First evidence of pathogenicity of V234I mutation of hVAPB found in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis is a motor neurodegenerative disease which is characterized by progressive loss of motor neurons followed by paralysis and eventually death. In human, VAMP-associated protein B (VAPB) is the causative gene of the familial form of ALS8. Previous studies have shown that P56S and T46I point mutations of hVAPB are present in this form of ALS. Recently, another mutation, V234I of hVAPB was found in one familial case of ALS. This is the first study where we have shown that V234I-VAPB does not form aggregate like other two mutants of VAPB and localizes differently than the wild type VAPB. It induces Ubiquitin aggregation followed by cell death. We propose that V234I-VAPB exhibits the characteristics of ALS in spite of not having the typical aggregation property of different mutations in various neurodegenerative diseases.     

Phytochemical analysis of <Emphasis Type="Italic">Andrographis paniculata</Emphasis> extract and its antimicrobial activity

The present study describes the phytochemical profile and antimicrobial activity of Andrographis paniculata. For the present investigation, two samples of A. paniculata extracts, obtained by extraction in chloroform and chloroform + HCl, respectively, were compared for their antimicrobial activity and further subjected to GC-MS analysis to find out the nature of the compounds responsible for the antimicrobial activity. The antibacterial activities were assessed by measuring the diameter of the inhibition zones, MIC and MBC values. Compared to the chloroform + HCl extract, the chloroform extract showed better antimicrobial activity against all the nine pathogenic bacterial strains tested. The chloroform extract was observed to be active against the opportunistic and pathogenic gram-negative bacteria, indicating its potential application related to noscomial infections. GC-MS results revealed phenols, aromatic carboxylic acids and esters in the chloroform extract to be the molecules responsible for the antimicrobial activity of A. paniculata. This is the first report on analysis of antimicrobial components from A. paniculata, and our results confer the utility of this plant extract in developing a novel broad spectrum antimicrobial agent.     

Cucurbitacin B Suppresses Hyperglycemia Associated with a High Sugar Diet and Promotes Sleep in Drosophila melanogaster

Secondary metabolites enable plants to protect themselves from herbivorous insects. Among these, cucurbitacin B (cuc-B) is a bitter-tasting compound with promising pharmacological potential. Dietary exposure to cuc-B lowered the hemolymph glucose levels of Drosophila melanogaster fed with a high carbohydrate diet, which is homologous to high blood glucose in humans, and its effect was comparable to that of metformin, a well-known glucose-lowering drug. Furthermore, cuc-B reduced tissue sugar levels and glycogen levels, as well as triacylglycerol levels. Our results thus highlight the potential applicability of this compound to treat chronic metabolic diseases such as diabetes and obesity. Additionally, we analyzed sleep quality and taste-associative memory enhancement after cuc-B and metformin treatment. Both supplements increased nighttime bout length and metformin increased memory consolidation. Therefore, discarded shell of Cucurbitaceae could be processed into health supplements.     

Determinants of chronic malnutrition among preschool children in Bangladesh

This study investigated the impact of some socioeconomic, demographic and health and community factors on chronic malnutrition or stunting in Bangladeshi children aged less than 5 years. The analysis revealed that the overall prevalence of stunting was 44%, of which 18% of children were severely stunted, and the demographic characteristics appeared to be the most significant factors for chronic malnutrition. Multinomial logistic regression analysis showed that parents' education, household economic status, media exposure, number of under-5 children, place of delivery, child's age, birth order, months of breast-feeding, birth size, mother's BMI, mother's height, age of household head, measles vaccine, supplementation of diet with liquids and regional differentials were significantly associated with severe as well as moderate stunting.     

Synthesis, crystal structures and magnetic studies of dicyanamide bridged two new 1D copper(II) complexes

Two new dicyanamide bridged 1D polynuclear copper(II) complexes [Cu(L¹){μ_1,5-N(CN)₂}]_n (1) [L¹H = C₆H₅C(O)NHNC(CH₃)C₅H₄N] and [Cu(L²){μ_1,5-N(CN)₂}]_n (2) [L²H=C₆H₅C(O)CHC(CH₃)NCH₂CH₂N(CH₃)₂] have been synthesised and structures of both the complexes and their crystal packing arrangements have been established by X-ray crystallography. For complex 1, a tridentate hydrazone ligand (L¹H) obtained by the condensation of benzhydrazide and 2-acetylpyridine is used, whereas a tridentate Schiff base (L²H) derived from benzoylacetone and 2-dimethylaminoethylamine is employed for the preparation of complex 2. Variable temperature magnetic susceptibility measurement studies indicate there are weak antiferromagnetic interactions with J values −0.10 and −1.41 cm⁻¹ for 1 and 2, respectively.     

Intracellular degradation of poly(3-hydroxybutyric acid) accumulated by Azotobacter chroococcum MAL-201

Azotobacter chroococcum MAL-201 accumulates poly(3-hydroxybutyric acid) [P(3HB)] accounting 69% of cell dry weight (CDW) from glucose during growth in nitrogen-free Stockdale medium. Degradation of the accumulated polymer by the organism was studied under carbon-free medium following two-step cultivation method. P(3HB) content of cells decreased rapidly from 69% to 4.8% of CDW after 35 h under carbon-deprived condition. Autodigestion of P(3HB) was evident from the estimation of intracellular P(3HB) depolymerase (i-depolymerase) activity in cell-free extract using artificial P(3HB) granules as substrate. Polymer content decreased rapidly along with the increase in i-depolymerase activity and rate of polymer degradation when medium was supplemented with (NH4)2SO4 at 0.1% (w/v) level. However, the effects were reverse when organic nitrogenous substrate, beef extract at similar concentration was present in the medium. The optimum temperature and pH for i-depolymerase activity were 35 degrees C and 7.7 respectively. The oxygen-limiting condition (culture volume per flask volume, 50%) decreased 10.7% activity of i-depolymerase over control resulting a slow P(3HB) degradation. The presence of NaCl (6 x 10(3) microg/ml) showed a positive effect on i-depolymerase whereas EDTA (40 microg/ml) resulted in 20% less activity. Furthermore, the intracellular degradation of P(3HB) decreased the intrinsic viscosity, molecular weight and tensile strength of the accumulated polymer.     

In silico prediction of yeast deletion phenotypes

Analysis of gene deletions is a fundamental approach for investigating gene function. We evaluated an algorithm that uses classification techniques to predict the phenotypic effects of gene deletions in yeast. We used a modified simulated annealing algorithm for feature selection and weighting. The selected features with high weights were phylogenetic conservation scores for bacteria, fungi (excluding Ascomycota), Ascomycota (excluding Saccharomyces cerevisiae), plants, and mammals, degree of paralogy, and number of protein-protein interactions. Classification was performed by weighted k-nearest neighbor and with support vector machine algorithms. To demonstrate how this approach might complement existing experimental procedures, we applied our algorithm to predict essential genes and genes causing morphological alterations in yeast.     

A new blue luminescent dichlorido-bridged dinuclear copper(II) complex with DNA binding and cytotoxic activities: Synthesis, structure and DFT studies

A blue luminescent dichlorido-bridged dinuclear copper(II) (S = 1/2) complex, [Cu^II₂(HL)₂(μ-Cl)₂]·2H₂O, 1a was synthesized with the 1:1 reaction of the acyclic tridentate salicylaldehyde 2-pyridyl hydrazone ligand, HL, 1. The complex 1a displays multiple bands in the visible region (400-470 nm). The association constant (K_ass, UV-Vis) was found to be 1.186 × 10⁴ for 1a at 298 K. The copper(II)-copper(III) oxidation potential lies near 0.32 V versus Ag/AgCl electrode. On excitation at 390 nm, the ligand 1 strongly emits at 444 nm due to an intraligand ¹(π-π^∗) transition. Upon complexation with copper(II) the emission peak is slightly red shifted (λ_ex 390 nm, λ_em 450 nm, F/F₀ 0.81) with little quenching. Molecular structure of 1a (Cu···Cu 3.523 Å) has been determined by single crystal X-ray diffraction studies. DFT and TDDFT calculations strongly support the spectral behavior of the ligand and the complex. The complex 1a exhibits a strong interaction towards DNA as revealed from the K_b (intrinsic binding constant) 2.05 × 10⁴ M⁻¹ and K_sv (Stern-Volmer quenching constant) 2.47 values. The complex exhibits cytotoxic effect and the LD₅₀ value for HeLa cells was calculated as 5.44 μM at which the cell cycle was arrested at G₂/M phase.     

Selective delivery of rifampicin incorporated into poly(DL-lactic-co-glycolic) acid microspheres after phagocytotic uptake by alveolar macrophages, and the killing effect against intracellular Mycobacterium bovis Calmette-Guérin

Macrophages and their phagocytotic abilities play a dominant role for defense against infected organisms. However, Mycobacterium tuberculosis can survive in the phagosomes of macrophages. In this study, the effective delivery of a drug and the killing effect of tubercle bacilli within macrophages were investigated utilizing the phagocytotic uptake of rifampicin (RFP) that had been incorporated into poly(DL-lactic-co-glycolic) acid (PLGA) microspheres. The microspheres were composed of PLGA that had a monomer ratio (lactic acid/glycolic acid) of either 50/50 or 75/25. They had molecular weights from 5000 to 20,000, and diameters of 1.5, 3.5, 6.2 and 8.9 microm. The most significant factor for phagocytotic activity of macrophages was the diameter of the microspheres. By contrast, molecular weight and monomer ratio of PLGA did not influence phagocytosis. The amount of RFP delivered into cells was also investigated. RFP-PLGA microspheres composed of PLGA with a molecular weight of 20,000 and monomer ratio of 75/25 showed the highest amount of delivery (4 microg/1 x 10(6) cells). Fourteen days after infection, the survival rate of treated intracellular bacilli was 1% when compared with untreated cells. There was almost no killing effect of free RFP (4 or 15 microg/ml) on intracellular bacilli. In vivo efficacy of RFP-PLGA was also examined in rats infected with M. tuberculosis Kurono. Intratracheal administration of RFP-PLGA microspheres was shown to be superior to free RFP for killing of intracellular bacilli and preventing granuloma formation in some lobes. These results suggest that phagocytotic activity could be part of a new drug delivery system that selectively targeted macrophages.     

Haplotype-based case-control study of CYP4A11 gene and myocardial infarction

CYP4A11, which is a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the maintenance of cardiovascular health. Recently, it was reported that many subfamilies of CYP genes have an association with myocardial infarction (MI). The aim of the present study was to assess the association between the human CYP4A11 gene and MI, using a haplotype-based case-control study with a separate analysis of the gender groups. A total of 239 MI patients and 285 controls were genotyped for 3 single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). The data obtained via haplotype-based case-control studies were assessed for 3 separate groups: total subjects, men, and women. For the total, men and women groups, the distribution of the genotypes and alleles of the 3 SNPs did not show any significant difference between the MI patients and the control subjects. For the total and the men groups, the overall distribution of the haplotypes constructed with the 3 SNPs significantly differed between the MI patients and control subjects (P < 0.001). Also, for the total and for the men, the frequency of the T-T-A haplotype constructed with the 3 SNPs was significantly lower for the MI patients than for the control subjects (both P 相似文献