Arf6 GTPase deficiency leads to porcine oocyte quality decline during aging.

Arf6 is a member of ADP-ribosylation factor (Arf) family, which is widely implicated in the regulation of multiple physiological processes including endocytic recycling, cytoskeletal organization, and membrane trafficking during mitosis. In this study, we investigated the potential relationship between Arf6 and aging-related oocyte quality, and its roles on organelle rearrangement and cytoskeleton dynamics in porcine oocytes. Arf6 expressed in porcine oocytes throughout meiotic maturation, and it decreased in aged oocytes. Disruption of Arf6 led to the failure of cumulus expansion and polar body extrusion. Further analysis indicated that Arf6 modulated ac-tubulin for meiotic spindle organization and microtubule stability. Besides, Arf6 regulated cofilin phosphorylation and fascin for actin assembly, which further affected spindle migration, indicating the roles of Arf6 on cytoskeleton dynamics. Moreover, the lack of Arf6 activity caused the dysfunction of Golgi and ER for protein synthesis and signal transduction. Mitochondrial dysfunction was also observed in Arf6-deficient porcine oocytes, which was supported by the increased ROS level and abnormal membrane potential. In conclusion, our results reported that insufficient Arf6 was related to aging-induced oocyte quality decline through spindle organization, actin assembly, and organelle rearrangement in porcine oocytes.

[Research and Application Progress of Biochar in Amelioration of Saline-Alkali Soil].

Saline-alkali land， as one of the farmland problems that seriously threatens grain yield in the 21st century， is widely distributed and has great potential for development. Biochar is a relatively efficient novel soil amendment， which can play an important role in alleviating the soil acid-base barrier， soil pollution control， carbon sequestration， and fertilizer slow release and has a great prospect in promoting sustainable agricultural development. In recent years， the research and application of biochar to improve saline-alkali soil have attracted much attention. However， due to the complexity and heterogeneity of the structural components of biochar， the improvement effect of biochar on saline-alkali soil is highly uncertain， and there is also a lack of systematic summary and in-depth discussion of the key mechanisms， which limits the further popularization and application of biochar technology in the improvement of saline-alkali soil. This study comprehensively analyzed the effects of biochar on physicochemical properties， nutrient availability， and biological characteristics of saline-alkali soil； summarized the improvement effects of biochar and modified biochar on saline-alkali soil and their effects on quality and efficiency； and elucidated the possible mechanism of biochar in the improvement of saline-alkali soil. The future research prospect of biochar was discussed in order to provide reference for further research and development of green， efficient， and accurate improvement technology of biochar in saline-alkali soil and its popularization and application.

Integration method of compressed sensing with variational mode decomposition based on gray wolf optimization and its denoising effect in mud pulse signal.

The continuous wave mud pulse transmission holds great promise for the future of downhole data communication. However, significant noise interference during the transmission process poses a formidable challenge for decoding. In particular, effectively eliminating random noise with a substantial amplitude that overlaps with the pulse signal spectrum has long been a complex issue. To address this, an enhanced integration algorithm that merges variational mode decomposition (VMD) and compressed sensing (CS) to suppress high-intensity random noise is proposed in this paper. In response to the inadequacy of manually preset parameters in VMD, which often leads to suboptimal decomposition outcomes, the gray wolf optimization algorithm is designed to obtain the optimal penalty factor and decomposition mode number in VMD. Subsequently, the optimized parameter combination decomposes the signal into a series of intrinsic modes. The mode exhibiting a stronger correlation with the original signal is retained to enhance signal sparsity, thereby fulfilling the prerequisite for compressed sensing. The signal is then observed and reconstructed using the compressed sensing method to yield the final signal. The proposed algorithm has been compared with VMD, CS, and CEEMD; the results demonstrate that the method can enhance the signal-noise ratio by up to ∼20.55 dB. Furthermore, it yields higher correlation coefficients and smaller mean square errors. Moreover, the experimental results using real field data show that the useful pulse waveforms can be recognized effectively, assisting surface workers in acquiring precise downhole information, enhancing drilling efficiency, and significantly reducing the risk of engineering accidents.

A city-level dataset of heavy metal emissions into the atmosphere across China from 2015-2020.

The absence of nationwide distribution data regarding heavy metal emissions into the atmosphere poses a significant constraint in environmental research and public health assessment. In response to the critical data deficiency, we have established a dataset covering Cr, Cd, As, and Pb emissions into the atmosphere (HMEAs, unit: ton) across 367 municipalities in China. Initially, we collected HMEAs data and covariates such as industrial emissions, vehicle emissions, meteorological variables, among other ten indicators. Following this, nine machine learning models, including Linear Regression (LR), Ridge, Bayesian Ridge (Bayesian), K-Neighbors Regressor (KNN), MLP Regressor (MLP), Random Forest Regressor (RF), LGBM Regressor (LGBM), Lasso, and ElasticNet, were assessed using coefficient of determination (R2), root-mean-square error (RMSE) and Mean Absolute Error (MAE) on the testing dataset. RF and LGBM models were chosen, due to their favorable predictive performance (R2: 0.58-0.84, lower RMSE/MAE), confirming their robustness in modelling. This dataset serves as a valuable resource for informing environmental policies, monitoring air quality, conducting environmental assessments, and facilitating academic research.

NAMPT regulates mitochondria function and lipid metabolism during porcine oocyte maturation.

Oocyte maturation defect can lead to maternal reproduction disorder. NAMPT is a rate-limiting enzyme in mammalian NAD+ biosynthesis pathway, which can regulate a variety of cellular metabolic processes including glucose metabolism and DNA damage repair. However, the function of NAMPT in porcine oocytes remains unknown. In this study, we showed that NAMPT involved into multiple cellular events during oocyte maturation. NAMPT expressed during all stages of porcine oocyte meiosis, and inhibition of NAMPT activity caused the cumulus expansion and polar body extrusion defects. Mitochondrial dysfunction was observed in NAMPT-deficient porcine oocytes, which showed decreased membrane potential, ATP and mitochondrial DNA content, increased oxidative stress level and apoptosis. We also found that NAMPT was essential for spindle organization and chromosome arrangement based on Ac-tubulin. Moreover, lack of NAMPT activity caused the increase of lipid droplet and affected the imbalance of lipogenesis and lipolysis. In conclusion, our study indicated that lack of NAMPT activity affected porcine oocyte maturation through its effects on mitochondria function, spindle assembly and lipid metabolism.

Clinical characteristics and prognosis of 28 cases of infant acute lymphoblastic leukemia / 中华儿科杂志

Objective: To analyze the clinical characteristics and prognosis of patients with infant acute lymphoblastic leukemia (IALL). Methods: A retrospective cohort study.Clinical data, treatment and prognosis of 28 cases of IALL who have been treated at Beijing Children's Hospital, Capital Medical University and Baoding Children's Hospital from October 2013 to May 2023 were analyzed retrospectively. Based on the results of fluorescence in situ hybridization (FISH), all patients were divided into KMT2A gene rearrangement (KMT2A-R) positive group and KMT2A-R negative group. The prognosis of two groups were compared. Kaplan-Meier method and Log-Rank test were used to analyze the survival of the patients. Results: Among 28 cases of IALL, there were 10 males and 18 females, with the onset age of 10.9 (9.4,11.8) months. In terms of immune classification, 25 cases were B-ALL (89%), while the remaining 3 cases were T-ALL (11%). Most infant B-ALL showed pro-B lymphocyte phenotype (16/25,64%). A total of 22 cases (79%) obtained chromosome karyotype results, of which 7 were normal karyotypes, no complex karyotypes and 15 were abnormal karyotypes were found. Among abnormal karyotypes, there were 4 cases of t (9; 11), 2 cases of t (4; 11), 2 cases of t (11; 19), 1 case of t (1; 11) and 6 cases of other abnormal karyotypes. A total of 19 cases (68%) were positive for KMT2A-R detected by FISH. The KMT2A fusion gene was detected by real-time PCR in 16 cases (57%). A total of 24 patients completed standardized induction chemotherapy and were able to undergo efficacy evaluation, 23 cases (96%) achieved complete remission through induction chemotherapy, 4 cases (17%) died of relapse. The 5-year event free survival rate (EFS) was (46±13)%, and the 5-year overall survival rate (OS) was (73±10)%.The survival time was 31.3 (3.3, 62.5) months. There was no significant statistical difference in 5-year EFS ((46±14)% vs. (61±18)%) and 5-year OS ((64±13)% vs. (86±13)%) between the KMT2A-R positive group (15 cases) and the KMT2A-R negative group (9 cases) (χ2=1.88, 1.47, P=0.170, 0.224). Conclusions: Most IALL patients were accompanied by KMT2A-R. They had poor tolerance to traditional chemotherapy, the relapse rate during treatment was high and the prognosis was poor.

SIRT3 Regulates Levels of Deacetylated SOD2 to Prevent Oxidative Stress and Mitochondrial Dysfunction During Oocyte Maturation in Pigs.

Mammalian oocyte maturation relies on mitochondrial ATP production, but this can lead to damaging reactive oxygen species (ROS). SIRT3, a mitochondrial sirtuin, plays a critical role in regulating mitochondrial redox balance in mouse oocytes under stress; however, its specific roles in porcine oocytes remain unclear. In this study, we utilized the SIRT3 inhibitor 3-TYP to investigate SIRT3's importance in porcine oocyte maturation. Our findings revealed that SIRT3 is expressed in porcine oocytes and its inhibition leads to maturation failure. This was evident through reduced polar body extrusion, arrested cell cycle, as well as disrupted spindle organization and actin distribution. Furthermore, SIRT3 inhibition resulted in a decrease in mitochondrial DNA copy numbers, disruption of mitochondrial membrane potential, and reduced ATP levels, all indicating impaired mitochondrial function in porcine oocytes. Additionally, the primary source of damaged mitochondria was associated with decreased levels of deacetylated superoxide dismutase 2 (SOD2) after SIRT3 inhibition, which led to ROS accumulation and oxidative stress-induced apoptosis. Taken together, our results suggest that SIRT3 regulates the levels of deacetylated SOD2 to maintain redox balance and preserve mitochondrial function during porcine oocyte maturation, with potential implications for improving pig reproduction.

Development and external validation of a novel prognostic nomogram for overall survival in prostate cancer patients with bone metastatic: a retrospective study of the SEER-based and a single Chinese center.

BACKGROUND: Prostate cancer (PCa) patients with bone metastases (BM) often face a poor prognosis, a leading contributor to mortality within this group. This study aims to develop a novel prognostic nomogram to predict overall survival for them. METHODS: We retrospectively analyzed PCa patients with BM from Surveillance, Epidemiology, and End Results (SEER) database and our hospital. Independent prognostic factors were identified using univariate and multivariate Cox regression analyses for the creation of a nomogram. Calibration curves and receiver operating characteristic (ROC) curves, along with the concordance index (C-index) and decision curve analysis (DCA), were employed to evaluate the performance of the constructed nomogram. RESULTS: A total of 12,344 PCa patients with BM, derived from 2010 to 2019 SEER database, were randomly allocated into a training cohort (n = 8640) and an internal validation cohort (n = 3704). Additionally, an external validation cohort (n = 126) from our hospital. The novel nomogram integrates multiple factors: age, race, histopathology, organ metastasis, chemotherapy, Gleason score, and prostate-specific antigen (PSA). C-index for the training, internal validation, and external validation cohorts were 0.770 (0.766-0.774), 0.756 (0.749-0.763), and 0.751 (0.745-0.757) respectively. Similarly, the area under the curve (AUC) for each cohort exhibited comparable results (training cohort-3-year: 0.682, 6-year: 0.775, 9-year: 0.824; internal validation cohort-3-year: 0.681, 6-year: 0.750, 9-year: 0.806; external validation cohort-2-year: 0.667, 3-year: 0.744, 4-year: 0.800), indicating that the nomogram possesses robust discriminative ability. Calibration curve and DCA curve further proved the reliability and accuracy of the prognostic nomogram. CONCLUSION: This study determined the independent risk factors for prostate cancer (PCa) patients with bone metastasis (BM) and subsequently developed a robust prognostic nomogram to predict overall survival (OS). This tool can serve to guide precise clinical treatment strategies for these patients.

Identification and Characterization of a New Regulator, TagR, for Environmental Stress Resistance Based on the DNA Methylome of Streptomyces roseosporus.

DNA methylation is a defense that microorganisms use against extreme environmental stress, and improving resistance against environmental stress is essential for industrial actinomycetes. However, research on strain optimization utilizing DNA methylation for breakthroughs is rare. Based on DNA methylome analysis and KEGG pathway assignment in Streptomyces roseosporus, we discovered an environmental stress resistance regulator, TagR. A series of in vivo and in vitro experiments identified TagR as a negative regulator, and it is the first reported regulator of the wall teichoic acid (WTA) ABC transport system. Further study showed that TagR had a positive self-regulatory loop and m4C methylation in the promoter improved its expression. The ΔtagR mutant exhibited better hyperosmotic resistance and higher decanoic acid tolerance than the wild type, which led to a 100% increase in the yield of daptomycin. Moreover, enhancing the expression of the WTA transporter resulted in better osmotic stress resistance in Streptomyces lividans TK24, indicating the potential for wide application of the TagR-WTA transporter regulatory pathway. This research confirmed the feasibility and effectiveness of mining regulators of environmental stress resistance based on the DNA methylome, characterized the mechanism of TagR, and improved the resistance and daptomycin yield of strains. Furthermore, this research provides a new perspective on the optimization of industrial actinomycetes. IMPORTANCE This study established a novel strategy for screening regulators of environmental stress resistance based on the DNA methylome and discovered a new regulator, TagR. The TagR-WTA transporter regulatory pathway improved the resistance and antibiotic yield of strains and has the potential for wide application. Our research provides a new perspective on the optimization and reconstruction of industrial actinomycetes.

Dietary Effects on Chronic Venous Disease.

BACKGROUND: Diet is fundamental to maintaining and improving human health. There is ample evidence identifying the beneficial and/or harmful effects of diet on noncommunicable diseases such as obesity, diabetes mellitus, and cardiovascular disease. However, the associations of the diet to chronic venous disease has not been fully described. METHODS: Data were collected through a cross-sectional survey conducted on 1,571 community-dwelling adults in 2018. Diet intake frequency was assessed using valid food group consumption frequency questionnaires. Multivariable logistic regression models were used to evaluate the association of diet with chronic venous disease. RESULTS: In total, 857 participants were diagnosed with chronic venous disease. Those who ate soybean products daily and 4-6 days/week had a 51-31% lower risk of chronic venous disease compared with those who only occasionally consumed soybean food, respectively. Participants who consumed eggs and egg products 1-3 days/week versus those who only occasionally ate eggs showed a lower risk of chronic venous disease [odds ratio (OR) 0.542, 95% confidence interval (CI) 0.375-0.782]. Eating fried food 4-6 days each week was associated with an increased risk of chronic venous disease (OR 3.872, 95% CI 1.263-11.599) compared with those who only occasionally ate fried foods. There is a decreasing tendency of the adjusted OR for eating soybean products daily with the severity of disease [chronic venous disease (C0-C2): OR 0.575, 95% CI 0.408-0.812; chronic venous insufficiency (C3-C6): OR 0.222, 95% CI 0.114-0.435]. CONCLUSIONS: A higher frequency in the consumption of soybean products and eggs were associated with a lower risk of chronic venous disease. High level of fried food consumption was positively associated with risk of chronic venous disease. There are certain specific trends in relation to dietary consumption and severity of disease, although these trends were less strong. These associations are largely independent of other dietary and nondietary factors.

Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK-129 and Its Protective Effects on Myocardial Remodeling and Fibrosis.

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 µM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.

m4C DNA methylation regulates biosynthesis of daptomycin in Streptomyces roseosporus L30.

Despite numerous studies on transcriptional level regulation by single genes in drug producing Actinomyces, the global regulation based on epigenetic modification is not well explored. N4-methylcytosine (m4C), an abundant epigenetic marker in Actinomycetes' genome, but its regulatory mechanism remains unclear. In this study, we identify a m4C methyltransferase (SroLm3) in Streptomyces roseosporus L30 and multi-omics studies were performed and revealed SroLm3 as a global regulator of secondary metabolism. Notably, three BGCs in ΔsroLm3 strain exhibited decreased expression compared to wild type. In-frame deletion of sroLm3 in S.roseosporus L30 further revealed its role in enhancing daptomycin production. In summary, we characterized a m4C methyltransferase, revealed the function of m4C in secondary metabolism regulation and biosynthesis of red pigment, and mapped a series of novel regulators for daptomycin biosynthesis dominated by m4C methylation. Our research further indicated that m4C DNA methylation may contribute to a metabolic switch from primary to secondary metabolism in Actinomyces.

Nivalenol affects Cyclin B1 level and activates SAC for cell cycle progression in mouse oocyte meiosis.

OBJECTIVES: Nivalenol (NIV) is a secondary metabolite of type B trichothecene mycotoxin produced by Fusarium genera, which is widely found in contaminated food and crops such as corn, wheat and peanuts. NIV is reported to have hepatotoxicity, immunotoxicity, genotoxicity, and reproductive toxicity. Previous studies indicate that NIV disturbs mammalian oocyte maturation. Here, we reported that delayed cell cycle progression might be the reason for oocyte maturation defect caused by NIV exposure. METHODS AND RESULTS: We set up a NIV exposure model and showed that NIV did not affect G2/M transition for meiosis resumption, but disrupted the polar body extrusion of oocytes. Further analysis revealed that oocytes were arrested at metaphase I, which might be due to the lower expression of Cyclin B1 after NIV exposure. After cold treatment, the microtubules were disassembled in the NIV-exposed oocytes, indicating that NIV disrupted microtubule stability. Moreover, NIV affected the attachment between kinetochore and microtubules, which further induced the activation of MAD2/BUBR1 at the kinetochores, suggesting that spindle assemble checkpoint (SAC) was continuously activated during oocyte meiotic maturation. CONCLUSIONS: Taken together, our study demonstrated that exposure to NIV affected Cyclin B1 expression and activated microtubule stability-dependent SAC to ultimately disturb cell cycle progression in mouse oocyte meiosis.

Improving the Yield and Quality of Daptomycin in Streptomyces roseosporus by Multilevel Metabolic Engineering.

Daptomycin is a cyclic lipopeptide antibiotic with a significant antibacterial action against antibiotic-resistant Gram-positive bacteria. Despite numerous attempts to enhance daptomycin yield throughout the years, the production remains unsatisfactory. This study reports the application of multilevel metabolic engineering strategies in Streptomyces roseosporus to reconstruct high-quality daptomycin overproducing strain L2797-VHb, including precursor engineering (i.e., refactoring kynurenine pathway), regulatory pathway reconstruction (i.e., knocking out negative regulatory genes arpA and phaR), byproduct engineering (i.e., removing pigment), multicopy biosynthetic gene cluster (BGC), and fermentation process engineering (i.e., enhancing O2 supply). The daptomycin titer of L2797-VHb arrived at 113 mg/l with 565% higher comparing the starting strain L2790 (17 mg/l) in shake flasks and was further increased to 786 mg/l in 15 L fermenter. This multilevel metabolic engineering method not only effectively increases daptomycin production, but can also be applied to enhance antibiotic production in other industrial strains.

A novel strategy of gene screen based on multi-omics in Streptomyces roseosporus.

Daptomycin is a new lipopeptide antibiotic for treatment of severe infection caused by multi-drug-resistant bacteria, but its production cost remains high currently. Thus, it is very important to improve the fermentation ability of the daptomycin producer Streptomyces roseosporus. Here, we found that the deletion of proteasome in S. roseosporus would result in the loss of ability to produce daptomycin. Therefore, transcriptome and 4D label-free proteome analyses of the proteasome mutant (Δprc) and wild type were carried out, showing 457 differential genes. Further, five genes were screened by integrated crotonylation omics analysis. Among them, two genes (orf04750/orf05959) could significantly promote the daptomycin synthesis by overexpression, and the fermentation yield in shake flask increased by 54% and 76.7%, respectively. By enhancing the crotonylation modification via lysine site mutation (K-Q), the daptomycin production in shake flask was finally increased by 98.8% and 206.3%, respectively. This result proved that the crotonylation modification of appropriate proteins could effectively modulate daptomycin biosynthesis. In summary, we established a novel strategy of gene screen for antibiotic biosynthesis process, which is more convenient than the previous screening method based on pathway-specific regulators. KEY POINTS: • Δprc strain has lost the ability of daptomycin production • Five genes were screened by multi-omics analysis • Two genes (orf04750/orf05959) could promote the daptomycin synthesis by overexpression.

Preparation of ball-milled phosphorus-loaded biochar and its highly effective remediation for Cd- and Pb-contaminated alkaline soil.

Pyrolytic biochar is a good material for remediating soils contaminated with heavy metals; however, it exhibits strong alkalinity, which easily causes soil alkalization and fertility reduction. Herein, a series of novel biochar materials (BPBCs) were prepared by combined ball milling and phosphorus (P)-loading. The optimized BPBC were fabricated in the basis of Cd and Pb adsorption capacities of the biochar, with pyrolysis at 700 °C, ball milling for 12 h and the addition of 5% red P (BPBC700). Ball milling could effectively grind pristine biochar into submicron particles and nanoscale P particles could be uniformly loaded on BPBC700. Moreover, the oxidative conversion of red P into phosphorus oxides, phosphoric acid and (hydro)phosphates was promoted due to reactions with the carbonates, alkaline minerals and O-containing functional groups of biochar. These reactions also decreased the biochar and soil pH to nearly neutral by acid-base neutralization. Pot experiments showed that BPBC700 had better effects than the pristine or ball-milled biochar in improving soil properties (e.g., cation exchange capacity and organic carbon), increasing the concentrations of soil nutrients (e.g., N and P), promoting alkaline phosphatase, catalase and urease activities, decreasing soil mobility and plant accumulation of Cd and Pb, and alleviating Cd and Pb stress on maize plants. Thus, BPBC is a promising and ecofriendly amendment to enhance its adsorption ability on Cd and Pb, soil quality and plant productivity in contaminated soil.

Multicenter study on the effect of early screening skills training for autism spectrum disorders in primary care hospitals in Chengdu / 四川精神卫生

ObjectiveTo investigate effect of conducting training of autism spectrum disorder （ASD） early screening skill on improving the ability to early identify ASD of medical staffs in primary care hospitals. MethodsIn September 2021， the training of ASD early screening skills was carried out for medical staffs from 20 primary care hospitals in Chengdu. After training， the training effect was evaluated. The numbers of referrals from primary care hospitals to superior hospitals， confirmed ASD as well as their average diagnostic age of children with ASD before and after training were used as evaluation indicators. ResultsAfter training， the number of children with suspected ASD referred by primary care hospitals was more than that before training ［（16.65±11.60） vs. （3.40±2.23）， t=5.431， P<0.01］， the number of children diagnosed with ASD was more than that before training［（6.85±4.93） vs. （2.45±1.67）， t=4.171， P<0.01］， and the differences were statistically significant. As for the diagnosed age of ASD children， after training， the average age was lower than that before training ［（34.95±11.67） vs. （42.2±14.64）， t=-2.553， P=0.019］. ConclusionTraining of ASD early screening skills for medical staffs in primary care hospitals may help to improve their ability to early screening ASD children.

Mesenchymal stem cells accelerated growth and metastasis of neuroblastoma and preferentially homed towards both primary and metastatic loci in orthotopic neuroblastoma model.

BACKGROUND: Majority of neuroblastoma patients develop metastatic disease at diagnosis and their prognosis is poor with current therapeutic approach. Major challenges are how to tackle the mechanisms responsible for tumorigenesis and metastasis. Human mesenchymal stem cells (hMSCs) may be actively involved in the constitution of cancer microenvironment. METHODS: An orthotopic neuroblastoma murine model was utilized to mimic the clinical scenario. Human neuroblastoma cell line SK-N-LP was transfected with luciferase gene, which were inoculated with/without hMSCs into the adrenal area of SCID-beige mice. The growth and metastasis of neuroblastoma was observed by using Xenogen IVIS 100 in vivo imaging and evaluating gross tumors ex vivo. The homing of hMSCs towards tumor was analyzed by tracing fluorescence signal tagged on hMSCs using CRI Maestro™ imaging system. RESULTS: hMSCs mixed with neuroblastoma cells significantly accelerated tumor growth and apparently enhanced metastasis of neuroblastoma in vivo. hMSCs could be recruited by primary tumor and also become part of the tumor microenvironment in the metastatic lesion. The metastatic potential was consistently reduced in lung and tumor when hMSCs were pre-treated with stromal cell derived factor-1 (SDF-1) blocker, AMD3100, suggesting that the SDF-1/CXCR4 axis was one of the prime movers in the metastatic process. CONCLUSIONS: hMSCs accelerated and facilitated tumor formation, growth and metastasis. Furthermore, the homing propensity of hMSCs towards both primary tumor and metastatic loci can also provide new therapeutic insights in utilizing bio-engineered hMSCs as vehicles for targeted anti-cancer therapy.

Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells.

To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 µM, compared with normal WPMY-1 cells with the IC50 value of 19.470 µM. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.

Vibrio parahaemolyticus infection impaired intestinal barrier function and nutrient absorption in Litopenaeus vannamei.

The intestine is the primary target of pathogenic microbes during invasion. However, the interaction of Vibrio parahaemolyticus (V. parahaemolyticus) with intestinal epithelial cells and its effects on the intestinal function of Litopenaeus vannamei (L. vannamei) are poorly studied. Therefore, the aim of this study was to investigate the influence of V. parahaemolyticus infection on intestinal barrier function and nutrient absorption in L. vannamei. In the present study, a total of 90 shrimp were randomly divided into two groups including the control group and V. parahaemolyticus infection group (final concentration of 1 × 105 CFU/mL), with three replicates per group. The result showed that compared with the control group, V. parahaemolyticus infection increased (P < 0.05) serum diamine oxidase activity and endotoxin quantification, and down-regulated (P < 0.05) the mRNA levels of intestinal peroxinectin, integrin, midline fasciclin at 48 h and 72 h; V. parahaemolyticus infection decreased (P < 0.05) the mRNA expression of intestinal amino acid transporter (CAT1, EAAT3 and ASCT1) and glucose transporter (SGLT-1, GLUT) at 24 h, 48 h and 72 h, and increased (P < 0.05) serum glucose and amino acid (Asp, Thr, Ser, Glu, Gly, Ala, Val, Ile, Leu, Tyr, Phe, Lys, His and Arg) concentration at 24 h. The results indicated that V. parahaemolyticus infection increased intestinal permeability, inhibited absorption of glucose and amino acid in L. vannamei.