IL-13 secreted by ILC2s promotes the self-renewal of intestinal stem cells through circular RNA circPan3.

Intestinal stem cells (ISCs) are maintained by stemness signaling for precise modulation of self-renewal and differentiation under homeostasis. However, the way in which intestinal immune cells regulate the self-renewal of ISCs remains elusive. Here we found that mouse and human Lgr5+ ISCs showed high expression of the immune cell-associated circular RNA circPan3 (originating from the Pan3 gene transcript). Deletion of circPan3 in Lgr5+ ISCs impaired their self-renewal capacity and the regeneration of gut epithelium in a manner dependent on immune cells. circPan3 bound mRNA encoding the cytokine IL-13 receptor subunit IL-13Rα1 (Il13ra1) in ISCs to increase its stability, which led to the expression of IL-13Rα1 in ISCs. IL-13 produced by group 2 innate lymphoid cells in the crypt niche engaged IL-13Rα1 on crypt ISCs and activated signaling mediated by IL-13‒IL-13R, which in turn initiated expression of the transcription factor Foxp1. Foxp1 is associated with ß-catenin in rendering its nuclear translocation, which caused activation of the ß-catenin pathway and the maintenance of Lgr5+ ISCs.

The Drosophila NPY-like system protects against chronic stress-induced learning deficit by preventing the disruption of autophagic flux.

Chronic stress may induce learning and memory deficits that are associated with a depression-like state in Drosophila melanogaster. The molecular and neural mechanisms underlying the etiology of chronic stress-induced learning deficit (CSLD) remain elusive. Here, we show that the autophagy-lysosomal pathway, a conserved cellular signaling mechanism, is associated with chronic stress in Drosophila, as indicated by time-series transcriptome profiling. Our findings demonstrate that chronic stress induces the disruption of autophagic flux, and chronic disruption of autophagic flux could lead to a learning deficit. Remarkably, preventing the disruption of autophagic flux by up-regulating the basal autophagy level is sufficient to protect against CSLD. Consistent with the essential role of the dopaminergic system in modulating susceptibility to CSLD, dopamine neuronal activity is also indispensable for chronic stress to induce the disruption of autophagic flux. By screening knockout mutants, we found that neuropeptide F, the Drosophila homolog of neuropeptide Y, is necessary for normal autophagic flux and promotes resilience to CSLD. Moreover, neuropeptide F signaling during chronic stress treatment promotes resilience to CSLD by preventing the disruption of autophagic flux. Importantly, neuropeptide F receptor activity in dopamine neurons also promotes resilience to CSLD. Together, our data elucidate a mechanism by which stress-induced excessive dopaminergic activity precipitates the disruption of autophagic flux, and chronic disruption of autophagic flux leads to CSLD, while inhibitory neuropeptide F signaling to dopamine neurons promotes resilience to CSLD by preventing the disruption of autophagic flux.

Polyoxometalates as Potential Artificial Enzymes toward Biological Applications.

Artificial enzymes, as alternatives to natural enzymes, have attracted enormous attention in the fields of catalysis, biosensing, diagnostics, and therapeutics because of their high stability and low cost. Polyoxometalates (POMs), a class of inorganic metal oxides, have recently shown great potential in mimicking enzyme activity due to their well-defined structure, tunable composition, high catalytic efficiency, and easy storage properties. This review focuses on the recent advances in POM-based artificial enzymes. Different types of POMs and their derivatives-based mimetic enzyme functions are covered, as well as the corresponding catalytic mechanisms (where available). An overview of the broad applications of representative POM-based artificial enzymes from biosensing to theragnostic is provided. Insight into the current challenges and the future directions for POMs-based artificial enzymes is discussed.

Surface Engineering Enhances Vanadium Carbide MXene-Based Nanoplatform Triggered by NIR-II for Cancer Theranostics.

Despite the advantages of high tissue penetration depth, selectivity, and non-invasiveness of photothermal therapy for cancer treatment, developing NIR-II photothermal agents with desirable photothermal performance and advanced theranostics ability remains a key challenge. Herein, a universal surface modification strategy is proposed to effectively improve the photothermal performance of vanadium carbide MXene nanosheets (L-V2C) with the removal of surface impurity ions and generation of mesopores. Subsequently, MnOx coating capable of T1-weighted magnetic resonance imaging can be in situ formed through surface redox reaction on L-V2C, and then, stable nanoplatforms (LVM-PEG) under physiological conditions can be obtained after further PEGylation. In the tumor microenvironment irradiated by NIR-II laser, multivalent Mn ions released from LVM-PEG, as a reversible electronic station, can consume the overexpression of glutathione and catalyze a Fenton-like reaction to produce ·OH, resulting in synchronous cellular oxidative damage. Efficient synergistic therapy promotes immunogenic cell death, improving tumor-related immune microenvironment and immunomodulation, and thus, LVM-PEG can demonstrate high accuracy and excellent anticancer efficiency guided by multimodal imaging. As a result, this study provides a new approach for the customization of 2D surface strategies and the study of synergistic therapy mechanisms, highlighting the application of MXene-based materials in the biomedical field.

An Ultrathin Composite Polymer Electrolyte Dual-Reinforced by a Polymer of Intrinsic Microporosity (PIM-1) and Poly(tetrafluoroethylene) (PTFE) Porous Membrane.

The performances of solid-state polymer electrolytes are urgently required to be further improved for high energy density lithium metal batteries. Herein, a highly reinforced ultrathin composite polymer electrolyte (PLPP) is successfully fabricated in a large scale by densely filling the well-dispersed mixture of polyethylene oxide (PEO), Li-salt (LiTFSI) and a polymer of intrinsic microporosity (PIM-1) into porous poly(tetrafluoroethylene) (PTFE) matrix. Based on the macro-plus-micro synergistic enhancement of the PTFE with excellent mechanical properties and the soluble PIM-1 with suitable functional groups, the PLPP electrolyte exhibits excellent properties including mechanical stress, thermal stability, lithium-ion transference number, voltage window and ionic conductivity, which are all superior to the typical PEO/LiTFSI electrolytes. As a result, the Li/PLPP/Li symmetric cell can stably cycle for > 2000 h, and the LiFePO4/PLPP/Li full cell exhibits excellent rate performance (>10 C) and high cycling stability with an initial capacity of 158.8 mAh g-1 and a capacity retention of 78.8% after 300 cycles. In addition, the excellent mechanical properties as well as the wide voltage window reasonably result in the stable operation of full cells with either high-loading cathode up to 28.1 mg cm-2 or high voltage cathode with high energy density.

Asymmetric and Chemoselective Iridium Catalyzed Hydrogenation of Conjugated Unsaturated Oxime Ethers.

Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P-iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π-bond was observed under the applied reaction conditions (20 bar H2, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α-carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed.

Development of Broad-Spectrum Nanobodies for the Therapy and Diagnosis of SARS-CoV-2 and Its Multiple Variants.

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evaded the efficacy of previously developed antibodies and vaccines, thus remaining a significant global public health threat. Therefore, it is imperative to develop additional antibodies that are capable of neutralizing emerging variants. Nanobodies, as the smallest functional single-domain antibodies, exhibit enhanced stability and penetration ability, enabling them to recognize numerous concealed epitopes that are inaccessible to conventional antibodies. Herein, we constructed an immune library based on the immunization of alpaca with the S1 subunit of the SARS-CoV-2 spike protein, from which two nanobodies, Nb1 and Nb2, were selected using phage display technology for further characterization. Both nanobodies, with the binding residues residing within the receptor-binding domain (RBD) region of the spike, exhibited high affinity toward the S1 subunit. Moreover, they displayed cross-neutralizing activity against both wild-type SARS-CoV-2 and 10 ο variants, including BA.1, BA.2, BA.3, BA.5, BA.2.75, BF.7, BQ.1, EG.5.1, XBB.1.5, and JN.1. Molecular modeling and dynamics simulations predicted that both nanobodies interacted with the viral RBD through their complementarity determining region 1 (CDR1) and CDR2. These two nanobodies are novel tools for the development of therapeutic and diagnostic countermeasures targeting SARS-CoV-2 variants and potentially emerging coronaviruses.

LNCHC directly binds and regulates YBX1 stability to ameliorate metabolic dysfunction-associated steatotic liver disease progression.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the foremost cause of chronic liver disease, yet its underlying mechanisms remain elusive. Our group previously discovered a novel long non-coding RNA (lncRNA) in rats, termed lncHC and its human counterpart, LNCHC. This study aimed to explore the role of LNCHC in the progression of MASLD. METHODS: RNA-binding proteins bound to LNCHC were searched by mass spectrometry. The target genes of LNCHC and Y-Box binding protein 1 (YBX1) were identified by RNA-seq. MASLD animal models were utilised to examine the roles of LNCHC, YBX1 and patatin-like phospholipase domain containing 3 (PNPLA3) in MASLD progression. RESULTS: Here, we identified LNCHC as a native restrainer during MASLD development. Notably, LNCHC directly binds YBX1 and prevents protein ubiquitination. Up-regulation of YBX1 then stabilises PNPLA3 mRNA to alleviate lipid accumulation in hepatocytes. Furthermore, both cell and animal studies demonstrate that LNCHC, YBX1 and PNPLA3 function to improve hepatocyte lipid accumulation and exacerbate metabolic dysfunction-associated steatohepatitis development. CONCLUSIONS: In summary, our findings unveil a novel LNCHC functionality in regulating YBX1 and PNPLA3 mRNA stability during MASLD development, providing new avenues in MASLD treatment.

Yes-Associated Protein Targets the Transforming Growth Factor ß Pathway to Mediate High-Fat/High-Sucrose Diet-induced Arterial Stiffness.

BACKGROUND: Metabolic syndrome is related to cardiovascular diseases, which is attributed in part, to arterial stiffness; however, the mechanisms remain unclear. The present study aimed to investigate the molecular mechanisms of metabolic syndrome-induced arterial stiffness and to identify new therapeutic targets. METHODS: Arterial stiffness was induced by high-fat/high-sucrose diet in mice, which was quantified by Doppler ultrasound. Four-dimensional label-free quantitative proteomic analysis, affinity purification and mass spectrometry, and immunoprecipitation and GST (glutathione S-transferase) pull-down experiments were performed to explore the mechanism of YAP (Yes-associated protein)-mediated TGF (transforming growth factor) ß pathway activation. RESULTS: YAP protein was upregulated in the aortic tunica media of mice fed a high-fat/high-sucrose diet for 2 weeks and precedes arterial stiffness. Smooth muscle cell-specific YAP knockdown attenuated high-fat/high-sucrose diet-induced arterial stiffness and activation of TGFß-Smad2/3 signaling pathway in arteries. By contrast, Myh11CreERT2-YapTg mice exhibited exacerbated high-fat/high-sucrose diet-induced arterial stiffness and enhanced TGFß-activated Smad2/3 phosphorylation in arteries. PPM1B (protein phosphatase, Mg2+/Mn2+-dependent 1B) was identified as a YAP-bound phosphatase that translocates into the nucleus to dephosphorylate Smads (mothers against decapentaplegic homologs) in response to TGFß. This process was inhibited by YAP through removal of the K63-linked ubiquitin chain of PPM1B at K326. CONCLUSIONS: This study provides a new mechanism by which smooth muscle cell YAP regulates the TGFß pathway and a potential therapeutic target in metabolic syndrome-associated arterial stiffness.

Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis.

BACKGROUND: Inflamed endothelial cells (ECs) trigger atherogenesis, especially at arterial regions experiencing disturbed blood flow. UCP2 (Uncoupling protein 2), a key mitochondrial antioxidant protein, improves endothelium-dependent relaxation in obese mice. However, whether UCP2 can be regulated by shear flow is unknown, and the role of endothelial UCP2 in regulating inflammation and atherosclerosis remains unclear. This study aims to investigate the mechanoregulation of UCP2 expression in ECs and the effect of UCP2 on endothelial inflammation and atherogenesis. METHODS: In vitro shear stress simulation system was used to investigate the regulation of UCP2 expression by shear flow. EC-specific Ucp2 knockout mice were used to investigate the role of UCP2 in flow-associated atherosclerosis. RESULTS: Shear stress experiments showed that KLF2 (Krüppel-like factor 2) mediates fluid shear stress-dependent regulation of UCP2 expression in human aortic and human umbilical vein ECs. Unidirectional shear stress, statins, and resveratrol upregulate whereas oscillatory shear stress and proinflammatory stimuli inhibit UCP2 expression through altered KLF2 expression. KLF2 directly binds to UCP2 promoter to upregulate its transcription in human umbilical vein ECs. UCP2 knockdown induced expression of genes involved in proinflammatory and profibrotic signaling, resulting in a proatherogenic endothelial phenotype. EC-specific Ucp2 deletion promotes atherogenesis and collagen production. Additionally, we found endothelial Ucp2 deficiency aggravates whereas adeno-associated virus-mediated EC-Ucp2 overexpression inhibits carotid atherosclerotic plaque formation in disturbed flow-enhanced atherosclerosis mouse model. RNA-sequencing analysis revealed FoxO1 (forkhead box protein O1) as the major proinflammatory transcriptional regulator activated by UCP2 knockdown, and FoxO1 inhibition reduced vascular inflammation and disturbed flow-enhanced atherosclerosis. We showed further that UCP2 level is critical for phosphorylation of AMPK (AMP-activated protein kinase), which is required for UCP2-induced inhibition of FoxO1. CONCLUSIONS: Altogether, our studies uncover that UCP2 is novel mechanosensitive gene under the control of fluid shear stress and KLF2 in ECs. UCP2 expression is critical for endothelial proinflammatory response and atherogenesis. Therapeutic strategies enhancing UCP2 level may have therapeutic potential against atherosclerosis.

Phase Transition and Luminescent Property Change Induced by Different Organic Cations in One-Dimensional Double Perovskites.

Double perovskites (DPs) have attracted attention in the field of luminescence due to their inherent broadband emission of self-trapping excitons. In this work, we choose [(CH3)3NCH2CHCH2]+ and [CH3CHOHCH2NH2]+ as organic cations to synthesize two new organic-inorganic hybrid DPs, [(CH3)3NCH2CHCH2]2KInCl6 (1) and [CH3CHOHCH2NH2]2KInCl6 (2). The [KCl6]3- and [InCl6]3- octahedra are interchangeably connected by sharing two opposite faces, forming a one-dimensional coordination chain. Each K atom coordinates with six chlorine atoms in 1, while it coordinates with two oxygen atoms in addition to the six chlorine atoms in 2. The coordination between ions K and O in compound 2 may have significantly reduced its luminescence. As a result, compound 1 shows bright-yellow light with a quantum yield of more than 90%, while 2 shows weak blue light with a quantum yield of only 0.98%. In addition, different from no phase transition found in 2, 1 undergoes a reversible phase transition at 324/307 K in the heating-cooling cycle. Through structural and spectral analysis and density functional theory calculation, we conclude that the larger degree of [InCl6]3- octahedral distortion and the larger anion distance (In···In) also cause the PLQY of compound 1 to be higher than that of compound 2.

Recombination of variable and host range regions of glycoprotein gp85 in different avian leukosis virus subgroup K isolates.

Given the high prevalence of avian leukosis virus subgroup K (ALV-K) in chickens in China, the positive rate of ALV-K in local chickens in Henan province was investigated, and the genetic region encoding the glycoprotein gp85 of isolates from positive chickens was analyzed. The positive rate of ALV-K in local chickens in Henan was found to be 87.2% (41/47). Phylogenetic analysis of gp85 sequences revealed six clusters that differed in their host range regions (hr1 and hr2) and variable regions (vr1, vr2, and vr3). Evidence of recombination of hr1, hr2, vr1, vr2, and vr3 was observed between the different clusters. The isolate HN23LS02 appears to have obtained its hr1 and hr2 regions from separate lineages via recombination but without having a significant affect on the replication capacity of the virus.

Molecular-Weight-Dependent Degradation of Plastics: Deciphering Host-Microbiome Synergy Biodegradation of High-Purity Polypropylene Microplastics by Mealworms.

The biodegradation of polypropylene (PP), a highly persistent nonhydrolyzable polymer, by Tenebrio molitor has been confirmed using commercial PP microplastics (MPs) (Mn 26.59 and Mw 187.12 kDa). This confirmation was based on the reduction of the PP mass, change in molecular weight (MW), and a positive Δδ13C in the residual PP. A MW-dependent biodegradation mechanism was investigated using five high-purity PP MPs, classified into low (0.83 and 6.20 kDa), medium (50.40 and 108.0 kDa), and high (575.0 kDa) MW categories to access the impact of MW on the depolymerization pattern and associated gene expression of gut bacteria and the larval host. The larvae can depolymerize/biodegrade PP polymers with high MW although the consumption rate and weight losses increased, and survival rates declined with increasing PP MW. This pattern is similar to observations with polystyrene (PS) and polyethylene (PE), i.e., both Mn and Mw decreased after being fed low MW PP, while Mn and/or Mw increased after high MW PP was fed. The gut microbiota exhibited specific bacteria associations, such as Kluyvera sp. and Pediococcus sp. for high MW PP degradation, Acinetobacter sp. for medium MW PP, and Bacillus sp. alongside three other bacteria for low MW PP metabolism. In the host transcriptome, digestive enzymes and plastic degradation-related bacterial enzymes were up-regulated after feeding on PP depending on different MWs. The T. molitor host exhibited both defensive function and degradation capability during the biodegradation of plastics, with high MW PP showing a relatively negative impact on the larvae.

Coprococcus protects against high-fat diet-induced nonalcoholic fatty liver disease in mice.

AIMS: The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing annually, leading to substantial medical and health burdens. Numerous studies have demonstrated the potential effectiveness of intestinal probiotics as a treatment strategy for NAFLD. Therefore, the objective of this study is to identify a probiotic for the treatment of NAFLD. METHODS AND RESULTS: In this study, blood and fecal samples were collected from 41 healthy volunteers and 44 patients diagnosed with NAFLD. Analysis of the 16S rDNA sequencing data and quantitative real-time PCR (RT-qPCR) revealed a significant reduction in the abundance of Coprococcus in NAFLD patients. Subsequent animal experiments demonstrated that Coprococcus was able to effectively reverse liver lipid accumulation, inflammation, and fibrosis induced by a high-fat diet (HFD) in mice. CONCLUSIONS: This study provides the first in vivo evidence that Coprococcus is a beneficial bacterium capable of preventing NAFLD and has the same probiotic effect in mice as Lactobacillus GG (LGG), a positive control. Therefore, Coprococcus has the potential to serve as a probiotic for the prevention and treatment of NAFLD in humans.

Cystathionine γ-lyase-derived H2S negatively regulates thymic egress via allosteric inhibition of sphingosine-1-phosphate lyase.

Thymic egress is a crucial process for thymocyte maturation, strictly regulated by sphingosine-1-phosphate lyase (S1PL). Recently, cystathionine γ-lyase (CSE), one of the enzymes producing hydrogen sulfide (H2S), has emerged as a vital immune process regulator. However, the molecular connection between CSE, H2S and thymic egress remains largely unexplored. In this study, we investigated the regulatory function of CSE in the thymic egress of immune cells. We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D,L-propargylglycine (PAG) significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood, and this redistribution effect could be reversed by treatment with NaHS, an exogenous donor of H2S. In addition, the CSE-generated H2S significantly increased the levels of S1P in the peripheral blood, thymus and spleen of mice, suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo. Notably, H2S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay. We found that this inhibition relied on a newly identified C203XC205 redox motif adjacent to the enzyme's active site, shedding light on the biochemical mechanism of S1PL regulation. In conclusion, this study uncovers a new function and mechanism for CSE-derived H2S in thymic egress and provides a potential drug target for treating S1P-related immune diseases.

Comparative efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet for the treatment of vascular calcification in patients with haemodialysis: a systematic review and network meta-analysis.

BACKGROUND: Up to now, there is no unequivocal intervention to mitigate vascular calcification (VC) in patients with hemodialysis. This network meta-analysis aimed to systematically evaluate the clinical efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet in treating vascular calcification. METHODS: A comprehensive study search was performed using PubMed, Web of Science, the Cochrane Library, EMBASE and China National Knowledge Internet (CNKI) to collect randomized controlled trials (RCTs) of sodium thiosulfate, bisphosphonates, and cinacalcet for vascular calcification among hemodialysis patients. Then, network meta-analysis was conducted using Stata 17.0 software. RESULTS: In total, eleven RCTs including 1083 patients were qualified for this meta-analysis. We found that cinacalcet (SMD - 0.59; 95% CI [-0.95, -0.24]) had significant benefit on vascular calcification compared with conventional therapy, while sodium thiosulfate or bisphosphonates did not show such efficiency. Furthermore, as for ranking the efficacy assessment, cinacalcet possessed the highest surface under the cumulative ranking curve (SUCRA) value (88.5%) of lessening vascular calcification and was superior to sodium thiosulfate (50.4%) and bisphosphonates (55.4%). Thus, above results suggested that cinacalcet might be the most promising drug for vascular calcification treatment in hemodialysis patients. Mechanistically, our findings illustrated that cinacalcet reduced serum calcium (SMD - 1.20; 95% CI [-2.08, - 0.33]) and showed the tendency in maintaining the balance of intact Parathyroid Hormone (iPTH) level. CONCLUSIONS: This network meta-analysis indicated that cinacalcet appear to be more effective than sodium thiosulfate and bisphosphonates in mitigating vascular calcification through decreasing serum calcium and iPTH. And cinacalcet might be a reasonable option for hemodialysis patients with VC in clinical practice. SYSTEMATIC REVIEW REGISTRATION: [ http://www.crd.york.ac.uk/PROSPERO ], identifier [CRD42022379965].

A pair of dopamine neurons mediate chronic stress signals to induce learning deficit in Drosophila melanogaster.

Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster The chronic stress-induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/ß neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress-induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.

Causal impact of DNA methylation on refracture in elderly individuals with osteoporosis - a prospective cohort study.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCF) in the elderly increase refracture risk post-surgery, leading to higher mortality rates. Genome-wide association studies (GWAS) have identified susceptibility genes for osteoporosis, but the phenotypic variance explained by these genes has been limited, indicating the need to explore additional causal factors. Epigenetic modifications, such as DNA methylation, may influence osteoporosis and refracture risk. However, prospective cohorts for assessing epigenetic alterations in Chinese elderly patients are lacking. Here, we propose to conduct a prospective cohort study to investigate the causal network of DNA polymorphisms, DNA methylation, and environmental factors on the development of osteoporosis and the risk of refracture. METHODS: We will collect vertebral and peripheral blood from 500 elderly OVCF patients undergoing surgery, extract DNA, and generate whole genome genotype data and DNA methylation data. Observation indicators will be collected and combined with one-year follow-up data. A healthy control group will be selected from a natural population cohort. Epigenome-wide association studies (EWAS) of osteoporosis and bone mineral density will be conducted. Differential methylation analysis will compare candidate gene methylation patterns in patients with and without refracture. Multi-omics prediction models using genetic variants and DNA methylation sites will be built to predict OVCF risk. DISCUSSION: This study will be the first large-scale population-based study of osteoporosis and bone mineral density phenotypes based on genome-wide data, multi-time point methylation data, and phenotype data. By analyzing methylation changes related to osteoporosis and bone mineral density in OVCF patients, the study will explore the feasibility of DNA methylation in evaluating postoperative osteoporosis intervention effects. The findings may identify new molecular markers for effective anti-osteoporosis treatment and inform individualized prevention and treatment strategies. TRIAL REGISTRATION: chictr.org.cn ChiCTR2200065316, 02/11/2022.

Linc00511 Promotes Thyroid Cancer Through the miR-4739/RNF38 Pathway.

Objective: To analyze the effect of Linc00511 on thyroid cancer through the miR-4739/RNF38 pathway. Methods: A total of 78 patients in our hospital from July 2020 to July 2021 were collected, which were diagnosed with thyroid cancer after clinicopathological examination. Their cancer tissue samples were included in the thyroid cancer tissue group, and the fat 2 cm tissue samples were included in the para-cancer tissue group. Real-time quantitative PCR was used to detect the expression of Linc00511, miR-4739 and RNF38 in tissue samples from the two groups. Statistical analysis of data was performed using SPSS26.0. The correlation between Linc00511, miR-4739 and RNF38 were analyzed by Pearson's correlation coefficient. The expression of Linc00511 in thyroid cancer tissues with different clinicopathological characteristics were compared. Results: The expression levels of Linc00511 and RNF38 in thyroid cancer group were significantly higher than paracancer group, while miR-4739 levels were significantly lower (P < .05). Pearson correlation coefficient analysis showed that there was significant negative correlation between Linc00511 and miR-4739 expression and significant positive correlation between Linc00511 and RNF38 expression (P < .05). There was no significant difference in the expression of Linc00511 among different ages, sexes, and cancer types (P > .05). The expression of Linc00511 in patients with TNM stages I, II, and III were increased with the increase of TNM stage (P < .05). The expression of Linc00511 in patients with tumor diameter ≥1 cm was higher than that in patients with tumor diameter <1 cm and the difference was statistically significant (P < .05). Conclusion: Linc00511 and RNF38 were significantly overexpressed in thyroid cancer tissues, while miR-4739 was significantly underexpressed. In thyroid cancer, Linc00511 can promote the invasion and metastasis of thyroid cancer cells by targeting miR-4739 and RNF38, and its expression level may reflect the progression of thyroid cancer, which can provide target reference for the clinical treatment of thyroid cancer.

The effect of polystyrene nanoplastics on arsenic-induced apoptosis in HepG2 cells.

Microplastics are detrimental to the environment. However, the combined effects of microplastics and arsenic (As) remain unclear. In this study, we investigated the combined effects of polystyrene (PS) microplastics and As on HepG2 cells. The results showed that PS microplastics 20, 50, 200, and 500 nm in size were taken up by HepG2 cells, causing a decrease in cellular mitochondrial membrane potential. The results of lactate dehydrogenase release and flow cytometry showed that PS microplastics, especially those of 50 nm, enhanced As-induced apoptosis. In addition, transcriptome analysis revealed that TP53, AKT1, CASP3, ACTB, BCL2L1, CASP8, XIAP, MCL1, NFKBIA, and CASP7 were the top 10 hub genes for PS that enhanced the role of As in HepG2 cell apoptosis. Our results suggest that nano-PS enhances As-induced apoptosis. Furthermore, this study is important for a better understanding of the role of microplastics in As-induced hepatotoxicity.