bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered AP-1, RUNX and EGR chromatin dynamics drive fibrotic lung disease
Authors: Valenzi Eleanor , Jia Minxue , Gerges Peter , Fan Jingyu , Tabib Tracy , Behara Rithika , Zhou Yuechen , Sembrat John , Das Jishnu , Benos Panayiotis V , Singh Harinder , Lafyatis Robert 
Published: October 2024

AbstractPulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1himacrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs. The neural network tool ChromBPNet inferred increased TF binding at single base pair resolution to profibrotic genes, including CTHRC1 and ADAM12, in fibroblasts and SPP1 and CCL18 in macrophages. The novel algorithm HALO confirmed AP-1, RUNX, and EGR TF activity controlling profibrotic gene programs and established TF-regulatory element-gene networks. This TF action atlas provides comprehensive insights into the transcriptional regulation of fibroblasts and macrophages in healthy and fibrotic human lungs.
Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer
Authors: Thomas-Jardin Shayna , Suresh Shruthy , Arce Ariana , Novaresi Nicole , Stein Emily , Thomas Lisa , Lewis Cheryl , Ahn Chul , Evers Bret M. , Salvatierra Maria E. , Lui Wei , Khan Khaja , Soto Luisa Maris Solis , Wistuba Ignacio , Minna John D. , O’Donnell Kathryn A. 
Published: October 2024

AbstractThe integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames (uORFs) in their 5′ UTRs. Analysis of primary human lung tumors identifies a significant correlation between PD-L1 and CD155 expression. ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 blockade with the ISR inhibitor ISRIB. These studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients.Statement of SignificanceThis study uncovers a novel mechanism for the coordinated translational regulation of the PD- L1/PD1 and CD155/TIGIT immune checkpoint pathways and highlights the ISR as a therapeutic vulnerability for lung cancer. Inhibition of the ISR pathway bolsters PD-1 blockade, potentially unveiling a new therapeutic strategy for lung cancer patients.
Probing Biomass Precursor Synthesis as a Key Factor in Microbial Adaptation to Unadapted Carbon Sources
Authors: Cai Jingyi , Liu Jiayu , Wei Fan , Wu Wenjun , Xu Wenqi , Mao Zhitao , Yuan Qianqian , Ma Hongwu 
Published: October 2024

SUMMARYIndustrial microorganisms often face challenges in utilizing renewable substrates such as methanol, formate, and xylose. We present findings that the proportion of biomass precursors that must be synthesized from unadapted carbon sources is a critical determinant of the evolutionary driving force and minimal substrate requirements, using a new computational framework, AdaptUC. We predict metabolic engineering strategies for Adaptive Laboratory Evolution (ALE). These strategies enable microorganisms to co-utilize an adapted co-substrate and an unadapted carbon source or, in some cases, rely exclusively on the unadapted source. AdaptUC was validated through experimental records and literature, confirming its effectiveness in identifying gene knockout strategies. Case studies inEscherichia coliandCorynebacterium glutamicumhighlight superior strategies with higher driving forces and reduced substrate requirements. This method has the potential to transform industrial biosynthesis by enabling more efficient use of renewable carbon sources.Graphic Abstract
Endothelial cell stiffness and type drive the formation of biomechanically-induced transcellular pores
Authors: Siadat Seyed Mohammad , Li Haiyan , Millette Brigid A. , Safa Babak N. , Wong Cydney A. , Fard M. Reza Bahrani , Braakman Sietse T , Tay Ian , Bertrand Jacques A. , Read A. Thomas , Schildmeyer Lisa A. , Perkumas Kristin M. , Stamer W. Daniel , Overby Darryl R. , Ethier C. Ross 
Published: October 2024

AbstractFormation of transcellular pores facilitates the transport of materials across endothelial barriers. In Schlemm’s canal (SC) endothelium, impaired pore formation is associated with glaucoma. However, our understanding of the cellular processes responsible for pore formation is limited by lack ofin vitroassays. Here, we present a novel platform for studying transcellular pore formation in human endothelial cells. We induced pores in SC cells by seeding them atop micron-sized magnetic beads followed by application of a magnetic field to subject cells to a basal to apical force, mimickingin vivobiomechanical forces. The pore formation process was dynamic, with pores opening and closing. Glaucomatous cells exhibited impaired pore formation that correlated with their increased stiffness. We further discovered that application of forces from the apical to basal direction did not induce pores in SC cells but resulted in formation of pores in other types of endothelial cells. Our studies reveal the central role of cell mechanics in formation of transcellular pores in endothelial cells, and provide a new approach for investigating their associated underlying mechanism/s.
CpGPT: a Foundation Model for DNA Methylation
Authors: de Lima Camillo Lucas Paulo , Sehgal Raghav , Armstrong Jenel , Higgins-Chen Albert T. , Horvath Steve , Wang Bo 
Published: October 2024

AbstractDNA methylation is a critical epigenetic modification that regulates gene expression and plays a significant role in development and disease processes. Here, we present the Cytosine-phosphate-Guanine Pretrained Transformer (CpGPT), a novel foundation model pretrained on over 1,500 DNA methylation datasets encompassing over 100,000 samples from diverse tissues and conditions. CpGPT leverages an improved transformer architecture to learn comprehensive representations of methylation patterns, allowing it to impute and reconstruct genome-wide methylation profiles from limited input data. By capturing sequence, positional, and epigenetic contexts, CpGPT outperforms specialized models when finetuned for aging-related tasks, including chronological age prediction, mortality risk, and morbidity assessments. The model is highly adaptable across different methylation platforms and tissue types. Furthermore, analysis of sample-specific attention weights enables the identification of the most influential CpG sites for individual predictions. As a foundation model, CpGPT sets a new benchmark for DNA methylation analysis, achieving strong performance in the Biomarkers of Aging Challenge, where it placed second overall in chronological age estimation and first on the public leaderboard in methylation-based mortality prediction.HighlightsCpGPT is a novel foundation model for DNA methylation analysis, pretrained on over 1,500 datasets encompassing 100,000+ samples.The model demonstrates strong performance in zero-shot tasks including imputation, array conversion, and reference mapping.CpGPT achieves state-of-the-art results in mortality prediction and chronological age estimation.Sample-specific interpretability is enabled through analysis of attention weights.
Hypermut 3: Identifying specific mutational patterns in a defined nucleotide context that allows multistate characters
Authors: Lapp Zena , Yoon Hyejin , Foley Brian , Leitner Thomas 
Published: October 2024

AbstractSummaryThe detection of APOBEC3F- and APOBEC3G-induced mutations in virus sequences is useful for identifying hypermutated sequences. These sequences are not representative of viral evolution and can therefore alter the results of downstream sequence analyses if included. We previously published the software Hypermut, which detects hypermutation events in sequences relative to a reference. Two versions of this method are available as a webtool. Neither of these methods consider multistate characters or gaps in the sequence alignment. Here, we present an updated, user-friendly web and command-line version of Hypermut with functionality to handle multistate characters and gaps in the sequence alignment. This tool allows for straightforward integration of hypermutation detection into sequence analysis pipelines. As with the previous tool, while the main purpose is to identify G to A hypermutation events, any mutational pattern and context can be specified.Availability and implementationHypermut 3 is written in Python 3. It is available as a command-line tool athttps://github.com/MolEvolEpid/hypermut3and as a webtool athttps://www.hiv.lanl.gov/content/sequence/HYPERMUT/hypermutv3.html.Contacttkl@lanl.govorseq-info@lanl.gov
Structural and functional insights into nuclear role of Parkinson’s Disease-associated α-Synuclein
Authors: Jos Sneha , Kambaru Archanalakshmi , Prasad Thazhe Kootteri , Parthasarathi Shylaja , Kamariah Neelagandan , Nath Sangeeta , Padmanabhan Balasundaram , Padavattan Sivaraman 
Published: October 2024

ABSTRACTα-Synuclein (αSyn) plays a critical role in the pathogenesis of ‘Synucleinopathies’. Although increased nuclear αSyn localization induces neurotoxicity, its definitive physiological role remains elusive. Previous studies on nuclear αSyn are limited to its interactions with individual histones and dsDNA, leaving a significant gap in understanding its interactions with assembled histone H2a-H2b dimer and (H3-H4)2tetramer, as well as its role in chromatin regulation. Here, we demonstrated that αSyn binds specifically to both H2a-H2b and (H3-H4)2with high affinity. Truncation studies revealed that αSyn(1-103) region interacts with (H3-H4)2, while the acidic (121-140) C-terminal end is crucial for H2a-H2b binding. Sequence analysis suggests αSyn-dimer binding region contains a conserved DEF/YxP motif present in other dimer-binding histone chaperones. High-resolution structure of αSyn- dimer binding region with H2a-H2b complex reveals that αSyn adopts two binding modes (BM1 and BM2). In BM-1, αSyn utilizes nucleosomal DNA-binding surface, while in BM-2, it engages with both DNA- and the H3-interaction interface. Additionally, dimer recognition by αSyn overlaps with other dimer-binding histone chaperones, suggesting αSyn’s potential role in the nucleosome assembly/disassembly process.
Tumor-specific antibodies elicited by engineered bacteria promote bladder cancer immunotherapy
Authors: Rouanne Mathieu , Chen Noah , Mariuzza Dylan L. , Li Fangda , de los Santos-Alexis Kenia , Savage Thomas M. , Vincent Rosa L. , Mendelsohn Cathy L. , Danino Tal , Arpaia Nicholas 
Published: October 2024

AbstractThe intratumoral microbiome has recently emerged as a new hallmark of cancer, with implications for response or resistance to therapy. While bacteria can either promote or inhibit cancer growth, intratumoral bacteria can also be engineered using synthetic biology to remodel the tumor microenvironment. Here, we engineered the probiotic bacteriumE. coliNissle 1917 (EcN) to express the human chemokine CXCL13, a critical component of germinal center (GC) formation. The GC reaction is a fundamental aspect of adaptive immunity by which antibody affinity develops in secondary lymphoid organs for defense against pathogens. Using orthotopic models of bladder cancer, engineered CXCL13-expressing EcN colonized bladder tumors and elicited GC responses in bladder tumor–draining lymph nodes after intravesical delivery. Furthermore, when combined with PD-1 blockade, engineered EcN amplified the antitumor antibody response and promoted long-term survival and protective immunity upon tumor rechallenge. Thus, we demonstrate that synthetically engineered CXCL13-expressing EcN can enhance the efficacy of PD-1 checkpoint blockade immunotherapy by amplifying tumor-specific humoral immunity.
Scalable Fabrication of a Tough and Recyclable Spore-Bearing Biocomposite Thermoplastic Polyurethane
Authors: Kim Han Sol , White Evan M. , Crane Grant , Patel Kush , Noh Myung Hyun , Rahman Md Arifur , Feist Adam M. , Locklin Jason J. , Pokorski Jonathan K. 
Published: October 2024

AbstractThermoplastic polyurethanes (TPUs) are a class of versatile thermoplastic elastomers where most of their products lack a proper recycling strategy or have no end-of-life solutions. To pursue a sustainable end-of-life solution for TPU based products, self-disintegrating biocomposite TPUs have recently been developed by embedding spores of TPU-degrading bacteria into TPUs using melt extrusion. Herein, we improve upon spore-bearing biocomposites and demonstrate industrially-relevant manufacturing conditions for the fabrication of biocomposite TPUs. Spore production was modified to reduce the innate brown color of the resulting materials and, effectively minimize the coloration of biocomposite TPUs. Reduction of FeSO4in a sporulation media generated white spores without compromising spore productivity, viability, morphology or heat-shock tolerance. Biocomposite TPUs containing white spores displayed a 45% increase in toughness compared to TPUs without spores, while retaining ∼90% spore viability post processing. Furthermore, biocomposite TPU fabrication was demonstrated using a scalable continuous extruder followed by injection molding. Biocomposite TPUs generated by these industry-relevant processes exhibited comparable toughness improvement and spore viability to biocomposite TPU prepared using a lab scale microcompounder, while enhancing productivity by 30-fold. Finally, spore addition improved biocomposite TPUs recyclability, enabling 80% toughness retention after 5 rounds of iterative melt processing. Additionally, no negative effect on the lifespan of the generated TPUs was observed over a duration of 1 year of storage. Overall, this study confirmed that spore-bearing biocomposite TPUs are promising for practical applications, offering an accessible method to enhance toughness and sustainability of commercial TPUs through the incorporation of spore-based living fillers.
Towards Robust Evaluation of Protein Generative Models: A Systematic Analysis of Metrics
Authors: Strashnov Pavel , Shevtsov Andrey , Meshchaninov Viacheslav , Ivanova Maria , Nikolaev Fedor , Kardymon Olga , Vetrov Dmitry 
Published: October 2024

AbstractThe rapid advancement of protein generative models necessitates robust and principled methods for their evaluation and comparison. As new models of increasing complexity continue to emerge, it is crucial to ensure that the metrics used for assessment are well-understood and reliable. In this work, we conduct a systematic investigation of commonly used metrics for evaluating protein generative models, focusing on quality, diversity, and distributional similarity. We examine the behavior of these metrics under various conditions, including synthetic perturbations and real-world generative models. Our analysis explores different design choices, parameters, and underlying representation models, revealing how these factors influence metric performance. We identify several challenges in applying these metrics, such as sample size dependencies, sensitivity to data distribution shifts, and computational efficiency trade-offs. By testing metrics on both synthetic datasets with controlled properties and outputs from state-of-the-art protein generators, we provide insights into each metric’s strengths, limitations, and practical applicability. Based on our findings, we offer a set of practical recommendations for researchers to consider when evaluating protein generative models, aiming to contribute to the development of more robust and meaningful evaluation practices in the field of protein design.
Mechanisms ofPseudomonas aeruginosaresistance to Type VI Secretion System attacks
Authors: Tejada-Arranz Alejandro , Plack Annika , Antelo-Varela Minia , Kaczmarczyk Andreas , Klotz Alexander , Jenal Urs , Basler Marek 
Published: October 2024

AbstractThe Type VI Secretion System (T6SS) is a molecular nanomachine that injects toxic effector proteins into the environment or neighbouring cells, playing an important role in interbacterial competition and host antagonism during infection. Pseudomonas aeruginosa encodes three T6SSs. The H1-T6SS delivers toxins in response to attacks mediated by the T6SS of aggressive bacteria, suggesting that P. aeruginosa can resist T6SS assaults. The mechanisms of resistance are poorly characterized. Here, we performed a CRISPRi screen to identify pathways involved in resistance to T6SS effectors of Acinetobacter baylyi and Vibrio cholerae. We show that members of the GacA/GacS regulon, such as the mag operon or aas, and GacA-independent factors, such as the outer membrane protein OprF, confer resistance to different types of T6SS toxins. Interestingly, some of these T6SS resistance mechanisms lead to higher antibiotic susceptibility, suggesting complex evolutionary links between T6SS and antibiotic resistance.
Sex difference in incidence of bipolar and anxiety disorders: findings from the Global Burden of Disease Study 2021
Authors: Zhu Xingke , Lv Qing 
Published: October 2024

AbstractBackgroundBipolar disorder and anxiety disorders are two prominent mental disorders that represent a significant global health challenge.ObjectiveThe Global Burden of Disease Study 2021 (GBD 2021) was employed to evaluate sex differences in the incidence of bipolar disorder (BD) and anxiety disorder (ANX) globally by year, age, and socioeconomic status.MethodWe estimated sex-specific incidence of BD and ANX from GBD 2021 globally and in 204 countries and territories from 1990 to 2021. The sociodemographic index (SDI) was used to gauge national socioeconomic development and the Health Organization (WHO) region was used as a division of regions. Differences in age-standardized incidence rates (ASRs) by sex (absolute and relative) and risk ratios (95% confidence interval) were calculated annually and by age. Annual percent change (APC) was calculated by joinpoint regression modeling and linear regression analyses were performed to explore the socioeconomic factors associated with sex differences in incidence.ResultsThe absolute and relative sex difference in ASRs of BD showed a slight declining trend during 1990 and 2021, with absolute difference decreasing from 2.50 to 1.83, and relative difference decreasing from 1.08 to 1.06; The absolute and relative sex difference in ASRs of ANX showed an increasing trend during 1990 and 2021, with absolute difference increasing from 170.02 to 208.08, and relative difference increasing from 1.35 to 1.36. Worldwide, females had a higher risk of BD and ANX than males in 1990and 2021. The highest Risk ratios of BD and ANX were observed in the European Region in 2021.The greatest relative sex difference of BD was 1.09 in the age group of 30-34. The greatest relative difference of ANX was 1.51 in the age group of 20-24. Relative sex differences of BD and ANX were significantly and positively correlated with SDI (BD, standardized β = 0.27 (95% CI, 0.22 to 0.33),P< 0.001; ANX, standardized β = 0.80 (95% CI, 0.47 to 1.14),P< 0.001).ConclusionsSex difference in the incidence of anxiety disorders and bipolar disorder have persisted worldwide over the past several decades, and the rates have consistently been higher among females than males. The sex difference in the global incidence of bipolar disorder has shown a slight improvement, but that in the global incidence of anxiety disorders has not been effectively mitigated. The sex difference is even more pronounced at younger ages and in more developed nations. The findings emphasize the significance of sex-specific health policies to reduce sex differences in the incidence of bipolar and anxiety disorders.
Clinical evolution and medical resource utilization in adult patients with respiratory syncytial virus infection at a community hospital in Argentina
Authors: Bengolea Agustin , Ruiz Juan I , Vega Celina G. , Manzotti Matias , Zuccarino Nadia , Rey Ares Lucila 
Published: October 2024

AbstractObjectiveTo describe the hospital medical resources used in adults hospitalized with respiratory syncytial virus infection and to evaluate the association of comorbidities with resource utilization and clinical outcomes.DesignA retrospective cohort study was conducted using the electronic healthcare database of Hospital Alemán, Buenos Aires, Argentina. It included hospitalized patients aged 18 years or older who had a positive test for respiratory syncytial virus between September 2010 and December 2023. Data were analyzed using standard statistical methods following STROBE guidelines.ResultsAmong 72 hospitalized adults with confirmed respiratory syncytial virus infection, the mean length of hospital stay was 12.18 days (SD 12.91), and 27 (37.5%) patients required intensive care unit admission. Healthcare resource utilization was substantial, with 26% needing non-invasive ventilation and 11% requiring mechanical ventilation. Additionally, 75% received antibiotics, and 68.05% were treated with corticosteroids. Cardiovascular comorbidities were significantly associated with severe disease outcomes and intensive care unit admission (OR 3.53, 95% CI: 1.00-12.54). Comparative analysis with 226 influenza patients showed respiratory syncytial virus patients had longer hospital stays and higher intensive care unit admission rates.ConclusionsRespiratory syncytial virus infection in adults resulted in substantial medical resource utilization and significant intensive care unit admission and ventilation support requirements. Cardiovascular comorbidities are associated with increased severity and intensive care unit admission admissions. Compared to influenza, respiratory syncytial virus leads to longer hospital stays and higher intensive care unit admissions, highlighting the need for tailored management strategies for respiratory syncytial virus in adult populations. Further research should focus on optimizing treatment protocols and preventive measures for respiratory syncytial virus.
Neural field theory as a framework for modeling and understanding consciousness states in the brain
Authors: Polyakov Daniel , Robinson P.A. , Makbili Avigail , Gosseries Olivia , Shriki Oren 
Published: October 2024

AbstractUnderstanding the neural correlates of consciousness remains a central challenge in neuroscience. In this study, we explore the potential of neural field theory (NFT) as a computational framework for representing consciousness states. While prior research has validated NFT’s capacity to differentiate between normal and pathological states of consciousness, the relationship of its parameters to the representation of consciousness levels remains unclear.Here, we fitted a corticothalamic NFT model to EEG data collected from healthy individuals and patients with disorders of consciousness. We then comprehensively explored the correlations between the fitted NFT parameters and features extracted from both experimental and simulated EEG data, across various states of consciousness. The identified correlations not only highlight the model’s ability to differentiate between states of consciousness, but also shed light on the physiological bases of these states, pinpointing potential biomarkers.Our results provide valuable insights into how consciousness levels are represented within the NFT framework and into the dynamics of brain activity across various consciousness states. This underscores the potential of NFT as a useful tool for consciousness research, facilitatingin-silicoexperimentation.