tbuckley/cabot-search huggingface dataset:
Spatiotemporal single-cell analysis elucidates the cellular and molecular dynamics of human cornea aging
Authors: Dan Jiang, Ke Li, Yining Sun, Zicheng Zhang, Shuang Xie, Xintong Yu, Ruoqi Wang, Ying Feng, Qinxiang Zheng, Yajing Wen, Peter S Reinach, Yuanyuan Du, Meng Zhou, Wei Chen
Journal: Genome Medicine (2025)

The human cornea is a transparent and uniquely ordered optical-biological system. Precise coordination of its cellular mechanisms is essential to maintain its transparency and functionality. However, the spatial, cellular and molecular architecture of the human cornea and its intercellular interactions during aging have not been elucidated. We performed single-cell RNA sequencing (scRNA-seq) and single-cell SpaTial Enhanced REsolution Omics-sequencing (scStereo-seq) analysis in corneal tissue from eight eyes of donors aged 33-88 years to elucidate the spatiotemporal cellular and molecular dynamics of human cornea aging. Immunofluorescence staining and Western blotting were performed to validate the findings. Spatiotemporal single-cell analysis revealed the complex cellular landscape, spatial organization and intercellular communication within the human cornea. The subpopulations of major cell types of the cornea were elucidated with precise spatial positions. In particular, we identified novel subpopulations, mapped the spatial positioning of limbal stem cells within the limbal niche, and delineated the interactions between major cell types. We observed that three basal cell subsets migrate centripetally from the peripheral to the central cornea with age, suggesting the "spatiotemporal centripetal pattern" as a novel paradigm for the age-related migration of corneal epithelial cells. Furthermore, we elucidated the age-related, region-specific molecular and functional characteristics of the corneal endothelium, demonstrating differential metabolic capacities and functional properties between the peripheral and central regions. As the first comprehensive spatiotemporal atlas, our work provides a valuable resource for understanding tissue homeostasis in the human cornea and advances research on corneal pathology, transplantation, senescence and regenerative medicine in the context of corneal aging.
The gene regulatory mechanisms shaping the heterogeneity of venom production in the Cape coral snake
Authors: Pedro G Nachtigall, Brett R Hamilton, Taline D Kazandjian, Paolo Stincone, Daniel Petras, Nicholas R Casewell, Eivind A B Undheim
Journal: Genome biology (2025)

Abstract Background Venoms and their associated glands and delivery structures have evolved numerous times among animals. Within these venom systems, the molecular, cellular, and morphological components interact and co-evolve to generate distinct, venom phenotypes that are increasingly recognized as models for studying adaptive evolution. However, toxins are often unevenly distributed across venom-producing tissues in patterns that are not necessarily adaptive but instead likely result from constraints associated with protein secretion. Results We generate a high-quality draft genome of the Cape coral snake ( Aspidelaps lubricus ) and combine analyses of venom gland single-cell RNA-seq data with spatial venom gland in situ toxin distributions. Our results reveal that while different toxin families are produced by distinct populations of cells, toxin expression is fine-tuned by regulatory modules that result in further specialization of toxin production within each cell population. We also find that the evolution of regulatory elements closely mirrors the evolution of their associated toxin genes, resulting in spatial association of closely related and functionally similar toxins in the venom gland. While this compartmentalization is non-adaptive, the modularity of the underlying regulatory network likely facilitated the repeated evolution of defensive venom in spitting cobras. Conclusions Our results provide new insight into the variability of toxin regulation across snakes, reveal the molecular mechanisms underlying the heterogeneous toxin production in snake venom glands, and provide an example of how constraints can result in non-adaptive character states that appear to be adaptive, which may nevertheless facilitate evolutionary innovation and novelty.
RobusTAD: reference panel based annotation of nested topologically associating domains
Authors: Yanlin Zhang, Rola Dali, Mathieu Blanchette
Journal: Genome biology (2025)

Abstract Topologically associating domains (TADs) are fundamental units of 3D genomes and play essential roles in gene regulation. Hi-C data suggests a hierarchical organization of TADs. Accurately annotating nested TADs from Hi-C data remains challenging, both in terms of the precise identification of boundaries and the correct inference of hierarchies. While domain boundary is relatively well conserved across cells, few approaches have taken advantage of this fact. Here, we present RobusTAD to annotate TAD hierarchies. It incorporates additional Hi-C data to refine boundaries annotated from the study sample. RobusTAD outperforms existing tools at boundary and domain annotation across several benchmarking tasks.
<scp>HLA</scp> class I‐downregulated senescent epidermal basal cells orchestrate skin pathology in cutaneous lupus erythematosus
Authors: Sena Yamamoto, Yuki Saito, Tsukasa Sato, Seina Nakano, Dain Kasseki, Ayaka Nagao, Norihiro Miura, Kentaro Nagaoka, Arisa Kita, Maki Miyajima, Shogo Ijima, Koji Taniguchi, Atsushi Niida, Takako S. Chikenji
Journal: Arthritis & Rheumatology (2025)

Objective To investigate the role of senescent epidermal basal cells in cutaneous lupus erythematosus (CLE) pathogenesis using skin samples from patients with CLE and a mouse model of systemic lupus erythematosus (SLE). Methods Cellular senescence profiling utilized datasets from the NCBI Gene Expression Omnibus database and Accelerating Medicines Partnership® (AMP®) Phase 1‐Metro. Gene array data from GSE184989 (CLE: n = 68, control: n = 4), single‐cell RNA sequencing data from GSE186476 (CLE: n = 7, control: n = 14), and AMP® Phase 1‐Metro (SLE: n = 17) were utilized. In vitro experiments further examined the expression of p21 WAF1/CIP1 , type I interferon (IFN), human leukocyte antigen class I (HLA‐I), and epidermal growth factor receptor (EGFR) signalling. Pharmacological clearance of senescent cells was performed using the senolytic drug fisetin in the SLE mouse model. Results p21 WAF1/CIP1 ‐high senescent epidermal basal cells in patients with CLE exhibit high type I IFN expression. These cells enhance IFN signalling in surrounding normal epidermal basal cells, leading to increased HLA‐I expression. In contrast, senescent epidermal cells upregulate EGFR signalling, which downregulates HLA‐I expression, allowing them to evade immune surveillance. This heterogeneity of HLA‐I expression promotes CD8‐positive T‐mediated toxicity against normal epidermal basal cells, resulting in their apoptosis. Pharmacological clearance of senescent epidermal basal cells improved SLE‐like skin lesions. Conclusion Senescent cells create a microenvironment that directs cytotoxic T‐cell‐mediated responses against normal epidermis in CLE, contributing to disease pathology. Targeting senescent cells and their signalling pathways may offer novel therapeutic strategies for CLE and SLE skin lesions.
Global burden of osteoarthritis attributable to high body mass index, 1990‐2021: insights from the Global Burden of Disease study 2021
Authors: Yi Lu, Wenyu Xiao, Kun Tao
Journal: Arthritis & Rheumatology (2025)

Objective This study quantifies the global burden of osteoarthritis (OA) attributable to high body mass index (BMI) from 1990 to 2021 using the Global Burden of Disease (GBD) 2021 data. Methods Utilizing GBD 2021 data, this research examines the OA burden related to high BMI across 204 countries and regions. Statistical analyses were performed to profile disease burdens, and joinpoint regression was used to identify temporal trends. The study also investigated the relationship between the Socio‐demographic Index (SDI) and OA burden attributable to high BMI. Results From 1990 to 2021, years lived with disability (YLDs) due to OA attributable to high BMI increased threefold globally, from 1,449,681 to 4,422,954. The age‐standardized YLD rates of OA attributable to high BMI increased from 33.97 (95% UI: ‐3.14, 102.31) to 50.59 (95% UI: ‐4.81, 141.35) per 100,000 population, with an average annual percentage change of 1.11 (95% CI: 1.07, 1.14). The burden of OA YLDs attributable to high BMI was higher in females than males across all age groups. The age‐standardized rates of OA YLDs attributable to high BMI were positively correlated with SDI levels, with higher burdens observed in regions with higher SDI. Conclusion Between 1990 and 2021, the global burden of OA attributable to high BMI increased markedly, with a consistent upward trend across most regions. The burden was more pronounced among females, middle‐aged and older adults, and populations in high SDI regions, reflecting a growing and uneven global health challenge.
Trio whole exome sequencing in Chinese childhood‐onset lupus reveals novel candidate genes
Authors: Jianyang Ma, Yuting Qin, Soon‐Min Hong, Thuvaraka Ware, Guojun Hou, Jingjing Tan, Chengmei Xie, Pingjing Zhang, Xiaoqian Wu, Todor Arsov, Lanfang Cao, T Daniel Andrews, Philip Wu, Qian Shen, Huihua Ding, Nan Shen, Carola G. Vinuesa, Yuke He
Journal: Arthritis & Rheumatology (2025)

Objectives Systemic lupus erythematosus (SLE) is an autoimmune disease in which rare and common gene variants contribute to pathogenesis. Severe sporadic disease in children is often explained by ‘de novo’ variants that can be uncovered by trio sequencing. Methods Whole exome sequencing was performed in 50 Chinese trios with childhood‐onset SLE (cSLE). Rare coding variants in SLE‐associated genes and all de novo variants were investigated. Gene pathway and expression analysis, and interferon‐β luciferase assays were used to predict contribution to disease. Results Each proband carried at least one rare variant in an SLE‐associated gene with a median of six per child. At least two probands had monogenic disease and one third carried novel or rare variants in genes well accepted to cause monogenic SLE: ACP5, C3, C4A, C4B, DNASE1, IFIH1, NRAS, RNASEH2B, RNASEH2C and SAMHD1. Probands carried a median of one de novo, rare, coding variant. Intriguingly, although only 2 de novo variants occurred in genes previously associated with SLE, 12 of the 50 genes were enriched in the top 20 SLE‐related pathways and were highly expressed in ABC/plasma B cells. These genes represent promising candidate lupus genes. Two de novo variants occurring in genes not previously linked to SLE or autoimmunity, DHX8 and ACTR5, enhanced type I IFN signaling. Conclusions This study highlights the abundance of lupus‐relevant rare gene variants in cSLE, supports frequent contribution of de novo variants to disease, and identifies genes that may constitute novel therapeutic targets of relevance to Chinese patients.
Exploration of automated measurement for ossicular chains based on 3-D geometric information
Authors: Mengshi Zhang, Yufan Zhang, Sihui Guo, Xiaoguang Li, Li Zhuo, Yuxue Ren, Wei Chen, Yili Feng, Ruowei Tang, Han Lv, Pengfei Zhao, Zhenchang Wang, Hongxia Yin
Journal: Cyborg and Bionic Systems (2025)
Mending the divide: integrating opioid analgesia and immunotherapy for optimal cancer care
Authors: Celia DeJohn, Emese Zsiros
Journal: Journal for ImmunoTherapy of Cancer (2025)

Opioids remain a mainstay for managing moderate-to-severe cancer pain, yet accumulating evidence suggests that opioid analgesics can impair antitumor immunity. In their recent study, McIlvried et al propose a mechanistic framework for how morphine administration compromises response to anti-programmed-death-1 immunotherapy in a syngeneic mouse model of oral squamous cell carcinoma. They identify mu-opioid receptor signaling on CD8+ T cells as the main conduit for morphine-induced immunosuppression, observing reduced T-cell infiltration, enhanced expression of inhibitory receptors, and diminished tumor control when morphine is used. Remarkably, these adverse effects are reversed by peripherally acting mu-opioid receptor antagonists (PAMORAs), which block immunosuppression in the tumor microenvironment while presumably preserving central pain relief. Their work highlights a critical intersection between opioid-based analgesia and immunotherapy, emphasizing the need for clinicians and researchers to weigh pain control approaches against potential immunologic consequences. This commentary explores the study's implications for head and neck cancer management, addresses practical ways to mitigate opioid-induced immune inhibition, and calls for prospective trials incorporating PAMORAs in immuno-oncology protocols. Balancing effective analgesia with optimal tumor-directed immunity may yield better outcomes for patients with oral cancer and beyond.
Reprogramming tumor-associated macrophages using STING or TLR agonists: a promising strategy to enhance immunotherapy in hormone-dependent cancers
Authors: Victor Sacristan Santos, Alba Pensado-López, Rosario García-Campelo, Silvia Antolin Novoa, Rosa Señaris Rodriguez, Fernando Torres Andón
Journal: Journal for ImmunoTherapy of Cancer (2025)

Hormone-dependent cancers, like breast and prostate cancers, represent a unique challenge in oncology due to their complex interplay between hormone signaling, immune evasion, and therapeutic resistance. While endocrine therapies effectively target hormone signaling to initially control disease, resistance mechanisms frequently emerge, leading to cancer progression and limited survival. These solid tumors further complicate treatment by establishing an immunosuppressive tumor microenvironment (TME), presenting variable numbers of immune cells depending on cancer type and stage, which hinders the efficacy of immune checkpoint inhibitors. In this TME, tumor-associated macrophages (TAMs) are the major cellular source of immunosuppression, supporting tumor growth. The ability of TAMs to hamper the effectiveness of endocrine therapy is becoming increasingly recognized. Reprogramming TAMs within solid tumors can restore their natural ability to fight cancer and also enhance antitumoral efficacy. In this line of research, Al-Janabi et al have recently developed lipid nanoparticles decorated with antibodies that bind to the folate receptor-beta overexpressed in perivascular TAMs and loaded with a STING agonist (cGAMP) for the reprogramming of these TAMs. In preclinical murine models of prostate cancer, this therapeutic approach demonstrated significant synergistic activity with androgen deprivation therapy. This work provides an excellent example of TAM reprogramming combined with endocrine therapy for the treatment of hormone-dependent cancers.
Tumor location as a risk factor for severe immune-related adverse events
Authors: Steven M Blum, Ben Ouyang, Leyre Zubiri, Daniel Leonard, Kamil Slowikowski, Mike Wang, Kelley A Grealish, Nora K Hathaway, Gabriel Molina, Nishi Shah, Donald P Lawrence, Michael Dougan, Alexandra-Chloe Villani, Mari Mino Kendusen, Kerry L Reynolds, Ryan J Sullivan
Journal: Journal for ImmunoTherapy of Cancer (2025)

Immune-related adverse events (irAEs) can cause severe morbidity and mortality, and they impair treatment with immune checkpoint inhibitors (ICI). Risk factors for irAEs are not well understood.We observed cases of patients having tumor deposits in their liver and lung during a workup of irAEs, which led us to hypothesize that the presence of tumor in an organ would increase the odds of developing severe irAEs in that organ. We then performed a retrospective cohort study that included patients who received an ICI for the treatment of cancer and were hospitalized between February 2011 and November 2021 at the Massachusetts General Hospital.We reviewed 384 patients hospitalized with concern for any irAE. A clinical diagnosis of ICI-related hepatitis occurred in 18% of patients with liver tumor deposits versus 8% of those without (OR 2.23, 95% CI (1.10 to 4.43), p=0.02). ICI-related pneumonitis occurred in 10% of patients with lung tumor deposits versus 4.4% of those without (OR 2.45, 95% CI (1.06 to 6.36), p=0.047). A combined analysis for liver and lung lesions demonstrated that the presence of tumor deposits in an organ increased the odds of having an irAE in that organ by over twofold (OR 2.31, 95% CI (1.34 to 3.99), p=0.002).Our results suggest that the presence of tumor deposits may represent a novel risk factor for severe irAEs in that organ.
Macrophage sensitivity to bexmarilimab-induced reprogramming is shaped by the tumor microenvironment
Authors: Jenna H Rannikko, Rita Turpin, Pia Boström, Reetta Virtakoivu, Chantal Harth, Akira Takeda, Anselm Tamminen, Ilkka Koskivuo, Maija Hollmén
Journal: Journal for ImmunoTherapy of Cancer (2025)

Tumor-associated macrophages (TAMs) adapt to the tumor microenvironment (TME), either aiding cancer eradication or promoting tumor growth and immune evasion. To manipulate TAMs therapeutically, a deep understanding of their interaction with the TME is essential. This study explores the responsiveness of TMEs to bexmarilimab, a macrophage reprogramming therapy showing clinical benefit in various solid tumors. We exploited a breast cancer patient-derived explant culture (PDEC) model to characterize bexmarilimab responses in both tumor and adjacent cancer-free tissues by RNA sequencing and multiplex cytokine profiling. Using single-cell RNA sequencing, spatial transcriptomics, and conditioned media treatment, we further investigated the effects of Clever-1+ macrophages and TME features on bexmarilimab sensitivity. The PDEC model captured key aspects of bexmarilimab's mode of action and validated a gene signature for determining treatment sensitivity. We identified three distinct responses to bexmarilimab in tumors and adjacent cancer-free tissues, shaped by the local microenvironment and macrophage phenotype, origin, and localization. The inflammatory state of the TME emerged as the primary determinant of response. Immune activation occurred in immunologically cold TMEs lacking late-stage activated TAMs, whereas interferon-regulated TMEs exhibited suppressed inflammation. In cancer-free breast tissue, bexmarilimab activated B cell responses independent of treatment sensitivity in the adjacent tumor. These findings reveal the complexity of TAM targeting in cancer and emphasize the need for patient selection to maximize bexmarilimab's efficacy.
High-protein diets alleviate tumour growth and drug resistance by promoting AKT aggregation and turnover
Authors: Lang Bu, Yi Zhang, Yaqing Su, Xueji Wu, Bing Gao, Lei Wang, Wei Xie, Qiwei Jiang, Jianping Guo
Journal: Gut (2025)

Despite the long-standing recommendations of high-protein diets for patients with cancer, the precise mechanisms of this dietary approach in benefiting tumour suppression and enhancing sensitivity to chemotherapy remain elusive. To investigate the effect and underlying mechanism of high-protein diets in promoting cancer drug resistance. Characterisation of AKT regulation in this setting will provide new strategies to combat liver cancer. The role of high-protein diets in cancer drug resistance was analysed in cells and in syngeneic mouse models. In vivo and in vitro kinase and ubiquitination assays were employed to detect AKT phosphorylation and ubiquitination modifications. Clustered regularly interspaced short palindromic repeats (CRISPR)-based screen was used to identify the E3 ligase for AKT. Generation of Akt1T72E knock-in mice and Traf5 knockout mice was employed. High-protein diets repress tumour growth and sensitise tumour to chemotherapies. Specifically, S6K1 directly phosphorylates AKT, leading to acute inactivation and long-term instability of AKT protein. S6K1 promotes AKT aggregation and facilitates its interaction with TRAF5, resulting in AKT degradation in response to amino acid stimuli. Traf5 knockout mice exhibit high AKT protein levels, insulin resistance and counteracting protein diet-induced tumour repression. While a reversible phenomenon has been observed in the constitutive phosphor-mimetic Akt1T72E knock-in mice, which manifest retarded liver tumourigenesis in C-Myc transgenic mice. Our results highlight a fine-tuned regulation of AKT by S6K1-mediated phosphorylation and TRAF5-dictated ubiquitination and degradation, offering a strategy for integrating chemotherapy with high-protein diets to enhance cancer treatment efficacy.
Ending nuclear weapons, before they end us
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Marion Birch, Inga Blum, Peter Doherty, Andy Haines, Ira Helfand, Richard Horton, Kati Juva, Jose F Lapena Jr, Robert Mash, Olga Mironova, Arun Mitra, Carlos Monteiro, Elena N Naumova, David Onazi, Tilman Ruff, Peush Sahni, James Tumwine, Carlos Umaña, Paul Yonga, Chris Zielinski
Journal: JNCI Journal of the National Cancer Institute (2025)
Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy
Authors: Shifeng Li, Hong Xu, Shupeng Liu, Jinkun Hou, Yueyin Han, Chen Li, Yupeng Li, Gaigai Zheng, Zhongqiu Wei, Fang Yang, Shuwei Gao, Shiyao Wang, Jing Geng, Huaping Dai, Chen Wang
Journal: Cellular and Molecular Immunology (2025)

Abstract Monocyte-derived macrophages (MoMacs) are the most important effector cells that cause pulmonary fibrosis. However, the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear. Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs, identified as Spp1 hi Macs, which remain in an immature transitional state of differentiation during silicosis. This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by Pla2g7 )–acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1)–cardiolipin (CL) signaling pathway, which interferes with Spp1 hi Mac differentiation. We demonstrated that in SiO 2 -induced MoMacs, Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1, resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects. Simultaneously, lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm, which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways. Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.
Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease
Authors: Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Jitika Rajpoot, Victoria Wendt, Ahad Hossain, Prageeth R Wijewardhane, Caitlin E Randolph, Yihao Chen, Sarah Stanko, Nadia Gasmi, Anxhela Gjojdeshi, Sophie Card, Jonathan Fine, Krupal P Jethava, Matthew G Clark, Bin Dong, Seohee Ma, Alexis Crockett, Elizabeth A Thayer, Marlo Nicolas, Ryann Davis, Dhruv Hardikar, Daniela Allende, Richard A Prayson, Chi Zhang, Dimitrios Davalos, Gaurav Chopra
Journal: Immunity (2025)
Systematic analysis of nonsense variants uncovers peptide release rate as a novel modifier of nonsense-mediated mRNA decay
Authors: Divya Kolakada, Rui Fu, Nikita Biziaev, Alexey Shuvalov, Mlana Lore, Amy E Campbell, Michael A Cortázar, Marcin P Sajek, Jay R Hesselberth, Neelanjan Mukherjee, Elena Alkalaeva, Zeynep H Coban-Akdemir, Sujatha Jagannathan
Journal: Cell Genomics (2025)