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81.
Alzheimer and prion diseases are neurodegenerative disorders characterised by the abnormal processing of amyloid-β (Aβ) peptide and prion protein (PrPC), respectively. Recent evidence indicates that PrPC may play a critical role in the pathogenesis of Alzheimer disease. PrPC interacts with and inhibits the β-secretase BACE1, the rate-limiting enzyme in the production of Aβ. More recently PrPC was identified as a receptor for Aβ oligomers and the expression of PrPC appears to be controlled by the amyloid intracellular domain (AICD). Here we review these observations and propose a feedback loop in the normal brain where PrPC exerts an inhibitory effect on BACE1 to decrease both Aβ and AICD production. In turn, the AICD upregulates PrPC expression, thus maintaining the inhibitory effect of PrPC on BACE1. In Alzheimer disease, this feedback loop is disrupted, and the increased level of Aβ oligomers bind to PrPC and prevent it from regulating BACE1 activity.Key words: alzheimer disease, amyloid-β, Aβ oligomers, amyloid intracellular domain, BACE1, presenilin, prion protein 相似文献
82.
Cielo Pasay Larry Arlian Marjorie Morgan Robin Gunning Louise Rossiter Deborah Holt Shelley Walton Simone Beckham James McCarthy 《PLoS neglected tropical diseases》2009,3(1)
Background
Permethrin is the active component of topical creams widely used to treat human scabies. Recent evidence has demonstrated that scabies mites are becoming increasingly tolerant to topical permethrin and oral ivermectin. An effective approach to manage pesticide resistance is the addition of synergists to counteract metabolic resistance. Synergists are also useful for laboratory investigation of resistance mechanisms through their ability to inhibit specific metabolic pathways.Methodology/Principal Findings
To determine the role of metabolic degradation as a mechanism for acaricide resistance in scabies mites, PBO (piperonyl butoxide), DEF (S,S,S-tributyl phosphorotrithioate) and DEM (diethyl maleate) were first tested for synergistic activity with permethrin in a bioassay of mite killing. Then, to investigate the relative role of specific metabolic pathways inhibited by these synergists, enzyme assays were developed to measure esterase, glutathione S-transferase (GST) and cytochrome P450 monooxygenase (cytochrome P450) activity in mite extracts. A statistically significant difference in median survival time of permethrin-resistant Sarcoptes scabiei variety canis was noted when any of the three synergists were used in combination with permethrin compared to median survival time of mites exposed to permethrin alone (p<0.0001). Incubation of mite homogenates with DEF showed inhibition of esterase activity (37%); inhibition of GST activity (73%) with DEM and inhibition of cytochrome P450 monooxygenase activity (81%) with PBO. A 7-fold increase in esterase activity, a 4-fold increase in GST activity and a 2-fold increase in cytochrome P450 monooxygenase activity were observed in resistant mites compared to sensitive mites.Conclusions
These findings indicate the potential utility of synergists in reversing resistance to pyrethroid-based acaricides and suggest a significant role of metabolic mechanisms in mediating pyrethroid resistance in scabies mites. 相似文献83.
Background
Cancer treatments are complex and involve different actions, which include many times a surgical procedure. Medical imaging provides important information for surgical planning, and it usually demands a proper segmentation, i.e., the identification of meaningful objects, such as organs and lesions. This study proposes a methodology to segment the liver, its vessels and nodules from computer tomography images for surgical planning. 相似文献84.
Jessica AB van Nies Celina Alves Audrey LS Radix-Bloemen Cécile Gaujoux-Viala Tom WJ Huizinga Johanna MW Hazes Elisabeth Brouwer Bruno Fautrel Annette HM van der Helm-van Mil 《Arthritis research & therapy》2015,17(1)
IntroductionMorning stiffness is assessed daily in the diagnostic process of arthralgia and arthritis, but large-scale studies on the discriminative ability are absent. This study explored the diagnostic value of morning stiffness in 5,202 arthralgia and arthritis patients and the prognostic value in early rheumatoid arthritis (RA).MethodsIn arthralgia patients referred to the Early Arthritis Recognition Clinics (EARC) of Leiden (n = 807) and Groningen (n = 481) or included in the Rotterdam Early Arthritis Cohort (REACH) study (n = 353), the associations (cross-sectional analyses) between morning stiffness and presence of arthritis at physical examination were studied. In early arthritis patients, included in the Leiden Early Arthritis Clinic (EAC) (n = 2,748) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n = 813), associations with fulfilling the 2010-RA criteria after one year were assessed. In 2010-RA patients included in the EAC (n = 1,140) and ESPOIR (n = 677), association with the long-term outcomes of disease-modifying antirheumatic drug (DMARD)-free sustained remission and radiological progression were determined. Morning stiffness was defined as a duration ≥60 minutes; sensitivity analyses were performed for other definitions.ResultsIn arthralgia, morning stiffness (≥60 minutes) associated with the presence of arthritis; Leiden EARC odds ratio (OR) 1.49 (95% CI 1.001 to 2.20), Groningen EARC OR 2.21 (1.33 to 3.69) and REACH OR 1.55 (0.97 to 2.47) but the areas under the receiver operating characteristic curve (AUCs) were low (0.52, 0.57, 0.54). In early arthritis, morning stiffness was associated with 2010-RA independent of other predictors (Leiden EAC OR 1.72 (95% CI 1.31 to 2.25, AUC 0.68), ESPOIR OR 1.68 (1.03 to 2.74, AUC 0.64)). Duration of ≥30 minutes provided optimal discrimination for RA in early arthritis. Morning stiffness was not associated with radiological progression or DMARD-free sustained remission.ConclusionsMorning stiffness in arthralgia and early arthritis is associated with arthritis and RA respectively. This supports the incorporation of morning stiffness in the diagnostic process.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0616-3) contains supplementary material, which is available to authorized users. 相似文献85.
86.
Interaction between RNA polymerase and a ribosomal RNA promoter of E. coli. 总被引:3,自引:2,他引:1
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The interaction between RNA polymerase and the E. coli ribosomal (r) RNA promoter(s) of the rrnE operon has been studied by the filter-binding method. The extent of complex formation between RNA polymerase and rrnE promoter(s) is salt-dependent; ppGpp specifically inhibits interaction of RNA polymerase with the rrnE promoter(s). A tentative model is proposed for the molecular events in the early steps of rRNA initiation: a transition of the primarily formed, labile RNA polymerase-rRNA promoter complex to a more stable form is the determining step. This step is salt-sensitive; ppGpp acts on this "isomerization". 相似文献
87.
Fernando J. Hidalgo Fausto N. Firstater Eugenia Fanjul M. Cielo Bazterrica Betina J. Lomovasky Juan Tarazona Oscar O. Iribarne 《Helgoland Marine Research》2008,62(1):73-83
Echinolittorina peruviana is the most common gastropod in the high intertidal zone of Peru, representing more than 80% of the individuals present at that zone. Experimental removal of snails was used to evaluate their effects on (a) abundance of epilithic biofilm, (b) barnacle recruitment, and (c) abundance of macroalgae under “normal” conditions of the El Niño Southern Oscillation (ENSO). Experiments were carried out from October 2005 to April 2007 at two intertidal levels of a semi-protected rocky shore of central Peru. Results demonstrated that E. peruviana is able to control biofilm abundance and barnacle recruitment at both heights investigated, with marked effects in the lower zone. Erect macroalgae (Ulva spp. and Gelidium spp.) were less affected by grazing; but negative effects were observed on macroalgal crusts. Season and physical stress seem to play a more important role in the abundance of macroalgae in the high intertidal. Our results are similar to those reported elsewhere for high shore littorinids and represent baseline data to understand how the role of intertidal consumers will vary under the cold (La Niña) and warm (El Niño) phases of ENSO on these shores. 相似文献
88.
89.
Ihab?AB?Awad Christian?A?Rees Tina?Hernandez-Boussard Catherine?A?Ball Gavin?SherlockEmail author 《BMC bioinformatics》2004,5(1):151
Background
Microarray-based comparative genome hybridization experiments generate data that can be mapped onto the genome. These data are interpreted more easily when represented graphically in a genomic context. 相似文献90.