The dual GGDEF/EAL domain enzyme PA0285 is a Pseudomonas species housekeeping phosphodiesterase regulating early attachment and biofilm architecture.

Bacterial lifestyles depend on conditions encountered during colonization. The transition between planktonic and biofilm growth is dependent on the intracellular second messenger c-di-GMP. High c-di-GMP levels driven by diguanylate cyclases (DGCs) activity favor biofilm formation, while low levels were maintained by phosphodiesterases (PDE) encourage planktonic lifestyle. The activity of these enzymes can be modulated by stimuli-sensing domains such as Per-ARNT-Sim (PAS). In Pseudomonas aeruginosa, more than 40 PDE/DGC are involved in c-di-GMP homeostasis, including 16 dual proteins possessing both canonical DGC and PDE motifs, that is, GGDEF and EAL, respectively. It was reported that deletion of the EAL/GGDEF dual enzyme PA0285, one of five c-di-GMP-related enzymes conserved across all Pseudomonas species, impacts biofilms. PA0285 is anchored in the membrane and carries two PAS domains. Here, we confirm that its role is conserved in various P. aeruginosa strains and in Pseudomonas putida. Deletion of PA0285 impacts the early stage of colonization, and RNA-seq analysis suggests that expression of cupA fimbrial genes is involved. We demonstrate that the C-terminal portion of PA0285 encompassing the GGDEF and EAL domains binds GTP and c-di-GMP, respectively, but only exhibits PDE activity in vitro. However, both GGDEF and EAL domains are important for PA0285 PDE activity in vivo. Complementation of the PA0285 mutant strain with a copy of the gene encoding the C-terminal GGDEF/EAL portion in trans was not as effective as complementation with the full-length gene. This suggests the N-terminal transmembrane and PAS domains influence the PDE activity in vivo, through modulating the protein conformation.

A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model.

Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. The aberrant activation of androgen receptor (AR) signaling has been recognized as a crucial oncogenic driver for PCa and AR antagonists are widely used in PCa therapy. To develop novel AR antagonist, a machine-learning MIEC-SVM model was established for the virtual screening and 51 candidates were selected and submitted for bioactivity evaluation. To our surprise, a new-scaffold AR antagonist C2 with comparable bioactivity with Enz was identified at the initial round of screening. C2 showed pronounced inhibition on the transcriptional function (IC50 = 0.63 µM) and nuclear translocation of AR and significant antiproliferative and antimetastatic activity on PCa cell line of LNCaP. In addition, C2 exhibited a stronger ability to block the cell cycle of LNCaP than Enz at lower dose and superior AR specificity. Our study highlights the success of MIEC-SVM in discovering AR antagonists, and compound C2 presents a promising new scaffold for the development of AR-targeted therapeutics.

HEVC extension for phase hologram compression.

Compressing digital holograms have growing attention nowadays due to their huge amount of original data sizes. Although many progresses have been reported for full-complex holograms, the coding performance for phase-only holograms (POHs) has been quite limited so far. In this paper, we present a very efficient compression method for POHs. It extends the conventional video coding standard HEVC (High Efficiency Video Coding) in such a way that the standard can be able to compress not only the natural images but also the phase images effectively. First, we suggest a proper way to calculate differences, distances and clipped values for phase signals by considering the inherent periodicity of phases. Then, some of the HEVC encoding and decoding processes are modified accordingly. The experimental results show that the proposed extension significantly outperforms the original HEVC for POH video sequences; specifically, average BD-rate reductions of 63.3% and 65.5% are achieved in phase domain and numerical reconstruction domain, respectively. It is worth mentioning that the modified encoding & decoding processes are very minimal and also applicable to the VVC (Versatile Video Coding), which is a successor of the HEVC.

PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats.

OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite technique for thoracotomy in advanced cardiovascular surgery. However, the consequent myocardial ischemia-reperfusion injury (MIRI) is the primary culprit behind cardiac dysfunction and fatal consequences post-operation. Prior research has posited that myocardial insulin resistance (IR) plays a vital role in exacerbating the progression of MIRI. Nonetheless, the exact mechanisms underlying this phenomenon remain obscure. METHODS: We constructed pyruvate dehydrogenase E1 α subunit (PDHA1) interference and overexpression rats and used ascending aorta occlusion in an in vivo model of CPB-MIRI. We devised an in vivo model of CPB-MIRI by constructing rat models with both pyruvate dehydrogenase E1α subunit (PDHA1) interference and overexpression through ascending aorta occlusion. We analyzed myocardial glucose metabolism and the degree of myocardial injury using functional monitoring, biochemical assays, and histological analysis. RESULTS: We discovered a clear downregulation of glucose transporter 4 (GLUT4) protein content expression in the CPB I/R model. In particular, cardiac-specific PDHA1 interference resulted in exacerbated cardiac dysfunction, significantly increased myocardial infarction area, more pronounced myocardial edema, and markedly increased cardiomyocyte apoptosis. Notably, the opposite effect was observed with PDHA1 overexpression, leading to a mitigated cardiac dysfunction and decreased incidence of myocardial infarction post-global ischemia. Mechanistically, PDHA1 plays a crucial role in regulating the protein content expression of GLUT4 on cardiomyocytes, thereby controlling the uptake and utilization of myocardial glucose, influencing the development of myocardial insulin resistance, and ultimately modulating MIRI. CONCLUSION: Overall, our study sheds new light on the pivotal role of PDHA1 in glucose metabolism and the development of myocardial insulin resistance. Our findings hold promising therapeutic potential for addressing the deleterious effects of MIRI in patients.

Effect of pelvic floor muscle training on urinary incontinence after radical prostatectomy: An umbrella review of meta-analysis and systematic review.

OBJECTIVE: To analyse the specific exercise effects of pelvic floor muscle training (PFMT) with or without biofeedback or electrical stimulation on urinary incontinence rehabilitation after radical prostatectomy. DATA SOURCES: We searched PubMed, Embase, Cochrane Database of Systematic Reviews, Web of Science and Scopus databases for systematic reviews and meta-analyses on PFMT for urinary incontinence after radical prostatectomy from inception to 3 October 2022. REVIEW METHODS: Two authors independently extracted key data from the included studies. The methodological quality of the included studies was assessed using the A Measure Tool to Assess Systematic Reviews-2 checklist. Grading of Recommendations Assessment Development and Evaluation was used to evaluate the quality of the outcomes. RESULTS: A total of 18 studies with 29,925 patients were included, all of which were of critically low methodological quality. Biofeedback therapy seemed to show additional benefits compared to PFMT alone; however, the adjunctive role of electrical stimulation remained more controversial due to the lack of strong evidence. Preoperative PFMT sometimes, but not always, showed the potential to improve urinary incontinence. PFMT with the guidance of a therapist could bring some benefits to the patient and was more acceptable to the patient, but consumed some medical resources. CONCLUSIONS: PFMT has a good effect on improving post-radical prostatectomy incontinence in men, and biofeedback can have an additional beneficial effect on patients, especially in the short-term and medium-term. However, there is insufficient evidence to suggest that electrical stimulation is beneficial for patients with urinary incontinence.

A novel nomogram and risk classification system for predicting overall survival in head and neck squamous cell cancer with distant metastasis at initial diagnosis.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is one of the most invasive cancer types globally, and distant metastasis (DM) is associated with a poor prognosis. The objective of this study was designed to construct a novel nomogram and risk classification system to predict overall survival (OS) in HNSCC patients presenting with DM at initial diagnosis. METHODS: HNSCC patients with initially diagnosed DM between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Firstly, all patients were randomly assigned to a training cohort and validation cohort (8:2), respectively. The Cox proportional hazards regression model was used to analyze the prognostic factors associated with OS. Then, the nomogram based on the prognostic factors and the predictive ability of the nomogram were assessed by the calibration curves, receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Finally, a risk classification system was established according to the nomogram scores. RESULTS: A total of 1240 patients initially diagnosed with HNSCC with DM were included, and the 6-, 12- and 18-month OS of HNSCC with DM were 62.7%, 40.8% and 30%, respectively. The independent prognostic factors for HNSCC patients with DM included age, marital status, primary site, T stage, N stage, bone metastasis, brain metastasis, liver metastasis, lung metastasis, surgery, radiotherapy and chemotherapy. Based on the independent prognostic factors, a nomogram was constructed to predict OS in HNSCC patients with DM. The C-index values of the nomogram were 0.713 in the training cohort and 0.674 in the validation cohort, respectively. The calibration curves and DCA also indicated the good predictability of the nomogram. Finally, a risk classification system was built and it revealed a statistically significant difference among the three groups of patients according to the nomogram scores. CONCLUSIONS: Factors associated with the overall survival of HNSCC patients with DM were found. According to the identified factors, we generated a nomogram and risk classification system to predict the OS of patients with initially diagnosed HNSCC with DM. The prognostic nomogram and risk classification system can help to assess survival time and provide guidance when making treatment decisions for HNSCC patients with DM.

Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury.

BACKGROUND: Previous studies proved that pyrin domain-containing protein 3 (NLRP3)-induced pyroptosis plays an important role in Myocardial ischemia-reperfusion injury (MIRI). Insulin can inhibit the activation of NLRP3 inflammasome, although the exact mechanism remains unclear. The aim of this study was to determine whether insulin reduces NLRP3-induced pyroptosis by regulating pyruvate dehydrogenase E1alpha subunit (PDHA1) dephosphorylation during MIRI. METHODS: Rat hearts were subject to 30 min global ischemia followed by 60 min reperfusion, with or without 0.5 IU/L insulin. Myocardial ischemia-reperfusion injury was evaluated by measuring myocardial enzymes release, Cardiac hemodynamics, pathological changes, infarct size, and apoptosis rate. Cardiac aerobic glycolysis was evaluated by measuring ATP, lactic acid content, and pyruvate dehydrogenase complex (PDHc) activity in myocardial tissue. Recombinant adenoviral vectors for PDHA1 knockdown were constructed. Pyroptosis-related proteins were measured by Western blotting analysis, immunohistochemistry staining, and ELISA assay, respectively. RESULTS: It was found that insulin significantly reduced the area of myocardial infarction, apoptosis rate, and improved cardiac hemodynamics, pathological changes, energy metabolism. Insulin inhibits pyroptosis-induced inflammation during MIRI. Subsequently, Adeno-associated virus was used to knock down cardiac PDHA1 expression. Knockdown PDHA1 not only promoted the expression of NLRP3 but also blocked the inhibitory effect of insulin on NLRP3-mediated pyroptosis in MIRI. CONCLUSIONS: Results suggest that insulin protects against MIRI by regulating PDHA1 dephosphorylation, its mechanism is not only to improve myocardial energy metabolism but also to reduce the NLRP3-induced pyroptosis.

Impacts of land use/land cover and soil property changes on soil erosion in the black soil region, China.

Soil erosion (SE) is seriously threatening grain production and the ecological environment in the black soil region. Understanding the impact of changes in land use/land cover (LULC) and soil properties on SE is critical for agricultural sustainability and soil management. However, the contribution of soil property changes to SE is often ignored in existing studies. This study analyzed changes in LULC and soil properties from 1980 to 2020 in the black soil region, China. Then, the revised universal soil loss equation was used to explore the spatiotemporal changes of SE from 1980 to 2020. Finally, the contribution of LULC change and soil property change to SE was separated by scenario comparison. The results showed that cropland increased (by 24,157 km2) at the expense of grassland and forest from 1980 to 2020. Sand in cropland decreased by 21.95%, while the silt, clay, and SOC increased by 21.37%, 1.43%, and 15.38%, respectively. Soil erodibility in cropland increased greatly (+9.85%), while in forest and grassland decreased (-6.05% and -4.72%). LULC change and soil properties change together aggravated SE in the black soil region. LULC change and soil property change resulted in a 22% increase in SE, of which LULC change resulted in a 14% increase, and soil property change resulted in an 8% increase. Agricultural development policy was the main reason driving LULC change. The combination of LULC change, climatic factors, and long-term tillage resulted in changes in soil properties. Ecosystem management and policy can reduce SE through vegetation restoration and soil improvement. This study can provide important references for soil conservation and agricultural development in the black soil region.

Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1/STAT3 Dual Inhibitors with Prospective Antitumor Effects.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 µM), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.

Self-Assembly of a U(VI)-Containing Polytungstate Tetramer with Lewis Acid-Base Catalytic Activity for a Dehydration Condensation Reaction.

A novel U(VI)-containing polytungstate (U-POW) tetramer, {K1.37Na26.63[K2(UO2)4Cl0.5(OH)5.5(γ-SiW10O36)4]}·ca66H2O (U4), was synthesized using the Keggin-type precursor [γ-SiW10O36]8- and UO2(NO3)2. U4 was further characterized by single-crystal X-ray diffraction, FT-IR, Raman spectroscopy, solid-state diffuse reflection spectroscopy, ICP-OES, ESI-MS, TGA, and PXRD. The central {K2(UO2)4Cl0.5(OH)5.5} chromophore was constructed dexterously from four uranyl, four halves of K ions, 5.5 bridging µ2-OH, and disordered Cl ions, and was further stabilized by four {γ-SiW10} moieties to construct the tetramer [K2(UO2)4Cl0.5(OH)5.5(γ-SiW10O36)4]28-. Notably, U4 could work as an effective bifunctional Lewis acid-base catalyst for the synthesis of pyrazoles via the condensation of hydrazines with 1,3-diketones under mild conditions, which is attributed to the synergetic effect of the Lewis acidity of U(VI) and the Lewis basicity of {γ-SiW10}.

Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex.

Initiation of eukaryotic DNA replication requires phosphorylation of the MCM complex by Dbf4-dependent kinase (DDK), composed of Cdc7 kinase and its activator, Dbf4. We report here that budding yeast Rif1 (Rap1-interacting factor 1) controls DNA replication genome-wide and describe how Rif1 opposes DDK function by directing Protein Phosphatase 1 (PP1)-mediated dephosphorylation of the MCM complex. Deleting RIF1 partially compensates for the limited DDK activity in a cdc7-1 mutant strain by allowing increased, premature phosphorylation of Mcm4. PP1 interaction motifs within the Rif1 N-terminal domain are critical for its repressive effect on replication. We confirm that Rif1 interacts with PP1 and that PP1 prevents premature Mcm4 phosphorylation. Remarkably, our results suggest that replication repression by Rif1 is itself also DDK-regulated through phosphorylation near the PP1-interacting motifs. Based on our findings, we propose that Rif1 is a novel PP1 substrate targeting subunit that counteracts DDK-mediated phosphorylation during replication. Fission yeast and mammalian Rif1 proteins have also been implicated in regulating DNA replication. Since PP1 interaction sites are evolutionarily conserved within the Rif1 sequence, it is likely that replication control by Rif1 through PP1 is a conserved mechanism.

[Chemical pattern recognition of Atractylodes chinensis from different producing areas and establishment of quantitative analysis of multi-components by single marker (QAMS) method for four components].

This study established the fingerprint and combined it with chemical pattern recognition to evaluate the quality of Atractylodes chinensis samples from different producing areas and then employed the quantitative analysis of multi-components by single marker(QAMS) method to verify the feasibility and applicability of the established method in the quality evaluation of A. chinensis. The fingerprints of A. chinensis samples were constructed via high performance liquid chromatography(HPLC) to evaluate the inter-batch consistency. With the quality control component atractylodin as the internal reference, the relative correction factors(RCFs) were established for atractylenolide Ⅰ, atractylenolide Ⅲ, and ß-eudesmol and the content of the four components was calculated. The external standard method was used to verify the accuracy of QAMS method. The quality of A. chinensis was further evaluated by similarity analysis, clustering analysis, and principal component analysis. The fingerprints of 13 batches of samples were calibrated with 21 common peaks, and 4 common peaks were identified with the similarities all above 0.9. The RCFs established with atractylodin as the internal reference represented good reproducibility under different experimental conditions. Specifically, the RCFs of atractylenolide Ⅰ, atractylenolide Ⅲ, and ß-eudesmol in A. chinensis were 2.091, 4.253, and 6.010, respectively. QAMS and ESM showed no significant difference in the results, indicating that the QAMS method established in this study was stable and reliable. Thus, HPLC fingerprint combined with QAMS can be used for the quality evaluation of A. chinensis, providing a basis for comprehensive and rapid quality evaluation of A. chinensis.

Sulfonate-Assisted Surface Iodide Management for High-Performance Perovskite Solar Cells and Modules.

Owing to the ionic nature of lead halide perovskites, their halide-terminated surface is unstable under light-, thermal-, moisture-, or electric-field-driven stresses, resulting in the formation of unfavorable surface defects. As a result, nonradiative recombination generally occurs on perovskite films and deteriorates the efficiency, stability, and hysteresis performances of perovskite solar cells (PSCs). Here, a surface iodide management strategy was developed through the use of cesium sulfonate to stabilize the perovskite surface. It was found that the pristine surface of common perovskite was terminated with extra iodide, that is, with an I-/Pb2+ ratio larger than 3, explaining the origination of surface-related problems. Through post-treatment of perovskite films by cesium sulfonate, the extra iodide on the surface was facilely removed and the as-exposed Pb2+ cations were chelated with sulfonate anions while maintaining the original 3D perovskite structure. Such iodide replacement and lead chelating coordination on perovskite could reduce the commonly existing surface defects and nonradiative recombination, enabling assembled PSCs with an efficiency of 22.06% in 0.12 cm2 cells and 18.1% in 36 cm2 modules with high stability.

ELAVL1 is transcriptionally activated by FOXC1 and promotes ferroptosis in myocardial ischemia/reperfusion injury by regulating autophagy.

AIMS: Myocardial ischemia is the most common form of cardiovascular disease and the leading cause of morbidity and mortality. Understanding the mechanisms is very crucial for the development of effective therapy. Therefore, this study aimed to investigate the functional roles and mechanisms by which ELAVL1 regulates myocardial ischemia and reperfusion (I/R) injury. METHODS: Mouse myocardial I/R model and cultured myocardial cells exposed to hypoxia/reperfusion (H/R) were used in this study. Features of ferroptosis were evidenced by LDH activity, GPx4 activity, cellular iron, ROS, LPO, and GSH levels. The expression levels of autophagy markers (Beclin-1, p62, LC3), ELAVL1 and FOXC1 were measured by qRT-PCR, immunostaining and western blot. RIP assay, biotin-pull down, ChIP and dual luciferase activity assay were employed to examine the interactions of ELAVL1/Beclin-1 mRNA and FOXC1/ELAVL1 promoter. CCK-8 assay was used to examine viability of cells. TTC staining was performed to assess the myocardial I/R injury. RESULTS: Myocardial I/R surgery induced ferroptosis and up-regulated ELAVL1 level. Knockdown of ELAVL1 decreased ferroptosis and ameliorated I/R injury. Si-ELAVL1 repressed autophagy and inhibition of autophagy by inhibitor suppressed ferroptosis and I/R injury in myocardial cells. Increase of autophagy could reverse the effects of ELAVL1 knockdown on ferroptosis and I/R injury. ELAVL1 directly bound with and stabilized Beclin-1 mRNA. Furthermore, FOXC1 bound to ELAVL1 promoter region and activated its transcription upon H/R exposure. CONCLUSION: FOXC1 transcriptionally activated ELAVL1 may promote ferroptosis during myocardial I/R by modulating autophagy, leading to myocardial injury. Inhibition of ELAVL1-mediated autophagic ferroptosis would be a new viewpoint in the treatment of myocardial I/R injury.

Laparoscopic versus open resection of hepatocellular carcinoma in patients with cirrhosis: meta-analysis.

BACKGROUND: The exact role of laparoscopic liver resection (LLR) in patients with hepatocellular carcinoma (HCC) and underlying liver cirrhosis (LC) is not well defined. In this meta-analysis, both long- and short-term outcomes following LLR versus open liver resection (OLR) were analysed. METHODS: PubMed, EMBASE, Scopus and Web of Science databases were searched systematically for randomised controlled trials (RCTs) and propensity-score matched (PSM) studies reporting outcomes of LLR versus OLR of HCC in patients with cirrhosis. Primary outcome was overall survival (OS). This was analysed using one-stage (individual participant data meta-analysis) and two-stage (aggregate data meta-analysis) approaches. Secondary outcomes were operation duration, blood loss, blood transfusion, Pringle manoeuvre utilization, overall and major complications, length of hospital stay (LOHS), 90-day mortality and R0 resection rates. RESULTS: Eleven studies comprising 1618 patients (690 LLR versus 928 OLR) were included for analysis. In the one-stage meta-analysis, an approximately 18.7 per cent lower hazard rate (HR) of death in the LLR group (random effects: HR 0.81, 95 per cent confidence interval [C.I.] 0.68 to 0.96; P = 0.018) was observed. Two-stage meta-analysis resulted in a pooled HR of 0.84 (95 per cent C.I. 0.74 to 0.96; P = 0.01) in the overall LLR cohort. This indicated a 16-26 per cent reduction in the HR of death for patients with HCC and cirrhosis who underwent LLR. For secondary outcomes, LLR was associated with less blood loss (mean difference [MD] -99 ml, 95 per cent C.I. -182 to -16 ml), reduced overall complications (odds ratio 0.49, 95 per cent C.I. 0.37 to 0.66) and major complications (odds ratio 0.45, 95 per cent C.I. 0.26 to 0.79), and shorter LOHS (MD -3.22 days, 95 per cent C.I. -4.38 to -2.06 days). CONCLUSION: Laparoscopic resection of HCC in patients with cirrhosis is associated with improved survival and perioperative outcomes.

The value of ultrasonography combined with clinical features for predicting carotid imaging progression of Takayasu's arteritis: a prospective cohort study.

OBJECTIVES: To identify valuable ultrasonography findings combined with clinical markers for predicting carotid progression of Takayasu's arteritis (TAK) on imaging during a 1-year follow-up period. METHODS: From May 2016 to June 2019, 77 Chinese TAK patients with carotid artery involvement were enrolled in the present study. The patients' clinical characteristics and serological test and carotid ultrasonography results were recorded at baseline and each visit. Carotid progression was evaluated by ultrasonography every 3 months during the 1-year follow-up. Baseline clinical characteristics and ultrasonography results for predicting progression on imaging were identified. RESULTS: Sixteen (20.8%) patients presented with carotid progression on imaging during the 1-year follow-up period. The patients in the progressive group were younger (23.4±3.7 vs. 32.3±9.8 years, p<0.01) than those in the non-progressive group. At baseline, the vessel wall was thicker in the progressive group than in the non-progressive group (2.4±0.8 vs. 1.9±0.5 mm, p=0.041). Furthermore, the proportion of patients with refractory disease (87.5% vs. 16.4%, p<0.01) was higher in the progressive group than in the non-progressive group. Patients with a thickened carotid wall (≥1.9 mm), refractory disease, and younger age (≤30 years) might be at a high risk of carotid progression on imaging (75%, AUC: 0.93, sensitivity: 75%, specificity: 93.4%). CONCLUSIONS: Younger patients with early vascular structural changes at baseline as well as refractory disease seemed more likely to show carotid progression on imaging.

Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure.

Programmed cell death (PCD), including apoptosis, apoptotic necrosis, and pyroptosis, is involved in various organ dysfunction syndromes. Recent studies have revealed that a substrate of caspase-3, gasdermin E (GSDME), functions as an effector for pyroptosis; however, few inhibitors have been reported to prevent pyroptosis mediated by GSDME. Here, we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD. Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity, exhibiting a lower IC50 than that of Z-DEVD-FMK. Functionally, Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3, preventing apoptotic and pyroptotic events in hepatocytes and macrophages. Furthermore, in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure, Ac-DMPD/DMLD-CMK significantly alleviated liver injury. Together, this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also, more importantly, shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.

Effects of different drying methods on the chemical constituents of Lilium lancifolium Thunb. based on UHPLC-MS analysis and antidepressant activity of the main chemical component regaloside A.

The Lilium lancifolium Thunb. is a herb with multiple functions in both medicine and food in China, and its extracts have shown antidepressant effects. In this study, fresh bulbs of Lilium lancifolium Thunb. were processed to study the effects of different drying processes on changes in its main chemical components. We found that different drying methods can affect the chemical constituents of the herb. Among these components, Regaloside A has been found as the characteristic component. Here, Cell Counting Kit-8 assay, and Western blotting were used to evaluate the neuroprotective antidepressant effects of Regaloside A. The results showed the cell survival rate was improved, the phosphorylation levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphatidylinositol 3 kinase, protein kinase B, and mammalian target of rapamycin were increased after Regaloside A treatment. In general, different drying methods have a significant influence on the chemical composition of the herb, and Regaloside A may be the main chemical component of the herb. It can alleviate the damage of corticosterone in SH-SY5Y cells, and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling mediated by brain-derived neurotrophic factor/tyrosine kinase receptor B may play an important role in the neuroprotective antidepressant effects of Regaloside A.

Type of Necrosis Influences Prognosis in Hepatocellular Carcinoma After the First Transarterial Chemoembolization.

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common tumors. Transarterial chemoembolization (TACE) is the first choice of treatment for intermediate HCC and an important treatment option for advanced HCC. This retrospective study compared the prognosis between patients showing coagulative necrosis and patients showing liquefactive necrosis after the first TACE procedure. MATERIAL AND METHODS We divided 171 patients with Barcelona Clinic Liver Cancer (BCLC) Stage B or C HCC into 2 groups; a coagulative necrosis group (79 patients) and a liquefactive necrosis group (92 patients). The coagulative and liquefactive necroses were identified by computed tomography after the first TACE procedure. Kaplan-Meier analysis was used to identify the differences in the overall survival (OS) and progression-free survival (PFS) between the 2 groups, and the associated risk factors and safety of TACE were analyzed. RESULTS The median OS durations were 23.27±1.40 months and 8.83±2.15 months (P=0.004) and the median PFS durations were 9.33±0.96 months and 3.70±0.44 months (P=0.002) in the coagulative necrosis and liquefactive necrosis groups, respectively. Intrahepatic in situ progression, new intrahepatic metastasis, and extrahepatic progression occurred significantly earlier in the liquefactive necrosis group (P<0.05). Univariate analysis and multivariate analyses showed liquefactive necrosis was the main risk factor for OS. There was no significant difference in the hepatic function impairment or post-embolism syndrome after TACE. CONCLUSIONS After the first TACE procedure, the patients with liquefactive necrosis experienced recurrence and metastasis earlier and had a worse prognosis. Therefore, these patients should be considered for earlier administration of targeted therapies or immunotherapies after TACE.

All-Inside Arthroscopic Modified Broström Technique to Repair Anterior Talofibular Ligament Provides a Similar Outcome Compared With Open Broström-Gould Procedure.

PURPOSE: To introduce an all-inside modified Broström technique to suture the anterior talofibular ligament (ATFL) and inferior extensor retinaculum (IER) under arthroscopy and to compare its outcomes with those of the conventional open procedure. METHODS: All patients who underwent arthroscopic or open repair of the ATFL between June 2014 and December 2017 were included in this study. Visual analog scale (VAS), Karlsson and Peterson (K-P), American Orthopedic Foot and Ankle Society (AOFAS) ankle/hindfoot, and Tegner activity scores, as well as manual anterior drawer test (ADT), were used to evaluate the patients preoperatively and ≥2 years after surgery. The Sefton grading system was used to assess the level of satisfaction after surgery. Detailed surgical data and intraoperative findings were documented at the time of surgery. RESULTS: A total of 67 patients, 31 in the arthroscopic group and 36 in the open group, were included in this study (43 men and 24 women, mean body mass index 24.00, range 19.53 to 30.03). The surgical duration in the arthroscopic group (median, 34 minutes; range, 25 to 74) was significantly shorter than that in the open group (mean, 43.08 ± 8.11 minutes; 95% confidence interval [CI] 40.34 to 45.83) (P = .007). At the last follow-up, the subjective functional scores and ADT results improved significantly in both cohorts (P < .001). However, no significant difference was found in the VAS score (1.74 ± 1.24, 95% CI 1.29 to 2.2, in the open group versus 1.58 ± 1.2, 95% CI 1.18 to 1.99, in the arthroscopic group; P = .581), AOFAS score (91.71 ± 5.46, 95% CI 89.71 to 93.71, versus 90.67 ± 5.59, 95% CI 88.78 to 92.56; P = .444), K-P score (87.52 ± 7.59, 95% CI 84.73 to 90.3, versus 88.75 ± 5.56, 95% CI 86.87 to 90.63; P = .446), and ADT evaluation (normal: 96.77% versus 94.44%, P = .557) between the arthroscopic and open groups, respectively. In addition, 28 cases (90.32%) in the arthroscopic group and 32 (88.89%) in the open group achieved satisfactory results based on the Sefton grading system (P = .736). Seventeen patients (47.2%) in the open group and 18 patients (58.1%) in the arthroscopic group underwent Tegner evaluation after surgery, which showed no significant difference (5, interquartile range [IQR] 1 in the open group versus 5, IQR 3 in the arthroscopic group; P = .883). Complications were reported in 4 (11.1%) and 2 (6.5%) patients who underwent open and arthroscopic surgeries, respectively (P = .813). CONCLUSIONS: Both open and arthroscopic modified Broström surgeries generated favorable outcomes, with a significant improvement compared with the preoperative condition. Compared with the open Broström-Gould procedure, the all-inside arthroscopic modified Broström technique produced equivalent functional and clinical results at a minimum of 2 years after the operation, with a shorter surgical duration. Arthroscopic repair might be a safe and viable alternative to open surgery for lateral ankle stabilization. LEVEL OF EVIDENCE: III.