Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation-driven hepatocarcinogenesis.

BACKGROUND AND AIMS: Gain-of-function (GOF) mutations of CTNNB1 and loss-of-function (LOF) mutations of AXIN1 are recurrent genetic alterations in hepatocellular carcinoma (HCC). We aim to investigate the functional contribution of Hippo/YAP/TAZ in GOF CTNNB1 or LOF AXIN1 mutant HCCs. APPROACH AND RESULTS: The requirement of YAP/TAZ in c-Met/ß-Catenin and c-Met/sgAxin1-driven HCC was analyzed using conditional Yap , Taz , and Yap;Taz knockout (KO) mice. Mechanisms of AXIN1 in regulating YAP/TAZ were investigated using AXIN1 mutated HCC cells. Hepatocyte-specific inducible TTR-CreER T2KO system was applied to evaluate the role of Yap;Taz during tumor progression. Cabozantinib and G007-LK combinational treatment were tested in vitro and in vivo . Nuclear YAP/TAZ was strongly induced in c-Met/sgAxin1 mouse HCC cells. Activation of Hippo via overexpression of Lats2 or concomitant deletion of Yap and Taz significantly inhibited c-Met/sgAxin1 driven HCC development, whereas the same approaches had mild effects in c-Met/ß-Catenin HCCs. YAP is the major Hippo effector in c-Met/ß-Catenin HCCs, and both YAP and TAZ are required for c-Met/sgAxin1-dependent hepatocarcinogenesis. Mechanistically, AXIN1 binds to YAP/TAZ in human HCC cells and regulates YAP/TAZ stability. Genetic deletion of YAP/TAZ suppresses already formed c-Met/sgAxin1 liver tumors, supporting the requirement of YAP/TAZ during tumor progression. Importantly, tankyrase inhibitor G007-LK, which targets Hippo and Wnt pathways, synergizes with cabozantinib, a c-MET inhibitor, leading to tumor regression in the c-Met/sgAxin1 HCC model. CONCLUSIONS: Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ is an effective treatment against AXIN1 mutant human HCCs.

Granulathiazole A protects 6-OHDA-induced Parkinson's disease from ferroptosis via activating Nrf2/HO-1 pathway.

Two pairs of enantiomers (1a-2b), namely (±)-alterpyrone F and (±)-alterpyrone G, along with a rare benzothiazole meroterpenoid granulathiazole A (3, GA), and two undescribed compounds called respectively granulahydeoate (4) and granulaone (5), were obtained from the co-cultivation of Alternaria brassicicola and Penicillium sp. HUBU0120. Exhaustive analyses of NMR, single crystal XRD, Mo2(OAc)4-induced circular dichroism data, and a modified Mosher's method distinguished the absolute configurations of isolates. Bioactive evaluations exhibited that GA possessed promising anti-PD activity in both in vitro and in vivo PD models viz. 6-OHDA-induced SH-SY5Y cells and 6-OHDA-induced zebrafish, respectively. Moreover, our research demonstrated that ferroptosis activated by 6-OHDA was mitigated in PD models after treated with GA. Extensive molecular mechanism studies in PD-modelled cells manifested that GA attenuated the decreased expressions of SLC7A11, GPX4, and FSP-1, and the increased level of ACSL4 via activating Nrf2/HO-1 pathway as well as ameliorated the accumulation of α-synuclein.

Brassisterol A, a new ergosterol from co-cultivation of fungi attenuates neuroinflammation via targeting NLRP3/caspase-1/GSDMD pathway.

Three new ergosterol derivatives brassisterol A-C (1-3) and two new epimeric bicycle-lactones brassictones A and B (4 and 5), were isolated from the co-cultivation of Alternaria brassicicola and Penicillium granulatum. The absolute configurations of these isolates were confirmed by extensive NMR spectra, TD-DFT ECD calculation, and the single crystal XRD data analysis. Amongst the metabolites, compound 1 exhibited potential anti-Parkinson's disease activity in both MPTP-induced zebrafish and MPP+-induced SH-SY5Y cells. Molecular mechanism studies in vitro showed that 1 attenuated the increase of α-synuclein, NLRP3, ASC, caspase-1, IL-1ß, IL-18, and GSDMD expression in the MPP+ induced PD model. Molecular docking in silico simulations exhibited that 1 was well accommodated to one of the binding pockets of NLRP3 8ETR in an appropriate conformation via forming typical hydrogen bonds as well as possessing a high negative binding affinity (-8.97 kcal/mol). Thus, our work suggested that 1 protected dopaminergic cell from neuroinflammation via targeting NLRP3/caspase-1/GSDMD signaling pathway.

Portal vein velocity predicts portal vein system thrombosis after splenectomy with esophagogastric devascularization.

BACKGROUND: Portal vein system thrombosis (PVST) is a potentially fatal complication after splenectomy with esophagogastric devascularization (SED) in cirrhotic patients with portal hypertension. However, the impact of portal vein velocity (PVV) on PVST after SED remains unclear. Therefore, this study aims to explore this issue. METHODS: Consecutive cirrhotic patients with portal hypertension who underwent SED at Tongji Hospital between January 2010 and June 2022 were enrolled. The patients were divided into two groups based on the presence or absence of PVST, which was assessed using ultrasound or computed tomography after the operation. PVV was measured by duplex Doppler ultrasound within one week before surgery. The independent risk factors for PVST were analyzed using univariate and multivariate logistic regression analysis. A nomogram based on these variables was developed and internally validated using 1000 bootstrap resamples. RESULTS: A total of 562 cirrhotic patients with portal hypertension who underwent SED were included, and PVST occurred in 185 patients (32.9%). Multivariate logistic regression analysis showed that PVV was the strongest independent risk factor for PVST. The incidence of PVST was significantly higher in patients with PVV ≤ 16.5 cm/s than in those with PVV > 16.5 cm/s (76.2% vs. 8.5%, p < 0.0001). The PVV-based nomogram was internally validated and showed good performance (optimism-corrected c-statistic = 0.907). Decision curve and clinical impact curve analyses indicated that the nomogram provided a high clinical benefit. CONCLUSION: A nomogram based on PVV provided an excellent preoperative prediction of PVST after splenectomy with esophagogastric devascularization.

Phenotypic correlations of carpal gland diverticular number with production traits and its genome-wide association analysis in multiple pig populations.

Pig carpal glands play crucial roles in territorial recognition, reproductive behavior, and information exchange; however, their effects on production traits and underlying genetic mechanisms remain unclear. In this study, 1028 pigs from six populations were counted for the carpal gland diverticular numbers (CGDNs) on the left (CGDNL) and right (CGDNR) legs, and their carcass and meat quality traits were assessed. The CGDNs were significantly different among the populations, and Licha Black pigs had a lower CGDN than the Bama Xiang breed. It was also significantly different between sexes, with males having more diverticula than females (p ≤ 0.0391). Moreover, the number was asymmetric, with CGDNR being significantly higher than CGDNL. Notably, CGDNs was significantly correlated with each other in phenotype and genetics and with 24-h pH, 24-h meat color score, 24-h marbling score, fat content, moisture content, sodium salt content, and saturated fatty acid content in phenotype. Furthermore, genome-wide association analyses identified seven SNPs in association with CGDNs at a 5% genome-wide significance level, all of which were located in a 1.78-Mb (35.347-37.129 Mb) region on chromosome 1. CNC10010837 and CNC10010840 were the top SNPs: both had an additive effect of 0.789 ± 0.120 on CGDNR with p = 8.31E-10. These findings provide important insights into the functions and underlying genetic mechanisms of swine carpal glands.

Characteristics of gut bacterial microbiota of black soldier fly (Diptera: Stratiomyidae) larvae effected by typical antibiotics.

As agents in an emerging technology, Hermetia illucens (Linnaeus, 1758) (Diptera: Stratiomyidae) larvae, black soldier fly, have shown exciting potential for degrading antibiotics in organic solid waste, a process for which gut microorganisms play an important role. This study investigated the characteristics of larval gut bacterial communities effected by typical antibiotics. Initially, antibiotics significantly reduced the diversity of gut bacterial species. After 8 days, diversity recovered to similar to that of the control group in the chlortetracycline, tylosin, and sulfamethoxazole groups. Proteobacteria, Firmicutes, and Actinobacteriota were the dominant phyla at the initial BSFL gut. However, after 4 days treatment, the proportion of Actinobacteriota significantly decreased, but Bacteroidota notably increased. During the conversion process, 18, 18, 17, 21, and 19 core genera were present in the chlortetracycline, sulfamethoxazole, tylosin, norfloxacin, and gentamicin groups, respectively. Pseudomonas, Actinomyces, Morganella, Providencia and Klebsiella might be the important genera with extraordinary resistance and degradation to antibiotics. Statistical analyses of COGs showed that antibiotics changed the microbial community functions of BSFL gut. Compared with the control group, (i) the chlortetracycline, sulfamethoxazole, and tylosin groups showed significant increase in the classification functions of transcription, RNA processing and modification，and so on, (ii) the norfloxacin and gentamicin groups showed significant increase in defense mechanisms and other functions. Note that we categorized the response mechanisms of these classification functions to antibiotics into resistance and degradation. This provides a new perspective to deeply understand the joint biodegradation behavior of antibiotics in environments, and serves as an important reference for further development and utilization of microorganisms-assisted larvae for efficient degradation of antibiotics.

Genomic Insights and Synthetic Biology Applications of Marine Actinomycete Streptomyces griseoincarnatus HNS054.

The marine bacterium Streptomyces sp. HNS054 shows promise as a platform for producing natural products. Isolated from a marine sponge, HNS054 possesses several desirable traits for bioengineering: rapid growth, salt tolerance, and compatibility with genetic tools. Its genome contains 21 potential biosynthetic gene clusters, offering a rich source of natural products. We successfully engineered HNS054 to increase the production of aborycin and actinorhodin by 4.5-fold and 1.2-fold, respectively, compared to S. coelicolor M1346 counterparts. With its unique features and amenability to genetic manipulation, HNS054 emerges as a promising candidate for developing novel marine-derived drugs and other valuable compounds.

Anatomical sectionectomy based on Takasaki's segmentation for solitary intrahepatic cholangiocarcinoma: a propensity-matched analysis.

BACKGROUND: Anatomical sectionectomy based on Takasaki's segmentation has shown advantages in hepatocellular carcinoma. However, whether this approach improves the survival of intrahepatic cholangiocarcinoma (ICC) remains unknown. METHODS: A series of 248 consecutive patients with solitary ICCs who underwent hepatectomy were studied retrospectively. The patients were classified into the groups of anatomical sectionectomy based on Takasaki's segmentation (TS group) and non-Takasaki's hepatectomy (NTH group). The bias between the two groups was minimized using propensity score matching (PSM). Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier analysis. The Cox proportional hazards model was performed to determine the adverse risk factors associated with survival. RESULTS: After PSM, 67 pairs of patients were compared. Both the RFS and OS rates in the TS group were significantly better than those in the NTH group (23.2 % vs. 16.5 %, and 40.4 % vs. 27.3 %, P = 0.035 and 0.032, respectively). Multivariate analysis showed that NTH was independently associated with worse RFS and OS than TS. The stratified analysis demonstrated that the RFS and OS rates in the TS group with tumor stage I and tumor size ≥3 cm were significantly better than those in the NTH group, while the survival rates for ICC with stage I and tumor size <3 cm or stage II-III showed no significant difference. CONCLUSION: TS was associated with improved RFS and OS in patients with solitary ICC even after PSM. TS may be preferred particularly in patients with tumor stage I and tumor size ≥3 cm.

AQP4-A25Q Point Mutation in Mice Depolymerizes Orthogonal Arrays of Particles and Decreases Polarized Expression of AQP4 Protein in Astrocytic Endfeet at the Blood-Brain Barrier.

Aquaporin-4 (AQP4) is characterized by the formation of orthogonal arrays of particles (OAPs) comprising its M1 and M23 isoforms in the plasma membrane. However, the biological importance of OAP formation is obscure. Here, we developed an OAP depolymerization male mouse model by transgenic knock-in of an AQP4-A25Q mutation. Analyses of the mutant brain tissue using blue native polyacrylamide gel electrophoresis, super-resolution imaging, and immunogold electron microscopy revealed remarkably reduced OAP structures and glial endfeet localization of the AQP4-A25Q mutant protein without effects on its overall mRNA and protein expression. AQP4A25Q/A25Q mice showed better survival and neurologic deficit scores when cerebral edema was induced by water intoxication or middle cerebral artery occlusion/reperfusion. The brain water content and swelling of pericapillary astrocytic endfeet processes in AQP4A25Q/A25Q mice were significantly reduced, functionally supporting decreased AQP4 protein expression at the blood-brain barrier. The infarct volume and neuronal damage were also reduced in AQP4A25Q/A25Q mice in the middle cerebral artery occlusion/reperfusion model. Astrocyte activation in the brain was alleviated in AQP4A25Q/A25Q mice, which may be associated with decreased cell swelling. We conclude that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.SIGNIFICANCE STATEMENT Aquaporin-4 (AQP4) is characterized by orthogonal arrays of particles (OAPs) comprising the M1 and M23 isoforms in the membrane. Here, an OAP depolymerization male mouse model induced by AQP4-A25Q mutation was first established, and the functions of OAP depolymerization in cerebral edema have been studied. The results revealed that AQP4 lost its OAP structure without affecting AQP4 mRNA and protein levels in AQP4-A25Q mice. AQP4-A25Q mutation mice has neuroprotective effects on cerebral edema induced by water intoxication and middle cerebral artery occlusion/reperfusion through relieving the activation of astrocytes and suppressed microglia-mediated neuroinflammation. We concluded that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.

A Prospective Study Using Propensity Score Matching to Compare Long-term Survival Outcomes After Robotic-assisted, Laparoscopic, or Open Liver Resection for Patients With BCLC Stage 0-A Hepatocellular Carcinoma.

OBJECTIVE: To compare the short- and long-term outcomes of robot-assisted (RALR), laparoscopic (LLR), or open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Following the Balliol IDEAL classification, long-term oncological outcomes can be used to evaluate the value of minimally invasive techniques in the treatment of HCC, and to assess whether they should become a standard practice. METHODS: Data from prospective cohorts of patients with BCLC stage 0-A HCC who underwent curative liver resection using OLR, LLR, or RALR at Tongji Hospital were reviewed. The short-term and long-term oncological outcomes of these 3 different surgical approaches after adequate follow-up were compared using propensity score matching to reduce selection bias. RESULTS: Of 369 patients included in this study (71, RALR; 141, LLR; and 157, OLR), 56 patients in each of the 3 groups were chosen for further comparison, after propensity score matching. In the minimally invasive group (RALR+LLR), both the operative time and duration of Pringle's maneuver were significantly longer than those in the OLR group; however, the length of hospital stay was significantly shorter. There were no significant differences in the other intraoperative parameters and the incidence of postoperative complications among the 3 groups. HCC recurrence in the minimally invasive group when compared with the OLR group was characterized by a significantly higher proportion of single lesion or early-stage HCC. However, there were no significant differences in the 5-year disease-free survival (63.8%, 54.4%, and 50.6%) or overall survival rates (80.8%, 78.6%, and 75.7%, respectively) among the 3 groups. Clinically significant portal hypertension was the only risk factor that negatively affected the 5-year disease-free survival rate. Multivariate Cox regression analysis showed that clinically significant portal hypertension, serum alpha-fetoprotein level (≥400 ng/mL), and Edmondson-Steiner grading (III+IV) were independent risk factors for poor long-term survival. CONCLUSION: Both robotic and laparoscopic hepatectomies were safe and effective for patients with BCLC stage 0-A HCC when compared with open hepatectomy.

A Preliminary Discussion on the Safety of Mild Therapeutic Hypothermia in Target Vessels after Endovascular Intervention in Acute Large Vessel Occlusion Cerebral Infarction.

INTRODUCTION: The aim of this study was to discuss the safety of rapid administration of 4°C hypothermic normal saline into the occluded vessels using an intra-arterial catheter to induce mild hypothermia following endovascular thrombectomy in patients with acute large vessel occlusion cerebral infarction. METHODS: We selected 78 patients with acute large vessel occlusion cerebral infarction who underwent endovascular thrombectomy in the Department of Neurology of our hospital from January 2020 to July 2022 and achieved TICI 2b recanalization. RESULT: Twenty-five patients were administered 500 mL of 4°C hypothermic normal saline in the occluded vessels at a rate of 25 mL/min to induce mild hypothermia. Twenty pairs of subjects conformed to strict matching and were finally included in the statistical analysis. The two groups of patients differed significantly in white blood cell count and percentage of neutrophils (p < 0.05); however, there were no significant differences in D-dimer, procalcitonin, and BNP levels. The two groups of patients did not differ significantly with respect to the incidence of the following indicators: upper gastrointestinal bleeding; pulmonary infection; venous thrombosis; vasospasms; seizures; and chills (p > 0.05). CONCLUSION: Mild therapeutic hypothermia in target vessels plus endovascular thrombectomy was shown to be safe in patients with acute large vessel occlusion cerebral infarction.

Transformation mechanism of methylphosphonate to methane by Burkholderia sp: Insight from multi-labeled water isotope probing and transcriptomic.

Methylphosphonate (MPn), has been identified as a likely source of methane in aerobic ocean and may be responsible for the "ocean methane paradox", that is oversaturation of dissolved methane in oxic sea waters. However, the mechanism underlying the cleavage of C-P bonds during microbial degradation is not well understood. Using multi-labeled water isotope probing (MLWIP) and transcriptome analysis, we investigated the phosphate oxygen isotope systematics and mechanisms of microbial-mediated degradation of MPn in this study. In the aerobic culture containing MPn as the only phosphorus source, there was a significant release of inorganic phosphate (149.4 µmol/L) and free methane (268.3 mg/L). The oxygen isotopic composition of inorganic phosphorus (δ18OP) of accumulated released phosphate was 4.50‰, 23.96‰, and 40.88‰, respectively, in the corresponding 18O-labeled waters of -10.3‰, 9.9‰, and 30.6‰, and the slope obtained in plots of δ18OP versus the oxygen isotopic composition of water (δ18OW) was 0.89. Consequently, 89% of the oxygen atoms (Os) in phosphate (PO4) were exchanged with 18O-labeled waters in the medium, while the rest were exchanged with intracellular metabolic water. It has been confirmed that the C-P bond cleavage of MPn occurs in the cell with both ambient and metabolic water participation. Moreover, phn gene clusters play significant roles to cleave the C-P bond of MPn for Burkholderia sp. HQL1813, in which phnJ, phnM and phnI genes are significantly up-regulated during MPn decomposition to methane. In conclusion, the aerobic biotransformation of MPn to free methane by Burkholderia sp. HQL1813 has been elucidated, providing new insights into the mechanism that bio-cleaves C-P bonds to produce methane aerobically in aqueous environments for representative phosphonates.

Synthetic algocyanobacterial consortium as an alternative to chemical fertilizers.

The use of unregulated pesticides and chemical fertilizers can have detrimental effects on biodiversity and human health. This problem is exacerbated by the growing demand for agricultural products. To address these global challenges and promote food and biological security, a new form of agriculture is needed that aligns with the principles of sustainable development and the circular economy. This entails developing the biotechnology market and maximizing the use of renewable and eco-friendly resources, including organic fertilizers and biofertilizers. Phototrophic microorganisms capable of oxygenic photosynthesis and assimilation of molecular nitrogen play a crucial role in soil microbiota, interacting with diverse microflora. This suggests the potential for creating artificial consortia based on them. Microbial consortia offer advantages over individual organisms as they can perform complex functions and adapt to variable conditions, making them a frontier in synthetic biology. Multifunctional consortia overcome the limitations of monocultures and produce biological products with a wide range of enzymatic activities. Biofertilizers based on such consortia present a viable alternative to chemical fertilizers, addressing the issues associated with their usage. The described capabilities of phototrophic and heterotrophic microbial consortia enable effective and environmentally safe restoration and preservation of soil properties, fertility of disturbed lands, and promotion of plant growth. Hence, the utilization of algo-cyano-bacterial consortia biomass can serve as a sustainable and practical substitute for chemical fertilizers, pesticides, and growth promoters. Furthermore, employing these bio-based organisms is a significant stride towards enhancing agricultural productivity, which is an essential requirement to meet the escalating food demands of the growing global population. Utilizing domestic and livestock wastewater, as well as CO2 flue gases, for cultivating this consortium not only helps reduce agricultural waste but also enables the creation of a novel bioproduct within a closed production cycle.

Chlorogenic Acid Inhibited Epithelial-Mesenchymal Transition to Treat Pulmonary Fibrosis through Modulating Autophagy.

Chlorogenic acid (CGA), derived from dicotyledons and ferns, has been demonstrated with anti-inflammatory, anti-bacterial, and free radical-scavenging effects and can be used to treat pulmonary fibrosis (PF). However, the specific mechanism by which CGA treats PF needs to be further investigated. In this study, in vivo experiment was firstly performed to evaluate the effects of CGA on epithelial-mesenchymal transition (EMT) and autophagy in bleomycin (BLM)-induced PF mice. Then, the effects of CGA on EMT and autophagy was assessed using transforming growth factor beta (TGF-ß) 1-induced EMT model in vitro. Furthermore, autophagy inhibitor (3-methyladenine) was used to verify that the inhibitory mechanism of CGA on EMT was associated with activating autophagy. Our results found that 60 mg/kg of CGA treatment significantly ameliorated lung inflammation and fibrosis in mice with BLM-induced PF. Besides, CGA inhibited EMT and promoted autophagy in mice with PF. In vitro studies also demonstrated that 50 µM of CGA treatment inhibited EMT and induced autophagy related factors in TGF-ß1-induced EMT cell model. Moreover, the inhibitory effect of CGA on autophagy and EMT in vitro was abolished after using autophagy inhibitor. In conclusion, CGA could inhibit EMT to treat BLM-induced PF in mice through, activating autophagy.

A novel prognostic signature of chemokines for survival and immune infiltration in kidney renal clear cell carcinoma.

Objective: Studies have revealed the alteration of chemokines in the tumour microenvironment in renal clear cell carcinoma (KIRC), which is closely related with immune infiltration and the prognosis of patients with KIRC. This research aims to comprehensively clarify the signature of chemokines in KIRC and the correlation between chemokines and immune infiltration in the TME of KIRC. Methods: The chemokine expression in KIRC were investigated by using multiple multiomics and bioinformatics tools. Hub-chemokines that were significantly related with the cancer stage and survival were identified. The role of hub-chemokines in the tumor microenvironment of KIRC was further assessed by using enrichment analysis, cancer-related pathway and immune infiltration analysis. Results: A total of 20 chemokines were significantly elevated in KIRC. Based on the correlation with KIRC stages and survival, 13 hub-chemokines were identified. Among the hub-chemokines, the high expression of CXCL2, CXCL5 and CXCL13 were related with worse survival of KIRC patients. The hub-chemokines were associated with the activation of multiple cancer-related signaling pathways. The functions of hub-chemokines were mainly enriched in chemokine-mediated signaling pathway, immunocytes chemotaxis and chemokine activity. CCL4, CCL5, CXCL9, CXCL10 and CXCL11 were related with various types immune infiltration such as CD8+T cell, neutrophil, B cell and dendritic cell. Using the hub-chemokine CXCL10, multiple immune checkpoints including LAG3, CTLA-4 and PD-1 were identified. Conclusion: Our research sheds light on the chemokines and their important role in promoting the tumor microenvironment of KIRC. The findings could provide more data about the prognosis prediction and treatment targets for KIRC.

Use of Virtual Reality in Burn Rehabilitation: A Systematic Review and Meta-analysis.

OBJECTIVES: We systematically reviewed published clinical trials to evaluate the effectiveness of virtual reality (VR) technology on functional improvement, pain relief, and reduction of mental distress among burn patients undergoing rehabilitation. DATA SOURCES: Systematic searches were conducted in 4 databases, including PubMed, the Cochrane Library, Embase, and Web of Science, from inception to August 2021. STUDY SELECTION: Randomized controlled trials (RCTs) evaluating any type of VR for the rehabilitation in burn patients with dysfunction were included. DATA EXTRACTION: Two reviewers evaluated the eligibility, and another 2 reviewers used the Cochrane risk of bias assessment tool to assess the risk of bias. The extracted data included the main results of rehabilitation evaluation (quality of life [QOL], work performance, range of motion [ROM] of joints, hand grip and pinch strength, pain, fun, anxiety), the application performance of VR (realness and presence), adverse effects (fatigue and nausea), and characteristics of the included studies. Heterogeneity was evaluated using the chi-square tests and I2 statistics. Random- or fixed-effects models were conducted to pool the effect sizes expressed as standardized mean differences (SMDs). DATA SYNTHESIS: Sixteen RCTs with 535 burn patients were included. VR-based interventions were superior to usual rehabilitation in QOL and work performance of burn patients and produced positive effect on the average gain of ROM (SMD=0.72) as well. VR was not associated with improved hand grip and pinch strength (SMD=0.50, 1.22, respectively) but was associated with reduced intensity, affective, and cognitive components of pain (SMD=-1.26, -0.71, -1.01, respectively) compared with control conditions. Ratings of fun in rehabilitation therapy were higher (SMD=2.38), and anxiety scores were lower (SMD=-0.73) than in control conditions. CONCLUSIONS: VR-based burn rehabilitation significantly improves the QOL and work performance of burn patients, increases the ROM gain in the joints, reduces the intensity and unpleasantness of pain and the time spent thinking about pain, increases the fun in the rehabilitation therapy, reduces the anxiety caused by the treatment, and has no obvious adverse effects. However, it did not significantly improve hand grip or pinch strength.

Multicopy Chromosome Integration and Deletion of Negative Global Regulators Significantly Increased the Heterologous Production of Aborycin in Streptomyces coelicolor.

Aborycin is a type I lasso peptide with a stable interlocked structure, offering a favorable framework for drug development. The aborycin biosynthetic gene cluster gul from marine sponge-associated Streptomyces sp. HNS054 was cloned and integrated into the chromosome of S. coelicolor hosts with different copies. The three-copy gul-integration strain S. coelicolor M1346::3gul showed superior production compared to the one-copy or two-copy gul-integration strains, and the total titer reached approximately 10.4 mg/L, i.e., 2.1 times that of the native strain. Then, five regulatory genes, phoU (SCO4228), wblA (SCO3579), SCO1712, orrA (SCO3008) and gntR (SCO1678), which reportedly have negative effects on secondary metabolism, were further knocked out from the M1346::3gul genome by CRISPR/Cas9 technology. While the ΔSCO1712 mutant showed a significant decrease (4.6 mg/L) and the ΔphoU mutant showed no significant improvement (12.1 mg/L) in aborycin production, the ΔwblA, ΔorrA and ΔgntR mutations significantly improved the aborycin titers to approximately 23.6 mg/L, 56.3 mg/L and 48.2 mg/L, respectively, which were among the highest heterologous yields for lasso peptides in both Escherichia coli systems and Streptomyces systems. Thus, this study provides important clues for future studies on enhancing antibiotic production in Streptomyces systems.

Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells.

Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases.

Outcomes Following the Endovascular Treatment of Renal Artery Stenosis Caused by Fibromuscular Dysplasia: A Systematic Review and Meta-Analysis.

OBJECTIVE: Renal artery revascularization has been performed to improve blood pressure control and to cure hypertension in patients with renal artery fibromuscular dysplasia (RAFMD). We herein conducted a systematic review and meta-analysis of studies assessing outcomes associated with the treatment of hypertensive RAFMD patients via endovascular angioplasty in order to offer an up-to-date overview of the relative costs and benefits of this approach to revascularization in RAFMD patients. METHODS: We systematically searched the PubMed and Embase databases and the Cochrane Central Register for Controlled Trials to identify relevant studies published as of January 15, 2020. Key outcomes of interest in these studies included technical success, the incidence of perioperative complications, cure rates, and overall improvement rates. RESULTS: In total, we identified 36 relevant studies of 1916 total repairs conducted in 1191 patients. Of these included studies, 33 were retrospective, while 3 were prospective. The overall technical success rate across these studies was 94.3%. Rates of total, major, and minor complications in these pooled studies were 12.9%, 4.6%, and 7.4%, respectively. Pooled rates of cured hypertension and improved hypertension following angioplasty, defined according to study-specific criteria, were 37.0% [95% CI: 27.0%-47.0%] and 80.0% [95% CI: 75.0% to 84.0%], respectively, although these rates varied highly among studies. Cure rates for studies used current clinical definitions for substantial variations across studies. Cure rates in studies using current definitions of cured hypertension (blood pressure <140/90 mm Hg without treatment) were just 18.1% following angioplasty. Cure rates fell markedly with increasing mean patient age (OR associated with an increase in mean age of 10 years: -0.24 [95% CI: -0.44 to -0.04, P = 0.019] and with mean known duration of hypertension (OR associated with an increase in mean hypertension duration of 5 years: -0.09 [95% CI: -0.12 to -0.05, P = 0.001]). CONCLUSIONS: These findings suggest that endovascular treatment yielded moderate benefits to RAFMD patients, with substantial variation across studies. The blood pressure outcome was strongly influenced by patient age.

Novel Prenylated Indole Alkaloids with Neuroprotection on SH-SY5Y Cells against Oxidative Stress Targeting Keap1-Nrf2.

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). Molecules non-covalently binding to the Keap1-Nrf2 complex could be a promising therapeutic approach for PD. Herein, two novel prenylated indole alkaloids asperpenazine (1), and asperpendoline (2) with a scarce skeleton of pyrimido[1,6-a]indole were discovered from the co-cultivated fungi of Aspergillus ochraceus MCCC 3A00521 and Penicillium sp. HUBU 0120. Compound 2 exhibited potential neuroprotective activity on SH-SY5Y cells against oxidative stress. Molecular mechanism research demonstrated that 2 inhibited Keap1 expression, resulting in the translocation of Nrf2 from the cytoplasm to the nucleus, activating the downstream genes expression of HO-1 and NQO1, leading to the reduction in reactive oxygen species (ROS) and the augment of glutathione. Molecular docking and dynamic simulation analyses manifested that 2 interacted with Keap1 (PDB ID: 1X2R) via forming typical hydrogen and hydrophobic bonds with residues and presented less fluctuation of RMSD and RMSF during a natural physiological condition.