bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒11‒17
57 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mind the fragmentation gap.
  2. Splitting the chains: ultra-basal insulin analog uncovers a redox mechanism of hormone clearance.
  3. Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis.
  4. Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ T cell immunity to inhibit hepatitis B virus.
  5. Virus-like elements.
  6. Grass-roots pressure grows to boost support for breastfeeding scientists.
  7. HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.
  8. Genetics and dietary restriction impact lifespan.
  9. To eat or not to eat.
  10. Cell type-divergent functions of senescence.
  11. Hepatic vagal afferents convey clock-dependent signals to regulate circadian food intake.
  12. Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression.
  13. Adult skull bone marrow is an expanding and resilient haematopoietic reservoir.
  14. VPS4A is the selective receptor for lipophagy in mice and humans.
  15. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
  16. Opposing roles for AMPK in regulating distinct mitophagy pathways.
  17. Misguided negative adaptation narratives are hurting the poor.
  18. US trust in scientists plunged during the pandemic - but it's starting to recover.
  19. Diversification of molecular pattern recognition in bacterial NLR-like proteins.
  20. Genetic basis of right and left ventricular heart shape.
  21. scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases.
  22. Navigating the mutation maze: An oncogenic driver's guide to macrophage reprogramming.
  23. Spermidine limits diabetes by modulating RIPK1-mediated cell death and inflammation.
  24. A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling.
  25. 8 million cells: virtual embryo shows organs forming in exquisite detail.
  26. Errors in cell division stopped by an atypical cyclin-dependent kinase.
  27. Population survey of repeat expansion mutations.
  28. How AI is reshaping science and society.
  29. No hearing aids needed: bats' ears stay keen well into old age.
  30. Experience-dependent, sexually dimorphic synaptic connectivity defined by sex-specific cadherin expression.
  31. Mating reconciles fitness and fecundity by switching diet preference in flies.
  32. Lipid droplet messengers.
  33. Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis.
  34. Engineered PsCas9 enables therapeutic genome editing in mouse liver with lipid nanoparticles.
  35. Specialized post-arterial capillaries facilitate adult bone remodelling.
  36. Lipid signatures of cardiometabolic risk in children and adolescents with obesity.
  37. Single-cell 3D multi-omics during human brain development.
  38. NK2R control of energy expenditure and feeding to treat metabolic diseases.
  39. A noncoding variant confers pancreatic differentiation defect and contributes to diabetes susceptibility by recruiting RXRA.
  40. Missense variation affects protein cellular localization.
  41. Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of type 1 diabetes.
  42. A tuneable minimal cell membrane reveals that two lipid species suffice for life.
  43. Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice.
  44. Mx1-ing it up-Mitochondrial relay for interferon-dependent, unconventional IL-1β release in SLE monocytes.
  45. Genetic legacy of ancient hunter-gatherer Jomon in Japanese populations.
  46. Nonvesicular lipid transfer drives myelin growth in the central nervous system.
  47. Should Alzheimer's be diagnosed with a blood test? Proposal sparks controversy.
  48. Two for one: candidate obesity drug boosts energy use and curbs calorie intake.
  49. Systemic biases are leading to an intersex research void.
  50. eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA.
  51. Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.
  52. Stress can disrupt memory and lead to needless anxiety - here's how.
  53. World-first stem-cell treatment restores vision in people.
  54. Age-related loss of intestinal barrier integrity plays an integral role in thymic involution and T cell ageing.
  55. Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.
  56. Navigating human embryogenesis through tailored model selection.
  57. A systemic effect for liver senescence.
  1. Nat Commun. 2024 Nov 13. 15(1): 9831
    Mind the fragmentation gap.
    Karin Kvale, Zhenna Azimrayat Andrews, Matthias Egger.
      
    DOI:  https://doi.org/10.1038/s41467-024-53962-3
  2. Nat Commun. 2024 Nov 11. 15(1): 9744
    Splitting the chains: ultra-basal insulin analog uncovers a redox mechanism of hormone clearance.
    Michael A Weiss.
      
    DOI:  https://doi.org/10.1038/s41467-024-54006-6
  3. Nat Commun. 2024 Nov 14. 15(1): 9859
    Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis.
    Accelerating Medicines Partnership: RA/SLE Network
      Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Little is known about what regulates the homeostatic functions of fibroblasts. Here, we perform RNA sequencing and identify a gene expression program in healthy synovial fibroblasts characterized by enhanced fatty acid metabolism and lipid transport. We identify cortisol as the key driver of the healthy fibroblast phenotype and that depletion of adipocytes, which express high levels of Hsd11b1, results in loss of the healthy fibroblast phenotype in mouse synovium. Additionally, fibroblast-specific glucocorticoid receptor Nr3c1 deletion in vivo leads to worsened arthritis. Cortisol signaling in fibroblasts mitigates matrix remodeling induced by TNF and TGF-β1 in vitro, while stimulation with these cytokines represses cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease.
    DOI:  https://doi.org/10.1038/s41467-024-52586-x
  4. Cell Rep Med. 2024 Nov 07. pii: S2666-3791(24)00593-7. [Epub ahead of print] 101822
    Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ T cell immunity to inhibit hepatitis B virus.
    Tixiao Wang, Yuchen Fan, Siyu Tan, Zehua Wang, Mengzhen Li, Xiaowei Guo, Xiangguo Yu, Qinghai Lin, Xiaojia Song, Leiqi Xu, Lixiang Li, Shiyang Li, Lifen Gao, Xiaohong Liang, Chunyang Li, Chunhong Ma.
      The therapeutic potential of commensal microbes and their metabolites is promising in the functional cure of chronic hepatitis B virus (HBV) infection, which is defined as hepatitis B surface antigen (HBsAg) loss. Here, using both specific-pathogen-free and germ-free mice, we report that probiotics significantly promote the decline of HBsAg and inhibit HBV replication by enhancing intestinal homeostasis and provoking intrahepatic interferon (IFN)-γ+CD4+ T cell immune response. Depletion of CD4+ T cells or blockage of IFN-γ abolishes probiotics-mediated HBV inhibition. Specifically, probiotics-derived spermidine accumulates in the gut and transports to the liver, where it exhibits a similar anti-HBV effect. Mechanistically, spermidine enhances IFN-γ+CD4+ T cell immunity by autophagy. Strikingly, administration of probiotics in HBV patients reveals a preliminary trend to accelerate the decline of serum HBsAg. In conclusion, probiotics and their derived spermidine promote HBV clearance via autophagy-enhanced IFN-γ+CD4+ T cell immunity, highlighting the therapeutic potential of probiotics and spermidine for the functional cure of HBV patients.
    Keywords:  IFN-γ(+)CD4(+) T cell; autophagy; fecal microbiota transplantation; gut microbiota; hepatitis B virus; probiotics; spermidine
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101822
  5. Nat Biotechnol. 2024 Nov;42(11): 1649
    Virus-like elements.
      
    DOI:  https://doi.org/10.1038/s41587-024-02452-4
  6. Nature. 2024 Nov 08.
    Grass-roots pressure grows to boost support for breastfeeding scientists.
    Amanda Heidt.
      
    Keywords:  Careers; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-03440-z
  7. Nat Commun. 2024 Nov 12. 15(1): 9797
    HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.
    Annmary Paul Erinjeri, Xunyan Wang, Rhianna Williams, Riccardo Zenezini Chiozzi, Konstantinos Thalassinos, Johnathan Labbadia.
      Increased activity of the heat shock factor, HSF-1, suppresses proteotoxicity and enhances longevity. However, the precise mechanisms by which HSF-1 promotes lifespan are unclear. Using an RNAi screen, we identify ubiquilin-1 (ubql-1) as an essential mediator of lifespan extension in worms overexpressing hsf-1. We find that hsf-1 overexpression leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondrial network dynamics are altered, leading to increased lifespan. Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.
    DOI:  https://doi.org/10.1038/s41467-024-54136-x
  8. Nat Genet. 2024 Nov;56(11): 2295
    Genetics and dietary restriction impact lifespan.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-024-02005-0
  9. Nat Cell Biol. 2024 Nov;26(11): 1825
    To eat or not to eat.
    Stylianos Lefkopoulos.
      
    DOI:  https://doi.org/10.1038/s41556-024-01560-2
  10. Nat Aging. 2024 Nov;4(11): 1520
    Cell type-divergent functions of senescence.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00764-3
  11. Science. 2024 Nov 08. 386(6722): 673-677
    Hepatic vagal afferents convey clock-dependent signals to regulate circadian food intake.
    Lauren N Woodie, Lily C Melink, Mohit Midha, Alan M de Araújo, Caroline E Geisler, Ahren J Alberto, Brianna M Krusen, Delaine M Zundell, Guillaume de Lartigue, Matthew R Hayes, Mitchell A Lazar.
      Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chronodisruption.
    DOI:  https://doi.org/10.1126/science.adn2786
  12. Nat Commun. 2024 Nov 12. 15(1): 9585
    Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression.
    Shota Okagawa, Masaji Sakaguchi, Yuma Okubo, Yuri Takekuma, Motoyuki Igata, Tatsuya Kondo, Naoki Takeda, Kimi Araki, Bruna Brasil Brandao, Wei-Jun Qian, Yu-Hua Tseng, Rohit N Kulkarni, Naoto Kubota, C Ronald Kahn, Eiichi Araki.
      Lipodystrophy and obesity are associated with insulin resistance and metabolic syndrome accompanied by fat tissue dysregulation. Here, we show that serine protease inhibitor A1 (SerpinA1) expression in the liver is increased during recovery from lipodystrophy caused by the adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces the proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to increased energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. SerpinA1 forms a complex with the Eph receptor B2 and regulates its downstream signaling in adipocytes. These results demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes.
    DOI:  https://doi.org/10.1038/s41467-024-53835-9
  13. Nature. 2024 Nov 13.
    Adult skull bone marrow is an expanding and resilient haematopoietic reservoir.
    Bong Ihn Koh, Vishal Mohanakrishnan, Hyun-Woo Jeong, Hongryeol Park, Kai Kruse, Young Jun Choi, Melina Nieminen-Kelhä, Rahul Kumar, Raquel S Pereira, Susanne Adams, Hyuek Jong Lee, M Gabriele Bixel, Peter Vajkoczy, Daniela S Krause, Ralf H Adams.
      The bone marrow microenvironment is a critical regulator of haematopoietic stem cell self-renewal and fate1. Although it is appreciated that ageing, chronic inflammation and other insults compromise bone marrow function and thereby negatively affect haematopoiesis2, it is not known whether different bone compartments exhibit distinct microenvironmental properties and functional resilience. Here we use imaging, pharmacological approaches and mouse genetics to uncover specialized properties of bone marrow in adult and ageing skull. Specifically, we show that the skull bone marrow undergoes lifelong expansion involving vascular growth, which results in an increasing contribution to total haematopoietic output. Furthermore, skull is largely protected against major hallmarks of ageing, including upregulation of pro-inflammatory cytokines, adipogenesis and loss of vascular integrity. Conspicuous rapid and dynamic changes to the skull vasculature and bone marrow are induced by physiological alterations, namely pregnancy, but also pathological challenges, such as stroke and experimental chronic myeloid leukaemia. These responses are highly distinct from femur, the most extensively studied bone marrow compartment. We propose that skull harbours a protected and dynamically expanding bone marrow microenvironment, which is relevant for experimental studies and, potentially, for clinical treatments in humans.
    DOI:  https://doi.org/10.1038/s41586-024-08163-9
  14. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00862-1. [Epub ahead of print]
    VPS4A is the selective receptor for lipophagy in mice and humans.
    Debajyoti Das, Mridul Sharma, Deepanshi Gahlot, Shervin S Nia, Chandrima Gain, Matthew Mecklenburg, Z Hong Zhou, Mathieu Bourdenx, Lipi Thukral, Nuria Martinez-Lopez, Rajat Singh.
      Lipophagy is a ubiquitous mechanism for degradation of lipid droplets (LDs) in lysosomes. Autophagy receptors selectively target organelles for lysosomal degradation. The selective receptor for lipophagy remains elusive. Using mouse liver phosphoproteomics and human liver transcriptomics, we identify vacuolar-protein-sorting-associated protein 4A (VPS4A), a member of a large family AAA+ ATPases, as a selective receptor for lipophagy. We show that phosphorylation of VPS4A on Ser95,97 and its localization to LDs in response to fasting drives lipophagy. Imaging/three-dimensional (3D) reconstruction and biochemical analyses reveal the concomitant degradation of VPS4A and LDs in lysosomes in an autophagy-gene-7-sensitive manner. Either silencing VPS4A or targeting VPS4AS95,S97 phosphorylation or VPS4A binding to LDs or LC3 blocks lipophagy without affecting other forms of selective autophagy. Finally, VPS4A levels and markers of lipophagy are markedly reduced in human steatotic livers-revealing a fundamental role of VPS4A as the lipophagy receptor in mice and humans.
    Keywords:  MASLD; VPS4A; autophagy; human; lipid droplet; lipophagy; liver; lysosome; phosphorylation; receptor
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.022
  15. Cell. 2024 Nov 07. pii: S0092-8674(24)01214-5. [Epub ahead of print]
    A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
    Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.
      β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.
    Keywords:  BHB; enzyme; ketone; metabolite; metabolomics; obesity
    DOI:  https://doi.org/10.1016/j.cell.2024.10.032
  16. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00865-7. [Epub ahead of print]
    Opposing roles for AMPK in regulating distinct mitophagy pathways.
    Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G Ganley.
      Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.
    Keywords:  14-3-3; AMPK; NIX; Parkin; ULK1; autophagy; liver; mito-QC; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.025
  17. Science. 2024 Nov 08. 386(6722): 624-626
    Misguided negative adaptation narratives are hurting the poor.
    E L F Schipper, A Mukherji.
      Measurement and maladaptation are being weaponized.
    DOI:  https://doi.org/10.1126/science.adq7821
  18. Nature. 2024 Nov 14.
    US trust in scientists plunged during the pandemic - but it's starting to recover.
    Alix Soliman.
      
    Keywords:  Communication; SARS-CoV-2; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-03723-5
  19. Nat Commun. 2024 Nov 14. 15(1): 9860
    Diversification of molecular pattern recognition in bacterial NLR-like proteins.
    Nathalie Béchon, Nitzan Tal, Avigail Stokar-Avihail, Alon Savidor, Meital Kupervaser, Sarah Melamed, Gil Amitai, Rotem Sorek.
      Antiviral STANDs (Avs) are bacterial anti-phage proteins evolutionarily related to immune pattern recognition receptors of the NLR family. Type 2 Avs proteins (Avs2) were suggested to recognize the phage large terminase subunit as a signature of phage infection. Here, we show that Avs2 from Klebsiella pneumoniae (KpAvs2) can recognize several different phage proteins as signature for infection. While KpAvs2 recognizes the large terminase subunit of Seuratvirus phages, we find that to protect against Dhillonvirus phages, KpAvs2 recognizes a different phage protein named KpAvs2-stimulating protein 1 (Ksap1). KpAvs2 directly binds Ksap1 to become activated, and phages mutated in Ksap1 escape KpAvs2 defense despite encoding an intact terminase. We further show that KpAvs2 protects against a third group of phages by recognizing another protein, Ksap2. Our results exemplify the evolutionary diversification of molecular pattern recognition in bacterial Avs2, and show that a single pattern recognition receptor evolved to recognize different phage-encoded proteins.
    DOI:  https://doi.org/10.1038/s41467-024-54214-0
  20. Nat Commun. 2024 Nov 14. 15(1): 9437
    Genetic basis of right and left ventricular heart shape.
    Richard Burns, William J Young, Nay Aung, Luis R Lopes, Perry M Elliott, Petros Syrris, Roberto Barriales-Villa, Catrin Sohrabi, Steffen E Petersen, Julia Ramírez, Alistair Young, Patricia B Munroe.
      Heart shape captures variation in cardiac structure beyond traditional phenotypes of mass and volume. Although observational studies have demonstrated associations with cardiometabolic risk factors and diseases, its genetic basis is less understood. We utilised cardiovascular magnetic resonance images from 45,683 UK Biobank participants to construct a heart shape atlas from bi-ventricular end-diastolic surface mesh models through principal component (PC) analysis. Genome-wide association studies were performed on the first 11 PCs that captured 83.6% of shape variance. We identified 43 significant loci, 14 were previously unreported for cardiac traits. Genetically predicted PCs were associated with cardiometabolic diseases. In particular two PCs (2 and 3) linked with more spherical ventricles being associated with increased risk of atrial fibrillation. Our study explores the genetic basis of multidimensional bi-ventricular heart shape using PCA, reporting new loci and biology, as well as polygenic risk scores for exploring genetic relationships of heart shape with cardiometabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-024-53594-7
  21. Nat Commun. 2024 Nov 15. 15(1): 9932
    scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases.
    Hongru Hu, Gerald Quon.
      Multimodal single-cell assays profile multiple sets of features in the same cells and are widely used for identifying and mapping cell states between chromatin and mRNA and linking regulatory elements to target genes. However, the high dimensionality of input features and shallow sequencing depth compared to unimodal assays pose challenges in data analysis. Here we present scPair, a multimodal single-cell data framework that overcomes these challenges by employing an implicit feature selection approach. scPair uses dual encoder-decoder structures trained on paired data to align cell states across modalities and predict features from one modality to another. We demonstrate that scPair outperforms existing methods in accuracy and execution time, and facilitates downstream tasks such as trajectory inference. We further show scPair can augment smaller multimodal datasets with larger unimodal atlases to increase statistical power to identify groups of transcription factors active during different stages of neural differentiation.
    DOI:  https://doi.org/10.1038/s41467-024-53971-2
  22. Immunity. 2024 Nov 12. pii: S1074-7613(24)00487-4. [Epub ahead of print]57(11): 2489-2491
    Navigating the mutation maze: An oncogenic driver's guide to macrophage reprogramming.
    Ziyi Li, Ankur Sharma.
      The mechanisms by which oncogenic mutations and anatomical locations work together to influence the immune environment within tumors are not well understood. In this issue of Immunity, Ross et al. show that H3.3K27M diffuse midline gliomas (DMGs) are enriched with disease-associated myeloid cells (DAMs). Myeloid-targeted strategies reprogram DAMs to a homeostatic state, reduce myeloid infiltration into tumors, and prolong survival.
    DOI:  https://doi.org/10.1016/j.immuni.2024.10.007
  23. Nat Cell Biol. 2024 Nov 07.
    Spermidine limits diabetes by modulating RIPK1-mediated cell death and inflammation.
      
    DOI:  https://doi.org/10.1038/s41556-024-01542-4
  24. Cell Rep. 2024 Nov 12. pii: S2211-1247(24)01325-1. [Epub ahead of print]43(11): 114974
    A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling.
    Bodie Curren, Tufael Ahmed, Ridwan B Rashid, Ismail Sebina, Md Al Amin Sikder, Daniel R Howard, Mariah Alorro, Md Ashik Ullah, Alec Bissell, Muhammed Mahfuzur Rahman, Michael A Pearen, Grant A Ramm, Antiopi Varelias, Stefan Rose-John, Kelli P A MacDonald, Robert Hoelzle, Páraic Ó Cuív, Kirsten M Spann, Paul G Dennis, Simon Phipps.
      A poor maternal diet during pregnancy predisposes the infant to severe lower respiratory tract infections (sLRIs), which, in turn, increases childhood asthma risk; however, the underlying mechanisms remain poorly understood. Here, we show that the offspring of high-fat diet (HFD)-fed mothers (HFD-reared pups) developed an sLRI following pneumovirus inoculation in early life and subsequent asthma in later life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyperneutropoiesis in the liver and elevated inflammatory cytokine expression, most notably granulocyte-colony stimulating factor (G-CSF), interleukin-17A (IL-17A), IL-6 and soluble IL-6 receptor (sIL-6R) (indicative of IL-6 trans-signaling) in the circulation and multiple organs but most prominently the liver. Inhibition of IL-6 trans-signaling using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.
    Keywords:  ALRI; CP: Immunology; CP: Metabolism; IL-6 trans-signaling; RSV; asthma; bronchiolitis; liver; low grade systemic inflammation; maternal diet; microbiome; neutrophils
    DOI:  https://doi.org/10.1016/j.celrep.2024.114974
  25. Nature. 2024 Nov 11.
    8 million cells: virtual embryo shows organs forming in exquisite detail.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Developmental biology
    DOI:  https://doi.org/10.1038/d41586-024-03615-8
  26. Nature. 2024 Nov 13.
    Errors in cell division stopped by an atypical cyclin-dependent kinase.
      
    Keywords:  Cell biology; Chemical biology; Genetics
    DOI:  https://doi.org/10.1038/d41586-024-03691-w
  27. Nat Genet. 2024 Nov;56(11): 2295
    Population survey of repeat expansion mutations.
    Kyle Vogan.
      
    DOI:  https://doi.org/10.1038/s41588-024-02007-y
  28. Nature. 2024 Nov;635(8038): 284-285
    How AI is reshaping science and society.
    Pablo M Tagarro.
      
    Keywords:  Computer science; Language; Machine learning; Neuroscience; Society
    DOI:  https://doi.org/10.1038/d41586-024-03679-6
  29. Nature. 2024 Nov;635(8038): 261
    No hearing aids needed: bats' ears stay keen well into old age.
      
    Keywords:  Zoology
    DOI:  https://doi.org/10.1038/d41586-024-03575-z
  30. Sci Adv. 2024 Nov 15. 10(46): eadq9183
    Experience-dependent, sexually dimorphic synaptic connectivity defined by sex-specific cadherin expression.
    Chien-Po Liao, Maryam Majeed, Oliver Hobert.
      Early-life experience influences subsequent maturation and function of the adult brain, sometimes even in a sex-specific manner, but underlying molecular mechanisms are poorly understood. We describe here how juvenile experience defines sexually dimorphic synaptic connectivity in the adult Caenorhabditis elegans nervous system. Starvation of juvenile males disrupts serotonin-dependent activation of the CREB transcription factor in a nociceptive sensory neuron, PHB. CREB acts through a cascade of transcription factors to control expression of an atypical cadherin protein, FMI-1/Flamingo/CELSR. During postembryonic development, FMI-1 promotes and maintains synaptic connectivity of PHB to a command interneuron, AVA, in both sexes, but a serotonin-dependent transcriptional regulatory cassette antagonizes FMI-1 expression in males, thereby establishing sexually dimorphic connectivity between PHB and AVA. A critical regulatory node is the CREB-target LIN-29, a Zn finger transcription factor that integrates four layers of information: sexual specificity, past experience, time and cell-type specificity. Our findings provide the mechanistic details of how an early juvenile experience defines sexually dimorphic synaptic connectivity.
    DOI:  https://doi.org/10.1126/sciadv.adq9183
  31. Nat Commun. 2024 Nov 15. 15(1): 9912
    Mating reconciles fitness and fecundity by switching diet preference in flies.
    Chenxi Liu, Ning Tian, Pei Chang, Wei Zhang.
      Protein-rich diets shorten lifespan but increase fecundity in many organisms. Animals actively adjust their feeding behavior to meet their nutritional requirements. However, the neural mechanisms underlying the dynamic regulation of protein consumption remain unclear. Here we find that both sexes of fruit flies exhibit a preference for protein food before mating to prepare for reproduction. Mated female flies display an increased appetite for yeast to benefit their offspring, albeit at the cost of stress resistance and lifespan. In contrast, males show a momentarily reduced yeast appetite after mating likely to restore their fitness. This mating state-dependent switch between sexes is mediated by a sexually dimorphic neural circuit labeled with leucokinin in the anterior brain. Furthermore, intermittent yeast consumption benefits both the lifespan and fecundity of males, while maximizing female fecundity without compromising lifespan.
    DOI:  https://doi.org/10.1038/s41467-024-54369-w
  32. Nat Cell Biol. 2024 Nov;26(11): 1825
    Lipid droplet messengers.
    Melina Casadio.
      
    DOI:  https://doi.org/10.1038/s41556-024-01563-z
  33. Cell Metab. 2024 Nov 13. pii: S1550-4131(24)00412-1. [Epub ahead of print]
    Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis.
    Jivani M Gengatharan, Michal K Handzlik, Zoya Y Chih, Maureen L Ruchhoeft, Patrick Secrest, Ethan L Ashley, Courtney R Green, Martina Wallace, Philip L S M Gordts, Christian M Metallo.
      Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells in vitro. Administering high-fat diets (HFDs) enriched in TFAs to Ldlr-/- mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.
    Keywords:  SPTLC3; TRL remnant; VLDL; atherosclerosis; lipoprotein; monounsaturated fatty acid; myriocin; sphingolipid; sphingomyelin; trans fatty acid
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.016
  34. Nat Commun. 2024 Nov 07. 15(1): 9173
    Engineered PsCas9 enables therapeutic genome editing in mouse liver with lipid nanoparticles.
    Dmitrii Degtev, Jack Bravo, Aikaterini Emmanouilidi, Aleksandar Zdravković, Oi Kuan Choong, Julia Liz Touza, Niklas Selfjord, Isabel Weisheit, Margherita Francescatto, Pinar Akcakaya, Michelle Porritt, Marcello Maresca, David Taylor, Grzegorz Sienski.
      Clinical implementation of therapeutic genome editing relies on efficient in vivo delivery and the safety of CRISPR-Cas tools. Previously, we identified PsCas9 as a Type II-B family enzyme capable of editing mouse liver genome upon adenoviral delivery without detectable off-targets and reduced chromosomal translocations. Yet, its efficacy remains insufficient with non-viral delivery, a common challenge for many Cas9 orthologues. Here, we sought to redesign PsCas9 for in vivo editing using lipid nanoparticles. We solve the PsCas9 ribonucleoprotein structure with cryo-EM and characterize it biochemically, providing a basis for its rational engineering. Screening over numerous guide RNA and protein variants lead us to develop engineered PsCas9 (ePsCas9) with up to 20-fold increased activity across various targets and preserved safety advantages. We apply the same design principles to boost the activity of FnCas9, an enzyme phylogenetically relevant to PsCas9. Remarkably, a single administration of mRNA encoding ePsCas9 and its guide formulated with lipid nanoparticles results in high levels of editing in the Pcsk9 gene in mouse liver, a clinically relevant target for hypercholesterolemia treatment. Collectively, our findings introduce ePsCas9 as a highly efficient, and precise tool for therapeutic genome editing, in addition to the engineering strategy applicable to other Cas9 orthologues.
    DOI:  https://doi.org/10.1038/s41467-024-53418-8
  35. Nat Cell Biol. 2024 Nov 11.
    Specialized post-arterial capillaries facilitate adult bone remodelling.
    Vishal Mohanakrishnan, Kishor K Sivaraj, Hyun-Woo Jeong, Esther Bovay, Backialakshmi Dharmalingam, M Gabriele Bixel, Van Vuong Dinh, Milena Petkova, Isidora Paredes Ugarte, Yi-Tong Kuo, Malarvizhi Gurusamy, Brian Raftrey, Nelson Tsz Long Chu, Soumyashree Das, Pamela E Rios Coronado, Martin Stehling, Lars Sävendahl, Andrei S Chagin, Taija Mäkinen, Kristy Red-Horse, Ralf H Adams.
      The vasculature of the skeletal system is crucial for bone formation, homoeostasis and fracture repair, yet the diversity and specialization of bone-associated vessels remain poorly understood. Here we identify a specialized type of post-arterial capillary, termed type R, involved in bone remodelling. Type R capillaries emerge during adolescence around trabecular bone, possess a distinct morphology and molecular profile, and are associated with osteoprogenitors and bone-resorbing osteoclasts. Endothelial cell-specific overexpression of the transcription factor DACH1 in postnatal mice induces a strong increase in arteries and type R capillaries, leading to local metabolic changes and enabling trabecular bone formation in normally highly hypoxic areas of the diaphysis. Indicating potential clinical relevance of type R capillaries, these vessels respond to anti-osteoporosis treatments and emerge during ageing inside porous structures that are known to weaken compact bone. Our work outlines fundamental principles of vessel specialization in the developing, adult and ageing skeletal system.
    DOI:  https://doi.org/10.1038/s41556-024-01545-1
  36. Nat Med. 2024 Nov 14.
    Lipid signatures of cardiometabolic risk in children and adolescents with obesity.
      
    DOI:  https://doi.org/10.1038/s41591-024-03399-4
  37. Nat Genet. 2024 Nov;56(11): 2296
    Single-cell 3D multi-omics during human brain development.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-024-02008-x
  38. Nature. 2024 Nov 13.
    NK2R control of energy expenditure and feeding to treat metabolic diseases.
    Frederike Sass, Tao Ma, Jeppe H Ekberg, Melissa Kirigiti, Mario G Ureña, Lucile Dollet, Jenny M Brown, Astrid L Basse, Warren T Yacawych, Hayley B Burm, Mette K Andersen, Thomas S Nielsen, Abigail J Tomlinson, Oksana Dmytiyeva, Dan P Christensen, Lindsay Bader, Camilla T Vo, Yaxu Wang, Dylan M Rausch, Cecilie K Kristensen, María Gestal-Mato, Wietse In Het Panhuis, Kim A Sjøberg, Stace Kernodle, Jacob E Petersen, Artem Pavlovskyi, Manbir Sandhu, Ida Moltke, Marit E Jørgensen, Anders Albrechtsen, Niels Grarup, M Madan Babu, Patrick C N Rensen, Sander Kooijman, Randy J Seeley, Anna Worthmann, Joerg Heeren, Tune H Pers, Torben Hansen, Magnus B F Gustafsson, Mads Tang-Christensen, Tuomas O Kilpeläinen, Martin G Myers, Paul Kievit, Thue W Schwartz, Jakob B Hansen, Zachary Gerhart-Hines.
      The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes1. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects2-4, and so far, no safe energy-expending option has reached the clinic. Here we show that activation of neurokinin 2 receptor (NK2R) is sufficient to suppress appetite centrally and increase energy expenditure peripherally. We focused on NK2R after revealing its genetic links to obesity and glucose control. However, therapeutically exploiting NK2R signalling has previously been unattainable because its endogenous ligand, neurokinin A, is short-lived and lacks receptor specificity5,6. Therefore, we developed selective, long-acting NK2R agonists with potential for once-weekly administration in humans. In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signalling. Additionally, a hyperinsulinaemic-euglycaemic clamp reveals that NK2R agonism acutely enhances insulin sensitization. In diabetic, obese macaques, NK2R activation significantly decreases body weight, blood glucose, triglycerides and cholesterol, and ameliorates insulin resistance. These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programmes to improve energy homeostasis and reverse cardiometabolic dysfunction across species.
    DOI:  https://doi.org/10.1038/s41586-024-08207-0
  39. Nat Commun. 2024 Nov 12. 15(1): 9771
    A noncoding variant confers pancreatic differentiation defect and contributes to diabetes susceptibility by recruiting RXRA.
    Yinglei Li, Ran Zheng, Lai Jiang, Chenchao Yan, Ran Liu, Luyi Chen, Wenwen Jin, Yuanyuan Luo, Xiafei Zhang, Jun Tang, Zhe Dai, Wei Jiang.
      Human genetics analysis has identified many noncoding SNPs associated with diabetic traits, but whether and how these variants contribute to diabetes is largely unknown. Here, we focus on a noncoding variant, rs6048205, and report that the risk-G variant impairs the generation of PDX1+/NKX6-1+ pancreatic progenitor cells and further results in the abnormal decrease of functional β cells during pancreatic differentiation. Mechanistically, this risk-G variant greatly enhances RXRA binding and over-activates FOXA2 transcription, specifically in the pancreatic progenitor stage, which in turn represses NKX6-1 expression. Consistently, inducible FOXA2 overexpression could phenocopy the differentiation defect. More importantly, mice carrying risk-G exhibit abnormal pancreatic islet architecture and are more sensitive to streptozotocin or a high-fat diet to develop into diabetes eventually. This study not only identifies a causal noncoding variant in diabetes susceptibility but also dissects the underlying gain-of-function mechanism by recruiting stage-specific factors.
    DOI:  https://doi.org/10.1038/s41467-024-54151-y
  40. Nat Genet. 2024 Nov;56(11): 2295
    Missense variation affects protein cellular localization.
    Michael Fletcher.
      
    DOI:  https://doi.org/10.1038/s41588-024-02003-2
  41. Diabetologia. 2024 Nov 07.
    Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of type 1 diabetes.
    Chaitra Rao, Daniel T Cater, Saptarshi Roy, Jerry Xu, Andre G De Oliveira, Carmella Evans-Molina, Jon D Piganelli, Decio L Eizirik, Raghavendra G Mirmira, Emily K Sims.
      AIMS/HYPOTHESIS: Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death protein 1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesised that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death.METHODS: Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry and ELISA. EV PD-L1 binding to PD-1 was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8+ T cells. Plasma EV and soluble PD-L1 were assayed in the plasma of islet autoantibody-positive (Ab+) individuals or individuals with recent-onset type 1 diabetes and compared with levels in non-diabetic control individuals.
    RESULTS: PD-L1 protein co-localised with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. Treatment with IFN-α or IFN-γ for 24 h induced a twofold increase in EV PD-L1 cargo without a corresponding increase in the number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8+ T cells. Plasma EV PD-L1 levels were increased in Ab+individuals, particularly in those positive for a single autoantibody. Additionally, in Ab+ individuals or those who had type 1 diabetes, but not in control individuals, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV PD-L1 could be protective for residual beta cell function.
    CONCLUSIONS/INTERPRETATION: IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8+ T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in Ab+ individuals than in control individuals. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death.
    Keywords:  Beta cell; Biomarker; Cell lines; Human; Immune cell; Immune suppression; Islets; Prevention and prediction of type 1 diabetes
    DOI:  https://doi.org/10.1007/s00125-024-06313-2
  42. Nat Commun. 2024 Nov 08. 15(1): 9679
    A tuneable minimal cell membrane reveals that two lipid species suffice for life.
    Isaac Justice, Petra Kiesel, Nataliya Safronova, Alexander von Appen, James P Saenz.
      All cells are encapsulated by a lipid membrane that facilitates their interactions with the environment. How cells manage diverse mixtures of lipids, which dictate membrane property and function, is experimentally challenging to address. Here, we present an approach to tune and minimize membrane lipid composition in the bacterium Mycoplasma mycoides and its derived 'minimal cell' (JCVI-Syn3A), revealing that a two-component lipidome can support life. Systematic reintroduction of phospholipids with different features demonstrates that acyl chain diversity is more important for growth than head group diversity. By tuning lipid chirality, we explore the lipid divide between Archaea and the rest of life, showing that ancestral lipidomes could have been heterochiral. However, in these simple organisms, heterochirality leads to impaired cellular fitness. Thus, our approach offers a tunable minimal membrane system to explore the fundamental lipidomic requirements for life, thereby extending the concept of minimal life from the genome to the lipidome.
    DOI:  https://doi.org/10.1038/s41467-024-53975-y
  43. J Clin Invest. 2024 Nov 12. pii: e182939. [Epub ahead of print]
    Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice.
    Wenli Liu, Brian D Hardaway, Eunyoung Kim, Jessica Pauli, Justus Leonard Wettich, Mustafa Yalcinkaya, Cheng-Chieh Hsu, Tong Xiao, Muredach P Reilly, Ira Tabas, Lars Maegdefessel, Kai Schlepckow, Haass Christian, Nan Wang, Alan R Tall.
      Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis but the mechanisms by which CH mutant cells transmit inflammatory signals to non-mutant cells are largely unknown. To address this question we transplanted 1.5% Jak2VF bone marrow (BM) cells with 98.5% WT BM cells into hyperlipidemic Ldlr-/- mice. Low allele burden (LAB) mice showed accelerated atherosclerosis with increased features of plaque instability, decreased levels of macrophage phagocytic receptors MERTK and TREM2, and increased neutrophil extracellular traps (NETs). These changes were reversed when Jak2VF BM was transplanted with Il1r1-/- BM. LAB mice with non-cleavable MERTK in WT BM showed improvements in necrotic core and fibrous cap formation and reduced NETs. An agonistic TREM2 antibody (4D9) markedly increased fibrous caps in both control and LAB mice eliminating the difference between groups. Mechanistically, 4D9 increased TREM2+PDGFB+ macrophages and PDGF receptor-α positive fibroblast-like cells in the cap region. TREM2 and PDGFB mRNA levels were positively correlated in human carotid plaques and co-expressed in macrophages. In summary, low frequency Jak2VF mutations promote atherosclerosis via IL-1 signaling from Jak2VF to WT macrophages and neutrophils promoting cleavage of phagocytic receptors and features of plaque instability. Therapeutic approaches that stabilize MERTK or TREM2 could promote plaque stabilization especially in CH- and inflammasome-driven atherosclerosis.
    Keywords:  Atherosclerosis; Vascular biology
    DOI:  https://doi.org/10.1172/JCI182939
  44. Immunity. 2024 Nov 12. pii: S1074-7613(24)00485-0. [Epub ahead of print]57(11): 2483-2486
    Mx1-ing it up-Mitochondrial relay for interferon-dependent, unconventional IL-1β release in SLE monocytes.
    Andrea Dorfleutner, Christian Stehlik, Caroline A Jefferies.
      The role of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) is well documented, but the role of interleukin (IL)-1β remains elusive. In this issue of Immunity, Caielli et al. identified an SLE monocyte population coproducing IL-1β and IFN-I and described how mitochondrial nucleic-acid-containing RBCs engage cGAS/STING, RIG-I, MDA5, and NLRP3 for unconventional IL-1β release.
    DOI:  https://doi.org/10.1016/j.immuni.2024.10.005
  45. Nat Commun. 2024 Nov 12. 15(1): 9780
    Genetic legacy of ancient hunter-gatherer Jomon in Japanese populations.
    Biobank Japan Project
      The tripartite ancestral structure is a recently proposed model for the genetic origin of modern Japanese, comprising indigenous Jomon hunter-gatherers and two additional continental ancestors from Northeast Asia and East Asia. To investigate the impact of the tripartite structure on genetic and phenotypic variation today, we conducted biobank-scale analyses by merging Biobank Japan (BBJ; n = 171,287) with ancient Japanese and Eurasian genomes (n = 22). We demonstrate the applicability of the tripartite model to Japanese populations throughout the archipelago, with an extremely strong correlation between Jomon ancestry and genomic variation among individuals. We also find that the genetic legacy of Jomon ancestry underlies an elevated body mass index (BMI). Genome-wide association analysis with rigorous adjustments for geographical and ancestral substructures identifies 132 variants that are informative for predicting individual Jomon ancestry. This prediction model is validated using independent Japanese cohorts (Nagahama cohort, n = 2993; the second cohort of BBJ, n = 72,695). We further confirm the phenotypic association between Jomon ancestry and BMI using East Asian individuals from UK Biobank (n = 2286). Our extensive analysis of ancient and modern genomes, involving over 250,000 participants, provides valuable insights into the genetic legacy of ancient hunter-gatherers in contemporary populations.
    DOI:  https://doi.org/10.1038/s41467-024-54052-0
  46. Nat Commun. 2024 Nov 11. 15(1): 9756
    Nonvesicular lipid transfer drives myelin growth in the central nervous system.
    Jianping Wu, Georg Kislinger, Jerome Duschek, Ayşe Damla Durmaz, Benedikt Wefers, Ruoqing Feng, Karsten Nalbach, Wolfgang Wurst, Christian Behrends, Martina Schifferer, Mikael Simons.
      Oligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive. Utilizing volume electron microscopy, we demonstrate that the oligodendroglial endoplasmic reticulum (ER) is enriched in developing myelin, extending into and making contact with the innermost myelin layer where growth occurs. We explore the possibility of transfer of lipids from the ER to myelin, and find that the glycolipid transfer protein (GLTP), implicated in nonvesicular lipid transport, is highly enriched in the growing myelin sheath. Mice with a specific knockout of Gltp in oligodendrocytes exhibit ER pathology, hypomyelination and a decrease in myelin glycolipid content. In summary, our results demonstrate a role for nonvesicular lipid transport in CNS myelin growth, revealing a cellular pathway in developmental myelination.
    DOI:  https://doi.org/10.1038/s41467-024-53511-y
  47. Nature. 2024 Nov 08.
    Should Alzheimer's be diagnosed with a blood test? Proposal sparks controversy.
    Max Kozlov.
      
    Keywords:  Alzheimer's disease; Brain; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-03629-2
  48. Nature. 2024 Nov 13.
    Two for one: candidate obesity drug boosts energy use and curbs calorie intake.
    Carlos G Ardanaz, Sophie M Steculorum.
      
    Keywords:  Drug discovery; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-03548-2
  49. Nature. 2024 Nov;635(8038): 290
    Systemic biases are leading to an intersex research void.
    Alexander J Stokes, Nick G Vary, Erika L Lorshbough.
      
    Keywords:  Genetics; Genomics; Public health; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03662-1
  50. J Cell Biol. 2024 Dec 02. pii: e202404094. [Epub ahead of print]223(12):
    eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA.
    Marina Barba-Aliaga, Vanessa Bernal, Cynthia Rong, Madeleine E Volfbeyn, Keguang Zhang, Brian M Zid, Paula Alepuz.
      Efficient import of nuclear-encoded proteins into mitochondria is crucial for proper mitochondrial function. The conserved translation factor eIF5A binds ribosomes, alleviating stalling at polyproline-encoding sequences. eIF5A impacts mitochondrial function across species, though the precise molecular mechanism is unclear. We found that eIF5A depletion in yeast reduces the translation and levels of the TCA cycle and oxidative phosphorylation proteins. Loss of eIF5A causes mitoprotein precursors to accumulate in the cytosol and triggers a mitochondrial import stress response. We identify an essential polyproline protein as a direct target of eIF5A: the mitochondrial inner membrane protein and translocase component Tim50. Thus, eIF5A controls mitochondrial protein import by alleviating ribosome stalling along Tim50 mRNA at the mitochondrial surface. Removal of polyprolines from Tim50 partially rescues the mitochondrial import stress response and translation of oxidative phosphorylation genes. Overall, our findings elucidate how eIF5A impacts the mitochondrial function by promoting efficient translation and reducing ribosome stalling of co-translationally imported proteins, thereby positively impacting the mitochondrial import process.
    DOI:  https://doi.org/10.1083/jcb.202404094
  51. Sci Immunol. 2024 Nov 08. 9(101): eadi7907
    Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.
    Shengxiang Sun, Miki Hodel, Xiang Wang, Javier De Vicente, Talin Haritunians, Anketse Debebe, Chen-Ting Hung, Changqing Ma, Atika Malique, Hoang N Nguyen, Maayan Agam, Michael T Maloney, Marisa S Goo, Jillian H Kluss, Richa Mishra, Jennifer Frein, Amanda Foster, Samuel Ballentine, Uday Pandey, Justin Kern, Shaohong Yang, Emebet Mengesha, Iyshwarya Balasubramanian, Annie Arguello, Anthony A Estrada, Nan Gao, Inga Peter, Dermot P B McGovern, Anastasia G Henry, Thaddeus S Stappenbeck, Ta-Chiang Liu.
      LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.
    DOI:  https://doi.org/10.1126/sciimmunol.adi7907
  52. Nature. 2024 Nov 15.
    Stress can disrupt memory and lead to needless anxiety - here's how.
    Smriti Mallapaty.
      
    Keywords:  Brain; Neuroscience; Physiology; Post-traumatic stress disorder
    DOI:  https://doi.org/10.1038/d41586-024-03724-4
  53. Nature. 2024 Nov 08.
    World-first stem-cell treatment restores vision in people.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Regeneration; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-03656-z
  54. Aging Cell. 2024 Nov 15. e14401
    Age-related loss of intestinal barrier integrity plays an integral role in thymic involution and T cell ageing.
    Jessica Conway, Erica N De Jong, Andrea J White, Ben Dugan, Nia Paddison Rees, Sonia M Parnell, Lisa E Lamberte, Archana Sharma-Oates, Jack Sullivan, Claudio Mauro, Willem van Schaik, Graham Anderson, Dawn M E Bowdish, Niharika A Duggal.
      The intestinal epithelium serves as a physical and functional barrier against harmful substances, preventing their entry into the circulation and subsequent induction of a systemic immune response. Gut barrier dysfunction has recently emerged as a feature of ageing linked to declining health, and increased intestinal membrane permeability has been shown to promote heightened systemic inflammation in aged hosts. Concurrent with age-related changes in the gut microbiome, the thymic microenvironment undergoes a series of morphological, phenotypical and architectural alterations with age, including disorganisation of the corticomedullary junction, increased fibrosis, increased thymic adiposity and the accumulation of senescent cells. However, a direct link between gut barrier dysbiosis and thymic involution leading to features of immune ageing has not been explored thus far. Herein, we reveal strong associations between enhanced microbial translocation and the peripheral accumulation of terminally differentiated, senescent and exhausted T cells and the compensatory expansion of regulatory T cells in older adults. Crucially, we demonstrate that aged germ-free mice are protected from age-related increases in intestinal permeability, highlighting the direct impact of mucosal permeability on thymic ageing. Together, these findings establish a novel mechanism by which gut barrier dysfunction drives systemic activation of the immune system during ageing through thymic involution. This enhances our understanding of drivers of T cell ageing and opens up the possibility for the use of microbiome-based interventions to restore immune homeostasis and promote healthy ageing in older adults.
    Keywords:  T cell ageing; immunesenescence; intestinal barrier leakage; thymic involution
    DOI:  https://doi.org/10.1111/acel.14401
  55. Nat Cell Biol. 2024 Nov 07.
    Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.
    Tian Zhang, Weixin Fu, Haosong Zhang, Jianlong Li, Beizi Xing, Yuping Cai, Mengmeng Zhang, Xuheng Liu, Chunting Qi, Lihui Qian, Xinbo Hu, Hua Zhu, Shuailong Yang, Min Zhang, Jianping Liu, Ganquan Li, Yang Li, Rong Xiang, Zhengqiang Qi, Junhao Hu, Ying Li, Chengyu Zou, Qin Wang, Xia Jin, Rui Pang, Peiying Li, Junli Liu, Yaoyang Zhang, Zhaoyin Wang, Zheng-Jiang Zhu, Bing Shan, Junying Yuan.
      It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41556-024-01540-6
  56. Nat Cell Biol. 2024 Nov;26(11): 1819-1821
    Navigating human embryogenesis through tailored model selection.
    Berna Sozen.
      
    DOI:  https://doi.org/10.1038/s41556-024-01525-5
  57. Nat Cell Biol. 2024 Nov 13.
    A systemic effect for liver senescence.
    Kuo Du, David Scott Umbaugh, Rajesh Kumar Dutta, Anna Mae Diehl.
      
    DOI:  https://doi.org/10.1038/s41556-024-01520-w
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