Deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency in humans and mice.

Premature ovarian insufficiency (POI) is a heterogeneous female disorder characterized by the loss of ovarian function before the age of 40. It represents a significant detriment to female fertility. However, the known POI-causative genes currently account for only a fraction of cases. To elucidate the genetic factors underlying POI, we conducted whole-exome sequencing on a family with three fertile POI patients and identified a deleterious missense variant in RNF111. In a subsequent replication study involving 1,030 POI patients, this variant was not only confirmed but also accompanied by the discovery of three additional predicted deleterious RNF111 variants. These variants collectively account for eight cases, representing 0.78% of the study cohort. A further study involving 500 patients with diminished ovarian reserve also identified two additional RNF111 variants. Notably, RNF111 encodes an E3 ubiquitin ligase with a regulatory role in the TGF-ß/BMP signaling pathway. Our analysis revealed that RNF111/RNF111 is predominantly expressed in the oocytes of mice, monkeys, and humans. To further investigate the functional implications of RNF111 variants, we generated two mouse models: one with a heterozygous missense mutation (Rnf111+/M) and another with a heterozygous null mutation (Rnf111+/-). Both mouse models exhibited impaired female fertility, characterized by reduced litter sizes and small ovarian reserve. Additionally, RNA-seq and quantitative proteomics analysis unveiled that Rnf111 haploinsufficiency led to dysregulation in female gonad development and negative regulation of the BMP signaling pathway within mouse ovaries. In conclusion, our findings strongly suggest that monoallelic deleterious variants in RNF111 can impair female fertility and induce POI in both humans and mice.

Jidong ovarian aging cohort study: Objective, design, and baseline characteristics.

BACKGROUND: Ovarian aging is a continuous process comprising a gradual decrease in both the quantity and the quality of the oocytes. A decline in ovarian function leads to chronic disease and physiological problems. The aim of this study is to establish a cohort for the purpose of examining the ovarian aging process and its relationship with health status and quality of life in women across all age groups. METHOD: This protocol outlines a community-based, prospective long-term observational study involving 1676 women recruited from Caofeidian District in Tangshan City, Hebei Province, China. Data are gathered by the administration of questionnaires, doing physical examinations, performing blood biochemistry tests, and measuring levels of female hormones. The primary outcomes will be the occurrence of cardiovascular disease, osteoporosis, hypertension, diabetes, hyperlipidemia, and other chronic diseases, assessed according to established diagnostic criteria for each disease. The secondary outcome will be the decline in quality of life during the follow-up period, assessed by the modified Kupperman Index. The study comprises a baseline cross-sectional assessment and a follow-up evaluation. The participants will undergo face-to-face interviews as part of their regular medical examinations until 2026 or until the occurrence of outcome events. DISCUSSION: The results of the prospective study will indicate the association between ovarian aging and the prevalence of chronic diseases as well as diminished quality of life among women across different age categories.

Clinical application of bronchoalveolar lavage fluid metagenomics next-generation sequencing in cancer patients with severe pneumonia.

OBJECTIVE: Metagenomic next-generation sequencing (mNGS), as an emerging technique for pathogen detection, has been widely used in clinic. However, reports on the application of mNGS in cancer patients with severe pneumonia remain limited. This study aims to evaluate the diagnostic performance of bronchoalveolar lavage fluid (BALF) mNGS in cancer patients complicated with severe pneumonia. METHODS: A total of 62 cancer patients with severe pneumonia simultaneously received culture and mNGS of BALF were enrolled in this study. We systematically analyzed the diagnostic significance of BALF mNGS. Subsequently, optimization of anti-infective therapy based on the distribution of pathogens obtained from BALF mNGS was also assessed. RESULTS: For bacteria and fungi, the positive detection rate of mNGS was significantly higher than culture method (91.94% versus 51.61%, P < 0.001), especially for poly-microbial infections (70.97% versus 12.90%, P < 0.001). Compared with the culture method, mNGS exhibited a diagnostic sensitivity of 100% and a specificity of 16.67%, with the positive predictive value (PPV) and negative predictive value (NPV) being 56.14% and 100%, respectively. The agreement rate between these two methods was 59.68%, whereas kappa consensus analysis indicated a poor concordance (kappa = 0.171). After receipt of BALF mNGS results, anti-infective treatment strategies in 39 out of 62 cases (62.90%) were optimized. Moreover, anti-tumor therapy was a high-risk factor for mixed infections (87.18% versus 65.22%, P = 0.04). CONCLUSIONS: The present study showed that cancer patients with severe pneumonia, especially those received anti-tumor therapy, were more likely to have poly-microbial infections. BALF mNGS can provide a rapid and comprehensive pathogen distribution of pulmonary infection, making it a promising technique in clinical practice, especially for optimizing therapeutic strategies for cancer patients.

Tegument protein UL3 of bovine herpesvirus 1 suppresses antiviral IFN-I signaling by targeting STING for autophagic degradation.

Bovine herpesvirus 1 (BoHV-1) is a highly contagious pathogen which causes infectious bovine rhinotracheitis in cattle worldwide. Although it has the ability to evade the host's antiviral innate immune response and establish persistent latent infections, the mechanisms are not fully understood, especially the function of the tegument protein to escape innate immunity and participate in viral replication. In this study, we showed that overexpression of tegument protein UL3 facilitates BoHV-1 replication and suppresses the expression of type-I interferon (IFN-I) and IFN-stimulated genes. Then, STING was identified as the target by which UL3 inhibits the IFN-I signaling pathway, and STING was degraded through the UL3-induced autophagy pathway. Furthermore, overexpression of UL3 promotes the expression of the autophagy-related protein ATG101, thereby inducing autophagy. Further study showed that UL3 enhances the interaction between ATG101 and STING, and then the degradation of STING was reversed following ATG101 silencing in UL3-overexpressing cells during BoHV-1 infection. Our research results demonstrate a novel function of UL3 in regulating host's antiviral response and provide a potential mechanism for BoHV-1 immune evasion.

Human Bone Marrow Derived-Mesenchymal Stem Cells Treatment for Autoimmune Premature Ovarian Insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) is a relatively common gynecologic endocrine disorder, which is hypogonadism associated with amenorrhea, increased levels of gonadotropins, and hypoestrogenism. POI resulting from ovarian autoimmunity is a poorly understood clinical condition lacking effective treatments. This study is aimed to investigate the therapeutic effect of mesenchymal stem cells (MSCs) on autoimmune premature ovarian insufficiency. METHODS: In this study, in vivo and in vitro experiments were conducted to clarify the therapeutic effects and possible mechanisms of human bone marrow-derived MSCs (hBMSCs) on autoimmune POI, and to provide an experimental evidence for the treatment of autoimmune POI by hBMSCs. Noteworthy, in this study, we used interferon-gamma (IFN-γ) to induce autoimmune inflammation in human granulosa cell line KGN, simulating the pathophysiological changes of granulosa cells in autoimmune POI, and therefore sought to establish an in vitro cell model of autoimmune POI, which is still lacking in experimental methodology. RESULTS: And we found that, in vitro, co-culture of hBMSCs could promote granulosa cell proliferation, inhibit apoptosis, improve hormone synthesis capacity, and reduce the occurrence of pyroptosis; and in vivo, hBMSCs resulted in improved estrous cycle disorders in autoimmune POI mice, increased serum estradiol, decreased follicle-stimulating hormone, improved ovarian morphology, increased number of primordial and primary follicles, decreased number of atretic follicles, and decreased ovarian granulosa cell apoptosis. CONCLUSIONS: hBMSCs have therapeutic effects on autoimmune POI both in vitro and in vivo.

Simultaneous denitrification and electricity generation in a methane-powered bioelectrochemical system.

Bioelectrochemical system is a novel method for controlling down nitrate pollution, yet the feasibility of using methane as the electron donors for denitrification in this system remains unknown. In this study, using the effluent from mother BESs as inocula, a denitrifying anaerobic methane oxidation bioelectrochemical system was successfully started up in 92 days. When operated with 50 mmol/L phosphate buffer solution at pH 7 and 30°C, the maximum methane consumption, nitrate, and total nitrogen removal load reached 0.23 ± 0.01 mmol/d, 551.0 ± 22.1 mg N/m3 /d, and 64.0 ± 18.8 mg N/m3 /d, respectively. Meanwhile, the peak voltage of 93 ± 4 mV, the anodic coulombic efficiency of 6.99 ± 0.20%, and the maximum power density of 219.86 mW/m3 were obtained. The metagenomics profiles revealed that the dominant denitrifying bacteria in the cathodic chamber reduced most nitrate to nitrite through denitrification and assimilatory reduction. In the anodic chamber, various archaea including methanotrophs and methanogens converted methane via reverse methanogenesis to form formate (or H2 ), acetate, and methyl compounds, which were than utilized by electroactive bacteria to generate electricity. PRACTITIONER POINTS: A denitrifying anaerobic methane oxidation BES was successfully started up in 92 d. Simultaneous removal of methane and nitrate was achieved in the DAMO-BES. Functional genes related to AMO and denitrification were detected in the DAMO-BES. Methylocystis can mediate AMO in the anode and denitrification in the cathode.

Duplex Interpenetrating-Phase FeNiZn and FeNi3 Heterostructure with Low-Gibbs Free Energy Interface Coupling for Highly Efficient Overall Water Splitting.

The sluggish kinetics of both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) generate the large overpotential in water electrolysis and thus high-cost hydrogen production. Here, multidimensional nanoporous interpenetrating-phase FeNiZn alloy and FeNi3 intermetallic heterostructure is in situ constructed on NiFe foam (FeNiZn/FeNi3@NiFe) by dealloying protocol. Coupling with the eminent synergism among specific constituents and the highly efficient mass transport from integrated porous backbone, FeNiZn/FeNi3@NiFe depicts exceptional bifunctional activities for water splitting with extremely low overpotentials toward OER and HER (η1000 = 367/245 mV) as well as the robust durability during the 400 h testing in alkaline solution. The as-built water electrolyzer with FeNiZn/FeNi3@NiFe as both anode and cathode exhibits record-high performances for sustainable hydrogen output in terms of much lower cell voltage of 1.759 and 1.919 V to deliver the current density of 500 and 1000 mA cm-2 as well long working lives. Density functional theory calculations disclose that the interface interaction between FeNiZn alloy and FeNi3 intermetallic generates the modulated electron structure state and optimized intermediate chemisorption, thus diminishing the energy barriers for hydrogen production in water splitting. With the merits of fine performances, scalable fabrication, and low cost, FeNiZn/FeNi3@NiFe holds prospective application potential as the bifunctional electrocatalyst for water splitting.

Assessment and quantification of ovarian reserve on the basis of machine learning models.

Background: Early detection of ovarian aging is of huge importance, although no ideal marker or acknowledged evaluation system exists. The purpose of this study was to develop a better prediction model to assess and quantify ovarian reserve using machine learning methods. Methods: This is a multicenter, nationwide population-based study including a total of 1,020 healthy women. For these healthy women, their ovarian reserve was quantified in the form of ovarian age, which was assumed equal to their chronological age, and least absolute shrinkage and selection operator (LASSO) regression was used to select features to construct models. Seven machine learning methods, namely artificial neural network (ANN), support vector machine (SVM), generalized linear model (GLM), K-nearest neighbors regression (KNN), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM) were applied to construct prediction models separately. Pearson's correlation coefficient (PCC), mean absolute error (MAE), and mean squared error (MSE) were used to compare the efficiency and stability of these models. Results: Anti-Müllerian hormone (AMH) and antral follicle count (AFC) were detected to have the highest absolute PCC values of 0.45 and 0.43 with age and held similar age distribution curves. The LightGBM model was thought to be the most suitable model for ovarian age after ranking analysis, combining PCC, MAE, and MSE values. The LightGBM model obtained PCC values of 0.82, 0.56, and 0.70 for the training set, the test set, and the entire dataset, respectively. The LightGBM method still held the lowest MAE and cross-validated MSE values. Further, in two different age groups (20-35 and >35 years), the LightGBM model also obtained the lowest MAE value of 2.88 for women between the ages of 20 and 35 years and the second lowest MAE value of 5.12 for women over the age of 35 years. Conclusion: Machine learning methods combining multi-features were reliable in assessing and quantifying ovarian reserve, and the LightGBM method turned out to be the approach with the best result, especially in the child-bearing age group of 20 to 35 years.

Regulatory T Cells Overexpressing Peli1 Show Better Efficacy in Repairing Ovarian Endocrine Function in Autoimmune Premature Ovarian Insufficiency.

Regulatory T (Treg) cell dysfunction is involved in the pathogenesis of autoimmune premature ovarian insufficiency (POI). Adoptive transfer of Treg cells has been shown to be effective in the treatment of autoimmune POI in mice. However, the therapeutic effect of Treg cell therapy is limited because the phenotype and function of Treg cells is not properly maintained when they are reinfused in an inflammatory environment. Therefore, enhancing the function of Treg cells using genetic engineering is of great significance for improving the efficacy of Treg cells in the treatment of immune diseases. In this study, we investigated the role of the E3 ubiquitinated ligase Pellino 1 (Peli1) in the proliferation and immunosuppressive function of Treg cells and the therapeutic effect of Treg cells overexpressing Peli1 on autoimmune POI. The results showed that the overexpression of Peli1 promoted cell proliferation and enhanced the immunosuppressive function of Treg cells in vitro. After the adoptive transfer of Treg cells overexpressing Peli1 in autoimmune POI mice, the apoptosis rate of ovarian granulosa cells declined. The levels of the inflammatory inhibitors interleukin 10 and transforming growth factor-ß as well as the ovarian hormone estradiol were elevated. The number of primordial, primary, secondary, and mature follicles was restored to a certain extent compared with those in control subjects. These results revealed that the adoptive transfer of Treg cells overexpressing Peli1 promoted its efficacy against zona pellucida protein 3 peptide-induced POI, which provides new insights into the treatment of autoimmune POI.

Study on the synthesis mechanism of sodalite, gismondine, and zeolite-P1 zeolite materials from ladle furnace slag and fly ash.

In this study, geopolymers were prepared using ladle furnace slag (LFS) and fly ash (FA), and hydrothermal treatment was then used to synthesize bulk zeolite molecular sieves with gismondine, zeolite-P1, and sodalite phases. The effect of the synthesis conditions on the crystalline phases of the zeolite molecular sieves was investigated by XRD. The results showed that the best zeolite molecular sieves were prepared with an LFS: FA ratio of 4: 6, a curing temperature of 40 °C, a curing time of 12 h, a sodium silicate modulus (Ms) of 1.4, a NaOH concentration of 4 mol/L, a hydrothermal temperature of 120 °C, and a hydrothermal time of 12 h. On this basis, the products were analyzed by SEM, N2 adsorption, and FT-IR. The results showed that the synthesized zeolite molecular sieves had mesoporous properties, and the degree of polymerization and cross-linking of the silica-aluminate gel were enhanced after hydrothermal treatment. In addition, the formation mechanism of the zeolite molecular sieves was explored through the changes of the silica-alumina during zeolite formation. This paper is the first to use the hydrothermal conversion of zeolite molecular sieves from LFS-FA based polymers to provide some guidance for the resource utilization of LFS and FA.

Electrochemical reduction of Cr (VI) using a palladium/graphene modified stainless steel electrode.

In this study, a palladium/graphene modified stainless steel electrode was successfully prepared and applied in an electrochemical reduction device to remove Cr (VI) from the wastewater. Pd was modified onto the electrode mainly via interacting with the carboxyl group of graphene. The Cr (VI) removal efficiency was up to 99.70 ± 0.00% under the optimal condition (Pd content proportion of 3%, electrode potential of -0.9 V, pH = 2 and electrolyte concentration of 6 g/L). It was found that Cr (VI) was removed via the following processes: (1) direct electrochemical reduction by accepting electrons, (2) indirect electrochemical reduction by H2O2 that was generated from H2 in the presence of Pd, (3) adsorption through hydrogen bond, and (4) chemical reduction through alkoxy groups donating electrons. The indirect electrochemical reduction considerably promoted the Cr (VI) removal while a small amount of Cr (VI) was removed via adsorption and chemical reduction. The method could not only be used as a pretreatment technology to solve the problem of excessive Cr (VI) concentration of industrial wastewater, but also could provide reference for the electrochemical reduction of similar metal ions.

Effects of Additional Dietary Fiber Supplements on Pregnant Women with Gestational Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

The efficacy of different types and doses of dietary fiber supplementation in the treatment of gestational diabetes (GDM) remains controversial. The purpose of this study is to investigate the effect of dietary fiber on blood glucose control in pregnant women with gestational diabetes mellitus, and further observe the effect on their blood lipids and pregnancy outcomes. We searched on Web of Science, PubMed, Embase, Scopus, and Cochrane, and included several articles on additional fortification with dietary fiber for gestational diabetes interventions. This meta-analysis included 8 trials. We found that additional dietary fiber supplements significantly reduced fasting glucose (Hedges'g = −0.3; 95% CI [−0.49, −0.1]), two-hour postprandial glucose (Hedges'g = −0.69; 95% CI [−0.88, −0.51]), glycated hemoglobin (Hedges'g = −0.5; 95% CI [−0.68, −0.31]), TC (Hedges'g = −0.44; 95% CI [−0.69, −0.19]), TG (Hedges'g = −0.3; 95% CI [−0.4, −0.2]) and LDL-C (Hedges'g = −0.48; 95% CI [−0.63, −0.33]). It also significantly reduced preterm delivery (Hedges'g = 0.4, 95% CI [0.19~0.84]), cesarean delivery (Hedges'g = 0.6; 95% CI [0.37~0.97]), fetal distress (Hedges'g = 0.51; 95% CI [0.22~1.19]), and neonatal weight (Hedges'g = −0.17; 95% CI [−0.27~−0.07]). In a subgroup analysis comparing dietary fiber type and dose, insoluble dietary fiber was more effective than soluble dietary fiber in reducing fasting glucose (Hedges'g = −0.44; 95% CI [−0.52, −0.35]). ≥12 g fiber per day may be more effective in improving glycemic lipid and pregnancy outcomes than <12 g/day, but the difference was not statistically significant. In conclusion, our meta-analysis showed that dietary fiber supplementation significantly improved glycolipid metabolism and pregnancy outcomes in gestational diabetes. Dietary fiber may be considered adjunctive therapy for gestational diabetes, and an additional supplement with insoluble dietary fiber is more recommended for those with poor fasting glucose. However, more high-quality studies are needed on the further effect of fiber type and the dose-effect relationship.

Lycium barbarum Polysaccharide Regulates the Lipid Metabolism and Alters Gut Microbiota in High-Fat Diet Induced Obese Mice.

Bioactive compounds provide new insights into the prevention and treatment of obesity. Lycium barbarum polysaccharide (LBP), a biological macromolecule extracted from Goji berry, has displayed potential for regulating lipid metabolism. However, the relationship between gut microbiota regulation and lipid metabolism is not entirely clear. In the present study, 50, 100, and 150 mg/kg LBP were intragastrically administered to C57BL/6J male mice fed with a high-fat diet simultaneously lasting for twelve weeks. The results showed that 150 mg/kg LBP showed significant results and all doses of LBP feeding (50, 100, 150 mg/kg) remarkably decreased both serum and liver total cholesterol (TC) and triglyceride (TG) levels. Treatment of 150 mg/kg LBP seems to be more effective in weight loss, lowering free fatty acid (FFA) levels in serum and liver tissues of mice. LBP feeding increased the gene expression of adiponectin and decreased the gene expression of peroxisome proliferator-activated receptor γ, Cluster of Differentiation 36, acetyl-coA carboxylase, and fatty acid synthase in a dose-dependent manner. In addition, the 16s rDNA Sequencing analysis showed that 150 mg/kg LBP feeding may significantly increase the richness of gut microbiota by up-regulation of the ACE and Chao1 index and altered ß-diversity among groups. Treatment of 150 mg/kg LBP feeding significantly regulated the microbial distribution by decreasing the relative abundance of Firmicutes and increasing the relative abundance of Bacteroidetes at the phylum level. Furthermore, the relative abundance of Faecalibaculum, Pantoea, and uncultured_bacterium_f_Muribaculaceae at the genus level was significantly affected by LBP feeding. A significant correlation was observed between body weight, TC, TG, FFA and bile acid and phyla at the genus level. The above results indicate that LBP plays a vital role in preventing obesity by co-regulating lipid metabolism and gut microbiota, but its effects vary with the dose.

Mechanisms of action of Zishen Yutai pills in treating premature ovarian failure determined by integrating UHPLC-Q-TOF-MS and network pharmacology analysis.

BACKGROUND: Zishen Yutai (ZSYT) pill, a patent Chinese medicine, has been widely used in the treatment of infertility, abortion, and adjunctive treatment of in vitro fertilization (IVF) for decades. Recently, the results of clinical observations showed that premature ovarian failure (POF) patients exhibited improved expression of steroids and clinical symptoms associated with hormone disorders after treatment with Zishen Yutai pills. However, the pharmacological mechanism of action of these pills remains unclear. METHODS: The compounds of Zishen Yutai pills found in blood circulation were identified via ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) technique in the serum of POF mice after oral administration of Zishen Yutai pills. The potential targets of compounds were screened using Traditional Chinese Medicine Systems Pharmacology Database, Traditional Chinese Medicine Database@Taiwan, Drugbank Database, PubChem, HIT, Pharmapper, and Swiss Target Prediction. The target genes associated with POF were collected from Online Mendelian Inheritance in Man Database, PharmGkb, Genecards, Therapeutic Target Database, and Genetic Association Database. The overlapping genes between the potential targets of Zishen Yutai pills' compounds and the target genes associated with POF were clarified via protein-protein interaction (PPI), pathway, and network analysis. RESULTS: Nineteen compounds in Zishen Yutai pills were detected in the serum of POF mice after oral administration. A total of 695 Zishen Yutai (ZSYT) pill-related targets were screened, and 344 POF-related targets were collected. From the results of Zishen Yutai (ZSYT) pill-POF PPI analysis, CYP19A1, AKR1C3, ESR1, AR, and SRD5A2 were identified as key targets via network analysis, indicating their core role in the treatment of POF with Zishen Yutai pills. Moreover, the pathway enrichment results suggested that Zishen Yutai pills treated POF primarily by regulating neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis. CONCLUSIONS: Via virtual screening, we found that regulation of neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis was the potential therapeutic mechanism of Zishen Yutai pills in treating POF. Our study suggested that combining the analysis of Zishen Yutai pills' compounds in blood in vivo in the POF model and network pharmacology prediction might offer a tool to characterize the mechanism of Zishen Yutai pills in the POF.

Synergistic effect of hydration and carbonation of ladle furnace aslag on cementitious substances.

Ladle furnace slag (LFS) can undergo hydration and carbonation reactions as cement. This article explores the effect of LFS hydration and carbonation reactions on cementitious substances at different temperatures and different LFS particle sizes, determining the effect of these varying conditions on the microstructure and formation mechanism of cementitious substances. The results show that in the early stages, C2S and C3S undergo hydration to generate C-S-H gel, which then undergoes decalcification and condensation to generate CaCO3 and Ca-deficient C-S-H gel; the hydration reaction and carbonation reaction promote and influence each other. The increase in temperature was found to hinder the formation of CaCO3 from Ca2+ and CO32-, thus reducing the efficiency of hydration carbonation. The increase in particle size was not conducive to the leaching of C2S and C3S to the surface of the reaction phase, which in turn reduced the degree of decalcification and polymerization of the C-S-H gel in the carbonation phase. It was concluded that the optimum LFS hydration and carbonation reactions were achieved at 20 °C and with a LFS particle sizes < 38 µm.

Trabectedin in Cancers: Mechanisms and Clinical Applications.

Trabectedin, a tetrahydroisoquinoline alkaloid, is the first marine antineoplastic agent approved with special anticancer mechanisms involving DNA binding, DNA repair pathways, transcription regulation and regulation of the tumor microenvironment. It has favorable clinical applications, especially for the treatment of patients with advanced soft tissue sarcoma, who failed in anthracyclines and ifosfamide therapy or could not receive these agents. Currently, trabectedin monotherapy regimen and regimens of combined therapy with other agents are both widely used for the treatment of malignancies, including soft tissue sarcomas, ovarian cancer, breast cancer, and non-small-cell lung cancer. In this review, we have summarized the basic information and some updated knowledge on trabectedin, including its molecular structure, metabolism in various cancers, pharmaceutical mechanisms, clinical applications, drug combination, and adverse reactions, along with prospects of its possibly more optimal use in cancer treatment.

Evaluation of the Effectiveness of Active and Passive Safety Measures in Preventing Ship-Bridge Collision.

The risk of ship-bridge collisions should be evaluated using advanced models to consider different anti-collision and bridge-protection measures. This study aimed to propose a method to evaluate the effectiveness of active and passive safety measures in preventing ship-bridge collision. A novel ship-bridge collision probability formulation taking into consideration different safety measures was proposed. The model was applied at Jintang Bridge in China where the surrounding vessel traffic is ultra-crowded. We calculated the collision probability between the bridge and passing traffic using automatic identification system (AIS) data, Monte Carlo simulation, and Bayesian networks. Results under four different safety measures (i.e., active measures, passive measures, both measures and none) were analyzed and compared. The analysis concluded that both active and passive safety measures are effective in reducing the ship-bridge collision probability. Active measures, if deployed properly, can provide protection at an equivalent level than passive measures against collision risks. However, passive measures, such as setting arresting cables, are necessary in cases where the response time of the active measures is long. The proposed method and the results obtained from the case study may be useful for robust and systematic effectiveness evaluation of safety measures in other cases worldwide.

DDIT3 antagonizes innate immune response to promote bovine alphaherpesvirus 1 replication via the DDIT3-SQSTM1-STING pathway.

DNA damage-inducible transcript 3 (DDIT3), a transcription factor, is typically involved in virus replication control. We are the first to report that DDIT3 promotes the replication of bovine viral diarrhea virus, an RNA virus, by inhibiting innate immunity. However, whether the DDIT3 gene participates in DNA virus replication by regulating innate immunity remains unclear. This study reported that DDIT3 suppressed the innate immune response caused by DNA viruses to promote bovine herpesvirus 1 (BoHV-1) replication. After BoHV-1 infection of Madin-Darby bovine kidney (MDBK) cells, upregulated expression of DDIT3 induced SQSTM1-mediated autophagy and promoted STING degradation. Overexpression of the SQSTM1 protein effectively reduced STING protein levels, whereas SQSTM1 knockdown increased STING protein levels. Coimmunoprecipitation experiments and confocal laser scanning microscopy revealed that the SQSTM1 protein interacts with and colocalizes with STING. Knockdown of SQSTM1 expression in DDIT3-overexpressing cell lines restored STING protein levels. Moreover, a dual-luciferase reporter assay revealed that DDIT3 directly binds to the bovine SQSTM1 promoter and induces SQSTM1 transcription. Overexpression of SQSTM1 promoted BoHV-1 replication by inhibiting IFN-ß and IFN-stimulated genes (ISGs) production; silencing of SQSTM1 promoted the expression of IFN-ß and ISGs to inhibit BoHV-1 replication. In conclusion, DDIT3 targets STING via SQSTM1-mediated autophagy to promote BoHV-1 replication. These results suggest a novel mechanism by which DDIT3 regulates DNA virus replication by targeting innate immunity. DDIT3 antagonizes the innate immune response to promote bovine alphaherpesvirus 1 replication via the DDIT3-SQSTM1-STING pathway.

SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy.

The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused severe morbidity and mortality in humans. It is urgent to understand the function of viral genes. However, the function of open reading frame 10 (ORF10), which is uniquely expressed by SARS-CoV-2, remains unclear. In this study, we showed that overexpression of ORF10 markedly suppressed the expression of type I interferon (IFN-I) genes and IFN-stimulated genes. Then, mitochondrial antiviral signaling protein (MAVS) was identified as the target via which ORF10 suppresses the IFN-I signaling pathway, and MAVS was found to be degraded through the ORF10-induced autophagy pathway. Furthermore, overexpression of ORF10 promoted the accumulation of LC3 in mitochondria and induced mitophagy. Mechanistically, ORF10 was translocated to mitochondria by interacting with the mitophagy receptor Nip3-like protein X (NIX) and induced mitophagy through its interaction with both NIX and LC3B. Moreover, knockdown of NIX expression blocked mitophagy activation, MAVS degradation, and IFN-I signaling pathway inhibition by ORF10. Consistent with our observations, in the context of SARS-CoV-2 infection, ORF10 inhibited MAVS expression and facilitated viral replication. In brief, our results reveal a novel mechanism by which SARS-CoV-2 inhibits the innate immune response; that is, ORF10 induces mitophagy-mediated MAVS degradation by binding to NIX.