Butcherisaksen1390

Pravastatin acid (PVA) can be isomerized to its inactive metabolite 3'α-iso-pravastatin acid (3αPVA) under acidic pH conditions. Previous studies reported interindividual differences in circulating concentrations of PVA and 3αPVA. This study investigated the functional consequences of PVA isomerization on OATP1B1-mediated transport. We characterized 3αPVA inhibition of OATP1B1-mediated PVA uptake into human embryonic kidney 293 cells expressing the four different OATP1B1 proteins (*1a, *1b, *5, and *15). 3αPVA inhibited OATP1B1-mediated PVA uptake in all four OATP1B1 gene products but with lower IC50/Ki values for OATP1B1*5 and *15 than for the reference proteins (*1a and *1b). PVA and 3αPVA were transported by all four OATP1B1 proteins. Kinetic experiments revealed that maximal transport rates (Vmax values) for OATP1B1 variants *5 and *15 were lower than for *1a and *1b for both substrates. Apparent affinities for 3αPVA transport were similar for all four variants. However, the apparent affinity of OATP1B1*5 for 3αPVA was higher (lower Km value) than for PVA. These data confirm that PVA conversion to 3αPVA can have functional consequences on PVA uptake and impacts OATP1B1 variants more than the reference protein, thus highlighting another source variation that must be taken into consideration when optimizing the PVA dose-exposure relationship for patients. SIGNIFICANCE STATEMENT 3'α-iso-pravastatin acid inhibits pravastatin uptake for all OATP1B1 protein types; however, the IC50 values were significantly lower in OATP1B1*5 and *15 transfected cells. This suggests that a lower concentration of 3'α-iso-pravastatin is needed to disrupt OATP1B1-mediated pravastatin uptake, secondary to decreased cell surface expression of functional OATP1B1 in variant-expressing cells. These data will refine previous pharmacokinetic models that are utilized to characterize pravastatin interindividual variability with an ultimate goal of maximizing efficacy at the lowest possible risk for toxicity.From the conception of Baddeley's visuospatial sketchpad, visual working memory and visual attention have been closely linked concepts. An attractive model has advocated unity of the two cognitive functions, with attention serving the active maintenance of sensory representations. However, empirical evidence from various paradigms and dependent measures has now firmly established an at least partial dissociation between visual attention and visual working memory maintenance - thus leaving unclear what the relationship between the two concepts is. Moreover, a focus on sensory storage has treated visual working memory as a reflection of the past, with attention as a limiting resource. This view ignores what storage is for immediate or future action. We argue that rather than serving sensory storage, attention emerges from coupling relevant sensory and action representations within working memory. Importantly, this coupling is bidirectional First, through recurrent feedback mechanisms, action coupling results in the enhancement of the appropriate sensory memory representation. Under this view, unattended memories are currently not coupled to an action plan, but are not necessarily lost and remain available for future tasks when necessary. Second, through the very same feedback projections, attention serves as the credit assignment mechanism for the action's outcome. When the action is successful, the associated representations are being reinforced, leading to more robust consolidation and more rapid retrieval in the future - thus explaining performance benefits for attended memories without assuming that attention serves as the maintenance mechanism. By firmly grounding VWM in the action system, the new framework integrates a range of behavioural and neurophysiological findings and avoids circularity in explaining the role of attention in working memory.Ocean warming and acidification caused by global climate change interferes with the shell growth of mollusks. In abalone Haliotis discus hannai, the microstructural changes in the shell under stress are unclear, and the effect of thermal stress on biomineralization is unknown. The lack of gene information has also hampered the study of abalone biomineralization mechanisms. In this study, the microstructure of reconstructed shell in H. discus hannai was observed to determine the effects of thermal and acidification stress on shell growth. Three nacre protein genes, Hdh-AP7, Hdh-AP24, and Hdh-perlustrin, were characterized, and their expression pattern during shell repair was measured under thermal and acidification stress and compared with those of two known biomineralization-related genes, Hdh-AP-1 and Hdh-defensin. NE 52-QQ57 research buy The stress resulted in aragonite plates with corroded or irregular microstructures. The gene expression of two nacre proteins (Hdh-AP7 and Hdh-AP24), which directly induce crystal formation, were more sensitive to thermal stress than to acidification, but the expression of the regulatory nacre protein (Hdh-perlustrin) and the two known genes (Hdh-AP-1 and Hdh-defensin), which are also related to immunity, showed an interlinked, complex pattern change. We concluded that high temperature and acidification damages the shell microstructure by disturbing the expression pattern of biomineralization-related genes.Reef-building species play key roles in promoting local species richness and regulating ecosystem functions like biogeochemical fluxes. We evaluated the functioning of a habitat engineered by the reef-building polychaete Sabellaria alveolata, by measuring oxygen and nutrient fluxes in the reef structures and in the soft-sediments nearby. Then, we investigated the relative importance of temperature, the engineer S. alveolata, and different facets of macrofauna diversity (taxonomic, functional diversity and identity), on the reef biogeochemical fluxes using multiple linear regressions and effect sizes. The reef fluxes were more intense than the soft-sediment fluxes and mainly driven by the engineer biomass and abundance, stressing the importance of these biogenic structures. Higher water temperatures and an intermediate level of associated macrofauna functional dispersion weighted only by abundance (i.e. intermediate biological trait variability) maximized the reef's global biogeochemical functioning. Ultimately, the physical degradation of the reefs could lead to lower levels of functioning.