CRISPR/Cas13a-based rapid detection method for porcine deltacoronavirus.

Background: Porcine deltacoronavirus (PDCoV) is a newly discovered porcine intestinal pathogenic coronavirus with a single-stranded positive-sense RNA genome and an envelope. PDCoV infects pigs of different ages and causes acute diarrhea and vomiting in newborn piglets. In severe cases, infection leads to dehydration, exhaustion, and death in sick piglets, entailing great economic losses on pig farms. The clinical symptoms of PDCoV infection are very similar to those of other porcine enteroviruses. Although it is difficult to distinguish these viral infections without testing, monitoring PDCoV is very important because it can spread in populations. The most commonly used methods for the detection of PDCoV is qPCR, which is time-consuming and require skilled personnel and equipment. Many farms cannot meet the conditions required for detection. Therefore, it is necessary to establish a faster and more convenient method for detecting PDCoV. Aims: To establish a rapid and convenient detection method for PDCoV by combining RPA (Recombinase Polymerase Isothermal Amplification) with CRISPR/Cas13a. Methods: Specific RPA primers and crRNA for PDCoV were designed, and the nucleic acids in the samples were amplified with RPA. Fluorescent CRISPR/Cas13a detection was performed. We evaluated the sensitivity and specificity of the RPA-CRISPR/Cas13a assay using qPCR as the control method. Results: CRISPR/Cas13a-assisted detection was completed within 90 min. The minimum detection limit of PDCoV was 5.7 × 101 copies/µL. A specificity analysis showed that the assay did not cross-react with three other porcine enteroviruses. Conclusion: The RPA-CRISPR/Cas13a method has the advantages of high sensitivity, strong specificity, fast response, and readily accessible results, and can be used for the detection of PDCoV.

SGLT2 inhibitors activate pantothenate kinase in the human heart.

Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.

Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells.

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

Ginsenoside Rb prevents the metastasis of hepatocarcinoma by blocking the platelet-tumor cell interaction.

BACKGROUND: The interaction between platelets and tumor cells is a crucial step in the progression of tumor metastasis. Blocking platelet-tumor cell interaction is a potential target against metastasis. Ginsenoside Rb (G-Rb) exhibits potential anti-tumor pharmacological properties and may offer a therapeutic option for cancer. PURPOSE: This study aimed to investigate anti-metastatic effects of G-Rb through regulating the crosstalk of platelets with tumor cells. METHODS: In order to explore anti-metastatic effects of G-Rb in vitro, HepG2 cell and platelets were co-cultured to mimic the interaction of platelets with tumor cells. Wound healing and Transwell assays were used to assess the effect of G-Rb on cell migration and invasion. The expression of epithelial-mesenchymal transition (EMT)-related markers was determined by RT-qPCR and western blot assays. The aggregation and activation of platelets were detected by flow cytometry. Moreover, a lung metastasis model of mice was established to evaluate inhibitory effects of G-Rb in vivo. Metastatic nodules on the lung surface were counted and sections of lung tissues were stained by H&E. RESULTS: G-Rb effectively suppressed tumor metastasis in the co-culture of platelets with HepG2 cell. First, G-Rb treatment significantly inhibited the migration and invasion of HepG2 cells induced by platelets. Second, the expressions of EMT-related markers, including N-cadherin, Snail, and MMP9, were decreased by the treatment of G-Rb in the presence of platelets. Meanwhile, G-Rb also suppressed platelet hyperactivity by regulating the adhesion to tumor cells, activation, TCIPA, and TGF-ß1 secretion of platelets in vitro. In addition, the results of in vivo experiments proved G-Rb administration not only significantly decreased lung metastasis but also attenuated platelets aberrant aggregation and activation in vivo. CONCLUSION: Our findings showed that G-Rb inhibited tumor metastasis and platelet activation through mediating platelet-tumor cell interaction, indicating the potential values of G-Rb in tumor metastasis therapy.

[Advances in Nanotechnology-Based Drug Delivery Systems in the Treatment of Hepatocellular Carcinoma].

Primary liver cancer is one of the most common malignant tumors of the digestive system,of which hepatocellular carcinoma (HCC) accounts for more than 90% of the total cases.The patients with early HCC treated by surgical resection generally demonstrate good prognosis.However,due to the insidious onset,HCC in the vast majority of patients has progressed to the mid-to-late stage when being diagnosed.As a result,surgical treatment has unsatisfactory effects,and non-surgical treatment methods generally have severe side effects and low tumor selectivity.Nanoparticles (NP) with small sizes,large specific surface areas,and unique physical and chemical properties have become potential carriers for the delivery of therapeutic agents such as drugs,genes,and cytokines.The nano-delivery systems with NP as the carrier can regulate the metabolism and transformation of drugs,genes,and cytokines in vivo from time,space,and dose via functional modification,showing great potential in the treatment of HCC.This paper introduces the current status and advantages of several common nano-delivery systems,including organic nano-carriers,inorganic nano-carriers,and exosomes,in the treatment of HCC.Furthermore,this paper summarizes the mechanisms of NP-based nano-carriers in treating HCC and provides reference for the development of new nano-delivery systems.

RPA-CRISPR-Cas13a-assisted detection method of transmissible gastroenteritis virus.

Background and aim: Transmissible gastroenteritis virus (TGEV) is a highly contagious gastrointestinal virus that causes diarrhea, vomiting, anorexia, dehydration, and weight loss in piglets. In clinical practice, it often occurs in mixed infections with other pathogens, and is therefore difficult to diagnose and prevent. It mainly harms piglets of about 2 weeks old, causing huge losses on farms. The clinical confirmation of TGEV usually requires a laboratory diagnosis, but traditional PCR and immunofluorescence assays have some limitations. Moreover, most farms in China are ill-equipped to accurately diagnose the disease. Therefore, a new detection method with high sensitivity and specificity and less dependence on instrumentation is required. Methods: We used recombinase polymerase amplification (RPA), combined with the nuclease characteristics of the activated Cas13a protein to establish a visual CRISPR-Cas13a-assisted detection method for TGEV by adding a reporter RNA with fluorescent and quenching moieties to the system. Result: We selected the optimal RPA primer and best CRISPR RNA (crRNA). The reaction system was optimized and its repeatability, specificity, and sensitivity verified. The TGEV detection system did not cross-react with other common diarrhea viruses, and its detection limit was 101 copies, which is similar with the sensitivity of qPCR. We successfully established an RPA-CRISPR-Cas13a-assisted detection method, and used this detection system to analyze 123 pig blood samples. qPCR was used as the gold standard method. The sensitivity, specificity, positive coincidence rate, and negative coincidence rate of the new method were 100, 98.93, 96.66, and 100%, respectively.

Recombinant collagen coating 3D printed PEGDA hydrogel tube loading with differentiable BMSCs to repair bile duct injury.

Bile duct injury presents a significant clinical challenge following hepatobiliary surgery, necessitating advancements in the repair of damaged bile ducts is a persistent issue in biliary surgery. 3D printed tubular scaffolds have emerged as a promising approach for the repair of ductal tissues, yet the development of scaffolds that balance exceptional mechanical properties with biocompatibility remains an ongoing challenge. This study introduces a novel, bio-fabricated bilayer bile duct scaffold using a 3D printing technique. The scaffold comprises an inner layer of polyethylene glycol diacrylate (PEGDA) to provide high mechanical strength, and an outer layer of biocompatible, methacryloylated recombinant collagen type III (rColMA) loaded with basic fibroblast growth factor (bFGF)-encapsulated liposomes (bFGF@Lip). This design enables the controlled release of bFGF, creating an optimal environment for the growth and differentiation of bone marrow mesenchymal stem cells (BMSCs) into cholangiocyte-like cells. These cells are instrumental in the regeneration of bile duct tissues, evidenced by the pronounced expression of cholangiocyte differentiation markers CK19 and CFTR. The PEGDA//rColMA/bFGF@Lip bilayer bile duct scaffold can well simulate the bile duct structure, and the outer rColMA/bFGF@Lip hydrogel can well promote the growth and differentiation of BMSCs into bile duct epithelial cells. In vivo experiments showed that the scaffold did not cause cholestasis in the body. This new in vitro pre-differentiated active 3D printed scaffold provides new ideas for the study of bile duct tissue replacement.

The Conservation Implications of the Gut Microbiome for Protecting the Critically Endangered Gray Snub-Nosed Monkey (Rhinopithecus brelichi).

The gut microbiota plays a crucial role in regulating energy metabolism, facilitating nutrient absorption, and supporting immune function, thereby assisting the host in adapting to seasonal dietary changes. Here, we compare the gut microbiome composition of wild gray snub-nosed monkeys during winter (from October to December) and spring (from January to March) to understand differences in seasonal nutrient intake patterns. Snub-nosed monkeys are foregut fermenters and consume difficult-to-digest carbohydrates and lichen. To examine the digestive adaptations of gray snub-nosed monkeys, we collected 14 fresh fecal samples for DNA analysis during the winter and spring. Based on 16S rRNA sequencing, metagenomic sequencing, and functional metagenomic analyses, we identified that Firmicutes, Actinobacteria, Verrucomicrobia, and Bacteroidetes constitute a keystone bacterial group in the gut microbiota during winter and spring and are responsible for degrading cellulose. Moreover, the transition in dietary composition from winter to spring was accompanied by changes in gut microbiota composition, demonstrating adaptive responses to varying food sources and availability. In winter, the bacterial species of the genera Streptococcus were found in higher abundance. At the functional level, these bacteria are involved in fructose and mannose metabolism and galactose metabolism c-related pathways, which facilitate the breakdown of glycogen, starch, and fiber found in fruits, seeds, and mature leaves. During spring, there was an increased abundance of bacteria species from the Prevotella and Lactobacillus genera, which aid the digestion of protein-rich buds. Combined, these findings reveal how the gut microbiota adjusts to fluctuations in energy balance and nutrient intake across different seasons in this critically endangered species. Moreover, we also identified Pseudomonas in two samples; the presence of potential pathogens within the gut could pose a risk to other troop members. Our findings highlight the necessity of a conservation plan that focuses on protecting vegetation and implementing measures to prevent disease transmission for this critically endangered species.

OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome.

PURPOSE: In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism. METHODS: Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis. RESULTS: Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes. CONCLUSIONS: Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.

Application of smart hydrogel materials in cartilage injury repair: A systematic review and meta-analysis.

OBJECTIVE: Cartilage injury is a common clinical condition, and treatment approaches have evolved over time from traditional conservative and surgical methods to regenerative repair. In this context, hydrogels, as widely used biomaterials in the field of cartilage repair, have garnered significant attention. Particularly, responsive hydrogels (also known as "smart hydrogels") have shown immense potential due to their ability to respond to various physicochemical properties and environmental changes. This paper aims to review the latest research developments of hydrogels in cartilage repair, utilizing a more systematic and comprehensive meta-analysis approach to evaluate the research status and application value of responsive hydrogels. The goal is to determine whether these materials demonstrate favorable therapeutic effects for subsequent clinical applications, thereby offering improved treatment methods for patients with cartilage injuries. METHOD: This study employed a systematic literature search method to summarize the research progress of responsive hydrogels by retrieving literature on the subject and review studies. The search terms included "hydrogel" and "cartilage," covering data from database inception up to October 2023. The quality of the literature was independently evaluated using Review Manager v5.4 software. Quantifiable data was statistically analyzed using the R language. RESULTS: A total of 7 articles were retrieved for further meta-analysis. In the quality assessment, the studies demonstrated reliability and accuracy. The results of the meta-analysis indicated that responsive hydrogels exhibit unique advantages and effective therapeutic outcomes in the field of cartilage repair. Subgroup analysis revealed potential influences of factors such as different types of hydrogels and animal models on treatment effects. CONCLUSION: Responsive hydrogels show significant therapeutic effects and substantial application potential in the field of cartilage repair. This study provides strong scientific evidence for their further clinical applications and research, with the hope of promoting advancements in the treatment of cartilage injuries.

Identifying the temporal contributors and their interactions during dynamic formation of black tea cream.

Tea cream formed in hot and strong tea infusion while cooling deteriorates quality and health benefits of tea. However, the interactions among temporal contributors during dynamic formation of tea cream are still elusive. Here, by deletional recombination experiments and molecular dynamics simulation, it was found that proteins, caffeine (CAF), and phenolics played a dominant role throughout the cream formation, and the contribution of amino acids was highlighted in the early stage. Furthermore, CAF was prominent due to its extensive binding capacity and the filling complex voids property, and caffeine-theaflavins (TFs) complexation may be the core skeleton of the growing particles in black tea infusion. In addition to TFs, the unidentified phenolic oxidation-derived products (PODP) were confirmed to contribute greatly to the cream formation.

Tandem Catalysts Enabling Efficient C-N Coupling toward the Electrosynthesis of Urea.

The development of a methodology for synthesizing value-added urea (CO(NH2)2) via a renewable electricity-driven C-N coupling reaction under mild conditions is highly anticipated. However, the complex catalytic active sites that act on the carbon and nitrogen species make the reaction mechanism unclear, resulting in a low efficiency of C-N coupling from the co-reduction of carbon dioxide (CO2) and nitrate (NO3 -). Herein, we propose a novel tandem catalyst of Mo-PCN-222(Co), in which the Mo sites serve to facilitate nitrate reduction to the *NH2 intermediate, while the Co sites enhance CO2 reduction to carbonic oxide (CO), thus synergistically promoting C-N coupling. The synthesized Mo-PCN-222(Co) catalyst exhibited a noteworthy urea yield rate of 844.11 mg h-1 g-1, alongside a corresponding Faradaic efficiency of 33.90 % at -0.4 V vs. reversible hydrogen electrode (RHE). By combining in situ spectroscopic techniques with density functional theory calculations, we demonstrate that efficient C-N coupling is attributed to a tandem system in which the *NH2 and *CO intermediates produced by the Mo and Co active sites of Mo-PCN-222(Co) stabilize the formation of the *CONH2 intermediate. This study provides an effective avenue for the design and synthesis of tandem catalysts for electrocatalytic urea synthesis.

Pluronic F127 hydrogel-loaded extracellular vesicles from adipose-derived mesenchymal stem cells promote tracheal cartilage regeneration via SCNN1B delivery.

Extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (AMSC-EVs) have been highlighted as a cell-free therapy due to their regenerative capability to enhance tissue and organ regeneration. Herein, we aimed to examine the mechanism of PF127-hydrogel@AMSC-EVs in promoting tracheal cartilage defect repair. Based on bioinformatics methods, SCNN1B was identified as a key gene for the osteogenic differentiation of AMSCs induced by AMSC-EVs. EVs were isolated from rat AMSCs and then loaded onto thermo-sensitive PF-127 hydrogel to develop PF127-hydrogel@AMSC-EVs. It was established that PF127-hydrogel@AMSC-EVs could effectively deliver SCNN1B into AMSCs, where SCNN1B promoted AMSC osteogenic differentiation. The promotive effect was evidenced by enhanced ALP activity, extracellular matrix mineralization, and expression of s-glycosaminoglycan, RUNX2, OCN, collagen II, PERK, and ATF4. Furthermore, the in vivo experiments revealed that PF127-hydrogel@AMSC-SCNN1B-EVs stimulated tracheal cartilage regeneration in rats through PERK/ATF4 signaling axis activation. Therefore, PF127-hydrogel@AMSC-SCNN1B-EVs may be a novel cell-free biomaterial to facilitate tracheal cartilage regeneration and cartilage injury repair.

Deciphering the spatial heterogeneity of groundwater arsenic in Quaternary aquifers of the Central Yangtze River Basin.

Significant spatial variability of groundwater arsenic (As) concentrations in South/Southeast Asia is closely associated with sedimentogenesis and biogeochemical cycling processes. However, the role of fine-scale differences in biogeochemical processes under similar sedimentological environments in controlling the spatial heterogeneity of groundwater As concentrations is poorly understood. Within the central Yangtze Basin, dissolved organic matter (DOM) and microbial functional communities in the groundwater and solid-phase As-Fe speciation in Jianghan Plain (JHP) and Jiangbei Plain (JBP) were compared to reveal mechanisms related to the spatial heterogeneity of groundwater As concentration. The optical signatures of DOM showed that low molecular terrestrial fulvic-like with highly humified was predominant in the groundwater of JHP, while terrestrial humic-like and microbial humic-like with high molecular weight were predominant in the groundwater of JBP. The inorganic carbon isotope, microbial functional communities, and solid-phase As-Fe speciation suggest that the primary process controlling As accumulation in JHP groundwater system is the degradation of highly humified OM by methanogens, which drive the reductive dissolution of amorphous iron oxides. While in JBP groundwater systems, anaerobic methane-oxidizing microorganisms (AOM) coupled with fermentative bacteria, iron reduction bacteria (IRB), and sulfate reduction bacteria (SRB) utilize low molecular weight DOM degradation to drive biotic/abiotic reduction of Fe oxides, further facilitating the formation of carbonate associated Fe and crystalline Fe oxides, resulting in As release into groundwater. Different biogeochemical cycling processes determine the evolution of As-enriched aquifer systems, and the coupling of multiple processes involving organic matter transformation­iron cycling­sulfur cycling-methane cycling leads to heterogeneity in the spatial distribution of As concentrations in groundwater. These findings provide new perspectives to decipher the spatial variability of As concentrations in groundwater.

Long noncoding RNA SNHG3 interacts with microRNA-502-3p to mediate ITGA6 expression in liver hepatocellular carcinoma.

SNHG3, a long noncoding RNA (lncRNA), has been linked to poor outcomes in patients with liver hepatocellular carcinoma (LIHC). In this study, we found that SNHG3 was overexpressed in LIHC and associated with poor outcomes in patients with LIHC. Functional assays, including colony formation, spheroid formation, and in vivo assays showed that SNHG3 promoted stemness of cancer stem cells (CSC) and tumor growth in vivo by interacting with microRNA-502-3p (miR-502-3p). miR-502-3p inhibitor repressed the tumor-suppressing effects of SNHG3 depletion. Finally, by RNA pull-down, dual-luciferase reporter assay, m6A methylation level detection, and m6A-IP-qPCR assays, we found that miR-502-3p targeted YTHDF3 to regulate the translation of integrin alpha-6 (ITGA6) and targeted HBXIP to inhibit the m6A modification of ITGA6 through methyltransferase-like 3 (METTL3). Our study revealed that SNHG3 controls the YTHDF3/ITGA6 and HBXIP/METTL3/ITGA6 pathways by repressing miR-502-3p expression to sustain the self-renewal properties of CSC in LIHC.

circRNA_8521 promotes Senecavirus A infection by sponging miRNA-324 to regulate LC3A.

Senecavirus A (SVA) causes outbreaks of vesicular disease in pigs, which imposes a considerable economic burden on the pork industry. As current SVA prevention measures are ineffective, new strategies for controlling SVA are urgently needed. Circular (circ)RNA is a newly characterized class of widely expressed, endogenous regulatory RNAs, which have been implicated in viral infection; however, whether circRNAs regulate SVA infection remains unknown. To investigate the influence of circRNAs on SVA infection in porcine kidney 15 (PK-15) cells, RNA sequencing technology was used to analyze the circRNA expression profiles of SVA-infected and uninfected PK-15 cells, the interactions between circRNAs, miRNAs, and mRNAs potentially implicated in SVA infection were predicted using bioinformatics tools. The prediction accuracy was verified using quantitative real-time (qRT)-PCR, Western blotting, as well as dual-luciferase reporter and RNA pull-down assays. The results showed that 67 circRNAs were differentially expressed as a result of SVA infection. We found that circ_8521 was significantly upregulated in SVA-infected PK-15 cells and promoted SVA infection. circ_8521 interacted with miR-324. miR-324 bound to LC3A mRNA which inhibited the expression of LC3A. Knockdown of LC3A inhibited SVA infection. However, circ_8521 promoted the expression of LC3A by binding to miR-324, thereby promoting SVA infection. We demonstrated that circ_8521 functioned as an endogenous miR-324 sponge to sequester miR-324, which promoted LC3A expression and ultimately SVA infection.

Stabilizing 4.6 V LiCoO2 via Er and Mg Trace Doping at Li-Site and Co-Site Respectively.

Charging LiCoO2 to high voltages yields alluring specific capacities, yet the deleterious phase-transitions lead to significant capacity degradation. Herein, this study demonstrates a novel strategy to stabilize LiCoO2 at 4.6 V by doping with Er and Mg at the Li-site and Co-site, respectively, which is different from the traditional method of doping foreign elements solely at the Co-site. Theoretical calculations and experiments jointly reveal that the inclusion of Mg2+-dopants at the Co-site curbs the hexagonal-monoclinic phase transitions ≈4.2 V. However, this unintentionally compromises the stability of lattice oxygen in LiCoO2, exacerbating the undesired phase transition (O3 to H1-3) above 4.45 V. Fascinatingly, the introduction of Er3+-dopants into Li-sites enhances the stability of lattice oxygen in LiCoO2, effectively mitigating phase transitions above 4.45 V. Therefore, the Er, Mg co-doped LiCoO2 exhibits high stability over 500 cycles when tested in a half-cell with a cut-off voltage of 4.6 V. Furthermore, the Er, Mg-doped LiCoO2//graphite pouch-type full cell demonstrates a high energy density of 310.8 Wh kg-1, preserving 91.3% of its energy over 100 cycles.

Thyroid Hormone Suppresses Medulloblastoma Progression Through Promoting Terminal Differentiation of Tumor Cells.

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). A possible link between thyroid hormone (TH) signaling and MB pathogenicity has not been reported. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

The causal effect of triglyceride and high blood pressure on IgA nephropathy: a Mendelian randomization study.

Background: It has been reported that high blood pressure (HBP) and triglyceride (TG) are considered risk factors in immunoglobulin A nephropathy (IgAN). This study aimed to explore the causalities between HBP and TG, and IgAN on the basis of Mendelian randomization (MR) analysis. Methods: Firstly, the genome-wide association study (GWAS) summary data of IgAN (GCST90018866) and two exposure factors, TG (ukb-d-30870_raw) and HBP (ukb-a-437), were sourced from the GWAS Catalog and Integrative Epidemiology Unit (IEU) OpenGWAS databases, respectively. In this study, five methods were utilized to perform MR analysis after picking out single nucleotide polymorphisms (SNPs) as instrumental variables, including MR-Egger, weighted median, simple mode, weighted mode, and inverse variance weighted (IVW), followed by the sensitivity analysis containing the heterogeneity, horizontal pleiotropy test and leave-one-out (LOO) analysis. Finally, the enrichment analysis and interaction network construction of genes corresponding to SNPs of HBP and TG were performed. Results: The univariate MR results revealed that HBP and TG regarded as risk factors were causally related to IgAN [TG: p = 0.046, odds ratio (OR) = 1.065, 95% confidence interval (CI) = 1.001-1.133; HBP: p = 7.09 × 10-7, OR = 1.970, 95% CI = 1.507-2.575] based on random-effect IVM method, of which TG had a weaker impact. The reliability of these univariate MR results was certified by the sensitivity analysis, in which there was no horizontal pleiotropy and exaggerated influence of each SNP. Furthermore, HBP was markedly causally related to IgAN (p = 0.000512) with the help of multivariate MR analysis, rather than TG (p = 0.332). Therefore, when HBP and TG occur simultaneously, HBP is a direct influencing factor on IgAN. Ultimately, a total of 208 and 153 genes separately corresponding to SNPs of TG and HBP were included in enrichment analysis, and thereinto, genes relevant to TG were mainly enriched in lipid homeostasis and cholesterol metabolism, while genes concerned with HBP played their roles in regulation of cell growth, aldosterone synthesis and secretion and so forth. Conclusion: TG and HBP as risk factors were causally connected with IgAN, of which HBP was strongly related to the onset of IgAN, providing more reliable evidence for further exploring the relationship between TG and HBP and IgAN.