Modulation of cytokines and transcription factors (T-Bet and GATA3) in CD4 enriched cervical cells of Chlamydia trachomatis infected fertile and infertile women upon stimulation with chlamydial inclusion membrane proteins B and C

Background  

Chlamydial Inclusion membrane proteins (Incs), are involved in biochemical interactions with host cells and infecting Chlamydiae. We have previously reported the role of two Chlamydia trachomatis (CT) Incs, namely IncB and IncC in generating host immunity in CT infected women. Emerging data shows involvement of Inc stimulated CD4 positive T cells in aiding host immunity in infected fertile and infertile women through the secretion of interferon gamma. However the lack of data on the intra-cytokine interplay to these Incs in infected cell milieu prompted us to investigate further.     

Design of Benzene-1,2-diamines as selective inducible nitric oxide synthase inhibitors: a combined de novo design and docking analysis

Selective inhibition of inducible nitric oxide synthases (iNOS) has been a challenging problem for researchers pursuing work in finding methods to treat inflammatory disorders, shock, etc. Though many inhibitors have been studied to date, all are associated with selectivity or potency problems. Additionally, most of the reported compounds have several similarities and fewer number of novel structures are being tried. There is an increasing need to design novel molecules for this target. In this work, de novo design using LUDI, combined with docking analysis using FlexX has been employed in an attempt to identify novel scaffolds. Benzene-1,2-diamines were identified which could mimic the interactions of the substrate analogs and other inhibitors. Comparative docking scores in each of the isoforms of nitric oxide synthase were employed to recognize hits for iNOS selectivity. Figure Figure shows the docked poses of the ligand M226 along with that of the reference GW274150. (FlexX analysis)     

Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist

Montelukast and Zafirlukast are known leukotriene receptor antagonists prescribed in asthma treatment. However, these fall short as mono therapy and are frequently used in combination with inhaled glucocorticosteroids with or without long acting beta 2 agonists. Therefore, it is of interest to apply ligand and structure based virtual screening strategies to identify compounds akin to lead compounds Montelukast and Zafirlukast. Hence, compounds with structures having 95% similarity to these compounds were retrieved from NCBI׳s PubChem database. Compounds similar to lead were grouped and docked at the antagonist binding site of cysteinyl leukotriene receptor 1. This exercise identified compounds UNII 70RV86E50Q (Pub Cid 71587778) and Sure CN 9587085 (Pub Cid 19793614) with higher predicted binding compared to Montelukast and Zafirlukast. It is shown that the compound Sure CN 9587085 showed appreciable ligand receptor interaction compared to UNII 70RV86E50Q. Thus, the compound Sure CN 9587085 is selected as a potent antagonist to cysteinyl leukotriene receptor 1 for further consideration in vitro and in vivo validation.     

TLR4‐mediated skin carcinogenesis is dependent on immune and radioresistant cells

Skin cancers are the most commonly diagnosed cancers. Understanding what are the factors contributing to skin tumour development can be instrumental to identify preventive therapies. The myeloid differentiation primary response gene (MyD)88, the downstream adaptor protein of most Toll‐like receptors (TLR), has been shown to be involved in several mouse tumourigenesis models. We show here that TLR4, but not TLR2 or TLR9, is upstream of MyD88 in skin tumourigenesis. TLR4 triggering is not dependent on lipopolysaccharide associated to skin‐colonizing bacteria, but on the high mobility group box‐1 protein (HMGB1), an endogenous ligand of TLR4. HMGB1 is released by necrotic keratinocytes and is required for the recruitment of inflammatory cells and for the initiation of inflammation. The expression of TLR4 on both bone marrow‐derived and radioresistant cells is necessary for carcinogenesis. Consistently, a human tissue microarray analysis showed that melanoma and colon cancer display an over‐expression of TLR4 and its downstream adaptor protein MyD88 within tumours. Together, our results suggest that the initial release of HMGB1 triggers a TLR4‐dependent inflammatory response that leads to tumour development.     

Effect of Organic Selenium Supplementation on Growth, Se Uptake, and Nutrient Utilization in Guinea Pigs

Forty weaned male guinea pigs (Cavia porcellus) of 152.6?±?7.96 g mean body weight were divided into four equal groups and fed a common basal diet comprised of 25% ground cowpea (Vigna unguiculata) hay, 30% ground maize (Zea mays) grain, 22% ground gram (Cicer arietinum) grain, 9.5% deoiled rice (Oryza sativa) bran, 6% soybean (Glycine max) meal, 6% fish meal, 1.5% mineral mixture (without Se), and ascorbic acid at 200 mg/kg to meet their nutrient requirements along with 0, 0.1, 0.2, and 0.3 ppm of organic selenium (Se) in groups I, II, III, and IV, respectively. Experimental feeding lasted for a period of 10 weeks, during which, daily feed intake and weekly body weights were recorded. Intake and digestibility of dry matter, organic matter, ether extract, crude fiber, and nitrogen-free extract as well as uptake of calcium and phosphorus were similar (P?>?0.05) among the four groups. Feed:gain ratio was also similar (P?>?0.05) in the four groups. However, digestibility of crude protein was significantly (P?<?0.001) higher in group II supplemented with 0.1 ppm organic Se as compared to other three group. Intake and absorption of Se was significantly (P?<?0.001) higher in all the Se supplemented groups as compared to control group. Average daily gain (ADG) was significantly (P?<?0.05) higher in group II (3.16 g/day) and III (3.38 g/day) as compared to group I (2.88 g/day). However, ADG in group IV (supplemented 0.3 ppm organic Se) was significantly (P?<?0.05) lower (2.83 g/day) than group II and III, but comparable (P?>?0.05) to group I. Findings of the present experiment suggests that Se requirements of guinea pigs are ≥0.2 ppm, as supplementation of 0.1 ppm organic Se in the diet (having 0.1 ppm Se) not only enhanced their growth rate but also improved the protein utilization.     

A coupled sharp-interface immersed boundary-finite-element method for flow-structure interaction with application to human phonation

A new flow-structure interaction method is presented, which couples a sharp-interface immersed boundary method flow solver with a finite-element method based solid dynamics solver. The coupled method provides robust and high-fidelity solution for complex flow-structure interaction (FSI) problems such as those involving three-dimensional flow and viscoelastic solids. The FSI solver is used to simulate flow-induced vibrations of the vocal folds during phonation. Both two- and three-dimensional models have been examined and qualitative, as well as quantitative comparisons, have been made with established results in order to validate the solver. The solver is used to study the onset of phonation in a two-dimensional laryngeal model and the dynamics of the glottal jet in a three-dimensional model and results from these studies are also presented.