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351.
Pinna GA Pirisi MA Chelucci G Mussinu JM Murineddu G Loriga G D'Aquila PS Serra G 《Bioorganic & medicinal chemistry》2002,10(8):2485-2496
Various new derivatives and structural analogues of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide (2a), a representative term of a series of 2-aminomethylpyrrolidinyl derived 4,5-dihydrobenzo[g]indolcarboxamides with good D(2)-like affinity, were synthesized and evaluated for their ability to bind to dopamine D(2)-like receptors in vitro. The structural contribution to D(2)-like receptor binding of the 4,5-dihydrobenzo[g]indole portion of the molecule was examined. From these studies, compound 2k, 2-chloro-N-(1-ethyl-2-pyrrolidinylmethyl)-5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide, was found to possess a potent affinity for D(2)-like receptors. Behavioural tests in rats have shown that this compound reduces the hyperactivity induced by amphetamine, a property shared by all antipsychotic drugs, at a dose which failed to induce catalepsy, an effect which is predictive of extrapyramidal side effects in humans. The other compounds demonstrated moderate (2c, 2h, and 2j) or no affinity for D(2)-like receptors. 相似文献
352.
Fabio Quondamatteo Dieter P Reinhardt Noe L Charbonneau Gabriele Pophal Lynn Y Sakai Rainer Herken 《Matrix biology》2002,21(8):637-646
The extracellular glycoproteins fibrillin-1 and fibrillin-2 are major components of connective tissue microfibrils. Mutations in the fibrillin-1 and fibrillin-2 genes are responsible for the phenotypical manifestations of Marfan syndrome and congenital contractural arachnodactyly respectively, which emphasizes their essential roles in developmental processes of various tissues. Consistent with this last notion, organ culture experiments have indirectly suggested morphogenic roles for fibrillins in lung and kidney development. In order to contribute to the understanding of the roles of fibrillins in developmental and morphogenetic events, we have investigated the distribution of fibrillin-1 and fibrillin-2 in human embryonic and early fetal tissues between the 5th and the 12th gestational week, i.e. at the beginning of organogenesis. Fibrillin-1 and fibrillin-2 were localized immunohistochemically using specific monoclonal antibodies, mAb 69 and mAb 48, respectively. Both fibrillins are widely distributed in various human anlagen, from early developmental stages. In most embryonic and early fetal human organs such as skin, lung, heart, aorta, central nervous system anlage, nerves, and ganglia, fibrillin-1 and fibrillin-2 follow the same temporo-spatial pattern of distribution. However, in other organs such as kidney, liver, rib anlagen, notochord fibrillin-1 and fibrillin-2 are distributed differentially. The present paper is focused on this aspect. These results suggest different roles for fibrillin-1 and -2 in the development of these structures. 相似文献
353.
Sic1, cyclin-dependent kinase inhibitor of budding yeast, is synthesized in anaphase and largely degraded at the S-phase onset to regulate timing of DNA synthesis. Sic1 interacts with phase-specific B-type cyclin (Clb)-kinase (Cdk1) complexes, central regulators in cell cycle control. Its appearance is timed to mediate reduction in kinase activities at appropriate stages. Clbs are unstable proteins with extremely short half-lives. Interactions of Sic1 with Clbs have been detected both in vitro and in vivo by high-throughput genome-wide screenings. Furthermore, we have recently shown that Sic1 regulates waves of Clbs, acting as a timer in their appearance, thus controlling Cdk1-Clbs activation. The molecular mechanism is not yet fully understood but is hypothesized to occur via stoichiometric binding of Sic1 to Cdk1-Clb complexes. Using F?rster resonance energy transfer (FRET) via fluorescence lifetime imaging microscopy (FLIM), we showed association of Sic1 to Clb cyclins in living yeast cells. This finding is consistent with the notion that inhibition of kinase activity can occur over the whole cell cycle progression despite variable Sic1 levels. Specifically, Sic1/Clb3 interaction was observed for the first time, and Sic1/Clb2 and Sic1/Clb5 pairs were confirmed, but no Sic1/Clb4 interaction was found, which suggests that, despite high functional homology between Clbs, only some of them can target Sic1 function in vivo. 相似文献
354.
Hood RL Lines MA Nikkel SM Schwartzentruber J Beaulieu C Nowaczyk MJ Allanson J Kim CA Wieczorek D Moilanen JS Lacombe D Gillessen-Kaesbach G Whiteford ML Quaio CR Gomy I Bertola DR Albrecht B Platzer K McGillivray G Zou R McLeod DR Chudley AE Chodirker BN Marcadier J;FORGE Canada Consortium Majewski J Bulman DE White SM Boycott KM 《American journal of human genetics》2012,90(2):308-313
Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS. 相似文献
355.
356.
Fanelli F Di Lallo VD Belluomo I De Iasio R Baccini M Casadio E Gasparini DI Colavita M Gambineri A Grossi G Vicennati V Pasquali R Pagotto U 《Journal of lipid research》2012,53(3):481-493
The elucidation of the role of endocannabinoids in physiological and pathological conditions and the transferability of the importance of these mediators from basic evidence into clinical practice is still hampered by the indefiniteness of their circulating reference intervals. In this work, we developed and validated a two-dimensional LC/MS/MS method for the simultaneous measurement of plasma endocannabinoids and related compounds such as arachidonoyl-ethanolamide, palmitoyl-ethanolamide, and oleoyl-ethanolamide, belonging to the N-acyl-ethanolamide (NAE) family, and 2-arachidonoyl-glycerol and its inactive isomer 1-arachidonoyl-glycerol from the monoacyl-glycerol (MAG) family. We found that several pitfalls in the endocannabinoid measurement may occur, from blood withdrawal to plasma processing. Plasma extraction with toluene followed by on-line purification was chosen, allowing high-throughput and reliability. We estimated gender-specific reference intervals on 121 healthy normal weight subjects fulfilling rigorous anthropometric and hematic criteria. We observed no gender differences for NAEs, whereas significantly higher MAG levels were found in males compared with females. MAGs also significantly correlated with triglycerides. NAEs increased with age in females, and arachidonoyl-ethanolamide correlated with adiposity and metabolic parameters in females. This work paves the way to the establishment of definitive reference intervals for circulating endocannabinoids to help physicians move from the speculative research field into the clinical field. 相似文献
357.
Keller MA Watschinger K Lange K Golderer G Werner-Felmayer G Hermetter A Wanders RJ Werner ER 《Journal of lipid research》2012,53(7):1410-1416
The lack of fatty aldehyde dehydrogenase function in Sjögren Larsson Syndrome
(SLS) patient cells not only impairs the conversion of fatty aldehydes into their
corresponding fatty acid but also has an effect on connected pathways. Alteration of
the lipid profile in these cells is thought to be responsible for severe symptoms
such as ichtyosis, mental retardation, and spasticity. Here we present a novel
approach to examine fatty aldehyde metabolism in a time-dependent manner by measuring
pyrene-labeled fatty aldehyde, fatty alcohol, fatty acid, and alkylglycerol in the
culture medium of living cells using HPLC separation and fluorescence detection. Our
results show that in fibroblasts from SLS patients, fatty aldehyde is not
accumulating but is converted readily into fatty alcohol. In control cells, in
contrast, exclusively the corresponding fatty acid is formed. SLS patient cells did
not display a hypersensitivity toward hexadecanal or hexadecanol, but 3-fold lower
concentrations of the fatty alcohol than the corresponding fatty aldehyde were needed
to induce toxicity in SLS patient and in control cells. 相似文献
358.
Gruss M Appenroth D Flubacher A Enzensperger C Bock J Fleck C Gille G Braun K 《Journal of neurochemistry》2012,121(6):924-931
β-Carbolines (BCs) belong to the heterogenous family of carbolines, which have been found exogenously, that is, in various fruits, meats, tobacco smoke, alcohol and coffee, but also endogenously, that is, blood, brain and CSF. These exogenous and endogenous BCs and some of their metabolites can exert neurotoxic effects, however, an unexpected stimulatory effect of 9-methyl-β-carboline (9-me-BC) on dopaminergic neurons in primary mesencephalic cultures was recently discovered. The aim of the present study was to extend our knowledge on the stimulatory effects of 9-me-BC and to test the hypothesis that 9-me-BC may act as a cognitive enhancer. We found that 10 days (but not 5 days) of pharmacological treatment with 9-me-BC (i) improves spatial learning in the radial maze, (ii) elevates dopamine levels in the hippocampal formation, and (iii) results after 10 days of treatment in elongated, more complex dendritic trees and higher spine numbers on granule neurons in the dentate gyrus of 9-me-BC-treated rats. Our results demonstrate that beyond its neuroprotective/neurorestorative and anti-inflammatory effects, 9-me-BC acts as a cognitive enhancer in a hippocampus-dependent task, and that the behavioral effects may be associated with a stimulatory impact on hippocampal dopamine levels and dendritic and synaptic proliferation. 相似文献
359.
Watschinger K Fuchs JE Yarov-Yarovoy V Keller MA Golderer G Hermetter A Werner-Felmayer G Hulo N Werner ER 《The Biochemical journal》2012,443(1):279-286
Alkylglycerol mono-oxygenase (EC 1.14.16.5) forms a third, distinct, class among tetrahydrobiopterin-dependent enzymes in addition to aromatic amino acid hydroxylases and nitric oxide synthases. Its protein sequence contains the fatty acid hydroxylase motif, a signature indicative of a di-iron centre, which contains eight conserved histidine residues. Membrane enzymes containing this motif, including alkylglycerol mono-oxygenase, are especially labile and so far have not been purified to homogeneity in active form. To obtain a first insight into structure-function relationships of this enzyme, we performed site-directed mutagenesis of 26 selected amino acid residues and expressed wild-type and mutant proteins containing a C-terminal Myc tag together with fatty aldehyde dehydrogenase in Chinese-hamster ovary cells. Among all of the acidic residues within the eight-histidine motif, only mutation of Glu137 to alanine led to an 18-fold increase in the Michaelis-Menten constant for tetrahydrobiopterin, suggesting a role in tetrahydrobiopterin interaction. A ninth additional histidine residue essential for activity was also identified. Nine membrane domains were predicted by four programs: ESKW, TMHMM, MEMSAT and Phobius. Prediction of a part of the structure using the Rosetta membrane ab initio method led to a plausible suggestion for a structure of the catalytic site of alkylglycerol mono-oxygenase. 相似文献
360.
Antonio Bianconi Gabriele Ciasca Alexander Tenenbaum Anna Battisti Gaetano Campi 《Journal of biological physics》2012,38(1):169-179
We report the variation with temperature of the ensemble distribution of conformations spanned by the tau protein in its dynamical
states measured by small-angle X-ray scattering (SAXS) using synchrotron radiation. The SAXS data show a clear temperature
variation of the distribution of occupied protein conformations from 293 to 318 K. More conformations with a smaller radius
of gyration are occupied at higher temperature. The protein–solvent interactions are shown by computer simulation to be essential
for controlling the dynamics of protein conformations, providing evidence for the key role of water solvent in the protein
dynamics, as proposed by Giorgio Careri. 相似文献