bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒07‒14
fifty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Unmasking immune suppression.
  2. A distinct aging-enriched platelet differentiation pathway.
  3. B cells instruct their own fate through IL-12.
  4. Neutrophil extracellular traps promote immunopathogenesis of virus-induced COPD exacerbations.
  5. Iran elects heart surgeon as president: scientists are hopeful.
  6. This lab-grown meat probably tastes like real beef.
  7. Pharmacological TERT activation attenuates phenotypes of natural aging.
  8. GeneMAP enables discovery of metabolic gene function.
  9. Daily briefing: Bionic leg moves like a natural limb.
  10. Alzheimer's plaques and tangles revealed by 3D microscopy.
  11. Cell atlas of the regenerating human liver after portal vein embolization.
  12. The Spinoff Prize 2024.
  13. Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression.
  14. A global initiative to deliver precision health in diabetes.
  15. Daily briefing: Older people's existing immunity could shape an H5N1 pandemic.
  16. Opening up.
  17. AI & robotics briefing: How to beat 'superhuman' AI.
  18. Daily briefing: How scientists balance work and faith.
  19. To explain biological sex, look to evolution.
  20. β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer's Disease.
  21. Understanding NK cell heterogeneity.
  22. Pension planning and psychosocial support: how institutions can help academics at the late career stage.
  23. Immune-checkpoint blockade protects aged mice from infection.
  24. Scientists relieved by far-right defeat in French election - but they still face uncertainty.
  25. Daily briefing: The mystery man at the centre of the Human Genome Project.
  26. Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis.
  27. Temperature sensitivity of bat antibodies links metabolic state of bats with antigen-recognition diversity.
  28. Maggie Aderin-Pocock on diversity: 'It's hard to find an argument against it'.
  29. Saliva-based tests offer an alternative to nasal swabbing.
  30. Scientists edit the genes of gut bacteria in living mice.
  31. B cells! Don't go the wrong way in this tumor.
  32. AI tool can pinpoint dementia's cause - from stroke to Alzheimer's.
  33. Some photos you might like.
  34. Gut microorganisms enhance bone mass after exercise.
  35. ITER delay: what it means for nuclear fusion.
  36. Elixir for DCs.
  37. High-resolution atlas of the developing, adult and diseased human brain vasculature.
  38. Stimulation history is epigenetically imprinted in memory B cells.
  39. A light-touch approach to intracellular delivery.
  40. Scavengers in islets fuel diabetic autoimmunity.
  41. Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance.
  42. Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses.
  43. Assigning function to an unexplored Integrator module.
  44. The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes.
  45. UPF1 plays critical roles in early B cell development.
  46. Unsupervised representation learning on high-dimensional clinical data improves genomic discovery and prediction.
  47. Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes.
  48. ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells.
  49. CryoET of β-amyloid and tau within postmortem Alzheimer's disease brain.
  50. HLTF disrupts Cas9-DNA post-cleavage complexes to allow DNA break processing.
  1. Science. 2024 Jul 12. 385(6705): 140-142
    Unmasking immune suppression.
    Jason R Pitarresi, Katherine A Fitzgerald.
      Inhibition of a mutated metabolic enzyme puts the sting back in antitumor immunity.
    DOI:  https://doi.org/10.1126/science.adq5196
  2. Nat Aging. 2024 Jul 09.
    A distinct aging-enriched platelet differentiation pathway.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00677-1
  3. Nat Immunol. 2024 Jul 09.
    B cells instruct their own fate through IL-12.
    Iñaki Sanz.
      
    DOI:  https://doi.org/10.1038/s41590-024-01887-w
  4. Nat Commun. 2024 Jul 09. 15(1): 5766
    Neutrophil extracellular traps promote immunopathogenesis of virus-induced COPD exacerbations.
    Orestis Katsoulis, Marie Toussaint, Millie M Jackson, Patrick Mallia, Joseph Footitt, Kyle T Mincham, Garance F M Meyer, Tata Kebadze, Amy Gilmour, Merete Long, Andrew D Aswani, Robert J Snelgrove, Sebastian L Johnston, James D Chalmers, Aran Singanayagam.
      Respiratory viruses are a major trigger of exacerbations in chronic obstructive pulmonary disease (COPD). Airway neutrophilia is a hallmark feature of stable and exacerbated COPD but roles played by neutrophil extracellular traps (NETS) in driving disease pathogenesis are unclear. Here, using human studies of experimentally-induced and naturally-occurring exacerbations we identify that rhinovirus infection induces airway NET formation which is amplified in COPD and correlates with magnitude of inflammation and clinical exacerbation severity. We show that inhibiting NETosis protects mice from immunopathology in a model of virus-exacerbated COPD. NETs drive inflammation during exacerbations through release of double stranded DNA (dsDNA) and administration of DNAse in mice has similar protective effects. Thus, NETosis, through release of dsDNA, has a functional role in the pathogenesis of COPD exacerbations. These studies open up the potential for therapeutic targeting of NETs or dsDNA as a strategy for treating virus-exacerbated COPD.
    DOI:  https://doi.org/10.1038/s41467-024-50197-0
  5. Nature. 2024 Jul 09.
    Iran elects heart surgeon as president: scientists are hopeful.
    Michele Catanzaro.
      
    DOI:  https://doi.org/10.1038/d41586-024-02262-3
  6. Nature. 2024 Jul 10.
    This lab-grown meat probably tastes like real beef.
    Helena Kudiabor.
      
    Keywords:  Cell biology; Nutrition
    DOI:  https://doi.org/10.1038/d41586-024-02273-0
  7. Nat Aging. 2024 Jul 08.
    Pharmacological TERT activation attenuates phenotypes of natural aging.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00673-5
  8. Nat Genet. 2024 Jul 11.
    GeneMAP enables discovery of metabolic gene function.
      
    DOI:  https://doi.org/10.1038/s41588-024-01828-1
  9. Nature. 2024 Jul 02.
    Daily briefing: Bionic leg moves like a natural limb.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02193-z
  10. Nature. 2024 Jul 10.
    Alzheimer's plaques and tangles revealed by 3D microscopy.
    Sjors H W Scheres.
      
    Keywords:  Alzheimer's disease; Microscopy; Neurodegeneration; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-02119-9
  11. Nat Commun. 2024 Jul 11. 15(1): 5827
    Cell atlas of the regenerating human liver after portal vein embolization.
    Agnieska Brazovskaja, Tomás Gomes, Rene Holtackers, Philipp Wahle, Christiane Körner, Zhisong He, Theresa Schaffer, Julian Connor Eckel, René Hänsel, Malgorzata Santel, Makiko Seimiya, Timm Denecke, Michael Dannemann, Mario Brosch, Jochen Hampe, Daniel Seehofer, Georg Damm, J Gray Camp, Barbara Treutlein.
      The liver has the remarkable capacity to regenerate. In the clinic, regeneration is induced by portal vein embolization, which redirects portal blood flow, resulting in liver hypertrophy in locations with increased blood supply, and atrophy of embolized segments. Here, we apply single-cell and single-nucleus transcriptomics on healthy, hypertrophied, and atrophied patient-derived liver samples to explore cell states in the regenerating liver. Our data unveils pervasive upregulation of genes associated with developmental processes, cellular adhesion, and inflammation in post-portal vein embolization liver, disrupted portal-central hepatocyte zonation, and altered cell subtype composition of endothelial and immune cells. Interlineage crosstalk analysis reveals mesenchymal cells as an interaction hub between immune and endothelial cells, and highlights the importance of extracellular matrix proteins in liver regeneration. Moreover, we establish tissue-scale iterative indirect immunofluorescence imaging for high-dimensional spatial analysis of perivascular microenvironments, uncovering changes to tissue architecture in regenerating liver lobules. Altogether, our data is a rich resource revealing cellular and histological changes in human liver regeneration.
    DOI:  https://doi.org/10.1038/s41467-024-49236-7
  12. Nature. 2024 Jul 11.
    The Spinoff Prize 2024.
    Herb Brody.
      
    Keywords:  Business; Careers; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-02156-4
  13. Nat Commun. 2024 Jul 12. 15(1): 5873
    Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression.
    Sara Zahraeifard, Zhiguang Xiao, Jae Young So, Abdul Ahad, Selina Montoya, Woo Yong Park, Trinadharao Sornapudi, Tiffany Andohkow, Abigail Read, Noemi Kedei, Vishal Koparde, Howard Yang, Maxwell Lee, Nathan Wong, Maggie Cam, Kun Wang, Eytan Ruppin, Ji Luo, Christine Hollander, Li Yang.
      Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-β RII as TSs regulating immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape, characterized by increased numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-β RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-β RII-inactivated cancers.
    DOI:  https://doi.org/10.1038/s41467-024-50262-8
  14. Nat Med. 2024 Jul 11.
    A global initiative to deliver precision health in diabetes.
    W T Cefalu, P W Franks, N D Rosenblum, N A Zaghloul, J C Florez, F Giorgino, L Ji, R C W Ma, C Mathieu, S Misra, A H Ramirez, M Roden, P E Scherer, W H-H Sheu, C D A Stehouwer, M Woo, M Pragnell, S S Anand, M Carnethon, J C Chambers, J M Dennis, A L Gloyn, C Herder, R I G Holt, D G Manuel, M J Redondo, N Tandon, J S Tsang, M S Udler, S S Rich.
      
    DOI:  https://doi.org/10.1038/s41591-024-03032-4
  15. Nature. 2024 Jul 10.
    Daily briefing: Older people's existing immunity could shape an H5N1 pandemic.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02290-z
  16. Science. 2024 Jul 12. 385(6705): 226
    Opening up.
    Albert W Li.
      
    DOI:  https://doi.org/10.1126/science.adr5420
  17. Nature. 2024 Jul 09.
    AI & robotics briefing: How to beat 'superhuman' AI.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-02283-y
  18. Nature. 2024 May 21.
    Daily briefing: How scientists balance work and faith.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-01535-1
  19. Nature. 2024 Jul;631(8020): 275
    To explain biological sex, look to evolution.
    Paul E Griffiths, Hamish G Spencer.
      
    Keywords:  Evolution; Human behaviour
    DOI:  https://doi.org/10.1038/d41586-024-02248-1
  20. Nat Commun. 2024 Jul 10. 15(1): 5819
    β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer's Disease.
    Benedikt Zott, Lea Nästle, Christine Grienberger, Felix Unger, Manuel M Knauer, Christian Wolf, Aylin Keskin-Dargin, Anna Feuerbach, Marc Aurel Busche, Arne Skerra, Arthur Konnerth.
      Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer's disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides before Aβ plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of β-amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aβ monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.
    DOI:  https://doi.org/10.1038/s41467-024-50153-y
  21. Nat Rev Immunol. 2024 Jul 12.
    Understanding NK cell heterogeneity.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-024-01068-8
  22. Nature. 2024 Jul 12.
    Pension planning and psychosocial support: how institutions can help academics at the late career stage.
    Julie Gould.
      
    Keywords:  Ageing; Careers; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-02296-7
  23. Nat Aging. 2024 Jul 08.
    Immune-checkpoint blockade protects aged mice from infection.
    Daniel Thiele, Nicole L La Gruta.
      
    DOI:  https://doi.org/10.1038/s43587-024-00664-6
  24. Nature. 2024 Jul 08.
    Scientists relieved by far-right defeat in French election - but they still face uncertainty.
    Barbara Casassus.
      
    Keywords:  Policy; Politics
    DOI:  https://doi.org/10.1038/d41586-024-02260-5
  25. Nature. 2024 Jul 11.
    Daily briefing: The mystery man at the centre of the Human Genome Project.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-02302-y
  26. Nature. 2024 Jul 10.
    Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis.
    Florian Gaertner, Hellen Ishikawa-Ankerhold, Susanne Stutte, Wenwen Fu, Jutta Weitz, Anne Dueck, Bhavishya Nelakuditi, Valeria Fumagalli, Dominic van den Heuvel, Larissa Belz, Gulnoza Sobirova, Zhe Zhang, Anna Titova, Alejandro Martinez Navarro, Kami Pekayvaz, Michael Lorenz, Louisa von Baumgarten, Jan Kranich, Tobias Straub, Bastian Popper, Vanessa Zheden, Walter Anton Kaufmann, Chenglong Guo, Guido Piontek, Saskia von Stillfried, Peter Boor, Marco Colonna, Sebastian Clauß, Christian Schulz, Thomas Brocker, Barbara Walzog, Christoph Scheiermann, William C Aird, Claus Nerlov, Konstantin Stark, Tobias Petzold, Stefan Engelhardt, Michael Sixt, Robert Hauschild, Martina Rudelius, Robert A J Oostendorp, Matteo Iannacone, Matthias Heinig, Steffen Massberg.
      Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.
    DOI:  https://doi.org/10.1038/s41586-024-07671-y
  27. Nat Commun. 2024 Jul 13. 15(1): 5878
    Temperature sensitivity of bat antibodies links metabolic state of bats with antigen-recognition diversity.
    Nia Toshkova, Violeta Zhelyzkova, Alejandra Reyes-Ruiz, Eline Haerens, Marina de Castro Deus, Robin V Lacombe, Maxime Lecerf, Gaelle Gonzalez, Nolwenn Jouvenet, Cyril Planchais, Jordan D Dimitrov.
      The bat immune system features multiple unique properties such as dampened inflammatory responses and increased tissue protection, explaining their long lifespan and tolerance to viral infections. Here, we demonstrated that body temperature fluctuations corresponding to different physiological states in bats exert a large impact on their antibody repertoires. At elevated temperatures typical for flight, IgG from the bat species Myotis myotis and Nyctalus noctula show elevated antigen binding strength and diversity, recognizing both pathogen-derived antigens and autoantigens. The opposite is observed at temperatures reflecting inactive physiological states. IgG antibodies of human and other mammals, or antibodies of birds do not appear to behave in a similar way. Importantly, diversification of bat antibody specificities results in preferential recognition of damaged endothelial and epithelial cells, indicating an anti-inflammatory function. The temperature-sensitivity of bat antibodies is mediated by the variable regions of immunoglobulin molecules. Additionally, we uncover specific molecular features of bat IgG, such as low thermodynamic stability and implication of hydrophobic interactions in antigen binding as well as high prevalence of polyreactivity. Overall, our results extend the understanding of bat tolerance to disease and inflammation and highlight the link between metabolism and immunity.
    DOI:  https://doi.org/10.1038/s41467-024-50316-x
  28. Nature. 2024 Jul 12.
    Maggie Aderin-Pocock on diversity: 'It's hard to find an argument against it'.
    Audrey Thompson.
      
    Keywords:  Astronomy and astrophysics; Careers; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-02303-x
  29. Nature. 2024 Jul 11.
    Saliva-based tests offer an alternative to nasal swabbing.
    Neil Savage.
      
    Keywords:  Business; Industry; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02165-3
  30. Nature. 2024 Jul 10.
    Scientists edit the genes of gut bacteria in living mice.
    Gemma Conroy.
      
    Keywords:  Gene therapy; Genomics
    DOI:  https://doi.org/10.1038/d41586-024-02238-3
  31. Immunity. 2024 Jul 09. pii: S1074-7613(24)00313-3. [Epub ahead of print]57(7): 1454-1456
    B cells! Don't go the wrong way in this tumor.
    Guilhem Pupier, Catherine Sautès-Fridman.
      The association of tertiary lymphoid structures (TLSs) with survival and immunotherapy response brought B cells to center stage. In a pan-cancer B cells atlas in Science, Ma et al. show that germinal center reaction generating anti-tumor antibody-secreting cells (ASCs) from B memory cells in mature TLSs co-exist in tumors with extra-follicular reaction generating auto-reactive ASCs from memory B cells in immature TLSs.
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.007
  32. Nature. 2024 Jul 04.
    AI tool can pinpoint dementia's cause - from stroke to Alzheimer's.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02202-1
  33. Nature. 2024 Jul 10.
    Some photos you might like.
    Bob McHugh.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-02189-9
  34. Nat Aging. 2024 Jul 10.
    Gut microorganisms enhance bone mass after exercise.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s43587-024-00676-2
  35. Nature. 2024 Jul 08.
    ITER delay: what it means for nuclear fusion.
    Elizabeth Gibney.
      
    Keywords:  Energy; Physics
    DOI:  https://doi.org/10.1038/d41586-024-02247-2
  36. Nat Rev Immunol. 2024 Jul 12.
    Elixir for DCs.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-024-01065-x
  37. Nature. 2024 Jul 11.
    High-resolution atlas of the developing, adult and diseased human brain vasculature.
      
    Keywords:  Computational biology and bioinformatics; Developmental biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02284-x
  38. Nat Immunol. 2024 Jul 09.
    Stimulation history is epigenetically imprinted in memory B cells.
      
    DOI:  https://doi.org/10.1038/s41590-024-01903-z
  39. Nature. 2024 Jul 11.
    A light-touch approach to intracellular delivery.
    Tim Vernimmen.
      
    Keywords:  Business; Industry; Nanoparticles
    DOI:  https://doi.org/10.1038/d41586-024-02167-1
  40. Immunity. 2024 Jul 09. pii: S1074-7613(24)00314-5. [Epub ahead of print]57(7): 1448-1451
    Scavengers in islets fuel diabetic autoimmunity.
    Jadie Y Moon, Katherine A Gallagher.
      Autoreactive lymphocytes that infiltrate the pancreatic islet environment and target β cells are primary drivers of type 1 diabetes. In this issue of Immunity, Srivastava et al.1 examine the role of the islet microenvironment in autoimmunity and find that the scavenging receptor CXCL16 on islet-resident macrophages uptakes oxidized low-density lipoproteins and promotes the differentiation and survival of infiltrating pathogenic CD8+ T cells.
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.008
  41. Commun Biol. 2024 Jul 11. 7(1): 849
    Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance.
    Ana Andres-Hernando, David J Orlicky, Masanari Kuwabara, Mehdi A Fini, Dean R Tolan, Richard J Johnson, Miguel A Lanaspa.
      Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P). No cure exists for HFI and treatment is limited to avoid exposure to fructose and sugar. Using aldolase B deficient mice, here we identify a yet unrecognized metabolic event activated in HFI and associated with the progression of the disease. Besides the accumulation of F1P, here we show that the activation of the purine degradation pathway is a common feature in aldolase B deficient mice exposed to fructose. The purine degradation pathway is a metabolic route initiated by adenosine monophosphate deaminase 2 (AMPD2) that regulates overall energy balance. We demonstrate that very low amounts of fructose are sufficient to activate AMPD2 in these mice via a phosphate trap. While blocking AMPD2 do not impact F1P accumulation and the risk of hypoglycemia, its deletion in hepatocytes markedly improves the metabolic dysregulation induced by fructose and corrects fat and glycogen storage while significantly increasing the voluntary tolerance of these mice to fructose. In summary, we provide evidence for a critical pathway activated in HFI that could be targeted to improve the metabolic consequences associated with fructose consumption.
    DOI:  https://doi.org/10.1038/s42003-024-06539-1
  42. Nat Commun. 2024 Jul 11. 15(1): 5842
    Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses.
    Naniye Malli Cetinbas, Travis Monnell, Jahna Soomer-James, Pamela Shaw, Kelly Lancaster, Kalli C Catcott, Melissa Dolan, Rebecca Mosher, Caitlin Routhier, Chen-Ni Chin, Dorin Toader, Jeremy Duvall, Raghida Bukhalid, Timothy B Lowinger, Marc Damelin.
      Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.
    DOI:  https://doi.org/10.1038/s41467-024-49932-4
  43. Mol Cell. 2024 Jul 11. pii: S1097-2765(24)00521-5. [Epub ahead of print]84(13): 2405-2406
    Assigning function to an unexplored Integrator module.
    William Garland, Jérôme O Rouvière, Torben Heick Jensen.
      In this issue of Molecular Cell, Razew et al.1 and Sabath et al.2 assign function to an unexplored module of the Integrator (INT) complex, expanding the toolbox of this genome-wide attenuator of RNA polymerase II (RNAPII) transcription.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.014
  44. Nat Commun. 2024 Jul 10. 15(1): 5745
    The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes.
    Sina Rhein, Riccardo Costalunga, Julica Inderhees, Tammo Gürtzgen, Teresa Christina Faupel, Zaib Shaheryar, Adriana Arrulo Pereira, Alaa Othman, Kimberly Begemann, Sonja Binder, Ines Stölting, Valentina Dorta, Peter P Nawroth, Thomas Fleming, Konrad Oexle, Vincent Prevot, Ruben Nogueiras, Svenja Meyhöfer, Sebastian M Meyhöfer, Markus Schwaninger.
      Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
    DOI:  https://doi.org/10.1038/s41467-024-50089-3
  45. Nat Commun. 2024 Jul 09. 15(1): 5765
    UPF1 plays critical roles in early B cell development.
    Noriki Iwai, Kotaro Akaki, Fabian Hia, Wei Li, Masanori Yoshinaga, Takashi Mino, Osamu Takeuchi.
      The ATP-dependent RNA helicase UPF1 plays a crucial role in various mRNA degradation pathways, most importantly in nonsense-mediated mRNA decay (NMD). Here, we show that UPF1 is upregulated during the early stages of B cell development and is important for early B cell development in the bone marrow. B-cell-specific Upf1 deletion in mice severely impedes the early to late LPre-B cell transition, in which VH-DHJH recombination occurs at the Igh gene. Furthermore, UPF1 is indispensable for VH-DHJH recombination, without affecting DH-JH recombination. Intriguingly, the genetic pre-arrangement of the Igh gene rescues the differentiation defect in early LPre-B cells under Upf1 deficient conditions. However, differentiation is blocked again following Ig light chain recombination, leading to a failure in development into immature B cells. Notably, UPF1 interacts with and regulates the expression of genes involved in immune responses, cell cycle control, NMD, and the unfolded protein response in B cells. Collectively, our findings underscore the critical roles of UPF1 during the early LPre-B cell stage and beyond, thus orchestrating B cell development.
    DOI:  https://doi.org/10.1038/s41467-024-50032-6
  46. Nat Genet. 2024 Jul 08.
    Unsupervised representation learning on high-dimensional clinical data improves genomic discovery and prediction.
    Taedong Yun, Justin Cosentino, Babak Behsaz, Zachary R McCaw, Davin Hill, Robert Luben, Dongbing Lai, John Bates, Howard Yang, Tae-Hwi Schwantes-An, Yuchen Zhou, Anthony P Khawaja, Andrew Carroll, Brian D Hobbs, Michael H Cho, Cory Y McLean, Farhad Hormozdiari.
      Although high-dimensional clinical data (HDCD) are increasingly available in biobank-scale datasets, their use for genetic discovery remains challenging. Here we introduce an unsupervised deep learning model, Representation Learning for Genetic Discovery on Low-Dimensional Embeddings (REGLE), for discovering associations between genetic variants and HDCD. REGLE leverages variational autoencoders to compute nonlinear disentangled embeddings of HDCD, which become the inputs to genome-wide association studies (GWAS). REGLE can uncover features not captured by existing expert-defined features and enables the creation of accurate disease-specific polygenic risk scores (PRSs) in datasets with very few labeled data. We apply REGLE to perform GWAS on respiratory and circulatory HDCD-spirograms measuring lung function and photoplethysmograms measuring blood volume changes. REGLE replicates known loci while identifying others not previously detected. REGLE are predictive of overall survival, and PRSs constructed from REGLE loci improve disease prediction across multiple biobanks. Overall, REGLE contain clinically relevant information beyond that captured by existing expert-defined features, leading to improved genetic discovery and disease prediction.
    DOI:  https://doi.org/10.1038/s41588-024-01831-6
  47. Nat Immunol. 2024 Jul 11.
    Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes.
    Yuanyuan You, Josefine Dunst, Kewei Ye, Patrick A Sandoz, Annika Reinhardt, Inga Sandrock, Natalia R Comet, Rupak Dey Sarkar, Emily Yang, Estelle Duprez, Judith Agudo, Brian D Brown, Paul J Utz, Wolfgang Kastenmüller, Carmen Gerlach, Immo Prinz, Björn Önfelt, Taras Kreslavsky.
      Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01899-6
  48. Nat Commun. 2024 Jul 06. 15(1): 5680
    ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells.
    Tu-Xiong Huang, Hui-Si Huang, Shao-Wei Dong, Jia-Yan Chen, Bin Zhang, Hua-Hui Li, Tian-Tian Zhang, Qiang Xie, Qiao-Yun Long, Yang Yang, Lin-Yuan Huang, Pan Zhao, Jiong Bi, Xi-Feng Lu, Fan Pan, Chang Zou, Li Fu.
      Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-β1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-β1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.
    DOI:  https://doi.org/10.1038/s41467-024-50077-7
  49. Nature. 2024 Jul 10.
    CryoET of β-amyloid and tau within postmortem Alzheimer's disease brain.
    Madeleine A G Gilbert, Nayab Fatima, Joshua Jenkins, Thomas J O'Sullivan, Andreas Schertel, Yehuda Halfon, Martin Wilkinson, Tjado H J Morrema, Mirjam Geibel, Randy J Read, Neil A Ranson, Sheena E Radford, Jeroen J M Hoozemans, René A W Frank.
      A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures1. In Alzheimer's disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer's disease donor brain. β-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles and cuboidal particles defined the non-amyloid constituents of β-amyloid plaques. By contrast, tau inclusions formed parallel clusters of unbranched filaments. Subtomogram averaging a cluster of 136 tau filaments in a single tomogram revealed the polypeptide backbone conformation and filament polarity orientation of paired helical filaments within tissue. Filaments within most clusters were similar to each other, but were different between clusters, showing amyloid heterogeneity that is spatially organized by subcellular location. The in situ structural approaches outlined here for human donor tissues have applications to a broad range of neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41586-024-07680-x
  50. Nat Commun. 2024 Jul 10. 15(1): 5789
    HLTF disrupts Cas9-DNA post-cleavage complexes to allow DNA break processing.
    Giordano Reginato, Maria Rosaria Dello Stritto, Yanbo Wang, Jingzhou Hao, Raphael Pavani, Michael Schmitz, Swagata Halder, Vincent Morin, Elda Cannavo, Ilaria Ceppi, Stefan Braunshier, Ananya Acharya, Virginie Ropars, Jean-Baptiste Charbonnier, Martin Jinek, Andrè Nussenzweig, Taekjip Ha, Petr Cejka.
      The outcome of CRISPR-Cas-mediated genome modifications is dependent on DNA double-strand break (DSB) processing and repair pathway choice. Homology-directed repair (HDR) of protein-blocked DSBs requires DNA end resection that is initiated by the endonuclease activity of the MRE11 complex. Using reconstituted reactions, we show that Cas9 breaks are unexpectedly not directly resectable by the MRE11 complex. In contrast, breaks catalyzed by Cas12a are readily processed. Cas9, unlike Cas12a, bridges the broken ends, preventing DSB detection and processing by MRE11. We demonstrate that Cas9 must be dislocated after DNA cleavage to allow DNA end resection and repair. Using single molecule and bulk biochemical assays, we next find that the HLTF translocase directly removes Cas9 from broken ends, which allows DSB processing by DNA end resection or non-homologous end-joining machineries. Mechanistically, the activity of HLTF requires its HIRAN domain and the release of the 3'-end generated by the cleavage of the non-target DNA strand by the Cas9 RuvC domain. Consequently, HLTF removes the H840A but not the D10A Cas9 nickase. The removal of Cas9 H840A by HLTF explains the different cellular impact of the two Cas9 nickase variants in human cells, with potential implications for gene editing.
    DOI:  https://doi.org/10.1038/s41467-024-50080-y
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