bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of Diffuse to Focal Myocardial Fibrosis by Cardiovascular Magnetic Resonance Against Histology in Mini-Swine
Authors: Zhang Huaying , Chen Cui , Yang Wenjing , Zhou Di , Wang Yining , Zhu Leyi , Jiang Mengdi , Zhang Qiang , Zhao Shihua , Piechnik Stefan K , Ferreira Vanessa M , Lu Minjie 
Published: January 2025

AbstractBackgroundMyocardial fibrosis predicts adverse outcomes in myocardial infarction (MI) and other cardiovascular conditions. Cardiovascular magnetic resonance (CMR) can non-invasively detect focal and diffuse myocardial fibrosis, but comprehensive validation against histology remains scarce.AimsTo assess the comparative diagnostic performance of CMR methods in detecting myocardial fibrosis, using a mini-swine model and histology as gold standard.MethodsEighteen mini-swine (16 MI; 2 healthy) underwent CMR cine, LGE, T1- and ECV-mapping. Two commonly-used T1-mapping methods – MOLLI 5(3)3 and ShMOLLI 5(1)1(1)1 – were included. Pathological sections were categorized as infarcted, peri-infarct, remote and healthy myocardium based on triphenyl tetrazolium chloride staining. Fibrotic burden was quantified by collagen volume fraction (CVF) into severe (CVF≥30%), moderate (CVF=10-25%), and mild (CVF=3-14%). The relationships between LGE, T1, ECV and CVF, and diagnostic performance using area-under-the-curve (AUC), were analyzed.ResultsFor detecting severe fibrosis, LGE, T1 and ECV all had excellent diagnostic performance (AUC: LGE=0.93, ECVShMOLLI=0.96, T1ShMOLLI=0.91, T1MOLLI=0.93, ECVMOLLI=0.88). ECVShMOLLIshowed significantly better discriminatory accuracy than ECVMOLLIin detecting severe fibrosis and MI (both p<0.05), with the highest correlation to CVF (ECVShMOLLIr=0.86, ECVMOLLIr=0.82, T1ShMOLLIr=0.77, T1MOLLIr=0.77, semi-quantitative LGE r=0.75). Only T1ShMOLLIand ECVShMOLLI, but not LGE or T1MOLLI/ECVMOLLI, differentiated remote myocardium with mild fibrosis (CVF=8.23%) from healthy myocardium (CVF=2.01%).ConclusionsCMR can detect severe to mild myocardial fibrosis as validated against histology. For low-grade fibrosis, T1-mapping significantly outperformed LGE. Choice of CMR methodologies matters for myocardial fibrosis detection, which has importance for clinical trial design.
Metabolic syndrome enhances SARS-CoV-2 disease severity and reduces mRNA vaccine efficacy in a mouse model
Authors: Geerling Elizabeth , Stone E. Taylor , Carpenter Danielle , Dickson Alexandria M. , Brien James D. , Pinto Amelia K. 
Published: January 2025

AbstractMetabolic syndrome (MetS) is a cluster of pathophysiological conditions linked to the disruption of metabolic processes associated with energy storage and consumption. Approximately one-third of adults in the United States are currently diagnosed with MetS. Patients with MetS experience higher mortality rates following SARS-CoV-2 infection and exhibit poor vaccine efficacy following influenza virus vaccination compared to metabolically healthy individuals. However, the specific impact of MetS on immune responses to SARS-CoV-2 infection and vaccination has not been widely studied. To address this gap, we utilized high-fat diet feeding to establish a murine model of MetS, in which mice exhibit the same diagnostic criteria for MetS as human patients. We then used high-fat diet-induced MetS mice and regular chow diet-fed wild-type mice to analyze immune responses to SARS-CoV-2 infection and vaccination. Following SARS-CoV-2 infection, we monitored mice for disease severity, measured levels of virally induced inflammation, and quantified viral titers in various tissues. Our results indicate that MetS mice exhibit accelerated mortality post-infection, accompanied by elevated mRNA levels of inflammatory cytokine transcripts at sites of infection. Additionally, MetS alters the degree of viral replication across various tissues. Furthermore, our vaccination studies revealed that MetS reduces the potency of vaccine-induced neutralizing antibodies against both the ancestral SARS-CoV-2 strain and the Delta variant. Overall, our findings suggest that MetS exacerbates SARS-CoV-2 disease severity and diminishes vaccine efficacy, underscoring the need for tailored strategies to protect individuals with MetS from severe outcomes following infection and vaccination.ImpactThis study represents the first detailed account of the failure to generate protective neutralizing antibody responses to SARS-CoV-2 in mice with metabolic syndrome (MetS) following vaccination. The insights gained from this research inform future vaccine design and aid in identifying individuals at greater risk of breakthrough infections. By specifically isolating the risk associated with MetS, rather than obesity alone, these findings lay the groundwork for future investigations aimed at enhancing immune responses in individuals with MetS. This work is highly relevant to a broad audience, as it addresses a critical unmet need in vaccine development and provides essential guidance for the rational design of vaccines to protect vulnerable populations affected by MetS.
Run-and-tumble dynamics ofE. coliis governed by its mechanical properties
Authors: Wu-Zhang Bohan , Zhang Peixin , Baillou Renaud , Lindner Anke , Clément Eric , Gompper Gerhard , Fedosov Dmitry A. 
Published: January 2025

AbstractThe huge variety of microorganisms motivates fundamental studies of their behavior with a possibility to construct artificial mimics. A prominent example is theE. colibacterium which employs several helical flagella to exhibit a motility pattern that alternates between run (directional swimming) and tumble (change in swimming direction) phases. We establish a detailedE. colimodel, coupled to fluid flow described by the dissipative particle dynamics method, and investigate its run-and-tumble behavior. DifferentE. colicharacteristics, including body geometry, flagella bending rigidity, the number of flagella and their arrangement at the body are considered. Experiments are also performed to directly compare with the model. Interestingly, in both simulations and experiments, the swimming velocity is nearly independent of the number of flagella. The rigidity of a hook (the short part of a flagellum which connects it directly to the motor), polymorphic transformation (spontaneous change in flagella helicity) of flagella, and their arrangement at the body surface strongly influence the run-and-tumble behavior. Mesoscale hydrodynamics simulations with the developed model help us better understand physical mechanisms which governE. colidynamics, yielding the run-and-tumble behavior that compares well with experimental observations. This model can further be used to explore the behavior ofE. coliand other peritrichous bacteria in more complex realistic environments.
Mechanistic Insights into Sphingomyelin Nanoemulsions as Drug Delivery Systems for Non-Small Cell Lung Cancer Therapy
Authors: Docampo Emma Ramos , García-Fernández Jenifer , Mármol Inés , Morín-Jiménez Irene , Baleato María Iglesias , de la Fuente Freire María 
Published: January 2025

AbstractSphingomyelin Nanoemulsions (SNs) are promising drug delivery systems with potential for treating challenging tumors, including Non-Small Cell Lung Cancer (NSCLC), which has poor prognosis and a 5-year survival rate below 5%. Understanding the toxicity mechanisms and intracellular behavior of SNs is crucial for optimizing their therapeutic application. This study aims to investigate the interaction between SNs and A549 lung adenocarcinoma cells, focusing on their cytotoxic effects and mechanisms of cellular toxicity. SNs were synthesized and characterized for size, surface charge, and stability. A549 cells were treated with varying concentrations of SNs, and cellular uptake pathways were assessed using inhibitors of energy-dependent processes. Cytotoxicity was evaluated through an MTT assay to determine the IC50 value after 24 hours. Mechanisms of toxicity, including lysosomal and mitochondrial involvement, were examined using co-localization studies, mitochondrial membrane potential assays, and markers of apoptosis. SNs exhibited rapid cellular uptake via energy-dependent pathways. The IC50 concentration for A549 cells was 0.89 ± 0.15 mg/mL, suggesting favorable cytocompatibility compared to other nanocarriers. At IC50, SNs induced apoptosis characterized by lysosomal damage, mitochondrial membrane permeabilization, and release of apoptotic factors. These effects disrupted autophagic flux and contributed to cell death, demonstrating potential for overcoming drug resistance. Resveratrol-loaded SNs showed enhanced cytotoxicity, supporting their application as targeted drug delivery vehicles. This study highlights the potential of SNs as efficient drug delivery systems for NSCLC therapy, offering insights into their cellular interactions and toxicity mechanisms. These findings pave the way for the rational design of SN-based therapeutic platforms for cancer and other mitochondria-related diseases.
PLMFit : Benchmarking Transfer Learning with Protein Language Models for Protein Engineering
Authors: Bikias Thomas , Stamkopoulos Evangelos , Reddy Sai. T. 
Published: January 2025

ABSTRACTProtein language models (PLMs) have emerged as a useful resource for protein engineering applications. Transfer learning (TL) leverages pre-trained parameters to extract features to train machine learning models or adjust the weights of PLMs for novel tasks via fine-tuning through back-propagation. TL methods have shown potential for enhancing protein predictions performance when paired with PLMs, however there is a notable lack of comparative analyses that benchmark TL methods applied to state-of-the-art PLMs, identify optimal strategies for transferring knowledge and determine the most suitable approach for specific tasks. Here, we report PLMFit, a benchmarking study that combines, three state-of-the-art PLMs (ESM2, ProGen2, ProteinBert), with three TL methods (feature extraction, low-rank adaptation, bottleneck adapters) for five protein engineering datasets. We conducted over >3,150in silicoexperiments, altering PLM sizes and layers, TL hyperparameters and different training procedures. Our experiments reveal three key findings: (i) utilizing a partial fraction of PLM for TL does not detrimentally impact performance, (ii) the choice between feature extraction and fine-tuning is primarily dictated by the amount and diversity of data and (iii) fine-tuning is most effective when generalization is necessary and only limited data is available. We provide PLMFit as an open-source software package, serving as a valuable resource for the scientific community to facilitate the feature extraction and fine-tuning of PLMs for various applications.ONE SENTENCE SUMMARYPLMFit is a comparative analysis aimed at identifying the most effective strategies for transfer knowledge from protein language models by benchmarking fine-tuning techniques on a range of protein engineering tasks.
Myositis-specific autoantibodies recognizing Mi2 also target the autoimmune regulator (AIRE) protein at a shared PHD-zinc finger
Authors: Musai Jon , Jayaraman Sahana , Pak Katherine , Pinal-Fernandez Iago , Muñoz-Braceras Sandra , Casal-Dominguez Maria , Cho Eric , Fitisemanu Fa’alataitaua M. , Burbelo Peter D. , Kaplan Mariana J. , Warner Blake M. , Schiffenbauer Adam I. , Selva-O’Callaghan Albert , Milisenda José César , Rider Lisa G. , Benjamin Larman H. , Mammen Andrew L. 
Published: January 2025

ABSTRACTObjectivesIn dermatomyositis patients with anti-Mi2 autoantibodies, autoantibodies can enter muscle cells, leading to the aberrant expression of genes normally repressed by the Mi2/nucleosome remodeling and deacetylation (NuRD) complex. However, the mechanism by which autoantibodies interfere with Mi2/NuRD function remains unclear. This study aimed to identify additional autoantibodies in anti-Mi2-positive patients as well as the specific epitopes recognized by anti-Mi2 and any novel autoantibodies.MethodsPhage ImmunoPrecipitation Sequencing (PhIP-Seq) was used to screen serum samples from anti-Mi2-positive myositis patients for autoantibodies. Enzyme-linked immunosorbent assays (ELISA) and luciferase immunoprecipitation system (LIPS) immunoassays were used to detect autoantibodies in serum samples from myositis patients and healthy controls.ResultsPhIP-Seq identified autoantibodies recognizing the autoimmune regulator (AIRE) in sera from anti-Mi2 autoantibody-positive patients. Both anti-AIRE and anti-Mi2 autoantibodies predominantly recognized a homologous region of the plant homeodomain zinc finger type I (PHD1), which is critical for AIRE and Mi2/NuRD function. ELISA and LIPS testing showed that anti-Mi2 autoantibody-positive patients were positive for anti-AIRE autoantibodies, while AIRE reactivity was largely absent in healthy comparators, anti-Mi2 autoantibody-negative-myositis, and other autoimmune diseases. Affinity-purified anti-Mi2 autoantibodies recognized both Mi2 and AIRE by ELISA, whereas anti-Mi2-depleted immunoglobulin fractions did not recognize either protein.ConclusionsAutoantibodies recognizing Mi2 also recognize AIRE at a homologous PHD1 finger. This region is required by the Mi2/NuRD complex to anchor the nucleosome and consequently repress gene expression. Our findings suggest that anti-Mi2 autoantibodies disrupt NuRD complex function by binding to the PHD1 domain. Further studies are needed to determine if anti-Mi2 autoantibodies bind other PHD1-containing proteins and their functional implications.
Stability of multi-species consortia during microbial metabolic evolution
Authors: Kehila Dan , Tafreshi Alireza G , Tokuriki Nobuhiko 
Published: January 2025

AbstractExplaining multi-genic adaptations is a major objective of evolutionary theory. Metabolic pathways require multiple functional enzymes to generate a phenotype, and their evolution in microbes remains underexplored. In particular, sites polluted with manmade chemicals or “xenobiotics”, like plastic or pesticides, provide evidence for the rapid adaptation of novel metabolic pathways in microbes, which degrade these xenobiotics into utilizable nutrients. Decades of microbiological studies revealed that these pathways often are not consolidated within a single microbial species, but are rather distributed across several different ones, which cooperatively degrade xenobiotics. These species form remarkably stable consortia in the laboratory, but the determinants of this stability have not been hereto addressed. In this study, we show that trade-offs in microbial life history explain stable co-existence in a mathematical model of a three-species consortium, growing on a xenobiotic as the sole source of a limiting nutrient. Stability is predicted to hinge on a specific “ecological matching” between a species’ metabolic role in the novel metabolic pathway and its nutrient utilization strategy.
TMPRSS2-ERGconfers resistance to antiandrogens: mechanism and therapeutic implications
Authors: Sekar Arunachalam , Chatterjee Rishita , Selvadurai Boobash Raj , Pal Lipika R. , Verma Aakanksha , Nataraj Nishanth Belugali , Garcia Diana Drago , Giri Suvendu , Genna Alessandro , Karatekin Feride , Gupta Nitin , Zerbib Mirie , Vinik Yaron , Avioz Tamir , Weizman Eviatar , David Eyal , Schaffer Alejändro A. , Pan Yunqian , Huang Haojie , van Weerden Wytske M. , Corey Eva , Hunt Hazel , Greenstein Andrew E. , Blecher-Gonen Ronnie , Oren Roni , Afek Ariel , Amit Ido , Lev Sima , Ku Anson , Kartal Sumeyra , Bright Jack R. , Lis Rosina T. , Dahut William L. , Sowalsky Adam G. , Ruppin Eytan , Yarden Yosef 
Published: January 2025

AbstractApproximately 50% of prostate cancer (PCa) patients harbor fusions involving theTMPRSS2andERGgenes. Despite this, tailored therapies targeting the fused gene,tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacies of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed thattERGpromotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in fusion-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlightTMPRSS2-ERGas a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefittERG-positine patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.
Genotype-specific roles of small extracellular vesicles in modulating metronidazole resistance inGiardia lamblia
Authors: Luna Pizarro Gabriel , Laiolo Jerónimo , Salas Nehuén , Patolsky Rocío G. , Díaz Pérez Luciano , Cotelo Camilo , Feliziani Constanza , Rópolo Andrea Silvana , Touz María Carolina 
Published: January 2025

AbstractGiardia lamblia, a eukaryotic intestinal parasite, produces small extracellular vesicles (sEVs) as a conserved evolutionary mechanism. This study investigates the functional role of sEVs in transferring drug-resistance traits among parasites. sEVs derived from metronidazole (MTZ)-resistant clones are shown to modify the expression of enzymes involved in MTZ metabolism and the production of reactive oxygen species (ROS) in recipient wild-type parasites. These changes significantly alter the drug sensitivity of recipient parasites. The transfer efficiency and phenotypic impact vary depending on the genetic background of the isolates, highlighting a genotype-specific mechanism. Our findings reveal that sEVs act as mediators of phenotypic adaptation inG. lamblia, enhancing parasite survival under drug-induced stress. This study underscores the importance of sEVs in drug-resistance dynamics and provides a basis for exploring therapeutic interventions targeting EV-mediated resistance in giardiasis.Highlights In briefSmall extracellular vesicles (sEVs) fromGiardia lambliamediate genotype-specific MTZ resistance transfer.Small extracellular vesicles from drug-resistant clones (RsEVs) alter enzyme expression and reactive oxygen species (ROS) production in recipient trophozoites.The genetic background ofG. lambliaisolates influences the effectiveness of resistance transfer.Findings provide insights into resistance mechanisms and potential targets for new giardiasis therapies.
HPV integration in head and neck cancer: downstream splicing events and expression ratios linked with poor outcomes
Authors: Li Shiting , Xia Shaomiao , Lawas Maria , Kulshreshtha Aishani , Garb Bailey F. , Perera AA Chamila , Li Chen , Qin Tingting , Welch Joshua D. , D’Silva Nisha J. , Rozek Laura S. , Sartor Maureen A. 
Published: January 2025

AbstractHPV integration (HPVint) is associated with carcinogenesis and tumor progression in HPV-associated cancers, including head and neck squamous cell carcinomas (HNSCC). While its impact on human DNA has been well characterized, its relationship with clinical outcomes remains unconfirmed. Here we investigate the consequences of HPVint both with respect to human and HPV characteristics by analyzing 261 HPV-associated HNSCC bulk and single-cell RNA-seq samples from five cohorts, and DNA HPVint events from 102 HPV+ participants in two of the cohorts. By leveraging this large meta-cohort, we first reveal an oncogenic network based on the recurrent HPV integration locations in HNSCC. We then classify HPVint-positive (HPVint(+)) participants by HPV RNA features, specifically based on spliced HPV-human fusion transcripts and ratios of HPV gene transcripts, showing that subsets of participants have worse clinical outcomes. Our analyses, focused mainly on RNA instead of DNA, expand our understanding of the carcinogenic mechanisms of HPVint, partially addressing the conflicting findings of whether HPVint is associated with aggressive phenotypes and worse clinical consequences, and provide potential biomarkers to advance precision oncology in HPV-associated HNSCC.
Multiple locomotion gaits in the mole cricket
Authors: Yuval Omer , Amir Avi , Ayali Amir 
Published: January 2025

AbstractInsects are exceptionally robust walkers. Although different species exhibit distinct anatomical and functional specializations, they are also highly adaptive within these constraints. How such adaptations enable insects to efficiently navigate diverse environments and perform mechanical tasks remains far from fully explored. The mole cricket, which dwells underground, is one of the least studied insects, largely due to its cryptic lifestyle. It excels at digging tunnels and exhibits extreme morphological adaptations, particularly its exceptional fossorial forelegs. Its versatile locomotion, above and below ground, makes the mole cricket an attractive model system for studying the biomechanics of insect movement. Here we provide the first quantitative characterization of mole cricket locomotion. Using a tunnel-like arena, we recorded freely-moving insects and analyzed their various locomotion gaits. We identified and described three main modes of locomotion, including a backward-bound gait that has not previously been reported in any insect. To test specific hypotheses regarding form-function relationships and the generation of thrust, we integrated biomechanical modeling and deep reinforcement learning to simulate the observed gaits. Our work opens several future directions, from exploring context-dependent gait transitions to bio-inspired technological innovations.