bluuebunny/crossref_metadata_2025_split huggingface dataset:
Constructing a holistic map of cell fate decision by hyper solution landscape
Authors: Zhang Xiaoyi , Li Zhiyuan , Zhang Lei 
Published: December 2024

SummaryThe Waddington landscape metaphor has inspired extensive quantitative studies of cell fate decisions using dynamical systems. While these approaches provide valuable insights, the intrinsic nonlinear complexity and the parameter dependence limits systematic analysis of fate transitions. Here, we introduce the Hyper Solution Landscape (HSL), a parameter-independent methodology showing a comprehensive structure of all possible landscape configurations for gene regulatory networks. Building on the concept of solution landscape that primarily captures the complete stationary points in static landscape, HSL connects different solution landscapes to reflect dynamic changes of the landscapes associated with bifurcations. Applied to the Cross-Inhibition with Self-activation motif, HSL analysis identifies key hyperparameters driving distinct directional changes in cell fate propensity. Importantly, different routes through the HSL between the same initial and final states can produce markedly different fate distributions. This enables rational design of transition strategies. We validate HSL’s utility in the seesaw model of cellular reprogramming, establishing a powerful framework for understanding and engineering cell fate decisions.
The impact of taxonomic change on the Amazonian palm flora
Authors: Stropp Juliana , Pereira Andreza S. S. , Emilio Thaise , Meyer Leila , Trad Rafaela , Alves-Martins Fernanda , Ladle Richard J. , Hortal Joaquín 
Published: December 2024

AbstractAlthough species taxonomy is an ever-evolving discipline, taxonomic change is rarely accounted for in macroecological studies. By tracking the history of species description and synonymizations of more than 900 described names of Amazonian palms, we reveal shifts in species counts across space and time, the factors associated with taxonomic lumping, and the time needed to detect synonyms. The Amazonian palm flora results from a gradual accumulation of new descriptions, followed by decline due to the recognition of approximately 800 heterotypic synonyms. Most of these synonyms were detected in the mid-1990s, leading to a 4.5-fold decrease in species counts in ten years. The time to detect synonyms ranged from 3 to 227 years. Species with large populations, widespread distributions, early descriptions, also those that occur in Western Amazonia were more frequently lumped. The impact of taxonomic change on species counts is dependent on taxa, region, and time period considered. Biases in these counts are pronounced in the absence of taxonomic revisions, as undetected synonyms can inflate estimates of species richness. By quantifying the magnitude of such bias, this study offers conceptual and methodological insights on how incorporating taxonomic progress into macroecological analyses can provide a more accurate understanding of biodiversity patterns.
NKG2A-mediated immune modulation of natural killer cells byStaphylococcus aureus
Authors: Davies Kate , Rizek Al-Motaz , Kollnberger Simon , Wang Eddie C. Y. , Eberl Matthias , Underwood Jonathan , McLaren James E. 
Published: December 2024

ABSTRACTNatural killer (NK) cells are specialized lymphocytes that help protect against viruses and cancer. However, in the context of bacterial infections, NK cells can be harmful, rather than protective. Such immune pathogenesis by NK cells has been linked to the over-production of pro-inflammatory cytokines like interferon-γ (IFN-γ). In this context, IFN-γ-deficient mice display increased survival rates in response toStaphylococcus aureus(S. aureus), which causes life-threatening, invasive systemic infections with high mortality rates in humans. However, little is known about how NK cells respond toS. aureusin humans. In this study, we found that the peripheral blood of patients with bloodstreamS. aureusinfection was enriched for NKG2A+NK cells with greater cytokine producing capacity, compared to those hospitalized withEscherichia colibloodstream infections. As a possible mechanistic cause, superantigens fromS. aureuspromoted the expansion of CD57−NKG2A+NK cells which produced IFN-γ through an IL-12-independent mechanism and exhibited reduced levels of CD16 compared to unstimulated NK cells. These data suggest thatS. aureusbloodstream infection in humans promotes a phenotypic shift towards NKG2A+NK cells with greater IFN-γ producing capacity, providing a plausible way to promote inflammation-driven disease pathogenesis.AUTHOR SUMMARYNatural Killer (NK) cells are specialized immune cells that provide crucial defence against viruses but can also respond to bacterial infections, especially in humans. During bloodstream infection byStaphylococcus aureus, a Gram-positive bacterial pathogen that causes life-threatening infections in humans, NK cells may actually be harmful, rather than protective, to the host. However, very little is known about the NK cell response to invasiveStaphylococcus aureusinfections in humans. Here, we show that human patients with bloodstreamStaphylococcus aureus, but notEscherichia coli, infections have an increased frequency of NK cells with increased pro-inflammatory capacity. Furthermore, we show that toxins produced byStaphylococcus aureus, which help the bacteria evade the protective effects of T cells the immune system (“superantigens”), promoted the expansion of these pro-inflammatory NK cells, providing a possible mechanistic cause for their increased presence in patients with bloodstreamStaphylococcus aureusinfections. Collectively, these results suggest thatStaphylococcus aureusinfection triggers phenotypic and functional changes in NK cells that provide a plausible way to promote inflammation-driven disease pathogenesis
Tracking antigen-specific T cell response to cancer immunotherapy
Authors: Shagina I.A. , Nakonechanaya T.O. , Izosimova A.V. , Yuzhakova D.V. , Skatova V.D. , Lupyr K.R. , Izraelson M. , Davydov A.N. , Shugay M. , Britanova O.V. , Chudakov D.M. , Sharonov G.V. 
Published: December 2024

AbstractIn each human or model animal, T cell receptor (TCR) of each effector/memory T cell clone recognizes from one to several cognate peptide-MHC complexes (pMHC). Limited knowledge on TCR repertoire specificities restricts our capacity to rationally interpret this information, both diagnostically and in preclinical research. Here we 1) develop cost-efficient wet lab and computational pipeline to identify mouse TCRs specific to particular peptides, 2) produce dataset of helper T cells (Th) TCR beta CDR3s specific to B16 melanoma neoantigens in the I-Ab pMHCII context, available in VDJdb, and 3) apply this dataset to track tumor-specific T cell response to the CTLA4 blocking immunotherapy on orthotopic B16 melanoma model. We show that tumor promotes clonally independent Tregs carrying tumor-specific TCRs characteristic for Th cells. We further show that CTLA4 blockade promotes Th clonal expansion and induces general, non-tumor-specific Th-to-Treg plasticity. Altogether, we provide a universal pipeline for the investigation of mouse T cell responses at the antigen-specific level, facilitating development and validation of immunotherapeutic and vaccination approaches.
Generative AI divide: How College Students’ Backgrounds Affect Their Gen AI Literacy
Authors: Jiang Jingbo , Shao Aiqun 
Published: December 2024

AbstractIn the field of education, generative artificial intelligence has a profound impact, mainly reflected in areas such as personalized learning, automated assignment evaluation, content generation, and open educational resources. However, some scholars have begun to discuss whether this technology may lead to new inequalities. Therefore, this study aims to explore how user background affects the performance of generative artificial intelligence technology through empirical research while focusing on the potential educational inequalities that may arise in the era of generative AI. The research found that generative artificial intelligence literacy is correlated with grade level, institutional tier, and academic discipline, with higher-grade students, those from prestigious universities, and those studying Applied Sciences and Natural Sciences demonstrating better performance.
Association of the timing and type of acute symptomatic seizures with post-stroke epilepsy and mortality
Authors: Schubert Kai Michael , Zieglgänsberger Dominik , Bicciato Giulio , Abraira Laura , Santamarina Estevo , Álvarez-Sabín José , Ferreira-Atuesta Carolina , Katan Mira , Sinka Lucia , Terziev Robert , Döhler Nico , Erdélyi-Canavese Barbara , Felbecker Ansgar , Siebel Philip , Winklehner Michael , von Oertzen Tim J , Wagner Judith N. , Gigli Gian Luigi , Nilo Annacarmen , Janes Francesco , Merlino Giovanni , Valente Mariarosaria , Zafra-Sierra María Paula , Mayor-Romero Luis Carlos , Conrad Julian , Evers Stefan , Alet Matias , Fukuma Kazuki , Ihara Masafumi , Landau Benjamin , Lochner Piergiorgio , Roell Frauke , Brigo Francesco , Bentes Carla , Peralta Ana Rita , Pinho e Melo Teresa , Keezer Mark R , Duncan John S , Sander Josemir W , Tettenborn Barbara , Koepp Matthias J , Galovic Marian 
Published: December 2024

AbstractBackgroundAcute symptomatic seizures (ASyS) increase the risk of epilepsy and mortality after a stroke. The impact of the timing and type of ASyS remains unclear.MethodsThis multicenter cohort study included data from nine centers between 2002 and 2018, with final analysis in February 2024. The study included 4,552 adults (2,005 female; median age 73 years) with ischemic stroke and no seizure history. We examined ASyS occurring within seven days after stroke. Main outcomes were all-cause mortality and epilepsy. Validation in three separate cohorts included 74 adults with ASyS.ResultsThe ten-year risk of post-stroke epilepsy ranged from 41% to 94%, and mortality from 36% to 100%, depending on ASyS type and timing. ASyS on stroke onset day had a higher epilepsy risk (aHR 2.3, 95% CI 1.3-4.0, p=0.003) compared to later ASyS. Status epilepticus had the highest epilepsy risk (aHR 9.6, 95% CI 3.5-26.7, p<0.001), followed by focal to bilateral tonic-clonic seizures (aHR 3.4, 95% CI 1.9-6.3, p<0.001). Mortality was higher in those with ASyS presenting as focal to bilateral tonic-clonic seizures on day 0 (aHR 2.8, 95% CI 1.4-5.6, p=0.004) and status epilepticus (aHR 14.2, 95% CI 3.5-58.8, p<0.001). The novel SeLECT-ASyS model, available as an app, outperformed a previous model in the derivation cohort (concordance statistic 0.68 vs. 0.58, p=0.02) and in the validation cohort (0.70 vs. 0.50, p=0.18).ConclusionsASyS timing and type significantly affect epilepsy and mortality risk after stroke, improving epilepsy prediction and guiding patient counseling.
Generative AI and genetic analyses indicate metformin as a drug repurposing candidate for normal tension glaucoma
Authors: Jiang Junhong , Hu Di , Zhang Qi , Lin Zenan 
Published: December 2024

AbstractBackgroundThe normal tension glaucoma (NTG) has limited drug options since current anti-glaucoma medications are mostly designed to decrease intraocular pressure (IOP). The emerging generative artificial intelligence (GAI) may provide an unprecedented approach for its drug repurposing research.MethodsFirst, we iteratively interactivated with ChatGPT using 10 independent queries. Each query consists of two prompts, which asked ChatGPT to offer 20 drug repurposing candidates (DRCs) for NTG. The same process was employed to find DRCs with other two GAI models (i.e Google Gemini Advance and Anthropic Claude). The DRCs were quantified and ranked by their appearing frequency and orders. By tasking GAI and DrugBank database, the targets for the selected DRCs were identified. Then, the ChEMBL database was utilized to find the target-associated genes. The relevant instrumental variables (IVs) mapped to these genes were then identified with the GTEX dataset. In order to quantify the drugs’ effect, the mediation exposures (e.g. HbA1c for metformin) for the identified drugs were introduced to the single SNP mendelian randomization (SSMR) to filter the IVs with significant causal influence on the mediation traits. The filtered IVs were then utilized to measure the DRCs’ causal effect on NTG.ResultsOur results showed that three drugs (i.e. Metformin, Losartan, Mementine) appeared simultaneously in the suggesting lists generated by three GAI models. By utilizing GAI and DrugBank database, 8, 2 and 7 targets were identified for them, respectively. After searching ChEMBL and GTEx, the targets associated genes were identified for selecting corresponding IVs. Finaly, the SSMR kept 308 IVs for metformin, 11 for losartan, 180 for memantine. Applying the target-based MR, we found that, metformin may exert causal influence on NTG through targets GLP-1 and gluconeogenic enzymes, while no obvious causal links were detected in the study on losartan and mementine.ConclusionsOur results offered novel evidences to support the metformin’s repurposing in NTG patients. Moreover, we firstly proposed a novel paradigm consisting of GAI and genetic tools, which could serve as an effective pipeline for drug repurposing investigations of other diseases.
Advance Transfer Learning Approach for Identification of Multiclass Skin Disease with LIME Explainable AI Technique
Authors: Mahmud Muhammad Zawad , Reza Md Shihab , Alve Shahran Rahman , Islam Samiha , Fahmid Nafis 
Published: December 2024

AbstractIn dermatological diagnosis, accurately and appropriately classifying skin diseases is crucial for timely treatment, thereby improving patient outcomes. Our goal is to develop transfer learning models that can detect skin disease from images. We performed our study in the “Skin Cancer: MNIST HAM10000” dataset. This dataset has seven categories, including melanocytic nevi, melanoma, benign keratosis (solar lentigo/seborrheic keratosis), basal cell carcinoma, actinic keratoses, intraepithelial carcinoma (Bowen’s disease), vascular lesions, and more. To leverage pre-trained feature extraction, we use five available models—ResNet50, InceptionV3, VGG16, VGG19, and MobileNetV2. Overall results from these models show that ResNet50 is the least time-intensive and has the best accuracy (99%) in comparison to other classification performances. Interestingly, with a notable accuracy of 97.5%, MobileNetV2 also seems to be adequate in scenarios with less computational power than ResNet50. Finally, to interpret our black box model, we have used LIME as an explainable AI technique (XAI) to identify how the model is classifying the disease. The results emphasize the utility of transfer learning for optimizing diagnostic accuracy in skin disease classification, blending performance and resource efficiency as desired. The findings from this study may contribute to the development of automated tools for dermatological diagnosis and enable clinicians to reduce skin conditions in a timely manner.
Hydrogel encapsulation of a designed fluorescent protein biosensor for continuous measurements of sub-100 nanomolar nicotine
Authors: Nichols Aaron L. , Marotta Christopher B. , Wagenaar Daniel A. , Mayo Stephen L. , Dougherty Dennis A. , Lester Henry A. 
Published: December 2024

ABSTRACTThe reinforcing and addictive properties of nicotine result from concentration- and time-dependent activation, desensitization, and upregulation of nicotinic acetylcholine receptors. However, time-resolved [nicotine] measurement in people who consume nicotine is challenging, as current approaches are expensive, invasive, tedious, and discontinuous. To address the challenge of continuous nicotine monitoring in human biofluids, we report the encapsulation of a purified, previously developed fluorescent biosensor protein, iNicSnFR12, into acrylamide hydrogels and polyethylene glycol diacrylate (PEGDA) hydrogels. We optimized the hydrogels for optical clarity and straightforward slicing. With fluorescence photometry of the hydrogels in a microscope and an integrated miniscope, [nicotine] is detected within a few min at the smoking- and vaping-relevant level of 10 - 100 nM (1.62 – 16.2 ng/ml), even in a 250 µm thick hydrogel at the end of 400 µm dia multimode fiber optic. Concentration-response relations are consistent with previous measurements on isolated iNicSnFR12. Leaching of iN-icSnFR12 from the hydrogel and inactivation of iNicSnFR12 are minimal for several days, and nicotine can be detected for at least 10 months after casting. This work provides the molecular, photophysical, and mechanical bases for personal, wearable continuous [nicotine] monitoring, with straightforward extensions to existing, homologous “iDrugSnFR” proteins for other abused and prescribed drugs.
Glucose-6-phosphatase is required for organelle reorganization, energy metabolism and motility ofDrosophilasperm
Authors: Hedjazi Sheida , Miyamoto Tetsuya , Ahn Ji-Eun , Sitcheran Raquel M. , Amrein Hubert 
Published: December 2024

SUMMARYGlucose-6-Phosphatase (G6Pase), a key enzyme in gluconeogenesis and glycogenolysis in the mammalian liver and kidney, converts glucose-6-phosphate to glucose for maintaining systemic blood glucose homeostasis during nutrient deprivation. However, its function has remained elusive in insects, which have no need for G6Pase in sugar homeostasis since they convert glucose-6-phosphate to trehalose, their main circulating sugar, via trehalose phosphate synthase (TPS1). In this study we identify an unexpected and essential requirement for G6Pase inDrosophilamale fertility, specifically to produce motile sperm. InG6Pmutant males, spermatogenesis and spermiogenesis appear to proceed normally, leading to the production and transfer of mature sperm. However, once inside the female reproductive tract,G6Pmutant sperm exhibit severely reduced tail beat frequency and only rarely enter an egg. Moreover, when compared to wild type sperm,G6P-deficient sperm are depleted more rapidly from the spermatheca and seminal receptacle, the female sperm storage organs. Immunohistochemical analyses show thatG6Pmutant spermatocytes present with an enlarged and stressed endoplasmic reticulum (ER) and a diminished Golgi apparatus. Additionally, the acrosome, a Golgi derived organelle that is critical for sperm capacitation, exhibits diminished expression of the transmembrane protein SNEAKY, which is essential to breakdown the sperm plasma membrane after fertilization. Metabolic analyses show impairment of both basal and compensatory glycolysis, as well as ATP production, in testes ofG6Pmutant males. Taken together, our investigations unveil a novel and crucial function for G6Pase in male fertility, highlighting its importance in regulating energy homeostasis in reproductive tissues.
A distinct mechanism of RNA recognition by the transcription factor GATA1
Authors: Ugay Daniella A. , Batey Robert T. , Wuttke Deborah S. 
Published: December 2024

ABSTRACTSeveral human transcription factors (TFs) have been reported to directly bind RNA through non-canonical RNA-binding domains; however, most of these TFs remain to be further validated asbona fideRNA-binding proteins (RBPs). Our systematic analysis of RBP discovery datasets reveals a varied set of candidate TF-RBPs that encompass most TF families. These candidate RBPs include members of the GATA family, which are essential factors in embryonic development. Investigation of the RNA-binding features of GATA1, a major hematopoietic TF, reveals robust non-sequence specific binding to RNAsin vitro. Moreover, RNA binding by GATA1 is competitive with DNA binding, which occurs through a shared binding surface spanning the DNA-binding domain and arginine-rich motif (ARM) like domain. We show that the ARM-like domain contributes both substantially to high-affinity DNA binding and electrostatically to plastic RNA recognition, suggesting that the separable RBD assigned to the ARM-domain in GATA1 is an oversimplification of a more complex recognition network. These biochemical data demonstrate a unified integration of DNA- and RNA-binding surfaces within GATA1, whereby the ARM-like domain provides an electrostatic surface for RNA binding but does not fully dominate GATA1-RNA interactions, which may also apply to other TF-RBPs. This competitive DNA/RNA binding activity using overlapping nucleic acid binding regions points to the possibility of RNA-mediated regulation of GATA1 function during hematopoiesis. Our study highlights the multifunctionality of DNA-binding domains in RNA recognition and supports the need for robust characterization of predicted non-canonical RNA-binding domains such as ARM-like domains.
The molecular basis of integrated stress response silencing
Authors: Yang Zhi , Haakonsen Diane L. , Heider Michael , Witus Samuel R. , Zelter Alex , Beschauner Tobias , MacCoss Michael J. , Rapé Michael 
Published: December 2024

AbstractChronic stress response activation impairs cell survival and causes devastating degenerative diseases. To counteract this, cells deploy dedicated silencing factors, such as the E3 ligase SIFI that terminates the mitochondrial stress response. How a single enzyme can sense stress across cells and elicit timely stress response inactivation is poorly understood. Here, we report the structure of human SIFI, which revealed how this 1.3MDa complex can target hundreds of proteins for accurate stress response silencing. SIFI attaches the first ubiquitin to substrates using flexible domains within an easily accessible scaffold, yet builds linkage-specific ubiquitin chains at distinct, sterically restricted elongation modules in its periphery. Ubiquitin handover via a ubiquitin-like domain couples versatile substrate modification to precise chain elongation. Stress response silencing therefore exploits a catalytic mechanism that is geared to process many diverse proteins and hence allows a single enzyme to monitor and, if appropriate, modulate a complex cellular state.
TET knockout cells transit between pluripotent states and exhibit precocious germline entry
Authors: Pantier Raphaël , Barbieri Elisa , Brito Sara Gonzalez , Thomson Ella , Tatar Tülin , Colby Douglas , Zhang Man , Chambers Ian 
Published: December 2024

SummaryTET1, TET2 and TET3 are DNA demethylases with critical roles in development and differentiation. To assess the contributions of TET proteins to cell function during early development, single and compound knockouts ofTetgenes in mouse pluripotent embryonic stem cells (ESCs) were generated. Here we show that TET proteins are not required to transit between naïve, formative and primed pluripotency. Moreover, ESCs with double-knockouts ofTet1andTet2or triple-knockouts ofTet1, Tet2andTet3are phenotypically indistinguishable. These TET-deficient ESCs exhibit differentiate defects; they fail to activate somatic gene expression and retain expression of pluripotency transcription factors. Therefore, TET1 and TET2, but not TET3 act redundantly to facilitate somatic differentiation. Importantly however, TET-deficient ESCs can differentiate into primordial germ cell-like cells (PGCLCs), and do so at high efficiency in the presence or absence of PGC-promoting cytokines. Moreover, acquisition of a PGCLC transcriptional programme occurs more rapidly in TET-deficient cells. These results establish that TET proteins act at the juncture between somatic and germline fates: without TET proteins, epiblast cell differentiation defaults to the germline.