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81.
25-Hydroxyvitamin D requirement for maintaining skeletal health utilising a Sprague-Dawley rat model
Anderson PH Sawyer RK May BK O'Loughlin PD Morris HA 《The Journal of steroid biochemistry and molecular biology》2007,103(3-5):592-595
To study the role of vitamin D to optimise bone architecture, we have developed an animal model to investigate the effects of frank vitamin D-deficiency as well as graded depletion of circulating 25-hydroxyvitamin D(3) (25D) levels on the skeleton. Rats fed on dietary vitamin D levels from 0 to 500 ng/day achieved diet-dependent circulating levels of 25D ranging from 11 to 115 nmol/L. Levels of serum 1,25-dihydroxyvitamin D(3) (1,25D) increased as dietary vitamin D increased between 0 and 200 ng/day at which point a maximum level was achieved and retained with higher vitamin D intakes. The renal levels of 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) mRNA were highest in animal groups fed on vitamin D between 0 and 300 ng/day. In contrast, renal 25-hydroxyvitamin D 24-hydroxylase (CYP24) mRNA levels increased as dietary vitamin D increased achieving maximum levels in animals receiving 500 ng vitamin D/day. This animal model of vitamin D depletion is suitable to provide invaluable information on the serum levels of 25D and dietary calcium intake necessary for optimal bone structure. Such information is essential for developing nutritional recommendations to reduce the incidence of osteoporotic hip fractures. 相似文献
82.
Benjamin S. Robb Jerod A. Merkle Hall Sawyer Jeffrey L. Beck Matthew J. Kauffman 《The Journal of wildlife management》2022,86(4):e22212
Animal movement can mediate the ecological consequences of fragmentation; however, barriers such as fences, roads, and railways are becoming a pervasive threat to wildlife. Pronghorn (Antilocapra americana) habitat in western North America has been fragmented by roads, railways, and fences. Although pronghorn are sensitive to barriers, neither the relative permeability of different barriers to crossing nor their influence on space use have been quantified. We used a large global positioning system (GPS)-collar dataset of pronghorn (n = 1,010 animal-years) in Wyoming, USA, to first quantify the likelihood that pronghorn cross each of 5 different anthropogenic barriers, including fences, county roads, railroads, state highways, and interstate highways (i.e., interstates). Next, we assessed how each barrier influenced pronghorn space use during the winter as indexed by the area occupied, and daily displacement relative to the density of barriers on an individual's winter range. The semi-permeability of the 5 barriers varied substantially, with the interstate being the most severe barrier to pronghorn movement. Pronghorn were >300 times less likely to cross interstates compared to state highways. Although pronghorn space use was rarely influenced by barriers within individual core winter ranges, pronghorn space use was constrained by barriers on the buffered periphery of individual winter ranges. Despite their different permeability to movement, the density of fences and combined interstates and railroads had similarly negative effects on pronghorn space use. Our results illustrate that the degree to which pronghorn avoid crossing barriers may scale up to affect access to habitat. Additionally, our results indicate that the effects of barriers on habitat access are not proportional to their permeability. Our results add to a growing consensus that effective management of mobile species depends on understanding how different kinds of semi-permeable barriers influence access and use of habitats. 相似文献
83.
Simard D Leblanc Y Berthelette C Zaghdane MH Molinaro C Wang Z Gallant M Lau S Thao T Hamel M Stocco R Sawyer N Sillaots S Gervais F Houle R Lévesque JF 《Bioorganic & medicinal chemistry letters》2011,21(2):841-845
A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed. 相似文献
84.
De Savi C Pape A Sawyer Y Milne D Davies C Cumming JG Ting A Lamont S Smith PD Tart J Page K Moore P 《Bioorganic & medicinal chemistry letters》2011,21(11):3301-3306
A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics. 相似文献
85.
Thomas M Huang WS Wen D Zhu X Wang Y Metcalf CA Liu S Chen I Romero J Zou D Sundaramoorthi R Li F Qi J Cai L Zhou T Commodore L Xu Q Keats J Wang F Wardwell S Ning Y Snodgrass JT Broudy MI Russian K Iuliucci J Rivera VM Sawyer TK Dalgarno DC Clackson T Shakespeare WC 《Bioorganic & medicinal chemistry letters》2011,21(12):3743-3748
Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML. 相似文献
86.
Zaghdane H Boyd M Colucci J Simard D Berthelette C Leblanc Y Wang Z Houle R Lévesque JF Molinaro C Hamel M Stocco R Sawyer N Sillaots S Gervais F Gallant M 《Bioorganic & medicinal chemistry letters》2011,21(11):3471-3474
A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified. 相似文献
87.
Bakker MF Verstappen SM Welsing PM Jacobs JW Jahangier ZN van der Veen MJ Bijlsma JW Lafeber FP;Utrecht Arthritis Cohort study group 《Arthritis research & therapy》2011,13(3):R70
Introduction
The aim of this study was to investigate whether serum biomarker levels of C2C, C1,2C, CS846, and CPII can predict the long-term course of disease activity and radiographic progression early in the disease course of rheumatoid arthritis (RA). 相似文献88.
The self-association of proteins into amyloid fibrils offers an alternative to the natively folded state of many polypeptides. Although commonly associated with disease, amyloid fibrils represent the natural functional state of some proteins, such as the chaplins from the soil-dwelling bacterium Streptomyces coelicolor, which coat the aerial mycelium and spores rendering them hydrophobic. We have undertaken a biophysical characterisation of the five short chaplin peptides ChpD-H to probe the mechanism by which these peptides self-assemble in solution to form fibrils. Each of the five chaplin peptides produced synthetically or isolated from the cell wall is individually surface-active and capable of forming fibrils under a range of solution conditions in vitro. These fibrils contain a highly similar cross-β core structure and a secondary structure that resembles fibrils formed in vivo on the spore and mycelium surface. They can also restore the growth of aerial hyphae to a chaplin mutant strain. We show that cysteine residues are not required for fibril formation in vitro and propose a role for the cysteine residues conserved in four of the five short chaplin peptides. 相似文献
89.
Travis ER Gaze WH Pontiroli A Sweeney FP Porter D Mason S Keeling MJ Jones RM Sawyer J Aranaz A Rizaldos EC Cork J Delahay RJ Wilson GJ Hewinson RG Courtenay O Wellington EM 《PloS one》2011,6(11):e27369
Advances in the diagnosis of Mycobacterium bovis infection in wildlife hosts may benefit the development of sustainable approaches to the management of bovine tuberculosis in cattle. In the present study, three laboratories from two different countries participated in a validation trial to evaluate the reliability and reproducibility of a real time PCR assay in the detection and quantification of M. bovis from environmental samples. The sample panels consisted of negative badger faeces spiked with a dilution series of M. bovis BCG Pasteur and of field samples of faeces from badgers of unknown infection status taken from badger latrines in areas with high and low incidence of bovine TB (bTB) in cattle. Samples were tested with a previously optimised methodology. The experimental design involved rigorous testing which highlighted a number of potential pitfalls in the analysis of environmental samples using real time PCR. Despite minor variation between operators and laboratories, the validation study demonstrated good concordance between the three laboratories: on the spiked panels, the test showed high levels of agreement in terms of positive/negative detection, with high specificity (100%) and high sensitivity (97%) at levels of 10(5) cells g(-1) and above. Quantitative analysis of the data revealed low variability in recovery of BCG cells between laboratories and operators. On the field samples, the test showed high reproducibility both in terms of positive/negative detection and in the number of cells detected, despite low numbers of samples identified as positive by any laboratory. Use of a parallel PCR inhibition control assay revealed negligible PCR-interfering chemicals co-extracted with the DNA. This is the first example of a multi-laboratory validation of a real time PCR assay for the detection of mycobacteria in environmental samples. Field studies are now required to determine how best to apply the assay for population-level bTB surveillance in wildlife. 相似文献
90.
Trueblood NA Inscore PR Brenner D Lugassy D Apstein CS Sawyer DB Colucci WS 《American journal of physiology. Heart and circulatory physiology》2005,288(1):H244-H249
After myocardial infarction (MI), there is progressive left ventricular (LV) remodeling and impaired exercise capacity. We tested the hypothesis that LV remodeling results in structural and functional changes that determine exercise impairment post-MI. Rats underwent coronary artery ligation (n = 12) or sham (n = 11) surgery followed by serial exercise tests and echocardiography for 16 wk post-MI. LV pressure-volume relationships were determined using a blood-perfused Langendorff preparation. Exercise capacity was 60% of shams immediately post-MI (P < 0.05) followed by a recovery to near normal during weeks 5-8. Thereafter, there was a progressive decline in exercise capacity to +/-40% of shams (P < 0.01). At both 8 and 16 wk post-MI, fractional shortening (FS) was reduced and end-diastolic diameter (EDD) was increased (P < 0.01). However, neither FS nor EDD correlated with exercise at 8 or 16 wk (r(2) < 0.12, P > 0.30). LV septal wall thickness was increased at both 8 (P = 0.17 vs. shams) and 16 wk (P = 0.035 vs. shams) post-MI and correlated with exercise at both times (r(2) >/= 0.50 and P = 0.02 at 8 and 16 wk). Neither end-diastolic volume nor maximum LV developed pressure at 16 wk correlated with exercise capacity. Exercise capacity follows a biphasic time course post-MI. An immediate decrease is followed by an early recovery phase that is associated with compensatory LV hypertrophy. Subsequently, there is a progressive decrease in exercise capacity that is independent of further changes in LV volume or contractile function. 相似文献