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31.
Folkert Reck Alun Bermingham Johanne Blais Vladimir Capka Taryn Cariaga Anthony Casarez Richard Colvin Charles R. Dean Alex Fekete Wanben Gong Ellie Growcott Hongqiu Guo Adriana K. Jones Cindy Li Fengxia Li Xiaodong Lin Mika Lindvall Sara Lopez Qingming Zhu 《Bioorganic & medicinal chemistry letters》2018,28(4):748-755
Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE). 相似文献
32.
Relationship between molecular and enological features of Patagonian wine yeasts: relevance in selection protocols 总被引:4,自引:0,他引:4
Christian A. Lopes María E. Rodríguez Amparo Querol Sergio Bramardi Adriana C. Caballero 《World journal of microbiology & biotechnology》2006,22(8):827-833
Summary In this paper, a study of the relationship between genetic patterns, obtained by the combination of mtDNA-RFLP and PCR-amplified inter-δ sequence DNA polymorphism analysis, and relevant enological phenotypic data (fermentative power, specific productivity, volatile and total acidity) was carried out on Argentinean Saccharomyces cerevisiae isolates from north Patagonia. The use of a powerful statistical tool, Generalized Procrustes analysis, allowed us to weigh the relationship for each isolate in particular, denoting a good enough degree of agreement between molecular and physiological data for most of the population analysed. The inclusion of a physiological feature, as the killer sensitivity biotype, within identification methods resulted in a higher degree of discrimination among isolates and in better correlation between both characterizations. The combined use of methods based on molecular polymorphisms and killer biotype could be applied so as not to miss any isolate with differential enological properties in selection protocols. 相似文献
33.
Hereditary cerebral hemorrhage with amyloidosis-Dutch type is a disorder associated with a missense mutation (E693Q) in the β-amyloid (Aβ)-coding region of the amyloid precursor protein (APP). This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer's disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild-type (WT) Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17-kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ-treated neurons when compared with WT Aβ-treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearing in the pathobiology of this familial AD form. 相似文献
34.
Tinto N Zagari A Capuano M De Simone A Capobianco V Daniele G Giugliano M Spadaro R Franzese A Sacchetti L 《PloS one》2008,3(4):e1870
Background
Maturity onset diabetes of the young type 2 (or GCK MODY) is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK).Methodology/Principal Findings
We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients'' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%); 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu) and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: ∼59%) than in the large (4/12: 33%) domain or in the connection (1/12: 8%) region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD) OGTT = 7.8 mMol/L (1.8)] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p = 0.04).Conclusions
The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings) but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation. 相似文献35.
María Florencia Gottardo Mariela Moreno Ayala Jimena Ferraris Sandra Zárate Daniel Pisera Marianela Candolfi Gabriela Jaita Adriana Seilicovich 《Journal of cell communication and signaling》2017,11(4):329-340
Humanin (HN) and Rattin (HNr), its homologous in the rat, are peptides with cytoprotective action in several cell types such as neurons, lymphocytes and testicular germ cells. Previously, we have shown that HNr is expressed in pituitary cells and that HN inhibited the apoptotic effect of TNF-α in both normal and tumor pituitary cells. The aim of the present study was to identify signaling pathways that mediate the antiapoptotic effect of HN in anterior pituitary cells from ovariectomized rats and in GH3 cells, a somatolactotrope cell line. We assessed the role of STAT3, JNK, Akt and MAPKs as well as proteins of the Bcl-2 family, previously implicated in the antiapoptotic effect of HN. We also evaluated the participation of NF-κB in the antiapoptotic action of HN. STAT3 inhibition reversed the inhibitory effect of HN on TNF-α-induced apoptosis in normal and pituitary tumor cells, indicating that STAT3 signaling pathway mediates the antiapoptotic effect of HN on pituitary cells. Inhibition of NF-κB pathway did not affect action of HN on normal anterior pituitary cells but blocked the cytoprotective effect of HN on TNF-α-induced apoptosis of GH3 cells, suggesting that the NF-κB pathway is involved in HN action in tumor pituitary cells. HN also induced NF-κB-p65 nuclear translocation in these cells. In pituitary tumor cells, JNK and MEK inhibitors also impaired HN cytoprotective action. In addition, HN increased Bcl-2 expression and decreased Bax mitochondrial translocation. Since HN expression in GH3 cells is higher than in normal pituitary cells, we may suggest that through multiple pathways HN could be involved in pituitary tumorigenesis. 相似文献
36.
Maria J. Martin Adriana Artola M Dolors Balaguer Miquel Rigola 《Biotechnology letters》2002,24(3):163-168
Surplus biological sludge from wastewater treatment operations was converted into activated carbon and then added to the aerated vessel of an activated sludge process treating phenol and glucose. The addition of activated carbon, either sludge-based or commercial, enhanced phenol removal from 58 to 98.7% and from 87 to 93% for COD with feed concentrations of 100 mg phenol l–1 and 2500 mg COD l–1. No differences were found between the activated sludge-activated carbon bench scale continuous reactors operating with either commercial or sludge-based activated carbon in spite of the higher adsorption capacity of the former. 相似文献
37.
38.
Adriana R. Rodrigues Henrique Almeida Alexandra M. Gouveia 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(7):1267-1275
The melanocortin system has a clear effect on the mobilisation of stored lipids in adipocytes. The aim of the current study was to investigate the role of melanocortin 5 receptor (MC5R) on α-melanocyte-stimulating hormone (α-MSH)-induced lipolysis in 3T3-L1 adipocytes. To this end, MC5R expression was decreased by small interfering RNA (siRNA), which significantly impaired the α-MSH stimulation of lipolysis, as determined by glycerol and nonesterified fatty-acid (NEFA) quantification. The functional role of α-MSH/MC5R on triglyceride (TG) hydrolysis was mediated by hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), perilipin 1 (PLIN1) and acetyl-CoA carboxylase (ACC). Immunofluorescence microscopy revealed that phosphorylated HSL clearly surrounded lipid droplets in α-MSH-stimulated adipocytes, whereas PLIN1 left the immediate periphery of lipids. These observations were lost when the expression of MC5R was suppressed. 相似文献
39.
Villalobos-Comparán M Teresa Flores-Dorantes M Teresa Villarreal-Molina M Rodríguez-Cruz M García-Ulloa AC Robles L Huertas-Vázquez A Saucedo-Villarreal N López-Alarcón M Sánchez-Muñoz F Domínguez-López A Gutiérrez-Aguilar R Menjivar M Coral-Vázquez R Hernández-Stengele G Vital-Reyes VS Acuña-Alonzo V Romero-Hidalgo S Ruiz-Gómez DG Riaño-Barros D Herrera MF Gómez-Pérez FJ Froguel P García-García E Teresa Tusié-Luna M Aguilar-Salinas CA Canizales-Quinteros S 《Obesity (Silver Spring, Md.)》2008,16(10):2296-2301
Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals. 相似文献
40.
Franco Chimenti Daniela Secci Adriana Bolasco Paola Chimenti Arianna Granese Simone Carradori Elias Maccioni M. Cristina Cardia Matilde Yáñez Francisco Orallo Stefano Alcaro Francesco Ortuso Roberto Cirilli Rosella Ferretti Simona Distinto Johannes Kirchmair Thierry Langer 《Bioorganic & medicinal chemistry》2010,18(14):5063-5070
The present study reports on synthesis in high yields (70–99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1–45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds. 相似文献