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Rashi Verma Monika Yadav Rajabrata Bhuyan Shweta Aggarwal Arnab Nayek 《Journal of receptor and signal transduction research》2016,36(6):601-616
Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen–antibody (Ag???Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag???Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases. 相似文献
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Behavioural responses of animals to volatiles in their environment are generally dependent on context. Most natural odours are mixtures of components that can each induce different behaviours when presented on their own. We have investigated how a complex of two olfactory stimuli is evaluated by Drosophila flies in a free-flying two-trap choice assay and how these stimuli are encoded in olfactory receptor neurons. We first observed that volatiles from apple cider vinegar attracted flies while carbon dioxide (CO2) was avoided, confirming their inherent positive and negative values. In contradiction with previous results obtained from walking flies in a four-field olfactometer, in the present assay the addition of CO2 to vinegar increased rather than decreased the attractiveness of vinegar. This effect was female-specific even though males and females responded similarly to CO2 and vinegar on their own. To test whether the female-specific behavioural response to the mixture correlated with a sexual dimorphism at the peripheral level we recorded from olfactory receptor neurons stimulated with vinegar, CO2 and their combination. Responses to vinegar were obtained from three neuron classes, two of them housed with the CO2-responsive neuron in ab1 sensilla. Sensitivity of these neurons to both CO2 and vinegar per se did not differ between males and females and responses from female neurons did not change when CO2 and vinegar were presented simultaneously. We also found that CO2-sensitive neurons are particularly well adapted to respond rapidly to small concentration changes irrespective of background CO2 levels. The ability to encode temporal properties of stimulations differs considerably between CO2- and vinegar-sensitive neurons. These properties may have important implications for in-flight navigation when rapid responses to fragmented odour plumes are crucial to locate odour sources. However, the flies’ sex-specific response to the CO2-vinegar combination and the context-dependent hedonics most likely originate from central rather than peripheral processing. 相似文献
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Lars Lundin Torbjörn Nilsson Sabine Jordan Elve Lode Monika Strömgren 《Wetlands Ecology and Management》2017,25(4):405-419
Restoration of wetlands is a high priority world-wide. Peat extraction areas can be restored by rewetting, however affecting the environment. It could be expected to turn the drained peat-cutover area from a source to a sink of most elements. This study examined effects of such rewetting on peat, hydrology and water chemistry over 15 years at two sites in Sweden; the nutrient-poor Porla peatland and the nutrient-rich Västkärr peatland. Rewetting caused minor changes to peat chemistry, but at the Västkärr site ammonium concentrations increased in superficial peat layers while nitrate decreased. In terms of hydrology, rewetting of the Porla site decreased annual runoff and both high and low discharges. Water pH at the Porla site stayed fairly stable, but at the Västkärr site pH, after an initial 4 years dip, gradually increased to higher values than before rewetting. Water colour and organic matter content were fairly stable, but slightly lower values were found after 15 years than in initial 4–5 years. The concentrations of base cations and of inorganic N were lower after rewetting, while total P was higher. However, these impacts could change from an initial phase as the wetlands in the long-term perspective develop into mires. 相似文献
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Hanna Gladh Erika Bergsten Folestad Lars Muhl Monika Ehnman Philip Tannenberg Anna-Lisa Lawrence Christer Betsholtz Ulf Eriksson 《PloS one》2016,11(3)
Platelet-derived growth factor D (PDGF-D) is the most recently discovered member of the PDGF family. PDGF-D signals through PDGF receptor β, but its biological role remains largely unknown. In contrast to other members of the PDGF family of growth factors, which have been extensively investigated using different knockout approaches in mice, PDGF-D has until now not been characterized by gene inactivation in mice. Here, we present the phenotype of a constitutive Pdgfd knockout mouse model (Pdgfd-/-), carrying a LacZ reporter used to visualize Pdgfd promoter activity. Inactivation of the Pdgfd gene resulted in a mild phenotype in C57BL/6 mice, and the offspring was viable, fertile and generally in good health. We show that Pdgfd reporter gene activity was consistently localized to vascular structures in both postnatal and adult tissues. The expression was predominantly arterial, often localizing to vascular bifurcations. Endothelial cells appeared to be the dominating source for Pdgfd, but reporter gene activity was occasionally also found in subpopulations of mural cells. Tissue-specific analyses of vascular structures revealed that NG2-expressing pericytes of the cardiac vasculature were disorganized in Pdgfd-/- mice. Furthermore, Pdgfd-/- mice also had a slightly elevated blood pressure. In summary, the vascular expression pattern together with morphological changes in NG2-expressing cells, and the increase in blood pressure, support a function for PDGF-D in regulating systemic arterial blood pressure, and suggests a role in maintaining vascular homeostasis. 相似文献
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Kai B. Kaufmann Nafisah Al-Rifai Felix Ulbrich Nils Schallner Hannelore Rücker Monika Enzinger Hermina Petkes Sebastian Pitzl Ulrich Goebel Sabine Amslinger 《PloS one》2015,10(11)
Cell protection against different noxious stimuli like oxidative stress or chemical toxins plays a central role in the treatment of many diseases. The inducible heme oxygenase isoform, heme oxygenase-1 (HO-1), is known to protect cells against a variety of harmful conditions including apoptosis. Because a number of medium strong electrophiles from a series of α-X-substituted 2’,3,4,4’-tetramethoxychalcones (α-X-TMCs, X = H, F, Cl, Br, I, CN, Me, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, CF3, COOEt, COOH) had proven to activate Nrf2 resulting in HO-1 induction and inhibit NF-κB downstream target genes, their protective effect against staurosporine induced apoptosis and reactive oxygen species (ROS) production was investigated. RAW264.7 macrophages treated with 19 different chalcones (15 α-X-TMCs, chalcone, 2’-hydroxychalcone, calythropsin and 2’-hydroxy-3,4,4’-trimethoxychalcone) prior to staurosporine treatment were analyzed for apoptosis and ROS production, as well as HO-1 protein expression and enzyme activity. Additionally, Nrf2 and NF-κB activity was assessed. We found that amongst all tested chalcones only E-α-(4-methoxyphenyl)-2’,3,4,4''-tetramethoxychalcone (E-α-p-OMe-C6H4-TMC) demonstrated a distinct, statistically significant antiapoptotic effect in a dose dependent manner, showing no toxic effects, while its double bond isomer Z-α-p-OMe-C6H4-TMC displayed no significant activity. Also, E-α-p-OMe-C6H4-TMC induced HO-1 protein expression and increased HO-1 activity, whilst inhibition of HO-1 by SnPP-IX abolished its antiapoptotic effect. The only weakly electrophilic chalcone E-α-p-OMe-C6H4-TMC reduced the staurosporine triggered formation of ROS, while inducing the translocation of Nrf2 into the nucleus. Furthermore, staurosporine induced NF-κB activity was attenuated following E-α-p-OMe-C6H4-TMC treatment. Overall, E-α-p-OMe-C6H4-TMC demonstrated its effective cytoprotective potential via a non-toxic induction of HO-1 in RAW264.7 macrophages. The observed cytoprotective effect may partly be related to both, the activation of the Nrf2- and inhibition of the NF-κB pathway. 相似文献