bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–12–08
forty-four papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A brain circuit that links hunger signals with the jaw movements of eating.
  2. Aberrant METTL1-mediated tRNA m7G modification alters B-cell responses in systemic autoimmunity in humans and mice.
  3. Humble scientists earn more trust.
  4. The liver converts fructose into lipids to fuel tumours.
  5. Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation.
  6. Cross-species single-cell RNA-seq analysis reveals disparate and conserved cardiac and extracardiac inflammatory responses upon heart injury.
  7. Fetal hepatocytes protect the HSPC genome via fetuin-A.
  8. Guardians of immune privilege.
  9. A step-by-step guide to landing your next job in science.
  10. A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis.
  11. Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages.
  12. Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer's Disease.
  13. Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system.
  14. What is ageing? Even the field's researchers can't agree.
  15. ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.
  16. Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs.
  17. Stress can dull our capacity for joy: mouse brain patterns hint at why.
  18. How to ensure only dying cells rupture.
  19. Pregnancy restructures the brain to prepare for childbirth and parenthood.
  20. ChatGPT turns two: how the AI chatbot has changed scientists' lives.
  21. Portable, low-field magnetic resonance imaging for evaluation of Alzheimer's disease.
  22. T-Switch: A specificity-based engineering platform for developing safe and effective T cell therapeutics.
  23. Sick animals suggest COVID pandemic started in Wuhan market.
  24. Enteric neurons and gut immunity.
  25. The dynamics of hematopoiesis over the human lifespan.
  26. Seipin governs phosphatidic acid homeostasis at the inner nuclear membrane.
  27. Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.
  28. The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression.
  29. Synthetic gene circuits drive disease-fighting T cells.
  30. 'Brutal' math test raises the bar for AI.
  31. How I put LinkedIn to work for my career as a scientist and entrepreneur.
  32. Daily briefing: How to get to 100 - centenarian cells teach us about ageing.
  33. Coordination of cytochrome bc1 complex assembly at MICOS.
  34. Banish the PDF-hunting blues with these AI and digital tools.
  35. Public trust in science can be diminished by communicating uncertainty.
  36. The complete telomere-to-telomere sequence of a mouse genome.
  37. Storm warnings for FDA and CDC.
  38. Science could solve some of the world's biggest problems. Why aren't governments using it?
  39. Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.
  40. Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy.
  41. Unexpected RNA modification protects bacteria against viral infection.
  42. Women in Autophagy: an initiative to promote gender parity in science.
  43. Decoding the molecular, cellular, and functional heterogeneity of zebrafish intracardiac nervous system.
  44. Implementation and validation of single-cell genomics experiments in neuroscience.
  1. Nature. 2024 Dec 04.
    A brain circuit that links hunger signals with the jaw movements of eating.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-03913-1
  2. Nat Commun. 2024 Dec 05. 15(1): 10599
    Aberrant METTL1-mediated tRNA m7G modification alters B-cell responses in systemic autoimmunity in humans and mice.
    Shuyi Wang, Hui Han, Yichao Qian, Xinyuan Ruan, Zhangmei Lin, Jin Li, Binfeng Chen, Yimei Lai, Zhaoyu Wang, Mengyuan Li, Jingping Wen, Xiaoyu Yin, Niansheng Yang, Shuibin Lin, Hui Zhang.
      Upon activation, naive B cells exit their quiescent state and enter germinal center (GC) responses, a transition accompanied by increased protein synthesis. How protein translation efficiency is adequately adjusted to meet the increased demand requires further investigation. Here, we identify the methyltransferase METTL1 as a translational checkpoint during GC responses. Conditional knockout of Mettl1 in mouse B cells blocks GC entry and impairs GC formation, whereas conditional knock-in of Mettl1 promotes GC responses. Mechanistically, METTL1 catalyzes m7G modification in a specific subset of tRNAs to preferentially translate BCR signaling-related proteins, ensuring mitochondrial electron transporter chain activity and sufficient bioenergetics in B cells. Pathologically, METTL1-mediated tRNA m7G modification controls B-cell autoreactivity in SLE patients or lupus-prone mice, and deletion of Mettl1 alleviates dysregulated B-cell responses during autoimmune induction. Thus, these results support the function of METTL1 in orchestrating an effective B-cell response and reveal that aberrant METTL1-mediated tRNA m7G modification promotes autoreactive B cells in systemic autoimmunity.
    DOI:  https://doi.org/10.1038/s41467-024-54941-4
  3. Nature. 2024 Dec;636(8041): 11
    Humble scientists earn more trust.
      
    Keywords:  Communication
    DOI:  https://doi.org/10.1038/d41586-024-03858-5
  4. Nature. 2024 Dec 04.
    The liver converts fructose into lipids to fuel tumours.
    Hyllana C D Medeiros, Sophia Y Lunt.
      
    Keywords:  Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03653-2
  5. Sci Transl Med. 2024 Dec 04. 16(776): eadq5796
    Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation.
    Immunology of Cardiac Arrest Network (I-CAN)
      Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (Cd1d-/-), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. Cd1d-/- mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.
    DOI:  https://doi.org/10.1126/scitranslmed.adq5796
  6. Commun Biol. 2024 Dec 03. 7(1): 1611
    Cross-species single-cell RNA-seq analysis reveals disparate and conserved cardiac and extracardiac inflammatory responses upon heart injury.
    Eric Cortada, Jun Yao, Yu Xia, Friederike Dündar, Paul Zumbo, Boris Yang, Alfonso Rubio-Navarro, Björn Perder, Miaoyan Qiu, Anthony M Pettinato, Edwin A Homan, Lisa Stoll, Doron Betel, Jingli Cao, James C Lo.
      The immune system coordinates the response to cardiac injury and controls regenerative and fibrotic scar outcomes in the heart and subsequent chronic low-grade inflammation associated with heart failure. Adult mice and humans lack the ability to fully recover while adult zebrafish spontaneously regenerate after heart injury. Here we profile the inflammatory response to heart cryoinjury in zebrafish and coronary artery ligation in mouse using single cell transcriptomics. We interrogate the extracardiac reaction to cardiomyocyte necrosis to assess the specific peripheral tissue and immune cell reaction to chronic stress. Cardiac macrophages play a critical role in determining tissue homeostasis by healing versus scarring. We identify distinct transcriptional clusters of monocytes/macrophages (mono/Mϕ) in each species and find analogous pairs in zebrafish and mice. However, the reaction to myocardial injury is largely disparate between mice and zebrafish. The dichotomous response to heart damage between the murine and zebrafish mono/Mϕ and/or the presence of distinct zebrafish mono/Mϕ subtypes may underlie the impaired regenerative process in adult mammals and humans. Our study furnishes a direct cross-species comparison of immune responses between regenerative and profibrotic myocardial injury models, providing a useful resource to the fields of regenerative biology and cardiovascular research.
    DOI:  https://doi.org/10.1038/s42003-024-07315-x
  7. Nature. 2024 Dec 04.
    Fetal hepatocytes protect the HSPC genome via fetuin-A.
    Xiao-Lin Guo, Yi-Ding Wang, Yan-Jun Liu, Lei Chu, Hua Zhu, Ye Hu, Ren-Yan Wu, Hong-Yu Xie, Juan Yu, Shui-Ping Li, Zhao-Yang Xiong, Ruo-Yan Li, Fang Ke, Lei Chen, Guo-Qiang Chen, Liang Chen, Fan Bai, Tariq Enver, Guo-Hong Li, Huai-Fang Li, Deng-Li Hong.
      The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development1-3. Although numerous cell-intrinsic mechanisms have been revealed4-7, little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes. Lineage tracing and depletion in mice demonstrated that delayed hepatocyte development in early fetal livers increased the chromosomal instability of newly colonizing HSPCs. In addition, HSPCs developed tolerance to genotoxins in hepatocyte-conditioned medium, suggesting that hepatocytes protect the HSPC genome in a paracrine manner. Proteomic analyses demonstrated the enrichment of fetuin-A in hepatocyte-conditioned medium but not in early fetal livers. Fetuin-A activates a Toll-like receptor pathway to prevent pathogenic R-loop accumulation in HSPCs undergoing DNA replication and gene transcription in the fetal liver. Numerous haematopoietic regulatory genes frequently involved in leukaemogenic mutations are associated with R-loop-enriched regions. In Fetua-knockout mice, HSPCs showed increased genome instability and susceptibility to malignancy induction. Moreover, low concentrations of fetuin-A correlated with the oncogenesis of childhood leukaemia. Therefore, we uncover a mechanism operating in developmental tissues that offers tissue-forming cell genome protection and is implicated in developmental-related diseases.
    DOI:  https://doi.org/10.1038/s41586-024-08307-x
  8. Nat Rev Immunol. 2024 Dec 03.
    Guardians of immune privilege.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-01121-6
  9. Nature. 2024 Dec;636(8041): 259-262
    A step-by-step guide to landing your next job in science.
    Linda Nordling.
      
    Keywords:  Lab life; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03926-w
  10. Sci Immunol. 2024 Dec 06. 9(102): eadl1467
    A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis.
    Sina Bohnacker, Fiona D R Henkel, Franziska Hartung, Arie Geerlof, Sandra Riemer, Ulrich F Prodjinotho, Eya Ben Salah, André Santos Dias Mourão, Stefan Bohn, Tarvi Teder, Dominique Thomas, Robert Gurke, Christiane Boeckel, Minhaz Ud-Dean, Ann-Christine König, Alessandro Quaranta, Francesca Alessandrini, Antonie Lechner, Benedikt Spitzlberger, Agnieszka M Kabat, Edward Pearce, Jesper Z Haeggström, Stefanie M Hauck, Craig E Wheelock, Per-Johan Jakobsson, Michael Sattler, David Voehringer, Matthias J Feige, Clarissa Prazeres da Costa, Julia Esser-von Bieren.
      The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using Heligmosomoides polygyrus bakeri (Hpb), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E2 (PGE2) as a major immune regulatory mechanism of heGDH. The induction of PGE2 and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme's catalytic activity suppressed the synthesis of type 2-promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.
    DOI:  https://doi.org/10.1126/sciimmunol.adl1467
  11. Nat Commun. 2024 Dec 04. 15(1): 10556
    Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages.
    Anna C Winnicki, Melanie H Dietrich, Lee M Yeoh, Lenore L Carias, Wanlapa Roobsoong, Chiara L Drago, Alyssa N Malachin, Karli R Redinger, Lionel Brice Feufack-Donfack, Lea Baldor, Nicolai C Jung, Olivia S McLaine, Yelenna Skomorovska-Prokvolit, Agnes Orban, D Herbert Opi, Payton Kirtley, Kiersey Nielson, Maya Aleshnick, Gigliola Zanghi, Nastaran Rezakhani, Ashley M Vaughan, Brandon K Wilder, Jetsumon Sattabongkot, Wai-Hong Tham, Jean Popovici, James G Beeson, Jürgen Bosch, Christopher L King.
      New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. In this manuscript we characterize 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv-exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. We show that humAb 826827 blocks the invasion of human reticulocytes using Pv clinical isolates and inhibits sporozoite invasion of human hepatocytes in vitro (IC50 of 0.3 - 3.7 µg/mL). Inoculation of human liver transgenic (FRG-humHep) female mice with humAb 826827 significantly reduces liver infection in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate-transcendent, blocks both pre-erythrocytic and blood stage infection, and could be a potential therapy for Pv.
    DOI:  https://doi.org/10.1038/s41467-024-53848-4
  12. Nat Commun. 2024 Dec 05. 15(1): 10634
    Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer's Disease.
    Nóra Baligács, Giulia Albertini, Sarah C Borrie, Lutgarde Serneels, Clare Pridans, Sriram Balusu, Bart De Strooper.
      The role of microglia in the amyloid cascade of Alzheimer's disease (AD) is debated due to conflicting findings. Using a genetic and a pharmacological approach we demonstrate that depletion of microglia before amyloid-β (Aβ) plaque deposition, leads to a reduction in plaque numbers and neuritic dystrophy, confirming their role in plaque initiation. Transplanting human microglia restores Aβ plaque formation. While microglia depletion reduces insoluble Aβ levels, soluble Aβ concentrations stay consistent, challenging the view that microglia clear Aβ. In later stages, microglial depletion decreases plaque compaction and increases neuritic dystrophy, suggesting a protective role. Human microglia with the TREM2R47H/R47H mutation exacerbate plaque pathology, emphasizing the importance of non-reactive microglia in the initiation of the amyloid cascade. Adaptive immune depletion (Rag2-/-) does not affect microglia's impact on plaque formation. These findings clarify conflicting reports, identifying microglia as key drivers of amyloid pathology, and raise questions about optimal therapeutic strategies for AD.
    DOI:  https://doi.org/10.1038/s41467-024-54779-w
  13. Nat Neurosci. 2024 Dec;27(12): 2278-2291
    Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system.
    Igor Adameyko, Trygve Bakken, Aparna Bhaduri, Chintan Chhatbar, Mariella G Filbin, David Gate, Hannah Hochgerner, Chang Nam Kim, Jordan Krull, Gioele La Manno, Qingyun Li, Sten Linnarsson, Qin Ma, Christian Mayer, Vilas Menon, Patricia Nano, Marco Prinz, Steve Quake, Christopher A Walsh, Jin Yang, Omer Ali Bayraktar, Ozgun Gokce, Naomi Habib, Genevieve Konopka, Shane A Liddelow, Tomasz J Nowakowski.
      Single-cell and single-nucleus genomic approaches can provide unbiased and multimodal insights. Here, we discuss what constitutes a molecular cell atlas and how to leverage single-cell omics data to generate hypotheses and gain insights into cell transitions in development and disease of the nervous system. We share points of reflection on what to consider during study design and implementation as well as limitations and pitfalls.
    DOI:  https://doi.org/10.1038/s41593-024-01827-9
  14. Nature. 2024 Dec 03.
    What is ageing? Even the field's researchers can't agree.
    Smriti Mallapaty.
      
    Keywords:  Ageing; Diseases
    DOI:  https://doi.org/10.1038/d41586-024-03936-8
  15. Sci Signal. 2024 Dec 03. 17(865): eadk7971
    ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.
    Xu Xu, Arturo Mendoza, Christopher S Krumm, Shi Su, Mariana Acuña, Curtis J Bare, Corey D Holman, Marissa Cortopassi, Hayley T Nicholls, Vincent Dartigue, Anthony N Hollenberg, Ann-Hwee Lee, Susan J Hagen, David E Cohen.
      Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that Them1 expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR) by nutrient excess. Under either condition, Them1 suppressed energy expenditure. Consequently, mice lacking Them1 in BAT and BeAT exhibited resistance to obesity and glucose intolerance induced by feeding with a high-fat diet. During chronic cold exposure or ISR activation, Them1 accumulated in the nucleus, where it interacted with ChREBP and reduced the expression of its target genes, including those encoding enzymes that mediate glycolysis and de novo lipogenesis. These findings demonstrate that in response to chronic cold- or nutrient-induced stress, the induction of Them1 by ChREBP limits thermogenesis while coordinately reducing glucose utilization and lipid biosynthesis through its distinct cytoplasmic and nuclear activities. Targeted inhibition of Them1 could be a potential therapeutic approach to increase the activity of BAT and BeAT to enhance energy expenditure in the management of obesity-associated metabolic disorders.
    DOI:  https://doi.org/10.1126/scisignal.adk7971
  16. Science. 2024 Dec 06. 386(6726): eadl4793
    Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs.
    Nishith R Reddy, Hasna Maachi, Yini Xiao, Milos S Simic, Wei Yu, Yurie Tonai, Daniela A Cabanillas, Ella Serrano-Wu, Philip T Pauerstein, Whitney Tamaki, Greg M Allen, Audrey V Parent, Matthias Hebrok, Wendell A Lim.
      Immune homeostasis requires a balance of inflammatory and suppressive activities. To design cells potentially useful for local immune suppression, we engineered conventional CD4+ T cells with synthetic Notch (synNotch) receptors driving antigen-triggered production of anti-inflammatory payloads. Screening a diverse library of suppression programs, we observed the strongest suppression of cytotoxic T cell attack by the production of both anti-inflammatory factors (interleukin-10, transforming growth factor-β1, programmed death ligand 1) and sinks for proinflammatory cytokines (interleukin-2 receptor subunit CD25). Engineered cells with bespoke regulatory programs protected tissues from immune attack without systemic suppression. Synthetic suppressor T cells protected transplanted beta cell organoids from cytotoxic T cells. They also protected specific tissues from unwanted chimeric antigen receptor (CAR) T cell cross-reaction. Synthetic suppressor T cells are a customizable platform to potentially treat autoimmune diseases, organ rejection, and CAR T cell toxicities with spatial precision.
    DOI:  https://doi.org/10.1126/science.adl4793
  17. Nature. 2024 Dec 04.
    Stress can dull our capacity for joy: mouse brain patterns hint at why.
    Max Kozlov.
      
    Keywords:  Brain; Depression; Neuroscience; Psychiatric disorders
    DOI:  https://doi.org/10.1038/d41586-024-03958-2
  18. Nature. 2024 Dec 04.
    How to ensure only dying cells rupture.
    Elliott M Bernard, Petr Broz.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-024-03851-y
  19. Nature. 2024 Dec 05.
    Pregnancy restructures the brain to prepare for childbirth and parenthood.
    Clare McCormack, Moriah Thomason.
      
    Keywords:  Brain; Imaging; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-03942-w
  20. Nature. 2024 Dec 02.
    ChatGPT turns two: how the AI chatbot has changed scientists' lives.
    Mariana Lenharo.
      
    Keywords:  Computer science; Machine learning; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03940-y
  21. Nat Commun. 2024 Dec 02. 15(1): 10488
    Portable, low-field magnetic resonance imaging for evaluation of Alzheimer's disease.
    Annabel J Sorby-Adams, Jennifer Guo, Pablo Laso, John E Kirsch, Julia Zabinska, Ana-Lucia Garcia Guarniz, Pamela W Schaefer, Seyedmehdi Payabvash, Adam de Havenon, Matthew S Rosen, Kevin N Sheth, Teresa Gomez-Isla, J Eugenio Iglesias, W Taylor Kimberly.
      Portable, low-field magnetic resonance imaging (LF-MRI) of the brain may facilitate point-of-care assessment of patients with Alzheimer's disease (AD) in settings where conventional MRI cannot. However, image quality is limited by a lower signal-to-noise ratio. Here, we optimize LF-MRI acquisition and develop a freely available machine learning pipeline to quantify brain morphometry and white matter hyperintensities (WMH). We validate the pipeline and apply it to outpatients presenting with mild cognitive impairment or dementia due to AD. We find hippocampal volumes from ≤ 3 mm isotropic LF-MRI scans have agreement with conventional MRI and are more accurate than anisotropic counterparts. We also show WMH volume has agreement between manual segmentation and the automated pipeline. The increased availability and reduced cost of LF-MRI, in combination with our machine learning pipeline, has the potential to increase access to neuroimaging for dementia.
    DOI:  https://doi.org/10.1038/s41467-024-54972-x
  22. Immunity. 2024 Nov 26. pii: S1074-7613(24)00524-7. [Epub ahead of print]
    T-Switch: A specificity-based engineering platform for developing safe and effective T cell therapeutics.
    Nouran S Abdelfattah, Tomasz Kula, Stephen J Elledge.
      Many promising targets for adoptive T cell therapy (ACT) are self-antigens, but self-reactive T cells are generally eliminated during thymic selection or diverted to regulatory phenotypes. To bypass T cell tolerance and obtain potent and safe T cell therapeutics, we developed T-Switch, an in vitro T cell receptor (TCR) engineering platform for the creation, modification, and comprehensive profiling of TCRs that can target self-antigens. T-Switch first expands T cells that recognize a "foreign" peptide closely related to a self-antigen. The fine specificity of the TCR is then modified by directed evolution of the peptide binding region to switch its specificity to the self-antigen of interest. We applied T-Switch to engineer synthetic TCRs reactive to a tumor-associated self-antigen, validated the safety and efficacy of this approach, and detected no off-target recognition as measured against the human proteome. Thus, T-Switch represents a resource for the creation of collections of highly sensitive synthetic TCRs for T cell-based immunotherapies.
    Keywords:  T cells; TCR evolution; epitope specificity; self-reactivity
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.009
  23. Nature. 2024 Dec 04.
    Sick animals suggest COVID pandemic started in Wuhan market.
    Smriti Mallapaty.
      
    Keywords:  Infection; Virology
    DOI:  https://doi.org/10.1038/d41586-024-03968-0
  24. Nat Neurosci. 2024 Dec;27(12): 2269
    Enteric neurons and gut immunity.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s41593-024-01841-x
  25. Nat Methods. 2024 Dec 05.
    The dynamics of hematopoiesis over the human lifespan.
    Hojun Li, Parker Côté, Michael Kuoch, Jideofor Ezike, Katie Frenis, Anton Afanassiev, Laura Greenstreet, Mayuri Tanaka-Yano, Giuseppe Tarantino, Stephen Zhang, Jennifer Whangbo, Vincent L Butty, Enrico Moiso, Marcelo Falchetti, Kate Lu, Guinevere G Connelly, Vivian Morris, Dahai Wang, Antonia F Chen, Giada Bianchi, George Q Daley, Salil Garg, David Liu, Stella T Chou, Aviv Regev, Edroaldo Lummertz da Rocha, Geoffrey Schiebinger, R Grant Rowe.
      Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear. To address this gap, we profiled individual transcriptome states of human hematopoietic stem and progenitor cells spanning gestation, maturation and aging. Here we define the gene expression networks dictating age-specific differentiation of HSCs and the dynamics of fate decisions and lineage priming throughout life. We additionally identifiy and functionally validate a fetal-specific HSC state with robust engraftment and multilineage capacity. Furthermore, we observe that classification of acute myeloid leukemia against defined transcriptional age states demonstrates that utilization of early life transcriptional programs associates with poor prognosis. Overall, we provide a disease-relevant framework for heterochronic orientation of stem cell ontogeny along the real time axis of the human lifespan.
    DOI:  https://doi.org/10.1038/s41592-024-02495-0
  26. Nat Commun. 2024 Dec 02. 15(1): 10486
    Seipin governs phosphatidic acid homeostasis at the inner nuclear membrane.
    Anete Romanauska, Edvinas Stankunas, Maya Schuldiner, Alwin Köhler.
      The nuclear envelope is a specialized subdomain of the endoplasmic reticulum and comprises the inner and outer nuclear membranes. Despite the crucial role of the inner nuclear membrane in genome regulation, its lipid metabolism remains poorly understood. Phosphatidic acid (PA) is essential for membrane growth as well as lipid storage. Using a genome-wide lipid biosensor screen in S. cerevisiae, we identify regulators of inner nuclear membrane PA homeostasis, including yeast Seipin, a known mediator of nuclear lipid droplet biogenesis. Here, we show that Seipin preserves nuclear envelope integrity by preventing its deformation and ectopic membrane formation. Mutations of specific regions of Seipin, some linked to human lipodystrophy, disrupt PA distribution at the inner nuclear membrane and nuclear lipid droplet formation. Investigating the Seipin co-factor Ldb16 reveals that a triacylglycerol binding site is crucial for lipid droplet formation, whereas PA regulation can be functionally separated. Our study highlights the potential of lipid biosensor screens for examining inner nuclear membrane lipid metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-54811-z
  27. J Clin Invest. 2024 Dec 02. pii: e185569. [Epub ahead of print]134(23):
    Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.
    Hong Wang, Maria Miranda, Eizo Marutani, Paul Lichtenegger, Gregory R Wojtkiewicz, Fumito Ichinose, Vamsi K Mootha.
      
    Keywords:  Genetics; Hypoxia
    DOI:  https://doi.org/10.1172/JCI185569
  28. Nat Commun. 2024 Dec 04. 15(1): 10579
    The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression.
    Jong Seok Park, Minjung Kang, Han Bit Kim, Hyebeen Hong, Jongeun Lee, Youngkwon Song, Yunjung Hur, Soeun Kim, Tae-Kyung Kim, Yoontae Lee.
      Follicular B (FOB) and marginal zone B (MZB) cells are pivotal in humoral immune responses against pathogenic infections. MZB cells can exacerbate endotoxic shock via interleukin-6 secretion. Here we show that the transcriptional repressor capicua (CIC) and its binding partner, ataxin-1-like (ATXN1L), play important roles in FOB and MZB cell development. CIC deficiency reduces the size of both FOB and MZB cell populations, whereas ATXN1L deficiency specifically affects MZB cells. B cell receptor signaling is impaired only in Cic-deficient FOB cells, whereas Notch signaling is disrupted in both Cic-deficient and Atxn1l-deficient MZB cells. Mechanistically, ETV4 de-repression leads to inhibition of Notch1 and Notch2 transcription, thereby inhibiting MZB cell development in B cell-specific Cic-deficient (Cicf/f;Cd19-Cre) and Atxn1l-deficient (Atxn1lf/f;Cd19-Cre) mice. In Cicf/f;Cd19-Cre and Atxn1lf/f; Cd19-Cre mice, humoral immune responses and lipopolysaccharide-induced sepsis progression are attenuated but are restored upon Etv4-deletion. These findings highlight the importance of the CIC-ATXN1L complex in MZB cell development and may provide proof of principle for therapeutic targeting in sepsis.
    DOI:  https://doi.org/10.1038/s41467-024-54803-z
  29. Science. 2024 Dec 06. 386(6726): 1094-1095
    Synthetic gene circuits drive disease-fighting T cells.
    Marco L Davila, Renier Brentjens.
      Immune cells can be programmed to deliver targeted therapies in models of brain and inflammatory disease.
    DOI:  https://doi.org/10.1126/science.adt9921
  30. Science. 2024 Dec 06. 386(6726): 1082
    'Brutal' math test raises the bar for AI.
    Zack Savitsky.
      Model-stumping benchmark shows human experts remain on top-for now.
    DOI:  https://doi.org/10.1126/science.adv0707
  31. Nature. 2024 Dec 03.
    How I put LinkedIn to work for my career as a scientist and entrepreneur.
    Ashley Ruba.
      
    Keywords:  Careers; Lab life; Research management
    DOI:  https://doi.org/10.1038/d41586-024-03865-6
  32. Nature. 2024 Nov 29.
    Daily briefing: How to get to 100 - centenarian cells teach us about ageing.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-03931-z
  33. EMBO Rep. 2024 Dec 02.
    Coordination of cytochrome bc1 complex assembly at MICOS.
    Ralf M Zerbes, Lilia Colina-Tenorio, Maria Bohnert, Karina von der Malsburg, Christian D Peikert, Carola S Mehnert, Inge Perschil, Rhena F U Klar, Rinse de Boer, Anita Kram, Ida van der Klei, Silke Oeljeklaus, Bettina Warscheid, Heike Rampelt, Martin van der Laan.
      The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for the formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as a determinant in the biogenesis of the cytochrome bc1 complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruiting complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, contributes to the spatial and temporal coordination of respiratory chain biogenesis.
    Keywords:   bc 1 Complex; Cristae; MICOS; Mitochondria; Respiratory Chain
    DOI:  https://doi.org/10.1038/s44319-024-00336-x
  34. Nature. 2024 Dec 04.
    Banish the PDF-hunting blues with these AI and digital tools.
    Candice P Chu.
      
    Keywords:  Authorship; Careers; Lab life; Technology
    DOI:  https://doi.org/10.1038/d41586-024-03775-7
  35. Nature. 2024 Dec;636(8041): 45
    Public trust in science can be diminished by communicating uncertainty.
    Hannah Little.
      
    Keywords:  Communication; Policy; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-03948-4
  36. Science. 2024 Dec 06. 386(6726): 1141-1146
    The complete telomere-to-telomere sequence of a mouse genome.
    Junli Liu, Qilin Li, Yixuan Hu, Yi Yu, Kai Zheng, Dengfeng Li, Lexin Qin, Xiaochun Yu.
      The current reference genome of Mus musculus, GRCm39, has major gaps in both euchromatic and heterochromatic regions associated with repetitive sequences. In this work, we have sequenced and assembled the telomere-to-telomere genome of mouse haploid embryonic stem cells. The results reveal more than 7.7% of previously uncovered sequences of the mouse genome, including ribosomal DNA arrays and pericentromeric and subtelomeric regions, as well as an additional 140 genes predicted to be protein-coding. This study helps to address knowledge gaps in the mouse genome.
    DOI:  https://doi.org/10.1126/science.adq8191
  37. Science. 2024 Dec 06. 386(6726): 1081
    Storm warnings for FDA and CDC.
    Jennifer Couzin-Frankel, Phie Jacobs.
      
    DOI:  https://doi.org/10.1126/science.adv0706
  38. Nature. 2024 Dec;636(8041): 26-30
    Science could solve some of the world's biggest problems. Why aren't governments using it?
    Helen Pearson.
      
    Keywords:  Government; Policy; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03906-0
  39. J Clin Invest. 2024 Dec 03. pii: e183409. [Epub ahead of print]
    Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.
    Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y Eugene Chen, Lin Chang.
      Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease (CVD). Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain-containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells (VSMC), is significantly associated with BP-related traits. However, the roles of PRDM16 in BP regulation are largely unknown. Here, we demonstrate that BP in VSMC-specific Prdm16 knockout (Prdm16SMKO) mice was significantly lower than that in control mice during the active period, resulting in aberrant BP circadian variation. Mesenteric artery rings from Prdm16SMKO mice showed reduced response to phenylephrine. Mechanistically, we identified adrenergic receptor alpha 1d (Adra1d) as a transcriptional target of PRDM16. Notably, PRDM16 exhibits a remarkable circadian expression pattern and regulates the expression of clock genes, particularly Npas2, which is crucial for BP circadian variation regulation. Consequently, PRDM16 deficiency in VSMC causes disrupted BP circadian variation through reduced response to adrenergic signaling and clock gene regulation. Our findings offer substantial insights into the intricate molecular pathways that govern circadian fluctuations in BP.
    Keywords:  Cardiovascular disease; Hypertension; Vascular biology
    DOI:  https://doi.org/10.1172/JCI183409
  40. Nat Commun. 2024 Dec 04. 15(1): 10592
    Yin Yang 1 and guanine quadruplexes protect dopaminergic neurons from cellular stress via transmissive dormancy.
    Kielen R Zuurbier, Rene Solano Fonseca, Sonja L B Arneaud, Jordan M Wall, Juhee Kim, Lexus Tatge, Gupse Otuzoglu, Sofia Bali, Patrick Metang, Peter M Douglas.
      Neurons deploy diverse adaptive strategies to ensure survival and neurotransmission amid cellular stress. When these adaptive pathways are overwhelmed, functional impairment or neurodegeneration follows. Here we show that stressed neurons actively induce a state of transmissive dormancy as a protective measure. Extending observations of neurotrauma in C. elegans and mice, human dopaminergic neurons capable of surviving severe cellular challenges both decrease spontaneous activity and modulate dopamine homeostasis through the transcriptional regulator Yin Yang 1 (YY1). To bolster stress resilience and mitigate dopamine toxicity, YY1 increases expression of the vesicular monoamine transporter 2, vMAT2, while coordinately inhibiting dopamine synthesis through stabilization of a guanine quadruplex in intron 10 of tyrosine hydroxylase, TH. This dopaminergic stress response has the potential to cause circuit inactivation, yet safeguards neurons by minimizing the toxic accumulation of cytosolic dopamine and inducing a state of neuronal dormancy. In essence, neurons appear to actively prioritize viability over functionality.
    DOI:  https://doi.org/10.1038/s41467-024-54958-9
  41. Nature. 2024 Dec 04.
    Unexpected RNA modification protects bacteria against viral infection.
      
    Keywords:  Microbiology; Virology
    DOI:  https://doi.org/10.1038/d41586-024-03923-z
  42. Nat Cell Biol. 2024 Dec 02.
    Women in Autophagy: an initiative to promote gender parity in science.
    Mericka McCabe, Patricia Boya, Ruey-Hwa Chen, Charleen T Chu, Maria Isabel Colombo, Laura Delgui, Eeva-Liisa Eskelinen, Maho Hamasaki, Malene Hansen, Congcong He, Marja Jäättelä, Adi Kimchi, Claudine Kraft, Mondira Kundu, Alicia Melendez, Sophie Pattingre, Tassula Proikas-Cezanne, Salwa Sebti, Anna Katharina Simon, Anne Simonsen, Sharon A Tooze, Maria Ines Vaccaro, Xiaochen Wang, Eileen White, Yan Zhao, Ana Maria Cuervo.
      
    DOI:  https://doi.org/10.1038/s41556-024-01566-w
  43. Nat Commun. 2024 Dec 04. 15(1): 10483
    Decoding the molecular, cellular, and functional heterogeneity of zebrafish intracardiac nervous system.
    Andrea Pedroni, Elanur Yilmaz, Lisa Del Vecchio, Prabesh Bhattarai, Inés Talaya Vidal, Yu-Wen E Dai, Konstantinos Koutsogiannis, Caghan Kizil, Konstantinos Ampatzis.
      The proper functioning of the heart relies on the intricate interplay between the central nervous system and the local neuronal networks within the heart itself. While the central innervation of the heart has been extensively studied, the organization and functionality of the intracardiac nervous system (IcNS) remain largely unexplored. Here, we present a comprehensive taxonomy of the IcNS, utilizing single-cell RNA sequencing, anatomical studies, and electrophysiological techniques. Our findings reveal a diverse array of neuronal types within the IcNS, exceeding previous expectations. We identify a subset of neurons exhibiting characteristics akin to pacemaker/rhythmogenic neurons similar to those found in Central Pattern Generator networks of the central nervous system. Our results underscore the heterogeneity within the IcNS and its key role in regulating the heart's rhythmic functionality. The classification and characterization of the IcNS presented here serve as a valuable resource for further exploration into the mechanisms underlying heart functionality and the pathophysiology of associated cardiac disorders.
    DOI:  https://doi.org/10.1038/s41467-024-54830-w
  44. Nat Neurosci. 2024 Dec;27(12): 2310-2325
    Implementation and validation of single-cell genomics experiments in neuroscience.
    Marco Colonna, Genevieve Konopka, Shane A Liddelow, Tomasz Nowakowski, Rajeshwar Awatramani, Helen S Bateup, Cathryn R Cadwell, Emre Caglayan, Jerry L Chen, Jesse Gillis, Martin Kampmann, Fenna Krienen, Samuel E Marsh, Michelle Monje, Michael R O'Dea, Rickie Patani, Alex A Pollen, Francisco J Quintana, Marissa Scavuzzo, Matthew Schmitz, Steven A Sloan, Paul J Tesar, Jessica Tollkuhn, Maria Antonietta Tosches, Madeleine E Urbanek, Jonathan M Werner, Omer A Bayraktar, Ozgun Gokce, Naomi Habib.
      Single-cell or single-nucleus transcriptomics is a powerful tool for identifying cell types and cell states. However, hypotheses derived from these assays, including gene expression information, require validation, and their functional relevance needs to be established. The choice of validation depends on numerous factors. Here, we present types of orthogonal and functional validation experiment to strengthen preliminary findings obtained using single-cell and single-nucleus transcriptomics as well as the challenges and limitations of these approaches.
    DOI:  https://doi.org/10.1038/s41593-024-01814-0
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒08 at 17:08.