 12-month period. In between interviews, young people will be asked to keep a record of their mental health care experiences, through their choice of media. Participant-produced materials will also form the basis for interviews, providing stimuli to discuss the lived experience of care.Through analysing the narratives of both young people and their GPs, the study will establish how young people understand value in mental health care delivery. The study will use longitudinal qualitative mapping of healthcare journeys to identify key barriers and enablers to establishing effective, person-centred health care for young people with mental ill health.
Chemical factors induce aggregative multicellularity in a close unicellular relative of animals
Authors: Ros-Rocher Núria , Kidner Ria Q. , Gerdt Catherine , Davidson W. Sean , Ruiz-Trillo Iñaki , Gerdt Joseph P. 
Published: December 2022

ABSTRACTRegulated cellular aggregation is an essential process for development and healing in many animal tissues. In some animals and a few distantly related unicellular species, cellular aggregation is regulated by diffusible chemical cues. However, it is unclear whether regulated cellular aggregation was part of the life cycles of the first multicellular animals and/or their unicellular ancestors. To fill this gap, we investigated the triggers of cellular aggregation in one of animals’ closest unicellular living relatives – the filastereanCapsaspora owczarzaki. We discovered thatCapsasporaaggregation is induced by chemical cues, as observed in some of the earliest branching animals and other unicellular species. Specifically, we found that calcium ions and lipids present in lipoproteins function together to induce aggregation of viableCapsasporacells. We also found that this multicellular stage is reversible, as depletion of the cues triggers disaggregation, which can be overcome upon re-induction. Our finding demonstrates that chemically regulated aggregation is important across diverse members of the holozoan clade. Therefore, this phenotype was plausibly integral to the life cycles of the unicellular ancestors of animals.
PI 3-kinase isoform p110α controls smooth muscle cell functionality and protects against aortic aneurysm formation
Authors: Vantler Marius , Schorscher Maximilian , Berghausen Eva Maria , Moore Joseph B. , Wong Dickson , Zhaolong Li , Wißmüller Max , Gnatzy-Feik Leoni , Zierden Mario , Mehrkens Dennis , Adam Matti , Zhao Xinlei , Odenthal Margarete , Sengle Gerhard , Boor Peter , Maegdefessel Lars , Baldus Stephan , Rosenkranz Stephan 
Published: December 2022

AbstractBackgroundCatalytic class IA PI 3-kinase isoform p110α is a crucial regulator of cellular proliferation and survival in numerous cell types. While p110α is critically involved in pathogenic vascular remodeling, its physiological role for vascular integrity under stress conditions has not been studied. We report a protective function of smooth muscle p110α against abdominal aortic aneurysm (AAA) formation.Methods & ResultsIn mice lacking p110α in smooth muscle cells (sm-p110α-/-), perfusion of the infrarenal aorta with porcine pancreatic elastase (PPE) yielded substantially enhanced AAA formation compared to wild type controls. This disease phenotype is partly attributable to a subtle preexisting vascular phenotype under basal conditions, as sm-p110α-/-mice displayed a smaller media area, deranged aortic wall structure (detached smooth muscle cells, increased apoptotic cell death), and a diminished functional responsiveness of aortic rings to vasodilators. Furthermore, p110α is also implicated in regenerative processes during AAA development: Whereas wild type mice showed increased media hypertrophy, neointima formation and proliferation upon PPE intervention, these vascular remodeling processes were diminished in sm-p110α-/-mice. Concomitantly, increased numbers of elastic fiber breaks and ECM degradation were detected in sm-p110α-/-aorta. Mechanistically, we found that lack of p110α expression impaired smooth muscle cell proliferation, expression of contractile marker genes and production of elastin fibers. This phenotype largely depended on reduced phosphorylation and inactivation of FOXO1, as specific FOXO1 inhibition fully rescued proliferation of p110α-/-smooth muscle cells, and knockdown of FOXO1 increased expression of calponin and elastin.ConclusionsSmooth muscle p110α protects against AAA disease by maintaining aortic wall homoeostasis and promoting SMC proliferation to compensate for cell loss during AAA development. Our findings have potential implications for current approaches aimed at p110α inhibition for cancer therapy and suggest new pharmacological strategies to activate p110α signaling in AAA disease.
Filter-based models of suppression in retinal ganglion cells: comparison and generalization across species and stimuli
Authors: Shahidi Neda , Rozenblit Fernando , Khani Mohammad H. , Schreyer Helene M. , Mietsch Matthias , Protti Dario A. , Gollisch Tim 
Published: December 2022

AbstractThe dichotomy of excitation and suppression is one of the canonical mechanisms explaining the complexity of neural activity. Computational models of the interplay of excitation and suppression in single neurons aim at investigating how this interaction affects a neuron’s spiking responses and shapes the encoding of sensory stimuli. Here, we compare the performance of three filter-based stimulus-encoding models for predicting retinal ganglion cell responses recorded from axolotl, mouse, and marmoset retina to different types of temporally varying visual stimuli. Suppression in these models is implemented via subtractive or divisive interactions of stimulus filters or by a response-driven feedback module. For the majority of ganglion cells, the subtractive and divisive models perform similarly and outperform the feedback model as well as a linear-nonlinear (LN) model with no suppression. Comparison between the subtractive and the divisive model depended on cell type, species, and stimulus components, with the divisive model generalizing best across temporal stimulus frequencies and visual contrast and the subtractive model capturing in particular responses for slow temporal stimulus dynamics and for slow axolotl cells. Overall, we conclude that the divisive and subtractive models are well suited for capturing interactions of excitation and suppression in ganglion cells and perform best for different temporal regimes of these interactions.
Liver transcriptomic and methylomic analyses identify transcriptional MAPK regulation in facultative hibernation of Syrian hamster
Authors: Oosterhof Marloes M. , Coussement Louis , Guryev Victor , Reitsema Vera A. , Bruintjes Jojanneke J. , Goris Maaike , Bouma Hjalmar R. , de Meyer Tim , Rots Marianne G. , Henning Robert H. 
Published: December 2022

AbstractHibernation consist of alternating torpor/arousal phases, during which animals cope with repetitive hypothermia and ischemia-reperfusion. Due to limited transcriptomic and methylomic information for facultative hibernators, we here conducted RNA and whole genome bisulfite sequencing in liver of hibernating Syrian hamster(Mesocricetus auratus). Gene Ontology analysis was performed on 844 differentially expressed genes (DEGs) and confirmed the shift in metabolic fuel utilization, inhibition of RNA transcription and cell cycle regulation as found in seasonal hibernators. We show a so far unreported suppression of MAPK and PP1 pathways. Notably, hibernating hamsters showed upregulation of MAPK inhibitors (DUSPs and SPRYs) and reduced levels of MAPK induced transcription factors. Promoter methylation was found to modulate the expression of genes targeted by these transcription factors. In conclusion, we document gene regulation between hibernation phases, which may aid the identification of pathways and targets to prevent organ damage in transplantation or ischemia-reperfusion.
Optimization of host cell-compatible, antimicrobial peptides effective against biofilms and clinical isolates of drug-resistant bacteria
Authors: Ghimire Jenisha , Hart Robert J. , Soldano Anabel , Chen Charles H. , Guha Shantanu , Hoffmann Joseph P. , Hall Kalen M. , Sun Leisheng , Nelson Benjamin J. , Lu Timothy K. , Kolls Jay K. , Rivera Mario , Morici Lisa A. , Wimley William C. 
Published: December 2022

AbstractHere, we describe the continued synthetic molecular evolution of a lineage of host-compatible antimicrobial peptides (AMP) intended for the treatment of wounds infected with drug-resistant, biofilm-forming bacteria. The peptides tested are variants of an evolved AMP called D-CONGA, which has excellent antimicrobial activitiesin vitroandin vivo. In this newest generation of rational D-CONGA variants, we tested multiple sequence-structure-function hypotheses that had not been tested in previous generations. Many of the peptide variants have lower antibacterial activity against Gram-positive or Gram-negative pathogens, especially variants that have altered hydrophobicity, secondary structure potential, or spatial distribution of charged and hydrophobic residues. Thus, D-CONGA is generally well tuned for antimicrobial activity. However, we identified a variant, D-CONGA-Q7, with a polar glutamine inserted into the middle of the sequence, that has higher activity against both planktonic and biofilm-forming bacteria as well as lower cytotoxicity against human fibroblasts. Against clinical isolates ofK. pneumoniae, innate resistance to D-CONGA was surprisingly common despite a lack of inducible resistance inP. aeruginosareported previously. Yet, these same isolates were susceptible to D-CONGA-Q7. D-CONGA-Q7 is much less vulnerable to AMP resistance in Gram-negative bacteria than its predecessor. Consistent with the spirit of synthetic molecular evolution, D-CONGA-Q7 achieved a critical gain-of-function and has a significantly better activity profile.
Mcr-dependent methanogenesis inArchaeoglobaceaeenriched from a terrestrial hot spring
Authors: Buessecker Steffen , Chadwick Grayson L. , Quan Melanie E. , Hedlund Brian P. , Dodsworth Jeremy A. , Dekas Anne E. 
Published: December 2022

AbstractThe preeminent source of biological methane on Earth is methyl coenzyme M reductase (Mcr)-dependent archaeal methanogenesis. A growing body of evidence suggests a diversity of archaea possess Mcr, however, experimental validation of hypothesized methane metabolisms has been missing. Here, we provide evidence of a functional Mcr-based methanogenesis pathway in a novel member of the familyArchaeoglobaceae, designatedMethanoproducendum nevadense, which we enriched from a terrestrial hot spring on the polysaccharide xyloglucan. Our incubation assays demonstrate methane production that is highly sensitive to the Mcr-inhibitor bromoethanesulfonate, stimulated by xyloglucan and xyloglucan-derived sugars, concomitant with the consumption of molecular hydrogen, and causing a deuterium fractionation in methane characteristic of hydrogenotrophic and methylotrophic methanogens. Combined with the recovery and analysis of a high-qualityM. nevadensemetagenome-assembled genome encoding a divergent Mcr and diverse potential electron and carbon transfer pathways, our observations suggest methanogenesis inM. nevadenseoccurs via Mcr and is fueled by the consumption of cross-fed byproducts of xyloglucan fermentation mediated by other community members. Phylogenetic analysis shows close affiliation of theM. nevadenseMcr with those from Korarchaeota, Nezhaarchaeota, Verstraetearchaeota, and otherArchaeoglobalesthat are divergent from well-characterized Mcrs. We propose these archaea likely also use functional Mcr complexes to generate methane on the basis of our experimental validation inM. nevadense. Although our stable isotope approach reveals that microbial methanogenesis contributes only a small proportion of the overall methane abundance in the native habitat, divergent Mcr-encoding archaea may be underestimated sources of biological methane in terrestrial and marine hydrothermal environments.
Kinetics and targeting of Vipp1 aggregation in cyanobacteria
Authors: Gates Colin , Hill Nicholas C. , Dahlgren Kelsey , Cameron Jeffrey C. 
Published: December 2022

AbstractThe kinetics of regulation of vesicle-inducing protein in plastids (Vipp1), an essential protein in all oxygenic phototrophs, are not completely understood. Vipp1 is responsible for both membrane maintenance and damage repair processes, aggregating at sites of damage (proton leakage) or physical strain (responding to presence of anionic lipids). Herein we spatiotemporally resolve exchange between inactive cytoplasmic Vipp1 and these two functionalities. We demonstrate that Vipp1 can be aggregated to a specific site in the thylakoid membrane by laser damage, but this behavior appears to be mediated by a rapidly resolved secondary process, as cytoplasmic Vipp1 is rendered unresponsive to nearby damage on a time scale three orders of magnitude faster than the aggregation process itself.One Sentence SummaryVipp1 aggregation to points on the thylakoid is induced in response to specific damage and repair kinetics are observed.
Neural mechanisms of parasite-induced summiting behavior in “zombie”Drosophila
Authors: Elya Carolyn , Lavrentovich Danylo , Lee Emily , Pasadyn Cassandra , Duval Jasper , Basak Maya , Saykina Valerie , de Bivort Benjamin 
Published: December 2022

AbstractFor at least two centuries, scientists have been enthralled by the “zombie” behaviors induced by mind-controlling parasites. Despite this interest, the mechanistic bases of these uncanny processes have remained mostly a mystery. Here, we leverage the recently establishedEntomophthora muscae-Drosophila melanogaster“zombie fly” system to reveal the molecular and cellular underpinnings of summit disease, a manipulated behavior evoked by many fungal parasites. Using a new, high-throughput behavior assay to measure summiting, we discovered that summiting behavior is characterized by a burst of locomotion and requires the host circadian and neurosecretory systems, specifically DN1p circadian neurons, pars intercerebralis to corpora allata projecting (PI-CA) neurons and corpora allata (CA), who are solely responsible for juvenile hormone (JH) synthesis and release. Summiting is a fleeting phenomenon, posing a challenge for physiological and biochemical experiments requiring tissue from summiting flies. We addressed this with a machine learning classifier to identify summiting animals in real time. PI-CA neurons and CA appear to be intact in summiting animals, despiteE. muscaecells invading the host brain, particularly in the superior medial protocerebrum (SMP), the neuropil that contains DN1p axons and PI-CA dendrites. The blood-brain barrier of flies late in their infection was significantly permeabilized, suggesting that factors in the hemolymph may have greater access to the central nervous system during summiting. Metabolomic analysis of hemolymph from summiting flies revealed differential abundance of several compounds compared to non-summiting flies. Transfusing the hemolymph of summiting flies into non-summiting recipients induced a burst of locomotion, demonstrating that factor(s) in the hemolymph likely cause summiting behavior. Altogether, our work reveals a neuro-mechanistic model for summiting wherein fungal cells perturb the fly’s hemolymph, activating the neurohormonal pathway linking clock neurons to juvenile hormone production in the CA, ultimately inducing locomotor activity in their host.
Orthogonal neural encoding of targets and distractors supports multivariate cognitive control
Authors: Ritz Harrison , Shenhav Amitai 
Published: December 2022

AbstractThe complex challenges of our mental life require us to coordinate multiple forms of neural information processing. Recent behavioral studies have found that people can coordinate multiple forms of attention, but the underlying neural control process remains obscure. We hypothesized that the brain implements multivariate control by independently monitoring feature-specific difficulty and independently prioritizing feature-specific processing. During fMRI, participants performed a parametric conflict task that separately tags target and distractor processing. Consistent with feature-specific monitoring, univariate analyses revealed spatially segregated encoding of target and distractor difficulty in dorsal anterior cingulate cortex. Consistent with feature-specific attentional priority, a novel multivariate analysis (Encoding Geometry Analysis) revealed overlapping, but orthogonal, representations of target and distractor coherence in intraparietal sulcus. Coherence representations were mediated by control demands and aligned with both performance and frontoparietal activity, consistent with top-down attention. Together, these findings provide evidence for the neural geometry necessary to coordinate multivariate cognitive control.