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61.
Mucopolysaccharidoses (MPS) are inherited metabolic diseases from the group of lysosomal storage disorders (LSD). They are caused by genetic defects resulting in the absence or severe deficiency in one of lysosmal hydrolases involved in degradation of glycosaminoglycans (GAG). Partially degraded GAGs are accumulated in lysosomes, causing dysfunction of cells, tissues and organs. Last years did bring some breakthrough discoveries, which were important to understand biochemical mechanisms of MPS appearance and course, as well as to develop therapeutic procedures for these inherited metabolic disorders. 相似文献
62.
63.
Vittorio Canale Anna Partyka Rafał Kurczab Martyna Krawczyk Tomasz Kos Grzegorz Satała Bartłomiej Kubica Magdalena Jastrzębska-Więsek Anna Wesołowska Andrzej J. Bojarski Piotr Popik Paweł Zajdel 《Bioorganic & medicinal chemistry》2017,25(10):2789-2799
A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT7R antagonists. Among the compounds evaluated herein, 3-chloro-N-{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide (25) exhibited antagonistic properties at 5-HT7R and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.625–2.5 mg/kg, i.p.) and in the tail suspension test (1.25 mg/kg, i.p.), augmented the antidepressant effect of inactive doses of escitalopram (selective serotonin reuptake inhibitor) and bupropion (dopamine reuptake inhibitor) in the FST in mice, and similarly to SB-269970, exerted pro-cognitive properties in the novel object recognition task in cognitively unimpaired conditions in rats (0.3 mg/kg, i.p.). Such an extended pharmacological profile, especially the augmentation effect of the identified 5-HT7R antagonist on SSRI activity, seems promising regarding the complexity of affective disorders and potentially improved outcomes, including mnemonic performance. 相似文献
64.
Jansen S Collins A Yang C Rebowski G Svitkina T Dominguez R 《The Journal of biological chemistry》2011,286(34):30087-30096
Fascin is the main actin filament bundling protein in filopodia. Because of the important role filopodia play in cell migration, fascin is emerging as a major target for cancer drug discovery. However, an understanding of the mechanism of bundle formation by fascin is critically lacking. Fascin consists of four β-trefoil domains. Here, we show that fascin contains two major actin-binding sites, coinciding with regions of high sequence conservation in β-trefoil domains 1 and 3. The site in β-trefoil-1 is located near the binding site of the fascin inhibitor macroketone and comprises residue Ser-39, whose phosphorylation by protein kinase C down-regulates actin bundling and formation of filopodia. The site in β-trefoil-3 is related by pseudo-2-fold symmetry to that in β-trefoil-1. The two sites are ~5 nm apart, resulting in a distance between actin filaments in the bundle of ~8.1 nm. Residue mutations in both sites disrupt bundle formation in vitro as assessed by co-sedimentation with actin and electron microscopy and severely impair formation of filopodia in cells as determined by rescue experiments in fascin-depleted cells. Mutations of other areas of the fascin surface also affect actin bundling and formation of filopodia albeit to a lesser extent, suggesting that, in addition to the two major actin-binding sites, fascin makes secondary contacts with other filaments in the bundle. In a high resolution crystal structure of fascin, molecules of glycerol and polyethylene glycol are bound in pockets located within the two major actin-binding sites. These molecules could guide the rational design of new anticancer fascin inhibitors. 相似文献
65.
Listeria monocytogenes strains isolated from clinical food and environmental samples were genotyped by Restriction Enzyme Analysis with Pulsed Field Gel Electrophoresis (REA-PFGE) using ApaI and AscI enzymes according to PulseNet Europe procedure. Analysis of DNA fragments profiles obtained by AscI digestion demonstrated presence of 62 REA-PFGE profiles grouped in 2 lineages (FI, FII). Diversity of strains source among both lineages was observed. Statistical analysis showed, that strains isolated from clinical samples more frequently are included to lineage FI, then lineage FII. Non-clinical strains were more frequently included to lineage FII. Combined analysis of REA-PFGE profiles for ApaI and AscI enzymes showed 8 unique pulsotypes characteristic for two or more L. monocytogenes isolates. Moreover researched L. monocytogenes strains were analyzed by multiplex-PCR according Doumith et al methodology. PCR-group 4B was most frequent among strains isolated from clinical samples. Correlation between PCR-group and pulsotype was observed only in few cases. 相似文献
66.
Marzec-Wróblewska U Kamiński P Lakota P Szymański M Wasilow K Ludwikowski G Kuligowska-Prusińska M Odrowąż-Sypniewska G Stuczyński T Michałkiewicz J 《Biological trace element research》2011,143(1):167-177
The aim of the present study was to measure zinc (Zn) and iron (Fe) concentration in human semen and superoxide dismutase
(SOD) activity in seminal plasma and correlate the results with sperm quality. Semen samples were obtained from men (N = 168) undergoing routine infertility evaluation. The study design included two groups based on the ejaculate parameters.
Group I (n = 39) consisted of males with normal ejaculate (normozoospermia), and group II (n = 129) consisted of males with pathological spermiogram. Seminal Zn and Fe were measured in 162 samples (group I, n = 38; group II, n = 124) and SOD activity in 149 samples (group I, n = 37; group II, n = 112). Correlations were found between SOD activity and Fe and Zn concentration, and between Fe and Zn concentration. SOD
activity was negatively associated with volume of semen and positively associated with rapid progressive motility, nonprogressive
motility, and concentration. Negative correlation was stated between Fe concentration and normal morphology. Mean SOD activity
in seminal plasma of semen from men of group I was higher than in seminal plasma of semen from men of group II. Fe concentration
was higher in teratozoospermic males than in males with normal morphology of spermatozoa in group II. Our results suggest
that Fe may influence spermatozoa morphology. 相似文献
67.
Grzegorz Piszczek Jennifer C. Lee Nico Tjandra Chang-Ro Lee Yeong-Jae Seok Rodney L. Levine Alan Peterkofsky 《Archives of biochemistry and biophysics》2011,(2):332
Enzyme INtr is the first protein in the nitrogen phosphotransferase pathway. Using an array of biochemical and biophysical tools, we characterized the protein, compared its properties to that of EI of the carbohydrate PTS and, in addition, examined the effect of substitution of all nonexchangeable protons by deuterium (perdeuteration) on the properties of EINtr. Notably, we find that the catalytic function (autophosphorylation and phosphotransfer to NPr) remains unperturbed while its stability is modulated by deuteration. In particular, the deuterated form exhibits a reduction of approximately 4 °C in thermal stability, enhanced oligomerization propensity, as well as increased sensitivity to proteolysis in vitro. We investigated tertiary, secondary, and local structural changes, both in the absence and presence of PEP, using near- and far-UV circular dichroism and Trp fluorescence spectroscopy. Our data demonstrate that the aromatic residues are particularly sensitive probes for detecting effects of deuteration with an enhanced quantum yield upon PEP binding and apparent decreases in tertiary contacts for Tyr and Trp side chains. Trp mutagenesis studies showed that the region around Trp522 responds to binding of both PEP and NPr. The significance of these results in the context of structural analysis of EINtr are evaluated. 相似文献
68.
Treatment of O-benzylated derivatives of glycosyl N-allyl thiocarbamate with racemic or enantiomerically pure glycidol and bromine provides the 1,2-cis-glycidyl glycosides. This protocol was mild, highly stereoselective and efficient. 相似文献
69.
Subspecific relationships of the European beaverCastor fiber have been obscured by failure to follow the rules of the International Code of Zoological Nomenclature and remain an open
issue. Inconsequence in the use of subspecies names caused a nomenclatural as well as a taxonomic confusion. We discuss these
controversial and incorrect nomenclatural decisions, and recognize 9 nominal subspecies of European beaver, bearing 9 available
names:C. f. fiber Linnaeus, 1758,C. f. galliae Geoffroy, 1803, C. f. albicus Matschie, 1907,C. f. vistulanus Matschie, 1907,C. f. pohlei Serebrennikov, 1929,C. f. birulai Serebrennikov, 1929,C. f. tuvinicus Lavrov, 1969,C. f. belorussicus Lavrov, 1981, andC. f. orientoeuropaeus Lavrov, 1981. 相似文献
70.
Crystal structures of two homologous pathogenesis-related proteins from yellow lupine 总被引:4,自引:0,他引:4
Pathogenesis-related class 10 (PR10) proteins are restricted to the plant kingdom where they are coded by multigene families and occur at high levels. In spite of their abundance, their physiological role is obscure although members of a distantly related subclass (cytokinin-specific binding proteins) are known to bind plant hormones. PR10 proteins are of special significance in legume plants where their expression patterns are related to infection by the symbiotic, nitrogen-fixing bacteria. Here we present the first crystal structures of classic PR10 proteins representing two homologues from one subclass in yellow lupine. The general fold is similar and, as in a birch pollen allergen, consists of a seven-stranded beta-sheet wrapped around a long C-terminal helix. The mouth of a large pocket formed between the beta-sheet and the helix seems a likely site for ligand binding. The shape of the pocket varies because, in variance with the rigid beta-sheet, the helix shows unusual conformational variability consisting in bending, disorder, and axial shifting. A surface loop, proximal to the entrance to the internal cavity, shows an unusual structural conservation and rigidity in contrast to the high glycine content in its sequence. The loop is different from the so-called glycine-rich P-loops that bind phosphate groups of nucleotides, but it is very likely that it does play a role in ligand binding in PR10 proteins. 相似文献