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101.
KINETICS OF HUMAN LYMPHOCYTE RESPONSES IN VITRO: DETERMINATION OF CLONE SIZE AND INITIAL RATE OF ENTRY INTO DNA SYNTHESIS 总被引:2,自引:0,他引:2
In this third paper on the kinetics of lymphocyte stimulation we present a simple stochastic model for the entry of mitogen stimulated human lymphocytes into the proliferative cycle. The model is based on the assumption that responder ‘recruitment’ is a process of simple exponential decay. The model can be applied to the initial rapid rise in thymidine uptake after stimulation and successfully predicts the behavior of colchicine inhibited mitogen responses. Application of the model allows the estimation of the following constants; the size of the responding clone, the rate of entry of committed cells into the initial cell cycle, the duration of the lag period before uptake of thymidine increases above background and the average duration of thymidine uptake in responding lymphocytes (Ts). If we analyze the experimental results of mitogen stimulation experiments in these terms we can show that the first three constants are sensitive functions of both the dose of mitogen and the source of the responding lymphocytes. The most interesting finding may be the fact that low doses of mitogen seem to decrease the rate of entry of committed lymphocytes into cell cycle. This would imply that the rate determining step in this process is not of an all or none type. 相似文献
102.
Selection for sexual dimorphism in body weight of mice 总被引:2,自引:0,他引:2
103.
Bogatcheva E Hanrahan C Nikonenko B de los Santos G Reddy V Chen P Barbosa F Einck L Nacy C Protopopova M 《Bioorganic & medicinal chemistry letters》2011,21(18):5353-5357
We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20 μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4 μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15 days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series. 相似文献
104.
Hanrahan CF 《Biologist (London, England)》2001,48(3):136-137
Emil von Behring was first in the line of distinguished immunologists to win the Nobel Prize for Physiology and Medicine. His contributions to our knowledge of immunity ignited an impassioned argument between French and German scientists at the end of the 19th century, the first of many scientific debates in the immunological world. 相似文献
105.
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel contains 12 membrane-spanning regions which are presumed to form the transmembrane pore. Although a number of findings have suggested that the sixth transmembrane region plays a key role in forming the pore and determining its functional properties, the role of other transmembrane regions is currently not well established. Here we assess the functional importance of the twelfth transmembrane region, which occupies a homologous position in the carboxy terminal half of the CFTR molecule to that of the sixth transmembrane region in the amino terminal half. Five residues in potentially important regions of the twelfth transmembrane region were mutated individually to alanines, and the function of the mutant channels was examined using patch clamp recording following expression in mammalian cell lines. Three of the five mutations significantly weakened block of unitary Cl(-) currents by SCN(-), implying a partial disruption of anion binding within the pore. Two of these mutations also caused a large reduction in the steady-state channel mean open probability, suggesting a role for the twelfth transmembrane region in channel gating. However, in direct contrast to analogous mutations in the sixth transmembrane region, all mutants studied here had negligible effects on the anion selectivity and unitary Cl(-) conductance of the channel. The relatively minor effects of these five mutations on channel permeation properties suggests that, despite their symmetrical positions within the CFTR protein, the sixth and twelfth transmembrane regions make highly asymmetric contributions to the functional properties of the pore. 相似文献
106.
Bates IR Hébert B Luo Y Liao J Bachir AI Kolin DL Wiseman PW Hanrahan JW 《Biophysical journal》2006,91(3):1046-1058
The cystic fibrosis transmembrane conductance regulator (CFTR) channel interacts with scaffolding and other proteins that are expected to restrict its lateral movement, yet previous studies have reported predominantly free diffusion. We examined the lateral mobility of CFTR channels on live baby hamster kidney cells using three complementary methods. Channels bearing an extracellular biotinylation target sequence were labeled with streptavidin conjugated with fluorescent dyes (Alexa Fluor 488 or 568) or quantum dots (qDot605). Fluorescence recovery after photobleaching and image correlation spectroscopy of the dye-labeled channels revealed a significant immobile population ( approximately 50%), which was confirmed by direct single particle tracking (SPT) of qDot605-labeled CFTR. Adding 10 histidine residues at the C-terminus of CFTR to mask the postsynaptic density 95, Discs large, ZO-1 (PDZ) binding motif abolished its association with EBP50/NHERF1, reduced the immobile fraction, and increased mobility. Other interactions that are not normally detected on this timescale became apparent when binding of PDZ domain proteins was disrupted. SPT revealed that CFTR(His-10) channels diffuse randomly, become immobilized for periods lasting up to 1 min, and in some instances are recaptured at the same location. The impact of transient confinement on the measured diffusion using the three fluorescence techniques were assessed using computer simulations of the biological experiments. Finally, the impact of endosomal CFTR on mobility measurements was assessed by fluorescence correlation spectroscopy. These results reveal unexpected features of CFTR dynamics which may influence its ion channel activity. 相似文献
107.
BE Himes X Jiang R Hu AC Wu JA Lasky-Su BJ Klanderman J Ziniti J Senter-Sylvia JJ Lima CG Irvin SP Peters DA Meyers ER Bleecker M Kubo M Tamari Y Nakamura SJ Szefler RF Lemanske RS Zeiger RC Strunk FD Martinez JP Hanrahan GH Koppelman DS Postma MA Nieuwenhuis JM Vonk RA Panettieri A Markezich E Israel VJ Carey KG Tantisira AA Litonjua Q Lu ST Weiss 《PLoS genetics》2012,8(7):e1002824
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV(1)) before and after the administration of a short-acting β(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β(2)-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV(1) after administration of a β(2)-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β(2)-agonists through GWAS. 相似文献
108.
Kenneth N. Mewett Sebastian P. Fernandez Anmol K. Pasricha Alice Pong Steven O. Devenish David E. Hibbs Mary Chebib Graham A.R. Johnston Jane R. Hanrahan 《Bioorganic & medicinal chemistry》2009,17(20):7156-7173
We herein describe the synthesis and positive modulatory activities of a small library of flavan-3-ol derivatives on α1β2γ2L GABAA receptors. Structure–activity relationships of various substituents on the A, B and C rings were evaluated in a functional electrophysiological assay. A trans configuration and a 3-acetoxy moiety are essential for activity. Substitution of the B ring appears to be well tolerated, with substituents on the A ring playing a major role in determining activity. 相似文献
109.
CD6 regulates T-cell responses through activation-dependent recruitment of the positive regulator SLP-76 下载免费PDF全文
Hassan NJ Simmonds SJ Clarkson NG Hanrahan S Puklavec MJ Bomb M Barclay AN Brown MH 《Molecular and cellular biology》2006,26(17):6727-6738
Deciphering the role of lymphocyte membrane proteins depends on dissecting the role of a protein in the steady state and on engagement with its ligand. We show that expression of CD6 in T cells limits their responsiveness but that engagement by the physiological ligand CD166 gives costimulation. This costimulatory effect of CD6 is mediated through phosphorylation-dependent binding of a specific tyrosine residue, 662Y, in its cytoplasmic region to the adaptor SLP-76. A direct interaction between SLP-76 and CD6 was shown by binding both to a phosphorylated peptide (equilibrium dissociation constant [K(D)] = 0.5 muM at 37 degrees C) and, using a novel approach, to native phosphorylated CD6. Evidence that CD6 and SLP-76 interact in cells was obtained in coprecipitation experiments with normal human T cells. Analysis of human CD6 mutants in a murine T-cell hybridoma model showed that both costimulation by CD6 and the interaction between CD6 and SLP-76 were dependent on 662Y. The results have implications for regulation by CD6 and the related T-cell surface protein, CD5. 相似文献
110.
Seavilleklein G Amer N Evagelidis A Chappe F Irvine T Hanrahan JW Chappe V 《American journal of physiology. Cell physiology》2008,295(5):C1366-C1375
Activity of the CFTR channel is regulated by phosphorylation of its regulatory domain (RD). In a previous study, we developed a bicistronic construct called DeltaR-Split CFTR, which encodes the front and back halves of CFTR as separate polypeptides without the RD. These fragments assemble to form a constitutively active CFTR channel. Coexpression of the third fragment corresponding to the missing RD restores regulation by PKA, and this is associated with dramatically enhanced binding of the phosphorylated RD. In the present study, we examined the effect of PKC phosphorylation on this PKA-induced interaction. We report here that PKC alone enhanced association of the RD with DeltaR-Split CFTR and that binding was further enhanced when the RD was phosphorylated by both kinases. Mutation of all seven PKC consensus sequences on the RD (7CA-RD) did not affect its association under basal (unphosphorylated) conditions but abolished phosphorylation-induced binding by both kinases. Iodide efflux responses provided further support for the essential role of RD binding in channel regulation. The basal activity of DeltaR-Split/7CA-RD channels was similar to that of DeltaR-Split/wild type (WT)-RD channels, whereas cAMP-stimulated iodide efflux was greatly diminished by removal of the PKC sites, indicating that 7CA-RD binding maintains channels in an inactive state that is unresponsive to PKA. These results suggest a novel mechanism for CFTR regulation in which PKC modulates PKA-induced domain-domain interactions. 相似文献