bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–12–29
25 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. That Christmas jumper is a marvel of complicated physics.
  2. Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes.
  3. Mutability and hypermutation antagonize immunoglobulin codon optimality.
  4. Broadscale dampening of uncertainty adjustment in the aging brain.
  5. Immunosuppressive dura-derived macrophages in leptomeningeal metastasis.
  6. Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.
  7. Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion.
  8. Digital origins for ancient digits.
  9. Self-maintenance of zonal hepatocytes during adult homeostasis and their complex plasticity upon distinct liver injuries.
  10. Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
  11. Skin layer-specific spatiotemporal assessment of micrometabolism during wound angiogenesis.
  12. Adipocyte-derived ferroptotic signaling mitigates obesity.
  13. RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I.
  14. Digital phenotyping from wearables using AI characterizes psychiatric disorders and identifies genetic associations.
  15. Synthetic organizer cells guide development via spatial and biochemical instructions.
  16. ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.
  17. Perception of a pathogenic signature initiates intergenerational protection.
  18. Quantitative profiling of human translation initiation reveals elements that potently regulate endogenous and therapeutically modified mRNAs.
  19. A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion.
  20. Structural determinants of co-translational protein complex assembly.
  21. Automated Insulin Delivery in Older Adults with Type 1 Diabetes.
  22. Mapping the gene space at single-cell resolution with gene signal pattern analysis.
  23. The α glycolipid rules the NKT cell TCR.
  24. Partial microglial depletion and repopulation exert subtle but differential effects on amyloid pathology at different disease stages.
  25. Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog.
  1. Nature. 2024 Dec 20.
    That Christmas jumper is a marvel of complicated physics.
      
    Keywords:  Physics
    DOI:  https://doi.org/10.1038/d41586-024-04173-9
  2. Cell. 2024 Dec 17. pii: S0092-8674(24)01347-3. [Epub ahead of print]
    Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes.
    Kevin Y Chen, Marco De Giovanni, Ying Xu, Jinping An, Nikhita Kirthivasan, Erick Lu, Kan Jiang, Stephen Brooks, Serena Ranucci, Jiuling Yang, Shuto Kanameishi, Kenji Kabashima, Kevin Brulois, Michael Bscheider, Eugene C Butcher, Jason G Cyster.
      Sustained lymphocyte migration from blood into lymph nodes (LNs) is important for immune responses. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that the oxysterol biosynthetic enzyme cholesterol-25-hydroxylase (Ch25h) is upregulated in LN high endothelial venules during viral infection. Lymphocytes become dependent on oxysterols, generated through a transcellular endothelial-fibroblast metabolic pathway, and the receptor EBI2 for inflamed LN entry. Additionally, Langerhans cells are an oxysterol source. Ch25h is also expressed in inflamed peripheral endothelium, and EBI2 mediates B cell recruitment in a tumor model. Finally, we demonstrate that LN CCL19 is critical in lymphocyte recruitment during inflammation. Thus, our work explains how naive precursor trafficking is sustained in responding LNs, identifies a role for oxysterols in cell recruitment into inflamed tissues, and establishes a logic for the CCR7 two-ligand system.
    Keywords:  CCL19; CCL21; GPR183; cholesterol metabolites; high endothelial venules; lymph nodes; lymphocyte trafficking; stromal cells; tumors; viral infection
    DOI:  https://doi.org/10.1016/j.cell.2024.11.031
  3. Mol Cell. 2024 Dec 12. pii: S1097-2765(24)00988-2. [Epub ahead of print]
    Mutability and hypermutation antagonize immunoglobulin codon optimality.
    Joshua J C McGrath, Juyeon Park, Chloe A Troxell, Jordan C Chervin, Lei Li, Johnathan R Kent, Siriruk Changrob, Yanbin Fu, Min Huang, Nai-Ying Zheng, G Dewey Wilbanks, Sean A Nelson, Jiayi Sun, Giorgio Inghirami, Maria Lucia L Madariaga, George Georgiou, Patrick C Wilson.
      The efficacy of antibody responses is inherently linked to paratope diversity, as generated through V(D)J recombination and somatic hypermutation. Despite this, it is unclear how genetic diversification mechanisms evolved alongside codon optimality and affect antibody expression. Here, we analyze germline immunoglobulin (IG) genes, natural V(D)J repertoires, serum IgG, and monoclonal antibody (mAb) expression through the lens of codon optimality. Germline variable genes (IGVs) exhibit diverse optimality that is inversely related to mutability. Hypermutation deoptimizes heavy-chain (IGH) VDJ repertoires within human tonsils, bone marrow, lymph nodes (including SARS-CoV-2-specific clones), blood (HIV-1-specific clones), mice, and zebrafish. Analyses of mutation-affected codons show that targeting to complementarity-determining regions constrains deoptimization. Germline IGHV optimality correlates with serum variable fragment (VH) usage after influenza vaccination, while synonymous deoptimization attenuated mAb yield. These findings provide unanticipated insights into an antagonistic relationship between diversification mechanisms and codon optimality. Ultimately, the need for diversity takes precedence over that for the most optimal codon usage.
    Keywords:  IGHV; antibody; codon optimality; evolution; immunogenetics; mutability; somatic hypermutation
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.033
  4. Nat Commun. 2024 Dec 23. 15(1): 10717
    Broadscale dampening of uncertainty adjustment in the aging brain.
    Julian Q Kosciessa, Ulrich Mayr, Ulman Lindenberger, Douglas D Garrett.
      The ability to prioritize among input features according to relevance enables adaptive behaviors across the human lifespan. However, relevance often remains ambiguous, and such uncertainty increases demands for dynamic control. While both cognitive stability and flexibility decline during healthy ageing, it is unknown whether aging alters how uncertainty impacts perception and decision-making, and if so, via which neural mechanisms. Here, we assess uncertainty adjustment across the adult lifespan (N = 100; cross-sectional) via behavioral modeling and a theoretically informed set of EEG-, fMRI-, and pupil-based signatures. On the group level, older adults show a broad dampening of uncertainty adjustment relative to younger adults. At the individual level, older individuals whose modulation more closely resembled that of younger adults also exhibit better maintenance of cognitive control. Our results highlight neural mechanisms whose maintenance plausibly enables flexible task-set, perception, and decision computations across the adult lifespan.
    DOI:  https://doi.org/10.1038/s41467-024-55416-2
  5. Nat Cancer. 2024 Dec;5(12): 1791-1792
    Immunosuppressive dura-derived macrophages in leptomeningeal metastasis.
    Michael Kilian, Francisco J Quintana.
      
    DOI:  https://doi.org/10.1038/s43018-024-00859-1
  6. Nat Commun. 2024 Dec 23. 15(1): 10719
    Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.
    Najla El Fissi, Florian A Rosenberger, Kai Chang, Alissa Wilhalm, Tom Barton-Owen, Fynn M Hansen, Zoe Golder, David Alsina, Anna Wedell, Matthias Mann, Patrick F Chinnery, Christoph Freyer, Anna Wredenberg.
      Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention.
    DOI:  https://doi.org/10.1038/s41467-024-55559-2
  7. Nat Cancer. 2024 Dec;5(12): 1940-1961
    Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion.
    Jiaxu Zhao, Rui Zeng, Xiaohui Li, Ying Lu, Zuoyun Wang, Haibao Peng, Hao Chen, Minjie Fu, Ye Zhang, Yang Huang, Wenhan Chen, Xin Wang, Yun Guan, Wei Han, Ruofan Huang, Chengjun Yao, Zhiyong Qin, Lingchao Chen, Liang Chen, Xue Feng, Hanting Yang, Patrícia M R Pereira, Xuemei Tong, Bin Li, Qiangqiang Zhang, Yudan Chi.
      The cerebrospinal fluid (CSF) border accommodates diverse immune cells that permit peripheral cell immunosurveillance. However, the intricate interactions between CSF immune cells and infiltrating cancer cells remain poorly understood. Here we use fate mapping, longitudinal time-lapse imaging and multiomics technologies to investigate the precise origin, cellular crosstalk and molecular landscape of macrophages that contribute to leptomeningeal metastasis (LM) progression. Mechanically, we find that dura-derived LM-associated macrophages (dLAMs) migrate into the CSF in a matrix metalloproteinase 14 (MMP14)-dependent manner. Furthermore, we identify that dLAMs critically require the presence of secreted phosphoprotein 1 (SPP1) in cancer cells for their recruitment, fostering an immunosuppressed microenvironment characterized by T cell exhaustion and inactivation. Conversely, inhibition of the SPP1-MMP14 axis can impede macrophages from bypassing the border barrier, prevent cancer cell growth and improve survival in LM mouse models. Our findings reveal an unexpectedly private source of innate immunity within the meningeal space, shed light on CSF barrier dysfunction dynamics and supply potential targets of clinical immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-024-00858-2
  8. Nature. 2024 Dec 23.
    Digital origins for ancient digits.
      
    Keywords:  Animal behaviour; Anthropology; History
    DOI:  https://doi.org/10.1038/d41586-024-04123-5
  9. Cell Rep. 2024 Dec 24. pii: S2211-1247(24)01444-X. [Epub ahead of print]44(1): 115093
    Self-maintenance of zonal hepatocytes during adult homeostasis and their complex plasticity upon distinct liver injuries.
    Chow Hiang Ang, Philip Arandjelovic, Jinming Cheng, Jicheng Yang, Fusheng Guo, Yuanquan Yu, Sarmilla Nelameham, Lachlan Whitehead, Jiangtao Li, David L Silver, Nick Barker, Jane E Visvader, Pierce K H Chow, Gordon K Smyth, Yunshun Chen, David M Virshup, Nai Yang Fu.
      Hepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2. Pericentral Cyp2e1+ and periportal Gls2+ hepatocytes maintain their own lineage during adult homeostasis, while Cyp2e1+ hepatocytes fuel neonatal liver growth. The Gls2+ and Cyp2e1+ populations can rapidly regenerate one another when one of the populations is severely damaged. Midlobular Ccnd1+ hepatocytes are enriched in the Cyp2e1+ zone in adult liver but have limited contributions to regeneration upon partial hepatectomy and severe pericentral injury. Remarkably, Lgr5+ hepatocytes, a unique Cyp2e1+ subset, contribute significantly to liver replenishment upon periportal injuries. Our findings unravel that zonal hepatocytes mainly self-maintain during homeostasis but exhibit complex plasticity in repair upon injury.
    Keywords:  CP: Stem cell research; cell plasticity; hepatocyte; lineage tracing; liver development; liver homeostasis; liver injury; liver lobule; liver regeneration; liver zonation; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2024.115093
  10. J Cell Biol. 2025 Mar 03. pii: e202403140. [Epub ahead of print]224(3):
    Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
    Alia R Edington, Olivia M Connor, Abigail C Love, Madeleine Marlar-Pavey, Jonathan R Friedman.
      While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear whether internal mitochondrial proteins in metazoans play a direct role in the process. Previously, the yeast inner membrane protein Mdm33 was shown to be required for normal mitochondrial morphology and has been hypothesized to be involved in mitochondrial fission. However, it is unknown whether Mdm33 plays a direct role, and it is not thought to have a mammalian homolog. Here, we use a bioinformatic approach to identify a structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK), whose depletion phenocopies loss of Mdm33. We find that knockdown of CCDC51 also leads to reduced rates of mitochondrial fission. Further, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 overexpression promotes its spatial association with Drp1 and induces mitochondrial fragmentation, suggesting it is a positive effector of mitochondrial fission. Together, our data reveal that Mdm33 and CCDC51 are functionally conserved and suggest that internal mitochondrial proteins are directly involved in at least a subset of mitochondrial fission events in human cells.
    DOI:  https://doi.org/10.1083/jcb.202403140
  11. Commun Biol. 2024 Dec 20. 7(1): 1574
    Skin layer-specific spatiotemporal assessment of micrometabolism during wound angiogenesis.
    Weiye Li, Yu-Hang Liu, Fumimasa Kubo, Sabine Werner, Daniel Razansky.
      Proper oxygen delivery through the microvasculature to injury site is essential to ensure the metabolic cascade during wound healing. Adaptation of vascular structure and oxygenation is key to unravel the regulation of blood perfusion, oxygen distribution and new tissue formation. Yet, visualizing micrometabolic responses at large scale in unperturbed living tissue remains challenging. We studied full-thickness excisional wounds in the mouse dorsal skin in vivo using ultrasound-aided spectroscopic large-scale optoacoustic microscopy. Skin layer-specific vascularization is visualized at capillary resolution over centimeter-scale field-of-view in a non-invasive, label-free manner. Different vascular parameters, including oxygenation, diameter and its irregularity, tortuosity and angular alignment, show distinct spatial and temporal variations. Elevated oxygenation is manifested close to the wound at day 4 with the trend accompanied by reduction in diameter over time. Angular alignment increases over time, indicating a more directed blood supply towards the wound. Our observations indicate that wound angiogenesis initiates as capillary sprouting with enlarged newborn vessels and elevated oxygenation around the wound, with the vessels normalizing in size and oxygenation during remodeling. Our study provides insight into micrometabolic profiles surrounding the healing wound, setting the stage for preclinical studies on oxygen delivery mechanisms in pathological skin conditions and during pharmacological interventions.
    DOI:  https://doi.org/10.1038/s42003-024-07257-4
  12. Cell Metab. 2024 Dec 21. pii: S1550-4131(24)00456-X. [Epub ahead of print]
    Adipocyte-derived ferroptotic signaling mitigates obesity.
    Xue Wang, Qian Wu, Meijuan Zhong, Ying Chen, Yudi Wang, Xin Li, Wenxi Zhao, Chaodong Ge, Xinhui Wang, Yingying Yu, Sisi Yang, Tianyi Wang, Enjun Xie, Wanting Shi, Junxia Min, Fudi Wang.
      Ferroptosis is characterized as an iron-dependent and lipophilic form of cell death. However, it remains unclear what role ferroptosis has in adipose tissue function and activity. Here, we find a lower ferroptotic signature in the adipose tissue of individuals and mice with obesity. We further find that activation of ferroptotic signaling by a non-lethal dose of ferroptosis agonists significantly reduces lipid accumulation in primary adipocytes and high-fat diet (HFD)-fed mice. Notably, adipocyte-specific overexpression of acyl-coenzyme A synthetase long-chain family member 4 (Acsl4) or deletion of ferritin heavy chain (Fth) protects mice from HFD-induced adipose expansion and metabolic disorders via activation of ferroptotic signaling. Mechanistically, we find that 5,15-dihydroxyeicosatetraenoic acid (5,15-DiHETE) activates ferroptotic signaling, resulting in the degradation of hypoxia-inducible factor-1α (HIF1α), thereby derepressing a thermogenic program regulated by the c-Myc-peroxisome proliferator-activated receptor gamma coactivator-1 beta (Pgc1β) pathway. Our findings suggest that activating ferroptosis signaling in adipose tissues might help to prevent and treat obesity and its related metabolic disorders.
    Keywords:  5,15-DiHETE; 5,15-dihydroxyeicosatetraenoic acid; ACSL4; HIF1α; acyl-coenzyme A synthetase long-chain family member 4; adipose tissue; ferritin; ferrology; ferroptosis; ferroptotic signaling; hypoxia-inducible factor-1α; iron metabolism; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.010
  13. EMBO J. 2024 Dec 20.
    RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I.
    Alexander Kirchhoff, Anna-Maria Herzner, Christian Urban, Antonio Piras, Robert Düster, Julia Mahlberg, Agathe Grünewald, Thais M Schlee-Guimarães, Katrin Ciupka, Petro Leka, Robert J Bootz, Christina Wallerath, Charlotte Hunkler, Ann Kristin de Regt, Beate M Kümmerer, Maria Hønholt Christensen, Florian I Schmidt, Min Ae Lee-Kirsch, Claudia Günther, Hiroki Kato, Eva Bartok, Gunther Hartmann, Matthias Geyer, Andreas Pichlmair, Martin Schlee.
      The cytosolic nucleic acid sensors RIG-I and cGAS induce type-I interferon (IFN)-mediated immune responses to RNA and DNA viruses, respectively. So far no connection between the two cytosolic pathways upstream of IKK-like kinase activation has been investigated. Here, we identify heterogeneous nuclear ribonucleoprotein M (hnRNPM) as a positive regulator of IRF3 phosphorylation and type-I IFN induction downstream of both cGAS and RIG-I. Combining interactome analysis with genome editing, we further uncover the RNA-binding protein ELAV-like protein 1 (ELAVL1; also known as human antigen R, HuR) as an hnRNPM interactor. Depletion of hnRNPM or ELAVL1 impairs type-I IFN induction by herpes simplex virus 1 or Sendai virus. In addition, we show that hnRNPM and ELAVL1 interact with TANK-binding kinase 1, IκB kinase ε, IκB kinase β, and NF-κB p65. Our confocal microscopy experiments demonstrate cytosolic and perinuclear interactions between hnRNPM, ELAVL1, and TBK1. Furthermore, pharmacological inhibition of ELAVL1 strongly reduces cytokine release from type-I interferonopathy patient fibroblasts. The RNA-binding proteins hnRNPM and ELAVL1 are the first non-redundant regulators to bridge the cGAS/STING and RIG-I/MAVS pathways. Overall, our study characterizes the hnRNPM-ELAVL1 complex as a novel system promoting antiviral defense, pointing to a potential therapeutic target to reduce auto-inflammation in patients with type-I interferonopathies.
    Keywords:  ELAVL1; IRF3; RIG-I Signaling; cGAS Signaling; hnRNPM
    DOI:  https://doi.org/10.1038/s44318-024-00331-x
  14. Cell. 2024 Dec 18. pii: S0092-8674(24)01329-1. [Epub ahead of print]
    Digital phenotyping from wearables using AI characterizes psychiatric disorders and identifies genetic associations.
    Jason J Liu, Beatrice Borsari, Yunyang Li, Susanna X Liu, Yuan Gao, Xin Xin, Shaoke Lou, Matthew Jensen, Diego Garrido-Martín, Terril L Verplaetse, Garrett Ash, Jing Zhang, Matthew J Girgenti, Walter Roberts, Mark Gerstein.
      Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including ELFN1 and ADORA3, demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics.
    Keywords:  AI; GWAS; brain; deep learning; digital phenotyping; genetics; genomics; personal health; psychiatry; wearable biosensors
    DOI:  https://doi.org/10.1016/j.cell.2024.11.012
  15. Cell. 2024 Dec 11. pii: S0092-8674(24)01323-0. [Epub ahead of print]
    Synthetic organizer cells guide development via spatial and biochemical instructions.
    Toshimichi Yamada, Coralie Trentesaux, Jonathan M Brunger, Yini Xiao, Adam J Stevens, Iain Martyn, Petr Kasparek, Neha P Shroff, Angelica Aguilar, Benoit G Bruneau, Dario Boffelli, Ophir D Klein, Wendell A Lim.
      In vitro development relies primarily on treating progenitor cells with media-borne morphogens and thus lacks native-like spatial information. Here, we engineer morphogen-secreting organizer cells programmed to self-assemble, via cell adhesion, around mouse embryonic stem (ES) cells in defined architectures. By inducing the morphogen WNT3A and its antagonist DKK1 from organizer cells, we generated diverse morphogen gradients, varying in range and steepness. These gradients were strongly correlated with morphogenetic outcomes: the range of minimum-maximum WNT activity determined the resulting range of anterior-to-posterior (A-P) axis cell lineages. Strikingly, shallow WNT activity gradients, despite showing truncated A-P lineages, yielded higher-resolution tissue morphologies, such as a beating, chambered cardiac-like structure associated with an endothelial network. Thus, synthetic organizer cells, which integrate spatial, temporal, and biochemical information, provide a powerful way to systematically and flexibly direct the development of ES or other progenitor cells in different directions within the morphogenetic landscape.
    Keywords:  developmental biology; differential adhesion; gastruloid; morphogen gradient; regenerative medicine; signaling center; synCAMs; synthetic biology; synthetic cell adhesion molecules; synthetic embryos; synthetic organizer
    DOI:  https://doi.org/10.1016/j.cell.2024.11.017
  16. Mol Psychiatry. 2024 Dec 23.
    ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.
    Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman, Maram Ganaiem, Shula Shazman, Paschalis Theotokis, Nikolaos Grigoriadis, Noam Shomron, Illana Gozes.
      Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer's disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer's disease. While autism is more prevalent in boys and Alzheimer's disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp+/-) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41380-024-02879-w
  17. Cell. 2024 Dec 24. pii: S0092-8674(24)01342-4. [Epub ahead of print]
    Perception of a pathogenic signature initiates intergenerational protection.
    Corinne L Pender, Julian G Dishart, Holly K Gildea, Kelsie M Nauta, Emily M Page, Talha F Siddiqi, Shannon S Cheung, Larry Joe, Nicholas O Burton, Andrew Dillin.
      Transmission of immune responses from one generation to the next represents a powerful adaptive mechanism to protect an organism's descendants. Parental infection by the natural C. elegans pathogen Pseudomonas vranovensis induces a protective response in progeny, but the bacterial cues and intergenerational signal driving this response were previously unknown. Here, we find that animals activate a protective stress response program upon exposure to P. vranovensis-derived cyanide and that a metabolic byproduct of cyanide detoxification, β-cyanoalanine, acts as an intergenerational signal to protect progeny from infection. Remarkably, this mechanism does not require direct parental infection; rather, exposure to pathogen-derived volatiles is sufficient to enhance the survival of the next generation, indicating that parental surveillance of environmental cues can activate a protective intergenerational response. Therefore, the mere perception of a pathogen-derived toxin, in this case cyanide, can protect an animal's progeny from future pathogenic challenges.
    Keywords:  C. elegans; CYSL-2; MDT-15; Pseudomonas; SKN-1; cyanide; intergenerational inheritance; pathogen sensing; volatile response; β-cyanoalanine
    DOI:  https://doi.org/10.1016/j.cell.2024.11.026
  18. Mol Cell. 2024 Dec 12. pii: S1097-2765(24)00955-9. [Epub ahead of print]
    Quantitative profiling of human translation initiation reveals elements that potently regulate endogenous and therapeutically modified mRNAs.
    Cole J T Lewis, Li H Xie, Shivani Milind Bhandarkar, Danni Jin, Kyrillos Abdallah, Austin S Draycott, Yixuan Chen, Carson C Thoreen, Wendy V Gilbert.
      mRNA therapeutics offer a potentially universal strategy for the efficient development and delivery of therapeutic proteins. Current mRNA vaccines include chemically modified nucleotides to reduce cellular immunogenicity. Here, we develop an efficient, high-throughput method to measure human translation initiation on therapeutically modified as well as endogenous RNAs. Using systems-level biochemistry, we quantify ribosome recruitment to tens of thousands of human 5' untranslated regions (UTRs) including alternative isoforms and identify sequences that mediate 200-fold effects. We observe widespread effects of coding sequences on translation initiation and identify small regulatory elements of 3-6 nucleotides that are sufficient to potently affect translational output. Incorporation of N1-methylpseudouridine (m1Ψ) selectively enhances translation by specific 5' UTRs that we demonstrate surpass those of current mRNA vaccines. Our approach is broadly applicable to dissecting mechanisms of human translation initiation and engineering more potent therapeutic mRNAs.
    Keywords:  5′ untranslated region; N1-methylpseudouridine; RNA modification; high-throughput screening; ribosome; therapeutic mRNA; translation initiation
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.030
  19. Neuron. 2024 Dec 19. pii: S0896-6273(24)00875-4. [Epub ahead of print]
    A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion.
    Anna Flury, Leen Aljayousi, Hye-Jin Park, Mohammadparsa Khakpour, Jack Mechler, Siaresh Aziz, Jackson D McGrath, Pragney Deme, Colby Sandberg, Fernando González Ibáñez, Olivia Braniff, Thi Ngo, Simira Smith, Matthew Velez, Denice Moran Ramirez, Dvir Avnon-Klein, John W Murray, Jia Liu, Martin Parent, Susana Mingote, Norman J Haughey, Sebastian Werneburg, Marie-Ève Tremblay, Pinar Ayata.
      The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes. Autonomous activation of ISR in microglia is sufficient to induce early features of the ultrastructurally distinct "dark microglia" linked to pathological synapse loss. In AD models, microglial ISR activation exacerbates neurodegenerative pathologies and synapse loss while its inhibition ameliorates them. Mechanistically, we present evidence that ISR activation promotes the secretion of toxic lipids by microglia, impairing neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR or lipid synthesis mitigates synapse loss in AD models. Our results demonstrate that microglial ISR activation represents a neurodegenerative phenotype, which may be sustained, at least in part, by the secretion of toxic lipids.
    Keywords:  Alzheimer’s disease; ISR; dark microglia; integrated stress response; lipid secretion; lipotoxicity; microglia; neurodegeneration; neurotoxic microglia; non-cell-autonomous stress
    DOI:  https://doi.org/10.1016/j.neuron.2024.11.018
  20. Cell. 2024 Dec 18. pii: S0092-8674(24)01330-8. [Epub ahead of print]
    Structural determinants of co-translational protein complex assembly.
    Saurav Mallik, Johannes Venezian, Arseniy Lobov, Meta Heidenreich, Hector Garcia-Seisdedos, Todd O Yeates, Ayala Shiber, Emmanuel D Levy.
      Protein assembly into functional complexes is critical to life's processes. While complex assembly is classically described as occurring between fully synthesized proteins, recent work showed that co-translational assembly is prevalent in human cells. However, the biological basis for the existence of this process and the identity of protein pairs that assemble co-translationally remain unknown. We show that co-translational assembly is governed by structural characteristics of complexes and involves mutually stabilized subunits. Accordingly, co-translationally assembling subunits are unstable in isolation and exhibit synchronized proteostasis with their partner. By leveraging structural signatures and AlphaFold2-based predictions, we accurately predicted co-translational assembly, including pair identities, at proteome scale and across species. We validated our predictions by ribosome profiling, stoichiometry perturbations, and single-molecule RNA-fluorescence in situ hybridization (smFISH) experiments that revealed co-localized mRNAs. This work establishes a fundamental connection between protein structure and the translation process, highlighting the overarching impact of three-dimensional structure on gene expression, mRNA localization, and proteostasis.
    Keywords:  AlphaFold; co-translational assembly; mRNA localization; protein complexes; protein interactions; protein structure; proteostasis; ribosome profiling; single-molecule FISH; translational regulation
    DOI:  https://doi.org/10.1016/j.cell.2024.11.013
  21. NEJM Evid. 2025 Jan;4(1): EVIDoa2400200
    Automated Insulin Delivery in Older Adults with Type 1 Diabetes.
    Yogish C Kudva, Robert J Henderson, Lauren G Kanapka, Ruth S Weinstock, Michael R Rickels, Richard E Pratley, Naomi Chaytor, Kamille Janess, Donna Desjardins, Vishwanath Pattan, Amy J Peleckis, Anna Casu, Shafaq Raza Rizvi, Suzan Bzdick, Keri J Whitaker, Jorge L Jo Kamimoto, Kellee Miller, Craig Kollman, Roy W Beck.
       BACKGROUND: Older adults with type 1 diabetes are at risk for serious hypoglycemia. Automated insulin delivery can reduce risk but has not been sufficiently evaluated in this population.
    METHODS: We conducted a multicenter, randomized crossover trial in adults older than or equal to 65 years of age with type 1 diabetes. Participants completed three 12-week periods of using hybrid closed loop, predictive low-glucose suspend, and sensor-augmented pump insulin delivery in a randomized order. The primary outcome was the percentage of time with continuous glucose monitoring glucose values less than 70 mg/dl.
    RESULTS: Eighty-two participants between 65 and 86 years of age were randomly assigned: 45% were female; the baseline mean (±SD) glycated hemoglobin level was 7.2±0.9%; and the baseline percentage of time with glucose values less than 70 mg/dl was 2.49±1.78%. In the sensor-augmented pump, hybrid closed-loop, and predictive low-glucose suspend periods, percentages of time with glucose less than 70 mg/dl were 2.57±1.54%, 1.58±0.95%, and 1.67±0.96%, respectively. Compared with the sensor-augmented pump results, the mean difference with the hybrid closed-loop system was -1.05 percentage points (95% confidence interval [CI], -1.48 to -0.73 percentage points; P<0.001) and with the predictive low-glucose suspend system it was -0.93 percentage points (95% CI, -1.27 to -0.66 percentage points; P<0.001). Comparing a hybrid closed-loop system with a sensor-augmented pump, time in the range 70 to 180 mg/dl changed by 8.9 percentage points (95% CI, 7.4 to 10.4 percentage points) and the glycated hemoglobin level changed by 0.2 percentage points (95% CI, -0.3 to -0.1 percentage points). Serious adverse events were uncommon. Severe hypoglycemia occurred in 4% or less of participants; there were two hospitalizations for diabetic ketoacidosis.
    CONCLUSIONS: In older adults with type 1 diabetes, automated insulin delivery decreased hypoglycemia compared with sensor-augmented pump delivery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number: NCT04016662.).
    DOI:  https://doi.org/10.1056/EVIDoa2400200
  22. Nat Comput Sci. 2024 Dec;4(12): 955-977
    Mapping the gene space at single-cell resolution with gene signal pattern analysis.
    Aarthi Venkat, Sam Leone, Scott E Youlten, Eric Fagerberg, John Attanasio, Nikhil S Joshi, Michael Perlmutter, Smita Krishnaswamy.
      In single-cell sequencing analysis, several computational methods have been developed to map the cellular state space, but little has been done to map or create embeddings of the gene space. Here we formulate the gene embedding problem, design tasks with simulated single-cell data to evaluate representations, and establish ten relevant baselines. We then present a graph signal processing approach, called gene signal pattern analysis (GSPA), that learns rich gene representations from single-cell data using a dictionary of diffusion wavelets on the cell-cell graph. GSPA enables characterization of genes based on their patterning and localization on the cellular manifold. We motivate and demonstrate the efficacy of GSPA as a framework for diverse biological tasks, such as capturing gene co-expression modules, condition-specific enrichment and perturbation-specific gene-gene interactions. Then we showcase the broad utility of gene representations derived from GSPA, including for cell-cell communication (GSPA-LR), spatial transcriptomics (GSPA-multimodal) and patient response (GSPA-Pt) analysis.
    DOI:  https://doi.org/10.1038/s43588-024-00734-0
  23. J Exp Med. 2025 Feb 03. pii: e20242099. [Epub ahead of print]222(2):
    The α glycolipid rules the NKT cell TCR.
    Mitchell Kronenberg, Gabriel Ascui.
      In this issue of JEM, Hosono et al. (https://doi.org/10.1084/jem.20240728) characterize a putative self- glycolipid that engages the iNKT cell TCR when bound to CD1d. The expression and distribution of this compound helps to explain some of the unusual properties of invariant NKT cells.
    DOI:  https://doi.org/10.1084/jem.20242099
  24. Sci Rep. 2024 Dec 28. 14(1): 30912
    Partial microglial depletion and repopulation exert subtle but differential effects on amyloid pathology at different disease stages.
    L H D Le, M K O'Banion, A K Majewska.
      Colony-stimulating factor-1-receptor (CSF1R) inhibitors have been widely used to rapidly deplete microglia from the brain, allowing the remaining microglia population to self-renew and repopulate. These new-born microglia are thought to be "rejuvenated" and have been shown to be beneficial in several disease contexts and in normal aging. Their role in Alzheimer's disease (AD) is thus of great interest as they represent a potential disease-modifying therapy. Here, we explored the differential effects of microglial depletion and repopulation during amyloid pathology progression using 5xFAD mice. We utilized the CSF1R inhibitor PLX3397 to induce microglial self-renewal and tracked microglia-plaque dynamics with in vivo imaging. We observed transient improvement in plaque burden on different timescales depending on the animal's age. While the improvement in plaque burden did not persist in any age group, renewing microglia during mid- to late-pathology might still be beneficial as we observed a potential improvement in microglial sensitivity to noradrenergic signaling. Altogether, our findings provide further insights into the therapeutic potential of microglial renewal in AD.
    DOI:  https://doi.org/10.1038/s41598-024-81910-0
  25. Nat Aging. 2024 Dec 27.
    Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog.
    Sophia Magkouta, Dimitris Veroutis, Angelos Papaspyropoulos, Maria Georgiou, Nikolaos Lougiakis, Natassa Pippa, Sophia Havaki, Anastasia Palaiologou, Dimitris-Foivos Thanos, Konstantinos Kambas, Nefeli Lagopati, Nikos Boukos, Nicole Pouli, Panagiotis Marakos, Athanassios Kotsinas, Dimitris Thanos, Konstantinos Evangelou, Fotios Sampaziotis, Constantin Tamvakopoulos, Stergios Pispas, Russell Petty, Nicholas Kotopoulos, Vassilis G Gorgoulis.
      The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond. As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.
    DOI:  https://doi.org/10.1038/s43587-024-00747-4
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