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71.
Synemin and vimentin are components of intermediate filaments in avian erythrocytes 总被引:11,自引:21,他引:11 下载免费PDF全文
Synemin, a high-molecular-weight protein associated with intermediate filaments in muscle, and vimentin, an intermediate-filament subunit found in many different cell types, have been identified by immunologic and electrophoretic criteria as components of intermediate filaments in mature avian erythrocytes. Desmin, the predominant subunit of intermediate filaments in muscle, has not been detected in these cells. Two dimensional immunoautoradiography of proteolytic fragments of synemin and vimentin demonstates that the erythrocyte proteins are highly homologous, if not identical, to their muscle counterparts. Double immunoflurorescence reaveals that erythrocyte synemin and vimentin co-localize in a cytoplasmic network of sinuous filaments that extends from the nucleus to the plasma membrane and resists aggregation by colcemid. Erythrocytes that are attached to glass cover slips can be sonicated to remove nuclei and nonadherent regions of the plasma membrane; this leaves elliptical patches of adherent membrane that retain mats of vimentin- and synemin-containing intermediate filaments, as seen by immunofluorescence and rotary shadowing. Similarly, mechanical enucleation of erythrocyte ghosts in suspension allows isolation of plasma membranes that retain a significant fraction of the synemin and vimentin, as assayed by electrophoresis, and intermediate filaments, as seen in thin sections. Both synemin and vimentin remain insoluble along with spectrin and actin, in solutions containing nonionic detergent and high salt. However, brief exposure of isolated membrane to distilled water releases the synemin and vimentin together in nearly pure form, before the release of significant amounts of spectrin and actin. These data suggest that avian erythrocyte intermeditate filaments are somehow anchored to the plasma membrane; erythrocytes may thus provide a simple system for the study of intermediate filaments and their mode of interaction with membranes. In addition, these data, in conjunction with previous data from muscle, indicate that synemin is capable of associating with either desmin or vimentin and may thus perform a special role in the structure or function of intermediate filaments in erythrocytes as well as muscle. 相似文献
72.
The structural features of the asymmetric activated states of the insulin receptor family are still poorly understood. We investigated hydrogen/deuterium (H/D)-exchange within the extracellular domain of the type-I insulin-like growth factor receptor (IGF-1R) in the absence and presence of IGF-1 (active state) and in the presence of antibody inhibitors (inactive state). Near complete coverage of the 210 kDa receptor sequence was obtained by mass mapping of proteolytically derived peptides at all H/D-exchange time points. The data provide details regarding solvent exposure and dynamics across the extracellular region as well as conformational changes induced by activation or inactivation. Multiple peptides, distant in structure, individually demonstrated two distinct H/D-exchange rates, suggesting that each of these peptides exists in two separate environments in IGF-1R. The dual-exchange behavior of these peptides was enhanced on ligand binding and eliminated on inhibitor binding, clearly associating these regions with active state asymmetry and enabling them to serve as reporters of receptor activity. 相似文献
73.
A simple, fast and sensitive method was developed to verify the presence of
the sialyl Lewis(x) antigen on an N-linked glycoprotein. High performance
liquid chromatography-electrospray mass spectrometry (HPLC-ESI/MS) was used
to identify which of the five N-linked glycosylation sites of human plasma
alpha1-acid-glycoprotein (orosomucoid, OMD) contain the sialyl Lewis(x)
antigen. OMD was digested with proteolytic enzymes and analyzed by reversed
phase chromatography coupled with on-line ESI/MS. A tandem mass
spectrometry experiment was designed to detect the presence of the sialyl
Lewis(x) antigen based on the observation of an 803 mass to charge ratio (
m/z ) ion produced in the intermediate pressure region of the ESI
interface. The ESI/MS signal at m/z 803 is consistent with an oxonium ion
for a glycan structure containing NeuAc, Gal, GlcNAc, and Fuc. The identity
of the m/z 803 ion was confirmed by ESI/MS/MS analysis of the m/z 803
fragment ion and comparison with a sialyl Lewis(x) standard. The
stereochemistry and linkage positions were assigned using previous NMR
analysis but could be determined with permethylation analysis if necessary.
The analysis of OMD gave a pattern showing signal for the sialyl Lewis(x)
antigen coeluting with each of the five N-linked glycopeptides. The ability
to monitor sialyl Lewis(x) expression at each of the five sites is of
interest in the study of OMD's role in inflammatory diseases.
相似文献
74.
Transient and stable CHO expression,purification and characterization of novel hetero‐dimeric bispecific IgG antibodies 下载免费PDF全文
Yashas Rajendra Robert B. Peery Maria D. Hougland Gavin C. Barnard Xiufeng Wu Jonathan R. Fitchett Michael Bacica Stephen J. Demarest 《Biotechnology progress》2017,33(2):469-477
IgG bispecific antibodies (BsAbs) represent one of the preferred formats for bispecific antibody therapeutics due to their native‐like IgG properties and their monovalent binding to each target. Most reported studies utilized transient expression in HEK293 cells to produce BsAbs. However, the expression of biotherapeutic molecules using stable CHO cell lines is commonly used for biopharmaceutical manufacturing. Unfortunately, limited information is available in the scientific literature on the expression of BsAbs in CHO cell lines. In this study we describe an alternative approach to express the multiple components of IgG BsAbs using a single plasmid vector (quad vector). This single plasmid vector contains both heavy chain genes and both light chain genes required for the expression and assembly of the IgG BsAb, along with a selectable marker. We expressed, purified, and characterized four different IgG BsAbs or “hetero‐mAbs” using transient CHO expression and stable CHO minipools. Transient CHO titers ranged from 90 to 160 mg/L. Stable CHO titers ranged from 0.4 to 2.3 g/L. Following a simple Protein A purification step, the percentage of correctly paired BsAbs ranged from 74% to 98% as determined by mass spectrometry. We also found that information generated from transient CHO expression was similar to information generated using stable CHO minipools. In conclusion, the quad vector approach represents a simple, but effective, alternative approach for the generation of IgG BsAbs in both transient CHO and stable CHO expression systems. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:469–477, 2017 相似文献
75.
Matthews JM Chen X Cryan E Hlasta DJ Rybczynski PJ Strauss K Tang Y Xu JZ Yang M Zhou L Demarest KT 《Bioorganic & medicinal chemistry letters》2007,17(24):6773-6778
A series of aminoindane derivatives were synthesized and shown to be potent PPARα agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARα activation and PPARα mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague–Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice. 相似文献
76.
1. The distribution of consumers among resources (trophic interaction network) may be shaped by asymmetric competition. Dominance hierarchy models predict that asymmetric interference competition leads to a domination of high quality resources by hierarchically superior species. 2. In order to determine the competitive dominance hierarchy and its effect on flower partitioning in a local stingless bee community in Borneo, interspecific aggressions were tested among eight species in arena experiments. 3. All species tested were strongly mutually aggressive in the arena, and the observed interactions were often lethal for one or both opponents. Aggression significantly increased with body size differences between fighting pairs and was asymmetric: larger aggressors were superior over smaller species. Additional aggression tests involved dummies with surface extracts, and results suggest that species‐ and colony‐specific surface profiles are important in triggering the aggressive behaviour. 4. Sixteen stingless bee species were observed foraging on 41 species of flowering plants. The resulting bee–flower interaction network showed a high degree of generalisation (network‐level specialisation H2’ = 0.11), corresponding to a random, opportunistic distribution of bee species among available flower species. 5. Aggressions on flowers were rare and only occurred at a low level. The dominance hierarchy obtained in the arena experiments did not correlate significantly with plant quality, estimated as the number of flowers per plant or as total bee visitation rate. 6. Our findings suggest that asymmetries in interference competition do not necessarily translate into actual resource partitioning in the context of complex interacting communities. 相似文献
77.
Sue Sha Damayanthi Devineni Atalanta Ghosh David Polidori Marcus Hompesch Sabine Arnolds Linda Morrow Heike Spitzer Keith Demarest Paul Rothenberg 《PloS one》2014,9(8)
Introduction
This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.Methods
Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days –1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.Results
Canagliflozin increased UGE dose-dependently (∼80–120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4–5 mM (72–90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.Conclusions
Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.Trial Registration
ClinicalTrials.gov NCT00963768相似文献78.
Zhang HC White KB Ye H McComsey DF Derian CK Addo MF Andrade-Gordon P Eckardt AJ Conway BR Westover L Xu JZ Look R Demarest KT Emanuel S Maryanoff BE 《Bioorganic & medicinal chemistry letters》2003,13(18):3049-3053
Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC(50)) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, -delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-betaII and increased glycogen synthase activity by inhibiting GSK-3beta. 相似文献
79.
Matthews JM Greco MN Hecker LR Hoekstra WJ Andrade-Gordon P de Garavilla L Demarest KT Ericson E Gunnet JW Hageman W Look R Moore JB Maryanoff BE 《Bioorganic & medicinal chemistry letters》2003,13(4):753-756
A series of novel 3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indoles was synthesized and tested for vasopressin receptor antagonist activity. We identified compounds with high affinity for the human V2 receptor and good selectivity over the human V1a receptor. Compound 6c bound to V2 receptors with an IC(50) value of 20 nM, had >100-fold selectivity over V1a receptors, and inhibited cAMP formation in a cellular V2 functional assay with an IC(50) value of 70 nM. 相似文献