bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–09–29
48 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Identifying genetic variants that influence the abundance of cell states in single-cell data.
  2. Inflammatory blood clots.
  3. Mitochondrial tonic for adoptive T cell therapies.
  4. The lipooligosaccharide of the gut symbiont Akkermansia muciniphila exhibits a remarkable structure and TLR signaling capacity.
  5. Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.
  6. HDAC3 integrates TGF-β and microbial cues to program tuft cell biogenesis and diurnal rhythms in mucosal immune surveillance.
  7. A hierarchical atlas of the human cerebellum for functional precision mapping.
  8. Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
  9. Massively parallel characterization of insulator activity across the genome.
  10. IRF8 as durable architect of the microglial chromatin landscape.
  11. Crinophagic granules in pancreatic β cells contribute to mouse autoimmune diabetes by diversifying pathogenic epitope repertoire.
  12. Why do obesity drugs seem to treat so many other ailments?
  13. Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.
  14. Genome-wide impact of codon usage bias on translation optimization in Drosophila melanogaster.
  15. Stem cells reverse woman's diabetes - a world first.
  16. Gender inequity persists among journal chief editors.
  17. Harassed? Intimidated? Guidebook offers help to scientists under attack.
  18. The human heart shows signs of ageing after just a month in space.
  19. Revolutionary drug for schizophrenia wins US approval.
  20. Single-cell multi-omics map of human fetal blood in Down syndrome.
  21. Structural basis of ligand recognition and activation of the histamine receptor family.
  22. Understanding species-specific and conserved RNA-protein interactions in vivo and in vitro.
  23. Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development.
  24. Predicting the heat release variability of Li-ion cells under thermal runaway with few or no calorimetry data.
  25. 'Substandard and unworthy': why it's time to banish bad-mannered reviews.
  26. A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.
  27. Food for thought: The molecular basis of nutrient uptake into the brain.
  28. CD5L associates with IgM via the J chain.
  29. Pain: recognizing the power of non-pharmaceutical interventions.
  30. Learning from inborn errors.
  31. Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient.
  32. Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity.
  33. IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs.
  34. Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
  35. Introducing synthetic thermostable RNase inhibitors to single-cell RNA-seq.
  36. Scientists are building giant 'evidence banks' to create policies that actually work.
  37. SpaTopic: A statistical learning framework for exploring tumor spatial architecture from spatially resolved transcriptomic data.
  38. How pain is misunderstood and ignored in women.
  39. Microbial transformation of dietary xenobiotics shapes gut microbiome composition.
  40. Daily briefing: What is a cell type, really?
  41. Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation.
  42. The gut microbiome and chronic pain.
  43. An inhibitory PRR reels in the neutrophil response to NETs.
  44. Recreating immune and epithelial interactions in organoids.
  45. Sprayable anti-adhesive hydrogel for peritoneal macrophage scavenging in post-surgical applications.
  46. Data integrity concerns flagged in 130 women's health papers - all by one co-author.
  47. Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition.
  48. Molecular architecture of the mammalian 2-oxoglutarate dehydrogenase complex.
  1. Nat Genet. 2024 Sep 26.
    Identifying genetic variants that influence the abundance of cell states in single-cell data.
    Laurie Rumker, Saori Sakaue, Yakir Reshef, Joyce B Kang, Seyhan Yazar, Jose Alquicira-Hernandez, Cristian Valencia, Kaitlyn A Lagattuta, Annelise Mah-Som, Aparna Nathan, Joseph E Powell, Po-Ru Loh, Soumya Raychaudhuri.
      Disease risk alleles influence the composition of cells present in the body, but modeling genetic effects on the cell states revealed by single-cell profiling is difficult because variant-associated states may reflect diverse combinations of the profiled cell features that are challenging to predefine. We introduce Genotype-Neighborhood Associations (GeNA), a statistical tool to identify cell-state abundance quantitative trait loci (csaQTLs) in high-dimensional single-cell datasets. Instead of testing associations to predefined cell states, GeNA flexibly identifies the cell states whose abundance is most associated with genetic variants. In a genome-wide survey of single-cell RNA sequencing peripheral blood profiling from 969 individuals, GeNA identifies five independent loci associated with shifts in the relative abundance of immune cell states. For example, rs3003-T (P = 1.96 × 10-11) associates with increased abundance of natural killer cells expressing tumor necrosis factor response programs. This csaQTL colocalizes with increased risk for psoriasis, an autoimmune disease that responds to anti-tumor necrosis factor treatments. Flexibly characterizing csaQTLs for granular cell states may help illuminate how genetic background alters cellular composition to confer disease risk.
    DOI:  https://doi.org/10.1038/s41588-024-01909-1
  2. Nat Immunol. 2024 Oct;25(10): 1771
    Inflammatory blood clots.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-024-01980-0
  3. Nat Rev Immunol. 2024 Sep 20.
    Mitochondrial tonic for adoptive T cell therapies.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01095-5
  4. Nat Commun. 2024 Sep 27. 15(1): 8411
    The lipooligosaccharide of the gut symbiont Akkermansia muciniphila exhibits a remarkable structure and TLR signaling capacity.
    Pilar Garcia-Vello, Hanne L P Tytgat, Janneke Elzinga, Matthias Van Hul, Hubert Plovier, Marta Tiemblo-Martin, Patrice D Cani, Simone Nicolardi, Marco Fragai, Cristina De Castro, Flaviana Di Lorenzo, Alba Silipo, Antonio Molinaro, Willem M de Vos.
      The cell-envelope of Gram-negative bacteria contains endotoxic lipopolysaccharides (LPS) that are recognized by the innate immune system via Toll-Like Receptors (TLRs). The intestinal mucosal symbiont Akkermansia muciniphila is known to confer beneficial effects on the host and has a Gram-negative architecture. Here we show that A. muciniphila LPS lacks the O-polysaccharide repeating unit, with the resulting lipooligosaccharide (LOS) having unprecedented structural and signaling properties. The LOS consists of a complex glycan chain bearing two distinct undeca- and hexadecasaccharide units each containing three 2-keto-3-deoxy-D-manno-octulosonic acid (Kdo) residues. The lipid A moiety appears as a mixture of differently phosphorylated and acylated species and carries either linear or branched acyl moieties. Peritoneal injection of the LOS in mice increased higher gene expression of liver TLR2 than TLR4 (100-fold) and induced high IL-10 gene expression. A. muciniphila LOS was found to signal both through TLR4 and TLR2, whereas lipid A only induced TLR2 in a human cell line. We propose that the unique structure of the A. muciniphila LOS allows interaction with TLR2, thus generating an anti-inflammatory response as to compensate for the canonical inflammatory signaling associated with LOS and TLR4, rationalizing its beneficial host interaction.
    DOI:  https://doi.org/10.1038/s41467-024-52683-x
  5. Nat Metab. 2024 Sep 27.
    Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.
    Sandeep Das, Alexandra C Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H Pearson-Gallion, M Peyton McKinney, Koral S E Richard, Jose A Gomez-Vidal, Chowdhury S Abdullah, Elizabeth D Cockerham, Joseph Eniafe, Andrew D Yurochko, Tarek Magdy, Christopher B Pattillo, Christopher G Kevil, Babak Razani, Md Shenuarin Bhuiyan, Erin H Seeley, Gretchen E Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T Garcia-Barrio, Philip L Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y Eugene Chen, Nirav Dhanesha, Paul T Thevenot, Ari J Cohen, Arif Yurdagul, Oren Rom.
      The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.
    DOI:  https://doi.org/10.1038/s42255-024-01134-4
  6. Sci Immunol. 2024 Sep 27. 9(99): eadk7387
    HDAC3 integrates TGF-β and microbial cues to program tuft cell biogenesis and diurnal rhythms in mucosal immune surveillance.
    Jianglin Zhang, Guoxun Wang, Junjie Ma, Yiran Duan, Samskrathi A Sharma, Sarah Oladejo, Xianda Ma, Giselle Arellano, Robert C Orchard, Tiffany A Reese, Zheng Kuang.
      The intestinal mucosal surface is directly exposed to daily fluctuations in food and microbes driven by 24-hour light and feeding cycles. Intestinal epithelial tuft cells are key sentinels that surveil the gut luminal environment, but how these cells are diurnally programmed remains unknown. Here, we show that histone deacetylase 3 (HDAC3) controls tuft cell specification and the diurnal rhythm of its biogenesis, which is regulated by the gut microbiota and feeding schedule. Disruption of epithelial HDAC3 decreases tuft cell numbers, impairing antihelminth immunity and norovirus infection. Mechanistically, HDAC3 functions noncanonically to activate transforming growth factor-β (TGF-β) signaling, which promotes rhythmic expression of Pou2f3, a lineage-defining transcription factor of tuft cells. Our findings reveal an environmental-epigenetic link that controls the diurnal differentiation of tuft cells and promotes rhythmic mucosal surveillance and immune responses in anticipation of exogenous challenges.
    DOI:  https://doi.org/10.1126/sciimmunol.adk7387
  7. Nat Commun. 2024 Sep 27. 15(1): 8376
    A hierarchical atlas of the human cerebellum for functional precision mapping.
    Caroline Nettekoven, Da Zhi, Ladan Shahshahani, Ana Luísa Pinho, Noam Saadon-Grosman, Randy Lee Buckner, Jörn Diedrichsen.
      The human cerebellum is activated by a wide variety of cognitive and motor tasks. Previous functional atlases have relied on single task-based or resting-state fMRI datasets. Here, we present a functional atlas that integrates information from seven large-scale datasets, outperforming existing group atlases. The atlas has three further advantages. First, the atlas allows for precision mapping in individuals: the integration of the probabilistic group atlas with an individual localizer scan results in a marked improvement in prediction of individual boundaries. Second, we provide both asymmetric and symmetric versions of the atlas. The symmetric version, which is obtained by constraining the boundaries to be the same across hemispheres, is especially useful in studying functional lateralization. Finally, the regions are hierarchically organized across three levels, allowing analyses at the appropriate level of granularity. Overall, the present atlas is an important resource for the study of the interdigitated functional organization of the human cerebellum in health and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52371-w
  8. Nat Commun. 2024 Sep 27. 15(1): 8301
    Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
    Katherine Labbé, Lauren LeBon, Bryan King, Ngoc Vu, Emily H Stoops, Nina Ly, Austin E Y T Lefebvre, Phillip Seitzer, Swathi Krishnan, Jin-Mi Heo, Bryson Bennett, Carmela Sidrauski.
      The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.
    DOI:  https://doi.org/10.1038/s41467-024-52538-5
  9. Nat Commun. 2024 Sep 27. 15(1): 8350
    Massively parallel characterization of insulator activity across the genome.
    Clarice K Y Hong, Yawei Wu, Alyssa A Erickson, Jie Li, Arnold J Federico, Barak A Cohen.
      A key question in regulatory genomics is whether cis-regulatory elements (CREs) are modular elements that can function anywhere in the genome, or whether they are adapted to certain genomic locations. To distinguish between these possibilities we develop MPIRE (Massively Parallel Integrated Regulatory Elements), a technology for recurrently assaying CREs at thousands of defined locations across the genome in parallel. MPIRE allows us to separate the intrinsic activity of CREs from the effects of their genomic environments. We apply MPIRE to assay three insulator sequences at thousands of genomic locations and find that each insulator functions in locations with distinguishable properties. All three insulators can block enhancers, but each insulator blocks specific enhancers at specific locations. However, only ALOXE3 appears to block heterochromatin silencing. We conclude that insulator function is highly context dependent and that MPIRE is a robust method for revealing the context dependencies of CREs.
    DOI:  https://doi.org/10.1038/s41467-024-52599-6
  10. Nat Immunol. 2024 Oct;25(10): 1784-1786
    IRF8 as durable architect of the microglial chromatin landscape.
    Maximilian Frosch, Marco Prinz.
      
    DOI:  https://doi.org/10.1038/s41590-024-01965-z
  11. Nat Commun. 2024 Sep 27. 15(1): 8318
    Crinophagic granules in pancreatic β cells contribute to mouse autoimmune diabetes by diversifying pathogenic epitope repertoire.
    Hao Hu, Anthony N Vomund, Orion J Peterson, Neetu Srivastava, Tiandao Li, Lisa Kain, Wandy L Beatty, Bo Zhang, Chyi-Song Hsieh, Luc Teyton, Cheryl F Lichti, Emil R Unanue, Xiaoxiao Wan.
      Autoimmune attack toward pancreatic β cells causes permanent loss of glucose homeostasis in type 1 diabetes (T1D). Insulin secretory granules store and secrete insulin but are also thought to be tissue messengers for T1D. Here, we show that the crinophagic granules (crinosome), a minor set of vesicles formed by fusing lysosomes with the conventional insulin dense-core granules (DCG), are pathogenic in T1D development in mouse models. Pharmacological inhibition of crinosome formation in β cells delays T1D progression without affecting the dominant DCGs. Mechanistically, crinophagy inhibition diminishes the epitope repertoire in pancreatic islets, including cryptic, modified and disease-relevant epitopes derived from insulin. These unconventional insulin epitopes are largely undetectable in the MHC-II epitope repertoire of the thymus, where only canonical insulin epitopes are presented. CD4+ T cells targeting unconventional insulin epitopes display autoreactive phenotypes, unlike tolerized T cells recognizing epitopes presented in the thymus. Thus, the crinophagic pathway emerges as a tissue-intrinsic mechanism that transforms insulin from a signature thymic self-protein to a critical autoantigen by creating a peripheral-thymic mismatch in the epitope repertoire.
    DOI:  https://doi.org/10.1038/s41467-024-52619-5
  12. Nature. 2024 Sep;633(8031): 758-760
    Why do obesity drugs seem to treat so many other ailments?
    Mariana Lenharo.
      
    Keywords:  Brain; Drug discovery; Neuroscience; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-03074-1
  13. Nat Commun. 2024 Sep 27. 15(1): 8390
    Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.
    Yuqin Wu, Ashish Foollee, Andrea Y Chan, Susanne Hille, Jana Hauke, Matthew P Challis, Jared L Johnson, Tomer M Yaron, Victoria Mynard, Okka H Aung, Maria Almira S Cleofe, Cheng Huang, Terry C C Lim Kam Sian, Mohammad Rahbari, Suchira Gallage, Mathias Heikenwalder, Lewis C Cantley, Ralf B Schittenhelm, Luke E Formosa, Greg C Smith, Jürgen G Okun, Oliver J Müller, Patricia M Rusu, Adam J Rose.
      The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. Through pathway analysis of the thousands of phosphopeptides identified, we reveal "membrane trafficking" as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments reveal that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identify several protein binding partners of SEC22B affected by glucagon, some of which were differentially enriched with SEC22B-S137 phosphorylation. In summary, we demonstrate that phosphorylation of SEC22B is a hepatocellular signaling node mediating the metabolic actions of glucagon and provide a rich resource for future investigations on the biology of glucagon action.
    DOI:  https://doi.org/10.1038/s41467-024-52703-w
  14. Nat Commun. 2024 Sep 27. 15(1): 8329
    Genome-wide impact of codon usage bias on translation optimization in Drosophila melanogaster.
    Xinkai Wu, Mengze Xu, Jian-Rong Yang, Jian Lu.
      Accuracy and efficiency are fundamental to mRNA translation. Codon usage bias is widespread across species. Despite the long-standing association between optimized codon usage and improved translation, our understanding of its evolutionary basis and functional effects remains limited. Drosophila is widely used to study codon usage bias, but genome-scale experimental data are scarce. Using high-resolution mass spectrometry data from Drosophila melanogaster, we show that optimal codons have lower translation errors than nonoptimal codons after accounting for these biases. Genomic-scale analysis of ribosome profiling data shows that optimal codons are translated more rapidly than nonoptimal codons. Although we find no long-term selection favoring synonymous mutations in D. melanogaster after diverging from D. simulans, we identify signatures of positive selection driving codon optimization in the D. melanogaster population. These findings expand our understanding of the functional consequences of codon optimization and serve as a foundation for future investigations.
    DOI:  https://doi.org/10.1038/s41467-024-52660-4
  15. Nature. 2024 Sep 26.
    Stem cells reverse woman's diabetes - a world first.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Diabetes; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-03129-3
  16. Nature. 2024 Sep;633(8031): 770
    Gender inequity persists among journal chief editors.
    M Hossein Nowroozzadeh, Somaye Tafraghe.
      
    Keywords:  Publishing; Research management; Society
    DOI:  https://doi.org/10.1038/d41586-024-03121-x
  17. Nature. 2024 Sep 20.
    Harassed? Intimidated? Guidebook offers help to scientists under attack.
    Jeff Tollefson.
      
    Keywords:  Communication; Politics; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03104-y
  18. Nature. 2024 Sep 24.
    The human heart shows signs of ageing after just a month in space.
    Gemma Conroy.
      
    Keywords:  Cardiovascular biology; Cell biology; Space physics
    DOI:  https://doi.org/10.1038/d41586-024-03105-x
  19. Nature. 2024 Sep 27.
    Revolutionary drug for schizophrenia wins US approval.
    Elie Dolgin.
      
    Keywords:  Drug discovery; Medical research; Psychiatric disorders; Schizophrenia
    DOI:  https://doi.org/10.1038/d41586-024-03123-9
  20. Nature. 2024 Sep 25.
    Single-cell multi-omics map of human fetal blood in Down syndrome.
    Andrew R Marderstein, Marco De Zuani, Rebecca Moeller, Jon Bezney, Evin M Padhi, Shuo Wong, Tim H H Coorens, Yilin Xie, Haoliang Xue, Stephen B Montgomery, Ana Cvejic.
      Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood1-3. Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are 'primed' to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress4,5, we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions.
    DOI:  https://doi.org/10.1038/s41586-024-07946-4
  21. Nat Commun. 2024 Sep 27. 15(1): 8296
    Structural basis of ligand recognition and activation of the histamine receptor family.
    Xuan Zhang, Guibing Liu, Ya-Ni Zhong, Ru Zhang, Chuan-Cheng Yang, Canyang Niu, Xuanyu Pu, Jingjing Sun, Tianyao Zhang, Lejin Yang, Chao Zhang, Xiu Li, Xinyuan Shen, Peng Xiao, Jin-Peng Sun, Weimin Gong.
      Histamine is a biogenic amine that is critical in various physiological and pathophysiological processes, including but not limited to allergic reactions, wakefulness, gastric acid secretion and neurotransmission. Here, we determine 9 cryo-electron microscopy (cryo-EM) structures of the 4 histamine receptors in complex with four different G protein subtypes, with endogenous or synthetic agonists bound. Inside the ligand pocket, we identify key motifs for the recognition of histamine, the distinct binding orientations of histamine and three subpockets that facilitate the design of specific ligands. In addition, we also identify key residues responsible for the selectivity of immethridine. Moreover, we reveal distinct structural features as determinants of Gq vs. Gs or Gs vs. Gi coupling differences among the histamine receptors. Our study provides a structural framework for understanding the ligand recognition and G protein coupling of all 4 histamine receptors, which may facilitate the rational design of ligands targeting these receptors.
    DOI:  https://doi.org/10.1038/s41467-024-52585-y
  22. Nat Commun. 2024 Sep 27. 15(1): 8400
    Understanding species-specific and conserved RNA-protein interactions in vivo and in vitro.
    Sarah E Harris, Maria S Alexis, Gilbert Giri, Francisco F Cavazos, Yue Hu, Jernej Murn, Maria M Aleman, Christopher B Burge, Daniel Dominguez.
      While evolution is often considered from a DNA- and protein-centric view, RNA-based regulation can also impact gene expression and protein sequences. Here we examine interspecies differences in RNA-protein interactions using the conserved neuronal RNA-binding protein, Unkempt (UNK) as model. We find that roughly half of mRNAs bound in human are also bound in mouse. Unexpectedly, even when transcript-level binding was conserved across species differential motif usage was prevalent. To understand the biochemical basis of UNK-RNA interactions, we reconstitute the human and mouse UNK-RNA interactomes using a high-throughput biochemical assay. We uncover detailed features driving binding, show that in vivo patterns are captured in vitro, find that highly conserved sites are the strongest bound, and associate binding strength with downstream regulation. Furthermore, subtle sequence differences surrounding motifs are key determinants of species-specific binding. We highlight the complex features driving protein-RNA interactions and how these evolve to confer species-specific regulation.
    DOI:  https://doi.org/10.1038/s41467-024-52231-7
  23. Nat Commun. 2024 Sep 27. 15(1): 8341
    Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development.
    Rebecca Fima, Sébastien Dussaud, Cheïma Benbida, Margault Blanchet, François Lanthiez, Lucie Poupel, Claudia Brambilla, Adélaïde Gélineau, Mattia Dessena, Marina Blanc, Cédric Lerévérend, Martine Moreau, Alexandre Boissonnas, Emmanuel L Gautier, Thierry Huby.
      Hypercholesterolemia is a major risk factor for atherosclerosis and associated cardiovascular diseases. The liver plays a key role in the regulation of plasma cholesterol levels and hosts a large population of tissue-resident macrophages known as Kupffer cells (KCs). KCs are located in the hepatic sinusoids where they ensure key functions including blood immune surveillance. However, how KCs homeostasis is affected by the build-up of cholesterol-rich lipoproteins that occurs in the circulation during hypercholesterolemia remains unknown. Here, we show that embryo-derived KCs (EmKCs) accumulate large amounts of lipoprotein-derived cholesterol, in part through the scavenger receptor CD36, and massively expand early after the induction of hypercholesterolemia. After this rapid adaptive response, EmKCs exhibit mitochondrial oxidative stress and their numbers gradually diminish while monocyte-derived KCs (MoKCs) with reduced cholesterol-loading capacities seed the KC pool. Decreased proportion of EmKCs in the KC pool enhances liver cholesterol content and exacerbates hypercholesterolemia, leading to accelerated atherosclerotic plaque development. Together, our data reveal that KC homeostasis is perturbed during hypercholesterolemia, which in turn alters the control of plasma cholesterol levels and increases atherosclerosis.
    DOI:  https://doi.org/10.1038/s41467-024-52735-2
  24. Nat Commun. 2024 Sep 27. 15(1): 8399
    Predicting the heat release variability of Li-ion cells under thermal runaway with few or no calorimetry data.
    Karina Masalkovaitė, Paul Gasper, Donal P Finegan.
      Accurate measurement of the variability of thermal runaway behavior of lithium-ion cells is critical for designing safe battery systems. However, experimentally determining such variability is challenging, expensive, and time-consuming. Here, we utilize a transfer learning approach to accurately estimate the variability of heat output during thermal runaway using only ejected mass measurements and cell metadata, leveraging 139 calorimetry measurements on commercial lithium-ion cells available from the open-access Battery Failure Databank. We show that the distribution of heat output, including outliers, can be predicted accurately and with high confidence for new cell types using just 0 to 5 calorimetry measurements by leveraging behaviors learned from the Battery Failure Databank. Fractional heat ejection from the positive vent, cell body, and negative vent are also accurately predicted. We demonstrate that by using low cost and fast measurements, we can predict the variability in thermal behaviors of cells, thus accelerating critical safety characterization efforts.
    DOI:  https://doi.org/10.1038/s41467-024-52653-3
  25. Nature. 2024 Sep 23.
    'Substandard and unworthy': why it's time to banish bad-mannered reviews.
    Jane Feinmann.
      
    Keywords:  Authorship; Careers; Peer review; Physics; Publishing
    DOI:  https://doi.org/10.1038/d41586-024-02943-z
  26. Nat Commun. 2024 Sep 27. 15(1): 8268
    A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.
    Arthur S Lee, Lauren J Ayers, Michael Kosicki, Wai-Man Chan, Lydia N Fozo, Brandon M Pratt, Thomas E Collins, Boxun Zhao, Matthew F Rose, Alba Sanchis-Juan, Jack M Fu, Isaac Wong, Xuefang Zhao, Alan P Tenney, Cassia Lee, Kristen M Laricchia, Brenda J Barry, Victoria R Bradford, Julie A Jurgens, Eleina M England, Monkol Lek, Daniel G MacArthur, Eunjung Alice Lee, Michael E Talkowski, Harrison Brand, Len A Pennacchio, Elizabeth C Engle.
      Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.
    DOI:  https://doi.org/10.1038/s41467-024-52463-7
  27. Science. 2024 Sep 27. 385(6716): 1429
    Food for thought: The molecular basis of nutrient uptake into the brain.
    Rosemary J Cater.
      The molecular basis of nutrient uptake into the brain.
    DOI:  https://doi.org/10.1126/science.ads1320
  28. Nat Commun. 2024 Sep 27. 15(1): 8397
    CD5L associates with IgM via the J chain.
    Yuxin Wang, Chen Su, Chenggong Ji, Junyu Xiao.
      CD5 antigen-like (CD5L), also known as Spα or AIM (Apoptosis inhibitor of macrophage), emerges as an integral component of serum immunoglobulin M (IgM). However, the molecular mechanism underlying the interaction between IgM and CD5L has remained elusive. In this study, we present a cryo-electron microscopy structure of the human IgM pentamer core in complex with CD5L. Our findings reveal that CD5L binds to the joining chain (J chain) in a Ca2+-dependent manner and further links to IgM via a disulfide bond. We further corroborate recently published data that CD5L reduces IgM binding to the mucosal transport receptor pIgR, but does not impact the binding of the IgM-specific receptor FcμR. Additionally, CD5L does not interfere with IgM-mediated complement activation. These results offer a more comprehensive understanding of IgM and shed light on the function of the J chain in the immune system.
    DOI:  https://doi.org/10.1038/s41467-024-52175-y
  29. Nature. 2024 Sep;633(8031): S25
    Pain: recognizing the power of non-pharmaceutical interventions.
    Herb Brody.
      
    Keywords:  Health care; Neuroscience; Personalized medicine
    DOI:  https://doi.org/10.1038/d41586-024-03002-3
  30. Nat Immunol. 2024 Oct;25(10): 1771
    Learning from inborn errors.
    Stephanie A Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-01981-z
  31. Cell. 2024 Sep 20. pii: S0092-8674(24)01022-5. [Epub ahead of print]
    Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient.
    Shusen Wang, Yuanyuan Du, Boya Zhang, Gaofan Meng, Zewen Liu, Soon Yi Liew, Rui Liang, Zhengyuan Zhang, Xiangheng Cai, Shuangshuang Wu, Wei Gao, Dewei Zhuang, Jiaqi Zou, Hui Huang, Mingyang Wang, Xiaofeng Wang, Xuelian Wang, Ting Liang, Tengli Liu, Jiabin Gu, Na Liu, Yanling Wei, Xuejie Ding, Yue Pu, Yixiang Zhan, Yu Luo, Peng Sun, Shuangshuang Xie, Jiuxia Yang, Yiqi Weng, Chunlei Zhou, Zhenglu Wang, Shuang Wang, Hongkui Deng, Zhongyang Shen.
      We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.
    Keywords:  abdominal anterior rectus sheath; cell therapy; chemical reprogramming; chemically induced pluripotent stem cells; diabetes; insulin independence; islet transplantation; personalized medicine; regenerative medicine; stem-cell-derived islets
    DOI:  https://doi.org/10.1016/j.cell.2024.09.004
  32. J Exp Med. 2024 Oct 07. pii: e20231193. [Epub ahead of print]221(10):
    Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity.
    Deeksha Deep, Herman Gudjonson, Chrysothemis C Brown, Samuel A Rose, Roshan Sharma, Yoselin A Paucar Iza, Seunghee Hong, Saskia Hemmers, Michail Schizas, Zhong-Min Wang, Yuezhou Chen, Duane R Wesemann, Virginia Pascual, Dana Pe'er, Alexander Y Rudensky.
      Upon antigenic stimulation, naïve CD4+ T cells can give rise to phenotypically distinct effector T helper cells and long-lived memory T cells. We computationally reconstructed the in vivo trajectory of CD4+ T cell differentiation during a type I inflammatory immune response and identified two distinct differentiation paths for effector and precursor central memory T cells arising directly from naïve CD4+ T cells. Unexpectedly, our studies revealed heterogeneity among naïve CD4+ T cells, which are typically considered homogeneous save for their diverse T cell receptor usage. Specifically, a previously unappreciated population of naïve CD4+ T cells sensing environmental type I IFN exhibited distinct activation thresholds, suggesting that naïve CD4+ T cell differentiation potential may be influenced by environmental cues. This population was expanded in human viral infection and type I IFN response-lined autoimmunity. Understanding the relevance of naïve T cell heterogeneity to beneficial and maladaptive T cell responses may have therapeutic implications for adoptive T cell therapies in cancer immunotherapy and vaccination.
    DOI:  https://doi.org/10.1084/jem.20231193
  33. Nat Immunol. 2024 Oct;25(10): 1928-1942
    IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs.
    Keita Saeki, Richard Pan, Eunju Lee, Daisuke Kurotaki, Keiko Ozato.
      Microglia are innate immune cells in the brain. Transcription factor IRF8 (interferon regulatory factor 8) is highly expressed in microglia. However, its role in postnatal microglia development is unknown. We demonstrate that IRF8 binds stepwise to enhancer regions of postnatal microglia along with Sall1 and PU.1, reaching a maximum after day 14. IRF8 binding correlated with a stepwise increase in chromatin accessibility, which preceded the initiation of microglia-specific transcriptome. Constitutive and postnatal Irf8 deletion led to a loss of microglia identity and gain of disease-associated microglia (DAM)-like genes. Combined analysis of single-cell (sc)RNA sequencing and single-cell transposase-accessible chromatin with sequencing (scATAC-seq) revealed a correlation between chromatin accessibility and transcriptome at a single-cell level. IRF8 was also required for microglia-specific DNA methylation patterns. Last, in the 5xFAD model, constitutive and postnatal Irf8 deletion reduced the interaction of microglia with amyloidβ plaques and the size of plaques, lessening neuronal loss. Together, IRF8 sets the epigenetic landscape, which is required for postnatal microglia gene expression.
    DOI:  https://doi.org/10.1038/s41590-024-01962-2
  34. Sci Immunol. 2024 Sep 20. 9(99): eadp3475
    Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
    Darren R Heintzman, Rachael C Sinard, Emilie L Fisher, Xiang Ye, Andrew R Patterson, Joel H Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J Rodriguez-Garcia, Nowrin U Chowdhury, Emily N Arner, Evan S Krystoviak, Frank M Mason, Yasmine T Toudji, KayLee K Steiner, Wasay Khan, Lana M Olson, Angela L Jones, Hanna S Hong, Lindsay Bass, Katherine L Beier, Wentao Deng, Costas A Lyssiotis, Dawn C Newcomb, Alexander G Bick, W Kimryn Rathmell, John T Wilson, Jeffrey C Rathmell.
      Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.
    DOI:  https://doi.org/10.1126/sciimmunol.adp3475
  35. Nat Commun. 2024 Sep 27. 15(1): 8373
    Introducing synthetic thermostable RNase inhibitors to single-cell RNA-seq.
    Joyce Carol Noble, Antonio Lentini, Michael Hagemann-Jensen, Rickard Sandberg, Björn Reinius.
      Single-cell RNA-sequencing (scRNAseq) is revolutionizing biomedicine, propelled by advances in methodology, ease of use, and cost reduction of library preparation. Over the past decade, there have been remarkable technical improvements in most aspects of single-cell transcriptomics. Yet, little to no progress has been made in advancing RNase inhibition despite maintained RNA integrity being critical during cell collection, storage, and cDNA library generation. Here, we demonstrate that a synthetic thermostable RNase inhibitor (SEQURNA) yields single-cell libraries of equal or superior quality compared to ubiquitously used protein-based recombinant RNase inhibitors (RRIs). Importantly, the synthetic RNase inhibitor provides additional unique improvements in reproducibility and throughput, enables new experimental workflows including retained RNase inhibition throughout heat cycles, and can reduce the need for dry-ice transports. In summary, replacing RRIs represents a substantial advancement in the field of single-cell transcriptomics.
    DOI:  https://doi.org/10.1038/s41467-024-52717-4
  36. Nature. 2024 Sep 21.
    Scientists are building giant 'evidence banks' to create policies that actually work.
    Helen Pearson.
      
    Keywords:  Policy; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03100-2
  37. Sci Adv. 2024 Sep 27. 10(39): eadp4942
    SpaTopic: A statistical learning framework for exploring tumor spatial architecture from spatially resolved transcriptomic data.
    Yuelei Zhang, Bianjiong Yu, Wenxuan Ming, Xiaolong Zhou, Jin Wang, Dijun Chen.
      Tumor tissues exhibit a complex spatial architecture within the tumor microenvironment (TME). Spatially resolved transcriptomics (SRT) is promising for unveiling the spatial structures of the TME at both cellular and molecular levels, but identifying pathology-relevant spatial domains remains challenging. Here, we introduce SpaTopic, a statistical learning framework that harmonizes spot clustering and cell-type deconvolution by integrating single-cell transcriptomics and SRT data. Through topic modeling, SpaTopic stratifies the TME into spatial domains with coherent cellular organization, facilitating refined annotation of the spatial architecture with improved performance. We assess SpaTopic across various tumor types and show accurate prediction of tertiary lymphoid structures and tumor boundaries. Moreover, marker genes derived from SpaTopic are transferrable and can be applied to mark spatial domains in other datasets. In addition, SpaTopic enables quantitative comparison and functional characterization of spatial domains across SRT datasets. Overall, SpaTopic presents an innovative analytical framework for exploring, comparing, and interpreting tumor SRT data.
    DOI:  https://doi.org/10.1126/sciadv.adp4942
  38. Nature. 2024 Sep;633(8031): S31-S33
    How pain is misunderstood and ignored in women.
    Bianca Nogrady.
      
    Keywords:  Health care; Neuroscience; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-024-03005-0
  39. Cell. 2024 Sep 19. pii: S0092-8674(24)00967-X. [Epub ahead of print]
    Microbial transformation of dietary xenobiotics shapes gut microbiome composition.
    Elizabeth J Culp, Nora T Nelson, Andrew A Verdegaal, Andrew L Goodman.
      Diet is a major determinant of gut microbiome composition, and variation in diet-microbiome interactions may contribute to variation in their health consequences. To mechanistically understand these relationships, here we map interactions between ∼150 small-molecule dietary xenobiotics and the gut microbiome, including the impacts of these compounds on community composition, the metabolic activities of human gut microbes on dietary xenobiotics, and interindividual variation in these traits. Microbial metabolism can toxify and detoxify these compounds, producing emergent interactions that explain community-specific remodeling by dietary xenobiotics. We identify the gene and enzyme responsible for detoxification of one such dietary xenobiotic, resveratrol, and demonstrate that this enzyme contributes to interindividual variation in community remodeling by resveratrol. Together, these results systematically map interactions between dietary xenobiotics and the gut microbiome and connect toxification and detoxification to interpersonal differences in microbiome response to diet.
    Keywords:  community composition; dietary xenobiotics; emergent interactions; gnotobiotics; microbial metabolism; microbiome
    DOI:  https://doi.org/10.1016/j.cell.2024.08.038
  40. Nature. 2024 Sep 24.
    Daily briefing: What is a cell type, really?
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-03158-y
  41. Nat Commun. 2024 Sep 27. 15(1): 8377
    Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation.
    Shuangshuang Sun, Zhe Xu, Liying He, Yihui Shen, Yuqing Yan, Xubing Lv, Xujing Zhu, Wei Li, Wei-Ya Tian, Yongjun Zheng, Sen Lin, Yadong Sun, Lei Li.
      Posttranslational modifications (PTMs) of tubulin, termed the "tubulin code", play important roles in regulating microtubule functions within subcellular compartments for specialized cellular activities. While numerous tubulin PTMs have been identified, a comprehensive understanding of the complete repertoire is still underway. In this study, we report that α-tubulin lactylation is catalyzed by HDAC6 by using lactate to increase microtubule dynamics in neurons. We identify lactylation on lysine 40 of α-tubulin in the soluble tubulin dimers. Notably, lactylated α-tubulin enhances microtubule dynamics and facilitates neurite outgrowth and branching in cultured hippocampal neurons. Moreover, we discover an unexpected function of HDAC6, acting as the primary lactyltransferase to catalyze α-tubulin lactylation. HDAC6-catalyzed lactylation is a reversible process, dependent on lactate concentrations. Intracellular lactate concentration triggers HDAC6 to lactylate α-tubulin, a process dependent on its deacetylase activity. Additionally, the lactyltransferase activity may be conserved in HDAC family proteins. Our study reveals the primary role of HDAC6 in regulating α-tubulin lactylation, establishing a link between cell metabolism and cytoskeleton functions.
    DOI:  https://doi.org/10.1038/s41467-024-52729-0
  42. Nature. 2024 Sep;633(8031): S34-S36
    The gut microbiome and chronic pain.
    Clare Watson.
      
    Keywords:  Medical research; Microbiology; Microbiome; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-03006-z
  43. Nat Rev Immunol. 2024 Sep 24.
    An inhibitory PRR reels in the neutrophil response to NETs.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-01096-4
  44. Nat Immunol. 2024 Oct;25(10): 1778-1780
    Recreating immune and epithelial interactions in organoids.
    Kevin Man, Axel Kallies.
      
    DOI:  https://doi.org/10.1038/s41590-024-01967-x
  45. Nat Commun. 2024 Sep 27. 15(1): 8364
    Sprayable anti-adhesive hydrogel for peritoneal macrophage scavenging in post-surgical applications.
    Wonmoon Song, Changyub Lee, Haein Jeong, Seoyeon Kim, Nathaniel S Hwang.
      Post-surgical adhesions frequently occur after intra-abdominal surgery, leading to severe complications. Despite the development of various types of adhesion barriers to address post-surgical adhesions, several limitations persist, including off-target localization, handling difficulties, and potential immunogenicity. Here, we report a spray-type adhesion barrier for broad, fast application, forming two sequential networks. The first network is formed by a polyelectrolyte complex of sulfated hyaluronic acid and chitosan, while the second network is established through pluronic® F127 thermogelation. This sprayable barrier served as both a physical protector for the damaged peritoneum and an immunomodulator for peritoneal macrophages, as evidenced its effectiveness in a rat ischemic button model. Taken together, this efficient adhesion barrier presents a promising solution for post-surgical adhesions.
    DOI:  https://doi.org/10.1038/s41467-024-52753-0
  46. Nature. 2024 Sep 25.
    Data integrity concerns flagged in 130 women's health papers - all by one co-author.
    Mariana Lenharo.
      
    Keywords:  Medical research; Publishing; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-02907-3
  47. Nat Cell Biol. 2024 Sep 20.
    Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition.
    Arseniy E Yuzhalin, Frank J Lowery, Yohei Saito, Xiangliang Yuan, Jun Yao, Yimin Duan, Jingzhen Ding, Sunil Acharya, Chenyu Zhang, Abigail Fajardo, Hao-Nien Chen, Yongkun Wei, Yutong Sun, Lin Zhang, Yi Xiao, Ping Li, Philip L Lorenzi, Jason T Huse, Huihui Fan, Zhongming Zhao, Mien-Chie Hung, Dihua Yu.
      Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.
    DOI:  https://doi.org/10.1038/s41556-024-01509-5
  48. Nat Commun. 2024 Sep 27. 15(1): 8407
    Molecular architecture of the mammalian 2-oxoglutarate dehydrogenase complex.
    Yitang Zhang, Maofei Chen, Xudong Chen, Minghui Zhang, Jian Yin, Zi Yang, Xin Gao, Sensen Zhang, Maojun Yang.
      The 2-oxoglutarate dehydrogenase complex (OGDHc) orchestrates a critical reaction regulating the TCA cycle. Although the structure of each OGDHc subunit has been solved, the architecture of the intact complex and inter-subunit interactions still remain unknown. Here we report the assembly of native, intact OGDHc from Sus scrofa heart tissue using cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET), and subtomogram averaging (STA) to discern native structures of the whole complex and each subunit. Our cryo-EM analyses revealed the E2o cubic core structure comprising eight homotrimers at 3.3-Å resolution. More importantly, the numbers, positions and orientations of each OGDHc subunit were determined by cryo-ET and the STA structures of the core were resolved at 7.9-Å with the peripheral subunits reaching nanometer resolution. Although the distribution of the peripheral subunits E1o and E3 vary among complexes, they demonstrate a certain regularity within the position and orientation. Moreover, we analyzed and validated the interactions between each subunit, and determined the flexible binding mode for E1o, E2o and E3, resulting in a proposed model of Sus scrofa OGDHc. Together, our results reveal distinctive factors driving the architecture of the intact, native OGDHc.
    DOI:  https://doi.org/10.1038/s41467-024-52792-7
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