We show that an innate defense-regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously. 相似文献
The strict anaerobic, thermophilic bacterium Moorella thermoacetica metabolizes C1 compounds for example CO(2)/H(2), CO, formate, and methanol into acetate via the Wood/Ljungdahl pathway. Some of the key steps in this pathway include the metabolism of the C1 compounds into the methyl group of methylenetetrahydrofolate (MTHF) and the transfer of the methyl group from MTHF to the methyl group of acetyl-CoA catalyzed by methyltransferase, corrinoid protein and CO dehydrogenase/acetyl CoA synthase. Recently, we reported the crystallization of a 25 kDa methanol-induced corrinoid protein from M. thermoacetica (Zhou et al., Acta Crystallogr F 2005; 61:537-540). In this study we analyzed the crystal structure of the 25 kDa protein and provide genetic and biochemical evidences supporting its role in the methanol metabolism of M. thermoacetia. The 25 kDa protein was encoded by orf1948 of contig 303 in the M. thermoacetica genome. It resembles similarity to MtaC the corrinoid protein of the methanol:CoM methyltransferase system of methane producing archaea. The latter enzyme system also contains two additional enzymes MtaA and MtaB. Homologs of MtaA and MtaB were found to be encoded by orf2632 of contig 303 and orf1949 of contig 309, respectively, in the M. thermoacetica genome. The orf1948 and orf1949 were co-transcribed from a single polycistronic operon. Metal analysis and spectroscopic data confirmed the presence of cobalt and the corrinoid in the purified 25 kDa protein. High resolution X-ray crystal structure of the purified 25 kDa protein revealed corrinoid as methylcobalamin with the imidazole of histidine as the alpha-axial ligand replacing benziimidazole, suggesting base-off configuration for the corrinoid. Methanol significantly activated the expression of the 25 kDa protein. Cyanide and nitrate inhibited methanol metabolism and suppressed the level of the 25 kDa protein. The results suggest a role of the 25 kDa protein in the methanol metabolism of M. thermoacetica. 相似文献
Hydrobiologia - Seed size can have an impact on angiosperm reproductive fitness. Ecological theory predicts plants that will produce larger seeds in stressful environments to increase the chances... 相似文献
Dehydrins (DHNs) as the member of the late embryogenesis abundant protein family, play critical roles in seed dehydration protection and plant adaptation to multiple abiotic stresses. As an important method of germplasm preservation, cryopreservation is also an ideal research system to study compound stress. Oxidative stress, as the critical stress in cryopreservation, directly affects cell viability. Our previous in vitro tests indicated that ApY2SK2 DHN can effectively protect enzyme activity and almost double the survival rate of Arabidopsis thaliana seedlings after cryopreservation, but the in vivo protective effect of ApY2SK2 on cryopreservation have not yet been elucidated. In this study, ApY2SK2 type DHN was genetically transformed into embryogenic callus (EC) of Agapanthus praecox by overexpression (OE) and RNA interference (RNAi) techniques to evaluate the in vivo oxidative stress protective effect of DHNs during cryopreservation. The results showed that the cell viability had a completely opposite trend between OE and RNAi cell lines, and the cell relative death ratio of ApY2SK2-OE EC was significantly decreased 18.5% and ApY2SK2-RNAi cells was significantly increased 23.5% after cryopreservation. Overexpression ApY2SK2 increased non-enzymatic antioxidant (AsA and GSH) contents, antioxidant enzyme (POD and SOD) activities and up-regulated CAT, POD and GPX expression, while ApY2SK2-RNAi cells decreased CAT, FeSOD, POD and GPX expression during cryopreservation. These findings suggested that ApY2SK2 can affect ROS metabolism, alleviate H2O2 and OH·excessive generation, activate the antioxidant system, improve cellular REDOX balance and reduce membrane lipid peroxidation damage of plant cells during cryopreservation. DHNs can effectively improve cell stress tolerance and have great potential for in vivo or in vitro applications in plant cryopreservation.
Maps of continental‐scale land cover are utilized by a range of diverse users but whilst a range of products exist that describe present and recent land cover in Europe, there are currently no datasets that describe past variations over long time‐scales. User groups with an interest in past land cover include the climate modelling community, socio‐ecological historians and earth system scientists. Europe is one of the continents with the longest histories of land conversion from forest to farmland, thus understanding land cover change in this area is globally significant. This study applies the pseudobiomization method (PBM) to 982 pollen records from across Europe, taken from the European Pollen Database (EPD) to produce a first synthesis of pan‐European land cover change for the period 9000 bp to present, in contiguous 200 year time intervals. The PBM transforms pollen proportions from each site to one of eight land cover classes (LCCs) that are directly comparable to the CORINE land cover classification. The proportion of LCCs represented in each time window provides a spatially aggregated record of land cover change for temperate and northern Europe, and for a series of case study regions (western France, the western Alps, and the Czech Republic and Slovakia). At the European scale, the impact of Neolithic food producing economies appear to be detectable from 6000 bp through reduction in broad‐leaf forests resulting from human land use activities such as forest clearance. Total forest cover at a pan‐European scale moved outside the range of previous background variability from 4000 bp onwards. From 2200 bp land cover change intensified, and the broad pattern of land cover for preindustrial Europe was established by 1000 bp . Recognizing the timing of anthropogenic land cover change in Europe will further the understanding of land cover‐climate interactions, and the origins of the modern cultural landscape. 相似文献
IntroductionThe aim of this study was to assess long-term golimumab therapy in rheumatoid arthritis (RA) patients who discontinued previous tumor necrosis factor-α (TNF)-inhibitor(s).MethodsPatients enrolled into this multicenter, randomized, double-blind, placebo-controlled study of active RA (≥4 tender, ≥4 swollen joints) received placebo (Group 1) or golimumab 50 mg (Group 2) or 100 mg (Group 3) injections every 4 weeks. Patients in Groups 1 and 2 with inadequate response at week 16 escaped to golimumab 50 and 100 mg, respectively. At week 24, Group 1 patients crossed-over to golimumab 50 mg, Group 2 continued golimumab 50/100 mg per escape status, and Group 3 maintained dosing. During the long-term-extension (LTE), golimumab 50 mg could be increased to 100 mg, and 100 mg could be decreased to 50 mg. Data through 5 years are reported for all patients (safety) and patients using methotrexate (efficacy, intention-to-treat (ITT) analysis with last-observation-carried-forward for missing data and non-responder imputation for unsatisfactory efficacy discontinuations).ResultsIn total, 459 of 461 randomized patients received the study agent, 304 of whom were methotrexate-treated and included in efficacy analyses. Through week 256, the proportions of methotrexate-treated patients achieving American-College-of-Rheumatology (ACR) responses were 37.6% to 47.0% for ACR20, 21.4% to 35.0% for ACR50, and 7.8% to 17.0% for ACR70 response across randomized groups. Golimumab safety through week 268 was generally consistent with that at week 24 and week 160 and other anti-TNF agents.ConclusionsIn some patients with active RA discontinuing previous TNF-antagonist therapy, golimumab safety and efficacy, assessed conservatively with ITT analyses, was confirmed through 5 years.
For both scientific and animal welfare reasons, training in basic surgical concepts and techniques should be undertaken before ever seeking to perform surgery on a rodent. Students, post-doctoral scholars, and others interested in performing surgery on rodents as part of a research protocol may not have had formal surgical training as part of their required coursework. Surgery itself is a technical skill, and one that will improve with practice. The principles of aseptic technique, however, often remain unexplained or untaught. For most new surgeons, this vital information is presented in piecemeal fashion or learned on the job, neither of which is ideal. It may also make learning how to perform a particular surgery difficult, as the new surgeon is learning both a surgical technique and the principles of asepsis at the same time. This article summarizes and makes recommendations for basic surgical skills and techniques necessary for successful rodent surgery. This article is designed to supplement hands-on training by the user''s institution. 相似文献
Accumulation and deposition of β-amyloid protein (Aβ) are the hallmark features of Alzheimer''s disease. The inhalation anesthetic isoflurane has been shown to induce caspase activation and increase Aβ accumulation. In addition, recent studies suggest that isoflurane may directly promote the formation of cytotoxic soluble Aβ oligomers, which are thought to be the key pathological species in AD. In contrast, propofol, the most commonly used intravenous anesthetic, has been reported to have neuroprotective effects. We therefore set out to compare the effects of isoflurane and propofol alone and in combination on caspase-3 activation and Aβ oligomerization in vitro and in vivo. Naïve and stably-transfected H4 human neuroglioma cells that express human amyloid precursor protein, the precursor for Aβ; neonatal mice; and conditioned cell culture media containing secreted human Aβ40 or Aβ42 were treated with isoflurane and/or propofol. Here we show for the first time that propofol can attenuate isoflurane-induced caspase-3 activation in cultured cells and in the brain tissues of neonatal mice. Furthermore, propofol-mediated caspase inhibition occurred when there were elevated levels of Aβ. Finally, isoflurane alone induces Aβ42, but not Aβ40, oligomerization, and propofol can inhibit the isoflurane-mediated oligomerization of Aβ42. These data suggest that propofol may mitigate the caspase-3 activation by attenuating the isoflurane-induced Aβ42 oligomerization. Our findings provide novel insights into the possible mechanisms of isoflurane-induced neurotoxicity that may aid in the development of strategies to minimize potential adverse effects associated with the administration of anesthetics to patients. 相似文献