Transcriptome classification reveals molecular subtypes in psoriasis

ABSTRACT: BACKGROUND: Psoriasis is an immune-mediated disease characterised by chronically elevated pro-inflammatory cytokine levels, leading to aberrant keratinocyte proliferation and differentiation. Although certain clinical phenotypes, such as plaque psoriasis, are well defined, it is currently unclear whether there are molecular subtypes that might impact on prognosis or treatment outcomes. RESULTS: We present a pipeline for patient stratification through a comprehensive analysis of gene expression in paired lesional and non-lesional psoriatic tissue samples, compared with controls, to establish differences in RNA expression patterns across all tissue types. Ensembles of decision tree predictors were employed to cluster psoriatic samples on the basis of gene expression patterns and reveal gene expression signatures that best discriminate molecular disease subtypes. This multi-stage procedure was applied to several published psoriasis studies and a comparison of gene expression patterns across datasets was performed. CONCLUSION: Overall, classification of psoriasis gene expression patterns revealed distinct molecular sub-groups within the clinical phenotype of plaque psoriasis. Enrichment for TGFb and ErbB signaling pathways, noted in one of the two psoriasis subgroups, suggested that this group may be more amenable to therapies targeting these pathways. Our study highlights the potential biological relevance of using ensemble decision tree predictors to determine molecular disease subtypes, in what may initially appear to be a homogenous clinical group. The R code used in this paper is available upon request.     

Preliminary studies on the toxicity and mutagenicity of 1-amino-2-naphthol-4-sulphonic acid inDrosophila melanogaster

The toxicity and mutagenicity of 1-amino-2-naphtho-4-sulphonic acid were analysed inDrosphila melanogaster. Rate of development and viability were the two parameters employed to study the toxicity. The frequency of dominant lethals was scored to evaluate the mutagenic effect of the chemical on male and female germ cells. Concentrations of 250 mg and above/100 ml wheat cream agar medium were found to be significantly toxic. Significant number of dominant lethals was induced even by a concentration as low as 50 mg/100 ml medium. Male germ cells were more sensitive than female germ cells.     

An <Emphasis Type="Italic">Insilico</Emphasis> approach to High Altitude Pulmonary Edema - Molecular modeling of human β<Subscript>2</Subscript> adrenergic receptor and its interaction with Salmeterol &; Nifedipine

Knowledge of the three-dimensional structures of protein targets from genomic data has the potential to accelerate researches pertaining to drug discovery. Human β₂ adrenergic receptor is a G-protein-coupled receptor with seven transmembrane helices, and is important in pharmaceutical targeting on pulmonary and cardiovascular diseases. The human β₂ adrenergic receptor has been found to play a very important role in the pathogenesis of high altitude pulmonary edema (HAPE). In the present study, a high quality of protein 3D structure has been predicted for the human β₂ adrenergic receptor sequence with primary accession number P07550. Homologous template protein sequence with known 3D structure was identified and the template-query protein sequence validation was done by multiple sequence alignment method. The homology model was performed through Modeller and depended on the quality of the sequence alignment by BLAST, template structure and the consolidated result performed by Gene silico meta-server. The statistical verification of the generated model was evaluated by PROCHECK which revealed that the structure modeled through Modeller to be of good quality with 84.1% of residues in the most favored region. Docking studies were carried out after modeling with two well known ligands namely Salmeterol and Nifedipine, and the fitness score revealed that Salmeterol has a higher fitness score than Nifedipine. Estimation of binding affinity by X-Score revealed that Salmeterol had −10.40 binding affinity while Nifedipine showed −9.62 binding affinity. From the present study, it can be concluded that the generated model of human β₂ adrenergic receptor can be used for further studies related to this receptor and Salmeterol was found to have a high binding affinity with human β₂ adrenergic receptor.     

Fructose ingestion acutely elevates blood pressure in healthy young humans

Overconsumption of fructose, particularly in the form of soft drinks, is increasingly recognized as a public health concern. The acute cardiovascular responses to ingesting fructose have not, however, been well-studied in humans. In this randomized crossover study, we compared cardiovascular autonomic regulation after ingesting water and drinks containing either glucose or fructose in 15 healthy volunteers (aged 21-33 yr). The total volume of each drink was 500 ml, and the sugar content 60 g. For 30 min before and 2 h after each drink, we recorded beat-to-beat heart rate, arterial blood pressure, and cardiac output. Energy expenditure was determined on a minute-by-minute basis. Ingesting the fructose drink significantly increased blood pressure, heart rate, and cardiac output but not total peripheral resistance. Glucose ingestion resulted in a significantly greater increase in cardiac output than fructose but no change in blood pressure and a concomitant decrease in total peripheral resistance. Ingesting glucose and fructose, but not water, significantly increased blood pressure variability and decreased cardiovagal baroreflex sensitivity. Energy expenditure increased by a similar amount after glucose and fructose ingestion, but fructose elicited a significantly greater increase in respiratory quotient. These results show that ingestion of glucose and fructose drinks is characterized by specific hemodynamic responses. In particular, fructose ingestion elicits an increase in blood pressure that is probably mediated by an increase in cardiac output without compensatory peripheral vasodilatation.     

Effect of onion (Allium cepa Linn.) and garlic (Allium sativum Linn.) on plasma triglyceride content in Japanese quail (Coturnix coturnix japonicum)

Dietary onion and garlic caused an increase in the level of plasma triglyceride which could be due to insulin like activity of dietary alliums and other factors that promote lipogenesisi in growing stages. Changes in the plasma triglyceride level in the control group due to change in age and sex were also noted. The triglyceride level was more in female birds when compared to males of similar age group. The plasma trigelyceride level increased with age in both sex except for the level being similar in the 6 and 9-week old females and 3 and 6-week old male birds. The results suggest that the effects of alliums in growing and adult stages may be different which needs further study.     

Juvenile hormone activity in Dysdercus cingulatus Fabr by juvenile hormone esterase inhibitor, OTFP

Application of juvenile hormone esterase inhibitor 3-octylthio-1,1,1- trifluropropan-2-one (OTFP) to 5th instar nymphs and virgin females of D. cingulatus revealed the profound role played by juvenile hormone esterase (JHE) in metamorphosis and reproduction. The ability of OTFP to cause delay and the formation of malformed nymphs, suggests that inhibition of JHE in vivo maintains a higher than normal hemolymph JH titer. It is obvious that OTFP does inhibit in vivo JHE activity in late instar nymphs. Further, the application of JHE inhibitor, OTFP to virgin females demonstrates that substituted trifluropropanones can indirectly stimulate egg development by inhibiting JHE activity in virgin females.     

Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease

The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.     

Formulation and evaluation of ketorolac tromethamine-loaded albumin microspheres for potential intramuscular administration

The objective of this work was to prepare and evaluate ketorolac tromethamine-loaded albumin microspheres using a factorial design. Albumin microspheres were prepared by emulsion cross-linking method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance (ANOVA) for entrapment efficiency indicated that entrapment efficiency is best fitted to a response surface linear model. From the statistical analysis it was observed that as the drug:polymer (D∶P) ratio and volume of glutaraldehyde increased, there was a significant increase in the encapsulation efficiency. Scanning electron microscopy of the microspheres revealed a spherical, nonporous and uniform appearance, with a smooth surface. Based on the entrapment efficiency and physical appearance, 9 formulations were selected for release study. The maximum particle size observed was below 40 μm. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microspheres, except those having less polymer proportion (D∶P ratio is 1∶1), exhibited a prolonged release for almost 24 hours. On comparingr ² values for Higuchi and Peppas kinetic models, different batches of microspheres showed Fickian, non-Fickian, and diffusion kinetics. The release mechanism was regulated by D∶P ratio and amount of cross-linking agent. From the experimental data obtained with respect to particle size and extent of drug relaase, it could be concluded that the prepared microspheres are useful for once-a-day intramuscular administration of ketorolac tromethamine. Published: February 23, 2007     

Modeling biogeochemical impacts of bioenergy buffers with perennial grasses for a row‐crop field in Illinois

Current research on the environmental sustainability of bioenergy has largely focused on the potential of bioenergy crops to sequester carbon and mitigate greenhouse gas emissions and possible impacts on water quality and quantity. A key assumption in these studies is that bioenergy crops will be grown in a manner similar to current agricultural crops such as corn and hence would affect the environment similarly. In this study, we investigate an alternative cropping system where bioenergy crops are grown in buffer strips adjacent to current agricultural crops such that nutrients present in runoff and leachate from the traditional row‐crops are reused by the bioenergy crops (switchgrass, miscanthus and native prairie grasses) in the buffer strips, thus providing environmental services and meeting economic needs of farmers. The process‐based biogeochemical model Denitrification‐Decomposition (DNDC) was used to simulate crop yield, nitrous oxide production and nitrate concentrations in leachate for a typical agricultural field in Illinois. Model parameters have been developed for the first time for miscanthus and switchgrass in DNDC. Results from model simulations indicated that growing bioenergy crops in buffer strips mitigated nutrient runoff, reduced nitrate concentrations in leachate by 60–70% and resulted in a reduction of 50–90% in nitrous oxide emissions compared with traditional cropping systems. While all the bioenergy crop buffers had significant positive environmental benefits, switchgrass performed the best with respect to minimizing nutrient runoff and nitrous oxide emissions, while miscanthus had the highest yield. Overall, our model results indicated that the bioenergy crops grown in these buffer strips achieved yields that are comparable to those obtained for traditional agricultural systems while simultaneously providing environmental services and could be used to design sustainable agricultural landscapes.