bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid Response of Neutrophils Determined by Shortest Differentiation Trajectory and New Insight into Cell Cycle Kinetics and Chronological Order of Progenitor States
Authors: Yue Yongjian 
Published: April 2024

AbstractDespite substantial advances in our understanding of hematopoietic stem cell self-renewal, differentiation, and proliferation, the underlying mechanisms and cell cycle kinetics remain elusive. Neutrophils, as primary rapid responders during infections, quickly generate an enormous number of mature cells for immune defense. This immune phenomena is effected by cell cycle kinetics. Our previous study redefined progenitors and reformed the hierarchy of hematopoiesis. Here, we aim to elucidate the cell cycle kinetics and chronological order of progenitor states, providing new insights into immune phenomena. We revealed the changes in cell cycle kinetics from differentiation (lineage commitment) to proliferation in peripheral hematopoiesis. Differentiating hematopoietic progenitor cells (HPCs) are maintained in the G1 phase of cell cycle, regulated by DNA replication. Once the progenitors complete their commitment, cell cycle states of progenitors convert from G1 to S phase, switching from differentiation to proliferation with DNA replication begins. Differentiation and proliferation of MPCs are independent processes, and fate determination takes precedence over proliferation. Since the differentiating HPCs do not undergo cell division, a committing progenitor will destined to mature into only one committed progenitor cell on its selected differentiation path. The chronological order of quiescence, self-renewal, differentiation, and proliferation, is clearly delineated. Our study reveals that initial progenitors in adult peripheral blood exhibit self-renewal capabilities, which are absent after lineage commitment is completed during hematopoiesis. Furthermore,GATA2andCSF3Rwere confirmed as key transcription factors determining the co-segregation among neutrophils and other lineages, deciphering the underlying molecular mechanisms. Neutrophil present the shortest differentiation trajectory in the hematopoietic hierarchy, which decide their role as rapid responders. Our results provide a clear characterization of the cell cycle kinetics of HPCs’ differentiation and proliferation, facilitating advancements in inflammation and disease treatment.
Testing frameworks for early life effects: the developmental constraints and adaptive response hypotheses do not explain key fertility outcomes in wild female baboons
Authors: Rosenbaum Stacy , Malani Anup , Lea Amanda J. , Tung Jenny , Alberts Susan C. , Archie Elizabeth A. 
Published: April 2024

AbstractIn evolutionary ecology, two classes of explanations are frequently invoked to explain “early life effects” on adult outcomes. Developmental constraints (DC) explanations contend that costs of early adversity arise from limitations adversity places on optimal development. Adaptive response (AR) hypotheses propose that later life outcomes will be worse when early and adult environments are poorly “matched.” Here, we use recently proposed mathematical definitions for these hypotheses and a quadratic-regression based approach to test the long-term consequences of variation in developmental environments on fertility in wild baboons. We evaluate whether low rainfall and/or dominance rank during development predict three female fertility measures in adulthood, and whether any observed relationships are consistent with DC and/or AR. Neither rainfall during development nor the difference between rainfall in development and adulthood predicted any fertility measures. Females who were low-ranking during development had an elevated risk of losing infants later in life, and greater change in rank between development and adulthood predicted greater risk of infant loss. However, both effects were statistically marginal and consistent with alternative explanations, including adult environmental quality effects. Consequently, our data do not provide compelling support for either of these common explanations for the evolution of early life effects.
Contrasting patterns of differentiation among three taxa of the rapidly diversifying orchid genusOphryssect.Insectifera(Orchidaceae) where their range overlap
Authors: Salvado Pascaline , Gibert Anaïs , Schatz Bertrand , Vandenabeele Lucas , Buscail Roselyne , Vilasís David , Feldmann Philippe , Bertrand Joris A. M. 
Published: April 2024

ABSTRACTIn rapidly diversifying groups, taxa defined on the basis of typological criteria can be difficult to support with genetic data. The diversity observed in the insect-mimicking orchid genusOphrysperfectly illustrates this situation; among 400 described species only 9-10 lineages are detectable by genetic markers such as nrITS. The three taxa described in theOphrys insectiferagroup:O. insectifera,O. subinsectiferaandO. aymoninii, can be clearly distinguished by their flowers, which have evolved different phenotypes as a result of adaptation to specific pollinator insect species from three different families. However, genetic differentiation between these three taxa has never been really supported by population genetic data and their taxonomic status is still debated. Using population genomic approaches, we found a clustering consistent with the existence of three genetic entities where the geographic distributions of the three taxa overlap. Two of these clusters correspond to France populations of the widespreadO. insectiferaand the micro-endemicO. aymoninii. However, the last cluster grouped together all the Iberian individuals, suggesting that individuals phenotypically identified as eitherO. insectiferaorO. subinsectiferaare genetically weakly differentiated there. Populations of the two pairs of taxa thus may have experienced different patterns of inter-specific gene flow.
Sperm derived H2AK119ub1 is required for embryonic development inXenopus laevis
Authors: Francois--Campion Valentin , Berger Florian , Oikawa Mami , Goumeidane Maissa , Mouniée Nolwenn , Chenouard Vanessa , Petrova Kseniya , Abreu Jose G , Fourgeux Cynthia , Poschmann Jeremie , Peshkin Leonid , Gibeaux Romain , Jullien Jérôme 
Published: April 2024

ABSTRACTDeposition of H2AK119ub1 by the polycomb repressive complexe-1 plays a key role in the initiation of facultative heterochromatin formation in somatic cells. Here we evaluate the contribution of sperm derived H2AK119ub1 to embryo development. InXenopus laeviswe found that H2AK119ub1 is present during spermiogenesis and into early embryonic development, highlighting its credential for a role in the transmission of epigenetic information from the sperm to the embryo.In vitrotreatment of sperm with USP21, a H2AK119ub1 deubiquitylase, just prior to injection to egg, results in developmental defects associated with gene upregulation. Sperm H2AK119ub1 editing disrupts egg factor mediated paternal chromatin remodelling processes. It leads to post-replication accumulation of H2AK119ub1 on repeat element of the genome instead of CpG islands. This shift in post-replication H2AK119ub1 distribution triggered by sperm epigenome editing entails a loss of H2AK119ub1 from genes misregulated in embryos derived from USP21 treated sperm. We conclude that sperm derived H2AK119ub1 instructs egg factor mediated epigenetic remodelling of paternal chromatin and is required for embryonic development.
Effect of seizures on the severity of myelin vacuolization in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts
Authors: Brouwers Eelke , Breur Marjolein , Jorge Maria Susana , Mansvelder Huibert D. , van der Knaap Marjo S. , Bugiani Marianna , Min Rogier 
Published: April 2024

ABSTRACTObjectiveMegalencephalic leukoencephalopathy with subcortical cysts (MLC) is a white matter disease characterized by myelin vacuolization and swollen perivascular astrocyte processes. Neuronal activity has been implicated as primary cause of myelin vacuolization and astrocyte swelling. Since acute and excessive increases in neuronal activity occur in MLC during seizures, we investigated whether seizure activity leads to the acute development of myelin vacuoles and swollen astrocyte processes.MethodsGlialcam-null mice (an established MLC mouse model) and wild-type mice received repeated i.p. low dose (5 mg / kg) kainic acid (KA) injections until severe seizures developed. Following a 60-minute period of severe seizure activity, mice were terminated and brains were fixed and processed. Brain tissue was analyzed for myelin vacuolization and astrocyte process thickness using H&E and GFAP stains, respectively.ResultsRepeated low-dose injections of KA resulted in prolonged severe seizure activity in mice of both genotypes. Total amount of seizure activity was comparable betweenGlialcam-null and wild-type mice. KA-induced severe seizure activity did not significantly increase myelin vacuolization in eitherGlialcam-null or wild-type mice. The width of perivascular astrocyte processes was also not affected by severe seizure activity.InterpretationWe show that (i) repeatedly injecting a low dose of KA provides the opportunity to regulate seizure development and generate severe seizures in both wild-type and seizure-sensitiveGlialcam-null mice, and that (ii) the two major pathological features of MLC, myelin vacuolization and swollen astrocyte endfeet, are not acutely aggravated in response to KA-induced severe seizure activity.
Graph Contrastive Learning as a Versatile Foundation for Advanced scRNA-seq Data Analysis
Authors: Zhang Zhenhao , Liu Yuxi , Xiao Meichen , Wang Kun , Huang Yu , Bian Jiang , Yang Ruolin , Li Fuyi 
Published: April 2024

AbstractSingle-cell RNA sequencing (scRNA-seq) offers unprecedented insights into transcriptome-wide gene expression at the single-cell level. Cell clustering has been long established in the analysis of scRNA-seq data to identify the groups of cells with similar expression profiles. However, cell clustering is technically challenging, as raw scRNA-seq data have various analytical issues, including high dimensionality and dropout values. Existing research has developed deep learning models, such as graph machine learning models and contrastive learning-based models, for cell clustering using scRNA-seq data and has summarized the unsupervised learning of cell clustering into a human-interpretable format. While advances in cell clustering have been profound, we are no closer to finding a simple yet effective framework for learning high-quality representations necessary for robust clustering. In this study, we propose scSimGCL, a novel framework based on the graph contrastive learning paradigm for self-supervised pretraining of graph neural networks. This framework facilitates the generation of high-quality representations crucial for cell clustering. Our scSimGCL incorporates cell-cell graph structure and contrastive learning to enhance the performance of cell clustering. Extensive experimental results on simulated and real scRNA-seq datasets suggest the superiority of the proposed scSimGCL. Moreover, clustering assignment analysis confirms the general applicability of scSimGCL, including state-of-the-art clustering algorithms. Further, ablation study and hyperparameter analysis suggest the efficacy of our network architecture with the robustness of decisions in the self-supervised learning setting. The proposed scSimGCL can serve as a robust framework for practitioners developing tools for cell clustering. The source code of scSimGCL is publicly available athttps://github.com/zhangzh1328/scSimGCL.
Efficacy of foramen magnum decompression with and without cranioplasty in a rat model of Chiari-like malformation
Authors: Jung Jae-Hwan , Cho Chang-Hyeon , Kim Woo-Suk , Yoon Hun-Young 
Published: April 2024

AbstractIn veterinary medicine, canine Chiari-like malformation (CLM) disease is surgically managed through foramen magnum decompression (FMD) with cranioplasty. This study aimed to assess the efficacy of cranioplasty surgery by establishing a rat CLM model and then applying FMD with and without cranioplasty and comparing the outcomes. Twenty-four 8-week-old male Sprague‒Dawley rats underwent surgery to induce CLM by reducing the caudal cranial fossa volume, mimicking cerebellum herniation. The rats were randomly and equally assigned to three groups: a control group (induced CLM), an FO group (induced CLM rats undergoing FMD only), and a CR group (induced CLM rats undergoing FMD with cranioplasty). At 11 weeks of age, the FO and CR groups underwent FMD surgery. Four weeks later, magnetic resonance imaging (MRI) was used to measure the cisterna magna volume to assess surgical outcomes. Post-surgery MRI revealed that the mean cisterna magna volume was 23.82 ± 1.70, 34.88 ± 4.39, and 29.48 ± 2.20 mm3in the control, FO, and CR groups, respectively. There was a significant increase in the cisterna magna volume in the FO and CR groups compared to that in the control group (p < 0.05), with the FO group showing a significantly greater increase than the CR group (p < 0.05). These findings suggest that FMD surgery alone is more effective at restoring the cisterna magna volume than FMD surgery with cranioplasty. FMD surgery alone resulted in a greater increase in cisterna magna volume than FMD with cranioplasty in our rat CLM model, suggesting that FMD alone may be more effective to treat canine CLM. These findings challenge the typical approach of combining FMD with cranioplasty in treating canine CLM disease and underscore the need for further investigation into optimizing surgical techniques for CLM.
Hair follicles modulate skin barrier function
Authors: Ford Noah C. , Benedeck Rachel E. , Mattoon Matthew T. , Peterson Jamie K. , Mesler Arlee L. , Veniaminova Natalia A. , Gardon Danielle J. , Tsai Shih-Ying , Uchida Yoshikazu , Wong Sunny Y. 
Published: April 2024

SummaryOur skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene,Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell autonomous responses in the epidermis. Third, deletingAbca12in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing Il17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
A chance insight into the mechanism of phosgene toxicity
Authors: Daplan Ekin , Turin Luca 
Published: April 2024

AbstractIt has long been known that phosgene, a deadly war gas and industrial reagent, causes intense oxidative stress, but how it does so remains unclear. Here we report an accidental discovery: electron spin resonance spectroscopy (ESR) of live fruit flies reveals that phosgene exposure results in a distinctive manganese (II) hyperfine spectrum. The Mn(II) signal correlates with mitochondrial SOD2 expression. We suggest that phosgene acylates a highly conserved SOD2 active site tyrosine. This prevents the Mn redox cycling between ESR-silent Mn(III) and ESR-active Mn(II) that is required for superoxide dismutation. We propose that mitochondrial SOD2 inactivation is responsible for phosgene toxicity.
Mathematical modeling unveils the timeline of CAR-T cell therapy and macrophage-mediated cytokine release syndrome
Authors: Santurio Daniela S. , Barros Luciana R. C. , Glauche Ingmar , Fassoni Artur C. 
Published: April 2024

AbstractChimeric antigen receptor (CAR)-T cell therapy holds significant potential for cancer treatment, although disease relapse and cytokine release syndrome (CRS) remain as frequent clinical challenges. To better understand the mechanisms underlying the temporal dynamics of CAR-T cell therapy response and CRS, we developed a novel multi-layer mathematical model incorporating antigen-mediated CAR-T cell expansion, antigen-negative resistance, and macrophage-associated cytokine release. Three key mechanisms of macrophage activation are considered: release of damage-associated molecular patterns, antigen-binding mediated activation, and CD40-CD40L contact. The model accurately describes 25 patient time courses with different responses and IL-6 cytokine kinetics. We successfully link the dynamic shape of the response to interpretable model parameters and investigate the influence of CAR-T cell dose and initial tumor burden on the occurrence of CRS and treatment outcome. By disentangling the timeline of macrophage activation, the model identified distinct contributions of each activation mechanism, suggesting the CD40-CD40L axis as a major driver of CRS and a clinically feasible target to control the activation process and modulate cytokine peak height. Our multi-layer model provides a comprehensive framework for understanding the complex interactions between CAR-T cells, tumor cells, and macrophages during therapy.
Chemical Coverage of the Human Reactome
Authors: Kwak Haejin Angela , Liu Lihua , Tredup Claudia , Röhm Sandra , Prinos Panagiotis , Böttcher Jark , Schapira Matthieu 
Published: April 2024

AbstractChemical probes and chemogenomic compounds are valuable tools to link gene to phenotype, explore human biology and uncover novel targets for precision medicine. A growing federation of scientists is contributing to the mission of Target 2035 – discovering chemical tools for all druggable human proteins by the year 2035. It is expected that these compounds will enable the understanding of the regulation of cellular machineries and biological processes across the compendium of signaling pathways that animate cellular life. Here, we draw a landscape of the current chemical coverage of the human Reactome. We find that even though available chemical probes and chemogenomic compounds are targeting only 3% of the human proteome, they cover 53% of the human Reactome, due to the fact that 46% of human proteins are involved in more than one cellular pathway. As such, existing chemical probes and chemogenomic compounds already represent a versatile toolkit to manipulate a vast portion of human biology. Pathways targeted by existing drugs may be enriched in unknown but valid drug targets and could be prioritized in future Target 2035 efforts.
Fish CDK2 recruits Dtx4 to degrade TBK1 through ubiquitination in the antiviral response
Authors: Lu Long-Feng , Zhang Can , Li Zhuo-Cong , Cui Bao-Jie , Wang Yang-Yang , Han Ke-Jia , Xu Xiao , Zhou Chu-Jing , Zhou Xiao-Yu , Wu Yue , Xu Na , Yang Xiao-Li , Chen Dan-Dan , Li Xi-Yin , Zhou Li , Li Shun 
Published: April 2024

AbstractAlthough the classical biological protein cell cycle protein kinase CDK2 has been extensively studied in higher vertebrates, its function in lower vertebrates beyond the regulation of mitosis remains unknown. In this study, we report a distinct mechanism whereby IFN expression is negatively regulated in fish by CDK2. After infection with the spring viremia of carp virus (SVCV), fish CDK2 expression significantly increased in tissues and cells. Moreover, antiviral resistance was improved incdk2−/−homozygotes, and the antiviral cytokine interferon (IFN) expression was significantly higher. At the cellular level, CDK2 overexpression reduced IFN expression, whilecdk2knockdown increased the ability of cells to produce IFN. Subsequently, it was discovered that fish CDK2 binds and degrades TBK1, resulting in reduced IFN. CDK2 increases the K48-linked ubiquitination of TBK1, causing its degradation, while E3 ubiquitin ligase Dtx4 was found to be involved in this process following the significant enhancement of TBK1 K48-linked ubiquitination. Protein mass spectrometry and immunoblot analysis confirmed that the K567 site on TBK1 is essential for CDK2 to engage with Dtx4 and degrade TBK1; thus, after mutating the K567 site, K48-linked ubiquitination of TBK1 was not enhanced by Dtx4, and TBK1 was not degraded by CDK2. Our data demonstrate that fish CDK2 recruits the E3 ubiquitin ligase Dtx4 to target the K567 site of TBK1 and promote its degradation. These results suggest that CDK2 in lower vertebrates is implicated in a specialized role for antiviral innate immunity.
Optimizing biomedical information retrieval with a keyword frequency-driven Prompt Enhancement Strategy
Authors: Aftab Wasim , Apostolou Zivkos , Bouazoune Karim , Straub Tobias 
Published: April 2024

AbstractBackgroundMining the enormous pool of biomedical literature to extract accurate responses and relevant references is a daunting challenge, made more difficult by the domain’s interdisciplinary nature, specialized jargon, and continuous evolution. Early natural language processing (NLP) approaches faced considerable hurdles in comprehending the nuances of natural language which frequently led to false answers. However, the discovery of transformer models has immensely boosted the cause by enabling researchers to create larger and more potent language models known as large language models (LLMs). These LLMs have opened up new possibilities for enhancing question-answering (QA) tasks. Even with these technological advances, the current LLM-based solutions for querying specialized domains like biology and biomedicine still have issues in generating up to date responses while preventing “hallucination” or the generation of plausible but factually incorrect responses.ResultsThis paper focuses on prompt enhancement using retrieval-augmented architecture as a strategy to guide LLMs towards generating more meaningful responses for biomedical question-answering tasks. We evaluated two prompt enhancement approaches using GPT-3 and GPT-4, examining their effectiveness in retrieving relevant information from complex landscape of biomedical literature. Our proposed approach leverages explicit signals in user queries to extract meaningful contexts from a vast pool of information, addressing the shortcomings of traditional text embedding-based prompt enhancement methods. We developed a QA bot ‘WeiseEule’ (https://github.com/wasimaftab/WeiseEule-LocalHost) utilizing these prompt enhancement methods and allowing for comparative analysis of their performances.ConclusionsOur findings highlight the importance of prompt enhancement methods that utilize explicit signals in user’s query over traditional text embedding based counterparts to improve LLM-generated responses in specialized domains such as biology and biomedicine. By providing users complete control over the information that goes into the LLM, our approach tackles some of the major drawbacks of existing web-based chatbots and LLM-based QA systems including hallucinations and the generation of irrelevant or outdated responses.