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Summary Fe deficiency is a widespread nutritional disorder in plants. The basic helix‐loop‐helix (bHLH) transcription factors (TFs), especially Ib subgroup bHLH TFs which are involved in iron uptake, have been identified. In this study, an IVc subgroup bHLH TF MdbHLH104 was identified and characterized as a key component in the response to Fe deficiency in apple. The overexpression of the MdbHLH104 gene noticeably increased the H+‐ATPase activity under iron limitation conditions and the tolerance to Fe deficiency in transgenic apple plants and calli. Further investigation showed that MdbHLH104 proteins bonded directly to the promoter of the MdAHA8 gene, thereby positively regulating its expression, the plasma membrane (PM) H+‐ATPase activity and Fe uptake. Similarly, MdbHLH104 directly modulated the expression of three Fe‐responsive bHLH genes, MdbHLH38, MdbHLH39 and MdPYE. In addition, MdbHLH104 interacted with 5 other IVc subgroup bHLH proteins to coregulate the expression of the MdAHA8 gene, the activity of PM H+‐ATPase and the content of Fe in apple calli. Therefore, MdbHLH104 acts together with other apple bHLH TFs to regulate Fe uptake by modulating the expression of the MdAHA8 gene and the activity of PM H+‐ATPase in apple.

Summary In this study, we characterized the role of an apple cytosolic malate dehydrogenase gene (MdcyMDH) in the tolerance to salt and cold stresses and investigated its regulation mechanism in stress tolerance. The MdcyMDH transcript was induced by mild cold and salt treatments, and MdcyMDH‐overexpressing apple plants possessed improved cold and salt tolerance compared to wild‐type (WT) plants. A digital gene expression tag profiling analysis revealed that MdcyMDH overexpression largely altered some biological processes, including hormone signal transduction, photosynthesis, citrate cycle and oxidation–reduction. Further experiments verified that MdcyMDH overexpression modified the mitochondrial and chloroplast metabolisms and elevated the level of reducing power, primarily caused by increased ascorbate and glutathione, as well as the increased ratios of ascorbate/dehydroascorbate and glutathione/glutathione disulphide, under normal and especially stress conditions. Concurrently, the transgenic plants produced a high H2O2 content, but a low O2·− production rate was observed compared to the WT plants. On the other hand, the transgenic plants accumulated more free and total salicylic acid (SA) than the WT plants under normal and stress conditions. Taken together, MdcyMDH conferred the transgenic apple plants a higher stress tolerance by producing more reductive redox states and increasing the SA level; MdcyMDH could serve as a target gene to genetically engineer salt‐ and cold‐tolerant trees.

Iron (Fe) homeostasis is crucial for plant growth and development. A network of basic helix-loop-helix (bHLH) transcription factors positively regulates Fe uptake during iron deficiency. However, their up-regulation or overexpression leads to Fe overload and reactive oxygen species generation, thereby damaging the plants. Here, we found that two BTB/TAZ proteins, MdBT1 and MdBT2, interact with the MbHLH104 protein in apple. In addition, the function of MdBT2 was characterized as a regulator of MdbHLH104 degradation via ubiquitination and the 26S proteasome pathway, thereby controlling the activity of plasma membrane H⁺-ATPases and the acquisition of iron. Furthermore, MdBT2 interacted with MdCUL3 proteins, which were required for the MdBT2-mediated ubiquitination modification of MdbHLH104 and its degradation. In sum, our findings demonstrate that MdBT proteins interact with MdCUL3 to bridge the formation of the MdBTsMdCUL3 complex, which negatively modulates the degradation of the MdbHLH104 protein in response to changes in Fe status to maintain iron homeostasis in plants.

ABSTRACT Background Tear trough deformities are indicative of aging, progressively manifesting as pronounced infraorbital hollows. Although hyaluronic acid (HA) dermal fillers are favored for their safety and efficacy, quantifiable evidence of their effect of action still remains insufficient. Aims To investigate the efficacy of non‐cross‐linked HA compound in tear trough enhancement. Methods Twenty‐one subjects with moderate to severe infraorbital hollows underwent a single treatment including subcutaneous to supraperiosteal injections of a non‐cross‐linked HA compound. The effectiveness was assessed through Allergan Infraorbital Hollows Scale (AIHS), satisfaction rates, the Global Aesthetic Improvement Scale (GAIS), and quantitative analyses via Canfield VECTRA 3D imaging and MRI measurements during the 6‐month follow‐up. Results A total of 0.67 ± 0.31 and 0.77 ± 0.42 mL of the non‐cross‐linked HA compound were injected into the left and right suborbital regions, respectively. Substantial improvements in AIHS were observed in 85.71% and 80.95% of subjects at 6 months posttreatment, as assessed by blinded evaluators and treating investigators, respectively. 3D imaging showed volume increases of 0.87 ± 0.32 (left) and 0.99 ± 0.45 mL (right). MRI analysis provided closely aligned results to the 3D analysis. The GAIS and satisfaction rate were 85.71%, 90.48% for treating investigators and were 90.48% and 95.24% for subjects 6 months posttreatment. Conclusions The non‐cross‐linked HA filler demonstrated a safe and efficacious profile for the correction of infraorbital hollows with significant patient satisfaction and sustained outcomes up to 6 months posttreatment. These results support their clinical value in periorbital rejuvenation and reduction of infraorbital hollowing.

The atypical protein kinase C (aPKC) in complex with PAR3 and PAR6 is required for axon-dendrite differentiation, but the upstream factors responsible for regulating its activity are largely unknown. Here, we report that in cultured hippocampal neurons aPKC is directly regulated by Dishevelled (Dvl), an immediate downstream effector of Wnt. We found that downregulation of Dvl abrogated axon differentiation, whereas Dvl overexpression resulted in multiple axon formation. Interestingly, Dvl was associated with aPKC and this interaction resulted in aPKC stabilization and activation. Furthermore, the multiple axon formation resulting from Dvl overexpression was attenuated by expressing a dominant–negative aPKC in these neurons and overexpression of aPKC prevented the loss of axon caused by Dvl downregulation. Finally, Wnt5a, a noncanonical Wnt, activated aPKC and promoted axon differentiation. The Wnt5a effect on axon differentiation was attenuated by downregulating Dvl or inhibiting aPKC. Thus, Dvl–aPKC interaction can promote axon differentiation mediated by the PAR3–PAR6–aPKC complex.

Differential expression of microRNA (miR)-335-5p, a key tumor suppressor, has been detected in pre-eclampsia (PE) placentas. However, the role of miR-335-5p in the pathogenesis of PE and the factor modulating its aberrant expression remain unknown. The present study used JEG-3 cells in vitro to investigate these mechanisms. The role of miR-335-5p in proliferation, apoptosis and migration of JEG-3 cells was investigated using MTT, Annexin V-FITC/PI, Transwell migration and wound healing assays, respectively. miR-335-5p expression levels were analyzed using reverse transcription-quantitative PCR. The expression levels of E-cadherin, N-cadherin, Snail, specificity protein 1 (Sp1) and p53 were assessed using western blot analysis. Cell viability analysis was performed using the Cell Counting Kit-8 assay. The intracellular reactive oxygen species (ROS) levels were detected using a 2,7-dichlorodihydrofluorescein diacetate assay. The present results suggested that miR-335-5p did not affect the proliferation or apoptotic rate of JEG-3 cells. Overexpression of miR-335-5p significantly inhibited the migration of JEG-3 cells, decreased the expression levels of Sp1, N-cadherin and Snail, and increased E-cadherin expression. Sp1 silencing produced similar results in JEG-3 cells. H2O2 significantly increased the intracellular ROS levels and miR-335-5p expression, whereas N-acetyl-cysteine pretreatment prior to H2O2 treatment reversed the increases in miR-335-5p expression. Knockdown of p53 significantly decreased the expression levels of miR-335-5p in JEG-3 cells and in H2O2-treated cells. The present results suggested that miR-335-5p expression levels in trophoblast cells could be increased by ROS in a p53-dependent manner, leading to the downregulation of Sp1 and subsequent inhibition of epithelial to mesenchymal transition and cell migration. The present results may provide novel evidence on the etiology of PE.

Water resources allocation decision-making in an arid region should consider the interaction of the economy, the environment, society, resources and other factors. In this paper, an index system for the comprehensive evaluation of water resources allocation in arid areas is established in response to the shortage of water resources, over-utilization of groundwater, and an unreasonable structure of agricultural water demand in the arid region of northwest China. It has been formulated based on current river basin water resources allocation practices and consideration of the fairness, efficiency and resource utilization rationality of water resources allocation. The projection tracking dynamic clustering approach was applied to analyze alternative water resource allocation schemes in the Kiz River Basin. It is concluded that the evaluation results demonstrate the following. (1) The PPDC model takes the actual measured value of the index as the basis for comprehensive evaluation, and it avoids the bias caused by the subjective formulation of weights. An optimal allocation scheme that has higher annual comprehensive benefits can better serve regional water resources management. (2) A projection pursuit dynamic cluster approach can deliver results which are more objective and reliable than existing evaluation approaches for water resources allocation. (3) Grey correlation analysis and projection tracking dynamic clustering are basically consistent with the evaluation results for water resources allocation in the Kiz River Basin. This suggests that the projection pursuit dynamic cluster is suitable for the evaluation of water resources allocation schemes.

The chemokine receptor CCR4 is preferentially expressed on certain immune cells and some hematological tumor cells, which play pivotal roles in suppression of host immune response. However, the reasons for the upmodulation of CCR4 and its immune functions in solid tumors remain unclear. Herein, we aimed to determine the expression profiles of CCR4 in gastric cancer cells and its role in regulating antitumor immunity. CCR4 expression was assessed in 63 cases of gastric carcinomas by immunohistochemistry. We found cancer cells in lymphocyte‐rich carcinomas more frequently showed moderate to strong positive staining for CCR4 than those in conventional carcinomas (P = 0.041), and also found a positive relationship between expression of CCR4 and tumor necrosis factor‐α (P = 0.012). Stimulation of gastric cell lines with various cytokines showed that tumor necrosis factor‐α uniquely upmodulated CCR4 expression through activation of nuclear factor‐κB. Additional coculture experiments showed the forced expression of CCR4 in SGC‐7901 cells caused a significant reduction of γ‐interferon and elevation of interleukin‐10 secretion in the supernatants from cocultured SGC‐7901 cells and PBMCs. In addition, granzyme A production in cancer cell‐cocultured CD56+ natural killer cells was significantly downregulated. Inhibition of the overexpressed CCR4 in cancer cells by an inhibitor of CCR4, compound 39, proved to partly restore the antitumor immunity in respect of the inverse changes in those factors. Our studies suggest that the aberrant expression of CCR4 in human gastric cancer could contribute to tumor‐induced immunosuppression. Conceivably, downmodulation of CCR4 expression could be a promising immunotherapy for human gastric cancer. (Cancer Sci 2011; 102: 1264–1271)

Objective The present study aimed to explore expression and clinical significance of chemerin, a newly discovered adipokine, in squamous cell carcinoma of the oral tongue (SCCOT). Methods mRNA expression of chemerin in 19 pairs of fresh SCCOT samples matched with peritumoral mucosa tissues was quantified by real-time quantitative transcription polymerase chain reaction (qRT-PCR). Chemerin protein expression and microvessel density (MVD) were measured by immunohistochemistry on 147 cases of primary SCCOT specimen and their corresponding peritumoral noncancerous tissues. The relationship of chemerin expression with angiogenesis, clinicopathologic parameters, and cancer-related survival of patients was evaluated. Results Both qRT-PCR and immunohistochemistry results revealed that chemerin was overexpressed in SCCOT compared with peritumoral noncancerous tissues ( P  < 0.01). Overexpression of chemerin in SCCOT was significantly associated with poor differentiation, lymph node metastasis, and high clinical stage ( P  = 0.000, 0.012, and 0.015, respectively). In addition, overexpression of chemerin was positively related to MVD in SCCOT ( r  = 0.671, P  = 0.002). SCCOT patients with overexpressed chemerin had a shorter cancer-related survival ( P  = 0.027). Moreover, multivariate survival analysis indicated that chemerin was an independent prognostic factor for SCCOT patients ( P  = 0.016). Conclusion These results demonstrated that overexpression of chemerin in SCCOT was correlated with tumor angiogenesis and poor clinical outcomes of SCCOT patients. Clinical relevance Our research implied that chemerin was a novel prognostic factor for SCCOT patients, and chemerin could be a new therapeutic target for regulating tumor angiogenesis and blocking tumor progression.

Through a case study of analyzing the print media coverage of an environmental controversy, this article aims to assess the status of transparency in China's environmental governance. The case study is based on a landmark January 2000 event in relation to the Nanjiang Industrial Park in Sihui, a county city located in the Pearl River Delta region of Guangdong Province. The findings of the case study send discordant and mixed signals, showing that transparency in the process of China's environmental governance is vulnerable to the extramedia factor—government control of information and the prior consideration of economic imperatives. Although substantial progress has been made in terms of increasing the degree of transparency in environmental protection work, administrative practices have simultaneously enriched the government's experience in the control of information for governance in the environmental arena, thus presenting an ongoing paradox.