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91.
de Oliveira RM Marijanovic Z Carvalho F Miltényi GM Matos JE Tenreiro S Oliveira S Enguita FJ Stone R Outeiro TF 《PloS one》2011,6(6):e20854
Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin-converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties. 相似文献
92.
Longatto-Filho A Maeda MY Erzen M Branca M Roteli-Martins C Naud P Derchain SF Hammes L Matos J Gontijo R Sarian LO Lima TP Tatti S Syrjänen S Syrjänen K 《Acta cytologica》2005,49(5):500-506
OBJECTIVE: To evaluate the performance of the conventional Pap test and liquid-based cytology (LBC) in an ongoing multicenter trial testing optional screening tools (cytology, screening colposcopy, visual inspection with acetic acid, visual inspection with Lugol's Iodine, cervicography and Hybrid Capture II [HCII] (Digene Brazil, S?o Paulo, Brazil) conventional and self-sampling), for cervical cancer in Brazil and Argentina. STUDY DESIGN: A cohort of 12,107 women attending four clinics (Campinas, S?o Paulo, Porto Alegre, Buenos Aires) were randomized into the 8 diagnostic arms. Women testing positive with any of the tests were referred for colposcopy, and cervical biopsies were used as the gold standard to assess performance characteristics of the diagnostic tests. Conventional Pap smears were sampled by all clinics (n = 10,240), and LBC (Autocyte PREP, [TriPath Imaging, Burlington, North Carolina, U.S.A.], n=320, and DNA-Citoliq [Digene Brazil], n =1,346) was performed by 1 of the clinics. RESULTS: Conventional Pap smears showed no squamous intraepithelial lesions (normal) in 8,946 (87.4%) and LBC in 1,373 (82.4%). Using high grade squamous intraepithelial lesions (HSIL) as the cutoff, Pap smears predicted high grade (cervical intraepithelial neoplasia [CIN] 3) with OR 63.0 (95% CI, 36.90-107.70), standard error (SE) 59%, SP 97.8%, positive predictive value (PPV) 68.1% and negative predictive value (NPV) 96.7%. The same figures for Autocyte PREP were: OR 9.0 (95% CI, 2.43-33.24), sensitivity (SE) 33.3%, specificity (SP) 100%, PPV 100% and negative PV (NPV) 88.8%. DNA-Citoliq detected CIN 3 as follows: OR 11.8 (95% CI 2.60-53.26), SE 40.0%, SP 94.6%, PPV 40.0% and NPV 94.6%. Lowering the cutoff to low grade squamous intraepithelial lesions increased SE and NPV but compromised SP and PPV. The detection rates for high grade lesions after an atypical squamous cells of undetermined significance diagnosis were similar with the 3 techniques. In our settings, the 3 methods of cervical cytology were slightly different in performance. The conventional Pap smear had the highest SE, while Autocyte PREP had 100% SP and PPV in detecting CIN3 with the HSIL cutoff. All 3 tests had lower SE but higher SP as compared to HCII. 相似文献
93.
One mechanism by which mammalian cells regulate the uptake of glucose is the number of glucose transporter proteins (GLUT) present at the plasma membrane. In insulin-responsive cells types, GLUT4 is released from intracellular stores through inactivation of the Rab GTPase activating protein Tre-2/USP6-BUB2-Cdc16 domain family member 4 (TBC1D4) (also known as AS160). Here we describe that TBC1D4 forms a protein complex with protein kinase WNK1 in human embryonic kidney (HEK293) cells. We show that WNK1 phosphorylates TBC1D4 in vitro and that the expression levels of WNK1 in these cells regulate surface expression of the constitutive glucose transporter GLUT1. WNK1 was found to increase the binding of TBC1D4 to regulatory 14-3-3 proteins while reducing its interaction with the exocytic small GTPase Rab8A. These effects were dependent on the catalytic activity because expression of a kinase-dead WNK1 mutant had no effect on binding of 14-3-3 and Rab8A, or on surface GLUT1 levels. Together, the data describe a pathway regulating constitutive glucose uptake via GLUT1, the expression level of which is related to several human diseases. 相似文献
94.
Matos KS da Cunha EF da Silva Gonçalves A Wilter A Kuča K França TC Ramalho TC 《Journal of biomolecular structure & dynamics》2012,30(5):546-558
We have applied a theoretical methodology, previously developed to evaluate the association and kinetic reactivation constants of oximes, comparing theoretical data obtained for human acetylcholinesterase (HsAChE) with in vitro results from Mus musculus AChE (MmAChE) previously reported in the literature. Our results, further checked by additional molecular dynamics simulations steps, showed a good correlation between the theoretical and experimental data, supporting the methodology as appropriate for prediction of thermodynamic and kinetic parameters and corroborated MmAChE as a suitable model for studies with HsAChE. 相似文献
95.
96.
Flavonoids have been reported to exert multiple biological effects that include acting as pro-oxidants at very high doses. The authors determined a structural alert to identify the clastogenic activity of a series of flavonoids with pro-oxidant activity. The methodology was based on a quantitative structure-activity relationship (QSAR) study. Specifically, the authors developed a virtual screening method for a clastogenic model using the topological substructural molecular design (TOPS-MODE) approach. It represents a useful platform for the automatic generation of structural alerts, based on the calculation of spectral moments of molecular bond matrices appropriately weighted, taking into account the hydrophobic, electronic, and steric molecular features. Therefore, it was possible to establish the structural criteria for maximal clastogenicity of pro-oxidant flavonoids: the presence of a 3-hydroxyl group and a 4-carbonyl group in ring C, the maximal number of hydroxyl groups in ring B, the presence of methoxyl and phenyl groups, the absence of a 2,3-double bond in ring C, and the presence of 5,7 hydroxyl groups in ring A. The presented clastogenic model may be useful for screening new pro-oxidant compounds. This alert could help in the design of new and efficient flavonoids, which could be used as bioactive compounds in nutraceuticals and functional food. 相似文献
97.
Mendes AI Matos P Moniz S Luz S Amaral MD Farinha CM Jordan P 《Molecular and cellular biology》2011,31(19):4076-4086
Members of the WNK (with-no-lysine [K]) subfamily of protein kinases regulate various ion channels involved in sodium, potassium, and chloride homeostasis by either inducing their phosphorylation or regulating the number of channel proteins expressed at the cell surface. Here, we describe findings demonstrating that the cell surface expression of the cystic fibrosis transmembrane conductance regulator (CFTR) is also regulated by WNK4 in mammalian cells. This effect of WNK4 is independent of the presence of kinase and involves interaction with and inhibition of spleen tyrosine kinase (Syk), which phosphorylates Tyr512 in the first nucleotide-binding domain 1 (NBD1) of CFTR. Transfection of catalytically active Syk into CFTR-expressing baby hamster kidney cells reduces the cell surface expression of CFTR, whereas that of WNK4 promotes it. This is shown by biotinylation of cell surface proteins, immunofluorescence microscopy, and functional efflux assays. Mutation of Tyr512 to either glutamic acid or phenylalanine is sufficient to alter CFTR surface levels. In human airway epithelial cells, downregulation of endogenous Syk and WNK4 confirms their roles as physiologic regulators of CFTR surface expression. Together, our results show that Tyr512 phosphorylation is a novel signal regulating the prevalence of CFTR at the cell surface and that WNK4 and Syk perform an antagonistic role in this process. 相似文献
98.
The red death meets the abdominal bristle: Polygenic mutation for susceptibility to a bacterial pathogen in Caenorhabditis elegans 下载免费PDF全文
Veronique Etienne Erik C. Andersen José Miguel Ponciano Dustin Blanton Analucia Cadavid Joanna Joyner‐Matos Chikako Matsuba Brandon Tabman Charles F. Baer 《Evolution; international journal of organic evolution》2015,69(2):508-519
Understanding the genetic basis of susceptibility to pathogens is an important goal of medicine and of evolutionary biology. A key first step toward understanding the genetics and evolution of any phenotypic trait is characterizing the role of mutation. However, the rate at which mutation introduces genetic variance for pathogen susceptibility in any organism is essentially unknown. Here, we quantify the per‐generation input of genetic variance by mutation (VM) for susceptibility of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa (defined as the median time of death, LT50). VM for LT50 is slightly less than VM for a variety of life‐history and morphological traits in this strain of C. elegans, but is well within the range of reported values in a variety of organisms. Mean LT50 did not change significantly over 250 generations of mutation accumulation. Comparison of VM to the standing genetic variance (VG) implies a strength of selection against new mutations of a few tenths of a percent. These results suggest that the substantial standing genetic variation for susceptibility of C. elegans to P. aeruginosa can be explained by polygenic mutation coupled with purifying selection. 相似文献
99.
This editorial highlights a study by Rodriguez, Sanchez‐Moran et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors describe a microcephalic boy carrying the novel heterozygous de novo missense mutation c.560A> G; p.Asp187Gly in Cdh1/Fzr1 encoding the APC/C E3‐ubiquitin ligase cofactor CDH1. A functional characterization of mutant APC/CCDH1 confirms an aberrant division of neural progenitor cells, a condition known to determine the mouse brain cortex size. These data suggest that APC/CCDH1 may contribute to the regulation of the human brain size.
100.
Maria I. B. de Oliveira Lorena V. de Matos Lídia A. da Silva Edsandra C. Chagas Grazyelle S. da Silva Ana L. S. Gomes 《Journal of fish biology》2019,94(4):648-659
The objective of the present study was to describe the histology and histochemistry of the mucosal layer of the digestive tube of Piaractus brachypomus, and the histopathology associated with parasitism by Neoechinorhynchus sp. The digestive tube of P. brachypomus consists of three macroscopically distinct portions: short, rectilinear and elastic-walled ooesophagus, J-shaped siphon stomach and a long intestine with rectilinear and curved portions, defined by patterns of villi as foregut, midgut, and hindgut. Histological and histochemical differences were observed in the mucosal layers of the different digestive tube regions, such as intense production of neutral and acidic mucous substances in the pseudostratified mucosal epithelium of the oesophagus; positive periodic acid Schiff reagent (PAS)reactions at the apex of the columnar epithelial cells of the stomach and increased intensity of histochemical reactions in the hindgut region. Neoechinorhynchus sp. was present in 85.7% of specimens examined, with a mean intensity of 7.4 ± 6.2 (±) and abundance of 6.33. Good health of the fish indicated by high relative condition factor values ( Kn) and occurrence of only mild to moderate alteration in the mucosal layer indicated that Neoechinorhynchus sp. exhibits low pathogenicity towards P. brachypomus hosts in farming environments, with low levels of infection. 相似文献