tbuckley/cabot-search huggingface dataset:
Single-cell RNA-seq data have prevalent blood contamination but can be rescued by Originator, a computational tool separating single-cell RNA-seq by genetic and contextual information
Authors: Thatchayut Unjitwattana, Qianhui Huang, Yiwen Yang, Leyang Tao, Youqi Yang, Mengtian Zhou, Yuheng Du, Lana X. Garmire
Journal: Genome biology (2025)

Abstract Single-cell RNA sequencing (scRNA-seq) data from complex human tissues have prevalent blood cell contamination during the sample preparation process. They may also comprise cells of different genetic makeups. We propose a new computational framework, Originator, which deciphers single cells by genetic origin and separates immune cells of blood contamination from those of expected tissue-resident cells. We demonstrate the accuracy of Originator at separating immune cells from the blood and tissue as well as cells of different genetic origins, using a variety of artificially mixed and real datasets, including pancreatic cancer and placentas as examples.
Phyloformer: Fast, accurate and versatile phylogenetic reconstruction with deep neural networks
Authors: Luca Nesterenko, Luc Blassel, Philippe Veber, Bastien Boussau, Laurent Jacob
Journal: Molecular Biology and Evolution (2025)

Abstract Phylogenetic inference aims at reconstructing the tree describing the evolution of a set of sequences descending from a common ancestor. The high computational cost of state-of-the-art maximum likelihood and Bayesian inference methods limits their usability under realistic evolutionary models. Harnessing recent advances in likelihood-free inference and geometric deep learning, we introduce Phyloformer, a fast and accurate method for evolutionary distance estimation and phylogenetic reconstruction. Sampling many trees and sequences under an evolutionary model, we train the network to learn a function that enables predicting a tree from a multiple sequence alignment. On simulated data, we compare Phyloformer to FastME –a distance method– and two maximum likelihood methods: FastTree and IQTree. Under a commonly used model of protein sequence evolution and exploiting GPU acceleration, Phyloformer outpaces all other approaches and exceeds their accuracy in the Kuhner-Felsenstein metric that accounts for both the topology and branch lengths. In terms of topological accuracy alone, Phyloformer outperforms FastME, but falls behind maximum likelihood approaches, especially as the number of sequences increases. When a model of sequence evolution that includes dependencies between sites is used, Phyloformer outperforms all other methods across all metrics on alignments with fewer than 80 sequences. On 3801 empirical gene alignments from 5 different datasets, Phyloformer matches the topological accuracy of the two maximum likelihood implementations. Our results pave the way for the adoption of sophisticated realistic models for phylogenetic inference.
A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases
Authors: Lutgarde Serneels, Annerieke Sierksma, Emanuela Pasciuto, Ivana Geric, Arya Nair, Anna Martinez-Muriana, An Snellinx, Bart De Strooper
Journal: Molecular Neurodegeneration (2025)

Abstract Background Recent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia. Methods We developed the hCSF1 Bdes mouse line, which is suitable as a new transplantation model and available to be crossed to any disease model of interest. The hCSF1 Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additionally, we crossed this model with two humanized App KI mice, the App Hu and the App SAA . Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimer’s disease. Results Our results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1 Bdes mice without triggering a NK-driven immune response. Furthermore, we confirmed the multipronged response of microglia in the context of Alzheimer’s disease. The hCSF1 Bdes and the crosses with the Alzheimer’s disease knock-in model App SAA and the humanized App knock-in control mice, App Hu are deposited with EMMA and fully accessible to the research community. Conclusion The hCSF1 Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.
Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis
Authors: Man Cheng, Dan Lu, Kexin Li, Yan Wang, Xiwen Tong, Xiaolong Qi, Chuanzhu Yan, Kunqian Ji, Junlin Wang, Wei Wang, Huijiao Lv, Xu Zhang, Weining Kong, Jian Zhang, Jiaxin Ma, Keru Li, Yaheng Wang, Jingyu Feng, Panpan Wei, Qiushuang Li, Chengyong Shen, Xiang-Dong Fu, Yuanwu Ma, Xiaorong Zhang
Journal: Nature Neuroscience (2025)
A curious concept of CNS clearance
Authors: Virginia Plá, Erik Kroesbergen, Saiyue Deng, Michael J. Giannetto, Lauren M. Hablitz, Evan Newbold, Antonio Ladrón-de-Guevara, Tina Esmail, Ryszard Stefan Gomolka, Yuki Mori, Steven A. Goldman, Douglas H. Kelley, John H. Thomas, Maiken Nedergaard
Journal: Nature Neuroscience (2025)
Semantic embeddings reveal and address taxonomic incommensurability in psychological measurement
Authors: Dirk U. Wulff, Rui Mata
Journal: Nature Human Behaviour (2025)

Abstract Taxonomic incommensurability denotes the difficulty in comparing scientific theories due to different uses of concepts and operationalizations. To tackle this problem in psychology, here we use language models to obtain semantic embeddings representing psychometric items, scales and construct labels in a vector space. This approach allows us to analyse different datasets (for example, the International Personality Item Pool) spanning thousands of items and hundreds of scales and constructs and show that embeddings can be used to predict empirical relations between measures, automatically detect taxonomic fallacies and suggest more parsimonious taxonomies. These findings suggest that semantic embeddings constitute a powerful tool for tackling taxonomic incommensurability in the psychological sciences.
Evidence from Tinshemet Cave in Israel suggests behavioural uniformity across Homo groups in the Levantine mid-Middle Palaeolithic circa 130,000–80,000 years ago
Authors: Yossi Zaidner, Marion Prévost, Ruth Shahack-Gross, Lior Weissbrod, Reuven Yeshurun, Naomi Porat, Gilles Guérin, Norbert Mercier, Asmodée Galy, Christophe Pécheyran, Gaëlle Barbotin, Chantal Tribolo, Hélène Valladas, Dustin White, Rhys Timms, Simon Blockley, Amos Frumkin, David Gaitero-Santos, Shimon Ilani, Sapir Ben-Haim, Antonella Pedergnana, Alyssa V. Pietraszek, Pedro García, Cristiano Nicosia, Susan Lagle, Oz Varoner, Chen Zeigen, Dafna Langgut, Onn Crouvi, Sarah Borgel, Rachel Sarig, Hila May, Israel Hershkovitz
Journal: Nature Human Behaviour (2025)

The south Levantine mid-Middle Palaeolithic (mid-MP; ~130–80 thousand years ago (ka)) is remarkable for its exceptional evidence of human morphological variability, with contemporaneous fossils of Homo sapiens and Neanderthal-like hominins. Yet, it remains unclear whether these hominins adhered to discrete behavioural sets or whether regional-scale intergroup interactions could have homogenized mid-MP behaviour. Here we report on our discoveries at Tinshemet Cave, Israel. The site yielded articulated Homo remains in association with rich assemblages of ochre, fauna and stone tools dated to ~100 ka. Viewed from the perspective of other key regional sites of this period, our findings indicate consolidation of a uniform behavioural set in the Levantine mid-MP, consisting of similar lithic technology, an increased reliance on large-game hunting and a range of socially elaborated behaviours, comprising intentional human burial and the use of ochre in burial contexts. We suggest that the development of this behavioural uniformity is due to intensified inter-population interactions and admixture between Homo groups ~130–80 ka. The Middle Palaeolithic of southwest Asia witnessed interactions and knowledge sharing between archaic and modern humans ~130,000–80,000 years ago. These interactions led to increased behavioural complexity and consolidation of a uniform behavioural set across Homo groups in the region.
Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma
Authors: Long Liang, Xinwei Kuang, Yi He, Lin Zhu, Poyee Lau, Xin Li, Dingan Luo, Lan Gong, Wenbin Zhou, Fanglin Zhang, Xiaowei Liang, Zhuofeng Li, Bin Hu, Dandan Liu, Tao Ding, Hui Li, Shuang Zhao, Juan Su, Mien-Chie Hung, Jing Liu, Hong Liu, Xiang Chen
Journal: Nature Genetics (2025)

Tumors undergo metabolic reprogramming to meet the energetic, synthetic and redox demands essential for malignancy, often characterized by increased glycolysis and lactate production. However, the role of mitochondrial metabolism in tumor immunity remains unclear. The present study integrates spatial transcriptomics, bulk transcriptomics and proteomics, revealing a strong link between the metabolite succinyl-CoA and tumor immunity as well as the efficacy of anti-programmed cell death protein-1 (PD-1) therapy in patients with melanoma. Elevated succinyl-CoA levels, through α-ketoglutarate or succinate supplementation, enhanced T cell-mediated tumor elimination, both in vitro and in vivo. Mechanistically, succinylation of the ligand of PD-1 (PD-L1) at lysine 129 led to its degradation. Increased carnitine palmitoyltransferase 1A (CPT1A), identified as a succinyltransferase for PD-L1, boosted anti-tumor activity. Preclinically, bezafibrate, a hyperlipidemia drug, upregulated CPT1A and synergized with CTLA-4 monoclonal antibody to inhibit tumor growth. Clinically, higher PD-L1 and lower CPT1A levels in tumors correlated with better anti-PD-1 therapy responses, suggesting potential biomarkers for prediction of treatment efficacy.
Glycogen drives tumour initiation and progression in lung adenocarcinoma
Authors: Harrison A. Clarke, Tara R. Hawkinson, Cameron J. Shedlock, Terrymar Medina, Roberto A. Ribas, Lei Wu, Zizhen Liu, Xin Ma, Yi Xia, Yu Huang, Xing He, Josephine E. Chang, Lyndsay E. A. Young, Jelena A. Juras, Michael D. Buoncristiani, Alexis N. James, Anna Rushin, Matthew E. Merritt, Annette Mestas, Jessica F. Lamb, Elena C. Manauis, Grant L. Austin, Li Chen, Pankaj K. Singh, Jiang Bian, Craig W. Vander Kooi, B. Mark Evers, Christine F. Brainson, Derek B. Allison, Matthew S. Gentry, Ramon C. Sun
Journal: Nature Metabolism (2025)
Atlas of genetic and phenotypic associations across 42 female reproductive health diagnoses
Authors: Natàlia Pujol Gualdo, Jelisaveta Džigurski, Valentina Rukins, Fanny-Dhelia Pajuste, Brooke N. Wolford, Mariann Võsa, Mia Golob, Lisette Haug, Maris Alver, Kristi Läll, Maire Peters, Ben M. Brumpton, Andres Metspalu, Lili Milani, Tõnu Esko, Mari Nelis, Georgi Hudjashov, Priit Palta, Reedik Mägi, Triin Laisk
Journal: Nature Medicine (2025)
Wearable device-measured physical activity and incident cardiovascular disease in cancer survivors
Authors: Chengqing Jiang, Ziang Li, Bo Guo, Lin Chen, Liang Zhu, Yu Liang, Yinghan Shen, Tianxin Long, Ming Zhai, Jiayun Shi, Haiyan Xu, Yongjian Wu
Journal: British Journal of Sports Medicine (2025)

Objective To explore the association of wearable device-measured moderate-to-vigorous intensity physical activity (MVPA) with cardiovascular disease (CVD) risk in long-term cancer survivors. Methods This retrospective analysis involved a prospective cohort of 6109 cancer survivors without CVD from the UK Biobank accelerometry subsample. The MVPA volume is categorised into four groups based on guideline recommendations (0–75 min/week, 75–150 min/week, 150–300 min/week, ≥300 min/week). Cox proportional hazard models are used to investigate the association of MVPA with incident CVD. Results Over a median follow-up of 7.88 years, there were 539 incident CVD events (361 incident coronary artery disease (CAD) events, 155 incident heart failure (HF) events, and 109 incident stroke events). Adjusted CVD incidence rates (95% CIs) across MVPA groups (0–75 min/week, 75–150 min/week, 150–300 min/week, ≥300 min/week) were 15.30 (12.90, 18.10), 13.50 (11.00, 16.40), 12.00 (10.20, 14.10) and 9.86 (8.35, 11.60) per 1000 person-years, respectively. Adjusted HRs (95% CI) for CVD, CAD, HF and stroke in the highest MVPA group (≥300 min/week) compared with those in the lowest MVPA group (0–75 min/week) were 0.63 (0.49, 0.80), 0.68 (0.51, 0.91), 0.66 (0.42,1.06) and 0.72 (0.42, 1.23), respectively. For obesity-related cancers, the beneficial effect on CVD was observed when exceeding 300 MVPA min/week (HR 0.54 (0.37–0.81)) compared with the lowest MVPA group. Conclusions Findings from the UK Biobank study suggest that longer MVPA durations are associated with reduced CVD risk in cancer survivors, underscoring the potential for physical activity to serve as a key component in cardio-oncology care.
Locoregional Infusion of EGFR806-CAR T Cells for Recurrent or Refractory Pediatric CNS Tumors: Results of the Completed BrainChild02 Phase 1 Clinical Trial
Authors: Juliane Gust, Bonnie L Cole, Rebecca Ronsley, Ashley L Wilson, Kristy Seidel, Jason Wendler, Sowmya Pattabhi, Christopher Brown, Stephanie D Rawlings-Rhea, Nadezhda Shtanukhina, Samuel R Browd, Jason S Hauptman, Amy Lee, Jeffrey G Ojemann, Erin E Crotty, Sarah E S Leary, Francisco A Perez, Jason N Wright, Catherine M Albert, Navin Pinto, Rebecca A Gardner, Nicholas A Vitanza, Michael C Jensen, Julie R Park
Journal: Neuro-Oncology (2025)

Abstract Background Relapsed/refractory pediatric CNS tumors have a poor prognosis. EGFR is commonly overexpressed, but EGFRvIII mutations are uncommon. To target these tumors, we used chimeric antigen receptor (CAR) T cells with a binder based on mAb806 which recognizes ectopically expressed wild-type EGFR and EGFRvIII. Methods In this open-label phase 1 clinical trial, patients age 1-26 years with EGFR+ CNS tumors received weekly infusions of 1-2.5 x 107 CAR T cells into the tumor resection bed or the lateral ventricle via an implanted catheter. No lymphodepletion was used. Results Eleven patients were enrolled. Four (3 with high-grade glioma, 1 with atypical teratoid-rhabdoid tumor) were treated and received 5-10 CAR T cell infusions without dose-limiting toxicities. The trial closed prior to reaching planned dose regimens. All treatment-related adverse events were no higher than CTCAE grade 2. The most common were headache and nausea. One patient had a grade 1 seizure, and three had new sensory changes, weakness and/or urinary changes (grade 1-2) that were possibly related to CAR T cell infusion. Three of the four treated patients had progressive disease. One patient with spinal cord diffuse midline glioma had progressive peritumoral edema that could not be conclusively attributed to either progression or pseudoprogression and was therefore defined as stable disease, followed by a complete response to subsequent chemotherapy. Conclusions Intracranially infused EGFR806-CAR T cells were tolerable at tested doses, with a best response of stable disease. EGFR is a potentially useful target for cellular therapy against pediatric brain tumors, particularly high-grade gliomas.
Sleep Disorders: Pathogenesis and Therapeutic Interventions
Authors: Cheng Liu, Zhigang He, Yanqiong Wu, Yanbo Liu, Zhixiao Li, Yifan Jia, Hongbing Xiang
Journal: MedComm (2025)

Sleep disorder significantly disrupts the quality of life for patients. Although it is clinically acknowledged, the fundamental neuropathological mechanisms are still not understood. Recent preclinical research has been directed toward understanding the fundamental mechanisms underlying the sleep deprivation and sleep/wake dysregulation. Sleep disorder is linked to changes in the structure and function of the neural basis of cognition. We reviewed the neural circuits related to sleep disorders, along with alterations in connectivity and brain region functions, based on advancements in electrophysiology and optogenetic/chemogenetic techniques. We subsequently outline the cellular and molecular modifications linked to sleep disorders in preclinical studies, primarily involving changes in neuronal metabolism, electrophysiological activity, synaptic plasticity, and glial cells. Correspondingly, on the basis of the crosstalk between the brain and peripheral organs, we elucidate the underlying mechanisms of the involvement of celiac disease and hepatic disease in the pathogenesis of sleep disorders. In this review, we mainly discussed the pathogenesis at molecular, cellular, and neural circuit levels that contribute to sleep disorder. The review also covered potential strategies for treating sleep disorders and future research avenues.
<i>Fusobacterium nucleatum</i> Promotes the Growth and Metastasis of Colorectal Cancer by Activating E‐Cadherin/Krüppel‐Like Factor 4/Integrin α5 Signaling in a Calcium‐Dependent Manner
Authors: Xuebing Yan, Xiao Qu, Jiaxin Wang, Ling Lu, Wenjuan Wu, Jingxian Mao, Donglin Li, Ying Wang, Qing Wei, Jianqiang Liu
Journal: MedComm (2025)

Gut microbiota and integrins are known to contribute to colorectal cancer (CRC), but whether they interact has been unclear. Here, we provided evidence that Fusobacterium nucleatum upregulated integrin α5 (ITGA5) in CRC in both human patients and murine models. Knocking down ITGA5 in CRC cells weakened the ability of F. nucleatum to stimulate their malignant characteristics. Fusobacterium nucleatum increased intracellular Ca2+ concentration, which in turn promoted interaction between E-cadherin and Krüppel-like factor 4 (KLF4), resulting in KLF4 phosphorylation and translocation in the nucleus, where it induced ITGA5 transcription and activated the downstream signaling. Knocking down E-cadherin or chelating Ca2+ with BAPTA-AM antagonized the impact of F. nucleatum on KLF4, whereas knocking down KLF4 or chelating Ca2+ antagonized the bacteria's oncogenic role. Knocking down KLF4 or ITGA5 attenuated F. nucleatum-induced growth of patient-derived organoids, subcutaneous xenografts, and orthotopic tumors, as well as liver metastasis in nude mice. Integrin α5 antibody antagonized the oncogenic role of F. nucleatum in vitro and in vivo. These findings suggest that F. nucleatum promotes the growth and metastasis of CRC by activating E-cadherin/KLF4/integrin α5 signaling in a Ca2+-dependent manner.
Heat Shock Protein Family A Member 1A Attenuates Apoptosis and Oxidative Stress via ERK/JNK Pathway in Hyperplastic Prostate
Authors: Huan Liu, Yongying Zhou, Zhen Wang, Daoquan Liu, Yan Li, Huan Lai, Jizhang Qiu, Shidong Shan, Feng Guo, Ping Chen, Yuming Guo, Guang Zeng, Michael E. DiSanto, Xinhua Zhang
Journal: MedComm (2025)

Benign prostatic hyperplasia (BPH) is a prevalent disorder in aging males. It is investigated whether heat shock protein family A member 1A (HSPA1A), a cytoprotective chaperone induced under stress, has been implicated in the development of BPH. RNA-sequencing and single-cell sequencing analyses revealed significant upregulation of HSPA1A in BPH compared to controls. In vitro experiments elucidated that HSPA1A was localized in prostatic epithelium and stroma, with upregulated expression in BPH tissues. Moreover, HSPA1A silencing augmented apoptosis and reactive oxygen species (ROS) accumulation, inhibiting proliferation via ERK/JNK activation, while overexpression reversed these effects in prostatic BPH-1 and WPMY-1 cells. Additionally, ERK1/2 suppression with U0126 rescued the effects of HSPA1A silencing. In vivo, testosterone-induced BPH (T-BPH) rat models treated with the HSPA1A antagonist KNK437 exhibited prostatic atrophy and molecular changes consistent with reduced HSPA1A activity. Finally, we conducted a tissue microarray (TMA) analysis of 139 BPH specimens from Zhongnan Hospital of Wuhan University, which revealed a positive correlation between HSPA1A expression and clinical parameters, including prostate volume (PV), tPSA, fPSA, and IPSS. In conclusion, our findings suggested that HSPA1A attenuated apoptosis and oxidative stress through the ERK/JNK signaling pathway, contributing to BPH pathogenesis.
Unlocking the Gates: A Novel Diagnostic Molecule for Quantifying Efflux Levels in Gram‐Positive Bacteria
Authors: Mrunal Patil, Tatiana Munteanu, Gaël Brasseur, Carolina Ferreira, Sofia Santos Costa, Isabel Couto, Mohd Athar, Elisa Asunis, Attilio Vittorio Vargiu, Miguel Viveiros, Carole DiGiorgio, Frédéric Brunel, Jean‐Manuel Raimundo, Michel Camplo, Olivier Siri, Jean‐Michel Bolla
Journal: Advanced Healthcare Materials (2025)

Efflux-mediated antibiotic resistance poses a significant global threat, affecting diverse bacterial species. Clinicians recognize the danger of efflux mechanisms during antibiotic treatment, yet precise diagnostic tools remain unavailable. The antibiogram currently infers abnormal efflux pump activity in clinical isolates, which is subsequently confirmed through transcriptomic or genomic analysis. This study harnesses the colorimetric, fluorescence, and solubility properties of phenazinium derivatives to develop a rapid protocol for detecting bacterial efflux. Among several synthesized phenazinium compounds, the compound demonstrating differential MIC in Staphylococcus efflux mutants and exhibiting appropriate physicochemical properties is selected. A diagnostic protocol is developed using the selected compound to assess efflux levels, categorized as no, weak, or strong, through colorimetry and spectroscopy techniques. Testing on Gram-positive efflux mutants and clinical Staphylococcus isolates further validates the approach. In-silico docking analysis confirms the interaction between the chosen compound and the NorA efflux pump in S. aureus. Flow cytometry is employed to re-evaluate the detection assays. The developed molecule and protocol represent the first known method to evaluate efflux levels in any Gram-positive species through a streamlined and user-friendly process. This pioneering test significantly advances the epidemiological analysis of efflux mechanisms and enables more informed therapeutic decision-making, leading to more effective treatment.
The Role of Yes‐Associated Protein in Inflammatory Diseases and Cancer
Authors: Bing Zhong, Jintao Du, Feng Liu, Silu Sun
Journal: MedComm (2025)

Yes-associated protein (YAP) plays a central role in the Hippo pathway, primarily governing cell proliferation, differentiation, and apoptosis. Its significance extends to tumorigenesis and inflammatory conditions, impacting disease initiation and progression. Given the increasing relevance of YAP in inflammatory disorders and cancer, this study aims to elucidate its pathological regulatory functions in these contexts. Specifically, we aim to investigate the involvement and molecular mechanisms of YAP in various inflammatory diseases and cancers. We particularly focus on how YAP activation, whether through Hippo-dependent or independent pathways, triggers the release of inflammation and inflammatory mediators in respiratory, cardiovascular, and digestive inflammatory conditions. In cancer, YAP not only promotes tumor cell proliferation and differentiation but also modulates the tumor immune microenvironment, thereby fostering tumor metastasis and progression. Additionally, we provide an overview of current YAP-targeted therapies. By emphasizing YAP's role in inflammatory diseases and cancer, this study aims to enhance our understanding of the protein's pivotal involvement in disease processes, elucidate the intricate pathological mechanisms of related diseases, and contribute to future drug development strategies targeting YAP.