bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesenchymal Stem Cell-Derived Extracellular Vesicles Mitigate Immune Cell Activation in an In Vitro Model of Post-Resuscitation Inflammation
Authors: Rolland Tyler J , Zahra Sumbule , Cucinotta Daniel , Young Rebeccah , Weil Brian 
Published: February 2025

ABSTRACTBackgroundSystemic inflammation is a well-established component of post-cardiac arrest syndrome (PCAS), a condition responsible for significant morbidity and mortality in patients who are initially resuscitated from sudden cardiac arrest. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising immunomodulatory agents in various inflammatory conditions, including after ischemia-reperfusion injury (IRI). Here, we investigated the therapeutic potential of MSC-EVs in porcine peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) or mitochondrial DNA (mtDNA) to mimic immune cell activation in PCAS.MethodsPBMCs were isolated from healthy pigs (Sus scrofa), culturedin vitro, stimulated with LPS or mtDNA, and treated with a range of MSC-EV concentrations. Flow cytometry, quantitative PCR, ELISA, and ROS/RNS measurements were performed to assess PBMC activation.ResultsMSC-EV treatment reduced LPS-induced inflammatory granulocyte activation and selectively modulated cytokine transcripts, including IFNα, IL-1β, and TNF-α, in a concentration-dependent manner. Similar immunosuppressive effects were observed in mtDNA-stimulated PBMCs, where MSC-EVs attenuated dendritic cell activation and inflammatory cytokine release. Furthermore, higher concentrations of MSC-EVs significantly decreased ROS/RNS production in both LPS- and mtDNA-challenged PBMCs.ConclusionsMSC-EVs exhibit potent immunomodulatory properties against LPS- and mtDNA-induced activation of porcine PBMCs, highlighting their broad capacity to modulate immune responses and mitigate oxidative stress induced by pro-inflammatory stimuli that are relevant to PCAS. These findings provide further support for the administration of MSCs, or MSC-EVs themselves, as a potential therapeutic intervention to target immune activation in PCAS and other disorders characterized by an acute systemic inflammatory state.
Identification of pyroptosis-related diagnostic model relate to immune infiltration in osteoarthritis
Authors: Xiao Meimei , Qiu Yue , Meng Jinzhi , Jiang Cancai , Chen Yanming , Yao Jun 
Published: February 2025

AbstractBackgroundOsteoarthritis (OA) is a common chronic diseases which were associated with aging and progressive joint dysfunction. Pyroptosis, a novel mode of cell death. The effect of pyroptosis on osteoarthritis (OA) progression is still in the exploratory stage, and the specific mechanism is unclear.MethodsOA data sets were obtained from the GEO databases website. Bioinformatics analysis was conducted to identify pyroptosis-related genes (PRGs), construct a pyroptosis-related diagnostic model, and identify subtypes. We established the random forest (RF) model as well as a nomogram of differentially expressed PRGs. The association between immunity and pyroptosis was comprehensively explored. Finally, the expression levels of 3 OA characteristic genes were verified by qRT-PCR and immunohistochemistry.ResultsSeven differentially expressed PRGs (CASP3, GPX4, NOD1, TIRAP, SCAF11, CASP4, and CASP9) were obtained by differential analysis to establish RF models, and three important OA genes (CASP9, TIRAP, and SCAF11) were obtained. ROC curve proved that the established model had high diagnostic accuracy. Based on the above three important PRGs, a high-precision nomogram model is constructed. Two PRG models are determined by consensus clustering method. The enrichment degree of immune cells in cluster A was higher than that in cluster B, suggesting that cluster A might be related to the occurrence and development of OA. GPX4 was found to be positively correlated with higher immune infiltration. Finally, the expression levels of 3 OA characteristic genes were verified by qRT-PCR and immunohistochemistry.ConclusionWe constructed an effective prognostic model according to PRGs in OA and integrated explored the association between pyroptosis and immunity-related elements. This article provides a strong point for investigating directed immunotherapy methods with novelty for OA.
The interplay of climate change, urbanization, and species traits shapes European butterfly population trends
Authors: Colom Pau , Tejeda Ashley , Bonelli Simona , Fontaine Benoît , Kuussaari Mikko , Maes Dirk , Mestdagh Xavier , Munguira Miguel L. , Musche Martin , Pettersson Lars B. , Roy David , Rüdisser Johannes , Šašić Martina , Schmucki Reto , Stefanescu Constanti , Titeux Nicolas , Settele Josef , van Swaay Chris , Gordillo Javier , Melero Yolanda 
Published: February 2025

ABSTRACTSpecies populations naturally fluctuate, yet long-term trend analysis can reveal patterns of success, decline, or stability under global change pressures. While responses to climate change are well-documented, its synergy with another major global driver, urbanization, remains understudied. Here, we analyzed long-term monitoring data from over 8,400 populations of 145 butterfly species across Europe, representing a high diversity of species traits, to assess population trends in response to climate change and urbanization. We examined how population responses vary between urban and rural contexts, providing insights into the influence of site-specific conditions. Climate warming was associated with population declines, which were more pronounced in urban areas. The effect of precipitation varied between environments: increases in precipitation generally benefited populations in rural areas but had detrimental effects in urban ones. Aridity consistently drove population declines across environments, with slightly stronger effects in urban areas. Species with colder climatic niches declined the most in response to warming, increased aridity, and reduced precipitation, while trophic specialists were particularly vulnerable to aridity and precipitation changes in urban environments. Although increasing urbanization did not explain overall population trends, its effects became evident when considering species traits, with certain traits being more vulnerable to urbanization. Specifically, species with narrow climatic niches declined the most in response to urbanization in rural areas, while those and larger body sizes decline the most in urban environments. Our findings highlight the complex interplay between environmental change, landscape context, and species traits in shaping biodiversity outcomes. Importantly, our results suggest that urbanization generally amplifies the impact of climate change on insect population trends.
Regioselectively Acetylated Silybin Derivatives and their Cytotoxic Activity in Liver Cancer Cells
Authors: Van Chien Tran , Phuong Thao Tran Thi , Anh Nguyen The , Van Loc Tran , Garrett Michelle D. , Nga Nguyen Thi , Thao Do Thi , Serpell Christopher J. , Van Sung Tran 
Published: February 2025

AbstractNatural products continue to serve as a valuable source of starting points for therapeutic agents. Six silybin derivatives have been synthesized and testedin vitrofor their cytotoxic effect on the human hepatocellular carcinoma line HepG2 using the MTT assay. Results indicate that the 3,5,7,20,23-penta-O-acetyl-2,3-dehydrosilybin possesses a stronger cytotoxic effect than that of the parent silybin by a factor of 12. This compound was further evaluated for its cytotoxic activity on Hep3B, Huh7, and Huh7R hepatocellular carcinoma cell lines, giving similar potencies, arresting the cell cycle at S phase and causing apoptosis. These results illustrate the potential of silybin derivatives as therapeutics against liver cancer.
Commonly used compositional data analysis implementations are not advantageous in microbial differential abundance analyses benchmarked against biological ground truth
Authors: Gamboa-Tuz Samuel D. , Ramos Marcel , Franzosa Eric , Huttenhower Curtis , Segata Nicola , Oh Sehyun , Waldron Levi 
Published: February 2025

AbstractPrevious benchmarking of differential abundance (DA) analysis methods in microbiome studies have employed synthetic data, simulations, and “real data” examples, but to the best of our knowledge, none have yet employed experimental data with known “ground truth” differential abundance. A key debate in the field centers on whether compositional methods are necessary for DA analysis, which is challenging to answer due to the lack of ground truth data. To address this gap, we created the Bioconductor data packageMicrobiomeBenchmarkData, featuring three microbiome datasets with established biological ground truths: 1) diverse oral microbiomes from supragingival and subgingival plaques, expected to favor aerobic and anaerobic bacteria, respectively, 2) low-diversity microbiomes from healthy vaginas and bacterial vaginosis, conditions that have been well-characterized through cell culture and microscopy, and 3) a spike-in dataset with constant, known absolute abundances of three bacteria. We benchmarked 17 DA approaches and demonstrated that compositional DA methods are not beneficial but rather lack sensitivity, show increased variability in constant-abundance spike-ins, and, most surprisingly, more frequently produce paradoxical results with DA in the wrong direction for the low-diversity microbiome. Conversely, commonly used methods in microbiome literature, such asLEfSe, the Wilcoxon test, and RNA-seq-derived methods, performed best. We conclude that researchers continue using widely adopted non-parametric or RNA-seq DA methods and that further development of compositional methods includes benchmarking against datasets with known biological ground truth.
Delayed transplantation of neural stem cells improves initial graft survival following stroke
Authors: Weber Rebecca Z , Rentsch Nora H , Buil Beatriz Achón , Nih Lina R. , Tackenberg Christian , Rust Ruslan 
Published: February 2025

AbstractNeural stem cell therapies hold great promise for improving stroke recovery, but the hostile stroke microenvironment can hinder the initial graft survival. It has long been well documented that the microenvironment evolves over time, making it crucial to identify the optimal transplantation window to maximize therapeutic efficacy. However, it remains uncertain whether acute or delayed local cell transplantations better supports graft viability after stroke. Here, we show that delayed intracerebral transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent cells (iPSCs) at 7 days post stroke significantly enhances graft proliferation and survival, compared to acute transplantation at 1 day post stroke, in a mouse model of large cortical stroke. Usingin vivobioluminescence imaging over a 6-week period post-transplantation, we observe a more than 5-fold increase in bioluminescence signal in mice that received delayed NPC therapy, compared to those that underwent acute NPC transplantation. The increased number of cell grafts in mice receiving delayed NPC transplantation was driven by increased proliferation rates early after transplantation, which subsequently declined to similarly low levels in both groups. Notably, we found that the majority of transplanted NPCs differentiated into neurons after 6 weeks, with no significant differences in the neuron-to-glia ratio between acute and delayed transplantation groups. These findings suggest that delayed NPC transplantation improves early graft survival and proliferation, which could help identify the optimal therapeutic window for maximizing the effectiveness of NPC-based therapies in stroke.
Effects of High-Intensity Interval Training on Physical and Cognitive Function in Middle-Aged Male Mice
Authors: Stephenson Justin C. , Tran Tuan D. , Graber Ted G. 
Published: February 2025

AbstractDeclining functional capacity, both physical and cognitive, is a consequence of aging. However, exercise is a promising intervention to mitigate normal age-related decline. While numerous studies have elucidated the benefits of exercise per se, less well-studied is the effect of high intensity interval training (HIIT) on a middle-aged population. Our primary purpose was to assess the effect of three months of HIIT on physical and cognitive performance in middle-aged (17-month-old) male C57BL/6J mice, compared to sedentary controls. We hypothesized that exercised mice would be resistant to any decline in cognitive and physical ability, both measured pre- and post-intervention. To measure physical function, we used the well-validated CFAB (comprehensive functional assessment battery) scoring system comprised of determinants including voluntary wheel running, inverted cling, grip test, treadmill max speed, and rotarod. We measured cognition with open field, novel object recognition, y-maze, and puzzle box. Further measures of sarcopenia/frailty included body composition (MRI) andin vivocontractile physiology (plantar flexor torque). Training resulted in significant aerobic capacity improvements for the HIIT group, increasing treadmill time by 28%, while the SED group demonstrated a 41.4% decline in treadmill time. However, no significant differences in cognitive function were determined. Contrary to our previous research in other age groups, the current study found a negligible effect of HIIT on body composition. We note that at 17 months old, mice did not experience any evidence of cognitive deterioration in either group over the three-month period, thus explaining the lack of exercise effect. We found that HIIT had less influence on either physical or cognitive function than we expected, which may be because function in this age group is stable. Future work will investigate older adult cognitive response to HITT at ages where there is well-documented cognitive decline.
Pneumo-Typer: a high-throughput capsule genotype visualization tool with integrated serotype and sequence type prediction forStreptococcus pneumoniae
Authors: Li Xiangyang , Zhu Yaoyao , Yang Zilin , Li Yanzi , Zhang Guohui , Wang Xiangyu , Zhao Xuan , Huang Yinyan , Zhang Huajie , Li Bingqing , Ma Zhongrui 
Published: February 2025

AbstractStreptococcus pneumoniaeremains a significant global pathogen, with capsule-based vaccines targeting only a subset of over 100 serotypes. Accurate serotyping is critical for evaluating vaccine impact and optimizing capsule formulations. While whole-genome sequencing (WGS)-based methods achieve high serotyping accuracy, they often struggle to identify serotype variants with altered capsule loci that may evade vaccine-induced immunity. Here, we present Pneumo-Typer, a high-throughput tool for capsule genotype (CapT) visualization, enabling rapid identification of isolates with capsular gene variations, including mutations and horizontal gene transfer. In addition, Pneumo-Typer integrates serotype and sequence type (ST) prediction, achieving 98.44% accuracy in predicting 93 serotypes across 17,683 genomes. Our analysis reveals substantial serotypes linked to multiple STs and CapTs, with STs and CapTs demonstrating relative evolutionary independence and limited CapT variation during ST expansion. Within multi-serotype serogroups, we observe striking CapT diversity, providing insights into the evolutionary dynamics of serogroup formation. These findings underscore the utility of Pneumo-Typer for epidemiological surveillance and vaccine design, contributing to efforts to mitigate the global burden of S. pneumoniae.
Deciphering population-level response under spatial drug heterogeneity on microhabitat structures
Authors: Hu Zhijian , Wood Kevin 
Published: February 2025

AbstractBacteria and cancer cells live in a spatially heterogeneous environment, where migration shapes the microhabitat structures critical for colonization and metastasis. The interplay between growth, migration, and microhabitat structure complicates the prediction of population responses to drugs, such as clearance or sustained growth, posing a longstanding challenge. Here, we disentangle growth-migration dynamics and identify that population decline is determined by two decoupled terms: a spatial growth variation term and a microhabitat structure term. Notably, the microhabitat structure term can be interpreted as a dynamic-related centrality measure. For fixed spatial drug arrangements, we show that interpreting these centralities reveals how different network structures, even with identical edge densities, microhabitat numbers, and spatial heterogeneity, can lead to distinct population-level responses. Increasing edge density shifts the population response from growth to clearance, supporting an inversed centrality-connectivity relationship, and mirroring the effects of higher migration rates. Furthermore, we derive a sufficient condition for robust population decline across various spatial growth rate arrangements, regardless of spatial-temporal fluctuations induced by drugs. Additionally, we demonstrate that varying the maximum growth-to-death ratio, determined by drug-bacteria interactions, can lead to distinct population decline profiles and a minimal decline phase emerges. These findings address key challenges in predicting population-level responses and provide insights into divergent clinical outcomes under identical drug dosages. This work may offer a new method of interpreting treatment dynamics and potential approaches for optimizing spatially explicit drug dosing strategies.
Evidence of functional connectivity disruptions between auditory and non-auditory regions in adolescents living with HIV
Authors: Madzime Joanah , Jankiewicz Marcin , Meintjes Ernesta M. , Torre Peter , Laughton Barbara , Holmes Martha J. 
Published: February 2025

AbstractChildren living with perinatally acquired HIV (CPHIV) demonstrate hearing impairments and language processing delays even in the presence of combination antiretroviral therapy (cART). Even though efficient processing of sound relies on the proper function of both the peripheral and central auditory auditory systems (PAS; CAS), investigations on the effect of HIV on the auditory system have predominantly focused on the PAS. Additionally, language processing requires the efficient interaction between CAS brain regions and non-auditory regions. Investigating the functional connectivity (FC) within the CAS and between the CAS and non-auditory regions may reveal the influence of HIV on regions involved in auditory function.Within a Bayesian stastical framework, we used resting-state functional magnetic resonance imaging (RS-fMRI) to map FC in the CAS as well as between CAS regions and non-auditory regions of 11-year-old CPHIV. Graph theory was used to investigate the regional effects of HIV on functional brain network properties. Finally we explored the relationships between FC and neurocognitive outcomes relating to auditory and language processing. We hypothesized that CPHIV would show disruptions in FC between CAS regions as well as between CAS and non-auditroy regions. Secondly, we hypothesized that in CPHIV, regional brain network properties would be altered compared to their uninfected peers (CHUU). Finally we hypothesized that FC and functional network regional outcomes would be related to neurocognitive outcomes.Our investigation revealed lower FC of the primary auditory cortex (PAC) in CPHIV as well as disruptions in FC between CAS regions (including the PAC) and non-auditry regions including hippocampal sub-regions, the lingual gyri and basal ganglia. Functional network analysis reavealed lower nodal degree and efficiency in CAS regions including the cochlear nucleus/superior olivary complex (CN/SOC) and the inferior colliculus (IC). We also report associations between the nodal efficiency of middle temporal and superior frontal regions and delayed recall, a neurocognitive marker of working memory, present in CHUU but not in CPHIV.Our results demonstrate FC alterations in the PAC and between CAS regions and non-auditory regions involved in limbic, visual and motor processing, as well as disruptions to the regional properties of the CAS regions as part of the functional brain network. These results provide insight into the state of the CAS FC in the presence of HIV and its possible role in the hearing and language impairments seen in this population.
Phosphorylation-State Modulated Binding of HSP70: Structural Insights and Compensatory Protein Engineering
Authors: Stewart Mariah , Paththamperuma Chathura , McCann Colleen , Cottingim Kelsey , Zhang Huaqun , DelVecchio Rian , Peng Ivy , Fennimore Erica , Nix Jay C. , Saeed Morcos N , George Kathleen , Makaroff Katherine , Colie Meagan , Paulakonis Ethan , Almeida Michael F. , Afolayan Adeleye J , Brown Nicholas G , Page Richard C. , Schisler Jonathan C 
Published: February 2025

ABSTRACTProtein quality control is crucial for cellular homeostasis, involving the heat shock response, the ubiquitin-proteasome system, and the autophagy-lysosome pathway. Central to these systems are the chaperone homologs heat shock protein 70 (HSP70) and heat shock cognate 70 (HSC70), which manage protein folding and degradation. This study investigated the impact of the C-terminal phosphorylation of HSP70 on its interaction with the co-chaperone CHIP (C-terminus of HSC70 interacting protein), an E3 ligase that ubiquitinates protein substrates for degradation. Using both cell-free and cell-based approaches, including X-ray crystallography, biolayer interferometry, and live cell biocomplementation assays, we demonstrate that phosphorylation at HSP70 T636 reduces CHIP’s binding affinity, shifting the preference toward other co-chaperones like HOP. Structural analysis reveals that phosphorylation disrupts key hydrogen bonds, altering binding dynamics. We engineered a CHIP variant (CHIP-G132N) to restore binding affinity to phosphorylated HSP70. While CHIP-G132N effectively restored binding without additional functional domains, its effectiveness was diminished in full-length phosphomimetic constructs in cell-free and in-cell assays, suggesting that additional interactions may influence binding. Functional assays indicate that phosphorylation of HSP70 affects its stability and degradation, with implications for diseases such as cancer and neurodegeneration. Our findings highlight the complexity of chaperone-co-chaperone interactions and underscore the importance of post-translational modifications in regulating protein quality control mechanisms. By elucidating the molecular details of HSP70 and CHIP interactions, our study provides a foundation for developing therapeutic interventions for diseases characterized by proteostasis imbalance.