bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒08‒25
35 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A balancing act in the control of self-antigen expression.
  2. Inner membrane turns inside out to exit mitochondrial organelles.
  3. Tumor-derived RHOA mutants interact with effectors in the GDP-bound state.
  4. PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
  5. Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.
  6. Non-human primate model of long-COVID identifies immune associates of hyperglycemia.
  7. Regulated insulin secretion from human and mouse islets exclusively composed of β-cells.
  8. A roadmap to the molecular human linking multiomics with population traits and diabetes subtypes.
  9. The partitioning of TCR repertoires by thymic selection.
  10. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.
  11. Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.
  12. High-fat feeding drives the intestinal production and assembly of C16:0 ceramides in chylomicrons.
  13. Child with ultra-rare disease gets a treatment just for her.
  14. Cells poised to divide can delay their commitment to proliferate.
  15. Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
  16. Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
  17. High-sensitivity in situ capture of endogenous RNA-protein interactions in fixed cells and primary tissues.
  18. Placebo effect involves unexpected brain regions.
  19. Regulated and adaptive in vivo insulin secretion from islets only containing β-cells.
  20. BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses.
  21. Five ways the brain can age: 50,000 scans reveal possible patterns of damage.
  22. Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.
  23. What will it take to open South Korean research to the world?
  24. WebAtlas pipeline for integrated single-cell and spatial transcriptomic data.
  25. 'There's a lot of privilege masquerading as merit': why inclusion matters in academia.
  26. Forever young: what science can and can't tell us about cheating ageing.
  27. High-resolution flexible iontronic skins for both negative and positive pressure measurement in room temperature wind tunnel applications.
  28. A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.
  29. A core proteome profile unites mouse models and patients in Alzheimer disease.
  30. The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
  31. Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure.
  32. Structural insights into i-motif DNA structures in sequences from the insulin-linked polymorphic region.
  33. Alzheimer's and metabolism wed with IDO1.
  34. A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.
  35. Hopes dashed for drug aimed at monkeypox virus spreading in Africa.
  1. Nat Immunol. 2024 Aug 21.
    A balancing act in the control of self-antigen expression.
    Michael R Waterfield, Mark S Anderson.
      
    DOI:  https://doi.org/10.1038/s41590-024-01940-8
  2. Nature. 2024 Aug;632(8027): 987-988
    Inner membrane turns inside out to exit mitochondrial organelles.
    David Pla-Martín, Andreas S Reichert.
      
    Keywords:  Biochemistry; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02528-w
  3. Nat Commun. 2024 Aug 21. 15(1): 7176
    Tumor-derived RHOA mutants interact with effectors in the GDP-bound state.
    Yuan Lin, Theresa A Ramelot, Simge Senyuz, Attila Gursoy, Hyunbum Jang, Ruth Nussinov, Ozlem Keskin, Yi Zheng.
      RHOA mutations are found at diverse residues in various cancer types, implying mutation- and cell-specific mechanisms of tumorigenesis. Here, we focus on the underlying mechanisms of two gain-of-function RHOA mutations, A161P and A161V, identified in adult T-cell leukemia/lymphoma. We find that RHOAA161P and RHOAA161V are both fast-cycling mutants with increased guanine nucleotide dissociation/association rates compared with RHOAWT and show reduced GTP-hydrolysis activity. Crystal structures reveal an altered nucleotide association in RHOAA161P and an open nucleotide pocket in RHOAA161V. Both mutations perturb the dynamic properties of RHOA switch regions and shift the conformational landscape important for RHOA activity, as shown by 31P NMR and molecular dynamics simulations. Interestingly, RHOAA161P and RHOAA161V can interact with effectors in the GDP-bound state. 1H-15N HSQC NMR spectra support the existence of an active population in RHOAA161V-GDP. The distinct interaction mechanisms resulting from the mutations likely favor an RHOAWT-like "ON" conformation, endowing GDP-bound state effector binding activity.
    DOI:  https://doi.org/10.1038/s41467-024-51445-z
  4. Sci Immunol. 2024 Aug 23. 9(98): eadn2717
    PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
    Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho.
      The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.
    DOI:  https://doi.org/10.1126/sciimmunol.adn2717
  5. Sci Immunol. 2024 Aug 23. 9(98): eadk3469
    Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.
    Merve Aksöz, Grigore-Aristide Gafencu, Bilyana Stoilova, Mario Buono, Ying Zhang, Sven Turkalj, Yiran Meng, Niels Asger Jakobsen, Marlen Metzner, Sally-Ann Clark, Ryan Beveridge, Supat Thongjuea, Paresh Vyas, Claus Nerlov.
      Hematopoietic stem cells (HSCs) reconstitute multilineage human hematopoiesis after clinical bone marrow (BM) transplantation and are the cells of origin of some hematological malignancies. Although HSCs provide multilineage engraftment, individual murine HSCs are lineage biased and contribute unequally to blood cell lineages. Here, we performed high-throughput single-cell RNA sequencing in mice after xenograft with molecularly barcoded adult human BM HSCs. We demonstrated that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identified platelet-biased and multilineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young and aged BM showed that both the proportion of platelet-biased HSCs and their level of transcriptional platelet priming increase with age. Therefore, platelet-biased HSCs and their increased prevalence and transcriptional platelet priming during aging are conserved features of mammalian evolution.
    DOI:  https://doi.org/10.1126/sciimmunol.adk3469
  6. Nat Commun. 2024 Aug 20. 15(1): 6664
    Non-human primate model of long-COVID identifies immune associates of hyperglycemia.
    Clovis S Palmer, Chrysostomos Perdios, Mohamed Abdel-Mohsen, Joseph Mudd, Prasun K Datta, Nicholas J Maness, Gabrielle Lehmicke, Nadia Golden, Linh Hellmers, Carol Coyne, Kristyn Moore Green, Cecily Midkiff, Kelsey Williams, Rafael Tiburcio, Marissa Fahlberg, Kyndal Boykin, Carys Kenway, Kasi Russell-Lodrigue, Angela Birnbaum, Rudolf Bohm, Robert Blair, Jason P Dufour, Tracy Fischer, Ahmad A Saied, Jay Rappaport.
      Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are manifestations of the post-acute sequelae of SARS-CoV-2. Our understanding of metabolic decline after acute COVID-19 remains unclear due to the lack of animal models. Here, we report a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 using SARS-CoV-2 infected African green monkeys. Using this model, we identify a dysregulated blood chemokine signature during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. Hyperglycemia also correlates with liver glycogen levels, but there is no evidence of substantial long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the African green monkey model exhibits important similarities to humans and can be utilized to assess therapeutic candidates to combat COVID-related metabolic defects.
    DOI:  https://doi.org/10.1038/s41467-024-50339-4
  7. Nat Metab. 2024 Aug 21.
    Regulated insulin secretion from human and mouse islets exclusively composed of β-cells.
      
    DOI:  https://doi.org/10.1038/s42255-024-01117-5
  8. Nat Commun. 2024 Aug 19. 15(1): 7111
    A roadmap to the molecular human linking multiomics with population traits and diabetes subtypes.
    Anna Halama, Shaza Zaghlool, Gaurav Thareja, Sara Kader, Wadha Al Muftah, Marjonneke Mook-Kanamori, Hina Sarwath, Yasmin Ali Mohamoud, Nisha Stephan, Sabine Ameling, Maja Pucic Baković, Jan Krumsiek, Cornelia Prehn, Jerzy Adamski, Jochen M Schwenk, Nele Friedrich, Uwe Völker, Manfred Wuhrer, Gordan Lauc, S Hani Najafi-Shoushtari, Joel A Malek, Johannes Graumann, Dennis Mook-Kanamori, Frank Schmidt, Karsten Suhre.
      In-depth multiomic phenotyping provides molecular insights into complex physiological processes and their pathologies. Here, we report on integrating 18 diverse deep molecular phenotyping (omics-) technologies applied to urine, blood, and saliva samples from 391 participants of the multiethnic diabetes Qatar Metabolomics Study of Diabetes (QMDiab). Using 6,304 quantitative molecular traits with 1,221,345 genetic variants, methylation at 470,837 DNA CpG sites, and gene expression of 57,000 transcripts, we determine (1) within-platform partial correlations, (2) between-platform mutual best correlations, and (3) genome-, epigenome-, transcriptome-, and phenome-wide associations. Combined into a molecular network of > 34,000 statistically significant trait-trait links in biofluids, our study portrays "The Molecular Human". We describe the variances explained by each omics in the phenotypes (age, sex, BMI, and diabetes state), platform complementarity, and the inherent correlation structures of multiomics data. Further, we construct multi-molecular network of diabetes subtypes. Finally, we generated an open-access web interface to "The Molecular Human" ( http://comics.metabolomix.com ), providing interactive data exploration and hypotheses generation possibilities.
    DOI:  https://doi.org/10.1038/s41467-024-51134-x
  9. J Exp Med. 2024 Oct 07. pii: e20230897. [Epub ahead of print]221(10):
    The partitioning of TCR repertoires by thymic selection.
    Wan-Lin Lo, Eric S Huseby.
      αβ T cells are critical components of the adaptive immune system; they maintain tissue and immune homeostasis during health, provide sterilizing immunity after pathogen infection, and are capable of eliminating transformed tumor cells. Fundamental to these distinct functions is the ligand specificity of the unique antigen receptor expressed on each mature T cell (TCR), which endows lymphocytes with the ability to behave in a cell-autonomous, disease context-specific manner. Clone-specific behavioral properties are initially established during T cell development when thymocytes use TCR recognition of major histocompatibility complex (MHC) and MHC-like ligands to instruct survival versus death and to differentiate into a plethora of inflammatory and regulatory T cell lineages. Here, we review the ligand specificity of the preselection thymocyte repertoire and argue that developmental stage-specific alterations in TCR signaling control cross-reactivity and foreign versus self-specificity of T cell sublineages.
    DOI:  https://doi.org/10.1084/jem.20230897
  10. Science. 2024 Aug 23. 385(6711): eabm6131
    Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.
    Paras S Minhas, Jeffrey R Jones, Amira Latif-Hernandez, Yuki Sugiura, Aarooran S Durairaj, Qian Wang, Siddhita D Mhatre, Takeshi Uenaka, Joshua Crapser, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Ling Liu, Praveena Prasad, Brenita C Jenkins, Yeonglong Albert Ay, Matthew Matrongolo, Ryan Goodman, Traci Newmeyer, Kelly Heard, Austin Kang, Edward N Wilson, Tao Yang, Erik M Ullian, Geidy E Serrano, Thomas G Beach, Marius Wernig, Joshua D Rabinowitz, Makoto Suematsu, Frank M Longo, Melanie R McReynolds, Fred H Gage, Katrin I Andreasson.
      Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.
    DOI:  https://doi.org/10.1126/science.abm6131
  11. Nat Commun. 2024 Aug 22. 15(1): 7215
    Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.
    Chih-Hao Wang, Tadataka Tsuji, Li-Hong Wu, Cheng-Ying Yang, Tian Lian Huang, Mari Sato, Farnaz Shamsi, Yu-Hua Tseng.
      Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-51579-0
  12. Sci Adv. 2024 Aug 23. 10(34): eadp2254
    High-fat feeding drives the intestinal production and assembly of C16:0 ceramides in chylomicrons.
    Michael Sm Mah, Enyuan Cao, Dovile Anderson, Alistair Escott, Surafel Tegegne, Gracia Gracia, Joel Schmitz, Susanne Brodesser, Colby Zaph, Darren J Creek, Jiwon Hong, John A Windsor, Anthony Rj Phillips, Natalie L Trevaskis, Mark A Febbraio, Sarah M Turpin-Nolan.
      Consumption of a diet rich in saturated fat increases lipid absorption from the intestine, assembly into chylomicrons, and delivery to metabolic tissues via the lymphatic and circulatory systems. Accumulation of ceramide lipids, composed of sphingosine and a fatty acid, in metabolic tissues contributes to the pathogenesis of cardiovascular diseases, type 2 diabetes mellitus and cancer. Using a mesenteric lymph duct cannulated rat model, we showed that ceramides are generated by the intestine and assembled into chylomicrons, which are transported via the mesenteric lymphatic system. A lipidomic screen of intestinal-derived chylomicrons identified a diverse range of fatty acid, sphingolipid, and glycerolipid species that have not been previously detected in chylomicrons, including the metabolically deleterious C16:0 ceramide that increased in response to high-fat feeding in rats and human high-lipid meal replacement enteral feeding. In conclusion, high-fat feeding increases the export of intestinal-derived C16:0 ceramide in chylomicrons, identifying a potentially unknown mechanism through which ceramides are transported systemically to contribute to metabolic dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.adp2254
  13. Nature. 2024 Aug 16.
    Child with ultra-rare disease gets a treatment just for her.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02611-2
  14. Nature. 2024 Aug 21.
    Cells poised to divide can delay their commitment to proliferate.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02640-x
  15. Nature. 2024 Aug 21.
    Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
    Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.
      Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41586-024-07835-w
  16. Sci Adv. 2024 Aug 23. 10(34): eadn6016
    Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
    Alexandros C Kokotos, Aldana M Antoniazzi, Santiago R Unda, Myung Soo Ko, Daehun Park, David Eliezer, Michael G Kaplitt, Pietro De Camilli, Timothy A Ryan.
      Although certain drivers of familial Parkinson's disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics. In vivo, viral expression of PGK1 confers protection of striatal dopamine axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD-associated pathologies and point to improving neuronal adenosine 5'-triphosphate production kinetics as a promising path forward in PD therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.adn6016
  17. Nat Commun. 2024 Aug 16. 15(1): 7067
    High-sensitivity in situ capture of endogenous RNA-protein interactions in fixed cells and primary tissues.
    Qishan Liang, Tao Yu, Eric Kofman, Pratibha Jagannatha, Kevin Rhine, Brian A Yee, Kevin D Corbett, Gene W Yeo.
      RNA-binding proteins (RBPs) have pivotal functions in RNA metabolism, but current methods are limited in retrieving RBP-RNA interactions within endogenous biological contexts. Here, we develop INSCRIBE (IN situ Sensitive Capture of RNA-protein Interactions in Biological Environments), circumventing the challenges through in situ RNA labeling by precisely directing a purified APOBEC1-nanobody fusion to the RBP of interest. This method enables highly specific RNA-binding site identification across a diverse range of fixed biological samples such as HEK293T cells and mouse brain tissue and accurately identifies the canonical binding motifs of RBFOX2 (UGCAUG) and TDP-43 (UGUGUG) in native cellular environments. Applicable to any RBP with available primary antibodies, INSCRIBE enables sensitive capture of RBP-RNA interactions from ultra-low input equivalent to ~5 cells. The robust, versatile, and sensitive INSCRIBE workflow is particularly beneficial for precious tissues such as clinical samples, empowering the exploration of genuine RBP-RNA interactions in RNA-related disease contexts.
    DOI:  https://doi.org/10.1038/s41467-024-50363-4
  18. Nature. 2024 Aug;632(8027): 990-991
    Placebo effect involves unexpected brain regions.
    Jeffrey S Mogil.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02373-x
  19. Nat Metab. 2024 Aug 21.
    Regulated and adaptive in vivo insulin secretion from islets only containing β-cells.
    Marta Perez-Frances, Eva Bru-Tari, Christian Cohrs, Maria Valentina Abate, Léon van Gurp, Kenichiro Furuyama, Stephan Speier, Fabrizio Thorel, Pedro L Herrera.
      Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing 'non-β-cells' (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ.
    DOI:  https://doi.org/10.1038/s42255-024-01114-8
  20. Immunity. 2024 Aug 14. pii: S1074-7613(24)00370-4. [Epub ahead of print]
    BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses.
    Sarah J Sun, Raúl Aguirre-Gamboa, L Charlotte J de Bree, Joaquin Sanz, Anne Dumaine, Walter J F M van der Velden, Leo A B Joosten, Shabaana Khader, Maziar Divangahi, Mihai G Netea, Luis B Barreiro.
      Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1β secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity.
    Keywords:  BCG vaccination; hematopoietic stem cells; innate immunity; single-cell genomics; trained immunity
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.021
  21. Nature. 2024 Aug 19.
    Five ways the brain can age: 50,000 scans reveal possible patterns of damage.
    Michael Eisenstein.
      
    Keywords:  Ageing; Brain; Machine learning; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02692-z
  22. Nat Commun. 2024 Aug 21. 15(1): 7173
    Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.
    Laurent L'homme, Benan Pelin Sermikli, Joel T Haas, Sébastien Fleury, Sandrine Quemener, Valentine Guinot, Emelie Barreby, Nathalie Esser, Robert Caiazzo, Hélène Verkindt, Benjamin Legendre, Violeta Raverdy, Lydie Cheval, Nicolas Paquot, Jacques Piette, Sylvie Legrand-Poels, Myriam Aouadi, François Pattou, Bart Staels, David Dombrowicz.
      Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.
    DOI:  https://doi.org/10.1038/s41467-024-51078-2
  23. Nature. 2024 Aug;632(8026): S2-S5
    What will it take to open South Korean research to the world?
    Raphael Rashid.
      
    Keywords:  Government; Institutions; Policy; Research management
    DOI:  https://doi.org/10.1038/d41586-024-02685-y
  24. Nat Methods. 2024 Aug 19.
    WebAtlas pipeline for integrated single-cell and spatial transcriptomic data.
    Tong Li, David Horsfall, Daniela Basurto-Lozada, Kenny Roberts, Martin Prete, John E G Lawrence, Peng He, Elisabeth Tuck, Josh Moore, Aybuke Kupcu Yoldas, Kolawole Babalola, Matthew Hartley, Shila Ghazanfar, Sarah A Teichmann, Muzlifah Haniffa, Omer Ali Bayraktar.
      
    DOI:  https://doi.org/10.1038/s41592-024-02371-x
  25. Nature. 2024 Aug 19.
    'There's a lot of privilege masquerading as merit': why inclusion matters in academia.
    Esme Hedley.
      
    Keywords:  Careers; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-02698-7
  26. Nature. 2024 Aug;632(8026): 729-730
    Forever young: what science can and can't tell us about cheating ageing.
    Jan H J Hoeijmakers.
      
    Keywords:  Ageing; Genetics; Genomics; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02677-y
  27. Nat Commun. 2024 Aug 17. 15(1): 7094
    High-resolution flexible iontronic skins for both negative and positive pressure measurement in room temperature wind tunnel applications.
    Jingxiao Wang, Xueyong Wei, Junli Shi, Ningning Bai, Xiao Wan, Bing Li, Yingchun Chen, Zhuangde Jiang, Chuan Fei Guo.
      Flexible skins that can be laminated on curved surfaces are a desired form for wind pressure measurement. Sensors for such applications need to detect both negative and positive wind pressure with ultrahigh pressure resolution over a wide range up to 600 kPa, whereas existing flexible sensors are unsatisfactory to such demands. Here, we report a flexible skin containing two iontronic pressure sensors for negative pressure and positive pressure sensing, respectively, and show the potential of the skin for pressure measurement in room temperature wind tunnels. We control the contact state of iontronic interface of a sensor to introduce a pre-pressure that enables negative pressure sensing, exhibiting a pressure resolution of -20 Pa (0.025%) within a broad pressure regime (from -100 kPa to -10 Pa). The other sensor for positive pressure sensing exhibits a pressure-resolution of 100 Pa (0.025%) over 600 kPa, in addition to a wide frequency bandwidth up to 400 Hz. The skin with the two types of sensors can be attached on curved surfaces of wing surface for pressure measurement at various free stream velocities and angles of attack. This study provides a promising technology of using flexible skins for pressure measurement in aviation applications.
    DOI:  https://doi.org/10.1038/s41467-024-51415-5
  28. Nat Commun. 2024 Aug 20. 15(1): 6902
    A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.
    Jeffrey S Berger, Macintosh G Cornwell, Yuhe Xia, Matthew A Muller, Nathaniel R Smilowitz, Jonathan D Newman, Florencia Schlamp, Caron B Rockman, Kelly V Ruggles, Deepak Voora, Judith S Hochman, Tessa J Barrett.
      Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction.
    DOI:  https://doi.org/10.1038/s41467-024-50994-7
  29. Cell Rep Med. 2024 Aug 20. pii: S2666-3791(24)00404-X. [Epub ahead of print]5(8): 101683
    A core proteome profile unites mouse models and patients in Alzheimer disease.
    Grigoria Tsaka, Frederic Rousseau, Joost Schymkowitz.
      Levites et al. demonstrate that mouse models of Alzheimer disease (AD), exhibiting amyloid-beta (Αβ) plaque formation, share Αβ responsome proteins with humans. Their work underscores the value of these models in studying Αβ aggregation, cellular vulnerability, and early-stage AD pathology.
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101683
  30. Nat Commun. 2024 Aug 21. 15(1): 7121
    The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
    Marta Llovera, Leonor Gouveia, Antonio Zorzano, Daniel Sanchis.
      
    DOI:  https://doi.org/10.1038/s41467-024-51447-x
  31. Nat Commun. 2024 Aug 22. 15(1): 7027
    Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure.
    Pawel Lisowski, Selene Lickfett, Agnieszka Rybak-Wolf, Carmen Menacho, Stephanie Le, Tancredi Massimo Pentimalli, Sofia Notopoulou, Werner Dykstra, Daniel Oehler, Sandra López-Calcerrada, Barbara Mlody, Maximilian Otto, Haijia Wu, Yasmin Richter, Philipp Roth, Ruchika Anand, Linda A M Kulka, David Meierhofer, Petar Glazar, Ivano Legnini, Narasimha Swamy Telugu, Tobias Hahn, Nancy Neuendorf, Duncan C Miller, Annett Böddrich, Amin Polzin, Ertan Mayatepek, Sebastian Diecke, Heidi Olzscha, Janine Kirstein, Cristina Ugalde, Spyros Petrakis, Sidney Cambridge, Nikolaus Rajewsky, Ralf Kühn, Erich E Wanker, Josef Priller, Jakob J Metzger, Alessandro Prigione.
      Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.
    DOI:  https://doi.org/10.1038/s41467-024-51216-w
  32. Nat Commun. 2024 Aug 20. 15(1): 7119
    Structural insights into i-motif DNA structures in sequences from the insulin-linked polymorphic region.
    Dilek Guneri, Effrosyni Alexandrou, Kamel El Omari, Zuzana Dvořáková, Rupesh V Chikhale, Daniel T S Pike, Christopher A Waudby, Christopher J Morris, Shozeb Haider, Gary N Parkinson, Zoë A E Waller.
      The insulin-linked polymorphic region is a variable number of tandem repeats region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of tandem repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression. Here we show that different sequence variants of the insulin linked polymorphic region form different DNA structures in vitro. Additionally, reporter genes in cellulo indicate that insulin expression may change depending on which DNA structures form. We report the crystal structure and dynamics of an intramolecular i-motif, which reveal sequences within the loop regions forming additional stabilising interactions that are critical to formation of stable i-motif structures. The outcomes of this work reveal the detail in formation of stable i-motif DNA structures, with potential for rational based drug design for compounds to target i-motif DNA.
    DOI:  https://doi.org/10.1038/s41467-024-50553-0
  33. Science. 2024 Aug 23. 385(6711): 826-827
    Alzheimer's and metabolism wed with IDO1.
    Lance A Johnson, Shannon L Macauley.
      Kynurenine pathway inhibition reverses deficits in Alzheimer's mouse models.
    DOI:  https://doi.org/10.1126/science.adr5836
  34. Nat Commun. 2024 Aug 19. 15(1): 7113
    A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.
    Teodora Nicola, Nancy Wenger, Xin Xu, Michael Evans, Luhua Qiao, Gabriel Rezonzew, Youfeng Yang, Tamas Jilling, Camilla Margaroli, Kristopher Genschmer, Kent Willis, Namasivayam Ambalavanan, J Edwin Blalock, Amit Gaggar, Charitharth Vivek Lal.
      Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51169-0
  35. Nature. 2024 Aug 16.
    Hopes dashed for drug aimed at monkeypox virus spreading in Africa.
    Mariana Lenharo.
      
    Keywords:  Medical research; Public health; Virology
    DOI:  https://doi.org/10.1038/d41586-024-02694-x
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