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51.
Kai T. Lohbeck Ulf Riebesell Sinéad Collins Thorsten B. H. Reusch 《Evolution; international journal of organic evolution》2013,67(7):1892-1900
Predicting the impacts of environmental change on marine organisms, food webs, and biogeochemical cycles presently relies almost exclusively on short‐term physiological studies, while the possibility of adaptive evolution is often ignored. Here, we assess adaptive evolution in the coccolithophore Emiliania huxleyi, a well‐established model species in biological oceanography, in response to ocean acidification. We previously demonstrated that this globally important marine phytoplankton species adapts within 500 generations to elevated CO2. After 750 and 1000 generations, no further fitness increase occurred, and we observed phenotypic convergence between replicate populations. We then exposed adapted populations to two novel environments to investigate whether or not the underlying basis for high CO2‐adaptation involves functional genetic divergence, assuming that different novel mutations become apparent via divergent pleiotropic effects. The novel environment “high light” did not reveal such genetic divergence whereas growth in a low‐salinity environment revealed strong pleiotropic effects in high CO2 adapted populations, indicating divergent genetic bases for adaptation to high CO2. This suggests that pleiotropy plays an important role in adaptation of natural E. huxleyi populations to ocean acidification. Our study highlights the potential mutual benefits for oceanography and evolutionary biology of using ecologically important marine phytoplankton for microbial evolution experiments. 相似文献
52.
François Bilodeau Murray D. Bailey Punit K. Bhardwaj Josée Bordeleau Pat Forgione Michel Garneau Elise Ghiro Vida Gorys Ted Halmos Eric S. Jolicoeur Mélissa Leblanc Christopher T. Lemke Julie Naud Jeff O’Meara Peter W. White Montse Llinàs-Brunet 《Bioorganic & medicinal chemistry letters》2013,23(14):4267-4271
In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported. 相似文献
53.
The response regulator/histidine kinase pair LiaRS of Bacillus subtilis, together with its membrane‐bound inhibitor protein LiaF, constitutes an envelope stress‐sensing module that is conserved in Firmicutes bacteria. LiaR positively autoregulates the expression of the liaIH‐liaGFSR operon from a strictly LiaR‐dependent promoter (PliaI). A comprehensive perturbation analysis revealed that the functionality of the LiaFSR system is very susceptible to alterations of its protein composition and amounts. A genetic analysis indicates a LiaF:LiaS:LiaR ratio of 18:4:1. An excess of LiaS over LiaR was subsequently verified by quantitative Western analysis. This stoichiometry, which is crucial to maintain a functional Lia system, differs from any other two‐component system studied to date, in which the response regulator is present in excess over the histidine kinase. Moreover, we demonstrate that LiaS is a bifunctional histidine kinase that acts as a phosphatase on LiaR in the absence of a suitable stimulus. An increased amount of LiaR – both in the presence and in the absence of LiaS – leads to a strong induction of PliaI activity due to phosphorylation of the response regulator by acetyl phosphate. Our data demonstrate that LiaRS, in contrast to other two‐component systems, is non‐robust with regard to perturbations of its stoichiometry. 相似文献
54.
Erawan Borkham-Kamphorst Eddy van de Leur Henning W. Zimmermann Karlin Raja Karlmark Lidia Tihaa Ute Haas Frank Tacke Thorsten Berger Tak W. Mak Ralf Weiskirchen 《生物化学与生物物理学报:疾病的分子基础》2013,1832(5):660-673
Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury induces rapid and sustained LCN2 production by injured hepatocytes. However, the precise biological function of LCN2 in liver is still unknown. In this study, LCN2?/? mice were exposed to short term application of CCl4, lipopolysaccharide and Concanavalin A, or subjected to bile duct ligation. Subsequent injuries were assessed by liver function analysis, qRT-PCR for chemokine and cytokine expression, liver tissue Western blot, histology and TUNEL assay. Serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Acute CCl4 intoxication showed increased liver damage in LCN2?/? mice indicated by higher levels of aminotransferases, and increased expression of inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1/CCL2, resulting in sustained activation of STAT1, STAT3 and JNK pathways. Hepatocytes of LCN2?/? mice showed lipid droplet accumulation and increased apoptosis. Hepatocyte apoptosis was confirmed in the Concanavalin A and lipopolysaccharide models. In chronic models (4 weeks bile duct ligation or 8 weeks CCl4 application), LCN2?/? mice showed slightly increased fibrosis compared to controls. Interestingly, serum LCN2 levels in diseased human livers were significantly higher compared to controls, but no differences were observed between cirrhotic and non-cirrhotic patients. Upregulation of LCN2 is a reliable indicator of liver damage and has significant hepato-protective effect in acute liver injury. LCN2 levels provide no correlation to the degree of liver fibrosis but show significant positive correlation to inflammation instead. 相似文献
55.
Oleg Timofeev Katharina Schlereth Michael Wanzel Attila Braun Bernhard Nieswandt Axel Pagenstecher Andreas Rosenwald Hans-Peter Elsässer Thorsten Stiewe 《Cell reports》2013,3(5):1512-1525
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56.
Background
Two-component signal transduction systems are one means of bacteria to respond to external stimuli. The LiaFSR two-component system of Bacillus subtilis consists of a regular two-component system LiaRS comprising the core Histidine Kinase (HK) LiaS and the Response Regulator (RR) LiaR and additionally the accessory protein LiaF, which acts as a negative regulator of LiaRS-dependent signal transduction. The complete LiaFSR system was shown to respond to various peptide antibiotics interfering with cell wall biosynthesis, including bacitracin.Methodology and Principal Findings
Here we study the response of the LiaFSR system to various concentrations of the peptide antibiotic bacitracin. Using quantitative fluorescence microscopy, we performed a whole population study analyzed on the single cell level. We investigated switching from the non-induced ‘OFF’ state into the bacitracin-induced ‘ON’ state by monitoring gene expression of a fluorescent reporter from the RR-regulated liaI promoter. We found that switching into the ‘ON’ state occurred within less than 20 min in a well-defined switching window, independent of the bacitracin concentration. The switching rate and the basal expression rate decreased at low bacitracin concentrations, establishing clear heterogeneity 60 min after bacitracin induction. Finally, we performed time-lapse microscopy of single cells confirming the quantitative response as obtained in the whole population analysis for high bacitracin concentrations.Conclusion
The LiaFSR system exhibits an immediate, heterogeneous and graded response to the inducer bacitracin in the exponential growth phase. 相似文献57.
Thorsten M. Leucker Zhi-Dong Ge Jesse Procknow Yanan Liu Yang Shi Martin Bienengraeber David C. Warltier Judy R. Kersten 《PloS one》2013,8(7)
Endothelial-myocardial interactions may be critically important for ischemia/reperfusion injury. Tetrahydrobiopterin (BH4) is a required cofactor for nitric oxide (NO) production by endothelial NO synthase (eNOS). Hyperglycemia (HG) leads to significant increases in oxidative stress, oxidizing BH4 to enzymatically incompetent dihydrobiopterin. How alterations in endothelial BH4 content impact myocardial ischemia/reperfusion injury remains elusive. The aim of this study was to examine the effect of endothelial-myocardial interaction on ischemia/reperfusion injury, with an emphasis on the role of endothelial BH4 content. Langendorff-perfused mouse hearts were treated by triton X-100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion. The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X-100 treated hearts compared with vehicle-treated hearts. Cardiomyocytes (CMs) were co-cultured with endothelial cells (ECs) and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation. Addition of ECs to CMs at a ratio of 1∶3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone. This EC-derived protection was abolished by HG. The addition of 100 µM sepiapterin (a BH4 precursor) or overexpression of GTP cyclohydrolase 1 (the rate-limiting enzyme for BH4 biosynthesis) in ECs by gene trasfer enhanced endothelial BH4 levels, the ratio of eNOS dimer/monomer, eNOS phosphorylation, and NO production and decreased lactate dehydrogenase activity in the presence of HG. These results demonstrate that increased BH4 content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia/reoxygenation in the presence of HG. Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia/reoxygenation injury. 相似文献
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59.
Erroneous behavior usually elicits a distinct pattern in neural waveforms. In particular, inspection of the concurrent recorded electroencephalograms (EEG) typically reveals a negative potential at fronto-central electrodes shortly following a response error (Ne or ERN) as well as an error-awareness-related positivity (Pe). Seemingly, the brain signal contains information about the occurrence of an error. Assuming a general error evaluation system, the question arises whether this information can be utilized in order to classify behavioral performance within or even across different cognitive tasks. In the present study, a machine learning approach was employed to investigate the outlined issue. Ne as well as Pe were extracted from the single-trial EEG signals of participants conducting a flanker and a mental rotation task and subjected to a machine learning classification scheme (via a support vector machine, SVM). Overall, individual performance in the flanker task was classified more accurately, with accuracy rates of above 85%. Most importantly, it was even feasible to classify responses across both tasks. In particular, an SVM trained on the flanker task could identify erroneous behavior with almost 70% accuracy in the EEG data recorded during the rotation task, and vice versa. Summed up, we replicate that the response-related EEG signal can be used to identify erroneous behavior within a particular task. Going beyond this, it was possible to classify response types across functionally different tasks. Therefore, the outlined methodological approach appears promising with respect to future applications. 相似文献
60.
Maria Guschlbauer Alexandra C. Maul Xiaowei Yan Holger Herff Thorsten Annecke Anja Sterner-Kock Bernd W. B?ttiger Daniel C. Schroeder 《PloS one》2016,11(3)
Hypothermia is a severe, unpleasant side effect during general anesthesia. Thus, temperature surveillance is a prerequisite in general anesthesia settings during experimental surgeries. The gold standard to measure the core body temperature (Tcore) is placement of a Swan-Ganz catheter in the pulmonary artery, which is a highly invasive procedure. Therefore, Tcore is commonly examined in the urine bladder and rectum. However, these procedures are known for their inaccuracy and delayed record of temperatures. Zero-heat-flux (ZHF) thermometry is an alternative, non-invasive method quantifying Tcore in human patients by applying a thermosensoric patch to the lateral forehead. Since the porcine cranial anatomy is different to the human’s, the optimal location of the patch remains unclear to date. The aim was to compare three different patch locations of ZHF thermometry in a porcine hypothermia model. Hypothermia (33.0°C Tcore) was conducted in 11 anesthetized female pigs (26-30kg). Tcore was measured continuously by an invasive Swan-Ganz catheter in the pulmonary artery (Tpulm). A ZHF thermometry device was mounted on three different defined locations. The smallest average difference between Tpulm and TZHF during stable temperatures was 0.21 ± 0.16°C at location A, where the patch was placed directly behind the eye. Also during rapidly changing temperatures location A showed the smallest bias with 0.48 ± 0.29°C. Location A provided the most reliable data for Tcore. Therefore, the ZHF thermometry patch should be placed directly behind the left temporal corner of the eye to provide a non-invasive method for accurate measurement of Tcore in pigs. 相似文献