Efforts toward the first total synthesis of a mixed-ligand siderophore: Gobichelin-A

The synthesis of Gobichelin-A, a naturally occurring mixed-ligand siderophore isolated from Streptomyces sp. NRRL F-4415, is described. The target molecule was planned to be synthesized by a convergent process involving the combination of two halves, Gob-A 1st half and Gob-A 2nd half, at the prefinal stage of the synthetic route. By adopting this method, fully protected Gobichelin-A was synthesized in excellent yield.     

Characterization of Early Disease Status in Treatment-Naive Male Paediatric Patients with Fabry Disease Enrolled in a Randomized Clinical Trial

Trial Design

This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.

Methods

Males aged 5–18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13–17 years), renal function, and glycolipid levels (plasma, urine).

Results

Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m² (range 90.4–161.0 mL/min/1.73 m²) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0–27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.

Conclusions

These data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.

Trial Registration

ClinicalTrials.gov NCT00701415     

Effect of cortisol on testis of freshwater fish Notopterus notopterus (Pallas).

Cortisol (20, 40 and 60 micrograms/fish for 10 days) treatment caused an increase in testicular-somatic index (TSI) in immature N. notopterus whereas in mature fish no change from that of controls was observed. Histology of testis indicated that spermatogenetic activity was activated in immature fish while it was inhibited in mature fish. Testicular cholesterol exhibited a similar response. The results indicate that cortisol inhibits spermatogenesis during mature phase while it promotes spermatogenesis during immature phase of the reproductive cycle in N. notopterus.     

Genetics of resistance to cotton leaf curl disease in Gossypium hirsutum L. under field conditions

One hundred and forty two cotton germplasm lines were screened for cotton leaf curl virus symptoms in field evaluations during 2003, 2004, and 2005. Fifty cross combinations involving 30 of these lines classified resistant or susceptible were used for inheritance study of the disease. All the F(1) plants of crosses involving resistant x resistant, resistant x susceptible, and susceptible x resistant parents were resistant, indicating dominant expression of the disease resistance and there were no maternal or cytoplasmic effects detected from reciprocal hybridization. In 22 crosses, 4 types of segregation patterns were obtained in the F(2) generations. A good fit for 15 (resistant):1 (susceptible), 13 (resistant):3 (susceptible), 9 (resistant):7 (susceptible) ratios indicated digenic control of the trait with duplicate dominant, dominant inhibitory, and duplicate recessive epistasis, respectively. Three-gene control with triplicate dominant epistasis was obtained in one of the crosses. This segregation pattern, however, needs further confirmation due to smaller population size. The absence of complementary gene action was obtained in 1 susceptible x susceptible and 27 resistant x resistant crosses as their F(1)s were susceptible and resistant, respectively, and F(2) generation lacked segregation.     

Ion pairs in non-redundant protein structures

Ion pairs contribute to several functions including the activity of catalytic triads, fusion of viral membranes, stability in thermophilic proteins and solvent-protein interactions. Furthermore, they have the ability to affect the stability of protein structures and are also a part of the forces that act to hold monomers together. This paper deals with the possible ion pair combinations and networks in 25% and 90% non-redundant protein chains. Different types of ion pairs present in various secondary structural elements are analysed. The ion pairs existing between different subunits of multisubunit protein structures are also computed and the results of various analyses are presented in detail. The protein structures used in the analysis are solved using X-ray crystallography, whose resolution is better than or equal to 1.5 A and R-factor better than or equal to 20%. This study can, therefore, be useful for analyses of many protein functions. It also provides insights into the better understanding of the architecture of protein structure.     

Prediction of enzymes and non-enzymes from protein sequences based on sequence derived features and PSSM matrix using artificial neural network

The problem of predicting the enzymes and non-enzymes from the protein sequence information is still an open problem in bioinformatics. It is further becoming more important as the number of sequenced information grows exponentially over time. We describe a novel approach for predicting the enzymes and non-enzymes from its amino-acid sequence using artificial neural network (ANN). Using 61 sequence derived features alone we have been able to achieve 79 percent correct prediction of enzymes/non-enzymes (in the set of 660 proteins). For the complete set of 61 parameters using 5-fold cross-validated classification, ANN model reveal a superior model (accuracy = 78.79 plus or minus 6.86 percent, Q(pred) = 74.734 plus or minus 17.08 percent, sensitivity = 84.48 plus or minus 6.73 percent, specificity = 77.13 plus or minus 13.39 percent). The second module of ANN is based on PSSM matrix. Using the same 5-fold cross-validation set, this ANN model predicts enzymes/non-enzymes with more accuracy (accuracy = 80.37 plus or minus 6.59 percent, Q(pred) = 67.466 plus or minus 12.41 percent, sensitivity = 0.9070 plus or minus 3.37 percent, specificity = 74.66 plus or minus 7.17 percent).     

Treatment of paper factory effluent using a phenol degrading Alcaligenes sp. under free and immobilized conditions

Treatment of the paper factory effluent was done with free and immobilized cells of a phenol degrading Alcaligenes sp. d(2). The free cells could bring a maximum of 99% reduction in phenol and 40% reduction in chemical oxygen demand (COD) after 32 and 20 h of treatment, respectively. In the case of immobilized cells, a maximum of 99% phenol reduction and 70% COD reduction was attained after 20 h of treatment under batch process. In the continuous mode of operation using packed bed reactor, the strain was able to give 99% phenol removal and 92% COD reduction in 8h of residence time The optimum flow rate was 2.5 ml/h and the half life period was 76 h. Even after the complete removal of phenol, the strain could further enhance reduction in chemical oxygen demand, which clearly indicated that in the paper factory effluent, this strain could also oxidize organic matter other than phenol.