bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homeodomain protein Sxi1α regulates cell-cell fusion during distinct sexual reproduction modes inCryptococcus deneoformans
Authors: Huang Jun , Peterson Patricia P. , Xu Ziyan , Xiong Liping , Sun Sheng , Heitman Joseph 
Published: February 2025

AbstractSex-specific homeodomain (HD) proteins are key regulators of cell identity and sexual development in fungi, typically functioning as heterodimers to regulate transcription. In the human fungal pathogensCryptococcus neoformansandCryptococcus deneoformans, theHDproteins Sxi1α and Sxi2a(sex-induced 1α and 2a) have been characterized as interacting partners that play critical roles in sexual development duringax α sexual reproduction. Given the dominance of α cells in natural populations ofCryptococcus, the roles of Sxi1α and Sxi2ain unisexual reproduction, which predominantly involves same-sex (α x α) mating, remain unclear. To elucidate the functions of Sxi1α and Sxi2ain unisexual reproduction, we first used AlphaFold3 to predict their structures, which revealed the potential for both heterodimeric and homodimeric complexes. We subsequently deletedSXI1α andSXI2ain the hyperfilamentous self-fertileC. deneoformansstrains XL280aand XL280α. Disruption of these genes did not result in noticeable defects in vegetative growth, virulence-associated traits, colony morphology, sporulation, or competitiveness during eitherax α or α x α crosses. Surprisingly, the absence ofSXI1α significantly increased the cell–cell fusion rate during both α x α andax α mating, suggesting a novel inhibitory role for Sxi1α, independent of the partner Sxi2a. Together, our findings revealed an unexpected function of Sxi1α in regulating cell fusion, which may contribute to the predominance ofMATα isolates in globalCryptococcuspopulations and the conservation ofSXI1α in a population that is predominantly α mating type.
Exploring the causal role of the human gut microbiome in breast cancer risk
Authors: Edmunds Grace L. , Robinson Tim , Yarmolinsky James , Lee Matthew A , Hayes Bryony , Hughes David A , Gibbs Lara , Braybrooke Jeremy P. , Raes Jeroen , Timpson Nicholas J. , Wade Kaitlin H. 
Published: February 2025

ABSTRACTThe relationship between the human gut microbiome and breast cancer (BC) risk is uncertain. We used Mendelian randomization (MR) and multivariable linear regression to investigate the causal relationship between the human gut microbiome and BC risk (overall and subtype-specific) and interrogate the role of circulating metabolites as potential mediators. Summary-level data from genome-wide association studies of gut microbial traits (N=3,890), circulating metabolites (N=7,824), overall (N=247,175) and subtype-specific (N=200,898) BC risk, including triple negative BC (TNBC; N=120,493), alongside individual-level data from the Flemish Gut Flora Project (N=2,242). Sensitivity analyses were applied to examine the robustness of causal estimates. Initial two-sample MR analyses suggested that the presence of bacteria within theRuminococcusgenus increased overall BC risk, that higher abundances of bacteria within theParabacteroidesgenus decreased and presence of unclassified bacteria within theBacteroidalesorder increased TNBC risk, and that several circulating metabolites altered BC risk (e.g., homostachydrine with overall BC and Luminal A BC, and betaine with TNBC). Whilst, in multivariable linear regression analyses, several of these metabolites were also associated with the microbial traits that influenced BC risk, importantly, given directional inconsistency of associations across analyses of microbial traits, metabolites and BC coupled with sensitivity analyses implying violations of MR assumptions, associations were unlikely to reflect causality nor a causal pathway between the gut microbiome, metabolites, and BC risk.
mRNA-LNP vaccines against Hepatitis B virus induce protective immune responses in preventive and chronic mouse challenge models
Authors: Limeres María José , Gambaro Rocio , Svensson Malin , Fraude-El Ghazi Silvia , Pretsch Leah , Frank Daniel , Islan German A. , Rivero Berti Ignacio , Bros Matthias , Tam Ying K. , Muramatsu Hiromi , Pardi Norbert , Gehring Stephan , Cacicedo Maximiliano L. 
Published: February 2025

AbstractOver 300 million people worldwide suffer from chronic hepatitis B virus infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic disease. This study investigated lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines encoding Hepatitis B surface antigen (HBsAg) for prophylactic and therapeutic applications. We found that HBsAg mRNA-LNP vaccines induced robust humoral and cellular immune responses, outperforming the protein-based vaccine approved for human use. The incorporation of an MHC class I signal peptide further enhanced Th1-biased responses preventing HBV infections in a mouse model. Importantly, mRNA-LNP vaccination led to seroconversion, HBsAg clearance, and strong T cell responses in a chronically infected mouse model. These findings highlight the potential of mRNA-LNP as an alternative and effective vaccine modality for HBV prophylaxis and therapeutic use in treating chronic infections.
Unravelling the Core and Accessory Genome Diversity ofEnterobacteriaceaein Carbon Metabolism
Authors: Näpflin Nicolas , Schubert Christopher , Malfertheiner Lukas , Hardt Wolf-Dietrich , von Mering Christian 
Published: February 2025

AbstractEnterobacteriaceaeare commonly colonizing animal guts and impact health. While strain-specific metabolic features can promote gut colonization, we lack systematic knowledge regarding metabolic diversity and the core metabolism shared amongEnterobacteriaceae. To address this gap, we have analyzed the pan-genome of nearly 20,000 genomes. We found that genes necessary for monosaccharide-fuelled mixed acid fermentation are part of theEnterobacteriaceaecore genome, while most genes for anaerobic respiration and most carbohydrate utilization genes belong to the accessory genome. UnderstandingEnterobacteriaceae’smetabolic capacity helps clarify the distinction of nutrients consumed by allEnterobacteriaceae, and niche-defining nutrient sources, which are genus-, species- or strain-specific. This knowledge sheds light on bacterial nutrient exploitation during gut colonization in health and disease, aiding in the development of targeted interventions for microbiome research and infectious disease control. The theoretical framework described here can also be adapted to analyze core physiological characteristics of other microbiota taxa.
Moremi Bio Agent: Application of A Foundation Model and End-to-End Automation in the Design and Validation of Monoclonal Antibodies TargetingPlasmodium falciparumInvasion Complex
Authors: Akogo Darlington , Ayensu Jeremiah , Sam Nana , Hattoh Gertrude , Nyarko Prince , Eshun Solomon , Alhasan Mohammed , Mensah-Brown Henrietta , Quashie Peter 
Published: February 2025

AbstractMalaria remains a significant global health challenge, withPlasmodium falciparumresponsible for the majority of severe cases and fatalities. Targeting the parasite’s invasion mechanisms offers a promising therapeutic strategy. In this study, we leveraged a novel agentic foundational model, Moremi Bio Agent, to design monoclonal antibodies targeting the AMA1-RON2 complex, a critical component in the parasite’s invasion of human red blood cells. Using advanced structural modeling, we generated 999 antibodies, which were evaluated for binding affinity, structural integrity, and physicochemical properties. Binding affinity analysis using PRODIGY identified 864 antibodies with successful target interactions, exhibiting binding free energies (ΔG) ranging from -116.8 kcal/mol to -5.6 kcal/mol. The strongest candidates demonstrated exceptionally tight binding, with dissociation constants (Kd) in the femtomolar to attomolar range, indicative of highly stable interactions. Additionally, structural validation confirmed that the antibodies were thermodynamically stable with robust fold reliability, essential for functional efficacy. Epitope mapping revealed highly conserved regions within the target complex, enhancing the likelihood of cross-strain efficacy. Glycosylation analysis identified key sites that could improve antibody stability and immune recognition, while BLAST comparison with known therapeutic antibodies demonstrated significant homology, underscoring their potential for clinical development. This study highlights the power of generative AI-driven computational pipelines in antibody discovery, providing a scalable and cost-effective framework for therapeutic development. The findings establish a foundation for experimental validation and optimization, with the potential to advance novel interventions against malaria and other infectious diseases.
WITHDRAWN: SA55 broadly neutralizes SARS-CoV-2 and robustly prevents viral escape by JN.1 sublineages
Authors: Shi Lanfang , Bowen Anthony , Han Juan , Zheng Xinhao , Luo Hongwei , Yao Tianjiao , Guo Ming , Yu Yuanling , Jian Fanchong , Cao Yunlong , Lan Ke , Guo Yicheng , Liu Lihong 
Published: February 2025

Withdrawal StatementThe authors have withdrawn this manuscript because of a conflict of interest. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Video-evoked neuromarkers of visual function in age-related macular degeneration
Authors: Renton Angela I. , Klein David J. , Livezey Jesse A. , Nemrodov Dan , Wolfer Stephanie , Hanina Adam , Van De Ville Dimitri 
Published: February 2025

ABSTRACTNeural markers of visual function in age-related macular degeneration (AMD) allow clinicians and researchers to directly evaluate the functional changes in visual processing which occur as a result of the progressive loss of afferent input from the macula. Unfortunately, few protocols exist that elicit such neural markers, and most of these are poorly adapted to AMD. Here, we propose a novel method of embedding frequency tags into full colour and motion videos by periodically manipulating the contrast of visual information of different spatial frequencies at different temporal frequencies. These videos elicit steady-state visual evoked potentials (SSVEPS) in viewers which, when measured using electrophysiological neuroimaging methods, independently represent the responses of populations of neurons tuned to the tagged spatial frequencies. We used electroencephalography (EEG) to record the SSVEPs of 15 AMD patients and 16 age-matched healthy controls watching a 6-minute series of natural scene videos filtered with this spatial frequency tagging method. Compared with healthy controls, AMD patients showed a lower SSVEP response to high spatial frequency information, and a stronger response to the low spatial frequency information in the video set. The ratio of the SSVEP response to lower relative to higher spatial frequency information was strongly predictive of both visual acuity and contrast sensitivity, and the topographic distributions of these responses suggested retinotopic reorganisation of the neural response to spatial frequency information.
MYRF is Essential in Mesothelial Cells to Promote Lung Development and Maturation
Authors: Luna Gidsela , Verheyden Jamie , Tan Chunting , Kim Estelle , Hwa Michelle , Sahi Jugraj , Shen Yufeng , Chung Wendy , McCulley David , Sun Xin 
Published: February 2025

SummaryThe mesothelium is a squamous monolayer that ensheathes internal organs, lines the body cavity, and the diaphragm. It serves as a protective barrier, coated in glycocalyx, and secretes lubricants to facilitate tissue movement. How the mesothelium forms is poorly understood. Here, we investigateMyrf, a transcription factor gene expressed in the mesothelium, because it carries variants in patients with Congenital Diaphragmatic Hernia (CDH), a disorder that affects the diaphragm, lung, and other organs. In mice, inactivation ofMyrfearly in organogenesis resulted in CDH and defective mesothelial specification, compromising its function as a signaling center for lung growth. Inactivation ofMyrflater led to enhanced mesothelium differentiation into mesenchymal cell types through partial epithelial-to-mesenchymal transition (EMT), resulting in a unique accumulation of smooth muscle encasing the lung. In this role, MYRF functions in parallel with YAP/TAZ. Together, these findings establish MYRF as a critical regulator of mesothelium development, and when mutated, causes CDH.
Pharmacophore modeling, 2D-QSAR, Molecular Docking and ADME studies for the discovery of inhibitors of PBP2a in MRSA
Authors: Mutie Musila Fredrick , Gitau Grace Wairimu , Amwayi Peris Wanza , Kingoo James Munyao , Kinyanyi Dickson Bennet , Njeru Patrisio Njiru 
Published: February 2025

AbstractMethicillin-resistantStaphylococcus aureus(MRSA) is considered to be a worldwide threat to human health and the global spread of MRSA has been associated with the emergence of different types of infections and resultant selection pressure due to exposure to many antibiotics. In the current era characterized by incessant antibiotic resistance, assessment of multiple molecular targets represents notable therapeutic opportunities in the medical and pharmaceutical industry and can aid in the discovery of novel molecules that inhibit various receptors effectively to replace the current weak antimicrobial agents. Penicillin binding protein 2a (PBP2a) of MRSA is a major determinant of resistance to β-lactam antibiotics. The activity of PBP2a is not inhibited by β-lactam antibiotics, allowing the strain to survive in the presence of β-lactams leading to resistance to β-lactam antibiotics. The study aimed at identifying potential inhibitors of PBP2a receptor of MRSA through ligand-based pharmacophore modeling, 2D-QSAR, structure-based drug design docking and molecular dynamic (MD) simulations. The study led to the development of a satisfactory, predictive and significant 2D-QSAR model for predicting anti-MRSA activity of compounds and also led to the identification of two molecules: C21H25N7O4S2(ChEMBL30602) and C20H17NO6S (ChEMBL304837) with favorable pharmacophore features and ADME properties with potential to bind strongly to PBP2a receptor of MRSA. MD simulation analysis showed that the interactions of C20H17NO6S (ChEMBL304837) with PBP2a over 100 ns was more stable and similar to the interaction of ceftobiprole with PBP2a and may become potential drug candidate against MRSA which has developed a lot of resistance to current antibiotics.
Systematic Metaproteomics Mapping Reveals Functional and Ecological Landscapes of Human Gut Microbiota Responses to Therapeutic Drugs
Authors: Li Leyuan , Simopoulos Caitlin M.A. , Mayne Janice , Ning Zhibin , Zhang Xin , Hamada Mona , Butcher James , Serrana Joeselle M. , Wang Luman , Cheng Kai , Qin Hongye , Walker Krystal , Zhang Xu , Stintzi Alain , Figeys Daniel 
Published: February 2025

SUMMARYTherapeutic compounds significantly alter the composition of the gut microbiota, yet their functional and ecological impacts, particularly at the protein level, remain largely unexplored. In this study, we systematically mapped metaproteomic responses ofex vivohuman gut microbiota to 312 compounds, generating 4.6 million microbial protein responses, available as an interactive resource (https://shiny.imetalab.ca/MPR_Viz/). Across protein-level, taxonomic composition-level, and ecosystem-level analyses, we simultaneously identified metaproteomic shifts in 47 compounds, a tri-stability taxonomic landscape, and, using our PhyloFunc beta-diversity metric, three distinct functional community state types with cross-individual ecological consistency. Notably, neuropharmaceuticals triggered profound metaproteomic alterations, marked by a decline in functional redundancy (FR) and an increase in antimicrobial resistance proteins (ARPs), shifting the community to alternative functional state on the functional landscape. We validated that enhancing FR maintained a microbiota’s resilience against neuropharmaceutical-induced ARP increase. These findings establish a novel landscape-based framework for understanding microbiome resilience and advancing targeted therapeutic interventions.
Transcranial Magnetic Stimulation Reduces Non-Decision Time in Perceptual Decisions
Authors: Gordleeva Susanna , Maksimenko Vladimir , Mohammad Usama , Grigoriev Nikita , Savosenkov Andrey , Kuc Alexander , Kurkin Semen , Udoratina Anna , Grubov Vadim , Hramov Alexander 
Published: February 2025

AbstractPerceptual decision-making enables humans to process sensory information and translate it into goal-directed actions. A critical component of this process is response time, which declines with age due to the slowing of both non-decision processes and evidence accumulation. While perceptual learning has been shown to counteract these declines, it remains unclear whether non-decision processes can be accelerated through direct neural stimulation, bypassing the need for long training sessions. Here, we propose that Transcranial Magnetic Stimulation (TMS) can enhance perceptual decision-making by specifically reducing non-decision time. To test this hypothesis, we tracked response times during a perceptual learning task while recording brain activity. Using the Drift Diffusion Model, we quantified the effects of TMS on mental speed and non-decision time. Our findings reveal that perceptual learning decreases response time by simultaneously increasing mental speed and reducing non-decision time. Crucially, TMS application to brain regions associated with perceptual learning further shortened non-decision time without altering mental speed. These results demonstrate that TMS can selectively accelerate non-decision processes, offering a promising intervention for mitigating age-related cognitive slowing and enhancing decision efficiency.Significance StatementPerceptual decision-making is a fundamental cognitive process that slows with age due to declines in both non-decision processes and mental speed. While perceptual learning can mitigate these declines through practice, we propose that non-decision time can also be reduced by directly stimulating neural ensembles using Transcranial Magnetic Stimulation (TMS). Our study demonstrates that TMS applied to task-relevant brain areas decreases non-decision time, thereby accelerating response speed without affecting mental speed. These findings reveal a novel mechanism for enhancing perceptual decision-making efficiency and highlight TMS as a potential tool for counteracting age-related cognitive slowing.
Design of Protein Sequences with Precisely Tuned Kinetic Properties
Authors: Brotzakis Z. Faidon , Vendruscolo Michele , Skretas Georgios 
Published: February 2025

AbstractRecent advances in computational biology have enabled solutions to the inverse folding problem - finding an amino acid sequence that folds into a target structure. An open question concerns the design of proteins that in addition to having the correct target structure also have precisely tuned kinetic properties, such as folding and unfolding rates. To address this problem, we formulate the inverse folding problem as a quest for a sequence with a target free energy landscape. To propose a procedure to address this problem, here we describe the Inverse Folding Molecular Dynamics (IF-MD) method, which combines inverse folding with enhanced sampling molecular dynamics and Bayesian optimization. IF-MD leverages ensemble averages from molecular dynamics simulations, reweighted according to a Bayesian framework, to guide the design of sequences exhibiting specific kinetic properties. We demonstrate the methodology by optisising the binding kinetics of H11, a nanobody against the SARS-CoV-2 spike receptor-binding domain (RBD), thus identifying nanobody variants with slower unbinding kinetics than H11. Mechanistic analysis reveals that this kinetic property arises from a shift towards configurations closer to the bound state and increased free energy barriers for dissociation. These findings highlight the power of IF-MD for efficiently navigating the vast sequence space to design proteins with a tailored free energy landscape.
CRISPR/Cas9-mediated elimination of theLMNAc.745C>G pathogenic mutation enhances survival and cardiac function inLMNA-associated congenital muscular dystrophy
Authors: Gómez-Domínguez Déborah , Epifano Carolina , Hernández Iván , Vilaplana-Martí Borja , Cesar Sergi , de Molina-Iracheta Antonio , Sena-Esteves Miguel , Sarquella-Brugada Georgia , Pérez de Castro Ignacio 
Published: February 2025

ABSTRACTLMNA-associated congenital muscular dystrophy is a currently incurable rare genetic disorder characterized by early-onset muscle weakness, dilated cardiomyopathy and respiratory failure, resulting from mutations in theLMNAgene. In this study, we assessed the potential of a CRISPR-mediated strategy to eliminate the mutant alleleLmnac.745C>T, p.R249W using a mutation specific guide (sg745T). Results from R249W-mutation-carrying cellular models showed specific activity of the Cas9/sg745T complex towards the mutant allele. This property varied depending on the concentration of CRISPR components, with a loss of specificity observed with increased dosage. We tested this strategyin vivousing adeno-associated virus delivery inLmnaR249Wmice. Despite being associated with a modest CRISPR activity, this therapeutic approach resulted in a 10% increase in the survival of R249W homozygous mice. Interestingly, a similar CRISPR activity improved the cardiac pathology developed byLmna+/R249Wanimals, significantly extending their median survival. These results represent the first therapeutic validation of a CRISPR/Cas9-mediated gene editing strategy for the treatment ofLMNA-associated congenital muscular dystrophy.
Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration
Authors: Maddineni Prabhavathi , Kodati Bindu , Kaipa Balasankara Reddy , Kesavan Karthikeyan , Cameron Millar J , Yacoub Sam , Kasetti Ramesh B , Clark Abbot F , Zode Gulab S 
Published: February 2025

AbstractProgressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve axons are the pathological hallmarks of glaucoma. Ocular hypertension (OHT) and mitochondrial dysfunction are linked to neurodegeneration and vision loss in glaucoma. However, the exact mechanism of mitochondrial dysfunction leading to glaucomatous neurodegeneration is poorly understood. Using multiple mouse models of OHT and human eyes from normal and glaucoma donors, we show that OHT induces impaired mitophagy in RGCs, resulting in the accumulation of dysfunctional mitochondria and contributing to glaucomatous neurodegeneration. Using mitophagy reporter mice, we show that impaired mitophagy precedes glaucomatous neurodegeneration. Notably, the pharmacological rescue of impaired mitophagy via Torin-2 or genetic upregulation of RGC-specific Parkin expression restores the structural and functional integrity of RGCs and their axons in mouse models of glaucoma andex-vivohuman retinal-explant cultures. Our study indicates that impaired mitophagy contributes to mitochondrial dysfunction and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing mitophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration.Graphical Abstract