Curcumin-Loaded Liposomes in Gel Protect the Skin of Mice against Oxidative Stress from Photodamage Induced by UV Irradiation.

Prolonged exposure to ultraviolet (UV) irradiation can cause oxidative stress in the skin, accompanied by rapid immunosuppressive effects, resulting in a peroxidation reaction throughout the body. Curcumin (Cur), as the bioactive compound of turmeric, is a natural polyphenol with potent antioxidant properties but is often overlooked due to its poor solubility and low bioavailability. In this study, curcumin-loaded liposomes in a sodium alginate gel complex preparation were designed to improve the bioavailability of curcumin and to study its preventive effect on photodamage. Cur-loaded liposomes (Cur-L), Cur-loaded gel (Cur-G) based on an alginate matrix, and curcumin-loaded liposomes in gel (Cur-LG) were prepared, and their antioxidant effects and drug diffusion abilities were evaluated. The antioxidant capacity of Cur, Cur-L, Cur-G, and Cur-LG was also studied in a mouse model of photodamage. Cur had the highest antioxidant activity at about 4 mg/mL. Cur-LG at this concentration showed antioxidant effects during 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) and H2O2 experiments. During the UV light damage test, Cur-LG demonstrated the ability to effectively neutralize free radicals generated as a result of lipid peroxidation in the skin, serum, and liver, thereby enhancing the overall activity of superoxide dismutase (SOD). In conclusion, using Cur-LG may protect against epidermal and cellular abnormalities induced by UV irradiation.

Phosphorus deficiency promotes root:shoot ratio and carbon accumulation via modulating sucrose utilization in maize.

Phosphorus deficiency usually promotes root:shoot ratio and sugar accumulation. However, how the allocation and utilization of carbon assimilates are regulated by phosphorus deficiency remains unclear. To understand how phosphorus deficiency affects the allocation and utilization of carbon assimilates, we systematically investigated the fixation and utilization of carbon, along with its diurnal and spatial patterns, in hydroponically grown maize seedlings under low phosphorus treatment. Under low phosphorus, sucrolytic activity was slightly inhibited by 12.0% in the root but dramatically inhibited by 38.8% in the shoot, corresponding to the promoted hexose/sucrose ratio and biomass in the root. Results point to a stable utilization of sucrose in the root facilitating competition for more assimilates, while increasing root:shoot ratio. Moreover, starch and sucrose accumulated in the leaves under low phosphorus. Spatially, starch and sucrose were oppositely distributed, starch mainly in the leaf tip, and sucrose mainly in the leaf base and sheath. Evidence of sucrose getting stuck in leaf base and sheath suggests that carbon accumulation is not attributed to carbon assimilation or export disturbance, but may be due to poor carbon utilization in the sinks. These findings improve the understanding of how low phosphorus regulates carbon allocation between shoot and root for acclimation to stress, and highlight the importance of improving carbon utilization in sinks to deal with phosphorus deficiency.

Single-Cell Transcriptomics Reveals Early Effects of Ionizing Radiation on Bone Marrow Mononuclear Cells in Mice.

Ionizing radiation exposure can cause damage to diverse tissues and organs, with the hematopoietic system being the most sensitive. However, limited information is available regarding the radiosensitivity of various hematopoietic cell populations in the bone marrow due to the high heterogeneity of the hematopoietic system. In this study, we observed that granulocyte-macrophage progenitors, hematopoietic stem/progenitor cells, and B cells within the bone marrow showed the highest sensitivity, exhibiting a rapid decrease in cell numbers following irradiation. Nonetheless, neutrophils, natural killer (NK) cells, T cells, and dendritic cells demonstrated a certain degree of radioresistance, with neutrophils exhibiting the most pronounced resistance. By employing single-cell transcriptome sequencing, we investigated the early responsive genes in various cell types following irradiation, revealing that distinct gene expression profiles emerged between radiosensitive and radioresistant cells. In B cells, radiation exposure led to a specific upregulation of genes associated with mitochondrial respiratory chain complexes, suggesting a connection between these complexes and cell radiosensitivity. In neutrophils, radiation exposure resulted in fewer gene alterations, indicating their potential for distinct mechanisms in radiation resistance. Collectively, this study provides insights into the molecular mechanism for the heterogeneity of radiosensitivity among the various bone marrow hematopoietic cell populations.

Spatiotemporal expression analysis of jasmonic acid and saponin-related genes uncovers a potential biosynthetic regulation in Panax notoginseng.

BACKGROUND: Sanqi, the root of Panax notoginseng, has long been recognized for its therapeutic effects on cardiovascular diseases. Saponins, including ginsenosides and notoginsenosides, are the main bioactive components of P. notoginseng. The biosynthesis of saponins is closely related to the defense responses orchestrated by endogenous hormones. RESULTS: To provide new insights into the underlying role of phytohormone jasmonic acid (JA) in the synthesis and regulation of saponins, we performed an ultra-performance liquid chromatography analysis of different tissues of P. notoginseng aged 2-4 years. Moreover, by combined evaluation of saponin content and transcriptome profiling of each tissue, the spatial and temporal distribution of saponins was analyzed. N notoginsenoside R1, ginsenoside Rb1 and ginsenoside Rd accumulated in the underground tissues, including the root, tuqi, fibril and rhizome. In agreement with this data, the corresponding genes of the endogenous hormone JAs, especially coronatine insensitive 1 (COI1) and myelocytomatosis proteins 2 (MYC2), were predominantly expressed in the underground tissues. The tissue- and age-specific distribution of saponins was consistent with the expression of genes involved in JA biosynthetic, metabolic and signaling pathways. CONCLUSION: The present study has revealed the temporal and spatial effects of endogenous phtohormones in the synthesis and regulation of notoginsenosides, which will provide a significant impact on improving the ecological planting technology, cultivating new high-quality varieties and protecting the rare resources of medicinal P. notoginseng. © 2024 Society of Chemical Industry.

Evaluation of pre-school pertussis booster vaccination in Shanghai, China: A cost-effectiveness analysis.

BACKGROUND: In recent years, notified pertussis cases have been increasingly documented in China. It raised a new public health concern of potential optimization in immunization strategy. This study was aimed to determine the cost-effectiveness of different immunization strategies against pertussis-containing vaccines for 6-year-old pre-school children in Shanghai. METHODS: A Markov-decision tree model was applied to evaluate two pertussis immunization strategies for 6-year-old pre-school children as following: (1) 1 dose of acellular pertussis (aP) contained vaccine (DTaP or Tdap) booster vaccinated at 6 years of age, and (2) no booster at 6 years of age regimen. Primary outcomes included quality-adjusted life years (QALYs), costs, and incremental cost-utility ratios (ICUR). Sensitivity analyses were performed. The analysis was conducted over a study period of 14 years from a societal perspective. RESULTS: Compared to no booster immunization strategy, administering 1 dose of acellular pertussis (aP) contained vaccine (DTaP or Tdap) booster at 6 years of age, resulted in an average cost reduction of CNY 814.16 (USD 116) per individual, an increase in QALYs by 0.00066, and a rise in per capita net monetary benefit (NMB) by CNY 933.51 (USD 132). The total costs over the study period were reduced by CNY 160.59 million (USD 23 million), utility increased by 130.49 QALYs, and NMB increased by CNY 184.14 million (USD 26 million). CONCLUSIONS: Implementing acellular pertussis booster immunization for 6-year-old pre-school children in Shanghai emerges as a cost-saving immunization strategy, with both cost savings and utility gains.

P4HA3 promotes head and neck squamous cell carcinoma progression via the WNT/ß-catenin signaling pathway.

Here, we explored the role of Prolyl 4-Hydroxylase Subunit Alpha 3 (P4HA3), the most recently identified member of the prolyl-4-hydroxylase (P4H) family, in head and neck squamous cell carcinoma (HNSCC) progression. P4HA3 is upregulated during cancer progression; however, its specific role in HNSCC progression remains elusive. Thus, this study aimed to elucidate the regulatory function of P4HA3 in HNSCC development and progression and to describe the underlying mechanisms. Initially, we analyzed the correlation between the expression of P4HA3 and the WNT pathway genes and clinicopathologic features in HNSCC based on microarray data from The Cancer Genome Atlas (TCGA). Next, we used Gene Oncology (GO) functional data to describe several potentially associated pathways in HNSCC. Then, we knocked down P4HA3 in SCC15 and SCC25 cells, two classic HNSCC cell lines, and assessed the resulting changes using RT-qPCR. Furthermore, we used Western blot to evaluate the regulatory role of P4HA3 in the epithelial-to-mesenchymal transition (EMT) and the WNT/ß-catenin signaling pathway. To explore the effect of P4HA3 knockdown on tumor progression, in vivo experiments were conducted using a murine model. Immunohistochemistry assays were then employed to identify proteins associated with EMT and the WNT/ß-catenin signaling pathway in tumor tissues. Upregulated P4HA3 in HNSCC patient tumor tissues was positively correlated with poor prognosis. Notably, P4HA3 knockdown significantly inhibited the proliferative and invasive abilities of HNSCC. The levels of genes and proteins associated with EMT and the WNT/ß-catenin signaling pathway were also markedly reduced by P4HA3 knockdown. Importantly, the in vivo experiments demonstrated that P4HA3 can promote subcutaneous tumorigenesis in nude mice and knockdown of P4HA3 induce a significant ihibitation of EMT and WNT/ß-catenin pathway detected by immunohistochemistry assay in tumor tissues. In summary, we demonstrated that P4HA3 is a promising diagnostic and therapeutic biomarker for HNSCC. As an oncogene, P4HA3 increases HNSCC proliferation by inducing the EMT and activating the WNT/ß-catenin signaling pathway.

Mogroside V reduced the excessive endoplasmic reticulum stress and mitigated the Ulcerative colitis induced by dextran sulfate sodium in mice.

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.

GPS2 promotes erythroid differentiation in K562 erythroleukemia cells primarily via NCOR1.

G protein pathway suppressor 2 (GPS2) has been shown to play a pivotal role in human and mouse definitive erythropoiesis in an EKLF-dependent manner. However, whether GPS2 affects human primitive erythropoiesis is still unknown. This study demonstrated that GPS2 positively regulates erythroid differentiation in K562 cells, which have a primitive erythroid phenotype. Overexpression of GPS2 promoted hemin-induced hemoglobin synthesis in K562 cells as assessed by the increased percentage of benzidine-positive cells and the deeper red coloration of the cell pellets. In contrast, knockdown of GPS2 inhibited hemin-induced erythroid differentiation of K562 cells. GPS2 overexpression also enhanced erythroid differentiation of K562 cells induced by cytosine arabinoside (Ara-C). GPS2 induced hemoglobin synthesis by increasing the expression of globin and ALAS2 genes, either under steady state or upon hemin treatment. Promotion of erythroid differentiation of K562 cells by GPS2 mainly relies on NCOR1, as knockdown of NCOR1 or lack of the NCOR1-binding domain of GPS2 potently diminished the promotive effect. Thus, our study revealed a previously unknown role of GPS2 in regulating human primitive erythropoiesis in K562 cells.

O-GlcNAcylation promotes the progression of nonalcoholic fatty liver disease by upregulating the expression and function of CD36.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH), constitute a burgeoning worldwide epidemic with no FDA-approved pharmacotherapies. The multifunctional immunometabolic receptor, fatty acid translocase CD36 (CD36), plays an important role in the progression of hepatic steatosis. O-GlcNAcylation is a crucial posttranslational modification that mediates the distribution and function of CD36, but its involvement in NAFLD remains poorly understood. METHODS: O-GlcNAcylation and CD36 expression were evaluated in human liver tissues obtained from NASH patients and normal control. Mice with hepatocyte-specific CD36 knockout were administered adeno-associated viral vectors expressing wild-type CD36 (WT-CD36) or CD36 O-GlcNAcylation site mutants (S468A&T470A-CD36) and were provided with a high-fat/high-cholesterol (HFHC) diet for 3 months. RT-qPCR analysis, immunoblotting, dual-luciferase reporter assays, chromatin immunoprecipitation, and coimmunoprecipitation were performed to explore the mechanisms by which O-GlcNAcylation regulates CD36 expression. Membrane protein extraction, immunofluorescence analysis, site-directed mutagenesis, and fatty acid uptake assays were conducted to elucidate the impact of O-GlcNAcylation on CD36 function. RESULTS: O-GlcNAcylation and CD36 expression were significantly increased in patients with NASH, mouse models of NASH, and palmitic acid-stimulated hepatocytes. Mechanistically, the increase in O-GlcNAcylation facilitated the transcription of CD36 via the NF-κB signalling pathway and stabilized the CD36 protein by inhibiting its ubiquitination, thereby promoting CD36 expression. On the other hand, O-GlcNAcylation facilitated the membrane localization of CD36, fatty acid uptake, and lipid accumulation. However, site-directed mutagenesis of residues S468 and T470 of CD36 reversed these effects. Furthermore, compared with their WT-CD36 counterparts, HFHC-fed S468A&T470A-CD36 mice exhibited decreases in systemic insulin resistance, steatosis severity, inflammation and fibrosis. Pharmacological inhibition of O-GlcNAcylation and CD36 also mitigated the progression of NASH. CONCLUSIONS: O-GlcNAcylation promotes the progression of NAFLD by upregulating CD36 expression and function. Inhibition of CD36 O-GlcNAcylation protects against NASH, highlighting a potentially effective therapeutic approach for individuals with NASH.

Intravesical Interferon Therapy vs Hyaluronic Acid for Pain Among Female Individuals With Interstitial Cystitis: A Randomized Clinical Trial.

Importance: Interstitial cystitis (IC) is a debilitating condition. Although viral infection is a potential etiological cause, few studies have detected the effect of antiviral treatment. Objective: To determine the efficacy and safety of intravesical interferon instillation compared with hyaluronic acid in female patients with IC. Design, Setting, and Participants: This double-masked, randomized phase 2/3 clinical trial with parallel group design was implemented from October 2022 to April 2023 and had a 6-month follow-up period. The study was conducted at a single center. Eligible participants were female patients aged 18 to 70 years with a diagnosis of IC for more than 6 months. The last visit took place in October 2023. Data were analyzed between October and November 2023. Intervention: Patients were randomized 1:1 to receive either intravesical instillation of interferon or hyaluronic acid. Main Outcomes and Measures: The primary end point was change in visual analog scale pain score. Secondary end points included changes in voiding frequency, functional bladder capacity, symptom index, and global response assessment. Adverse events were closely monitored. Results: Among the 52 patients, the mean (SD) age was 50.0 (14.1) years and they were randomized to either the interferon group (26 [50%]) or hyaluronic acid (26 [50%]). The visual analog pain score showed the interferon group decreased more significantly than hyaluronic acid (-1.3; 95% CI, -2.3 to -0.3; P = .02) at month 6, with 20 patients (77%) exhibiting a 30% or higher reduction in pain compared with baseline. Secondary end points of voiding frequency, functional bladder capacity, and nocturia episodes showed no significant difference between 2 therapies. However, interferon showed a significantly higher reduction in the Interstitial Cystitis Symptom Index (-3.0; 95% CI, -5.3 to -0.7; P = .01) and the Problem Index (-2.5; 95% CI, -4.5 to -0.4; P = .02) at month 6, with 22 patients (85%) presenting as moderately or markedly improved. The frequencies of adverse events were similar between 2 groups. Only 1 patient discontinued hyaluronic acid because of poor effectiveness. Conclusions and Relevance: In this randomized clinical trial, female patients with IC could benefit from intravesical interferon therapy, without serious adverse events. These results offered hope for antiviral approaches in IC, but larger-scale, multicenter trials and long-term follow-up should be considered. Trial Registration: ClinicalTrials.gov Identifier: NCT05912946.

Evaluation of Antioxidant Activity and Treatment of Eczema by Berberine Hydrochloride-Loaded Liposomes-in-Gel.

In this paper, berberine hydrochloride-loaded liposomes-in-gel were designed and developed to investigate their antioxidant properties and therapeutic effects on the eczema model of the mouse. Berberine hydrochloride-liposomes (BBH-L) as the nanoparticles were prepared by the thin-film hydration method and then dispersed BBH-L evenly in the gel matrix to prepare the berberine hydrochloride liposomes-gel (BBH-L-Gel) by the natural swelling method. Their antioxidant capacity was investigated by the free radical scavenging ability on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and H2O2 and the inhibition of lipid peroxides malondialdehyde (MDA). An eczema model was established, and the efficacy of the eczema treatment was preliminarily evaluated using ear swelling, the spleen index, and pathological sections as indicators. The results indicate that the entrapment efficiency of BBH-L prepared by the thin-film hydration method was 78.56% ± 0.7%, with a particle size of 155.4 ± 9.3 nm. For BBH-L-Gel, the viscosity and pH were 18.16 ± 6.34 m Pas and 7.32 ± 0.08, respectively. The cumulative release in the unit area of the in vitro transdermal study was 85.01 ± 4.53 µg/cm2. BBH-L-Gel had a good scavenging capacity on DPPH and H2O2, and it could effectively inhibit the production of hepatic lipid peroxides MDA in the concentration range of 0.4-2.0 mg/mL. The topical application of BBH-L-Gel could effectively alleviate eczema symptoms and reduce oxidative stress injury in mice. This study demonstrates that BBH-L-Gel has good skin permeability, excellent sustained release, and antioxidant capabilities. They can effectively alleviate the itching, inflammation, and allergic symptoms caused by eczema, providing a new strategy for clinical applications in eczema treatment.

UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

Engineered plant extracellular vesicles for natural delivery across physiological barriers.

Extracellular vesicles (EVs) are nanoscale luminal vesicles that participate in the information transfer of proteins, nucleic acids, and lipids between cells, thereby playing a role in the treatment of diseases and the delivery of nutrients. In recent years, plant-derived EVs (PDEVs) containing bioactive compounds have attracted increasing interest due to their better biocompatibility and lower cytotoxicity in healthy tissues. In the biomedical field, PDEVs have been used as cargo carriers to achieve various functions through engineering modification techniques. This review focuses on the biogenesis, isolation, and identification of PDEVs. We discuss the surface functionalization of PDEVs to enhance therapeutic efficacy, thereby improving their efficiency as a next-generation drug delivery vehicle and their feasibility to treat diseases across the physiological barriers, while critically analyzing the current challenges and opportunities.

The design and evaluation of a quick checklist for urodynamic quality control: A prospective single-center small sample study.

PURPOSE: To design a quick checklist for urodynamic study (UDS), aiming to reduce the occurrence of errors in the process, which may help to increase the quality of UDS. And further to analyze the effectiveness of this quick checklist for UDS quality control. METHODS: First, a quick checklist for uroflow study and pressure-flow study was developed, based on the International Continence Society-Good Urodynamic Practice standards, our previous studies, and recent literature, as well as expert suggestions. Then, patients who underwent UDS between January 2023 to February 2023 were randomly assigned to a study group or a control group. For the study group, the quick checklist was used throughout the UDS process, while the control group did not. The main artefacts were chosen to verify the effectiveness of the quick checklist for improving the UDS quality. RESULTS: The quick checklist comprised three subtypes: checklist for patients, checklist for environment and device, and checklist for UDS test process. 38 UDS traces per group were included. The incidence of missing the standard cough test decreased significantly from 18.4% to 0 (p = 0.012), with the checklist implementation. The baseline drift frequency rate also declined significantly from 39.5% to 5.3% (p < 0.05). Volume < 150 mL on uroflow study occurred in 68.4% of cases and its frequency rate decreased significantly with checklist implementation (p < 0.05). CONCLUSION: A quick checklist for quality control of UDS was developed. The quick checklist as a convenient, quick, and easy used urodynamic quality control method, may help to reduce the technical artefacts and improve fundamental urodynamic quality control. Future research with a larger sample size is needed to confirm the effectiveness of the checklist.

Exogenous methylglyoxal alleviates drought-induced 'plant diabetes' and leaf senescence in maize.

Drought-induced leaf senescence is associated with high sugar levels, which bears some resemblance to the syndrome of diabetes in humans; however, the underlying mechanisms of such 'plant diabetes' on carbon imbalance and the corresponding detoxification strategy are not well understood. Here, we investigated the regulatory mechanism of exogenous methylglyoxal (MG) on 'plant diabetes' in maize plants under drought stress applied via foliar spraying during the grain-filling stage. Exogenous MG delayed leaf senescence and promoted photoassimilation, thereby reducing the yield loss induced by drought by 14%. Transcriptome and metabolite analyses revealed that drought increased sugar accumulation in leaves through inhibition of sugar transporters that facilitate phloem loading. This led to disequilibrium of glycolysis and overaccumulation of endogenous MG. Application of exogenous MG up-regulated glycolytic flux and the glyoxalase system that catabolyses endogenous MG and glycation end-products, ultimately alleviating 'plant diabetes'. In addition, the expression of genes facilitating anabolism and catabolism of trehalose-6-phosphate was promoted and suppressed by drought, respectively, and exogenous MG reversed this effect, implying that trehalose-6-phosphate signaling in the mediation of 'plant diabetes'. Furthermore, exogenous MG activated the phenylpropanoid biosynthetic pathway, promoting the production of lignin and phenolic compounds, which are associated with drought tolerance. Overall, our findings indicate that exogenous MG activates defense-related pathways to alleviate the toxicity derived from 'plant diabetes', thereby helping to maintain leaf function and yield production under drought.

A Y-shape connection device for pediatric patients with an indwelling catheter (Dia = 8Fr) during urodynamic studies, especially for filling phase measurements: a single-center prospective study for safety and effectiveness.

Introduction: This prospective study aimed to assess the effectiveness of a Y-shape connection device in reducing pain and bleeding in pediatric patients with indwelling catheters during urodynamic studies (UDS), while also obtaining effective results in the filling phase. Methods: A total of 45 pediatric patients with a mean age of 13 years were included, all of whom underwent both a UDS with the Y-shape connection device (Method A) and a standard UDS procedure (Method B). Results: The Y-shape connection device demonstrated similar overall urodynamic parameters compared to the standard procedure, while also resulting in significantly less bleeding (P = 0.006) and lower VAS scores during (1.12 ± 0.58 vs. 3.88 ± 1.01, P = 0.001) and after (0.12 ± 0.08 vs 2.91 ± 0.89, P = 0.001) the procedure. No adverse events were reported at the 1-month follow-up. Discussion: These findings suggest that the Y-shape connection device can effectively reduce pain and bleeding during and after UDS in pediatric patients with indwelling catheters (Dia = 8Fr), while also obtaining effective results in the filling phase. Therefore, this Y-shape connection device has a more significant value for children who require urodynamic studies and place more emphasis on filling phase parameters. Clinical trial registration: ChiCTR2300068280.

BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury.

BRISC (BRCC3 isopeptidase complex) is a deubiquitinating enzyme that has been linked with inflammatory processes, but its role in liver diseases and the underlying mechanism are unknown. Here, we investigated the pathophysiological role of BRISC in acute liver failure using a mice model induced by D-galactosamine (D-GalN) plus lipopolysaccharide (LPS). We found that the expression of BRISC components was dramatically increased in kupffer cells (KCs) upon LPS treatment in vitro or by the injection of LPS in D-GalN-sensitized mice. D-GalN plus LPS-induced liver damage and mortality in global BRISC-null mice were markedly attenuated, which was accompanied by impaired hepatocyte death and hepatic inflammation response. Constantly, treatment with thiolutin, a potent BRISC inhibitor, remarkably alleviated D-GalN/LPS-induced liver injury in mice. By using bone marrow-reconstituted chimeric mice and cell-specific BRISC-deficient mice, we demonstrated that KCs are the key effector cells responsible for protection against D-GalN/LPS-induced liver injury in BRISC-deficient mice. Mechanistically, we found that hepatic and circulating levels of TNF-α, IL-6, MCP-1, and IL-1ß, as well as TNF-α- and MCP-1-producing KCs, in BRISC-deleted mice were dramatically decreased as early as 1 h after D-GalN/LPS challenge, which occurred prior to the elevation of the liver injury markers. Moreover, LPS-induced proinflammatory cytokines production in KCs was significantly diminished by BRISC deficiency in vitro, which was accompanied by potently attenuated NF-κB activation. Restoration of NF-κB activation by two small molecular activators of NF-κB p65 effectively reversed the suppression of cytokines production in ABRO1-deficient KCs by LPS. In conclusion, BRISC is required for optimal activation of NF-κB-mediated proinflammatory cytokines production in LPS-treated KCs and contributes to acute liver injury. This study opens the possibility to develop new strategies for the inhibition of KCs-driven inflammation in liver diseases.

MSI-XGNN: an explainable GNN computational framework integrating transcription- and methylation-level biomarkers for microsatellite instability detection.

Microsatellite instability (MSI) is a hypermutator phenotype caused by DNA mismatch repair deficiency. MSI has been reported in various human cancers, particularly colorectal, gastric and endometrial cancers. MSI is a promising biomarker for cancer prognosis and immune checkpoint blockade immunotherapy. Several computational methods have been developed for MSI detection using DNA- or RNA-based approaches based on next-generation sequencing. Epigenetic mechanisms, such as DNA methylation, regulate gene expression and play critical roles in the development and progression of cancer. We here developed MSI-XGNN, a new computational framework for predicting MSI status using bulk RNA-sequencing and DNA methylation data. MSI-XGNN is an explainable deep learning model that combines a graph neural network (GNN) model to extract features from the gene-methylation probe network with a CatBoost model to classify MSI status. MSI-XGNN, which requires tumor-only samples, exhibited comparable performance with two well-known methods that require tumor-normal paired sequencing data, MSIsensor and MANTIS and better performance than several other tools. MSI-XGNN also showed good generalizability on independent validation datasets. MSI-XGNN identified six MSI markers consisting of four methylation probes (EPM2AIP1|MLH1:cg14598950, EPM2AIP1|MLH1:cg27331401, LNP1:cg05428436 and TSC22D2:cg15048832) and two genes (RPL22L1 and MSH4) constituting the optimal feature subset. All six markers were significantly associated with beneficial tumor microenvironment characteristics for immunotherapy, such as tumor mutation burden, neoantigens and immune checkpoint molecules such as programmed cell death-1 and cytotoxic T-lymphocyte antigen-4. Overall, our study provides a powerful and explainable deep learning model for predicting MSI status and identifying MSI markers that can potentially be used for clinical MSI evaluation.