Improved tests for heterogeneity across a region of DNA sequence in the ratio of polymorphism to divergence

The neutral theory of molecular evolution predicts that the ratio of polymorphisms to fixed differences should be fairly uniform across a region of DNA sequence. Significant heterogeneity in this ratio can indicate the effects of balancing selection, selective sweeps, mildly deleterious mutations, or background selection. Comparing an observed heterogeneity statistic with simulations of the heterogeneity resulting from random phylogenetic and sampling variation provides a test of the statistical significance of the observed pattern. When simulated data sets containing heterogeneity in the polymorphism-to-divergence ratio are examined, different statistics are most powerful for detecting different patterns of heterogeneity. The number of runs is most powerful for detecting patterns containing several peaks of polymorphism; the Kolmogorov-Smirnov statistic is most powerful for detecting patterns in which one end of the gene has high polymorphism and the other end has low polymorphism; and a newly developed statistic, the mean sliding G statistic, is most powerful for detecting patterns containing one or two peaks of polymorphism with reduced polymorphism on either side. Nine out of 27 genes from the Drosophila melanogaster subgroup exhibit heterogeneity that is significant under at least one of these three tests, with five of the nine remaining significant after a correction for multiple comparisons, suggesting that detectable evidence for the effects of some kind of selection is fairly common.      

Repeated triggering of sporulation in Bacillus subtilis selects against a protein that affects the timing of cell division

Bacillus subtilis sporulation is a last-resort phenotypical adaptation in response to starvation. The regulatory network underlying this developmental pathway has been studied extensively. However, how sporulation initiation is concerted in relation to the environmental nutrient availability is poorly understood. In a fed-batch fermentation set-up, in which sporulation of ultraviolet (UV)-mutagenized B. subtilis is repeatedly triggered by periods of starvation, fitter strains with mutated tagE evolved. These mutants display altered timing of phenotypical differentiation. The substrate for the wall teichoic acid (WTA)-modifying enzyme TagE, UDP-glucose, has recently been shown to be an intracellular proxy for nutrient availability, and influences the timing of cell division. Here we suggest that UDP-glucose also influences timing of cellular differentiation.     

Synthesis of a New Tri-Branched PEG-IFNα2 and Its Impact on Anti Viral Bioactivity

Efficacy of proteins can be enhanced by using polyethylene glycol (PEG) conjugation (PEGylation) to the protein molecules. Mobile non-toxic PEG chains conjugated to bio-therapeutics increase their hydrodynamic volume and in turn can prolong their plasma retention time and increase their solubility. An important aspect of PEGylation is the selection of PEG molecule with suitable structure and molecular weight. In this study, conceiving the idea that branched PEG-conjugates show superior efficacy over the linear PEG-conjugates, a tri-branched PEG-interferon (mPEG₃L₂-IFN) was synthesized by reacting a 30 KDa tri-branched mPEG₃L₂-NHS reagent with IFN to improve its pharmacokinetic properties and reduce the loss of in vitro bioactivity (which is generally exhibited by PEGylation) of the conjugated protein to some extent. The PEGylation procedure was optimized in terms of concentration and molar ratios of reactants, reaction time, temperature and pH conditions of the reaction mix. The conjugate was purified by cation exchange chromatography and characterized by SDS-PAGE and SE-HPLC. Trypsin digestion of mPEG₃L₂-IFN indicated a single site specificity of PEGylation. Anti viral bioactivity of mPEG₃L₂-IFN was found to be 2.38 × 10⁷ IU/mg which is approximately 9.52% of native IFNα2 (2.5 × 10⁸ IU/mg) and better than PEGasys from Roche Pharma. Therefore, it is reported that the tri-branched mPEG₃L₂-NHS reagent has the potential to be used to conjugate proteins for the promising therapeutic results.     

Time of day effect on balance performance,functional capacities and risk of fall in women with rheumatoid arthritis

ABSTRACT

Objective: This study explored the time of day effect of balance performance, functional capacities and risk of fall in three different times in patients with rheumatoid arthritis (RA) and the association between these variations and those of RA symptoms.

Methods: A “discontinual” protocol, composed of three test sessions, carried out at 6 am, 2 pm and 10 pm was set up, in order to investigate the time of day effect of balance performance, functional capacities, risk of fall, stiffness, range of motion, swollen and painful joints in women with RA.

Results: Time Up and Go Test (TUGT), Functional Reach Test (FRT) and tinetti test scores were significantly higher (p < .01) at 6 am and at 10 pm compared to 2 pm. Stiffness, range of motion, swollen and painful joints values were significantly higher (p < .01) at 6 am and at 10 pm compared to 2 pm. A significant difference was observed on the stiffness, range of motion and swollen joints values between 6 am and 10 pm that were higher at 6 am (p < .05).

Using Pearson’s coefficient, correlations were found between RA symptom values; and TUGT, FRT and Tinetti test scores.

Conclusion: Results showed a time of day effect of balance performance, functional capacities and risk of falls in women with RA. This variation indicates an alteration of performance at 6 am and 10 pm. Fluctuations of stiffness, limited range of motion, swollen and painful joints noted are concomitant to those of balance performance, functional capacities, and risk of fall.

Abbreviations: RA: rheumatoid arthritis; H&O questionnaire: Horne and Ostberg questionnaire; PSQI: Pittsburgh sleep quality index; HAQ: health assessment questionnaire; SF-36: the short form-36; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; TUGT: Time Up and Go Test; FRT: Functional Reach Test     

STRA6-Catalyzed Vitamin A Influx, Efflux, and Exchange

Vitamin A has diverse biological functions and is essential for human survival. STRA6 is the high-affinity membrane receptor for plasma retinol binding protein (RBP), the principle and specific carrier of vitamin A (retinol) in the blood. It was previously shown that STRA6 couples to lecithin retinol acyltransferase (LRAT) and cellular retinol binding protein I (CRBP-I), but poorly to CRBP-II, for retinol uptake from holo-RBP. STRA6 catalyzes both retinol release from holo-RBP, which is responsible for its retinol uptake activity, and the loading of free retinol into apo-RBP, which can cause retinol efflux. Although STRA6-catalyzed retinol efflux into apo-RBP can theoretically deplete cells of retinoid, it is unclear to what extent this efflux happens and in what context. We show here that STRA6 can couple strongly to both CRBP-I and CRBP-II for retinol efflux to apo-RBP. Strikingly, pure apo-RBP can cause almost complete depletion of retinol taken up by CRBP-I in a STRA6-dependent manner. However, if STRA6 encounters both holo-RBP and apo-RBP (as in blood), holo-RBP blocks STRA6-mediated retinol efflux by competing with apo-RBP’s binding to STRA6 and by counteracting retinol efflux with influx. We also found that STRA6 catalyzes efficient retinol exchange between intracellular CRBP-I and extracellular RBP, even in the presence of holo-RBP. STRA6’s retinol exchange activity may serve to refresh the intracellular retinoid pool. This exchange is also a previously unknown function of CRBP-I and distinguishes CRBP-I from LRAT.     

Chipping away at major depressive disorder

An intriguing recent study examines the role of miR-1202, a glutamate receptor regulating microRNA, in regulating major depressive disorder.     

Comparative analysis of genetic structure of 2 species of marine fish Dicentrarchus labrax and Dicentrarchus punctatus

We present here the genetic structure existing among five samples of the spotted sea bass Dicentrarchus punctatus, and we compare it to what prevails in the common sea bass D. labrax, a congeneric species sampled on almost the same geographical range. A genetic distance tree inferred from the polymorphism at six microsatellite loci shows a distinct pattern for the two species. D. labrax samples appears to be genetically more homogeneous with a global Fst of 3% as compared to the 10% observed at D. punctatus, indicating a lesser level of gene flow in the latter species. While appearing more differentiated, D. punctatus presents no clear geographical organisation of its genetic variability in opposition to D. labrax samples. This allows us to propose this pair of closely relative species as a good candidate for the study by comparative analysis of the biological and/or historical factors affecting genetic differentiation in marine environment.