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31.
There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE) introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr Ian A Stokes. It evaluates the hypothesis that in progressive scoliosis vertebral body wedging during adolescent growth results from asymmetric muscular loading in a "vicious cycle" (vicious cycle hypothesis of pathogenesis) by affecting vertebral body growth plates (endplate physes). A frontal plane mathematical simulation tested whether the calculated loading asymmetry created by muscles in a scoliotic spine could explain the observed rate of scoliosis increase by measuring the vertebral growth modulation by altered compression. The model deals only with vertebral (not disc) wedging. It assumes that a pre-existing scoliosis curve initiates the mechanically-modulated alteration of vertebral body growth that in turn causes worsening of the scoliosis, while everything else is anatomically and physiologically 'normal' The results provide quantitative data consistent with the vicious cycle hypothesis. Dr Stokes' biomechanical research engenders controversy. A new speculative concept is proposed of vertebral symphyseal dysplasia with implications for Dr Stokes' research and the etiology of AIS. What is not controversial is the need to test this hypothesis using additional factors in his current model and in three-dimensional quantitative models that incorporate intervertebral discs and simulate thoracic as well as lumbar scoliosis. The growth modulation process in the vertebral body can be viewed as one type of the biologic phenomenon of mechanotransduction. In certain connective tissues this involves the effects of mechanical strain on chondrocytic metabolism a possible target for novel therapeutic intervention. 相似文献
32.
Linsey M Raaijmakers Patricia A Possik Bas van Breukelen Salvatore Cappadona Albert JR Heck AF Maarten Altelaar Daniel S Peeper 《Molecular systems biology》2014,10(12)
Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibition sensitizes melanoma cells to BRAF inhibition. We found many proteins to be induced upon PLX4720 (BRAF inhibitor) treatment that are known to be involved in BRAF inhibitor resistance, including FOXD3 and ErbB3. Several proteins were down‐regulated, including Rnd3, a negative regulator of ROCK1 kinase. For our genomic approach, we performed two parallel shRNA screens using a kinome library to identify genes whose inhibition sensitizes to BRAF or ERK inhibitor treatment. By integrating our functional genomic and (phospho)proteomic data, we identified ROCK1 as a potential drug target for BRAF mutant melanoma. ROCK1 silencing increased melanoma cell elimination when combined with BRAF or ERK inhibitor treatment. Translating this to a preclinical setting, a ROCK inhibitor showed augmented melanoma cell death upon BRAF or ERK inhibition in vitro. These data merit exploration of ROCK1 as a target in combination with current BRAF mutant melanoma therapies. 相似文献
33.
Monica L Andersen Raquel CS Martins Tathiana AF Alvarenga Isabela B Antunes Ligia A Papale Sergio Tufik 《Reproductive biology and endocrinology : RB&E》2007,5(1):1-12
Background
The rate-limiting step in prostaglandin (PG) biosynthesis is catalyzed by phospholipase A2 (PLA2) enzymes which hydrolyze arachidonic acid from membrane phospholipids. Despite their importance in uterine PG production, little is known concerning the specific PLA2 enzymes that regulate arachidonic acid liberation in the uterine endometrium. The objectives of this study were to evaluate the expression and activities of calcium-independent Group VI and Group IVC PLA2 (PLA2G6 and PLA2G4C) and calcium-dependent Group IVA PLA2 (PLA2G4A) enzymes in the regulation of bovine uterine endometrial epithelial cell PG production.Methods
Bovine endometrial epithelial cells in culture were treated with oxytocin, interferon-tau and the PLA2G6 inhibitor bromoenol lactone, alone and in combination. Concentrations of PGF2alpha and PGE2 released into the medium were analyzed. Western blot analysis was performed on cellular protein to determine the effects of treatments on expression of PLA2G4A, PLA2G6 and PLA2G4C. Group-specific PLA2 activity assays were performed on cell lysates following treatment with oxytocin, interferon-tau or vehicle (control), alone and in combination. To further evaluate the role of specific PLA2 enzymes in uterine cell PG biosynthesis, cells were transfected with cDNAs encoding human PLA2G6 and PLA24C, treated as described above and PG assays performed.Results
Constitutive cell production of PGF2alpha was about two-fold higher than PGE2. Oxytocin stimulated production of both PGs but the increase of PGF2alpha was significantly greater. Interferon-tau diminished oxytocin stimulation of both PGs. The PLA2G6 inhibitor, bromoenol lactone, abolished oxytocin-stimulated production of PGF2alpha. Treatments had little effect on PLA2G4A protein expression. In contrast, oxytocin enhanced expression of PLA2G6 and this effect was diminished in the presence of interferon-tau. Expression of PLA2G4C was barely detectable in control and oxytocin treated cells but it was enhanced in cells treated with interferon-tau. Oxytocin stimulated PLA2 activity in assays designed to evaluate PLA2G6 activity and interferon-tau inhibited this response. In assays designed to measure PLA2G4C activity, only interferon-tau was stimulatory. Cells overexpressing PLA2G6 produced similar quantities of the two PGs and these values were significantly higher than PG production by non-transfected cells. Oxytocin stimulated production of both PGs and this response was inhibited by interferon-tau. Bromoenol lactone inhibited oxtocin stimulation of PGF2alpha production but stimulated PGE2 production, both in the absence and presence of oxytocin. Cells over-expressing PLA2G4C produced more PGE2 than PGF2alpha and interferon-tau stimulated PGE2 production.Conclusion
Results from these studies indicate that oxytocin stimulation of uterine PGF2alpha production is mediated, at least in part, by up-regulation of PLA2G6 expression and activity. In addition to its known inhibitory effect on oxytocin receptor expression, interferon-tau represses oxytocin-stimulated PLA2G6 expression and activity and this contributes to diminished PGF2alpha production. Furthermore, endometrial cell PGE2 biosynthesis was associated with PLA2G4C expression and activity and interferon-tau was stimulatory to this process. 相似文献34.
Monica L Andersen Raquel CS Martins Tathiana AF Alvarenga Isabela B Antunes Ligia A Papale Sergio Tufik 《Reproductive biology and endocrinology : RB&E》2007,5(1):7
Background
Paradoxical sleep deprivation (PSD) associated with cocaine has been shown to enhance genital reflexes (penile erection-PE and ejaculation-EJ) in Wistar rats. Since hypertension predisposes males to erectile dysfunction, the aim of the present study was to investigate the effects of PSD on genital reflexes in the spontaneously hypertensive rat (SHR) compared to the Wistar strain. We also extended our study to examine how PSD affect steroid hormone concentrations involved in genital events in both experimental models. 相似文献35.
Núbia Boechat Alcione S Carvalho Kelly Salom?o Solange L de Castro Carlos F Araujo-Lima Francisco VC Mello Israel Felzenszwalb Claudia AF Aiub Taline Ramos Conde Helena PS Zamith Rolf Skupin Günter Haufe 《Memórias do Instituto Oswaldo Cruz》2015,110(4):492-499
Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic and
cytotoxic properties have been attributed to the presence of the nitro group.
However, we synthesised nitroimidazoles with activity against the trypomastigotes of
Trypanosoma cruzi, but that were not genotoxic. Herein,
nitroimidazoles (11-19) bearing different substituent groups were investigated for
their potential induction of genotoxicity (comet assay) and mutagenicity
(Salmonella/Microsome assay) and the correlations of these
effects with their trypanocidal effect and with megazol were investigated. The
compounds were designed to analyse the role played by the position of the nitro group
in the imidazole nucleus (C-4 or C-5) and the presence of oxidisable
groups at N-1 as an anion receptor group and the role of a methyl group at C-2.
Nitroimidazoles bearing NO2 at C-4 and CH3 at C-2 were not genotoxic compared to
those bearing NO2 at C-5. However, when there was a CH3
at C-2, the position of the NO2 group had no influence on the genotoxic activity.
Fluorinated compounds exhibited higher genotoxicity regardless of the presence of CH3
at C-2 or NO2 at C-4 or C-5. However, in compounds 11 (2-CH3; 4-NO2; N-CH2OHCH2Cl)
and 12 (2-CH3; 4-NO2; N-CH2OHCH2F), the fluorine atom had no influence on
genotoxicity. This study contributes to the future search for new and safer
prototypes and provide. 相似文献
36.
Lurá MC Fuentes MB Cabagna M González AM Nepote AF Giugni MC Rico M Latorre MG 《Revista iberoamericana de micología》2001,18(4):183-186
The aims of this work were to study the influence of secondary metabolites produced by a Penicillium citrinum strain. Mus musculus mice were fed with a diet containing those metabolites to determine both its influence on their development and the pathological and biochemical changes on experimental animals. Male and female including pregnant females, were studied. One group received commercial feed (A.B.) to which the citrinin- producing mould had been added (LF), another received A.B. contaminated with commercial citrinin (LC). The last group received noncontaminated feed (LT). The animals were weighed weekly, and sacrificed after sixty days, so that they could be studied both macro and microscopically. In LF and LT mice, haematological analysis was carried out and hemosiderin was looked for in urine. The diet of the newborne mice, after weaning, was identical to that of their parent. The treated animals (LF and LC) showed morphological alterations, a significant decrease in weight and morphologic alterations and hemosiderin granules were detected in some of their organs. In LT all breeds survived, none of the mice showed neither macro nor microscopic anomalies and had normal biochemical parameters. Fewer breeds in LF survived, male infertility was detected and some of their haematologic parameters were also measurably lower. 相似文献
37.
A report on the 15th International Society of Developmental Biologists Congress, Sydney, Australia, 3-7 September 2005. 相似文献
38.
Complete nucleotide sequences of bovine alpha S2- and beta-casein cDNAs: comparisons with related sequences in other species 总被引:2,自引:0,他引:2
Stewart AF; Bonsing J; Beattie CW; Shah F; Willis IM; Mackinlay AG 《Molecular biology and evolution》1987,4(3):231-241
The nucleotide sequences corresponding to bovine alpha S2- and beta- casein
mRNAs have been determined by cDNA analysis. Both sequences appear to be
complete at their 5' ends. The nucleotide sequence of alpha S2-casein, when
compared with the corresponding cavine A sequence, helps to define the
boundaries of a large amino acid repeat (approximately 80 residues) whereas
comparisons with the nucleotide sequences of rat gamma- and mouse
epsilon-casein mRNAs also reveal extensive sequence similarities. An
alignment of these four sequences shows that the divergence of their
translated regions has been characterized by the duplication and deletion
of discrete segments of sequence that probably correspond to exons. A high
degree of nucleotide substitution is also found when the four sequences are
compared, except for well-conserved leader-peptide and phosphorylation-site
sequences and, to a lesser extent, the 5'-untranslated regions. Similar
comparison of the bovine and rat beta-caseins shows that their divergence
has involved a high rate of nucleotide substitution but that no major
insertions or deletions of sequence have occurred. The several splice sites
that have veen defined in the rat beta-casein gene are likely to have been
conserved in the bovine. The contrasting evolutionary histories of the
alpha- and beta-casein coding sequences correlate with the distinctive
functions of these proteins in the casein micelle system in milk.
相似文献
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