The emerging role of Arf/Arl small GTPases in cilia and ciliopathies

Once overlooked as an evolutionary vestige, the primary cilium has recently been the focus of intensive studies. Mounting data show that this organelle is a hub for various signaling pathways during vertebrate embryonic development and pattern formation. However, how cilia form and how cilia execute the sensory function still remain poorly understood. Cilia dysfunction is correlated with a wide spectrum of human diseases, now termed ciliopathies. Various small GTPases, including the members in Arf/Arl, Rab, and Ran subfamilies, have been implicated in cilia formation and/or function. Here we review and discuss the role of one particular group of small GTPase, Arf/Arl, in the context of cilia and ciliopathy.     

Human apolipoprotein L1 (ApoL1) in cancer and chronic kidney disease

Human apolipoprotein L1 (ApoL1) possesses both extra- and intra-cellular functions crucial in host defense and cellular homeostatic mechanisms. Alterations in ApoL1 function due to genetic, environmental, and lifestyle factors have been associated with African sleeping sickness, atherosclerosis, lipid disorders, obesity, schizophrenia, cancer, and chronic kidney disease (CKD). Importantly, two alleles of APOL1 carrying three coding-sequence variants have been linked to CKD, particularly in Sub-Saharan Africans and African Americans. Intracellularly, elevated ApoL1 can induce autophagy and autophagy-associated cell death, which may be critical in the maintenance of cellular homeostasis in the kidney. Similarly, ApoL1 may protect kidney cells against renal cell carcinoma (RCC). We summarize the role of ApoL1 in RCC and CKD, highlighting the critical function of ApoL1 in autophagy.     

Design, synthesis and biological evaluation of novel acrylamide analogues as inhibitors of BCR-ABL kinase

A series of acrylamide analogues were designed and synthesized from Imatinib and Nilotinib as novel BCR-ABL inhibitors by application of the principle of nonclassical electronic isostere. All new compounds were evaluated for their inhibitory effects on the activity of BCR-ABL kinase and the proliferation of K562 leukemia cancer cells in vitro. The acrylamide analogues in which the substituent in C ring was trifluoromethyl group were identified as highly potent BCR-ABL kinase inhibitors. Compound 13f exhibited an IC(50) value as low as 20.6nM in ABL kinase inhibition and an IC(50) value of 32.3nM for antiproliferative activity, about 10.5-fold and 12-fold lower than those of Imatinib respectively. These results suggest that compound 13f is a promising candidate as a novel BCR-ABL kinase inhibitor for further development.     

The p53-Bak Apoptotic Signaling Axis Plays an Essential Role in Regulating Differentiation of the Ocular Lens

The tumor suppressor p53 is a master regulator of apoptosis and also plays a key role in cell cycle checking. In our previous studies, we demonstrated that p53 directly regulates Bak in mouse JB6 cells (Qin et al. 2008. Cancer Research. 68(11):4150) and that p53-Bak signaling axis plays an important role in mediating EGCG-induced apoptosis. Here, we demonstrate that the same p53-Bak apoptotic signaling axis executes an essential role in regulating lens cell differentiation. First, during mouse lens development, p53 is expressed and differentially phosphorylated at different residues. Associated with p53 expression, Bak is also significantly expressed during mouse lens development. Second, human p53 directly regulates Bak promoter and Bak expression in p53 knockout mice (p53-/-) was significantly downregulated. Third, during in vitro bFGF-induced lens cell differentiation, knockdown of p53 or Bak leads to significant inhibition of lens cell differentiation. Fourth, besides the major distribution of Bak in cytoplasm, it is also localized in the nucleus in normal lens or bFGF-induced differentiating lens cells. Finally, p53 and Bak are co-localized in both cytoplasm and nucleus, and their interaction regulates the stability of p53. Together, these results demonstrate for the first time that the p53-Bak apoptotic signaling axis plays an essential role in regulating lens differentiation.     

A high sensitivity iron-dependent bioreporter used to measure iron bioavailability in freshwaters

A Nostoc sp. PCC 7120 iron bioreporter containing iron-regulated schizokinen transporter gene alr0397 promoter fused to the luxAB genes was examined to optimize its response to bioavailable iron. Dose-response relationships between luciferase activity and free ferric ion (Fe(3+) ) concentrations pFe (-lg [Fe(3+) ]) were generated by measuring luciferase activities of the bioreporter in trace metal-buffered Fraquil medium with various incubation times. The results were best demonstrated by sigmoidal curves (pFe 18.8-21.7, Fe(3+) =?10(-18.8) -10(-21.7) M) with the linear range extending from pFe 19.6-21.5 (Fe(3+) =?10(-19.6) -10(-21.5) M) after a 12-h incubation time. Optimal conditions for the use of this bioreporter to sense the iron bioavailability were determined to be: a 12-h exposure time, initial cell density of OD(730?nm) =?0.06, high nitrate (100?μM), high phosphate (10?μM), moderate Co(2+) (0.1-22.5?nM), Zn(2+) (0.16-12?nM), Cu(2+) (0.04-50?nM), and wide range of Mn(2+) concentration (0.92-2300?nM). The applicability of using this iron bioreporter to assess iron availability in the natural environment has been tested using water samples from eutrophic Taihu, Donghu, and Chaohu lakes. It is indicated that the bioreporter is a useful tool to assess bioavailable iron in various water quality samples, especially in eutrophic lakes with high bioavailable iron.     

An acoustic glucose sensor

In vivo glucose monitoring is required for tighter glycaemic control. This report describes a new approach to construct a miniature implantable device based on a magnetic acoustic resonance sensor (MARS). A ≈ 600-800 nm thick glucose-responsive poly(acrylamide-co-3-acrylamidophenylboronic acid) (poly(acrylamide-co-3-APB)) film was polymerised on the quartz disc (12 mm in diameter and 0.25 mm thick) of the MARS. The swelling/shrinking of the polymer film induced by the glucose binding to the phenylboronate caused changes in the resonance amplitude of the quartz disc in the MARS. A linear relationship between the response of the MARS and the glucose concentration in the range ≈ 0-15 mM was observed, with the optimum response of the MARS sensor being obtained when the polymer films contained ≈ 20 mol% 3-APB. The MARS glucose sensor also functioned under flow conditions (9 μl/min) with a response almost identical to the sensor under static or non-flow conditions. The results suggest that the MARS could offer a promising strategy for developing a small subcutaneously implanted continuous glucose monitor.     

Decreased tumstatin-mRNA is associated with poor outcome in patients with NSCLC

Tumstatin is a candidate tumor suppressor that plays an important role in tumor growth and angiogenesis. The purpose of this study was to evaluate the correlation between tumstatin-mRNA expression and the clinicopathologic characteristics, tumor angiogenesis, outcome of patients with non-small cell lung cancer (NSCLC). Specimens from 68 patients with NSCLC were recruited in this study. Tumstatin-mRNA expression and protein level in tumor tissues were quantified respectively by quantitative RT-PCR and ELISA. Microvessel density (MVD) was determined by CD34 immunostaining. The correlation of tumstatin-mRNA expression levels with clinicopathologic variables, tumor angiogenesis, and prognosis was analyzed. Tumstatin-mRNA expression levels were decreased in tumor. Tumstatin-mRNA expression level was significantly correlated with its protein level in tumor (r = 0.562; P = 0.001). Tumstatin-mRNA expression levels in poorly differentiated tumor tissues were significantly lower than in well-differentiated tumor tissues (P < 0.004). Furthermore, tumor tumstatin-mRNA expression were also significantly related to tumor pathologic stage (P = 0.032) and MVD (r = -0.77, P < 0.0001). Overall survival (OS) and disease-free survival (DFS) analysis indicated that NSCLC patients with low tumstatin-mRNA expression had poorer OS and DFS than those with high expression (P = 0.015 and 0.037; respectively). Multivariable Cox regression analysis revealed that the tumstatin-mRNA expression could be an independent prognostic indicators in both DFS and OS. Tumstatin-mRNA expression levels are down-regulated in NSCLC tissues. Tumstatin-mRNA expression level correlates with prognosis, which suggests that tumstatin-mRNA is a new potential independent marker of favorable prognosis in NSCLC.     

Trophic status determines the nirS-denitrifier community in shallow freshwater lakes

To explore whether trophic status is involved in identifying the denitrifier communities in shallow freshwater lakes, comparative studies regarding the variation of nirS-denitrifier communities were performed in water columns of six shallow freshwater lakes, ranging from mesotrophic to hypereutrophic status, in Jiangsu province of China. Restriction fragment length polymorphism (RFLP) analysis and cloning, followed by sequence analysis of selected samples were performed to examine the nirS-denitrifier communities. Results showed that a same predominant nirS unique operational taxonomic unit (OTU) appeared in mesotrophic, light eutrophic and middle eutrophic lakes, while a different nirS OTU appeared in the hypereutrophic lake. The nirS dendrogram could be divided into four clusters, and suggested a habitat-specific observation. The nirS libraries from lakes having mesotrophic and light eutrophic statuses grouped together, while those from lakes having middle eutrophic and hypereutrophic statuses diverged. The hypereutrophic lake had the lowest richness and evenness of nirS. Thus, the observed variation of nirS distribution and diversity was mainly affected by the trophic status, via some environmental factors such as pH, dissolved oxygen, nitrite, nitrate and chlorophyll-a concentrations.     

多情景式模拟教学在人际沟通双语实践课的应用

目的:探讨多情景式模拟教学在护理人际沟通双语实践课的应用。方法:采用不对等对照组组间设计方法,2011级全日制护理专业本科78名学生为对照组,2012级全日制护理专业本科生72名为实验组,在相同《护理人际沟通》双语理论教学的基础上,对照组进行常规实践教学;实验组应用多情景式的模拟教学。结果:对照组实践成绩为35.02±18.44,实验组实践成绩为40.27±12.61,实验组实践课成绩高于对照组,有统计学意义(P0.05)。结论:将多情景式的模拟教学应用于《护理人际沟通》双语课程的实践教学,有助于提升英语水平,建立团队协作意识,学会合理利用沟通技巧处理不同情景中的人际矛盾,更能够提高护理人际沟通教学质量,为人际沟通课程改革提供指导。     

MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling

Accumulating evidences have proved that dysregulation of microRNAs (miRNAs) is involved in cancer initiation and progression. In this study, we showed that miRNA-145 level was significantly decreased in hepatocellular cancer (HCC) tissues and cell lines, and its low expression was inversely associated with the abundance of insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling. We verified IRS1 as a direct target of miR-145 using Western blotting and luciferase reporter assay. Further, the restoration of miR-145 in HCC cell lines suppressed cancer cell growth, owing to down-regulated IRS1 expression and its downstream Akt/FOXO1 signaling. Our results demonstrated that miR-145 could inhibit HCC through targeting IRS1 and its downstream signaling, implicating the loss of miR-145 regulation may be a potential molecular mechanism causing aberrant oncogenic signaling in HCC.