bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–09–17
sixty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Finding my community.
  2. Cancer- and infection-induced T cell exhaustion are distinct.
  3. People.
  4. An integrated single-cell islet atlas in health and disease.
  5. Microbiomics.
  6. Ironman training for NK cells.
  7. Antigen receptor signaling and cell death resistance controls intestinal humoral response zonation.
  8. Dynamic lipidome alterations associated with human health, disease and ageing.
  9. Control of nutrient uptake by IRF4 orchestrates innate immune memory.
  10. Complex regulatory processes control exercise adaptations of skeletal muscle.
  11. Navigating T cell brain entry in MS.
  12. Disorder-based T cell developmental order.
  13. A landscape of complex tandem repeats within individual human genomes.
  14. Role for cell death pathway in Alzheimer's disease.
  15. Pausing pluripotency via RNA methylation.
  16. Brief diet changes affect immunity.
  17. Defining microglial-synapse interactions.
  18. Extracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4.
  19. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.
  20. Solar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary-lung axis.
  21. Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.
  22. Structural basis of insulin fibrillation.
  23. Plaque attack by microglial PLCγ2.
  24. Complex effects of sequence variants on lipid levels and coronary artery disease.
  25. STING as a proton channel.
  26. Leveraging the secretory machinery to eliminate senescent cells.
  27. Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
  28. SiGra: single-cell spatial elucidation through an image-augmented graph transformer.
  29. PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation.
  30. HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer.
  31. Five questions with Mor Nitzan.
  32. Structural landscape of the respiratory syncytial virus nucleocapsids.
  33. Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation.
  34. Getting an aMPLe grasp on hematopoiesis.
  35. Endogenous fluctuations in cortical state selectively enhance different modes of sensory processing in human temporal lobe.
  36. An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development.
  37. Spatiotemporal insight into early pregnancy governed by immune-featured stromal cells.
  38. Allergen exposure functionally alters influenza-specific CD4+ Th1 memory cells in the lung.
  39. ADuLT: An efficient and robust time-to-event GWAS.
  40. TGF-β Promotes the Postselection Thymic Development and Peripheral Function of IFN-γ-Producing Invariant NKT cells.
  41. Chemical-induced phase transition and global conformational reorganization of chromatin.
  42. COVID boosters are back: what scientists say about whether to get one.
  43. The maths of how we wait in crowded places.
  44. Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.
  45. NK cell expansion requires HuR and mediates control of solid tumors and long-term virus infection.
  46. Albert Eschenmoser (1925-2023).
  47. BugSigDB - a database for identifying unusual abundance patterns in human microbiome studies.
  48. Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.
  49. Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.
  50. Mechanism of outer membrane destabilization by global reduction of protein content.
  51. In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity.
  52. Bone marrow immune cells respond to fluctuating nutritional stress to constrain weight regain.
  53. Death-seq identifies regulators of cell death and senolytic therapies.
  54. Monolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification.
  55. Illuminating the human yolk sac through single-cell omics.
  56. A cross-species proteomic map reveals neoteny of human synapse development.
  57. Delineating mouse β-cell identity during lifetime and in diabetes with a single cell atlas.
  58. Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD.
  59. TSLP shapes the pathogenic responses of memory CD4+ T cells in eosinophilic esophagitis.
  60. Transcriptional and epigenetic decoding of the microglial aging process.
  1. Science. 2023 Sep 15. 381(6663): 1250
    Finding my community.
    Kwabena Boahen Asare.
      
    DOI:  https://doi.org/10.1126/science.adk7629
  2. Nat Immunol. 2023 Sep 14.
    Cancer- and infection-induced T cell exhaustion are distinct.
    Jessica Buck, Nikhil S Joshi.
      
    DOI:  https://doi.org/10.1038/s41590-023-01624-9
  3. Nat Biotechnol. 2023 Sep;41(9): 1356
    People.
      
    DOI:  https://doi.org/10.1038/s41587-023-01941-2
  4. Nat Metab. 2023 Sep 12.
    An integrated single-cell islet atlas in health and disease.
      
    DOI:  https://doi.org/10.1038/s42255-023-00884-x
  5. Nat Biotechnol. 2023 Sep;41(9): 1200
    Microbiomics.
      
    DOI:  https://doi.org/10.1038/s41587-023-01922-5
  6. Nat Immunol. 2023 Sep 11.
    Ironman training for NK cells.
    Nicholas D Huntington.
      
    DOI:  https://doi.org/10.1038/s41590-023-01626-7
  7. Immunity. 2023 Sep 11. pii: S1074-7613(23)00374-6. [Epub ahead of print]
    Antigen receptor signaling and cell death resistance controls intestinal humoral response zonation.
    Fiona Raso, Shuozhi Liu, Mikala J Simpson, Gregory M Barton, Christian T Mayer, Mridu Acharya, Jagan R Muppidi, Ann Marshak-Rothstein, Andrea Reboldi.
      Immunoglobulin A (IgA) maintains commensal communities in the intestine while preventing dysbiosis. IgA generated against intestinal microbes assures the simultaneous binding to multiple, diverse commensal-derived antigens. However, the exact mechanisms by which B cells mount broadly reactive IgA to the gut microbiome remains elusive. Here, we have shown that IgA B cell receptor (BCR) is required for B cell fitness during the germinal center (GC) reaction in Peyer's patches (PPs) and for generation of gut-homing plasma cells (PCs). We demonstrate that IgA BCR drove heightened intracellular signaling in mouse and human B cells, and as a consequence, IgA+ B cells received stronger positive selection cues. Mechanistically, IgA BCR signaling offset Fas-mediated death, possibly rescuing low-affinity B cells to promote a broad humoral response to commensals. Our findings reveal an additional mechanism linking BCR signaling, B cell fate, and antibody production location, which have implications for how intestinal antigen recognition shapes humoral immunity.
    Keywords:  B cell receptor; Fas; IgA; Peyer's patch; germinal center; gut homing
    DOI:  https://doi.org/10.1016/j.immuni.2023.08.018
  8. Nat Metab. 2023 Sep 11.
    Dynamic lipidome alterations associated with human health, disease and ageing.
    Daniel Hornburg, Si Wu, Mahdi Moqri, Xin Zhou, Kevin Contrepois, Nasim Bararpour, Gavin M Traber, Baolong Su, Ahmed A Metwally, Monica Avina, Wenyu Zhou, Jessalyn M Ubellacker, Tejaswini Mishra, Sophia Miryam Schüssler-Fiorenza Rose, Paula B Kavathas, Kevin J Williams, Michael P Snyder.
      Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.
    DOI:  https://doi.org/10.1038/s42255-023-00880-1
  9. Nat Immunol. 2023 Sep 11.
    Control of nutrient uptake by IRF4 orchestrates innate immune memory.
    Endi K Santosa, Hyunu Kim, Timo Rückert, Jean-Benoît Le Luduec, Aamna J Abbasi, Claire K Wingert, Lila Peters, Joe N Frost, Katharine C Hsu, Chiara Romagnani, Joseph C Sun.
      Natural killer (NK) cells are innate cytotoxic lymphocytes with adaptive immune features, including antigen specificity, clonal expansion and memory. As such, NK cells share many transcriptional and epigenetic programs with their adaptive CD8+ T cell siblings. Various signals ranging from antigen, co-stimulation and proinflammatory cytokines are required for optimal NK cell responses in mice and humans during virus infection; however, the integration of these signals remains unclear. In this study, we identified that the transcription factor IRF4 integrates signals to coordinate the NK cell response during mouse cytomegalovirus infection. Loss of IRF4 was detrimental to the expansion and differentiation of virus-specific NK cells. This defect was partially attributed to the inability of IRF4-deficient NK cells to uptake nutrients required for survival and memory generation. Altogether, these data suggest that IRF4 is a signal integrator that acts as a secondary metabolic checkpoint to orchestrate the adaptive response of NK cells during viral infection.
    DOI:  https://doi.org/10.1038/s41590-023-01620-z
  10. Nat Metab. 2023 Sep 14.
    Complex regulatory processes control exercise adaptations of skeletal muscle.
      
    DOI:  https://doi.org/10.1038/s42255-023-00894-9
  11. Nat Neurosci. 2023 Sep 14.
    Navigating T cell brain entry in MS.
    Magda Ali, Adrian Liston.
      
    DOI:  https://doi.org/10.1038/s41593-023-01433-1
  12. Nat Immunol. 2023 Sep 14.
    Disorder-based T cell developmental order.
    Shuai Liu, Keji Zhao.
      
    DOI:  https://doi.org/10.1038/s41590-023-01623-w
  13. Nat Commun. 2023 Sep 14. 14(1): 5530
    A landscape of complex tandem repeats within individual human genomes.
    Kazuki Ichikawa, Riki Kawahara, Takeshi Asano, Shinichi Morishita.
      Markedly expanded tandem repeats (TRs) have been correlated with ~60 diseases. TR diversity has been considered a clue toward understanding missing heritability. However, haplotype-resolved long TRs remain mostly hidden or blacked out because their complex structures (TRs composed of various units and minisatellites containing >10-bp units) make them difficult to determine accurately with existing methods. Here, using a high-precision algorithm to determine complex TR structures from long, accurate reads of PacBio HiFi, an investigation of 270 Japanese control samples yields several genome-wide findings. Approximately 322,000 TRs are difficult to impute from the surrounding single-nucleotide variants. Greater genetic divergence of TR loci is significantly correlated with more events of younger replication slippage. Complex TRs are more abundant than single-unit TRs, and a tendency for complex TRs to consist of <10-bp units and single-unit TRs to be minisatellites is statistically significant at loci with ≥500-bp TRs. Of note, 8909 loci with extended TRs (>100b longer than the mode) contain several known disease-associated TRs and are considered candidates for association with disorders. Overall, complex TRs and minisatellites are found to be abundant and diverse, even in genetically small Japanese populations, yielding insights into the landscape of long TRs.
    DOI:  https://doi.org/10.1038/s41467-023-41262-1
  14. Science. 2023 Sep 15. 381(6663): 1156-1157
    Role for cell death pathway in Alzheimer's disease.
    Daniel W Sirkis, Jennifer S Yokoyama.
      Human neurons transplanted into mice with amyloid plaques die by necroptosis.
    DOI:  https://doi.org/10.1126/science.adk2009
  15. Nat Cell Biol. 2023 Sep;25(9): 1241-1242
    Pausing pluripotency via RNA methylation.
    Xueting Xu, Baoming Qin.
      
    DOI:  https://doi.org/10.1038/s41556-023-01203-y
  16. Nat Rev Immunol. 2023 Sep 14.
    Brief diet changes affect immunity.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-023-00944-z
  17. Science. 2023 Sep 15. 381(6663): 1155-1156
    Defining microglial-synapse interactions.
    Ukpong Eyo, Anna Victoria Molofsky.
      The brain's resident macrophages have many roles beyond synaptic pruning.
    DOI:  https://doi.org/10.1126/science.adh7906
  18. Nat Commun. 2023 Sep 11. 14(1): 5592
    Extracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4.
    Panpan Zhang, Masahiro Maruoka, Ryo Suzuki, Hikaru Katani, Yu Dou, Daniel M Packwood, Hidetaka Kosako, Motomu Tanaka, Jun Suzuki.
      The "eat me" signal, phosphatidylserine is exposed on the surface of dying cells by phospholipid scrambling. Previously, we showed that the Xkr family protein Xkr4 is activated by caspase-mediated cleavage and binding of the XRCC4 fragment. Here, we show that extracellular calcium is an additional factor needed to activate Xkr4. The constitutively active mutant of Xkr4 is found to induce phospholipid scrambling in an extracellular, but not intracellular, calcium-dependent manner. Importantly, other Xkr family members also require extracellular calcium for activation. Alanine scanning shows that D123 and D127 of TM1 and E310 of TM3 coordinate calcium binding. Moreover, lysine scanning demonstrates that the E310K mutation-mediated salt bridge between TM1 and TM3 bypasses the requirement of calcium. Cysteine scanning proves that disulfide bond formation between TM1 and TM3 also activates phospholipid scrambling without calcium. Collectively, this study shows that extracellular calcium functions as a molecular glue for TM1 and TM3 of Xkr proteins for activation, thus demonstrating a regulatory mechanism for multi-transmembrane region-containing proteins.
    DOI:  https://doi.org/10.1038/s41467-023-40934-2
  19. Nat Commun. 2023 Sep 13. 14(1): 5660
    De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.
    Anindya Roy, Lei Shi, Ashley Chang, Xianchi Dong, Andres Fernandez, John C Kraft, Jing Li, Viet Q Le, Rebecca Viazzo Winegar, Gerald Maxwell Cherf, Dean Slocum, P Daniel Poulson, Garrett E Casper, Mary L Vallecillo-Zúniga, Jonard Corpuz Valdoz, Marcos C Miranda, Hua Bai, Yakov Kipnis, Audrey Olshefsky, Tanu Priya, Lauren Carter, Rashmi Ravichandran, Cameron M Chow, Max R Johnson, Suna Cheng, McKaela Smith, Catherine Overed-Sayer, Donna K Finch, David Lowe, Asim K Bera, Gustavo Matute-Bello, Timothy P Birkland, Frank DiMaio, Ganesh Raghu, Jennifer R Cochran, Lance J Stewart, Melody G Campbell, Pam M Van Ry, Timothy Springer, David Baker.
      The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.
    DOI:  https://doi.org/10.1038/s41467-023-41272-z
  20. Nat Commun. 2023 Sep 12. 14(1): 5601
    Solar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary-lung axis.
    Yuying Huang, Lin Zhu, Shipeng Cheng, Ranran Dai, Chunrong Huang, Yanyan Song, Bo Peng, Xuezhen Li, Jing Wen, Yi Gong, Yunqian Hu, Ling Qian, Linyun Zhu, Fengying Zhang, Li Yu, Chunyan Yi, Wangpeng Gu, Zhiyang Ling, Liyan Ma, Wei Tang, Li Peng, Guochao Shi, Yaguang Zhang, Bing Sun.
      The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar ultraviolet (UV) radiation is not fully understood. Here, we show a possible negative correlation between solar UVB radiation and asthmatic inflammation in humans and mice. UVB exposure to the eyes induces hypothalamus-pituitary activation and α-melanocyte-stimulating hormone (α-MSH) accumulation in the serum to suppress allergic airway inflammation by targeting group 2 innate lymphoid cells (ILC2) through the MC5R receptor in mice. The α-MSH/MC5R interaction limits ILC2 function through attenuation of JAK/STAT and NF-κB signaling. Consistently, we observe that the plasma α-MSH concentration is negatively correlated with the number and function of ILC2s in the peripheral blood mononuclear cells (PBMC) of patients with asthma. We provide insights into how solar UVB radiation-driven neuroendocrine α-MSH restricts ILC2-mediated lung inflammation and offer a possible strategy for controlling allergic diseases.
    DOI:  https://doi.org/10.1038/s41467-023-41319-1
  21. Sci Adv. 2023 Sep 15. 9(37): eadh0831
    Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.
    Ebru Boslem, Saskia Reibe, Rodrigo Carlessi, Benoit Smeuninx, Surafel Tegegne, Casey L Egan, Emma McLennan, Lauren V Terry, Max Nobis, Andre Mu, Cameron Nowell, Neil Horadagoda, Natalie A Mellett, Paul Timpson, Matthew Jones, Elena Denisenko, Alistair R R Forrest, Janina E E Tirnitz-Parker, Peter J Meikle, Stefan Rose-John, Michael Karin, Mark A Febbraio.
      The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.
    DOI:  https://doi.org/10.1126/sciadv.adh0831
  22. Sci Adv. 2023 Sep 15. 9(37): eadi1057
    Structural basis of insulin fibrillation.
    Liwei Wang, Catherine E Hall, Emiko Uchikawa, Dailu Chen, Eunhee Choi, Xuewu Zhang, Xiao-Chen Bai.
      Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-β fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the β sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes.
    DOI:  https://doi.org/10.1126/sciadv.adi1057
  23. Immunity. 2023 Sep 12. pii: S1074-7613(23)00368-0. [Epub ahead of print]56(9): 1985-1987
    Plaque attack by microglial PLCγ2.
    Ashley L Comer, Timothy R Hammond.
      PLCγ2 is genetically linked to Alzheimer's disease (AD), but it is unclear how PLCγ2 contributes to pathology. Tsai et al. demonstrate that AD-associated PLCG2 variants bidirectionally orchestrate microglial responses to plaques and impact neural function in an AD mouse model. This positions PLCγ2 as a key microglial signaling node and shows that targeting PLCγ2 could have therapeutic benefits in AD.
    DOI:  https://doi.org/10.1016/j.immuni.2023.08.012
  24. Cell. 2023 Sep 14. pii: S0092-8674(23)00901-7. [Epub ahead of print]186(19): 4085-4099.e15
    Complex effects of sequence variants on lipid levels and coronary artery disease.
    DBDS Genomic Consortium
      Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.
    Keywords:  blood lipids; cholesterol; coronary artery disease; correlation effects; dominance effects; epistasis; gene-environment interaction effects; gene-gene interaction effects; genome-wide association study; variance effects
    DOI:  https://doi.org/10.1016/j.cell.2023.08.012
  25. Nat Cell Biol. 2023 Sep;25(9): 1240
    STING as a proton channel.
    Melina Casadio.
      
    DOI:  https://doi.org/10.1038/s41556-023-01230-9
  26. Nat Aging. 2023 Sep 14.
    Leveraging the secretory machinery to eliminate senescent cells.
      
    DOI:  https://doi.org/10.1038/s43587-023-00500-3
  27. Nat Struct Mol Biol. 2023 Sep 11.
    Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
    Xueyin Zhou, Yuqi Yang, Guopeng Wang, Shanshan Wang, Dongjie Sun, Xiaomin Ou, Yuke Lian, Long Li.
      Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.
    DOI:  https://doi.org/10.1038/s41594-023-01103-7
  28. Nat Commun. 2023 Sep 12. 14(1): 5618
    SiGra: single-cell spatial elucidation through an image-augmented graph transformer.
    Ziyang Tang, Zuotian Li, Tieying Hou, Tonglin Zhang, Baijian Yang, Jing Su, Qianqian Song.
      Recent advances in high-throughput molecular imaging have pushed spatial transcriptomics technologies to subcellular resolution, which surpasses the limitations of both single-cell RNA-seq and array-based spatial profiling. The multichannel immunohistochemistry images in such data provide rich information on the cell types, functions, and morphologies of cellular compartments. In this work, we developed a method, single-cell spatial elucidation through image-augmented Graph transformer (SiGra), to leverage such imaging information for revealing spatial domains and enhancing substantially sparse and noisy transcriptomics data. SiGra applies hybrid graph transformers over a single-cell spatial graph. SiGra outperforms state-of-the-art methods on both single-cell and spot-level spatial transcriptomics data from complex tissues. The inclusion of immunohistochemistry images improves the model performance by 37% (95% CI: 27-50%). SiGra improves the characterization of intratumor heterogeneity and intercellular communication and recovers the known microscopic anatomy. Overall, SiGra effectively integrates different spatial modality data to gain deep insights into spatial cellular ecosystems.
    DOI:  https://doi.org/10.1038/s41467-023-41437-w
  29. Nat Commun. 2023 Sep 09. 14(1): 5555
    PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation.
    Mathias Linnerbauer, Tobias Beyer, Lucy Nirschl, Daniel Farrenkopf, Lena Lößlein, Oliver Vandrey, Anne Peter, Thanos Tsaktanis, Hania Kebir, David Laplaud, Rupert Oellinger, Thomas Engleitner, Jorge Ivan Alvarez, Roland Rad, Thomas Korn, Bernhard Hemmer, Francisco J Quintana, Veit Rothhammer.
      Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages.
    DOI:  https://doi.org/10.1038/s41467-023-40982-8
  30. Nat Commun. 2023 Sep 13. 14(1): 5631
    HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer.
    Emily N Neubert, Julia M DeRogatis, Sloan A Lewis, Karla M Viramontes, Pedro Ortega, Monique L Henriquez, Rémi Buisson, Ilhem Messaoudi, Roberto Tinoco.
      Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2-/- CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-023-41352-0
  31. Nat Biotechnol. 2023 Sep;41(9): 1355
    Five questions with Mor Nitzan.
    Julie Chuong.
      
    DOI:  https://doi.org/10.1038/s41587-023-01926-1
  32. Nat Commun. 2023 Sep 15. 14(1): 5732
    Structural landscape of the respiratory syncytial virus nucleocapsids.
    Lorène Gonnin, Ambroise Desfosses, Maria Bacia-Verloop, Didier Chevret, Marie Galloux, Jean-François Éléouët, Irina Gutsche.
      Human Respiratory Syncytial Virus (HRSV) is a prevalent cause of severe respiratory infections in children and the elderly. The helical HRSV nucleocapsid is a template for the viral RNA synthesis and a scaffold for the virion assembly. This cryo-electron microscopy analysis reveals the non-canonical arrangement of the HRSV nucleocapsid helix, composed of 16 nucleoproteins per asymmetric unit, and the resulting systematic variations in the RNA accessibility. We demonstrate that this unique helical symmetry originates from longitudinal interactions by the C-terminal arm of the HRSV nucleoprotein. We explore the polymorphism of the nucleocapsid-like assemblies, report five structures of the full-length particles and two alternative arrangements formed by a C-terminally truncated nucleoprotein mutant, and demonstrate the functional importance of the identified longitudinal interfaces. We put all these findings in the context of the HRSV RNA synthesis machinery and delineate the structural basis for its further investigation.
    DOI:  https://doi.org/10.1038/s41467-023-41439-8
  33. Nat Commun. 2023 Sep 11. 14(1): 5585
    Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation.
    Alexandria C Wells, Kaito A Hioki, Constance C Angelou, Adam C Lynch, Xueting Liang, Daniel J Ryan, Iris Thesmar, Saule Zhanybekova, Saulius Zuklys, Jacob Ullom, Agnes Cheong, Jesse Mager, Georg A Hollander, Elena L Pobezinskaya, Leonid A Pobezinsky.
      The success of the CD8 T cell-mediated immune response against infections and tumors depends on the formation of a long-lived memory pool, and the protection of effector cells from exhaustion. The advent of checkpoint blockade therapy has significantly improved anti-tumor therapeutic outcomes by reversing CD8 T cell exhaustion, but fails to generate effector cells with memory potential. Here, using in vivo mouse models, we show that let-7 miRNAs determine CD8 T cell fate, where maintenance of let-7 expression during early cell activation results in memory CD8 T cell formation and tumor clearance. Conversely, let-7-deficiency promotes the generation of a terminal effector population that becomes vulnerable to exhaustion and cell death in immunosuppressive environments and fails to reject tumors. Mechanistically, let-7 restrains metabolic changes that occur during T cell activation through the inhibition of the PI3K/AKT/mTOR signaling pathway and production of reactive oxygen species, potent drivers of terminal differentiation and exhaustion. Thus, our results reveal a role for let-7 in the time-sensitive support of memory formation and the protection of effector cells from exhaustion. Overall, our data suggest a strategy in developing next-generation immunotherapies by preserving the multipotency of effector cells rather than enhancing the efficacy of differentiation.
    DOI:  https://doi.org/10.1038/s41467-023-40959-7
  34. Cell. 2023 Sep 14. pii: S0092-8674(23)00904-2. [Epub ahead of print]186(19): 4005-4006
    Getting an aMPLe grasp on hematopoiesis.
    Samantha Joubran, Vijay G Sankaran.
      Hematopoiesis requires balance between self-renewal of stem cells and differentiation into mature blood cells, orchestrated by pathways such as thrombopoietin signaling. In this issue of Cell, Tsutsumi et al. report the structure of the thrombopoietin ligand-receptor complex and demonstrate the potential to decouple its roles in self-renewal and hematopoietic differentiation.
    DOI:  https://doi.org/10.1016/j.cell.2023.08.015
  35. Nat Commun. 2023 Sep 11. 14(1): 5591
    Endogenous fluctuations in cortical state selectively enhance different modes of sensory processing in human temporal lobe.
    Arun Parajuli, Diego Gutnisky, Nitin Tandon, Valentin Dragoi.
      The degree of synchronized fluctuations in neocortical network activity can vary widely during alertness. One influential idea that has emerged over the past few decades is that perceptual decisions are more accurate when the state of population activity is desynchronized. This suggests that optimal task performance may occur during a particular cortical state - the desynchronized state. Here we show that, contrary to this view, cortical state can both facilitate and suppress perceptual performance in a task-dependent manner. We performed electrical recordings from surface-implanted grid electrodes in the temporal lobe while human subjects completed two perceptual tasks. We found that when local population activity is in a synchronized state, network and perceptual performance are enhanced in a detection task and impaired in a discrimination task, but these modulatory effects are reversed when population activity is desynchronized. These findings indicate that the brain has adapted to take advantage of endogenous fluctuations in the state of neural populations in temporal cortex to selectively enhance different modes of sensory processing during perception in a state-dependent manner.
    DOI:  https://doi.org/10.1038/s41467-023-41406-3
  36. Cell. 2023 Sep 06. pii: S0092-8674(23)00908-X. [Epub ahead of print]
    An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development.
    Zeshuai Wang, Zhisheng Wu, Hao Wang, Ruoqing Feng, Guanlin Wang, Muxi Li, Shuang-Yin Wang, Xiaoyan Chen, Yiyi Su, Jun Wang, Weiwen Zhang, Yuzhou Bao, Zhenwei Lan, Zhuo Song, Yiheng Wang, Xianyang Luo, Lingyu Zhao, Anli Hou, Shuye Tian, Hongliang Gao, Wenbin Miao, Yingyu Liu, Huilin Wang, Cui Yin, Zhi-Liang Ji, Mingqian Feng, Hongkun Liu, Lianghui Diao, Ido Amit, Yun Chen, Yong Zeng, Florent Ginhoux, Xueqing Wu, Yuanfang Zhu, Hanjie Li.
      Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4-26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development.
    Keywords:  angiogenesis; developmental immunology; human immunology; immune cell atlas; macrophage; microglia; microglia-like cells; neural crest cells; perivascular macrophages; scRNA-seq
    DOI:  https://doi.org/10.1016/j.cell.2023.08.019
  37. Cell. 2023 Sep 07. pii: S0092-8674(23)00909-1. [Epub ahead of print]
    Spatiotemporal insight into early pregnancy governed by immune-featured stromal cells.
    Min Yang, Jennie Ong, Fanju Meng, Feixiang Zhang, Hui Shen, Kerstin Kitt, Tengfei Liu, Wei Tao, Peng Du.
      Endometrial decidualization connecting embryo implantation and placentation is transient but essential for successful pregnancy, which, however, is not systematically investigated. Here, we use a scStereo-seq technology to spatially visualize and define the dynamic functional decidual hubs assembled by distinct immune, endothelial, trophoblast, and decidual stromal cells (DSCs) in early pregnant mice. We unravel the DSC transdifferentiation trajectory and surprisingly discover a dual-featured type of immune-featured DSCs (iDSCs). We find that immature DSCs attract immune cells and induce decidual angiogenesis at the mesenchymal-epithelial transition hub during decidualization initiation. iDSCs enable immune cell recruitment and suppression, govern vascularization, and promote cytolysis at immune cell assembling and vascular hubs, respectively, to establish decidual homeostasis at a later stage. Interestingly, dysfunctional and spatially disordered iDSCs cause abnormal accumulation of immune cells in the vascular hub, which disrupts decidual hub specification and eventually leads to pregnancy complications in DBA/2-mated CBA/J mice.
    Keywords:  decidual stromal cells; decidualization; functional decidual hubs; immune cell recruitment; pregnancy; recurrent spontaneous abortion; spatial transcriptomics; vascularization
    DOI:  https://doi.org/10.1016/j.cell.2023.08.020
  38. J Exp Med. 2023 Nov 06. pii: e20230112. [Epub ahead of print]220(11):
    Allergen exposure functionally alters influenza-specific CD4+ Th1 memory cells in the lung.
    Mikel J Rüterbusch, Brian D Hondowicz, Kennidy K Takehara, Kurt B Pruner, Thomas S Griffith, Marion Pepper.
      CD4+ lung-resident memory T cells (TRM) generated in response to influenza infection confer effective protection against subsequent viral exposures. Whether these cells can be altered by environmental antigens and cytokines released during heterologous, antigen-independent immune responses is currently unclear. We therefore investigated how influenza-specific CD4+ Th1 TRM in the lung are impacted by a subsequent Th2-inducing respiratory house dust mite (HDM) exposure. Although naïve influenza-specific CD4+ T cells in the lymph nodes do not respond to HDM, influenza-specific CD4+ TRM in the lungs do respond to a subsequent allergen exposure by decreasing expression of the transcription factor T-bet. This functional alteration is associated with decreased IFN-γ production upon restimulation and improved disease outcomes following heterosubtypic influenza challenge. Further investigation revealed that ST2 signaling in CD4+ T cells during allergic challenge is necessary to induce these changes in lung-resident influenza-specific CD4+ TRM. Thus, heterologous antigen exposure or ST2-signaling can drive persistent changes in CD4+ Th1 TRM populations and impact protection upon reinfection.
    DOI:  https://doi.org/10.1084/jem.20230112
  39. Nat Commun. 2023 Sep 09. 14(1): 5553
    ADuLT: An efficient and robust time-to-event GWAS.
    Emil M Pedersen, Esben Agerbo, Oleguer Plana-Ripoll, Jette Steinbach, Morten D Krebs, David M Hougaard, Thomas Werge, Merete Nordentoft, Anders D Børglum, Katherine L Musliner, Andrea Ganna, Andrew J Schork, Preben B Mortensen, John J McGrath, Florian Privé, Bjarni J Vilhjálmsson.
      Proportional hazards models have been proposed to analyse time-to-event phenotypes in genome-wide association studies (GWAS). However, little is known about the ability of proportional hazards models to identify genetic associations under different generative models and when ascertainment is present. Here we propose the age-dependent liability threshold (ADuLT) model as an alternative to a Cox regression based GWAS, here represented by SPACox. We compare ADuLT, SPACox, and standard case-control GWAS in simulations under two generative models and with varying degrees of ascertainment as well as in the iPSYCH cohort. We find Cox regression GWAS to be underpowered when cases are strongly ascertained (cases are oversampled by a factor 5), regardless of the generative model used. ADuLT is robust to ascertainment in all simulated scenarios. Then, we analyse four psychiatric disorders in iPSYCH, ADHD, Autism, Depression, and Schizophrenia, with a strong case-ascertainment. Across these psychiatric disorders, ADuLT identifies 20 independent genome-wide significant associations, case-control GWAS finds 17, and SPACox finds 8, which is consistent with simulation results. As more genetic data are being linked to electronic health records, robust GWAS methods that can make use of age-of-onset information will help increase power in analyses for common health outcomes.
    DOI:  https://doi.org/10.1038/s41467-023-41210-z
  40. J Immunol. 2023 Sep 13. pii: ji2200809. [Epub ahead of print]
    TGF-β Promotes the Postselection Thymic Development and Peripheral Function of IFN-γ-Producing Invariant NKT cells.
    Roxroy C Morgan, Cameron Frank, Munmun Greger, Mary Attaway, Mikael Sigvardsson, Elizabeth T Bartom, Barbara L Kee.
      IFN-γ-producing invariant NKT (iNKT)1 cells are lipid-reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated, but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell, and thymic epithelial cell numbers or function. In this study, we show that a subset of murine thymic iNKT1 cells required TGF-β-induced signals for their postselection development, to maintain hallmark TGF-β-induced genes, and for expression of the adhesion receptors CD49a and CD103. However, the residency-associated receptor CD69 was not TGF-β signaling-dependent. Recently described CD244+ c2 thymic iNKT1 cells, which produce IFN-γ without exogenous stimulation and have NK-like characteristics, reside in this TGF-β-responsive population. Liver and spleen iNKT1 cells do not share this TGF-β gene signature, but nonetheless TGF-β impacts liver iNKT1 cell phenotype and function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-β-producing cells in the thymus that support their development.
    DOI:  https://doi.org/10.4049/jimmunol.2200809
  41. Nat Commun. 2023 Sep 09. 14(1): 5556
    Chemical-induced phase transition and global conformational reorganization of chromatin.
    Tengfei Wang, Shuxiang Shi, Yuanyuan Shi, Peipei Jiang, Ganlu Hu, Qinying Ye, Zhan Shi, Kexin Yu, Chenguang Wang, Guoping Fan, Suwen Zhao, Hanhui Ma, Alex C Y Chang, Zhi Li, Qian Bian, Chao-Po Lin.
      Chemicals or drugs can accumulate within biomolecular condensates formed through phase separation in cells. Here, we use super-resolution imaging to search for chemicals that induce phase transition within chromatin at the microscale. This microscopic screening approach reveals that adriamycin (doxorubicin) - a widely used anticancer drug that is known to interact with chromatin - specifically induces visible local condensation and global conformational change of chromatin in cancer and primary cells. Hi-C and ATAC-seq experiments systematically and quantitatively demonstrate that adriamycin-induced chromatin condensation is accompanied by weakened chromatin interaction within topologically associated domains, compartment A/B switching, lower chromatin accessibility, and corresponding transcriptomic changes. Mechanistically, adriamycin complexes with histone H1 and induces phase transition of H1, forming fibrous aggregates in vitro. These results reveal a phase separation-driven mechanism for a chemotherapeutic drug.
    DOI:  https://doi.org/10.1038/s41467-023-41340-4
  42. Nature. 2023 Sep 12.
    COVID boosters are back: what scientists say about whether to get one.
    Mariana Lenharo.
      
    Keywords:  Immunology; Public health; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-023-02840-x
  43. Nature. 2023 Sep 13.
    The maths of how we wait in crowded places.
      
    Keywords:  Computational biology and bioinformatics
    DOI:  https://doi.org/10.1038/d41586-023-02828-7
  44. Nat Genet. 2023 Sep 14.
    Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.
    Yanhua Chen, Xiaomeng Du, Annapurna Kuppa, Mary F Feitosa, Lawrence F Bielak, Jeffrey R O'Connell, Solomon K Musani, Xiuqing Guo, Bratati Kahali, Vincent L Chen, Albert V Smith, Kathleen A Ryan, Gudny Eirksdottir, Matthew A Allison, Donald W Bowden, Matthew J Budoff, John Jeffrey Carr, Yii-Der I Chen, Kent D Taylor, Antonino Oliveri, Adolfo Correa, Breland F Crudup, Sharon L R Kardia, Thomas H Mosley, Jill M Norris, James G Terry, Jerome I Rotter, Lynne E Wagenknecht, Brian D Halligan, Kendra A Young, John E Hokanson, George R Washko, Vilmundur Gudnason, Michael A Province, Patricia A Peyser, Nicholette D Palmer, Elizabeth K Speliotes.
      Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.
    DOI:  https://doi.org/10.1038/s41588-023-01497-6
  45. J Exp Med. 2023 Nov 06. pii: e20231154. [Epub ahead of print]220(11):
    NK cell expansion requires HuR and mediates control of solid tumors and long-term virus infection.
    Sytse J Piersma, Sushant Bangru, Jeesang Yoon, Tom W Liu, Liping Yang, Chyi-Song Hsieh, Beatrice Plougastel-Douglas, Auinash Kalsotra, Wayne M Yokoyama.
      Natural killer (NK) cells are lymphocytes capable of controlling tumors and virus infections through direct lysis and cytokine production. While both T and NK cells expand and accumulate in affected tissues, the role of NK cell expansion in tumor and viral control is not well understood. Here, we show that posttranscriptional regulation by the RNA-binding protein HuR is essential for NK cell expansion without negatively affecting effector functions. HuR-deficient NK cells displayed defects in the metaphase of the cell cycle, including decreased expression and alternative splicing of Ska2, a component of the spindle and kinetochore complex. HuR-dependent NK cell expansion contributed to long-term cytomegalovirus control and facilitated control of subcutaneous tumors but not tumor metastases in two independent tumor models. These results show that posttranscriptional regulation by HuR specifically affects NK cell expansion, which is required for the control of long-term virus infection and solid tumors, but not acute infection or tumor metastases, highlighting fundamental differences with antigen-specific T cell control.
    DOI:  https://doi.org/10.1084/jem.20231154
  46. Science. 2023 Sep 15. 381(6663): 1158
    Albert Eschenmoser (1925-2023).
    Scott E Denmark, Erik J Sorensen.
      Organic chemist who demystified the logic of natural product structures.
    DOI:  https://doi.org/10.1126/science.adk2553
  47. Nat Biotechnol. 2023 Sep 11.
    BugSigDB - a database for identifying unusual abundance patterns in human microbiome studies.
      
    DOI:  https://doi.org/10.1038/s41587-023-01930-5
  48. Nat Commun. 2023 Sep 15. 14(1): 5727
    Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.
    Yufeng Wang, David L Drum, Ruochuan Sun, Yida Zhang, Feng Chen, Fengfei Sun, Emre Dal, Ling Yu, Jingyu Jia, Shahrzad Arya, Lin Jia, Song Fan, Steven J Isakoff, Allison M Kehlmann, Gianpietro Dotti, Fubao Liu, Hui Zheng, Cristina R Ferrone, Alphonse G Taghian, Albert B DeLeo, Marco Ventin, Giulia Cattaneo, Yongxiang Li, Youssef Jounaidi, Peigen Huang, Cristina Maccalli, Hanyu Zhang, Cheng Wang, Jibing Yang, Genevieve M Boland, Ruslan I Sadreyev, LaiPing Wong, Soldano Ferrone, Xinhui Wang.
      The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.
    DOI:  https://doi.org/10.1038/s41467-023-41282-x
  49. Nat Commun. 2023 Sep 12. 14(1): 5627
    Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.
    Graham A Heieis, Thiago A Patente, Luís Almeida, Frank Vrieling, Tamar Tak, Georgia Perona-Wright, Rick M Maizels, Rinke Stienstra, Bart Everts.
      Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still poorly defined. Here, using high-dimensional spectral flow cytometry, we observe distinct metabolic profiles between different organs and functionally link acetyl CoA carboxylase activity to efferocytotic capacity. Additionally, differences in metabolism are evident within populations from a specific site, corresponding to relative stages of macrophage maturity. Immune perturbation with intestinal helminth infection increases alternative activation and metabolic rewiring of monocyte-derived macrophage populations, while resident TIM4+ intestinal macrophages remain immunologically and metabolically hyporesponsive. Similar metabolic signatures in alternatively-activated macrophages are seen from different tissues using additional helminth models, but to different magnitudes, indicating further tissue-specific contributions to metabolic states. Thus, our high-dimensional, flow-based metabolic analyses indicates complex metabolic heterogeneity and dynamics of tissue-resident macrophage populations at homeostasis and during helminth infection.
    DOI:  https://doi.org/10.1038/s41467-023-41353-z
  50. Nat Commun. 2023 Sep 15. 14(1): 5715
    Mechanism of outer membrane destabilization by global reduction of protein content.
    Irina V Mikheyeva, Jiawei Sun, Kerwyn Casey Huang, Thomas J Silhavy.
      The outer membrane (OM) of Gram-negative bacteria such as Escherichia coli is an asymmetric bilayer with the glycolipid lipopolysaccharide (LPS) in the outer leaflet and glycerophospholipids in the inner. Nearly all integral OM proteins (OMPs) have a characteristic β-barrel fold and are assembled in the OM by the BAM complex, which contains one essential β-barrel protein (BamA), one essential lipoprotein (BamD), and three non-essential lipoproteins (BamBCE). A gain-of-function mutation in bamA enables survival in the absence of BamD, showing that the essential function of this protein is regulatory. Here, we demonstrate that the global reduction in OMPs caused by BamD loss weakens the OM, altering cell shape and causing OM rupture in spent medium. To fill the void created by OMP loss, phospholipids (PLs) flip into the outer leaflet. Under these conditions, mechanisms that remove PLs from the outer leaflet create tension between the OM leaflets, which contributes to membrane rupture. Rupture is prevented by suppressor mutations that release the tension by halting PL removal from the outer leaflet. However, these suppressors do not restore OM stiffness or normal cell shape, revealing a possible connection between OM stiffness and cell shape.
    DOI:  https://doi.org/10.1038/s41467-023-40396-6
  51. Nat Mater. 2023 Sep 11.
    In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity.
    Ningqiang Gong, Xuexiang Han, Lulu Xue, Rakan El-Mayta, Ann E Metzloff, Margaret M Billingsley, Alex G Hamilton, Michael J Mitchell.
      Chimeric antigen receptor T (CAR T) cell immunotherapy is successful at treating many cancers. However, it often induces life-threatening cytokine release syndrome (CRS) and neurotoxicity. Here, we show that in situ conjugation of polyethylene glycol (PEG) to the surface of CAR T cells ('PEGylation') creates a polymeric spacer that blocks cell-to-cell interactions between CAR T cells, tumour cells and monocytes. Such blockage hinders intensive tumour lysing and monocyte activation by CAR T cells and, consequently, decreases the secretion of toxic cytokines and alleviates CRS-related symptoms. Over time, the slow expansion of CAR T cells decreases PEG surface density and restores CAR T cell-tumour-cell interactions to induce potent tumour killing. This occurs before the restoration of CAR T cell-monocyte interactions, opening a therapeutic window for tumour killing by CAR T cells before monocyte overactivation. Lethal neurotoxicity is also lower when compared with treatment with the therapeutic antibody tocilizumab, demonstrating that in situ PEGylation of CAR T cells provides a materials-based strategy for safer cellular immunotherapy.
    DOI:  https://doi.org/10.1038/s41563-023-01646-6
  52. Cell Metab. 2023 Sep 07. pii: S1550-4131(23)00304-2. [Epub ahead of print]
    Bone marrow immune cells respond to fluctuating nutritional stress to constrain weight regain.
    Hai-Yan Zhou, Xu Feng, Li-Wen Wang, Rui Zhou, Heng Sun, Xin Chen, Ren-Bin Lu, Yan Huang, Qi Guo, Xiang-Hang Luo.
      Weight regain after weight loss is a major challenge in the treatment of obesity. Immune cells adapt to fluctuating nutritional stress, but their roles in regulating weight regain remain unclear. Here, we identify a stem cell-like CD7+ monocyte subpopulation accumulating in the bone marrow (BM) of mice and humans that experienced dieting-induced weight loss. Adoptive transfer of CD7+ monocytes suppresses weight regain, whereas inducible depletion of CD7+ monocytes accelerates it. These cells, accumulating metabolic memories via epigenetic adaptations, preferentially migrate to the subcutaneous white adipose tissue (WAT), where they secrete fibrinogen-like protein 2 (FGL2) to activate the protein kinase A (PKA) signaling pathway and facilitate beige fat thermogenesis. Nevertheless, CD7+ monocytes gradually enter a quiescent state after weight loss, accompanied by increased susceptibility to weight regain. Notably, administration of FMS-like tyrosine kinase 3 ligand (FLT3L) remarkably rejuvenates CD7+ monocytes, thus ameliorating rapid weight regain. Together, our findings identify a unique bone marrow-derived metabolic-memory immune cell population that could be targeted to combat obesity.
    Keywords:  CD7+ monocytes; bone marrow; obesity; thermogenesis; weight regain
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.009
  53. Cell Metab. 2023 Sep 05. pii: S1550-4131(23)00303-0. [Epub ahead of print]
    Death-seq identifies regulators of cell death and senolytic therapies.
    Alex Colville, Jie-Yu Liu, Cristina Rodriguez-Mateo, Samantha Thomas, Heather D Ishak, Ronghao Zhou, Julian D D Klein, David W Morgens, Armon Goshayeshi, Jayesh S Salvi, David Yao, Kaitlyn Spees, Scott J Dixon, Chun Liu, June-Wha Rhee, Celine Lai, Joseph C Wu, Michael C Bassik, Thomas A Rando.
      Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263. The screen also identified inducers of cell death and senescent cell clearance in models of age-related diseases by a related compound, ABT-199, which alone is not senolytic but exhibits less toxicity than ABT-263. Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identifies drug targets for the treatment of diverse pathological states such as senescence, cancer, and fibrosis.
    Keywords:  CRISPR; Death-seq; cell death; death screen; genome-wide; positive selection; pulmonary fibrosis; senescence; senolytics; synthetic lethality
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.008
  54. Nat Commun. 2023 Sep 14. 14(1): 5690
    Monolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification.
    Sivakamasundari Vijayakumar, Roberta Sala, Gugene Kang, Angela Chen, Michelle Ann Pablo, Abidemi Ismail Adebayo, Andrea Cipriano, Jonas L Fowler, Danielle L Gomes, Lay Teng Ang, Kyle M Loh, Vittorio Sebastiano.
      Generating primordial germ cell-like cells (PGCLCs) from human pluripotent stem cells (hPSCs) advances studies of human reproduction and development of infertility treatments, but often entails complex 3D aggregates. Here we develop a simplified, monolayer method to differentiate hPSCs into PGCs within 3.5 days. We use our simplified differentiation platform and single-cell RNA-sequencing to achieve further insights into PGCLC specification. Transient WNT activation for 12 h followed by WNT inhibition specified PGCLCs; by contrast, sustained WNT induced primitive streak. Thus, somatic cells (primitive streak) and PGCLCs are related-yet distinct-lineages segregated by temporally-dynamic signaling. Pluripotency factors including NANOG are continuously expressed during the transition from pluripotency to posterior epiblast to PGCs, thus bridging pluripotent and germline states. Finally, hPSC-derived PGCLCs can be easily purified by virtue of their CXCR4+PDGFRA-GARP- surface-marker profile and single-cell RNA-sequencing reveals that they harbor transcriptional similarities with fetal PGCs.
    DOI:  https://doi.org/10.1038/s41467-023-41302-w
  55. Nat Rev Genet. 2023 Sep 15.
    Illuminating the human yolk sac through single-cell omics.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41576-023-00658-x
  56. Nature. 2023 Sep 13.
    A cross-species proteomic map reveals neoteny of human synapse development.
    Li Wang, Kaifang Pang, Li Zhou, Arantxa Cebrián-Silla, Susana González-Granero, Shaohui Wang, Qiuli Bi, Matthew L White, Brandon Ho, Jiani Li, Tao Li, Yonatan Perez, Eric J Huang, Ethan A Winkler, Mercedes F Paredes, Rothem Kovner, Nenad Sestan, Alex A Pollen, Pengyuan Liu, Jingjing Li, Xianhua Piao, José Manuel García-Verdugo, Arturo Alvarez-Buylla, Zhandong Liu, Arnold R Kriegstein.
      The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.
    DOI:  https://doi.org/10.1038/s41586-023-06542-2
  57. Nat Metab. 2023 Sep 11.
    Delineating mouse β-cell identity during lifetime and in diabetes with a single cell atlas.
    Karin Hrovatin, Aimée Bastidas-Ponce, Mostafa Bakhti, Luke Zappia, Maren Büttner, Ciro Salinno, Michael Sterr, Anika Böttcher, Adriana Migliorini, Heiko Lickert, Fabian J Theis.
      Although multiple pancreatic islet single-cell RNA-sequencing (scRNA-seq) datasets have been generated, a consensus on pancreatic cell states in development, homeostasis and diabetes as well as the value of preclinical animal models is missing. Here, we present an scRNA-seq cross-condition mouse islet atlas (MIA), a curated resource for interactive exploration and computational querying. We integrate over 300,000 cells from nine scRNA-seq datasets consisting of 56 samples, varying in age, sex and diabetes models, including an autoimmune type 1 diabetes model (NOD), a glucotoxicity/lipotoxicity type 2 diabetes model (db/db) and a chemical streptozotocin β-cell ablation model. The β-cell landscape of MIA reveals new cell states during disease progression and cross-publication differences between previously suggested marker genes. We show that β-cells in the streptozotocin model transcriptionally correlate with those in human type 2 diabetes and mouse db/db models, but are less similar to human type 1 diabetes and mouse NOD β-cells. We also report pathways that are shared between β-cells in immature, aged and diabetes models. MIA enables a comprehensive analysis of β-cell responses to different stressors, providing a roadmap for the understanding of β-cell plasticity, compensation and demise.
    DOI:  https://doi.org/10.1038/s42255-023-00876-x
  58. Nat Commun. 2023 Sep 11. 14(1): 5581
    Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD.
    Malgorzata J Latallo, Shaopeng Wang, Daoyuan Dong, Blake Nelson, Nathan M Livingston, Rong Wu, Ning Zhao, Timothy J Stasevich, Michael C Bassik, Shuying Sun, Bin Wu.
      C9ORF72 hexanucleotide repeat expansion is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the accumulation of toxic dipeptide repeat (DPR) proteins like poly-GA, GP and GR, produced by the noncanonical translation of the expanded RNA repeats. However, how different DPRs are synthesized remains elusive. Here, we use single-molecule imaging techniques to directly measure the translation dynamics of different DPRs. Besides initiation, translation elongation rates vary drastically between different frames, with GP slower than GA and GR the slowest. We directly visualize frameshift events using a two-color single-molecule translation assay. The repeat expansion enhances frameshifting, but the overall frequency is low. There is a higher chance of GR-to-GA shift than in the reversed direction. Finally, the ribosome-associated protein quality control (RQC) factors ZNF598 and Pelota modulate the translation dynamics, and the repeat RNA sequence is important for invoking the RQC pathway. This study reveals that multiple translation steps modulate the final DPR production. Understanding repeat RNA translation is critically important to decipher the DPR-mediated pathogenesis and identify potential therapeutic targets in C9ORF72-ALS/FTD.
    DOI:  https://doi.org/10.1038/s41467-023-41339-x
  59. Sci Signal. 2023 Sep 12. 16(802): eadg6360
    TSLP shapes the pathogenic responses of memory CD4+ T cells in eosinophilic esophagitis.
    Yrina Rochman, Michael Kotliar, Netali Ben-Baruch Morgenstern, Artem Barski, Ting Wen, Marc E Rothenberg.
      The cytokine thymic stromal lymphopoietin (TSLP) mediates type 2 immune responses, and treatments that interfere with TSLP activity are in clinical use for asthma. Here, we investigated whether TSLP contributes to allergic inflammation by directly stimulating human CD4+ T cells and whether this process is operational in eosinophilic esophagitis (EoE), a disease linked to variants in TSLP. We showed that about 10% of esophageal-derived memory CD4+ T cells from individuals with EoE and less than 3% of cells from control individuals expressed the receptor for TSLP and directly responded to TSLP, as determined by measuring the phosphorylation of STAT5, a transcription factor activated downstream of TSLP stimulation. Accordingly, increased numbers of TSLP-responsive memory CD4+ T cells were present in the circulation of individuals with EoE. TSLP increased the proliferation of CD4+ T cells, enhanced type 2 cytokine production, induced the increased abundance of its own receptor, and modified the expression of 212 genes. The epigenetic response to TSLP was associated with an enrichment in BATF and IRF4 chromatin-binding sites, and these transcription factors were induced by TSLP, providing a feed-forward loop. The numbers of circulating and esophageal CD4+ T cells responsive to TSLP correlated with the numbers of esophageal eosinophils, supporting a potential functional role for TSLP in driving the pathogenesis of EoE and providing the basis for a blood-based diagnostic test based on the extent of TSLP-induced STAT5 phosphorylation in circulating CD4+ T cells. These findings highlight the potential therapeutic value of TSLP inhibitors for the treatment of EoE.
    DOI:  https://doi.org/10.1126/scisignal.adg6360
  60. Nat Aging. 2023 Sep 11.
    Transcriptional and epigenetic decoding of the microglial aging process.
    Xiaoyu Li, Yuxin Li, Yuxiao Jin, Yuheng Zhang, Jingchuan Wu, Zhen Xu, Yubin Huang, Lin Cai, Shuai Gao, Taohui Liu, Fanzhuo Zeng, Yafei Wang, Wenxu Wang, Ti-Fei Yuan, Hengli Tian, Yousheng Shu, Feifan Guo, Wei Lu, Ying Mao, Xifan Mei, Yanxia Rao, Bo Peng.
      As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, the longitudinal characteristics of microglia remain poorly understood. In this study, we mapped the transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We first discovered unexpected sex differences and identified age-dependent microglia (ADEM) genes during the aging process. We then compared the features of aging and reactivity in female microglia at single-cell resolution and epigenetic level. To dissect functions of aged microglia excluding the influence from other aged brain cells, we established an accelerated microglial turnover model without directly affecting other brain cells. By this model, we achieved aged-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cognitive decline. Collectively, our work provides a comprehensive resource for decoding the aging process of microglia, shedding light on how microglia maintain brain functions.
    DOI:  https://doi.org/10.1038/s43587-023-00479-x
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