Description: Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis, Published online: 13 November 2017; doi:10.1038/nmat5024 NatureArticleSnippet(type=short-summary, markup= Angiogenesis has been implicated in fibrotic diseases of the liver. Here, the authors developed microniches that mimic angiogenesis during different stages of liver fibrosis, and demonstrate the role of mechanotransduction in fibrogenesis. , isJats=true)

Description: The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed a novel class of agents (thailanstatins, TSTs, spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3' splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application. This article is protected by copyright. All rights reserved.

Description: Purpose To evaluate the response in patients undergoing SBRT using dynamic contrast-enhanced (DCE) integrated magnetic resonance positron emission tomography (MR-PET). Stereotactic body radiation therapy (SBRT) is efficacious as a front-line local treatment for non-small cell lung cancer (NSCLC). Materials and Methods We prospectively enrolled 19 lung tumors in 17 nonmetastatic NSCLC patients who were receiving SBRT as a primary treatment. They underwent DCE-integrated 3T MR-PET before and 6 weeks after SBRT. The following image parameters were analyzed: tumor size, standardized uptake value (SUV), apparent diffusion coefficient, K trans , k ep , v e , v p , and iAUC 60 . Chest computed tomography (CT) was performed at 3 months after SBRT. Results SBRT treatment led to tumor changes including significant decreases in the SUV max (–61%, P 〈 0.001), K trans mean (–72%, P = 0.005), K trans standard deviation (SD; –85%, P = 0.046), k ep mean (–53%, P = 0.014), k ep SD (–63%, P = 0.001), and v p SD (–58%, P = 0.002). The PET SUV max was correlated with the MR k ep mean ( P = 0.002) and k ep SD ( P 〈 0.001). The percentage reduction in K trans mean ( P 〈 0.001) and k ep mean ( P = 0.034) at 6 weeks post-SBRT were significantly correlated with the percentage reduction in tumor size, as measured using CT at 3 months after SBRT. Univariate analyses revealed a trend toward disease progression when the initial SUV max 〉 10 ( P = 0.083). Conclusion In patients with NSCLC who are receiving SBRT, DCE-integrated MR-PET can be used to evaluate the response after SBRT and to predict the local treatment outcome. Level of Evidence : 2 Technical Efficacy : Stage 1 J. Magn. Reson. Imaging 2017.

Description: Ischemia-reperfusion injury (IRI), induced by abnormal mitochondrial fission related apoptosis, is a major concern in liver transplantation settings. Our previous studies have demonstrated that hepatic stimulator substance (HSS) is an anti-apoptotic effector and could protect liver from IRI. However, the underlying mechanism remains unclear. In the present study, we report that in vitro and in vivo HSS could regulate mitochondrial fission and hepatocyte apoptosis during liver IRI by orchestrating the translocation and activation of dynamin-related protein 1 (Drp1). Using a mouse model of IR-induced liver injury, we found that HSS haploinsufficient (HSS +/- ) mice displayed exacerbated liver damage based on their increased serum aminotransferase levels, cell structural destruction, and apoptosis levels compared to the wild type (HSS +/+ ) littermates. Disruption of HSS markedly increased cyclin-dependent kinase 1 (CDK1) and Bax expression, accompanied with elevated p-Drp1 and release of cytochrome c. In parallel in vitro studies, we found that HSS could inhibit the expression of CDK1 and that HSS inhibits hepatocytes apoptosis through its suppression of CDK1/cyclin B -mediated phosphorylation at Ser-616 of Drp1, thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. On the contrary, knockdown of HSS increased of CDK1 as well as Drp1 phosphorylation and aggravated hepatocellular apoptosis. Mechanistic investigation showed that HSS was able to reduce the stability and translation of CDK1 mRNA by modulating the expression of several miRNAs, including miR-410-3p, miR-490-3p and miR-582-5p. Our data reveal a novel mechanism for HSS in regulating the mitochondrial fission machinery and further suggest that modulation of HSS may provide a therapeutic approach for combating liver damage. This article is protected by copyright. All rights reserved.

Description: During the summers of 2009 and 2013, seawater pH and concentrations of dissolved oxygen, inorganic carbon, and nutrients were measured off the Changjiang estuary in the East China Sea. The 2009 cruise captured the effects of Typhoon Morakot; the 2013 cruise sampled more typical conditions (no typhoon). Data from both years indicate a close correlation between high primary productivity in surface waters and hypoxia in bottom waters. Based on these observations, we developed a conceptual model to guide an exploration of processes contributing to the formation of summertime bottom hypoxia. A mixing-model analysis of the 2009 data identified a surface diatom bloom as the major (70–80%) source of the organic carbon that decomposed and ultimately led to bottom water hypoxia. Within the Changjiang River plume, depth-integrated net biological production in the water column was 1.8 g C m −2 d −1 , indicating strong autotrophic production, which in turn led to a high respiration rate of 1.2 g C m −2 d −1 in the bottom water. During both cruises, strong surface-to-bottom physical and metabolic coupling was evident. In 2009, storm-driven inputs of nutrients from elevated river discharge and strong vertical mixing helped to fuel the rapid development of a surface diatom bloom. Afterwards, stratified conditions re-established, newly formed labile organic matter sank, and bottom water oxygen was quickly consumed to an extent that hypoxia and acidification developed. To our knowledge, the observed rate of hypoxia and acidification development (within 6 d) is the fastest yet reported for the Changjiang River plume.

Description: Tripterygium wilfordii (Celastraceae) is a traditional Chinese medicine; and the dried root and rhizome constitute the main officinal parts. Tripterygium wilfordii has been identified as a potential candidate for the treatment of systemic lupus erythematosus, rheumatoid arthritis, nephritis, asthma, leprosy, and cancer. The phylogenetic relationships within the Tripterygium genus are ambiguous; thus, our aim is to clarify the relationships within this genus using phylogeographic and phylogenetic analyses. Here, we first sequenced three plastid DNA regions (i.e., psb A -trn H, rpl32-trn L, and trn L- trn F) and found that Tripterygium hypoglaucum and T. wilfordii were clustered together based on the strength of the topology in the phylogenetic analysis: T .  hypoglaucum is polyphyletic, and T. wilfordii is paraphyletic. A spatial analysis of molecular variance showed that the best group value is 4, and the groups were almost consistent with the topology of in the phylogenetic analysis. The Mantel analyses of Tripterygium using IBD web showed statistically significant relationships between genetic and geographical distance distributions ( r  = .3479, p  〈 .0001). The molecular dating using Fossil calibration indicated that the divergence in Tripterygium was approximately 8.13 Ma. Furthermore, we also analyzed four DNA regions (i.e., ITS2, psb A- trn H, mat K, and rbc L) that were obtained from the NCBI nucleotide database; these results showed that T. wilfordii and T. hypoglaucum clustered together, while Tripterygium regelii represented a separate cluster. Tripterygium hypoglaucum and T. wilfordii were never distinct lineages, and the species circumscriptions are artificial. We propose that T. wilfordii and T. hypoglaucum are conspecific, while T. regelii likely constitutes a separate species. We attempted to clarify the relationships in Tripterygium using phylogeographic and phylogenetic analyses based on cpDNA regions. We analyzed the haplotype distribution and network and differentiation among populations and performed a spatial analysis of molecular variance, Mantel's test, phylogenetic tree, and divergence time estimates. We propose that Tripterygium wilfordii and Tripterygium hypoglaucum are conspecific, while Tripterygium regelii likely constitutes a separate species.

Description: Organic nitrogen aerosols are complex mixtures and important compositions in ambient fine particulate matters (PM 2.5 ), yet their sources and spatiotemporal patterns are not well understood particularly in regions influenced by intensive human activities. In this study, filter-based ambient PM 2.5 samples at four stations (one urban, two rural plus one urban roadside) and PM samples from combustion sources (vehicle exhaust, ship emission and biomass burning) were collected in the coastal megacity Guangzhou, south China for determining water soluble organic nitrogen (WSON) along with other organic and inorganic species. The annual average WSON concentrations, as well as the ratios of WSON to water soluble total nitrogen (WSON/WSTN), were all significantly higher at rural sites than urban sites. Average WSON concentrations at the four sites during the wet season were quite near each other, ranging from 0.41 to 0.49 ug/m 3 ; however, they became 2 times higher at the rural sites than at the urban sites during the dry season. Five major sources for WSON were identified through positive matrix factorization (PMF) analysis. Vehicle emission (29.3%), biomass burning (22.8%) and secondary formation (20.2%) were three dominant sources of WSON at the urban station while vehicle emission (45.4%) and dust (28.6%) were two dominant sources at the urban roadside station. At the two rural sites biomass burning (51.1% and 34.1%, respectively) and secondary formation (17.8% and 30.5%, respectively) were dominant sources of WSON. Ship emission contributed 8-12% of WSON at the four sites. Natural vegetation seemed to have very minor contribution to WSON.

Description: Background Doxorubicin (Dox) is an effective anticancer agent. However, its effectiveness is limited by its cardiotoxic effects. It has also been reported that the mitogen-activated protein kinase family and NF-κB can be activated by Dox treatment. DATS has been shown to be a potent antioxidant with cardioprotective effects. We investigate whether Dox induces cardiac apoptosis through JNK- and ERK-dependent NF-κB upregulation that can be reduced by DATS treatment. Methods and Material H9c2 cells were treated with 0.5–1.5 μM Dox for 24 hours. Dox promoted apoptosis and ROS generation and inhibited viability in a dose-dependent manner. Then, the phosphorylation levels of JNK, ERK, and NF-κB evaluated by western blot were elevated. We used inhibitors of JNK, ERK, and NF-κB to determine which of these proteins were involved in Dox-induced apoptosis. Furthermore, Dox-exposed cells were treated with DATS at doses of 1, 5, and 10 μM, and the data demonstrated that ROS generation and apoptotic proteins were decreased and that ERK and NF-κB were downregulated in a dose-dependent manner. Additionally, six-week-old rats were divided into three groups ( n  = 6 per group) designed as an eight-week study. Normal, Dox (at dose 3.75 mg/kg by ip) administered with or without DATS (at dose 40 mg/kg by gavage) treatment groups. The results indicate that cardiac dysfunction, apoptosis, and JNK, ERK, and NF-κB activation by Dox were reversed by treatment with DATS. Conclusion DATS appears to suppress Dox-induced cardiomyocyte apoptosis by inhibiting NADPH oxidase-related ROS production and the downstream JNK/ERK/NF-κB signaling pathway; DATS may possess clinical therapeutic potential by blocking Dox-induced cardiotoxicity.

Description: Human skin aging is a progressive process that includes intrinsic aging and extrinsic photodamage, both of which can cause an accumulation of reactive oxygen species (ROS), resulting in dermal fibrosis dysfunction and wrinkle formation. Galangin is a flavonoid that exhibits anti-inflammatory and antioxidative potential. Previous studies have reported that galangin has antioxidative activity against ROS-mediated stress. The aim of the present study is to determine the antiaging effects of galangin on dermal fibroblasts exposed to H 2 O 2 . In this study, we established a hydrogen peroxide-induced inflammation and aging model using human HS68 dermal fibroblasts. Stimulation of fibroblasts with H 2 O 2 is associated with skin aging and increased expression of inflammation-related proteins, along with downregulation of collagen I/III formation and expression of antioxidative proteins. Galangin effectively reduced NF-κB activation, the expression of inflammation-related proteins and cell aging. Galangin also reversed H 2 O 2 -activated cell senescence in HS68 cells. Our results reveal that galangin protects human dermal fibroblasts by inhibiting NF-κB activation, decreases the expression of inflammatory factors and upregulates IGF1R/Akt-related proteins, indicating that galangin may be a potential candidate for developing natural antiaging products that protect skin from damage caused by ROS.

Description: Because of their low trap densities and remarkable carrier transport properties, organic-inorganic hybrid perovskite single crystals have been used as active materials in photodetectors to provide high photodetection responses. While the ideal methylammonium lead bromide (MAPbBr 3 ) perovskite has a cubic crystal structure, the structures and carrier transport properties of the actual crystals may have low symmetry as a result of low-temperature fabrication processes used. In this work, the variable temperature crystallization method was proposed to fabricate large MAPbBr 3 single crystals. The unsymmetrical structures of the MAPbBr 3 single crystals were characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The electrical properties and photodetection responses of these MAPbBr 3 single crystals along the different axial directions were then investigated. The asymmetrical trap density, the carrier mobility, and the photocurrent gain were all estimated from the measurement results. The best photodetection response was obtained along the vertical channel located between the top and bottom faces of the MAPbBr 3 single crystal. The photocurrent gain was 900, and the fall time for transient photodetection was 30 μs. The work presented here is expected to provide useful design information for photodetectors based on perovskite single crystals. The authors demonstrate the asymmetry in large-sized methylammonium lead bromide perovskite single crystal (MAPbBr 3 ) by investigating its optical and transport properties in different growth channels. Photodetectors based on different channels of perovskite single crystal are fabricated and photodetections of the channels are studied as well. The work provides useful information for photovoltaic devices based on perovskite single crystals.