bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒07‒07
fifty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice.
  2. What drives mosquitoes' bloodlust? Their hormones.
  3. PD-L1 senses fungi.
  4. Ultra-detailed brain map shows neurons that encode words' meaning.
  5. IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.
  6. IL-12 drives the differentiation of human T follicular regulatory cells.
  7. Genetic gear switches drive cancer immune evasion.
  8. A unified model-based framework for doublet or multiplet detection in single-cell multiomics data.
  9. An ILC3-intrinsic, CTLA4-dependent intestinal checkpoint.
  10. Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.
  11. An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases.
  12. Japan's scientists demand more money for basic science.
  13. A chemogenetic approach for dopamine imaging with tunable sensitivity.
  14. GTPBP8 plays a role in mitoribosome formation in human mitochondria.
  15. Primary nasal influenza infection rewires tissue-scale memory response dynamics.
  16. Mitochondrial genetics through the lens of single-cell multi-omics.
  17. Illuminating the dark space of neutral glycosphingolipidome by selective enrichment and profiling at multi-structural levels.
  18. Bionic leg moves like a natural limb - without conscious thought.
  19. Breaking boundaries: Bacteria act as architects of host T cell modulators using bile acids.
  20. Mapping the lung fibrosis transcriptome of mice and men.
  21. Identification of unique cell type responses in pancreatic islets to stress.
  22. "Who am I if not a scientist?" How to find identity and purpose in retirement.
  23. [18F]F-AraG imaging reveals association between neuroinflammation and brown- and bone marrow adipose tissue.
  24. TIGIT predominantly regulates the immune response via regulatory T cells.
  25. Killer immune cells pile on the pressure to slay their foes.
  26. What causes migraines? Study of 'brain blackout' offers clues.
  27. Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
  28. From whence it came: Mitochondrial mRNA leaves, a protein returns.
  29. HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages.
  30. Blooming plants and sunken cities, Books in brief.
  31. Daily briefing: How obesity drugs like Ozempic create a full feeling.
  32. Blueprints for ATP machinery will aid tuberculosis drug design.
  33. Shared functional specialization in transformer-based language models and the human brain.
  34. PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.
  35. Dimeric transport mechanism of human vitamin C transporter SVCT1.
  36. Platelet TGF-β triggers immunosuppression in ITP.
  37. Epigenetic recording of stimulation history reveals BLIMP1-BACH2 balance in determining memory B cell fate upon recall challenge.
  38. CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment.
  39. White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models.
  40. Ants amputate their nest-mates' legs to save lives.
  41. Spy on millions of sleeping butterflies and more - June's best science images.
  42. Semantic encoding during language comprehension at single-cell resolution.
  43. There will be blood.
  44. CD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites.
  45. Unchanged power dynamics still block progress for under-represented groups in academia.
  46. High-throughput discovery of MHC class I- and II-restricted T cell epitopes using synthetic cellular circuits.
  47. Microbiota licenses protective CD8+ T cell responses against neonatal influenza.
  48. The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.
  49. Did the diarist who chronicled the Great Fire of London make up a scientific instrument?
  50. Lab-grown embryo models: UK unveils first ever rules to guide research.
  51. Faecal transplants can treat some cancers - but probably won't ever be widely used.
  52. Abdominal aortic aneurysm and cardiometabolic traits share strong genetic susceptibility to lipid metabolism and inflammation.
  1. Nat Commun. 2024 Jul 05. 15(1): 5654
    CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice.
    Pasqualina Colella, Ruhi Sayana, Maria Valentina Suarez-Nieto, Jolanda Sarno, Kwamina Nyame, Jian Xiong, Luisa Natalia Pimentel Vera, Jessica Arozqueta Basurto, Marco Corbo, Anay Limaye, Kara L Davis, Monther Abu-Remaileh, Natalia Gomez-Ospina.
      Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines busulfan myeloablation and six days of Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity of microglia-like cells with most cells expressing genes characteristic of homeostatic microglia, brain-border-associated macrophages, and unique markers. Cytokine analysis in the CNS showed transient inductions of myeloproliferative and chemoattractant cytokines that help repopulate the microglia niche. Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid metabolism. This study advances our understanding of CNS repopulation by hematopoietic-derived cells and demonstrates its therapeutic potential for treating progranulin-dependent neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-024-49908-4
  2. Nature. 2024 Jul 01.
    What drives mosquitoes' bloodlust? Their hormones.
    Gemma Conroy.
      
    Keywords:  Infection; Zoology
    DOI:  https://doi.org/10.1038/d41586-024-02126-w
  3. Nat Immunol. 2024 Jul;25(7): 1125
    PD-L1 senses fungi.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-024-01893-y
  4. Nature. 2024 Jul 03.
    Ultra-detailed brain map shows neurons that encode words' meaning.
    Sara Reardon.
      
    Keywords:  Brain; Language; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02146-6
  5. Nat Commun. 2024 Jun 29. 15(1): 5506
    IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.
    Randall H Friedline, Hye Lim Noh, Sujin Suk, Mahaa Albusharif, Sezin Dagdeviren, Suchaorn Saengnipanthkul, Bukyung Kim, Allison M Kim, Lauren H Kim, Lauren A Tauer, Natalie M Baez Torres, Stephanie Choi, Bo-Yeon Kim, Suryateja D Rao, Kaushal Kasina, Cheng Sun, Benjamin J Toles, Chan Zhou, Zixiu Li, Vivian M Benoit, Payal R Patel, Doris X T Zheng, Kunikazu Inashima, Annika Beaverson, Xiaodi Hu, Duy A Tran, Werner Muller, Dale L Greiner, Alan C Mullen, Ki Won Lee, Jason K Kim.
      Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.
    DOI:  https://doi.org/10.1038/s41467-024-49633-y
  6. Sci Immunol. 2024 Jul 05. 9(97): eadf2047
    IL-12 drives the differentiation of human T follicular regulatory cells.
    Diana Castaño, Sidney Wang, Segovia Atencio-Garcia, Emily J Shields, Maria C Rico, Hannah Sharpe, Jacinta Bustamante, Allan Feng, Carole Le Coz, Neil Romberg, John W Tobias, Paul J Utz, Sarah E Henrickson, Jean-Laurent Casanova, Roberto Bonasio, Michela Locci.
      T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.
    DOI:  https://doi.org/10.1126/sciimmunol.adf2047
  7. Nat Genet. 2024 Jul 03.
    Genetic gear switches drive cancer immune evasion.
      
    DOI:  https://doi.org/10.1038/s41588-024-01778-8
  8. Nat Commun. 2024 Jul 02. 15(1): 5562
    A unified model-based framework for doublet or multiplet detection in single-cell multiomics data.
    Haoran Hu, Xinjun Wang, Site Feng, Zhongli Xu, Jing Liu, Elisa Heidrich-O'Hare, Yanshuo Chen, Molin Yue, Lang Zeng, Ziqi Rong, Tianmeng Chen, Timothy Billiar, Ying Ding, Heng Huang, Richard H Duerr, Wei Chen.
      Droplet-based single-cell sequencing techniques rely on the fundamental assumption that each droplet encapsulates a single cell, enabling individual cell omics profiling. However, the inevitable issue of multiplets, where two or more cells are encapsulated within a single droplet, can lead to spurious cell type annotations and obscure true biological findings. The issue of multiplets is exacerbated in single-cell multiomics settings, where integrating cross-modality information for clustering can inadvertently promote the aggregation of multiplet clusters and increase the risk of erroneous cell type annotations. Here, we propose a compound Poisson model-based framework for multiplet detection in single-cell multiomics data. Leveraging experimental cell hashing results as the ground truth for multiplet status, we conducted trimodal DOGMA-seq experiments and generated 17 benchmarking datasets from two tissues, involving a total of 280,123 droplets. We demonstrated that the proposed method is an essential tool for integrating cross-modality multiplet signals, effectively eliminating multiplet clusters in single-cell multiomics data-a task at which the benchmarked single-omics methods proved inadequate.
    DOI:  https://doi.org/10.1038/s41467-024-49448-x
  9. Nat Rev Immunol. 2024 Jul 04.
    An ILC3-intrinsic, CTLA4-dependent intestinal checkpoint.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01063-z
  10. Nat Commun. 2024 Jul 04. 15(1): 5631
    Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.
    Tiantian Jing, Dianhui Wei, Xiaoli Xu, Chengsi Wu, Lili Yuan, Yiwen Huang, Yizhen Liu, Yanyi Jiang, Boshi Wang.
      Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.
    DOI:  https://doi.org/10.1038/s41467-024-49926-2
  11. Science. 2024 Jul 05. 385(6704): eadd8394
    An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases.
    ITEC Consortium‡
      Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4+ T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.
    DOI:  https://doi.org/10.1126/science.add8394
  12. Nature. 2024 Jul 04.
    Japan's scientists demand more money for basic science.
    Anna Ikarashi.
      
    Keywords:  Funding; Policy; Politics
    DOI:  https://doi.org/10.1038/d41586-024-00942-8
  13. Nat Commun. 2024 Jul 02. 15(1): 5551
    A chemogenetic approach for dopamine imaging with tunable sensitivity.
    Marie A Labouesse, Maria Wilhelm, Zacharoula Kagiampaki, Andrew G Yee, Raphaelle Denis, Masaya Harada, Andrea Gresch, Alina-Măriuca Marinescu, Kanako Otomo, Sebastiano Curreli, Laia Serratosa Capdevila, Xuehan Zhou, Reto B Cola, Luca Ravotto, Chaim Glück, Stanislav Cherepanov, Bruno Weber, Xin Zhou, Jason Katner, Kjell A Svensson, Tommaso Fellin, Louis-Eric Trudeau, Christopher P Ford, Yaroslav Sych, Tommaso Patriarchi.
      Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.
    DOI:  https://doi.org/10.1038/s41467-024-49442-3
  14. Nat Commun. 2024 Jul 05. 15(1): 5664
    GTPBP8 plays a role in mitoribosome formation in human mitochondria.
    Miriam Cipullo, Genís Valentín Gesé, Shreekara Gopalakrishna, Annika Krueger, Vivian Lobo, Maria A Pirozhkova, James Marks, Petra Páleníková, Dmitrii Shiriaev, Yong Liu, Jelena Misic, Yu Cai, Minh Duc Nguyen, Abubakar Abdelbagi, Xinping Li, Michal Minczuk, Markus Hafner, Daniel Benhalevy, Aishe A Sarshad, Ilian Atanassov, B Martin Hällberg, Joanna Rorbach.
      Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.
    DOI:  https://doi.org/10.1038/s41467-024-50011-x
  15. Immunity. 2024 Jun 28. pii: S1074-7613(24)00311-X. [Epub ahead of print]
    Primary nasal influenza infection rewires tissue-scale memory response dynamics.
    Samuel W Kazer, Colette Matysiak Match, Erica M Langan, Marie-Angèle Messou, Thomas J LaSalle, Elise O'Leary, Jessica Marbourg, Katherine Naughton, Ulrich H von Andrian, Jose Ordovas-Montanes.
      The nasal mucosa is often the initial site of respiratory viral infection, replication, and transmission. Understanding how infection shapes tissue-scale primary and memory responses is critical for designing mucosal therapeutics and vaccines. We generated a single-cell RNA-sequencing atlas of the murine nasal mucosa, sampling three regions during primary influenza infection and rechallenge. Compositional analysis revealed restricted infection to the respiratory mucosa with stepwise changes in immune and epithelial cell subsets and states. We identified and characterized a rare subset of Krt13+ nasal immune-interacting floor epithelial (KNIIFE) cells, which concurrently increased with tissue-resident memory T (TRM)-like cells. Proportionality analysis, cell-cell communication inference, and microscopy underscored the CXCL16-CXCR6 axis between KNIIFE and TRM cells. Secondary influenza challenge induced accelerated and coordinated myeloid and lymphoid responses without epithelial proliferation. Together, this atlas serves as a reference for viral infection in the upper respiratory tract and highlights the efficacy of local coordinated memory responses.
    Keywords:  airway; epithelial cells; inflammation; influenza; memory; nasal mucosa; respiratory infection; scRNA-seq; single-cell; viral infection
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.005
  16. Nat Genet. 2024 Jul 01.
    Mitochondrial genetics through the lens of single-cell multi-omics.
    Lena Nitsch, Caleb A Lareau, Leif S Ludwig.
      Mitochondria carry their own genetic information encoding for a subset of protein-coding genes and translational machinery essential for cellular respiration and metabolism. Despite its small size, the mitochondrial genome, its natural genetic variation and molecular phenotypes have been challenging to study using bulk sequencing approaches, due to its variation in cellular copy number, non-Mendelian modes of inheritance and propensity for mutations. Here we highlight emerging strategies designed to capture mitochondrial genetic variation across individual cells for lineage tracing and studying mitochondrial genetics in primary human cells and clinical specimens. We review recent advances surrounding single-cell mitochondrial genome sequencing and its integration with functional genomic readouts, including leveraging somatic mitochondrial DNA mutations as clonal markers that can resolve cellular population dynamics in complex human tissues. Finally, we discuss how single-cell whole mitochondrial genome sequencing approaches can be utilized to investigate mitochondrial genetics and its contribution to cellular heterogeneity and disease.
    DOI:  https://doi.org/10.1038/s41588-024-01794-8
  17. Nat Commun. 2024 Jul 04. 15(1): 5627
    Illuminating the dark space of neutral glycosphingolipidome by selective enrichment and profiling at multi-structural levels.
    Zidan Wang, Donghui Zhang, Junhan Wu, Wenpeng Zhang, Yu Xia.
      Glycosphingolipids (GSLs) are essential components of cell membranes, particularly enriched in the nervous system. Altered molecular distributions of GSLs are increasingly associated with human diseases, emphasizing the significance of lipidomic profiling. Traditional GSL analysis methods are hampered by matrix effect from phospholipids and the difficulty in distinguishing structural isomers. Herein, we introduce a highly sensitive workflow that harnesses magnetic TiO2 nanoparticle-based selective enrichment, charge-tagging Paternò-Büchi reaction, and liquid chromatography-tandem mass spectrometry. This approach enables mapping over 300 distinct GSLs in brain tissues by defining sugar types, long chain bases, N-acyl chains, and the locations of desaturation and hydroxylation. Relative quantitation of GSLs across multiple structural levels provides evidence of dysregulated gene and protein expressions of FA2H and CerS2 in human glioma tissue. Based on the structural features of GSLs, our method accurately differentiates human glioma with/without isocitrate dehydrogenase genetic mutation, and normal brain tissue.
    DOI:  https://doi.org/10.1038/s41467-024-50014-8
  18. Nature. 2024 Jul 01.
    Bionic leg moves like a natural limb - without conscious thought.
    Miryam Naddaf.
      
    Keywords:  Medical research; Neuroscience; Technology
    DOI:  https://doi.org/10.1038/d41586-024-02157-3
  19. Science. 2024 Jul 05. 385(6704): 37
    Breaking boundaries: Bacteria act as architects of host T cell modulators using bile acids.
    Lina Yao.
      Bacteria act as architects of host T cell modulators using bile acids.
    DOI:  https://doi.org/10.1126/science.adq2341
  20. Nat Genet. 2024 Jul 05.
    Mapping the lung fibrosis transcriptome of mice and men.
      
    DOI:  https://doi.org/10.1038/s41588-024-01833-4
  21. Nat Commun. 2024 Jul 02. 15(1): 5567
    Identification of unique cell type responses in pancreatic islets to stress.
    Marlie M Maestas, Matthew Ishahak, Punn Augsornworawat, Daniel A Veronese-Paniagua, Kristina G Maxwell, Leonardo Velazco-Cruz, Erica Marquez, Jiameng Sun, Mira Shunkarova, Sarah E Gale, Fumihiko Urano, Jeffrey R Millman.
      Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that β-, α-, and ductal cells have the greatest transcriptional response. We utilize stem cell-derived islets to study islet health through the candidate gene CIB1, which was upregulated under stress in primary human islets. Our findings provide insights into cell type-specific responses to diabetes-associated stress and establish a resource to identify targets for diabetes therapeutics.
    DOI:  https://doi.org/10.1038/s41467-024-49724-w
  22. Nature. 2024 Jul 05.
    "Who am I if not a scientist?" How to find identity and purpose in retirement.
    Julie Gould.
      
    Keywords:  Ageing; Careers; Lab life; Society
    DOI:  https://doi.org/10.1038/d41586-024-02246-3
  23. Commun Biol. 2024 Jul 01. 7(1): 793
    [18F]F-AraG imaging reveals association between neuroinflammation and brown- and bone marrow adipose tissue.
    Jelena Levi, Caroline Guglielmetti, Timothy J Henrich, John C Yoon, Prafulla C Gokhale, David A Reardon, Juliet Packiasamy, Lyna Huynh, Hilda Cabrera, Marisa Ruzevich, Joseph Blecha, Michael J Peluso, Tony L Huynh, Sung-Min An, Mark Dornan, Anthony P Belanger, Quang-Dé Nguyen, Youngho Seo, Hong Song, Myriam M Chaumeil, Henry F VanBrocklin, Hee-Don Chae.
      Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.
    DOI:  https://doi.org/10.1038/s42003-024-06494-x
  24. J Clin Invest. 2024 Jul 01. pii: e183278. [Epub ahead of print]134(13):
    TIGIT predominantly regulates the immune response via regulatory T cells.
    Sema Kurtulus, Kaori Sakuishi, Shin-Foong Ngiow, Nicole Joller, Dewar J Tan, Michele Wl Teng, Mark J Smyth, Vijay K Kuchroo, Ana C Anderson.
      
    DOI:  https://doi.org/10.1172/JCI183278
  25. Nature. 2024 Jul 02.
    Killer immune cells pile on the pressure to slay their foes.
      
    Keywords:  Immunology
    DOI:  https://doi.org/10.1038/d41586-024-02137-7
  26. Nature. 2024 Jul 05.
    What causes migraines? Study of 'brain blackout' offers clues.
    Miryam Naddaf.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02222-x
  27. Nat Genet. 2024 Jul 01.
    Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
    ABCTB Investigators
      Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.
    DOI:  https://doi.org/10.1038/s41588-024-01798-4
  28. Cell Metab. 2024 Jul 02. pii: S1550-4131(24)00227-4. [Epub ahead of print]36(7): 1433-1435
    From whence it came: Mitochondrial mRNA leaves, a protein returns.
    Kevin A Janssen, Angela Song.
      Small peptides have previously been reported to be encoded in mitochondrial rRNA and translated by cytosolic ribosomes. In this issue of Cell Metabolism, Hu et al. use mass spectrometry to identify a cytosolically translated protein, encoded instead in mitochondrial mRNA, that is surprisingly targeted back into the mitochondrial matrix.
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.002
  29. Nat Commun. 2024 Jun 29. 15(1): 5514
    HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages.
    Maria C Virgilio, Barkha Ramnani, Thomas Chen, W Miguel Disbennett, Jay Lubow, Joshua D Welch, Kathleen L Collins.
      HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
    DOI:  https://doi.org/10.1038/s41467-024-49635-w
  30. Nature. 2024 Jul 05.
    Blooming plants and sunken cities, Books in brief.
    Andrew Robinson.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-02220-z
  31. Nature. 2024 Jun 28.
    Daily briefing: How obesity drugs like Ozempic create a full feeling.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02152-8
  32. Nature. 2024 Jul 03.
    Blueprints for ATP machinery will aid tuberculosis drug design.
    Gregory M Cook, Matthew B McNeil.
      
    Keywords:  Antibiotics; Drug discovery; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-02094-1
  33. Nat Commun. 2024 Jun 29. 15(1): 5523
    Shared functional specialization in transformer-based language models and the human brain.
    Sreejan Kumar, Theodore R Sumers, Takateru Yamakoshi, Ariel Goldstein, Uri Hasson, Kenneth A Norman, Thomas L Griffiths, Robert D Hawkins, Samuel A Nastase.
      When processing language, the brain is thought to deploy specialized computations to construct meaning from complex linguistic structures. Recently, artificial neural networks based on the Transformer architecture have revolutionized the field of natural language processing. Transformers integrate contextual information across words via structured circuit computations. Prior work has focused on the internal representations ("embeddings") generated by these circuits. In this paper, we instead analyze the circuit computations directly: we deconstruct these computations into the functionally-specialized "transformations" that integrate contextual information across words. Using functional MRI data acquired while participants listened to naturalistic stories, we first verify that the transformations account for considerable variance in brain activity across the cortical language network. We then demonstrate that the emergent computations performed by individual, functionally-specialized "attention heads" differentially predict brain activity in specific cortical regions. These heads fall along gradients corresponding to different layers and context lengths in a low-dimensional cortical space.
    DOI:  https://doi.org/10.1038/s41467-024-49173-5
  34. Nat Metab. 2024 Jul 03.
    PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.
    Qingzhang Zhu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Qian Lin, Shangang Zhao, Chanmin Joung, Zhuzhen Zhang, Dae-Seok Kim, Na Li, Christy M Gliniak, Charlotte Lee, Alberto Cebrian-Serrano, Line Pedersen, Nils Halberg, Ruth Gordillo, Christine M Kusminski, Philipp E Scherer.
      PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.
    DOI:  https://doi.org/10.1038/s42255-024-01078-9
  35. Nat Commun. 2024 Jul 02. 15(1): 5569
    Dimeric transport mechanism of human vitamin C transporter SVCT1.
    Takaaki A Kobayashi, Hiroto Shimada, Fumiya K Sano, Yuzuru Itoh, Sawako Enoki, Yasushi Okada, Tsukasa Kusakizako, Osamu Nureki.
      Vitamin C plays important roles as a cofactor in many enzymatic reactions and as an antioxidant against oxidative stress. As some mammals including humans cannot synthesize vitamin C de novo from glucose, its uptake from dietary sources is essential, and is mediated by the sodium-dependent vitamin C transporter 1 (SVCT1). Despite its physiological significance in maintaining vitamin C homeostasis, the structural basis of the substrate transport mechanism remained unclear. Here, we report the cryo-EM structures of human SVCT1 in different states at 2.5-3.5 Å resolutions. The binding manner of vitamin C together with two sodium ions reveals the counter ion-dependent substrate recognition mechanism. Furthermore, comparisons of the inward-open and occluded structures support a transport mechanism combining elevator and distinct rotational motions. Our results demonstrate the molecular mechanism of vitamin C transport with its underlying conformational cycle, potentially leading to future industrial and medical applications.
    DOI:  https://doi.org/10.1038/s41467-024-49899-2
  36. Blood. 2024 Jul 04. 144(1): 7-8
    Platelet TGF-β triggers immunosuppression in ITP.
    Rick Kapur, John W Semple.
      
    DOI:  https://doi.org/10.1182/blood.2024024825
  37. Nat Immunol. 2024 Jul 05.
    Epigenetic recording of stimulation history reveals BLIMP1-BACH2 balance in determining memory B cell fate upon recall challenge.
    Wen Shao, Yifeng Wang, Qian Fang, Wenjuan Shi, Hai Qi.
      Memory B cells (MBCs) differentiate into plasma cells (PCs) or germinal centers (GCs) upon antigen recall. How this decision is programmed is not understood. We found that the relative strength between two antagonistic transcription factors, B lymphocyte-induced maturation protein 1 (BLIMP1) and BTB domain and CNC homolog 2 (BACH2), progressively increases in favor of BLIMP1 in antigen-responding B cells through the course of primary responses. MBC subsets that preferentially produce secondary GCs expressed comparatively higher BACH2 but lower BLIMP1 than those predisposed for PC development. Skewing the BLIMP1-BACH2 balance in otherwise fate-predisposed MBC subsets could switch their fate preferences. Underlying the changing BLIMP1-over-BACH2 balance, we observed progressively increased accessibilities at chromatin loci that are specifically opened in PCs, particularly those that contain interferon-sensitive response elements (ISREs) and are controlled by interferon regulatory factor 4 (IRF4). IRF4 is upregulated by B cell receptor, CD40 or innate receptor signaling and it induces graded levels of PC-specifying epigenetic imprints according to the strength of stimulation. By analyzing history-stamped GC B cells, we found progressively increased chromatin accessibilities at PC-specific, IRF4-controlled gene loci over time. Therefore, the cumulative stimulation history of B cells is epigenetically recorded in an IRF4-dependent manner, determines the relative strength between BLIMP1 and BACH2 in individual MBCs and dictates their probabilities to develop into GCs or PCs upon restimulation.
    DOI:  https://doi.org/10.1038/s41590-024-01900-2
  38. Nat Commun. 2024 Jul 01. 15(1): 5524
    CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment.
    Jie Zhang, Gongcheng Hu, Yuli Lu, Huawei Ren, Yin Huang, Yulin Wen, Binrui Ji, Diyang Wang, Haidong Wang, Huisheng Liu, Ning Ma, Lingling Zhang, Guangjin Pan, Yibo Qu, Hua Wang, Wei Zhang, Zhichao Miao, Hongjie Yao.
      The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41467-024-49684-1
  39. J Clin Invest. 2024 Jul 01. pii: e172360. [Epub ahead of print]134(13):
    White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models.
    Liang Li, Brian J Feldman.
      Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15's direct regulation of Adrb1 is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.
    Keywords:  Adipose tissue; Cell biology; Endocrinology
    DOI:  https://doi.org/10.1172/JCI172360
  40. Nature. 2024 Jul 02.
    Ants amputate their nest-mates' legs to save lives.
      
    Keywords:  Animal behaviour
    DOI:  https://doi.org/10.1038/d41586-024-02138-6
  41. Nature. 2024 Jul 02.
    Spy on millions of sleeping butterflies and more - June's best science images.
    Emma Stoye, Helena Kudiabor.
      
    Keywords:  Media
    DOI:  https://doi.org/10.1038/d41586-024-02140-y
  42. Nature. 2024 Jul 03.
    Semantic encoding during language comprehension at single-cell resolution.
    Mohsen Jamali, Benjamin Grannan, Jing Cai, Arjun R Khanna, William Muñoz, Irene Caprara, Angelique C Paulk, Sydney S Cash, Evelina Fedorenko, Ziv M Williams.
      From sequences of speech sounds1,2 or letters3, humans can extract rich and nuanced meaning through language. This capacity is essential for human communication. Yet, despite a growing understanding of the brain areas that support linguistic and semantic processing4-12, the derivation of linguistic meaning in neural tissue at the cellular level and over the timescale of action potentials remains largely unknown. Here we recorded from single cells in the left language-dominant prefrontal cortex as participants listened to semantically diverse sentences and naturalistic stories. By tracking their activities during natural speech processing, we discover a fine-scale cortical representation of semantic information by individual neurons. These neurons responded selectively to specific word meanings and reliably distinguished words from nonwords. Moreover, rather than responding to the words as fixed memory representations, their activities were highly dynamic, reflecting the words' meanings based on their specific sentence contexts and independent of their phonetic form. Collectively, we show how these cell ensembles accurately predicted the broad semantic categories of the words as they were heard in real time during speech and how they tracked the sentences in which they appeared. We also show how they encoded the hierarchical structure of these meaning representations and how these representations mapped onto the cell population. Together, these findings reveal a finely detailed cortical organization of semantic representations at the neuron scale in humans and begin to illuminate the cellular-level processing of meaning during language comprehension.
    DOI:  https://doi.org/10.1038/s41586-024-07643-2
  43. Science. 2024 Jul 05. 385(6704): 16-20
    There will be blood.
    Andrew Zaleski.
      Is mimicking the cells that carry hemoglobin the key to a blood substitute?
    DOI:  https://doi.org/10.1126/science.adr4067
  44. Nat Commun. 2024 Jun 28. 15(1): 5497
    CD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites.
    Hyun Jae Lee, Marcela L Moreira, Shihan Li, Takahiro Asatsuma, Cameron G Williams, Oliver P Skinner, Saba Asad, Michael Bramhall, Zhe Jiang, Zihan Liu, Ashlyn S Kerr, Jessica A Engel, Megan S F Soon, Jasmin Straube, Irving Barrera, Evan Murray, Fei Chen, Jason Nideffer, Prasanna Jagannathan, Ashraful Haque.
      Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4+ T cell subsets remain unresolved. Here, we examine antigen-experienced CD4+ T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic TEM cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with TCM/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4+ T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4+ T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection.
    DOI:  https://doi.org/10.1038/s41467-024-49879-6
  45. Nature. 2024 Jul;631(8019): 28
    Unchanged power dynamics still block progress for under-represented groups in academia.
    Susanne Täuber, Morteza Mahmoudi.
      
    Keywords:  Lab life; Policy; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-02130-0
  46. Nat Biotechnol. 2024 Jul 02.
    High-throughput discovery of MHC class I- and II-restricted T cell epitopes using synthetic cellular circuits.
    Ayano C Kohlgruber, Mohammad H Dezfulian, Brandon M Sie, Charlotte I Wang, Tomasz Kula, Uri Laserson, H Benjamin Larman, Stephen J Elledge.
      Antigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC class II-restricted and mouse TCR reactivities relatively undeveloped. Here we present TCR mapping of antigenic peptides (TCR-MAP), an antigen discovery method that uses a synthetic TCR-stimulated circuit in immortalized T cells to activate sortase-mediated tagging of engineered antigen-presenting cells (APCs) expressing processed peptides on MHCs. Live, tagged APCs can be directly purified for deconvolution by sequencing, enabling TCRs with unknown specificity to be queried against barcoded peptide libraries in a pooled screening context. TCR-MAP accurately captures self-reactivities or viral reactivities with high throughput and sensitivity for both MHC class I-restricted and class II-restricted TCRs. We elucidate problematic cross-reactivities of clinical TCRs targeting the cancer/testis melanoma-associated antigen A3 and discover targets of myocarditis-inciting autoreactive T cells in mice. TCR-MAP has the potential to accelerate T cell antigen discovery efforts in the context of cancer, infectious disease and autoimmunity.
    DOI:  https://doi.org/10.1038/s41587-024-02248-6
  47. Nat Rev Immunol. 2024 Jul 04.
    Microbiota licenses protective CD8+ T cell responses against neonatal influenza.
    Boyan K Tsankov, Dana J Philpott.
      
    DOI:  https://doi.org/10.1038/s41577-024-01059-9
  48. Cell Metab. 2024 Jun 28. pii: S1550-4131(24)00231-6. [Epub ahead of print]
    The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.
    Ralph Patrick, Marina Naval-Sanchez, Nikita Deshpande, Yifei Huang, Jingyu Zhang, Xiaoli Chen, Ying Yang, Kanupriya Tiwari, Mohammadhossein Esmaeili, Minh Tran, Amin R Mohamed, Binxu Wang, Di Xia, Jun Ma, Jacqueline Bayliss, Kahlia Wong, Michael L Hun, Xuan Sun, Benjamin Cao, Denny L Cottle, Tara Catterall, Hila Barzilai-Tutsch, Robin-Lee Troskie, Zhian Chen, Andrea F Wise, Sheetal Saini, Ye Mon Soe, Snehlata Kumari, Matthew J Sweet, Helen E Thomas, Ian M Smyth, Anne L Fletcher, Konstantin Knoblich, Matthew J Watt, Majid Alhomrani, Walaa Alsanie, Kylie M Quinn, Tobias D Merson, Ann P Chidgey, Sharon D Ricardo, Di Yu, Thierry Jardé, Seth W Cheetham, Christophe Marcelle, Susan K Nilsson, Quan Nguyen, Melanie D White, Christian M Nefzger.
      A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.
    Keywords:  AP-1; CTCF; aging; cell identity; chromatin; development; maturation; polycomb repressive complex 2; redistribution; transcription factors
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.006
  49. Nature. 2024 Jul;631(8019): 35
    Did the diarist who chronicled the Great Fire of London make up a scientific instrument?
      
    Keywords:  History; Zoology
    DOI:  https://doi.org/10.1038/d41586-024-02184-0
  50. Nature. 2024 Jul 03.
    Lab-grown embryo models: UK unveils first ever rules to guide research.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Developmental biology
    DOI:  https://doi.org/10.1038/d41586-024-02171-5
  51. Nature. 2024 Jul 04.
    Faecal transplants can treat some cancers - but probably won't ever be widely used.
    Liam Drew.
      
    Keywords:  Cancer; Microbiology; Microbiome; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-024-02212-z
  52. Nat Commun. 2024 Jul 05. 15(1): 5652
    Abdominal aortic aneurysm and cardiometabolic traits share strong genetic susceptibility to lipid metabolism and inflammation.
    Shufen Zheng, Philip S Tsao, Cuiping Pan.
      Abdominal aortic aneurysm has a high heritability and often co-occurs with other cardiometabolic disorders, suggesting shared genetic susceptibility. We investigate this commonality leveraging recent GWAS studies of abdominal aortic aneurysm and 32 cardiometabolic traits. We find significant genetic correlations between abdominal aortic aneurysm and 21 of the cardiometabolic traits investigated, including causal relationships with coronary artery disease, hypertension, lipid traits, and blood pressure. For each trait pair, we identify shared causal variants, genes, and pathways, revealing that cholesterol metabolism and inflammation are shared most prominently. Additionally, we show the tissue and cell type specificity in the shared signals, with strong enrichment across traits in the liver, arteries, adipose tissues, macrophages, adipocytes, and fibroblasts. Finally, we leverage drug-gene databases to identify several lipid-lowering drugs and antioxidants with high potential to treat abdominal aortic aneurysm with comorbidities. Our study provides insight into the shared genetic mechanism between abdominal aortic aneurysm and cardiometabolic traits, and identifies potential targets for pharmacological intervention.
    DOI:  https://doi.org/10.1038/s41467-024-49921-7
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