bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–10–27
fifty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Wall of fame.
  2. Machine-guided design of cell-type-targeting cis-regulatory elements.
  3. Dominant immune tolerance in the intestinal tract imposed by RelB-dependent migratory dendritic cells regulates protective type 2 immunity.
  4. Giant Turkish quake shifted the ground hundreds of kilometres away.
  5. The Staggering Success of Vaccines.
  6. Chromatin remodelling drives immune cell-fibroblast communication in heart failure.
  7. Human macrophages in pancreas and skin shape prenatal organogenesis.
  8. Targeting Unc5b in macrophages drives atherosclerosis regression and pro-resolving immune cell function.
  9. How to run a successful internship programme.
  10. How the Mpox Response Has Learned from History.
  11. How to Make Progress in Health Equity.
  12. Metformin slows signs of primate aging.
  13. Remyelination protects neurons from DLK-mediated neurodegeneration.
  14. Reading the signs of dementia.
  15. METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.
  16. Exposing predatory journals: anonymous sleuthing account goes public.
  17. Attenuated kidney oxidative metabolism in young adults with type 1 diabetes.
  18. Brain stimulation at home helps to treat depression.
  19. Electric cars could save billions in health-care costs.
  20. IL-1β-induced epithelial cell and fibroblast transdifferentiation promotes neutrophil recruitment in chronic rhinosinusitis with nasal polyps.
  21. Nuclear release of eIF1 restricts start-codon selection during mitosis.
  22. DNA stores data in bits after epigenetic upgrade.
  23. From periphery to center stage: 50 years of advancements in innate immunity.
  24. Targeting immune-fibroblast cell communication in heart failure.
  25. Cultural Competency in Health Care Can Save Lives.
  26. Trainees' perspectives and recommendations for catalyzing the next generation of NeuroAI researchers.
  27. How job-seeking scientists should walk the line between high-calibre and humble.
  28. Innovations from Rural Communities Are Improving Health Care.
  29. Transcription-dependent mobility of single genes and genome-wide motions in live human cells.
  30. ASI-RIM neuronal axis regulates systemic mitochondrial stress response via TGF-β signaling cascade.
  31. Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
  32. Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice.
  33. Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke.
  34. Interpretable GWAS by linking clinical phenotypes to quantifiable immune repertoire components.
  35. Journals with high rates of suspicious papers flagged by science-integrity start-up.
  36. Uncovering a lost mountain metropolis.
  37. Transgelin 2 guards T cell lipid metabolism and antitumour function.
  38. Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy.
  39. SpliceTransformer predicts tissue-specific splicing linked to human diseases.
  40. Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.
  41. KCNB1-Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus.
  42. Why a fortunate few don't get ill after HIV infection.
  43. Socio-demographic and genetic risk factors for drug adherence and persistence across 5 common medication classes.
  44. Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.
  45. Microbiome-based correction for random errors in nutrient profiles derived from self-reported dietary assessments.
  46. Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.
  47. Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.
  48. AMBRA1 controls the translation of immune-specific genes in T lymphocytes.
  49. DiffModeler: large macromolecular structure modeling for cryo-EM maps using a diffusion model.
  50. A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
  1. Science. 2024 Oct 25. 386(6720): 462
    Wall of fame.
    Yutan Getzler.
      
    DOI:  https://doi.org/10.1126/science.adt9934
  2. Nature. 2024 Oct 23.
    Machine-guided design of cell-type-targeting cis-regulatory elements.
    Sager J Gosai, Rodrigo I Castro, Natalia Fuentes, John C Butts, Kousuke Mouri, Michael Alasoadura, Susan Kales, Thanh Thanh L Nguyen, Ramil R Noche, Arya S Rao, Mary T Joy, Pardis C Sabeti, Steven K Reilly, Ryan Tewhey.
      Cis-regulatory elements (CREs) control gene expression, orchestrating tissue identity, developmental timing and stimulus responses, which collectively define the thousands of unique cell types in the body1-3. While there is great potential for strategically incorporating CREs in therapeutic or biotechnology applications that require tissue specificity, there is no guarantee that an optimal CRE for these intended purposes has arisen naturally. Here we present a platform to engineer and validate synthetic CREs capable of driving gene expression with programmed cell-type specificity. We take advantage of innovations in deep neural network modelling of CRE activity across three cell types, efficient in silico optimization and massively parallel reporter assays to design and empirically test thousands of CREs4-8. Through large-scale in vitro validation, we show that synthetic sequences are more effective at driving cell-type-specific expression in three cell lines compared with natural sequences from the human genome and achieve specificity in analogous tissues when tested in vivo. Synthetic sequences exhibit distinct motif vocabulary associated with activity in the on-target cell type and a simultaneous reduction in the activity of off-target cells. Together, we provide a generalizable framework to prospectively engineer CREs from massively parallel reporter assay models and demonstrate the required literacy to write fit-for-purpose regulatory code.
    DOI:  https://doi.org/10.1038/s41586-024-08070-z
  3. Nat Commun. 2024 Oct 23. 15(1): 9143
    Dominant immune tolerance in the intestinal tract imposed by RelB-dependent migratory dendritic cells regulates protective type 2 immunity.
    Anna-Lena Geiselhöringer, Daphne Kolland, Arisha Johanna Patt, Linda Hammann, Amelie Köhler, Luisa Kreft, Nina Wichmann, Miriam Hils, Christiane Ruedl, Marc Riemann, Tilo Biedermann, David Anz, Andreas Diefenbach, David Voehringer, Carsten B Schmidt-Weber, Tobias Straub, Maria Pasztoi, Caspar Ohnmacht.
      Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-53112-9
  4. Nature. 2024 Oct 17.
    Giant Turkish quake shifted the ground hundreds of kilometres away.
      
    Keywords:  Geophysics
    DOI:  https://doi.org/10.1038/d41586-024-03378-2
  5. Nature. 2024 Oct;634(8035): S34-S39
    The Staggering Success of Vaccines.
    Tara Haelle.
      
    Keywords:  Diseases; Health care; Public health; Society; Vaccines
    DOI:  https://doi.org/10.1038/d41586-024-03412-3
  6. Nature. 2024 Oct 23.
    Chromatin remodelling drives immune cell-fibroblast communication in heart failure.
    Michael Alexanian, Arun Padmanabhan, Tomohiro Nishino, Joshua G Travers, Lin Ye, Angelo Pelonero, Clara Youngna Lee, Nandhini Sadagopan, Yu Huang, Kirsten Auclair, Ada Zhu, Yuqian An, Christina A Ekstrand, Cassandra Martinez, Barbara Gonzalez Teran, Will R Flanigan, Charis Kee-Seon Kim, Koya Lumbao-Conradson, Zachary Gardner, Li Li, Mauro W Costa, Rajan Jain, Israel Charo, Alexis J Combes, Saptarsi M Haldar, Katherine S Pollard, Ronald J Vagnozzi, Timothy A McKinsey, Pawel F Przytycki, Deepak Srivastava.
      Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers2, the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1+ cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1+ cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling.
    DOI:  https://doi.org/10.1038/s41586-024-08085-6
  7. Nat Rev Immunol. 2024 Oct 22.
    Human macrophages in pancreas and skin shape prenatal organogenesis.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01106-5
  8. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2412690121
    Targeting Unc5b in macrophages drives atherosclerosis regression and pro-resolving immune cell function.
    Martin Schlegel, Yannick Cyr, Alexandra A C Newman, Korbinian Schreyer, José Gabriel Barcia Durán, Monika Sharma, Fazli K Bozal, Morgane Gourvest, Maxwell La Forest, Milessa S Afonso, Coen van Solingen, Edward A Fisher, Kathryn J Moore.
      Atherosclerosis results from lipid-driven inflammation of the arterial wall that fails to resolve. Imbalances in macrophage accumulation and function, including diminished migratory capacity and defective efferocytosis, fuel maladaptive inflammation and plaque progression. The neuroimmune guidance cue netrin-1 has dichotomous roles in inflammation partly due to its multiple receptors; in atherosclerosis, netrin-1 promotes macrophage survival and retention via its receptor Unc5b. To minimize the pleiotropic effects of targeting netrin-1, we tested the therapeutic potential of deleting Unc5b in mice with advanced atherosclerosis. We generated Unc5bfl/flCx3cr1creERT2/WT mice, which allowed conditional deletion of Un5b (∆Unc5bMØ) in monocytes and macrophages by tamoxifen injection. After inducing advanced atherosclerosis by hepatic PCSK9 overexpression and western diet feeding for 20 wk, Unc5b was deleted and hypercholesterolemia was normalized to simulate clinical lipid management. Deletion of myeloid Unc5b led to a 40% decrease in atherosclerotic plaque burden and reduced plaque complexity compared to Unc5bfl/flCx3cr1WT/WT littermate controls (CtrlMØ). Consistently, plaque macrophage content was reduced by 50% in ∆Unc5bMØ mice due to reduced plaque Ly6Chi monocyte recruitment and macrophage retention. Compared to CtrlMØ mice, plaques in ∆Unc5bMØ mice had reduced necrotic area and fewer apoptotic cells, which correlated with improved efferocytotic capacity by Unc5b-deficient macrophages in vivo and in vitro. Beneficial changes in macrophage dynamics in the plaque upon Unc5b deletion were accompanied by an increase in atheroprotective T cell populations, including T-regulatory and Th2 cells. Our data identify Unc5b in advanced atherosclerosis as a therapeutic target to induce pro-resolving restructuring of the plaque immune cells and to promote atherosclerosis regression.
    Keywords:  Treg; atherosclerosis; efferocytosis; inflammation; regression
    DOI:  https://doi.org/10.1073/pnas.2412690121
  9. Nature. 2024 Oct 23.
    How to run a successful internship programme.
    Nikki Forrester.
      
    Keywords:  Careers; Education; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-03461-8
  10. Nature. 2024 Oct;634(8035): S49-S51
    How the Mpox Response Has Learned from History.
    Charles Ebikeme.
      
    Keywords:  Diseases; Health care; Public health; Society
    DOI:  https://doi.org/10.1038/d41586-024-03416-z
  11. Nature. 2024 Oct;634(8035): S26
    How to Make Progress in Health Equity.
    Lauren Gravitz.
      
    Keywords:  Diseases; Health care; Public health; Society
    DOI:  https://doi.org/10.1038/d41586-024-03409-y
  12. Nat Aging. 2024 Oct 22.
    Metformin slows signs of primate aging.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00748-3
  13. Nat Commun. 2024 Oct 23. 15(1): 9148
    Remyelination protects neurons from DLK-mediated neurodegeneration.
    Greg J Duncan, Sam D Ingram, Katie Emberley, Jo Hill, Christian Cordano, Ahmed Abdelhak, Michael McCane, Jennifer E Jenks, Nora Jabassini, Kirtana Ananth, Skylar J Ferrara, Brittany Stedelin, Benjamin Sivyer, Sue A Aicher, Thomas S Scanlan, Trent A Watkins, Anusha Mishra, Jonathan W Nelson, Ari J Green, Ben Emery.
      Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons.
    DOI:  https://doi.org/10.1038/s41467-024-53429-5
  14. Nature. 2024 Oct 24.
    Reading the signs of dementia.
    Neil Savage.
      
    Keywords:  Alzheimer's disease; Brain; Health care; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-03456-5
  15. Nat Commun. 2024 Oct 22. 15(1): 9110
    METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.
    Bishoy Wadie, Lachlan Stuart, Christopher M Rath, Bernhard Drotleff, Sergii Mamedov, Theodore Alexandrov.
      Imaging mass spectrometry is a powerful technology enabling spatial metabolomics, yet metabolites can be assigned only to a fraction of the data generated. METASPACE-ML is a machine learning-based approach addressing this challenge which incorporates new scores and computationally-efficient False Discovery Rate estimation. For training and evaluation, we use a comprehensive set of 1710 datasets from 159 researchers from 47 labs encompassing both animal and plant-based datasets representing multiple spatial metabolomics contexts derived from the METASPACE knowledge base. Here we show that, METASPACE-ML outperforms its rule-based predecessor, exhibiting higher precision, increased throughput, and enhanced capability in identifying low-intensity and biologically-relevant metabolites.
    DOI:  https://doi.org/10.1038/s41467-024-52213-9
  16. Nature. 2024 Oct 22.
    Exposing predatory journals: anonymous sleuthing account goes public.
    Jackson Ryan.
      
    Keywords:  Authorship; Publishing; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03321-5
  17. J Clin Invest. 2024 Oct 22. pii: e183984. [Epub ahead of print]
    Attenuated kidney oxidative metabolism in young adults with type 1 diabetes.
    Ye Ji Choi, Gabriel Richard, Guanshi Zhang, Jeffrey B Hodgin, Dawit S Demeke, Yingbao Yang, Jennifer A Schaub, Ian M Tamayo, Bhupendra K Gurung, Abhijit S Naik, Viji Nair, Carissa Birznieks, Alexis MacDonald, Phoom Narongkiatikhun, Susan Gross, Lynette Driscoll, Maureen Flynn, Kalie Tommerdahl, Kristen J Nadeau, Viral N Shah, Tim Vigers, Janet K Snell-Bergeon, Jessica Kendrick, Daniel H van Raalte, Lu-Ping Li, Pottumarthi Prasad, Patricia Ladd, Bennett B Chin, David Z Cherney, Phillip J McCown, Fadhl Alakwaa, Edgar A Otto, Frank C Brosius, Pierre Jean Saulnier, Victor G Puelles, Jesse A Goodrich, Kelly Street, Manjeri A Venkatachalam, Aaron Ruiz, Ian H de Boer, Robert G Nelson, Laura Pyle, Denis P Blondin, Kumar Sharma, Matthias Kretzler, Petter Bjornstad.
       BACKGROUND: In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.
    METHODS: Young adults with T1D (n = 30) and healthy controls (HC, n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA sequencing, and spatial metabolomics to assess this relationship.
    RESULTS: Participants with T1D had significantly higher glomerular basement membrane thickness compared to HC. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HC, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, GBM, and lower insulin sensitivity and cortical oxidative metabolism.
    CONCLUSION: These early structural and metabolic changes in T1D kidneys may precede clinical DKD.
    TRIAL REGISTRATION:
    CLINICALTRIALS: gov NCT04074668.
    Keywords:  Diabetes; Endocrinology; Metabolism
    DOI:  https://doi.org/10.1172/JCI183984
  18. Nature. 2024 Oct 21.
    Brain stimulation at home helps to treat depression.
    Miryam Naddaf.
      
    Keywords:  Brain; Depression; Medical research; Psychiatric disorders
    DOI:  https://doi.org/10.1038/d41586-024-03446-7
  19. Nature. 2024 Oct;634(8035): 785
    Electric cars could save billions in health-care costs.
    Abigail Klopper.
      
    Keywords:  Economics; Human behaviour; Sustainability
    DOI:  https://doi.org/10.1038/d41586-024-03313-5
  20. Nat Commun. 2024 Oct 22. 15(1): 9101
    IL-1β-induced epithelial cell and fibroblast transdifferentiation promotes neutrophil recruitment in chronic rhinosinusitis with nasal polyps.
    Xinyu Xie, Pin Wang, Min Jin, Yue Wang, Lijie Qi, Changhua Wu, Shu Guo, Changqing Li, Xiaojun Zhang, Ye Yuan, Xinyi Ma, Fangying Liu, Weiyuan Liu, Heng Liu, Chen Duan, Ping Ye, Xuezhong Li, Larry Borish, Wei Zhao, Xin Feng.
      Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identify two IL-1 signaling-induced cell subsets-LY6D+ club cells and IDO1+ fibroblasts-that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1β, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation of LY6D+ club cells and IDO1+ fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1β activity with a receptor antagonist significantly reduces the numbers of LY6D+ club cells and IDO1+ fibroblasts and mitigates nasal inflammation. This study implicates the function of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.
    DOI:  https://doi.org/10.1038/s41467-024-53307-0
  21. Nature. 2024 Oct 23.
    Nuclear release of eIF1 restricts start-codon selection during mitosis.
    Jimmy Ly, Kehui Xiang, Kuan-Chung Su, Gunter B Sissoko, David P Bartel, Iain M Cheeseman.
      Regulated start-codon selection has the potential to reshape the proteome through the differential production of upstream open reading frames, canonical proteins, and alternative translational isoforms1-3. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation-initiation-site profiling4, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This enhanced stringency of start-codon selection during mitosis results from increased association between the 40S ribosome and the key regulator of start-codon selection, eIF1. We find that increased eIF1-40S ribosome interaction during mitosis is mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the change to translational stringency during mitosis, resulting in altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapies. Thus, cells globally control stringency of translation initiation, which has critical roles during the mammalian cell cycle in preserving mitotic cell physiology.
    DOI:  https://doi.org/10.1038/s41586-024-08088-3
  22. Nature. 2024 Oct 23.
    DNA stores data in bits after epigenetic upgrade.
    Heidi Ledford.
      
    Keywords:  Epigenetics; Molecular biology; Nanoscience and technology
    DOI:  https://doi.org/10.1038/d41586-024-03443-w
  23. Cell. 2024 Oct 18. pii: S0092-8674(24)01189-9. [Epub ahead of print]
    From periphery to center stage: 50 years of advancements in innate immunity.
    Susan Carpenter, Luke A J O'Neill.
      
    DOI:  https://doi.org/10.1016/j.cell.2024.10.013
  24. Nature. 2024 Oct 23.
    Targeting immune-fibroblast cell communication in heart failure.
    Junedh M Amrute, Xin Luo, Vinay Penna, Steven Yang, Tracy Yamawaki, Sikander Hayat, Andrea Bredemeyer, In-Hyuk Jung, Farid F Kadyrov, Gyu Seong Heo, Rajiu Venkatesan, Sally Yu Shi, Alekhya Parvathaneni, Andrew L Koenig, Christoph Kuppe, Candice Baker, Hannah Luehmann, Cameran Jones, Benjamin Kopecky, Xue Zeng, Tore Bleckwehl, Pan Ma, Paul Lee, Yuriko Terada, Angela Fu, Milena Furtado, Daniel Kreisel, Atilla Kovacs, Nathan O Stitziel, Simon Jackson, Chi-Ming Li, Yongjian Liu, Nadia A Rosenthal, Rafael Kramann, Brandon Ason, Kory J Lavine.
      Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction1,2. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis3,4. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin-1β (IL-1β) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1β ligand in CCR2+ monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
    DOI:  https://doi.org/10.1038/s41586-024-08008-5
  25. Nature. 2024 Oct;634(8035): S42-S44
    Cultural Competency in Health Care Can Save Lives.
    Rod McCullom.
      
    Keywords:  Diseases; Health care; Public health; Society
    DOI:  https://doi.org/10.1038/d41586-024-03414-1
  26. Nat Commun. 2024 Oct 23. 15(1): 9152
    Trainees' perspectives and recommendations for catalyzing the next generation of NeuroAI researchers.
    Andrea I Luppi, Jascha Achterberg, Samuel Schmidgall, Isil Poyraz Bilgin, Peer Herholz, Maximilian Sprang, Benjamin Fockter, Andrew Siyoon Ham, Sushrut Thorat, Rojin Ziaei, Filip Milisav, Alexandra M Proca, Hanna M Tolle, Laura E Suárez, Paul Scotti, Helena M Gellersen.
      
    DOI:  https://doi.org/10.1038/s41467-024-53375-2
  27. Nature. 2024 Oct;634(8035): 1005-1007
    How job-seeking scientists should walk the line between high-calibre and humble.
    Linda Nordling.
      
    Keywords:  Careers; Industry; Lab life; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03406-1
  28. Nature. 2024 Oct;634(8035): S30-S33
    Innovations from Rural Communities Are Improving Health Care.
    Carrie Arnold.
      
    Keywords:  Diseases; Health care; Public health; Society
    DOI:  https://doi.org/10.1038/d41586-024-03411-4
  29. Nat Commun. 2024 Oct 22. 15(1): 8879
    Transcription-dependent mobility of single genes and genome-wide motions in live human cells.
    Fang-Yi Chu, Alexis S Clavijo, Suho Lee, Alexandra Zidovska.
      The human genome is highly dynamic across all scales. At the gene level, chromatin is persistently remodeled and rearranged during active processes such as transcription, replication and DNA repair. At the genome level, chromatin moves in micron-scale domains that break up and re-form over seconds, but the origin of these coherent motions is unknown. Here, we investigate the connection between genomic motions and gene-level activity. Simultaneous mapping of single-gene and genome-wide motions shows that the coupling of gene transcriptional activity to flows of the nearby genome is modulated by chromatin compaction. A motion correlation analysis suggests that a single active gene drives larger-scale motions in low-compaction regions, but high-compaction chromatin drives gene motion regardless of its activity state. By revealing unexpected connections among gene activity, spatial heterogeneities of chromatin and its emergent genome-wide motions, these findings uncover aspects of the genome's spatiotemporal organization that directly impact gene regulation and expression.
    DOI:  https://doi.org/10.1038/s41467-024-51149-4
  30. Nat Commun. 2024 Oct 19. 15(1): 8997
    ASI-RIM neuronal axis regulates systemic mitochondrial stress response via TGF-β signaling cascade.
    Zihao Wang, Qian Zhang, Yayun Jiang, Jun Zhou, Ye Tian.
      Morphogens play a critical role in coordinating stress adaptation and aging across tissues, yet their involvement in neuronal mitochondrial stress responses and systemic effects remains unclear. In this study, we reveal that the transforming growth factor beta (TGF-β) DAF-7 is pivotal in mediating the intestinal mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans under neuronal mitochondrial stress. Two ASI sensory neurons produce DAF-7, which targets DAF-1/TGF-β receptors on RIM interneurons to orchestrate a systemic UPRmt response. Remarkably, inducing mitochondrial stress specifically in ASI neurons activates intestinal UPRmt, extends lifespan, enhances pathogen resistance, and reduces both brood size and body fat levels. Furthermore, dopamine positively regulates this UPRmt activation, while GABA acts as a systemic suppressor. This study uncovers the intricate mechanisms of systemic mitochondrial stress regulation, emphasizing the vital role of TGF-β in metabolic adaptations that are crucial for organismal fitness and aging during neuronal mitochondrial stress.
    DOI:  https://doi.org/10.1038/s41467-024-53093-9
  31. Nat Commun. 2024 Oct 21. 15(1): 9063
    Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
    Cristiane Dos Santos, Amanda Cambraia, Shristi Shrestha, Melanie Cutler, Matthew Cottam, Guy Perkins, Varda Lev-Ram, Birbickram Roy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Danielle Dean, Jean Philippe Cartailler, Patrick E MacDonald, Martin Hetzer, Mark Ellisman, Rafael Arrojo E Drigo.
      Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.
    DOI:  https://doi.org/10.1038/s41467-024-53127-2
  32. Cell Stem Cell. 2024 Oct 18. pii: S1934-5909(24)00358-8. [Epub ahead of print]
    Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice.
    Rong Mou, Junkai Ma, Xuan Ju, Yixin Wu, Qiuli Chen, Jinglin Li, Tongyao Shang, Siying Chen, Yue Yang, Yue Li, Kaosheng Lv, Xuequn Chen, Qi Zhang, Tingbo Liang, Ye Feng, Xinjiang Lu.
      Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy.
    Keywords:  arginine vasopressin; bone marrow; depression; hematopoietic stem cells; neuroinflammation
    DOI:  https://doi.org/10.1016/j.stem.2024.09.018
  33. Nat Commun. 2024 Oct 24. 15(1): 9095
    Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke.
    Suvra Nath, Jose C Martínez Santamaría, Yu-Hsuan Chu, James S Choi, Pasquale Conforti, Jia-Di Lin, Roman Sankowski, Lukas Amann, Christos Galanis, Kexin Wu, Sachin S Deshpande, Andreas Vlachos, Marco Prinz, Jae K Lee, Christian Schachtrup.
      After a stroke, the neurogenic response from the subventricular zone (SVZ) to repair the brain is limited. Microglia, as an integral part of the distinctive SVZ microenvironment, control neural stem / precursor cell (NSPC) behavior. Here, we show that discrete stroke-associated SVZ microglial clusters negatively impact the innate neurogenic response, and we propose a repository of relevant microglia-NSPC ligand-receptor pairs. After photothrombosis, a mouse model of ischemic stroke, the altered SVZ niche environment leads to immediate activation of microglia in the niche and an abnormal neurogenic response, with cell-cycle arrest of neural stem cells and neuroblast cell death. Pharmacological restoration of the niche environment increases the SVZ-derived neurogenic repair and microglial depletion increases the formation and survival of newborn neuroblasts in the SVZ. Therefore, we propose that altered cross-communication between microglial subclusters and NSPCs regulates the extent of the innate neurogenic repair response in the SVZ after stroke.
    DOI:  https://doi.org/10.1038/s41467-024-53217-1
  34. Commun Biol. 2024 Oct 20. 7(1): 1357
    Interpretable GWAS by linking clinical phenotypes to quantifiable immune repertoire components.
    Yuhao Tan, Lida Wang, Hongyi Zhang, Mingyao Pan, Dajiang J Liu, Xiaowei Zhan, Bo Li.
      Bridging the gap between genotype and phenotype in GWAS studies is challenging. A multitude of genetic variants have been associated with immune-related diseases, including cancer, yet the interpretability of most variants remains low. Here, we investigate the quantitative components in the T cell receptor (TCR) repertoire, the frequency of clusters of TCR sequences predicted to have common antigen specificity, to interpret the genetic associations of diverse human diseases. We first developed a statistical model to predict the TCR components using variants in the TRB and HLA loci. Applying this model to over 300,000 individuals in the UK Biobank data, we identified 2309 associations between TCR abundances and various immune diseases. TCR clusters predicted to be pathogenic for autoimmune diseases were significantly enriched for predicted autoantigen-specificity. Moreover, four TCR clusters were associated with better outcomes in distinct cancers, where conventional GWAS cannot identify any significant locus. Collectively, our results highlight the integral role of adaptive immune responses in explaining the associations between genotype and phenotype.
    DOI:  https://doi.org/10.1038/s42003-024-07010-x
  35. Nature. 2024 Oct 22.
    Journals with high rates of suspicious papers flagged by science-integrity start-up.
    Richard Van Noorden.
      
    Keywords:  Publishing; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03427-w
  36. Nature. 2024 Oct 23.
    Uncovering a lost mountain metropolis.
    Dan Fox.
      
    Keywords:  Archaeology; Geography; Imaging; Technology
    DOI:  https://doi.org/10.1038/d41586-024-03464-5
  37. Nature. 2024 Oct 23.
    Transgelin 2 guards T cell lipid metabolism and antitumour function.
    Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito A Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matías Marin Falco, Camilla Salvagno, Alexander Emmanuelli, Ian T McBain, Bikash Mishra, Lionel B Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana K Morales, Xiaoqing Yu, Paulo C Rodriguez, Jose R Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song, Juan R Cubillos-Ruiz.
      Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.
    DOI:  https://doi.org/10.1038/s41586-024-08071-y
  38. Nat Commun. 2024 Oct 21. 15(1): 9062
    Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy.
    Zachary Dewald, Oluwafolajimi Adesanya, Haneui Bae, Andrew Gupta, Jessica M Derham, Ullas V Chembazhi, Auinash Kalsotra.
      Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment.
    DOI:  https://doi.org/10.1038/s41467-024-53378-z
  39. Nat Commun. 2024 Oct 23. 15(1): 9129
    SpliceTransformer predicts tissue-specific splicing linked to human diseases.
    Ningyuan You, Chang Liu, Yuxin Gu, Rong Wang, Hanying Jia, Tianyun Zhang, Song Jiang, Jinsong Shi, Ming Chen, Min-Xin Guan, Siqi Sun, Shanshan Pei, Zhihong Liu, Ning Shen.
      We present SpliceTransformer (SpTransformer), a deep-learning framework that predicts tissue-specific RNA splicing alterations linked to human diseases based on genomic sequence. SpTransformer outperforms all previous methods on splicing prediction. Application to approximately 1.3 million genetic variants in the ClinVar database reveals that splicing alterations account for 60% of intronic and synonymous pathogenic mutations, and occur at different frequencies across tissue types. Importantly, tissue-specific splicing alterations match their clinical manifestations independent of gene expression variation. We validate the enrichment in three brain disease datasets involving over 164,000 individuals. Additionally, we identify single nucleotide variations that cause brain-specific splicing alterations, and find disease-associated genes harboring these single nucleotide variations with distinct expression patterns involved in diverse biological processes. Finally, SpTransformer analysis of whole exon sequencing data from blood samples of patients with diabetic nephropathy predicts kidney-specific RNA splicing alterations with 83% accuracy, demonstrating the potential to infer disease-causing tissue-specific splicing events. SpTransformer provides a powerful tool to guide biological and clinical interpretations of human diseases.
    DOI:  https://doi.org/10.1038/s41467-024-53088-6
  40. Nat Cardiovasc Res. 2024 Oct 21.
    Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.
    Farid F Kadyrov, Andrew L Koenig, Junedh M Amrute, Hao Dun, Wenjun Li, Carla J Weinheimer, Jessica M Nigro, Attila Kovacs, Andrea L Bredemeyer, Steven Yang, Shibali Das, Vinay R Penna, Alekhya Parvathaneni, Lulu Lai, Niklas Hartmann, Benjamin J Kopecky, Daniel Kreisel, Kory J Lavine.
      Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia-reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction.
    DOI:  https://doi.org/10.1038/s44161-024-00553-6
  41. FASEB J. 2024 Oct 31. 38(20): e70111
    KCNB1-Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus.
    Elena Forzisi-Kathera-Ibarra, Chanmee Jo, Leonard Castillo, Anika Gaur, Prachi Lad, Alessandro Bortolami, Christian Roser, Srinidi Venkateswaran, Stefania Dutto, Matthew Selby, Harini Sampath, Ping-Yue Pan, Federico Sesti.
      The neurons of the melanocortin system regulate feeding and energy homeostasis through a combination of electrical and endocrine mechanisms. However, the molecular basis for this functional heterogeneity is poorly understood. Here, a voltage-gated potassium (Kv+) channel named KCNB1 (alias Kv2.1) forms stable complexes with the leptin receptor (LepR) in a subset of hypothalamic neurons including proopiomelanocortin (POMC) expressing neurons of the Arcuate nucleus (ARHPOMC). Mice lacking functional KCNB1 channels (NULL mice) have less adipose tissue and circulating leptin than WT animals and are insensitive to anorexic stimuli induced by leptin administration. NULL mice produce aberrant amounts of POMC at any developmental stage. Canonical LepR-STAT3 signaling-which underlies POMC production-is impaired, whereas non-canonical insulin receptor substrate PI3K/Akt/FOXO1 and ERK signaling are constitutively upregulated in NULL hypothalami. The levels of proto-oncogene c-Fos-that provides an indirect measure of neuronal activity-are higher in arcuate NULL neurons compared to WT and most importantly do not increase in the former upon leptin stimulation. Hence, a Kv channel provides a molecular link between neuronal excitability and endocrine function in hypothalamic neurons.
    Keywords:  K+ channel; POMC; hypothalamus; leptin; melanocortin; obesity; potassium channel
    DOI:  https://doi.org/10.1096/fj.202401931R
  42. Nature. 2024 Oct 23.
    Why a fortunate few don't get ill after HIV infection.
      
    Keywords:  HIV infections
    DOI:  https://doi.org/10.1038/d41586-024-03380-8
  43. Nat Commun. 2024 Oct 23. 15(1): 9156
    Socio-demographic and genetic risk factors for drug adherence and persistence across 5 common medication classes.
    FinnGen
      Low drug adherence is a major obstacle to the benefits of pharmacotherapies and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1,814,591 individuals from Finnish nationwide registries, 217,005 with genetic data from Finland and Estonia). Need for social assistance and immigration status show a notable negative effect on persistence and adherence across the examined medications (odd ratios between 0.48 and 0.82 for persistence and between 1.1% to 4.3% decrease in adherence) while demographic and health factors show comparably modest or inconsistent effects. A genome-wide scan does not identify genetic variants associated with the two phenotypes, while some pharmacogenes (i.e. CYP2C9 and SLCO1B1) are modestly associated with persistence, but not with adherence. We observe significant genetic correlations between medication adherence and participation in research studies. Overall, our findings suggest that socio-economically disadvantaged groups would benefit from targeted interventions to improve the dispensing and uptake of pharmacological treatments.
    DOI:  https://doi.org/10.1038/s41467-024-53556-z
  44. Nat Genet. 2024 Oct 23.
    Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.
    Simone M Haag, Shiqi Xie, Celine Eidenschenk, Jean-Philippe Fortin, Marinella Callow, Mike Costa, Aaron Lun, Chris Cox, Sunny Z Wu, Rachana N Pradhan, Jaclyn Lock, Julia A Kuhn, Loryn Holokai, Minh Thai, Emily Freund, Ariane Nissenbaum, Mary Keir, Christopher J Bohlen, Scott Martin, Kathryn Geiger-Schuller, Hussein A Hejase, Brian L Yaspan, Sandra Melo Carlos, Shannon J Turley, Aditya Murthy.
      Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.
    DOI:  https://doi.org/10.1038/s41588-024-01962-w
  45. Nat Commun. 2024 Oct 22. 15(1): 9112
    Microbiome-based correction for random errors in nutrient profiles derived from self-reported dietary assessments.
    Tong Wang, Yuanqing Fu, Menglei Shuai, Ju-Sheng Zheng, Lu Zhu, Andrew T Chan, Qi Sun, Frank B Hu, Scott T Weiss, Yang-Yu Liu.
      Since dietary intake is challenging to directly measure in large-scale cohort studies, we often rely on self-reported instruments (e.g., food frequency questionnaires, 24-hour recalls, and diet records) developed in nutritional epidemiology. Those self-reported instruments are prone to measurement errors, which can lead to inaccuracies in the calculation of nutrient profiles. Currently, few computational methods exist to address this problem. In the present study, we introduce a deep-learning approach-Microbiome-based nutrient profile corrector (METRIC), which leverages gut microbial compositions to correct random errors in self-reported dietary assessments using 24-hour recalls or diet records. We demonstrate the excellent performance of METRIC in minimizing the simulated random errors, particularly for nutrients metabolized by gut bacteria in both synthetic and three real-world datasets. Additionally, we find that METRIC can still correct the random errors well even without including gut microbial compositions. Further research is warranted to examine the utility of METRIC to correct actual measurement errors in self-reported dietary assessment instruments.
    DOI:  https://doi.org/10.1038/s41467-024-53567-w
  46. Nat Commun. 2024 Oct 22. 15(1): 9098
    Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.
    Adel Beghiah, Patricia Saura, Sofia Badolato, Hyunho Kim, Johanna Zipf, Dirk Auman, Ana P Gamiz-Hernandez, Johan Berg, Grant Kemp, Ville R I Kaila.
      The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts in recent decades, its long-range energy transduction principles remain highly debated. We create here minimal proton-conducting membrane modules by engineering and dissecting the key elements of the bacterial Complex I. By combining biophysical, biochemical, and computational experiments, we show that the isolated antiporter-like modules of Complex I comprise all functional elements required for conducting protons across proteoliposome membranes. We find that the rate of proton conduction is controlled by conformational changes of buried ion-pairs that modulate the reaction barriers by electric field effects. The proton conduction is also modulated by bulky residues along the proton channels that are key for establishing a tightly coupled proton pumping machinery in Complex I. Our findings provide direct experimental evidence that the individual antiporter modules are responsible for the proton transport activity of Complex I. On a general level, our findings highlight electrostatic and conformational coupling mechanisms in the modular energy-transduction machinery of Complex I with distinct similarities to other enzymes.
    DOI:  https://doi.org/10.1038/s41467-024-53194-5
  47. Commun Biol. 2024 Oct 22. 7(1): 1373
    Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.
    Seda Yasa, Elisabeth S Butz, Alessio Colombo, Uma Chandrachud, Luca Montore, Sarah Tschirner, Matthias Prestel, Steven D Sheridan, Stephan A Müller, Janos Groh, Stefan F Lichtenthaler, Sabina Tahirovic, Susan L Cotman.
      Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic signatures are indicative of defects in lysosomal function and abnormal lipid metabolism. Consistent with these findings, CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Accordingly, we also observe impaired myelin integrity in aged Cln3∆ex7/8 mouse brain. Autophagy inducers and cholesterol-lowering drugs correct the observed microglial phenotypes. Taken together, these data implicate a cell-autonomous defect in CLN3-deficient microglia that impacts their ability to support neuronal cell health, suggesting microglial targeted therapies should be considered for CLN3 disease.
    DOI:  https://doi.org/10.1038/s42003-024-07057-w
  48. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2416722121
    AMBRA1 controls the translation of immune-specific genes in T lymphocytes.
    Simone Gottlieb, Wanjing Shang, Deji Ye, Satoshi Kubo, Ping Du Jiang, Samantha Shafer, Leilei Xu, Lixin Zheng, Ann Y Park, Jian Song, Waipan Chan, Zhiqin Zeng, Tingyan He, Benjamin Schwarz, Björn Häupl, Thomas Oellerich, Michael J Lenardo, Yikun Yao.
      T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cell cycle regulation, and cell death. The molecular regulation of mRNA translation in these processes is poorly understood. Using a whole-genome CRISPR screen for regulators of CD95 (FAS/APO-1)-mediated T cell death, we identified AMBRA1, a protein previously studied for its roles in autophagy, E3 ubiquitin ligase activity, and cyclin regulation. T cells lacking AMBRA1 resisted FAS-mediated cell death by down-regulating FAS expression at the translational level. We show that AMBRA1 is a vital regulator of ribosome protein biosynthesis and ribosome loading on select mRNAs, whereby it plays a key role in balancing TCR signaling with cell cycle regulation pathways. We also found that AMBRA1 itself is translationally controlled by TCR stimulation via the CD28-PI3K-mTORC1-EIF4F pathway. Together, these findings shed light on the molecular control of translation after T cell activation and implicate AMBRA1 as a translational regulator governing TCR signaling, cell cycle progression, and T cell death.
    Keywords:  AMBRA1; FAS signaling pathway; T cell activation; T cell death; protein translation
    DOI:  https://doi.org/10.1073/pnas.2416722121
  49. Nat Methods. 2024 Oct 21.
    DiffModeler: large macromolecular structure modeling for cryo-EM maps using a diffusion model.
    Xiao Wang, Han Zhu, Genki Terashi, Manav Taluja, Daisuke Kihara.
      Cryogenic electron microscopy (cryo-EM) has now been widely used for determining multichain protein complexes. However, modeling a large complex structure, such as those with more than ten chains, is challenging, particularly when the map resolution decreases. Here we present DiffModeler, a fully automated method for modeling large protein complex structures. DiffModeler employs a diffusion model for backbone tracing and integrates AlphaFold2-predicted single-chain structures for structure fitting. DiffModeler showed an average template modeling score of 0.88 and 0.91 for two datasets of cryo-EM maps of 0-5 Å resolution and 0.92 for intermediate resolution maps (5-10 Å), substantially outperforming existing methodologies. Further benchmarking at low resolutions (10-20 Å) confirms its versatility, demonstrating plausible performance.
    DOI:  https://doi.org/10.1038/s41592-024-02479-0
  50. Cell. 2024 Oct 19. pii: S0092-8674(24)00903-6. [Epub ahead of print]
    A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
    Jian Zhang, Ruonan Tian, Jia Liu, Jie Yuan, Siwen Zhang, Zhexu Chi, Weiwei Yu, Qianzhou Yu, Zhen Wang, Sheng Chen, Mobai Li, Dehang Yang, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Rongbin Zhou, Xue Zhang, Wanlu Liu, Di Wang.
      The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.
    Keywords:  adaptation; breakfast skipping; in vivo metabolite tracing; metabolic heterogeneity; multi-omics; the small intestine; two-front nutrient supply; zonated function of enterocyte
    DOI:  https://doi.org/10.1016/j.cell.2024.08.012
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