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31.
32.
Storelli S Verdijk P Verzijl D Timmerman H van de Stolpe AC Tensen CP Smit MJ De Esch IJ Leurs R 《Bioorganic & medicinal chemistry letters》2005,15(11):2910-2913
A series of 3-phenyl-3H-quinazolin-4-ones have been synthesized and tested for affinity and activity at the chemokine CXCR3 receptor. The most potent compound (1d) has been evaluated using radioligand binding and calcium mobilization assays and is considered a useful tool for further characterization of the CXCR3 receptor. 相似文献
33.
Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males
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Van Esch H Bauters M Ignatius J Jansen M Raynaud M Hollanders K Lugtenberg D Bienvenu T Jensen LR Gecz J Moraine C Marynen P Fryns JP Froyen G 《American journal of human genetics》2005,77(3):442-453
Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients. 相似文献
34.
Rodenko B Toebes M Hadrup SR van Esch WJ Molenaar AM Schumacher TN Ovaa H 《Nature protocols》2006,1(3):1120-1132
Major histocompatibility complex (MHC) class I molecules present peptide ligands on the cell surface for recognition by appropriate cytotoxic T cells. MHC-bound peptides are critical for the stability of the MHC complex, and standard strategies for the production of recombinant MHC complexes are based on in vitro refolding reactions with specific peptides. This strategy is not amenable to high-throughput production of vast collections of MHC molecules. We have developed conditional MHC ligands that form stable complexes with MHC molecules but can be cleaved upon UV irradiation. The resulting empty, peptide-receptive MHC molecules can be charged with epitopes of choice under native conditions. Here we describe in-depth procedures for the high-throughput production of peptide-MHC (pMHC) complexes by MHC exchange, the analysis of peptide exchange efficiency by ELISA and the parallel production of MHC tetramers for T-cell detection. The production of the conditional pMHC complex by an in vitro refolding reaction can be achieved within 2 weeks, and the actual high-throughput MHC peptide exchange and subsequent MHC tetramer formation require less than a day. 相似文献
35.
Henry F. Vischer Janneke W. Hulshof Saskia Hulscher Silvina A. Fratantoni Mark H.P. Verheij Jane Victorina Martine J. Smit Iwan J.P. de Esch Rob Leurs 《Bioorganic & medicinal chemistry》2010,18(2):675-688
Human cytomegalovirus (HCMV) is a widespread human pathogen, possessing onco-modulatory properties. Constitutive signaling of the HCMV-encoded chemokine receptor US28 and its ability to bind a broad spectrum of chemokines might facilitate HCMV-associated tumor progression. Novel nonpeptidergic chemotypes were identified as neutral antagonists or inverse agonists on US28, that allosterically inhibit chemokine binding to US28. 相似文献
36.
Di Ilio V Pasquariello N van der Esch AS Cristofaro M Scarsella G Risuleo G 《Molecular and cellular biochemistry》2006,287(1-2):69-77
Neem oil is a natural product obtained from the seeds of the tree Azadirachta indica. Its composition is very complex and the oil exhibits a number of biological activities. The most studied component is the terpenoid azadirachtin which is used for its insecticidal and putative antimicrobial properties. In this report we investigate the biological activity of partially purified components of the oil obtained from A. indica. We show that the semi-purified fractions have moderate to strong cytotoxicity. However, this is not attributable to azadirachtin but to other active compounds present in the mixture. Each fraction was further purified by appropriate extraction procedures and we observed a differential cytotoxicity in the various sub-fractions. This led us to investigate the mode of cell death. After treatment with the oil fractions we observed positivity to TUNEL staining and extensive internucleosomal DNA degradation both indicating apoptotic death. The anti-proliferative properties of the neem oil-derived compounds were also assayed by evaluation of the nuclear PCNA levels (Proliferating Cell Nuclear Antigen). PCNA is significantly reduced in cells treated with a specific fraction of neem oil. Finally, our results strongly suggest a possible involvement of the mitochondrial pathway in the apoptotic death. 相似文献
37.
Michael D Kennedy Mark J Haykowsky Carol A Boliek Ben TA Esch Jessica M Scott Darren ER Warburton 《Dynamic medicine : DM》2006,5(1):8
Background
Near infrared spectroscopy (NIRS) is used to assess muscle oxygenation (MO) within skeletal muscle at rest and during aerobic exercise. Previous investigations have used a single probe placement to measure MO during various forms of exercise. However, regional MO differences have been shown to exist within the same muscle which suggests that different areas of the same muscle may have divergent MO. Thus, the aim of this study was to examine whether regional differences in MO exist within the same muscle during different types of incremental (rest, 25, 50, 75, 100 % of maximum) exercise (1 leg knee extension (KE), 2 leg KE, or cycling).Methods
Nineteen healthy active males (Mean ± SD: Age 27 ± 4 yrs; VO2max: 55 ± 11 mL/kg/min) performed incremental exercise to fatigue using each mode of exercise. NIRS probes were placed on the distal and proximal portion of right leg vastus lateralis (VL). Results were analyzed with a 3-way mixed model ANOVA (probe × intensity × mode).Results
Differences in MO exist within the VL for each mode of exercise, however these differences were not consistent for each level of intensity. Comparison of MO revealed that the distal region of VL was significantly lower throughout KE exercise (1 leg KE proximal MO – distal MO = 9.9 %; 2 leg KE proximal MO – distal MO = 13 %). In contrast, the difference in MO between proximal and distal regions of VL was smaller in cycling and was not significantly different at heavy workloads (75 and 100 % of maximum).Conclusion
MO is different within the same muscle and the pattern of the difference will change depending on the mode and intensity of exercise. Future investigations should limit conclusions on MO to the area under assessment as well as the type and intensity of exercise employed.38.
van den Noort JC van der Esch M Steultjens MP Dekker J Schepers HM Veltink PH Harlaar J 《Journal of biomechanics》2012,45(2):281-288
The external knee adduction moment (KAdM) during gait is an important parameter in patients with knee osteoarthritis (OA). KAdM measurement is currently restricted to instruments only available in gait laboratories. However, ambulatory movement analysis technology, including instrumented force shoes (IFS) and inertial and magnetic measurement systems (IMMS), can measure kinetics and kinematics of human gait free of laboratory restrictions. The objective of this study was a quantitative validation of the accuracy of the KAdM in patients with knee OA, when estimated with an ambulatory-based method (AmbBM) versus a laboratory-based method (LabBM). AmbBM is employing the IFS and a linked-segment model, while LabBM is based on a force plate and optoelectronic marker system. Effects of ground reaction force (GRF), centre of pressure (CoP), and knee joint position measurement are evaluated separately. Twenty patients with knee OA were measured. The GRFs showed differences up to 0.22 N/kg, the CoPs showed differences up to 4 mm, and the medio-lateral and vertical knee position showed differences to 9 mm, between AmbBM and LabBM. The GRF caused an under-estimation in KAdM in early stance. However, this effect was counteracted by differences in CoP and joint position, resulting in a net 5% over-estimation. In midstance and late stance the accuracy of the KAdM was mainly limited by use of the linked-segment model for joint position estimation, resulting in an under-estimation (midstance 6% and late stance 22%). Further improvements are needed in the estimation of joint position from segment orientation. 相似文献
39.
Taher YA van Esch BC Hofman GA Henricks PA van Oosterhout AJ 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(8):5211-5221
1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a potent inhibitor of NF-kappaB expression, can prevent the maturation of dendritic cells in vitro leading to tolerogenic dendritic cells with increased potential to induce regulatory T cells. Herein, we investigated whether the combination of allergen immunotherapy with 1,25(OH)(2)D(3) potentiates the suppressive effects of immunotherapy and whether the immunoregulatory cytokines IL-10 and TGF-beta are involved in the effector phase. OVA-sensitized and challenged BALB/c mice displayed airway hyperresponsiveness (AHR) and increased serum OVA-specific IgE levels, bronchoalveolar lavage eosinophilia, and Th2 cytokine levels. In this model, the dose response of allergen immunotherapy 10 days before OVA inhalation challenge shows strong suppression of asthma manifestations at 1 mg of OVA, but partial suppression of bronchoalveolar lavage eosinophilia, IgE up-regulation, and no reduction of AHR at 100 microg. Interestingly, coadministration of 10 ng of 1,25(OH)(2)D(3) with 100 microg of OVA immunotherapy significantly inhibited AHR and potentiated the reduction of serum OVA-specific IgE levels, airway eosinophilia, and Th2-related cytokines concomitant with increased IL-10 levels in lung tissues and TGF-beta and OVA-specific IgA levels in serum. Similar effects on suboptimal immunotherapy were observed by inhibition of the NF-kappaB pathway using the selective IkappaB kinase 2 inhibitor PS-1145. The suppressive effects of this combined immunotherapy were partially reversed by treatment with mAb to either IL-10R or TGF-beta before OVA inhalation challenge but completely abrogated when both Abs were given. These data demonstrate that 1,25(OH)(2)D(3) potentiates the efficacy of immunotherapy and that the regulatory cytokines IL-10 and TGF-beta play a crucial role in the effector phase of this mouse model. 相似文献
40.
Parasitism has the potential to affect key life history traits of an infected host. Perhaps the most studied interactions are in snail-trematode systems, where infection can result in altered growth rates, survival, and/or fecundity of the individual. Positive correlations between host size and parasite prevalence are often attributed to changes in growth rates or mortality, which have been observed in the laboratory. Extending lab-based conclusions to the natural setting is problematic, especially when environmental conditions differ between the laboratory and the field. The present study uses reproduction experiments and mark-recapture methods to directly measure key life history traits of the pulmonate snail Helisoma anceps in Charlie's Pond. Based on previous laboratory and field experiments on H. anceps, we predict a significant reduction in fecundity, but not growth rate or survival, of infected snails. Individual capture histories were analyzed with multistate models to obtain estimates of survival and infection probabilities throughout the year. Recaptured individuals were used to calculate specific growth rates. Trematode infection resulted in complete castration of the host. However, neither survival nor growth rates were found to differ between infected and uninfected individuals. The probability of infection exhibited seasonal variation, but it did not vary with size of the snail. These results suggest that the correlation between host size and trematode prevalence is not due to differential mortality or changes in growth rates. Instead, the infection accumulates in large snails via the growth of smaller, infected individuals. 相似文献