bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in adult survival drive divergent demographic responses to a decade of field warming on the Tibetan Plateau
Authors: Miao Hai-Tao , Salguero-Gómez Roberto , Shea Katriona , Keller Joseph A. , Zhang Zhenhua , He Jin-Sheng , Li Shou-Li 
Published: October 2023

AbstractA central question in biodiversity conservation is whether species will maintain viable population dynamics under future climate change. Assessing species extinction risk under climate warming requires demographic studies integrating vital rate responses to long-term warming throughout species’ life cycle. However, studies of this nature are rare.Here, we examine the demographic responses of two co-occurring herbaceous plants,Elymus nutansGriseb. andHelictotrichon tibeticum(Roshev.) Holub, after a decade (2011-2020) ofin situactive warming by 2°C in the grasslands of the Tibetan Plateau. We parameterise Integral Projection Models (IPMs) to project the population dynamics under ambient and long-term warming conditions, and examine the key vital rates responsible for any potential differences in population growth rates.Warming has contrasting effects on the two functionally similar co-occurring species: warming promotes the population growth rate ofH. tibeticum, but intensifies the population decline ofE. nutans. Our elasticity analyses show that survival is the most important vital rate for population viability in both species under both ambient and warmed conditions. Furthermore, our retrospective Life Table Response Experiment (LTRE) analysis reveals that the contrasting fates of the two species under warming mainly arise from the different responses of adult survival, which is significantly promoted inH. tibeticumbut slightly reduced inE. nutans.Individual shrinkage occurred 1.6-fold more frequently under warming than ambient conditions for both species, and made considerable negative contributions to their population growth rates in warmed plots. However, such negative effects are offset inH. tibeticum(but notE. nutans) by the positive contribution to population growth rate of the associated increased survival.Synthesis. Our study illustrates that the responses to climate warming may vary considerably between similar co-occurring species, and species with a demographically compensatory strategy may avoid population collapse. Additionally, caution is needed when generalizing findings among functionally similar species, and that conservation measures should be tailored at the species level.
Cell fate dynamics reconstruction identifies TPT1 and PTPRZ1 feedback loops as master regulators of differentiation in pediatric glioblastoma-immune cell networks
Authors: Uthamacumaran Abicumaran 
Published: October 2023

ABSTRACTPediatric glioblastoma is a complex dynamical disease that is difficult to treat due to its multiple adaptive behaviors driven largely by phenotypic plasticity. Integrated data science and network theory pipelines offer novel approaches to study glioblastoma cell fate dynamics, particularly phenotypic transitions over time. Here we used various single-cell trajectory inference algorithms to infer signaling dynamics regulating pediatric glioblastoma-immune cell networks. We identified GATA2, PTPRZ1, TPT1, MTRNR2L1/2, OLIG1/2, SOX11, PDGFRA, EGFR, S100B, WNT, TNFα, and NF-kB as critical transition genes or signals regulating glioblastoma-immune network dynamics, revealing potential clinically relevant targets. Further, we reconstructed glioblastoma cell fate attractors and found complex bifurcation dynamics within glioblastoma phenotypic transitions, suggesting that a causal pattern may be driving glioblastoma evolution and cell fate decision-making. Together, our findings have implications for the development of targeted therapies against glioblastoma, and the continued integration of quantitative approaches to understand pediatric glioblastoma tumour-immune interactions.
Characterization of Gαsand Gαolfactivation by catechol and non-catechol dopamine D1 receptor agonists
Authors: Nguyen Anh Minh , Semeano Ana , Quach Vianna , Inoue Asuka , Nichols David E. , Yano Hideaki 
Published: October 2023

SUMMARYThe dopamine D1 receptor (D1R) couples to Gαsand Gαolfand plays a crucial role in regulating voluntary movement and other cognitive functions, making it a potential therapeutic target for several neurological and neuropsychiatric disorders, such as Parkinson’s disease and schizophrenia. In the central nervous system, Gαsis widely expressed in the cortex and Gαolfis predominantly found in the striatum. We used two different configurations of bioluminescence resonance energy transfer (BRET) assays and a fluorescence-based cyclic AMP (cAMP) production functional assay to test a series of tetracyclic catechol (dihydrexidine, methyl-dihydrexidine, doxanthrine) and non-catechol (tavapadon, PF-8294, PF-6142) D1R agonists for their activity at these G proteins. We discovered that these tetracyclic catechol compounds, PF-8294 and PF-6142 exerted full agonism when D1R coupled to Gαsbut partial agonism when D1R coupled to Gαolf. In contrast, tavapadon acted as a full agonist at Gαolfand a partial agonist at Gαs. The effects of these compounds on the cortical and nigral electrophysiological events agree with their selectivity profiles. This suggests the possibility of achieving region-specific pharmacology and opens new directions for developing D1R drugs to treat relevant neurological and neuropsychiatric disorders.
Intraoperative Bioprinting of Human Adipose-derived Stem cells and Extra-cellular Matrix Induces Hair Follicle-Like Downgrowths and Adipose Tissue Formation during Full-thickness Craniomaxillofacial Skin Reconstruction
Authors: Kang Youngnam , Yeo Miji , Derman Irem Deniz , Ravnic Dino J. , Singh Yogendra Pratap , Alioglu Mecit Altan , Wu Yang , Makkar Jasson , Driskell Ryan R. , Ozbolat Ibrahim T. 
Published: October 2023

ABSTRACTCraniomaxillofacial (CMF) reconstruction is a challenging clinical dilemma. It often necessitates skin replacement in the form of autologous graft or flap surgery, which differ from one another based on hypodermal/dermal content. Unfortunately, both approaches are plagued by scarring, poor cosmesis, inadequate restoration of native anatomy and hair, alopecia, donor site morbidity, and potential for failure. Therefore, new reconstructive approaches are warranted, and tissue engineered skin represents an exciting alternative. In this study, we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting (IOB), which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting. Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix (adECM) and stem cells (ADSCs), skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies. adECM, even at a very low concentration such as 2% or less, has shown to be bioprintable via droplet-based bioprinting and exhibitedde novoadipogenic capabilities bothin vitroandin vivo. Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects, accomplishing near-complete wound closure within two weeks. More importantly, both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame. Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.
High diversity, abundance and expression of hydrogenases in groundwater
Authors: Li Shengjie , Mosier Damon , Kouris Angela , Humez Pauline , Mayer Bernhard , Strous Marc , Diao Muhe 
Published: October 2023

AbstractHydrogen may be the most important electron donor available in the subsurface. Here we analyze the diversity, abundance and expression of hydrogenases in 5 proteomes, 25 metagenomes and 265 amplicon datasets of groundwaters with diverse geochemistry. A total of 1,772 new [NiFe]-hydrogenase gene sequences were recovered, which almost doubled the number of sequences in a widely used database. [NiFe]-hydrogenases were highly abundant, almost as abundant as the DNA-directed RNA polymerase. The abundance of hydrogenase genes increased with depth from 0 to 129 m. Hydrogenases were present in 502 out of 1,245 metagenome-assembled-genomes. The populations with hydrogenases accounted for ∼50% of all populations. Hydrogenases were actively expressed, making up as much as 5.9% of methanogen proteomes. Most of the newly discovered diversity of hydrogenases was in “Group 3b”, which was linked to sulfur metabolism. “Group 3d” was the most abundant, which was previously linked to fermentation, but we observed this group mainly in methanotrophs and chemoautotrophs. “Group 3a”, associated with methanogenesis, was the most active in proteomes. Two newly discovered groups of [NiFe]-hydrogenases further expanded the biodiversity. Our results highlight the vast diversity, abundance and expression of hydrogenases in the sampled groundwaters, suggesting a high potential for hydrogen oxidation in subsurface habitats.
A cautionary tale about properly vetting datasets used in supervised learning predicting metabolic pathway involvement
Authors: Huckvale Erik D. , Moseley Hunter N.B. 
Published: October 2023

AbstractThe mapping of metabolite-specific data to pathways within cellular metabolism is a major data analysis step needed for biochemical interpretation. A variety of machine learning approaches, particularly deep learning approaches, have been used to predict these metabolite-to-pathway mappings, utilizing a training dataset of known metabolite-to-pathway mappings. A few such training datasets have been derived from the Kyoto Encyclopedia of Gene and Genomes (KEGG). However, several prior published machine learning approaches utilized an erroneous KEGG-derived training dataset that used SMILES molecular representations strings (KEGG-SMILES dataset) and contained a sizable proportion (∼26%) duplicate entries. The presence of so many duplicates taint the training and testing sets generated from k-fold cross-validation of the KEGG-SMILES dataset. Therefore, the k-fold cross-validation performance of the resulting machine learning models was grossly inflated by the erroneous presence of these duplicate entries. Here we describe and evaluate the KEGG-SMILES dataset so that others may avoid using it. We also identify the prior publications that utilized this erroneous KEGG-SMILES dataset so their machine learning results can be properly and critically evaluated. In addition, we demonstrate the reduction of model k-fold cross-validation performance after de-duplicating the KEGG-SMILES dataset. This is a cautionary tale about properly vetting prior published benchmark datasets before using them in machine learning approaches. We hope others will avoid similar mistakes.
Peptidoglycan-Chi3l1 interaction shapes gut microbiota in intestinal mucus layer
Authors: Chen Yan , Yang Ruizhi , Qi Bin , Shan Zhao 
Published: October 2023

AbstractThe balanced gut microbiota in intestinal mucus layer plays an instrumental role in the health of the host. However, the mechanisms by which the host regulates microbial communities in the mucus layer remain largely unknown. Here, we discovered that the host regulates bacterial colonization in the gut mucus layer by producing a protein called Chitinase 3-like protein 1 (Chi3l1). Intestinal epithelial cells are stimulated by the gut microbiota to express Chi3l1. Once expressed, Chi3l1 is secreted into the mucus layer where it interacts with the gut microbiota, specifically through a component of bacterial cell walls called peptidoglycan. This interaction between Chi3l1 and bacteria is beneficial for the colonization of bacteria in the mucus, particularly for gram-positive bacteria likeLactobacillus. Moreover, a deficiency of Chi3l1 leads to an imbalance in the gut microbiota, which exacerbates colitis induced by dextran sodium sulfate (DSS). By performing fecal microbiota transplantation from Villin-cre mice or replenishingLactobacillusin IECΔChil1mice, we were able to restore their colitis to the same level as that of Villin-cre mice. In summary, this study shows a “scaffold model” for microbiota homeostasis by interaction between intestinal Chi3l1 and bacteria cell wall interaction, and it also highlights that an unbalanced gut microbiota in the intestinal mucus contributes to the development of colitis.
YlaN is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression inStaphylococcus aureus
Authors: Boyd Jeffrey M. , Esquilín-Lebrón Karla , Campbell Courtney J. , Kaler Kylie Ryan , Norambuena Javiera , Foley Mary E. , Stephens Timothy G. , Rios Gustavo , Mereddy Gautam , Zheng Vincent , Bovermann Hannah , Kim Jisun , Kulczyk Arkadiusz W. , Yang Jason H. , Greco Todd M. , Cristea Ileana M. , Carabetta Valerie J. , Beavers William N. , Bhattacharya Debashish , Skaar Eric P. , Parker Dane , Carroll Ronan K. , Stemmler Timothy L. 
Published: October 2023

AbstractIron (Fe) is a trace nutrient required by nearly all organisms. As a result of the demand for Fe and the toxicity of non-chelated cytosolic ionic Fe, regulatory systems have evolved to tightly balance Fe acquisition and usage while limiting overload. In most bacteria, including the mammalian pathogenStaphylococcus aureus, the ferric uptake regulator (Fur) is the primary transcriptional regulator that controls the transcription of genes that code for Fe uptake and utilization proteins. YlaN was demonstrated to be essential inBacillus subtilisunless excess Fe is added to the growth medium, suggesting a role in Fe homeostasis. Here, we demonstrate that YlaN is expendable inS. aureus; however, YlaN became essential upon Fe deprivation. A nullfurallele bypassed the essentiality of YlaN. The transcriptional response of Fur derepression resulted in a reprogramming of metabolism to prioritize fermentative growth over respiratory growth. The absence of YlaN diminished the derepression of Fur-dependent transcription during Fe limitation. Bioinformatic analyses suggest thatylaNwas recruited to Gram positive bacteria and once acquired was maintained in the genome as it co-evolved with Fur. Consistent with a role for YlaN in influencing Fur-dependent regulation, YlaN and Fur interactedin vivo. YlaN bound Fe(II)in vitrousing oxygen or nitrogen ligands with an association constant that is consistent with a physiological role in Fe sensing and/or buffering. These findings have led to a model wherein YlaN is an Fe(II) binding protein that influences Fur-dependent regulation through direct interaction.ImportanceIron (Fe) is an essential nutrient for nearly all organisms. If Fe homeostasis is not maintained, Fe can accumulate in the cytosol where it is toxic. Questions remain about how cells efficiently balance Fe uptake and usage to prevent imbalance. Iron uptake and proper metalation of proteins are essential processes in the mammalian bacterial pathogenStaphylococcus aureus. Understanding the gene products involved in Fe ion regulation, uptake, and usage, as well as the physiological adaptations thatS. aureususes to survive in Fe-depleted conditions, will provide insight into the role that Fe has in pathogenesis. These data will also provide insight into the selective pressures imparted by the mammalian host.
A polarized cell system amenable to subcellular resolution imaging of influenza virus infection
Authors: Jean-Baptiste Brault , Catherine Thouvenot , Magda Cannata Serio , Sylvain Paisant , Julien Fernandes , David Gény , Lydia Danglot , Adeline Mallet , Nadia Naffakh 
Published: October 2023

AbstractThe life cycle of influenza A viruses (IAV), and notably intracellular trafficking of the viral genome, depend on multiple interactions with the cellular cytoskeleton and endomembrane system. A limitation of the conventional cellular models used for mechanistic study and subcellular imaging of IAV infection is that they are cultured in two dimensions (2D) under non-polarizing conditions, and therefore they do not recapitulate the intracellular organization of the polarized respiratory epithelial cells naturally targeted by IAVs. To overcome this limitation, we developed an IAV-infection assay in a 3D cell culture system which allows imaging along the baso-lateral axis of polarized cells, with subcellular resolution. Here we describe a protocol to grow polarized monolayers of Caco2-TC7 cells on static Cytodex-3 microcarrier beads, infect them with IAV, and subsequently perform immunostaining and confocal imaging, or electron microscopy, on polarized IAV-infected cells. This method can be extended to other pathogens that infect human polarized epithelial cells.
Reassessing Fragility: A Comparative Analysis of the Fragility Index With the Relative Risk Index
Authors: Heston Thomas F. 
Published: October 2023

AbstractBackgroundIn biostatistics, assessing the fragility of research findings is crucial for understanding their clinical significance. This study focuses on the fragility index, unit fragility index, and relative risk index as measures to evaluate statistical fragility. The relative risk index quantifies the deviation of observed findings from therapeutic equivalence. In contrast, the fragility indices assess the susceptibility of p-values to change significance with minor alterations in outcomes within a 2×2 contingency table. While the fragility indices have intuitive appeal and have been widely applied, their behavior across a wide range of contingency tables has not been rigorously evaluated.MethodsUsing a Python software program, a simulation approach was employed to generate random 2×2 contingency tables. All tables under consideration exhibited p-values < 0.05 according to Fisher’s exact test. Subsequently, the fragility indices and the relative risk index were calculated. To account for sample size variations, fragility, and risk quotients were also calculated. A correlation matrix assessed the collinearity between each metric and the p-value.ResultsThe analysis included 2,000 contingency tables with cell counts ranging from 20 to 480. Notably, the formulas for calculating the fragility indices encountered limitations when cell counts approached zero or duplicate cell counts hindered standardized application. The correlation coefficients with p-values were as follows: unit fragility index (-0.806), fragility index (-0.802), fragility quotient (-0.715), unit fragility quotient (-0.695), relative risk index (-0.403), and relative risk quotient (-0.261).ConclusionCompared with the relative risk index and quotient, in the context of p-values < 0.05, the fragility indices and their quotients exhibited stronger correlations. This implies that the fragility indices offer limited additional information beyond the p-value alone. In contrast, the relative risk index displays relative independence, suggesting that it provides meaningful insights into statistical fragility by assessing how far observed findings deviate from therapeutic equivalence, regardless of the p-value.
Axonopathy and altered synaptic development in early hippocampal epileptogenesis of Dravet syndrome
Authors: Layer Nikolas , Müller Peter , Ayash Maya , Pfeiffer Friederike , Saile Meret , Klopfer Fabian , Iavarone Stefano , Santuy Andrea , Fallier-Becker Petra , Hedrich Ulrike B. S. , Lerche Holger , Koch Henner , Wuttke Thomas V. 
Published: October 2023

AbstractDravet syndrome caused bySCN1Avariants is a severe developmental epileptic encephalopathy (DEE) characterized by pharmaco-resistant epileptic seizures and progressive neurodevelopmental decline with cognitive impairment and autism-spectrum-traits. Numerous preceding studies indicate that the initial pathophysiology due to impaired NaV1.1 function mainly derives from reduced interneuron firing leading to a network hyperexcitability (Bender et al. 2012). However, little is known how epileptogenesis and generally disease pathogenesis progress from the inborn molecular defect to infantile seizure onset. We address this question in a Dravet mouse model by comprehensive single-cell RNA sequencing and selected downstream analysis via single-cell electrophysiology, histology, live cell imaging and electron microscopy. Our data reveal a continuum of early primary (preseizure) and secondary (post-seizure onset) transcriptomic changes in various cell populations in the hippocampus. Focusing oncornu ammonis, we find a number of transcriptional pathways that are dysregulated including synaptic transmembrane adhesion molecules of the neurexin superfamily and voltage-gated ion channels. Further investigations support an ultrastructural and functional axonopathy and synaptopathy of parvalbumin interneurons. These processes precede somatic firing impairment and seizures suggesting they underlie fundamental early-phase disease mechanisms. Taken together we provide a cellularly resolved transcriptomic resource of early disease phases of Dravet syndrome and demonstrate epileptogenesis beyond NaV1.1 loss-of-function during an early developmental time window of CNS maturation. Altogether these data establish proof-of principle that the concept of epileptogenesis, originally devised for acquired forms of epilepsy, similarly applies to genetic epilepsies and DEEs.
Compact Programmable Control of Protein Secretion in Mammalian Cells
Authors: Vlahos Alexander E. , Call Connor C. , Kadaba Samarth E. , Guo Siqi , Gao Xiaojing J. 
Published: October 2023

AbstractSynthetic biology currently holds immense potential to engineer the spatiotemporal control of intercellular signals for biomedicine. Programming behaviors using protein-based circuits has advantages over traditional gene circuits such as compact delivery and direct interactions with signaling proteins. Previously, we described a generalizable platform called RELEASE to enable the control of intercellular signaling through the proteolytic removal of ER-retention motifs compatible with pre-existing protease-based circuits. However, these tools lacked the ability to reliably program complex expression profiles and required numerous proteases, limiting delivery options. Here, we harness the recruitment and antagonistic behavior of endogenous 14-3-3 proteins to create RELEASE-NOT to turn off protein secretion in response to protease activity. By combining RELEASE and RELEASE-NOT, we establish a suite of protein-level processing and output modules called Compact RELEASE (compRELEASE). This innovation enables functions such as logic processing and analog signal filtering using a single input protease. Furthermore, we demonstrate the compactness of the post-translational design by using polycistronic single transcripts to engineer cells to control protein secretion via lentiviral integration and leverage mRNA delivery to selectively express cell surface proteins only in engineered cells harboring inducible proteases. CompRELEASE enables complex control of protein secretion and enhances the potential of synthetic protein circuits for therapeutic applications, while minimizing the overall genetic payload.