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261.
Mounir Andaloussi Herman D. Lim Tiffany van der Meer Maarten Sijm Chris B.M. Poulie Iwan J.P. de Esch Rob Leurs Rogier A. Smits 《Bioorganic & medicinal chemistry letters》2013,23(9):2663-2670
In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H4R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease. 相似文献
262.
Andrea Egger Roland Kreis Sabin Allemann Christoph Stettler Peter Diem Tania Buehler Chris Boesch Emanuel R. Christ 《PloS one》2013,8(8)
Background
Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass).Aim
To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy.Methods
Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO2max) using 1H-MR-spectroscopy.Results
Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO2max, 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (−22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity.Conclusions
IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions.Trial Registration
ClinicalTrial.gov NCT00491582相似文献263.
Kim CB Shashikant CS Sumiyama K Wang WC Amemiya CT Ruddle FH 《Journal of structural and functional genomics》2003,3(1-4):195-199
The non-coding intergenic regions of Hox genes are remarkably conserved among mammals. To determine the usefulness of this sequence for phylogenetic comparisons, we sequenced an 800-bp fragment of the Hoxc9–Hoxc8 intergenic region from several species belonging to different mammalian clades. Results obtained from the phylogenetic analysis are congruent with currently accepted mammalian phylogeny. Additionally, we found a TC mini satellite repeat polymorphism unique to felines. This polymorphism may serve as a useful marker to differentiate between mammalian species or as a genetic marker in feline matings. This study demonstrates usefulness of a comparative approach employing non-coding regions of Hox gene complexes. 相似文献
264.
Cooper CE 《IUBMB life》2003,55(10-11):591-597
In the mid 1990s a number of research groups recognized that mitochondrial oxygen consumption could be reversibly inhibited by nitric oxide at the level of the enzyme cytochrome c oxidase. The inhibition was apparently competitive with respect to the oxygen concentration. This review critically assesses the present state of knowledge as regards the hypothesis that nitric oxide is a competitive, reversible, physiological inhibitor of cytochrome oxidase. 相似文献
265.
Richard Peagam Kirstie McIntyre Lauren Basson Chris France 《Journal of Industrial Ecology》2013,17(2):224-237
Business‐to‐business (B2B) electronics account for a significant volume of the electrical and electronic equipment (EEE) put on the market. Very little B2B waste electrical and electronic equipment (WEEE) is reported as collected in the European Union (EU) in compliance with the WEEE Directive, which uses the policy principle of extended producer responsibility (EPR) to ensure that WEEE is managed correctly. This presents a barrier to parties looking for access to the waste. Company practice dictates the channels into which B2B WEEE flows following primary use. This article presents a study that engaged with company actors directly to get a better understanding of business information technology (IT) EEE asset management. Data were collected to determine the barriers current practice could present to the collection of B2B IT EEE at end of life and the implications of these for the development of policies and strategies for EPR. A questionnaire was developed and data were gathered from organizations in three EU countries—the United Kingdom, Germany, and France—stratified by size. Some notable findings were that there are several routes by which end‐of‐life B2B WEEE can flow. The recycling and refurbishment of B2B IT units at end of use was shown to be commonplace, but it is likely that these units enter streams where they are not reported. The actors disposing of their units did not have information on the management or disposition of these streams. It is concluded that to achieve the goals of EPR for B2B IT WEEE, the networks and the operational practices of these streams need to be better understood when developing strategies and policies. 相似文献
266.
Hui Yang Seth M. Munson Chris Huntingford Nuno Carvalhais Alan K. Knapp Xiangyi Li Josep Peñuelas Jakob Zscheischler Anping Chen 《Global Change Biology》2023,29(8):2351-2362
Negative extreme anomalies in vegetation growth (NEGs) usually indicate severely impaired ecosystem services. These NEGs can result from diverse natural and anthropogenic causes, especially climate extremes (CEs). However, the relationship between NEGs and many types of CEs remains largely unknown at regional and global scales. Here, with satellite-derived vegetation index data and supporting tree-ring chronologies, we identify periods of NEGs from 1981 to 2015 across the global land surface. We find 70% of these NEGs are attributable to five types of CEs and their combinations, with compound CEs generally more detrimental than individual ones. More importantly, we find that dominant CEs for NEGs vary by biome and region. Specifically, cold and/or wet extremes dominate NEGs in temperate mountains and high latitudes, whereas soil drought and related compound extremes are primarily responsible for NEGs in wet tropical, arid and semi-arid regions. Key characteristics (e.g., the frequency, intensity and duration of CEs, and the vulnerability of vegetation) that determine the dominance of CEs are also region- and biome-dependent. For example, in the wet tropics, dominant individual CEs have both higher intensity and longer duration than non-dominant ones. However, in the dry tropics and some temperate regions, a longer CE duration is more important than higher intensity. Our work provides the first global accounting of the attribution of NEGs to diverse climatic extremes. Our analysis has important implications for developing climate-specific disaster prevention and mitigation plans among different regions of the globe in a changing climate. 相似文献
267.
Philippe Fuchs Nils Rugen Chris Carrie Marlene Elssser Iris Finkemeier Jonas Giese Tatjana M. Hildebrandt Kristina Kühn Veronica G. Maurino Cristina Ruberti Mareike Schallenberg‐Rüdinger Janina Steinbeck Hans‐Peter Braun Holger Eubel Etienne H. Meyer Stefanie J. Müller‐Schüssele Markus Schwarzlnder 《The Plant journal : for cell and molecular biology》2020,101(2):420-441
268.
Paul-Christian Burda Matthias A. Roelli Marco Schaffner Shahid M. Khan Chris J. Janse Volker T. Heussler 《PLoS pathogens》2015,11(3)
The coordinated exit of intracellular pathogens from host cells is a process critical to the success and spread of an infection. While phospholipases have been shown to play important roles in bacteria host cell egress and virulence, their role in the release of intracellular eukaryotic parasites is largely unknown. We examined a malaria parasite protein with phospholipase activity and found it to be involved in hepatocyte egress. In hepatocytes, Plasmodium parasites are surrounded by a parasitophorous vacuole membrane (PVM), which must be disrupted before parasites are released into the blood. However, on a molecular basis, little is known about how the PVM is ruptured. We show that Plasmodium berghei phospholipase, PbPL, localizes to the PVM in infected hepatocytes. We provide evidence that parasites lacking PbPL undergo completely normal liver stage development until merozoites are produced but have a defect in egress from host hepatocytes. To investigate this further, we established a live-cell imaging-based assay, which enabled us to study the temporal dynamics of PVM rupture on a quantitative basis. Using this assay we could show that PbPL-deficient parasites exhibit impaired PVM rupture, resulting in delayed parasite egress. A wild-type phenotype could be re-established by gene complementation, demonstrating the specificity of the PbPL deletion phenotype. In conclusion, we have identified for the first time a Plasmodium phospholipase that is important for PVM rupture and in turn for parasite exit from the infected hepatocyte and therefore established a key role of a parasite phospholipase in egress. 相似文献
269.
Zi Feng Yang Chris Ka Pun Mok Xiao Qing Liu Xiao Bo Li Jian Feng He Wen Da Guan Yong Hao Xu Wei Qi Pan Li Yan Chen Yong Ping Lin Shi Guan Wu Si Hua Pan Ji Cheng Huang Guo Yun Ding Kui Zheng Chang Wen Ke Jin Yan Lin Yong Hui Zhang Horace Hok Yeung Lee Wen Kuan Liu Chun Guang Yang Rong Zhou Joseph Sriyal Malik Peiris Yi Min Li Rong Chang Chen Ling Chen Nan Shan Zhong 《PloS one》2015,10(2)
BackgroundThe second wave of avian influenza H7N9 virus outbreak in humans spread to the Guangdong province of China by August of 2013 and this virus is now endemic in poultry in this region.MethodsFive patients with H7N9 virus infection admitted to our hospital during August 2013 to February 2014 were intensively investigated. Viral load in the respiratory tract was determined by quantitative polymerase chain reaction (Q-PCR) and cytokine levels were measured by bead-based flow cytometery.ResultsFour patients survived and one died. Viral load in different clinical specimens was correlated with cytokine levels in plasma and broncho-alveolar fluid (BALF), therapeutic modalities used and clinical outcome. Intravenous zanamivir appeared to be better than peramivir as salvage therapy in patients who failed to respond to oseltamivir. Higher and more prolonged viral load was found in the sputum or endotracheal aspirates compared to throat swabs. Upregulation of proinflammatory cytokines IP-10, MCP-1, MIG, MIP-1α/β, IL-1β and IL-8 was found in the plasma and BALF samples. The levels of cytokines in the plasma and viral load were correlated with disease severity. Reactivation of herpes simplex virus type 1(HSV-1) was found in three out of five patients (60%).ConclusionExpectorated sputum or endotracheal aspirate specimens are preferable to throat swabs for detecting and monitoring H7N9 virus. Severity of the disease was correlated to the viral load in the respiratory tract as well as the extents of cytokinemia. Reactivation of HSV-1 may contribute to clinical outcome. 相似文献
270.
Déjà vu and tip-of-the-tongue (TOT) are retrieval-related subjective experiences whose study relies on participant self-report. In four experiments (ns = 224, 273, 123 and 154), we explored the effect of questioning method on reported occurrence of déjà vu and TOT in experimental settings. All participants carried out a continuous recognition task, which was not expected to induce déjà vu or TOT, but were asked about their experiences of these subjective states. When presented with contemporary definitions, between 32% and 58% of participants nonetheless reported experiencing déjà vu or TOT. Changing the definition of déjà vu or asking participants to bring to mind a real-life instance of déjà vu or TOT before completing the recognition task had no impact on reporting rates. However, there was an indication that changing the method of requesting subjective reports impacted reporting of both experiences. More specifically, moving from the commonly used retrospective questioning (e.g. “Have you experienced déjà vu?”) to free report instructions (e.g. “Indicate whenever you experience déjà vu.”) reduced the total number of reported déjà vu and TOT occurrences. We suggest that research on subjective experiences should move toward free report assessments. Such a shift would potentially reduce the presence of false alarms in experimental work, thereby reducing the overestimation of subjective experiences prevalent in this area of research. 相似文献