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Introduction: Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing a manageable safety profile and favorable clinical benefits. This study aimed to identify the biomarkers of clinical response and explore the immune response within the tumor microenvironment upon the AK104 therapy in advanced solid tumors. Material and methods: Gene expression profiles of paired pre- and post-treatment tumor tissues from twenty-one patients were analyzed. The association of gene expression levels with either clinical efficacy or prognosis was evaluated and subsequently validated with published datasets using log-rank for Kaplan–Meier estimates. Comparative immune profile analyses of tumor microenvironment before and after AK104 treatment were conducted. The visualization of tumor-infiltrating lymphocytes was performed using multiplex immunohistochemistry. The predictive value of CD74 was further validated with protein expression by immunohistochemistry. Results: Baseline CD74 gene expression was associated with favorable patient outcomes (overall survival [OS], HR = 0.33, 95% CI 0.11–1.03, p = 0.0463), which was further confirmed with the published datasets. Tumors with high CD74 gene expression at baseline were more likely to exhibit an immune-inflamed microenvironment. AK104 efficiently enhanced the infiltration of immune cells in the tumor microenvironment. Additionally, high CD74 protein expression (≥ 10% of the tumor area occupied by CD74 stained immune cells) at baseline was associated with better progressive-free survival (HR = 0.21, 95% CI 0.06–0.68, p = 0.0065) and OS (HR = 0.35, 95% CI 0.12–1.08, p = 0.0615). Conclusions: Our findings demonstrate that CD74 is a promising predictive biomarker for AK104 therapeutic response in advanced solid tumors. Trial registration number NCT03261011. [ABSTRACT FROM AUTHOR]

This study explored the potential of granite stone powder (GSP) as a supplementary cementitious material (SCM). The 72 h early hydration process stages of GSP-mixed slurry were analyzed in depth, and the mechanical properties of manufactured sand concrete (MSC) mixed with GSP were investigated. Physical phase types, morphological characteristics, and pore structure evolution were investigated using an X-ray diffractometer, scanning electron microscope, and mercury intrusion approach (MIP). Atomic force microscopy was used to show the interface transition zone between aggregate and slurry in phase images, height images, and 3D images, allowing quantification of ITZ and slurry by calculating the roughness. Gray entropy analysis was used to evaluate the significance of the effect of pore size distribution parameters on mechanical strength, and the GSP-content-mechanical-strength gray model GM (1, 1) was established to predict mechanical strength. The results indicate that, compared with the reference group, the GSP cement slurry system exhibited a delayed hydration process acceleration rate, with a 1.04% increase in cumulative heat of hydration observed in the 5% test group and an 11.05% decrease in the 15% test group. Incorporating GSP in MSC led to decreased mechanical properties at all ages, with significant decay observed when incorporation ranged from 10% to 15%. Although the type of hydration products remained unchanged, there was a decrease in the number of C-S-H gels and gel pores, while large pores increased, resulting in increased porosity and roughness of the interface transition zone and slurry. Large pores (>1000 nm) were found to have the greatest influence on mechanical strength, with gray correlation above 0.86. The GM (1, 1) model yielded accurate predictions, showing good agreement with measured data and thus it can be identified as belonging to a high-precision prediction model category. These findings provide theoretical support and a reference for applying GSP as an SCM, laying the groundwork for data-based specification development. [ABSTRACT FROM AUTHOR]

IL-28B, belonging to type III interferons (IFN-λs), exhibits a potent antitumor activity with reduced regulated T cells (Tregs) population, yet the effect of IL-28B on the tumor microenvironment (TME) and if IL-28B can downregulate Tregs directly in vitro are still unknown. In this study, we investigated the effects of IL-28B on Tregs in the spleen and TME in H22 tumor-bearing mice and verified the downregulation of IL-28B on Tregs in vitro. We found that rAd-mIL-28B significantly inhibited tumor growth and reduced the frequency of splenic CD4+Foxp3+ T cells. The levels of CXCL13, ICAM-1, MCP-5, and IL-7 in the serum, and the levels of IL-15 and sFasL in the tumor tissue decreased significantly after rAd-mIL-28B treatment relative to rAd-EGFP. Furthermore, the percentage of CD8+ cells in the TME was significantly increased in the rAd-mIL-28B group compared with the untreated group. In vitro, splenocytes were stimulated with anti-CD3/CD28 and IL-2 in the presence of TGF-β with or without IL-28B for three days and followed by flow cytometric, RT-PCR, and IL-10 production analysis. The results showed that IL-28B significantly reduced the proportion of induced Foxp3+ cells. It demonstrated that IL-28B may be used as a promising immunotherapy strategy against cancer. [ABSTRACT FROM AUTHOR]

The metacestode stage of Echinococcus granulosus can cause cystic echinococcosis (CE), which still widely occurs around the world. Since the early 1970s, benzimidazoles have been shown to inhibit the growth of cysts and used to treat CE. However, benzimidazoles are still ineffective in 20%-40% of cases. In order to explore the new agents against CE, we have investigated the therapeutic effect of the recombinant adenoviral vector expressing mouse IL-28B (rAd-mIL-28B) on protoscoleces-infected mice. In our study, we successfully established the model mice which infected with protoscoleces intraperitoneally. At 18 weeks post-infection, the mice received rAd-mIL-28B (1×107 PFU) weekly by intramuscular injection for 6 weeks. Compared with the untreated control (13.1 ± 2.2 g), there was a significant reduction in cysts wet weight in rAd-mIL-28B group (8.3 ± 3.5 g) (P < 0.05), especially in Albendazole (ABZ) + rAd-mIL-28B group (5.8 ± 1.4 g) (P < 0.01). We also observed the severe damage of the germinal layer and the laminated layer of cysts after treatment. rAd-mIL-28B group showed a prominent increase in the level of Th1 type cytokines (such as IFN-γ, IL-2 and TNF-α). Meanwhile, the frequency of Foxp3+ T cells was decreased in the rAd-mIL-28B group (4.83 ± 0.81%) and ABZ + rAd-mIL-28B group (4.60 ± 0.51%), comparing with the untreated group (8.13 ± 2.60%) (P < 0.05). In addition, compared with the untreated control (122.14 ± 81.09 pg/ml), the level of IFN-γ significantly increased in peritoneal fluid in the rAd-mIL-28B group (628.87 ± 467.16 pg/ml) (P < 0.05) and ABZ + rAd-mIL-28B group (999.76 ± 587.60 pg/ml) (P < 0.001). Taken together, it suggested that ABZ + IL-28B may be a potential therapeutic agent against CE. Author summary: Echinococcosis is a chronic zoonotic parasitic disease, which is caused by the larval stage of Echinococcus granulosus (E. granulosus) and Echinococcus multiocularis (E. multiocularis). This disease is still widely prevalent in the world and seriously endangers human health and life, causing heavy burdens and economic losses to agriculture and animal husbandry. China is also one of the high incidence areas of the disease. At present, the preferred treatment is surgical excision of the parasitic mass, but patients with multiple cysts appear in multiple organs have to receive drug therapy. The approved chemotherapeutic drugs in clinic, such as albendazole (ABZ) and mebendazole, often do not work expectedly with a high rate of recurrence. Therefore, it is urgent to develop the new anti-echinococcal drug. IL-28B is an important member of type-III IFNs, which is equipped with the capacity of anti-viral activity and anti-tumor. In our previous study, we found that IL-28B could inhibit the proliferation of cervical cancer cells via down-regulating Treg cells in mice. This study mainly studied the therapeutic effect of rAd-mIL-28B on E. granulosus-infected mice, and the results showed that rAd-mIL-28B could relieve the parasitic burden and inhibit Treg cells meanwhile improve the Th1 and Th17 immune responses. It may contribute to another choice for the anti-echinococcal treatment. [ABSTRACT FROM AUTHOR]

Nanovaccines have attracted booming interests in vaccinology studies, but the profound impacts of their delivery mode on immune response remain unrealized. Herein, immunostimulatory CpG‐modified tumor‐derived nanovesicles (CNVs) are used as a nanovaccine testbed to initially evaluate the impacts of three distinct delivery modes, including mono‐pulse CNVs, staggered‐pulse CNVs, and gel‐confined CNVs. Fundamentally, delivery mode has enormous impacts on the immunomodulatory effects, altering the spatiotemporal distribution of nanovaccine residence and dendritic cell–T cell interaction in lymph nodes, and finally affecting subsequent T cell‐mediated immune performance. As a result, the gel‐confined delivery mode offers the best therapeutic performance in multiple tumor models. When extending evaluation to examine how the various delivery modes impact the performance of liposome‐based nanovaccines, similar trends in intralymph node distribution and antitumor effect are observed. This work provides a strong empirical foundation that nanovaccine researchers should position delivery mode near the top of their considerations for the experimental design, which should speed up nanovaccine development and facilitate efficient selection of appropriate delivery modes in the clinic. [ABSTRACT FROM AUTHOR]

In this study, for the purpose of finite-time tracking control of quad-rotor Unmanned Aerial Vehicle (UAV) system under modeling uncertainties and external disturbances, an adaptive command-filtered backstepping sliding mode control scheme is presented. At first, a state-space model of quad-rotor's system is considered in the existence of bounded model uncertainties and exterior perturbations. Then, a command-filter according to the virtual control input is planned to reduce the computing complications. Subsequently, the output of command filter is considered instead of high-order derivative of virtual input. Besides, in order to remove the differential signals which are obtained during design of command-filter, the compensation error is used. Afterward, the sliding surfaces are designed according to tracking errors which are defined between actual states of the quad-rotor, desired values and compensation error system. Furthermore, backstepping control procedure combined with Lyapunov stability theory is used for finite-time convergence of switching surface. Besides, the adaptive control strategy is applied to estimate the upper bound of uncertainty and disturbance which is unknown in advance. At last, in order to validate the high efficacy of the designed control scheme, simulation results based on the actual parameters of quadrotor are provided. In addition, the comparison outcomes are provided to show proficiency and validity of the recommended technique compared with the existing method. [ABSTRACT FROM AUTHOR]

A PCR array, based on expression of genes along the hypothalamic–pituitary–gonadal–liver (HPGL) axis of fish, has been suggested as a useful method for screening of endocrine-disrupting chemicals (EDCs). However, effects of circadian rhythm on responses of the HPGL axis to exposure to chemicals were unknown. In this study, profiles of expression of genes along the HPGL axis and concentrations of 17β-estradiol (E2) in blood plasma of female zebrafish were compared at two sampling times of day (8:00 AM and 7:00 PM). Prochloraz (PCZ) was selected as a model chemical to evaluate differences in responses of the HPGL axis at these two times of day. Profiles of responses of concentrations of E2 in plasma and expressions of genes along the HPGL axis genes were different between the two times of sampling. Concentrations of E2 were less, and abundances of mRNA for several genes along the HPGL axis were significantly greater or lesser when samples were collected at 7:00 PM than they were when samples were collected at 8:00 AM. Exposure to three concentrations of PCZ (3, 30 or 300 μg/L) for 48 h resulted in significantly lesser concentrations of plasma E2 and caused compensatory up-regulation of genes included in hypothalamus, pituitary and ovary. Expressions of genes along the HPGL were more responsive to PCZ at 8:00 AM than they were when samples were collected at 7:00 PM. Correlations among parameters in samples collected at the two times indicated the effects might be due to different concentrations of E2 in plasma due to exposure to PCZ. [ABSTRACT FROM AUTHOR]

Highlights: [•] MCLR significantly impaired LTP in a concentration-dependent manner. [•] GSK-3β inhibitors prevents the effects of MCLR on hippocampal LTP in vivo. [•] MCLR increased the activity of GSK-3β via regulating phosphorylation at Ser9 site. [Copyright &y& Elsevier]

An abstract of the article "Long-Term Rapamycin Control of Transgene Expression in Mouse Salivary Glands in a Single AAV Vector," by Jianghua Wang, Antonis Voutetakis, Milton Papa, Victor M. Rivera, Tim Clackson, Beatrijs M. Lodde, Fumi Mineshiba and Bruce J. Baum is presented.

An abstract of the article "Microvessel Injury and Irradiation Damage in Salivary Glands," by Ana Paola P. Cotrim, Jianghua Wang, Antonis Voutetakis, Anastasia L. Sowers, James B. Mitchell and Bruce J. Baum is presented.

The lack of an efficient way to screen patients who are responsive to immunotherapy challenges PD1/CTLA4-targeting cancer treatment. Immunotherapeutic efficacy cannot be clearly determined by peripheral blood analyses, tissue gene markers or CT/MR value. Here, we used a radionuclide and imaging techniques to investigate the novel dual targeted antibody cadonilimab (AK104) in PD1/CTLA4-positive cells in vivo. First, humanized PD1/CTLA4 mice were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. to express hPD1/CTLA4 in T-cells. Then, mouse colon cancer MC38-hPD-L1 cell xenografts were established in humanized mice. A bispecific antibody targeting PD1/CTLA4 (AK104) was labeled with radio-nuclide iodine isotopes. Immuno-PET/CT imaging was performed using a bispecific monoclonal antibody (mAb) probe 124I-AK104, developed in-house, to locate PD1+/CTLA4+ tumor-infiltrating T cells and monitor their distribution in mice to evaluate the therapeutic effect. The 124I-AK104 dual-antibody was successfully constructed with ideal radiochemical characteristics, in vitro stability and specificity. The results of immuno-PET showed that 124I-AK104 revealed strong hPD1/CTLA4-positive responses with high specificity in humanized mice. High uptake of 124I-AK104 was observed not only at the tumor site but also in the spleen. Compared with PD1- or CTLA4-targeting mAb imaging, 124I-AK104 imaging had excellent standard uptake values at the tumor site and higher tumor to nontumor (T/NT) ratios. The results demonstrated the potential of translating 124I-AK104 into a method for screening patients who benefit from immunotherapy and the efficacy, as well as the feasibility, of this method was verified by immuno-PET imaging of humanized mice. [Display omitted] • An antibody-PET probe targeting PD1/CTLA4 was radiolabeled. • High affinity to PD1/CTLA4 in vitro and in vivo. • This tracer can noninvasively demonstrate the presence of PD1/CTLA4-positive infiltrating T cells at the tumor site in humanized mice using an imaging method. [ABSTRACT FROM AUTHOR]

Compensation responses and adaptability of hypothalamic-pituitary-gonadal (HPG) axis have been reported in fish exposed to model chemicals, however due to its importance in predictive toxicology further study was needed to elucidate details of the integrated responses to model chemicals. Transcriptional profiles of the hypothalamic-pituitary-gonadal (HPG) axis and concentrations of 17β-estradiol (E2) in plasma were measured in male and female zebrafish that had been exposed to one of seven concentrations of the fungicide, prochloraz: low (1, 3 or 10 μg/L), medium (30 or 100 μg/L) or high concentrations (300 or 1000 μg/L) for 4 days. In zebrafish exposed to the low and medium concentrations of prochloraz, compensation responses of the HPG axis through transcription, occurred in brain (up-regulation of gnrh , gnrhr and lhβ ) and both brain and gonad (up-regulation of steroidogenic genes), respectively. Concentrations of E2 in plasma and expression of estrogen receptor 1 ( er1 ) and vitellogenins ( vtgs ) in liver did not change. This result suggested that compensatory responses were successful in maintaining homeostasis. In zebrafish exposed to the two greatest concentrations, compensatory responses occurred in brain, gonad and liver through up-regulation of er2β , but it failed to maintain concentration of E2 in blood plasma and expression of er1 and vtgs in liver. Collectedly, the results observed in this study allowed characterization of dose-dependent compensatory responses along the HPG axis and liver and identified key linkages between compensatory responses occurring in brain, gonad and liver after exposure to prochloraz. [ABSTRACT FROM AUTHOR]

Linear polyglycidol (LPG) has emerged as a polyethylene glycol (PEG) alternative in novel surfactant development due to its unique advantages, such as high bioavailability and multiple functionalization sites. In this study, a series of LPG based acylhydrazones, including copolymers CLPG1–3 with different length (n = 7–11) of alkyl chains and a curcumin (CUR) drug conjugate CLPG4 were synthesized for the first time. CLPG1 - 4 exhibited a decreasing trend in their surface-active properties as the molecular hydrophobicity increased. Among them, CLPG1 revealed the most powerful foaming ability, emulsion stability than the other analogs and tested commercial references, attributing to its optimal hydrophilic/hydrophobic balance. On the other hand, the drug conjugate CLPG4 revealed significantly enhanced selective tumor cell inhibition and cellular uptake than free CUR in the in vitro experiments. The established structure-property profile in this study provides a useful reference for their practical applications in the chemical and pharmaceutical fields. [Display omitted] • Novel LPG acylhydrazones (CLPG 1 - 3) and CUR-LPG conjugate (CLPG 4) were synthesized. • Structure-activity profile was established for CLPG1 - 3 as potent surfactants. • Enhanced drug loading and stability were observed for CLPG4 compared to physically encapsulated complexes. • CLPG4 revealed improved permeability and selective cancer cell inhibition. [ABSTRACT FROM AUTHOR]

Selenium (Se), an indispensable micronutrient for living organisms, has been extensively studied for its heavy metal-detoxifying properties in diverse biological systems and tissues. Nevertheless, it is not entirely certain whether Se can effectively protect against Cadmium (Cd)-induced gut inflammation, especially in aquatic animals. In this study, we employed various approaches, including transcriptome profiling, histological examinations, assessment of antioxidant enzyme activities, and analysis of gut microbiota composition to investigate the effects on crayfish growth and intestinal health after exposure to dietary Cd (15 mg kg−1 diet) and Se (15 mg kg−1 diet) individually or in combination for 8 weeks. The results revealed that dietary Cd exposure resulted in reduced body weight and survival rates, along with an increased occurrence of intestinal inflammation. Nevertheless, Se supplementation proved effective in mitigating the adverse effects of Cd on growth and gut health. Se exhibited a remarkable ability to counteract the disruption of gut antioxidant abilities induced by dietary Cd, as evidenced by the observed increases in ROS and MDA contents, decrease in GSH levels, and inhibition of antioxidative enzyme activities. At the concentration of 6 mg kg−1 in the diet, Se was found beneficial for maintaining gut microbiota richness and diversity. Among them, Flavobacterium , Thermomonas , and Chloronema displayed a weak negative correlation with the rate of gut inflammation. Meanwhile, the levels of short chain fatty acids (SCFAs), including acetic acid (AA) and butanoic acid (BA), showed a significant increase in the Se–Cd group compared to the Cd-only group. Furthermore, transcriptome analysis exhibited significant responses of the PI3K/Akt and NF-κB pathways following crayfish exposure to dietary Se and Cd, either separately or in combination. In short, this study provides a new evidence regarding the molecular mechanisms through which Se could regulate the PI3K/Akt and NF-κB pathways, either directly or indirectly via ROS and SCFAs, thereby alleviating Cd-induced gut inflammation in crayfish. [Display omitted] • Chronic Cd exposure (15 mg/kg) markedly induced gut inflammation and apoptosis. • Cd decreased crayfish weight and survival, but Se supplementation mitigated this. • Se countered the disruption of gut antioxidant capabilities induced by dietary Cd. • Se antagonized Cd-induced gut inflammation by boosting SCFA content. • PI3K/Akt/NF-κB pathways mediated Se's counteraction of Cd toxicity in the gut. [ABSTRACT FROM AUTHOR]

It has been reported that monoclonal antibodies (MAbs) to the E1E2 glycoproteins may have the potential to prevent hepatitis C virus (HCV) infection. The protective epitopes targeted by these MAbs have been mapped to the regionsencompassing amino acids 313–327 and 432–443. In this study, we synthesized these two peptides and tested the reactivity of serum samples from 336 patients, 210 of whichwere from Chronic Hepatitis C (CHC) patients infected with diverse HCV genotypes.The remaining 126 samples were isolated from patients who had spontaneously clearedHCV infection.In the chronic HCV-infected group (CHC group), the prevalence of human serum antibodies reactive to epitopes 313–327 and 432–443was 24.29%(51 of 210) and4.76%(10 of 210),respectively. In thespontaneousclearance group (SC group),the prevalence was 0.79%(1 of 126) and 12.70%(16 of 126), respectively.The positive serum samples that contained antibodies reactive to epitope 313–327 neutralizedHCV pseudoparticles (HCVpp) bearing the envelope glycoproteins of genotypes 1a or 1b and/or 4, but genotypes 2a, 3a, 5 and 6 were not neutralized. The neutralizing activity of these serum samples could not be inhibited by peptide 313–327. Six samples (SC17, SC38, SC86, SC92, CHC75 and CHC198) containing antibodies reactive to epitope 432–443 had cross-genotype neutralizing activities. Theneutralizing activityof SC38, SC86, SC92 and CHC75waspartiallyinhibited by peptide 432–443. However,the neutralizing activity of sample SC17 for genotype 4HCVpp and sample CHC198 for genotype 1b HCVppwere notinhibited by the peptide.This study identifies the neutralizing ability of endogenous anti-HCV antibodies and warrants the exploration of antibodies reactive to epitope432–443as sources for future antibody therapies. [ABSTRACT FROM AUTHOR]

Several mechanisms regarding the developmental and reproductive toxicity of l -selenomethionine (SeMet) in freshwater fish have been widely reported. However, limited information was available on endocrine-disrupting effects of SeMet. In this study, zebrafish larvae (day 24 post-fertilization) were exposed to environmentally-relevant levels of dietary SeMet (control, 1.11 ± 0.11, 3.59 ± 0.20, 10.80 ± 0.52, 29.19 ± 0.46, and 58.63 ± 0.70 μg Se/g d.w. diet) for 90 days until sexual maturity. For the first time, a gender difference in the effect of SeMet on body mass of zebrafish was observed. The lowest observed adverse effect level (LOAEL) in male was 10.80 ± 0.52 μg Se/g d.w., while it was 29.19 ± 0.46 μg Se/g d.w. in female. Chronic exposure to dietary SeMet reduced the percentage of early vitellogenic oocyte in female and the percentage of spermatid in male by inhibiting the growth hormone/insulin-like growth factors (GH/IGFs) and hypothalamus-pituitary-gonad (HPG) systems, which was characterized by significant decreases in the transcriptional levels of gh , igf1 , era , and ar. Se content in the liver of male was significantly higher than that in female when dietary Se level reached 10.80 ± 0.52 μg Se/g d.w.. Furthermore, the zinc content in the livers and gonads of both female and male treated with 29.19 ± 0.46 and 58.63 ± 0.70 μg Se/g d.w. diets was significantly reduced. Reduction of zinc ion not only led to the significantly upregulated transcriptional levels of zip1 and znt2 , but also downregulated transcriptional levels of znf219l and sp7. In summary, this study provides a new evidence that chronic exposure to high level of dietary SeMet (≥10.80 μg Se/g d.w.) could impair the development and reproduction of zebrafish with gender difference by interfering the GH/IGFs and HPG systems. Moreover, disruption of zinc ion homeostasis might exacerbate the toxicity of Se to zebrafish. Image 1 • The LOAEL in male was 10.80 μg Se/g, while it was 29.19 μg Se/g in female. • SeMet impaired growth and reproduction by interfering GH/IGFs and HPG systems. • Chronic exposure to high level of dietary SeMet disrupted zinc ion homeostasis. [ABSTRACT FROM AUTHOR]

The alveolar echinococcosis of human is a severe helminthic disease caused by the larva of Echinococcus multilocularis tapeworms. Novel compounds or therapy strategies for the treatment of alveolar echinococcosis are urgently needed due to the limitation of the widely used albendazole. Magnetic microspheres as drug carriers in magnetically targeted therapy of tumor have gained growing interests advantaged by delivering the drug to the aimed site, achieving localized therapeutic effect effectively under the influence of an external magnetic field. In this study, we formulated magnetic microspheres loaded with E2-a (PLGA-Fe-E2-a) and identified the activity in E. multilocularis-infected mice which infected with 3,000 protoscoleces intraperitoneally. Compared with the untreated control, with the help of a magnet, there was a significant reduction in parasite burden with PLGA-Fe-E2-a treatment and similar reduction observed with albendazole. PLGA-Fe-E2-a treatment group also showed a significant increase in the IFN-γ level and impaired morphological and ultrastructural alterations. Most importantly, one-third concentrations of E2-a from PLGA-Fe-E2 based on the release profile of E2-a was equally effective in inhibiting metacestode growth as E2-a treated group, supporting efficacy and bioavailability of a drug. It will be an alternative treatment for alveolar echinococcosis using magnetic microspheres as drug carriers. [ABSTRACT FROM AUTHOR]

Abstract Pentachlorophenol (PCP) and its byproduct hexachlorobenze (HCB) are two co-existing persistent environmental chemicals, but their combined toxicity remains unclear. In this study, adult zebrafish were exposed to 5 (low dose) and 25 μg·L−1 (high dose) of PCP, HCB or their combination for 21 days, and the impact on endocrine and reproduction was investigated. Results showed that combined exposure to 25 μg·L−1 PCP and 25 μg· L−1 HCB significantly increased the plasma estradiol (E2) and testosterone (T) levels, altered the expressions of genes along the hypothalamic-pituitary-gonadal-liver (HPGL) axis, inhibited gonadal development, and eventually lead to decreased egg production of F0 zebrafish as well as inhibited development of F1 eggs/larvae. Compared to the combined exposure of high doses, significantly lower levels of plasma E2 and T were observed for either the high PCP or high HCB alone exposure, indicating a synergistic effect of the two chemicals on endocrine disruption after combination. Furthermore, the high PCP alone exposure inhibited the gonadal development in both the males and females, while the HCB alone exposure did not. Comparison of exposure effects indicated a greater decrease of mature gametes levels and egg production in the high combined group when compared to the high HCB alone group, but no significant difference was observed between the high combined group and the high PCP alone group. Taken together, the results suggested that combined exposure to PCP and HCB may synergistically affect endocrine of zebrafish, and result in reproduction impairments, with PCP being the primary contributor. Highlights • Combined exposure to PCP and HCB resulted in reproductive impairments in zebrafish. • Combined exposure to PCP and HCB may synergistically affect endocrine of zebrafish. • Decreased GSI value and inhibited gonadal development in females might be associated with the decrease of egg production. • Reproductive impairments in the high combined group may be more attributable to the PCP toxicity. [ABSTRACT FROM AUTHOR]

Abstract Tris (2-butoxyethyl) phosphate (TBOEP) is a ubiquitous environmental contaminant due to its overuse. TBOEP has been found to cause reproductive toxicity and endocrine disruption during acute toxic experiment. In this study, we examined the effects of TBOEP on growth in initial generation (F0) zebrafish and transgenerational effects on growth of first generation (F1) larvae after parental long-term exposure (120 d) to environmentally relevant concentrations (0, 0.1, 1, 10 and 100 μg/L). Exposure to TBOEP resulted in significantly less growth as measured by body length, body weight and gonadosomatic index (GSI) in F0 females but not F0 males. Furthermore, the bioaccumulation of TBOEP in gonad, the alteration of the gene transcriptions in the hypothalamic-pituitary-gonadal (HPG) axis, and the delay in gonadal development in both female and male zebrafish were demonstrated. In addition, the residues of TBOEP were detected in F1 larvae after parental exposure, resulting in lower survival and shorter body length, as well as faster heart rate. And no significant changes in gene expressions along the growth hormone/insulin-like growth factor (GH/IGF) axis and the hypothalamic-pituitary-thyroid (HPT) axis were found in F1 larvae. In conclusion, these results indicated that long-term parental exposure to environmentally relevant concentrations of TBOEP could inhibit the development of progeny by parental gonadal impairment and by TBOEP transfer to offspring, instead of gene transcription in GH/IGF and HPT axes. Highlights • TBOEP caused significantly less growth in F0 females but not F0 males. • TBOEP at environmentally relevant concentrations caused gonadal impairment. • The residues of TBOEP were detected in F1 larvae after exposure of parents. • Long-term parental exposure to TBOEP inhibited the development of progeny. [ABSTRACT FROM AUTHOR]

Abstract Tris (2-butoxyethyl) phosphate (TBOEP), as one of the most widely used organophosphate flame retardants (OPFRs), is applied in nearly all manufactured items and materials. It has been reported that TBOEP could cause developmental impairments and disrupt the endocrine regulation of fish growth during acute toxic experiments. However, concentrations to which fish were exposed in these studies were greater than environmentally relevant concentrations ever reported. This study examined effects on growth associated with exposure of zebrafish to 0, 0.1, 1 and 10 μg/L TBOEP during 20–90 days post fertilization (dpf). The changes in growth indicators and bioaccumulation of TBOEP were examined along with the transcription of related genes in the growth hormone/insulin-like growth factor (GH/IGF) axis and the hypothalamic-pituitary-thyroid (HPT) axis. The average body contents of TBOEP were higher in females than in males in all the exposure groups. Exposure to environmentally relevant concentrations of TBOEP significantly decreased body length and body mass and down-regulated expression of several genes involved in the GH/IGF and HPT axes. Exposure to TBOEP decreased plasma thyroxine (T4) content accompanied by decreased mRNA level of thyrotropin β-subunit (tshβ) in females at 60 dpf, but no effects were observed at 90 dpf. These results suggested that bioaccumulation of TBOEP and down-regulation of genes involved in the GH/IGF axis might be responsible for the observed growth inhibition in zebrafish exposed to TBOEP. Highlights • Growth of zebrafish was inhibited by environmentally relevant levels of TBOEP. • TBOEP had no persistent effect on concentrations of THs. • Bioaccumulation of TBOEP contributed to the growth inhibition. • Disruption of GH/IGF axis was induced by environmentally relevant levels of TBOEP. [ABSTRACT FROM AUTHOR]

• TDCIPP could selectively inhibited the growth of female zebrafish. • TDCIPP altered the microbial communities in the intestine of zebrafish. • TDCIPP induced an increase in α-diversity of the gut microbiome in male zebrafish. • TDCIPP induced histological injury and inflammation responses in female intestine. • Abundances of pathogenic bacteria were negatively correlated with female growth. Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is ubiquitous in aquatic environment, but its effect on intestinal health of fish has yet not been investigated. In the present study, the AB strain zebrafish embryos were exposed to environmentally realistic concentrations (0, 30, 300, and 3000 ng·L−1) of TDCIPP for 90 days, after which the fish growth and physiological activities were evaluated, and the intestinal microbes were analyzed by 16S rRNA gene high-throughput sequencing. Our results manifested that the body length and body weight were significantly reduced in the female zebrafish but not in males. Further analyses revealed that TDCIPP resulted in notable histological injury of intestine, which was accompanied by impairment of epithelial barrier integrity (decreased tight junction protein 2), inflammation responses (increased interleukin 1β) , and disruption of neurotransmission (increased serotonin) in female intestine. Male intestines maintained intact intestinal structure, and the remarkably increased activity of glutathione peroxidase (GPx) might protect the male zebrafish from inflammation and intestinal damage. Furthermore, 16S rRNA sequencing analysis showed that TDCIPP significantly altered the microbial communities in the intestine in a gender-specific manner, with a remarkable increase in alpha diversity of the gut microbiome in male zebrafish, which might be another mechanism for male fish to protect their intestines from damage by TDCIPP. Correlation analysis revealed that abnormal abundances of pathogenic bacteria (Chryseobacterium, Enterococcus, and Legionella) might be partially responsible for the impaired epithelial barrier integrity and inhibition in female zebrafish growth. Taken together, our study for the first time demonstrates the high susceptibility of intestinal health and gut microbiota of zebrafish to TDCIPP, especially for female zebrafish, which could be partially responsible for the female-biased growth inhibition. [ABSTRACT FROM AUTHOR]

Tris (2-butoxyethyl) phosphate (TBOEP) is an environmental contaminant that poses serious risks to aquatic organisms and their associated ecosystem. Recently, the reproductive and developmental toxicology of TBOEP has been reported. However, fewer studies have assessed the neurotoxic effects in zebrafish ( Danio rerio ) larvae. In this study, zebrafish embryos were subjected to waterborne exposure of TBOEP at 0, 50, 500, 1500 and 2500 μg/L from 2 to 144-h post-fertilization (hpf). Behavioral measurements showed that TBOEP exposure reduced embryonic spontaneous movement and decreased swimming speed of larvae in response to dark stimulation. In accordance with these motor effects, TBOEP treatment reduced neuron-specific GFP expression in transgenic Tg ( HuC -GFP) zebrafish larvae and inhibited the growth of secondary motoneurons, as well as decreased expression of marker genes related to central nervous system development in TBOEP treated group. Furthermore, increased concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as reduction of SOD activity were detected in TBOEP exposure group. The present results showed that the alteration in motor neuron and oxidative stress could together lead to the motor behavior alterations induced by TBOEP. [ABSTRACT FROM AUTHOR]

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) could have neurotoxic effects and alter motor behaviors in zebrafish ( Danio rerio ) larvae, however, the underlying mechanisms are still unknown. In this study, zebrafish embryos were subjected to waterborne exposure of TDCIPP at 100, 300, 600, 900 μg/L from 2 to 120-h post-fertilization (hpf). Behavioral measurements indicate that TDCIPP exposure significantly elevated spontaneous movement, and altered swimming behavior response of larvae to both light and dark stimulation. Interestingly, in accordance with these motor effects, TDCIPP significantly decreased expression of the neuron-specific GFP in transgenic ( HuC -GFP) zebrafish larvae as well as decreased expression of the neural marker genes elavl3 and ngn1 , inhibited the axonal growth of the secondary motoneurons and altered the expressions of axon-related genes ( α1-tubulin , shha and netrin2 ) in zebrafish larvae. Furthermore, TDCIPP exposure at 900 μg/L significantly increased the activity of acetylcholinesterase (AChE) enzyme, and decreased the total acetylcholine (ACh) concentration. Our data indicate that the alteration in motor neuron and inhibition of cholinergic system could together lead to the TDCIPP induced motor behavior alterations in zebrafish larvae. [ABSTRACT FROM AUTHOR]

Tris (2-butoxyethyl) phosphate (TBOEP), is used as a flame retardant worldwide. It is an additive in materials and can be easily discharged into the surrounding environment. There is evidence linking TBOEP exposure to abnormal development and growth in zebrafish embryos/larvae. Here, using zebrafish embryo as a model, we investigated toxicological effects on developing zebrafish ( Danio rerio ) caused by TBOEP at concentrations of 0, 20, 200, 1000, 2000 μg/L starting from 2 h post-fertilization (hpf). Our findings revealed that TBOEP exposure caused developmental toxicity, such as malformation, growth delay and decreased heart rate in zebrafish larvae. Correlation analysis indicated that inhibition of growth was possibly due to down-regulation of expression of genes related to the growth hormone/insulin-like growth factor (GH/IGF) axis. Furthermore, exposure to TBOEP significantly increased thyroxine (T4) and 3,5,3′-triiodothyronine (T3) in whole larvae. In addition, changed expression of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis was observed, indicating that perturbation of HPT axis might be responsible for the developmental damage and growth delay induced by TBOEP. The present study provides a new set of evidence that exposure of embryo-larval zebrafish to TBOEP can cause perturbation of GH/IGF axis and HPT axis, which could result in developmental impairment and growth inhibition. [ABSTRACT FROM AUTHOR]

Tris (2-butoxyethyl) phosphate (TBOEP) is widely used as a substitute of polybrominated diphenyl ethers (PBDEs). It has been frequently measured at concentrations of micrograms per liter (μg/L) in surface waters and waste water. However, limited information is available about the reproduction toxicology of TBOEP. In this study, adult zebrafish pairs were exposed to TBOEP at concentrations of 0, 5, 50, and 500 μg/L for 21 days. The effects on reproduction, hormone concentration, transcription of genes along the hypothalamic-pituitary-gonadal (HPG) axis, and gonadal development were investigated. After exposure to TBOEP, plasma concentrations of 17β-estradiol were significantly increased in both sexes of fish, while increase of testosterone was observed only in male fish. Transcription of genes along the HPG axis was significantly influenced by exposure to TBOEP in both male and female fish. Moreover, TBOEP decreases the average number of eggs production, as well as hatching success and survival rates in offspring. Histological examination shows inhibition of oocyte maturation in females and retardation spermiation in males, respectively. The results demonstrate that TBOEP could disturb the sex hormone balance by altering regulatory circuits of the HPG axis, affect gonadal development, eventually leading to disruption of reproductive performance and the development of progeny. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated that cyanobacteria-derived Microcystin-LR (MC-LR) can cause developmental toxicity and trigger apoptosis in zebrafish ( Danio rerio ) larvae, but the underlying mechanisms remain largely unknown. In this study, we tested the hypothesis that the mechanism by which MC-LR induces developmental toxicity is through activation of endoplasmic reticulum (ER) stress. MC-LR (4.0 μM) exposure through submersion caused serious developmental toxicity, such as malformation, growth delay and decreased heart rates in zebrafish larvae, which could be inhibited by ER stress blocker, tauroursodeoxycholic acid (TUDCA, 20 μM). Meanwhile, acridine orange (AO) staining showed TUDCA could rescue cell apoptosis in heart area in zebrafish larvae resulted by MC-LR exposure. Real-time polymerase chain reaction (real-time PCR) analysis demonstrated that MC-LR induced activation of ER stress which consequently triggered apoptosis in zebrafish larvae. Protein expression examined by western blot indicated that MC-LR could activate MAPK8/Bcl-2/Bax pathway and caspase-dependent apoptotic pathway in zebrafish larva and the effects were mitigated by inhibition of ER stress. Taken together, the results observed in this study suggested that ER stress plays a critical role in developmental toxicity and apoptosis in zebrafish embryos exposed to MC-LR. [ABSTRACT FROM AUTHOR]

Bacillus subtilis is frequently used commercially in rice-crayfish coculture system (RCCS) to modify the physicochemical characteristics of soil and water. However, given the intensification of cadmium (Cd) contamination in RCCS and potential implications for food safety, the impacts of this modulation on the Cd bioavailability and accumulation need to be more thoroughly assessed. Here, B. subtilis was inoculated into RCCS containing different levels of soil Cd through an outdoor mesocosm experiment. Results showed that the abundance of B. subtilis in the soil was highest on the 1st day after inoculation and appeared the second peak on the 2nd week. 40–128-fold increase in B. subtilis abundance in crayfish intestines was found in the B. subtilis added groups compared to the non- B. subtilis added groups. Additionally, the Cd accumulation in crayfish and rice tissues rose significantly when the soil Cd content raised. However, with the improvement of soil pH, oxidation-reduction potential (ORP), nitrification potential (NP), acid volatile sulfide (AVS) and sulfur reducing bacteria abundance, and the decrease of organic matter (OM) at 2 W and 8 W, the addition of B. subtilis into RCCS with various Cd contents significantly reduced the Cd accumulation and the soil Cd bioavailability. The low bioavailability of Cd was characterized by the reduction of exchangeable Cd (EXC-Cd) and the grows of Fe–Mn oxides bound Cd (FeMnOx-Cd) and residual Cd (RES-Cd). Specifically, the soil EXC-Cd was negatively correlated with soil pH (−0.647), OPR (−0.663) and NP (−0.811). In short, the obtained results demonstrated that B. subtilis was able to stabilize the physicochemical properties of soil and water in RCCS, while mineralizing Cd and attenuating Cd accumulation in the crayfish and rice, suggesting that B. subtilis can be used as a cleaning probiotic applied in rice and aquatic animals coculture system. [Display omitted] • Application of B. subtilis mitigated RCCS Cd accumulation in Cd-polluted soil. • The stable colonization of B. subtilis in crayfish gut might limit Cd absorption. • B. subtilis inhibited soil Cd bioactivity by improving physicochemical properties. • The supply of B. subtilis also played a vital part in Cd mineralization. [ABSTRACT FROM AUTHOR]

• KrasV12 transgenic zebrafish was used to study the promoting effect of liver tumor. • MC-LR aggravates the progression of HCC at an environmentally relevant level. • Exposure to MC-LR decreased activity of protein phosphatase 2A. • Activation of Wnt signaling by MC-LR might be responsible for HCC promotion. Microcystin-LR (MC-LR) is a kind of natural toxin which exists widely in aquatic environments and has been reported to be hepatotoxic and carcinogenic. At present, the promoting mechanism of MC-LR on hepatocellular carcinoma (HCC) remains largely unexplored. In this study, the hepatocellular promoting effect of MC-LR was described in KrasV12 transgenic zebrafish, a doxycycline (DOX) inducible HCC model. Our results showed that MC-LR could aggravate the progression of HCC at an environmentally relevant concentration (3 μg/L), which was accompanied by the decreased activity and down-regulated transcription level of serine/threonine phosphatase 2A (PP2A). Using TMT labeling quantitative phosphoproteomics, we found that the 1049 phosphopeptides were significantly changed (508 up-regulated and 541 down-regulated) in liver from combined exposure to DOX and 3 μg/L MC-LR group compared to the DOX group. Enriched pathways by KEGG analysis suggested that differentially phosphorylated proteins were mainly related to Wnt signaling pathway. Furthermore, the mRNA expression and protein abundance of β-Catenin in Wnt signaling pathway were significantly up-regulated following exposure to MC-LR. In short, our results suggested that MC-LR significantly inhibited the activity of PP2A, which in turn activated Wnt signaling, eventually resulting in progression of liver tumor in transgenic zebrafish. [ABSTRACT FROM AUTHOR]

An abstract of the article "Transgenic Vasoactive Intestinal Peptide Shows Local Disease Modifying Effects in a Murine Model of Sjögren's Syndrome," by Beatrijs M. Lodde and colleagues is presented.

An abstract of the article "The Effect of Serine Protease Inhibitor 6 (SPI-6) Gene Transfer on a Mouse Model of Sjögren's Syndrome," by Fumi Mineshiba, Beatrijs M. Lodde, Jianghua Wang, Livia A. Casciola-Rosen, Antony Rosen, and Bruce J. Baum is presented.

Although Notch signaling is deregulated in prostate cancer, the role of this pathway in disease development and progression is not fully understood. Here, we analyzed 2 human prostate cancer data sets and found that higher Notch signaling correlates with increased metastatic potential and worse disease survival rates. We used the Pten-null mouse prostate cancer model to investigate the function of Notch signaling in the initiation and progression of prostate cancer. Disruption of the transcription factor RBPJ in Pten-null mice revealed that endogenous canonical Notch signaling is not required for disease initiation and progression. However, augmentation of Notch activity in this model promoted both proliferation and apoptosis of prostate epithelial cells, which collectively reduced the primary tumor burden. The increase in cellular apoptosis was linked to DNA damage-induced p53 activation. Despite a reduced primary tumor burden, Notch activation in Pten-null mice promoted epithelial-mesenchymal transition and FOXC2-dependent tumor metastases but did not confer resistance to androgen deprivation. Notch activation also resulted in transformation of seminal vesicle epithelial cells in Pten-null mice. Our study highlights a multifaceted role for Notch signaling in distinct aspects of prostate cancer biology and supports Notch as a potential therapeutic target for metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

Background/Aims: Elucidation of the molecular mechanisms governing osteoblast differentiation and angiogenesis are of great importance for improving the treatment of bone-related diseases. In this study, we examined the role of microRNA (miR)-10a in the differentiation of MC3T3-E1 cells and pro angiogenic activity of mouse umbilical vein endothelial cells (MUVECs). Methods: The murine pre-osteoblast cell line MC3T3-E1 and MUVECs were used in the experiment. After transfected with miR-10a mimics or inhibitors, with or without LiCl pretreatment, the miR-10a, ALP, Runx2, Osx, OC and Dlx5 expression were assessed by RT-PCR. MC3T3-E1 cells were cultured with BMP2 to differentiate into bone cells, osteogenic differentiation of MC3T3-E1 cells were detected by ALP and ARS staining. Cell viability were analyzed by MTT and the protein expression of β-catenin, LEF1, cyclinDl, MMP2, and VEGF were detected by Western blotting; VEGF and VE-cadherin release were assessed by ELISA, and the migration of MUVECs, as well as tube formation were also detected. Results: MiR-10a expression was obviously down-regulated during osteogenic differentiation. Overexpression of miR-10a inhibited osteogenic differentiation of MC3T3-E1 cells, effectively decreasing MUVECs proliferation, migration, VEGF expression, VE-cadherin concentrations, and tube formation in vitro, whereas miR-10a silence enhanced those processes. Further mechanism assays demonstrated that overexpression of miR-10a reduced the β-catenin at both protein and transcription level, while pretreatment with Wnt signaling activator Licl partially attenuated the suppression effects of miR-10a overexpression on osteoblast differentiation and angiogenesis. Conclusion: Our findings imply that miR-10a plays a suppressive role in osteoblast differentiation of MC3T3-E1 cells and pro angiogenic activity of MUVECs by regulating the β-catenin expression, representing a novel and potential therapeutic target for the treatment of bone regeneration-related diseases. [ABSTRACT FROM AUTHOR]

Currently, there is no effective vaccine to prevent hepatitis C virus (HCV) infection, partly due to our insufficient understanding of the virus glycoprotein immunology. Most neutralizing antibodies (nAbs) were identified using glycoprotein immunogens, such as recombinant E1E2, HCV pseudoparticles or cell culture derived HCV. However, the fact that in the HCV acute infection phase, only a small proportion of patients are self-resolved accompanied with the emergence of nAbs, indicates the limited immunogenicity of glycoprotein itself to induce effective antibodies against a highly evolved virus. Secondly, in previous reports, the immunogen sequence was mostly the genotype of the 1a H77 strain. Rarely, other genotypes/subtypes have been studied, although theoretically one genotype/subtype immunogen is able to induce cross-genotype neutralizing antibodies. To overcome these drawbacks and find potential novel neutralizing epitopes, 57 overlapping peptides encompassing the full-length glycoprotein E1E2 of subtype 1b were synthesized to immunize BALB/c mice, and the neutralizing reactive of the induced antisera against HCVpp genotypes 1–6 was determined. We defined a domain comprising amino acids (aa) 192–221, 232–251, 262–281 and 292–331 of E1, and 421–543, 564–583, 594–618 and 634–673 of E2, as the neutralizing regions of HCV glycoprotein. Peptides PUHI26 (aa 444–463) and PUHI45 (aa 604–618)-induced antisera displayed the most potent broad neutralizing reactive. Two monoclonal antibodies recognizing the PUHI26 and PUHI45 epitopes efficiently precluded genotype 2 viral (HCVcc JFH and J6 strains) infection, but they did not neutralize other genotypes. Our study mapped a neutralizing epitope region of HCV glycoprotein using a novel immunization strategy, and identified two monoclonal antibodies effective in preventing genotype 2 virus infection. [ABSTRACT FROM AUTHOR]

Recent studies have shown that cyanobacteria-derived microcystins (MCs) have the potential to disrupt endocrine systems. However, the effects of microcystin-RR (MC-RR) and their underlying mechanisms are poorly resolved in fish. In this study, MC-RR exposure through submersion caused serious developmental toxicity, such as growth delay and depressed heart rates in zebrafish larvae. We also detected decreased levels of thyroid hormones (THs), suggesting that MC-RR-triggered thyroid endocrine disruption might contribute to the growth impairment observed in developing zebrafish. To further our understanding of mechanisms of MC-RR-induced endocrine toxicity, quantitative real-time PCR (QPCR) analysis was performed on hypothalamic–pituitary–thyroid (HPT) axis related genes, i.e., corticotropin-releasing factor (CRF), thyroid-stimulating hormone (TSH), sodium/iodide symporter (NIS), thyroglobulin (TG), thyroid receptors (TRα and TRβ) and iodothyronine deiodinases (Dio1 and Dio2), of developing zebrafish embryos exposed to 0, 0.3, 1.0 or 3.0 mg L −1 MC-RR until 96 h post-fertilization. Our results showed that transcription pattern of HPT axis related genes were greatly changed by MC-RR exposure, except TG gene. Furthermore, western blot was used to validate the results of gene expression. The results showed protein synthesis of TG was not affected, while that of NIS was significantly up-regulated, which are in accordance with gene expression. The overall results indicated that exposure to MC-RR can induce developmental toxicity, which might be associated with thyroid endocrine disruption in developing zebrafish larvae. [ABSTRACT FROM AUTHOR]

Highlights: [•] MCLR-induced apoptosis in the heart of developing embryos leads to the growth delay in zebrafish. [•] MCLR-triggered apoptosis might be induced by ROS. [•] P53–Bax–Bcl-2 and caspase-dependent apoptotic pathway contribute greatly to MCLR-induced apoptosis. [ABSTRACT FROM AUTHOR]

The TMPRSS2/ERG (T/E) fusion gene is present in the majority of all prostate cancers (PCa). We have shown previously that NF-kB signaling is highly activated in these T/E fusion expressing cells via phosphorylation of NF-kB p65 Ser536 (p536). We therefore hypothesize that targeting NF-kB signaling may be an efficacious approach for the subgroup of PCas that carry T/E fusions. Celastrol is a well known NF-kB inhibitor, and thus may inhibit T/E fusion expressing PCa cell growth. We therefore evaluated Celastrol’s effects in vitro and in vivo in VCaP cells, which express the T/E fusion gene. VCaP cells were treated with different concentrations of Celastrol and growth inhibition and target expression were evaluated. To test its ability to inhibit growth in vivo, 0.5 mg/kg Celastrol was used to treat mice bearing subcutaneous VCaP xenograft tumors. Our results show Celastrol can significantly inhibit the growth of T/E fusion expressing PCa cells both in vitro and in vivo through targeting three critical signaling pathways: AR, ERG and NF-kB in these cells. When mice received 0.5 mg/kg Celastrol for 4 times/week, significant growth inhibition was seen with no obvious toxicity or significant weight loss. Therefore, Celastrol is a promising candidate drug for T/E fusion expressing PCa. Our findings provide a novel strategy for the targeted therapy which may benefit the more than half of PCa patients who have T/E fusion expressing PCas. [ABSTRACT FROM AUTHOR]

Abstract: This study was conducted to evaluate possible bystander effects induced by the model chemical 6-propyl-2-thiouracil (PTU) on melanin synthesis. Zebrafish (Danio rerio) embryos were treated with PTU by either microinjection exposure, via waterborne exposure or indirectly through bystander exposure. Melanin content, related mRNA and protein expression were examined at the end of exposure (36h post-fertilization). Direct exposure to PTU decreased the melanin content, up-regulated mRNA expressions of oculocutaneous albinism type 2 (OCA2), tyrosinase (TYR), dopachrometautomerase (DCT), tyrosinase-related protein 1 (TYRP1) and silver (SILV), and increased the protein expressions of TYR and SILV. Bystander exposure also up-regulated mRNA and protein expressions of TYR and SILV but increased melanin contents. Correlation analysis demonstrated that mRNA expressions of OCA2, TYR, DCT, TYRP1, SILV and protein expressions of TYR and SILV in bystander exposure groups were positively correlated with corresponding expressions in microinjection exposure groups. The results might have environmental implications and highlight the need to consider the bystander effects when assessing potential risks of endocrine-disrupting chemicals. [Copyright &y& Elsevier]

Abstract: Microcystin–leucine–arginine (MCLR) is the most toxic and the most commonly encountered variant of microcystins (MCs) in aquatic environment, and it has the potential for disrupting thyroid hormone homeostasis, but the molecular mechanisms underlying this process have not yet been clarified. In the present study, we observed body growth retardation associated with decreased levels of thyroid hormones (THs) in zebrafish larvae, highlighting the interferences of MCLR with the growth of fish larvae. To further our understanding of mechanisms of MCLR-induced endocrine toxicity, quantitative real-time PCR analysis was performed on hypothalamic–pituitary–thyroid (HPT) axis related genes of developing zebrafish embryos exposed to 100, 300 and 500μgL−1 MCLR until 96h post-fertilization. The expression of several genes in the HPT system, i.e., corticotropin-releasing factor (CRF), thyroid-stimulating hormone (TSH), sodium/iodide symporter (NIS), thyroglobulin (TG), thyroid receptors (TRα and TRβ) and iodothyronine deiodinases (Dio1 and Dio2) was examined using quantitatively real-time PCR. The gene expression levels of CRF, TSH, NIS and TG were significantly induced after exposure to 500μgL−1 MCLR. The transcription of TRs gene was down-regulated in a concentration-dependent manner. Up-regulation and down-regulation of Deio1 and Deio2 gene expression, respectively, were observed upon exposure to MCLR. The above results indicated that MCLR could alter gene expression in the HPT axis which might subsequently contribute to MCLR-induced thyroid disruption. [Copyright &y& Elsevier]

Abstract: A solid heteropolyacid salt Ag3PW12O40 has been used as a heterogeneous catalyst for the production of 5-hydroxymethylfurfural (HMF) from fructose and glucose. The fructose was selectively dehydrated into HMF with the HMF yield as high as 77.7% and selectivity of 93.8% within 60 min at 120 °C. In addition, Ag3PW12O40 also exhibited catalytic activity for conversion of glucose into HMF. Moreover, the catalyst is tolerant to high concentration feedstock and can be recycled. The results illustrate that the Ag3PW12O40 is an excellent acid and environmentally benign solid catalyst for the production of HMF from fructose and glucose. [Copyright &y& Elsevier]

A superconducting magnet with the center field of 9.4 T is designed and fabricated for 400 MHz Nuclear Magnetic Resonance. Superconducting coil with NbTi/Cu superconducting wire is employed and cooled by re-condensed liquid helium and the magnet system with the clear-bore of 54 mm. The pulsed tube refrigerator with separated valve is employed to cool the magnet system. The superconducting magnet has an active shield with high pure copper shield to protect during quench of the shielding coil. The paper reports the electromagnetic design, and fabrication is detailed. [ABSTRACT FROM AUTHOR]

The use of critical-for-life organs (e.g., liver or lung) for systemic gene therapeutics can lead to serious safety concerns. To circumvent such issues, we have considered salivary glands (SGs) as an alternative gene therapeutics target tissue. Given the high secretory abilities of SGs, we hypothesized that administration of low doses of recombinant adeno-associated virus (AAV) vectors would allow for therapeutic levels of transgene-encoded secretory proteins in the bloodstream. We administered 109 particles of an AAV vector encoding human erythropoietin (hEPO) directly to individual mouse submandibular SGs. Serum hEPO reached maximum levels 8-12 weeks after gene delivery and remained relatively stable for 54 weeks (longest time studied). Hematocrit levels were similarly increased. Moreover, these effects proved to be vector dose-dependent, and even a dosage as low as 108 particles per animal led to significant increases in hEPO and hematocrit levels. Vector DNA was detected only within the targeted SGs, and levels of AAV copies within SGs were highly correlated with serum hEPO levels (r = 0.98). These results show that SGs appear to be promising targets with potential clinical applicability for systemic gene therapeutics. [ABSTRACT FROM AUTHOR]

Microcystin-LR (MCLR) was commonly regarded as a potent hepatotoxin and has been reported to cause neurotoxicity. This study was aimed to investigate how maternal MCLR exposure during pregnancy alters behavioral responses in offspring mice and the possible molecular mechanism involved in this procedure. Three doses of MCLR solutions (0, 3 or 15 μg/kg body weight) were administered subcutaneously to pregnant C57bl/6 from gestation day (GD) 6–19. Our results showed that MCLR prenatal exposure led to the impairment of learning and memory function in offspring on postnatal days (PND) 35, accompanied by endoplasmic reticulum (ER) stress and neuronal apoptosis in hippocampal CA1 regions of mice. Sixteen miRNAs in hippocampus of pups on PND 35 were significantly affected by MCLR exposure with the markedly decreased transcription of miR-181a-5p. We then found that miR-181a-5p was down-regulated, accompanied by activation of ER stress after prenatal exposure to MCLR using qPCR analysis. Furthermore, glucose-regulated protein, 78kDa/binding immunoglobulin protein (Grp78/BIP), a major ER chaperone and signaling regulator, was identified as a target of miR-181a-5p. Our study showed that miR-181a could lead to a decrease in the mRNA expression and protein levels of Grp78 by directly binding to its 3′-untranslated region (3′-UTR) in primary hippocampal neurons. Our findings indicate that the up-regulation of Grp78 mediated by inhibition of miR-181a-5p is a possible mechanism resulting in ER stress and cognitive impairment in pups following prenatal MCLR exposure. • Maternal MC-LR exposure altered behavioral responses in offspring mice. • MC-LR prenatal exposure led to endoplasmic reticulum (ER) stress and neuronal apoptosis in offspring. • Inhibition in miR-181a resulted in the activation of ER stress and subsequent apoptosis. [ABSTRACT FROM AUTHOR]

Microcystin-LR (MCLR) is a commonly acting potent hepatotoxin and has been pointed out of potentially causing neurotoxicity, but the exact mechanisms of action still remain unclear. Using proteomic analysis, forty-five proteins were identified to be significantly altered in hippocampal neurons of rats treated with MCLR. Among them, Ca2+-activated phosphatase calcineurin (CaN) and the nuclear factor of activated T-cells isoform c3 (NFATc3) were up-regulated remarkably. Validation of the changes in CaN and NFATc3 expression by Western blotting demonstrated CaN cleavage and subsequent NFATc3 nuclear translocation were generated, suggesting that exposure to MCLR leads to activation of CaN, which in turn activates NFATc3. Activation of CaN signaling has been reported to result in apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. In agreement with this, our results revealed that treatment of neurons with the CaN inhibitor FK506 blocked the reduction in Bad dephosphorylation and cytochrome c (cyt c) release triggered by MCLR. Consistent with these biochemical results, we observed a marked decrease in apoptotic and necrotic cell death after MCLR exposure in the presence of FK506, supporting the hypothesis that MCLR appeared to cause neuronal toxicity by activation of CaN and the CaN-mediated mitochondrial apoptotic pathway. [ABSTRACT FROM AUTHOR]

Abstract: The high pressure and high temperature (HPHT) behavior and phase stability of titanium-aluminium carbide (Ti2AlC) were investigated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron micrograph (SEM), and energy-dispersive X-ray analysis (EDXA). The results show that the decomposition temperature of Ti2AlC decreases against pressure. At pressures of 3, 4 and 5GPa, the low temperature limits of phase segregation of the sample Ti2AlC lie between 1300 and 1200°C, 1100 and 1000°C, 900 and 800°C, respectively. The decomposition products are identified to be titanium carbide and titanium aluminium. [Copyright &y& Elsevier]