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141.
142.
Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine biosynthesis pathway and is a potential new antibacterial drug target. No target-based high-throughput screening (HTS) assay for this enzyme has been reported to date. Here, we optimized two colorimetric-based enzymatic assays that detect the ureido moiety of the DHOase substrate, carbamyl-aspartate (Ca-asp). Each assay was developed in a 40-μl assay volume using 384-well plates with a different color mix, diacetylmonoxime (DAMO)–thiosemicarbazide (TSC) or DAMO–antipyrine. The sensitivity and color interference of both color mixes were compared in the presence of common HTS buffer additives, including dimethyl sulfoxide, reducing agents, detergents, and bovine serum albumin. DAMO–TSC (Z′-factors 0.7–0.8) was determined to be superior to DAMO–antipyrine (Z′-factors 0.5–0.6) with significantly less variability within replicates. An HTS pilot screening with 29,552 compounds from four structurally diverse libraries confirmed the quality of our newly optimized colorimetric assay with DAMO–TSC. This robust method has no heating requirement, which was the main obstacle to applying previous assays to HTS. More important, this well-optimized HTS assay for DHOase, the first of its kind, should make it possible to screen large-scale compound libraries to develop new inhibitors against any enzymes that produce ureido functional groups. 相似文献
143.
Nafizal Hossain Svetlana Ivanova Åsa Sjöholm Timén Jonas Bergare Tesfaledet Mussie Lena Bergström 《Bioorganic & medicinal chemistry letters》2013,23(14):4026-4030
A series of zwitterionic spirocyclic compounds were synthesised. In vitro data revealed that these compounds were potent CCR1 antagonists. In particular, 2, 4, 11 and 20 inhibited CCR1 mediated chemotaxis of THP-1 cells in a functional assay. 相似文献
144.
David J. Richard Ryan Lena Thomas Bannister Noel Blake William E. Pierceall Nicole E. Carlson Christina Eberhart Keller Marcel Koenig Yuanjun He Dmitriy Minond Jitendra Mishra Michael Cameron Timothy Spicer Peter Hodder Michael H. Cardone 《Bioorganic & medicinal chemistry》2013,21(21):6642-6649
Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic. 相似文献
145.
One of the ultimate goals of individual human development is to be an adult and to life life independently and autonomously, and maybe even to make a contribution to the community. This may seem impossible in the case of a severe physical disability (e.g., if a muscular disease does not even allow a person to hold a fork to eat). To reach adulthood and also to be an adult (e.g., to live their own initiative and self-determination) is possible even if the pure physical strength is lacking. We report on our lives with spinal muscular atrophy (SMA) type II, 3 survival motor neuron 2 (SMN2) copies, full of challenges and being dependent, and yet a completely normal life. 相似文献
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148.
Ali Moukadem Alain Dieterlen Nicolas Hueber Christian Brandt 《Biomedical signal processing and control》2013,8(3):273-281
This paper presents a new module for heart sounds segmentation based on S-transform. The heart sounds segmentation process segments the PhonoCardioGram (PCG) signal into four parts: S1 (first heart sound), systole, S2 (second heart sound) and diastole. It can be considered one of the most important phases in the auto-analysis of PCG signals. The proposed segmentation module can be divided into three main blocks: localization of heart sounds, boundaries detection of the localized heart sounds and classification block to distinguish between S1 and S2. An original localization method of heart sounds are proposed in this study. The method named SSE calculates the Shannon energy of the local spectrum calculated by the S-transform for each sample of the heart sound signal. The second block contains a novel approach for the boundaries detection of S1 and S2. The energy concentrations of the S-transform of localized sounds are optimized by using a window width optimization algorithm. Then the SSE envelope is recalculated and a local adaptive threshold is applied to refine the estimated boundaries. To distinguish between S1 and S2, a feature extraction method based on the singular value decomposition (SVD) of the S-matrix is applied in this study. The proposed segmentation module is evaluated at each block according to a database of 80 sounds, including 40 sounds with cardiac pathologies. 相似文献
149.
Alcohol consumption and alcohol problems after bariatric surgery in the swedish obese subjects study
150.
Linnea B?rebring Maria Bullarbo Anna Glantz Monica Leu Agelii ?se Jagner Joy Ellis Lena Hulthén Inez Schoenmakers Hanna Augustin 《PloS one》2016,11(3)
Every tenth pregnancy is affected by hypertension, one of the most common complications and leading causes of maternal death worldwide. Hypertensive disorders in pregnancy include pregnancy-induced hypertension and preeclampsia. The pathophysiology of the development of hypertension in pregnancy is unknown, but studies suggest an association with vitamin D status, measured as 25-hydroxyvitamin D (25(OH)D). The aim of this study was to investigate the association between gestational 25(OH)D concentration and preeclampsia, pregnancy-induced hypertension and blood pressure trajectory. This cohort study included 2000 women. Blood was collected at the first (T1) and third (T3) trimester (mean gestational weeks 10.8 and 33.4). Blood pressure at gestational weeks 10, 25, 32 and 37 as well as symptoms of preeclampsia and pregnancy-induced hypertension were retrieved from medical records. Serum 25(OH)D concentrations (LC-MS/MS) in T1 was not significantly associated with preeclampsia. However, both 25(OH)D in T3 and change in 25(OH)D from T1 to T3 were significantly and negatively associated with preeclampsia. Women with a change in 25(OH)D concentration of ≥30 nmol/L had an odds ratio of 0.22 (p = 0.002) for preeclampsia. T1 25(OH)D was positively related to T1 systolic (β = 0.03, p = 0.022) and T1 diastolic blood pressure (β = 0.02, p = 0.016), and to systolic (β = 0.02, p = 0.02) blood pressure trajectory during pregnancy, in adjusted analyses. There was no association between 25(OH)D and pregnancy-induced hypertension in adjusted analysis. In conclusion, an increase in 25(OH)D concentration during pregnancy of at least 30 nmol/L, regardless of vitamin D status in T1, was associated with a lower odds ratio for preeclampsia. Vitamin D status was significantly and positively associated with T1 blood pressure and gestational systolic blood pressure trajectory but not with pregnancy-induced hypertension. 相似文献