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31.
Oliv Eidam Chiara Romagnoli Guillaume Dalmasso Sarah Barelier Emilia Caselli Richard Bonnet Brian K. Shoichet Fabio Prati 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(43):17448-17453
Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a Ki of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge. 相似文献
32.
Danillo Barbosa Renato Aparecido de Souza Wellington Roberto Gomes de Carvalho Murilo Xavier Paula Kariluce de Carvalho Tereza Cristina Rodrigues Cunha Emilia Ângela Loschiavo Arisawa Landulfo Silveira Jr Antonio Balbin Villaverde 《Lasers in medical science》2013,28(6):1489-1494
The objective of this study was to investigate the effects of low-level laser therapy (LLLT) treatment alone (λ?=?660 nm and λ?=?830 nm) or associated with platelet-rich plasma (PRP). We used 54 male rats divided into six groups, with nine animals each: group 1, partial tenotomy; group 2 (GII), PRP; group 3 (GIII): λ660?nm; group 4 (GIV), λ830?nm; group 5 (GV), PRP + λ660?nm; and group 6 (GVI), PRP + λ830?nm. The protocol used was power density 0.35 W/cm2, energy 0.2 J, energy density 7.0 J/cm2, time 20 s per irradiated point, and number of points 3. Animals in groups GII, GV, and GVI received treatment with PRP, consisting of a single dose of 0.2 mL directly into the surgical site, on top of the tenotomy. Animals were killed on the 13th day post-tenotomy and their tendons were surgically removed for a quantitative analysis using polarization microscopy. The percentages of collagen fibers of types I and III were expressed as mean ± SD. Higher values of collagen fibers type I were obtained for groups GV and GVI when compared with all other groups (p?<?0.05), whereas groups GIII and GIV showed no significant difference between them (p?>?0.05). For collagen type III, a significant difference was observed between GII and all other groups (p?<?0.5), but no significant difference was found between GIII and GIV and between GV and GVI. Results showed that the deposition of collagen type I was higher when treatment with PRP and LLLT was combined, suggesting a faster regeneration of the tendon. 相似文献
33.
Domínguez-González Cristina Fernández-Torrón Roberto Moore Ursula de Fuenmayor-Fernández de la Hoz Carlos Pablo Vélez-Gómez Beatriz Cabezas Juan Antonio Alonso-Pérez Jorge González-Mera Laura Olivé Montse García-García Jorge Moris Germán León Hernández Juan Carlos Muelas Nuria Servian-Morilla Emilia Martin Miguel A. Díaz-Manera Jordi Paradas Carmen 《Journal of neurology》2022,269(7):3550-3562
Journal of Neurology - TK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of... 相似文献
34.
Aquila S Middea E Catalano S Marsico S Lanzino M Casaburi I Barone I Bruno R Zupo S Andò S 《Human reproduction (Oxford, England)》2007,22(10):2594-2605
BACKGROUND: Results from mice lacking the androgen receptor (AR) showed that it is critical for the proper development and function of the testes. The aim of this study was to investigate whether a functional AR is present in human sperm. METHODS: The expression of AR and its effects on sperm were evaluated by RT-PCR, Western Blot, Immunocytochemistry, PI3Kinase and DNA laddering assays. RESULTS: We showed in human sperm that AR is located at the head region. Dihydrotestosterone (DHT), in a dose-dependent manner, leads to the rapid phosphorylation of the AR on tyrosine, serine and threonine residues and this effect was reduced by the AR antagonist hydroxyflutamide (OH-Flut). The effects of AR were evaluated on the phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) pathway. Specifically, 0.1 and 1 nM DHT stimulated PI3K activity, whereas 10 nM DHT decreased PI3K activity and levels of p-AKT S473 and p-AKT T308, p-BCL2, and enhanced phosphatase and tensin homologue (PTEN) phosphorylation. In addition, 10 nM DHT was able to induce the cleavage of caspases 8, 9 and 3 and cause DNA laddering, and these effects were reversed either by casodex or OHFlut. By using wortmannin, a specific PI3K inhibitor, the cleavage of caspase 3 was reproduced, confirming that in sperm the PI3K/AKT pathway is involved in caspase activation. CONCLUSIONS: Human sperm express a functional AR that have the ability to modulate the PI3K/AKT pathway, on the basis of androgen concentration. 相似文献
35.
Rodriguez-Tudela JL Gomez-Lopez A Alastruey-Izquierdo A Mellado E Bernal-Martinez L Cuenca-Estrella M 《Diagnostic microbiology and infectious disease》2007,58(4):435-440
The sequence polymorphisms of intergenic transcribed spacer and the antifungal susceptibility profile of 18 Trichosporon asahii isolates from Spain, Argentina, and Brazil together with 43 intergenic transcribed spacer 1 sequences deposited in the GenBank were analyzed. Six genotypes were detected instead of 5 genotypes described previously. Genotype 1 was the most common found comprising 57.3% of all strains, followed by genotype 3 (14.7%) and genotype 5 (13.1%). Spanish strains had members in all genotypes except 2, whereas South American isolates were grouped with genotypes 1, 3, and 6. Our results indicate that all genotypes are present in at least 2 countries suggesting a worldwide distribution. On the other hand, genotype 6 was not previously described but was only composed of 2 South American strains isolated from a subcutaneous abscess and skin. All isolates showed amphotericin B MICs>or=2 mg/L supporting the in vitro resistance of this species to this antifungal. Three isolates from South America showed high MICs to all antifungals analyzed. The true epidemiologic usefulness of classifying T. asahii in genotypes should be ascertaining analyzing a high number of isolates from many countries. 相似文献
36.
Diego Emilia J. Rosenberger Laura H. Deng Xiaoyan McGuire Kandace P. 《Annals of surgical oncology》2022,29(10):6162-6162
Annals of Surgical Oncology - 相似文献
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38.
Harpreet S. Bajaj MD MPH Melonie Burrows PhD Jessica Blavignac PhD Emilia Paron PhD Fernando Camacho PhD Errol Gould PhD Maxime Barakat MD 《Diabetes, obesity & metabolism》2021,23(3):861-865
Sustained weight loss improves liver histology in non-alcoholic fatty liver disease. This post hoc analysis of four phase III, 56-week, randomized controlled trials investigated if extended-release naltrexone and bupropion (NB) affects alanine aminotransferase (ALT) and Fibrosis-4 (FIB-4) index in adults with overweight or obesity. Two thousand and seventy-three subjects (NB = 1310; placebo = 763; 79.0% female; 81.6% Caucasian) had baseline mean weight 101 kg, body mass index 36.2 kg/m2, ALT 26.9 IU/L and FIB-4 0.79. At 56 weeks, NB-treated subjects experienced more weight loss than placebo (8.7 vs. 3.2 kg, respectively, P < .0001). Weight loss, independent of treatment, was associated with improved ALT and FIB-4 (P < .0001). There was a significant independent effect of NB on change from baseline for FIB-4 (P < .0001), but not for ALT (P = .54). Categorical ALT response (from above to within normal ranges: 10-40 IU/L for men; 7-35 IU/L for women) and achievement of 25% and 50% reduction in ALT were greater for NB versus placebo, and independently affected by weight loss (P < .0001), but not treatment. NB-associated weight loss may improve liver health by normalizing ALT values for those with high baseline levels. 相似文献
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