bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–03–24
forty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A fast-acting lipid checkpoint in G1 prevents mitotic defects.
  2. How the body's cholesterol factory avoids producing too much.
  3. Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
  4. Why menopause keeps evolving in whales.
  5. Mapping human hematopoiesis.
  6. Mapping human tissues with highly multiplexed RNA in situ hybridization.
  7. GAS41 modulates ferroptosis by anchoring NRF2 on chromatin.
  8. Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
  9. Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.
  10. A host-microbiota interactome reveals extensive transkingdom connectivity.
  11. An OLD protein teaches us new tricks: prokaryotic antiviral defense.
  12. GNTI-122: an autologous antigen-specific engineered Treg cell therapy for type 1 diabetes.
  13. Mathematician who tamed randomness wins Abel Prize.
  14. One in, one out: Commensal fungus protects against infection.
  15. Astrocyte cells in the brain have immune memory.
  16. Disease-associated astrocyte epigenetic memory promotes CNS pathology.
  17. Reply to: Does the KDEL receptor cycle between the Golgi and the ER?
  18. A code within the genetic code.
  19. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
  20. A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
  21. First pig liver transplanted into a person lasts for 10 days.
  22. AI & robotics briefing: LLMs harbour hidden racism.
  23. A pre-TCRα-independent pathway of αβ T cell differentiation.
  24. Nuclei-specific hypothalamus networks predict a dimensional marker of stress in humans.
  25. cGAS meets its demise in the nucleus.
  26. Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.
  27. Structural and mechanistic insights into activation of the human RNA ligase RTCB by Archease.
  28. The power of memory T cells minus antibodies.
  29. Maternal dietary fat during lactation shapes single nucleus transcriptomic profile of postnatal offspring hypothalamus in a sexually dimorphic manner in mice.
  30. Population imaging cerebellar growth for personalized neuroscience.
  31. The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
  32. Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
  33. p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice.
  34. First US drug approved for a liver disease surging around the world.
  35. Lac-Phe mediates the effects of metformin on food intake and body weight.
  36. Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies.
  37. Cutting-edge CAR-T cancer therapy is now made in India - at one-tenth the cost.
  38. Single cell atlas of Xenoturbella bocki highlights limited cell-type complexity.
  39. Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers.
  40. AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
  41. Revealing clinical heterogeneity in a large brain bank cohort.
  42. Metformin induces a Lac-Phe gut-brain signalling axis.
  43. Resilient anatomy and local plasticity of naive and stress haematopoiesis.
  44. Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface.
  45. Hearing loss promotes Alzheimer's disease.
  46. Complex motions emerge from robot interactions.
  1. Nat Commun. 2024 Mar 18. 15(1): 2441
    A fast-acting lipid checkpoint in G1 prevents mitotic defects.
    Marielle S Köberlin, Yilin Fan, Chad Liu, Mingyu Chung, Antonio F M Pinto, Peter K Jackson, Alan Saghatelian, Tobias Meyer.
      Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.
    DOI:  https://doi.org/10.1038/s41467-024-46696-9
  2. Nature. 2024 Mar 18.
    How the body's cholesterol factory avoids producing too much.
      
    Keywords:  Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-00765-7
  3. Nat Commun. 2024 Mar 18. 15(1): 1878
    Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
    Ana Belén Plata-Gómez, Lucía de Prado-Rivas, Alba Sanz, Nerea Deleyto-Seldas, Fernando García, Celia de la Calle Arregui, Camila Silva, Eduardo Caleiras, Osvaldo Graña-Castro, Elena Piñeiro-Yáñez, Joseph Krebs, Luis Leiva-Vega, Javier Muñoz, Ajay Jain, Guadalupe Sabio, Alejo Efeyan.
      The metabolic functions of the liver are spatially organized in a phenomenon called zonation, linked to the differential exposure of portal and central hepatocytes to nutrient-rich blood. The mTORC1 signaling pathway controls cellular metabolism in response to nutrients and insulin fluctuations. Here we show that simultaneous genetic activation of nutrient and hormone signaling to mTORC1 in hepatocytes results in impaired establishment of postnatal metabolic and zonal identity of hepatocytes. Mutant hepatocytes fail to upregulate postnatally the expression of Frizzled receptors 1 and 8, and show reduced Wnt/β-catenin activation. This defect, alongside diminished paracrine Wnt2 ligand expression by endothelial cells, underlies impaired postnatal maturation. Impaired zonation is recapitulated in a model of constant supply of nutrients by parenteral nutrition to piglets. Our work shows the role of hepatocyte sensing of fluctuations in nutrients and hormones for triggering a latent metabolic zonation program.
    DOI:  https://doi.org/10.1038/s41467-024-46032-1
  4. Nature. 2024 Mar 15.
    Why menopause keeps evolving in whales.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-00834-x
  5. Nat Immunol. 2024 Mar 21.
    Mapping human hematopoiesis.
    Kathrin M Bernt.
      
    DOI:  https://doi.org/10.1038/s41590-024-01793-1
  6. Nat Commun. 2024 Mar 20. 15(1): 2511
    Mapping human tissues with highly multiplexed RNA in situ hybridization.
    Kian Kalhor, Chien-Ju Chen, Ho Suk Lee, Matthew Cai, Mahsa Nafisi, Richard Que, Carter R Palmer, Yixu Yuan, Yida Zhang, Xuwen Li, Jinghui Song, Amanda Knoten, Blue B Lake, Joseph P Gaut, C Dirk Keene, Ed Lein, Peter V Kharchenko, Jerold Chun, Sanjay Jain, Jian-Bing Fan, Kun Zhang.
      In situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections. We introduce an omni-cell type cytoplasmic stain that substantially improves the segmentation of cell bodies. Our enzyme-free isothermal decoding procedure allows us to image 121 genes in large sections from the human neocortex in <10 h. We successfully recapitulated the cytoarchitecture of 20 neuronal and non-neuronal subclasses. We further performed in situ mapping of 300 genes on a diseased human kidney, profiled >20 healthy and pathological cell states, and identified diseased niches enriched in transcriptionally altered epithelial cells and myofibroblasts.
    DOI:  https://doi.org/10.1038/s41467-024-46437-y
  7. Nat Commun. 2024 Mar 21. 15(1): 2531
    GAS41 modulates ferroptosis by anchoring NRF2 on chromatin.
    Zhe Wang, Xin Yang, Delin Chen, Yanqing Liu, Zhiming Li, Shoufu Duan, Zhiguo Zhang, Xuejun Jiang, Brent R Stockwell, Wei Gu.
      YEATS domain-containing protein GAS41 is a histone reader and oncogene. Here, through genome-wide CRISPR-Cas9 screenings, we identify GAS41 as a repressor of ferroptosis. GAS41 interacts with NRF2 and is critical for NRF2 to activate its targets such as SLC7A11 for modulating ferroptosis. By recognizing the H3K27-acetylation (H3K27-ac) marker, GAS41 is recruited to the SLC7A11 promoter, independent of NRF2 binding. By bridging the interaction between NRF2 and the H3K27-ac marker, GAS41 acts as an anchor for NRF2 on chromatin in a promoter-specific manner for transcriptional activation. Moreover, the GAS41-mediated effect on ferroptosis contributes to its oncogenic role in vivo. These data demonstrate that GAS41 is a target for modulating tumor growth through ferroptosis. Our study reveals a mechanism for GAS41-mediated regulation in transcription by anchoring NRF2 on chromatin, and provides a model in which the DNA binding activity on chromatin by transcriptional factors (NRF2) can be directly regulated by histone markers (H3K27-ac).
    DOI:  https://doi.org/10.1038/s41467-024-46857-w
  8. Nat Metab. 2024 Mar 19.
    Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.
    J Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B Harbauer.
      Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42255-024-01007-w
  9. Nat Genet. 2024 Mar 21.
    Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.
    Masashi Fujita, Zongmei Gao, Lu Zeng, Cristin McCabe, Charles C White, Bernard Ng, Gilad Sahar Green, Orit Rozenblatt-Rosen, Devan Phillips, Liat Amir-Zilberstein, Hyo Lee, Richard V Pearse, Atlas Khan, Badri N Vardarajan, Krzysztof Kiryluk, Chun Jimmie Ye, Hans-Ulrich Klein, Gao Wang, Aviv Regev, Naomi Habib, Julie A Schneider, Yanling Wang, Tracy Young-Pearse, Sara Mostafavi, David A Bennett, Vilas Menon, Philip L De Jager.
      The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.
    DOI:  https://doi.org/10.1038/s41588-024-01685-y
  10. Nature. 2024 Mar 20.
    A host-microbiota interactome reveals extensive transkingdom connectivity.
    Nicole D Sonnert, Connor E Rosen, Andrew R Ghazi, Eric A Franzosa, Brianna Duncan-Lowey, Jaime A González-Hernández, John D Huck, Yi Yang, Yile Dai, Tyler A Rice, Mytien T Nguyen, Deguang Song, Yiyun Cao, Anjelica L Martin, Agata A Bielecka, Suzanne Fischer, Changhui Guan, Julia Oh, Curtis Huttenhower, Aaron M Ring, Noah W Palm.
      The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown1-3. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the 'exoproteome'). Commensal microorganisms may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct exoproteome-microbiota interactions remain largely unexplored. Here we developed and validated a novel technology, BASEHIT, that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, we interrogated more than 1.7 million potential interactions between 519 human-associated bacterial strains from diverse phylogenies and tissues of origin and 3,324 human exoproteins. The resulting interactome revealed an extensive network of transkingdom connectivity consisting of thousands of previously undescribed host-microorganism interactions involving 383 strains and 651 host proteins. Specific binding patterns within this network implied underlying biological logic; for example, conspecific strains exhibited shared exoprotein-binding patterns, and individual tissue isolates uniquely bound tissue-specific exoproteins. Furthermore, we observed dozens of unique and often strain-specific interactions with potential roles in niche colonization, tissue remodelling and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and effects on the host immune system in vivo. Overall, these studies expose a previously unexplored landscape of molecular-level host-microbiota interactions that may underlie causal effects of indigenous microorganisms on human health and disease.
    DOI:  https://doi.org/10.1038/s41586-024-07162-0
  11. Nat Commun. 2024 Mar 21. 15(1): 2527
    An OLD protein teaches us new tricks: prokaryotic antiviral defense.
    Eirene Marie Q Ednacot, Benjamin R Morehouse.
      
    DOI:  https://doi.org/10.1038/s41467-024-46925-1
  12. JCI Insight. 2024 Feb 08. pii: e171844. [Epub ahead of print]9(6):
    GNTI-122: an autologous antigen-specific engineered Treg cell therapy for type 1 diabetes.
    Gene I Uenishi, Marko Repic, Jennifer Y Yam, Ashley Landuyt, Priya Saikumar-Lakshmi, Tingxi Guo, Payam Zarin, Martina Sassone-Corsi, Adam Chicoine, Hunter Kellogg, Martina Hunt, Travis Drow, Ritika Tewari, Peter J Cook, Soo Jung Yang, Karen Cerosaletti, Darius Schweinoch, Benjamin Guiastrennec, Eddie James, Chandra Patel, Tiffany F Chen, Jane H Buckner, David J Rawlings, Thomas J Wickham, Karen T Mueller.
      Tregs have the potential to establish long-term immune tolerance in patients recently diagnosed with type 1 diabetes (T1D) by preserving β cell function. Adoptive transfer of autologous thymic Tregs, although safe, exhibited limited efficacy in previous T1D clinical trials, likely reflecting a lack of tissue specificity, limited IL-2 signaling support, and in vivo plasticity of Tregs. Here, we report a cell engineering strategy using bulk CD4+ T cells to generate a Treg cell therapy (GNTI-122) that stably expresses FOXP3, targets the pancreas and draining lymph nodes, and incorporates a chemically inducible signaling complex (CISC). GNTI-122 cells maintained an expression profile consistent with Treg phenotype and function. Activation of CISC using rapamycin mediated concentration-dependent STAT5 phosphorylation and, in concert with T cell receptor engagement, promoted cell proliferation. In response to the cognate antigen, GNTI-122 exhibited direct and bystander suppression of polyclonal, islet-specific effector T cells from patients with T1D. In an adoptive transfer mouse model of T1D, a mouse engineered-Treg analog of GNTI-122 trafficked to the pancreas, decreased the severity of insulitis, and prevented progression to diabetes. Taken together, these findings demonstrate in vitro and in vivo activity and support further development of GNTI-122 as a potential treatment for T1D.
    Keywords:  Autoimmunity; Diabetes; Gene therapy; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.171844
  13. Nature. 2024 Mar 20.
    Mathematician who tamed randomness wins Abel Prize.
    Davide Castelvecchi.
      
    Keywords:  Mathematics and computing
    DOI:  https://doi.org/10.1038/d41586-024-00839-6
  14. J Exp Med. 2024 May 06. pii: e20240220. [Epub ahead of print]221(5):
    One in, one out: Commensal fungus protects against infection.
    Rebecca A Drummond.
      Gut-resident fungi have a broad influence over health and disease. In this issue of JEM, Sekeresova Kralova et al. (https://doi.org/10.1084/jem.20231686) identify a commensal yeast that displaced fungal pathogen Candida albicans and protected against subsequent invasive infections that originate from the gut.
    DOI:  https://doi.org/10.1084/jem.20240220
  15. Nature. 2024 Mar 20.
    Astrocyte cells in the brain have immune memory.
    Michael V Sofroniew.
      
    Keywords:  Immunology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00676-7
  16. Nature. 2024 Mar 20.
    Disease-associated astrocyte epigenetic memory promotes CNS pathology.
    Hong-Gyun Lee, Joseph M Rone, Zhaorong Li, Camilo Faust Akl, Seung Won Shin, Joon-Hyuk Lee, Lucas E Flausino, Florian Pernin, Chun-Cheih Chao, Kilian L Kleemann, Lena Srun, Tomer Illouz, Federico Giovannoni, Marc Charabati, Liliana M Sanmarco, Jessica E Kenison, Gavin Piester, Stephanie E J Zandee, Jack P Antel, Veit Rothhammer, Michael A Wheeler, Alexandre Prat, Iain C Clark, Francisco J Quintana.
      Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1-8 (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR-Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+ memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+ astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.
    DOI:  https://doi.org/10.1038/s41586-024-07187-5
  17. Nat Commun. 2024 Mar 20. 15(1): 2454
    Reply to: Does the KDEL receptor cycle between the Golgi and the ER?
    Jurgen Denecke.
      
    DOI:  https://doi.org/10.1038/s41467-024-45850-7
  18. Nat Rev Mol Cell Biol. 2024 Mar 21.
    A code within the genetic code.
    Susanne Bornelöv.
      
    DOI:  https://doi.org/10.1038/s41580-024-00724-0
  19. Nat Metab. 2024 Mar 19.
    Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
    Mathieu Membrez, Eugenia Migliavacca, Stefan Christen, Keisuke Yaku, Jennifer Trieu, Alaina K Lee, Francesco Morandini, Maria Pilar Giner, Jade Stiner, Mikhail V Makarov, Emma S Garratt, Maria F Vasiloglou, Lucie Chanvillard, Emilie Dalbram, Amy M Ehrlich, José Luis Sanchez-Garcia, Carles Canto, Leonidas G Karagounis, Jonas T Treebak, Marie E Migaud, Ramin Heshmat, Farideh Razi, Neerja Karnani, Afshin Ostovar, Farshad Farzadfar, Stacey K H Tay, Matthew J Sanders, Karen A Lillycrop, Keith M Godfrey, Takashi Nakagawa, Sofia Moco, René Koopman, Gordon S Lynch, Vincenzo Sorrentino, Jerome N Feige.
      Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.
    DOI:  https://doi.org/10.1038/s42255-024-00997-x
  20. Mol Cell. 2024 Mar 14. pii: S1097-2765(24)00170-9. [Epub ahead of print]
    A kinetic dichotomy between mitochondrial and nuclear gene expression processes.
    Erik McShane, Mary Couvillion, Robert Ietswaart, Gyan Prakash, Brendan M Smalec, Iliana Soto, Autum R Baxter-Koenigs, Karine Choquet, L Stirling Churchman.
      Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC and FASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.
    Keywords:  LRPPRC; Leighs disease; RNA life cycle; gene regulation; genetic conflict; metabolic regulation; mitochondrial gene expression; mitochondrial translation; mitonuclear balance; organellular biogenesis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.028
  21. Nature. 2024 Mar 20.
    First pig liver transplanted into a person lasts for 10 days.
    Smriti Mallapaty.
      
    Keywords:  Immunology; Medical research; Physiology
    DOI:  https://doi.org/10.1038/d41586-024-00853-8
  22. Nature. 2024 Mar 19.
    AI & robotics briefing: LLMs harbour hidden racism.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-00856-5
  23. Nat Rev Immunol. 2024 Mar 19.
    A pre-TCRα-independent pathway of αβ T cell differentiation.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01024-6
  24. Nat Commun. 2024 Mar 18. 15(1): 2426
    Nuclei-specific hypothalamus networks predict a dimensional marker of stress in humans.
    Daria E A Jensen, Klaus P Ebmeier, Sana Suri, Matthew F S Rushworth, Miriam C Klein-Flügge.
      The hypothalamus is part of the hypothalamic-pituitary-adrenal axis which activates stress responses through release of cortisol. It is a small but heterogeneous structure comprising multiple nuclei. In vivo human neuroimaging has rarely succeeded in recording signals from individual hypothalamus nuclei. Here we use human resting-state fMRI (n = 498) with high spatial resolution to examine relationships between the functional connectivity of specific hypothalamic nuclei and a dimensional marker of prolonged stress. First, we demonstrate that we can parcellate the human hypothalamus into seven nuclei in vivo. Using the functional connectivity between these nuclei and other subcortical structures including the amygdala, we significantly predict stress scores out-of-sample. Predictions use 0.0015% of all possible brain edges, are specific to stress, and improve when using nucleus-specific compared to whole-hypothalamus connectivity. Thus, stress relates to connectivity changes in precise and functionally meaningful subcortical networks, which may be exploited in future studies using interventions in stress disorders.
    DOI:  https://doi.org/10.1038/s41467-024-46275-y
  25. Nat Immunol. 2024 Mar 21.
    cGAS meets its demise in the nucleus.
    Calvin Jon A Leonen, Hironori Funabiki.
      
    DOI:  https://doi.org/10.1038/s41590-024-01794-0
  26. Nat Commun. 2024 Mar 20. 15(1): 2497
    Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.
    Salome Funes, Jonathan Jung, Del Hayden Gadd, Michelle Mosqueda, Jianjun Zhong, Shankaracharya, Matthew Unger, Karly Stallworth, Debra Cameron, Melissa S Rotunno, Pepper Dawes, Megan Fowler-Magaw, Pamela J Keagle, Justin A McDonough, Sivakumar Boopathy, Miguel Sena-Esteves, Jeffrey A Nickerson, Cathleen Lutz, William C Skarnes, Elaine T Lim, Dorothy P Schafer, Francesca Massi, John E Landers, Daryl A Bosco.
      Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders.
    DOI:  https://doi.org/10.1038/s41467-024-46695-w
  27. Nat Commun. 2024 Mar 16. 15(1): 2378
    Structural and mechanistic insights into activation of the human RNA ligase RTCB by Archease.
    Janina Lara Gerber, Suria Itzel Morales Guzmán, Lorenz Worf, Petra Hubbe, Jürgen Kopp, Jirka Peschek.
      RNA ligases of the RTCB-type play an essential role in tRNA splicing, the unfolded protein response and RNA repair. RTCB is the catalytic subunit of the pentameric human tRNA ligase complex. RNA ligation by the tRNA ligase complex requires GTP-dependent activation of RTCB. This active site guanylylation reaction relies on the activation factor Archease. The mechanistic interplay between both proteins has remained unknown. Here, we report a biochemical and structural analysis of the human RTCB-Archease complex in the pre- and post-activation state. Archease reaches into the active site of RTCB and promotes the formation of a covalent RTCB-GMP intermediate through coordination of GTP and metal ions. During the activation reaction, Archease prevents futile RNA substrate binding to RTCB. Moreover, monomer structures of Archease and RTCB reveal additional states within the RNA ligation mechanism. Taken together, we present structural snapshots along the reaction cycle of the human tRNA ligase.
    DOI:  https://doi.org/10.1038/s41467-024-46568-2
  28. Nat Immunol. 2024 Mar 15.
    The power of memory T cells minus antibodies.
    Thi H O Nguyen, Katherine Kedzierska.
      
    DOI:  https://doi.org/10.1038/s41590-024-01796-y
  29. Nat Commun. 2024 Mar 16. 15(1): 2382
    Maternal dietary fat during lactation shapes single nucleus transcriptomic profile of postnatal offspring hypothalamus in a sexually dimorphic manner in mice.
    Yi Huang, Anyongqi Wang, Wenjiang Zhou, Baoguo Li, Linshan Zhang, Agata M Rudolf, Zengguang Jin, Catherine Hambly, Guanlin Wang, John R Speakman.
      Maternal overnutrition during lactation predisposes offspring to develop metabolic diseases and exacerbates the relevant syndromes in males more than females in later life. The hypothalamus is a heterogenous brain region that regulates energy balance. Here we combined metabolic trait quantification of mother and offspring mice under low and high fat diet (HFD) feeding during lactation, with single nucleus transcriptomic profiling of their offspring hypothalamus at peak lacation to understand the cellular and molecular alterations in response to maternal dietary pertubation. We found significant expansion in neuronal subpopulations including histaminergic (Hdc), arginine vasopressin/retinoic acid receptor-related orphan receptor β (Avp/Rorb) and agouti-related peptide/neuropeptide Y (AgRP/Npy) in male offspring when their mothers were fed HFD, and increased Npy-astrocyte interactions in offspring responding to maternal overnutrition. Our study provides a comprehensive offspring hypothalamus map at the peak lactation and reveals how the cellular subpopulations respond to maternal dietary fat in a sex-specific manner during development.
    DOI:  https://doi.org/10.1038/s41467-024-46589-x
  30. Nat Commun. 2024 Mar 18. 15(1): 2352
    Population imaging cerebellar growth for personalized neuroscience.
    Zi-Xuan Zhou, Xi-Nian Zuo.
      
    DOI:  https://doi.org/10.1038/s41467-024-46545-9
  31. Nat Commun. 2024 Mar 21. 15(1): 2487
    The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions.
    Marine Lanfranchi, Sozerko Yandiev, Géraldine Meyer-Dilhet, Salma Ellouze, Martijn Kerkhofs, Raphael Dos Reis, Audrey Garcia, Camille Blondet, Alizée Amar, Anita Kneppers, Hélène Polvèche, Damien Plassard, Marc Foretz, Benoit Viollet, Kei Sakamoto, Rémi Mounier, Cyril F Bourgeois, Olivier Raineteau, Evelyne Goillot, Julien Courchet.
      The cellular mechanisms underlying axonal morphogenesis are essential to the formation of functional neuronal networks. We previously identified the autism-linked kinase NUAK1 as a central regulator of axon branching through the control of mitochondria trafficking. However, (1) the relationship between mitochondrial position, function and axon branching and (2) the downstream effectors whereby NUAK1 regulates axon branching remain unknown. Here, we report that mitochondria recruitment to synaptic boutons supports collateral branches stabilization rather than formation in mouse cortical neurons. NUAK1 deficiency significantly impairs mitochondrial metabolism and axonal ATP concentration, and upregulation of mitochondrial function is sufficient to rescue axonal branching in NUAK1 null neurons in vitro and in vivo. Finally, we found that NUAK1 regulates axon branching through the mitochondria-targeted microprotein BRAWNIN. Our results demonstrate that NUAK1 exerts a dual function during axon branching through its ability to control mitochondrial distribution and metabolic activity.
    DOI:  https://doi.org/10.1038/s41467-024-46146-6
  32. Mol Cell. 2024 Mar 11. pii: S1097-2765(24)00176-X. [Epub ahead of print]
    Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
    Tristen Wright, Meghan E Turnis, Christy R Grace, Xiao Li, Lauren A Brakefield, Yong-Dong Wang, Haiyan Xu, Ewa Kaminska, Leslie K Climer, Tresor O Mukiza, Chi-Lun Chang, Tudor Moldoveanu, Joseph T Opferman.
      MCL-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to modulating mitochondrial metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that MCL-1 supports essential steps in long-chain (but not short-chain) fatty acid β-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of MCL-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic MCL-1 facilitates mitochondrial metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of MCL-1 inhibitors in clinical trials.
    Keywords:  MCL-1; acyl-coenzyme A synthetase; apoptosis; fatty acid; metabolism; mitochondria; β-oxidation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.035
  33. Nat Commun. 2024 Mar 21. 15(1): 2518
    p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice.
    Ross J Hill, Nazareno Bona, Job Smink, Hannah K Webb, Alastair Crisp, Juan I Garaycoechea, Gerry P Crossan.
      DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-46844-1
  34. Nature. 2024 Mar 15.
    First US drug approved for a liver disease surging around the world.
    Heidi Ledford.
      
    Keywords:  Medical research; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-00747-9
  35. Nat Metab. 2024 Mar 18.
    Lac-Phe mediates the effects of metformin on food intake and body weight.
    Shuke Xiao, Veronica L Li, Xuchao Lyu, Xudong Chen, Wei Wei, Fahim Abbasi, Joshua W Knowles, Alan Sheng-Hwa Tung, Shuliang Deng, Gaurav Tiwari, Xu Shi, Shuning Zheng, Laurie Farrell, Zsu-Zsu Chen, Kent D Taylor, Xiuqing Guo, Mark O Goodarzi, Alexis C Wood, Yii-Der Ida Chen, Leslie A Lange, Stephen S Rich, Jerome I Rotter, Clary B Clish, Usman A Tahir, Robert E Gerszten, Mark D Benson, Jonathan Z Long.
      Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.
    DOI:  https://doi.org/10.1038/s42255-024-00999-9
  36. Nat Cancer. 2024 Mar 19.
    Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies.
    Anton Dobrin, Pieter L Lindenbergh, Yuzhe Shi, Karlo Perica, Hongyao Xie, Nayan Jain, Andrew Chow, Jedd D Wolchok, Taha Merghoub, Michel Sadelain, Mohamad Hamieh.
      Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies.
    DOI:  https://doi.org/10.1038/s43018-024-00744-x
  37. Nature. 2024 Mar 21.
    Cutting-edge CAR-T cancer therapy is now made in India - at one-tenth the cost.
    Smriti Mallapaty.
      
    Keywords:  Cancer; Diseases; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00809-y
  38. Nat Commun. 2024 Mar 19. 15(1): 2469
    Single cell atlas of Xenoturbella bocki highlights limited cell-type complexity.
    Helen E Robertson, Arnau Sebé-Pedrós, Baptiste Saudemont, Yann Loe-Mie, Anne-C Zakrzewski, Xavier Grau-Bové, Marie-Pierre Mailhe, Philipp Schiffer, Maximilian J Telford, Heather Marlow.
      Phylogenetic analyses over the last two decades have united a few small, and previously orphan clades, the nematodermatids, acoels and xenoturbelids, into the phylum Xenacoelomorpha. Some phylogenetic analyses support a sister relationship between Xenacoelomorpha and Ambulacraria (Xenambulacraria), while others suggest that Xenacoelomorpha may be sister to the rest of the Bilateria (Nephrozoa). An understanding of the cell type complements of Xenacoelomorphs is essential to assessing these alternatives as well as to our broader understanding of bilaterian cell type evolution. Employing whole organism single-cell RNA-seq in the marine xenacoelomorph worm Xenoturbella bocki, we show that Xenambulacrarian nerve nets share regulatory features and a peptidergic identity with those found in cnidarians and protostomes and more broadly share muscle and gland cell similarities with other metazoans. Taken together, these data are consistent with broad homologies of animal gland, muscle, and neurons as well as more specific affinities between Xenoturbella and acoel gut and epidermal tissues, consistent with the monophyly of Xenacoelomorpha.
    DOI:  https://doi.org/10.1038/s41467-024-45956-y
  39. Nat Commun. 2024 Mar 19. 15(1): 2130
    Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers.
    R Sumanth Iyer, Sarah R Needham, Ioannis Galdadas, Benjamin M Davis, Selene K Roberts, Rico C H Man, Laura C Zanetti-Domingues, David T Clarke, Gilbert O Fruhwirth, Peter J Parker, Daniel J Rolfe, Francesco L Gervasio, Marisa L Martin-Fernandez.
      The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this therapeutic challenge are hindered by a poor understanding of how and why cancer mutations specifically amplify ligand-independent EGFR auto-phosphorylation signals to enhance cell survival and how this amplification is related to ligand-dependent cell proliferation. Here we show that drug-resistant EGFR mutations manipulate the assembly of ligand-free, kinase-active oligomers to promote and stabilize the assembly of oligomer-obligate active dimer sub-units and circumvent the need for ligand binding. We reveal the structure and assembly mechanisms of these ligand-free, kinase-active oligomers, uncovering oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Importantly, we find that the active dimer sub-units within ligand-free oligomers are the high affinity binding sites competent to bind physiological ligand concentrations and thus drive tumor growth, revealing a link with tumor proliferation. Our findings provide a framework for future drug discovery directed at tackling oncogenic EGFR mutations by disabling oligomer-assembling interactions.
    DOI:  https://doi.org/10.1038/s41467-024-46284-x
  40. Nat Metab. 2024 Mar 19.
    AMPK and insulin control the switch between mitochondrial hitchhiking of Pink1 mRNA and mitophagy in neurons.
      
    DOI:  https://doi.org/10.1038/s42255-024-01006-x
  41. Nat Med. 2024 Mar 20.
    Revealing clinical heterogeneity in a large brain bank cohort.
      
    DOI:  https://doi.org/10.1038/s41591-024-02871-5
  42. Nat Metab. 2024 Mar 18.
    Metformin induces a Lac-Phe gut-brain signalling axis.
    Tara TeSlaa.
      
    DOI:  https://doi.org/10.1038/s42255-024-01014-x
  43. Nature. 2024 Mar 20.
    Resilient anatomy and local plasticity of naive and stress haematopoiesis.
    Qingqing Wu, Jizhou Zhang, Sumit Kumar, Siyu Shen, Morgan Kincaid, Courtney B Johnson, Yanan Sophia Zhang, Raphaël Turcotte, Clemens Alt, Kyoko Ito, Shelli Homan, Bryan E Sherman, Tzu-Yu Shao, Anastasiya Slaughter, Benjamin Weinhaus, Baobao Song, Marie Dominique Filippi, H Leighton Grimes, Charles P Lin, Keisuke Ito, Sing Sing Way, J Matthew Kofron, Daniel Lucas.
      The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.
    DOI:  https://doi.org/10.1038/s41586-024-07186-6
  44. Nat Commun. 2024 Mar 20. 15(1): 2502
    Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface.
    Camden M Driggers, Yi-Ying Kuo, Phillip Zhu, Assmaa ElSheikh, Show-Ling Shyng.
      ATP-sensitive potassium (KATP) channels, composed of four pore-lining Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic β-cells. KATP channel opening is stimulated by PIP2 and inhibited by ATP. Mutations that increase channel opening by PIP2 reduce ATP inhibition and cause neonatal diabetes. Although considerable evidence has implicated a role for PIP2 in KATP channel function, previously solved open-channel structures have lacked bound PIP2, and mechanisms by which PIP2 regulates KATP channels remain unresolved. Here, we report the cryoEM structure of a KATP channel harboring the neonatal diabetes mutation Kir6.2-Q52R, in the open conformation, bound to amphipathic molecules consistent with natural C18:0/C20:4 long-chain PI(4,5)P2 at two adjacent binding sites between SUR1 and Kir6.2. The canonical PIP2 binding site is conserved among PIP2-gated Kir channels. The non-canonical PIP2 binding site forms at the interface of Kir6.2 and SUR1. Functional studies demonstrate both binding sites determine channel activity. Kir6.2 pore opening is associated with a twist of the Kir6.2 cytoplasmic domain and a rotation of the N-terminal transmembrane domain of SUR1, which widens the inhibitory ATP binding pocket to disfavor ATP binding. The open conformation is particularly stabilized by the Kir6.2-Q52R residue through cation-π bonding with SUR1-W51. Together, these results uncover the cooperation between SUR1 and Kir6.2 in PIP2 binding and gating, explain the antagonistic regulation of KATP channels by PIP2 and ATP, and provide a putative mechanism by which Kir6.2-Q52R stabilizes an open channel to cause neonatal diabetes.
    DOI:  https://doi.org/10.1038/s41467-024-46751-5
  45. Nat Aging. 2024 Mar 15.
    Hearing loss promotes Alzheimer's disease.
    Hong-Bo Zhao, Yang Yang.
      
    DOI:  https://doi.org/10.1038/s43587-024-00606-2
  46. Nature. 2024 Mar;627(8004): 499-500
    Complex motions emerge from robot interactions.
    Sebastian D Huber, Kukka-Emilia Huhtinen.
      
    Keywords:  Condensed-matter physics; Engineering; Physics
    DOI:  https://doi.org/10.1038/d41586-024-00622-7
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