bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–03–02
twenty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Calcium signaling is essential for T helper 1 cell differentiation.
  2. Neutrophils release inflammation-resolving vesicles.
  3. Mitochondrial superoxide regulates pro-inflammatory macrophages.
  4. A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration.
  5. Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.
  6. Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.
  7. Move beyond 'publish or perish' by measuring behaviours that benefit academia.
  8. Autophagy repression in effector T lymphocytes redefines paradigms in T cell biology.
  9. See fat cells forming in super-sharp focus - February's best science images.
  10. Epigenetic editing of PCSK9 for a durable reduction in cholesterol.
  11. Endocannabinoid protection of the brain vasculature leads to stress resilience.
  12. Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.
  13. Cecelia: a multifunctional image analysis toolbox for decoding spatial cellular interactions and behaviour.
  14. Vesuvius volcano turned this brain to glass.
  15. Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.
  16. Cortical representations of affective pain shape empathic fear in male mice.
  17. Identification of splenic IRF7 as a nanotherapy target for tele-conditioning myocardial reperfusion injury.
  18. How to develop a good writing style.
  19. PD-1 or PD-L1-A Difference That Makes No Difference?
  20. Synthetic short mRNA prevents metastasis via innate-adaptive immunity.
  21. Systems-level design principles of metabolic rewiring in an animal.
  22. Universal organelle analyzer enables complex analyses with just one click.
  23. Efficient cell-wide mapping of mitochondria in electron microscopic volumes using webKnossos.
  24. MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
  25. Comparative characterization of human accelerated regions in neurons.
  26. Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.
  1. Nat Immunol. 2025 Feb 25.
    Calcium signaling is essential for T helper 1 cell differentiation.
      
    DOI:  https://doi.org/10.1038/s41590-025-02101-1
  2. Nat Rev Immunol. 2025 Feb 25.
    Neutrophils release inflammation-resolving vesicles.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-025-01151-8
  3. Nat Metab. 2025 Feb 24.
    Mitochondrial superoxide regulates pro-inflammatory macrophages.
      
    DOI:  https://doi.org/10.1038/s42255-025-01223-y
  4. Nat Commun. 2025 Feb 25. 16(1): 1965
    A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration.
    Friederike Grandke, Tobias Fehlmann, Fabian Kern, David M Gate, Tobias William Wolff, Olivia Leventhal, Divya Channappa, Pascal Hirsch, Edward N Wilson, Eckart Meese, Chuanyu Liu, Quan Shi, Matthias Flotho, Yongping Li, Cynthia Chen, Yeya Yu, Jiangshan Xu, Michael Junkin, Zhifeng Wang, Tao Wu, Longqi Liu, Yong Hou, Katrin I Andreasson, Jenny S Gansen, Elvira Mass, Kathleen Poston, Tony Wyss-Coray, Andreas Keller.
      The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson's disease (PD), 27 with Alzheimer's disease (AD), and 15 with both PD and MCI. The dataset is interactively accessible through a freely available website ( https://www.ccb.uni-saarland.de/adrcsc ). In this work, we identify disease-associated changes in blood cell type composition and the gene expression in a sex-specific manner, offering insights into peripheral and solid tissue signatures in AD and PD.
    DOI:  https://doi.org/10.1038/s41467-025-56833-7
  5. Nat Immunol. 2025 Feb 27.
    Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.
    Linda V Sinclair, Tom Youdale, Laura Spinelli, Milica Gakovic, Alistair J Langlands, Shalini Pathak, Andrew J M Howden, Ian G Ganley, Doreen A Cantrell.
      Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive T cells, mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T cell migration and survival. Autophagy thus differentially prunes naive and effector T cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T cell differentiation.
    DOI:  https://doi.org/10.1038/s41590-025-02090-1
  6. Nat Commun. 2025 Feb 26. 16(1): 1982
    Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.
    Ge Gao, Yong Shi, Han-Xiang Deng, Dimitri Krainc.
      Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41467-025-57142-9
  7. Nature. 2025 Feb;638(8052): 861
    Move beyond 'publish or perish' by measuring behaviours that benefit academia.
    Kelly-Ann Allen.
      
    Keywords:  Careers; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-00563-9
  8. Nat Immunol. 2025 Feb 27.
    Autophagy repression in effector T lymphocytes redefines paradigms in T cell biology.
    Ruchi Saxena, You-Wen He.
      
    DOI:  https://doi.org/10.1038/s41590-025-02091-0
  9. Nature. 2025 Feb 27.
    See fat cells forming in super-sharp focus - February's best science images.
    Emma Stoye.
      
    Keywords:  Media
    DOI:  https://doi.org/10.1038/d41586-025-00576-4
  10. Nat Med. 2025 Feb 25.
    Epigenetic editing of PCSK9 for a durable reduction in cholesterol.
      
    DOI:  https://doi.org/10.1038/s41591-025-03583-0
  11. Nat Neurosci. 2025 Feb 26.
    Endocannabinoid protection of the brain vasculature leads to stress resilience.
      
    DOI:  https://doi.org/10.1038/s41593-025-01892-8
  12. Nat Commun. 2025 Feb 24. 16(1): 1910
    Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.
    Alzheimer’s Disease Neuroimaging Initiative
      Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.
    DOI:  https://doi.org/10.1038/s41467-025-57032-0
  13. Nat Commun. 2025 Feb 24. 16(1): 1931
    Cecelia: a multifunctional image analysis toolbox for decoding spatial cellular interactions and behaviour.
    Dominik Schienstock, Jyh Liang Hor, Sapna Devi, Scott N Mueller.
      With the ever-increasing complexity of microscopy modalities, it is imperative to have computational workflows that enable researchers to process and perform in-depth quantitative analysis of the resulting images. However, workflows that allow flexible, interactive and intuitive analysis from raw images to analysed data are lacking for many experimental use-cases. Notably, integrated software solutions for analysis of complex 3D and live cell images are sorely needed. To address this, we present Cecelia, a toolbox that integrates various open-source packages into a coherent data management suite to make quantitative multidimensional image analysis accessible for non-specialists. We describe the application of Cecelia to several immunologically relevant scenarios and the development of an unbiased approach to distinguish dynamic cell behaviours from live imaging data. Cecelia is available as a software package with a Shiny app interface ( https://github.com/schienstockd/cecelia ). We envision that this framework and its approaches will be of broad use for biological researchers.
    DOI:  https://doi.org/10.1038/s41467-025-57193-y
  14. Nature. 2025 Feb 27.
    Vesuvius volcano turned this brain to glass.
    Shamini Bundell.
      
    Keywords:  Archaeology; Materials science
    DOI:  https://doi.org/10.1038/d41586-025-00643-w
  15. Nat Immunol. 2025 Feb 25.
    Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.
    Tomer Itkin, Sean Houghton, Ryan Schreiner, Yang Lin, Chaitanya R Badwe, Veronique Voisin, Alex Murison, Negar Seyedhassantehrani, Kerstin B Kaufmann, Laura Garcia-Prat, Gregory T Booth, Fuqiang Geng, Ying Liu, Jesus M Gomez-Salinero, Jae-Hung Shieh, David Redmond, Jenny Z Xiang, Steven Z Josefowicz, Cole Trapnell, Eric M Pietras, Joel A Spencer, Ross Levine, Wenbin Xiao, Lior Zangi, Brandon Hadland, John E Dick, Stephanie Z Xie, Shahin Rafii.
      Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.
    DOI:  https://doi.org/10.1038/s41590-025-02087-w
  16. Nat Commun. 2025 Feb 24. 16(1): 1937
    Cortical representations of affective pain shape empathic fear in male mice.
    Jiye Choi, Young-Beom Lee, Dahm So, Jee Yeon Kim, Sungjoon Choi, Sowon Kim, Sehoon Keum.
      Affect sharing, the ability to vicariously feel others' emotions, constitutes the primary component of empathy. However, the neural basis for encoding others' distress and representing shared affective experiences remains poorly understood. Here, using miniature endoscopic calcium imaging, we identify distinct and dynamic neural ensembles in the anterior cingulate cortex (ACC) that encode observational fear across both excitatory and inhibitory neurons in male mice. Notably, we discover that the population dynamics encoding vicarious freezing information are conserved in ACC pyramidal neurons and are specifically represented by affective, rather than sensory, responses to direct pain experience. Furthermore, using circuit-specific imaging and optogenetic manipulations, we demonstrate that distinct populations of ACC neurons projecting to the periaqueductal gray (PAG), but not to the basolateral amygdala (BLA), selectively convey affective pain information and regulate observational fear. Taken together, our findings highlight the critical role of ACC neural representations in shaping empathic freezing through the encoding of affective pain.
    DOI:  https://doi.org/10.1038/s41467-025-57230-w
  17. Nat Commun. 2025 Feb 24. 16(1): 1909
    Identification of splenic IRF7 as a nanotherapy target for tele-conditioning myocardial reperfusion injury.
    Qiang Long, Kristina Rabi, Yu Cai, Lihui Li, Shixing Huang, Bei Qian, Yiming Zhong, Zhaoxi Qi, Yecen Zhang, Kaichen Huang, Xinming Wang, Lan Chang, Weichang Xie, Huaiyu Jiang, Haonan Zhang, Junjie Zhang, Ting Ren, Zichen Wang, Tambet Teesalu, Caisheng Wu, Lin Lu, Zhengbin Zhu, Yiwei Chu, Hélder A Santos, Zehua Liu, Qiang Zhao, Xiaofeng Ye.
      The sequestration of nanoparticles by mononuclear phagocyte system is a challenge for the use of nanotherapy for treating cardiovascular diseases due to the conventionally perceived loss of therapeutic potency. Here, we revitalize cardiovascular nanotherapy by unlocking an alternative route in which nanomedicines are redirected to the spleen, leveraging its potential as a highly efficient and targeted site for remote conditioning, or tele-conditioning myocardial reperfusion injury. The theoretical foundation underpinning is the splenogenic nature of recruited monocytes upon myocardial reperfusion in the acute stage, which is confirmed through murine heterotopic spleen transplantation. Single-cell RNA-seq analysis identifies IRF7 as a pivotal mediator in the spleen-heart communication network that is initially induced in the spleen and orchestrates functional changes in myocardial macrophages. Spleen-related induction of IRF7 is also valid in human myocardial reperfusion scenarios. In addition, in a murine preclinical model of male mice, temporal inhibition of splenic IRF7 through the designed spleen-targeting erythrosome engineered with the targeting peptide RP182, termed as STEER nanoparticles, mitigates the acute-stage innate immune responses and improves the cardiac function in the long term. In contrast, systemic inhibition, genetic knockout of IRF7 or absolute depletion of splenic monocytes does not have therapeutic benefits, indicating the superiority of nanoparticle-based targeted treatment. These findings establish the spleen as a naturally favored site for nanoparticle-based treatments, offering promising avenues for managing myocardial reperfusion injury.
    DOI:  https://doi.org/10.1038/s41467-025-57048-6
  18. Nature. 2025 Feb 25.
    How to develop a good writing style.
      
    Keywords:  Communication; History; Infection
    DOI:  https://doi.org/10.1038/d41586-025-00465-w
  19. JAMA. 2025 Feb 24.
    PD-1 or PD-L1-A Difference That Makes No Difference?
    Samuel J Klempner, Jeeyun Lee, Raghav Sundar.
      
    DOI:  https://doi.org/10.1001/jama.2025.0630
  20. Nat Commun. 2025 Feb 25. 16(1): 1925
    Synthetic short mRNA prevents metastasis via innate-adaptive immunity.
    Hikaru Hayashi, Sayaka Seki, Takeshi Tomita, Masayoshi Kato, Norihiro Ashihara, Tokuhiro Chano, Hideki Sanjo, Miwa Kawade, Chenhui Yan, Hiroki Sakai, Hidenori Tomida, Miyuki Tanaka, Mai Iwaya, Shinsuke Taki, Yozo Nakazawa, Yuji Soejima, Yoshihito Ueno, Sachie Hiratsuka.
      Although most cancer deaths are caused by metastasis, there are no effective therapeutic approaches. This study describes the efficacy of a short synthetic mRNA (s-mRNA) designed by the sequence of non-vesicular extracellular IL1β-mRNA found in the pre-metastatic lung of tumor-bearing mice. The administration of s-mRNA inhibits murine lung metastasis by inducing the innate and adaptive immune systems. s-mRNA binds to ZC3H12D, an RNA-binding protein on natural killer cells and cytotoxic T lymphocytes. The ZC3H12D-s-mRNA complex translocated to the nucleus without being involved in translation. This process induces cytolytic activity and cell death in cancer cells without inducing a cytokine storm, and immune cells retain their antitumor activity. Although the antitumor activity of cytotoxic lymphocytes declines as the disease progresses in cancer patients, s-mRNA induces sustained high killing capacities of natural killer cells and cytotoxic T lymphocytes from colon cancer patients. Therefore, s-mRNA could be a breakthrough solution to prevent metastasis.
    DOI:  https://doi.org/10.1038/s41467-025-57123-y
  21. Nature. 2025 Feb 26.
    Systems-level design principles of metabolic rewiring in an animal.
    Xuhang Li, Hefei Zhang, Thomas Hodder, Wen Wang, Chad L Myers, L Safak Yilmaz, Albertha J M Walhout.
      The regulation of metabolism is vital to any organism and can be achieved by transcriptionally activating or repressing metabolic genes1-3. Although many examples of transcriptional metabolic rewiring have been reported4, a systems-level study of how metabolism is rewired in response to metabolic perturbations is lacking in any animal. Here we apply Worm Perturb-Seq (WPS)-a high-throughput method combining whole-animal RNA-interference and RNA-sequencing5-to around 900 metabolic genes in the nematode Caenorhabditis elegans. We derive a metabolic gene regulatory network (mGRN) in which 385 perturbations are connected to 9,414 genes by more than 110,000 interactions. The mGRN has a highly modular structure in which 22 perturbation clusters connect to 44 gene expression programs. The mGRN reveals different modes of transcriptional rewiring from simple reaction and pathway compensation to rerouting and more complex network coordination. Using metabolic network modelling, we identify a design principle of transcriptional rewiring that we name the compensation-repression (CR) model. The CR model explains most transcriptional responses in metabolic genes and reveals a high level of compensation and repression in five core metabolic functions related to energy and biomass. We provide preliminary evidence that the CR model may also explain transcriptional metabolic rewiring in human cells.
    DOI:  https://doi.org/10.1038/s41586-025-08636-5
  22. Nat Methods. 2025 Feb 27.
    Universal organelle analyzer enables complex analyses with just one click.
      
    DOI:  https://doi.org/10.1038/s41592-025-02613-6
  23. Cell Rep Methods. 2025 Feb 24. pii: S2667-2375(25)00025-6. [Epub ahead of print]5(2): 100989
    Efficient cell-wide mapping of mitochondria in electron microscopic volumes using webKnossos.
    Yi Jiang, Haoyu Wang, Kevin M Boergens, Norman Rzepka, Fangfang Wang, Yunfeng Hua.
      Recent technical advances in volume electron microscopy (vEM) and artificial-intelligence-assisted image processing have facilitated high-throughput quantifications of cellular structures, such as mitochondria, that are ubiquitous and morphologically diversified. A still often-overlooked computational challenge is to assign a cell identity to numerous mitochondrial instances, for which both mitochondrial and cell membrane contouring used to be required. Here, we present a vEM reconstruction procedure (called mito-SegEM) that utilizes virtual-path-based annotation to assign automatically segmented mitochondrial instances at the cellular scale, therefore bypassing the requirement of membrane contouring. The embedded toolset in webKnossos (an open-source online annotation platform) is optimized for fast annotation, visualization, and proofreading of cellular organelle networks. We demonstrate the broad applications of mito-SegEM on volumetric datasets from various tissues, including the brain, intestine, and testis, to achieve an accurate and efficient reconstruction of mitochondria in a use-dependent fashion.
    Keywords:  CP: Cell biology; CP: Imaging; cell biology; image processing; mitochondrion; software; volume electron microscopy
    DOI:  https://doi.org/10.1016/j.crmeth.2025.100989
  24. Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]
    MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
    Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.
      Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.
    Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
  25. Nature. 2025 Feb 26.
    Comparative characterization of human accelerated regions in neurons.
    Xiekui Cui, Han Yang, Charles Cai, Cooper Beaman, Xiaoyu Yang, Hongjiang Liu, Xingjie Ren, Zachary Amador, Ian R Jones, Kathleen C Keough, Meng Zhang, Tyler Fair, Armen Abnousi, Shreya Mishra, Zhen Ye, Ming Hu, Alex A Pollen, Katherine S Pollard, Yin Shen.
      Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees1,2. HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation3. However, their target genes and functional contributions to human brain development remain largely uncharacterized. Here we elucidate the cis-regulatory functions of HARs in human and chimpanzee induced pluripotent stem (iPS) cell-induced excitatory neurons. Using genomic4 and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologues for functional characterization via single-cell CRISPR interference, and demonstrated their species-specific gene regulatory functions. Our findings reveal diverse functional outcomes of HAR-mediated cis-regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPS cell pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we used prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons. Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.
    DOI:  https://doi.org/10.1038/s41586-025-08622-x
  26. Nature. 2025 Feb 26.
    Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.
    Juliette Lesbats, Aurélia Brillac, Julie A Reisz, Parnika Mukherjee, Charlène Lhuissier, Mónica Fernández-Monreal, Jean-William Dupuy, Angèle Sequeira, Gaia Tioli, Celia De La Calle Arregui, Benoît Pinson, Daniel Wendisch, Benoît Rousseau, Alejo Efeyan, Leif Erik Sander, Angelo D'Alessandro, Johan Garaude.
      Macrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation1,2. Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1β secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies.
    DOI:  https://doi.org/10.1038/s41586-025-08629-4
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