bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global Stability and Tipping Point Prediction of the cell fate decision making model
Authors: Xu Li , Wang Jin 
Published: December 2024

This study investigates global stability and tipping point prediction in cell fate decision-making systems through non-equilibrium landscape flux theory. We demonstrate that cell fate dynamics are governed by the interplay between potential landscape and curl flux, where the landscape guides systems toward stable states while curl flux mediates transitions between them.Our analysis reveals that non-zero curl flux generates irreversible dominant pathways between multi-stable states. We identify several quantitative measures for transition prediction, including barrier heights, kinetic switching times, entropy production rates, and average flux. We introduce novel non-equilibrium early warning indicators based on time irreversibility of cross-correlations (ΔC), average flux, and entropy production rate. These indicators exhibit significant changes near bifurcations, enabling transition prediction before state stability loss, with superior predictive capability compared to traditional critical slowing down theory.The rotational nature of curl flux is shown to destabilize attractor states, providing a dynamical foundation for phase transitions in cell differentiation, reprogramming, and transdifferentiation processes. These findings advance our understanding of non-equilibrium dynamics in cell fate decisions and offer practical implications for stem cell research and regenerative medicine, potentially enabling more precise therapeutic strategies in stem cell applications.
Bayesian Inference of NosocomialMethicillin-resistant Staphylococcus aureusTransmission Rates in an Urban Safety-Net Hospital
Authors: Corkran Kiel , Bani-Yaghoub Majid , Sutkin Gary , Arjmand Arash , Paschal Susanna 
Published: December 2024

AbstractMethicillin-resistantStaphylococcus aureus(MRSA) is a strain ofStaphylococcus aureusthat poses significant challenges in treatment and infection control within healthcare settings. Recent research suggests that the incidence of healthcare-associated MRSA (HA-MRSA) is higher among patients treated in safety-net hospitals compared to those in non-safety-net hospitals.This study aimed to identify HA-MRSA transmission patterns across various nursing units of a safety-net hospital to improve to enhance patient outcomes and facilitate the implementation of targeted infection control measures.A retrospective analysis was conducted using surveillance data from 2019 to 2023. A compartmental disease model was applied to estimate MRSA transmission rates and basic reproduction number (R0) for each nursing unit of an urban, multicenter safety-net hospital before and during the COVID-19 pandemic. Posterior probability distributions for transmission, isolation, and hospital discharge rates were computed using the Delayed Rejection Adaptive Metropolis (DRAM) Bayesian algorithm.Analysis of 187,040 patient records revealed that inpatient nursing units exhibited the highest MRSA transmission rates in three out of the five years studied. Notable transmission rates were observed in certain inpatient and progressive care units (0.55 per individual per month; 0.018 per individual per day) and the surgical ICU (0.44 per individual per month; 0.015 per individual per day). In contrast, the Nursery NICU and Medical ICU had the lowest transmission rates. Although MRSA transmission rates significantly declined across all units in 2021, these rates rebounded to pre-pandemic levels in subsequent years. Notably, outbreaks emerged in units such as ICUs and progressive care units that had not experienced prior MRSA outbreaks since 2019.While MRSA transmission significantly declined during the initial phase of the pandemic, the pathogen reestablished itself in later years. These findings highlight the need for sustained resources and adaptive infection control strategies to reduce the incidence of HA-MRSA in safety-net hospitals.
A Bi-Specific T Cell-Engaging Antibody Triggers Protective Immune Memory and Glioma Microenvironment Remodeling in Immune Competent Preclinical Models
Authors: Zannikou Markella , Duffy Joseph T. , Procissi Daniele , Najem Hinda J. , Levine Rebecca N. , Hambardzumyan Dolores , Lee-Chang Catalina , Leoni Lara , Horbinski Craig M. , Zhang Bin , Heimberger Amy B , Miska Jason M. , Balyasnikova Irina V 
Published: December 2024

AbstractBackgroundBispecific T cell-engagers (BTEs) are engineered antibodies that redirect T cells to target antigen-expressing tumors. BTEs targeting tumor-specific antigens such as interleukin 13 receptor alpha 2 (IL13Rα2) and EGFRvIII have been developed for glioblastoma (GBM). However, there is limited mechanistic understanding of the action of BTE since prior studies were mostly conducted in immunocompromised animal models. To close this gap, the function of BTEs was assessed in the immunosuppressive glioma microenvironment (TME) of orthotopic and genetically engineered mouse models (GEMM) with intact immune systems.MethodsA BTE that bridges CD3 epsilon on murine T cells to IL13Rα2-positive GBM cells was developed and the therapeutic mechanism investigated in immunocompetent mouse models of GBM. Multi-color flow cytometry, single-cell RNA sequencing (scRNA-Seq), multiplex immunofluorescence, and multiparametric magnetic resonance imaging (MRI) across multiple pre-clinical models of GBM were used to evaluate the mechanism and action and response.ResultsBTE-mediated interactions between murine T cells and GBM cells triggered T cell activation and antigen-dependent killing of GBM cells. BTE treatment significantly extended the survival of mice bearing IL13Rα2-expressing orthotopic glioma andde novoforming GBM in the GEMM. Quantified parametric MR imaging validated the survival data showing a reduction in glioma volume and decreased glioma viability. Flow cytometric and scRNA-seq analyses of the TME revealed robust increases in activated and memory T cells and decreases in immunosuppressive myeloid cells in the brains of mice following BTE treatment.ConclusionsOur data demonstrate that the survival benefits of BTEs in preclinical models of glioma are due to the ability to engage the host immune system in direct killing, induction of immunological memory, and modulation of the TME. These findings provide a deeper insight into the mechanism of BTE actions in GBM.WHAT IS ALREADY KNOWN ABOUT THIS TOPICBi-specific T cell engaging antibodies (BTEs) targeting IL13Rα2 and EGFRvIII have been developed and shown to activate T cells that mediate killing of glioma cellsin vitroand in in vivo.WHAT THIS STUDY ADDSBy using immune competent preclinical models, this study reveals that BTEs trigger in situ tumor immune memory within the central nervous system.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYInsights into the mechanism of action of BTEs inform response biomarkers that should be considered for inclusion in window-of-opportunity clinical trial assessments and for the rational selection of future combinatorial strategies.
Mechanism of catalytic apparatus of human chitotriosidase-1 and its dual inactivation mode by thefirst-in-classOATD-01 inhibitor
Authors: Niedzialek Dorota , Wieczorek Grzegorz , Drzewicka Katarzyna , Antosiewicz Anna , Milewski Mariusz , Bartoszewicz Agnieszka , Olczak Jacek , Zasłona Zbigniew 
Published: December 2024

AbstractDespite extensive research over the past three decades, there are still uncertainties regarding the catalytic mechanism of human chitotriosidase-1. To fill the gap, we reanalysed the structural information available for this enzyme. Based on the existing and new experimental data, complemented by multi-scale simulations, we modelled the full-length structure of human chitotriosidase-1 and proposed the general model of its catalytic mechanism. We have elucidated the catalytic role of the four highly conserved structural motifs present in glycoside hydrolases 18 family and demonstrated the impact of ions on achieving optimal catalytic conditions. Furthermore, we have identified distinct mechanical motions within the catalytic domain that collectively facilitate the catalysis. Finally, we demonstrate how subtle dynamical changes observed within the active site upon binding of the OATD-01 inhibitor correspond to long-range effects that are transmitted across enzyme subunits, leading to profound biological consequences.
Acute infectious mononucleosis generates persistent, functional EBNA-1 antibodies with high cross-reactivity to alpha crystalline beta
Authors: Ganta Krishna Kumar , McManus Margaret , Blanc Ross , Wang Qixin , Jung Wonyeong , Brody Robin , Carrington Mary , Paris Robert , Chandramouli Sumana , McNamara Ryan , Luzuriaga Katherine 
Published: December 2024

AbstractEpstein-Barr Virus (EBV) infects over 95% of the world’s population and is the most common cause of infectious mononucleosis (IM). Epidemiologic studies have linked EBV with certain cancers or autoimmune conditions, including multiple sclerosis (MS). Recent studies suggest that molecular mimicry between EBV proteins, particularly EBV nuclear antigen 1 (EBNA-1), and self-proteins is a plausible mechanism through which EBV infection may contribute to the development of autoimmune disorders. We used a systems immunology approach to investigate the magnitude, specificity, and functional properties of EBNA-1 specific antibodies in a cohort of 97 young adults with IM from presentation through 1-year post-primary infection compared to a control cohort of EBV-seropositive individuals. Levels of EBNA-1 specific IgG1 and IgG3 binding antibodies increased over the course of infection. EBNA-1 antibodies capable of mediating antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) were detected at or after 6 months. Binding and ADCP- and ADCD-leveraged antibodies primarily targeted a region of EBNA-1 known to elicit cross-reactive antibodies to several self-peptides in individuals with MS. Significantly higher binding and ADCD-active antibodies targeting EBNA-1 were observed in individuals with at least one HLA-DRB1*15:01 allele, a known genetic risk factor for MS; Importantly, high levels of antibodies capable of binding alpha crystalline beta (CRYAB) and mediating complement deposition were detected at 6 months and 1-year following IM; CRYAB antibodies were resistant to denaturing forces, indicating an affinity matured response. Blocking experiments confirmed that CRYAB antibodies were cross-reactive with EBNA-1. Altogether, these results demonstrate that high levels of functional antibodies targeting EBNA-1 are generated in early EBV infection, some of which are cross-reactive with CRYAB. Further investigation is warranted to determine how these antibody responses may contribute to the subsequent development of MS.
Continuous Titration Based Method For Rapid In-solution Analysis Of Non-covalent Interactions
Authors: Willmer Philipp , Hundahl Adam C. , Marie Rodolphe , Jensen Henrik 
Published: December 2024

ABSTRACTDevelopment of new drugs typically involves the identification and validation of molecular inhibitors or promotors of endogenous biological processes. The identification of ligands that can bind the target of interest is typically achieved by screening large libraries of small molecules, using analytical methods that only provide yes/no answers. These methods are only qualitative and often associated with unacceptable amounts of false positives and negatives. Quantitative methods are in general more accurate but time intensive. This is mainly due to repeating measurements of a dilution series in order to generate a titration curve and measure the dissociation constant (Kd). In this work, we introduce Continuous Titration Based Spectral Related Intensity Change (cSPRING), that combines Taylor dispersion analysis (TDA) with ratiometric fluorescence detection to measure aKdin a single experiment. cSPRING is an in-solution method that reduces the sample preparation time 8-fold and requires only nanograms of protein. We show a good agreement of cSPRING with other quantitative methods for three well-known protein-small molecule interactions with binding affinities ranging from the low nanomolar to high micromolar. In addition, we show that cSPRING is able to measure binding affinities in under a minute, highlighting its efficiency and potential for screening applications.
A Leadfield-Free Optimization Framework for Transcranially Applied Electric Currents
Authors: Weise Konstantin , Madsen Kristoffer H. , Worbs Torge , Knösche Thomas R. , Korshøj Anders , Thielscher Axel 
Published: December 2024

AbstractBackgroundTranscranial Electrical Stimulation (TES), Temporal Interference Stimulation (TIS), Electroconvulsive Therapy (ECT) and Tumor Treating Fields (TTFields) are based on the application of electric current patterns to the brain.ObjectiveThe optimal electrode positions, shapes and alignments for generating a desired current pattern in the brain vary between persons due to anatomical variability. The aim is to develop a flexible and efficient computational approach to determine individually optimal montages based on electric field simulations.MethodsWe propose a leadfield-free optimization framework that allows the electrodes to be placed freely on the head surface. It is designed for the optimization of montages with a low to moderate number of spatially extended electrodes or electrode arrays. Spatial overlaps are systematically prevented during optimization, enabling arbitrary electrode shapes and configurations. The approach supports maximizing the field intensity in target region-of-interests (ROI) and optimizing for a desired focality-intensity tradeoff.ResultsWe demonstrate montage optimization for standard two-electrode TES, focal center-surround TES, TIS, ECT and TTFields. Comparisons against reference simulations are used to validate the performance of the algorithm. The system requirements are kept moderate, allowing the optimization to run on regular notebooks and promoting its use in basic and clinical research.Conclusion(s)The new framework complements existing optimization methods that require small electrodes, a predetermined discretization of the electrode positions on the scalp and work best for multi-channel systems. It strongly extends the possibilities to optimize electrode montages towards application-specific aims and supports researchers in discovering innovative stimulation schemes. The framework is available in SimNIBS.
The genetic architecture of cortical similarity networks
Authors: Sebenius Isaac , Warrier Varun , Bethlehem Richard A.I. , Dear Richard , Stauffer Eva-Maria , Gu Yuanjun , Romero-Garcia Rafael , Seidlitz Jakob , Bullmore Edward , Morgan Sarah 
Published: December 2024

AbstractThe genetic architecture of human brain networks is central to understanding the organization and evolution of the cortex, the causal relationships between brain structure and function, and the pathogenesis of heritable neuropsychiatric disorders. However, the current understanding of the genetics of brain networks remains fragmented. Here, we investigated common genetic effects on Morphometric INverse Divergence (MIND), a biologically-validated, heritable, and multimodal MRI metric of inter-areal similarity and connectivity. Using a discovery dataset (N>30,000 adults), we estimated subject-specific MIND networks from the multivariate distributions of four MRI features at each of 23 cortical areas and performed genome-wide association studies (GWAS) at each of the 276 inter-areal edges. These edge-level genetic effects were highly replicated by parallel GWAS of an independent validation dataset (N>18,000 adults). We found that strong genetic correlations between multiple edges were largely reducible to two gradients of genetically-determined cortical similarity, each of which was aligned with geodesic distance from one of the two phylogenetically primitive areas (paleocortex and archicortex) predicted by the dual origin theory of cortical evolution. Genetic MIND gradients were more heritable than comparable gradients derived from GWAS of functional MRI connectivity networks; and the paleocortical trend was genetically correlated with, and causally predictive of, functional connectivity. Finally, we identified multiple global and local genetic correlations between both MIND gradients and nine clinical diagnoses or biomedical traits, indicating that the normative genetic architecture of human brain networks is pleiotropically associated with inherited risk of neuropsychiatric disorders and systemic metabolic and immune traits. These results provide fresh insight into the dual origins of the human cortex and their implications for brain function and health.
Exploring Meiosis in Brown Algae: Meiotic Axis Proteins in the model brown algaEctocarpus
Authors: Kane Emma I. , Trefs Lioba S. , Eckert Lena , Coelho Susana M. , Weir John R. 
Published: December 2024

AbstractMost extant eukaryotic systems share core meiosis-specific genes, suggesting meiosis evolved only once in the last eukaryotic common ancestor (LECA). These genes have been characterized as master regulators of meiotic recombination, ensuring genetically diverse lineages. However, our understanding is limited as eukaryotic organisms beyond the animal, plant, and yeast lineages remain poorly understood. Recently, core meiotic genes have been identified in the genome of the model brown algaEctocarpus, but currently lack proper characterization. Here, we combine bioinformatic, structural, and biochemical approaches to characterise the axial element orthologs, meioticEctocarpusHORMA domain protein (ecHOP1) and its interactor, reductional division protein 1 (ecRED1), in order to elucidate the molecular mechanisms of synaptonemal complex (SC) and double strand break (DSB) formation in brown algae. We highlight novel domain architecture within ecHOP1 and ecRED1 that support HORMA domain conformational switches and quantify the thermodynamic parameters of these interactions. Together, our data suggests that brown algae may employ alternative HORMA domain regulation mechanisms compared with animal, plant and yeast systems, and provide clues for future studies on the evolutionary constraints and adaptation of meiosis across the tree of life.
Cortical connectivity, local dynamics and stability correlates of global conscious states
Authors: Zhao Yun , Tsuchiya Naotsugu , Boley Mario , Liu Yueyang , Karoly Philippa J. , Pelentritou Andria , Woods William , Liley David , Kuhlmann Levin 
Published: December 2024

AbstractConsciousness emerges from complex neural processes, yet its precise neurobiological correlates remain uncertain. Here a space-time-resolved inference-based framework is applied to estimate the neurophysiological variables of a wholecortex model and analyze the neural mechanism correlates of global consciousness by way of a correlation analysis between behavioural and neural variable time-series. Using magnetoencephalography (MEG) data from 15 participants under Xenon-induced anesthesia, interconnected neural mass models (NMMs) were developed and time-evolving regional neurophysiological variables and inter-regional connectivity strengths were inferred from the data. Analyses revealed significant correlations between consciousness levels and inter-regional connectivity, particularly in posterior parietal, occipital, and prefrontal regions. Moreover, results support a parietal, rather than frontal, network backbone to facilitate global consciousness. Regional-level analyses further identified correlates of consciousness within the posterior parietal and occipital regions. Lastly, reductions in consciousness were linked to stabilized cortical dynamics, reflected by changes in the eigenmodes of the system. This framework provides a novel, inference-based approach to investigating consciousness, offering a time-resolved perspective on neural mechanism correlates during altered states.
Recurrence patterns in a large contemporary cohort of patients with non-muscle invasive bladder cancer
Authors: Hof Jasper P. , Kiemeney Lambertus A. , Aben Katja K.H. , van der Heijden Antoine G. , Vrieling Alina , Vermeulen Sita H. 
Published: December 2024

AbstractBackground and ObjectivePatients with non-muscle invasive bladder cancer (NMIBC) frequently experience recurrences, yet, the timing and characteristics of subsequent recurrences are understudied. We aim to describe subsequent recurrences in a large, contemporary, population-based cohort.MethodsWe included 1,915 patients from the UroLife study and the Nijmegen Bladder Cancer Study, diagnosed with primary NMIBC between 2011 and 2021. The conditional 1-, 3- and 5-year risks of first to fourth recurrence were calculated using Kaplan-Meier risks, stratified by clinicopathological factors. Patterns of subsequent tumours were described and visualised.Key Findings and LimitationsWe observed 671 first recurrences and 400 subsequent recurrences. The 3-year conditional recurrence risks for first, second and third recurrence were 31%, 45% and 54%, respectively, and were similar for NMIBC risk groups. Recurrence after a low-, intermediate- or high-risk tumour (either primary or recurrent) was again of low-, intermediate- or high-risk in 74%, 62% and 44% of cases, respectively. Ten patients with low/intermediate-risk NMIBC and 89 patients with high-risk NMIBC progressed to muscle-invasive or metastatic bladder cancer. Seven out of these ten (70%) and 13 out of these 89 (15%) patients had a high-risk recurrence before progression. This study was limited to a patient cohort from The Netherlands.Conclusions and Clinical ImplicationsOur study provides novel and reliable estimates of recurrence rates and patterns in NMIBC from a large, contemporary, population-based cohort. Recurring NMIBC tumours often exhibit similar clinicopathological characteristics, and patients with primary low- or intermediate-risk NMIBC who progress to MIBC/mBC often have a high-risk recurrence before progression. These results can inform research into NMIBC recurrences and surveillance schedules.