Comparative evaluation of gene-set analysis methods

Background  

Multiple data-analytic methods have been proposed for evaluating gene-expression levels in specific biological pathways, assessing differential expression associated with a binary phenotype. Following Goeman and Bühlmann's recent review, we compared statistical performance of three methods, namely Global Test, ANCOVA Global Test, and SAM-GS, that test "self-contained null hypotheses" Via. subject sampling. The three methods were compared based on a simulation experiment and analyses of three real-world microarray datasets.     

Co-endemicity of Loiasis and Onchocerciasis in Rain Forest Communities in Southwestern Nigeria

BackgroundLoiasis is currently receiving attention as a disease of public health importance because of the possibility of increased risk of developing neurologic serious adverse event following mass ivermectin treatment against onchocerciasis in individual co-infected with Onchocerca volvulus and Loa loa.Conclusions/SignificanceLow prevalence of onchocerciasis and loiasis co-infection in this study suggests that loiasis may not pose a serious epidemiological threat to the continuous distribution and sustainability of ivermectin for the treatment of onchocerciasis. Evaluation of the interruption of onchocerciasis transmissions in this region using all the indicators set forth by WHO is therefore suggested.     

Biosynthesis and defensive function of Nδ-acetylornithine, a jasmonate-induced Arabidopsis metabolite

Since research on plant interactions with herbivores and pathogens is often constrained by the analysis of already known compounds, there is a need to identify new defense-related plant metabolites. The uncommon nonprotein amino acid N(δ)-acetylornithine was discovered in a targeted search for Arabidopsis thaliana metabolites that are strongly induced by the phytohormone methyl jasmonate (MeJA). Stable isotope labeling experiments show that, after MeJA elicitation, Arg, Pro, and Glu are converted to Orn, which is acetylated by NATA1 to produce N(δ)-acetylornithine. MeJA-induced N(δ)-acetylornithine accumulation occurs in all tested Arabidopsis accessions, other Arabidopsis species, Capsella rubella, and Boechera stricta, but not in less closely related Brassicaceae. Both insect feeding and Pseudomonas syringae infection increase NATA1 expression and N(δ)-acetylornithine accumulation. NATA1 transient expression in Nicotiana tabacum and the addition of N(δ)-acetylornithine to an artificial diet both decrease Myzus persicae (green peach aphid) reproduction, suggesting a direct toxic or deterrent effect. However, since broad metabolic changes that are induced by MeJA in wild-type Arabidopsis are attenuated in a nata1 mutant strain, there may also be indirect effects on herbivores and pathogens. In the case of P. syringae, growth on a nata1 mutant is reduced compared with wild-type Arabidopsis, but growth in vitro is unaffected by N(δ)-acetylornithine addition.     

Cometabolic Degradation of Polychlorinated Biphenyls at Low Temperature by Psychrotolerant Bacterium Hydrogenophaga sp. IA3-A

A biphenyl-utilizing bacterium isolated from polychlorinated biphenyls (PCBs)-contaminated soils grew on tryptic soy at temperatures between 4 and 40°C. The Gram-negative rod bacterium formed yellow colonies on nutrient agar and it denitrified nitrate to nitrogen. Analysis of cellular fatty acids showed that it was most closely related to Hydrogenophaga taeniospiralis. At 5°C, biphenyl-grown cells cometabolically degraded di- and trichlorinated isomers of PCBs in 10 ppm of Aroclor 1248. At 30°C, PCBs that were removed included a congener with four chlorine substituents. At 5°C, cells transformed 2,4′-dichlorobiphenyl (2,4′-DCB) and accumulated ortho-chlorinated meta-cleavage product as a stable metabolite. Analysis of extracts of culture supernatant by gas chromatography–mass spectrometry indicated that products of transformation of 2,4′-DCB included 2- and 4-chlorobenzoic acid (2- and 4-CBA), suggesting that (chloro)biphenyl-degrading upper-pathway enzymes of the bacterium are active at low temperature. The bacterium Hydrogenophaga sp. IA3-A is a PCB-degrading psychrotolerant strain.     

Mathematical analysis of the pharmacokinetic-pharmacodynamic (PKPD) behaviour of monoclonal antibodies: predicting in vivo potency

We consider the relationship between the target affinity of a monoclonal antibody and its in vivo potency. The dynamics of the system is described mathematically by a target-mediated drug disposition model. As a measure of potency, we consider the minimum level of the free receptor following a single bolus injection of the ligand into the plasma compartment. From the differential equations, we derive two expressions for this minimum level in terms of the parameters of the problem, one of which is valid over the full range of values of the equilibrium dissociation constant K_D and the other which is valid only for a large drug dose or for a small value of K_D. Both of these formulae show that the potency achieved by increasing the association constant k_on can be very different from the potency achieved by decreasing the dissociation constant k_off. In particular, there is a saturation effect when decreasing k_off where the increase in potency that can be achieved is limited, whereas there is no such effect when increasing k_on. Thus, for certain monoclonal antibodies, an increase in potency may be better achieved by increasing k_on than by decreasing k_off.     

Phytoremediation of Water Using Phragmites karka and Veteveria nigritana in Constructed Wetland

Constructed wetland is an innovative and emerging ecological technology for wastewater treatment. This study was conducted to investigate the effectiveness of a Vegetated Submerged Bed Constructed Wetland (VSBCW) for removal of heavy metals from industrial wastewater in a steel manufacturing company. A pilot Effluent Treatment Plant (ETP) consisting of equalization basin, two VSBCW basins and a storage tank was constructed. The VSBCW was constructed using 10–30 mm round granite for the different zones. This was overlaid by 200 mm deep granite and 150 mm washed sand with Phragmites karka, Vetiveria nigritana and Cana lilies as macrophytes. Irrigation of macrophytes using effluent from the industry was done after 3 months of planting and ETP monitored. Industrial wastewater samples were collected and analyzed for heavy metals such as zinc (Zn), lead (Pb), iron (Fe), manganese (Mn), magnesium (Mg) and chromium (Cr) to know the treatment efficiency of the ETP. Results indicated that the removal efficiencies of the VSBCW for Pb, Mg and Cr were 15.4%, 79.7% and 97.9% respectively. Fe and Mn were seen to increase by 1.8% and 33% respectively. The ETP using locally available macrophytes is effective in the phytoremediation of heavy metals, particularly Cr from the wastewater.     

Mitochondrial membranes modify mutant huntingtin aggregation

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ tracts are prone to aggregate into oligomers and insoluble fibrils. Mutant htt (mhtt) localizes to variety of organelles, including mitochondria. Specifically, mitochondrial defects, morphological alteration, and dysfunction are observed in HD. Mitochondrial lipids, cardiolipin (CL) in particular, are essential in mitochondria function and have the potential to directly interact with htt, altering its aggregation. Here, the impact of mitochondrial membranes on htt aggregation was investigated using a combination of mitochondrial membrane mimics and tissue-derived mitochondrial-enriched fractions. The impact of exposure of outer and inner mitochondrial membrane mimics (OMM and IMM respectively) to mhtt was explored. OMM and IMM reduced mhtt fibrillization, with IMM having a larger effect. The role of CL in mhtt aggregation was investigated using a simple PC system with varying molar ratios of CL. Lower molar ratios of CL (<5%) promoted fibrillization; however, increased CL content retarded fibrillization. As revealed by in situ AFM, mhtt aggregation and associated membrane morphological changes at the surface of OMM mimics was markedly different compared to IMM mimics. While globular deposits of mhtt with few fibrillar aggregates were observed on OMM, plateau-like domains were observed on IMM. A similar impact on htt aggregation was observed with exposure to purified mitochondrial-enriched fractions. Collectively, these observations suggest mitochondrial membranes heavily influence htt aggregation with implication for HD.     

Lifestyle interventions for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a multi-factorial disease and the most common of chronic liver diseases worldwide. The four clinical-pathological entities which are usually followed by NAFLD course include non-alcoholic steatosis, non-alcoholic steatohepatitis, advanced fibrosis/cirrhosis, and hepatocellular carcinoma. The cornerstones of NAFLD management and treatment, however, are healthy lifestyles such as dietary modifications, regular physical activity, and gradual weight loss. At present, no drugs or pharmacological agents have been approved for long-term treatment of NAFLD. Therefore, lifestyle modification is considered the main clinical recommendation and an initial step for the management of NAFLD.     

Efficacy and Mechanism of Angiotensin II Receptor Blocker Treatment in Experimental Abdominal Aortic Aneurysms

Background

Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease.

Methodology/Principal Findings

AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE^−/− mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE^−/− mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion.

Conclusion/Significance

Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.