Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,351 records · Page 75Linked to original sources
PubMed1993

Modulation of voltage-activated Ca currents by pain-inducing agents in a dorsal root ganglion neuronal line, F-11.

Whole cell currents evoked by pain-inducing agents--bradykinin (Bk), capsaicin (Cap), and reciniferatoxin (RTX), and their modulation of voltage-activated Ca currents were examined in F-11 cells using a patch electrode voltage clamp technique. Most F-11 cells generated action potentials under current clamp if their membrane potentials were held sufficiently negative. Average peak inward Na current (INa) was 100 microA/cm2 and the INa was abolished by 10(-6) M tetrodotoxin. At least two types of Ca currents could be clearly distinguished on the basis of voltage dependency and kinetics; a low threshold transient ICa(t) and a high threshold sustained ICa(l). In addition, another high threshold transient Ca current, presumably ICa(n), was observed. About 30% of the cells produced inward current for these pain-inducing agents, when activated at the membrane holding potential of -70 mV. In some F-11 cells, the amplitude of action potential was observed to increase during 10(-6) M Cap-induced depolarization. Both low and high threshold Ca currents were reduced by 10(-6) M Bk in the majority of the cells. Similarly, both 10(-6) M Cap and 10(-9) M RTX reduced these Ca currents. However, a considerable number of cells showed an initial enhancement followed by reduction in the amplitude of these Ca currents. With higher concentrations of these ligands, all Ca currents were suppressed. Such modulation of voltage-activated Ca currents by pain-inducing agents occurred in both the presence and absence of apparent receptor-activated current flows in the cells. In pertussis toxin (PTX)-treated cells, the inhibitory modulation of Ca currents by pain-inducing agents was suppressed. In contrast, in cholera toxin (CTX)-treated cells, this inhibitory modulation appeared to be enhanced. These data indicate that the inhibitory modulation of Ca channel currents by Cap and RTX, similarly to that of Bk, involves a PTX-sensitive inhibitory G protein (Gi).

Action Potentials↗
PubMed2006

Microenvironmental pH modulation based release enhancement of a weakly basic drug from hydrophilic matrices.

For weakly basic drugs, pH-dependent solubility characteristics can translate into low and incomplete release of these drugs from sustained release formulations. The objective of this study was to quantitatively analyze the relationship between microenvironmental pH modulation and release enhancement of a weakly basic drug in the free base form. A prototype matrix system primarily consisting of trimethoprim (pK(a) 6.6), hydroxypropyl methylcellulose (HPMC), and a polymeric or nonpolymeric pH modulator was used. Incorporation of the methacrylic acid polymer, Eudragit L100-55 resulted in marginal release enhancement as the pH modulation effected by this polymer was attenuated by the basicity of the drug. Water uptake and scanning electron microscopy (SEM) studies suggested that Eudragit L100-55 incorporation also resulted in reduced water uptake and matrix permeability. The effect of nonpolymeric pH modulators on release enhancement was also studied. The lowering in microenvironmental pH by malic acid was sufficiently high and persistent to result in pH-independent release. A correlation plot between the experimentally determined microenvironmental pH, effected by the polymeric and nonpolymeric pH modulators, and percent drug release, exhibited good linearity with a correlation coefficient of 0.83; thereby, indicating that drug diffusion across the gel barrier is the predominating mechanism of release.

Acrylic Resins↗
PubMed1978

Modulator binding protein antagonizes activation of (Ca2+ + Mg2+)-ATPase and Ca2+ transport of red blood cell membranes.

Red blood cells contain a protein that activates membrane-bound (Ca2+ + Mg2+)-ATPase and Ca2+ transport. The red blood cell activator protein is similar to a modulator protein that stimulates cyclic AMP phosphodiesterase. Wang and Desai [Journal of Biological Chemistry 252:4175--4184, 1977] described a modulator-binding protein that antagonizes the activation of cyclic AMP phosphodiesterase by modulator protein. In the present work, modulator-binding protein was shown to antagonize the activation of (Ca2+ + Mg2+)-ATPase and Ca2+ transport by red blood cell activator protein. The results further demonstrate the similarity between the activator protein from human red blood cells and the modulator protein from bovine brain.

Biological Transport, Active↗
PubMed2005

A simple approach for phase-modulated single-scan 2D NMR spectroscopy.

Conventional NMR spectroscopy techniques require long acquisition times due to the recovery time between the repeated excitations necessary for each increment of the evolution times in the indirectly detected dimensions. Here we outline a pulse sequence element for gradient-assisted ultrafast multidimensional NMR spectroscopy using frequency-modulated 'chirp' pulses to generate phase-modulated magnetization in an indirectly detected spectral dimension. The potential of this sequence element is demonstrated by acquiring a correlation spectroscopy (COSY) spectrum in 96 ms. This new pulse sequence element is an extension of ultrafast spectroscopy techniques based on the generation of amplitude modulation of the NMR signal in the indirectly detected spectral dimensions. The use of phase modulation instead of amplitude modulation helps broaden the applicability and may provide an increase of sensitivity in some experiments due to the ability to distinguish between positive and negative frequency offsets relative to the carrier frequency of the sequence element.

Magnetic Resonance Spectroscopy↗
PubMed2005

Providing specialist clinical skills in soft tissue and intra-articular injection through a postgraduate masters module.

Current philosophy and policy changes in the National Health Service are encouraging healthcare practitioners to extend their clinical skills to create a more patient-centred approach thus allowing patients to be seen in a timely and more appropriate manner. This often requires further development of the practitioners' skills and knowledge. One approach to achieve this is through collaboration between employers and educational providers to ensure that educational experience is not only evidence based but also responsive to the needs of the current and future workforce. A postgraduate module was developed to raise critical and evaluative skills, as well as the technical skills of practitioners using injections in the management of joint and soft tissue pathology, while developing a professional responsibility towards injection practice. The module emphasized learning though experience by contextualizing the theoretical aspects of the module and by its student centred assessments. Further strengths of this module are that it has utilized academic and clinical expertise and knowledge to enable clinicians to gain additional skills and the multidisciplinary approach engendered good working practice Overall the module was evaluated positively by both tutors and students and not only met its aims but also addressed the current professional and policy issues around continuing professional development.

Journal Article↗
PubMed2007

The PedsQL Brain Tumor Module: initial reliability and validity.

BACKGROUND: Brain tumors (BT) are second only to acute lymphoblastic leukemia as the most prevalent form of pediatric cancer, with BT 5-year survival rates approaching 70%. With increased survival, quality of life has emerged as an essential health outcome. This investigation examines the internal consistency reliability and construct validity of the Pediatric Quality of Life Inventory (PedsQL) Brain Tumor Module. METHODS: The PedsQL 4.0 Generic Core Scales, PedsQL Multidimensional Fatigue Scale, and PedsQL Brain Tumor Module were administered to 99 families. The average age of the 56 boys and 43 girls was 9.76 years (range=2-18 years). The sample included children with tumors located in the posterior fossa/brainstem (N=62, 62.6%), supratentorial (N=15, 15.2%), and midline (N=22, 22.2%). Children were on treatment (N=46, 46.5%), off treatment<12 months (N=19, 19.2%), or off treatment>12 months/long-term survivor (N=34, 34.3%). Treatment included radiation (N=61, 61.6%), surgery (N=83, 83.8%), chemotherapy (N=87, 87.9%), and bone marrow transplant (N=5, 5.1%). RESULTS: Internal consistency reliability was demonstrated for the 24-item PedsQL Brain Tumor Module (average alpha=0.78-0.92, parent proxy-report, n=99; average alpha=0.76-0.87, child self-report, n=51). Construct validity for the PedsQL Brain Tumor Module was supported through an analysis of the intercorrelations with the Generic Core Scales and Fatigue Scale. CONCLUSIONS: The findings provide support for the measurement properties of the PedsQL Brain Tumor Module.

Adolescent↗
PubMed2004

Detection of functional modules from protein interaction networks.

Complex cellular processes are modular and are accomplished by the concerted action of functional modules (Ravasz et al., Science 2002;297:1551-1555; Hartwell et al., Nature 1999;402:C47-52). These modules encompass groups of genes or proteins involved in common elementary biological functions. One important and largely unsolved goal of functional genomics is the identification of functional modules from genomewide information, such as transcription profiles or protein interactions. To cope with the ever-increasing volume and complexity of protein interaction data (Bader et al., Nucleic Acids Res 2001;29:242-245; Xenarios et al., Nucleic Acids Res 2002;30:303-305), new automated approaches for pattern discovery in these densely connected interaction networks are required (Ravasz et al., Science 2002;297:1551-1555; Bader and Hogue, Nat Biotechnol 2002;20:991-997; Snel et al., Proc Natl Acad Sci USA 2002;99:5890-5895). In this study, we successfully isolate 1046 functional modules from the known protein interaction network of Saccharomyces cerevisiae involving 8046 individual pair-wise interactions by using an entirely automated and unsupervised graph clustering algorithm. This systems biology approach is able to detect many well-known protein complexes or biological processes, without reference to any additional information. We use an extensive statistical validation procedure to establish the biological significance of the detected modules and explore this complex, hierarchical network of modular interactions from which pathways can be inferred.

Algorithms↗
PubMed2006

Structure/function of KRAB repression domains: structural properties of KRAB modules inferred from hydrodynamic, circular dichroism, and FTIR spectroscopic analyses.

The abundant zinc finger proteins (ZFPs) sharing the KRAB motif, a potent transcription repression domain, direct the assembly on templates of multiprotein repression complexes. A pivotal step in this pathway is the assembly of a KRAB domain-directed complex with a primary corepressor, KAP1/KRIP-1/TIF1beta. The structure/function dependence of KRAB/TIF1beta protein-protein interaction and properties of the complex, therefore, play pivotal roles in diverse cellular processes depending on KRAB-ZFPs regulation. KRAB domains are functionally bipartite. The 42 amino acid-long KRAB-A module, indeed, is necessary and sufficient for transcriptional repression and for the interaction with the tripartite RBCC region of TIF1beta, while the KRAB-B motif seems to potentiate the assembly of the complex. The structural properties of KRAB-A and KRAB-AB domains from the human ZNF2 protein have been investigated by characterizing highly purified lone (A) and composite (AB) modules. Hydrodynamic and spectroscopic features, investigated by means of gel filtration, circular dichroism, and infrared spectroscopy, provide evidence that both KRAB-A and KRAB-AB domains present low compactness, structural disorder, residual secondary structure content, flexibility, and tendency to molecular aggregation. Comparative analysis among KRAB-A and KRAB-AB modules suggests that the presence of the -B module may influence the properties of lone KRAB-A by affecting the structural flexibility and stability of the conformers. The combined experimental data and the intrinsic features of KRAB-A and KRAB-AB primary structures indicate a potential role of specific subregions within the modules in driving structural flexibility, which is proposed to be of importance for their function.

Amino Acid Sequence↗
PubMed1998

Modulation of human flavin-containing monooxygenase 3 activity by tricyclic antidepressants and other agents: importance of residue 428.

Human flavin-containing monooxygenase 3 (FMO3) is subject to modulation by tricyclic antidepressants and other agents. Imipramine activates FMO3-catalyzed metabolism of methimazole at all substrate concentrations tested. This distinguishes FMO3 from rabbit FMO1 and FMO2, which are activated at high substrate concentration and inhibited at low substrate concentration, and pig FMO1, which is inhibited at all substrate concentrations. The response of FMO3 is also unique in that chlorpromazine is markedly more effective as a modulator than is imipramine. n-Octylamine, MgCl2, and HgCl2 all inhibit FMO3, the first two in a biphasic manner. Substitution of lysine for threonine at position 428 significantly alters the response of FMO3 to modulators without changing the kinetic parameters for the metabolism of the substrate. Activation by imipramine and chlorpromazine is reduced or abolished and inhibition, most obvious at low substrate concentrations, is observed. This is consistent with elimination of self-activation in the metabolism of imipramine. The mutation at 428 also eliminates the biphasic nature of the inhibition by n-octylamine and MgCl2, but does not alter the effect of HgCl2. Our findings show that the activity of FMO3 can be modulated by large drug molecules as well as short-chain amines and metal ions. This modulation can be markedly altered by changing a single amino acid in the enzyme.

Amines↗
PubMed1997

Stronger territorial responses to frequency modulated coos in collared doves

Playback experiments were used to investigate the perception of frequency variations in perch coos by collared doves, Streptopelia decaoctoTerritorial males responded more strongly to modulated than to unmodulated coos. This effect was seen whether all three elements of the coo, or just the first element, were modulated. Modulated coos differed from unmodulated coos in two ways, first by an increased average frequency, and second, by the presence of a discrete change in frequency. We show that it was the change in frequency that was responsible for the level of response to modulated coos. The stronger responses to modulated coos are interpreted as a result of the receiver rating the sender as a stronger competitor.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour

Journal Article↗
PubMed1998

Neither extended sequential nor simultaneous feature positive training result in modulation of evaluative flavor-flavor conditioning in humans.

In previous attempts to induce Pavlovian modulation of human evaluative flavor-flavor associations, the recurrent finding was that exposure to a Feature Positive (FP) schedule (XA+/A-), in which flavor A was reinforced by the aversive flavor Tween20 if and only if it was accompanied by a feature stimulus X, did not result in the expected X-modulated dislike for target A, but in simple unconditional A-US associations. The first experiment reported here investigated if more extended training results in a shift from simple A-US learning to the development of X-modulated A-US associations. Participants were exposed to a 32-trial, 4-session sequential FP schedule using flavors both for feature and target stimuli. The modulatory and/or excitatory power of the stimuli was assessed after each training session. After initial training, participants again acquired a simple unmodulated target A-US association. Contrary to expectations, the additional training sessions did not result in participants gradually learning the XA+/A- discrimination, but rather seemed to corroborate the already established A-US association. This was true whether or not participants acquired valid explicit knowledge about the conditional X-->(A-US) relation. The second experiment tested the hypothesis that what can be described as conditional flavor preferences may actually be based on a configural learning process. Participants were exposed to a single-session, eight-trial XA+/A- simultaneous discrimination schedule, the parameters of which were selected so as to enhance the probability of configuring XA, while simultaneously making it likely to observe a pattern of evaluations similar to an X-modulated dislike for A (X was less salient than A). Even though there was good evidence that participants noticed flavor X, they again failed to solve the XA+/A- discrimination and most probably acquired an association between the more salient flavor A and the US. The possibility is discussed that evaluative learning, unlike expectancy learning, might ultimately prove not to be subject to modulation.

Adult↗
PubMed1995

Modulation of cloned neuronal calcium channels through membrane-delimited pathway.

Modulation of voltage-gated Ca2+ channels by the receptor coupled GTP-binding proteins (G-proteins) is essential for controlling secretion and muscle contraction. We have expressed cloned Ca2+ channels in dysgenic myotubes to study G-protein modulation through the membrane-delimited pathway. The results obtained by the expression of alpha 1B channels and mutant channels of alpha 1B suggest that the two effects observed in G-protein modulated N-type channels (depression of current and slowing of activation) are through two independent mechanisms. In addition, neither the region linking repeat II and III nor carboxy-terminal region, which were demonstrated in L-type channels to determine some of their specific functions, are directly involved in G-protein modulation. The results obtained by the expression of the alpha 1A channel suggest that this channel is modulated through a novel membrane-delimited pathway that may not involve G-protein activation.

Animals↗
PubMed2000

Ligand binding properties of binary complexes of heparin and immunoglobulin-like modules of FGF receptor 2.

Epithelial cells, which express FGFR2IIIb, bind and respond to FGF-1, FGF-7 and FGF-10, but not FGF-2. Stromal cells, which bind and respond to FGF-1 and FGF-2, but not FGF-7 and FGF-10, express FGFR2IIIc or FGFR1IIIc. Here we show that when both isolated FGFR2betaIIIb and FGFR2betaIIIc or their common Ig module II are allowed to affinity select heparin from a mixture, the resultant binary complexes bound FGF-1, FGF-2, and FGF-7 with nearly equal affinity. In addition, FGF-2 and FGF-7 bound to both heparin-Ig module IIIb and IIIc complexes, but FGF-1 bound to neither Ig module III. The results show that in isolation both Ig modules II and III of FGFR2 can interact with heparin and that each exhibits a binding site for FGF. We suggest that the specificity of FGFR2IIIb and FGFR2IIIc is dependent on the cell membrane environment and heparin/heparan sulfate. Ig modules II and III cooperate both within monomers and across dimers with cellular heparan sulfates to confer cell type-dependent specificity of the FGFR complex for FGF.

Amino Acid Sequence↗
PubMed2003

Analysis of the signal transduction properties of a module of spatial sensing in eukaryotic chemotaxis.

The movement of cells in response to a gradient in chemical concentration-known as chemotaxis-is crucial for the proper functioning of uni- and multicellular organisms. How a cell senses the chemical concentration gradient surrounding it, and what signal is transmitted to its motion apparatus is known as gradient sensing. The ability of a cell to sense gradients persists even when the cell is immobilized (i.e., its motion apparatus is deactivated). This suggests that important features of gradient sensing can be studied in isolation, decoupling this phenomenon from the movement of the cell. A mathematical model for gradient sensing in Dictyostelium cells and neutrophils was recently proposed. This consists of an adaptation/spatial sensing module. This spatial sensing module feeds into an amplification module, magnifying the effects of the former. In this paper, we analyze the spatial sensing module in detail and examine its signal transduction properties. We examine the response of this module to several inputs of experimental and biological relevance.

Animals↗
PubMed1996

Extracellular matrix components of the mouse thymus microenvironment. V. Interferon-gamma modulates thymic epithelial cell/thymocyte interactions via extracellular matrix ligands and receptors.

Extracellular matrix (ECM) proteins influence cell migration and differentiation in a variety of cell systems. Within the thymus, the ECM distribution pattern is conserved among various mammalian species, but its physiological role is not completely understood. Interferon-gamma (IFN-gamma), a cytokine produced by thymocytes, is able to in vitro modulate ECM production by thymic epithelial cells (TEC) in a dose-dependent biphasic pattern. In the same model, we determined herein that the expression of VLA-5 and VLA-6 (fibronectin and laminin receptors, respectively) were upregulated by low doses of IFN-gamma, whereas high doses of the cytokine induced an opposite effect. In a second in vitro system, we evidenced that thymocyte adhesion to a TEC line was also modulated by IFN-gamma. Importantly, such effects were due to the biphasic modulation of ECM ligands and receptors since they could be specifically prevented by preincubating the TEC cultures with anti-ECM or anti-ECM receptor antibodies. Additionally, spontaneous thymocyte release from thymic nurse cells was similarly biphasically modulated by IFN-gamma. Our data provide support for the notion that thymocyte-derived products can play a role in the dialogue that exists in the thymus, involving differentiating thymocytes and microenvironmental cells. Moreover, we bring arguments indicating that one of the implicated mechanisms involved is the modulation of ECM ligands and receptors by the thymic epithelium.

Animals↗
PubMed1993

Apoptosis and its modulation in human promyelocytic HL-60 cells treated with DNA topoisomerase I and II inhibitors.

Electron microscopy studies demonstrate unequivocally that the observed oligonucleosome-sized secondary DNA fragmentation in human promyelocytic HL-60 cells treated with the topoisomerase inhibitors camptothecin and teniposide is correlated with the morphological changes in cell structure typical of programmed cell death (apoptosis). Since apoptosis has been associated with potential involvement of intracellular signaling linked to the Ca2+/calmodulin and protein kinase C transduction pathways, we also investigated the effects of signaling modulators on camptothecin- and teniposide-induced secondary DNA fragmentation in HL-60 cells. Neither calcium chelators, calcium/calmodulin inhibitors (calmidazolium or cyclosporine A), protein kinase C stimulation by TPA, protein phosphatase inhibition by okadaic acid, protein kinase inhibition by staurosporine, calphostin C, genistein or H7, nor cell cycle alterations by caffeine had any detectable effect. Interestingly, most of these intracellular signaling modulators were able to induce DNA fragmentation in HL-60 cells by themselves. These results may suggest that even though modulation of these signaling pathways was unable to prevent topoisomerase inhibitor-induced apoptosis, their sole deregulations could induce apoptosis in HL-60 cells. In contrast, aphidicolin blocked camptothecin-induced secondary DNA fragmentation, indicating that replication-induced DNA damage is required for camptothecin- but not teniposide-induced secondary DNA fragmentation. Zinc, 3-aminobenzamide, and spermine also modulated both camptothecin- and teniposide-induced secondary DNA fragmentation without significant alteration of topoisomerase-mediated primary DNA strand breaks. Hence, poly(ADP-ribosyl)ation and chromatin structure may be important in modulating oligonucleosome-sized DNA fragmentation associated with apoptosis in HL-60 cells treated with topoisomerase inhibitors.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Soluble expression in E. coli of a functional interphotoreceptor retinoid-binding protein module fused to thioredoxin: correlation of vitamin A binding regions with conserved domains of C-terminal processing proteases.

The exchange of all-trans retinol and 11-cis retinal between the photoreceptors and retinal pigmented epithelium is mediated by interphotoreceptor retinoid-binding protein (IRBP). IRBP contains binding sites for retinoids, docosahexaenoic acid and probably cell surface and matrix receptors. IRBP arose through the quadruplication of an ancient protein, represented by its carboxy-terminal module (module 4 in amphibians and mammals). Module 4 has retinol binding activity and is composed of regions coded for by each of IRBP's four exons. Determining the function of the exons has been hampered by insoluble expression of module 4 in Escherichia coli. Here, we found that module 4 of Xenopus IRBP (X4IRBP), as well as its exon segments, can be expressed in a soluble form as thioredoxin fusion proteins. The recombinant proteins were purified by ion exchange and arsenical-based affinity chromatography. Liquid chromatography/mass spectrometry confirmed that the sequence of X4IRBP is correct. All-trans retinol binding was characterized by monitoring enhancement of retinol fluorescence, quenching of intrinsic protein fluorescence, and transfer of energy to the bound retinol. Retinol bound to X4IRBP at 2.20+/-0.29 sites with a KD=1.25+/-0.39. One of the two sites was localized to Exons(2+3) and had a KD=0.26+/-0.13 micron. This site, which supported protein quenching and energy transfer, probably contains at least one of the two conserved tryptophans present in this segment. The second site was localized to Exon 4. This site supported the enhancement of retinol fluorescence but not protein quenching or energy transfer and had a KD=1.94+/-0.20 micron. Exon 1 had no retinol binding activity. The location of the retinol binding regions correlated with the distribution of domains conserved between IRBPs and the newly recognized family of C-terminal processing proteases (CtpAs), proteins which bind and cleave non-polar carboxy termini.

Amino Acid Sequence↗
PubMed1997

Solution structure of the albumin-binding GA module: a versatile bacterial protein domain.

The albumin-binding GA module is found in a family of surface proteins of different bacterial species. It comprises 45 amino acid residues and represents the first known example of contemporary module shuffling. Using 1H NMR spectroscopy we have determined the solution structure of the GA module from protein PAB, a protein of the anaerobic human commensal and pathogen Peptostreptococcus magnus. This structure, the first three-dimensional structure of an albumin-binding protein domain described, was shown to be composed of a left-handed three-helix-bundle. Sequence differences between GA modules with different affinities for albumin indicated that a conserved region in the C-terminal part of the second helix and the flexible sequence between helices 2 and 3 could contribute to the albumin-binding activity. The effect on backbone amide proton exchange rates upon binding to albumin support this assumption. The GA module has a fold that is strikingly similar to the immunoglobulin-binding domains of staphylococcal protein A but it shows no resemblance to the fold shared by the immunoglobulin-binding domains of streptococcal protein G and peptostreptococcal protein L. When the gene sequences, binding properties and thermal stability of these four domains are analysed in relation to their global folds an evolutionary pattern emerges. Thus, in the evolution of novel binding properties mutations are allowed only as long as the energetically favourable global fold is maintained.

Amino Acid Sequence↗