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PubMed1993

Mutually exclusive expression of alternatively spliced FMRFamide transcripts in identified neuronal systems of the snail Lymnaea.

The FMRFamide gene of the snail Lymnaea encodes tetrapeptides (FMRFamide/FLRFamide) and heptapeptides (GDPFLRFamide/SDPFLRFamide) on separate exons. In situ hybridization probes specific to these exons were used to map the expression of the two exons in identified neuronal systems of the CNS. Analysis of more than 200 preparations showed that cytoplasmic expression of mRNA was exclusively of one type, with individual neurons expressing either the tetrapeptide or heptapeptide exon. Of the approximately 340 neurons expressing the two exons, the majority (80%) expressed the tetrapeptide exon. The tetrapeptide exon was more widespread, occurring in neurons from all 11 ganglia of the CNS. The heptapeptide was mainly confined to two ganglia (visceral and right parietal), with a small number of cells in three other ganglia. Mapping studies combined with dye marking of identified neurons showed the presence of the tetrapeptide exon in several behaviorally important networks: heart motoneurons, whole body withdrawal response motoneurons, and probably penis motoneurons as well as giant identified neurons (LP1, RPD1). The heptapeptides were prominent in two main clusters of cells (Bgp and Fgp) together with a smaller number of tetrapeptide-expressing cells.

Amino Acid Sequence↗
PubMed1996

True values. While ethical decisionmaking and managed care aren't mutually exclusive, executives are struggling to find a common denominator.

Whether they're fulfilling a mission or just trying to avoid bad publicity, health care executives are facing a tough new world of deal- and decisionmaking based on managed care and the often murky area of ethics. Some are trying to solve the dilemma by developing a set of ethical guidelines from which to work. "It's an exercise in self-understanding," says one health care ethicist who's helping to write such guidelines. Ultimately, he says, it comes down to one question: "What are we really about?"

Contract Services↗
PubMed1997

Domains of retinoid signalling and neurectodermal expression of zebrafish otx1 and goosecoid are mutually exclusive.

Retinoid signalling plays an important role in embryonic pattern formation. Excess of retinoic acid during gastrulation results in axial defects in vertebrate embryos, suggesting that retinoids are involved in early anteroposterior patterning. To study retinoid signalling in zebrafish embryos, we developed a novel method to detect endogenous retinoids in situ in embryos, using a fusion protein of the ligand inducible transactivation domain of a retinoic acid receptor and a heterologous DNA binding domain. Using this method, we show that retinoid signalling is localized in zebrafish embryos in the region of the embryonic shield, and towards the end of gastrulation in a posterior dorsal domain. To investigate the relationships between the spatial distribution of retinoid signalling and the regulation of retinoid target genes, we studied the downregulation by retinoic acid of two genes expressed in anterior regions of the embryo, goosecoid and otx1. These experiments show that expression of both genes is strongly downregulated in the anterior neurectoderm of zebrafish embryos treated with retinoic acid, whereas mesendodermal expression is only mildly affected. Interestingly, a significant downregulation of goosecoid expression by retinoic acid was observed only during midgastrulation but not in earlier stages. In agreement with these results, spatial expression of goosecoid and otx1 does not overlap with the region of retinoid signalling in the late gastrula. Our data support the hypothesis that a localized retinoid signal is involved in axial patterning during early development, at least in part through the repression of anterior genes in posterior regions of the embryo. Furthermore, our data suggest that the action of retinoids is spatially as well as temporally regulated in the developing embryo.

Animals↗
PubMed1976

A virus-specified mechanism for the prevention of multiple infection--T7- and T3-mutual and superinfection exclusion.

Co- and superinfection of cells with T3/T7 result in exclusion (mutual or superinfection exclusion). The exclusion mechanism is also directed against homologous (or identical) virus. Exclusion is established after the adsorption but before the genome becomes available for gene expression or replication, that is only one virus per cell develops. The exclusion is triggered by a constituant of the viral particle. An early T7 gene (M gene) (Schweiger et al., 1975) is essential for the formation of exclusion competent virions.

Bacterial Proteins↗
PubMed1988

Interaction of fibrinogen with its platelet receptor. Differential effects of alpha and gamma chain fibrinogen peptides on the glycoprotein IIb-IIIa complex.

The platelet membrane glycoprotein IIb-IIIa complex (GPIIb-IIIa) recognizes peptides containing the amino acid sequence Arg-Gly-Asp, a sequence present at two locations in the alpha chain of fibrinogen. GPIIb-IIIa also interacts with peptides containing the carboxyl-terminal 10-15 residues of the fibrinogen gamma chain. We found that the alpha chain tetrapeptide, Arg-Gly-Asp-Ser (RGDS), and the gamma chain peptide, Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (LGGAKQAG-DV), each inhibited fibrinogen binding to ADP-stimulated platelets with Ki values of 15.6 +/- 2.7 and 46.2 +/- 8.2 microM, respectively. Furthermore, the inhibitory effect of the peptides was additive, indicating that they interact with GPIIb-IIIa in a mutually exclusive manner. Mutually exclusive binding suggests that either the alpha and gamma chain peptides bind to identical or overlapping sites on the GPIIb-IIIa complex or that one peptide induces a change in the complex that excludes the other. To differentiate between these possibilities, we compared the ability of RGDS and LGGAKQAGDV to inhibit the binding of fibrinogen and two GPIIb-IIIa complex-specific monoclonal antibodies, A2A9 and PAC-1, to ADP-stimulated platelets. A2A9 and PAC-1 appear to bind to different sites on GPIIb-IIIa because A2A9 binds to both stimulated and unstimulated platelets while PAC-1 only binds to stimulated platelets. RGDS specifically inhibited fibrinogen and PAC-1 binding with nearly identical Ki values of 15.6 +/- 2.7 and 20.2 +/- 3.5 microM, respectively. In contrast, LGGAKQAGDV had a differential effect on fibrinogen and PAC-1 binding, inhibiting PAC-1 binding with a Ki of 116.1 +/- 12.9 microM and fibrinogen binding with a Ki of 46.2 +/- 8.2 microM (p less than 0.005). Furthermore, while RGDS had no effect on the binding of the monoclonal antibody A2A9, LGGAKQAGDV was a partial inhibitor of A2A9 binding to activated platelets. These results suggest that the bindings sites for RGDS and LGGAKQAGDV are spatially distinct. They also suggest that ligand-induced changes in GPIIb-IIIa conformation are likely to be responsible for the mutually exclusive nature of alpha and gamma chain peptide binding.

Adenosine Diphosphate↗
PubMed1991

Distinctions in ligand binding sites on the nicotinic acetylcholine receptor.

Ligand-gated ion channels possess intrinsic binding sites for noncompetitive inhibitors that differ substantially in ligand specificity and structural characteristics from most binding sites found on globular proteins. We have used the nicotinic acetylcholine receptor to examine the characteristics of such diverse sites because the high-affinity binding site in the proximity of the ion channel has unusual binding interactions and ligand specificity, whereas the site of agonist activation exhibits classical structure-activity characteristics. Noncompetitive inhibitors that bind to the former site show a wide degree of structural variation and appear to associate at separate loci and in distinct orientations in the vicinity of the channel. The receptor structure appears to provide a large domain with multiple hydrophobic crevices that can bind noncompetitive inhibitors, yet binding of these inhibitors is mutually exclusive. The mutually exclusive behavior suggests that association of a single ligand is sufficient to prevent access of additional ligands to distinct sites. This could occur either by physical occlusion to the site of binding or by formation of a conformational state that will not allow entry of additional noncompetitive inhibitors.

Amino Acid Sequence↗
PubMed1996

Complex ionic control of [3H]GBR 12783 binding to the dopamine neuronal carrier.

At 20 degrees C, [3H]GBR 12783, {1-[2-(diphenylmethoxy)ethyl]4-(3-phenyl-2-([1-3H]propenyl)-pip era zine} dissociated from the dopamine neuronal carrier present in rat striatal membranes with a t1/2 value of 27 min. At this temperature, KCI, CaCl2 and MgCl2 increased the binding dissociation, revealing that they recognize a binding site which is not mutually exclusive with that of [3H]GBR 12783. The comparison of the ability of KCl to increase the binding dissociation (by 160% at 30 mM KCl) with its potency as a binding inhibitor (Ki-2.6 +/- 0.3 mM) suggests an involvement of two recognition sites for K+ in binding inhibition, a not mutually exclusive site and another, mutually exclusive, site. Divalent cations mainly inhibited the binding via a mutually exclusive site since 3 mM Ca2+ and 10 mM Mg2+ increased the binding dissociation by 90% at 20 degrees C whereas their Ki values were 0.049 +/- 0.006 and 0.141 +/- 0.035 mM, respectively. Involvement of this mutually exclusive site was also supported by the persistence of the binding inhibition elicited by Ca2+ and Mg2+ at 0 degree C, a temperature at which they reduced the binding dissociation. At 20 degrees C, 100 mM NaCl did not modify [3H]GBR 12783 binding but it antagonized the binding dissociation elicited by inhibitory cations. Ca2+ reduced the off-rate of [3H]GBR 12783 binding at 0 degree C and in the presence of 100 mM Na+. Finally, [3H]GBR 12783-binding dissociation was increased by high 'cytosolic' K+ while 'synaptic' concentrations of Na+, K+, Ca2+, Mg2+ and Cl- were ineffective. A reduction of H2PO4-/HCO3- from 10 to 5 mM and a substitution of 5 mM H2PO4-/HCO3- by 5 mM Cl- increased the binding dissociation, suggesting that an anion-binding site could also regulate the binding.

Animals↗
PubMed1998

Multidrug resistance transporter P-glycoprotein has distinct but interacting binding sites for cytotoxic drugs and reversing agents.

P-Glycoprotein, the plasma membrane protein responsible for the multidrug resistance of some tumour cells, is an active transporter of a number of structurally unrelated hydrophobic drugs. We have characterized the modulation of its ATPase activity by a multidrug-resistance-related cytotoxic drug, vinblastine, and different multidrug-resistance-reversing agents, verapamil and the dihydropyridines nicardipine, nimodipine, nitrendipine, nifedipine and azidopine. P-Glycoprotein ATPase activity was measured by using native membrane vesicles containing large amounts of P-glycoprotein, prepared from the highly multidrug-resistant lung fibroblasts DC-3F/ADX. P-Glycoprotein ATPase is activated by verapamil and by nicardipine but not by vinblastine. Among the five dihydropyridines tested, the higher the hydrophobicity, the higher was the activation factor with respect to the basal activity and the lower was the half-maximal activating concentration. The vinblastine-specific binding on P-glycoprotein is reported by the inhibitions of the verapamil- and the nicardipine-stimulated ATPase. These inhibitions are purely competitive, which means that the bindings of vinblastine and verapamil, or vinblastine and nicardipine, on P-glycoprotein are mutually exclusive. In contrast, verapamil and nicardipine display mutually non-competitive interactions. This demonstrates the existence of two distinct specific sites for these two P-glycoprotein modulators on which they can bind simultaneously and separately to the vinblastine site. The nicardipine-stimulated ATPase activity in the presence of the other dihydropyridines shows mixed-type inhibitions. These dihydropyridines have thus different binding sites that interact mutually to decrease their respective, separately determined affinities. This could be due to steric constraints between sites close to each other. This is supported by the observation that vinblastine binding is not mutually exclusive with nifedipine or nitrendipine binding, whereas it is mutually exclusive with nicardipine. Moreover, verapamil binding also interacts with the five dihydropyridines by mixed inhibitions, with different destabilization factors. On the whole our enzymic data show that P-glycoprotein has distinct but interacting binding sites for various modulators of its ATPase function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Polypyrimidine tract binding protein functions as a repressor to regulate alternative splicing of alpha-actinin mutally exclusive exons.

The smooth muscle (SM) and nonmuscle (NM) isoforms of alpha-actinin are produced by mutually exclusive splicing of an upstream NM exon and a downstream SM-specific exon. A rat alpha-actinin genomic clone encompassing the mutually exclusive exons was isolated and sequenced. The SM exon was found to utilize two branch points located 382 and 386 nucleotides (nt) upstream of the 3' splice site, while the NM exon used a single branch point 191 nt upstream. Mutually exclusive splicing arises from the proximity of the SM branch points to the NM 5' splice site, and this steric repression could be relieved in part by the insertion of spacer elements. In addition, the SM exon is repressed in non-SM cells and extracts. In vitro splicing of spacer-containing transcripts could be activated by (i) truncation of the transcript between the SM polypyrimidine tract and exon, (ii) addition of competitor RNAs containing the 3' end of the actinin intron or regulatory sequences from alpha-tropomyosin (TM), and (iii) depletion of the splicing extract by using biotinylated alpha-TM RNAs. A number of lines of evidence point to polypyrimidine tract binding protein (PTB) as the trans-acting factor responsible for repression. PTB was the only nuclear protein observed to cross-link to the actinin RNA, and the ability of various competitor RNAs to activate splicing correlated with their ability to bind PTB. Furthermore, repression of alpha-actinin splicing in the nuclear extracts depleted of PTB by using biotinylated RNA could be specifically restored by the addition of recombinant PTB. Thus, alpha-actinin mutually exclusive splicing is enforced by the unusual location of the SM branch point, while constitutive repression of the SM exon is conferred by regulatory elements between the branch point and 3' splice site and by PTB.

Actinin↗
PubMed2002

Feasibility trial of methotrexate-paclitaxel as a second line therapy in advanced urothelial cancer.

To evaluate the clinical value of the concurrent use of methotrexate administered immediately before paclitaxel, we investigated the efficacy and toxicity of this two-drug combination administered as palliative second line therapy in patients with advanced urothelial cancer. The design of the schedule and sequence used was based on our previous preclinical data from a comparative study on sequential combinations of paclitaxel and methotrexate in a human bladder cancer cell line. As a confirmation study, we further extended our analysis of in vitro synergism. Twenty patients with advanced transitional cell carcinoma of the urinary tract previously treated with platinum-based therapy, with adequate renal function and a performance status > or = 60 were considered eligible. They received therapy with methotrexate 30 mg/m2 administered as an intravenous bolus, followed immediately by paclitaxel 175 mg/m2 given as a 3-hr infusion, both on day 1 every 21 days. Therapy was given on a compassionate-use basis until either disease progression was documented or the patient became intolerant to therapy. In vitro data were further analyzed using the median-effect principle and the combination index method. Twenty patients with metastatic (16 patients) or locally advanced disease (four patients) received a median of three cycles of therapy. Of the 19 patients assessable for response, there were six partial responses and seven disease stabilizations with no complete responses. Median duration of response was 3 months (range, 2-7) and median survival was 5 months. Three patients developed grade 3-4 neutropenia, one patient had grade 3 anemia, four patients had grade 2-3 sensory neuropathy, and three patients had myalgias. Eighteen patients developed alopecia. Gastrointestinal toxicity was mild. One patient died after the first cycle due to pulmonary thrombo-embolism and could not be evaluated for response. The synergistic in vitro effect of the concurrent combination was confirmed in analyses performed under mutually exclusive and mutually nonexclusive criteria. In conclusion, the combination of methotrexate and paclitaxel at this dose and sequence is feasible and active as a palliative therapy in patients with advanced urothelial cancer previously treated with platinum-based therapies. This schedule merits further investigation in a phase-II trial.

Adenocarcinoma↗
PubMed2005

Potential applicability of recombinant factor VIIa for intracerebral hemorrhage.

BACKGROUND AND PURPOSE: To date, there are no proven, effective treatments for intracerebral hemorrhage (ICH) beyond supportive medical care. A recent randomized, blinded, placebo-controlled trial of recombinant factor VIIa (rFVIIa) administered intravenously within 4 hours of ICH onset reported a reduction in morbidity and mortality compared with placebo. We sought to determine the potential applicability of rFVIIa in a large, population-based cohort of ICH patients. METHODS: All of the patients age > or =18 years hospitalized with nontraumatic ICH in the Greater Cincinnati region were identified from May 1998 to July 2001 and August 2002 to April 2003. Patient demographics were compared with the inclusion and exclusion criteria from the rFVIIa trial to determine eligibility for treatment and reasons for exclusion. Mortality in the eligible patient group was compared with the placebo group in the rFVIIa trial. RESULTS: Over 4 calendar years, 1018 ICH patients were identified; of these, 133 (13.1%) had no exclusions and presented within the prescribed time window. An additional 45 patients (4.4%) may have been eligible but had uncertain onset or computed tomography scan times. The most common reasons for exclusion (not mutually exclusive) were late presentation (n=398), vaso-occlusive disease (n=369), deep coma (n=219), and prolonged international normalized ratio or partial thromboplastin time (n=200). Mortality at 90 days among potentially eligible patients was the same as for the placebo group in the rFVIIa trial (29% versus 29%; P=0.99). CONCLUSIONS: In this large, population-based ICH cohort, 13.1% to 17.5% of patients would have qualified for treatment with rFVIIa by trial criteria.

Aged↗
PubMedDate not supplied

A working classification of scleroderma spectrum disorders: a proposal and the results of testing on a sample of patients.

OBJECTIVE: To propose a working classification for scleroderma spectrum disorders (SDS), based on criteria shown in the past to be specific for the condition: sclerodermatous skin involvement, specific autoantibodies and specific microvascular abnormalities, to obtain mutually exclusive subgroups of SDS and to test this classification on a sample of patients. This is an attempt to improve the current classifications used in research studies, which are all based on the extent of skin involvement only. METHODS: Patients (n= 165) referred to the Microvascular Laboratory of the Division of Rheumatology between 1976 and 1992, who had participated in various other studies in the Division and for whom therefore systematically collected clinical and laboratory data were available. Evaluation of skin involvement, clinical, laboratory, and microvascular studies were performed independently and a subgroup assignment was made "blindly" from coded data. RESULTS: Results demonstrated that significant differences were present between our subgroups of SDS with regard to meaningful variables. Comparisons of our results with previously used classifications such as the ACR preliminary criteria study and later subsets used by more recent investigators, demonstrated that our classification permitted us to include less severe cases than those meeting ACR criteria. CONCLUSION: Our results show that by dividing SDS into groups using the cutaneous, microvascular and autoantibody characteristics, while using well-defined criteria and inclusion-exclusion rules to obtain mutually exclusive subgroups, can reveal differences that may otherwise be masked. This study has suggested new avenues of research. A replication study should be performed with a systematic follow-up. This is a working classification, i.e. it can be modified as new findings using updated technology become available. The focus should be on clearly defining criteria for classification and collected data. Then between-center comparisons will be possible.

Autoantibodies↗
PubMed1983

The interaction between full and partial inhibitors acting on a single enzyme. A theoretical analysis.

A theoretical analysis has been made of multiple inhibition systems involving a full and a partial inhibitor. This analysis applies to single- and multisubstrate enzyme systems obeying Michaelis-Menten kinetics. It has been shown that a plot of the reciprocal of the enzyme velocity versus the concentration of the full inhibitor, at constant substrate concentration, is linear in either the presence or the absence of a fixed level of the partial inhibitor. If the slope of the plot is increased or unaltered in the presence of a fixed concentration of the partial inhibitor, the two inhibitors are mutually nonexclusive. If the slope of the plot is decreased, the two inhibitors may be either mutually exclusive or nonexclusive. When a decrease in slope is observed, mutual exclusivity can be distinguished from nonexclusivity by the use of secondary plots based on the effect of the partial inhibitor on the slope or the abscissal intercept of the primary plot. The rules proposed for distinguishing mutually exclusive from nonexclusive inhibitors hold irrespective of the type of inhibition (competitive, noncompetitive, uncompetitive, mixed), so that a knowledge of the kinetic nature of the inhibitors is not required. The results of such an analysis are also discussed in terms of summation, antagonism, and synergism between inhibitors. It has been pointed out that independent inhibitor binding does not necessarily result in independent inhibitor effects, and the conditions necessary for observation of independent inhibitory effects have been defined.

Binding, Competitive↗
PubMed1981

Nitrate reductase from Penicillium chrysogenum. Purification and kinetic mechanism.

Nitrate reductase (NADPH:nitrate oxidoreductase; EC 1.6.6.1-3) was purified to apparent homogeneity from mycelium of Penicillium chrysogenum. The final preparation catalyzed the NADPH-dependent, FAD-mediated reduction of nitrate with a specific activity of 170-225 units X mg of protein-1. Gel filtration and glycerol density centrifugation yielded, respectively, a Stokes radius of 6.3 nm and an s20,w of 7.4. The molecular weight was calculated to be 199,000. On sodium dodecyl sulfate gels, the enzyme displayed two almost contiguous dye-staining bands corresponding to molecular weights of about 97,000 and 98,000. The enzyme prefers NADPH to NADH (kspec ratio = 2813), FAD to FMN (kspec ratio = 141), FAD (+ NADPH) to FADH2 (kspec ratio = 12,000), and nitrate to chlorate (kspec ratio = 4.33), where the kspec (the specificity constant for a given substrate) represents Vmax/Km. The Penicillium enzyme will also catalyze te NADPH-dependent, FAD-mediated reduction of cytochrome c with a specific activity of 647 units X mg of protein-1 (Kmcyt = 1.25 X 10(-5) M), and the reduced methyl viologen (MVH2, i.e. methyl viologen + dithionite)-dependent, NADPH and FAD-independent reduction of nitrate with a specific activity of 250 units X mg of protein-1 kmMVH2 = 3.5 X 10(-6) M). Initial velocity studies showed intersecting NADPH-FAD and nitrate-FAD reciprocal plot patterns. The NADPH-nitrate pattern was a series of parallel lines at saturating and unsaturating FAD levels. NADP+ was competitive with NADPH, uncompetitive with nitrate (at saturating and unsaturating FAD levels), and a mixed-type inhibitor with respect to FAD. Nitrite was competitive with nitrate, uncompetitive with NADPH (at saturating and unsaturating FAD levels), and a mixed-type inhibitor with respect to FAD. At unsaturating nitrate and FAD, NADPH exhibited substrate inhibition, perhaps as a result of binding to the FAD site(s). At very low FAD concentrations, low concentrations of NADP+ activated the reaction slightly. The initial velocity and product inhibition patterns are consistent with either of the two kinetic mechanisms. One (rather unlikely) mechanism involves the rapid equilibrium random binding of all ligands with (a) NADP+ and NADPH mutually exclusive, (b) nitrate and nitrite mutually exclusive, (c) the binding of NADPH strongly inhibiting the binding of nitrate and vice versa, (d) the binding of NADPH strongly promoting the binding of nitrite and vice versa, and (e) the binding of nitrate strongly promoting the binding of NADP+ and vice versa...

Binding Sites↗
PubMed2000

Sleep EEG synchronization mechanisms and activation of interictal epileptic spikes.

OBJECTIVE: The temporal course of sleep interictal epileptic discharges (IEDs) has been studied focusing their relationship with the temporal course of the main sleep-EEG frequency bands that is thought to reflect the action of different synchronization neural mechanisms. The existence of a mutually exclusive mechanism between spindles and delta waves should be reflected in a mutually exclusive facilitation of IEDs activation by slow wave activity (SWA) and sigma activity (SA) during synchronized NREM sleep. METHODS: We reanalyzed data from 19 children and 15 adult patients affected by different partial epileptic syndromes. The temporal series of SWA, SA and theta band (TB), derived from spectral analysis, were obtained from a spike-free and pathologic alteration-free derivation, controlateral to the most active lead, where the IEDs count was performed. Relationships between SA, SWA and TB and time series of IEDs were tested by means of correlation techniques after data normalization. RESULTS: A positive correlation of spike distribution with SWA time course has been found in the majority of adults. Only a few adult patients showed IEDs that were correlated with SA or TB. Conversely SA was shown to be positively correlated with spiking in many different epileptic syndromes of childhood. Moreover, in the contest of the NREM sleep cycle an inverse relationship between the SWA and SA mode of spike activation has been detected. CONCLUSIONS: Overall results give evidence that 3 main rhythmic spectral components that characterize sleep EEG can exert positive influences on IEDs production. Our studies demonstrate that within NREM sleep the facilitating influences on IEDs production exerted separately by either spindle activity or delta synchronization mechanisms can be detected. Moreover, a mutually exclusive mechanism between SA and SWA oscillations is detectable in the opposite relationship of the correlation between IEDs and the two bands in the central part of the NREM cycle.

Brain↗