bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–11–19
47 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Gut Treg cells release IL-27 to regulate TH17 cell responses.
  2. Working up an appetite to promote repair.
  3. Emergence of task-related spatiotemporal population dynamics in transplanted neurons.
  4. Imaging nuclear architecture in single cells.
  5. Combining a first-in-class SLAMF7 antibody with SIRPα blockade for anti-tumor immunity.
  6. The E3 ligase Riplet promotes RIG-I signaling independent of RIG-I oligomerization.
  7. Manganese controls lipoprotein secretion via biomolecular condensation.
  8. Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB-CD8+ memory T cells and accumulation of type 2 memory T cells.
  9. Dietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15.
  10. Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.
  11. Altered corollary discharge signaling in the auditory cortex of a mouse model of schizophrenia predisposition.
  12. Embryo-scale reverse genetics at single-cell resolution.
  13. Dimension-agnostic and granularity-based spatially variable gene identification using BSP.
  14. HSP47 levels determine the degree of body adiposity.
  15. Profiling stress-triggered RNA condensation with photocatalytic proximity labeling.
  16. Germinal centers output clonally diverse plasma cell populations expressing high- and low-affinity antibodies.
  17. Single-cell, whole-embryo phenotyping of mammalian developmental disorders.
  18. Deep learning of human polyadenylation sites at nucleotide resolution reveals molecular determinants of site usage and relevance in disease.
  19. SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway.
  20. Plasma Cell Differentiation, Antibody Quality, and Initial Germinal Center B Cell Population Depend on Glucose Influx Rate.
  21. Start codon-associated ribosomal frameshifting mediates nutrient stress adaptation.
  22. Giant UK programme to lower people's blood-sugar levels really works.
  23. GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.
  24. The molecular genetic landscape of human brain size variation.
  25. Primate-specific ZNF808 is essential for pancreatic development in humans.
  26. Clinically relevant antibiotic resistance genes are linked to a limited set of taxa within gut microbiome worldwide.
  27. SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
  28. Constructing temporal networks with bursty activity patterns.
  29. Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.
  30. Single-cell transcriptomics stratifies organoid models of metabolic dysfunction-associated steatotic liver disease.
  31. A robotic sensory system with high spatiotemporal resolution for texture recognition.
  32. Targeted suppression of mTORC2 reduces seizures across models of epilepsy.
  33. A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors.
  34. A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan.
  35. Fatty acid desaturation and lipoxygenase pathways support trained immunity.
  36. Trained immunity induced by high-salt diet impedes stroke recovery.
  37. Superior colliculus bidirectionally modulates choice activity in frontal cortex.
  38. Actomyosin and CSI1/POM2 cooperate to deliver cellulose synthase from Golgi to cortical microtubules in Arabidopsis.
  39. A Cre-dependent massively parallel reporter assay allows for cell-type specific assessment of the functional effects of non-coding elements in vivo.
  40. Dynamics and durability of HIV-1 neutralization are determined by viral replication.
  41. m6A methylation of super-enhancer RNAs facilitates chromatin accessibility.
  42. Distinct Functional Humoral Immune Responses Are Induced after Live Attenuated and Inactivated Seasonal Influenza Vaccination.
  43. Zika virus prM protein contains cholesterol binding motifs required for virus entry and assembly.
  44. Determining the longevity and dynamics of HIV-1 neutralizing activity.
  45. Age-associated H3K9me2 loss alters the regenerative equilibrium between murine lung alveolar and bronchiolar progenitors.
  46. ACD15, ACD21, and SLN regulate the accumulation and mobility of MBD6 to silence genes and transposable elements.
  47. Design principles of 3D epigenetic memory systems.
  1. Nat Immunol. 2023 Nov 16.
    Gut Treg cells release IL-27 to regulate TH17 cell responses.
      
    DOI:  https://doi.org/10.1038/s41590-023-01681-0
  2. Science. 2023 Nov 17. 382(6672): 780
    Working up an appetite to promote repair.
    Rachel M Kratofil.
      Immune-derived hunger hormones restore tissue after infection.
    DOI:  https://doi.org/10.1126/science.adl4292
  3. Nat Commun. 2023 Nov 11. 14(1): 7320
    Emergence of task-related spatiotemporal population dynamics in transplanted neurons.
    Harman Ghuman, Kyungsoo Kim, Sapeeda Barati, Karunesh Ganguly.
      Loss of nervous system tissue after severe brain injury is a main determinant of poor functional recovery. Cell transplantation is a promising method to restore lost tissue and function, yet it remains unclear if transplanted neurons can demonstrate the population level dynamics important for movement control. Here we present a comprehensive approach for long-term single neuron monitoring and manipulation of transplanted embryonic cortical neurons after cortical injury in adult male mice performing a prehension task. The observed patterns of population activity in the transplanted network strongly resembled that of healthy networks. Specifically, the task-related spatiotemporal activity patterns of transplanted neurons could be represented by latent factors that evolve within a low dimensional manifold. We also demonstrate reliable modulation of the transplanted networks using minimally invasive epidural stimulation. Our approach may allow greater insight into how restoration of cell-type specific network dynamics in vivo can restore motor function.
    DOI:  https://doi.org/10.1038/s41467-023-43081-w
  4. Science. 2023 Nov 17. 382(6672): 780
    Imaging nuclear architecture in single cells.
    Yodai Takei.
      Multiplexed imaging uncovers precise three-dimensional maps of single nuclei.
    DOI:  https://doi.org/10.1126/science.adl4460
  5. Nat Immunol. 2023 Nov 13.
    Combining a first-in-class SLAMF7 antibody with SIRPα blockade for anti-tumor immunity.
      
    DOI:  https://doi.org/10.1038/s41590-023-01673-0
  6. Nat Commun. 2023 Nov 11. 14(1): 7308
    The E3 ligase Riplet promotes RIG-I signaling independent of RIG-I oligomerization.
    Wenshuai Wang, Benjamin Götte, Rong Guo, Anna Marie Pyle.
      RIG-I is an essential innate immune receptor that responds to infection by RNA viruses. The RIG-I signaling cascade is mediated by a series of post-translational modifications, the most important of which is ubiquitination of the RIG-I Caspase Recruitment Domains (CARDs) by E3 ligase Riplet. This is required for interaction between RIG-I and its downstream adapter protein MAVS, but the mechanism of action remains unclear. Here we show that Riplet is required for RIG-I signaling in the presence of both short and long dsRNAs, establishing that Riplet activation does not depend upon RIG-I filament formation on long dsRNAs. Likewise, quantitative Riplet-RIG-I affinity measurements establish that Riplet interacts with RIG-I regardless of whether the receptor is bound to RNA. To understand this, we solved high-resolution cryo-EM structures of RIG-I/RNA/Riplet complexes, revealing molecular interfaces that control Riplet-mediated activation and enabling the formulation of a unified model for the role of Riplet in signaling.
    DOI:  https://doi.org/10.1038/s41467-023-42982-0
  7. Nat Cell Biol. 2023 Nov 17.
    Manganese controls lipoprotein secretion via biomolecular condensation.
      
    DOI:  https://doi.org/10.1038/s41556-023-01300-y
  8. Immunity. 2023 Nov 05. pii: S1074-7613(23)00453-3. [Epub ahead of print]
    Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB-CD8+ memory T cells and accumulation of type 2 memory T cells.
    Marina Terekhova, Amanda Swain, Pavla Bohacova, Ekaterina Aladyeva, Laura Arthur, Anwesha Laha, Denis A Mogilenko, Samantha Burdess, Vladimir Sukhov, Denis Kleverov, Barbora Echalar, Petr Tsurinov, Roman Chernyatchik, Kamila Husarcikova, Maxim N Artyomov.
      Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25-85 years old. From this, we generated a dataset from ∼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZMK+CD8+ T cells and HLA-DR+CD4+ T cells. In contrast to other T cell memory subsets, transcriptionally distinct NKG2C+GZMB-CD8+ T cells counterintuitively decreased with age. Furthermore, we found a concerted age-associated increase in type 2/interleukin (IL)4-expressing memory subpopulations across CD4+ and CD8+ T cell compartments (CCR4+CD8+ Tcm and Th2 CD4+ Tmem), suggesting a systematic functional shift in immune homeostasis with age. Our work provides novel insights into healthy human aging and a comprehensive annotated resource.
    Keywords:  CCR4(+)CD8(+) T cells; NKG2C(+)GZMB(-)CD8(+) T cells; PBMC; TCR/BCR sequencing; Th2; aging; human; scRNA-seq; surface protein
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.013
  9. Nat Commun. 2023 Nov 14. 14(1): 7363
    Dietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15.
    Nguyen T Van, Karen Zhang, Rachel M Wigmore, Anne I Kennedy, Carolina R DaSilva, Jialing Huang, Manju Ambelil, Jose H Villagomez, Gerald J O'Connor, Randy S Longman, Miao Cao, Adam E Snook, Michael Platten, Gerard Kasenty, Luis J Sigal, George C Prendergast, Sangwon V Kim.
      Environmental factors are the major contributor to the onset of immunological disorders such as ulcerative colitis. However, their identities remain unclear. Here, we discover that the amount of consumed L-Tryptophan (L-Trp), a ubiquitous dietary component, determines the transcription level of the colonic T cell homing receptor, GPR15, hence affecting the number of colonic FOXP3+ regulatory T (Treg) cells and local immune homeostasis. Ingested L-Trp is converted by host IDO1/2 enzymes, but not by gut microbiota, to compounds that induce GPR15 transcription preferentially in Treg cells via the aryl hydrocarbon receptor. Consequently, two weeks of dietary L-Trp supplementation nearly double the colonic GPR15+ Treg cells via GPR15-mediated homing and substantially reduce the future risk of colitis. In addition, humans consume 3-4 times less L-Trp per kilogram of body weight and have fewer colonic GPR15+ Treg cells than mice. Thus, we uncover a microbiota-independent mechanism linking dietary L-Trp and colonic Treg cells, that may have therapeutic potential.
    DOI:  https://doi.org/10.1038/s41467-023-43211-4
  10. Nat Commun. 2023 Nov 17. 14(1): 7471
    Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.
    Marlies Cortés, Agnese Brischetto, M C Martinez-Campanario, Chiara Ninfali, Verónica Domínguez, Sara Fernández, Raquel Celis, Anna Esteve-Codina, Juan J Lozano, Julia Sidorova, Gloria Garrabou, Anna-Maria Siegert, Carlos Enrich, Belén Pintado, Manuel Morales-Ruiz, Pedro Castro, Juan D Cañete, Antonio Postigo.
      Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.
    DOI:  https://doi.org/10.1038/s41467-023-42277-4
  11. Nat Commun. 2023 Nov 15. 14(1): 7388
    Altered corollary discharge signaling in the auditory cortex of a mouse model of schizophrenia predisposition.
    Brian P Rummell, Solmaz Bikas, Susanne S Babl, Joseph A Gogos, Torfi Sigurdsson.
      The ability to distinguish sensations that are self-generated from those caused by external events is disrupted in schizophrenia patients. However, the neural circuit abnormalities underlying this sensory impairment and its relationship to the risk factors for the disease is not well understood. To address this, we examined the processing of self-generated sounds in male Df(16)A+/- mice, which model one of the largest genetic risk factors for schizophrenia, the 22q11.2 microdeletion. We find that auditory cortical neurons in Df(16)A+/- mice fail to attenuate their responses to self-generated sounds, recapitulating deficits seen in schizophrenia patients. Notably, the auditory cortex of Df(16)A+/- mice displayed weaker motor-related signals and received fewer inputs from the motor cortex, suggesting an anatomical basis underlying the sensory deficit. These results provide insights into the mechanisms by which a major genetic risk factor for schizophrenia disrupts the top-down processing of sensory information.
    DOI:  https://doi.org/10.1038/s41467-023-42964-2
  12. Nature. 2023 Nov 15.
    Embryo-scale reverse genetics at single-cell resolution.
    Lauren M Saunders, Sanjay R Srivatsan, Madeleine Duran, Michael W Dorrity, Brent Ewing, Tor H Linbo, Jay Shendure, David W Raible, Cecilia B Moens, David Kimelman, Cole Trapnell.
      The maturation of single-cell transcriptomic technologies has facilitated the generation of comprehensive cellular atlases from whole embryos1-4. A majority of these data, however, has been collected from wild-type embryos without an appreciation for the latent variation that is present in development. Here we present the 'zebrafish single-cell atlas of perturbed embryos': single-cell transcriptomic data from 1,812 individually resolved developing zebrafish embryos, encompassing 19 timepoints, 23 genetic perturbations and a total of 3.2 million cells. The high degree of replication in our study (eight or more embryos per condition) enables us to estimate the variance in cell type abundance organism-wide and to detect perturbation-dependent deviance in cell type composition relative to wild-type embryos. Our approach is sensitive to rare cell types, resolving developmental trajectories and genetic dependencies in the cranial ganglia neurons, a cell population that comprises less than 1% of the embryo. Additionally, time-series profiling of individual mutants identified a group of brachyury-independent cells with strikingly similar transcriptomes to notochord sheath cells, leading to new hypotheses about early origins of the skull. We anticipate that standardized collection of high-resolution, organism-scale single-cell data from large numbers of individual embryos will enable mapping of the genetic dependencies of zebrafish cell types, while also addressing longstanding challenges in developmental genetics, including the cellular and transcriptional plasticity underlying phenotypic diversity across individuals.
    DOI:  https://doi.org/10.1038/s41586-023-06720-2
  13. Nat Commun. 2023 Nov 14. 14(1): 7367
    Dimension-agnostic and granularity-based spatially variable gene identification using BSP.
    Juexin Wang, Jinpu Li, Skyler T Kramer, Li Su, Yuzhou Chang, Chunhui Xu, Michael T Eadon, Krzysztof Kiryluk, Qin Ma, Dong Xu.
      Identifying spatially variable genes (SVGs) is critical in linking molecular cell functions with tissue phenotypes. Spatially resolved transcriptomics captures cellular-level gene expression with corresponding spatial coordinates in two or three dimensions and can be used to infer SVGs effectively. However, current computational methods may not achieve reliable results and often cannot handle three-dimensional spatial transcriptomic data. Here we introduce BSP (big-small patch), a non-parametric model by comparing gene expression pattens at two spatial granularities to identify SVGs from two or three-dimensional spatial transcriptomics data in a fast and robust manner. This method has been extensively tested in simulations, demonstrating superior accuracy, robustness, and high efficiency. BSP is further validated by substantiated biological discoveries in cancer, neural science, rheumatoid arthritis, and kidney studies with various types of spatial transcriptomics technologies.
    DOI:  https://doi.org/10.1038/s41467-023-43256-5
  14. Nat Commun. 2023 11 11. 14(1): 7319
    HSP47 levels determine the degree of body adiposity.
    Jihoon Shin, Shinichiro Toyoda, Yosuke Okuno, Reiko Hayashi, Shigeki Nishitani, Toshiharu Onodera, Haruyo Sakamoto, Shinya Ito, Sachiko Kobayashi, Hirofumi Nagao, Shunbun Kita, Michio Otsuki, Atsunori Fukuhara, Kazuhiro Nagata, Iichiro Shimomura.
      Adiposity varies among individuals with the influence of diverse physiological, pathological, environmental, hormonal, and genetic factors, but a unified molecular basis remains elusive. Here, we identify HSP47, a collagen-specific chaperone, as a key determinant of body adiposity. HSP47 expression is abundant in adipose tissue; increased with feeding, overeating, and obesity; decreased with fasting, exercise, calorie restriction, bariatric surgery, and cachexia; and correlated with fat mass, BMI, waist, and hip circumferences. Insulin and glucocorticoids, respectively, up- and down-regulate HSP47 expression. In humans, the increase of HSP47 gene expression by its intron or synonymous variants is associated with higher body adiposity traits. In mice, the adipose-specific knockout or pharmacological inhibition of HSP47 leads to lower body adiposity compared to the control. Mechanistically, HSP47 promotes collagen dynamics in the folding, secretion, and interaction with integrin, which activates FAK signaling and preserves PPARγ protein from proteasomal degradation, partly related to MDM2. The study highlights the significance of HSP47 in determining the amount of body fat individually and under various circumstances.
    DOI:  https://doi.org/10.1038/s41467-023-43080-x
  15. Nat Commun. 2023 Nov 15. 14(1): 7390
    Profiling stress-triggered RNA condensation with photocatalytic proximity labeling.
    Ziqi Ren, Wei Tang, Luxin Peng, Peng Zou.
      Stress granules (SGs) are highly dynamic cytoplasmic membrane-less organelles that assemble when cells are challenged by stress. RNA molecules are sorted into SGs where they play important roles in maintaining the structural stability of SGs and regulating gene expression. Herein, we apply a proximity-dependent RNA labeling method, CAP-seq, to comprehensively investigate the content of SG-proximal transcriptome in live mammalian cells. CAP-seq captures 457 and 822 RNAs in arsenite- and sorbitol-induced SGs in HEK293T cells, respectively, revealing that SG enrichment is positively correlated with RNA length and AU content, but negatively correlated with translation efficiency. The high spatial specificity of CAP-seq dataset is validated by single-molecule FISH imaging. We further apply CAP-seq to map dynamic changes in SG-proximal transcriptome along the time course of granule assembly and disassembly processes. Our data portray a model of AU-rich and translationally repressed SG nanostructure that are memorized long after the removal of stress.
    DOI:  https://doi.org/10.1038/s41467-023-43194-2
  16. Cell. 2023 Nov 07. pii: S0092-8674(23)01173-X. [Epub ahead of print]
    Germinal centers output clonally diverse plasma cell populations expressing high- and low-affinity antibodies.
    Adrien Sprumont, Ana Rodrigues, Simon J McGowan, Colin Bannard, Oliver Bannard.
      Germinal centers (GCs) form in lymph nodes after immunization or infection to facilitate antibody affinity maturation and memory and plasma cell (PC) development. PC differentiation is thought to involve stringent selection for GC B cells expressing the highest-affinity antigen receptors, but how this plays out during complex polyclonal responses is unclear. We combine temporal lineage tracing with antibody characterization to gain a snapshot of PCs developing during influenza infection. GCs co-mature B cell clones with antibody affinities spanning multiple orders of magnitude; however, each generates PCs with similar efficiencies, including weak binders. Within lineages, PC selection is not restricted to variants with the highest-affinity antibodies. Differentiation is commonly associated with proliferative expansion to produce "nodes" of identical PCs. Immunization-induced GCs generate fewer PCs but still of low- and high-antibody affinities. We propose that generating low-affinity antibody PCs reflects an evolutionary compromise to facilitate diverse serum antibody responses.
    Keywords:  B cells; antibody; antibody affinity maturation; germinal center; immunology; influenza infection; lymph node; lymphocyte differentiation; plasma cells; vaccines
    DOI:  https://doi.org/10.1016/j.cell.2023.10.022
  17. Nature. 2023 Nov 15.
    Single-cell, whole-embryo phenotyping of mammalian developmental disorders.
    Xingfan Huang, Jana Henck, Chengxiang Qiu, Varun K A Sreenivasan, Saranya Balachandran, Oana V Amarie, Martin Hrabě de Angelis, Rose Yinghan Behncke, Wing-Lee Chan, Alexandra Despang, Diane E Dickel, Madeleine Duran, Annette Feuchtinger, Helmut Fuchs, Valerie Gailus-Durner, Natja Haag, Rene Hägerling, Nils Hansmeier, Friederike Hennig, Cooper Marshall, Sudha Rajderkar, Alessa Ringel, Michael Robson, Lauren M Saunders, Patricia da Silva-Buttkus, Nadine Spielmann, Sanjay R Srivatsan, Sascha Ulferts, Lars Wittler, Yiwen Zhu, Vera M Kalscheuer, Daniel M Ibrahim, Ingo Kurth, Uwe Kornak, Axel Visel, Len A Pennacchio, David R Beier, Cole Trapnell, Junyue Cao, Jay Shendure, Malte Spielmann.
      Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.
    DOI:  https://doi.org/10.1038/s41586-023-06548-w
  18. Nat Commun. 2023 Nov 15. 14(1): 7378
    Deep learning of human polyadenylation sites at nucleotide resolution reveals molecular determinants of site usage and relevance in disease.
    Emily Kunce Stroup, Zhe Ji.
      The genomic distribution of cleavage and polyadenylation (polyA) sites should be co-evolutionally optimized with the local gene structure. Otherwise, spurious polyadenylation can cause premature transcription termination and generate aberrant proteins. To obtain mechanistic insights into polyA site optimization across the human genome, we develop deep/machine learning models to identify genome-wide putative polyA sites at unprecedented nucleotide-level resolution and calculate their strength and usage in the genomic context. Our models quantitatively measure position-specific motif importance and their crosstalk in polyA site formation and cleavage heterogeneity. The intronic site expression is governed by the surrounding splicing landscape. The usage of alternative polyA sites in terminal exons is modulated by their relative locations and distance to downstream genes. Finally, we apply our models to reveal thousands of disease- and trait-associated genetic variants altering polyadenylation activity. Altogether, our models represent a valuable resource to dissect molecular mechanisms mediating genome-wide polyA site expression and characterize their functional roles in human diseases.
    DOI:  https://doi.org/10.1038/s41467-023-43266-3
  19. Nat Commun. 2023 Nov 17. 14(1): 7441
    SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway.
    Beibei Fu, Yan Xiong, Zhou Sha, Weiwei Xue, Binbin Xu, Shun Tan, Dong Guo, Feng Lin, Lulu Wang, Jianjian Ji, Yang Luo, Xiaoyuan Lin, Haibo Wu.
      Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection.
    DOI:  https://doi.org/10.1038/s41467-023-43283-2
  20. J Immunol. 2023 Nov 13. pii: ji2200756. [Epub ahead of print]
    Plasma Cell Differentiation, Antibody Quality, and Initial Germinal Center B Cell Population Depend on Glucose Influx Rate.
    Shawna K Brookens, Sung Hoon Cho, Yeeun Paik, Kaylor Meyer, Ariel L Raybuck, Chloe Park, Dalton L Greenwood, Jeffrey C Rathmell, Mark R Boothby.
      Serum Ab concentrations, selection for higher affinity BCRs, and generation of higher Ab affinities are important elements of immune response optimization and functions of germinal center (GC) reactions. B cell proliferation requires nutrients to support the anabolism inherent in clonal expansion. Glucose usage by mouse GC B cells has been reported to contribute little to their energy needs, with questions raised as to whether glucose uptake or glycolysis increases in GC B cells compared with their naive precursors. Indeed, metabolism can be highly flexible, such that supply shortage along one pathway may be compensated by increased flux on others. We now show that reduction of the glucose transporter GLUT1 in mice after establishment of a preimmune B cell repertoire, even after initiation of the GC B cell gene expression program, decreased initial GC B cell population numbers, affinity maturation, and plasma cell outputs. Glucose oxidation was heightened in GC B cells, but this hexose flowed more into the pentose phosphate pathway, whose activity was important in controlling reactive oxygen species (ROS) and Ab-secreting cell production. In modeling how glucose usage by B cells promotes the Ab response, the control of ROS appeared insufficient. Surprisingly, the combination of galactose, which mitigated ROS, with provision of mannose, an efficient precursor to glycosylation, supported robust production of and normal Ab secretion by Ab-secreting cells under glucose-free conditions. Collectively, the findings indicate that GCs depend on normal glucose influx, especially in plasma cell production, but reveal an unexpected metabolic flexibility in hexose requirements.
    DOI:  https://doi.org/10.4049/jimmunol.2200756
  21. Nat Struct Mol Biol. 2023 Nov;30(11): 1816-1825
    Start codon-associated ribosomal frameshifting mediates nutrient stress adaptation.
    Yuanhui Mao, Longfei Jia, Leiming Dong, Xin Erica Shu, Shu-Bing Qian.
      A translating ribosome is typically thought to follow the reading frame defined by the selected start codon. Using super-resolution ribosome profiling, here we report pervasive out-of-frame translation immediately from the start codon. Start codon-associated ribosomal frameshifting (SCARF) stems from the slippage of ribosomes during the transition from initiation to elongation. Using a massively paralleled reporter assay, we uncovered sequence elements acting as SCARF enhancers or repressors, implying that start codon recognition is coupled with reading frame fidelity. This finding explains thousands of mass spectrometry spectra that are unannotated in the human proteome. Mechanistically, we find that the eukaryotic initiation factor 5B (eIF5B) maintains the reading frame fidelity by stabilizing initiating ribosomes. Intriguingly, amino acid starvation induces SCARF by proteasomal degradation of eIF5B. The stress-induced SCARF protects cells from starvation by enabling amino acid recycling and selective mRNA translation. Our findings illustrate a beneficial effect of translational 'noise' in nutrient stress adaptation.
    DOI:  https://doi.org/10.1038/s41594-023-01119-z
  22. Nature. 2023 Nov 15.
    Giant UK programme to lower people's blood-sugar levels really works.
    Heidi Ledford.
      
    Keywords:  Diabetes; Epidemiology; Metabolism; Nutrition; Public health
    DOI:  https://doi.org/10.1038/d41586-023-03524-2
  23. Nat Commun. 2023 Nov 17. 14(1): 7476
    GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.
    Di-Xian Wang, Zhao-Jun Dong, Sui-Xin Deng, Ying-Ming Tian, Yu-Jie Xiao, Xinran Li, Xiao-Ru Ma, Liang Li, Pengxiao Li, Hui-Zhong Chang, Longqi Liu, Fan Wang, Yang Wu, Xiang Gao, Shuang-Shuang Zheng, Hui-Min Gu, Ya-Nan Zhang, Jian-Bin Wu, Fan Wu, Yonglin Peng, Xiao-Wen Zhang, Ren-Ya Zhan, Li-Xia Gao, Qiming Sun, Xing Guo, Xiao-Dong Zhao, Jian-Hong Luo, Ruhong Zhou, Lei Han, Yousheng Shu, Jing-Wei Zhao.
      As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.
    DOI:  https://doi.org/10.1038/s41467-023-43292-1
  24. Cell Rep. 2023 Nov 13. pii: S2211-1247(23)01451-1. [Epub ahead of print]42(11): 113439
    The molecular genetic landscape of human brain size variation.
    Lifespan Brain Chart Consortium
      Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease.
    Keywords:  CP: Neuroscience; TWAS; brain development; imaging genetics; psychiatric disorders; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2023.113439
  25. Nat Genet. 2023 Nov 16.
    Primate-specific ZNF808 is essential for pancreatic development in humans.
    Pancreatic Agenesis Gene Discovery Consortium
      Identifying genes linked to extreme phenotypes in humans has the potential to highlight biological processes not shared with all other mammals. Here, we report the identification of homozygous loss-of-function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein family, a large and rapidly evolving group of epigenetic silencers which target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of regulatory potential contained in the primate-specific transposable elements it represses during early pancreas development. This leads to inappropriate specification of cell fate with induction of genes associated with liver identity. Our results highlight the essential role of ZNF808 in pancreatic development in humans and the contribution of primate-specific regions of the human genome to congenital developmental disease.
    DOI:  https://doi.org/10.1038/s41588-023-01565-x
  26. Nat Commun. 2023 Nov 14. 14(1): 7366
    Clinically relevant antibiotic resistance genes are linked to a limited set of taxa within gut microbiome worldwide.
    Peter J Diebold, Matthew W Rhee, Qiaojuan Shi, Nguyen Vinh Trung, Fayaz Umrani, Sheraz Ahmed, Vandana Kulkarni, Prasad Deshpande, Mallika Alexander, Ngo Thi Hoa, Nicholas A Christakis, Najeeha Talat Iqbal, Syed Asad Ali, Jyoti S Mathad, Ilana L Brito.
      The acquisition of antimicrobial resistance (AR) genes has rendered important pathogens nearly or fully unresponsive to antibiotics. It has been suggested that pathogens acquire AR traits from the gut microbiota, which collectively serve as a global reservoir for AR genes conferring resistance to all classes of antibiotics. However, only a subset of AR genes confers resistance to clinically relevant antibiotics, and, although these AR gene profiles are well-characterized for common pathogens, less is known about their taxonomic associations and transfer potential within diverse members of the gut microbiota. We examined a collection of 14,850 human metagenomes and 1666 environmental metagenomes from 33 countries, in addition to nearly 600,000 isolate genomes, to gain insight into the global prevalence and taxonomic range of clinically relevant AR genes. We find that several of the most concerning AR genes, such as those encoding the cephalosporinase CTX-M and carbapenemases KPC, IMP, NDM, and VIM, remain taxonomically restricted to Proteobacteria. Even cfiA, the most common carbapenemase gene within the human gut microbiome, remains tightly restricted to Bacteroides, despite being found on a mobilizable plasmid. We confirmed these findings in gut microbiome samples from India, Honduras, Pakistan, and Vietnam, using a high-sensitivity single-cell fusion PCR approach. Focusing on a set of genes encoding carbapenemases and cephalosporinases, thus far restricted to Bacteroides species, we find that few mutations are required for efficacy in a different phylum, raising the question of why these genes have not spread more widely. Overall, these data suggest that globally prevalent, clinically relevant AR genes have not yet established themselves across diverse commensal gut microbiota.
    DOI:  https://doi.org/10.1038/s41467-023-42998-6
  27. Immunity. 2023 Nov 14. pii: S1074-7613(23)00455-7. [Epub ahead of print]56(11): 2459-2461
    SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
    Heegwon Shin, Hachung Chung.
      Liver X receptor (LXR), well known for its role in cholesterol metabolism, also has anti-inflammatory properties. In this issue of Immunity, Hou et al. demonstrate that LXR signaling induces SMPDL3A, a cGAMP-degrading enzyme that restricts cGAS-cGAMP-STING innate immune signaling, providing a mechanistic link between lipid metabolism and inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.015
  28. Nat Commun. 2023 Nov 11. 14(1): 7311
    Constructing temporal networks with bursty activity patterns.
    Anzhi Sheng, Qi Su, Aming Li, Long Wang, Joshua B Plotkin.
      Human social interactions tend to vary in intensity over time, whether they are in person or online. Variable rates of interaction in structured populations can be described by networks with the time-varying activity of links and nodes. One of the key statistics to summarize temporal patterns is the inter-event time, namely the duration between successive pairwise interactions. Empirical studies have found inter-event time distributions that are heavy-tailed, for both physical and digital interactions. But it is difficult to construct theoretical models of time-varying activity on a network that reproduce the burstiness seen in empirical data. Here we develop a spanning-tree method to construct temporal networks and activity patterns with bursty behavior. Our method ensures any desired target inter-event time distributions for individual nodes and links, provided the distributions fulfill a consistency condition, regardless of whether the underlying topology is static or time-varying. We show that this model can reproduce burstiness found in empirical datasets, and so it may serve as a basis for studying dynamic processes in real-world bursty interactions.
    DOI:  https://doi.org/10.1038/s41467-023-42868-1
  29. Nat Commun. 2023 Nov 11. 14(1): 7322
    Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.
    Tuo Wei, Yehui Sun, Qiang Cheng, Sumanta Chatterjee, Zachary Traylor, Lindsay T Johnson, Melissa L Coquelin, Jialu Wang, Michael J Torres, Xizhen Lian, Xu Wang, Yufen Xiao, Craig A Hodges, Daniel J Siegwart.
      Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.
    DOI:  https://doi.org/10.1038/s41467-023-42948-2
  30. EMBO J. 2023 Nov 14. e113898
    Single-cell transcriptomics stratifies organoid models of metabolic dysfunction-associated steatotic liver disease.
    Anja Hess, Stefan D Gentile, Amel Ben Saad, Raza-Ur Rahman, Tim Habboub, Daniel S Pratt, Alan C Mullen.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of morbidity with limited treatment options. Thus, accurate in vitro systems to test new therapies are indispensable. While recently, human liver organoid models have emerged to assess steatotic liver disease, a systematic evaluation of their translational potential is still missing. Here, we evaluated human liver organoid models of MASLD, comparatively testing disease induction in three conditions: oleic acid, palmitic acid, and TGF-β1. Through single-cell analyses, we find that all three models induce inflammatory signatures, but only TGF-β1 promotes collagen production, fibrosis, and hepatic stellate cell expansion. In striking contrast, oleic acid ameliorates fibrotic signatures and reduces the hepatic stellate cell population. Linking data from each model to gene expression signatures associated with MASLD disease progression further demonstrates that palmitic acid and TGF-β1 more robustly model inflammation and fibrosis. Our findings highlight the importance of stratifying MASLD organoid models by signatures of clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage human in vitro system.
    Keywords:  MASLD; NAFLD; fibrosis; liver organoids; single-cell RNA-sequencing
    DOI:  https://doi.org/10.15252/embj.2023113898
  31. Nat Commun. 2023 Nov 14. 14(1): 7121
    A robotic sensory system with high spatiotemporal resolution for texture recognition.
    Ningning Bai, Yiheng Xue, Shuiqing Chen, Lin Shi, Junli Shi, Yuan Zhang, Xingyu Hou, Yu Cheng, Kaixi Huang, Weidong Wang, Jin Zhang, Yuan Liu, Chuan Fei Guo.
      Humans can gently slide a finger on the surface of an object and identify it by capturing both static pressure and high-frequency vibrations. Although modern robots integrated with flexible sensors can precisely detect pressure, shear force, and strain, they still perform insufficiently or require multi-sensors to respond to both static and high-frequency physical stimuli during the interaction. Here, we report a real-time artificial sensory system for high-accuracy texture recognition based on a single iontronic slip-sensor, and propose a criterion-spatiotemporal resolution, to corelate the sensing performance with recognition capability. The sensor can respond to both static and dynamic stimuli (0-400 Hz) with a high spatial resolution of 15 μm in spacing and 6 μm in height, together with a high-frequency resolution of 0.02 Hz at 400 Hz, enabling high-precision discrimination of fine surface features. The sensory system integrated on a prosthetic fingertip can identify 20 different commercial textiles with a 100.0% accuracy at a fixed sliding rate and a 98.9% accuracy at random sliding rates. The sensory system is expected to help achieve subtle tactile sensation for robotics and prosthetics, and further be applied to haptic-based virtual reality and beyond.
    DOI:  https://doi.org/10.1038/s41467-023-42722-4
  32. Nat Commun. 2023 Nov 14. 14(1): 7364
    Targeted suppression of mTORC2 reduces seizures across models of epilepsy.
    James Okoh, Jacqunae Mays, Alexandre Bacq, Juan A Oses-Prieto, Stefka Tyanova, Chien-Ju Chen, Khalel Imanbeyev, Marion Doladilhe, Hongyi Zhou, Paymaan Jafar-Nejad, Alma Burlingame, Jeffrey Noebels, Stephanie Baulac, Mauro Costa-Mattioli.
      Epilepsy is a neurological disorder that poses a major threat to public health. Hyperactivation of mTOR complex 1 (mTORC1) is believed to lead to abnormal network rhythmicity associated with epilepsy, and its inhibition is proposed to provide some therapeutic benefit. However, mTOR complex 2 (mTORC2) is also activated in the epileptic brain, and little is known about its role in seizures. Here we discover that genetic deletion of mTORC2 from forebrain neurons is protective against kainic acid-induced behavioral and EEG seizures. Furthermore, inhibition of mTORC2 with a specific antisense oligonucleotide robustly suppresses seizures in several pharmacological and genetic mouse models of epilepsy. Finally, we identify a target of mTORC2, Nav1.2, which has been implicated in epilepsy and neuronal excitability. Our findings, which are generalizable to several models of human seizures, raise the possibility that inhibition of mTORC2 may serve as a broader therapeutic strategy against epilepsy.
    DOI:  https://doi.org/10.1038/s41467-023-42922-y
  33. Science. 2023 Nov 17. 382(6672): eabq8173
    A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors.
    Huan Wang, Tongrui Qian, Yulin Zhao, Yizhou Zhuo, Chunling Wu, Takuya Osakada, Peng Chen, Zijun Chen, Huixia Ren, Yuqi Yan, Lan Geng, Shengwei Fu, Long Mei, Guochuan Li, Ling Wu, Yiwen Jiang, Weiran Qian, Li Zhang, Wanling Peng, Min Xu, Ji Hu, Man Jiang, Liangyi Chen, Chao Tang, Yingjie Zhu, Dayu Lin, Jiang-Ning Zhou, Yulong Li.
      Neuropeptides are key signaling molecules in the endocrine and nervous systems that regulate many critical physiological processes. Understanding the functions of neuropeptides in vivo requires the ability to monitor their dynamics with high specificity, sensitivity, and spatiotemporal resolution. However, this has been hindered by the lack of direct, sensitive, and noninvasive tools. We developed a series of GRAB (G protein-coupled receptor activation‒based) sensors for detecting somatostatin (SST), corticotropin-releasing factor (CRF), cholecystokinin (CCK), neuropeptide Y (NPY), neurotensin (NTS), and vasoactive intestinal peptide (VIP). These fluorescent sensors, which enable detection of specific neuropeptide binding at nanomolar concentrations, establish a robust tool kit for studying the release, function, and regulation of neuropeptides under both physiological and pathophysiological conditions.
    DOI:  https://doi.org/10.1126/science.abq8173
  34. Nat Aging. 2023 Nov 13.
    A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan.
    Manish Chamoli, Anand Rane, Anna Foulger, Shankar J Chinta, Azar Asadi Shahmirzadi, Caroline Kumsta, Dhanya K Nambiar, David Hall, Angelina Holcom, Suzanne Angeli, Minna Schmidt, Sharon Pitteri, Malene Hansen, Gordon J Lithgow, Julie K Andersen.
      Autophagy-lysosomal function is crucial for maintaining healthy lifespan and preventing age-related diseases. The transcription factor TFEB plays a key role in regulating this pathway. Decreased TFEB expression is associated with various age-related disorders, making it a promising therapeutic target. In this study, we screened a natural product library and discovered mitophagy-inducing coumarin (MIC), a benzocoumarin compound that enhances TFEB expression and lysosomal function. MIC robustly increases the lifespan of Caenorhabditis elegans in an HLH-30/TFEB-dependent and mitophagy-dependent manner involving DCT-1/BNIP3 while also preventing mitochondrial dysfunction in mammalian cells. Mechanistically, MIC acts by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12/FXR, which, in turn, induces mitophagy and extends lifespan. In conclusion, our study uncovers MIC as a promising drug-like molecule that enhances mitochondrial function and extends lifespan by targeting DAF-12/FXR. Furthermore, we discovered DAF-12/FXR as a previously unknown upstream regulator of HLH-30/TFEB and mitophagy.
    DOI:  https://doi.org/10.1038/s43587-023-00524-9
  35. Nat Commun. 2023 Nov 15. 14(1): 7385
    Fatty acid desaturation and lipoxygenase pathways support trained immunity.
    Anaísa V Ferreira, Juan Carlos Alarcon-Barrera, Jorge Domínguez-Andrés, Özlem Bulut, Gizem Kilic, Priya A Debisarun, Rutger J Röring, Hatice N Özhan, Eva Terschlüsen, Athanasios Ziogas, Sarantos Kostidis, Yassene Mohammed, Vasiliki Matzaraki, George Renieris, Evangelos J Giamarellos-Bourboulis, Mihai G Netea, Martin Giera.
      Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.
    DOI:  https://doi.org/10.1038/s41467-023-43315-x
  36. EMBO Rep. 2023 Nov 15. e57164
    Trained immunity induced by high-salt diet impedes stroke recovery.
    Tze-Yen Lin, Danye Jiang, Wan-Ru Chen, Jhih Syuan Lin, Xin-Yu Zhang, Chih-Hung Chen, Chia-Lang Hsu, Liang-Chuan Lai, Ping-Hung Chen, Kai-Chien Yang, Lauren H Sansing, Che-Feng Chang.
      A high-salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long-term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte-derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD-fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD-induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD-induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.
    Keywords:  high-salt diet; intracerebral hemorrhage; macrophages; nr4a1; trained immunity
    DOI:  https://doi.org/10.15252/embr.202357164
  37. Nat Commun. 2023 Nov 14. 14(1): 7358
    Superior colliculus bidirectionally modulates choice activity in frontal cortex.
    Alyse Thomas, Weiguo Yang, Catherine Wang, Sri Laasya Tipparaju, Guang Chen, Brennan Sullivan, Kylie Swiekatowski, Mahima Tatam, Charles Gerfen, Nuo Li.
      Action selection occurs through competition between potential choice options. Neural correlates of choice competition are observed across frontal cortex and downstream superior colliculus (SC) during decision-making, yet how these regions interact to mediate choice competition remains unresolved. Here we report that SC can bidirectionally modulate choice competition and drive choice activity in frontal cortex. In the mouse, topographically matched regions of frontal cortex and SC formed a descending motor pathway for directional licking and a re-entrant loop via the thalamus. During decision-making, distinct neuronal populations in both frontal cortex and SC encoded opposing lick directions and exhibited competitive interactions. SC GABAergic neurons encoded ipsilateral choice and locally inhibited glutamatergic neurons that encoded contralateral choice. Activating or suppressing these cell types could bidirectionally drive choice activity in frontal cortex. These results thus identify SC as a major locus to modulate choice competition within the broader action selection network.
    DOI:  https://doi.org/10.1038/s41467-023-43252-9
  38. Nat Commun. 2023 Nov 17. 14(1): 7442
    Actomyosin and CSI1/POM2 cooperate to deliver cellulose synthase from Golgi to cortical microtubules in Arabidopsis.
    Lu Liu, Ting Wang, Yifan Bai, Pengcheng Yan, Liufeng Dai, Pingzhou Du, Staffan Persson, Yi Zhang.
      As one of the major components of plant cell walls, cellulose is crucial for plant growth and development. Cellulose is synthesized by cellulose synthase (CesA) complexes (CSCs), which are trafficked and delivered from the Golgi apparatus to the plasma membrane. How CesAs are released from Golgi remains largely unclear. In this study, we observed that STELLO (STL) family proteins localized at a group of small CesA-containing compartments called Small CesA compartments (SmaCCs) or microtubule-associated CesA compartments (MASCs). The STL-labeled SmaCCs/MASCs were directly derived from Golgi through a membrane-stretching process: membrane-patches of Golgi attached to cortical microtubules, which led to emergence of membrane-tails that finally ruptured to generate SmaCCs/MASCs associated with the cortical microtubules. While myosin propelled the movement of Golgi along actin filaments to stretch the tails, the CesA-microtubule linker protein, CSI1/POM2 was indispensable for the tight anchor of the membrane-tail ends at cortical microtubules. Together, our data reveal a non-canonical delivery route to the plasma membrane of a major enzyme complex in plant biology.
    DOI:  https://doi.org/10.1038/s41467-023-43325-9
  39. Commun Biol. 2023 Nov 13. 6(1): 1151
    A Cre-dependent massively parallel reporter assay allows for cell-type specific assessment of the functional effects of non-coding elements in vivo.
    Tomas Lagunas, Stephen P Plassmeyer, Anthony D Fischer, Ryan Z Friedman, Michael A Rieger, Din Selmanovic, Simona Sarafinovska, Yvette K Sol, Michael J Kasper, Stuart B Fass, Alessandra F Aguilar Lucero, Joon-Yong An, Stephan J Sanders, Barak A Cohen, Joseph D Dougherty.
      The function of regulatory elements is highly dependent on the cellular context, and thus for understanding the function of elements associated with psychiatric diseases these would ideally be studied in neurons in a living brain. Massively Parallel Reporter Assays (MPRAs) are molecular genetic tools that enable functional screening of hundreds of predefined sequences in a single experiment. These assays have not yet been adapted to query specific cell types in vivo in a complex tissue like the mouse brain. Here, using a test-case 3'UTR MPRA library with genomic elements containing variants from autism patients, we developed a method to achieve reproducible measurements of element effects in vivo in a cell type-specific manner, using excitatory cortical neurons and striatal medium spiny neurons as test cases. This targeted technique should enable robust, functional annotation of genetic elements in the cellular contexts most relevant to psychiatric disease.
    DOI:  https://doi.org/10.1038/s42003-023-05483-w
  40. Nat Med. 2023 Nov 13.
    Dynamics and durability of HIV-1 neutralization are determined by viral replication.
    Philipp Schommers, Dae Sung Kim, Maike Schlotz, Christoph Kreer, Ralf Eggeling, Anna Hake, Melanie Stecher, Juyeon Park, Caelan E Radford, Adam S Dingens, Meryem S Ercanoglu, Henning Gruell, Stanley Odidika, Marten Dahlhaus, Lutz Gieselmann, Elvin Ahmadov, Rene Y Lawong, Eva Heger, Elena Knops, Christoph Wyen, Tim Kümmerle, Katja Römer, Stefan Scholten, Timo Wolf, Christoph Stephan, Isabelle Suárez, Nagarajan Raju, Anurag Adhikari, Stefan Esser, Hendrik Streeck, Ralf Duerr, Aubin J Nanfack, Susan Zolla-Pazner, Christof Geldmacher, Otto Geisenberger, Arne Kroidl, Wiston William, Lucas Maganga, Nyanda Elias Ntinginya, Ivelin S Georgiev, Jörg J Vehreschild, Michael Hoelscher, Gerd Fätkenheuer, Jason J Lavinder, Jesse D Bloom, Michael S Seaman, Clara Lehmann, Nico Pfeifer, George Georgiou, Florian Klein.
      Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers-persons with HIV-1 who naturally develop broad and potent nAbs-can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4+ T cell counts <200 µl-1, being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response.
    DOI:  https://doi.org/10.1038/s41591-023-02582-3
  41. Nat Genet. 2023 Nov 17.
    m6A methylation of super-enhancer RNAs facilitates chromatin accessibility.
      
    DOI:  https://doi.org/10.1038/s41588-023-01567-9
  42. J Immunol. 2024 Nov 17. pii: ji2200956. [Epub ahead of print]
    Distinct Functional Humoral Immune Responses Are Induced after Live Attenuated and Inactivated Seasonal Influenza Vaccination.
    Xin Tong, Yixiang Deng, Deniz Cizmeci, Laura Fontana, Michael A Carlock, Hannah B Hanley, Ryan P McNamara, Daniel Lingwood, Ted M Ross, Galit Alter.
      Influenza viruses infect 5-30% of the world's population annually, resulting in millions of incidents of hospitalization and thousands of mortalities worldwide every year. Although annual vaccination has significantly reduced hospitalization rates in vulnerable populations, the current vaccines are estimated to offer a wide range of protection from 10 to 60% annually. Such incomplete immunity may be related to both poor antigenic coverage of circulating strains, as well as to the insufficient induction of protective immunity. Beyond the role of hemagglutinin (HA) and neuraminidase (NA), vaccine-induced Abs have the capacity to induce a broader array of Ab effector functions, including Ab-dependent cellular cytotoxicity, that has been implicated in universal immunity against influenza viruses. However, whether different vaccine platforms can induce functional humoral immunity in a distinct manner remains incompletely defined. In this study, we compared vaccine-induced humoral immune responses induced by two seasonal influenza vaccines in Homo sapiens, the i.m. inactivated vaccine (IIV/Fluzone) and the live attenuated mucosal vaccine (LAIV/FluMist). Whereas the inactivated influenza vaccine induced superior Ab titers and FcγR binding capacity to diverse HA and NA Ags, the live attenuated influenza mucosal vaccine induced a more robust functional humoral immune response against both the HA and NA domains. Multivariate Ab analysis further highlighted the significantly different overall functional humoral immune profiles induced by the two vaccines, marked by differences in IgG titers, FcR binding, and both NK cell-recruiting and opsonophagocytic Ab functions. These results highlight the striking differences in Ab Fc-effector profiles induced systemically by two distinct influenza vaccine platforms.
    DOI:  https://doi.org/10.4049/jimmunol.2200956
  43. Nat Commun. 2023 Nov 13. 14(1): 7344
    Zika virus prM protein contains cholesterol binding motifs required for virus entry and assembly.
    Sarah Goellner, Giray Enkavi, Vibhu Prasad, Solène Denolly, Sungmin Eu, Giulia Mizzon, Leander Witte, Waldemar Kulig, Zina M Uckeley, Teresa M Lavacca, Uta Haselmann, Pierre-Yves Lozach, Britta Brügger, Ilpo Vattulainen, Ralf Bartenschlager.
      For successful infection of host cells and virion production, enveloped viruses, including Zika virus (ZIKV), extensively rely on cellular lipids. However, how virus protein-lipid interactions contribute to the viral life cycle remains unclear. Here, we employ a chemo-proteomics approach with a bifunctional cholesterol probe and show that cholesterol is closely associated with the ZIKV structural protein prM. Bioinformatic analyses, reverse genetics alongside with photoaffinity labeling assays, and atomistic molecular dynamics simulations identified two functional cholesterol binding motifs within the prM transmembrane domain. Loss of prM-cholesterol association has a bipartite effect reducing ZIKV entry and leading to assembly defects. We propose a model in which membrane-resident M facilitates cholesterol-supported lipid exchange during endosomal entry and, together with cholesterol, creates a platform promoting virion assembly. In summary, we identify a bifunctional role of prM in the ZIKV life cycle by mediating viral entry and virus assembly in a cholesterol-dependent manner.
    DOI:  https://doi.org/10.1038/s41467-023-42985-x
  44. Nat Med. 2023 Nov 13.
    Determining the longevity and dynamics of HIV-1 neutralizing activity.
      
    DOI:  https://doi.org/10.1038/s41591-023-02592-1
  45. Dev Cell. 2023 Nov 14. pii: S1534-5807(23)00554-3. [Epub ahead of print]
    Age-associated H3K9me2 loss alters the regenerative equilibrium between murine lung alveolar and bronchiolar progenitors.
    Samuel P Rowbotham, Patrizia Pessina, Carolina Garcia-de-Alba, Jake Jensen, Yvonne Nguyen, Joon Yoon, Jingyun Li, Irene G Wong, Caroline Fahey, Aaron L Moye, Joann Chongsaritsinsuk, Roderick Bronson, Shannan J Ho Sui, Carla F Kim.
      The lung contains multiple progenitor cell types, but how their responses are choreographed during injury repair and whether this changes with age is poorly understood. We report that histone H3 lysine 9 di-methylation (H3K9me2), mediated by the methyltransferase G9a, regulates the dynamics of distal lung epithelial progenitor cells and that this regulation deteriorates with age. In aged mouse lungs, H3K9me2 loss coincided with fewer alveolar type 2 (AT2) cell progenitors and reduced alveolar regeneration but increased the frequency and activity of multipotent bronchioalveolar stem cells (BASCs) and bronchiolar progenitor club cells. H3K9me2 depletion in young mice decreased AT2 progenitor activity and impaired alveolar injury repair. Conversely, H3K9me2 depletion increased chromatin accessibility of bronchiolar cell genes, increased BASC frequency, and accelerated bronchiolar cell injury repair. These findings indicate that during aging, the epigenetic regulation that coordinates lung progenitor cells' regenerative responses becomes dysregulated, aiding our understanding of age-related susceptibility to lung disease.
    Keywords:  EHMT2; G9a; aging; alveolar; bronchiolar; epigenetics; injury repair; lung stem cell; regeneration
    DOI:  https://doi.org/10.1016/j.devcel.2023.10.011
  46. Sci Adv. 2023 Nov 17. 9(46): eadi9036
    ACD15, ACD21, and SLN regulate the accumulation and mobility of MBD6 to silence genes and transposable elements.
    Brandon A Boone, Lucia Ichino, Shuya Wang, Jason Gardiner, Jaewon Yun, Yasaman Jami-Alahmadi, Jihui Sha, Cristy P Mendoza, Bailey J Steelman, Aliya van Aardenne, Sophia Kira-Lucas, Isabelle Trentchev, James A Wohlschlegel, Steven E Jacobsen.
      DNA methylation mediates silencing of transposable elements and genes in part via recruitment of the Arabidopsis MBD5/6 complex, which contains the methyl-CpG binding domain (MBD) proteins MBD5 and MBD6, and the J-domain containing protein SILENZIO (SLN). Here, we characterize two additional complex members: α-crystalline domain (ACD) containing proteins ACD15 and ACD21. We show that they are necessary for gene silencing, bridge SLN to the complex, and promote higher-order multimerization of MBD5/6 complexes within heterochromatin. These complexes are also highly dynamic, with the mobility of MBD5/6 complexes regulated by the activity of SLN. Using a dCas9 system, we demonstrate that tethering the ACDs to an ectopic site outside of heterochromatin can drive a massive accumulation of MBD5/6 complexes into large nuclear bodies. These results demonstrate that ACD15 and ACD21 are critical components of the gene-silencing MBD5/6 complex and act to drive the formation of higher-order, dynamic assemblies at CG methylation (meCG) sites.
    DOI:  https://doi.org/10.1126/sciadv.adi9036
  47. Science. 2023 Nov 17. 382(6672): eadg3053
    Design principles of 3D epigenetic memory systems.
    Jeremy A Owen, Dino Osmanović, Leonid Mirny.
      Cells remember their identities, in part, by using epigenetic marks-chemical modifications placed along the genome. How can mark patterns remain stable over cell generations despite their constant erosion by replication and other processes? We developed a theoretical model that reveals that three-dimensional (3D) genome organization can stabilize epigenetic memory as long as (i) there is a large density difference between chromatin compartments, (ii) modifying "reader-writer" enzymes spread marks in three dimensions, and (iii) the enzymes are limited in abundance relative to their histone substrates. Analogous to an associative memory that encodes memory in neuronal connectivity, mark patterns are encoded in a 3D network of chromosomal contacts. Our model provides a unified account of diverse observations and reveals a key role of 3D genome organization in epigenetic memory.
    DOI:  https://doi.org/10.1126/science.adg3053
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