Differential Network Analysis with Multiply Imputed Lipidomic Data

The importance of lipids for cell function and health has been widely recognized, e.g., a disorder in the lipid composition of cells has been related to atherosclerosis caused cardiovascular disease (CVD). Lipidomics analyses are characterized by large yet not a huge number of mutually correlated variables measured and their associations to outcomes are potentially of a complex nature. Differential network analysis provides a formal statistical method capable of inferential analysis to examine differences in network structures of the lipids under two biological conditions. It also guides us to identify potential relationships requiring further biological investigation. We provide a recipe to conduct permutation test on association scores resulted from partial least square regression with multiple imputed lipidomic data from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, particularly paying attention to the left-censored missing values typical for a wide range of data sets in life sciences. Left-censored missing values are low-level concentrations that are known to exist somewhere between zero and a lower limit of quantification. To make full use of the LURIC data with the missing values, we utilize state of the art multiple imputation techniques and propose solutions to the challenges that incomplete data sets bring to differential network analysis. The customized network analysis helps us to understand the complexities of the underlying biological processes by identifying lipids and lipid classes that interact with each other, and by recognizing the most important differentially expressed lipids between two subgroups of coronary artery disease (CAD) patients, the patients that had a fatal CVD event and the ones who remained stable during two year follow-up.     

Empirical evaluation of cytonuclear models incorporating genetic drift and tests for neutrality of mtDNA variants: data from experimental Gambusia hybrid zones

Statistical tests of genetic drift and of the neutrality of mtDNA are presented using empirical time‐series data on multi‐generational changes in cytonuclear disequilibria within replicated experimental hybrid populations of two species of live‐bearing Poeciliid fishes (Gambusia holbrooki and G.affinis) which were monitored over a period of two years (three generations). Cytonuclear disequilibria D and D (which measure departures from random associations of cytoplasmic and nuclear genotypes) over the three generations of the experiment were non‐zero for all replicate populations. For each of five nuclear loci, the observed measures of D and D were highly concordant between replicates during each generation. Significant departures from expectations were observed after one and two generations. A statistical measure of goodness of fit of observed changes in cytonuclear disequilibria (and implicitly of the neutrality of the mtDNA markers) was calculated for each nuclear locus. When the results for the replicates were combined into an overall test of neutrality, the fit to the random union of zygotes (RUZ) model was rejected for four of the five nuclear loci (P < 0.05). A simple genetic drift model does not explain the temporal changes in composite cytonuclear genotypic frequencies. Frequencies of parental G. holbrooki mitochondrial alleles and nuclear genotypes exceeded expected values during most time periods, implying some selective advantage of offspring produced by G. holbrooki females. Expansion of cytonuclear models to explicitly address questions of genetic drift and neutrality have general relevance to studies of natural populations. This revised version was published online in July 2006 with corrections to the Cover Date.     

Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome

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Computational biology touches all bases

A report of the 6th Annual Rocky Mountain Bioinformatics Conference, Aspen, USA, 4-7 December 2008.     

Unit Cost of Medical Services at Different Hospitals in India

Institutional care is a growing component of health care costs in low- and middle-income countries, but local health planners in these countries have inadequate knowledge of the costs of different medical services. In India, greater utilisation of hospital services is driven both by rising incomes and by government insurance programmes that cover the cost of inpatient services; however, there is still a paucity of unit cost information from Indian hospitals. In this study, we estimated operating costs and cost per outpatient visit, cost per inpatient stay, cost per emergency room visit, and cost per surgery for five hospitals of different types across India: a 57-bed charitable hospital, a 200-bed private hospital, a 400-bed government district hospital, a 655-bed private teaching hospital, and a 778-bed government tertiary care hospital for the financial year 2010–11. The major cost component varied among human resources, capital costs, and material costs, by hospital type. The outpatient visit cost ranged from Rs. 94 (district hospital) to Rs. 2,213 (private hospital) (USD 1 = INR 52). The inpatient stay cost was Rs. 345 in the private teaching hospital, Rs. 394 in the district hospital, Rs. 614 in the tertiary care hospital, Rs. 1,959 in the charitable hospital, and Rs. 6,996 in the private hospital. Our study results can help hospital administrators understand their cost structures and run their facilities more efficiently, and we identify areas where improvements in efficiency might significantly lower unit costs. The study also demonstrates that detailed costing of Indian hospital operations is both feasible and essential, given the significant variation in the country’s hospital types. Because of the size and diversity of the country and variations across hospitals, a large-scale study should be undertaken to refine hospital costing for different types of hospitals so that the results can be used for policy purposes, such as revising payment rates under government-sponsored insurance schemes.     

The α5 Subunit Regulates the Expression and Function of α4*-Containing Neuronal Nicotinic Acetylcholine Receptors in the Ventral-Tegmental Area

Human genetic association studies have shown gene variants in the α5 subunit of the neuronal nicotinic receptor (nAChR) influence both ethanol and nicotine dependence. The α5 subunit is an accessory subunit that facilitates α4* nAChRs assembly in vitro. However, it is unknown whether this occurs in the brain, as there are few research tools to adequately address this question. As the α4*-containing nAChRs are highly expressed in the ventral tegmental area (VTA) we assessed the molecular, functional and pharmacological roles of α5 in α4*-containing nAChRs in the VTA. We utilized transgenic mice α5+/+(α4YFP) and α5-/-(α4YFP) that allow the direct visualization and measurement of α4-YFP expression and the effect of the presence (α5+/+) and absence of α5 (-/-) subunit, as the antibodies for detecting the α4* subunits of the nAChR are not specific. We performed voltage clamp electrophysiological experiments to study baseline nicotinic currents in VTA dopaminergic neurons. We show that in the presence of the α5 subunit, the overall expression of α4 subunit is increased significantly by 60% in the VTA. Furthermore, the α5 subunit strengthens baseline nAChR currents, suggesting the increased expression of α4* nAChRs to be likely on the cell surface. While the presence of the α5 subunit blunts the desensitization of nAChRs following nicotine exposure, it does not alter the amount of ethanol potentiation of VTA dopaminergic neurons. Our data demonstrates a major regulatory role for the α5 subunit in both the maintenance of α4*-containing nAChRs expression and in modulating nicotinic currents in VTA dopaminergic neurons. Additionally, the α5α4* nAChR in VTA dopaminergic neurons regulates the effect of nicotine but not ethanol on currents. Together, the data suggest that the α5 subunit is critical for controlling the expression and functional role of a population of α4*-containing nAChRs in the VTA.     

Influence of ethnicity, geography and climate on the variation of stature among Indian populations

This paper analyzes the variation in the mean stature of adult males of a variety of population groups in India and examines the influence of geographical, climatic and ethnic factors on it. A considerable variation in mean stature has been found with respect to these three attributes. Variation "between" ethnic groups compared with "within" ethnic groups was found to be much more than that of geographical and climatic zones. Scheduled Castes (SC) and Scheduled Tribes (ST) populations have much low average height than that of General Castes (GC). Climatically dry and semiarid zones have a tendency to have higher stature than in the Monsoon areas. The mean height has been found to be the highest in north India. It is closely followed by west India. An interesting feature is that as one goes towards east and south the mean height gradually decreases. It is the lowest in islands. The mean heights have been regressed on geographical, climatic and ethnic factors, after converting these factors into binary variables. The regression analysis has strengthened the findings, that there is a highly significant relationship between height and geographical, climatic and ethnic factors.     

Socioeconomic differentials in nutritional status of children in the states of West Bengal and Assam, India

Malnutrition among children is prevalent in almost all the states in India. This study assesses the extent and causes of malnutrition in two eastern Indian states with similar climates, namely West Bengal and Assam, using data from the National Family Health Survey 1998-99 (NFHS-2). The three indices of malnutrition taken for analysis are weight-for-height (WHZ), height-for-age (HAZ) and weight-for-age (WAZ). These are assumed to depend on birth order, preceding birth interval, parent's educational status, working status of the mother, mother's age at delivery of the children, source of drinking water, toilet facilities and standard of living of the household. Logistic regression was carried out separately for each of the three indices on the explanatory variables for both the states. It was found that not all variables are equally important in determining whether a baby is underweight, or suffering from acute or chronic malnutrition. Also, the importance of variables is not the same in the two states. It was observed that the coefficients associated with the variables in determining weight-for-height are not significant compared with those for weight-for-age and height-for-age.     

Equilibrium and structural studies on Co(II), Ni(II), Cu(II) and Zn(II) complexes with N-(2-benzimidazolyl)methyliminodiacetic acid: crystal structures of Ni(II) and Cu(II) complexes

Combined pH-metric, UV-Vis, ¹H NMR and EPR spectral investigations on the complex formation of M(II) ions (M=Co, Ni, Cu and Zn) with N-(2-benzimidazolyl)methyliminodiacetic acid (H₂bzimida, hereafter H₂L) in aqueous solution at a fixed ionic strength, I=10⁻¹ mol dm⁻³, at 25 ± 1 °C indicate the formation of M(L), M(H₋₁L)⁻ and M₂(H₋₁L)⁺ complexes. Proton-ligand and metal-ligand constants and the complex formation equilibria have been elucidated. Solid complexes, [M(L)(H₂O)₂] · nH₂O (n=1 for M = Co and Zn, n=2 for M = Ni) and {Cu (μ-L) · 4H₂O}_n, have been isolated and characterized by elemental analysis, spectral, conductance and magnetic measurements and thermal studies. Structures of [Ni(L)(H₂O)₂] · 2H₂O and {Cu(μ-L) · 4H₂O}_n have been determined by single crystal X-ray diffraction. The nickel(II) complex exists in a distorted octahedral environment in which the metal ion is coordinated by the two carboxylate O atoms, the amino-N atom of the iminodiacetate moiety and the pyridine type N-atom of the benzimidazole moiety. Two aqua O atoms function as fifth and sixth donor atoms. The copper(II) complex is made up of interpenetrating polymeric chains of antiferromagnetically coupled Cu(II) ions linked by carboxylato bridges in syn-anti (apical-equatorial) bonding mode and stabilized via interchain hydrogen bonds and π-π stacking interactions.