bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–09–28
24 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A consensus guide to preclinical indirect calorimetry experiments.
  2. Mitochondria expel tainted DNA - spurring age-related inflammation.
  3. A common chromosome fusion in humans explained.
  4. She lived to 117: what her genes and lifestyle tell us about longevity.
  5. Mapping chromatin and DNA methylation landscapes at single-cell and single-molecule resolution.
  6. A non-apoptotic caspase-8-meteorin pathway in hepatocytes promotes MASH fibrosis.
  7. Swapping old immune cells in the brain with fresh ones could treat disease.
  8. Cholesterol fuels microglia in chronic stroke.
  9. Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
  10. Comparative single-cell and spatial profiling of anti-SSA-positive and anti-centromere-positive Sjögren's disease reveals common and distinct immune activation and fibroblast-mediated inflammation.
  11. The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.
  12. Clonal tracing of blood stem cells across mouse and human lifespans.
  13. Time to act now on the rise of dementia in Africa.
  14. Acute exogenous acyl-GIP treatment enhances lipid handling and fatty acid oxidation by involving brown fat.
  15. Clinical implications of bone marrow adiposity identified by phenome-wide association and Mendelian randomization in the UK Biobank.
  16. Gestational diabetes linked to autism in study: what scientists say.
  17. Tylenol is over 130 years old - why is it still the gold-standard painkiller?
  18. Design of facilitated dissociation enables timing of cytokine signalling.
  19. Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.
  20. Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.
  21. Real-time molecular recorders expose the inner lives of cells.
  22. Softer nuclei for whiter brown fat.
  23. The Biodiversity Cell Atlas: mapping the tree of life at cellular resolution.
  24. These 99 'lab hacks' will make your scientific work easier.
  1. Nat Metab. 2025 Sep;7(9): 1765-1780
    A consensus guide to preclinical indirect calorimetry experiments.
    International Indirect Calorimetry Consensus Committee (IICCC)
      Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.
    DOI:  https://doi.org/10.1038/s42255-025-01360-4
  2. Nature. 2025 Sep 26.
    Mitochondria expel tainted DNA - spurring age-related inflammation.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03064-x
  3. Nature. 2025 Sep 24.
    A common chromosome fusion in humans explained.
      
    Keywords:  Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-03061-0
  4. Nature. 2025 Sep 24.
    She lived to 117: what her genes and lifestyle tell us about longevity.
    Mariana Lenharo.
      
    Keywords:  Ageing; Genomics; Microbiome; Proteomics
    DOI:  https://doi.org/10.1038/d41586-025-03112-6
  5. Nat Methods. 2025 Sep 26.
    Mapping chromatin and DNA methylation landscapes at single-cell and single-molecule resolution.
      
    DOI:  https://doi.org/10.1038/s41592-025-02848-3
  6. Nat Metab. 2025 Sep 26.
    A non-apoptotic caspase-8-meteorin pathway in hepatocytes promotes MASH fibrosis.
    Xiaobo Wang, Mary P Moore, Hongxue Shi, Yang Xiao, Jiayu Zhang, Lanuza A P Faccioli, Zhiping Hu, Shareef Khalid, Danish Saleheen, Dwayne G Stupack, Tatiana Kisseleva, Alejandro Soto Gutierrez, Mitchell A Lazar, Ira Tabas.
      Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8-YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit-STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin.
    DOI:  https://doi.org/10.1038/s42255-025-01355-1
  7. Nature. 2025 Sep 25.
    Swapping old immune cells in the brain with fresh ones could treat disease.
    Heidi Ledford.
      
    Keywords:  Brain; Immunology; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-03008-5
  8. Nat Metab. 2025 Sep 23.
    Cholesterol fuels microglia in chronic stroke.
    Stefano Pluchino, Cory M Willis.
      
    DOI:  https://doi.org/10.1038/s42255-025-01362-2
  9. Nature. 2025 Sep 24.
    Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
    Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.
      Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.
    DOI:  https://doi.org/10.1038/s41586-025-09541-7
  10. Nat Commun. 2025 Sep 22. 16(1): 8299
    Comparative single-cell and spatial profiling of anti-SSA-positive and anti-centromere-positive Sjögren's disease reveals common and distinct immune activation and fibroblast-mediated inflammation.
    Jun Inamo, Masaru Takeshita, Katsuya Suzuki, Kazuyuki Tsunoda, Satoshi Usuda, Junko Kuramoto, Jonathan Moody, Chung-Chau Hon, Yoshinari Ando, Takashi Sasaki, Kazutoshi Yoshitake, Susumu Mitsuyama, Shuichi Asakawa, Yae Kanai, Tsutomu Takeuchi, Yuko Kaneko.
      Sjögren's disease (SjD) is an autoimmune disease that causes salivary gland dysfunction due to immune-mediated destruction. While autoantibodies such as anti-SSA and anti-centromere (CENT) are associated with distinct clinical manifestations, the molecular features remain to be elucidated. In this study, we apply multi-modal single-cell technologies: single-cell RNA sequencing, T cell and B cell receptor sequencing and spatial transcriptomics to salivary gland lesions, aiming to elucidate common and unique cellular and transcriptional signatures linked to different autoantibody profiles. Our analysis demonstrates that GZMB+GNLY+ CD8+ T cells are the main expanded subset across different autoantibody statuses, highlighting their central role in SjD pathogenesis, while the enrichment of memory B cells is more prominent in anti-CENT-positive patients. Cytokine signaling also differs by autoantibody profile, with an activated interferon signature in anti-SSA-positive patients, whereas TGFβ signaling is enhanced in anti-CENT-positive patients. Furthermore, spatial profiling reveals THY1+ fibroblasts, expressing complement genes and chemokines, as key hubs orchestrating inflammation within the salivary glands. These findings deepen our understanding of the pathogenesis of SjD, and may inform the development of targeted and personalized therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-63935-9
  11. Nat Metab. 2025 Sep 22.
    The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.
    Femke M Feringa, Sascha J Koppes-den Hertog, Lian Y Wang, Rico J E Derks, Iris Kruijff, Lena Erlebach, Jorin Heijneman, Ricardo Miramontes, Nadine Pömpner, Niek Blomberg, Damien Olivier-Jimenez, Lill Eva Johansen, Alexander J Cammack, Ashling Giblin, Christina E Toomey, Indigo V L Rose, Hebao Yuan, Michael E Ward, Adrian M Isaacs, Martin Kampmann, Deborah Kronenberg-Versteeg, Tammaryn Lashley, Leslie M Thompson, Alessandro Ori, Yassene Mohammed, Martin Giera, Rik van der Kant.
      Lipid alterations in the brain have been implicated in many neurodegenerative diseases. To facilitate comparative lipidomic research across brain diseases, we establish a data common named the Neurolipid Atlas that we prepopulated with isogenic induced pluripotent stem cell (iPS cell)-derived lipidomics data for different brain diseases. Additionally, the resource contains lipidomics data of human and mouse brain tissue. Leveraging multiple datasets, we demonstrate that iPS cell-derived neurons, microglia and astrocytes exhibit distinct lipid profiles that recapitulate in vivo lipotypes. Notably, the Alzheimer disease (AD) risk gene ApoE4 drives cholesterol ester (CE) accumulation specifically in human astrocytes and we also observe CE accumulation in whole-brain lipidomics from persons with AD. Multiomics interrogation of iPS cell-derived astrocytes revealed that altered cholesterol metabolism has a major role in astrocyte immune pathways such as the immunoproteasome and major histocompatibility complex class I antigen presentation. Our data commons, available online ( https://neurolipidatlas.com/ ), allows for data deposition by the community and provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01365-z
  12. Blood. 2025 Sep 22. pii: blood.2024028195. [Epub ahead of print]
    Clonal tracing of blood stem cells across mouse and human lifespans.
    Alejo E Rodriguez-Fraticelli.
      For over sixty years, blood researchers have been counting clones with every tool at their disposal. Inspired by phage and fly geneticists, Till and McCulloch irradiated mice to induce chromosomal aberrations. Using this labeling strategy, they demonstrated that different types of blood cells shared the same mutation in every spleen colony, thereby proving the existence of hematopoietic stem cells. Since their breakthrough, technological advances have enabled researchers to quantify hematopoiesis at single-cell resolution in increasingly complex samples across both mice and humans. With these modern sophisticated lineage tracing methods, our foundational understanding of the blood system is being reshaped. For instance, we now interpret hematopoietic architecture as arising from stem and progenitor cells of diverse developmental origins, each with distinct fate biases encoded by unique regulatory states. Interacting with this regulatory layer, genetic mutations and epimutations arise, expanding clonally and becoming pervasive with age. Together, clonal heterogeneity and age-driven clonal selection may underlie the perplexing diversity of therapy responses in cancer and beyond. As these paradigm-shifting insights gain traction, clonal tracing is being adopted across dozens of biological and clinical studies. Here, we review the modern toolbox of clonal tracking technologies, with a focus on next-generation sequencing-based approaches, and provide a practical guide for matching specific research questions with optimal experimental strategies.
    DOI:  https://doi.org/10.1182/blood.2024028195
  13. Nat Aging. 2025 Sep 23.
    Time to act now on the rise of dementia in Africa.
    WHO Regional Office for Africa
      
    DOI:  https://doi.org/10.1038/s43587-025-00978-z
  14. EMBO Rep. 2025 Sep 22.
    Acute exogenous acyl-GIP treatment enhances lipid handling and fatty acid oxidation by involving brown fat.
    Sulayman A Lyons, Micah B S Lea, Mihir Parikh, Zhengzhang Guo, Samrin Kagdi, Abigail R Bisnauth, Jonathan R Pitino, Sabrina Ziai, Negar Mir, Aidan D Tyrrell, Yan Fu, Chuck T Chen, Adam H Metherel, Richard P Bazinet, Bin Yang, Patrick J Knerr, Jonathan D Douros, Jonathan E Campbell, Jacqueline L Beaudry.
      The contribution of glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling in brown adipose tissue (BAT) remains underexplored. We studied the acute effects of exogenous acyl-GIP (1 nmol/kg) administration on whole-body lipid handling and fatty acid oxidation, using lipid tolerance tests (LTT) and indirect calorimetry, respectively. We demonstrate that in obese male mice, acute acyl-GIP administration improves lipid tolerance; however, pharmacological inhibition of GIPR, or genetic removal of GIPR globally or with the Myf5-Cre driver, completely abolishes GIP-mediated improvements in lipid tolerance, implicating GIPR in BAT. GIP-mediated improvements in lipid tolerance are associated with an increase in BAT lipid uptake, linked to increases in BAT lipoprotein lipase activity. Our data also reveal that BAT GIPR signalling is necessary for GIP-mediated increases in whole-body fatty acid oxidation, as Myf5-Cre: Gipr mice do not shift substrate oxidation upon GIP administration. Our findings suggest that BAT should be more closely considered in studies examining GIP's effects on whole-body metabolism in rodent models.
    Keywords:  Brown Adipose Tissue; Glucose-dependent Insulinotropic Polypeptide; Lipid Metabolism
    DOI:  https://doi.org/10.1038/s44319-025-00582-7
  15. Nat Commun. 2025 Sep 23. 16(1): 8332
    Clinical implications of bone marrow adiposity identified by phenome-wide association and Mendelian randomization in the UK Biobank.
    Wei Xu, Ines Mesa-Eguiagaray, David M Morris, Chengjia Wang, Calum D Gray, Samuel Sjöström, Giorgos Papanastasiou, Sammy Badr, Julien Paccou, Lijuan Wang, Xue Li, Paul R H J Timmers, Maria Timofeeva, Scott Ik Semple, Tom MacGillivray, Evropi Theodoratou, William P Cawthorn.
      Bone marrow adiposity changes in diverse diseases, but the full scope of these, and whether they are directly influenced by marrow adiposity, remains unknown. To address this, we previously measured the bone marrow fat fraction of the femoral head, total hip, femoral diaphysis, and spine of over 48,000 UK Biobank participants. Here, we first use these data for PheWAS to identify diseases associated with marrow adiposity at each site. This reveals associations with 47 incident diseases across 12 disease categories, including osteoporosis, fracture, type 2 diabetes, cardiovascular diseases, cancers, and other conditions that burden public health worldwide. Intriguingly, type 2 diabetes associates positively with spine bone marrow adiposity but negatively with marrow adiposity at femoral sites. We then establish PRSs based on bone-marrow-fat-fraction-associated SNPs and use PRS-PheWAS and Mendelian randomization to explore causal associations between marrow adiposity and disease. PRS-PheWAS reveals that genetic predisposition to increased marrow adiposity is positively associated with osteoporosis and fractures. Mendelian randomization further suggests that increased marrow adiposity at the diaphysis and total hip is causally associated with osteoporosis. Our findings substantially advance understanding of how marrow adiposity impacts human health and highlight its potential as a biomarker and/or therapeutic target for diverse human diseases.
    DOI:  https://doi.org/10.1038/s41467-025-63395-1
  16. Nature. 2025 Sep 22.
    Gestational diabetes linked to autism in study: what scientists say.
    Rachel Fieldhouse.
      
    Keywords:  Diabetes; Genetics; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-03024-5
  17. Nature. 2025 Sep 24.
    Tylenol is over 130 years old - why is it still the gold-standard painkiller?
    David Adam.
      
    Keywords:  Brain
    DOI:  https://doi.org/10.1038/d41586-025-03116-2
  18. Nature. 2025 Sep 24.
    Design of facilitated dissociation enables timing of cytokine signalling.
    Adam J Broerman, Christoph Pollmann, Yang Zhao, Mauriz A Lichtenstein, Mark D Jackson, Maxx H Tessmer, Won Hee Ryu, Masato Ogishi, Mohamad H Abedi, Danny D Sahtoe, Aza Allen, Alex Kang, Joshmyn De La Cruz, Evans Brackenbrough, Banumathi Sankaran, Asim K Bera, Daniel M Zuckerman, Stefan Stoll, K Christopher Garcia, Florian Praetorius, Jacob Piehler, David Baker.
      Protein design has focused on the design of ground states, ensuring that they are sufficiently low energy to be highly populated1. Designing the kinetics and dynamics of a system requires, in addition, the design of excited states that are traversed in transitions from one low-lying state to another2,3. This is a challenging task because such states must be sufficiently strained to be poorly populated, but not so strained that they are not populated at all, and because protein design methods have focused on generating near-ideal structures4-7. Here we describe a general approach for designing systems that use an induced-fit power stroke8 to generate a structurally frustrated9 and strained excited state, allosterically driving protein complex dissociation. X-ray crystallography, double electron-electron resonance spectroscopy and kinetic binding measurements show that incorporating excited states enables the design of effector-induced increases in dissociation rates as high as 5,700-fold. We highlight the power of this approach by designing rapid biosensors, kinetically controlled circuits and cytokine mimics that can be dissociated from their receptors within seconds, enabling dissection of the temporal dynamics of interleukin-2 signalling.
    DOI:  https://doi.org/10.1038/s41586-025-09549-z
  19. Nat Metab. 2025 Sep 23.
    Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.
    Qiang Zhao, Jiajian Li, Jingjing Feng, Xin Wang, Yueting Liu, Fei Wang, Liang Liu, Bingxue Jin, Ming Lin, Ya-Chao Wang, Xiuhua Guo, Jieli Chen, Junwei Hao.
      Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.
    DOI:  https://doi.org/10.1038/s42255-025-01379-7
  20. Nat Commun. 2025 Sep 25. 16(1): 8392
    Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.
    Mihaly Badonyi, Joseph A Marsh.
      Molecular disease mechanisms caused by mutations in protein-coding regions are diverse, but they can be broadly categorised into loss-of-function, gain-of-function and dominant-negative effects. Accurately predicting these mechanisms is important, since therapeutic strategies can exploit these mechanisms. Computational predictors tend to perform less well at the identification of pathogenic gain-of-function and dominant-negative variants. Here, we develop a protein structure-based missense loss-of-function likelihood score that can separate recessive loss of function and dominant loss of function from alternative disease mechanisms. Using missense loss-of-function scores, we estimate the prevalence of molecular mechanisms across 2,837 phenotypes in 1,979 Mendelian disease genes, finding that dominant-negative and gain-of-function mechanisms account for 48% of phenotypes in dominant genes. Applying missense loss-of-function scores to genes with multiple phenotypes reveals widespread intragenic mechanistic heterogeneity, with 43% of dominant and 49% of mixed-inheritance genes harbouring both loss-of-function and non-loss-of-function mechanisms. Furthermore, we show that combining missense loss-of-function scores with phenotype semantic similarity enables the prioritisation of dominant-negative mechanisms in mixed-inheritance genes. Our structure-based approach, accessible via a Google Colab notebook, offers a scalable tool for predicting disease mechanisms and advancing personalised medicine.
    DOI:  https://doi.org/10.1038/s41467-025-63234-3
  21. Nature. 2025 Sep;645(8082): 1094-1096
    Real-time molecular recorders expose the inner lives of cells.
    Elie Dolgin.
      
    Keywords:  CRISPR-Cas9 genome editing; Developmental biology; Systems biology; Technology
    DOI:  https://doi.org/10.1038/d41586-025-03035-2
  22. Sci Signal. 2025 Sep 23. 18(905): eaec3820
    Softer nuclei for whiter brown fat.
    Wei Wong.
      Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.
    DOI:  https://doi.org/10.1126/scisignal.aec3820
  23. Nature. 2025 Sep;645(8082): 877-885
    The Biodiversity Cell Atlas: mapping the tree of life at cellular resolution.
    Biodiversity Cell Atlas meeting participants
      Cell types are fundamental functional units that can be traced across the tree of life. Rapid advances in single-cell technologies, coupled with the phylogenetic expansion in genome sequencing, present opportunities for the molecular characterization of cells across a broad range of organisms. Despite these developments, our understanding of eukaryotic cell diversity remains limited and we are far from decoding this diversity from genome sequences. Here we introduce the Biodiversity Cell Atlas initiative, which aims to create comprehensive single-cell molecular atlases across the eukaryotic tree of life. This community effort will be phylogenetically informed, rely on high-quality genomes and use shared standards to facilitate comparisons across species. The Biodiversity Cell Atlas aspires to deepen our understanding of the evolution and diversity of life at the cellular level, encompassing gene regulatory programs, differentiation trajectories, cell-type-specific molecular profiles and inter-organismal interactions.
    DOI:  https://doi.org/10.1038/s41586-025-09312-4
  24. Nature. 2025 Sep 23.
    These 99 'lab hacks' will make your scientific work easier.
    Jack Leeming.
      
    Keywords:  Careers; Chemistry; Lab life
    DOI:  https://doi.org/10.1038/d41586-025-02719-z
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