Biology subjects

Zhong, R.

Publications and source records attributed to Zhong, R..

12 recordsLinked to original sources

bioRxiv2026

Endotoxemia and TLR4 via tissue resident macrophages triggers anemia in mouse model of colitis

Anemia is one of the most debilitating and frequent complication of inflammatory bowel diseases (IBD) and is often treated with iron supplementation, which has limited efficacy and causes additional co-morbidities. Damaged intestinal barrier function is a hallmark of IBD and causes the translocation of endotoxins from gut bacteria into the bloodstream. A previous study in mice reported that endotoxins suppress erythropoiesis by reprogramming erythroblastic island macrophages (EBI M{varphi}). Here, we show that IBD patients and mice with acute colitis developed endotoxemia associated with anemia. Endotoxemia in IBD patients was negatively correlated with blood erythrocyte counts. In line with this, mice with acute colitis caused by drinking water containing dextrin sodium sulphate (DSS) had endotoxemia together with anemia characterized by reduced red blood cell counts, hemoglobin content and hematocrit, and reduced medullary erythropoiesis which was in part compensated by increased extramedullary erythropoiesis. As the endotoxin receptor TLR4 is expressed by CD169+ gut-resident macrophages as well as erythroid island macrophages in the bone marrow, we tested the hypothesis that TLR4 expressed by these CD169+ macrophages mediate both inflammatory colitis and anemia. Indeed, mice with a conditional deletion of the Tlr4 gene specifically in CD169+ tissue-resident macrophages were protected from DSS-induced anemia, inflammation and colitis. In addition, treatment with the TLR4 inhibitor C34 abated inflammation and anemia in DSS mice. These results suggest that endotoxins leaking from the inflamed gut may play a crucial role in IBD and associated anemia via CD169+ tissue-resident macrophages and that drugs targeting TLR4 may protect against IBD-associated anemia.

immunology↗

bioRxiv2026

Morphological, molecular, and functional evidence for a CNS-like oral nerve ring in the sea anemone Nematostella vectensis

The emergence of centralized nervous systems reflects a major inflection point in evolution, enabling animals to integrate diverse inputs and coordinate complex behaviors. Neural centralization is typically associated with Bilateria, whereas their sister group, Cnidaria (jellyfish, anemones, and corals), has long been thought to rely on diffuse nerve nets mediating simple reflexes. This view, reinforced by limited anatomical and molecular data, has left unresolved whether cnidarians can form localized centers for neural processing, a question sharpened by the growing recognition of their diverse behavioral repertoires. Here we show that the sea anemone Nematostella vectensis possesses an oral nerve ring composed of ganglion-like condensations, a hallmark of centralized organization. These neurons are enriched for excitatory, inhibitory, and modulatory receptors but lack sensory or ciliary markers, yielding a molecular profile most consistent with bilaterian interneurons. Genetic disruption of a conserved inhibitory receptor subunit predominantly expressed in the oral nerve ring delayed the initiation of swallowing in a novel feeding paradigm, demonstrating a potential role in behavioral regulation. Together, these findings provide converging anatomical, molecular, and functional evidence that cnidarians can assemble localized integrative centers, suggesting that key elements of neural centralization predated the cnidarian-bilaterian split.

evolutionary biology↗

bioRxiv2025

Spatiotemporal dynamics and migration pathways of the transboundary Beet Webworm Loxostege sticticalis (Linnaeus) between Northern China and Mongolia in 2022

Clarifying the population dynamics, source-landing relationships, and migration pathways of the beet webworm Loxostege sticticalis (Linnaeus) both domestically and internationally, as well as understanding the meteorological mechanisms shaping these patterns, is pivotal for remote, accurate, and location-specific pest forecasting. Based on light trap data from northern China and field survey data from Mongolia in 2022, we simulated the migration trajectories, source regions, and primary landing areas of L. sticticalis, and analyzed the synoptic systems and processes during its migration. The results indicate frequent exchange of L. sticticalis populations between China and Mongolia in 2022. The L. sticticalis migrants initiating their flights from Mongolia primarily undertook a southeastward migration pathway, supplemented by eastward cyclonic and southwestward paths. The main landing areas were located in North China and Northeast China, with migration events potentially extending to Shandong, Heilongjiang, and Xinjiang provinces. Populations originating from North China exhibited a capacity for migrating into Northeast China and Mongolia through 1 to 5 consecutive nights of flight. During this period, the Northeast China Cold Vortex (NCCV) and the Mongolian Cyclone alternately regulated the synoptic circulation pattern governing the migration of L. sticticalis. The spatiotemporal distributions and intensities of these systems were key determinants of the transboundary migration routes and distances of L. sticticalis. The NCCV dominated, and the precipitation and downdrafts it induced were crucial for the massive landing of L. sticticalis in northern China.

ecology↗

bioRxiv2024

TFEB/HLH-30-mediated expansion of neuronal lysosomal capacity in early adulthood protects dendrite maintenance during aging in Caenorhabditis elegans

Lysosomes are essential for neuronal homeostasis, providing degradation and recycling functions necessary to support neurons complex operations and long lifespans. However, the regulation of lysosomal degradative capacity in healthy neurons is poorly understood. Here, we investigate the role of HLH-30, the sole Caenorhabditis elegans homolog of Transcription Factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy that it is thought to predominantly function in the context of starvation or stress. We demonstrate that HLH-30 is dispensable for neuronal development but acts cell-intrinsically to expand lysosomal degradative capacity during early adulthood. Loss of HLH-30 leads to lysosomal dysfunction and delayed turnover of synaptic vesicle proteins from the synapse. Notably, we show that basal HLH-30 activity is sufficient to expand neuronal lysosomal capacity without nuclear enrichment, in contrast to the nuclear translocation associated with starvation- and stress-induced activation of TFEB and HLH-30. Furthermore, we show that neuronal lysosomal function declines with age in wild-type animals, and this corresponds to a decrease in basal HLH-30-mediated transcription. We further demonstrate that basal HLH-30 activity is crucial for neuron maintenance: lysosomal dysfunction due to inadequate HLH-30 activity leads to dendrite degeneration and aberrant outgrowths. In summary, our study establishes a critical role for HLH-30/TFEB in promoting lysosomal capacity to preserve neuronal homeostasis and structural integrity of mature neurons in vivo.

cell biology↗

bioRxiv2024

Cell-type-specific splicing of transcription regulators and Ptbp1 by Rbfox1/2/3 in the developing neocortex

How master splicing regulators crosstalk with each other and to what extent transcription regulators are differentially spliced remain unclear in the developing brain. Here, cell-type-specific RNA-Seq of the developing neocortex uncover that transcription regulators are enriched for differential splicing, altering protein isoforms or inducing nonsense-mediated mRNA decay. Transient expression of Rbfox proteins in radial glia progenitors induces neuronal splicing events preferentially in transcription regulators such as Meis2 and Tead1. Surprisingly, Rbfox proteins promote the inclusion of a mammal-specific alternative exon and a previously undescribed poison exon in Ptbp1. Simultaneous ablation of Rbfox1/2/3 in the neocortex downregulates neuronal isoforms and disrupts radial neuronal migration. Furthermore, the progenitor isoform of Meis2 promotes Tgfb3 transcription, while the Meis2 neuron isoform promotes neuronal differentiation. These observations indicate that transcription regulators are differentially spliced between cell types in the developing neocortex.

developmental biology↗

bioRxiv2024

Loss of calpain 3 dysregulates store-operated calcium entry and its exercise response in mice

Limb-Girdle Muscular Dystrophy 2A (LGMD2A) is caused by mutations in the CAPN3 gene encoding Calpain 3, a skeletal-muscle specific, Ca2+-dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca2+ homeostasis. Through live-cell Ca2+ measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) in Capn3 deficient (C3KO) and wildtype (WT) mice, we determined if loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity. Direct Ca2+ influx measurements revealed loss of Capn3 elicits elevated resting SOCE and increased resting cytosolic Ca2+, supported by high incidence of calcium entry units (CEUs) observed by EM. C3KO and WT mice were subjected to a single bout of treadmill running to elicit SOCE. Within 1HR post-treadmill running, C3KO mice exhibited diminished force production in extensor digitorum longus muscles and a greater decay of Ca2+ transients in flexor digitorum brevis muscle fibers during repetitive stimulation. Striking evidence for impaired exercise-induced SOCE activation in C3KO mice included poor colocalization of key SOCE proteins, stromal-interacting molecule 1 (STIM1) and ORAI1, combined with disappearance of CEUs in C3KO muscles. These results demonstrate that Calpain 3 is a key regulator of SOCE in skeletal muscle and identify SOCE dysregulation as a contributing factor to LGMD2A pathology.

physiology↗

bioRxiv2023

Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

Alzheimers disease (AD) is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. Recent genome-wide association studies (GWAS) identified TREM2 (triggering receptor expressed on myeloid cells 2) as one of the major risk factors for AD. TREM2 is a surface receptor expressed on microglia and largely mediates microglial functions and immune homeostasis in the brain. The functions of TREM2 in AD pathogenesis, including in the formation of the key pathology parenchymal amyloid-{beta} (A{beta}) plaques, have been investigated by introducing Trem2 deficiency in AD mouse models. However, the role of TREM2 in cerebrovascular amyloidosis, in particular cerebral amyloid angiopathy (CAA) remains unexplored. CAA features A{beta} deposition along the cerebral vessels, signifying an intersection between AD and vascular dysfunction. Using a well-characterized CAA-prone, transgenic mouse model of AD, Tg-SwDI (SwDI), we found that loss of TREM2 led to a marked increase in overall A{beta} load in the brain, but a dramatic decrease in CAA in microvessel-rich regions, along with reduced microglial association with CAA. Transcriptomic analysis revealed that in the absence of Trem2, microglia were activated but trapped in transition to the fully reactive state. Like microglia, perivascular macrophages were activated with upregulation of cell junction related pathways in Trem2-deficient SwDI mice. In addition, vascular mural cells and astrocytes exhibited distinct responses to Trem2 deficiency, contributing to the pathological changes in the brain of Trem2-null SwDI mice. Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular A{beta} pathologies, which may have significant implications for both TREM2- and A{beta}-targeting therapies for AD.

neuroscience↗

bioRxiv2023

Epigenetically silenced DACT3 promotes tumor growth via affecting Wnt/beta-catenin signaling and supports chidamide plus azacitidine therapy in acute myeloid leukemia

BackgroundDACT gene is a potential Wnt antagonist and tumor suppressor gene. However, the expression of DACT gene in acute myeloid leukemia (AML) and its role are still unknown. MethodsIn this study, we first multidimensionally analyzed the expression of DACT gene in AML through RNA seq, qRT-PCR and Western blotting analysis as well as TCGA database analysis. Then DACT3 was identified as playing a critical role in AML, and its clinical significance was further explored. The molecular mechanism of DACT3 down-regulation in AML from aspects of DNA methylation and histone acetylation were inquired. Finally, the biological functions of DACT3 in AML were investigated by cell models in vitro and animal experiments in vivo. ResultsCompared with DACT1 and DACT2, DACT3 was the most differentially expressed DACT family member in AML, suggesting that DACT3 plays the major role. The mRNA and protein expression levels of DACT3 were significantly decreased and positively correlated in AML. Moreover, low expression of DACT3 is associated with no remission disease status and poor prognosis in AML patients. In addition, down-regulation of DACT3 in AML was not completely dependent on promoter methylation, but also affected by histone deacetylation. We found that loss of DACT3 in AML is related to activation of Wnt signaling pathway. Furthermore, DACT3 inhibits the growth of AML cells in vitro and in severe immunodeficiency (SCID) mice. Importantly, DACT3 improved the sensitivity of adriamycin in treating AML cells. Further research showed that co-treatment of chidamide and azacytidine up-regulates DACT3 expression and promotes cell apoptosis via inhibiting Wnt/{beta}-catenin signaling in AML, suggesting a promising therapeutic prospects in FLT3-mutant AML. ConclusionThis is the first study revealing the epigenetic regulatory molecular mechanism of the down regulated expression of DACT3 in AML. Our data also shows that DACT3 is a candidate gene for therapeutic target and targeting DACT3 has the potential to validate the combination therapy of DNMT inhibitors and HDAC inhibitors.

molecular biology↗

bioRxiv2021

Gut-testis axis: microbiota-(n-3) PUFA improving semen quality in type 1 diabetes

Gut dysbiosis and type 1 diabetes (T1D) are closely related, and gut dysbiosis and male infertility are correlated, too. Moreover, most male T1D patients are of active reproductive age. Therefore, it is crucial to explore possible means for improving their semen quality. Here, we found that fecal microbiota transplantation (FMT) from alginate oligosaccharide (AOS) improved gut microbiota (A10-FMT) significantly decreased blood glucose and glycogen, and increased semen quality in streptozotocin-induced T1D subjects. A10-FMT improved T1D-disturbed gut microbiota, especially the increase in small intestinal lactobacillus, and blood and testicular metabolome to produce n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to ameliorate spermatogenesis and semen quality. Moreover, A10-FMT can improve spleen and liver function to strengthen the systemic environment for sperm development. FMT from gut microbiota of control animals (Con-FMT) produced some beneficial effects; however, to a smaller extent. Thus, AOS improved gut microbiota may be a useful protocol for improving semen quality and male fertility in T1D patients. ImportanceClinical data suggest that male reproductive dysfunction especially infertility is a critical issue for type 1 diabetic patient (T1D) because most of them are at the reproductive age. Gut dysbiosis is involved in T1D related male infertility. However, improved gut microbiota can be used to improve spermatogenesis and male fertility in T1D remains incompletely understood. We discovered that alginate oligosaccharide-improved gut microbiota (A10-FMT) significantly ameliorated spermatogenesis and semen quality. AOS-improved gut microbiota (specific microbes) may serve as a novel, promising therapeutic approach for the improvement of semen quality and male fertility in T1D patients.

developmental biology↗

bioRxiv2021

Profiling tumor immune microenvironment of non-small cell lung cancer using multiplex immunofluorescence

PurposeWe attempt to profile the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) by multiplex immunofluorescence (MIF). Experimental DesignMIF test was performed on 681 NSCLC cases in our center between 2009 and 2011. The number, density, proportion and correlation of 26 types of immune cells in tumor nest and tumor stroma were evaluated. An unsupervised consensus clustering approach was utilized to identify robust clusters of patients. Immune-related risk score (IRRS) was constructed for prognosis prediction for disease-free survival (DFS). ResultsThe landscape of TIME was illustrated, revealing some close interactions particularly between intrastromal neutrophils and intratumoral regulatory T cells (Treg) (r2 = 0.439, P < 0.001), intrastromal CD4+CD38+ T cells and intrastromal CD20-positive B cells (r2 = 0.539, P < 0.001), and intratumoral CD8-positive T cells and intratumoral M2 macrophages expressing PD-L1 (r2 = 0.339, P < 0.001). Three immune subtypes correlated with distinct immune characteristics and clinical outcomes were identified. The immune-activated subtype had the longest DFS and demonstrated the highest infiltration of CD4-positive T cells and CD20-positive B cells. The immune-defected subtype had the highest levels of cancer stem cells and macrophages. The immune-exempted subtype had the highest levels of neutrophils and Treg. The IRRS based on six robust prognostic biomarkers showed potential ability for risk stratification (high vs. median vs. low) and prediction of five-year DFS rates (43.1% vs. 37.9% vs. 23.2%, P<0.001). ConclusionsOur study profiled the intricate and intrinsic structure of TIME in NSCLC, which showed potency in subtyping and prognostication. Translational RelevanceSignificant unmet need exists in understanding the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) and its correlation with prognosis. In this retrospective cohort study (n = 681), we profiled the immune landscape of NSCLC in situ and identified a novel stratification of TIME by three immune subtypes: immune-activated, immune-exempted, and immune-defected using multiplex immunofluorescence for testing 26 kinds of immune cells. Each of the immune subtypes was correlated with distinct composition, spatial distribution, and functional orientation of immune cells, and accordingly indicating significantly different disease-free survival (DFS). Close interactions were observed for several kinds of immune cells, including neutrophils and regulatory T cells, CD4+CD38+ T cells and CD20-positive B cells, and CD8-positive T cells and M2 macrophages. We also developed the immune-related risk score (IRRS) with different immune characteristics based on six robust immune biomarkers in TIME and evaluated its role in risk stratification and prognosis prediction of DFS. This study might bring potential clinical implementations for the design of novel immunotherapies and the optimization of combined strategies.

cancer biology↗

bioRxiv2021

Protein farnesylation is upregulated in Alzheimer's human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer's model mice

The pathogenic mechanisms underlying the development of Alzheimers disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimers dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.

neuroscience↗

bioRxiv2018

Loss of muscle stem cells in aged mice is replenished by muscle-secreted niche factor G-CSF

Function and number of muscle stem cells (satellite cells, SCs) declines with muscle aging. Although SCs are heterogeneous and different subpopulations have been identified, it remains unknown if a specific subpopulation of muscle SCs selectively decreases during aging. Here, we find Pax7Hi cells are dramatically reduced in aged mice and this aged-dependent loss of Pax7Hi cells is metabolically mediated by myofiber-secreted granulocyte-colony stimulating factor G-CSF as the Pax7Hi SCs are replenished by exercise-induced G-CSF in aged mice. Mechanistically, we show that transcription of G-CSF (Csf3) gene in myofibers is regulated by MyoD in a metabolism-dependent manner and the myofibers-secreted G-CSF acts as a metabolic niche factor required for establishing and maintaining the Pax7Hi SC subpopulation in adult and physiological aged mice by promoting the asymmetric division of Pax7Hi and Pax7Mi SCs. Together, our findings uncover a metabolic niche role of muscle metabolism in regulating Pax7 SC heterogeneity in mice.\n\nHighlightsO_LISingle cell RNA-seq unveils Pax7Hi and Pax7Lo cells are two distinct subpopulations.\nC_LIO_LIPax7Hi SCs are enriched in glycolytic fibers and reduced in aging muscle.\nC_LIO_LIMetabolic niche factor G-CSF is required for regulating dynamic change of Pax7 SCs.\nC_LIO_LIG-CSF replenishes Pax7Hi cells by stimulating asymmetric division of Pax7Mi cells.\nC_LI

cell biology↗