bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design of a Water-Soluble CD20 Antigen with Computational Epitope Scaffolding
Authors: Yao Zhiyuan , Kuhlman Brian 
Published: December 2024

AbstractThe poor solubility of integral membrane proteins in water frequently hinders studies with these proteins, presenting challenges for structure determination and binding screens. For instance, the transmembrane protein CD20, which is an important target for treating B-cell malignancies, is not soluble in water and cannot be easily screened against potential protein binders with techniques like phage display or yeast display. Here, we usede novoprotein design to create a water-soluble mimic of the CD20 dimer (“soluble CD20”). Soluble CD20 replaces the central transmembrane helix of CD20 with a water-soluble helix that dimerizes to form a coiled coil that structurally matches the dimer interface of native CD20 and presents the central extracellular loop of CD20 in a binding competent conformation. Unlike peptides derived from CD20, soluble CD20 binds tightly to monoclonal antibodies that recognize quaternary epitopes on the extracellular face of CD20. We demonstrate that soluble CD20 is easy to produce, remains folded above 60°C, and is compatible with binder screening via yeast display. Our results highlight the ability of computational protein design to scaffold conformational epitopes from membrane proteins for use in binding and protein engineering studies.ImportanceThis study demonstrates that computational protein design can be used to create water soluble variants of transmembrane proteins. The water-soluble CD20 mimic created here is compatible with high throughput binding screens and should be useful for developing next generation anti-CD20 therapeutics.
The Epidemiology of Scrub typhus in Thiruvarur, Tamil Nadu
Authors: Farhat SK , Nataraj M , Behara Sujit Kumar , Rajalakshmi A , Sweta S , Jeevitha Sathya , Binduja S , Shanti S , Srivastava P.K. , Vellingiri Balachandar , Malik Mansi , Krishnan Jayalakshmi 
Published: December 2024

AbstractNational Vector-Borne Disease Control Programme (NVBDCP) under the National Center for Vector Borne Diseases Control (NCVBDC), Govt. of India, Delhi has put forth efforts to combat diseases transmitted by vectors, under the overarching umbrella of the National Health Mission (NHM). NCVBDC focuses mainly on six Vector Borne Diseases (VBD) but at the state and district level the VBD officials have to deal with all the VBDs covered under NCVBDC or outside the purview of NCVBDC. The advancement in modern technologies has increased attention to neglected tropical diseases, emphasizing their importance in public health discussions. Scrub typhus, a rickettsial infection with a harmless bite of infected chigger mite on humans, transmits the gram-negative bacteria Orientia tsutsugamushi causing the infection with rising mortality and morbidity rates across the globe. The living environment of the people plays a pivotal role in scrub typhus disease transmission. Rodents are the major reservoirs carrying the vector mites with additionally the environment, sanitation and hygiene as a crucial factor in the spread of scrub typhus.A study was conducted from December 2023-July 2024, in the delta district of Thiruvarur covering the household participants of 730 from both rural and urban households. The statistical analysis of both quantitative and categorical variables was done using the SPSS software Version 16.0. The spacio-temporal mapping of the household areas enhanced the study with the representation of the study participants who were exposed to the risk factors but were susceptible hosts to scrub typhus. The univariate analysis showed a significant association between scrub typhus exposure with the people working in the agricultural fields, location of toilets, kitchen, presence of animals in homes, barren land and paddy fields near living areas, lack of protective implements against rodents, drying clothes on bushes, walking barefoot with more chances of being bitten by insects, mites or ticks resulting in rashes or Eschars, hospitalization due to fever, sneezing and headache. The Multivariate regression analysis showed that the association between scrub typhus exposure to the kitchen located outdoors (aOR=3.768, CI: 1.036 - 13.699, p = 0.044), people living near paddy fields (aOR=2.140, CI: 1.019-4.492, p=0.044), the use of protective implements (aOR = 0.071 (CI: 0.034 - 0.147, p < 0.001), drying clothes on bushes (aOR = 3.012 CI: 1.579 - 5.745, p = 0.001) showed strong association to exposure to scrub typhus.
Temporary fun, permanent damage: a systematic review on the effects of musical characteristics on participants’ experience and behavior during leisure activities
Authors: Daelemans Céline , Bonapart Casper , Smit Adriana L. , Stegeman Inge 
Published: December 2024

AbstractBackgroundExcessively loud music is frequently played at leisure activities, posing significant health risks. However, the lack of consensus on consumers’ preferred music settings makes it difficult to implement preventive measures against high noise levels. Therefore, our objective is to systematically evaluate how different musical characteristics influence the experiences and behaviors of individuals engaged in leisure activities.MethodsWe conducted a search for studies examining the effects of musical characteristics on individuals at leisure activities where the musical experience is of primary focus. The search was performed using the Medline Pubmed, Embase Elsevier, Cochrane, PsychInfo, andClinicalTrial.govdatabases. The exclusion criteria included: leisure activities related to sports, studies evaluating music as a treatment, lab settings, case studies, and participants below 15 years old. The NOS, RoB2, and ROBINS-I tools were used to assess risk of bias. Results relevant to our outcomes of interest were extracted and summarized in tables.ResultsWe identified 2503 studies, of which 37 studies were included for data extraction. The total number of participants in this systematic review was 16843. Among the 37 studies, 23 were observational with the remainder being experimental control trials. Risk of bias in the studies was high. Our findings indicate that musical characteristics such as low frequencies, high groove, high tempo, and live performance enhanced participants’ movements and emotions. Excessively high levels, such as those found in nightclubs, were deemed unnecessary by those exposed. These extreme volumes also caused discomfort and posed a risk to hearing health.InterpretationThe high risk of bias makes it difficult to draw conclusions based on the data in this systematic review. Therefore, and in order to inform policy makers, we need adequate randomized controlled trials in order to assess the effects of different levels of loudness on music experience.FundingDorhout Mees StichtingRegistrationPROSPERO registration: CRD42023412634
Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy
Authors: Hunter Benjamin , Zhang Yunwei , Harney Dylan , McEwen Holly , Koay Yen Chin , Pan Michael , Malecki Cassandra , Khor Jasmine , Hume Robert D. , Guglielmi Giovanni , Walker Alicia , Dutta Shashwati , Rajagopal Vijay , Don Anthony , Larance Mark , O’Sullivan John F. , Yang Jean , Lal Sean 
Published: December 2024

AbstractIschaemic cardiomyopathy is the most common cause of heart failure and often coexists with diabetes mellitus which worsens patient symptom burden and outcomes. Yet, their combined effects are seldom investigated and are poorly understood. To uncover the influencing molecular signature defining ischaemic cardiomyopathy with diabetes, we performed multi-omic analyses of ischaemic and non-ischaemic cardiomyopathy with and without diabetes against healthy age-matched donors. Tissue was sourced from pre-mortem human left ventricular myocardium. Fatty acid transport and oxidation proteins were most down-regulated in ischaemic cardiomyopathy with diabetes relative to donors. However, the down-regulation of acylcarnitines, perilipin, and ketone body, amino acid and glucose metabolising proteins indicated lipid metabolism may not be entirely impaired. Oxidative phosphorylation, oxidative stress, myofibrosis, and cardiomyocyte cytoarchitecture also appeared exacerbated principally in ischaemic cardiomyopathy with diabetes. These findings indicate diabetes confounds the pathological phenotype in heart failure, and the need for a paradigm shift regarding lipid metabolism.
Potent antitumor activity of a designed interleukin-21 mimic
Authors: Chun Jung-Ho , Lim Birkley S. , Roy Suyasha , Walsh Michael J. , Abhiraman Gita C. , Zhangxu Kevin , Atajanova Tavus , Revach Or-Yam , Clark Elisa C. , Li Peng , Palin Claire A. , Khanna Asheema , Tower Samantha , Kureshi Rakeeb , Hoffman Megan T. , Sharova Tatyana , Lawless Aleigha , Cohen Sonia , Boland Genevieve M. , Nguyen Tina , Peprah Frank , Tello Julissa G. , Liu Samantha Y. , Kim Chan Johng , Shin Hojeong , Quijano-Rubio Alfredo , Jude Kevin M. , Gerben Stacey , Murray Analisa , Heine Piper , DeWitt Michelle , Ulge Umut Y. , Carter Lauren , King Neil P. , Silva Daniel-Adriano , Kueh Hao Yuan , Kalia Vandana , Sarkar Surojit , Jenkins Russell W. , Garcia K. Christopher , Leonard Warren J. , Dougan Michael , Dougan Stephanie K. , Baker David 
Published: December 2024

AbstractLong-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report ade novoIL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and inex vivohuman melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity. 21h10 generates significantly prolonged STAT signalingin vivocompared with native IL-21, and has considerably stronger anti-tumor activity. Toxicities associated with systemic administration of 21h10 could be mitigated by TNFα blockade without compromising antitumor efficacy. In the tumor microenvironment, 21h10 induced highly cytotoxic antitumor T cells from clonotypes with a range of affinities for endogenous tumor antigens, robustly expanding low-affinity cytotoxic T cells and driving high expression of interferon-𝛾 (IFN-𝛾) and granzyme B compared to native IL-21, while increasing the frequency of IFN-𝛾+Th1 cells and reducing that of Foxp3+Tregs. As 21h10 has full human/mouse cross-reactivity, high stability and potency, and potentiates low-affinity antitumor responses, it has considerable translational potential.
Establishing reliable blood biomarkers for trimethylamine N-oxide status in rodents: effects of oral choline challenge, dietary choline and fasting conditions
Authors: Din Ahmad Ud , Sweet Michael G. , McAmis Ashley M. , Ratliff Juanita G. , Pon Velayutham Anandh Babu , Neilson Andrew P. 
Published: December 2024

AbstractCirculating concentrations of the gut microbial-mammalian metabolite trimethylamine N-oxide (TMAO) is linked to atherosclerosis risk. TMAO biosynthesis begins when dietary choline is converted to trimethylamine (TMA) by gut microbial TMA lyase. TMA is transported to the liver, where flavin-containing monooxygenases convert it to TMAO. While dietary modifications regulate TMAO production, the impact of different intake methods, including oral gavage, dietary supplementation, and conditions such as fasting versus non-fasting, has not been fully explored. Twelve female Sprague-Dawley rats were divided into three diet groups (n= 4 per group): no-choline (0% choline), low-choline (0.08% choline), and high-choline (1% choline). Choline and TMAO fasting and non-fasting blood concentrations, and their kinetics following an acute choline challenge, were assessed before and after a 2-week dietary intervention with the distinct choline dietary levels. Fasting choline was under tight control, with little effect of dietary choline. Non-fasting choline was more variable, with high dietary choline reflected in higher blood choline. Greater levels of dietary choline were reflected in significantly greater levels of TMAO, particularly for non-fasting levels. Kinetic profiling demonstrated additional information regarding the appearance and clearance of these compounds from blood. These results suggest that acute oral choline gavage is likely most suitable for studies targeting acute (direct) inhibitors, whereas a choline-rich diet with assessment of fasting and non-fasting blood levels is more suitable for studying alterations to TMAO production capacity. Future research should examine the impact on atherosclerosis biomarkers and microbiome diversity to deepen the understanding of TMAO regulation and its cardiovascular implications.
MCSPACE: inferring microbiome spatiotemporal dynamics from high-throughput co-localization data
Authors: Uppal Gurdip , Urtecho Guillaume , Richardson Miles , Comba Isin Y. , Lee Jeongchan , Moody Thomas , Wang Harris H. , Gerber Georg K. 
Published: December 2024

SummaryRecent advances in high-throughput approaches for estimating co-localization of microbes, such as SAMPL-seq, allow characterization of the biogeography of the gut microbiome longitudinally and at unprecedented scale. However, these high-dimensional data are complex and have unique noise properties. To address these challenges, we developed MCSPACE, a probabilistic AI method that infers from microbiome co-localization data spatially coherent assemblages of taxa, their dynamics over time, and their responses to perturbations. To evaluate MCSPACE’s capabilities, we generated the largest longitudinal microbiome co-localization dataset to date, profiling spatial relationships of microbes in the guts of mice subjected to serial dietary perturbations over 76 days. Analyses of these data and an existing human longitudinal dataset demonstrated superior benchmarking performance of MCSPACE over existing methods, and moreover yielded insights into spatiotemporal structuring of the gut microbiome, including identifying temporally persistent and dynamic microbial assemblages in the human gut, and shifts in assemblages in the murine gut induced by specific dietary components. Our results highlight the utility of our method, which we make available to the community as an open-source software tool, for elucidating dynamics of microbiome biogeography and gaining insights into the role of spatial relationships in host-microbial ecosystem function.
Genome-wide characterization of hypothiocyanite stress response ofEscherichia colireveals a potential role for RclB and RclC in lowering cell envelope permeability
Authors: Meredith Julia D. , Gray Michael J. 
Published: December 2024

ABSTRACTOxidative stress is one of the major methods of microbial population control and pathogen clearing by the mammalian immune system. The methods by which bacteria are able to escape damage by host-derived oxidants such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) have been relatively well described, while other oxidants’ effect on bacteria and their genetic responses are not as well understood. Hypothiocyanite/hypothiocyanous acid (-OSCN/HOSCN) is one such antimicrobial oxidant. In this study, we used RNA-sequencing to characterize the global transcriptional response ofEscherichia colito treatment with HOSCN and observed that the response is different from the responses ofE. colito other oxidants such as H2O2, superoxide, or HOCl, and distinct from the responses of other bacteria such asStreptococcus pneumoniaeandPseudomonas aeruginosato HOSCN. Furthermore, we found that deletion of the genes encoded downstream of HOSCN reductaserclAinE. coli,rclBandrclC,has a transcriptional effect onompCand may play a role in membrane permeability to HOSCN.IMPORTANCEUnderstanding how bacteria sense and respond to oxidative stress provides insights into how our bodies interact with the microbial population within us. In this study, we have characterized the genetic response ofE. colito important immune oxidant hypothiocyanite and investigated the role of therclABCgenes in that response.
Matrix porosity is associated withStaphylococcus aureusbiofilm survival during prosthetic joint infection
Authors: Bhattacharya Mohini , Scherr Tyler D. , Lister Jessica , Kielian Tammy , Horswill Alexander R. 
Published: December 2024

AbstractBiofilms are a cause of chronic, non-healing infections.Staphylococcus aureusis a proficient biofilm forming pathogen commonly isolated from prosthetic joint infections that develop following primary arthroplasty. Extracellular adhesion protein (Eap), previously characterized in planktonic or non-biofilm populations as being an adhesin and immune evasion factor, was recently identified in the exoproteome ofS. aureusbiofilms. This work demonstrates that Eap and its two functionally orphaned homologs EapH1 and EapH2, contribute to biofilm structure and prevent macrophage invasion and phagocytosis into these communities. Biofilms unable to express Eap proteins demonstrated increased porosity and reduced biomass. We describe a role for Eap proteinsin vivousing a mouse model ofS. aureusprosthetic joint infection. Results suggest that the protection conferred to biofilms by Eap proteins is a function of biofilm structural stability that interferes with the leukocyte response to biofilm-associated bacteria.
A systematic review and meta-synthesis of factors that influence clinical decision making for organ support interventions within the critical care unit
Authors: Matsumoto Kenki , Fazzini Brigitta , Malcolm Hannah , Eldridge Jack , Puthucheary Zudin , Osman Magda , Stephens Timothy J 
Published: December 2024

AbstractBackgroundThe critical care unit is a dynamic environment that necessitates a high volume of daily clinical decisions regarding organ support. It is known that decision-making varies significantly between clinicians, even where internationally accepted treatment guidance exists and overall the processes and influences on clinical decision-making are poorly understood. Our aim was to summarise the evidence on the decision-making process and the factors that influence organ support decisions in the critical care setting and 2) conduct a meta-synthesis to generate a model of medical decision-making, illustrating how different factors interact and affect the process.MethodsWe conducted a systematic search on three databases (PubMed, Embase and CINAHL) to find relevant papers exploring factors that influenced organ support decisions made by critical care clinicians. A meta-synthesis was then completed on included papers. The data were collated into a common format and cross-compared. This enable the generation of distinct themes/subthemes that were synthesised to develop a higher order interpretation.Results33 studies (from 8967 citations) met the inclusion criteria. 21 of these only included nurses, 7 only doctors and 5 were interprofessional. 11 factors that influenced a clinician’s decision-making were identified: experience; professional and personal risk; uncertainty; characteristics of individuals; senior support; team hierarchy; decision making by colleagues; protocols, guidelines and evidence; time and workload; hospital structure; and clinical condition. These were grouped into four themes: human, team, system and patient factors. From our interpretation of the data, we found decision-making is often linear and primarily dictated by disease factors (i.e. patient’s clinical parameters). However, the identified human, team and system factors can place strain on decision-makers and make clinical scenarios more complex. There is scope however to modify these to optimise critical care decision-making.ConclusionWhile decision-making surrounding organ support is complex and dynamic, we identified recurring themes that influenced these decisions across different professions and environments. Further studies should focus on understanding how different decision-making processes directly affect patients’ outcomes.
HCN1 channels in GABAergic amygdalar neurons underpin male-biased aggressive behaviors
Authors: Li Kaiyuan , Zhu Zhenggang , Wang Quan , Pan Lina , Miao Lu , Deng Guochuang , Wu JinRong , Lou Huifang , Zeng Ling-Hui , Liu Yijun , Li Xiao-ming , Duan Shumin , Sun Li , Yu Yan-qin 
Published: December 2024

AbstractAggression behaviors typically vary between sexes, but the molecular mechanisms driving these disparities in neural coding are unclear. We found that aggression selectively activates GABAergic neurons in the posterior substantia innominata (pSI), an extend amygdala region critical for aggressive behaviors in both sexes of mice, with males exhibiting higher neuronal activity during the attack. Utilizing single-nucleus RNA sequencing, we characterized the diverse molecular landscape of pSI neurons, revealing significant differences in ion channels and hormone regulator genes that may underpin sex-specific aggression. Male GABAergic pSI neurons exhibited remarkable hyperexcitability due to increased Ih currents. Strikingly, modulating HCN1 expression not only adjusted this hyperexcitability but also influenced sexual dimorphism in aggression: silencing HCN1 in the GABAergic pSI neurons reduced male aggression, while its overexpression markedly heightened aggression in females. Furthermore, testosterone was shown to intensify aggression by upregulating HCN1 and remodeling pSI circuits. These findings provide detailed sex-specific molecular mechanisms underlying social behaviors.
Superresolution Imaging Reveals the Spatial Organization of CD81 Microdomains in Regulating Membrane Signaling on Jurkat T Cell Microvilli
Authors: Ramseier Neal T. , Jing Haoran , Anderson Jesse , Hu Ying S. 
Published: December 2024

AbstractTetraspanin proteins are closely associated with high-curvature membrane structures and play key roles in organizing membrane domains and regulating membrane signaling in immune cells. However, their specific roles in regulating T cell membrane signaling, particularly within the microvilli often characteristic of these cells, remain poorly understood. Here, we used Jurkat T cells as a model system and investigated CD81 as a member of the tetraspanin family. Using total internal reflection fluorescence (TIRF) microscopy and structured illumination microscopy (SIM), we identified an enrichment of the tetraspanin CD81 microdomains along the actin-rich membrane microvilli. At the distal end of the microvilli, SIM images revealed the spatial colocalization of CD81 with T cell receptors (TCR) and CD63, implying a potential role for CD81 in regulating TCR signaling in conjunction with CD63. Spatial analysis of CD81 and CD63 microdomains from the dual-color SIM data revealed their preference for associating with each other. Cluster analysis of direct stochastic optical reconstruction microscopy (dSTORM) data revealed thatin vitroT cell activation results in reduced domain sizes and increased domain separation of CD81. These findings provide visual evidence of the spatial organization and rearrangement of CD81 on the T cell microvilli, highlighting its potential role in signal regulation on specialized membrane protrusions.