No difference in oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving radical nephroureterectomy.

Patients with end stage renal disease (ESRD) are at high risk of developing upper tract urothelial carcinoma (UTUC). Due to high recurrence rate of UTUC in contralateral kidney and ureter, and high risk of complications related to surgery and anesthesia, whether it's necessary to remove both kineys and ureters at one time remains in debate. We utilized Taiwanese UTUC Registry Database to valuate the difference of oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving surgical resection. Patients with ESRD and UTUC were divided into three groups, unilateral UTUC, previous history of unilateral UTUC with metachronous contralateral UTUC, and concurrent bilatetral UTUC. Oncological outcomes, perioperative complications, and length of hospital stays were investiaged. We found that there is no diffence of oncological outcomes including overall survival, cancer specific survival, disease free survival and bladder recurrence free survival between these three groups. Complication rate and length of hospital stay are similar. Adverse oncological features such as advanced tumor stage, lymph node involvement, lymphovascular invasion, and positive surgical margin would negatively affect oncological outcomes.

Intranasal LAG3 antibody infusion induces a rapid antidepressant effect via the hippocampal ERK1/2-BDNF signaling pathway in chronically stressed mice.

The decline of microglia in the dentate gyrus is a new phenomenon that may explain the pathogenesis of depression, and reversing this decline has an antidepressant effect. The development of strategies that restore the function of dentate gyrus microglia in under stressful conditions is becoming a new focus. Lymphocyte-activating gene-3 (LAG3) is an immune checkpoint expressed by immune cells including microglia. One of its functions is to suppress the expansion of immune cells. In a recent study, chronic systemic administration of a LAG3 antibody that readily penetrates the brain was reported to reverse chronic stress-induced hippocampal microglia decline and depression-like behaviors. We showed here that a single intranasal infusion of a LAG3 antibody (In-LAG3 Ab) reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in a dose-dependent manner, which was accompanied by an increase in brain-derived neurotrophic factor (BDNF) in the dentate gyrus. Infusion of an anti-BDNF antibody into the dentate gyrus, construction of knock-in mice with the BDNF Val68Met allele, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of In-LAG3 Ab. Activation of extracellular signal-regulated kinase1/2 (ERK1/2) is required for the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and BDNF decrease in the dentate gyrus. Moreover, both inhibition and depletion of microglia prevented the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and impairment of ERK1/2-BDNF signaling in the dentate gyrus. These results suggest that In-LAG3 Ab exhibits an antidepressant effect through microglia-mediated activation of ERK1/2 and synthesis of BDNF in the dentate gyrus.

A comparative analysis of MMR immunohistochemistry panels: Evaluating the utility of four-protein versus two-protein panels in endometrial cancer patients.

AIMS: This study aimed to assess the accuracy of a two-protein panel for mismatch repair (MMR) immunohistochemistry (IHC) compared to a four-protein panel in a cohort of endometrial cancer patients. METHODS: The study included patients diagnosed with endometrial cancer between January 2018 and December 2023 with patients underwent MMR IHC staining for the four-protein panel (MSH2, MSH6, MLH1, and PMS2) serving as the reference standard. Various combinations of two proteins were examined and evaluated for their accuracy against the four-protein panel. Sensitivity, negative predictive value (NPV), and negative likelihood ratio were calculated for each combination. McNemar's test was performed to assess discordance, and receiver operating characteristic (ROC) curves were generated to evaluate diagnostic accuracy. RESULTS: Of 593 patients, MMR deficiency defined as at least one protein loss was observed in 146 patients (24.62%). When compared with four-protein panel, the highest sensitivity was observed with the MSH6/PMS2 combination (99.32%), followed sequentially by MSH6/MLH1 (97.26%), MSH2/PMS2 (93.15%), MSH2/MLH1 (91.10%), MLH1/PMS2 (79.45%), and MSH2/MSH6 (21.92%). The MSH6/PMS2 combination also demonstrated the best NPV of 99.78% and negative likelihood ratio of 0.01, while MSH6/MLH1 showed satisfactory NPV of 99.11% and negative likelihood ratio of 0.03. McNemar's test revealed no statistical difference between the four-protein panel and the MSH6/PMS2 panel (p = 1.000), and the MSH6/MLH1 panel (p = 0.125). CONCLUSIONS: The two-protein panel, particularly MSH6/PMS2, offers high sensitivity and negative predictive value, suggesting its potential as a cost-effective alternative to the four-protein panel in MMR testing for endometrial cancer patients.

Determining the optimum high-flow nasal cannula flow rate to achieve the desired fraction of inspired oxygen: A bench study.

BACKGROUND: Purpose: High-flow nasal cannula (HFNC) has many benefits in various clinical conditions. The original hypothesis suggests that the high and constant fraction of inspired oxygen (FiO2) is one of the main physiological effects. However, increasing evidence shows that there is a gap between the actual FiO2 and administered FiO2. We aimed to determine the actual FiO2 under different respiratory conditions and develop a regression model using a spontaneous breathing lung model. METHODS: A spontaneous breathing simulation model was built using an airway manikin and a model lung. The FiO2 was measured under different respiratory conditions with varying tidal volumes and respiratory and HFNC flow rates. The relationships between the respiratory parameters and actual FiO2 were determined and used to build the predictive model. RESULTS: The actual FiO2 was negatively correlated with respiratory rate and tidal volume and positively correlated with HFNC flow. The regression model could not be developed using simple respiratory parameters. Therefore, we introduced a new variable, defined as flow ratio, which equaled the HFNC flow divided by inspiratory flow. Our equation demonstrated that the actual FiO2 was mainly determined by the flow ratio in a non-linear relationship. Accordingly, a flow ratio greater than 1 did not ensure a constant high FiO2, whereas a flow ratio >1.435 could produce FiO2 >0.9. CONCLUSION: The FiO2 during HFNC was not constant even at sufficiently high oxygen flow compared with inspiratory flow. The predictive model showed that the actual FiO2 was mainly determined by the flow ratio.

A novel probiotic formula, BLLL, ameliorates chronic stress-induced depression-like behaviors in mice by reducing neuroinflammation and increasing neurotrophic factors.

Introduction: Probiotics have been recognized for their various biological activities, including antioxidant and anti-inflammatory properties. This study investigates the therapeutic effect of a novel probiotic formula, BLLL, consisting of Bifidobacterium breve, Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus helveticus, on chronic stress-induced depression-like behaviors in mice. Methods: The BLLL formula or phosphate-buffered saline (PBS) was given orally at a dose of 2, 4, or 8 × 1010 CFU/kg once daily for 10 days in mice treated with chronic unpredictable stress (CUS) treated or vehicle. Depression-like behaviors were assessed using the sucrose preference test (SPT), the forced swimming test (FST), and the tail suspension test (TST). The mRNA and/or protein expression of interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), IL-4, IL-10, and chitinase-3-like protein 3 (CHI3L1, also known as Ym-1), as well as the concentration of nitrite, malondialdehyde (MDA), glutathione (GSH), and brain-derived neurotrophic factor (BDNF) in the hippocampus and medial prefrontal cortex were examined. Results: The BLLL formula treatment at a dose of 8 × 1010 CFU/kg, but not at a dose of 2 or 4 × 1010 CFU/kg, improved CUS-induced depression-like behaviors in mice, as shown by the decrease in immobility time in the TST and FST and the increase in sucrose intake in the SPT. Further analysis revealed that BLLL treatment suppressed the CUS-induced increase in IL-1ß, IL-6, and TNF-α mRNA and protein levels, as well as the CUS-induced decrease in IL-4, IL-10, and Ym-1 mRNA and/or protein levels in the hippocampus and medial prefrontal cortex. In addition, treatment with the BLLL formula countered the CUS-induced increase in nitrite and MDA levels and the CUS-induced decrease in GSH content and BDNF concentration in the hippocampus and medial prefrontal cortex. Conclusion: These results demonstrate that the novel probiotic formula BLLL ameliorates chronic stress-induced depression-like behavior in mice by suppressing neuroinflammation and oxido-nitrosative stress in the brain.

Trefoil factor 1 (TFF1) reduces cerebral edema and gastric mucosal injury by regulating the EGFR/Src/FAK pathway in an intracerebral hemorrhage rat model.

The destruction of the blood-brain barrier and damage to the gastrointestinal mucosa after intracerebral hemorrhage (ICH) are important reasons for its high disability and mortality rates. However, the exact etiology is not yet clear. In addition, there are currently no effective treatments for improving cerebral edema and gastric mucosal damage after ICH. Trefoil factor 1 (TFF1) is a secretory protein that plays a crucial role in maintaining the integrity and barrier function of the gastric mucosa, and it has been reported to have a protective effect on brain damage induced by various causes. This study utilized a rat model of ICH induced by type IV collagenase was utilized, and intervened with recombinant TFF1 protein from an external institute to investigate the protective mechanisms of TFF1 against brain edema and gastric mucosal damage after ICH. The results demonstrated that TFF1 alleviated the neurological function and gastric mucosal damage in the rat model of ICH induced by type IV collagenase. TFF1 may ensure the integrity of the blood-brain and gastric mucosal barriers by regulating the EGFR (epidermal growth factor receptor)/Src (non-receptor tyrosine kinase)/FAK (focal adhesion kinase) pathway. Clearly, the disruption of the blood-brain barrier and the destruction of the gastric mucosal barrier are key pathological features of ICH, and TFF1 can improve the progression of blood-brain barrier and gastric mucosal barrier disruption in ICH by regulating the EGFR/Src/FAK pathway. Therefore, TFF1 may be a potential target for the treatment of ICH.

Application Effect of 18F-FDG PET/CT Technique in Diagnosis and Prognosis Evaluation of Lymphoma.

The objective of the study was to research diagnostic and prognostic values of 18F fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in patients with diffuse large B-cell lymphoma (DLBCL). The diagnostic sensitivity (Sen) of PET/CT (94.75%) was remarkably higher than 83.56% of B-US. Age ≥ 65 years old, maximum focal diameter ≥5 cm, clinical stages III-IV, systemic symptoms, increased lactate dehydrogenase level, high modified international prognostic index score, Ecog score ≥1, B-cell lymphoma 2 (Bcl-2) gene, MYC protein expression rate, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were all factors that influenced the recurrence or progression of DLBCL. With higher MTV and TLG, patients would have a greater probability of recurrence or progression. 18F-FDG PET/CT showed a high diagnostic Sen in lymphoma lesions, and could accurately guide clinical staging. Combined with clinical parameters, laboratory indicators, and metabolic parameters, prognostic indicators of patients could be evaluated more accurately.

Evaluating the significance of ECSCR in the diagnosis of ulcerative colitis and drug efficacy assessment.

Background: The main challenge in diagnosing and treating ulcerative colitis (UC) has prompted this study to discover useful biomarkers and understand the underlying molecular mechanisms. Methods: In this study, transcriptomic data from intestinal mucosal biopsies underwent Robust Rank Aggregation (RRA) analysis to identify differential genes. These genes intersected with UC key genes from Weighted Gene Co-expression Network Analysis (WGCNA). Machine learning identified UC signature genes, aiding predictive model development. Validation involved external data for diagnostic, progression, and drug efficacy assessment, along with ELISA testing of clinical serum samples. Results: RRA integrative analysis identified 251 up-regulated and 211 down-regulated DEGs intersecting with key UC genes in WGCNA, yielding 212 key DEGs. Subsequently, five UC signature biomarkers were identified by machine learning based on the key DEGs-THY1, SLC6A14, ECSCR, FAP, and GPR109B. A logistic regression model incorporating these five genes was constructed. The AUC values for the model set and internal validation data were 0.995 and 0.959, respectively. Mechanistically, activation of the IL-17 signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway in UC was indicated by KEGG and GSVA analyses, which were positively correlated with the signature biomarkers. Additionally, the expression of the signature biomarkers was strongly correlated with various UC types and drug efficacy in different datasets. Notably, ECSCR was found to be upregulated in UC serum and exhibited a positive correlation with neutrophil levels in UC patients. Conclusions: THY1, SLC6A14, ECSCR, FAP, and GPR109B can serve as potential biomarkers of UC and are closely related to signaling pathways associated with UC progression. The discovery of these markers provides valuable information for understanding the molecular mechanisms of UC.

Spontaneous Photonic Jammed Packing of Core-Shell Colloids in Conductive Aqueous Inks for Non-Iridescent Structural Coloration.

Integrating structural colors and conductivity into aqueous inks has the potential to revolutionize wearable electronics, providing flexibility, sustainability, and artistic appeal to electronic components. This study aims to introduce bioinspired color engineering to conductive aqueous inks. Our self-assembly approach involves mixing poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) with sulfonic acid-modified polystyrene (sPS) colloids to generate non-iridescent structural colors in the inks. This spontaneous structural coloration occurs because PEDOT:PSS and sPS colloids can self-assemble into core-shell structures and reversibly cluster into photonic aggregates of maximally random jammed packing within the aqueous environment, as demonstrated by small-angle X-ray scattering. Dissipative particle dynamics simulation confirms that the self-assembly aggregation of PEDOT:PSS chains and sPS colloids can be manipulated by the polymer-colloid interactions. Utilizing the finite-difference time-domain method, we demonstrate that the photonic aggregates of the core-shell colloids achieve close to maximum jammed packing, making them suitable for producing vivid structural colors. These versatile conductive inks offer adjustable color saturation and conductivity, with conductivity levels reaching 36 S cm-1 through the addition of polyethylene glycol oligomer, while enhanced water resistance and mechanical stability are achieved by doping with a cross-linker, poly(ethylene glycol) diglycidyl ether. With these unique features, the inks can create flexible, patterned circuits through processes like coating, writing, and dyeing on large areas, providing eco-friendly, visually appealing colors for customizable, stylish, comfortable, and wearable electronic devices.

Disulfidptosis signature predicts immune microenvironment and prognosis of gastric cancer.

BACKGROUND: Disulfidptosis is a newly identified mechanism of cell death triggered by disulfide stress. Thus, gaining a comprehensive understanding of the disulfidptosis signature present in gastric cancer (GC) could greatly enhance the development of personalized treatment strategies for this disease. METHODS: We employed consensus clustering to identify various subtypes of disulfidptosis and examined the distinct tumor microenvironment (TME) associated with each subtype. The Disulfidptosis (Dis) score was used to quantify the subtype of disulfidptosis in each patient. Subsequently, we assessed the predictive value of Dis score in terms of GC prognosis and immune efficacy. Finally, we conducted in vitro experiments to explore the impact of Collagen X (COL10A1) on the progression of GC. RESULTS: Two disulfidptosis-associated molecular subtypes (Discluster A and B) were identified, each with distinct prognosis, tumor microenvironment (TME), immune cell infiltration, and biological pathways. Discluster A, characterized by high expression of disulfidptosis genes, exhibited a high immune score but poor prognosis. Furthermore, the Dis score proved useful in predicting the prognosis and immune response in GC patients. Those in the low Dis score group showed better prognosis and increased sensitivity to immunotherapy. Finally, our experimental findings validated that downregulation of COL10A1 expression attenuates the proliferation and migration capabilities of GC cells while promoting apoptosis. CONCLUSIONS: This study demonstrates that the disulfidptosis signature can assist in risk stratification and personalized treatment for patients with GC. The results offer valuable theoretical support for anti-tumor strategies.

Head-to-head comparison of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET in the detection of cancer recurrence: a systematic review and meta-analysis.

Background: The comparative diagnostic performance of [68Ga]Ga-fibroblast activation protein inhibitors-04 {[68Ga]Ga-FAPI-04} positron emission tomography (PET) and fluorodeoxyglucose F 18 {[18F]FDG} PET in identifying cancer recurrence remains uncertain. The purpose of our study was to compare the diagnostic performance of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET imaging in cancer recurrence. Methods: Up until March 1, 2024, we searched PubMed, Embase, and Web of Science for pertinent papers. Studies examining the diagnostic utility of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET for cancer recurrence were included. Using a bivariate fixed-effect model and random-effect model, the pooled sensitivity and specificity for [68Ga]Ga-FAPI-04 PET and [18F]FDG PET were reported as estimates with 95% confidence intervals (CIs). The I2 statistic was used to evaluate the heterogeneity among the pooled studies. The included studies' quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) approach. Results: In all, 508 papers were found during the first search; ultimately, 12 studies totaling 224 patients were included. The pooled sensitivity of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET for cancer recurrence were 0.97 (95% CI: 0.90-1.00) and 0.69 (95% CI: 0.60-0.77). The pooled sensitivity of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET for gastrointestinal cancer recurrence were 1.00 (95% CI: 0.97-1.00) and 0.57 (95% CI: 0.42-0.74). The pooled specificity of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET for gastrointestinal cancer recurrence were 0.66 (95% CI: 0.15-1.00) and 0.46 (95% CI, 0.00-1.00). Conclusions: Based on the previous studies, [68Ga]Ga-FAPI-04 PET shows higher sensitivity compared to [18F]FDG PET in detecting tumor recurrence, especially in detecting gastrointestinal cancer recurrence. [68Ga]Ga-FAPI-04 PET shows similar specificity compared to [18F]FDG PET in detecting gastrointestinal cancer recurrence. The detection results, however, came from investigations using modest sample numbers. In this matter, more extensive prospective study is required.

History of stroke as a predictor of high left atrial fibrosis in patients with persistent atrial fibrillation-insight from the DECAAF II randomized trial.

BACKGROUND: There is a strong relationship between left atrial (LA) remodeling and ischemic stroke (IS) risk in atrial fibrillation (AF) patients. The Efficacy of Delayed Enhancement MRI-Guided Ablation vs. Conventional Catheter Ablation of Atrial Fibrillation (DECAAF-II) is the biggest MRI-based, randomized, multicenter clinical trial performed on persistent AF patients. The aim of this study is to evaluate the relationship between history of stroke and atrial fibrosis in the DECAAF II population. METHODS: Persistent AF patients who underwent Late Gadolinium Enhancement Magnetic Resonance Imaging (LGE-MRI) were included in the study and divided into two different groups: those with a history of stroke and those without. Propensity score matching was performed to adjust for covariates. Atrial fibrosis was compared in both groups. Then, patients were divided into different fibrosis groups, using three different cut-offs of baseline atrial fibrosis: ≥ 15%, ≥ 20%, and ≥ 25%. Univariate logistic regression and adjusted multivariate analysis were performed to assess the effect of clinical characteristics and risk factors on baseline fibrosis. RESULTS: Eight-hundred forty-three patients were recruited in DECAAF II, of whom 70 (8.3%) had a history of stroke. Patients with history of stroke had a higher prevalence of hypertension (p = 0.043), diabetes (p = 0.014), and hyperlipidemia (p = 0.001). Seventy patients with no history of strokes were matched with patients with history of stroke to adjust for covariates using propensity score analysis. Patients in the stroke group had a significantly higher level of fibrosis than those without (20.2% vs. 8.1%, p = 0.017). Increased age was a significant predictor of all three baseline fibrosis classes (≥ 15%, ≥ 20%, and ≥ 25%). Additionally, history of stroke was found to be a predictor of baseline fibrosis ≥ 25% even after adjusting for other clinical characteristics and risk factors (OR = 1.98 [1.14-3.43], p = 0.01). CONCLUSIONS: Left atrial fibrosis level greater than 25% correlates with the history of previous stroke episodes in patients with persistent atrial fibrillation.

The causal relationship between human brain morphometry and knee osteoarthritis: a two-sample Mendelian randomization study.

Background: Knee Osteoarthritis (KOA) is a prevalent and debilitating condition affecting millions worldwide, yet its underlying etiology remains poorly understood. Recent advances in neuroimaging and genetic methodologies offer new avenues to explore the potential neuropsychological contributions to KOA. This study aims to investigate the causal relationships between brain-wide morphometric variations and KOA using a genetic epidemiology approach. Method: Leveraging data from 36,778 UK Biobank participants for human brain morphometry and 487,411 UK Biobank participants for KOA, this research employed a two-sample Mendelian Randomization (TSMR) approach to explore the causal effects of 83 brain-wide volumes on KOA. The primary method of analysis was the Inverse Variance Weighted (IVW) and Wald Ratio (WR) method, complemented by MR Egger and IVW methods for heterogeneity and pleiotropy assessments. A significance threshold of p < 0.05 was set to determine causality. The analysis results were assessed for heterogeneity using the MR Egger and IVW methods. Brain-wide volumes with Q_pval < 0.05 were considered indicative of heterogeneity. The MR Egger method was employed to evaluate the pleiotropy of the analysis results, with brain-wide volumes having a p-value < 0.05 considered suggestive of pleiotropy. Results: Our findings revealed significant causal associations between KOA and eight brain-wide volumes: Left parahippocampal volume, Right posterior cingulate volume, Left transverse temporal volume, Left caudal anterior cingulate volume, Right paracentral volume, Left paracentral volume, Right lateral orbitofrontal volume, and Left superior temporal volume. These associations remained robust after tests for heterogeneity and pleiotropy, underscoring their potential role in the pathogenesis of KOA. Conclusion: This study provides novel evidence of the causal relationships between specific brain morphometries and KOA, suggesting that neuroanatomical variations might contribute to the risk and development of KOA. These findings pave the way for further research into the neurobiological mechanisms underlying KOA and may eventually lead to the development of new intervention strategies targeting these neuropsychological pathways.

Antibacterial and therapeutic effects of low energy shock waves on uropathogenic E. coli investigated by in vitro and in vivo cystitis rat model.

AIMS: Low-energy shock waves (LESWs) are known to alter cell-membrane permeability. This study aimed to investigate the effect of LESWs on Escherichia coli and E. coli-induced cystitis in rats. MAIN METHODS: Standardized suspensions of E. coli ATCC25922 were treated with or without LESWs (100 or 300 pulses; 0.12 mJ/mm2; 2 pulses/s) followed by bacterial counting, an antibiotic sensitivity test, and gene ontology analysis and gene-set enrichment analysis. Intravesical administration of saline or E. coli (0.5 mL with 108 CFU/mL) for 30 min was performed in female Sprague-Dawley rats. The rats were treated with or without LESWs (300 pulses; 0.12 mJ/mm2; 2 pulses/s) on days 4 and 5. The changes in inflammatory reactions, uroplakin IIIa staining, and correlation with urodynamic findings were assessed on day 8. KEY FINDINGS: LESW treatment induced a decrease in CFU and the autoaggregation rate and increased the inhibition zone sizes in a cefazolin-sensitivity study. These changes were associated with gene expression in regulation of cellular membrane components, biofilm formation, and the ATP-binding cassette transporter pathway. E. coli induced bladder hyperactivity and an inflammatory reaction as well as decreased uroplakin IIIa staining; these effects were partially reversed by LESW treatment. SIGNIFICANCE: The LESW antibacterial effect occurs by altering bacterial cell-membrane gene expression, enhancing antibiotic sensitivity, and inhibiting bladder inflammatory reaction and overactivity. These findings support the potential benefits of LESWs for treatment of recurrent or refractory bacterial cystitis.

The RAE1-STOP1-GL2-RHD6 module regulates the ALMT1-dependent aluminum resistance in Arabidopsis.

Aluminum (Al) toxicity is one of the major constraints for crop production in acid soils, Al-ACTIVATED MALATE TRANSPORTER1 (ALMT1)-dependent malate exudation from roots is essential for Al resistance in Arabidopsis, in which the C2H2-type transcription factor SENSITIVE TO PROTONRHIZOTOXICITY1 (STOP1) play a critical role. In this study, we reveal that the RAE1-GL2-STOP1-RHD6 protein module regulated the ALMT1-mediated Al resistance. GL2, STOP1 and RHD6 directly target the promoter of ALMT1 to suppress or activate its transcriptional expression, respectively, and mutually influence their action on the promoter of ALMT1 by forming a protein complex. STOP1 mediates the expression of RHD6 and RHD6-regulated root growth inhibition, while GL2 and STOP1 suppress each other's expression at the transcriptional and translational level and regulate Al-inhibited root growth. F-box protein RAE1 degrades RHD6 via the 26S proteasome, leading to suppressed activity of the ALMT1 promoter. RHD6 inhibits the transcriptional expression of RAE1 by directly targeting its promoter. Unlike RHD6, RAE1 promotes the GL2 expression at the protein level and GL2 activates the expression of RAE1 at the transcriptional level by directly targeting its promoter. The study provides insights into the transcriptional regulation of ALMT1, revealing its significance in Al resistance and highlighting the crucial role of the STOP1-associated regulatory networks.

Modulation of external and internal aluminum resistance by ALS3-dependent STAR1-mediated promotion of STOP1 degradation.

The ALMT1 transporter aids malate secretion, chelating Al3+ ions to form nontoxic Al-malate complexes, believed to exclude Al from the roots. However, the extent to which malate secreted by ALMT1 is solely used for the exclusion of Al3+ or can be reutilized by plant roots for internal Al tolerance remains uncertain. In our investigation, we explored the impact of malate secretion on both external and internal Al resistance in Arabidopsis thaliana. Additionally, we delved into the mechanism by which the tonoplast-localized bacterial-type ATP-binding cassette (ABC) transporter complex STAR1/ALS3 promotes the degradation of the Al resistance transcription factor STOP1 to regulate ALMT1 expression. Our study demonstrates that the level of secreted malate influences whether the Al-malate complex is excluded from the roots or transported into root cells. The nodulin 26-like intrinsic protein (NIP) subfamily members NIP1;1 and NIP1;2, located in the plasma membrane, coordinate with STAR1/ALS3 to facilitate Al-malate transport from root apoplasm to the symplasm and eventually to the vacuoles for the internal Al detoxification. ALS3-dependent STAR1 interacts with and promotes the degradation of STOP1, regulating malate exudation. Our findings demonstrate the dual roles of malate exudation in external Al exclusion and Al absorption for internal Al detoxification.

Dynamic change of MASLD in chronic hepatitis C patients after viral eradication: A nationwide registry study in Taiwan.

Background/Aims: Steatotic liver disease (SLD) is a common manifestation in chronic hepatitis C (CHC). Metabolic alterations in CHC are associated with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to elucidate whether hepatitis C virus (HCV) eradication mitigates MASLD occurrence or resolution. Methods: We enrolled 5,840 CHC patients whose HCV was eradicated by direct-acting antivirals in a nationwide HCV registry. MASLD and the associated cardiometabolic risk factors (CMRFs) were evaluated at baseline and 6 months after HCV cure. Results: There were 2,147 (36.8%) patients with SLD, and 1,986 (34.0%) of them met the MASLD criteria before treatment. After treatment, HbA1C (6.0% vs. 5.9%, P<0.001) and BMI (24.8 kg/m2 vs. 24.7 kg/m2, P<0.001) decreased, whereas HDL-C (49.1 mg/dL vs. 51.9 mg/dL, P<0.001) and triglycerides (102.8 mg/dL vs. 111.9 mg/dL, P<0.001) increased significantly. The proportion of patients with SLD was 37.5% after HCV eradication, which did not change significantly compared with the pretreatment status. The percentage of the patients who had post-treatment MASLD was 34.8%, which did not differ significantly from the pretreatment status (P=0.17). Body mass index (BMI) (odds ratio [OR]/95% confidence intervals [CI]: 0.89/0.85-0.92, P<0.001) was the only factor associated with MASLD resolution. In contrast, unfavorable CMRFs, including BMI (OR/CI: 1.10/1.06-1.14, P<0.001) and HbA1c (OR/CI: 1.19/1.04-1.35, P=0.01), were independently associated with MASLD development after HCV cure. Conclusions: HCV eradication mitigates MASLD in CHC patients. CMRF surveillance is mandatory for CHC patients with metabolic alterations, which are altered after HCV eradication and predict the evolution of MASLD.

A novel tissue-engineered corneal epithelium based on ultra-thin amniotic membrane and mesenchymal stem cells.

Currently, in vitro cultured corneal epithelial transplantation is effective in treating limbal stem cell dysfunction (LSCD). Selecting carriers is crucial for constructing the corneal epithelium through tissue engineering. In this study, the traditional amniotic membrane (AM) was modified, and mesenchymal stem cells (MSCs) were inoculated into the ultra-thin amniotic membrane (UAM) stroma to construct a novel UAM-MSC tissue-engineered corneal epithelial carrier, that could effectively simulate the limbal stem cells (LSCs) microenvironment. The structure of different carriers cultured tissue-engineered corneal epithelium and the managed rabbit LSCD model corneas were observed through hematoxylin-eosin staining. Cell phenotypes were evaluated through fluorescence staining, Western blotting, and RT-qPCR. Additionally, cell junction genes and expression markers related to anti-neovascularization were evaluated using RT-qPCR. Corneal epithelium cell junctions were observed via an electron microscope. The tissue-engineered corneal epithelium culture medium was analyzed through mass spectrometry. Tissue-engineered corneal epithelial cells expanded by LSCs on UAM-MSCs had good transparency. Simultaneously, progenitor cell (K14, PNCA, p63) and corneal epithelial (PAX6) gene expression in tissue-engineered corneal epithelium constructed using UAM-MSCs was higher than that in corneal epithelial cells amplified by UAM and de-epithelialized amniotic membrane. Electron microscopy revealed that corneal epithelial cells grafted with UAM-MSCs were closely connected. In conclusion, the UAM-MSCs vector we constructed could better simulate the limbal microenvironment; the cultured tissue-engineered corneal epithelium had better transparency, anti-neovascularization properties, closer intercellular connections, and closer resemblance to the natural corneal epithelial tissue phenotype.