bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–07–28
thirty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Antimicrobial resistance: a silent pandemic.
  2. Memory for music doesn't diminish with age.
  3. Dietary glutamine supports mucosal germinal center B cell lymphomas.
  4. Single-cell multiregion dissection of Alzheimer's disease.
  5. Epigenetic control of memory formation.
  6. Barcoding distinct neurons.
  7. Meet the retired scientists who collaborate with younger colleagues.
  8. Effort to 'Trump-proof' US science grows, but will it succeed?
  9. Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration.
  10. How does the spliceosome dismantle itself?
  11. A dumpster full of mercury and other things to avoid: lab closures made simple.
  12. Unravelling the origins and forces that shape mtDNA mutations in human cells.
  13. LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.
  14. IRF8 and MAFB drive distinct transcriptional machineries in different resident macrophages of the central nervous system.
  15. Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.
  16. Three ways AI is changing the 2024 Olympics for athletes and fans.
  17. Diabetes mellitus-Progress and opportunities in the evolving epidemic.
  18. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.
  19. A stroke derailed my academic career. Now I'm getting back on track.
  20. Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.
  21. NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.
  22. Epigenetic editing works like a CHARM.
  23. Daily briefing: What it's like to attend a predatory conference.
  24. Metabolic heterogeneity in humans.
  25. Directing risky traffic in B cells with TNIP1.
  26. The molecular basis underlying T cell specificity towards citrullinated epitopes presented by HLA-DR4.
  27. Complex roles for mitochondrial complexes in microglia.
  28. Seventh patient 'cured' of HIV: why scientists are excited.
  29. C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial.
  30. mTOR links nutrients, inflammaging and lifespan.
  31. Single-nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents.
  32. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  33. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
  34. We are junior scientists from emerging economies - the world needs more researchers like us solving global problems.
  35. Strokes can damage the heart - but reining in the immune system might help.
  36. Condensin I folds the Caenorhabditis elegans genome.
  1. Nat Commun. 2024 Jul 23. 15(1): 6198
    Antimicrobial resistance: a silent pandemic.
      
    DOI:  https://doi.org/10.1038/s41467-024-50457-z
  2. Nature. 2024 Jul 24.
    Memory for music doesn't diminish with age.
    Bianca Nogrady.
      
    Keywords:  Ageing; Alzheimer's disease; Brain
    DOI:  https://doi.org/10.1038/d41586-024-02369-7
  3. Nat Immunol. 2024 Jul 22.
    Dietary glutamine supports mucosal germinal center B cell lymphomas.
      
    DOI:  https://doi.org/10.1038/s41590-024-01911-z
  4. Nature. 2024 Jul 24.
    Single-cell multiregion dissection of Alzheimer's disease.
    Hansruedi Mathys, Carles A Boix, Leyla Anne Akay, Ziting Xia, Jose Davila-Velderrain, Ayesha P Ng, Xueqiao Jiang, Ghada Abdelhady, Kyriaki Galani, Julio Mantero, Neil Band, Benjamin T James, Sudhagar Babu, Fabiola Galiana-Melendez, Kate Louderback, Dmitry Prokopenko, Rudolph E Tanzi, David A Bennett, Li-Huei Tsai, Manolis Kellis.
      Alzheimer's disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1-3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer's disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer's disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer's disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer's disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer's disease pathology.
    DOI:  https://doi.org/10.1038/s41586-024-07606-7
  5. Science. 2024 Jul 26. 385(6707): 367-368
    Epigenetic control of memory formation.
    Sabine Krabbe.
      A neuron's suitability to participate in a memory trace is modulated by its epigenetic state.
    DOI:  https://doi.org/10.1126/science.adq8496
  6. Science. 2024 Jul 26. 385(6707): 370-371
    Barcoding distinct neurons.
    Jane Kawaoka, Stavros Lomvardas.
      The genomic landscape of a cell surface protein reveals how neuron identity is displayed.
    DOI:  https://doi.org/10.1126/science.adq5225
  7. Nature. 2024 Jul 26.
    Meet the retired scientists who collaborate with younger colleagues.
    Julie Gould.
      
    Keywords:  Ageing; Careers; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-02482-7
  8. Nature. 2024 Jul 26.
    Effort to 'Trump-proof' US science grows, but will it succeed?
    Jeff Tollefson.
      
    Keywords:  Government; Policy; Politics
    DOI:  https://doi.org/10.1038/d41586-024-02484-5
  9. Nat Commun. 2024 Jul 23. 15(1): 5970
    Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration.
    Cheng Fu, Nan Yang, Jen-Zen Chuang, Nobuyuki Nakajima, Satoshi Iraha, Neeta Roy, Zhenquan Wu, Zhichun Jiang, Wataru Otsu, Roxana A Radu, Howard Hua Yang, Maxwell Ping Lee, Tilla S Worgall, Wen-Cheng Xiong, Ching-Hwa Sung.
      Vacuolar protein sorting 35 (VPS35), the core component of the retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson's disease (PD). Impaired vision is a common non-motor manifestation of PD. Here, we show mouse retinas with VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant with the emergence of Lewy body-like inclusions and phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal VPS35-deficient rods accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, we uncover a protein network of VPS35 and its interaction with HSC70. VPS35 deficiency promotes sequestration of HSC70 and P-αSyn aggregation in late endosomes. Microglia which engulf lipofuscins and P-αSyn aggregates are activated, displaying autofluorescence, observed as bright dots in fundus imaging of live animals, coinciding with pathology onset and progression. The Rod∆Vps35 mouse line is a valuable tool for further mechanistic investigation of αSyn lesions and retinal degenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-024-50189-0
  10. Nature. 2024 Jul 24.
    How does the spliceosome dismantle itself?
    Shasha Shi, Rui Zhao.
      
    Keywords:  Biochemistry; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-02327-3
  11. Nature. 2024 Jul 22.
    A dumpster full of mercury and other things to avoid: lab closures made simple.
    Julie Gould.
      
    Keywords:  Ageing; Careers; Lab life; Society
    DOI:  https://doi.org/10.1038/d41586-024-02372-y
  12. Nat Genet. 2024 Jul 26.
    Unravelling the origins and forces that shape mtDNA mutations in human cells.
      
    DOI:  https://doi.org/10.1038/s41588-024-01837-0
  13. Nat Commun. 2024 Jul 20. 15(1): 6126
    LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.
    Olga Kubrak, Anne F Jørgensen, Takashi Koyama, Mette Lassen, Stanislav Nagy, Jacob Hald, Gianluca Mazzoni, Dennis Madsen, Jacob B Hansen, Martin Røssel Larsen, Michael J Texada, Jakob L Hansen, Kenneth V Halberg, Kim Rewitz.
      Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.
    DOI:  https://doi.org/10.1038/s41467-024-50468-w
  14. Commun Biol. 2024 Jul 24. 7(1): 896
    IRF8 and MAFB drive distinct transcriptional machineries in different resident macrophages of the central nervous system.
    Ayato Yamasaki, Iroha Imanishi, Kaori Tanaka, Yasuyuki Ohkawa, Makoto Tsuda, Takahiro Masuda.
      The central nervous system (CNS) includes anatomically distinct macrophage populations including parenchyma microglia and CNS-associated macrophages (CAMs) localized at the interfaces like meninges and perivascular space, which play specialized roles for the maintenance of the CNS homeostasis with the help of precisely controlled gene expressions. However, the transcriptional machinery that determines their cell-type specific states of microglia and CAMs remains poorly understood. Here we show, by myeloid cell-specific deletion of transcription factors, IRF8 and MAFB, that both adult microglia and CAMs utilize IRF8 to maintain their core gene signatures, although the genes altered by IRF8 deletion are different in the two macrophage populations. By contrast, MAFB deficiency robustly affected the gene expression profile of adult microglia, whereas CAMs are almost independent of MAFB. Our data suggest that distinct transcriptional machineries regulate different macrophages in the CNS.
    DOI:  https://doi.org/10.1038/s42003-024-06607-6
  15. Immunity. 2024 Jul 16. pii: S1074-7613(24)00320-0. [Epub ahead of print]
    Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.
    Frank A Buquicchio, Raissa Fonseca, Patrick K Yan, Fangyi Wang, Maximilien Evrard, Andreas Obers, Jacob C Gutierrez, Colin J Raposo, Julia A Belk, Bence Daniel, Pirooz Zareie, Kathryn E Yost, Yanyan Qi, Yajie Yin, Katherine F Nico, Flora M Tierney, Michael R Howitt, Caleb A Lareau, Ansuman T Satpathy, Laura K Mackay.
      The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.
    Keywords:  chromatin accessibility; development; epigenetics; regulatory elements; single-cell genomics; tissue immunity; tissue-resident memory T cells; transcriptional regulators
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.014
  16. Nature. 2024 Jul 25.
    Three ways AI is changing the 2024 Olympics for athletes and fans.
    Sumeet Kulkarni.
      
    Keywords:  Machine learning; Society
    DOI:  https://doi.org/10.1038/d41586-024-02427-0
  17. Cell. 2024 Jul 25. pii: S0092-8674(24)00703-7. [Epub ahead of print]187(15): 3789-3820
    Diabetes mellitus-Progress and opportunities in the evolving epidemic.
    E Dale Abel, Anna L Gloyn, Carmella Evans-Molina, Joshua J Joseph, Shivani Misra, Utpal B Pajvani, Judith Simcox, Katalin Susztak, Daniel J Drucker.
      Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.
    DOI:  https://doi.org/10.1016/j.cell.2024.06.029
  18. Sci Adv. 2024 Jul 26. 10(30): eado3141
    Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.
    Shuwei Hu, Rui Li, Dongxu Gong, Pei Hu, Jitu Xu, Yingjie Ai, Xiaojie Zhao, Chencheng Hu, Minghuan Xu, Chenxi Liu, Shuyu Chen, Jie Fan, Zhonghua Zhao, Zhigang Zhang, Huijuan Wu, Yanyong Xu.
      Metabolic dysfunction-associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet-fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.
    DOI:  https://doi.org/10.1126/sciadv.ado3141
  19. Nature. 2024 Jul 23.
    A stroke derailed my academic career. Now I'm getting back on track.
    Parisa Hosseinzadeh.
      
    Keywords:  Brain; Careers; Lab life; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02413-6
  20. Nat Commun. 2024 Jul 23. 15(1): 6213
    Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.
    Pallavi Kompella, Guliang Wang, Russell E Durrett, Yanhao Lai, Celeste Marin, Yuan Liu, Samy L Habib, John DiGiovanni, Karen M Vasquez.
      Obesity is associated with increased cancer risk, yet the underlying mechanisms remain elusive. Obesity-associated cancers involve disruptions in metabolic and cellular pathways, which can lead to genomic instability. Repetitive DNA sequences capable of adopting alternative DNA structures (e.g., H-DNA) stimulate mutations and are enriched at mutation hotspots in human cancer genomes. However, it is not known if obesity impacts DNA repeat-mediated endogenous mutation hotspots. We address this gap by measuring mutation frequencies in obese and normal-weight transgenic reporter mice carrying either a control human B-DNA- or an H-DNA-forming sequence (from a translocation hotspot in c-MYC in Burkitt lymphoma). Here, we discover that H-DNA-induced DNA damage and mutations are elevated in a tissue-specific manner, and DNA repair efficiency is reduced in obese mice compared to those on the control diet. These findings elucidate the impact of obesity on cancer-associated endogenous mutation hotspots, providing mechanistic insight into the link between obesity and cancer.
    DOI:  https://doi.org/10.1038/s41467-024-50006-8
  21. JCI Insight. 2024 Jul 23. pii: e178563. [Epub ahead of print]
    NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.
    Rachael A Gordon, Haylee A Cosgrove, Anthony Marinov, Sebastien Gingras, Jeremy S Tilstra, Allison M Campbell, Sheldon I Bastacky, Michael Kashgarian, Andras Perl, Kevin M Nickerson, Mark J Shlomchik.
      Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional knockout (KO) and chimera approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr lupus-prone mice. Deletion of Cybb in macrophages/monocytes exacerbated lupus nephritis, though not to the degree observed in the Cybb global KOs. Unexpectedly, the absence of Cybb in B cells resulted in profound glomerulonephritis and interstitial nephritis, rivaling that seen with global deletion. Further, we identified that NOX2 is a key regulator of TLR7, a driver of SLE pathology, both globally and specifically in B cells. This is mediated in part through suppression of TLR7-mediated NF-kB signaling in B cells. Thus, NOX2's immunomodulatory effect in SLE is orchestrated not only by its function in the myeloid compartment, but through a pivotal role in B cells by selectively inhibiting TLR7 signaling.
    Keywords:  Autoimmunity; Lupus
    DOI:  https://doi.org/10.1172/jci.insight.178563
  22. Nat Rev Genet. 2024 Jul 22.
    Epigenetic editing works like a CHARM.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41576-024-00765-3
  23. Nature. 2024 Jul 19.
    Daily briefing: What it's like to attend a predatory conference.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02379-5
  24. Cell. 2024 Jul 25. pii: S0092-8674(24)00708-6. [Epub ahead of print]187(15): 3821-3823
    Metabolic heterogeneity in humans.
    Heather Christofk, Christian Metallo, Guanghui Liu, Joshua Rabinowitz, Lauren Sparks, David James.
      Recent advancements in technology, especially the emergence of single-cell technologies, genomic sequencing, metabolomics, and artificial intelligence, have enabled us to understand the distinct metabolic changes in different cell types, tissues, genders, disease states, ages, and populations. Six scientists whose work intersects with metabolism in various capacities tell us about their vision for human metabolic heterogeneity.
    DOI:  https://doi.org/10.1016/j.cell.2024.06.033
  25. Nat Immunol. 2024 Jul 26.
    Directing risky traffic in B cells with TNIP1.
    Michael P Cancro, Ann Marshak-Rothstein.
      
    DOI:  https://doi.org/10.1038/s41590-024-01913-x
  26. Nat Commun. 2024 Jul 23. 15(1): 6201
    The molecular basis underlying T cell specificity towards citrullinated epitopes presented by HLA-DR4.
    Tiing Jen Loh, Jia Jia Lim, Claerwen M Jones, Hien Thy Dao, Mai T Tran, Daniel G Baker, Nicole L La Gruta, Hugh H Reid, Jamie Rossjohn.
      CD4+ T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit59-71 and α-enolase-15cit10-22 remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen β-74cit69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6+ and human TRAV26-1+ TCR-HLA-DR4 complexes presenting vimentin-64cit59-71 and α-enolase-15cit10-22, respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes.
    DOI:  https://doi.org/10.1038/s41467-024-50511-w
  27. Nat Metab. 2024 Jul 24.
    Complex roles for mitochondrial complexes in microglia.
    Rosa C Paolicelli, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s42255-024-01095-8
  28. Nature. 2024 Jul 26.
    Seventh patient 'cured' of HIV: why scientists are excited.
    Smriti Mallapaty.
      
    Keywords:  HIV infections
    DOI:  https://doi.org/10.1038/d41586-024-02463-w
  29. Nat Commun. 2024 Jul 22. 15(1): 6155
    C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial.
    Shiyu Zuo, Chuo Li, Xiaolei Sun, Biping Deng, Yibing Zhang, Yajing Han, Zhuojun Ling, Jinlong Xu, Jiajia Duan, Zelin Wang, Xinjian Yu, Qinlong Zheng, Xiuwen Xu, Jiao Zong, Zhenglong Tian, Lingling Shan, Kaiting Tang, Huifang Huang, Yanzhi Song, Qing Niu, Dongming Zhou, Sizhou Feng, Zhongchao Han, Guoling Wang, Tong Wu, Jing Pan, Xiaoming Feng.
      Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1-2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.
    DOI:  https://doi.org/10.1038/s41467-024-50485-9
  30. Nat Aging. 2024 Jul 26.
    mTOR links nutrients, inflammaging and lifespan.
    Helena M Cochemé, Jesús Gil.
      
    DOI:  https://doi.org/10.1038/s43587-024-00681-5
  31. Nat Commun. 2024 Jul 24. 15(1): 6232
    Single-nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents.
    Daniel Bormann, Michael Knoflach, Emilia Poreba, Christian J Riedl, Giulia Testa, Cyrille Orset, Anthony Levilly, Andréa Cottereau, Philipp Jauk, Simon Hametner, Nadine Stranzl, Bahar Golabi, Dragan Copic, Katharina Klas, Martin Direder, Hannes Kühtreiber, Melanie Salek, Stephanie Zur Nedden, Gabriele Baier-Bitterlich, Stefan Kiechl, Carmen Haider, Verena Endmayr, Romana Höftberger, Hendrik J Ankersmit, Michael Mildner.
      Neuroglia critically shape the brain´s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition of the early ischemic lesion. Here we present a single cell resolution transcriptomics dataset of the brain´s acute response to infarction. Oligodendrocyte lineage cells and astrocytes range among the most transcriptionally perturbed populations and exhibit infarction- and subtype-specific molecular signatures. Specifically, we find infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and reactive astrocytes, exhibiting transcriptional commonalities in response to ischemic injury. OPCs and reactive astrocytes are involved in a shared immuno-glial cross talk with stroke-specific myeloid cells. Within the perilesional zone, osteopontin positive myeloid cells accumulate in close proximity to CD44+ proliferating OPCs and reactive astrocytes. In vitro, osteopontin increases the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition of acutely infarcted brain tissue.
    DOI:  https://doi.org/10.1038/s41467-024-50465-z
  32. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
  33. Nat Commun. 2024 Jul 22. 15(1): 6172
    Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
    Benjamin S Johnson, Daniela Farkas, Rabab El-Mergawy, Jessica A Adair, Ajit Elhance, Moemen Eltobgy, Francesca M Coan, Lexie Chafin, Jessica A Joseph, Alex Cornwell, Finny J Johns, Lorena Rosas, Mauricio Rojas, Laszlo Farkas, Joseph S Bednash, James D Londino, Prabir Ray, Anuradha Ray, Valerian Kagan, Janet S Lee, Bill B Chen, Rama K Mallampalli.
      The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.
    DOI:  https://doi.org/10.1038/s41467-024-50031-7
  34. Nature. 2024 Jul 26.
    We are junior scientists from emerging economies - the world needs more researchers like us solving global problems.
    Mohammed Shaaban, Abib Duut, Nana Mensah.
      
    Keywords:  Careers; Developing world; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-02485-4
  35. Nature. 2024 Jul 26.
    Strokes can damage the heart - but reining in the immune system might help.
      
    Keywords:  Immunology
    DOI:  https://doi.org/10.1038/d41586-024-02426-1
  36. Nat Genet. 2024 Jul 22.
    Condensin I folds the Caenorhabditis elegans genome.
    Moushumi Das, Jennifer I Semple, Anja Haemmerli, Valeriia Volodkina, Janik Scotton, Todor Gitchev, Ahrmad Annan, Julie Campos, Cyril Statzer, Alexander Dakhovnik, Collin Y Ewald, Julien Mozziconacci, Peter Meister.
      The structural maintenance of chromosome (SMC) complexes-cohesin and condensins-are crucial for chromosome separation and compaction during cell division. During the interphase, mammalian cohesins additionally fold the genome into loops and domains. Here we show that, in Caenorhabditis elegans, a species with holocentric chromosomes, condensin I is the primary, long-range loop extruder. The loss of condensin I and its X-specific variant, condensin IDC, leads to genome-wide decompaction, chromosome mixing and disappearance of X-specific topologically associating domains, while reinforcing fine-scale epigenomic compartments. In addition, condensin I/IDC inactivation led to the upregulation of X-linked genes and unveiled nuclear bodies grouping together binding sites for the X-targeting loading complex of condensin IDC. C. elegans condensin I/IDC thus uniquely organizes holocentric interphase chromosomes, akin to cohesin in mammals, as well as regulates X-chromosome gene expression.
    DOI:  https://doi.org/10.1038/s41588-024-01832-5
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