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Q Yu, L Li, N Zhao
OBJECTIVE: To investigate the correlation between three-dimensional echocardiography and the expressions of hypoxia-inducible factor-1 alpha (HIF-1α), heme oxygenase 1 (HO-1) and vascular endothelial growth factor (VEGF) in patients with myocardial infarction. PATIENTS AND METHODS: A total of 40 patients with acute myocardial infarction treated with three-dimensional echocardiography and 40 patients receiving normal physical examination were selected. According to whether the disease occurred, they were divided into the myocardial infarction group and the normal group...
May 2018: European Review for Medical and Pharmacological Sciences
Charuta C Palsuledesai, Zurab Surviladze, Anna Waller, T Fabiola Miscioscia, Yuna Guo, Yang Wu, Jake Strouse, Elsa Romero, Virginia M Salas, Ramona Curpan, Susan Young, Mark Carter, Terry Foutz, Zhanna Galochkina, Harold Ames, Mark K Haynes, Bruce S Edwards, Orazio Nicolotti, Li Luo, Oleg Ursu, Cristian G Bologa, Tudor I Oprea, Angela Wandinger-Ness, Larry A Sklar
Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characterization of small molecule agonists of one or more of six Rho, Rab and Ras family GTPases that were first identified through flow cytometry based, multi-plexed high throughput screening of 200,000 compounds. The activators were categorized into three distinct chemical families that are represented by three lead compounds having the highest activity...
May 10, 2018: ACS Chemical Biology
Wenwu Zhang, Bhupal P Bhetwal, Susan J Gunst
KEY POINTS: The mechanisms by which Rho kinase (ROCK) regulates airway smooth muscle contraction were determined in tracheal smooth muscle tissues. ROCK may mediate smooth muscle contraction by inhibiting myosin regulatory light chain (RLC) phosphatase. ROCK can also regulate F-actin dynamics during cell migration, and actin polymerization is critical for airway smooth muscle contraction. Our results show that ROCK does not regulate airway smooth muscle contraction by inhibiting myosin RLC phosphatase or by stimulating myosin RLC phosphorylation...
May 10, 2018: Journal of Physiology
Mugdha Sathe, Gayatri Muthukrishnan, James Rae, Andrea Disanza, Mukund Thattai, Giorgio Scita, Robert G Parton, Satyajit Mayor
Using real-time TIRF microscopy imaging, we identify sites of clathrin and dynamin-independent CLIC/GEEC (CG) endocytic vesicle formation. This allows spatio-temporal localisation of known molecules affecting CG endocytosis; GBF1 (a GEF for ARF1), ARF1 and CDC42 which appear sequentially over 60 s, preceding scission. In an RNAi screen for BAR domain proteins affecting CG endocytosis, IRSp53 and PICK1, known interactors of CDC42 and ARF1, respectively, were selected. Removal of IRSp53, a negative curvature sensing protein, abolishes CG endocytosis...
May 9, 2018: Nature Communications
Nitchakan Nakwan, Ply Chichareon, Bodin Khwannimit
The aim of this study was to compare the cardiac function index (CFI) and global ejection fraction (GEF) obtained by VolumeView/EV1000™, with the left ventricular ejection fraction (LVEF) by echocardiography in septic shock patients. A prospective observational study was conducted in a medical intensive care unit of a tertiary, teaching university hospital. Thirty-two, mechanical-ventilated septic shock patients were included in this study. We simultaneously measured CFI and GEF with LVEF. The correlation of CFI, GEF along with LVEF and ability of CFI and GEF to predict LVEF ≥ 40, 50 and 60% were evaluated...
May 8, 2018: Journal of Clinical Monitoring and Computing
Christin Hanke-Gogokhia, Jeanne M Frederick, Houbin Zhang, Wolfgang Baehr
UNC119 and PDEδ are lipid-binding proteins and are thought to form diffusible complexes with transducin-α and prenylated OS proteins, respectively, to mediate their trafficking to photoreceptor outer segments. Here, we investigate mechanisms of trafficking which are controlled by Arf-like protein 3 (Arl3), a small GTPase. The activity of ARL3 is regulated by a GEF (ARL13b) and a GAP (RP2). In a mouse germline knockout of RP2, ARL3-GTP is abundant as its intrinsic GTPase activity is extremely low. High levels of ARL3-GTP impair binding and trafficking of cargo to the outer segment...
2018: Advances in Experimental Medicine and Biology
Xuelian Chen, Qin Wen, Andres Stucky, Yunjing Zeng, Shengjia Gao, William G Loudon, Hector W Ho, Mustafa H Kabeer, Shengwen Calvin Li, Xi Zhang, Jiang F Zhong
Glioblastoma multiforme (GBM) remains an incurable brain tumor. The highly malignant behavior of GBM may, in part, be attributed to its intraclonal genetic and phenotypic diversity (subclonal evolution). Identifying the molecular pathways driving GBM relapse may provide novel, actionable targets for personalized diagnosis, characterization of prognosis and improvement of precision therapy. We screened single-cell transcriptomes, namely RNA-seq data of primary and relapsed GBM tumors from a patient, to define the molecular profile of relapse...
April 28, 2018: Carcinogenesis
Alain-Pierre Petit, Christel Garcia-Petit, Juan A Bueren-Calabuig, Laurent M Vuillard, Gilles Ferry, Jean A Boutin
The GTPase RhoA is a major player in many different regulatory pathways. RhoA catalyzes GTP hydrolysis, and its catalysis is accelerated when RhoA forms heterodimers with proteins of the guanine nucleotide exchange factor (GEF) family. Neuroepithelial cell transforming 1 (Net1) is a RhoA-interacting GEF implicated in cancer, but the structural features supporting the RhoA/Net1 interaction are unknown. Taking advantage of a simple production and purification process, here we solved the structure of a RhoA/Net1 heterodimer with X-ray crystallography at 2 Å resolution...
April 25, 2018: Journal of Biological Chemistry
Zixing Li, Yohei Takahashi, Alexander Scavo, Benjamin Brandt, Desiree Nguyen, Philippe Rieu, Julian I Schroeder
Abscisic acid (ABA) plays essential roles in plant development and responses to environmental stress. ABA induces subcellular translocation and degradation of the guanine nucleotide exchange factor RopGEF1, thus facilitating ABA core signal transduction. However, the underlying mechanisms for ABA-triggered RopGEF1 trafficking/degradation remain unknown. Studies have revealed that RopGEFs associate with receptor-like kinases to convey developmental signals to small ROP GTPases. However, how the activities of RopGEFs are modulated is not well understood...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Chiara Pantarelli, Heidi C E Welch
Rac-GTPases and their Rac-GEF activators play important roles in the recruitment and host defense functions of neutrophils. These proteins control the activation of adhesion molecules and the cytoskeletal dynamics that enable the adhesion, migration and tissue recruitment of neutrophils. They also regulate the effector functions that allow neutrophils to kill bacterial and fungal pathogens, and to clear debris. This review focusses on the roles of Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment...
April 23, 2018: European Journal of Clinical Investigation
Cornelis Tm van Houwelingen, Roelof Ga Ettema, Michelangelo Gef Antonietti, Helianthe Sm Kort
BACKGROUND: The Dutch Ministry of Health has formulated ambitious goals concerning the use of telehealth, leading to subsequent changes compared with the current health care situation, in which 93% of care is delivered face-to-face. Since most care is delivered to older people, the prospect of telehealth raises the question of whether this population is ready for this new way of receiving care. To study this, we created a theoretical framework consisting of 6 factors associated with older people's intention to use technology...
April 6, 2018: Journal of Medical Internet Research
Aaron A Cook, Wei Deng, Jinqi Ren, Renhao Li, John Sondek, Wolfgang Bergmeier
Platelets are recruited to sites of vascular injury where they are activated and aggregate to form a hemostatic plug. This process requires the activation of the small GTPase Rap1B by its cognate guanine nucleotide exchange factor CalDAG-GEFI. Studies on platelet function suggest that CalDAG-GEFI activity is regulated by changes in cytosolic calcium, but the exact molecular mechanism is poorly understood. Here, we show that purified CalDAG-GEFI is autoinhibited and directly regulated by calcium. Substitutions of putative calcium-binding residues within the canonical EF hands of CalDAG-GEFI diminish its capacity to activate Rap1B...
April 5, 2018: Journal of Biological Chemistry
Xiumin Chen, Yanhua Qu, Yalin Cheng, Jing Wang, Xiaohua Lei, Gang Song, Huishan Zhang, Haitao Wang, Fumin Lei
BACKGROUND/AIMS: Genomic adaptations to high altitudes have been well studied in the last several years; however, the roles of microRNAs (miRNAs), which are essential modulators of a variety of genes and key cellular processes, have rarely been explored. Here, we explored the interactions between miRNAs and their target genes as an adaptation to high altitude in an avian species, the great tit (Parus major), which is widely distributed across the Eurasian continent at altitudes between 4500 m and sea level...
March 28, 2018: Cellular Physiology and Biochemistry
Wen Li, Ka Ming Vincent Tam, Wai Wan Ray Chan, Alex Chun Koon, Jacky Chi Ki Ngo, Ho Yin Edwin Chan, Kwok-Fai Lau
Neurite outgrowth is a crucial process in developing neurons for neural network formation. Understanding the regulatory mechanisms of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration after nerve injury and in neurodegenerative disorders. FE65 is a brain-enriched adaptor that stimulates Rac1-mediated neurite elongation. However, the precise mechanism by which FE65 promotes the process remains elusive. Here, we show that ELMO1, a subunit of ELMO1-DOCK180 bipartite Rac1 GEF, interacts with the FE65 N-terminal region...
April 3, 2018: Journal of Biological Chemistry
Zhao-Zhong Feng, An-Jie Jiang, An-Wen Mao, Yuhan Feng, Weinan Wang, Jingjing Li, Xiaoyan Zhang, Ke Xing, Xue Peng
In mammalian cells, autophagy plays crucial roles in restricting further spread of invading bacterial pathogens. Previous studies have established that the Salmonella virulence factors SseF and SseG are required for intracellular bacterial survival and replication. However, the underlying mechanism by which these two effectors facilitate bacterial infection remains elusive. Here, we report that SseF and SseG secreted by Salmonella Typhimurium (S. Typhimurium) inhibit autophagy in host cells and thereby establish a replicative niche for the bacteria in the cytosol...
April 2, 2018: Journal of Biological Chemistry
Pradeep Bandaru, Yasushi Kondo, John Kuriyan
The guanine-nucleotide exchange factor (GEF) Son-of-Sevenless (SOS) plays a critical role in metazoan signaling by converting Ras•GDP (guanosine diphosphate) to Ras•GTP (guanosine triphosphate) in response to tyrosine kinase activation. Structural studies have shown that SOS differs from other Ras-specific GEFs in that SOS is itself activated by Ras•GTP binding to an allosteric site, distal to the site of nucleotide exchange. The activation of SOS involves membrane recruitment and conformational changes, triggered by lipid binding, that open the allosteric binding site for Ras•GTP...
April 2, 2018: Cold Spring Harbor Perspectives in Medicine
Xiaowei Li, Mingzuo Jiang, Di Chen, Bing Xu, Rui Wang, Yi Chu, Weijie Wang, Lin Zhou, Zhijie Lei, Yongzhan Nie, Daiming Fan, Yulong Shang, Kaichun Wu, Jie Liang
BACKGROUND: Our previous work showed that some Rho GTPases, including Rho, Rac1 and Cdc42, play critical roles in gastric cancer (GC); however, how they are regulated in GC remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of Dock6, an atypical Rho guanine nucleotide exchange factor (GEF), in GC metastasis. METHODS: The expression levels of Dock6 and miR-148b-3p in GC tissues and paired nontumor tissues were determined by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively...
March 27, 2018: Journal of Experimental & Clinical Cancer Research: CR
Orsolya Dömötör, Karla Pelivan, Attila Borics, Bernhard K Keppler, Christian R Kowol, Éva A Enyedy
Binding interactions between human serum albumin (HSA) and four approved epidermal growth factor receptor (EGFR) inhibitors gefitinib (GEF), erlotinib (ERL), afatinib (AFA), osimertinib (OSI), as well as the experimental drug KP2187, were investigated by means of spectrofluorometric and molecular modelling methods. Steady-state and time resolved spectrofluorometric techniques were carried out, including direct quenching of protein fluorescence and site marker displacement measurements. Proton dissociation processes and solvent dependent fluorescence properties were investigated as well...
March 11, 2018: Journal of Pharmaceutical and Biomedical Analysis
Dan Chen, Chao Yang, Sha Liu, Weijian Hang, Xianghong Wang, Juan Chen, Anbing Shi
Arf6/ARF-6 is a crucial regulator of the endosomal phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) pool in endocytic recycling. To further characterize ARF-6 regulation, we performed an ARF-6 interactor screen in Caenorhabditis elegans and identified SAC-1, the homologue of the phosphoinositide phosphatase Sac1p in yeast, as a novel ARF-6 partner. In the absence of ARF-6, basolateral endosomes show a loss of SAC-1 staining in epithelial cells. Steady-state cargo distribution assays revealed that loss of SAC-1 specifically affected apical secretory delivery and basolateral recycling...
March 21, 2018: Journal of Cell Biology
Teklab Gebregiworgis, Christopher B Marshall, Tadateru Nishikawa, Nikolina Radulovich, María-José Sandí, Zhenhao Fang, Robert Rottapel, Ming-Sound Tsao, Mitsuhiko Ikura
Small GTPases (sGTPases) are critical switch-like regulators that mediate several important cellular functions and are often mutated in human cancers. They are activated by guanine nucleotide exchange factors (GEFs), which specifically catalyze the exchange of GTP for GDP. GEFs coordinate signaling networks in normal cells, and are frequently deregulated in cancers. sGTPase signaling pathways are complex and interconnected; however, most GEF assays do not reveal such complexity. In this Communication, we describe the development of a unique real-time NMR-based multiplexed GEF assay that employs distinct isotopic labeling schemes for each sGTPase protein to enable simultaneous observation of six proteins of interest...
April 4, 2018: Journal of the American Chemical Society
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