bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–12–15
fifty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Constraint reveals the mitochondrial genome sites most important for health and disease.
  2. Improved tool for scRNA-seq analysis.
  3. A 60-minute guide to landing your next job in science.
  4. Central control of dynamic gene circuits governs T cell rest and activation.
  5. Stem cells reverse type 1 diabetes.
  6. Identification of distinct types of steatotic liver disease with specific clinical trajectories.
  7. Getting RAMPed up: Neuropeptides boost T helper 1 cell fate.
  8. Asparagine availability controls germinal center B cell homeostasis.
  9. Atlases galore: where to next?
  10. Systematic identification of cell state-specific transcription factors in T cells.
  11. Clonal hematopoiesis-related mutant ASXL1 promotes atherosclerosis in mice via dysregulated innate immunity.
  12. Worrying through the ECM.
  13. A neuronal gene that loops the loop.
  14. A lipid made by tumour cells reprograms immune cells.
  15. A little bird flies high thanks to mighty mitochondria.
  16. The best science images of 2024 - Nature's picks.
  17. A guide to the Nature Index.
  18. Keiji Tanaka (1949-2024).
  19. Haematological setpoints are a stable and patient-specific deep phenotype.
  20. Nutrient-driven histone code determines exhausted CD8+ T cell fates.
  21. DRAGEN optimizes genomic variant detection.
  22. Ancient stacks of dishes tell tale of society's dissolution.
  23. The harms of ultra-processed foods.
  24. How measurement noise limits the accuracy of brain-behaviour predictions.
  25. Mechanics of Drosophila wing deployment.
  26. Thermally induced neuronal plasticity in the hypothalamus mediates heat tolerance.
  27. Genetic synchronization of the brain and liver molecular clocks defend against chrono-metabolic disease.
  28. A new understanding of tissue biology from MS-based proteomics at single-cell resolution.
  29. Lipid-delivery system could treat life-threatening pregnancy complication.
  30. Supporting the sexual healthcare needs of aging women.
  31. Multi-organ benefits of incretin agonists.
  32. Functional genomics of height heritability.
  33. Fasting can reduce weight - but also hair growth.
  34. How the latest materials are taking biosensors to the next level.
  35. Making stronger T cells.
  36. Self-organization of the hematopoietic vascular niche and emergent innate immunity on a chip.
  37. Personalized ranges for blood-test results enable precision diagnostics.
  38. Subcellular spatial proteomics.
  39. Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway.
  40. Molecular motion in situ.
  41. Highly multiplexed imaging in the omics era: understanding tissue structures in health and disease.
  42. Human body's ageing 'clock' ticks faster after heat stress.
  43. Engineered cells take drugs deep into the brain - and nowhere else.
  44. Cyclin-dependent kinase inhibitor p18 regulates lineage transitions of excitatory neurons, astrocytes, and interneurons in the mouse cortex.
  45. Reactive oxygen species control protein degradation at the mitochondrial import gate.
  46. From clinical to biological definitions of neurological diseases.
  47. Vascular cells of blood vessels and organs across the human body.
  48. Long-acting PrEP prevents HIV in women.
  49. Lipidome profiling in advanced metabolic liver disease identifies phosphatidylserine synthase 1 as a regulator of hepatic lipoprotein metabolism.
  50. How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot.
  1. Nature. 2024 Dec 11.
    Constraint reveals the mitochondrial genome sites most important for health and disease.
      
    Keywords:  Databases; Diseases; Genetics
    DOI:  https://doi.org/10.1038/d41586-024-04039-0
  2. Nat Genet. 2024 Dec;56(12): 2589
    Improved tool for scRNA-seq analysis.
    Michael Fletcher.
      
    DOI:  https://doi.org/10.1038/s41588-024-02040-x
  3. Nature. 2024 Dec 09.
    A 60-minute guide to landing your next job in science.
    David Payne.
      
    Keywords:  Careers; Industry; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-03938-6
  4. Nature. 2024 Dec 11.
    Central control of dynamic gene circuits governs T cell rest and activation.
    Maya M Arce, Jennifer M Umhoefer, Nadia Arang, Sivakanthan Kasinathan, Jacob W Freimer, Zachary Steinhart, Haolin Shen, Minh T N Pham, Mineto Ota, Anika Wadhera, Rama Dajani, Dmytro Dorovskyi, Yan Yi Chen, Qi Liu, Yuan Zhou, Danielle L Swaney, Kirsten Obernier, Brian R Shy, Julia Carnevale, Ansuman T Satpathy, Nevan J Krogan, Jonathan K Pritchard, Alexander Marson.
      The ability of cells to maintain distinct identities and respond to transient environmental signals requires tightly controlled regulation of gene networks1-3. These dynamic regulatory circuits that respond to extracellular cues in primary human cells remain poorly defined. The need for context-dependent regulation is prominent in T cells, where distinct lineages must respond to diverse signals to mount effective immune responses and maintain homeostasis4-8. Here we performed CRISPR screens in multiple primary human CD4+ T cell contexts to identify regulators that control expression of IL-2Rα, a canonical marker of T cell activation transiently expressed by pro-inflammatory effector T cells and constitutively expressed by anti-inflammatory regulatory T cells where it is required for fitness9-11. Approximately 90% of identified regulators of IL-2Rα had effects that varied across cell types and/or stimulation states, including a subset that even had opposite effects across conditions. Using single-cell transcriptomics after pooled perturbation of context-specific screen hits, we characterized specific factors as regulators of overall rest or activation and constructed state-specific regulatory networks. MED12 - a component of the Mediator complex - serves as a dynamic orchestrator of key regulators, controlling expression of distinct sets of regulators in different T cell contexts. Immunoprecipitation-mass spectrometry revealed that MED12 interacts with the histone methylating COMPASS complex. MED12 was required for histone methylation and expression of genes encoding key context-specific regulators, including the rest maintenance factor KLF2 and the versatile regulator MYC. CRISPR ablation of MED12 blunted the cell-state transitions between rest and activation and protected from activation-induced cell death. Overall, this work leverages CRISPR screens performed across conditions to define dynamic gene circuits required to establish resting and activated T cell states.
    DOI:  https://doi.org/10.1038/s41586-024-08314-y
  5. Nat Med. 2024 Dec;30(12): 3393
    Stem cells reverse type 1 diabetes.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-024-03394-9
  6. Nat Med. 2024 Dec;30(12): 3441-3442
    Identification of distinct types of steatotic liver disease with specific clinical trajectories.
      
    DOI:  https://doi.org/10.1038/s41591-024-03366-z
  7. Immunity. 2024 Dec 10. pii: S1074-7613(24)00528-4. [Epub ahead of print]57(12): 2720-2722
    Getting RAMPed up: Neuropeptides boost T helper 1 cell fate.
    Camille A Spinner, Vanja Lazarevic.
      CD4+ T helper (Th) cell differentiation depends on regulatory networks that enforce lineage commitment while suppressing alternative fates. In a recent issue of Nature, Hou et al. reveal that calcitonin gene-related peptide (CGRP) directs Th1 commitment, highlighting neuro-immune crosstalk in T cell fate decisions.
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.013
  8. Sci Immunol. 2024 Dec 13. 9(102): eadl4613
    Asparagine availability controls germinal center B cell homeostasis.
    Yavuz F Yazicioglu, Eros Marin, Hana F Andrew, Karolina Bentkowska, Julia C Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G A Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L Furlani, James I MacRae, Michael J Devine, Mark Coles, Christopher D Buckley, Susanna J Dunachie, Alexander J Clarke.
      The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
    DOI:  https://doi.org/10.1126/sciimmunol.adl4613
  9. Nat Methods. 2024 Dec;21(12): 2203-2208
    Atlases galore: where to next?
    Vivien Marx.
      
    DOI:  https://doi.org/10.1038/s41592-024-02536-8
  10. Nat Rev Immunol. 2024 Dec 09.
    Systematic identification of cell state-specific transcription factors in T cells.
    Didem Ağaç Çobanoğlu.
      
    DOI:  https://doi.org/10.1038/s41577-024-01118-1
  11. Nat Cardiovasc Res. 2024 Dec;3(12): 1568-1583
    Clonal hematopoiesis-related mutant ASXL1 promotes atherosclerosis in mice via dysregulated innate immunity.
    Naru Sato, Susumu Goyama, Yu-Hsuan Chang, Masashi Miyawaki, Takeshi Fujino, Shuhei Koide, Tamami Denda, Xiaoxiao Liu, Koji Ueda, Keita Yamamoto, Shuhei Asada, Reina Takeda, Taishi Yonezawa, Yosuke Tanaka, Hiroaki Honda, Yasunori Ota, Takuma Shibata, Motohiro Sekiya, Tomoya Isobe, Chrystelle Lamagna, Esteban Masuda, Atsushi Iwama, Hitoshi Shimano, Jun-Ichiro Inoue, Kensuke Miyake, Toshio Kitamura.
      Certain somatic mutations provide a fitness advantage to hematopoietic stem cells and lead to clonal expansion of mutant blood cells, known as clonal hematopoiesis (CH). Among the most common CH mutations, ASXL1 mutations pose the highest risk for cardiovascular diseases (CVDs), yet the mechanisms by which they contribute to CVDs are unclear. Here we show that hematopoietic cells harboring C-terminally truncated ASXL1 mutant (ASXL1-MT) accelerate the development of atherosclerosis in Ldlr-/- mice. Transcriptome analyses of plaque cells showed that monocytes and macrophages expressing ASXL1-MT exhibit inflammatory signatures. Mechanistically, we demonstrate that wild-type ASXL1 has an unexpected non-epigenetic role by suppressing innate immune signaling through the inhibition of IRAK1-TAK1 interaction in the cytoplasm. This regulatory function is lost in ASXL1-MT, resulting in NF-κB activation. Inhibition of IRAK1/4 alleviated atherosclerosis driven by ASXL1-MT and decreased inflammatory monocytes. The present work provides a mechanistic and cellular explanation linking ASXL1 mutations, CH and CVDs.
    DOI:  https://doi.org/10.1038/s44161-024-00579-w
  12. Nat Cell Biol. 2024 Dec;26(12): 2013
    Worrying through the ECM.
    Daryl J V David.
      
    DOI:  https://doi.org/10.1038/s41556-024-01579-5
  13. Science. 2024 Dec 13. 386(6727): 1223-1224
    A neuronal gene that loops the loop.
    Kyle S Czarnecki, Elizabeth A Heller.
      Noncoding RNA controls the expression of a gene implicated in drug- and stress-induced behaviors.
    DOI:  https://doi.org/10.1126/science.adu0431
  14. Nature. 2024 Dec 11.
    A lipid made by tumour cells reprograms immune cells.
    Anthony C Buzzai, Thomas Tüting.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-03855-8
  15. Nature. 2024 Dec 11.
    A little bird flies high thanks to mighty mitochondria.
      
    Keywords:  Physiology
    DOI:  https://doi.org/10.1038/d41586-024-04010-z
  16. Nature. 2024 Dec;636(8043): 536-541
    The best science images of 2024 - Nature's picks.
    Nisha Gaind, Emma Stoye.
      
    Keywords:  Media
    DOI:  https://doi.org/10.1038/d41586-024-03969-z
  17. Nature. 2024 Dec 11.
    A guide to the Nature Index.
      
    Keywords:  Databases; Materials science
    DOI:  https://doi.org/10.1038/d41586-024-04005-w
  18. Cell. 2024 Dec 12. pii: S0092-8674(24)01335-7. [Epub ahead of print]187(25): 7064-7065
    Keiji Tanaka (1949-2024).
    Shigeo Murata, Kazuhiro Iwai.
      
    DOI:  https://doi.org/10.1016/j.cell.2024.11.019
  19. Nature. 2024 Dec 11.
    Haematological setpoints are a stable and patient-specific deep phenotype.
    Brody H Foy, Rachel Petherbridge, Maxwell T Roth, Cindy Zhang, Daniel C De Souza, Christopher Mow, Hasmukh R Patel, Chhaya H Patel, Samantha N Ho, Evie Lam, Camille E Powe, Robert P Hasserjian, Konrad J Karczewski, Veronica Tozzo, John M Higgins.
      The complete blood count (CBC) is an important screening tool for healthy adults and a common test at periodic exams. However, results are usually interpreted relative to one-size-fits-all reference intervals1,2, undermining the precision medicine goal to tailor care for patients on the basis of their unique characteristics3,4. Here we study thousands of diverse patients at an academic medical centre and show that routine CBC indices fluctuate around stable values or setpoints5, and setpoints are patient-specific, with the typical healthy adult's nine CBC setpoints distinguishable as a group from those of 98% of other healthy adults, and setpoint differences persist for at least 20 years. Haematological setpoints reflect a deep physiologic phenotype enabling investigation of acquired and genetic determinants of haematological regulation and its variation among healthy adults. Setpoints in apparently healthy adults were associated with significant variation in clinical risk: absolute risk of some common diseases and morbidities varied by more than 2% (heart attack and stroke, diabetes, kidney disease, osteoporosis), and absolute risk of all-cause 10 year mortality varied by more than 5%. Setpoints also define patient-specific reference intervals and personalize the interpretation of subsequent test results. In retrospective analysis, setpoints improved sensitivity and specificity for evaluation of some common conditions including diabetes, kidney disease, thyroid dysfunction, iron deficiency and myeloproliferative neoplasms. This study shows CBC setpoints are sufficiently stable and patient-specific to help realize the promise of precision medicine for healthy adults.
    DOI:  https://doi.org/10.1038/s41586-024-08264-5
  20. Science. 2024 Dec 12. eadj3020
    Nutrient-driven histone code determines exhausted CD8+ T cell fates.
    Shixin Ma, Michael S Dahabieh, Thomas H Mann, Steven Zhao, Bryan McDonald, Won-Suk Song, H Kay Chung, Yagmur Farsakoglu, Lizmarie Garcia-Rivera, Filipe Araujo Hoffmann, Shihao Xu, Victor Y Du, Dan Chen, Jesse Furgiuele, Michael LaPorta, Emily Jacobs, Lisa M DeCamp, Brandon M Oswald, Ryan D Sheldon, Abigail E Ellis, Longwei Liu, Peixiang He, Yingxiao Wang, Cholsoon Jang, Russell G Jones, Susan M Kaech.
      Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
    DOI:  https://doi.org/10.1126/science.adj3020
  21. Nat Genet. 2024 Dec;56(12): 2589
    DRAGEN optimizes genomic variant detection.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-024-02042-9
  22. Nature. 2024 Dec;636(8042): 279
    Ancient stacks of dishes tell tale of society's dissolution.
      
    Keywords:  Archaeology
    DOI:  https://doi.org/10.1038/d41586-024-03977-z
  23. Nat Med. 2024 Dec;30(12): 3392
    The harms of ultra-processed foods.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-024-03386-9
  24. Nat Commun. 2024 Dec 12. 15(1): 10678
    How measurement noise limits the accuracy of brain-behaviour predictions.
    Martin Gell, Simon B Eickhoff, Amir Omidvarnia, Vincent Küppers, Kaustubh R Patil, Theodore D Satterthwaite, Veronika I Müller, Robert Langner.
      Major efforts in human neuroimaging strive to understand individual differences and find biomarkers for clinical applications by predicting behavioural phenotypes from brain imaging data. To identify generalisable and replicable brain-behaviour prediction models, sufficient measurement reliability is essential. However, the selection of prediction targets is predominantly guided by scientific interest or data availability rather than psychometric considerations. Here, we demonstrate the impact of low reliability in behavioural phenotypes on out-of-sample prediction performance. Using simulated and empirical data from four large-scale datasets, we find that reliability levels common across many phenotypes can markedly limit the ability to link brain and behaviour. Next, using 5000 participants from the UK Biobank, we show that only highly reliable data can fully benefit from increasing sample sizes from hundreds to thousands of participants. Our findings highlight the importance of measurement reliability for identifying meaningful brain-behaviour associations from individual differences and underscore the need for greater emphasis on psychometrics in future research.
    DOI:  https://doi.org/10.1038/s41467-024-54022-6
  25. Nat Commun. 2024 Dec 11. 15(1): 10577
    Mechanics of Drosophila wing deployment.
    Simon Hadjaje, Ignacio Andrade-Silva, Marie-Julie Dalbe, Raphaël Clément, Joel Marthelot.
      During their final transformation, insects emerge from the pupal case and deploy their wings within minutes. The wings deploy from a compact origami structure, to form a planar and rigid blade that allows the insect to fly. Deployment is powered by a rapid increase in internal pressure, and by the subsequent flow of hemolymph into the deployable wing structure. Using a combination of imaging techniques, we characterize the internal and external structure of the wing in Drosophila melanogaster, the unfolding kinematics at the organ scale, and the hemolymph flow during deployment. We find that, beyond the mere unfolding of the macroscopic folds, wing deployment also involves wing expansion, with the stretching of epithelial cells and the unwrinkling of the cuticle enveloping the wing. A quantitative computational model, incorporating mechanical measurements of the viscoelastic properties and microstructure of the wing, predicts the existence of an operating point for deployment and captures the dynamics of the process. This model shows that insects exploit material and geometric nonlinearities to achieve rapid and efficient reconfiguration of soft deployable structures.
    DOI:  https://doi.org/10.1038/s41467-024-54527-0
  26. Nat Neurosci. 2024 Dec 09.
    Thermally induced neuronal plasticity in the hypothalamus mediates heat tolerance.
    Wojciech Ambroziak, Sara Nencini, Jörg Pohle, Kristina Zuza, Gabriela Pino, Sofia Lundh, Carolina Araujo-Sousa, Larissa I L Goetz, Katrin Schrenk-Siemens, Gokul Manoj, Mildred A Herrera, Claudio Acuna, Jan Siemens.
      Heat acclimation is an adaptive process that improves physiological performance and supports survival in the face of increasing environmental temperatures, but the underlying mechanisms are not well understood. Here we identified a discrete group of neurons in the mouse hypothalamic preoptic area (POA) that rheostatically increase their activity over the course of heat acclimation, a property required for mice to become heat tolerant. In non-acclimated mice, peripheral thermoafferent pathways via the parabrachial nucleus activate POA neurons and mediate acute heat-defense mechanisms. However, long-term heat exposure promotes the POA neurons to gain intrinsically warm-sensitive activity, independent of thermoafferent parabrachial input. This newly gained cell-autonomous warm sensitivity is required to recruit peripheral heat tolerance mechanisms in acclimated animals. This pacemaker-like, warm-sensitive activity is driven by a combination of increased sodium leak current and enhanced utilization of the NaV1.3 ion channel. We propose that this salient neuronal plasticity mechanism adaptively drives acclimation to promote heat tolerance.
    DOI:  https://doi.org/10.1038/s41593-024-01830-0
  27. Proc Natl Acad Sci U S A. 2024 Dec 17. 121(51): e2417678121
    Genetic synchronization of the brain and liver molecular clocks defend against chrono-metabolic disease.
    Lauren N Woodie, Ahren J Alberto, Brianna M Krusen, Lily C Melink, Mitchell A Lazar.
      Nearly every cell of the body contains a circadian clock mechanism that is synchronized with the light-entrained clock in the suprachiasmatic nucleus (SCN). Desynchrony between the SCN and the external environment leads to metabolic dysfunction in shift workers. Similarly, mice with markedly shortened endogenous period due to the deletion of circadian REV-ERBα/β nuclear receptors in the SCN (SCN DKO) exhibit increased sensitivity to diet-induced obesity (DIO) on a 24 h light:dark cycle while mice with REV-ERBs deleted in hepatocytes (HepDKO) display exacerbated hepatosteatosis in response to a high-fat diet. Here, we show that inducing deletion of hepatocyte REV-ERBs in SCN DKO mice (Hep-SCN DDKO) rescued the exacerbated DIO and hepatic triglyceride accumulation, without affecting the shortened behavioral period. These findings suggest that metabolic disturbances due to environmental desynchrony with the central clock are due to effects on peripheral clocks which can be mitigated by matching peripheral and central clock periods even in a desynchronous environment. Thus, maintaining synchrony within an organism, rather than between endogenous and exogenous clocks, may be a viable target for the treatment of metabolic disorders associated with circadian disruption.
    Keywords:  REV-ERB; circadian rhythms; metabolism; obesity; suprachiasmatic Nucleus
    DOI:  https://doi.org/10.1073/pnas.2417678121
  28. Nat Methods. 2024 Dec;21(12): 2220-2222
    A new understanding of tissue biology from MS-based proteomics at single-cell resolution.
    Thierry M Nordmann, Andreas Mund, Matthias Mann.
      
    DOI:  https://doi.org/10.1038/s41592-024-02541-x
  29. Nature. 2024 Dec 11.
    Lipid-delivery system could treat life-threatening pregnancy complication.
    Ravi Thadhani, S Ananth Karumanchi.
      
    Keywords:  Biotechnology; Diseases; Nanoparticles; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-024-03853-w
  30. Nat Aging. 2024 Dec;4(12): 1660-1662
    Supporting the sexual healthcare needs of aging women.
    Holly N Thomas.
      
    DOI:  https://doi.org/10.1038/s43587-024-00725-w
  31. Nat Med. 2024 Dec;30(12): 3393
    Multi-organ benefits of incretin agonists.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-024-03391-y
  32. Nat Genet. 2024 Dec;56(12): 2589
    Functional genomics of height heritability.
    Tiago Faial.
      
    DOI:  https://doi.org/10.1038/s41588-024-02043-8
  33. Nature. 2024 Dec 13.
    Fasting can reduce weight - but also hair growth.
    Max Kozlov.
      
    Keywords:  Cell biology; Metabolism; Regeneration; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-04084-9
  34. Nature. 2024 Dec;636(8042): S16-S17
    How the latest materials are taking biosensors to the next level.
    Neil Savage.
      
    Keywords:  Biomaterials; Health care; Materials science; Medical research; Public health
    DOI:  https://doi.org/10.1038/d41586-024-04003-y
  35. Nat Cell Biol. 2024 Dec;26(12): 2013
    Making stronger T cells.
    Stylianos Lefkopoulos.
      
    DOI:  https://doi.org/10.1038/s41556-024-01577-7
  36. Cell Stem Cell. 2024 Dec 05. pii: S1934-5909(24)00402-8. [Epub ahead of print]31(12): 1847-1864.e6
    Self-organization of the hematopoietic vascular niche and emergent innate immunity on a chip.
    Andrei Georgescu, Joseph Hai Oved, Jonathan H Galarraga, Thomas Cantrell, Samira Mehta, Brian M Dulmovits, Timothy S Olson, Pouria Fattahi, Anni Wang, Pelin L Candarlioglu, Asli Muvaffak, Michele M Kim, Sezin Aday Aydin, Jeongyun Seo, Eric S Diffenderfer, Anthony Lynch, G Scott Worthen, Dan Dongeun Huh.
      Here, we present a bioengineering approach to emulate the human bone marrow in vitro. Our developmentally inspired method uses self-organization of human hematopoietic stem and progenitor cells and vascular endothelial cells cultured in a three-dimensional microphysiological system to create vascularized, perfusable tissue constructs that resemble the hematopoietic vascular niche of the human marrow. The microengineered niche is capable of multilineage hematopoiesis and can generate functionally mature human myeloid cells that can intravasate into perfused blood vessels, providing a means to model the mobilization of innate immune cells from the marrow. We demonstrate the application of this system by presenting a specialized model of ionizing radiation-induced bone marrow injury and a multiorgan model of acute innate immune responses to bacterial lung infection. Furthermore, we introduce an advanced platform that enables large-scale integration and automated experimentation of the engineered hematopoietic tissues for preclinical screening of myelotoxicity due to anti-cancer drugs.
    Keywords:  bone marrow; drug testing; hematopoiesis; hematopoietic stem cells; immune cells; in vitro models; lung-on-a-chip; microphysiological systems; myelosuppresion; organ-on-a-chip
    DOI:  https://doi.org/10.1016/j.stem.2024.11.003
  37. Nature. 2024 Dec 11.
    Personalized ranges for blood-test results enable precision diagnostics.
    Steven J R Meex, Kristin Moberg Aakre.
      
    Keywords:  Biological techniques; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-03854-9
  38. Nat Methods. 2024 Dec;21(12): 2227
    Subcellular spatial proteomics.
    Rita Strack.
      
    DOI:  https://doi.org/10.1038/s41592-024-02546-6
  39. Nat Commun. 2024 Dec 10. 15(1): 10376
    Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway.
    Yoshitaka Adachi, Seitaro Terakura, Masahide Osaki, Yusuke Okuno, Yoshitaka Sato, Ken Sagou, Yuki Takeuchi, Hirofumi Yokota, Kanae Imai, Peter Steinberger, Judith Leitner, Ryo Hanajiri, Makoto Murata, Hitoshi Kiyoi.
      Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antigen stimulations. We find that genetic ablation of CUL5, encoding a core element of the multi-protein E3 ubiquitin-protein ligase complex, cullin-RING ligase 5, enhances human CD19 CAR T cell expansion potential and effector functions, potentially via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. In this regard, CUL5 knockout CD19 CAR T cells show sustained STAT3 and STAT5 phosphorylation, as well as delayed phosphorylation and degradation of JAK1 and JAK3. In vivo, shRNA-mediated knockdown of CUL5 enhances CD19 CAR T treatment outcomes in tumor-bearing mice. Our findings thus imply that targeting CUL5 in the ubiquitin system may enhance CAR T cell effector functions to enhance immunotherapy efficacy.
    DOI:  https://doi.org/10.1038/s41467-024-54794-x
  40. Nat Methods. 2024 Dec;21(12): 2229-2230
    Molecular motion in situ.
    Arunima Singh.
      
    DOI:  https://doi.org/10.1038/s41592-024-02551-9
  41. Nat Methods. 2024 Dec;21(12): 2209-2211
    Highly multiplexed imaging in the omics era: understanding tissue structures in health and disease.
    Bernd Bodenmiller.
      
    DOI:  https://doi.org/10.1038/s41592-024-02538-6
  42. Nature. 2024 Dec 09.
    Human body's ageing 'clock' ticks faster after heat stress.
    Heidi Ledford.
      
    Keywords:  Ageing; Climate change; Epigenetics
    DOI:  https://doi.org/10.1038/d41586-024-04007-8
  43. Nature. 2024 Dec 10.
    Engineered cells take drugs deep into the brain - and nowhere else.
      
    Keywords:  Biotechnology
    DOI:  https://doi.org/10.1038/d41586-024-04008-7
  44. EMBO J. 2024 Dec 12.
    Cyclin-dependent kinase inhibitor p18 regulates lineage transitions of excitatory neurons, astrocytes, and interneurons in the mouse cortex.
    Wonyoung Lee, Byunghee Kang, Hyo-Min Kim, Tsuyoshi Ishida, Minkyung Shin, Misato Iwashita, Masahiro Nitta, Aki Shiraishi, Hiroshi Kiyonari, Koichiro Shimoya, Kazuto Masamoto, Tae-Young Roh, Yoichi Kosodo.
      Neural stem cells (NSCs) can give rise to both neurons and glia, but the regulatory mechanisms governing their differentiation transitions remain incompletely understood. Here, we address the role of cyclin-dependent kinase inhibitors (CDKIs) in the later stages of dorsal cortical development. We find that the CDKIs p18 and p27 are upregulated at the onset of astrocyte generation. Acute manipulation of p18 and p27 levels shows that CDKIs modulate lineage switching between upper-layer neurons and astrocytes at the transitional stage. We generate a conditional knock-in mouse model to induce p18 in NSCs. The transcriptomic deconvolution of microdissected tissue reveals that increased levels of p18 promote glial cell development and activate Delta-Notch signaling. Furthermore, we show that p18 upregulates the homeobox transcription factor Dlx2 to subsequently induce the differentiation of olfactory bulb interneurons while reducing the numbers of upper-layer neurons and astrocytes at the perinatal stage. Clonal analysis using transposon-based reporters reveals that the transition from the astrocyte to the interneuron lineage is potentiated by p18 at the single-cell level. In sum, our study reports a function of p18 in determining the developmental boundaries among different cellular lineages arising sequentially from NSCs in the dorsal cortex.
    Keywords:  Astrocyte Differentiation; Brain Development; Cyclin-dependent Kinase Inhibitors; Ink4 Family; Neural Stem Cells
    DOI:  https://doi.org/10.1038/s44318-024-00325-9
  45. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00909-2. [Epub ahead of print]84(23): 4612-4628.e13
    Reactive oxygen species control protein degradation at the mitochondrial import gate.
    Rachael McMinimy, Andrew G Manford, Christine L Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y Shih, Christopher M Rose, John Kuriyan, Baris Bingol, Michael Rapé.
      While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2FEM1B), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.
    Keywords:  FEM1B; TOM complex; electron transport chain; mitochondria; proteasome; reductive stress response; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.004
  46. Nat Med. 2024 Dec;30(12): 3392
    From clinical to biological definitions of neurological diseases.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-024-03387-8
  47. Nat Med. 2024 Dec;30(12): 3431-3432
    Vascular cells of blood vessels and organs across the human body.
      
    DOI:  https://doi.org/10.1038/s41591-024-03410-y
  48. Nat Med. 2024 Dec;30(12): 3393
    Long-acting PrEP prevents HIV in women.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-024-03393-w
  49. Cell Rep. 2024 Dec 11. pii: S2211-1247(24)01358-5. [Epub ahead of print]43(12): 115007
    Lipidome profiling in advanced metabolic liver disease identifies phosphatidylserine synthase 1 as a regulator of hepatic lipoprotein metabolism.
    Marziyeh Anari, Hamzeh Karimkhanloo, Shuai Nie, Li Dong, Gio Fidelito, Jacqueline Bayliss, Stacey N Keenan, John Slavin, Sihan Lin, Zhili Cheng, Jie Lu, Paula M Miotto, William De Nardo, Camille J Devereux, Nicholas A Williamson, Matthew J Watt, Magdalene K Montgomery.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by defective lipid metabolism, which causes disease progression. MASH is also linked to various cardiometabolic risk factors, including obesity and type 2 diabetes. The contribution of defective lipid metabolism in MASH to cardiometabolic comorbidities is incompletely understood. Using hepatic lipidome profiling in eight mouse strains that differ in MASH susceptibility and patients with MASH, we show that phosphatidylserine (PS) accumulation and preservation of PS synthase 1 (PSS1) expression is associated with resistance to MASH and hypertriglyceridemia. Mechanistically, hepatocyte-specific PSS1 overexpression remodels the hepatic and very-low-density lipoprotein (VLDL) lipidome in mice with MASH. Specifically, we show an increase in VLDL ceramide that suppresses the expression and activity of lipoprotein lipase in skeletal muscle, thereby reducing VLDL-triglyceride clearance, fatty acid uptake, and lipid accumulation in muscle, overall exacerbating hypertriglyceridemia. Together, the results of this study identify hepatic PSS1 as a regulator of systemic lipoprotein metabolism.
    Keywords:  CP: Metabolism; ceramide; lipid metabolism; lipoprotein lipase; phospholipid; tissue communication; very low-density lipoprotein
    DOI:  https://doi.org/10.1016/j.celrep.2024.115007
  50. Cell. 2024 Dec 03. pii: S0092-8674(24)01337-0. [Epub ahead of print]
    How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot.
    Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai.
      Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.
    Keywords:  NINJ1; NINJ2; inflammatory cell death; lytic cell death; membrane solubilization; necroptosis; ninjurin-1; ninjurin-2; plasma membrane rupture; pyroptosis
    DOI:  https://doi.org/10.1016/j.cell.2024.11.021
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