bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative single-cell lineage bias in human and murine hematopoietic stem cells
Authors: Shamie Isaac , Bliss-Moreau Meghan , Lee Jamie Casey , Mathieu Ronald , Hoffman Harold M. , Geng Bob , Lewis Nathan E. , Zhu Yanfang Peipei , Croker Ben A. 
Published: November 2024

AbstractThe commitment of hematopoietic stem cells (HSC) to myeloid, erythroid, and lymphoid lineages is influenced by microenvironmental cues, and governed by cell-intrinsic and epigenetic characteristics that are unique to the HSC population. To investigate the nature of lineage commitment bias in human HSC, mitochondrial single cell (sc) ATAC-Sequencing (mt-scATAC-Seq) was used to identify somatic mutations in mitochondrial DNA to act as natural genetic barcodes for tracking theex vivodifferentiation potential of HSC to mature cells. Clonal lineages of human CD34+cells and their mature progeny were normally distributed across the hematopoietic lineage tree without evidence of significant skewing. To investigate commitment biasin vivo, mice were transplanted with limited numbers of long-term HSC (LT-HSC). Variation in the ratio of myeloid and lymphoid cells between donors, although suggestive of a skewed output, was not altered by increasing numbers of LT-HSC. These data suggest that the variation in myeloid and lymphoid engraftment is a stochastic process influenced by the irradiated recipient niche and not a cell-intrinsic lineage bias of LT-HSC.
Cell-type specific prediction of RNA stability from RNA-protein interactions
Authors: Saran Sepideh , Lebedeva Svetlana , Hirsekorn Antje , Ohler Uwe 
Published: November 2024

AbstractRNA-binding proteins (RBPs) are important contributors to post-transcriptional regulatory processes. The combinatorial action of expressed RBPs and non-coding factors bound to the same transcript determines post-transcriptional properties of the mRNA in a context-dependent manner. To gain a better understanding of RNA stability and translational activity across different conditions, we have compiled and analyzed a set of ribosome profiling datasets for four human cell lines and used existing and newly generated metabolic labeling data to determine matching RNA degradation rates. We then used machine learning methods to predict RNA degradation rate and translation level from RBP binding information, which comprised existing in vivo binding datasets and computationally predicted binding sites. Utilizing this new RNA stability resource, we predicted RNA degradation rate and translation level from RBP binding alone. In vivo binding sites had higher importance for prediction compared to computationally predicted binding sites, likely due to confounding effects. We further explored the feature importance of different RBPs for stability prediction in the context of differential stability conferred by 3’UTR isoforms. Taken together, an RNA stability machine learning model trained on one context successfully generalizes but is impacted by the availability and reliability of current data.
HUMAN SPINAL CORD ORGANOIDS REVEAL CELL INTERCALATION AS A CONSERVED MECHANISM FOR SECONDARY NEURULATION
Authors: Blanco-Ameijeiras José , García-Valero Mar , El Majzoub Yara , Rebollo Elena , Macho-Rendón Javier , Corbacho Jorge , Martínez-Morales Juan Ramón , Martí Elisa 
Published: November 2024

SUMMARYThe spinal cord originates from bipotent stem cells called neuromesodermal progenitors, which are organized in a transient embryonic structure called the neural tube. The development of neural organoids is offering unprecedented tools to advance in the limited understanding of the initial construction and subsequent maturation of the human neural tube. In this study, we have generated human neural tube organoids with defined anterior and posterior identities. Through transcriptome profiling, we identified that the posterior organoids possessed a spinal cord identity. By modifying the culture conditions, we recapitulated the morphogenetic events for secondary neurulation in vivo, and revealed that de novo lumen formation in the spinal cord organoids involves a conserved Yap-dependent cell intercalation process. We believe that these findings will contribute to our understanding of the mechanisms required for building the human spinal cord in the embryo, and to understand the biological basis of neurodevelopmental disorders, which are among the most common birth defects.INCLUSION AND DIVERSITYWe support inclusive, diverse, and equitable conduct of research
Host origin of microbiota drives functional recovery andClostridioides difficileclearance in mice
Authors: Millard Sophie A. , Vendrov Kimberly C. , Young Vincent B. , Seekatz Anna M. 
Published: November 2024

AbstractColonization resistance provided by the gut microbiota is essential for resisting both initialClostridioides difficileinfection (CDI) and potential recurrent infection (rCDI). Although fecal microbiota transplantation (FMT) has been successful in treating rCDI by restoring microbial composition and function, mechanisms underlying efficacy of standardized stool-derived products remain poorly understood. Using a combination of 16S rRNA gene-based and metagenomic sequencing alongside metabolomics, we investigated microbiome recovery following FMT from human and murine donor sources in a mouse model of rCDI. We found that a human-derived microbiota was less effective in clearingC. difficilecompared to a mouse-derived microbiota, despite successful microbial engraftment and recovery of bacterial functional potential. Metabolomic analysis revealed deficits in secondary metabolites, suggesting a functional remodeling between human microbes in their new host environment. Collectively, our data revealed additional environmental, ecological, or host factors involved in FMT-based recovery from rCDI.ImportanceClostridioides difficileis a significant healthcare-associated pathogen, with recurrent infections presenting a major treatment challenge due to further disruption of the microbiota after antibiotic administration. Despite the success of fecal microbiota transplantation (FMT) for the treatment of recurrent infection, the mechanisms mediating its efficacy remain largely underexplored. This study reveals that effectiveness of FMT may be compromised by a mismatch between donor microbes and the recipient environment, leading to deficits in key microbial metabolites. These findings highlight additional factors to consider when assessing the efficacy of microbial-based therapeutics for CDI and other conditions.
Dual Computational Systems in the Development and Evolution of Mammalian Brains
Authors: Imam Nabil , Kielo Matthew , Trude Brandon M. , Finlay Barbara L. 
Published: November 2024

AbstractAnalyses of brain sizes across mammalian taxonomic groups reveal a consistent pattern of covariation between major brain components, including a robust inverse covariation between the limbic system and the neocortex. To find the functional basis of this inverse relationship, we mapped the multidimensional representations of task-optimized machine learning systems onto two-dimensional surfaces resembling the forebrain cortices. We found that visual, somatosensory and auditory systems develop ordered spatiotopic maps where units draw information from localized regions of the sensory input. Olfactory and relational memory systems, in contrast, develop fractured maps with distributed patterns of information convergence. Evolutionary optimization of multimodal systems for varying task objectives results in inverse covariation between spatiotopic and disordered system components that compete for representational space. These results suggest that the observed pattern of covariation between brain components reflect an essential computational duality in brain evolution.
Knockdown of TTLL1 reduces Aβ-induced TAU pathology in human iPSC-derived cortical neurons
Authors: Al Kabbani Mohamed Aghyad , Wied Tamara , Adam Daniel , Klimek Jennifer , Zempel Hans 
Published: November 2024

AbstractMicrotubules play a crucial role in neuronal structure and function, with their stability and dynamics regulated by post-translational modifications (PTMs) such as polyglutamylation. In Alzheimer disease (AD), the microtubule-associated protein TAU becomes mislocalized into the somatodendritic compartment (TAU missorting), dissociates from microtubules, aggregates into neurofibrillary tangles, and contributes to microtubule destabilization and neuronal death. Here, we investigated the role of Tubulin-Tyrosine-Ligase-Like proteins (TTLLs) in TAU missorting and microtubule dysregulation using human induced pluripotent stem cell (hiPSC)-derived cortical neurons treated with oligomeric amyloid-beta (oAβ) to replicate AD-like conditions. TTLL1, TTLL4, TTLL6 were selectively knocked down (KD) to assess their impact on TAU missorting and microtubule stability. Fluorescence resonance energy transfer (FRET) microscopy was used to examine interactions between TAU and TTLL proteins. We observed TAU missorting, increased tubulin polyglutamylation, decreased microtubule stability, and synaptic declustering in oAβ-treated neurons. TTLL1 KD significantly reduced TAU missorting, tubulin polyglutamylation, and synaptic disintegration, while TTLL4 KD showed moderate effects, and TTLL6 KD restored microtubule acetylation. Importantly, TTLL KD did not impair neuritic networks, dendritic complexity, or neuronal activity. FRET microscopy revealed a potential interaction between TAU and TTLL1, but not other TTLLs, suggesting a direct role of TTLL1 in TAU-mediated toxicity. Our findings indicate that targeting TTLL1, either alone or in combination with other TTLLs, may be a promising therapeutic strategy to counteract microtubule and synaptic dysfunction in AD and related neurodegenerative disorders.
CRAGE-RB-PI-seq enables transcriptional profiling of rhizobacteria during plant-root colonization
Authors: Honda Tomoya , Yu Sora , Mai Dung , Baumgart Leo , Babnigg Gyorgy , Yoshikuni Yasuo 
Published: November 2024

AbstractPlant roots release a wide array of metabolites into the rhizosphere, shaping microbial communities and their functions. While metagenomics has expanded our understanding of these communities, little is known about the physiology of their members in host environments. Transcriptome analysis via RNA sequencing is a common approach to learning more, but its use has been challenging because plant RNA masks bacterial transcripts. To overcome this, we developed randomly-barcoded promoter-library insertion sequencing (RB-PI-seq) and combined it with chassis-independent recombinase-assisted genome engineering (CRAGE), usingPseudomonas simiaeWCS417 as a model rhizobacterium. This method enables targeted amplification of barcoded transcripts, bypassing plant RNA interference and allowing measurement of thousands of promoter activities during root colonization. We identified promoters involved in biofilm formation, reactive oxygen species response, and root immune suppression, which all contribute to root colonization. Additionally, we discovered that transcriptional activation of xanthine dehydrogenase and a lysozyme inhibitor are crucial for evading plant immune system defenses. This framework is scalable to other bacterial species and provides new opportunities for understanding rhizobacterial gene regulation in native environments.
Endothelial Rho kinase controls blood vessel integrity and angiogenesis
Authors: Lange Martin , Francis Caitlin , Furtado Jessica , Kim Young-Bum , Liao James K , Eichmann Anne 
Published: November 2024

AbstractBackgroundThe Rho kinases 1 and 2 (ROCK1/2) are serine-threonine specific protein kinases that control actin cytoskeleton dynamics. They are expressed in all cells throughout the body, including cardiomyocytes, smooth muscle cells and endothelial cells, and intimately involved in cardiovascular health and disease. Pharmacological ROCK inhibition is beneficial in mouse models of hypertension, atherosclerosis, and neointimal thickening that display overactivated ROCK. However, the consequences of endothelial ROCK signaling deficiency in vivo remain unknown. To address this issue, we analyzed endothelial cell (EC) specificROCK1and2deletions.MethodsWe generated Cdh5-CreERT2 driven, tamoxifen inducible loss of function alleles ofROCK1andROCK2and analyzed mouse survival and vascular defects through cellular, biochemical, and molecular biology approaches.ResultsWe observed that postnatal or adult loss of endothelialROCK1and2was lethal within a week. Mice succumbed to multi-organ hemorrhage that occurred because of loss of vascular integrity. ECs displayed deficient cytoskeletal actin polymerization that prevented focal adhesion formation and disrupted junctional integrity. Retinal sprouting angiogenesis was also perturbed, as sprouting vessels exhibited lack of polymerized actin and defective lumen formation. In a three-dimensional endothelial sprouting assay, combined knockdown ofROCK1/2or knockdown orROCK2but notROCK1led to reduced sprouting, lumenization and cell polarization defects caused by defective actin and altered VE-cadherin dynamics. The isoform specific role of endothelial ROCK2 correlated with ROCK2 substrate specificity for FAK and LIMK. By analyzing single and three allele mutants we show that one intact allele ofROCK2is sufficient to maintain vascular integrityin vivo.ConclusionEndothelial ROCK1 and 2 maintain junctional integrity and ensure proper angiogenesis and lumen formation. The presence of one allele ofROCK2is sufficient to maintain vascular growth and integrity. These data indicate the need of careful consideration for the use of ROCK inhibitors in disease settings.
Ovarian germline stem cell dedifferentiation is cytoneme-dependent
Authors: Sutcliffe Catherine , Nandy Nabarun , Ashe Hilary L. , Wilcockson Scott G. 
Published: November 2024

AbstractProgenitor cell dedifferentiation is important for stem cell maintenance during tissue repair and age-related stem cell decline. Here, we useDrosophilaovarian germ cells as a model to study the role of cytonemes in BMP signalling-directed dedifferentiation to germline stem cells. We provide evidence that differentiating germ cell cysts extend cytonemes towards the niche during dedifferentiation to reactivate BMP signalling. We show that the Enabled (Ena) actin polymerase is localised to the tips of germ cell cytonemes and is necessary for robust cytoneme formation, as its mislocalisation reduces the frequency, length and directionality of cytonemes. Furthermore, specifically perturbing cytoneme function through Ena mislocalisation reduces germ cell BMP responsiveness and the ability of differentiating cysts to dedifferentiate. We discuss how cytonemes may be widely used by differentiating cells to re-establish niche contact and signal responsiveness following stem cell loss, promoting robust dedifferentiation of stem cells in diverse contexts.
Modifying the aggregation state may improve the activity of Ozempic
Authors: Bolaño Alvarez Alain , Arvesen Kristian B. , Hjuler Kasper F. , Bjerring Peter , Petersen Steffen B. 
Published: November 2024

AbstractWe here report a study of aggregation of Semaglutide at different temperatures, using resonance light scattering (RLS), fluorescence polarization and back-scattering techniques. Fluorescence emission spectra were obtained by exciting the samples at 275 nm and 295 nm, revealing a peak emission at 600 nm associated with the aggregation process. The size of the aggregates is around 100 nm according to back-scattering measurements. Two distinct thermal transitions were observed by RLS: the first melting point (Tm1) at 30°C and the second (Tm2) at 91°C, indicating changes in aggregation state. The fluorescence polarization revealed a fast rotational dynamics of the aggregates at Tm2, leading to greater depolarization of the emitted light. The structural organization of the Ozempic aggregates was studied using two dyes, Laurdan for lipid components and 1,8-ANS for protein component (GLP1). Thus, revealing a stable PEG-lipid core which hold the GLP1, increasing their exposition to the solvent. An enhanced FRET event inside the aggregates in presence of Fe2+and Fe3+was observed. We conclude that the PEG-lipid core plays a significant role in the aggregates structure stability, being a key to improve the biological activity of Ozempic. This methodology can be used to study similar aggregation constructs in the pharmaceutical industry.
Prematurity and Genetic Liability for Autism Spectrum Disorder
Authors: Zhang Yali , Yahia Ashraf , Sandin Sven , Åden Ulrika , Tammimies Kristiina 
Published: November 2024

AbstractBackgroundAutism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by diverse presentations and a strong genetic component. Environmental factors, such as prematurity, have also been linked to increased liability for ASD, though the interaction between genetic predisposition and prematurity remains unclear. This study aims to investigate the impact of genetic liability and preterm birth on ASD conditions.MethodsWe analyzed phenotype and genetic data from two large ASD cohorts, the Simons Foundation Powering Autism Research for Knowledge (SPARK) and Simons Simplex Collection (SSC), encompassing 78,559 individuals for phenotype analysis, 12,519 individuals with genome sequencing data, and 8,104 individuals with exome sequencing data. Statistical significance of differences in clinical measures were evaluated between individuals with different ASD and preterm status. We assessed the rare variants burden using generalized estimating equations (GEE) models and polygenic load using ASD-associated polygenic risk score (PRS). Furthermore, we developed a machine learning model to predict ASD in preterm children using phenotype and genetic features available at birth.ResultsIndividuals with both preterm birth and ASD exhibit more severe phenotypic outcomes despite similar levels of genetic liability for ASD across the term and preterm groups. Notable, preterm ASD individuals showed an elevated rate of de novo variants identified in exome sequencing (GEE model with Poisson family, p-value = 0.005) in comparison to the non-ASD preterm group. Additionally, a GEE model showed that a higher ASD PRS, preterm birth, and male sex were positively associated with a higher predicted probability for ASD, reaching a probability close to 90%. Lastly, we developed a machine learning model using phenotype and genetic features available at birth with limited predictive power (AUROC = 0.65).ConclusionsPreterm birth may exacerbate the multimorbidity present in ASD, which was not due to the ASD genetic factors. However, increased genetic factors may elevate the likelihood of a preterm child being diagnosed with ASD. Additionally, a polygenic load of ASD-associated variants had an additive role with preterm birth in the predicted probability for ASD, especially for boys. We propose that incorporating genetic assessment into neonatal care could benefit early ASD identification and intervention for preterm infants.
A hybrid approach for modelling safety hazards in China subways: multi-stakeholders’ perspective
Authors: Ahmad Abdulaziz , Wang Weidong , Qiu Shi , Wang Wenjuan , Wang Tian-Yi , Aliyu Bamaiyi Usman , Sun Ying , Ismail Abubakar Sadiq 
Published: November 2024

PurposeUnlike previous research that primarily utilized structural equation modelling (SEM) to evaluate safety hazards in subway projects, this research aims to utilize a hybrid approach to investigate and scrutinize the key indicators of safety hazards leading to accidents, thereby hindering the progress of subway projects in China, taking into cognizance the multiple stakeholder’s perspective.Design/methodology/approachBy administering a survey questionnaire to 373 highly involved stakeholders in subway projects spanning Changsha, Beijing and Qingdao, China, our approach incorporated a four-staged composite amalgamation of exploratory factor analysis (EFA), confirmatory factor analysis (CFA), covariance-based structural equation modelling (CB-SEM) and artificial neural network (ANN) to develop an optimized model that determines the causal relationships and interactions among safety hazards in subway construction projects.FindingsThe optimized model delineated the influence of individual safety hazards on subway projects. The feasibility and applicability of the model developed was demonstrated on an actual subway project under construction in Changsha city. The outcomes revealed that the progress of subway projects is significantly influenced by risks associated with project management, environmental factors, subterranean conditions and technical hazards. In contrast, risks related to construction and human factors did not exhibit a significant impact on subway construction progress.Research limitations/implicationsWhile our study provides valuable insights, it is important to acknowledge the limitation of relying on theoretical approaches without empirical validation from experiments or the field. In future research, we plan to address this limitation by assessing the SEM using empirical data. This will involve a comprehensive comparison of outcomes derived from CB-SEM with those obtained through SEM-ANN methods. Such an empirical validation process is crucial for enhancing the overall efficiency and robustness of the proposed methodologies.Originality/valueThe established hybrid model revealed complex non-linear connections among indicators in the intricate project, enabling the recognition of primary hazards and offering direction to improve management of safety in the construction of subways.
Tourism direct GDP: configuration of antecedents and tourism future performance in high-income countries’
Authors: Agostinho Mario Nuno , Dias Alvaro , F. Pereira Leandro 
Published: November 2024

PurposeThis study aims to provide a new perspective on the factors determining a country’s tourism performance, understand the interrelationships among these factors and explore their implications for the future of tourism in high-income countries.Design/methodology/approachThe study employs a fuzzy-set qualitative comparative analysis (fsQCA) using five variables from the World Economic Forum’s Travel and Tourism Development Index (TTDI). The focus is on identifying seven configurations of antecedents of Travel and Tourism Industry Gross Domestic Product (T&T Industry GDP).FindingsThe study identifies seven configurations of antecedents influencing T&T Industry GDP, revealing how these factors operate in different scenarios, specifically in countries with high and low T&T GDP. These configurations offer insights into potential future pathways for tourism development.Research limitations/implicationsThe study implies that tourism is a complex phenomenon influenced by multiple interacting factors. It provides a framework for understanding how different combinations of factors can lead to high or low tourism performance, offering valuable insights for anticipating and shaping the future of tourism.Originality/valueThis study adds value by providing a more nuanced understanding of the tourism industry, challenging the notion of singular effects of variables and highlighting the importance of analyzing multiple, interacting factors in understanding and predicting tourism performance. It contributes to the field of futures studies by offering a tool for anticipating potential future scenarios and their impact on the tourism industry.