bluuebunny/crossref_metadata_2025_split huggingface dataset:
SIDERITE: Unveiling Hidden Siderophore Diversity in the Chemical Space Through Digital Exploration
Authors: He Ruolin , Gu Shaohua , Xu Jiazheng , Li Xuejian , Chen Haoran , Shao Zhengying , Wang Fanhao , Shao Jiqi , Yin Wen-Bing , Qian Long , Wei Zhong , Li Zhiyuan 
Published: September 2023

AbstractSiderophores, a highly diverse family of secondary metabolites, play a crucial role in facilitating the acquisition of the essential iron. However, the current discovery of siderophore relies largely on manual approaches. In this work, we introduced SIDERTE, a digitized siderophore information database containing 872 siderophore records with 649 unique structures. Leveraging this digitalized dataset, we gained a systematic overview of siderophores by their clustering patterns in the chemical space. Building upon this, we developed a functional group-based method for predicting new iron-binding molecules. Applying this method to 4,314 natural product molecules from TargetMol’s Natural Product Library for high throughput screening, we experimentally confirmed that 40 out of the 48 molecules predicted as siderophore candidates possessed iron-binding abilities. Expanding our approach to the COCONUT natural product database, we predicted a staggering 3,199 siderophore candidates, showcasing remarkable structure diversity that are largely unexplored. Our study provides a valuable resource for accelerating the discovery of novel iron-binding molecules and advancing our understanding towards siderophores.
Single-cell RNA sequencing identifies SLC6A3 as a biomarker and prognostic marker in clear cell renal cell carcinoma
Authors: Narayanan Sathiya Pandi , Gopal Ramani , Jenifer Sebastian Arockia , Masoodi Tariq Ahmad 
Published: September 2023

AbstractBackgroundThe SLC6A3 gene encodes dopamine protein and is a member of the sodium and chloride-dependent neurotransmitter transporter family. While the role of SLC6A3 in Parkinson’s disease is well established, its function in cancer, especially in clear cell renal cell carcinoma (ccRCC), remains unclear.MethodsTo investigate the expression and function of SLC6A3 in ccRCC, we conducted a study using single-cell transcriptomics and bulk RNA sequencing data. We analyzed advanced ccRCC single-cell RNA sequencing profiles, bulk RNA sequencing, and microarray data to assess the expression of SLC6A3 in tumor cells, benign kidney tubule cells, and immune cells.ResultsOur analysis showed that SLC6A3 expression is specific to ccRCC tumor cells and is not present in benign kidney tubule cells or immune cells of benign kidney and kidney tumors. Further, we found an elevated expression of SLC6A3 in ccRCC tumors compared to the benign kidney. Receiver operating characteristics analysis suggests that SLC6A3 is highly sensitive and specific to ccRCC. Additionally, we found a correlation between HNF4A signaling and SLC6A3 expression in two independent mRNA expression profiles. Interestingly, elevated expression of SLC6A3 is a predictor of better overall and progression-free survival of ccRCC patients.ConclusionsOur findings suggest that SLC6A3 is a potential diagnostic and prognostic marker for ccRCC. The study highlights the importance of understanding the role of SLC6A3 in cancer and provides new insights into ccRCC diagnosis and treatment.
A single-cell atlas of pig gastrulation as a resource for comparative embryology
Authors: Simpson Luke , Strange Andrew , Klisch Doris , Kraunsoe Sophie , Azami Takuya , Goszczynski Daniel , Le Triet , Planells Benjamin , Holmes Nadine , Sang Fei , Henson Sonal , Loose Matthew , Nichols Jennifer , Alberio Ramiro 
Published: September 2023

AbstractEarly mammalian gastrulation’s cell-fate decisions are poorly understood due to difficulties obtaining non-rodent embryos. The bilaminar disc of pig embryos mirrors humans, making them a useful proxy for studying gastrulation. Here we present a single-cell transcriptomic atlas of pig gastrulation, revealing cell-fate emergence dynamics, as well as conserved and divergent gene programs governing early porcine, primate, and murine development. We highlight heterochronicity in extraembryonic cell-type development, despite the broad conservation of cell-type-specific transcriptional programs. We apply these findings in combination with functional investigations, to outline conserved spatial, molecular, and temporal events during definitive endoderm (DE). We find early FOXA2+/TBXT-embryonic disc cells directly from DE, contrasting later-emerging FOXA2/TBXT+ node/notochord progenitors. Unlike mesoderm, none of these progenitors undergo epithelial-to-mesenchymal transition. DE/Node fate hinges on balanced WNT and hypoblast-derived NODAL, which is extinguished upon DE differentiation. These findings emphasise the interplay between temporal and topological signalling in early fate decisions during gastrulation.
Metabolic Dependency Shapes Bivalent Antiviral Response in Host Cells in response to poly:IC: The Role of Glutamine
Authors: Lebeau Grégorie , Paulo-Ramos Aurélie , Hoarau Mathilde , El Safadi Daed , Meilhac Olivier , Krejbich-Trotot Pascale , Roche Marjolaine , Viranaicken Wildriss 
Published: September 2023

AbstractThe establishment of effective antiviral responses within host cells is intricately related to their metabolic status, shedding light on immunometabolism. In this study, we investigated the hypothesis that cellular reliance on glutamine metabolism contributes to the development of a potent antiviral response. We evaluated the antiviral response in the presence or absence of L-glutamine in the culture medium, revealing a bivalent response hinging on cellular metabolism. While certain interferon-stimulated genes (ISGs) exhibited higher expression in an oxidative phosphorylation (OXPHOS)-dependent manner, others were surprisingly upregulated in a glycolytic-dependent manner. This metabolic dichotomy was influenced in part by variations in IFN-β expression. We initially demonstrated that the presence of L-glutamine induced an enhancement of OXPHOS in A549 cells. Furthermore, in cells either stimulated poly:IC or infected with Dengue Virus and Zika Virus, a marked increase in ISGs expression was observed in a dose-dependent manner with L-glutamine supplementation. Interestingly, our findings unveiled a metabolic dependency in the expression of specific ISGs. In particular, genes such as ISG54, ISG12 and ISG15 exhibited heightened expression in cells cultured with L-glutamine, corresponding to higher OXPHOS rates and IFN-β signaling. Conversely, the expression of viperin and 2’-5’-oligoadenylate synthetase 1 was inversely related to L-glutamine concentration, suggesting a glycolysis-dependent regulation, confirmed by inhibition experiments. This study highlights the intricate interplay between cellular metabolism, especially glutaminergic and glycolytic, and the establishment of the canonical antiviral response characterized by the expression of antiviral effectors, potentially paving the way for novel strategies to modulate antiviral responses through metabolic interventions.
Single-cell immune multi-omics and repertoire analyses in pancreatic ductal adenocarcinoma reveal differential immunosuppressive mechanisms within different tumour microenvironments
Authors: Sivakumar Shivan , Jainarayanan Ashwin , Arbe-Barnes Edward , Sharma Piyush Kumar , Leathlobhair Maire Ni , Amin Sakina , Heij Lara , Hegde Samarth , Magen Assaf , Tucci Felicia , Sun Bo , Wu Shihong , Anand Nithishwer Mouroug , Slawinski Hubert , Revale Santiago , Nassiri Isar , Webber Jonathon , Frampton Adam , Wiltberger Georg , Neumann Ulf , Charlton Philip , Spiers Laura , Elliott Tim , Sivakumar Pallavur V. , Ratushny Alexander V. , Middleton Mark , Peppa Dimitra , Fairfax Benjamin , Merad Miriam , Dustin Michael L. , Abu-Shah Enas , Bashford-Rogers Rachael 
Published: September 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Understanding the multiple mechanisms by which the tumour evades immune control, and how these mechanisms may be disrupted is critical to developing targeted immunotherapies. Previous studies have shown that higher lymphocyte infiltration is associated with better survival, and here we investigated what mediates these differences. We performed a comprehensive analysis of PDAC-associated immune cells using single cell multi-omics coupled with re-analysis of public PDAC scRNA-seq datasets. We introduce novel single-cell and repertoire analyses that have uncoupled diverse roles and contributions of various immune cell populations within different tumour microenvironments (TMEs). They revealed clear distinctions in the clonal characteristics among different patient groups, provided valuable insights into the mechanisms of immune cell migration and tissue adaptation underlying these disparities. These results point to differential CD4 polarisation of intra-tumoural T cells, differential B cell differentiation, GC reactions, antigen presentation pathways, and distinct cell-cell communication between the myeloid-enriched and adaptive-enriched groups. Overall, we identified two major distinct themes for future immune intervention within PDAC patients between those with higher adaptive versus myeloid immune cell infiltration.
Exploring the Druggable Conformational Space of Protein Kinases Using AI-Generated Structures
Authors: Herrington Noah B. , Stein David , Li Yan Chak , Pandey Gaurav , Schlessinger Avner 
Published: September 2023

AbstractProtein kinase function and interactions with drugs are controlled in part by the movement of the DFG and ɑC-Helix motifs, which enable kinases to adopt various conformational states. Small molecule ligands elicit therapeutic effects with distinct selectivity profiles and residence times that often depend on the kinase conformation(s) they bind. However, the limited availability of experimentally determined structural data for kinases in inactive states restricts drug discovery efforts for this major protein family. Modern AI-based structural modeling methods hold potential for exploring the previously experimentally uncharted druggable conformational space for kinases. Here, we first evaluated the currently explored conformational space of kinases in the PDB and models generated by AlphaFold2 (AF2) (1) and ESMFold (2), two prominent AI-based structure prediction methods. We then investigated AF2’s ability to predict kinase structures in different conformations at various multiple sequence alignment (MSA) depths, based on this parameter’s ability to explore conformational diversity. Our results showed a bias within the PDB and predicted structural models generated by AF2 and ESMFold toward structures of kinases in the active state over alternative conformations, particularly those conformations controlled by the DFG motif. Finally, we demonstrate that predicting kinase structures using AF2 at lower MSA depths allows the exploration of the space of these alternative conformations, including identifying previously unobserved conformations for 398 kinases. The results of our analysis of structural modeling by AF2 create a new avenue for the pursuit of new therapeutic agents against a notoriously difficult-to-target family of proteins.Significance StatementGreater abundance of kinase structural data in inactive conformations, currently lacking in structural databases, would improve our understanding of how protein kinases function and expand drug discovery and development for this family of therapeutic targets. Modern approaches utilizing artificial intelligence and machine learning have potential for efficiently capturing novel protein conformations. We provide evidence for a bias within AlphaFold2 and ESMFold to predict structures of kinases in their active states, similar to their overrepresentation in the PDB. We show that lowering the AlphaFold2 algorithm’s multiple sequence alignment depth can help explore kinase conformational space more broadly. It can also enable the prediction of hundreds of kinase structures in novel conformations, many of whose models are likely viable for drug discovery.
Multifaceted proteome analysis at solubility, redox, and expression dimensions for target identification
Authors: Saei Amir Ata , Lundin Albin , Lyu Hezheng , Gharibi Hassan , Luo Huqiao , Teppo Jaakko , Zhang Xuepei , Gaetani Massimiliano , Végvári Ákos , Holmdahl Rikard , Gygi Steven P. , Zubarev Roman A. 
Published: September 2023

AbstractMultifaceted interrogation of the proteome deepens the system-wide understanding of biological systems; however, mapping the redox changes in the proteome has so far been significantly more challenging than expression and solubility/stability analyses. Here, we devise the first high- throughput redox proteomics approach integrated with expression analysis (REX) and combine it with Proteome Integral Solubility Alteration (PISA) assay. The whole PISA-REX experiment with up to four biological replicates can be multiplexed into a single tandem mass tag TMTpro set. For benchmarking this compact tool, we analyzed HCT116 cells treated with auranofin, showing great improvement compared with previous such studies. Then we applied PISA-REX to study proteome remodeling upon stimulation of human monocytes by interferon α. We also studied the proteome changes in plasmacytoid dendritic cells isolated from wild type vs.Ncf1- mutant mice treated with interferon α, showing that NCF1 deficiency enhances the STAT1 pathway and modulates the expression, solubility and redox state of interferon-induced proteins. Providing comprehensive multifaceted information on the proteome, the compact PISA-REX has the potential to become an industry standard in proteomics and to open new windows into the biology of health and disease.
AToxoplasma gondiiputative arginine transporter localizes to the plant-like vacuolar compartment and controls parasite extracellular survival and stage differentiation
Authors: Piro Federica , Masci Silvia , Kannan Geetha , Focaia Riccardo , Schultz Tracey L. , Carruthers Vern B. , Di Cristina Manlio 
Published: September 2023

AbstractToxoplasma gondiiis a protozoan parasite that infects a broad spectrum of hosts and can colonize many organs and cell types. The ability to reside within a wide range of different niches requires substantial adaptability to diverse microenvironments. Very little is known about how this parasite senses various milieus and adapts its metabolism to survive, replicate during the acute stage, and then differentiate to the chronic stage. Most eukaryotes, from yeast to mammals, rely on a nutrient sensing machinery involving the TORC complex as master regulator of cell growth and cell cycle progression. The lysosome functions as a signaling hub where TORC complex assembles and is activated by transceptors, which both sense and transport amino acids, including the arginine transceptor SLC38A9. While most of the TORC components are lost inT. gondii, indicating the evolution of a distinct nutrient sensing mechanism, the parasite’s lysosomal plant-like vacuolar compartment (PLVAC) may still serve as a sensory platform for controlling parasite growth and differentiation. Using SLC38A9 to query theT. gondiiproteome, we identified four putative amino acid transporters, termed TgAAT1-4, that structurally resemble the SLC38A9 arginine transceptor. Assessing their expression and sub-cellular localization, we found that one of them, TgAAT1, localized to the PLVAC and is necessary for normal parasite extracellular survival and bradyzoite differentiation. Moreover, we show that TgAAT1 is involved in the PLVAC efflux of arginine, an amino acid playing a key role inT. gondiidifferentiation, further supporting the hypothesis that TgAAT1 might play a role in nutrient sensing.IMPORTANCET. gondiiis a highly successful parasite infecting a broad range of warm-blood organisms including about one third of all humans. AlthoughToxoplasmainfections rarely result in symptomatic disease in individuals with a healthy immune system, the incredibly high number of persons infected along with the risk of severe infection in immunocompromised patients and the potential link of chronic infection to mental disorders make this infection a significant public health concern. As a result, there is a pressing need for new treatment approaches that are both effective and well-tolerated. The limitations in understanding howToxoplasma gondiimanages its metabolism to adapt to changing environments and triggers its transformation into bradyzoites have hindered the discovery of vulnerabilities in its metabolic pathways or nutrient acquisition mechanisms to identify new therapeutic targets. In this work, we have shown that the lysosome-like organelle PLVAC, acting through the putative arginine transporter TgAAT1, plays a pivotal role in regulating the parasite’s extracellular survival and differentiation into bradyzoites.
Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway
Authors: Park Jooman , Hu Ruoci , Xiong Shaolei , Qian Yanyu , El-Sabbagh Asma Sana , Ibrahim Meram , Song Qing , Yan Gege , Song Zhenyuan , Mahmoud Abeer M. , He Yanlin , Layden Brian T. , Chen Jiwang , Ong Sang-Ging , Xu Pingwen , Jiang Yuwei 
Published: September 2023

AbstractThermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age, to mice can counteract the aging- related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process.HighlightsEstrogen restores beige adipocyte failure along with improved energy metabolism in old mice.Estrogen enhances the thermogenic gene program by mitigating age-induced ER stress.Estrogen enhances the beige adipogenesis derived from SMA+ APCs.Inhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis.
The Quest for Dynamic Consistency — A Comparison of OpenSim Tools for Residual Reduction in Simulations of Human Running
Authors: Fox Aaron S. 
Published: September 2023

AbstractThe use of synchronous kinematic and kinetic data in simulations of human running will typically lead to dynamic inconsistencies (i.e. residual forces and moments) being present. Minimising the residual forces and moments in such simulations is important to ensure plausible model outputs (e.g. joint moments, muscle forces) are obtained. A variety of approaches suitable for residual reduction are available in OpenSim, however a detailed comparison of these is yet to be conducted. This study compared a variety of OpenSim tools applicable for residual reduction in simulations of human running. A series of approaches (i.e. singular and iterative Residual Reduction Algorithm,MocoTrack, AddBiomechanics) designed to reduce residual forces and moments were examined using an existing dataset of 10 male participants running on a treadmill at 5.0 m·s-1(n= 3 gait cycles per participant). The computational time, resultant residual forces and moments, and output joint kinematics and kinetics from each approach were compared. A computational cost to residual reduction trade-off was identified, where lower residual forces and moments were achieved using approaches that required longer computational times. All of the tested approaches regularly reduced residual forces below recommended thresholds, however only theMocoTrackapproach could consistently achieve acceptable levels for residual moments. TheAddBiomechanicsandMocoTrackapproaches produced variable lower and upper body kinematics, respectively, versus the remaining approaches; with minimal other qualitative differences were identified between joint kinematics from each approach. Joint kinetics were qualitatively similar between approaches, howeverMocoTrackgenerated much noisier joint kinetic signals. TheMocoTrackapproach was the most consistent and best performing approach for reducing residuals to near-zero levels, at the cost of longer computational times and potentially noisier joint kinetic signals. This study provides OpenSim users with evidence to inform decision-making at the residual reduction step of their modelling and simulation workflow when analysing human running.
Versatile Tissue-Injectable Hydrogels with Extended Hydrolytic Release of Bioactive Protein Therapeutics
Authors: Nealy Eric S. , Reed Steven J. , Adelmund Steve M. , Badeau Barry A. , Shadish Jared A. , Girard Emily J. , Pakiam Fiona J. , Mhyre Andrew J. , Price Jason P. , Sarkar Surojit , Kalia Vandana , DeForest Cole A. , Olson James M. 
Published: September 2023

AbstractHydrogels generally have broad utilization in healthcare due to their tunable structures, high water content, and inherent biocompatibility. FDA-approved applications of hydrogels include spinal cord regeneration, skin fillers, and local therapeutic delivery. Drawbacks exist in the clinical hydrogel space, largely pertaining to inconsistent therapeutic exposure, short-lived release windows, and difficulties inserting the polymer into tissue. In this study, we engineered injectable, biocompatible hydrogels that function as a local protein therapeutic depot with a high degree of user-customizability. We showcase a PEG-based hydrogel functionalized with bioorthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) handles for its polymerization and functionalization with a variety of payloads. Small-molecule and protein cargos, including chemokines and antibodies, were site-specifically modified with hydrolysable “azidoesters” of varying hydrophobicity via direct chemical conjugation or sortase-mediated transpeptidation. These hydrolysable esters afforded extended release of payloads linked to our hydrogels beyond diffusion; with timescales spanning days to months dependent on ester hydrophobicity. Injected hydrogels polymerizein situand remain in tissue over extended periods of time. Hydrogel-delivered protein payloads elicit biological activity after being modified with SPAAC-compatible linkers, as demonstrated by the successful recruitment of murine T-cells to a mouse melanoma model by hydrolytically released murine CXCL10. These results highlight a highly versatile, customizable hydrogel-based delivery system for local delivery of protein therapeutics with payload release profiles appropriate for a variety of clinical needs.Translational ImpactWe developed injectable hydrogels that provide loco-regional, controlled release of protein therapeutics. Local delivery is especially suitable for potent, protein-based drugs like chemokines and monoclonal antibodies whose systemic toxicities can be life threatening. Our hydrogel is equipped with slowly hydrolyzing linkers for transient payload coupling, prolonging its therapeutic window and minimizing the need for repeat surgeries in a clinical setting. A range of release profiles, spanning days to over a month, and a broad compatibility to therapeutically relevant, recombinant proteins provide clinicians with flexible therapeutic options to suit a variety of circumstances.