Biology subjects

Yao, C.

Publications and source records attributed to Yao, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Mechanistic Modeling of Sleep-Wake Transitions via Circadian-Modulated Threshold Dynamics

Human sleep-wake cycles emerge from complex interactions between homeostatic sleep pressure and circadian rhythms. In this study, we extend the Phillips-Robinson model by introducing circadian-dependent dynamic thresholds for sleep and wake transitions, yielding a more physiologically grounded framework for sleep regulation. Using bifurcation analysis, we show that the transition from sustained wakefulness to rhythmic sleep-wake cycles is governed by a saddle-node on invariant circle (SNIC) bifurcation, and that these oscillations become entrained to external 24 h light-dark cues. We analytically derive circadian-modulated sleep and wake thresholds, revealing how the interaction between circadian and homeostatic drives governs sleep-wake transitions. Our model captures key physiological phenomena, including: (1) the onset and entrainment of sleep-wake rhythms, (2) immediate sleep onset and partial rebound following sleep deprivation, and (3) sleep fragmentation under shift work-like conditions. These results offer new mechanistic insights into how circadian misalignment alters sleep timing and quality. Together, our findings establish an updated theoretical framework for modeling sleep-wake regulation in both natural and disrupted environments, with implications for shift work management, sleep disorder interventions, and personalized chronotherapy. Author summarySleep and wakefulness are regulated by a complex interaction between circadian rhythms and homeostatic sleep pressure. While existing computational models have provided valuable insights, most rely on fixed or heuristic thresholds for sleep and wake transitions that lack direct physiological basis, limiting their ability to account for the full range of sleep behaviors-especially under disrupted conditions. In this study, we substantially update the computational framework in which sleep-wake transitions are governed by dynamically circadian-dependent thresholds. It captures how internal biological time shapes sleep patterns and explains key phenomena such as sleep rebound following deprivation and sleep fragmentation during shift work. It provides new insights into how circadian misalignment leads to sleep disorders and lays the groundwork for more effective, personalized interventions.

neuroscience↗

bioRxiv2025

Activation of the impaired NAMPT/SIRT7/SOD2 axis restores alveolar progenitor cell homeostasis in idiopathic pulmonary fibrosis and reverses pulmonary fibrosis in mice

Alveolar type II (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD+) functions as a central regulator of cellular energy metabolism. We have reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor function of IPF AT2s. In this study, we identified that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is significantly downregulated in IPF AT2s. NAMPT deficiency impairs AT2 renewal and enhances lung fibrosis through downregulation of SIRT7 and SOD2, which results in increased oxidative stress, mitochondrial dysfunction, induction of pathological transitional gene expression and impaired regenerative capacity to generate alveolar type I (AT1) cell required for gas exchange. Mice with deletion of Nampt in AT2s showed severely impaired AT2 renewal and increased susceptibility to bleomycin lung injury and spontaneous fibrois. Activation of NAMPT by small molecule activators promoted AT2 renewal, restored homeostasis, and reversed lung fibrosis. NAMPT activation could be a therapeutic strategy for restoring AT2 progenitor function and halting or reversing progressive pulmonary fibrosis.

cell biology↗

bioRxiv2025

Spatial and single-cell transcriptomics capture two distinct cell states in plant immunity

Unlike animals, plants are sessile organisms that must adapt to localized and fluctuating environmental stimuli, including abiotic and biotic stresses. While animals use mobile immune cells to eliminate pathogens, plants rely on localized cells in contact with the pathogen to detect and mount immune responses. Although bulk RNA sequencing (RNA-seq) has enabled the assessment of plant responses to pathogen infection at the whole transcriptome level, the spatial coordination of plant immune responses remains elusive. In this study, we performed both spatial and single-nuclei transcriptomic experiments to capture the spatial pattern of soybean plant responses to Asian soybean rust infection caused by the pathogen Phakopsora pachyrhizi. Through the analysis of both spatial and single-nuclei transcriptomics data, we identified two distinct host cell states with specific spatial localization in response to pathogen infection: the infected regions with the presence of the pathogen and the surrounding regions bordering the infected regions. Importantly, the surrounding regions exhibited higher expression of defense response-related genes than the infected regions, despite having minimal presence of the pathogen, indicating a cell non-autonomous defense response in the surrounding regions. Additionally, gene co-expression network analysis with single-cell resolution identified a key immune response-related gene module activated in the stressed cells captured in our single-nuclei RNA-seq data. This study reveals the intricate spatial coordination of plant defense responses against pathogen infection and enhances our understanding of the importance of localized cell non-autonomous defense responses in plant-pathogen interactions.

plant biology↗

bioRxiv2025

Senescent mast cells contribute to the progression of benign prostatic hyperplasia via SCF/c-KIT mediated endothelial-mesenchymal transition

Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-{beta}1) through the stem cell factor (SCF)/c-KIT-MAPK-JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo. Thus, these findings revealed a senescence-linked immune-stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.

cell biology↗

bioRxiv2025

The XPF-like domain in SHOC1 required for homologous recombination and safeguarding autosome from meiotic silencing of unsynapsed chromatin

During meiosis, a group of evolutionarily conserved ZMM proteins plays essential roles in stabilizing the recombination intermediates and promoting crossover (CO) formation. In mice, SHOC1 forms a trimeric complex with the other two ZMM proteins, SPO16 and TEX11, to bind recombination intermediates after strand invasion. Although genetic variants of SHOC1 are clinically associated with meiotic arrest and male infertility, their precise molecular mechanisms and evolutionarily conserved functions in human gametogenesis remain enigmatic. Here, we delineated species-specific divergences between human and mouse SHOC1 complex, and identified a missense variant within the XPF-like domain in SHOC1 (c.A1769G:p.Q590R) that was associated with meiotic arrest and non-obstructive azoospermia (NOA). The disorder of the XPF-like domain in SHOC1 impaired DNA double-strand breaks repair by compromising its ability to bind branched DNA structures and the recruitment of M1AP, REDIC1, and ZMM factors to recombination intermediates, ultimately abolishing CO formation. Furthermore, the variant disrupted dynamic 3D chromatin structure in pachytene spermatocytes and induced defects in homologous chromosome synapsis. More importantly, the XPF-like domain in SHOC1 was revealed to prevent autosome intrusion into the sex body compartment, thereby safeguarding critical autosomal loci from meiotic silencing of unsynapsed chromatin (MSUC). Overall, our study demonstrated that the XPF-like domain in SHOC1 is required for homologous recombination and safeguarding autosome from MSUC in meiosis.

developmental biology↗

bioRxiv2025

Testicular mRNA-LNP Delivery: A Novel Therapy for Genetic Spermatogenic Disorders

Uniform testicular maturation arrest is a severe form of male infertility characterized by the presence of germ cells that do not complete spermatogenic development. It is usually caused by meiotic arrest with genetic variants and difficult to treat via drugs or surgery. mRNA-lipid nanoparticle (LNP) delivery is a promising therapeutic option for maturation arrest with monogenic variants via protein replacement therapy. Herein, a spermatocytes-tropic LNP (Pool1-LNP3) was identified via a library of 30 ionizable lipids screening. And in vivo delivery of this novel LNP composition using rete testis microinjection was showed to be high spermatocytes targeting with high transfection efficiency. Thereafter, it was revealed that in vivo delivery of Pool1-LNP3 encapsulating Msh5 mRNA could promote crossover formation and restore spermatogenesis in Msh5D486Y/D486Y mouse models with DSB recombination defects. Notably, the offspring without genomic integration was born using intracytoplasmic sperm injection (ICSI) derived from rescue of Msh5D486Y/D486Ymouse and embryo transfer. Furthermore, no obvious inflammation and histologic damage in any tissue were detected after in vivo delivery of mRNA-LNP. In addition, it was demonstrated that Maps mRNA-LNP3 recovered spermatogenesis in Maps KO mouse with meiotic arrest. Altogether, these findings suggested that this spermatocytes-tropic mRNA-LNP delivery could become a viable and broad applicable strategy for treatment of spermatogenic disorders with genetic defects, providing a foundation for future clinical application.

molecular biology↗

bioRxiv2024

Global transcription factors analyses reveal hierarchy and synergism of regulatory networks and master virulence regulators in Pseudomonas aeruginosa

The transcription factor (TF) regulatory network in Pseudomonas aeruginosa is complex and involves multiple regulators that respond to various environmental signals and physiological cues by regulating gene expression. However, the biological functions of at least half of its 373 putative TFs remain uncharacterised. Herein, chromatin immunoprecipitation sequencing (ChIP-seq) was used to investigate the binding sites of 172 TFs in the P. aeruginosa PAO1 strain. The results revealed 81,009 significant binding peaks in the genome, more than half of which were located in the promoter regions. To further decode the diverse regulatory relationships among TFs, a hierarchical network was assembled into three levels: top, middle, and bottom. Thirteen ternary regulatory motifs revealed flexible relationships among TFs in small hubs, and a comprehensive co-association atlas was established, showing the enrichment of seven core associated clusters. Twenty-four TFs were identified as the master regulators of virulence-related pathways. The pan-genome analysis revealed the conservation and evolution of TFs in P. aeruginosa complex and other species. A Web-based database combining existing and new data from ChIP-seq and the high-throughput systematic evolution of ligands by exponential enrichment was established for searching TF-binding sites. This study provides important insights into the pathogenic mechanisms of P. aeruginosa and related bacteria and is expected to contribute to the development of effective therapies for infectious diseases caused by this pathogen.

microbiology↗

bioRxiv2024

Survival of hepatocytes from executioner caspase activation promotes liver regeneration by enhancing JAK/STAT3 activity

Activation of executioner caspases, which is a key step in the apoptotic process, has been reported to promote tissue regeneration by sending pro-proliferation signals to the surrounding cells. However, whether executioner caspase activation (ECA) has cell-autonomous effect on tissue regeneration is not clear. Here, by generating transgenic mice carrying a lineage tracing system for cells that have experienced ECA, we demonstrate that transient ECA occurs in hepatocytes during liver regeneration after partial hepatectomy (PHx) or carbon tetrachloride (CCl4) treatment. Instead of committing apoptotic cell death, the majority of hepatocytes with ECA survive and proliferate to contribute to liver regeneration. Interestingly, inhibition of ECA in livers results in reduced hepatocyte proliferation and impaired regeneration, whereas increasing ECA to a level sufficient to kill hepatocytes also impedes regeneration, suggesting that ECA needs to be precisely controlled during liver regeneration. Mechanistic studies show that ECA promotes hepatocyte proliferation during regeneration through enhancing JAK/STAT3 activity. Our work reveals an essential role of survival of hepatocytes from ECA in liver regeneration.

developmental biology↗

bioRxiv2024

AutoMorFi: Automated Whole-image Morphometry in Fiji/ImageJ for Diverse Image Analysis Needs

Running on the highly popular and accessible ImageJ/Fiji platform for biological image analysis, we have established AutoMorFi as a streamlined interface for automated whole-image morphometric analysis that generates at least 47 measurements per cell or object in under 1 minute. We performed multiple validated cluster and principal component analyses on nonredundant morphometric parameters derived from AutoMorFi for various cell types, objects, and organisms. We used images of rodent macrophages, human postmortem brain tissues from multiple sclerosis (MS) and Alzheimers disease (AD) patients, iPSC/animal models for Downs syndrome and autism spectrum disorder (ASD), and organisms such as sea anemone and corals. AutoMorFis adaptability extends across diverse imaging modalities including brightfield, confocal, or widefield fluorescence microscopy as well as underwater photography. Due to its unlimited and unbiased sampling across any image and high potential for modification and customization, using AutoMorFi has led to the discovery of new distinguishing features in previously studied cell types and organisms as well as the development of rapid diagnostic approaches. AutoMorFi represents a transformative tool that will accelerate morphometric analysis and offer broad relevance in biological studies.

cell biology↗

bioRxiv2024

NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion

The progressive decline of CD8 T cell effector function--also known as terminal exhaustion--is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-{gamma} and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states. One Sentence SummaryThe KEAP1-NRF2 pathway is hyperactivated in terminally exhausted CD8 T cells and drives T cell dysfunction via transcriptional regulation of the prostacyclin receptor, Ptgir.

immunology↗

bioRxiv2024

Transcranial Direct Current Stimulation over the Posterior Parietal Cortex Increases Non-target Retrieval during Visual Working Memory

Accurate visual working memory (VWM) requires precise content-context binding. Previous studies have revealed a close relationship between the posterior parietal cortex (PPC) and feature binding during VWM, this study further examined their causal relationship through three transcranial direct current stimulation (tDCS) experiments. In Experiment 1 (N = 57), participants underwent three sessions of tDCS separately, including PPC stimulation, occipital cortex stimulation, and sham stimulation, and completed a series of delayed estimation tasks for orientations before and after stimulation. Results showed that tDCS over PPC selectively prolonged recall response time (RT) and increased the probability of non-target responses (a.k.a. failure of feature binding). In Experiment 2 (N = 29), combining metacognition estimation during the task, we further investigated whether the effects of PPC stimulation on RT and increased probability of non-target responses were attributed to more mis-binding (i.e., participants self-reported "remembered" in non-target responses) or informed guessing (participants self-reported "forgotten" in non-target responses). We replicated the main findings in Experiment 1, and we also observed greater tDCS effects of PPC on RT in informed guessing trials than mis-binding trials while comparable effects on non-target response rates in these two types of trials. In Experiment 3 (N = 28), we then examined whether the effects of tDCS over PPC specifically influenced the memory retrieval process by using a change detection task. We found that PPC stimulation did not influence the recognition RT or accuracy. Together, this study provides causal evidence supporting the involvement of PPC in feature binding during VWM retrieval. Significance StatementVisual working memory (VWM) enables humans to temporarily store and process visual information, which requires accurate binding of items to their unique context. Accumulating studies posited that the posterior parietal cortex (PPC) is closely related to this binding process, the current study further examined their causal relationship. Through three strictly within-subject well-designed non-invasive neural stimulation experiments, we found that PPC stimulation selectively increased response time (RT) and binding error during VWM. Moreover, we found these changes were modulated by individual metacognition and only occurred during memory recall instead of recognition. Together, our results provided strong evidence that PPC is causally involved in the binding process during visual working memory retrieval.

neuroscience↗

bioRxiv2023

Identification of Lactuca sativa transcription factors impacting resistance to Botrytis cinerea through predictive network inference

Lettuce is susceptible to a wide range of plant pathogens including the fungal pathogens Botrytis cinerea and Sclerotinia sclerotiorum, causal agents of grey mould and lettuce drop, respectively. Chemical control is routinely used but there is an urgent need to develop varieties with enhanced resistance given the economic and environmental costs of preventative pesticide sprays, the prevalence of fungicide-resistant isolates of both pathogens in the field, and the increasing withdrawal of approved fungicides through legislation. Resistance against Botrytis cinerea and Sclerotinia sclerotiorum is quantitative, governed by multiple small-medium impact loci, with plant responses involving large-scale transcriptional reprogramming. The elucidation of the gene regulatory networks (GRNs) mediating these responses will not only identify key transcriptional regulators but also interactions between regulators and show how the defence response is fine-tuned to a particular pathogen. We generated high-resolution (14 time points) time series expression data from lettuce leaves following mock-inoculation or inoculation with B. cinerea, capturing the dynamics of the transcriptional response to infection. Integrating this data with a time series dataset from S. sclerotiorum infection of lettuce identified a core set of 4362 genes similarly differentially expressed in response to both pathogens. Using the expression data for these core genes (with additional single time point data from 21 different lettuce accessions) we inferred a GRN underlying the lettuce defence response to these pathogens. Using the GRN, we have predicted and validated key regulators of lettuce immunity, identifying both positive (LsBOS1) and negative (LsNAC53) regulators of defence against B. cinerea, as well as downstream target genes. These data provide a high level of detail on defence-induced transcriptional change in a crop species and a GRN with the ability to predict transcription factors mediating disease resistance both in lettuce and other species.

plant biology↗

bioRxiv2023

A transcriptional cell atlas identifies the decline in the AT2 niche in aged human lungs

Aging poses a global public health challenge, associated with molecular and physiological changes in the lungs. It increases susceptibility to acute and chronic lung diseases, yet the underlying molecular and cellular drivers in aged populations are not fully appreciated. To systematically profile the genetic changes associated with age, we present a single-cell transcriptional atlas comprising nearly half a million cells from the healthy lungs of human subjects spanning various ages, sexes, and smoking statuses. Most annotated cell lineages in aged lungs exhibit dysregulated genetic programs. Specifically, the aged alveolar epithelial cells, including both alveolar type II (AT2) and type I (AT1) cells, demonstrate loss of epithelial identities, heightened inflammaging characterized by increased expression of AP-1 transcription factor and chemokine genes, and significantly increased cellular senescence. Furthermore, the aged mesenchymal cells display a remarkable decrease in Collagen and Elastin transcription. The decline of the AT2 niche is further exacerbated by a weakened endothelial cell phenotype and a dysregulated genetic program in macrophages. These findings highlight the dysregulation observed in both AT2 stem cells and their supportive niche cells, potentially contributing to the increased susceptibility of aged populations to lung diseases.

cell biology↗

bioRxiv2023

U1 AMO (antisense morpholino oligos) disrupts U1 snRNP structure to promote intronic PCPA (premature cleavage and polyadenylation)

Functional depletion of U1 snRNP with a 25 nt U1 AMO (antisense morpholino oligonucleotides) may lead to intronic premature cleavage and polyadenylation (PCPA) of thousands of genes, a phenomenon known as U1 snRNP telescripting; however, the underlying mechanism remains elusive. In this study, we demonstrated that U1 AMO could disrupt U1 snRNP structure both in vitro and in vivo, thereby affecting U1 snRNP/RNAP polymerase II (RNAPII) interaction. We further showed that U1 AMO treatment might promote RNAPII disassociation with pre-mRNA in an RNA pull-down assay. By performing ChIP-seq for phosphorylation of Ser2 (Ser2P) and Ser5 (Ser5P) of the C-terminal domain (CTD) of RNA polymerase II (RNAPII), we showed that transcription elongation was disturbed upon U1 AMO treatment, with a particular high Ser2P signal at intronic cryptic polyadenylation sites (PASs). In addition, we showed that core 3 processing factors CPSF/CstF are involved in the processing of intronic cryptic PAS. Their recruitment accumulated toward cryptic PASs upon U1 AMO treatment, as indicated by ChIP-seq and iCLIP-seq analysis. Furthermore, we showed that most of these PCPAed transcripts could be exported to cytoplasm and have the potential to be translated. Conclusively, our data provide more insight into U1 snRNP telescripting, and suggest a common theme that modulation of transcription elongation may be an important mode for the regulation of mRNA polyadenylation.

molecular biology↗

bioRxiv2022

Neurological Disorder after Severe Pneumonia is Associated with Translocation of Bacteria from Lung to Brain

The neurological disorder is a common feature in patients who recovered from severe acute pneumonia. However, the underline mechanisms remain not very clear. Here we show that these neurological syndromes after severe acute pneumonia are partly attributed to the translocation of bacteria from the lung to the brain during pneumonia. We detected an emerging and increased bacteria in the brain tissue of mice with lipopolysaccharide-induced experimental severe pneumonia. Interestingly, using 16S rDNA amplification sequencing, similarities were found between the brains flora species and those of the lungs, indicating the bacteria in the brain may originate from the lung. We also observed the impairment of the lung-blood barrier and brain-blood barrier, simultaneously, allowing lung bacteria invade the brain during pneumonia. An elevated microglia and astrocytes activation signature through bacterial infection-related pathways is observed by single-cell RNA sequencing, indicating a bacteria-induced disruption of brain homeostasis. Rapamycin delivered by platelet-derived extracellular vesicles provides an effective strategy to rescue the dysfunction of microglia and astrocytes, and relief neurological disorders. Collectively, we identify lung bacteria that play a role in altering brain homeostasis, which provides new insight into the mechanism of neurological syndromes after severe pneumonia.

neuroscience↗

bioRxiv2022

A systematic evaluation revealed that detecting translated non-canonical ORFs from ribosome profiling data remains challenging

Non-canonical open reading frames (ORFs), which are ORFs that are not included in reference genome annotations, are gaining more and more research interest in recent years. While vast numbers of non-canonical ORFs have been identified with ribosome profiling (Ribo-Seq) by various state-of-the-art computational methods, the performance of these methods has not been assessed systematically. To this end, we evaluated the four most popular methods for translated non-canonical ORF prediction using various public datasets. We found that non-canonical ORFs predicted by different methods differ substantially and are not saturated at typical sequence depths. Furthermore, the precision and accuracy of all four methods are not satisfactory, especially for ORFs with near-cognate start codons. Based on these results, we suggest that improved sequence depth, biological repetitions, and translation initiation site profiling should be considered to obtain a high-quality catalog of translated non-canonical ORFs in future studies.

genomics↗

bioRxiv2022

Dietary fibre controls blood pressure and cardiovascular risk by lowering large intestinal pH and activating the proton-sensing receptor GPR65

High blood pressure (BP) is the most common cause of death globally, due to increasing the risk of cardiovascular diseases. Dietary fiber regulates BP through gut microbial production of acidic metabolites known as short-chain fatty acids (SCFAs). The specific mechanisms of how SCFAs regulate BP are still emerging. In a phenome-wide association study, we identified that the proton-sensing G-protein-coupled receptor GPR65 gene is associated with hypertension and its associated end-organ damage phenotypes. We hypothesized that acidic metabolites produced from the gut microbiota may activate GPR65, thus conferring BP regulating effects. We found that dietary fiber levels determined the luminal and interstitial tissue pH in the large intestine through production of SCFAs by the gut microbiota. We identified that low pH produced by high fiber intake, acting via GPR65 signaling, increased cAMP production and phosphorylation of CREB, and restricted the production of hypertension-promoting inflammatory cytokines by CD8+ T cells. Gpr65-/- mice spontaneously developed higher BP, cardiac and renal hypertrophy and fibrosis. We showed that the benefits of a diet high in fiber, which prevented hypertension and associated end-organ damage, were decreased in Gpr65-/- mice. Finally, adoptive transfers revealed that GPR65 deficiency in CD8+ T cells causally explained this phenotype. In conclusion, we showed that pH sensing by GPR65 in CD8+ T cells mediates much of the cardiovascular benefits of dietary fiber. pH sensing represents a novel gene-by-environment interaction of gut microbiota-to-host biological effects and may form the basis for new therapeutic strategies for hypertension.

molecular biology↗

bioRxiv2022

"Double-Effect" strategy against Triple-Negative Breast Cancer via a synergistic therapy of Magneto-mechanical Force enhancing NIR-II Hypothermal Ablation

Triple-negative breast cancer (TNBC) is a form of breast cancer that is more aggressive and harder to treat than others, with a higher probability of relapse. Its highly efficient capabilities for migrating and invading other parts of the body together with the current lack of clinically established effective therapies account for a low survival rate. Thus, we propose the in-tandem use of two complementary therapeutic routes to effectively combat TNBC. Herein, a versatile magnetic-photothermal converter (MPC) is elaborately designed via integrating zinc-doped ferrite nanoparticles and polyethene glycol, synergistically enhanced through magneto-mechanical force (MMF) and near-infrared-II (NIR-II) hypothermal ablation, thereby displaying excellent therapeutic efficiency. Their combined use, which is less aggressive to the human body compared to conventional chemotherapeutic approaches, results in the splendid suppression of TNBC migration and invasion. Remotely controlling the MPCs by an external magnetic stimulus, results in cellular MMF effects that cause direct mechanical destruction to the cancer cell membrane, leading to its necrosis. Furthermore, the MMF disrupts intracellular lysosomes, thereby triggering the release of large amounts of protein hydrolases, which induce intracellular oxidative stress, and accelerate the induction of apoptosis. Complementing the therapeutic approach based on MMF, the excellent photothermal performance of the MPC in the NIR-II region (1064nm) is exploited to enable effective hypothermal ablation of the tumours, which can be achieved in deep tissue layers. The proposed multifunctional nanocomposites, together with the demonstrated "double effect" therapeutic approach, hold significant potential to pave the way for future cutting-edge weapons against the dreadful TNBC.

cancer biology↗