Chronic pain affects over 20% of the global population, yet frontline treatments remain limited in efficacy and are often hampered by serious side effects. In search of novel and effective neuromodulation alternatives, w...Chronic pain affects over 20% of the global population, yet frontline treatments remain limited in efficacy and are often hampered by serious side effects. In search of novel and effective neuromodulation alternatives, we discovered that 40 Hz flickering light effectively alleviates inflammatory and neuropathic pain in mice. We identified the retina-central amygdala (CeA) pathway as a critical conduit for the analgesic effects of 40 Hz flickering light. Using circuit-specific manipulations, we demonstrated that activation of the retina-CeA pathway is both sufficient to mimic and necessary to mediate the analgesic outcomes of 40 Hz light stimulation. In terms of mechanism, we found that 40 Hz light flickering significantly increases extracellular adenosine levels in the CeA. Local pharmacological blockade of equilibrative nucleoside transporters prevented this adenosine increase and abolished the analgesic effects of 40 Hz light flickering, whereas focal adenosine infusion phenocopied the light-induced analgesia. Both interventions required A receptor signaling to suppress nociceptive responses. Furthermore, we found that hyperalgesia could be destabilized in the CeA and reversed by 40 Hz light stimulation or adenosine infusion, mirroring memory reconsolidation processes and implicating the CeA as a key locus for pain memory erasure. Collectively, our findings demonstrate the multifaceted therapeutic benefits of 40 Hz light flickering as a novel non-invasive approach for pain management and reveal a distinct retina-CeA circuit and adenosine signaling mechanism for control of chronic pain and pain memory.
Organisms leverage environmental cues to anticipate and adapt to changing conditions. Here, we show that Caenorhabditis elegans, despite being eyeless, utilizes photoperception as an anticipatory cue to enhance survival...Organisms leverage environmental cues to anticipate and adapt to changing conditions. Here, we show that Caenorhabditis elegans, despite being eyeless, utilizes photoperception as an anticipatory cue to enhance survival under thermal stress. Exposure to low-intensity light activates a heat-shock response via the photoreceptor LITE-1, triggering serotonin signaling that promotes thermotolerance through the serotonin receptor SER-5 in the intestine and muscle. Beyond acute stress protection, light perception modulates reproductive behavior by delaying egg laying under unfavorable conditions and induces intergenerational thermotolerance, enhancing progeny survival at elevated temperatures. Photoperception also improves population competitiveness, providing a competitive advantage in dynamic environments. These findings reveal a previously unrecognized role for photoperception in a non-photosynthetic animal and establish it as a key mechanism for thermal adaptation and fitness.
Zhang L, Li X, Luo H
… +22 more, Huo Y, Zhou G, Wang P, Wu S, Lin X, Dai K, Shi J, Wang Z, Xu J, Li R, Chen S, Sun Z, Zhao C, Zhou Z, Wang Z, Liang C, Zhu J, Chen X, Luo J, Yu Y, Zhang Z, Wang G
Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61...Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer's disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.
A fundamental question in biology is whether all cells age. Embryonic stem cells (ESCs) defy the norm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortalit...A fundamental question in biology is whether all cells age. Embryonic stem cells (ESCs) defy the norm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortality remain unresolved. Using long-term live-cell imaging to follow the fates of single ESCs, we show that ESC lineage renewal is achieved through sporadic entry into a state characterized by the expression of two-cell embryo-specific markers. During this state, cells undergo asymmetric fate divisions, enriching accumulated DNA damage into one daughter lineage that is destined for elimination, while producing a second lineage that reverts to the pluripotent state. Importantly, the latter lineage exhibits signs of rejuvenation, including reduced DNA damage and enhanced chimeric efficiency. These findings underscore the crucial role of asymmetric cell division in maintaining the long-term health of the ESC lineage against mounting damage within individual cells and provide a potential model for studying cellular aging and rejuvenation in mammalian cells.
Li Y, Zheng M, Zhu Z
… +31 more, Zhang Y, Ning P, Chen H, Gao R, Xu C, Wei X, Liu Y, Wang Y, Zhou R, Li Y, Li Z, Lv C, Liu C, Xu J, Guo Z, Hu Z, Fang L, Wei K, Feng M, Zhou C, She Y, Sun W, Chen E, Plaza GR, He B, Miska J, Yang W, Tang Y, Liu H, Chen C, Cheng Y
Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and...Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.
Pancreatic β-cell identity loss is increasingly recognized as a critical pathogenic contributor to β-cell failure in type 2 diabetes (T2D), but the specific mechanism remains to be characterized. In this study, we demons...Pancreatic β-cell identity loss is increasingly recognized as a critical pathogenic contributor to β-cell failure in type 2 diabetes (T2D), but the specific mechanism remains to be characterized. In this study, we demonstrate that zinc accumulation contributes to β-cell identity loss during diabetes progression in both human and mouse islets. Using a model of human embryonic stem cell-derived islets (SC-islets), we reveal that accumulated zinc triggers the integrated stress response (ISR), with elevated ATF4 expression in SC-β cells. This, in turn, initiates expression of the α cell-specific transcription factor ARX, resulting in the conversion of β cells to α cells, thus forming a zinc-ATF4-ARX regulatory axis. Like primary β cells, SC-β cells also undergo identity loss after transplantation into diabetic animals, which can be prevented by an ISR inhibitor, resulting in improved glycemic control. Furthermore, both genetic depletion and chemical inhibition of zinc accumulation effectively safeguard SC-β cells from identity loss and enhance their efficacy in diabetic animals. Our study thus reveals a pathogenic mechanism in which zinc accumulation induces β-cell identity loss through lineage-tracing approaches and proposes a protective strategy to counteract this process.
Wu W, Cui C, Zhu Y
… +17 more, Chen J, Zhuang Q, Wang Y, Liu Z, Gao H, Ou GZ, Liu C, Tao M, Chen Y, Pan R, Zhang G, Cai H, Yang J, Chen XX, Zhou X, Wang S, Shen XX
Protein structure bridges the sequence-function relationship, enabling deep exploration of biological processes across diverse organisms. Insects, the most diverse animal lineage, accounting for over 50% of all described...Protein structure bridges the sequence-function relationship, enabling deep exploration of biological processes across diverse organisms. Insects, the most diverse animal lineage, accounting for over 50% of all described animal species, provide an exceptional system for exploring sequence-structure-function relationships. Here, we reconstructed a comprehensive and well-resolved phylogeny of 4854 insects, spanning all orders. Leveraging this framework, we created an atlas of 13.29 million predicted protein structures from 824 representative species, including 11.63 million newly predicted structures. Structural clustering revealed that proteins with divergent sequences but similar structures could be effectively grouped together. Structural similarity searches against proteins with well-characterized functions yielded annotations for 7.61 million insect proteins, including up to 14% of previously unannotated proteins. We further identified 750 million remote homologs between insect proteins, many of which trace back to ancient branches of the insect phylogeny. Remarkably, despite extensive sequence divergence, cGAS-like receptors (cGLRs) were structurally conserved across all 824 insects. Experimental assays demonstrated that these structurally identified cGLRs play a crucial role in antiviral defense in the yellow fever mosquito. Our findings highlight the significance of structural genomics for understanding protein function and evolution across the tree of life.
As innate immune cells in the brain, microglia directly contact excitatory neurons and regulate their activities under various conditions; however, the mechanisms of direct microglia-neuron functional interactions remain...As innate immune cells in the brain, microglia directly contact excitatory neurons and regulate their activities under various conditions; however, the mechanisms of direct microglia-neuron functional interactions remain largely unknown. Here, we identified one special population of neocortical microglia that specifically associate with the axon initial segments (AISs) of excitatory neurons, and could regulate their activities and contribute to visual perception. We found that brief depolarization of AIS-associated microglia, but not the AIS-non-associated microglia, significantly promoted the action potential firing of related excitatory neurons, which relied mechanistically on microglial K release through the outward K channel THIK-1. Interestingly, in vivo visual stimulation with drifting gratings evoked microglial transient depolarizations specifically on the processes, which depended on muscarinic receptors and triggered K release through THIK-1; meanwhile, visual stimulation induced more robust calcium responses in neurons associated with microglia at their AISs compared with nearby unassociated neurons. Disruption of the AIS-microglia interaction disturbed calcium responses specifically in neurons associated with microglia at their AISs, impaired the coordinated activity of the entire neural ensemble, and thereby affected the visual discrimination behavior of awake mice. Collectively, our findings identified a new type of microglia-neuron functional interaction that may be critical for higher-order brain functions.
Methionine metabolism generates the substrate S-adenosylmethionine (SAM), which regulates epigenetic modifications crucial for various cellular processes, particularly tumorigenesis. However, whether methionine metabolis...Methionine metabolism generates the substrate S-adenosylmethionine (SAM), which regulates epigenetic modifications crucial for various cellular processes, particularly tumorigenesis. However, whether methionine metabolism involves epigenetic mechanisms independent of SAM and what roles such mechanisms play in tumorigenesis remain unclear. We show here that the adenosylhomocysteinase (AHCY)-adenosine complex increases mRNA mA levels in a non-global manner, promoting fatty acid synthesis and tumorigenesis. Adenosine increases mRNA mA levels by binding to the methionine metabolism enzyme AHCY to form a complex, rather than depending on adenosine receptors. The AHCY-adenosine complex facilitates AHCY dimerization, with adenosine being crucial for dimer stability. AHCY dimers hinder the binding of fat mass and obesity-associated protein (FTO) at the Q86 site to RNA containing the VWDRACH motif, increasing mA levels and upregulating lipogenesis genes, especially ACACA and SCD1, thus leading to reprogramming of lipid metabolism. Conversely, AHCY mutants that have lost dimerization or FTO-binding ability but retain hydrolase activity suppress lipogenesis and tumor growth without significantly affecting methionine catabolism mediated by AHCY. Loss of AHCY in mice and disruption of AHCY dimerization in tumor cells and patient-derived xenograft models restricted tumor growth. Our findings demonstrate a key SAM-independent link between methionine metabolism and mRNA mA modification that affects demethylase substrate specificity. This novel link between the methionine cycle and lipid metabolism suggests new strategies for anticancer therapy.
The gut microbiome is recognized as a determinant of response to immune checkpoint inhibitor (ICI) therapies in cancer. However, the clinical translation of microbiome science has been hampered by inconsistent definition...The gut microbiome is recognized as a determinant of response to immune checkpoint inhibitor (ICI) therapies in cancer. However, the clinical translation of microbiome science has been hampered by inconsistent definitions of dysbiosis, inadequate biomarker frameworks, and limited mechanistic understanding. In this review, we synthesize the current state of knowledge on how gut microbial composition and function influence ICI efficacy, highlighting both correlative and causal evidence. We discuss computational approaches based on α-diversity or taxonomic abundance and argue for more functionally and clinically informative models, such as the topological score (TOPOSCORE) and other dysbiosis indices derived from machine learning. Using retrospective analyses of metagenomic datasets from thousands of patients and healthy controls, we examine microbial patterns that distinguish responders from non-responders. We also explore how dysbiosis perturbs immunoregulatory pathways, including bile acid metabolism, gut permeability, and mucosal immunomodulation. Finally, we assess emerging therapeutic strategies aimed at correcting microbiome dysfunction - including dietary modification, bacterial consortia, and fecal microbiota transplantation - and describe how they are being deployed in multiple clinical trials. We conclude with a brief discussion of the ONCOBIOME initiative, which works with international partners to incorporate microbiome science into oncology workflows. By refining our understanding of gut-immune interactions and translating it into action, microbiome-informed oncology may unlock new therapeutic potential for patients previously resistant to immunotherapy.