Effects of cadmium and phenanthrene mixtures on aquatic fungi and microbially mediated leaf litter decomposition

This version does not correspond to the published one. To access the final version go to: http://www.springerlink.com/content/t8t302617003m078/Urbanization and industrial activities have contributed to widespread contamination by metals and polycyclic aromatic hydrocarbons, but the combined effects of these toxics on aquatic biota and processes are poorly understood. We examined the effects of cadmium (Cd) and phenanthrene on the activity and diversity of fungi associated with decomposing leaf litter in streams. Leaves of Alnus glutinosa were immersed for 10 days in an unpolluted low-order stream in northwest Portugal to allow microbial colonization. Leaves were then exposed in microcosms for 14 days to Cd (0.06–4.5 mg L−1) and phenanthrene (0.2 mg L−1) either alone or in mixture. A total of 19 aquatic hyphomycete species were found sporulating on leaves during the whole study. The dominant species was Articulospora tetracladia, followed by Alatospora pulchella, Clavatospora longibrachiata, and Tetrachaetum elegans. Exposure to Cd and phenanthrene decreased the contribution of A. tetracladia to the total conidial production, whereas it increased that of A. pulchella. Fungal diversity, assessed as denaturing gradient gel electrophoresis fingerprinting or conidial morphology, was decreased by the exposure to Cd and/or phenanthrene. Moreover, increased Cd concentrations decreased leaf decomposition and fungal reproduction but did not inhibit fungal biomass production. Exposure to phenanthrene potentiated the negative effects of Cd on fungal diversity and activity, suggesting that the co-occurrence of these stressors may pose additional risk to aquatic biodiversity and stream ecosystem functioning.The Portuguese Foundation for the Science and Technology supported this work (POCI/MAR/56964/2004) and S. Duarte (SFRH/BPD/47574/2008

Phase I, Single-Dose Study to Assess the Pharmacokinetics and Safety of Suramin in Healthy Chinese Volunteers

Guolan Wu,1– 3 Huili Zhou,1,2 Duo Lv,1,2 Ruling Zheng,4 Lihua Wu,1 Songxia Yu,1,2 Jiejing Kai,1,2 Nana Xu,1,2 Lie Gu,5 Nanfang Hong,5 Jianzhong Shentu1,2 1Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Polytechnic Institute, Zhejiang University, Hangzhou, People’s Republic of China; 4The Fifth Affiliated Hospital, College of Medicine, Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Hainan Honz Pharmaceutical Co. Ltd, Haikou, Hainan, People’s Republic of ChinaCorrespondence: Jianzhong Shentu, Email [email protected]: Suramin is a multifunctional molecule with a wide range of potential applications, including parasitic and viral diseases, as well as cancer.Methods: A double-blinded, randomized, placebo-controlled single ascending dose study was conducted to investigate the safety, tolerability, and pharmacokinetics of suramin in healthy Chinese volunteers. A total of 36 healthy subjects were enrolled. All doses of suramin sodium and placebo were administered as a 30-minute infusion. Blood and urine samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.Results: After a single dose, suramin maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The plasma half-life (t1/2) was dose-independent, average 48 days (range 28– 105 days). The cumulative percentages of the dose excreted in urine over 7 days were less than 4%. Suramin can be detected in urine samples for longer periods (more than 140 days following infusion). Suramin was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild in severity.Conclusion: The PK and safety profiles of suramin in Chinese subjects indicated that 10 mg/kg or 15 mg/kg could be an appropriate dose in a future multiple-dose study.Keywords: suramin, clinical pharmacokinetics, antiviral, safety, drug repurposin

AMP-Activated Protein Kinase and Sirtuin 1 Coregulation of Cortactin Contributes to Endothelial Function

ObjectiveCortactin translocates to the cell periphery in vascular endothelial cells (ECs) on cortical-actin assembly in response to pulsatile shear stress. Because cortactin has putative sites for AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) deacetylation, we examined the hypothesis that AMPK and SIRT1 coregulate cortactin dynamics in response to shear stress.Approach and resultsAnalysis of the ability of AMPK to phosphorylate recombinant cortactin and oligopeptides whose sequences matched AMPK consensus sequences in cortactin pointed to Thr-401 as the site of AMPK phosphorylation. Mass spectrometry confirmed Thr-401 as the site of AMPK phosphorylation. Immunoblot analysis with AMPK siRNA and SIRT1 siRNA in human umbilical vein ECs and EC-specific AMPKα2 knockout mice showed that AMPK phosphorylation of cortactin primes SIRT1 deacetylation in response to shear stress. Immunoblot analyses with cortactin siRNA in human umbilical vein ECs, phospho-deficient T401A and phospho-mimetic T401D mutant, or aceto-deficient (9K/R) and aceto-mimetic (9K/Q) showed that cortactin regulates endothelial nitric oxide synthase activity. Confocal imaging and sucrose-density gradient analyses revealed that the phosphorylated/deacetylated cortactin translocates to the EC periphery facilitating endothelial nitric oxide synthase translocation from lipid to nonlipid raft domains. Knockdown of cortactin in vitro or genetic reduction of cortactin expression in vivo in mice substantially decreased the endothelial nitric oxide synthase-derived NO bioavailability. In vivo, atherosclerotic lesions increase in ApoE-/-/cortactin+/- mice, when compared with ApoE-/-/cortactin+/+ littermates.ConclusionsAMPK phosphorylation of cortactin followed by SIRT1 deacetylation modulates the interaction of cortactin and cortical-actin in response to shear stress. Functionally, this AMPK/SIRT1 coregulated cortactin-F-actin dynamics is required for endothelial nitric oxide synthase subcellular translocation/activation and is atheroprotective

AMP-Activated Protein Kinase and Sirtuin 1 Coregulation of Cortactin Contributes to Endothelial Function

Objective-Cortactin translocates to the cell periphery in vascular endothelial cells (ECs) on cortical-actin assembly in response to pulsatile shear stress. Because cortactin has putative sites for AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) deacetylation, we examined the hypothesis that AMPK and SIRT1 coregulate cortactin dynamics in response to shear stress. Approach and Results-Analysis of the ability of AMPK to phosphorylate recombinant cortactin and oligopeptides whose sequences matched AMPK consensus sequences in cortactin pointed to Thr-401 as the site of AMPK phosphorylation. Mass spectrometry confirmed Thr-401 as the site of AMPK phosphorylation. Immunoblot analysis with AMPK siRNA and SIRT1 siRNA in human umbilical vein ECs and EC-specific AMPK alpha 2 knockout mice showed that AMPK phosphorylation of cortactin primes SIRT1 deacetylation in response to shear stress. Immunoblot analyses with cortactin siRNA in human umbilical vein ECs, phospho-deficient T401A and phospho-mimetic T401D mutant, or aceto-deficient (9K/R) and aceto-mimetic (9K/Q) showed that cortactin regulates endothelial nitric oxide synthase activity. Confocal imaging and sucrose-density gradient analyses revealed that the phosphorylated/deacetylated cortactin translocates to the EC periphery facilitating endothelial nitric oxide synthase translocation from lipid to nonlipid raft domains. Knockdown of cortactin in vitro or genetic reduction of cortactin expression in vivo in mice substantially decreased the endothelial nitric oxide synthase-derived NO bioavailability. In vivo, atherosclerotic lesions increase in ApoE(-/-)/cortactin(+/-) mice, when compared with ApoE(-/-)/cortactin(+/+) littermates. Conclusions-AMPK phosphorylation of cortactin followed by SIRT1 deacetylation modulates the interaction of cortactin and cortical-actin in response to shear stress. Functionally, this AMPK/SIRT1 coregulated cortactin-F-actin dynamics is required for endothelial nitric oxide synthase subcellular translocation/activation and is atheroprotective.National Institutes of Health [R01HL105318, R01HL106579, R01HL108735, R01ES019873]SCI(E)[email protected]

BER Analysis of OFDM Systems Impaired by Phase Noise in Frequency-Selective Fading Channels

100學年度研究獎補助論文[[abstract]]In this paper, we study the effect of finite-power, phase-locked loop based phase noise on the bit-error-rate (BER) performance of orthogonal frequency division multiplexing (OFDM) systems in frequency-selective fading channels. It is well known the impact of phase noise on the performance of an OFDM system can be divided into a multiplicative term called common phase error (CPE) and an additive term called intercarrier interference (ICI). Based on the conditional Gaussian approximation technique, we first derive the BER formulas for BPSK, QPSK, 16-QAM, and 64-QAM modulated OFDM signals in frequency-selective Rayleigh fading channels. To further quantify the individual influence of the CPE and the ICI on system performance for different phase noise spectra, we derive the BER expressions for perfect CPE compensation cases. The analytical results obtained for frequency-selective Rayleigh fading channels are then generalized to frequency-selective Rician fading channels. Simulation results not only validate the accuracy of our analysis but also show the dependency of BERs on the shapes of phase noise spectra.[[incitationindex]]SCI[[booktype]]紙