tbuckley/cabot-search huggingface dataset:
Digital sequencing is improved by using structured unique molecular identifiers
Authors: Peter Micallef, Manuel Luna Santamaría, Mandy Escobar, Daniel Andersson, Tobias Österlund, Pia Mouhanna, Stefan Filges, Gustav Johansson, Henrik Fagman, Christoffer Vannas, Anders Ståhlberg
Journal: Genome biology (2025)

Abstract Digital sequencing uses unique molecular identifiers (UMIs) to correct for polymerase induced errors and amplification biases. Here, we design 19 different structured UMIs to minimize the capacity of primers to form non-specific PCR products during library construction using SiMSen-Seq, a PCR-based digital sequencing approach with flexible multiplexing capabilities suitable for tumor-informed mutation analysis. All structured UMI designs demonstrate enhanced assay performance compared with an unstructured reference UMI. The best performing structured UMI design shows significant improvements in all tested aspects of assay and sequencing performance with the ability to reliable detect low variant allele frequencies.
Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1
Authors: Thomas R. W. Oliver, Andrew R. J. Lawson, Henry Lee-Six, Anna Tollit, Hyunchul Jung, Yvette Hooks, Rashesh Sanghvi, Matthew D. Young, Timothy M. Butler, Pantelis A. Nicola, Taryn D. Treger, Stefanie V. Lensing, G. A. Amos Burke, Kristian Aquilina, Ulrike Löbel, Isidro Cortes-Ciriano, Darren Hargrave, Mette Jorgensen, Flora A. Jessop, Tim H. H. Coorens, Adrienne M. Flanagan, Kieren Allinson, Inigo Martincorena, Thomas S. Jacques, Sam Behjati
Journal: Nature Genetics (2025)

Abstract Cancer predisposition syndromes mediated by recessive cancer genes generate tumors via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here we performed whole-genome and whole-exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multisystem cancer-predisposing syndrome mediated by constitutive monoallelic NF1 inactivation. We identified multiple independent NF1 driver variants in histologically normal tissues, but not in 610 biopsies from two nonpredisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating NF1 mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbor second hits in NF1 , the extent and pattern of which may underpin the syndrome’s cancer phenotype.
Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing
Authors: Tomer Itkin, Sean Houghton, Ryan Schreiner, Yang Lin, Chaitanya R. Badwe, Veronique Voisin, Alex Murison, Negar Seyedhassantehrani, Kerstin B. Kaufmann, Laura Garcia-Prat, Gregory T. Booth, Fuqiang Geng, Ying Liu, Jesus M. Gomez-Salinero, Jae-Hung Shieh, David Redmond, Jenny Z. Xiang, Steven Z. Josefowicz, Cole Trapnell, Eric M. Pietras, Joel A. Spencer, Ross Levine, Wenbin Xiao, Lior Zangi, Brandon Hadland, John E. Dick, Stephanie Z. Xie, Shahin Rafii
Journal: Nature Immunology (2025)
An antibody–toxin conjugate targeting CD47 linked to the bacterial toxin listeriolysin O for cancer immunotherapy
Authors: Benjamin R. Schrank, Yifan Wang, Annette Wu, Nhat Tran, DaeYong Lee, Jared Edwards, Kristin Huntoon, Shiyan Dong, JongHoon Ha, Yifan Ma, Adam J. Grippin, Seong Dong Jeong, Abin Antony, Mengyu Chang, Minjeong Kang, Thomas D. Gallup, Albert C. Koong, Jing Li, Kyuson Yun, Betty Y. S. Kim, Wen Jiang
Journal: Nature Cancer (2025)
Neuronal polyunsaturated fatty acids are protective in ALS/FTD
Authors: Ashling Giblin, Alexander J. Cammack, Niek Blomberg, Sharifah Anoar, Alla Mikheenko, Mireia Carcolé, Magda L. Atilano, Alex Hull, Dunxin Shen, Xiaoya Wei, Rachel Coneys, Lele Zhou, Yassene Mohammed, Damien Olivier-Jimenez, Lian Y. Wang, Kerri J. Kinghorn, Teresa Niccoli, Alyssa N. Coyne, Rik van der Kant, Tammaryn Lashley, Martin Giera, Linda Partridge, Adrian M. Isaacs
Journal: Nature Neuroscience (2025)

Abstract Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila , induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.
ASH2L Deficiency in Smooth Muscle Drives Pulmonary Vascular Remodeling
Authors: Jing Zhang, Xia Gu, Tian-Le Cheng, Yong-Jia Qi, Dao-Yan Liu, Na Wu, Da-Peng Wang, Yu Huang, Zhi-Ming Zhu, Ye Fan
Journal: Circulation Research (2025)

BACKGROUND: Histone H3 lysine 4 methylation is one of the most abundant epigenetic modifications, which has been recently linked to vascular remodeling in pulmonary hypertension (PH). SET1/MLL methyltransferase complexes comprise the main enzymes responsible for methylating H3 lysine 4, yet their roles in vascular remodeling and PH are not fully understood. We aim to assess the contribution of ASH2L, a core SET1/MLL family member, to the pathogenesis of PH. METHODS: Human pulmonary artery specimens and primary vascular cells, smooth muscle cell (SMC)-specific ASH2L-deficient mice, rats with SMC-specific ASH2L overexpression, mass spectrometry, immunoprecipitation, and chromatin immunoprecipitation were used to define the role of ASH2L in PH. RESULTS: Analysis of bulk RNA-sequencing data sets from human lung vessels identified ASH2L as the only differentially expressed SET1/MLL family member in PH compared with healthy controls. Decreased ASH2L expression in human pulmonary arteries correlated with the clinical severity of PH, which contrasted with elevated H3 lysine 4 methylation and was primarily localized to SMCs. Depletion of ASH2L promoted whereas its restoration ameliorated SMC proliferation and vascular remodeling in PH. Mechanistically, we revealed that ASH2L functioned independently of the canonical H3 lysine 4 trimethylation-based transcriptional activation, while it formed a protein complex with KLF5 and FBXW7, thereby accelerating the ubiquitin-proteasomal degradation of KLF5. NOTCH3 was discovered as a new downstream target of KLF5, and the loss of ASH2L promoted the recruitment of KLF5 to the NOTCH3 promoter, thus enhancing NOTCH3 expression. Pharmacological blockage of KLF5 attenuated PH in chronic hypoxia-exposed SMC-specific ASH2L-deficient mice and sugen/hypoxia-challenged rats. CONCLUSIONS: This study demonstrated that ASH2L deficiency causatively affects SMC proliferation and lung vascular remodeling that is partially mediated through KLF5-dependent NOTCH3 transcription. Activating ASH2L or targeting KLF5 might represent potential therapeutic strategies for PH.
Endothelial PPARδ Ablation Exacerbates Vascular Hyperpermeability via STAT1/CXCL10 Signaling in Acute Lung Injury
Authors: Huiling Hong, Yalan Wu, Yangxian Li, Yumeng Han, Xiaoyun Cao, Vivian Wei Yan Wu, Thomas Ting Hei Chan, Jingying Zhou, Qin Cao, Kathy O. Lui, Chun-Kwok Wong, Zhiyu Dai, Xiao Yu Tian
Journal: Circulation Research (2025)

BACKGROUND: Vascular hyperpermeability is one of the hallmarks of acute lung injury, contributing to excessive inflammation and respiratory failure. The PPARδ (peroxisome proliferator-activated receptor delta) is an anti-inflammatory transcription factor, although its role in endothelial barrier function remains unclear. Here, we studied the essential role of PPARδ in maintaining vascular endothelial barrier integrity during lung inflammation and investigated the underlying mechanisms. METHODS: Endothelial cell (EC)–selective PPARδ knockout mice (Ppard EC-KO ) and littermate control mice (Ppard EC-WT ) received lipopolysaccharide injection to induce acute lung injury. Lung inflammation, pulmonary vascular leakage, and mouse mortality were monitored. Single-cell RNA sequencing was performed on sorted mouse lung ECs. RESULTS: Ppard EC-KO mice exhibited aggravated lung inflammation, characterized by increased leukocyte infiltration, elevated production of proinflammatory cytokines, and higher mortality rates. The enhanced inflammatory responses were associated with increased protein leakage, interstitial edema, and impaired endothelial barrier structure, leading to vascular hyperpermeability in Ppard EC-KO mice. Mechanistically, with single-cell RNA sequencing, we identified the emergence of an interferon-activated capillary EC population marked by CXCL10 (C-X-C motif chemokine 10) expression following lipopolysaccharide challenge. PPARδ silencing significantly increased CXCL10 expression in ECs through activating STAT1. Notably, CXCL10 treatment induced degradation of tight junction proteins ZO-1 (zonula occluden-1) and claudin-5 through the ubiquitin-proteasome system, disrupting membrane junction continuity in ECs. Administration of anti-CXCL10 antibody or CXCL10 receptor antagonist AMG487 suppressed both lipopolysaccharide-induced lung inflammation and vascular leakage in Ppard EC-KO mice. CONCLUSIONS: These results highlighted a novel anti-inflammatory role of PPARδ in ECs by suppressing CXCL10-mediating vascular hyperpermeability. Targeting the CXCL10 signaling shows therapeutic potential against vascular injury in acute lung injury.
The effects of L-theanine consumption on sleep outcomes: a systematic review and meta-analysis.
Authors: Amanda Bulman, Nathan M D'Cunha, Wolfgang Marx, Murray Turner, Andrew McKune, Nenad Naumovski
Journal: Sleep Medicine Reviews (2025)

This systematic review ansd meta-analysis aimed to evaluate the effects of L-theanine, a non-proteinogenic amino acid found in tea, on sleep outcomes. Literature searches were conducted in five electronic databases (APA PsycINFO, CINAHL, Medline, Scopus, Web of Science), and one register (Cochrane Central Register of Controlled Trials) from inception until September 2024. Randomised controlled trials investigating the effects of L-theanine supplementation on sleep quality in humans of all ages and health status were included. Nineteen articles (N = 897 participants) were selected and 18 included in the meta-analysis. L-theanine was shown to significantly improve subjective sleep onset latency (SMD = 0.15, 95 % CI [0.01, 0.29], p = 0.04; n = 10 studies), subjective daytime dysfunction (SMD = 0.33, 95 % CI [0.16, 0.49], p < 0.001; n = 9 studies), and overall subjective sleep quality score (SMD = 0.43, 95 % CI [0.04, 0.83], p = 0.03; n = 12 studies). The findings indicate the potential use of L-theanine in the management of sleep disturbances; however, the lack of studies on "pure" L-theanine warrants further investigation. Future studies are needed to determine the adequate dose and duration of L-theanine supplementation for improving and maintaining sleep quality in healthy and clinical populations.
Guanidinylation compromises the anti-inflammatory and anti-oxidative properties of apolipoprotein A-I in chronic kidney disease progression
Authors: Andrea Bonnin-Marquez, Joachim Jankowski, Sanne L Maas, Juliane Hermann, Florian Kahles, Michaela Lellig, Danilo Fliser, Stefan Schunk, Eleni Stamellou, Martin Berger, Thimoteus Speer, Sahir Kalim, Dickson Wai Leong Wong, Emiel P C van der Vorst, Vera Jankowski
Journal: Kidney International (2025)
Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer
Authors: Dan Feng, Jian Zhang, Huanmin Niu, Xiaoxue Zheng, Mengqi Jia, Qiqi Lu, Jing Wang, Wenxue Guo, Qi Sun, Huiqing Yuan, Hongxiang Lou
Journal: Acta Pharmaceutica Sinica B (2025)
EIF4E-mediated biogenesis of circPHF14 promotes the growth and metastasis of pancreatic ductal adenocarcinoma via Wnt/β-catenin pathway
Authors: Zhou Fang, Zhuo Wu, Chao Yu, Qingyu Xie, Liangtang Zeng, Rufu Chen
Journal: Molecular Cancer (2025)

CircRNAs are critically involved in the development and progression of various cancers. However, their functions and mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. CircPHF14 (hsa_circ_0079440) was identified through the analysis of RNA sequencing data from PDAC and normal adjacent tissues. The biological functions of circPHF14 were then evaluated using CCK8, EdU, transwell, colony formation, wound healing assays, as well as pancreatic orthotopic xenograft and liver metastasis models. The interaction mechanisms between circPHF14 and PABPC1, which enhance the stability of WNT7A mRNA, were investigated through RNA pull-down, mass spectrometry, RNA Immunoprecipitation (RIP), and actinomycin D assays. The role of EIF4E in promoting circPHF14 biogenesis was examined using RIP, and western blotting. In this study, we observed a significant upregulation of circPHF14 in both clinical PDAC samples and cell lines. Functionally, circPHF14 enhanced PDAC proliferation and metastasis both in vitro and in vivo. Mechanistically, circPHF14 interacted with PABPC1 to stabilize WNT7A mRNA, thereby activating the Wnt/β-catenin pathway, which subsequently upregulated SNAI2 and initiated Epithelial-Mesenchymal Transition (EMT) in PDAC. Additionally, EIF4E was found to bind PHF14 pre-mRNA, facilitating circPHF14 biogenesis. Finally, we developed a lipid nanoparticle (LNP) formulation encapsulating sh-circPHF14 plasmids and confirmed its anti-tumor efficacy in a patient-derived xenograft (PDX) model. EIF4E-mediated biogenesis of circPHF14 stabilizes WNT7A mRNA via interaction with PABPC1, which subsequently activates the Wnt/β-catenin pathway, promoting the growth and metastasis of PDAC. These findings indicate that circPHF14 holds promise as a biomarker and therapeutic target for PDAC.
Early Initiation of Hydroxychloroquine in Cutaneous Lupus Erythematosus to Prevent Progression to Systemic Lupus Erythematosus: A Long-term Follow-up Study
Authors: Danielle Bar, Sharon Baum, Zvi Segal, Aviv Barzilai, Amit Druyan, Merav Lidar
Journal: Journal of the American Academy of Dermatology (2025)
Exosome-Capturing Scaffold Promotes Endogenous Bone Regeneration Through Neutrophil-Derived Exosomes by Enhancing Fast Vascularization
Authors: Le Wang, Luying Yang, Lei Tian, Baolin Guo, Taiqiang Dai, Qianxin Lv, Jirong Xie, Fuwei Liu, Han Bao, Feng Cao, Ya Liu, Ye Gao, Yan Hou, Zhou Ye, Shenqiang Wang, Qiuyu Zhang, Liang Kong, Bolei Cai
Journal: Biomaterials (2025)
Targeting macrophage polarization by inhibiting Pim2 alleviates inflammatory arthritis via metabolic reprogramming
Authors: Xiaojun Xu, Peitao Xu, Guozhen Shen, Xiaoshuai Peng, Zhidong Liu, Chaoqiang Chen, Wenhui Yu, Zepeng Su, Jiajie Lin, Guan Zheng, Guiwen Ye, Peng Wang, Zhongyu Xie, Yanfeng Wu, Huiyong Shen, Jinteng Li
Journal: Cellular and Molecular Immunology (2025)

Abstract Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis. Moreover, although previous studies have reported that the proviral integration of Moloney virus 2 (Pim2) kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells, its role in inflammatory arthritis remains unclear. In this study, we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization. Specifically, Pim2 directly phosphorylates PGK1-S203, PDHA1-S300, and PFKFB2-S466, thereby promoting glycolytic reprogramming. Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collagen-induced arthritis (CIA) model mice. Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization. Through molecular docking and dynamic simulation, bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization, thereby mitigating the progression of inflammatory arthritis. For targeted treatment, neutrophil membrane-coated bexarotene (Bex)-loaded PLGA-based nanoparticles (NM@NP-Bex) were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages, and these nanoparticles (NPs) exhibited superior therapeutic effects with fewer side effects. Taken together, the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance. NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.
Dual-corn-derived nanofiber membrane for subconjunctival injury: Sequential release of dual-natural products for programmed anti-inflammation and anti-fibrosis
Authors: Qingyun Ning, Xue Sun, Haohao Cui, Xing Wang, Huayang Feng, Boyuan An, Zhanrong Li, Jun Shi, Jingguo Li
Journal: Journal of Controlled Release (2025)
Partial ampullary endoscopic mucosal resection in patients with difficult biliary cannulation: A prospective cohort study
Authors: Salih Tokmak, Mehmet Fuat Cetin, Abdullatif Sirin, Sevki Konur, Serkan Torun
Journal: Endoscopy (2025)

Backgrounds and study aims: Rescue techniques applied in case of cannulation failure are limited in number and have severe limitations. We recently described partial ampullary endoscopic mucosal resection (PA-EMR) as a novel technique for difficult biliary cannulation. We aimed to demonstrate the efficacy and safety of PA-EMR for patients with difficult biliary cannulation in a larger cohort Patients and methods: We conducted a prospective cohort study at our tertiary-care referral hospital. We recorded demographic factors, procedure-related characteristics, and adverse event rates in patients who received PA-EMR in case of difficult biliary cannulation. Results: Between June 2021 and June 2022, we performed 1073 consecutive ERCP procedures on 962 patients; 40 patients (12 male, 28 female, with a mean age of 68.1± 4 years) had difficult biliary cannulation and had PA-EMR. Technical success was 100%, and none of the patients required a second session. None of the patients had an adverse event, and we encountered no 30-day mortality. The most typical indication was bile duct stones with 60% (n=24), followed by periampullary tumors with 15% (n=6). The total procedure time was 923 (min-max, 392-1224) seconds. Conclusions: PA-EMR is an effective and safe rescue technique in patients with difficult biliary cannulation.
Resistance to Immunotherapy in Non-small Cell Lung Cancer: Unraveling Causes, Developing Effective Strategies, and Exploring Potential Breakthroughs
Authors: Shuang Dong, Xiaoyu Li, Qing Huang, Yuanxiang Li, Jinjiao Li, Xianmin Zhu, Chang Xue, Runzhi Chen, Yuan Zeng, Jingyi Wu, Yi Zhong, Sheng Hu
Journal: Drug Resistance Updates (2025)
Author correction to “Sphingosine-1-phosphate, a novel TREM2 ligand, promotes microglial phagocytosis to protect against ischemic brain injury” [Acta Pharm Sin B (2022) 1885-1898]
Authors: Tengfei Xue, Juan Ji, Yuqin Sun, Xinxin Huang, Zhenyu Cai, Jin Yang, Wei Guo, Ruobing Guo, Hong Cheng, Xiulan Sun
Journal: Acta Pharmaceutica Sinica B (2025)
Leaving colorectal polyps in situ with endocytoscopy assisted by computer-aided diagnosis: a cost-effectiveness study
Authors: Natalie Halvorsen, Ishita Barua, Michael Bretthauer, Yuichi Mori, Shin-ei Kudo, Shraddha Gulati, Masashi Misawa, Kensaku Mori, Bu'Hussain Hayee, Olaolu Olabintan, Jens Aksel Nilsen, Svein Oskar Frigstad, James E. East, Amit Rastogi, Cesare Hassan, Mette Kalager, Magnus Løberg, Øyvind Holme, Amyn Haji
Journal: Endoscopy (2025)

Background Computer-aided diagnosis (CADx) enables the distinction between neoplastic and non-neoplastic polyps during colonoscopy. We aimed to estimate the patient-level benefit and harm of CADx. Methods We conducted a comparative analysis on data from the EndoBRAIN international clinical trial, evaluating the effect of optical diagnosis during colonoscopy with and without CADx. Three hypothetical scenarios were compared: “endoscopist-alone” and “CADx-assisted” leave-in-situ strategies (leaving non-neoplastic rectosigmoid polyps ≤ 5 mm), and “total removal” (removing all detected polyps). Primary outcomes included patient-level colonoscopy-related cost and surveillance interval agreement (colorectal cancer risk category). Estimates were calculated based on national reimbursement rates and guidelines in four countries. Results We analyzed 1134 patients (59 % men, median age 67 years) with 1716 polyps. Compared with total removal, the endoscopist-alone and CADx-assisted leave-in-situ strategies reduced the removed polyps per patient from 1.51 (95 %CI 1.48–1.54) to 1.18 (95 %CI 1.16–1.20) and 1.12 (95 %CI 1.00–1.14), respectively; however, 0.023 (95 %CI 0.015–0.033) and 0.021 (95 %CI 0.014–0.031) neoplasms per patient were left in situ, respectively. The mean colonoscopy cost decreased by $44 (endoscopist alone) and $46 (CADx assistance) in the USA, $22 and $19 in the UK, $21 and $19 in Japan, and $32 and $30 in Norway, respectively. Surveillance interval agreement decreased to 99.2 % (endoscopist alone) and 99.0 % (CADx assistance) in the USA, 99.8 % and 99.8 % in the UK, 97.9 % and 97.1 % in Japan, and 99.9 % and 99.9 % in Norway, respectively. Conclusions Both endoscopist-alone and CADx-assisted optical diagnosis reduce colonoscopy costs. The risk of missed adenomas and surveillance interval deviations appear marginal.
Silent Synapses in the Adult Brain
Authors: Dimitra Vardalaki, Courtney E. Yaeger, Mark T. Harnett
Journal: Annual Review of Neuroscience (2025)

The formation of new synapses, the connections between neurons, is the critical step for neural circuit assembly. Newly formed glutamatergic synapses are initially silent and require activity-dependent plasticity to become fully functional connections. While these synapses have long been considered a vital part of the developmental program for neural networks, recent findings now indicate that silent synapses are a key source of neural circuit plasticity in the adult brain. Here, we review current evidence for silent synapses in the adult brain and explore the potential roles of these highly plastic structures. We argue that silent synapses may be instrumental in adult neural circuit remodeling and can serve as a latent reservoir of plasticity that enhances information processing and storage. This previously underappreciated aspect of adult plasticity underscores the need for innovative approaches and further investigation into the dynamic contribution of silent synapses to learning and memory in the adult brain.