On partial local smoothing rules for curve estimation

We compare the performances of local and global rules for smoothingparameter choice, in terms of asymptotic mean squared errorsof the resulting estimators. In some instances there is surprisinglylittle to choose between local and global approaches; our analysisidentifies contexts where the differences are small or large.This work motivates development of smoothing rules that forma ‘half-way house’ between local and global smoothing.There, interpolation provides a basis for partial local smoothing.A key result shows that interpolation on even a coarse gridcan produce a very good approximation to full local smoothing.Our theoretical and numerical results lead us to suggest linearinterpolation of a bandwidth obtained by integral approximationson discrete intervals.     

Denitrifying population dynamic and evolution of nitrogen gas during a composting process

Abstract Little information exists about nitrogen losses through microbial activity during treatment of solid urban waste (SUW) by processes such as composting. In the present study, in addition to evaluating the pattern of nitrogen losses by denitrification at different stages of the process, a comparison between the method of Pochon and Tardieux, and an improved gas chromatographic method for estimating denitrifying populations was undertaken, Though the MPN (Most Probable Number) enumerations were higher using the colorimetric method than the gas chromatographic one, the patterns of the two graphs showing numbers of denitrifiers during composing were the same. The highest numbers were revealed immediately after loading the reactor (10⁷–10⁸/g d.w.), lower numbers of denitrifiers were found in the second sampling corresponding to the thermophilic phase (10³–10⁴/g d.w.). These numbers increased gradually as the waste material stabilized (10th to 123rd day of composting) to again reach values of 10⁷–10⁸/g d.w.     

Saroglitazar is noninferior to fenofibrate in reducing triglyceride levels in hypertriglyceridemic patients in a randomized clinical trial

Saroglitazar, being a dual PPAR-α/γ agonist, has shown beneficial effect in diabetic dyslipidemia and hypertriglyceridemia. Fibrates are commonly used to treat severe hypertriglyceridemia. However, the effect of saroglitazar in patients with moderate to severe hypertriglyceridemia was not evaluated. We conducted a study to compare the efficacy and safety of saroglitazar (4 mg) with fenofibrate (160 mg) in patients with moderate to severe hypertriglyceridemia. This was a multicenter, randomized, double-blinded, double-dummy, active-control, and noninferiority trial in adult patients with fasting triglyceride (TG) levels of 500–1,500 mg/dl. The patients were randomized in a 1:1 ratio to receive daily dose of saroglitazar or fenofibrate for 12 weeks. The primary efficacy end point was the percent change in TG levels at week 12 relative to baseline. The study comprised of 41 patients in the saroglitazar group and 41 patients in the fenofibrate group. We found that the percent reduction from baseline in TG levels at week 12 was significantly higher in the saroglitazar group (least square mean = ?55.3%; SE = 4.9) compared with the fenofibrate group (least square mean = ?41.1%; SE = 4.9; P = 0.048). Overall, 37 treatment-emergent adverse events (AEs) were reported in 24 patients (saroglitazar: 13; fenofibrate: 11). No serious AEs were reported, and no patient discontinued the study because of AEs. We conclude that saroglitazar (4 mg) is noninferior to fenofibrate (160 mg) in reducing TG levels after 12 weeks of treatment, was safe, and well tolerated.     

Site-specific modification of the bovine genome using Cre recombinase-mediated gene targeting.

Cre recombinase (Cre)-mediated targeted insertion of a transgene is a powerful technique that can be used to tailor genomes. When combined with somatic cell nuclear transfer it could offer an efficient way to generate transgenic livestock with site-specific genetic modifications that are free of antibiotic selection markers. We have engineered primary bovine fibroblasts to contain a chromosomal acceptor site with incompatible loxP/lox2272 sites for Cre-mediated cassette exchange and show for the first time that Cre-mediated targeting can be applied in these acceptor cells. Molecular characterization of the resulting cell clones revealed Cre-mediated transgene insertion efficiencies of up to 98% when antibiotic selection was used to identify transgene containing cell clones. Most clonal lines also contained random insertions of the targeting and Cre expression plasmids with only about 10% of the clones being exclusively modified by the intended targeted insertion. This targeting efficiency was sufficient to enable the isolation of correctly targeted clones without the help of antibiotic selection. Therefore, this recombinase-mediated insertion strategy has the potential to produce transgenic cattle from antibiotic selection marker-free somatic cells with transgenes inserted into proven genomic loci ensuring reliable expression levels.     

A Conservative Point Mutation in a Dynamic Antigen-binding Loop of Human Immunoglobulin λ6 Light Chain Promotes Pathologic Amyloid Formation

Immunoglobulin light chain (LC) amyloidosis (AL) is a life-threatening human disease wherein free mono-clonal LCs deposit in vital organs. To determine what makes some LCs amyloidogenic, we explored patient-based amyloidogenic and non-amyloidogenic recombinant LCs from the λ6 subtype prevalent in AL. Hydrogen-deuterium exchange mass spectrometry, structural stability, proteolysis, and amyloid growth studies revealed that the antigen-binding CDR1 loop is the least protected part in the variable domain of λ6 LC, particularly in the AL variant. N32T substitution in CRD1 is identified as a driver of amyloid formation. Substitution N32T increased the amyloidogenic propensity of CDR1 loop, decreased its protection in the native structure, and accelerated amyloid growth in the context of other AL substitutions. The destabilizing effects of N32T propagated across the molecule increasing its dynamics in regions ∼30 Å away from the substitution site. Such striking long-range effects of a conservative point substitution in a dynamic surface loop may be relevant to Ig function. Comparison of patient-derived and engineered proteins showed that N32T interactions with other substitution sites must contribute to amyloidosis. The results suggest that CDR1 is critical in amyloid formation by other λ6 LCs.     

Reductive Biotransformation of Benzaldehyde Derivatives by Baker's Yeast in Non-Conventional Media: Effect of Substrate Hydrophobicity on the Biocatalytic Reaction

The reduction of six derivatives of benzaldehyde, α,α,α-trifluorotolualdehyde, nitrobenzaldehyde, anisaldehyde, fluorobenzaldehyde, tolualdehyde, chlorobenzaldehyde, each of which was substituted in the ortho-, meta- and para-positions, was investigated in whole cell yeast biotransformations conducted in non-conventional media. Correlation between hydrophobic (π) and electronic (σ) parameters of the substituent of the substrate and biocatalytic activity in organic solvent media (hexane containing 2% v/v water) was evaluated. While catalytic activity in general decreased as the substituent hydrophobicity (π) increased, the trend was more pronounced for ortho- substituents compared to meta- and para-. When the electronic parameters (σ) of the meta- and para- substituents were correlated with the catalytic activity, the opposite was observed, namely the catalytic activity increased as the electronic parameter of the substituent increased. This observation was similar for meta- and para- substituents.

Preliminary studies on the relationships between solvent and substrate polarity on the one hand and catalytic activity on the other are also presented and discussed.     

Pockmarks enhance deep‐sea benthic biodiversity: a case study in the western Mediterranean Sea

Aim Pockmarks are craters on the sea floor formed by sub‐sea‐floor fluid expulsions, which occur world‐wide at all ocean depths. These habitats potentially host a highly specialized fauna that can exploit the hydrocarbons released. Pockmarks at relatively shallow depths can be easily destroyed by human activities, such as bottom trawling. In the present study, we investigated the combined effects of sea‐floor heterogeneity, rate of fluid emission and trophic conditions of different pockmarks on the biodiversity of the deep‐sea assemblages. Location Continental slope of the Gulf of Lions, western Mediterranean Sea, at water depths from 265 to 434 m. Methods We investigated the biodiversity associated with sea‐floor pockmarks that are both inactive and that have active gas emissions. Control sites were selected on the sea floor outside the influence of the gas seepage, both within and outside the pockmark fields. We examined the combined effects of: (i) sea‐floor heterogeneity; (ii) variable levels of fluid (gas) emissions; and (iii) trophic characteristics of the meiofaunal assemblage structure and nematode diversity. Results Sediments within the pockmark fields had lower meiofaunal abundance and biomass when compared with the surrounding sediments that were not influenced by the gas seepage. Although several higher taxa were absent in the pockmarks (e.g. Turbellaria, Tardigrada, Cumacea, Isopoda, Tanaidacea, Nemertina and Priapulida, which were present in the control areas), the richness of the nematode species within all of these pockmarks was very high. About 25% of the total species encountered in the deep‐sea sediments of the investigated areas was exclusively associated with these pockmarks. Main conclusions We conclude that both active and inactive pockmarks provide significant contributions to the regional (gamma) diversity of the continental slope in the western Mediterranean Sea, and thus the protection of these special and fragile habitats is highly relevant to the conservation of deep‐sea biodiversity.     

Sequential polypeptides: 5. Statistical mechanical analysis of helix-coil transition in sequential polypeptides

A statistical mechanical theory of the helix-coil transition in sequential polypeptides is developed assuming that the statistical weights of the Zimm-Bragg parameters of a given residue depend on the type of adjacent residues. In the case of a sequential polypeptide consisting of two kinds of residues, the theory describes the helix- coil transition of the polypeptide in terms of the Zimm-Bragg parameters associated with the corresponding residues. The theory is then used to determine this parameter, as a function of temperature, from experimental data for transition temperature as a function of solvent composition, for a series of sequential polypeptides consisting of Glu(OBzl) and Lys(Chz) residues in mixtures of dichloroacetic acid and 1,2-dichlorethane. This parameter is then combined with the Zimm-Bragg parameters for the parent homopolypeptides, and the theory used to predict helix coil transition curves which are in good agreement with the experimental ones for the sequential polypeptides studied.