bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒06‒09
fifty-nine papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Non-hierarchically related HSCs replenish platelets by distinct progenitor pathways.
  2. Sex differences are skin deep.
  3. Father's diet influences son's metabolic health through sperm RNA.
  4. The PASC microbiome.
  5. Bactericidal effect of tetracycline in E. coli strain ED1a may be associated with ribosome dysfunction.
  6. Cis-regulatory evolution of the recently expanded Ly49 gene family.
  7. A guide to the Nature Index.
  8. Peripheral apoptosis and limited clonal deletion during physiologic murine B lymphocyte development.
  9. Two rare UNC93B1 variants contribute to childhood-onset lupus.
  10. Cells cope with altered chromosome numbers by enhancing protein breakdown.
  11. Yersinia infection induces glucose depletion and AMPK-dependent inhibition of pyroptosis in mice.
  12. A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.
  13. Daily briefing: Landmark Alzheimer's paper will be retracted.
  14. Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.
  15. 'I saw that discrimination wasn't hearsay or rumours - it really did exist'.
  16. Circadian checkpoint.
  17. Epigenetic predictors of species maximum life span and other life-history traits in mammals.
  18. The ribotoxic stress response drives UV-mediated cell death.
  19. TREM1 is the new kid on the block for the aging-associated innate immune response and Alzheimer's disease.
  20. Single-cell analysis reveals a subpopulation of adipose progenitor cells that impairs glucose homeostasis.
  21. Transfer of modified gut viromes improves symptoms associated with metabolic syndrome in obese male mice.
  22. FBI asks scientists for trust in taking anti-Asian bias seriously.
  23. Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.
  24. A huge outbreak of butterflies hit three continents - here's why.
  25. Why female students at an inner London school are seeing scientists in a different light.
  26. eIF4E integrates into stress response.
  27. Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
  28. MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease.
  29. Sparrow massacres and Cuban vaccines: Books in Brief.
  30. Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.
  31. Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells.
  32. Profiling phagosome proteins identifies PD-L1 as a fungal-binding receptor.
  33. A dad's diet affects his sperm - and his sons' health.
  34. Daily briefing: Evidence grows that cows spread bird flu through their milk.
  35. TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.
  36. Protein translation rate determines neocortical neuron fate.
  37. Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown.
  38. Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti.
  39. Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.
  40. HeteroTCR: A heterogeneous graph neural network-based method for predicting peptide-TCR interaction.
  41. Daily briefing: Anthony Fauci denies 'preposterous' accusations of COVID origins cover-up.
  42. Capturing totipotency in human cells through spliceosomal repression.
  43. Resmetirom for treatment of MASH.
  44. Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging.
  45. Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease.
  46. PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein.
  47. Meta's AI translation model embraces overlooked languages.
  48. Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure.
  49. Bacteriophage defends murine gut from Escherichia coli invasion via mucosal adherence.
  50. On mechanical phase and form.
  51. Diffusion-based deep learning method for augmenting ultrastructural imaging and volume electron microscopy.
  52. Senescent glia link mitochondrial dysfunction and lipid accumulation.
  53. SenNet recommendations for detecting senescent cells in different tissues.
  54. Voluntary imaging goes magnetic.
  55. Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression.
  56. Extraembryonic gut endoderm cells undergo programmed cell death during development.
  57. Opioid drugs drive electrical insulation of reward circuitry.
  58. A single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD).
  59. Do scientists make good presidents? How five national leaders performed.
  1. Nat Immunol. 2024 Jun;25(6): 955-956
    Non-hierarchically related HSCs replenish platelets by distinct progenitor pathways.
      
    DOI:  https://doi.org/10.1038/s41590-024-01878-x
  2. Nat Immunol. 2024 Jun;25(6): 931
    Sex differences are skin deep.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-01877-y
  3. Nature. 2024 Jun 05.
    Father's diet influences son's metabolic health through sperm RNA.
    Chen Cai, Qi Chen.
      
    Keywords:  Metabolism; Non-coding RNAs; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-01502-w
  4. Nat Immunol. 2024 Jun;25(6): 931
    The PASC microbiome.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-024-01866-1
  5. Nat Commun. 2024 Jun 05. 15(1): 4783
    Bactericidal effect of tetracycline in E. coli strain ED1a may be associated with ribosome dysfunction.
    Iskander Khusainov, Natalie Romanov, Camille Goemans, Beata Turoňová, Christian E Zimmerli, Sonja Welsch, Julian D Langer, Athanasios Typas, Martin Beck.
      Ribosomes translate the genetic code into proteins. Recent technical advances have facilitated in situ structural analyses of ribosome functional states inside eukaryotic cells and the minimal bacterium Mycoplasma. However, such analyses of Gram-negative bacteria are lacking, despite their ribosomes being major antimicrobial drug targets. Here we compare two E. coli strains, a lab E. coli K-12 and human gut isolate E. coli ED1a, for which tetracycline exhibits bacteriostatic and bactericidal action, respectively. Using our approach for close-to-native E. coli sample preparation, we assess the two strains by cryo-ET and visualize their ribosomes at high resolution in situ. Upon tetracycline treatment, these exhibit virtually identical drug binding sites, yet the conformation distribution of ribosomal complexes differs. While K-12 retains ribosomes in a translation-competent state, tRNAs are lost in the vast majority of ED1a ribosomes. These structural findings together with the proteome-wide abundance and thermal stability assessments indicate that antibiotic responses are complex in cells and can differ between different strains of a single species, thus arguing that all relevant bacterial strains should be analyzed in situ when addressing antibiotic mode of action.
    DOI:  https://doi.org/10.1038/s41467-024-49084-5
  6. Nat Commun. 2024 Jun 06. 15(1): 4839
    Cis-regulatory evolution of the recently expanded Ly49 gene family.
    Changxu Fan, Xiaoyun Xing, Samuel J H Murphy, Jennifer Poursine-Laurent, Heather Schmidt, Bijal A Parikh, Jeesang Yoon, Mayank N K Choudhary, Naresha Saligrama, Sytse J Piersma, Wayne M Yokoyama, Ting Wang.
      Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition, we show that in mice, inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs, likely resulting from lineage-specific losses of CRE activity. Furthermore, we find that some Ly49 genes are cross-regulated by the CREs of other Ly49 genes, suggesting that the Ly49 family has begun to evolve a concerted cis-regulatory mechanism. Collectively, we demonstrate the different modes of cis-regulatory evolution for a rapidly expanding gene family.
    DOI:  https://doi.org/10.1038/s41467-024-48990-y
  7. Nature. 2024 Jun 05.
    A guide to the Nature Index.
      
    Keywords:  Databases; Publishing
    DOI:  https://doi.org/10.1038/d41586-024-01601-8
  8. Nat Commun. 2024 Jun 01. 15(1): 4691
    Peripheral apoptosis and limited clonal deletion during physiologic murine B lymphocyte development.
    Mikala JoAnn Simpson, Anna Minh Newen, Christopher McNees, Sukriti Sharma, Dylan Pfannenstiel, Thomas Moyer, David Stephany, Iyadh Douagi, Qiao Wang, Christian Thomas Mayer.
      Self-reactive and polyreactive B cells generated during B cell development are silenced by either apoptosis, clonal deletion, receptor editing or anergy to avoid autoimmunity. The specific contribution of apoptosis to normal B cell development and self-tolerance is incompletely understood. Here, we quantify self-reactivity, polyreactivity and apoptosis during physiologic B lymphocyte development. Self-reactivity and polyreactivity are most abundant in early immature B cells and diminish significantly during maturation within the bone marrow. Minimal apoptosis still occurs at this site, however B cell receptors cloned from apoptotic B cells show comparable self-reactivity to that of viable cells. Apoptosis increases dramatically only following immature B cells leaving the bone marrow sinusoids, but above 90% of cloned apoptotic transitional B cells are not self-reactive/polyreactive. Our data suggests that an apoptosis-independent mechanism, such as receptor editing, removes most self-reactive B cells in the bone marrow. Mechanistically, lack of survival signaling rather than clonal deletion appears to be the underpinning cause of apoptosis in most transitional B cells in the periphery.
    DOI:  https://doi.org/10.1038/s41467-024-49062-x
  9. Nat Immunol. 2024 Jun;25(6): 951-952
    Two rare UNC93B1 variants contribute to childhood-onset lupus.
      
    DOI:  https://doi.org/10.1038/s41590-024-01850-9
  10. Nature. 2024 Jun;630(8015): 41-43
    Cells cope with altered chromosome numbers by enhancing protein breakdown.
    Zuzana Storchová.
      
    Keywords:  Cell biology; Genomics; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-024-01360-6
  11. Nat Microbiol. 2024 Jun 06.
    Yersinia infection induces glucose depletion and AMPK-dependent inhibition of pyroptosis in mice.
    Yuanxin Yang, Hongwen Fang, Zhangdan Xie, Fandong Ren, Lingjie Yan, Mengmeng Zhang, Guifang Xu, Ziwen Song, Zezhao Chen, Weimin Sun, Bing Shan, Zheng-Jiang Zhu, Daichao Xu.
      Nutritional status and pyroptosis are important for host defence against infections. However, the molecular link that integrates nutrient sensing into pyroptosis during microbial infection is unclear. Here, using metabolic profiling, we found that Yersinia pseudotuberculosis infection results in a significant decrease in intracellular glucose levels in macrophages. This leads to activation of the glucose and energy sensor AMPK, which phosphorylates the essential kinase RIPK1 at S321 during caspase-8-mediated pyroptosis. This phosphorylation inhibits RIPK1 activation and thereby restrains pyroptosis. Boosting the AMPK-RIPK1 cascade by glucose deprivation, AMPK agonists, or RIPK1-S321E knockin suppresses pyroptosis, leading to increased susceptibility to Y. pseudotuberculosis infection in mice. Ablation of AMPK in macrophages or glucose supplementation in mice is protective against infection. Thus, we reveal a molecular link between glucose sensing and pyroptosis, and unveil a mechanism by which Y. pseudotuberculosis reduces glucose levels to impact host AMPK activation and limit host pyroptosis to facilitate infection.
    DOI:  https://doi.org/10.1038/s41564-024-01734-6
  12. Nat Aging. 2024 Jun 07.
    A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.
    Ana Ortega-Molina, Cristina Lebrero-Fernández, Alba Sanz, Miguel Calvo-Rubio, Nerea Deleyto-Seldas, Lucía de Prado-Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González-García, Yurena Vivas-García, Elena Sánchez García, Osvaldo Graña-Castro, Nathan L Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Consuelo Borrás, María Casanova-Acebes, Rafael de Cabo, Alejo Efeyan.
      The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.
    DOI:  https://doi.org/10.1038/s43587-024-00635-x
  13. Nature. 2024 Jun 05.
    Daily briefing: Landmark Alzheimer's paper will be retracted.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-01699-w
  14. Dev Cell. 2024 May 30. pii: S1534-5807(24)00327-7. [Epub ahead of print]
    Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.
    Brian T Do, Peggy P Hsu, Sidney Y Vermeulen, Zhishan Wang, Taghreed Hirz, Keene L Abbott, Najihah Aziz, Joseph M Replogle, Stefan Bjelosevic, Jonathan Paolino, Samantha A Nelson, Samuel Block, Alicia M Darnell, Raphael Ferreira, Hanyu Zhang, Jelena Milosevic, Daniel R Schmidt, Christopher Chidley, Isaac S Harris, Jonathan S Weissman, Yana Pikman, Kimberly Stegmaier, Sihem Cheloufi, Xiaofeng A Su, David B Sykes, Matthew G Vander Heiden.
      Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.
    Keywords:  cancer; cell fate; cell state; dependencies; differentiation; epigenetics; hematopoiesis; metabolism; nucleotides; replication; replication stress
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.010
  15. Nature. 2024 Jun 05.
    'I saw that discrimination wasn't hearsay or rumours - it really did exist'.
    Robin Donovan.
      
    Keywords:  Careers; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-01685-2
  16. Nat Immunol. 2024 Jun;25(6): 931
    Circadian checkpoint.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-024-01876-z
  17. Sci Adv. 2024 Jun 07. 10(23): eadm7273
    Epigenetic predictors of species maximum life span and other life-history traits in mammals.
    Caesar Z Li, Amin Haghani, Qi Yan, Ake T Lu, Joshua Zhang, Zhe Fei, Jason Ernst, X William Yang, Vadim N Gladyshev, Todd R Robeck, Andreas S Chavez, Joseph A Cook, Jonathan L Dunnum, Ken Raj, Andrei Seluanov, Vera Gorbunova, Steve Horvath.
      By analyzing 15,000 samples from 348 mammalian species, we derive DNA methylation (DNAm) predictors of maximum life span (R = 0.89), gestation time (R = 0.96), and age at sexual maturity (R = 0.85). Our maximum life-span predictor indicates a potential innate longevity advantage for females over males in 17 mammalian species including humans. The DNAm maximum life-span predictions are not affected by caloric restriction or partial reprogramming. Genetic disruptions in the somatotropic axis such as growth hormone receptors have an impact on DNAm maximum life span only in select tissues. Cancer mortality rates show no correlation with our epigenetic estimates of life-history traits. The DNAm maximum life-span predictor does not detect variation in life span between individuals of the same species, such as between the breeds of dogs. Maximum life span is determined in part by an epigenetic signature that is an intrinsic species property and is distinct from the signatures that relate to individual mortality risk.
    DOI:  https://doi.org/10.1126/sciadv.adm7273
  18. Cell. 2024 May 31. pii: S0092-8674(24)00527-0. [Epub ahead of print]
    The ribotoxic stress response drives UV-mediated cell death.
    Niladri K Sinha, Connor McKenney, Zhong Y Yeow, Jeffrey J Li, Ki Hong Nam, Tomer M Yaron-Barir, Jared L Johnson, Emily M Huntsman, Lewis C Cantley, Alban Ordureau, Sergi Regot, Rachel Green.
      While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage.
    Keywords:  DNA damage response; GCN2; UV radiation; ZAK; apoptosis; collisions; phosphoproteomics; ribosomes; ribotoxic stress; signaling
    DOI:  https://doi.org/10.1016/j.cell.2024.05.018
  19. Nat Immunol. 2024 Jun;25(6): 938-940
    TREM1 is the new kid on the block for the aging-associated innate immune response and Alzheimer's disease.
    Michael T Heneka.
      
    DOI:  https://doi.org/10.1038/s41590-024-01854-5
  20. Nat Commun. 2024 Jun 06. 15(1): 4827
    Single-cell analysis reveals a subpopulation of adipose progenitor cells that impairs glucose homeostasis.
    Hongdong Wang, Yanhua Du, Shanshan Huang, Xitai Sun, Youqiong Ye, Haixiang Sun, Xuehui Chu, Xiaodong Shan, Yue Yuan, Lei Shen, Yan Bi.
      Adipose progenitor cells (APCs) are heterogeneous stromal cells and help to maintain metabolic homeostasis. However, the influence of obesity on human APC heterogeneity and the role of APC subpopulations on regulating glucose homeostasis remain unknown. Here, we find that APCs in human visceral adipose tissue contain four subsets. The composition and functionality of APCs are altered in patients with type 2 diabetes (T2D). CD9+CD55low APCs are the subset which is significantly increased in T2D patients. Transplantation of these cells from T2D patients into adipose tissue causes glycemic disturbance. Mechanistically, CD9+CD55low APCs promote T2D development through producing bioactive proteins to form a detrimental niche, leading to upregulation of adipocyte lipolysis. Depletion of pathogenic APCs by inducing intracellular diphtheria toxin A expression or using a hunter-killer peptide improves obesity-related glycemic disturbance. Collectively, our data provide deeper insights in human APC functionality and highlights APCs as a potential therapeutic target to combat T2D. All mice utilized in this study are male.
    DOI:  https://doi.org/10.1038/s41467-024-48914-w
  21. Nat Commun. 2024 Jun 03. 15(1): 4704
    Transfer of modified gut viromes improves symptoms associated with metabolic syndrome in obese male mice.
    Xiaotian Mao, Sabina Birgitte Larsen, Line Sidsel Fisker Zachariassen, Anders Brunse, Signe Adamberg, Josue Leonardo Castro Mejia, Frej Larsen, Kaarel Adamberg, Dennis Sandris Nielsen, Axel Kornerup Hansen, Camilla Hartmann Friis Hansen, Torben Sølbeck Rasmussen.
      Metabolic syndrome encompasses amongst other conditions like obesity and type-2 diabetes and is associated with gut microbiome (GM) dysbiosis. Fecal microbiota transplantation (FMT) has been explored to treat metabolic syndrome by restoring the GM; however, concerns on accidentally transferring pathogenic microbes remain. As a safer alternative, fecal virome transplantation (FVT, sterile-filtrated feces) has the advantage over FMT in that mainly bacteriophages are transferred. FVT from lean male donors have shown promise in alleviating the metabolic effects of high-fat diet in a preclinical mouse study. However, FVT still carries the risk of eukaryotic viral infections. To address this, recently developed methods are applied for removing or inactivating eukaryotic viruses in the viral component of FVT. Modified FVTs are compared with unmodified FVT and saline in a diet-induced obesity model on male C57BL/6 N mice. Contrasted with obese control, mice administered a modified FVT (nearly depleted for eukaryotic viruses) exhibits enhanced blood glucose clearance but not weight loss. The unmodified FVT improves liver pathology and reduces the proportions of immune cells in the adipose tissue with a non-uniform response. GM analysis suggests that bacteriophage-mediated GM modulation influences outcomes. Optimizing these approaches could lead to the development of safe bacteriophage-based therapies targeting metabolic syndrome through GM restoration.
    DOI:  https://doi.org/10.1038/s41467-024-49152-w
  22. Nature. 2024 Jun 07.
    FBI asks scientists for trust in taking anti-Asian bias seriously.
    Neil Savage.
      
    Keywords:  Government; Law; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-01704-2
  23. Commun Biol. 2024 Jun 03. 7(1): 681
    Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.
    Ayaka Iwata, Juri Maruyama, Shibata Natsuki, Akira Nishiyama, Tomohiko Tamura, Minoru Tanaka, Shigeyuki Shichino, Takao Seki, Toshihiko Komai, Tomohisa Okamura, Keishi Fujio, Masato Tanaka, Kenichi Asano.
      Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.
    DOI:  https://doi.org/10.1038/s42003-024-06357-5
  24. Nature. 2024 Jun 06.
    A huge outbreak of butterflies hit three continents - here's why.
      
    Keywords:  Zoology
    DOI:  https://doi.org/10.1038/d41586-024-01653-w
  25. Nature. 2024 Jun 06.
    Why female students at an inner London school are seeing scientists in a different light.
    Julie Gould.
      
    Keywords:  Careers; Education; Lab life; Society
    DOI:  https://doi.org/10.1038/d41586-024-01689-y
  26. Mol Cell. 2024 Jun 06. pii: S1097-2765(24)00399-X. [Epub ahead of print]84(11): 2009-2010
    eIF4E integrates into stress response.
    Xincheng Wu, Shu-Bing Qian.
      In this issue, Diamond et al.1 and Kim et al.2 report that depletion of eIF4E leads to translational upregulation of GCN4, a key player in the integrated stress response, in an eIF2α phosphorylation-independent manner, suggesting a new mode of translational adaptation.
    DOI:  https://doi.org/10.1016/j.molcel.2024.05.006
  27. Nat Commun. 2024 Jun 03. 15(1): 4700
    Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
    Shashank Dadsena, Rodrigo Cuevas Arenas, Gonçalo Vieira, Susanne Brodesser, Manuel N Melo, Ana J García-Sáez.
      BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.
    DOI:  https://doi.org/10.1038/s41467-024-49067-6
  28. Nat Commun. 2024 Jun 07. 15(1): 4884
    MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease.
    Sarah M Urbut, Ming Wai Yeung, Shaan Khurshid, So Mi Jemma Cho, Art Schuermans, Jakob German, Kodi Taraszka, Kaavya Paruchuri, Akl C Fahed, Patrick T Ellinor, Ludovic Trinquart, Giovanni Parmigiani, Alexander Gusev, Pradeep Natarajan.
      Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model's potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.
    DOI:  https://doi.org/10.1038/s41467-024-49296-9
  29. Nature. 2024 Jun 07.
    Sparrow massacres and Cuban vaccines: Books in Brief.
    Andrew Robinson.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-01725-x
  30. Nat Commun. 2024 Jun 04. 15(1): 4757
    Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.
    Yu-Lan Ma, Chun-Yan Kong, Zhen Guo, Ming-Yu Wang, Pan Wang, Fang-Yuan Liu, Dan Yang, Zheng Yang, Qi-Zhu Tang.
      Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-48970-2
  31. Sci Immunol. 2024 Jun 07. 9(96): eadl2388
    Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells.
    Benjamin Y Winer, Alexander H Settle, Alexandrina M Yakimov, Carlos Jeronimo, Tomi Lazarov, Murray Tipping, Michelle Saoi, Anjelique Sawh, Anna-Liisa L Sepp, Michael Galiano, Justin S A Perry, Yung Yu Wong, Frederic Geissmann, Justin Cross, Ting Zhou, Lance C Kam, H Amalia Pasolli, Tobias Hohl, Jason G Cyster, Orion D Weiner, Morgan Huse.
      Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ4-deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ4. In Gβ4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.
    DOI:  https://doi.org/10.1126/sciimmunol.adl2388
  32. Nature. 2024 Jun 05.
    Profiling phagosome proteins identifies PD-L1 as a fungal-binding receptor.
    Kai Li, Avradip Chatterjee, Chen Qian, Katherine Lagree, Yang Wang, Courtney A Becker, Michael R Freeman, Ramachandran Murali, Wei Yang, David M Underhill.
      Phagocytosis is the process by which myeloid phagocytes bind to and internalize potentially dangerous microorganisms1. During phagocytosis, innate immune receptors and associated signalling proteins are localized to the maturing phagosome compartment, forming an immune information processing hub brimming with microorganism-sensing features2-8. Here we developed proximity labelling of phagosomal contents (PhagoPL) to identify proteins localizing to phagosomes containing model yeast and bacteria. By comparing the protein composition of phagosomes containing evolutionarily and biochemically distinct microorganisms, we unexpectedly identified programmed death-ligand 1 (PD-L1) as a protein that specifically enriches in phagosomes containing yeast. We found that PD-L1 directly binds to yeast upon processing in phagosomes. By surface display library screening, we identified the ribosomal protein Rpl20b as a fungal protein ligand for PD-L1. Using an auxin-inducible depletion system, we found that detection of Rpl20b by macrophages cross-regulates production of distinct cytokines including interleukin-10 (IL-10) induced by the activation of other innate immune receptors. Thus, this study establishes PhagoPL as a useful approach to quantifying the collection of proteins enriched in phagosomes during host-microorganism interactions, exemplified by identifying PD-L1 as a receptor that binds to fungi.
    DOI:  https://doi.org/10.1038/s41586-024-07499-6
  33. Nature. 2024 Jun 05.
    A dad's diet affects his sperm - and his sons' health.
    Julian Nowogrodzki.
      
    Keywords:  Epigenetics; Metabolism; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-01623-2
  34. Nature. 2024 Jun 06.
    Daily briefing: Evidence grows that cows spread bird flu through their milk.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-01709-x
  35. Cell Biosci. 2024 Jun 01. 14(1): 68
    TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.
    Canrong Li, Yuguo Yi, Yingyi Ouyang, Fengzhi Chen, Chuxin Lu, Shujun Peng, Yifan Wang, Xinyu Chen, Xiao Yan, Haolun Xu, Shuiming Li, Lin Feng, Xiaoduo Xie.
      BACKGROUND: Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is an effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration. However, an efficient tool for monitoring mTORC1 inhibition in living cells or tissues is lacking.RESULTS: We developed a genetically encoded mTORC1 sensor called TORSEL. This sensor changes its fluorescence pattern from diffuse to punctate when 4EBP1 dephosphorylation occurs and interacts with eIF4E. TORSEL can specifically sense the physiological, pharmacological, and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, TORSEL is a valuable tool for imaging-based visual screening of mTORC1 inhibitors. Using TORSEL, we identified histone deacetylase inhibitors that selectively block nutrient-sensing signaling to inhibit mTORC1.
    CONCLUSIONS: TORSEL is a unique living cell sensor that efficiently detects the inhibition of mTORC1 activity, and histone deacetylase inhibitors such as panobinostat target mTORC1 signaling through amino acid sensing.
    Keywords:  Amino acid sensing; HDAC inhibitor; Live-cell sensor; Panobinostat; mTORC1
    DOI:  https://doi.org/10.1186/s13578-024-01250-4
  36. Nat Commun. 2024 Jun 07. 15(1): 4879
    Protein translation rate determines neocortical neuron fate.
    Ekaterina Borisova, Andrew G Newman, Marta Couce Iglesias, Rike Dannenberg, Theres Schaub, Bo Qin, Alexandra Rusanova, Marisa Brockmann, Janina Koch, Marieatou Daniels, Paul Turko, Olaf Jahn, David R Kaplan, Marta Rosário, Takao Iwawaki, Christian M T Spahn, Christian Rosenmund, David Meierhofer, Matthew L Kraushar, Victor Tarabykin, Mateusz C Ambrozkiewicz.
      The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5'-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.
    DOI:  https://doi.org/10.1038/s41467-024-49198-w
  37. Nat Commun. 2024 Jun 03. 15(1): 4707
    Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown.
    Rishi Kumar Nageshan, Raquel Ortega, Nevan Krogan, Julia Promisel Cooper.
      Persisting replication intermediates can confer mitotic catastrophe. Loss of the fission yeast telomere protein Taz1 (ortholog of mammalian TRF1/TRF2) causes telomeric replication fork (RF) stalling and consequently, telomere entanglements that stretch between segregating mitotic chromosomes. At ≤20 °C, these entanglements fail to resolve, resulting in lethality. Rif1, a conserved DNA replication/repair protein, hinders the resolution of telomere entanglements without affecting their formation. At mitosis, local nuclear envelope (NE) breakdown occurs in the cell's midregion. Here we demonstrate that entanglement resolution occurs in the cytoplasm following this NE breakdown. However, in response to taz1Δ telomeric entanglements, Rif1 delays midregion NE breakdown at ≤20 °C, in turn disfavoring entanglement resolution. Moreover, Rif1 overexpression in an otherwise wild-type setting causes cold-specific NE defects and lethality, which are rescued by membrane fluidization. Hence, NE properties confer the cold-specificity of taz1Δ lethality, which stems from postponement of NE breakdown. We propose that such postponement promotes clearance of simple stalled RFs, but resolution of complex entanglements (involving strand invasion between nonsister telomeres) requires rapid exposure to the cytoplasm.
    DOI:  https://doi.org/10.1038/s41467-024-48382-2
  38. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00176-1. [Epub ahead of print]36(6): 1269-1286.e9
    Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti.
    Wei Xie, Jing Gan, Xiaodong Zhou, Huiying Tian, Xingchao Pan, Wenyue Liu, Xiaokun Li, Jie Du, Aimin Xu, Minghua Zheng, Fan Wu, Yuling Li, Zhuofeng Lin.
      Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.
    Keywords:  MASH; MASLD; immunoinflammatory response; myocardial infarction; periostin
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.020
  39. Nat Commun. 2024 Jun 04. 15(1): 4755
    Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.
    Jialin Xia, Hong Chen, Xiaoxiao Wang, Weixuan Chen, Jun Lin, Feng Xu, Qixing Nie, Chuan Ye, Bitao Zhong, Min Zhao, Chuyu Yun, Guangyi Zeng, Yuejian Mao, Yongping Wen, Xuguang Zhang, Sen Yan, Xuemei Wang, Lulu Sun, Feng Liu, Chao Zhong, Pengyan Xia, Changtao Jiang, Huiying Rao, Yanli Pang.
      Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.
    DOI:  https://doi.org/10.1038/s41467-024-48954-2
  40. Commun Biol. 2024 Jun 04. 7(1): 684
    HeteroTCR: A heterogeneous graph neural network-based method for predicting peptide-TCR interaction.
    Zilan Yu, Mengnan Jiang, Xun Lan.
      Identifying interactions between T-cell receptors (TCRs) and immunogenic peptides holds profound implications across diverse research domains and clinical scenarios. Unsupervised clustering models (UCMs) cannot predict peptide-TCR binding directly, while supervised predictive models (SPMs) often face challenges in identifying antigens previously unencountered by the immune system or possessing limited TCR binding repertoires. Therefore, we propose HeteroTCR, an SPM based on Heterogeneous Graph Neural Network (GNN), to accurately predict peptide-TCR binding probabilities. HeteroTCR captures within-type (TCR-TCR or peptide-peptide) similarity information and between-type (peptide-TCR) interaction insights for predictions on unseen peptides and TCRs, surpassing limitations of existing SPMs. Our evaluation shows HeteroTCR outperforms state-of-the-art models on independent datasets. Ablation studies and visual interpretation underscore the Heterogeneous GNN module's critical role in enhancing HeteroTCR's performance by capturing pivotal binding process features. We further demonstrate the robustness and reliability of HeteroTCR through validation using single-cell datasets, aligning with the expectation that pMHC-TCR complexes with higher predicted binding probabilities correspond to increased binding fractions.
    DOI:  https://doi.org/10.1038/s42003-024-06380-6
  41. Nature. 2024 Jun 04.
    Daily briefing: Anthony Fauci denies 'preposterous' accusations of COVID origins cover-up.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-01682-5
  42. Cell. 2024 Jun 03. pii: S0092-8674(24)00519-1. [Epub ahead of print]
    Capturing totipotency in human cells through spliceosomal repression.
    Shiyu Li, Min Yang, Hui Shen, Li Ding, Xuehui Lyu, Kexin Lin, Jennie Ong, Peng Du.
      The cleavage of zygotes generates totipotent blastomeres. In human 8-cell blastomeres, zygotic genome activation (ZGA) occurs to initiate the ontogenesis program. However, capturing and maintaining totipotency in human cells pose significant challenges. Here, we realize culturing human totipotent blastomere-like cells (hTBLCs). We find that splicing inhibition can transiently reprogram human pluripotent stem cells into ZGA-like cells (ZLCs), which subsequently transition into stable hTBLCs after long-term passaging. Distinct from reported 8-cell-like cells (8CLCs), both ZLCs and hTBLCs widely silence pluripotent genes. Interestingly, ZLCs activate a particular group of ZGA-specific genes, and hTBLCs are enriched with pre-ZGA-specific genes. During spontaneous differentiation, hTBLCs re-enter the intermediate ZLC stage and further generate epiblast (EPI)-, primitive endoderm (PrE)-, and trophectoderm (TE)-like lineages, effectively recapitulating human pre-implantation development. Possessing both embryonic and extraembryonic developmental potency, hTBLCs can autonomously generate blastocyst-like structures in vitro without external cell signaling. In summary, our study provides key criteria and insights into human cell totipotency.
    Keywords:  ZGA-like cells; blastocyst-like structure; blastomere; pluripotent; splicing inhibition; stem cell culture; totipotency; totipotent blastomere-like cells; zygotic genomic activation
    DOI:  https://doi.org/10.1016/j.cell.2024.05.010
  43. Cell. 2024 Jun 06. pii: S0092-8674(24)00518-X. [Epub ahead of print]187(12): 2897-2897.e1
    Resmetirom for treatment of MASH.
    Silvia Sookoian, Carlos Jose Pirola.
      Resmetirom is an oral selective THR-β agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom restores mitochondrial and hepatic metabolic function; reduces atherogenic lipids; improves hepatic steatosis, inflammation, and fibrosis; and has no significant effect on THR-α. To view this Bench to Bedside, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cell.2024.05.009
  44. J Neuroinflammation. 2024 Jun 05. 21(1): 150
    Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging.
    Seokjo Kang, Emily Y Ko, Amelia E Andrews, Juliana E Shin, Karina J Nance, Pijus K Barman, Peter S Heeger, Willard M Freeman, Bérénice A Benayoun, Helen S Goodridge.
      Microglia, the brain's resident macrophages, maintain brain homeostasis and respond to injury and infection. During aging they undergo functional changes, but the underlying mechanisms and their contributions to neuroprotection versus neurodegeneration are unclear. Previous studies suggested that microglia are sex dimorphic, so we compared microglial aging in mice of both sexes. RNA-sequencing of hippocampal microglia revealed more aging-associated changes in female microglia than male microglia, and more sex differences in old microglia than young microglia. Pathway analyses and subsequent validation assays revealed a stronger AKT-mTOR-HIF1α-driven shift to glycolysis among old female microglia and indicated that C3a production and detection was elevated in old microglia, especially in females. Recombinant C3a induced AKT-mTOR-HIF1α signaling and increased the glycolytic and phagocytic activity of young microglia. Single cell analyses attributed the aging-associated sex dimorphism to more abundant disease-associated microglia (DAM) in old female mice than old male mice, and evaluation of an Alzheimer's Disease mouse model revealed that the metabolic and complement changes are also apparent in the context of neurodegenerative disease and are strongest in the neuroprotective DAM2 subset. Collectively, our data implicate autocrine C3a-C3aR signaling in metabolic reprogramming of microglia to neuroprotective DAM during aging, especially in females, and also in Alzheimer's Disease.
    Keywords:  Aging; Alzheimer’s disease; Microglia; Sex differences
    DOI:  https://doi.org/10.1186/s12974-024-03130-7
  45. Nat Commun. 2024 Jun 01. 15(1): 4695
    Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease.
    Zengjie Xia, Emily E Prescott, Agnieszka Urbanek, Hollie E Wareing, Marianne C King, Anna Olerinyova, Helen Dakin, Tom Leah, Katy A Barnes, Martyna M Matuszyk, Eleni Dimou, Eric Hidari, Yu P Zhang, Jeff Y L Lam, John S H Danial, Michael R Strickland, Hong Jiang, Peter Thornton, Damian C Crowther, Sohvi Ohtonen, Mireia Gómez-Budia, Simon M Bell, Laura Ferraiuolo, Heather Mortiboys, Adrian Higginbottom, Stephen B Wharton, David M Holtzman, Tarja Malm, Rohan T Ranasinghe, David Klenerman, Suman De.
      Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.
    DOI:  https://doi.org/10.1038/s41467-024-49028-z
  46. Nat Commun. 2024 Jun 06. 15(1): 4847
    PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein.
    Scott M Johnson, Hanmei Bao, Cailin E McMahon, Yongbin Chen, Stephanie D Burr, Aaron M Anderson, Katja Madeyski-Bengtson, Daniel Lindén, Xianlin Han, Jun Liu.
      The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.
    DOI:  https://doi.org/10.1038/s41467-024-49224-x
  47. Nature. 2024 Jun 05.
    Meta's AI translation model embraces overlooked languages.
    David I Adelani.
      
    Keywords:  Computer science; Machine learning
    DOI:  https://doi.org/10.1038/d41586-024-00964-2
  48. Nat Commun. 2024 Jun 03. 15(1): 4724
    Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure.
    Sudipta Das, Tomasz W Kaminski, Brent T Schlegel, William Bain, Sanmei Hu, Akruti Patel, Sagar L Kale, Kong Chen, Janet S Lee, Rama K Mallampalli, Valerian E Kagan, Dhivyaa Rajasundaram, Bryan J McVerry, Prithu Sundd, Georgios D Kitsios, Anuradha Ray, Prabir Ray.
      Respiratory infection by Pseudomonas aeruginosa, common in hospitalized immunocompromised and immunocompetent ventilated patients, can be life-threatening because of antibiotic resistance. This raises the question of whether the host's immune system can be educated to combat this bacterium. Here we show that prior exposure to a single low dose of lipopolysaccharide (LPS) protects mice from a lethal infection by P. aeruginosa. LPS exposure trained the innate immune system by promoting expansion of neutrophil and interstitial macrophage populations distinguishable from other immune cells with enrichment of gene sets for phagocytosis- and cell-killing-associated genes. The cell-killing gene set in the neutrophil population uniquely expressed Lgals3, which encodes the multifunctional antibacterial protein, galectin-3. Intravital imaging for bacterial phagocytosis, assessment of bacterial killing and neutrophil-associated galectin-3 protein levels together with use of galectin-3-deficient mice collectively highlight neutrophils and galectin-3 as central players in LPS-mediated protection. Patients with acute respiratory failure revealed significantly higher galectin-3 levels in endotracheal aspirates (ETAs) of survivors compared to non-survivors, galectin-3 levels strongly correlating with a neutrophil signature in the ETAs and a prognostically favorable hypoinflammatory plasma biomarker subphenotype. Taken together, our study provides impetus for harnessing the potential of galectin-3-expressing neutrophils to protect from lethal infections and respiratory failure.
    DOI:  https://doi.org/10.1038/s41467-024-48796-y
  49. Nat Commun. 2024 Jun 04. 15(1): 4764
    Bacteriophage defends murine gut from Escherichia coli invasion via mucosal adherence.
    Jiaoling Wu, Kailai Fu, Chenglin Hou, Yuxin Wang, Chengyuan Ji, Feng Xue, Jianluan Ren, Jianjun Dai, Jeremy J Barr, Fang Tang.
      Bacteriophage are sophisticated cellular parasites that can not only parasitize bacteria but are increasingly recognized for their direct interactions with mammalian hosts. Phage adherence to mucus is known to mediate enhanced antimicrobial effects in vitro. However, little is known about the therapeutic efficacy of mucus-adherent phages in vivo. Here, using a combination of in vitro gastrointestinal cell lines, a gut-on-a-chip microfluidic model, and an in vivo murine gut model, we demonstrated that a E. coli phage, øPNJ-6, provided enhanced gastrointestinal persistence and antimicrobial effects. øPNJ-6 bound fucose residues, of the gut secreted glycoprotein MUC2, through domain 1 of its Hoc protein, which led to increased intestinal mucus production that was suggestive of a positive feedback loop mediated by the mucus-adherent phage. These findings extend the Bacteriophage Adherence to Mucus model into phage therapy, demonstrating that øPNJ-6 displays enhanced persistence within the murine gut, leading to targeted depletion of intestinal pathogenic bacteria.
    DOI:  https://doi.org/10.1038/s41467-024-48560-2
  50. Cell. 2024 Jun 06. pii: S0092-8674(24)00471-9. [Epub ahead of print]187(12): 2898-2900
    On mechanical phase and form.
    Windie Höfs, Sara A Wickström.
      Epithelial folding is a fundamental biological process that requires epithelial interactions with the underlying mesenchyme. In this issue of Cell, Huycke et al. investigate intestinal villus formation. They discover that water-droplet-like behavior of mesenchymal cells drives their coalescence into uniformly patterned aggregates, which generate forces on the epithelium to initiate folding.
    DOI:  https://doi.org/10.1016/j.cell.2024.04.045
  51. Nat Commun. 2024 Jun 01. 15(1): 4677
    Diffusion-based deep learning method for augmenting ultrastructural imaging and volume electron microscopy.
    Chixiang Lu, Kai Chen, Heng Qiu, Xiaojun Chen, Gu Chen, Xiaojuan Qi, Haibo Jiang.
      Electron microscopy (EM) revolutionized the way to visualize cellular ultrastructure. Volume EM (vEM) has further broadened its three-dimensional nanoscale imaging capacity. However, intrinsic trade-offs between imaging speed and quality of EM restrict the attainable imaging area and volume. Isotropic imaging with vEM for large biological volumes remains unachievable. Here, we developed EMDiffuse, a suite of algorithms designed to enhance EM and vEM capabilities, leveraging the cutting-edge image generation diffusion model. EMDiffuse generates realistic predictions with high resolution ultrastructural details and exhibits robust transferability by taking only one pair of images of 3 megapixels to fine-tune in denoising and super-resolution tasks. EMDiffuse also demonstrated proficiency in the isotropic vEM reconstruction task, generating isotropic volume even in the absence of isotropic training data. We demonstrated the robustness of EMDiffuse by generating isotropic volumes from seven public datasets obtained from different vEM techniques and instruments. The generated isotropic volume enables accurate three-dimensional nanoscale ultrastructure analysis. EMDiffuse also features self-assessment functionalities on predictions' reliability. We envision EMDiffuse to pave the way for investigations of the intricate subcellular nanoscale ultrastructure within large volumes of biological systems.
    DOI:  https://doi.org/10.1038/s41467-024-49125-z
  52. Nature. 2024 Jun 05.
    Senescent glia link mitochondrial dysfunction and lipid accumulation.
    China N Byrns, Alexandra E Perlegos, Karl N Miller, Zhecheng Jin, Faith R Carranza, Palak Manchandra, Connor H Beveridge, Caitlin E Randolph, V Sai Chaluvadi, Shirley L Zhang, Ananth R Srinivasan, F C Bennett, Amita Sehgal, Peter D Adams, Gaurav Chopra, Nancy M Bonini.
      Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.
    DOI:  https://doi.org/10.1038/s41586-024-07516-8
  53. Nat Rev Mol Cell Biol. 2024 Jun 03.
    SenNet recommendations for detecting senescent cells in different tissues.
    Vidyani Suryadevara, Adam D Hudgins, Adarsh Rajesh, Alberto Pappalardo, Alla Karpova, Amit K Dey, Ann Hertzel, Anthony Agudelo, Azucena Rocha, Bikem Soygur, Birgit Schilling, Chase M Carver, Cristina Aguayo-Mazzucato, Darren J Baker, David A Bernlohr, Diana Jurk, Dilyana B Mangarova, Ellen M Quardokus, Elizabeth Ann L Enninga, Elizabeth L Schmidt, Feng Chen, Francesca E Duncan, Francesco Cambuli, Gagandeep Kaur, George A Kuchel, Gung Lee, Heike E Daldrup-Link, Helene Martini, Hemali Phatnani, Iman M Al-Naggar, Irfan Rahman, Jia Nie, João F Passos, Jonathan C Silverstein, Judith Campisi, Julia Wang, Kanako Iwasaki, Karina Barbosa, Kay Metis, Kerem Nernekli, Laura J Niedernhofer, Li Ding, Lichao Wang, Lisa C Adams, Liu Ruiyang, Madison L Doolittle, Marcos G Teneche, Marissa J Schafer, Ming Xu, Mohammadjavad Hajipour, Mozhgan Boroumand, Nathan Basisty, Nicholas Sloan, Nikolai Slavov, Olena Kuksenko, Paul Robson, Paul T Gomez, Periklis Vasilikos, Peter D Adams, Priscila Carapeto, Quan Zhu, Ramalakshmi Ramasamy, Rolando Perez-Lorenzo, Rong Fan, Runze Dong, Ruth R Montgomery, Sadiya Shaikh, Sanja Vickovic, Shanshan Yin, Shoukai Kang, Sonja Suvakov, Sundeep Khosla, Vesna D Garovic, Vilas Menon, Yanxin Xu, Yizhe Song, Yousin Suh, Zhixun Dou, Nicola Neretti.
      Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.
    DOI:  https://doi.org/10.1038/s41580-024-00738-8
  54. Nat Neurosci. 2024 Jun;27(6): 1039
    Voluntary imaging goes magnetic.
    Luis A Mejia.
      
    DOI:  https://doi.org/10.1038/s41593-024-01687-3
  55. Nat Commun. 2024 Jun 07. 15(1): 4890
    Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression.
    Ruo-Han Hao, Tian-Pei Zhang, Feng Jiang, Jun-Hui Liu, Shan-Shan Dong, Meng Li, Yan Guo, Tie-Lin Yang.
      The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.
    DOI:  https://doi.org/10.1038/s41467-024-49263-4
  56. Nat Cell Biol. 2024 Jun 07.
    Extraembryonic gut endoderm cells undergo programmed cell death during development.
    Julia Batki, Sara Hetzel, Dennis Schifferl, Adriano Bolondi, Maria Walther, Lars Wittler, Stefanie Grosswendt, Bernhard G Herrmann, Alexander Meissner.
      Despite a distinct developmental origin, extraembryonic cells in mice contribute to gut endoderm and converge to transcriptionally resemble their embryonic counterparts. Notably, all extraembryonic progenitors share a non-canonical epigenome, raising several pertinent questions, including whether this landscape is reset to match the embryonic regulation and if extraembryonic cells persist into later development. Here we developed a two-colour lineage-tracing strategy to track and isolate extraembryonic cells over time. We find that extraembryonic gut cells display substantial memory of their developmental origin including retention of the original DNA methylation landscape and resulting transcriptional signatures. Furthermore, we show that extraembryonic gut cells undergo programmed cell death and neighbouring embryonic cells clear their remnants via non-professional phagocytosis. By midgestation, we no longer detect extraembryonic cells in the wild-type gut, whereas they persist and differentiate further in p53-mutant embryos. Our study provides key insights into the molecular and developmental fate of extraembryonic cells inside the embryo.
    DOI:  https://doi.org/10.1038/s41556-024-01431-w
  57. Nature. 2024 Jun 05.
    Opioid drugs drive electrical insulation of reward circuitry.
      
    Keywords:  Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-01630-3
  58. Nat Commun. 2024 Jun 06. 15(1): 4710
    A single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD).
    Cankun Wang, Diana Acosta, Megan McNutt, Jiang Bian, Anjun Ma, Hongjun Fu, Qin Ma.
      Alzheimer's Disease (AD) pathology has been increasingly explored through single-cell and single-nucleus RNA-sequencing (scRNA-seq & snRNA-seq) and spatial transcriptomics (ST). However, the surge in data demands a comprehensive, user-friendly repository. Addressing this, we introduce a single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD). It offers a broader spectrum of AD-related datasets, an optimized analytical pipeline, and improved usability. The database encompasses 1,053 samples (277 integrated datasets) from 67 AD-related scRNA-seq & snRNA-seq studies, totaling 7,332,202 cells. Additionally, it archives 381 ST datasets from 18 human and mouse brain studies. Each dataset is annotated with details such as species, gender, brain region, disease/control status, age, and AD Braak stages. ssREAD also provides an analysis suite for cell clustering, identification of differentially expressed and spatially variable genes, cell-type-specific marker genes and regulons, and spot deconvolution for integrative analysis. ssREAD is freely available at https://bmblx.bmi.osumc.edu/ssread/ .
    DOI:  https://doi.org/10.1038/s41467-024-49133-z
  59. Nature. 2024 Jun 06.
    Do scientists make good presidents? How five national leaders performed.
    Smriti Mallapaty, Jeff Tollefson, Carissa Wong.
      
    Keywords:  Government; Policy; Politics
    DOI:  https://doi.org/10.1038/d41586-024-01693-2
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