bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒08‒13
sixty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Sustained by science.
  2. Promoting the science of One Health.
  3. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions.
  4. People.
  5. Malonyl-CoA links lipid metabolism to nutrient signalling by directly inhibiting mTORC1.
  6. High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation.
  7. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
  8. Immunology of food aversion.
  9. Spatial multiomics of the human heart.
  10. Australia.
  11. Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
  12. Runx factors launch T cell and innate lymphoid programs via direct and gene network-based mechanisms.
  13. RNA-based therapies.
  14. Multi-PGS enhances polygenic prediction by combining 937 polygenic scores.
  15. Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+ uptake into the Golgi apparatus.
  16. Modulation of translational decoding by m6A modification of mRNA.
  17. A membrane-associated MHC-I inhibitory axis for cancer immune evasion.
  18. Targeting STING oligomerization with small-molecule inhibitors.
  19. SONAR enables cell type deconvolution with spatially weighted Poisson-Gamma model for spatial transcriptomics.
  20. Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition.
  21. Mechanisms underlying pathological cortical bursts during metabolic depletion.
  22. A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis.
  23. Loss of Paip1 causes translation reduction and induces apoptotic cell death through ISR activation and Xrp1.
  24. Neurexin-3 subsynaptic densities are spatially distinct from Neurexin-1 and essential for excitatory synapse nanoscale organization in the hippocampus.
  25. spinDrop: a droplet microfluidic platform to maximise single-cell sequencing information content.
  26. Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
  27. Dopamine and glutamate regulate striatal acetylcholine in decision-making.
  28. Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer.
  29. Avast, here cometh Actual Physics Man!
  30. Cleaning crew: Soluble TREM2 mops up complement.
  31. Modulatory dynamics of periodic and aperiodic activity in respiration-brain coupling.
  32. Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease.
  33. SNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development.
  34. Spatial transcriptomics of the human heart.
  35. Structure, catalysis, chitin transport, and selective inhibition of chitin synthase.
  36. HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells.
  37. Cross-species transcriptomics reveals bifurcation point during the arterial-to-hemogenic transition.
  38. Brain criticality predicts individual levels of inter-areal synchronization in human electrophysiological data.
  39. Effector-dependent structural transformation of a crystalline framework with allosteric effects on molecular recognition ability.
  40. Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC.
  41. Determination of key events in mouse hepatocyte maturation at the single-cell level.
  42. Universal DNA methylation age across mammalian tissues.
  43. Backbone spiking sequence as a basis for preplay, replay, and default states in human cortex.
  44. Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets.
  45. Neural manifolds for odor-driven innate and acquired appetitive preferences.
  46. A mammalian DNA methylation landscape.
  47. Complementarity-determining region clustering may cause CAR-T cell dysfunction.
  48. Drug treatment and phenotypic diversity.
  49. Getting personal with epigenetics: towards individual-specific epigenomic imputation with machine learning.
  50. Sharp resolution, big samples: ExA-SPIM microscope accelerates brain imaging.
  51. Distinct molecular profiles of skull bone marrow in health and neurological disorders.
  52. Stepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription.
  53. Resident dendritic cell density in the lymph node paracortex is preDC-estined.
  54. Clonal hematopoiesis reduces risk of Alzheimer's disease.
  55. Molecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel.
  56. DNA methylation networks underlying mammalian traits.
  57. Genomic dissection of endemic carbapenem resistance reveals metallo-beta-lactamase dissemination through clonal, plasmid and integron transfer.
  58. Droplet-based single-cell joint profiling of histone modifications and transcriptomes.
  59. Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway.
  60. BtuB TonB-dependent transporters and BtuG surface lipoproteins form stable complexes for vitamin B12 uptake in gut Bacteroides.
  61. Cooperative assembly confers regulatory specificity and long-term genetic circuit stability.
  1. Science. 2023 Aug 11. 381(6658): 706
    Sustained by science.
    Matthew Jordan Dean.
      
    DOI:  https://doi.org/10.1126/science.adk1505
  2. Nat Commun. 2023 08 07. 14(1): 4735
    Promoting the science of One Health.
      
    DOI:  https://doi.org/10.1038/s41467-023-40293-y
  3. Cell. 2023 Aug 01. pii: S0092-8674(23)00795-X. [Epub ahead of print]
    Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions.
    AlcHepNet
      Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.
    Keywords:  FZD5; WNT2; bile acid conjugation; cholesterol; fibrosis; humanized liver; lipidomics; liver sinusoidal endothelial cells; non-alcoholic fatty liver disease; stellate cells
    DOI:  https://doi.org/10.1016/j.cell.2023.07.017
  4. Nat Biotechnol. 2023 Aug;41(8): 1176
    People.
      
    DOI:  https://doi.org/10.1038/s41587-023-01896-4
  5. Nat Cell Biol. 2023 Aug 10.
    Malonyl-CoA links lipid metabolism to nutrient signalling by directly inhibiting mTORC1.
      
    DOI:  https://doi.org/10.1038/s41556-023-01206-9
  6. Nat Commun. 2023 08 09. 14(1): 4809
    High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation.
    Brooke D Huisman, Ning Guan, Timo Rückert, Lee Garner, Nishant K Singh, Andrew J McMichael, Geraldine M Gillespie, Chiara Romagnani, Michael E Birnbaum.
      HLA-E is a non-classical class I MHC protein involved in innate and adaptive immune recognition. While recent studies have shown HLA-E can present diverse peptides to NK cells and T cells, the HLA-E repertoire recognized by CD94/NKG2x has remained poorly defined, with only a limited number of peptide ligands identified. Here we screen a yeast-displayed peptide library in the context of HLA-E to identify 500 high-confidence unique peptides that bind both HLA-E and CD94/NKG2A or CD94/NKG2C. Utilizing the sequences identified via yeast display selections, we train prediction algorithms and identify human and cytomegalovirus (CMV) proteome-derived, HLA-E-presented peptides capable of binding and signaling through both CD94/NKG2A and CD94/NKG2C. In addition, we identify peptides which selectively activate NKG2C+ NK cells. Taken together, characterization of the HLA-E-binding peptide repertoire and identification of NK activity-modulating peptides present opportunities for studies of NK cell regulation in health and disease, in addition to vaccine and therapeutic design.
    DOI:  https://doi.org/10.1038/s41467-023-40220-1
  7. Nature. 2023 Aug 09.
    Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
    Liliana M Sanmarco, Joseph M Rone, Carolina M Polonio, Gonzalo Fernandez Lahore, Federico Giovannoni, Kylynne Ferrara, Cristina Gutierrez-Vazquez, Ning Li, Anna Sokolovska, Agustin Plasencia, Camilo Faust Akl, Payal Nanda, Evelin S Heck, Zhaorong Li, Hong-Gyun Lee, Chun-Cheih Chao, Claudia M Rejano-Gordillo, Pedro H Fonseca-Castro, Tomer Illouz, Mathias Linnerbauer, Jessica E Kenison, Rocky M Barilla, Daniel Farrenkopf, Nikolas A Stevens, Gavin Piester, Elizabeth N Chung, Lucas Dailey, Vijay K Kuchroo, David Hava, Michael A Wheeler, Clary Clish, Roni Nowarski, Eduardo Balsa, Jose M Lora, Francisco J Quintana.
      Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.
    DOI:  https://doi.org/10.1038/s41586-023-06409-6
  8. Nat Rev Immunol. 2023 Aug 08.
    Immunology of food aversion.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-023-00928-z
  9. Nat Genet. 2023 Aug;55(8): 1253
    Spatial multiomics of the human heart.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-023-01481-0
  10. Science. 2023 Aug 11. 381(6658): 614-615
    Australia.
    Caroline Ash, Bianca Lopez, Ekeoma E Uzogara, Sacha Vignieri.
      
    DOI:  https://doi.org/10.1126/science.adj9747
  11. Nat Commun. 2023 Aug 10. 14(1): 4726
    Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
    Ayelet M Rosenberg, Manish Saggar, Anna S Monzel, Jack Devine, Peter Rogu, Aaron Limoges, Alex Junker, Carmen Sandi, Eugene V Mosharov, Dani Dumitriu, Christoph Anacker, Martin Picard.
      The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.
    DOI:  https://doi.org/10.1038/s41467-023-39941-0
  12. Nat Immunol. 2023 Aug 10.
    Runx factors launch T cell and innate lymphoid programs via direct and gene network-based mechanisms.
    Boyoung Shin, Wen Zhou, Jue Wang, Fan Gao, Ellen V Rothenberg.
      Runx factors are essential for lineage specification of various hematopoietic cells, including T lymphocytes. However, they regulate context-specific genes and occupy distinct genomic regions in different cell types. Here, we show that dynamic Runx binding shifts in mouse early T cell development are mostly not restricted by local chromatin state but regulated by Runx dosage and functional partners. Runx cofactors compete to recruit a limited pool of Runx factors in early T progenitor cells, and a modest increase in Runx protein availability at pre-commitment stages causes premature Runx occupancy at post-commitment binding sites. This increased Runx factor availability results in striking T cell lineage developmental acceleration by selectively activating T cell-identity and innate lymphoid cell programs. These programs are collectively regulated by Runx together with other, Runx-induced transcription factors that co-occupy Runx-target genes and propagate gene network changes.
    DOI:  https://doi.org/10.1038/s41590-023-01585-z
  13. Nat Biotechnol. 2023 Aug;41(8): 1071
    RNA-based therapies.
      
    DOI:  https://doi.org/10.1038/s41587-023-01885-7
  14. Nat Commun. 2023 08 05. 14(1): 4702
    Multi-PGS enhances polygenic prediction by combining 937 polygenic scores.
    Clara Albiñana, Zhihong Zhu, Andrew J Schork, Andrés Ingason, Hugues Aschard, Isabell Brikell, Cynthia M Bulik, Liselotte V Petersen, Esben Agerbo, Jakob Grove, Merete Nordentoft, David M Hougaard, Thomas Werge, Anders D Børglum, Preben Bo Mortensen, John J McGrath, Benjamin M Neale, Florian Privé, Bjarni J Vilhjálmsson.
      The predictive performance of polygenic scores (PGS) is largely dependent on the number of samples available to train the PGS. Increasing the sample size for a specific phenotype is expensive and takes time, but this sample size can be effectively increased by using genetically correlated phenotypes. We propose a framework to generate multi-PGS from thousands of publicly available genome-wide association studies (GWAS) with no need to individually select the most relevant ones. In this study, the multi-PGS framework increases prediction accuracy over single PGS for all included psychiatric disorders and other available outcomes, with prediction R2 increases of up to 9-fold for attention-deficit/hyperactivity disorder compared to a single PGS. We also generate multi-PGS for phenotypes without an existing GWAS and for case-case predictions. We benchmark the multi-PGS framework against other methods and highlight its potential application to new emerging biobanks.
    DOI:  https://doi.org/10.1038/s41467-023-40330-w
  15. Nat Commun. 2023 08 08. 14(1): 4770
    Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+ uptake into the Golgi apparatus.
    Han Ba Bui, Satoshi Watanabe, Norimichi Nomura, Kehong Liu, Tomoko Uemura, Michio Inoue, Akihisa Tsutsumi, Hiroyuki Fujita, Kengo Kinoshita, Yukinari Kato, So Iwata, Masahide Kikkawa, Kenji Inaba.
      Zinc ions (Zn2+) are vital to most cells, with the intracellular concentrations of Zn2+ being tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. We herein present the 2.2-3.1 Å-resolution cryo-EM structures of a Golgi-localized human Zn2+/H+ antiporter ZnT7 (hZnT7) in Zn2+-bound and unbound forms. Cryo-EM analyses show that hZnT7 exists as a dimer via tight interactions in both the cytosolic and transmembrane (TM) domains of two protomers, each of which contains a single Zn2+-binding site in its TM domain. hZnT7 undergoes a TM-helix rearrangement to create a negatively charged cytosolic cavity for Zn2+ entry in the inward-facing conformation and widens the luminal cavity for Zn2+ release in the outward-facing conformation. An exceptionally long cytosolic histidine-rich loop characteristic of hZnT7 binds two Zn2+ ions, seemingly facilitating Zn2+ recruitment to the TM metal transport pathway. These structures permit mechanisms of hZnT7-mediated Zn2+ uptake into the Golgi to be proposed.
    DOI:  https://doi.org/10.1038/s41467-023-40521-5
  16. Nat Commun. 2023 08 08. 14(1): 4784
    Modulation of translational decoding by m6A modification of mRNA.
    Sakshi Jain, Lukasz Koziej, Panagiotis Poulis, Igor Kaczmarczyk, Monika Gaik, Michal Rawski, Namit Ranjan, Sebastian Glatt, Marina V Rodnina.
      N6-methyladenosine (m6A) is an abundant, dynamic mRNA modification that regulates key steps of cellular mRNA metabolism. m6A in the mRNA coding regions inhibits translation elongation. Here, we show how m6A modulates decoding in the bacterial translation system using a combination of rapid kinetics, smFRET and single-particle cryo-EM. We show that, while the modification does not impair the initial binding of aminoacyl-tRNA to the ribosome, in the presence of m6A fewer ribosomes complete the decoding process due to the lower stability of the complexes and enhanced tRNA drop-off. The mRNA codon adopts a π-stacked codon conformation that is remodeled upon aminoacyl-tRNA binding. m6A does not exclude canonical codon-anticodon geometry, but favors alternative more dynamic conformations that are rejected by the ribosome. These results highlight how modifications outside the Watson-Crick edge can still interfere with codon-anticodon base pairing and complex recognition by the ribosome, thereby modulating the translational efficiency of modified mRNAs.
    DOI:  https://doi.org/10.1038/s41467-023-40422-7
  17. Cell. 2023 Aug 02. pii: S0092-8674(23)00783-3. [Epub ahead of print]
    A membrane-associated MHC-I inhibitory axis for cancer immune evasion.
    Xufeng Chen, Qiao Lu, Hua Zhou, Jia Liu, Bettina Nadorp, Audrey Lasry, Zhengxi Sun, Baoling Lai, Gergely Rona, Jiangyan Zhang, Michael Cammer, Kun Wang, Wafa Al-Santli, Zoe Ciantra, Qianjin Guo, Jia You, Debrup Sengupta, Ahmad Boukhris, Hongbing Zhang, Cheng Liu, Peter Cresswell, Patricia L M Dahia, Michele Pagano, Iannis Aifantis, Jun Wang.
      Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers.
    Keywords:  MHC-I; SUSD6; T cell; TMEM127; WWP2; antigen presentation; cancer; immune evasion; lysosomal degradation; ubiquitination
    DOI:  https://doi.org/10.1016/j.cell.2023.07.016
  18. Proc Natl Acad Sci U S A. 2023 08 15. 120(33): e2305420120
    Targeting STING oligomerization with small-molecule inhibitors.
    Fiachra Humphries, Liraz Shmuel-Galia, Zhaozhao Jiang, Jeffrey Y Zhou, Leonard Barasa, Santanu Mondal, Ruth Wilson, Nadia Sultana, Scott A Shaffer, Sze-Ling Ng, G Scott Pesiridis, Paul R Thompson, Katherine A Fitzgerald.
      Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3- and NFκB-dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of autophagy. Aberrant activation of STING is now linked to a growing number of both rare as well as common chronic inflammatory diseases. Here, we identify and characterize a potent small-molecule inhibitor of STING. This compound, BB-Cl-amidine inhibits STING signaling and production of type I IFNs, IFN-stimulated genes (ISGs) and NFκB-dependent cytokines, but not other pattern recognition receptors. In vivo, BB-Cl-amidine alleviated pathology resulting from accrual of cytosolic DNA in Trex-1 mutant mice. Mechanistically BB-Cl-amidine inhibited STING oligomerization through modification of Cys148. Collectively, our work uncovers an approach to inhibit STING activation and highlights the potential of this strategy for the treatment of STING-driven inflammatory diseases.
    Keywords:  Trex-1; cytokines; protein arginine deiminases; small-molecule inhibitor; stimulator of interferon genes
    DOI:  https://doi.org/10.1073/pnas.2305420120
  19. Nat Commun. 2023 08 07. 14(1): 4727
    SONAR enables cell type deconvolution with spatially weighted Poisson-Gamma model for spatial transcriptomics.
    Zhiyuan Liu, Dafei Wu, Weiwei Zhai, Liang Ma.
      Recent advancements in spatial transcriptomic technologies have enabled the measurement of whole transcriptome profiles with preserved spatial context. However, limited by spatial resolution, the measured expressions at each spot are often from a mixture of multiple cells. Computational deconvolution methods designed for spatial transcriptomic data rarely make use of the valuable spatial information as well as the neighboring similarity information. Here, we propose SONAR, a Spatially weighted pOissoN-gAmma Regression model for cell-type deconvolution with spatial transcriptomic data. SONAR directly models the raw counts of spatial transcriptomic data and applies a geographically weighted regression framework that incorporates neighboring information to enhance local estimation of regional cell type composition. In addition, SONAR applies an additional elastic weighting step to adaptively filter dissimilar neighbors, which effectively prevents the introduction of local estimation bias in transition regions with sharp boundaries. We demonstrate the performance of SONAR over other state-of-the-art methods on synthetic data with various spatial patterns. We find that SONAR can accurately map region-specific cell types in real spatial transcriptomic data including mouse brain, human heart and human pancreatic ductal adenocarcinoma. We further show that SONAR can reveal the detailed distributions and fine-grained co-localization of immune cells within the microenvironment at the tumor-normal tissue margin in human liver cancer.
    DOI:  https://doi.org/10.1038/s41467-023-40458-9
  20. Nat Commun. 2023 08 09. 14(1): 4794
    Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition.
    Bernhard Kuhle, Marscha Hirschi, Lili K Doerfel, Gabriel C Lander, Paul Schimmel.
      Animal mitochondrial gene expression relies on specific interactions between nuclear-encoded aminoacyl-tRNA synthetases and mitochondria-encoded tRNAs. Their evolution involves an antagonistic interplay between strong mutation pressure on mtRNAs and selection pressure to maintain their essential function. To understand the molecular consequences of this interplay, we analyze the human mitochondrial serylation system, in which one synthetase charges two highly divergent mtRNASer isoacceptors. We present the cryo-EM structure of human mSerRS in complex with mtRNASer(UGA), and perform a structural and functional comparison with the mSerRS-mtRNASer(GCU) complex. We find that despite their common function, mtRNASer(UGA) and mtRNASer(GCU) show no constrain to converge on shared structural or sequence identity motifs for recognition by mSerRS. Instead, mSerRS evolved a bimodal readout mechanism, whereby a single protein surface recognizes degenerate identity features specific to each mtRNASer. Our results show how the mutational erosion of mtRNAs drove a remarkable innovation of intermolecular specificity rules, with multiple evolutionary pathways leading to functionally equivalent outcomes.
    DOI:  https://doi.org/10.1038/s41467-023-40354-2
  21. Nat Commun. 2023 08 08. 14(1): 4792
    Mechanisms underlying pathological cortical bursts during metabolic depletion.
    Shrey Dutta, Kartik K Iyer, Sampsa Vanhatalo, Michael Breakspear, James A Roberts.
      Cortical activity depends upon a continuous supply of oxygen and other metabolic resources. Perinatal disruption of oxygen availability is a common clinical scenario in neonatal intensive care units, and a leading cause of lifelong disability. Pathological patterns of brain activity including burst suppression and seizures are a hallmark of the recovery period, yet the mechanisms by which these patterns arise remain poorly understood. Here, we use computational modeling of coupled metabolic-neuronal activity to explore the mechanisms by which oxygen depletion generates pathological brain activity. We find that restricting oxygen supply drives transitions from normal activity to several pathological activity patterns (isoelectric, burst suppression, and seizures), depending on the potassium supply. Trajectories through parameter space track key features of clinical electrophysiology recordings and reveal how infants with good recovery outcomes track toward normal parameter values, whereas the parameter values for infants with poor outcomes dwell around the pathological values. These findings open avenues for studying and monitoring the metabolically challenged infant brain, and deepen our understanding of the link between neuronal and metabolic activity.
    DOI:  https://doi.org/10.1038/s41467-023-40437-0
  22. Nat Commun. 2023 08 09. 14(1): 4816
    A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis.
    Anna S Dickson, Tekle Pauzaite, Esther Arnaiz, Brian M Ortmann, James A West, Norbert Volkmar, Anthony W Martinelli, Zhaoqi Li, Niek Wit, Dennis Vitkup, Arthur Kaser, Paul J Lehner, James A Nathan.
      Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.
    DOI:  https://doi.org/10.1038/s41467-023-40541-1
  23. Cell Death Discov. 2023 Aug 05. 9(1): 288
    Loss of Paip1 causes translation reduction and induces apoptotic cell death through ISR activation and Xrp1.
    Maoguang Xue, Fei Cong, Wanling Zheng, Ruoqing Xu, Xiaoyu Liu, Hongcun Bao, Ying Ying Sung, Yongmei Xi, Feng He, Jun Ma, Xiaohang Yang, Wanzhong Ge.
      Regulation of protein translation initiation is tightly associated with cell growth and survival. Here, we identify Paip1, the Drosophila homolog of the translation initiation factor PAIP1, and analyze its role during development. Through genetic analysis, we find that loss of Paip1 causes reduced protein translation and pupal lethality. Furthermore, tissue specific knockdown of Paip1 results in apoptotic cell death in the wing imaginal disc. Paip1 depletion leads to increased proteotoxic stress and activation of the integrated stress response (ISR) pathway. Mechanistically, we show that loss of Paip1 promotes phosphorylation of eIF2α via the kinase PERK, leading to apoptotic cell death. Moreover, Paip1 depletion upregulates the transcription factor gene Xrp1, which contributes to apoptotic cell death and eIF2α phosphorylation. We further show that loss of Paip1 leads to an increase in Xrp1 translation mediated by its 5'UTR. These findings uncover a novel mechanism that links translation impairment to tissue homeostasis and establish a role of ISR activation and Xrp1 in promoting cell death.
    DOI:  https://doi.org/10.1038/s41420-023-01587-8
  24. Nat Commun. 2023 08 05. 14(1): 4706
    Neurexin-3 subsynaptic densities are spatially distinct from Neurexin-1 and essential for excitatory synapse nanoscale organization in the hippocampus.
    Brian A Lloyd, Ying Han, Rebecca Roth, Bo Zhang, Jason Aoto.
      Proteins critical for synaptic transmission are non-uniformly distributed and assembled into regions of high density called subsynaptic densities (SSDs) that transsynaptically align in nanocolumns. Neurexin-1 and neurexin-3 are essential presynaptic adhesion molecules that non-redundantly control NMDAR- and AMPAR-mediated synaptic transmission, respectively, via transsynaptic interactions with distinct postsynaptic ligands. Despite their functional relevance, fundamental questions regarding the nanoscale properties of individual neurexins, their influence on the subsynaptic organization of excitatory synapses and the mechanisms controlling how individual neurexins engage in precise transsynaptic interactions are unknown. Using Double Helix 3D dSTORM and neurexin mouse models, we identify neurexin-3 as a critical presynaptic adhesion molecule that regulates excitatory synapse nano-organization in hippocampus. Furthermore, endogenous neurexin-1 and neurexin-3 form discrete and non-overlapping SSDs that are enriched opposite their postsynaptic ligands. Thus, the nanoscale organization of neurexin-1 and neurexin-3 may explain how individual neurexins signal in parallel to govern different synaptic properties.
    DOI:  https://doi.org/10.1038/s41467-023-40419-2
  25. Nat Commun. 2023 08 08. 14(1): 4788
    spinDrop: a droplet microfluidic platform to maximise single-cell sequencing information content.
    Joachim De Jonghe, Tomasz S Kaminski, David B Morse, Marcin Tabaka, Anna L Ellermann, Timo N Kohler, Gianluca Amadei, Charlotte E Handford, Gregory M Findlay, Magdalena Zernicka-Goetz, Sarah A Teichmann, Florian Hollfelder.
      Droplet microfluidic methods have massively increased the throughput of single-cell sequencing campaigns. The benefit of scale-up is, however, accompanied by increased background noise when processing challenging samples and the overall RNA capture efficiency is lower. These drawbacks stem from the lack of strategies to enrich for high-quality material or specific cell types at the moment of cell encapsulation and the absence of implementable multi-step enzymatic processes that increase capture. Here we alleviate both bottlenecks using fluorescence-activated droplet sorting to enrich for droplets that contain single viable cells, intact nuclei, fixed cells or target cell types and use reagent addition to droplets by picoinjection to perform multi-step lysis and reverse transcription. Our methodology increases gene detection rates fivefold, while reducing background noise by up to half. We harness these properties to deliver a high-quality molecular atlas of mouse brain development, despite starting with highly damaged input material, and provide an atlas of nascent RNA transcription during mouse organogenesis. Our method is broadly applicable to other droplet-based workflows to deliver sensitive and accurate single-cell profiling at a reduced cost.
    DOI:  https://doi.org/10.1038/s41467-023-40322-w
  26. Nat Cell Biol. 2023 Aug 10.
    Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
    Raffaele Nicastro, Laura Brohée, Josephine Alba, Julian Nüchel, Gianluca Figlia, Stefanie Kipschull, Peter Gollwitzer, Jesus Romero-Pozuelo, Stephanie A Fernandes, Andreas Lamprakis, Stefano Vanni, Aurelio A Teleman, Claudio De Virgilio, Constantinos Demetriades.
      Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here we show that mTORC1 senses the capacity of a cell to synthesise fatty acids by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When fatty acid synthase (FASN) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with acetyl-CoA carboxylase 1 (ACC1) and FASN. Our findings represent a conserved and unique homeostatic mechanism whereby impaired fatty acid biogenesis leads to reduced mTORC1 activity to coordinately link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the existence of a physiological metabolite that directly inhibits the activity of a signalling kinase in mammalian cells by competing with ATP for binding.
    DOI:  https://doi.org/10.1038/s41556-023-01198-6
  27. Nature. 2023 Aug 09.
    Dopamine and glutamate regulate striatal acetylcholine in decision-making.
    Lynne Chantranupong, Celia C Beron, Joshua A Zimmer, Michelle J Wen, Wengang Wang, Bernardo L Sabatini.
      Striatal dopamine (DA) and acetylcholine (Ach) are essential for the selection and reinforcement of motor actions and decision-making1. In vitro studies have revealed an intrastriatal circuit in which Ach, released by cholinergic interneurons (CINs), drives DA release, and DA in turn inhibits CIN activity via dopamine D2 receptors (D2R). Whether and how this circuit contributes to striatal function in vivo is largely unknown. To define the role of this circuit in vivo, we monitored Ach and DA signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that DA and Ach exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. DA dynamics and reward encoding do not require Ach release by CINs. However, DA inhibits Ach transients in a D2R-dependent manner and loss of this regulation impairs decision-making. To determine how other striatal inputs shape Ach signals, we assessed the contribution of cortical and thalamic projections and found that glutamate release from both sources is required for Ach release. Altogether, we uncover a dynamic relationship between DA and Ach during decision-making and reveal multiple modes of CIN regulation. These findings deepen our understanding of the neurochemical basis of decision-making and behavior.
    DOI:  https://doi.org/10.1038/s41586-023-06492-9
  28. Nat Commun. 2023 Aug 11. 14(1): 4857
    Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer.
    Valentina Cigliola, Adam Shoffner, Nutishia Lee, Jianhong Ou, Trevor J Gonzalez, Jiaul Hoque, Clayton J Becker, Yanchao Han, Grace Shen, Timothy D Faw, Muhammad M Abd-El-Barr, Shyni Varghese, Aravind Asokan, Kenneth D Poss.
      Unlike adult mammals, zebrafish regenerate spinal cord tissue and recover locomotor ability after a paralyzing injury. Here, we find that ependymal cells in zebrafish spinal cords produce the neurogenic factor Hb-egfa upon transection injury. Animals with hb-egfa mutations display defective swim capacity, axon crossing, and tissue bridging after spinal cord transection, associated with disrupted indicators of neuron production. Local recombinant human HB-EGF delivery alters ependymal cell cycling and tissue bridging, enhancing functional regeneration. Epigenetic profiling reveals a tissue regeneration enhancer element (TREE) linked to hb-egfa that directs gene expression in spinal cord injuries. Systemically delivered recombinant AAVs containing this zebrafish TREE target gene expression to crush injuries of neonatal, but not adult, murine spinal cords. Moreover, enhancer-based HB-EGF delivery by AAV administration improves axon densities after crush injury in neonatal cords. Our results identify Hb-egf as a neurogenic factor necessary for innate spinal cord regeneration and suggest strategies to improve spinal cord repair in mammals.
    DOI:  https://doi.org/10.1038/s41467-023-40486-5
  29. Nature. 2023 Aug 09.
    Avast, here cometh Actual Physics Man!
    Filip Wiltgren.
      
    DOI:  https://doi.org/10.1038/d41586-023-02465-0
  30. Immunity. 2023 08 08. pii: S1074-7613(23)00325-4. [Epub ahead of print]56(8): 1701-1703
    Cleaning crew: Soluble TREM2 mops up complement.
    Kathryn M Monroe, Joseph W Lewcock.
      Whether soluble TREM2 has a functional role in the central nervous system has been unclear. In this issue of Immunity, Zhong et al. show that soluble TREM2 inhibits aberrant synaptic pruning by sopping up the complement factor C1q to protect neurons and mitigate neurodegeneration.
    DOI:  https://doi.org/10.1016/j.immuni.2023.07.012
  31. Nat Commun. 2023 08 05. 14(1): 4699
    Modulatory dynamics of periodic and aperiodic activity in respiration-brain coupling.
    Daniel S Kluger, Carina Forster, Omid Abbasi, Nikos Chalas, Arno Villringer, Joachim Gross.
      Bodily rhythms such as respiration are increasingly acknowledged to modulate neural oscillations underlying human action, perception, and cognition. Conversely, the link between respiration and aperiodic brain activity - a non-oscillatory reflection of excitation-inhibition (E:I) balance - has remained unstudied. Aiming to disentangle potential respiration-related dynamics of periodic and aperiodic activity, we applied recently developed algorithms of time-resolved parameter estimation to resting-state MEG and EEG data from two labs (total N = 78 participants). We provide evidence that fluctuations of aperiodic brain activity (1/f slope) are phase-locked to the respiratory cycle, which suggests that spontaneous state shifts of excitation-inhibition balance are at least partly influenced by peripheral bodily signals. Moreover, differential temporal dynamics in their coupling to non-oscillatory and oscillatory activity raise the possibility of a functional distinction in the way each component is related to respiration. Our findings highlight the role of respiration as a physiological influence on brain signalling.
    DOI:  https://doi.org/10.1038/s41467-023-40250-9
  32. Nat Med. 2023 Aug 07.
    Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease.
    Dominantly Inherited Alzheimer Network
      Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.
    DOI:  https://doi.org/10.1038/s41591-023-02476-4
  33. Nat Commun. 2023 08 08. 14(1): 4754
    SNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development.
    Yurika Matsui, Mohamed Nadhir Djekidel, Katherine Lindsay, Parimal Samir, Nina Connolly, Gang Wu, Xiaoyang Yang, Yiping Fan, Beisi Xu, Jamy C Peng.
      Stem cell survival versus death is a developmentally programmed process essential for morphogenesis, sizing, and quality control of genome integrity and cell fates. Cell death is pervasive during development, but its programming is little known. Here, we report that Smad nuclear interacting protein 1 (SNIP1) promotes neural progenitor cell survival and neurogenesis and is, therefore, integral to brain development. The SNIP1-depleted brain exhibits dysplasia with robust induction of caspase 9-dependent apoptosis. Mechanistically, SNIP1 regulates target genes that promote cell survival and neurogenesis, and its activities are influenced by TGFβ and NFκB signaling pathways. Further, SNIP1 facilitates the genomic occupancy of Polycomb complex PRC2 and instructs H3K27me3 turnover at target genes. Depletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia and to partially restore genetic programs in the SNIP1-depleted brain in vivo. These findings suggest a loci-specific regulation of PRC2 and H3K27 marks to toggle cell survival and death in the developing brain.
    DOI:  https://doi.org/10.1038/s41467-023-40487-4
  34. Nat Biotechnol. 2023 Aug;41(8): 1072
    Spatial transcriptomics of the human heart.
    Jared B Fudge.
      
    DOI:  https://doi.org/10.1038/s41587-023-01918-1
  35. Nat Commun. 2023 08 08. 14(1): 4776
    Structure, catalysis, chitin transport, and selective inhibition of chitin synthase.
    Dan-Dan Chen, Zhao-Bin Wang, Le-Xuan Wang, Peng Zhao, Cai-Hong Yun, Lin Bai.
      Chitin is one of the most abundant natural biopolymers and serves as a critical structural component of extracellular matrices, including fungal cell walls and insect exoskeletons. As a linear polymer of β-(1,4)-linked N-acetylglucosamine, chitin is synthesized by chitin synthases, which are recognized as targets for antifungal and anti-insect drugs. In this study, we determine seven different cryo-electron microscopy structures of a Saccharomyces cerevisiae chitin synthase in the absence and presence of glycosyl donor, acceptor, product, or peptidyl nucleoside inhibitors. Combined with functional analyses, these structures show how the donor and acceptor substrates bind in the active site, how substrate hydrolysis drives self-priming, how a chitin-conducting transmembrane channel opens, and how peptidyl nucleoside inhibitors inhibit chitin synthase. Our work provides a structural basis for understanding the function and inhibition of chitin synthase.
    DOI:  https://doi.org/10.1038/s41467-023-40479-4
  36. Nat Commun. 2023 Aug 10. 14(1): 4588
    HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells.
    Mark F Santos, Germana Rappa, Jana Karbanová, Patrizia Diana, Girolamo Cirrincione, Daniela Carbone, David Manna, Feryal Aalam, David Wang, Cheryl Vanier, Denis Corbeil, Aurelio Lorico.
      The mechanism of human immunodeficiency virus 1 (HIV-1) nuclear entry, required for productive infection, is not fully understood. Here, we report that in HeLa cells and activated CD4+ T cells infected with HIV-1 pseudotyped with VSV-G and native Env protein, respectively, Rab7+ late endosomes containing endocytosed HIV-1 promote the formation of nuclear envelope invaginations (NEIs) by a molecular mechanism involving the VOR complex, composed of the outer nuclear membrane protein VAP-A, hyperphosphorylated ORP3 and Rab7. Silencing VAP-A or ORP3 and drug-mediated impairment of Rab7 binding to ORP3-VAP-A inhibited the nuclear transfer of the HIV-1 components and productive infection. In HIV-1-resistant quiescent CD4+ T cells, ORP3 was not hyperphosphorylated and neither VOR complex nor NEIs were formed. This new cellular pathway and its molecular players are potential therapeutic targets, perhaps shared by other viruses that require nuclear entry to complete their life cycle.
    DOI:  https://doi.org/10.1038/s41467-023-40227-8
  37. Commun Biol. 2023 08 09. 6(1): 827
    Cross-species transcriptomics reveals bifurcation point during the arterial-to-hemogenic transition.
    Shaokang Mo, Kengyuan Qu, Junfeng Huang, Qiwei Li, Wenqing Zhang, Kuangyu Yen.
      Hemogenic endothelium (HE) with hematopoietic stem cell (HSC)-forming potential emerge from specialized arterial endothelial cells (AECs) undergoing the endothelial-to-hematopoietic transition (EHT) in the aorta-gonad-mesonephros (AGM) region. Characterization of this AECs subpopulation and whether this phenomenon is conserved across species remains unclear. Here we introduce HomologySeeker, a cross-species method that leverages refined mouse information to explore under-studied human EHT. Utilizing single-cell transcriptomic ensembles of EHT, HomologySeeker reveals a parallel developmental relationship between these two species, with minimal pre-HSC signals observed in human cells. The pre-HE stage contains a conserved bifurcation point between the two species, where cells progress towards HE or late AECs. By harnessing human spatial transcriptomics, we identify ligand modules that contribute to the bifurcation choice and validate CXCL12 in promoting hemogenic choice using a human in vitro differentiation system. Our findings advance human arterial-to-hemogenic transition understanding and offer valuable insights for manipulating HSC generation using in vitro models.
    DOI:  https://doi.org/10.1038/s42003-023-05190-6
  38. Nat Commun. 2023 08 07. 14(1): 4736
    Brain criticality predicts individual levels of inter-areal synchronization in human electrophysiological data.
    Marco Fuscà, Felix Siebenhühner, Sheng H Wang, Vladislav Myrov, Gabriele Arnulfo, Lino Nobili, J Matias Palva, Satu Palva.
      Neuronal oscillations and their synchronization between brain areas are fundamental for healthy brain function. Yet, synchronization levels exhibit large inter-individual variability that is associated with behavioral variability. We test whether individual synchronization levels are predicted by individual brain states along an extended regime of critical-like dynamics - the Griffiths phase (GP). We use computational modelling to assess how synchronization is dependent on brain criticality indexed by long-range temporal correlations (LRTCs). We analyze LRTCs and synchronization of oscillations from resting-state magnetoencephalography and stereo-electroencephalography data. Synchronization and LRTCs are both positively linearly and quadratically correlated among healthy subjects, while in epileptogenic areas they are negatively linearly correlated. These results show that variability in synchronization levels is explained by the individual position along the GP with healthy brain areas operating in its subcritical and epileptogenic areas in its supercritical side. We suggest that the GP is fundamental for brain function allowing individual variability while retaining functional advantages of criticality.
    DOI:  https://doi.org/10.1038/s41467-023-40056-9
  39. Nat Commun. 2023 Aug 10. 14(1): 4490
    Effector-dependent structural transformation of a crystalline framework with allosteric effects on molecular recognition ability.
    Ryunosuke Hayashi, Shohei Tashiro, Masahiro Asakura, Shinya Mitsui, Mitsuhiko Shionoya.
      Structurally flexible porous crystals that combine high regularity and stimuli responsiveness have received attracted attention in connection with natural allostery found in regulatory systems of activity and function in biological systems. Porous crystals with molecular recognition sites in the inner pores are particularly promising for achieving elaborate functional control, where the local binding of effectors triggers their distortion to propagate throughout the structure. Here we report that the structure of a porous molecular crystal can be allosterically controlled by local adsorption of effectors within low-symmetry nanochannels with multiple molecular recognition sites. The exchange of effectors at the allosteric site triggers diverse conversion of the framework structure in an effector-dependent manner. In conjunction with the structural conversion, it is also possible to switch the molecular affinity at different recognition sites. These results may provide a guideline for the development of supramolecular materials with flexible and highly-ordered three-dimensional structures for biological applications.
    DOI:  https://doi.org/10.1038/s41467-023-40091-6
  40. Nat Immunol. 2023 Aug 10.
    Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC.
    John M Baer, Chong Zuo, Liang-I Kang, Angela Alarcon de la Lastra, Nicholas C Borcherding, Brett L Knolhoff, Savannah J Bogner, Yu Zhu, Liping Yang, Jennifer Laurent, Mark A Lewis, Nan Zhang, Ki-Wook Kim, Ryan C Fields, Wayne M Yokoyama, Jason C Mills, Li Ding, Gwendalyn J Randolph, David G DeNardo.
      Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.
    DOI:  https://doi.org/10.1038/s41590-023-01579-x
  41. Dev Cell. 2023 Jul 31. pii: S1534-5807(23)00348-9. [Epub ahead of print]
    Determination of key events in mouse hepatocyte maturation at the single-cell level.
    Li Yang, Xin Wang, Jia-Xi Zheng, Zi-Ran Xu, Lin-Chen Li, Yu-Long Xiong, Bi-Chen Zhou, Jie Gao, Cheng-Ran Xu.
      Hepatocytes, the liver's predominant cells, perform numerous essential biological functions. However, crucial events and regulators during hepatocyte maturation require in-depth investigation. In this study, we performed single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) to explore the precise hepatocyte development process in mice. We defined three maturation stages of postnatal hepatocytes, each of which establishes specific metabolic functions and exhibits distinct proliferation rates. Hepatic zonation is gradually formed during hepatocyte maturation. Hepatocytes or their nuclei with distinct ploidies exhibit zonation preferences in distribution and asynchrony in maturation. Moreover, by combining gene regulatory network analysis with in vivo genetic manipulation, we identified critical maturation- and zonation-related transcription factors. This study not only delineates the comprehensive transcriptomic profiles of hepatocyte maturation but also presents a paradigm to identify genes that function in the development of hepatocyte maturation and zonation by combining genetic manipulation and measurement of coordinates in a single-cell developmental trajectory.
    Keywords:  developmental trajectory; gene regulatory network; hepatic zonation; hepatocyte; liver maturation; metabolic function; polyploidy; proliferation; single-cell RNA-seq; single-nucleus RNA-seq
    DOI:  https://doi.org/10.1016/j.devcel.2023.07.006
  42. Nat Aging. 2023 Aug 10.
    Universal DNA methylation age across mammalian tissues.
    A T Lu, Z Fei, A Haghani, T R Robeck, J A Zoller, C Z Li, R Lowe, Q Yan, J Zhang, H Vu, J Ablaeva, V A Acosta-Rodriguez, D M Adams, J Almunia, A Aloysius, R Ardehali, A Arneson, C S Baker, G Banks, K Belov, N C Bennett, P Black, D T Blumstein, E K Bors, C E Breeze, R T Brooke, J L Brown, G G Carter, A Caulton, J M Cavin, L Chakrabarti, I Chatzistamou, H Chen, K Cheng, P Chiavellini, O W Choi, S M Clarke, L N Cooper, M L Cossette, J Day, J DeYoung, S DiRocco, C Dold, E E Ehmke, C K Emmons, S Emmrich, E Erbay, C Erlacher-Reid, C G Faulkes, S H Ferguson, C J Finno, J E Flower, J M Gaillard, E Garde, L Gerber, V N Gladyshev, V Gorbunova, R G Goya, M J Grant, C B Green, E N Hales, M B Hanson, D W Hart, M Haulena, K Herrick, A N Hogan, C J Hogg, T A Hore, T Huang, J C Izpisua Belmonte, A J Jasinska, G Jones, E Jourdain, O Kashpur, H Katcher, E Katsumata, V Kaza, H Kiaris, M S Kobor, P Kordowitzki, W R Koski, M Krützen, S B Kwon, B Larison, S G Lee, M Lehmann, J F Lemaitre, A J Levine, C Li, X Li, A R Lim, D T S Lin, D M Lindemann, T J Little, N Macoretta, D Maddox, C O Matkin, J A Mattison, M McClure, J Mergl, J J Meudt, G A Montano, K Mozhui, J Munshi-South, A Naderi, M Nagy, P Narayan, P W Nathanielsz, N B Nguyen, C Niehrs, J K O'Brien, P O'Tierney Ginn, D T Odom, A G Ophir, S Osborn, E A Ostrander, K M Parsons, K C Paul, M Pellegrini, K J Peters, A B Pedersen, J L Petersen, D W Pietersen, G M Pinho, J Plassais, J R Poganik, N A Prado, P Reddy, B Rey, B R Ritz, J Robbins, M Rodriguez, J Russell, E Rydkina, L L Sailer, A B Salmon, A Sanghavi, K M Schachtschneider, D Schmitt, T Schmitt, L Schomacher, L B Schook, K E Sears, A W Seifert, A Seluanov, A B A Shafer, D Shanmuganayagam, A V Shindyapina, M Simmons, K Singh, I Sinha, J Slone, R G Snell, E Soltanmaohammadi, M L Spangler, M C Spriggs, L Staggs, N Stedman, K J Steinman, D T Stewart, V J Sugrue, B Szladovits, J S Takahashi, M Takasugi, E C Teeling, M J Thompson, B Van Bonn, S C Vernes, D Villar, H V Vinters, M C Wallingford, N Wang, R K Wayne, G S Wilkinson, C K Williams, R W Williams, X W Yang, M Yao, B G Young, B Zhang, Z Zhang, P Zhao, Y Zhao, W Zhou, J Zimmermann, J Ernst, K Raj, S Horvath.
      Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.
    DOI:  https://doi.org/10.1038/s43587-023-00462-6
  43. Nat Commun. 2023 08 07. 14(1): 4723
    Backbone spiking sequence as a basis for preplay, replay, and default states in human cortex.
    Alex P Vaz, John H Wittig, Sara K Inati, Kareem A Zaghloul.
      Sequences of spiking activity have been heavily implicated as potential substrates of memory formation and retrieval across many species. A parallel line of recent evidence also asserts that sequential activity may arise from and be constrained by pre-existing network structure. Here we reconcile these two lines of research in the human brain by measuring single unit spiking sequences in the temporal lobe cortex as participants perform an episodic memory task. We find the presence of an average backbone spiking sequence identified during pre-task rest that is stable over time and different cognitive states. We further demonstrate that these backbone sequences are composed of both rigid and flexible sequence elements, and that flexible elements within these sequences serve to promote memory specificity when forming and retrieving new memories. These results support the hypothesis that pre-existing network dynamics serve as a scaffold for ongoing neural activity in the human cortex.
    DOI:  https://doi.org/10.1038/s41467-023-40440-5
  44. Cell Rep. 2023 Aug 08. pii: S2211-1247(23)00981-6. [Epub ahead of print]42(8): 112970
    Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets.
    Tom Barsby, Eliisa Vähäkangas, Jarkko Ustinov, Hossam Montaser, Hazem Ibrahim, Väinö Lithovius, Emilia Kuuluvainen, Vikash Chandra, Jonna Saarimäki-Vire, Pekka Katajisto, Ville Hietakangas, Timo Otonkoski.
      Pancreatic islets regulate blood glucose homeostasis through the controlled release of insulin; however, current metabolic models of glucose-sensitive insulin secretion are incomplete. A comprehensive understanding of islet metabolism is integral to studies of endocrine cell development as well as diabetic islet dysfunction. Human pluripotent stem cell-derived islets (SC-islets) are a developmentally relevant model of human islet function that have great potential in providing a cure for type 1 diabetes. Using multiple 13C-labeled metabolic fuels, we demonstrate that SC-islets show numerous divergent patterns of metabolite trafficking in proposed insulin release pathways compared with primary human islets but are still reliant on mitochondrial aerobic metabolism to derive function. Furthermore, reductive tricarboxylic acid cycle activity and glycolytic metabolite cycling occur in SC-islets, suggesting that non-canonical coupling factors are also present. In aggregate, we show that many facets of SC-islet metabolism overlap with those of primary islets, albeit with a retained immature signature.
    Keywords:  Beta cells; CP: Metabolism; diabetes; insulin; islets; metabolism; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2023.112970
  45. Nat Commun. 2023 08 05. 14(1): 4719
    Neural manifolds for odor-driven innate and acquired appetitive preferences.
    Rishabh Chandak, Baranidharan Raman.
      Sensory stimuli evoke spiking neural responses that innately or after learning drive suitable behavioral outputs. How are these spiking activities intrinsically patterned to encode for innate preferences, and could the neural response organization impose constraints on learning? We examined this issue in the locust olfactory system. Using a diverse odor panel, we found that ensemble activities both during ('ON response') and after stimulus presentations ('OFF response') could be linearly mapped onto overall appetitive preference indices. Although diverse, ON and OFF response patterns generated by innately appetitive odorants (higher palp-opening responses) were still limited to a low-dimensional subspace (a 'neural manifold'). Similarly, innately non-appetitive odorants evoked responses that were separable yet confined to another neural manifold. Notably, only odorants that evoked neural response excursions in the appetitive manifold could be associated with gustatory reward. In sum, these results provide insights into how encoding for innate preferences can also impact associative learning.
    DOI:  https://doi.org/10.1038/s41467-023-40443-2
  46. Science. 2023 Aug 11. 381(6658): 602-603
    A mammalian DNA methylation landscape.
    Alex de Mendoza.
      A study of 348 species offers clues into the diversity of mammalian life spans.
    DOI:  https://doi.org/10.1126/science.adj4904
  47. Nat Commun. 2023 Aug 10. 14(1): 4732
    Complementarity-determining region clustering may cause CAR-T cell dysfunction.
    Tina Sarén, Giulia Saronio, Paula Marti Torrell, Xu Zhu, Josefin Thelander, Yasmin Andersson, Camilla Hofström, Marika Nestor, Anna Dimberg, Helena Persson, Mohanraj Ramachandran, Di Yu, Magnus Essand.
      Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells.
    DOI:  https://doi.org/10.1038/s41467-023-40303-z
  48. Nat Genet. 2023 08;55(8): 1253
    Drug treatment and phenotypic diversity.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-023-01484-x
  49. Nat Commun. 2023 08 07. 14(1): 4750
    Getting personal with epigenetics: towards individual-specific epigenomic imputation with machine learning.
    Alex Hawkins-Hooker, Giovanni Visonà, Tanmayee Narendra, Mateo Rojas-Carulla, Bernhard Schölkopf, Gabriele Schweikert.
      Epigenetic modifications are dynamic mechanisms involved in the regulation of gene expression. Unlike the DNA sequence, epigenetic patterns vary not only between individuals, but also between different cell types within an individual. Environmental factors, somatic mutations and ageing contribute to epigenetic changes that may constitute early hallmarks or causal factors of disease. Epigenetic modifications are reversible and thus promising therapeutic targets for precision medicine. However, mapping efforts to determine an individual's cell-type-specific epigenome are constrained by experimental costs and tissue accessibility. To address these challenges, we developed eDICE, an attention-based deep learning model that is trained to impute missing epigenomic tracks by conditioning on observed tracks. Using a recently published set of epigenomes from four individual donors, we show that transfer learning across individuals allows eDICE to successfully predict individual-specific epigenetic variation even in tissues that are unmapped in a given donor. These results highlight the potential of machine learning-based imputation methods to advance personalized epigenomics.
    DOI:  https://doi.org/10.1038/s41467-023-40211-2
  50. Nature. 2023 Aug 11.
    Sharp resolution, big samples: ExA-SPIM microscope accelerates brain imaging.
    Alla Katsnelson.
      
    Keywords:  Brain; Imaging; Microscopy; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-02570-0
  51. Cell. 2023 Aug 03. pii: S0092-8674(23)00742-0. [Epub ahead of print]
    Distinct molecular profiles of skull bone marrow in health and neurological disorders.
    Zeynep Ilgin Kolabas, Louis B Kuemmerle, Robert Perneczky, Benjamin Förstera, Selin Ulukaya, Mayar Ali, Saketh Kapoor, Laura M Bartos, Maren Büttner, Ozum Sehnaz Caliskan, Zhouyi Rong, Hongcheng Mai, Luciano Höher, Denise Jeridi, Muge Molbay, Igor Khalin, Ioannis K Deligiannis, Moritz Negwer, Kenny Roberts, Alba Simats, Olga Carofiglio, Mihail I Todorov, Izabela Horvath, Furkan Ozturk, Selina Hummel, Gloria Biechele, Artem Zatcepin, Marcus Unterrainer, Johannes Gnörich, Jay Roodselaar, Joshua Shrouder, Pardis Khosravani, Benjamin Tast, Lisa Richter, Laura Díaz-Marugán, Doris Kaltenecker, Laurin Lux, Ying Chen, Shan Zhao, Boris-Stephan Rauchmann, Michael Sterr, Ines Kunze, Karen Stanic, Vanessa W Y Kan, Simon Besson-Girard, Sabrina Katzdobler, Carla Palleis, Julia Schädler, Johannes C Paetzold, Sabine Liebscher, Anja E Hauser, Ozgun Gokce, Heiko Lickert, Hanno Steinke, Corinne Benakis, Christian Braun, Celia P Martinez-Jimenez, Katharina Buerger, Nathalie L Albert, Günter Höglinger, Johannes Levin, Christian Haass, Anna Kopczak, Martin Dichgans, Joachim Havla, Tania Kümpfel, Martin Kerschensteiner, Martina Schifferer, Mikael Simons, Arthur Liesz, Natalie Krahmer, Omer A Bayraktar, Nicolai Franzmeier, Nikolaus Plesnila, Suheda Erener, Victor G Puelles, Claire Delbridge, Harsharan Singh Bhatia, Farida Hellal, Markus Elsner, Ingo Bechmann, Benjamin Ondruschka, Matthias Brendel, Fabian J Theis, Ali Erturk.
      The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.
    Keywords:  3D-imaging; DISCO clearing; PET imaging; immune cell trafficking; neuroinflammation; neurological disorders; non-invasive monitoring; proteomics; scRNA-seq; skull-brain connection
    DOI:  https://doi.org/10.1016/j.cell.2023.07.009
  52. Nat Commun. 2023 Aug 10. 14(1): 4848
    Stepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription.
    Chun-Yi Cho, Patrick H O'Farrell.
      Binding of transcription factors (TFs) promotes the subsequent recruitment of coactivators and preinitiation complexes to initiate eukaryotic transcription, but this time course is usually not visualized. It is commonly assumed that recruited factors eventually co-reside in a higher-order structure, allowing distantly bound TFs to activate transcription at core promoters. We use live imaging of endogenously tagged proteins, including the pioneer TF Zelda, the coactivator dBrd4, and RNA polymerase II (RNAPII), to define a cascade of events upstream of transcriptional initiation in early Drosophila embryos. These factors are sequentially and transiently recruited to discrete clusters during activation of non-histone genes. Zelda and the acetyltransferase dCBP nucleate dBrd4 clusters, which then trigger pre-transcriptional clustering of RNAPII. Subsequent transcriptional elongation disperses clusters of dBrd4 and RNAPII. Our results suggest that activation of transcription by eukaryotic TFs involves a succession of distinct biomolecular condensates that culminates in a self-limiting burst of transcription.
    DOI:  https://doi.org/10.1038/s41467-023-40485-6
  53. Immunity. 2023 08 08. pii: S1074-7613(23)00326-6. [Epub ahead of print]56(8): 1699-1701
    Resident dendritic cell density in the lymph node paracortex is preDC-estined.
    Rafael S Czepielewski, Gwendalyn J Randolph.
      Dendritic cells (DCs) are relatively short lived, yet DC frequencies in lymph nodes are stable. In this issue of Immunity, Ugur et al. reveal that type 1 conventional DCs (cDC1s) are maintained in the deep paracortex of the lymph node from a supply of preDCs that proliferate in nearby medullary vessels. Transition from preDC to cDC1 is regulated by Flt3L sensing.
    DOI:  https://doi.org/10.1016/j.immuni.2023.07.013
  54. Nat Aging. 2023 Aug 07.
    Clonal hematopoiesis reduces risk of Alzheimer's disease.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-023-00474-2
  55. Nat Commun. 2023 08 05. 14(1): 4713
    Molecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel.
    Ming Li, Yang Li, Yue Lu, Jianhui Li, Xuhang Lu, Yue Ren, Tianlei Wen, Yaojie Wang, Shenghai Chang, Xing Zhang, Xue Yang, Yuequan Shen.
      Mitochondrial RNA splicing 2 (Mrs2), a eukaryotic CorA ortholog, enables Mg2+ to permeate the inner mitochondrial membrane and plays an important role in mitochondrial metabolic function. However, the mechanism by which Mrs2 permeates Mg2+ remains unclear. Here, we report four cryo-electron microscopy (cryo-EM) reconstructions of Homo sapiens Mrs2 (hMrs2) under various conditions. All of these hMrs2 structures form symmetrical pentamers with very similar pentamer and protomer conformations. A special structural feature of Cl--bound R-ring, which consists of five Arg332 residues, was found in the hMrs2 structure. Molecular dynamics simulations and mitochondrial Mg2+ uptake assays show that the R-ring may function as a charge repulsion barrier, and Cl- may function as a ferry to jointly gate Mg2+ permeation in hMrs2. In addition, the membrane potential is likely to be the driving force for Mg2+ permeation. Our results provide insights into the channel assembly and Mg2+ permeation of hMrs2.
    DOI:  https://doi.org/10.1038/s41467-023-40516-2
  56. Science. 2023 Aug 11. 381(6658): eabq5693
    DNA methylation networks underlying mammalian traits.
    Amin Haghani, Caesar Z Li, Todd R Robeck, Joshua Zhang, Ake T Lu, Julia Ablaeva, Victoria A Acosta-Rodríguez, Danielle M Adams, Abdulaziz N Alagaili, Javier Almunia, Ajoy Aloysius, Nabil M S Amor, Reza Ardehali, Adriana Arneson, C Scott Baker, Gareth Banks, Katherine Belov, Nigel C Bennett, Peter Black, Daniel T Blumstein, Eleanor K Bors, Charles E Breeze, Robert T Brooke, Janine L Brown, Gerald Carter, Alex Caulton, Julie M Cavin, Lisa Chakrabarti, Ioulia Chatzistamou, Andreas S Chavez, Hao Chen, Kaiyang Cheng, Priscila Chiavellini, Oi-Wa Choi, Shannon Clarke, Joseph A Cook, Lisa N Cooper, Marie-Laurence Cossette, Joanna Day, Joseph DeYoung, Stacy Dirocco, Christopher Dold, Jonathan L Dunnum, Erin E Ehmke, Candice K Emmons, Stephan Emmrich, Ebru Erbay, Claire Erlacher-Reid, Chris G Faulkes, Zhe Fei, Steven H Ferguson, Carrie J Finno, Jennifer E Flower, Jean-Michel Gaillard, Eva Garde, Livia Gerber, Vadim N Gladyshev, Rodolfo G Goya, Matthew J Grant, Carla B Green, M Bradley Hanson, Daniel W Hart, Martin Haulena, Kelsey Herrick, Andrew N Hogan, Carolyn J Hogg, Timothy A Hore, Taosheng Huang, Juan Carlos Izpisua Belmonte, Anna J Jasinska, Gareth Jones, Eve Jourdain, Olga Kashpur, Harold Katcher, Etsuko Katsumata, Vimala Kaza, Hippokratis Kiaris, Michael S Kobor, Pawel Kordowitzki, William R Koski, Michael Krützen, Soo Bin Kwon, Brenda Larison, Sang-Goo Lee, Marianne Lehmann, Jean-François Lemaître, Andrew J Levine, Xinmin Li, Cun Li, Andrea R Lim, David T S Lin, Dana M Lindemann, Schuyler W Liphardt, Thomas J Little, Nicholas Macoretta, Dewey Maddox, Craig O Matkin, Julie A Mattison, Matthew McClure, June Mergl, Jennifer J Meudt, Gisele A Montano, Khyobeni Mozhui, Jason Munshi-South, William J Murphy, Asieh Naderi, Martina Nagy, Pritika Narayan, Peter W Nathanielsz, Ngoc B Nguyen, Christof Niehrs, Batsaikhan Nyamsuren, Justine K O'Brien, Perrie O'Tierney Ginn, Duncan T Odom, Alexander G Ophir, Steve Osborn, Elaine A Ostrander, Kim M Parsons, Kimberly C Paul, Amy B Pedersen, Matteo Pellegrini, Katharina J Peters, Jessica L Petersen, Darren W Pietersen, Gabriela M Pinho, Jocelyn Plassais, Jesse R Poganik, Natalia A Prado, Pradeep Reddy, Benjamin Rey, Beate R Ritz, Jooke Robbins, Magdalena Rodriguez, Jennifer Russell, Elena Rydkina, Lindsay L Sailer, Adam B Salmon, Akshay Sanghavi, Kyle M Schachtschneider, Dennis Schmitt, Todd Schmitt, Lars Schomacher, Lawrence B Schook, Karen E Sears, Ashley W Seifert, Aaron B A Shafer, Anastasia V Shindyapina, Melanie Simmons, Kavita Singh, Ishani Sinha, Jesse Slone, Russel G Snell, Elham Soltanmohammadi, Matthew L Spangler, Maria Spriggs, Lydia Staggs, Nancy Stedman, Karen J Steinman, Donald T Stewart, Victoria J Sugrue, Balazs Szladovits, Joseph S Takahashi, Masaki Takasugi, Emma C Teeling, Michael J Thompson, Bill Van Bonn, Sonja C Vernes, Diego Villar, Harry V Vinters, Ha Vu, Mary C Wallingford, Nan Wang, Gerald S Wilkinson, Robert W Williams, Qi Yan, Mingjia Yao, Brent G Young, Bohan Zhang, Zhihui Zhang, Yang Zhao, Peng Zhao, Wanding Zhou, Joseph A Zoller, Jason Ernst, Andrei Seluanov, Vera Gorbunova, X William Yang, Ken Raj, Steve Horvath.
      Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.
    DOI:  https://doi.org/10.1126/science.abq5693
  57. Nat Commun. 2023 08 08. 14(1): 4764
    Genomic dissection of endemic carbapenem resistance reveals metallo-beta-lactamase dissemination through clonal, plasmid and integron transfer.
    Nenad Macesic, Jane Hawkey, Ben Vezina, Jessica A Wisniewski, Hugh Cottingham, Luke V Blakeway, Taylor Harshegyi, Katherine Pragastis, Gnei Zweena Badoordeen, Amanda Dennison, Denis W Spelman, Adam W J Jenney, Anton Y Peleg.
      Infections caused by metallo-beta-lactamase-producing organisms (MBLs) are a global health threat. Our understanding of transmission dynamics and how MBLs establish endemicity remains limited. We analysed two decades of blaIMP-4 evolution in a hospital using sequence data from 270 clinical and environmental isolates (including 169 completed genomes) and identified the blaIMP-4 gene across 7 Gram-negative genera, 68 bacterial strains and 7 distinct plasmid types. We showed how an initial multi-species outbreak of conserved IncC plasmids (95 genomes across 37 strains) allowed endemicity to be established through the ability of blaIMP-4 to disseminate in successful strain-genetic setting pairs we termed propagators, in particular Serratia marcescens and Enterobacter hormaechei. From this reservoir, blaIMP-4 persisted through diversification of genetic settings that resulted from transfer of blaIMP-4 plasmids between bacterial hosts and of the integron carrying blaIMP-4 between plasmids. Our findings provide a framework for understanding endemicity and spread of MBLs and may have broader applicability to other carbapenemase-producing organisms.
    DOI:  https://doi.org/10.1038/s41467-023-39915-2
  58. Nat Struct Mol Biol. 2023 Aug 10.
    Droplet-based single-cell joint profiling of histone modifications and transcriptomes.
    Yang Xie, Chenxu Zhu, Zhaoning Wang, Melodi Tastemel, Lei Chang, Yang Eric Li, Bing Ren.
      We previously reported Paired-Tag, a combinatorial indexing-based method that can simultaneously map histone modifications and gene expression at single-cell resolution at scale. However, the lengthy procedure of Paired-Tag has hindered its general adoption in the community. To address this bottleneck, we developed a droplet-based Paired-Tag protocol that is faster and more accessible than the previous method. Using cultured mammalian cells and primary brain tissues, we demonstrate its superior performance at identifying candidate cis-regulatory elements and associating their dynamic chromatin state to target gene expression in each constituent cell type in a complex tissue.
    DOI:  https://doi.org/10.1038/s41594-023-01060-1
  59. Proc Natl Acad Sci U S A. 2023 08 15. 120(33): e2303809120
    Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway.
    Akiko Nakano-Kobayashi, Andres Canela, Toru Yoshihara, Masatoshi Hagiwara.
      Neuroinflammation is a common feature of neurodegenerative disorders such as Alzheimer's disease (AD). Neuroinflammation is induced by dysregulated glial activation, and astrocytes, the most abundant glial cells, become reactive upon neuroinflammatory cytokines released from microglia and actively contribute to neuronal loss. Therefore, blocking reactive astrocyte functions is a viable strategy to manage neurodegenerative disorders. However, factors or therapeutics directly regulating astrocyte subtypes remain unexplored. Here, we identified transcription factor NF-E2-related factor 2 (Nrf2) as a therapeutic target in neurotoxic reactive astrocytes upon neuroinflammation. We found that the absence of Nrf2 promoted the activation of reactive astrocytes in the brain tissue samples obtained from AD model 5xFAD mice, whereas enhanced Nrf2 expression blocked the induction of reactive astrocyte gene expression by counteracting NF-κB subunit p65 recruitment. Neuroinflammatory astrocytes robustly up-regulated genes associated with type I interferon and the antigen-presenting pathway, which were suppressed by Nrf2 pathway activation. Moreover, impaired cognitive behaviors observed in AD mice were rescued upon ALGERNON2 treatment, which potentiated the Nrf2 pathway and reduced the induction of neurotoxic reactive astrocytes. Thus, we highlight the potential of astrocyte-targeting therapy by promoting the Nrf2 pathway signaling for neuroinflammation-triggered neurodegeneration.
    Keywords:  Nrf2; neuroinflammation; neurotoxic reactive astrocytes
    DOI:  https://doi.org/10.1073/pnas.2303809120
  60. Nat Commun. 2023 08 05. 14(1): 4714
    BtuB TonB-dependent transporters and BtuG surface lipoproteins form stable complexes for vitamin B12 uptake in gut Bacteroides.
    Javier Abellon-Ruiz, Kalyanashis Jana, Augustinas Silale, Andrew M Frey, Arnaud Baslé, Matthias Trost, Ulrich Kleinekathöfer, Bert van den Berg.
      Vitamin B12 (cobalamin) is required for most human gut microbes, many of which are dependent on scavenging to obtain this vitamin. Since bacterial densities in the gut are extremely high, competition for this keystone micronutrient is severe. Contrasting with Enterobacteria, members of the dominant genus Bacteroides often encode several BtuB vitamin B12 outer membrane transporters together with a conserved array of surface-exposed B12-binding lipoproteins. Here we show that the BtuB transporters from Bacteroides thetaiotaomicron form stable, pedal bin-like complexes with surface-exposed BtuG lipoprotein lids, which bind B12 with high affinities. Closing of the BtuG lid following B12 capture causes destabilisation of the bound B12 by a conserved BtuB extracellular loop, causing translocation of the vitamin to BtuB and subsequent transport. We propose that TonB-dependent, lipoprotein-assisted small molecule uptake is a general feature of Bacteroides spp. that is important for the success of this genus in colonising the human gut.
    DOI:  https://doi.org/10.1038/s41467-023-40427-2
  61. Cell. 2023 Aug 01. pii: S0092-8674(23)00745-6. [Epub ahead of print]
    Cooperative assembly confers regulatory specificity and long-term genetic circuit stability.
    Meghan D J Bragdon, Nikit Patel, James Chuang, Ethan Levien, Caleb J Bashor, Ahmad S Khalil.
      A ubiquitous feature of eukaryotic transcriptional regulation is cooperative self-assembly between transcription factors (TFs) and DNA cis-regulatory motifs. It is thought that this strategy enables specific regulatory connections to be formed in gene networks between otherwise weakly interacting, low-specificity molecular components. Here, using synthetic gene circuits constructed in yeast, we find that high regulatory specificity can emerge from cooperative, multivalent interactions among artificial zinc-finger-based TFs. We show that circuits "wired" using the strategy of cooperative TF assembly are effectively insulated from aberrant misregulation of the host cell genome. As we demonstrate in experiments and mathematical models, this mechanism is sufficient to rescue circuit-driven fitness defects, resulting in genetic and functional stability of circuits in long-term continuous culture. Our naturally inspired approach offers a simple, generalizable means for building high-fidelity, evolutionarily robust gene circuits that can be scaled to a wide range of host organisms and applications.
    Keywords:  cooperativity; fitness; gene circuits; gene regulation; modeling; specificity; synthetic biology; transcription factor; yeast; zinc fingers
    DOI:  https://doi.org/10.1016/j.cell.2023.07.012
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