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排序方式: 共有356条查询结果,搜索用时 321 毫秒
161.
162.
Austin NE Avenell KY Boyfield I Branch CL Hadley MS Jeffrey P Johnson CN Macdonald GJ Nash DJ Riley GJ Smith AB Stemp G Thewlis KM Vong AK Wood M 《Bioorganic & medicinal chemistry letters》2000,10(22):2553-2555
Starting from the dopamine D3 receptor antagonist SB-277011 1, a series of 2,3,4,5-tetrahydro-1H-3-benzazepines has been identified with high affinity for the dopamine D3 receptor and selectivity over the D2 receptor. The 3-acetamido-2-fluorocinnamide derivative 20 gave high D3 receptor affinity (pKi 8.4) with 130-fold selectivity over the 2, receptor. 相似文献
163.
Role of lipid trimming and CD1 groove size in cellular antigen presentation 总被引:1,自引:0,他引:1 下载免费PDF全文
Cheng TY Relloso M Van Rhijn I Young DC Besra GS Briken V Zajonc DM Wilson IA Porcelli S Moody DB 《The EMBO journal》2006,25(13):2989-2999
Cellular CD1 proteins bind lipids that differ in length (C(12-80)), including antigens that exceed the capacity of the CD1 groove. This could be accomplished by trimming lipids to a uniform length before loading or by inserting each lipid so that it penetrates the groove to a varying extent. New assays to detect antigen fragments generated within human dendritic cells showed that bacterial antigens remained intact, even after delivery to lysosomes, where control lipids were cleaved. Further, recombinant CD1b proteins could bind and present C(80) lipid antigens using a mechanism that did not involve cellular enzymes or lipid cleavage, but was regulated by pH in the physiologic range. We conclude that endosomal acidification acts directly, rather than through enzymatic trimming, to insert lipids into CD1b. Lipids are loaded in an intact form, so that they likely protrude through a portal near the bottom of the groove, which represents an escape hatch for long lipids from mycobacterial pathogens. 相似文献
164.
Surface chemistry is one of the main factors that contributes to the longevity and compliance of cell patterning. Two to three weeks are required for dissociated, embryonic rat neuronal cultures to mature to the point that they regularly produce spontaneous and evoked responses. Though proper surface chemistry can be achieved through the use of covalent protein attachment, often it is not maintainable for the time periods necessary to study neuronal growth. Here we report a new and effective covalent linking approach using (3-glycidoxypropyl) trimethoxysilane (3-GPS) for creating long term neuronal patterns. Micrometer scale patterns of cell adhesive proteins were formed using microstamping; hippocampal neurons, cultured up to 1 month, followed those patterns. Cells did not grow on unmodified 3-GPS surfaces, producing non-permissive regions for the long-term cell patterning. Patterned neuronal networks were formed on two different types of MEA (polyimide or silicon nitride insulation) and maintained for 3 weeks. Even though the 3-GPS layer increased the impedance of metal electrodes by a factor of 2-3, final impedance levels were low enough that low noise extracellular recordings were achievable. Spontaneous neural activity was recorded as early as 10 days in vitro. Neural recording and stimulation were readily achieved from these networks. Our results showed that 3-GPS could be used on surfaces to immobilize biomolecules for a variety of neural engineering applications. 相似文献
165.
Branch Craige Che-Chia Tsao Dennis R. Diener Yuqing Hou Karl-Ferdinand Lechtreck Joel L. Rosenbaum George B. Witman 《The Journal of cell biology》2010,190(5):927-940
Mutations in human CEP290 cause cilia-related disorders that range in severity from isolated blindness to perinatal lethality. Here, we describe a Chlamydomonas reinhardtii mutant in which most of the CEP290 gene is deleted. Immunoelectron microscopy indicated that CEP290 is located in the flagellar transition zone in close association with the prominent microtubule–membrane links there. Ultrastructural analysis revealed defects in these microtubule–membrane connectors, resulting in loss of attachment of the flagellar membrane to the transition zone microtubules. Biochemical analysis of isolated flagella revealed that the mutant flagella have abnormal protein content, including abnormal levels of intraflagellar transport proteins and proteins associated with ciliopathies. Experiments with dikaryons showed that CEP290 at the transition zone is dynamic and undergoes rapid turnover. The results indicate that CEP290 is required to form microtubule–membrane linkers that tether the flagellar membrane to the transition zone microtubules, and is essential for controlling flagellar protein composition. 相似文献
166.
Purpose
Group-wise analyses of DTI in mTBI have demonstrated evidence of traumatic axonal injury (TAI), associated with adverse clinical outcomes. Although mTBI is likely to have a unique spatial pattern in each patient, group analyses implicitly assume that location of injury will be the same across patients. The purpose of this study was to optimize and validate a procedure for analysis of DTI images acquired in individual patients, which could detect inter-individual differences and be applied in the clinical setting, where patients must be assessed as individuals.Materials and Methods
After informed consent and in compliance with HIPAA, 34 mTBI patients and 42 normal subjects underwent 3.0 Tesla DTI. Four voxelwise assessment methods (standard Z-score, “one vs. many” t-test, Family-Wise Error Rate control using pseudo t-distribution, EZ-MAP) for use in individual patients, were applied to each patient’s fractional anisotropy (FA) maps and tested for its ability to discriminate patients from controls. Receiver Operating Characteristic (ROC) analyses were used to define optimal thresholds (voxel-level significance and spatial extent) for reliable and robust detection of mTBI pathology.Results
ROC analyses showed EZ-MAP (specificity 71%, sensitivity 71%), “one vs. many” t-test and standard Z-score (sensitivity 65%, specificity 76% for both methods) resulted in a significant area under the curve (AUC) score for discriminating mTBI patients from controls in terms of the total number of abnormal white matter voxels detected while the FWER test was not significant. EZ-MAP is demonstrated to be robust to assumptions of Gaussian behavior and may serve as an alternative to methods that require strict Gaussian assumptions.Conclusion
EZ-MAP provides a robust approach for delineation of regional abnormal anisotropy in individual mTBI patients. 相似文献167.
Although native herbivores can alter fire regimes by consuming herbaceous vegetation that serves as fine fuel and, less commonly,
accumulating fuel as nest material and other structures, simultaneous considerations of contrasting effects of herbivores
on fire have scarcely been addressed. We proposed that a colonial rodent, vizcacha (Lagostomus maximus), reduces and increases fire intensity at different stages in its population cycle in the semiarid scrub of Argentina. Specifically,
we hypothesized that, when colonies are active, vizcachas create natural fire-breaks through intense grazing, generating over
time patches of large unburned shrubs in grazed zones. In contrast, when colonies are abandoned, recovery of fine fuels and
previous accumulation of coarse wood on colonies during territorial displays increases fire intensity, creating patches of
high shrub mortality. To test these hypotheses, we estimated stem age of the dominant shrub (Larrea divaricata) and measured aboveground biomass in zones actively grazed by vizcachas and in ungrazed zones, and compared densities of
live and dead shrubs on abandoned colonies and adjacent zones following fire. In active colonies, age and biomass of shrubs
were much greater in grazed than ungrazed zones. In abandoned colonies that had been burnt, density of dead, burned shrubs
was higher and density of live shrubs was lower than in adjacent zones. These results support our hypotheses and reveal a
new interaction between native herbivores and fire, in which herbivores augment fire intensity by gathering fuel. Our findings
indicate that, through opposing effects on fire, native herbivores enhance the heterogeneity of vegetation in woody-dominated
ecosystems. 相似文献
168.
Di Fabio R Pellacani A Faedo S Roth A Piccoli L Gerrard P Porter RA Johnson CN Thewlis K Donati D Stasi L Spada S Stemp G Nash D Branch C Kindon L Massagrande M Poffe A Braggio S Chiarparin E Marchioro C Ratti E Corsi M 《Bioorganic & medicinal chemistry letters》2011,21(18):5562-5567
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep. 相似文献
169.
Lily Li Marvin Lin Maria Krassilnikova Katya Ostrow Amanda Bader Brian Radbill Jaime Uribarri Joji Tokita Staci Leisman Vijay Lapsia Randy A. Albrecht Adolfo García-Sastre Andrea D. Branch Peter S. Heeger Anita Mehrotra 《PloS one》2014,9(10)
Background
Memory T-cells are mediators of transplant injury, and no therapy is known to prevent the development of cross-reactive memory alloimmunity. Activated vitamin D is immunomodulatory, and vitamin D deficiency, common in hemodialysis patients awaiting transplantation, is associated with a heightened alloimmune response. Thus, we tested the hypothesis that vitamin D3 supplementation would prevent alloreactive T-cell memory formation in vitamin D-deficient hemodialysis patients.Methods and Findings
We performed a 12-month single-center pilot randomized, controlled trial of 50,000 IU/week of cholecalciferol (D3) versus no supplementation in 96 hemodialysis patients with serum 25(OH)D<25 ng/mL, measuring effects on serum 25(OH)D and phenotypic and functional properties of T-cells. Participants were randomized 2∶1 to active treatment versus control. D3 supplementation increased serum 25(OH)D at 6 weeks (13.5 [11.2] ng/mL to 42.5 [18.5] ng/mL, p<0.001) and for the duration of the study. No episodes of sustained hypercalcemia occurred in either group. Results of IFNγ ELISPOT-based panel of reactive T-cell assays (PRT), quantifying alloreactive memory, demonstrated greater increases in the controls over 1 year compared to the treatment group (delta PRT in treatment 104.8+/−330.8 vs 252.9+/−431.3 in control), but these changes in PRT between groups did not reach statistical significance (p = 0.25).Conclusions
D3 supplements are safe, effective at treating vitamin D deficiency, and may prevent time-dependent increases in T-cell alloimmunity in hemodialysis patients, but their effects on alloimmunity need to be confirmed in larger studies. These findings support the routine supplementation of vitamin D-deficient transplant candidates on hemodialysis and highlight the need for large-scale prospective studies of vitamin D supplementation in transplant candidates and recipients.Trial Registration
Clinicaltrials.gov NCT01175798相似文献170.
Larimore J Tornieri K Ryder PV Gokhale A Zlatic SA Craige B Lee JD Talbot K Pare JF Smith Y Faundez V 《Molecular biology of the cell》2011,22(24):4854-4867
Dysbindin assembles into the biogenesis of lysosome-related organelles complex 1 (BLOC-1), which interacts with the adaptor protein complex 3 (AP-3), mediating a common endosome-trafficking route. Deficiencies in AP-3 and BLOC-1 affect synaptic vesicle composition. However, whether AP-3-BLOC-1-dependent sorting events that control synapse membrane protein content take place in cell bodies upstream of nerve terminals remains unknown. We tested this hypothesis by analyzing the targeting of phosphatidylinositol-4-kinase type II α (PI4KIIα), a membrane protein present in presynaptic and postsynaptic compartments. PI4KIIα copurified with BLOC-1 and AP-3 in neuronal cells. These interactions translated into a decreased PI4KIIα content in the dentate gyrus of dysbindin-null BLOC-1 deficiency and AP-3-null mice. Reduction of PI4KIIα in the dentate reflects a failure to traffic from the cell body. PI4KIIα was targeted to processes in wild-type primary cultured cortical neurons and PC12 cells but failed to reach neurites in cells lacking either AP-3 or BLOC-1. Similarly, disruption of an AP-3-sorting motif in PI4KIIα impaired its sorting into processes of PC12 and primary cultured cortical neuronal cells. Our findings indicate a novel vesicle transport mechanism requiring BLOC-1 and AP-3 complexes for cargo sorting from neuronal cell bodies to neurites and nerve terminals. 相似文献