bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–06–11
thirty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Heritable transcriptional defects from aberrations of nuclear architecture.
  2. Dynamic measures of insulin action identify genetic determinants of dysglycemia.
  3. Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation.
  4. Epigenetic dysregulation from chromosomal transit in micronuclei.
  5. A cytosolic surveillance mechanism activates the mitochondrial UPR.
  6. A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver.
  7. The technological landscape and applications of single-cell multi-omics.
  8. Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease.
  9. Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice.
  10. Taurine deficiency as a driver of aging.
  11. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.
  12. Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.
  13. Linking genome structures to functions by simultaneous single-cell Hi-C and RNA-seq.
  14. Distinct longevity mechanisms across and within species and their association with aging.
  15. Taurine linked with healthy aging.
  16. Requirements of IL-4 during the Generation of B Cell Memory.
  17. Defining blood-induced microglia functions in neurodegeneration through multiomic profiling.
  18. ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal.
  19. TRIM5α recruits HDAC1 to p50 and Sp1 and promotes H3K9 deacetylation at the HIV-1 LTR.
  20. Does shingles vaccination cut dementia risk? Large study hints at a link.
  21. Super-resolved trajectory-derived nanoclustering analysis using spatiotemporal indexing.
  22. Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis.
  23. Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions.
  24. STAT1 is required to establish but not maintain interferon-γ-induced transcriptional memory.
  25. THRONCAT: metabolic labeling of newly synthesized proteins using a bioorthogonal threonine analog.
  26. Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner.
  27. Neuroprotective protein ADNP-dependent histone remodeling complex promotes T helper 2 immune cell differentiation.
  28. Architecture and dynamics of a desmosome-endoplasmic reticulum complex.
  29. Tox4 regulates transcriptional elongation and reinitiation during murine T cell development.
  30. Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity.
  31. Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging.
  32. A CMOS-based highly scalable flexible neural electrode interface.
  33. CaMK1D signalling in AgRP neurons promotes ghrelin-mediated food intake.
  34. Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.
  35. In-vivo programmable acoustic manipulation of genetically engineered bacteria.
  36. Is nicotine bad for long-term health? Scientists aren't sure yet.
  1. Nature. 2023 Jun 07.
    Heritable transcriptional defects from aberrations of nuclear architecture.
    Stamatis Papathanasiou, Nikos A Mynhier, Shiwei Liu, Gregory Brunette, Ema Stokasimov, Etai Jacob, Lanting Li, Caroline Comenho, Bas van Steensel, Jason D Buenrostro, Cheng-Zhong Zhang, David Pellman.
      Transcriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance1-3. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer4,5, as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.
    DOI:  https://doi.org/10.1038/s41586-023-06157-7
  2. Nat Genet. 2023 Jun 08.
    Dynamic measures of insulin action identify genetic determinants of dysglycemia.
    Miriam S Udler.
      
    DOI:  https://doi.org/10.1038/s41588-023-01346-6
  3. Nat Commun. 2023 Jun 06. 14(1): 3298
    Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation.
    Lin Du, Bo Man Ho, Linbin Zhou, Yolanda Wong Ying Yip, Jing Na He, Yingying Wei, Clement C Tham, Sun On Chan, Andrew V Schally, Chi Pui Pang, Jian Li, Wai Kit Chu.
      Dysregulation of Th17 cell differentiation and pathogenicity contributes to multiple autoimmune and inflammatory diseases. Previously growth hormone releasing hormone receptor (GHRH-R) deficient mice have been reported to be less susceptible to the induction of experimental autoimmune encephalomyelitis. Here, we show GHRH-R is an important regulator of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation. We find that GHRH-R is not expressed in naïve CD4+ T cells, while its expression is induced throughout Th17 cell differentiation in vitro. Mechanistically, GHRH-R activates the JAK-STAT3 pathway, increases the phosphorylation of STAT3, enhances both non-pathogenic and pathogenic Th17 cell differentiation and promotes the gene expression signatures of pathogenic Th17 cells. Enhancing this signaling by GHRH agonist promotes, while inhibiting this signaling by GHRH antagonist or GHRH-R deficiency reduces, Th17 cell differentiation in vitro and Th17 cell-mediated ocular and neural inflammation in vivo. Thus, GHRH-R signaling functions as a critical factor that regulates Th17 cell differentiation and Th17 cell-mediated autoimmune ocular and neural inflammation.
    DOI:  https://doi.org/10.1038/s41467-023-39023-1
  4. Nature. 2023 Jun 07.
    Epigenetic dysregulation from chromosomal transit in micronuclei.
    Albert S Agustinus, Duaa Al-Rawi, Bhargavi Dameracharla, Ramya Raviram, Bailey S C L Jones, Stephanie Stransky, Lorenzo Scipioni, Jens Luebeck, Melody Di Bona, Danguole Norkunaite, Robert M Myers, Mercedes Duran, Seongmin Choi, Britta Weigelt, Shira Yomtoubian, Andrew McPherson, Eléonore Toufektchan, Kristina Keuper, Paul S Mischel, Vivek Mittal, Sohrab P Shah, John Maciejowski, Zuzana Storchova, Enrico Gratton, Peter Ly, Dan Landau, Mathieu F Bakhoum, Richard P Koche, Simone Sidoli, Vineet Bafna, Yael David, Samuel F Bakhoum.
      Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.
    DOI:  https://doi.org/10.1038/s41586-023-06084-7
  5. Nature. 2023 Jun 07.
    A cytosolic surveillance mechanism activates the mitochondrial UPR.
    F X Reymond Sutandy, Ines Gößner, Georg Tascher, Christian Münch.
      The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.
    DOI:  https://doi.org/10.1038/s41586-023-06142-0
  6. Nat Aging. 2023 Jun 05.
    A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver.
    Chenbo Ding, Zhibin Yu, Esen Sefik, Jing Zhou, Eleanna Kaffe, Gaoyang Wang, Bin Li, Richard A Flavell, Weiguo Hu, Youqiong Ye, Hua-Bing Li.
      Regulatory T (Treg) cells modulate several aging-related liver diseases. However, the molecular mechanisms regulating Treg function in this context are unknown. Here we identified a long noncoding RNA, Altre (aging liver Treg-expressed non-protein-coding RNA), which was specifically expressed in the nucleus of Treg cells and increased with aging. Treg-specific deletion of Altre did not affect Treg homeostasis and function in young mice but caused Treg metabolic dysfunction, inflammatory liver microenvironment, liver fibrosis and liver cancer in aged mice. Depletion of Altre reduced Treg mitochondrial integrity and respiratory capacity, and induced reactive oxygen species accumulation, thus increasing intrahepatic Treg apoptosis in aged mice. Moreover, lipidomic analysis identified a specific lipid species driving Treg aging and apoptosis in the aging liver microenvironment. Mechanistically, Altre interacts with Yin Yang 1 to orchestrate its occupation on chromatin, thereby regulating the expression of a group of mitochondrial genes, and maintaining optimal mitochondrial function and Treg fitness in the liver of aged mice. In conclusion, the Treg-specific nuclear long noncoding RNA Altre maintains the immune-metabolic homeostasis of the aged liver through Yin Yang 1-regulated optimal mitochondrial function and the Treg-sustained liver immune microenvironment. Thus, Altre is a potential therapeutic target for the treatment of liver diseases affecting older adults.
    DOI:  https://doi.org/10.1038/s43587-023-00428-8
  7. Nat Rev Mol Cell Biol. 2023 Jun 06.
    The technological landscape and applications of single-cell multi-omics.
    Alev Baysoy, Zhiliang Bai, Rahul Satija, Rong Fan.
      Single-cell multi-omics technologies and methods characterize cell states and activities by simultaneously integrating various single-modality omics methods that profile the transcriptome, genome, epigenome, epitranscriptome, proteome, metabolome and other (emerging) omics. Collectively, these methods are revolutionizing molecular cell biology research. In this comprehensive Review, we discuss established multi-omics technologies as well as cutting-edge and state-of-the-art methods in the field. We discuss how multi-omics technologies have been adapted and improved over the past decade using a framework characterized by optimization of throughput and resolution, modality integration, uniqueness and accuracy, and we also discuss multi-omics limitations. We highlight the impact that single-cell multi-omics technologies have had in cell lineage tracing, tissue-specific and cell-specific atlas production, tumour immunology and cancer genetics, and in mapping of cellular spatial information in fundamental and translational research. Finally, we discuss bioinformatics tools that have been developed to link different omics modalities and elucidate functionality through the use of better mathematical modelling and computational methods.
    DOI:  https://doi.org/10.1038/s41580-023-00615-w
  8. Nat Neurosci. 2023 Jun 08.
    Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease.
    Zhuoran Yin, Shawn Herron, Sebastian Silveira, Kilian Kleemann, Christian Gauthier, Dania Mallah, Yiran Cheng, Milica A Margeta, Kristen M Pitts, Jen-Li Barry, Ayshwarya Subramanian, Hannah Shorey, Wesley Brandao, Ana Durao, Jean-Christophe Delpech, Charlotte Madore, Mark Jedrychowski, Amrendra K Ajay, Gopal Murugaiyan, Samuel W Hersh, Seiko Ikezu, Tsuneya Ikezu, Oleg Butovsky.
      Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer's disease (AD) pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces a pre-MGnD activation state via interferon-γ (IFN-γ) signaling, and blocking IFN-γ signaling attenuates MGnD induction and microglial phagocytosis. Single-cell RNA-sequencing analysis of microglia from an AD mouse model identifies Stat1 and Clec2d as pre-MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque-associated synaptic degradation and improves cognition. Our study demonstrates a miR-155-mediated regulatory mechanism of MGnD and the beneficial role of IFN-γ-responsive pre-MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR-155 and IFN-γ as potential therapeutic targets for AD.
    DOI:  https://doi.org/10.1038/s41593-023-01355-y
  9. Nat Commun. 2023 Jun 08. 14(1): 3383
    Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice.
    Xin Zhang, Can Hu, Zhen-Guo Ma, Min Hu, Xiao-Pin Yuan, Yu-Pei Yuan, Sha-Sha Wang, Chun-Yan Kong, Teng Teng, Qi-Zhu Tang.
      The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to facilitate O-linked GlcNAc (O-GlcNAc) protein modifications, and subsequently enhance cell survival under lethal stresses. Transcript induced in spermiogenesis 40 (Tisp40) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. Here, we show that Tisp40 expression, cleavage and nuclear accumulation are increased by cardiac ischemia/reperfusion (I/R) injury. Global Tisp40 deficiency exacerbates, whereas cardiomyocyte-restricted Tisp40 overexpression ameliorates I/R-induced oxidative stress, apoptosis and acute cardiac injury, and modulates cardiac remodeling and dysfunction following long-term observations in male mice. In addition, overexpression of nuclear Tisp40 is sufficient to attenuate cardiac I/R injury in vivo and in vitro. Mechanistic studies indicate that Tisp40 directly binds to a conserved unfolded protein response element (UPRE) of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) promoter, and subsequently potentiates HBP flux and O-GlcNAc protein modifications. Moreover, we find that I/R-induced upregulation, cleavage and nuclear accumulation of Tisp40 in the heart are mediated by endoplasmic reticulum stress. Our findings identify Tisp40 as a cardiomyocyte-enriched UPR-associated transcription factor, and targeting Tisp40 may develop effective approaches to mitigate cardiac I/R injury.
    DOI:  https://doi.org/10.1038/s41467-023-39159-0
  10. Science. 2023 Jun 09. 380(6649): eabn9257
    Taurine deficiency as a driver of aging.
    Parminder Singh, Kishore Gollapalli, Stefano Mangiola, Daniela Schranner, Mohd Aslam Yusuf, Manish Chamoli, Sting L Shi, Bruno Lopes Bastos, Tripti Nair, Annett Riermeier, Elena M Vayndorf, Judy Z Wu, Aishwarya Nilakhe, Christina Q Nguyen, Michael Muir, Michael G Kiflezghi, Anna Foulger, Alex Junker, Jack Devine, Kunal Sharan, Shankar J Chinta, Swati Rajput, Anand Rane, Philipp Baumert, Martin Schönfelder, Francescopaolo Iavarone, Giorgia di Lorenzo, Swati Kumari, Alka Gupta, Rajesh Sarkar, Costerwell Khyriem, Amanpreet S Chawla, Ankur Sharma, Nazan Sarper, Naibedya Chattopadhyay, Bichitra K Biswal, Carmine Settembre, Perumal Nagarajan, Kimara L Targoff, Martin Picard, Sarika Gupta, Vidya Velagapudi, Anthony T Papenfuss, Alaattin Kaya, Miguel Godinho Ferreira, Brian K Kennedy, Julie K Andersen, Gordon J Lithgow, Abdullah Mahmood Ali, Arnab Mukhopadhyay, Aarno Palotie, Gabi Kastenmüller, Matt Kaeberlein, Henning Wackerhage, Bhupinder Pal, Vijay K Yadav.
      Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.
    DOI:  https://doi.org/10.1126/science.abn9257
  11. Nat Metab. 2023 Jun 05.
    The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.
    Kimberley El, Jonathan D Douros, Francis S Willard, Aaron Novikoff, Ashot Sargsyan, Diego Perez-Tilve, David B Wainscott, Bin Yang, Alex Chen, Donald Wothe, Callum Coupland, Mattias H Tschöp, Brian Finan, David A D'Alessio, Kyle W Sloop, Timo D Müller, Jonathan E Campbell.
      The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance1. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity2, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity3,4. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control5. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.
    DOI:  https://doi.org/10.1038/s42255-023-00811-0
  12. Nat Genet. 2023 Jun 08.
    Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.
    Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)
      Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
    DOI:  https://doi.org/10.1038/s41588-023-01408-9
  13. Science. 2023 Jun 09. 380(6649): 1070-1076
    Linking genome structures to functions by simultaneous single-cell Hi-C and RNA-seq.
    Zhiyuan Liu, Yujie Chen, Qimin Xia, Menghan Liu, Heming Xu, Yi Chi, Yujing Deng, Dong Xing.
      Much progress has been made recently in single-cell chromosome conformation capture technologies. However, a method that allows simultaneous profiling of chromatin architecture and gene expression has not been reported. Here, we developed an assay named "Hi-C and RNA-seq employed simultaneously" (HiRES) and performed it on thousands of single cells from developing mouse embryos. Single-cell three-dimensional genome structures, despite being heavily determined by the cell cycle and developmental stages, gradually diverged in a cell type-specific manner as development progressed. By comparing the pseudotemporal dynamics of chromatin interactions with gene expression, we found a widespread chromatin rewiring that occurred before transcription activation. Our results demonstrate that the establishment of specific chromatin interactions is tightly related to transcriptional control and cell functions during lineage specification.
    DOI:  https://doi.org/10.1126/science.adg3797
  14. Cell. 2023 May 26. pii: S0092-8674(23)00476-2. [Epub ahead of print]
    Distinct longevity mechanisms across and within species and their association with aging.
    Alexander Tyshkovskiy, Siming Ma, Anastasia V Shindyapina, Stanislav Tikhonov, Sang-Goo Lee, Perinur Bozaykut, José P Castro, Andrei Seluanov, Nicholas J Schork, Vera Gorbunova, Sergey E Dmitriev, Richard A Miller, Vadim N Gladyshev.
      Lifespan varies within and across species, but the general principles of its control remain unclear. Here, we conducted multi-tissue RNA-seq analyses across 41 mammalian species, identifying longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. An integrative analysis uncovered shared longevity mechanisms within and across species, including downregulated Igf1 and upregulated mitochondrial translation genes, and unique features, such as distinct regulation of the innate immune response and cellular respiration. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes, involved in proteolysis and PI3K-Akt signaling. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed longevity interventions, including KU0063794, which extended mouse lifespan and healthspan. Overall, this study uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for discovering longevity interventions.
    Keywords:  Igf1, KU0063794; aging; bowhead whale; gene expression; lifespan extension; longevity; longevity signatures; mSALT; naked mole rat
    DOI:  https://doi.org/10.1016/j.cell.2023.05.002
  15. Science. 2023 Jun 09. 380(6649): 1010-1011
    Taurine linked with healthy aging.
    Joseph McGaunn, Joseph A Baur.
      Reversing age-associated taurine loss improves mouse longevity and monkey health.
    DOI:  https://doi.org/10.1126/science.adi3025
  16. J Immunol. 2023 Jun 15. 210(12): 1853-1860
    Requirements of IL-4 during the Generation of B Cell Memory.
    Clarissa R Chakma, Kim L Good-Jacobson.
      IL-4 has long been established as a key regulator of Th cells and for promoting effective B cell survival and isotype class switching. Yet, despite having been extensively studied, the specific role of IL-4 in generating humoral memory in vivo is unclear. In this review, we explore the recent studies that unravel the cellular sources and spatiotemporal production of IL-4, the relationship between IL-4 and IL-21 during germinal center responses and the formation of Ab-secreting cells, and the current understanding of whether IL-4 promotes or suppresses memory B cell generation in vitro and in vivo.
    DOI:  https://doi.org/10.4049/jimmunol.2200922
  17. Nat Immunol. 2023 Jun 08.
    Defining blood-induced microglia functions in neurodegeneration through multiomic profiling.
    Andrew S Mendiola, Zhaoqi Yan, Karuna Dixit, Jeffrey R Johnson, Mehdi Bouhaddou, Anke Meyer-Franke, Min-Gyoung Shin, Yu Yong, Ayushi Agrawal, Eilidh MacDonald, Gayathri Muthukumar, Clairice Pearce, Nikhita Arun, Belinda Cabriga, Rosa Meza-Acevedo, Maria Del Pilar S Alzamora, Scott S Zamvil, Alexander R Pico, Jae Kyu Ryu, Nevan J Krogan, Katerina Akassoglou.
      Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.
    DOI:  https://doi.org/10.1038/s41590-023-01522-0
  18. Proc Natl Acad Sci U S A. 2023 Jun 13. 120(24): e2216310120
    ROS signaling-induced mitochondrial Sgk1 expression regulates epithelial cell renewal.
    Yingxiang Li, Chengdong Liu, Luke Rolling, Veronica Sikora, Zhimin Chen, Jack Gurwin, Caroline Barabell, Jiandie Lin, Cunming Duan.
      Many types of differentiated cells can reenter the cell cycle upon injury or stress. The underlying mechanisms are still poorly understood. Here, we investigated how quiescent cells are reactivated using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. A robust and sustained increase in mitochondrial membrane potential was observed in the reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Further analyses showed that elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Genetic deletion and inhibition of Sgk1 in zebrafish abolished epithelial cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, SGK1 coordinates mitochondrial activity with ATP synthesis by phosphorylating F1Fo-ATP synthase. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal.
    Keywords:  F1Fo-ATP synthase; IGF/insulin signaling; mitochondrial membrane potential; reactive oxygen species; serum- and glucocorticoid-regulated kinase 1
    DOI:  https://doi.org/10.1073/pnas.2216310120
  19. Nat Commun. 2023 Jun 08. 14(1): 3343
    TRIM5α recruits HDAC1 to p50 and Sp1 and promotes H3K9 deacetylation at the HIV-1 LTR.
    Xiang-Hong Ran, Jia-Wu Zhu, Run-Ze Ni, Yong-Tang Zheng, Ya-Yun Chen, Wei-Hua Zheng, Dan Mu.
      Tripartite motif-containing protein 5α (TRIM5α) is generally known to block the postentry events of HIV-1. Here, we report an uncharacterized role for TRIM5α in the maintenance of viral latency. Knockdown of TRIM5α potentiates the transcription of HIV-1 in multiple latency models, which is reversed by shRNA-resistant TRIM5α. TRIM5α suppresses TNFα-activated HIV-1 LTR-driven as well as NF-κB- and Sp1-driven gene expression, with the RING and B-box 2 domains being the essential determinants. Mechanistically, TRIM5α binds to and enhances the recruitment of histone deacetylase 1 (HDAC1) to NF-κB p50 and Sp1. ChIP‒qPCR analyses further reveal that the association of TRIM5α with HIV-1 LTR induces HDAC1 recruitment and local H3K9 deacetylation. Conserved suppression effects of TRIM5α orthologs from multiple species on both HIV-1 and endo-retroelement HERV-K LTR activities have also been demonstrated. These findings provide new insights into the molecular mechanisms by which proviral latency is initially established and activatable proviruses are resilenced by histone deacetylase recruitment.
    DOI:  https://doi.org/10.1038/s41467-023-39056-6
  20. Nature. 2023 Jun 06.
    Does shingles vaccination cut dementia risk? Large study hints at a link.
    Sara Reardon.
      
    Keywords:  Alzheimer's disease; Epidemiology; Neurodegeneration; Public health; Vaccines
    DOI:  https://doi.org/10.1038/d41586-023-01824-1
  21. Nat Commun. 2023 Jun 08. 14(1): 3353
    Super-resolved trajectory-derived nanoclustering analysis using spatiotemporal indexing.
    Tristan P Wallis, Anmin Jiang, Kyle Young, Huiyi Hou, Kye Kudo, Alex J McCann, Nela Durisic, Merja Joensuu, Dietmar Oelz, Hien Nguyen, Rachel S Gormal, Frédéric A Meunier.
      Single-molecule localization microscopy techniques are emerging as vital tools to unravel the nanoscale world of living cells by understanding the spatiotemporal organization of protein clusters at the nanometer scale. Current analyses define spatial nanoclusters based on detections but neglect important temporal information such as cluster lifetime and recurrence in "hotspots" on the plasma membrane. Spatial indexing is widely used in video games to detect interactions between moving geometric objects. Here, we use the R-tree spatial indexing algorithm to determine the overlap of the bounding boxes of individual molecular trajectories to establish membership in nanoclusters. Extending the spatial indexing into the time dimension allows the resolution of spatial nanoclusters into multiple spatiotemporal clusters. Using spatiotemporal indexing, we found that syntaxin1a and Munc18-1 molecules transiently cluster in hotspots, offering insights into the dynamics of neuroexocytosis. Nanoscale spatiotemporal indexing clustering (NASTIC) has been implemented as a free and open-source Python graphic user interface.
    DOI:  https://doi.org/10.1038/s41467-023-38866-y
  22. Nat Immunol. 2023 Jun 05.
    Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis.
    Melanie H Smith, Vianne R Gao, Preethi K Periyakoil, Alejandro Kochen, Edward F DiCarlo, Susan M Goodman, Thomas M Norman, Laura T Donlin, Christina S Leslie, Alexander Y Rudensky.
      Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1β or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium.
    DOI:  https://doi.org/10.1038/s41590-023-01527-9
  23. Nat Commun. 2023 Jun 08. 14(1): 3368
    Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions.
    Shengjie Fan, Yingxuan Yan, Ying Xia, Zhenyu Zhou, Lingling Luo, Mengnan Zhu, Yongli Han, Deqiang Yao, Lijun Zhang, Minglv Fang, Lina Peng, Jing Yu, Ying Liu, Xiaoyan Gao, Huida Guan, Hongli Li, Changhong Wang, Xiaojun Wu, Huanhu Zhu, Yu Cao, Cheng Huang.
      Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals' lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.
    DOI:  https://doi.org/10.1038/s41467-023-39118-9
  24. EMBO J. 2023 Jun 05. e112259
    STAT1 is required to establish but not maintain interferon-γ-induced transcriptional memory.
    Sahar Sh Tehrani, Pawel Mikulski, Izma Abdul-Zani, João F Mata, Wojciech Siwek, Lars Et Jansen.
      Exposure of human cells to interferon-γ (IFNγ) results in a mitotically heritable yet reversible state called long-term transcriptional memory. We previously identified the clustered GBP genes as strongly primed by IFNγ. Here, we discovered that in primed cells, both interferon-responsive transcription factors STAT1 and IRF1 target chromatin with accelerated kinetics upon re-exposure to IFNγ, specifically at promotors of primed genes. Priming does not alter the degree of IFNγ-induced STAT1 activation or nuclear import, indicating that memory does not alter upstream JAK-STAT signaling. We found STAT1 to be critical to establish transcriptional memory but in a manner that is independent of mere transcription activation. Interestingly, while Serine 727 phosphorylation of STAT1 was maintained during the primed state, STAT1 is not required for the heritability of GBP gene memory. Our results suggest that the memory of interferon exposure constitutes a STAT1-mediated, heritable state that is established during priming. This renders GBP genes poised for subsequent STAT1 and IRF1 binding and accelerated gene activation upon a secondary interferon exposure.
    Keywords:  GBPs; IRF1; STAT1; epigenetic memory; epigenetics; trained immunity
    DOI:  https://doi.org/10.15252/embj.2022112259
  25. Nat Commun. 2023 Jun 08. 14(1): 3367
    THRONCAT: metabolic labeling of newly synthesized proteins using a bioorthogonal threonine analog.
    Bob J Ignacio, Jelmer Dijkstra, Natalia Mora, Erik F J Slot, Margot J van Weijsten, Erik Storkebaum, Michiel Vermeulen, Kimberly M Bonger.
      Profiling the nascent cellular proteome and capturing early proteomic changes in response to external stimuli provides valuable insights into cellular physiology. Existing metabolic protein labeling approaches based on bioorthogonal methionine- or puromycin analogs allow for the selective visualization and enrichment of newly synthesized proteins. However, their applications are limited as they often require methionine-free conditions, auxotrophic cells and/or are toxic to cells. Here, we introduce THRONCAT, a threonine-derived non-canonical amino acid tagging method based on the bioorthogonal threonine analog β-ethynylserine (βES) that enables efficient labeling of the nascent proteome in complete growth media within minutes. We use THRONCAT for the visualization and enrichment of nascent proteins in bacteria, mammalian cells and Drosophila melanogaster. We profile immediate proteome dynamics of B-cells in response to B-cell receptor activation simply by adding βES to the culture medium, demonstrating the ease-of-use of the method and its potential to address diverse biological questions. In addition, using a Drosophila model of Charcot-Marie-Tooth peripheral neuropathy, we show that THRONCAT enables visualization and quantification of relative protein synthesis rates in specific cell types in vivo.
    DOI:  https://doi.org/10.1038/s41467-023-39063-7
  26. Nat Commun. 2023 Jun 08. 14(1): 3364
    Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner.
    Tianyu Tang, Xing Huang, Minghao Lu, Gang Zhang, Xu Han, Tingbo Liang.
      Cancer cell metabolism contributes to the establishment of an immunosuppressive tumor microenvironment. Aberrant expression of CD73, a critical enzyme in ATP metabolism, on the cell surface results in the extracellular accumulation of adenosine, which exhibits direct inhibitory effects on tumor-infiltrating lymphocytes. However, little is known about the influence of CD73 on negative immune regulation-associated signaling molecules and transduction pathways inside tumor cells. This study aims to demonstrate the moonlighting functions of CD73 in immunosuppression in pancreatic cancer, an ideal model characterized by complex crosstalk among cancer metabolism, immune microenvironment, and immunotherapeutic resistance. The synergistic effect of CD73-specific drugs in combination with immune checkpoint blockade is observed in multiple pancreatic cancer models. Cytometry by time-of-flight analysis shows that CD73 inhibition reduces tumor-infiltrating Tregs in pancreatic cancer. Tumor cell-autonomous CD73 is found to facilitate Treg recruitment, in which CCL5 is identified as a significant downstream effector of CD73 using integrated proteomic and transcriptomic analyses. CD73 transcriptionally upregulates CCL5 through tumor cell-autocrine adenosine-Adora2a signaling-mediated activation of the p38-STAT1 axis, recruiting Tregs to pancreatic tumors and causing an immunosuppressive microenvironment. Together, this study highlights that CD73-adenosine metabolism transcriptionally controls pancreatic cancer immunosuppression in a tumor-autonomous and -autocrine manner.
    DOI:  https://doi.org/10.1038/s41467-023-38578-3
  27. Immunity. 2023 May 26. pii: S1074-7613(23)00227-3. [Epub ahead of print]
    Neuroprotective protein ADNP-dependent histone remodeling complex promotes T helper 2 immune cell differentiation.
    Ana C F Ferreira, Aydan C H Szeto, Paula A Clark, Alastair Crisp, Patrycja Kozik, Helen E Jolin, Andrew N J McKenzie.
      Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanistically, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the transition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization.
    Keywords:  ADNP; AP-1; GATA3; IL-13; T helper 2 cells; Th2; asthma; histone remodeling; immunity; type 2 cytokines
    DOI:  https://doi.org/10.1016/j.immuni.2023.05.010
  28. Nat Cell Biol. 2023 Jun 08.
    Architecture and dynamics of a desmosome-endoplasmic reticulum complex.
    COSEM Project Team
      The endoplasmic reticulum (ER) forms a dynamic network that contacts other cellular membranes to regulate stress responses, calcium signalling and lipid transfer. Here, using high-resolution volume electron microscopy, we find that the ER forms a previously unknown association with keratin intermediate filaments and desmosomal cell-cell junctions. Peripheral ER assembles into mirror image-like arrangements at desmosomes and exhibits nanometre proximity to keratin filaments and the desmosome cytoplasmic plaque. ER tubules exhibit stable associations with desmosomes, and perturbation of desmosomes or keratin filaments alters ER organization, mobility and expression of ER stress transcripts. These findings indicate that desmosomes and the keratin cytoskeleton regulate the distribution, function and dynamics of the ER network. Overall, this study reveals a previously unknown subcellular architecture defined by the structural integration of ER tubules with an epithelial intercellular junction.
    DOI:  https://doi.org/10.1038/s41556-023-01154-4
  29. Commun Biol. 2023 06 07. 6(1): 613
    Tox4 regulates transcriptional elongation and reinitiation during murine T cell development.
    Talang Wang, Ruoyu Zhao, Junhong Zhi, Ziling Liu, Aiwei Wu, Zimei Yang, Weixu Wang, Ting Ni, Lili Jing, Ming Yu.
      HMG protein Tox4 is a regulator of PP1 phosphatases with unknown function in development. Here we show that Tox4 conditional knockout in mice reduces thymic cellularity, partially blocks T cell development, and decreases ratio of CD8 to CD4 through decreasing proliferation and increasing apoptosis of CD8 cells. In addition, single-cell RNA-seq discovered that Tox4 loss also impairs proliferation of the fast-proliferating double positive (DP) blast population within DP cells in part due to downregulation of genes critical for proliferation, notably Cdk1. Moreover, genes with high and low expression level are more dependent on Tox4 than genes with medium expression level. Mechanistically, Tox4 may facilitate transcriptional reinitiation and restrict elongation in a dephosphorylation-dependent manner, a mechanism that is conserved between mouse and human. These results provide insights into the role of TOX4 in development and establish it as an evolutionarily conserved regulator of transcriptional elongation and reinitiation.
    DOI:  https://doi.org/10.1038/s42003-023-04992-y
  30. Nat Commun. 2023 Jun 05. 14(1): 3239
    Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity.
    Antje Häder, Sascha Schäuble, Jan Gehlen, Nadja Thielemann, Benedikt C Buerfent, Vitalia Schüller, Timo Hess, Thomas Wolf, Julia Schröder, Michael Weber, Kerstin Hünniger, Jürgen Löffler, Slavena Vylkova, Gianni Panagiotou, Johannes Schumacher, Oliver Kurzai.
      Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.
    DOI:  https://doi.org/10.1038/s41467-023-38994-5
  31. Nat Aging. 2023 Jun 05.
    Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging.
    Philip V Seegren, Logan R Harper, Taylor K Downs, Xiao-Yu Zhao, Shivapriya B Viswanathan, Marta E Stremska, Rachel J Olson, Joel Kennedy, Sarah E Ewald, Pankaj Kumar, Bimal N Desai.
      Mitochondrial dysfunction is linked to age-associated inflammation or inflammaging, but underlying mechanisms are not understood. Analyses of 700 human blood transcriptomes revealed clear signs of age-associated low-grade inflammation. Among changes in mitochondrial components, we found that the expression of mitochondrial calcium uniporter (MCU) and its regulatory subunit MICU1, genes central to mitochondrial Ca2+ (mCa2+) signaling, correlated inversely with age. Indeed, mCa2+ uptake capacity of mouse macrophages decreased significantly with age. We show that in both human and mouse macrophages, reduced mCa2+ uptake amplifies cytosolic Ca2+ oscillations and potentiates downstream nuclear factor kappa B activation, which is central to inflammation. Our findings pinpoint the mitochondrial calcium uniporter complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to systemic macrophage-mediated age-associated inflammation. The findings raise the exciting possibility that restoring mCa2+ uptake capacity in tissue-resident macrophages may decrease inflammaging of specific organs and alleviate age-associated conditions such as neurodegenerative and cardiometabolic diseases.
    DOI:  https://doi.org/10.1038/s43587-023-00436-8
  32. Sci Adv. 2023 Jun 09. 9(23): eadf9524
    A CMOS-based highly scalable flexible neural electrode interface.
    Eric T Zhao, Jacob M Hull, Nofar Mintz Hemed, Hasan Uluşan, Julian Bartram, Anqi Zhang, Pingyu Wang, Albert Pham, Silvia Ronchi, John R Huguenard, Andreas Hierlemann, Nicholas A Melosh.
      Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. However, existing electrophysiological devices are limited by their scalability in capturing this cortex-wide activity. Here, we developed an electrode connector based on an ultra-conformable thin-film electrode array that self-assembles onto silicon microelectrode arrays enabling multithousand channel counts at a millimeter scale. The interconnects are formed using microfabricated electrode pads suspended by thin support arms, termed Flex2Chip. Capillary-assisted assembly drives the pads to deform toward the chip surface, and van der Waals forces maintain this deformation, establishing Ohmic contact. Flex2Chip arrays successfully measured extracellular action potentials ex vivo and resolved micrometer scale seizure propagation trajectories in epileptic mice. We find that seizure dynamics in absence epilepsy in the Scn8a+/- model do not have constant propagation trajectories.
    DOI:  https://doi.org/10.1126/sciadv.adf9524
  33. Nat Metab. 2023 Jun 05.
    CaMK1D signalling in AgRP neurons promotes ghrelin-mediated food intake.
    Karl Vivot, Gergö Meszaros, Evanthia Pangou, Zhirong Zhang, Mengdi Qu, Eric Erbs, Gagik Yeghiazaryan, Mar Quiñones, Erwan Grandgirard, Anna Schneider, Etienne Clauss-Creusot, Alexandre Charlet, Maya Faour, Claire Martin, Fedor Berditchevski, Izabela Sumara, Serge Luquet, Peter Kloppenburg, Ruben Nogueiras, Romeo Ricci.
      Hypothalamic AgRP/NPY neurons are key players in the control of feeding behaviour. Ghrelin, a major orexigenic hormone, activates AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signalling mechanisms in AgRP/NPY neurons remain poorly defined. Here we show that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated upon ghrelin stimulation and acts in AgRP/NPY neurons to mediate ghrelin-dependent food intake. Global Camk1d-knockout male mice are resistant to ghrelin, gain less body weight and are protected against high-fat-diet-induced obesity. Deletion of Camk1d in AgRP/NPY, but not in POMC, neurons is sufficient to recapitulate above phenotypes. In response to ghrelin, lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY in fibre projections to the paraventricular nucleus (PVN). Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons.
    DOI:  https://doi.org/10.1038/s42255-023-00814-x
  34. J Exp Med. 2023 Sep 04. pii: e20212276. [Epub ahead of print]220(9):
    Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.
    Kunihiko Moriya, Tomohiro Nakano, Yoshitaka Honda, Miyuki Tsumura, Masato Ogishi, Motoshi Sonoda, Masahiko Nishitani-Isa, Takashi Uchida, Mohamed Hbibi, Yoko Mizoguchi, Masataka Ishimura, Kazushi Izawa, Takaki Asano, Fumihiko Kakuta, Daiki Abukawa, Darawan Rinchai, Peng Zhang, Naotomo Kambe, Aziz Bousfiha, Takahiro Yasumi, Bertrand Boisson, Anne Puel, Jean-Laurent Casanova, Ryuta Nishikomori, Shouichi Ohga, Satoshi Okada, Yoji Sasahara, Shigeo Kure.
      Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.
    DOI:  https://doi.org/10.1084/jem.20212276
  35. Nat Commun. 2023 Jun 06. 14(1): 3297
    In-vivo programmable acoustic manipulation of genetically engineered bacteria.
    Ye Yang, Yaozhang Yang, Dingyuan Liu, Yuanyuan Wang, Minqiao Lu, Qi Zhang, Jiqing Huang, Yongchuan Li, Teng Ma, Fei Yan, Hairong Zheng.
      Acoustic tweezers can control target movement through the momentum interaction between an acoustic wave and an object. This technology has advantages over optical tweezers for in-vivo cell manipulation due to its high tissue penetrability and strong acoustic radiation force. However, normal cells are difficult to acoustically manipulate because of their small size and the similarity between their acoustic impedance and that of the medium. In this study, we use the heterologous expression of gene clusters to generate genetically engineered bacteria that can produce numerous sub-micron gas vesicles in the bacterial cytoplasm. We show that the presence of the gas vesicles significantly enhances the acoustic sensitivity of the engineering bacteria, which can be manipulated by ultrasound. We find that by employing phased-array-based acoustic tweezers, the engineering bacteria can be trapped into clusters and manipulated in vitro and in vivo via electronically steered acoustic beams, enabling the counter flow or on-demand flow of these bacteria in the vasculature of live mice. Furthermore, we demonstrate that the aggregation efficiency of engineering bacteria in a tumour is improved by utilizing this technology. This study provides a platform for the in-vivo manipulation of live cells, which will promote the progress of cell-based biomedical applications.
    DOI:  https://doi.org/10.1038/s41467-023-38814-w
  36. Nature. 2023 Jun;618(7964): S10-S11
    Is nicotine bad for long-term health? Scientists aren't sure yet.
    Anthony King.
      
    Keywords:  Medical research; Public health; Toxicology
    DOI:  https://doi.org/10.1038/d41586-023-01840-1
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