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PubMed2001

Dietary restraint and negative affect as mediators of body dissatisfaction and bulimic behavior in adolescent girls and boys.

Stice's dual pathway model of dietary restraint and negative affect was examined in both adolescent girls and boys. Self-report measures assessing body dissatisfaction, dietary restraint, negative affect and bulimic behavior were administered to 267 girls and 199 boys aged between 12 and 16 years. The findings for the girls were consistent with Stice's model, in that they indicated that both dietary restraint and negative affect mediated the relationship between body dissatisfaction and bulimic behavior. For the boys who desired a thinner body size, only negative affect was found to mediate the relationship between body dissatisfaction and bulimic behavior. On the other hand, for boys who desired a larger body size, both body dissatisfaction and dietary restraint were found to exert an independent effect on bulimic behavior. As boys can aspire to two contrasting and seemingly opposite body size ideals, the findings highlight that the relationship between body dissatisfaction, dietary restraint, negative affect and bulimic behavior are more complex in males than in females. Further research using longitudinal designs is needed in order to test the directional and bidirectional nature of the observed interrelationships.

Adolescent↗

PubMed2000

Gene regulation of heme oxygenase-1 as a therapeutic target.

Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation. HO regulates the cellular content of the pro-oxidant heme and produces catabolites with physiological functions. HO-1 is induced by a host of oxidative stress stimuli, and the activation of HO-1 gene expression is considered to be an adaptive cellular response to survive exposure to environmental stresses. Since overexpression of the HO-1 gene is also protective against the deleterious effects of experimental injuries, the specific induction of HO-1 by 'non-stressful' stimuli, eg. stimuli that are not associated with oxidative stress, such as adenosine 3', 5'-cyclic monophosphate or cyclic guanosine 3',5'-monophosphate, may have important clinical implications. This review summarizes recent advances in the understanding of regulatory mechanisms of HO-1 gene expression, in particular the role of various redox-dependent and redox-independent signaling pathways. Models of experimental injuries are highlighted in which specific overexpression of the HO-1 gene either by targeted gene transfer or by pharmacological modulation has been demonstrated to provide therapeutic effects.

Animals↗

PubMed1987

Diffusion of dihydropyridine calcium channel antagonists in cardiac sarcolemmal lipid multibilayers.

A membrane bilayer pathway model has been proposed for the interaction of dihydropyridine (DHP) calcium channel antagonists with receptors in cardiac sarcolemma (Rhodes, D.G., J.G. Sarmiento, and L.G. Herbette. 1985. Mol. Pharmacol. 27:612-623) involving drug partition into the bilayer with subsequent receptor binding mediated (though probably not rate-limited) by diffusion within the bilayer. Recently, we have characterized the partition step, demonstrating that DHPs reside, on a time-average basis, near the bilayer hydrocarbon core/water interface. Drug distribution about this interface may define a plane of local concentration for lateral diffusion within the membrane. The studies presented herein examine the diffusional dynamics of an active rhodamine-labeled DHP and a fluorescent phospholipid analogue (DiIC16) in pure cardiac sarcolemmal lipid multibilayer preparations as a function of bilayer hydration. At maximal bilayer hydration, the drug diffuses over macroscopic distances within the bilayer at a rate identical to that of DiI (D = 3.8 X 10(-8) cm2/s), demonstrating the overall feasibility of the membrane diffusion model. The diffusion coefficients for both drug and lipid decreased substantially as the bilayers were dehydrated. While identical at maximal hydration, drug diffusion was significantly slower than that of DiIC16 in partially dehydrated bilayers, probably reflecting differences in mass distribution of these probes in the bilayer.

Animals↗

PubMed1989

Diffusional dynamics of an active rhodamine-labeled 1,4-dihydropyridine in sarcolemmal lipid multibilayers.

A "membrane bilayer pathway" model, involving ligand partition into the bilayer, lateral diffusion, and receptor binding has been invoked to describe the 1,4-dihydropyridine (DHP) calcium channel antagonist receptor binding mechanism. In an earlier study (Chester et al. 1987. Biophys. J. 52:1021-1030), the diffusional component of this model was examined using an active fluorescence labeled DHP calcium channel antagonist, nisoldipine-lissamine rhodamine B (Ns-R), in purified cardiac sarcolemmal (CSL) lipid multibilayers. Diffusion coefficient measurements on membrane-bound drug and phospholipid at maximum bilayer hydration yielded similar values (3.8 x 10(-8) cm2/s). However, decreases in bilayer hydration resulted in dramatically reduced diffusion coefficient values for both probes with substantially greater impact on Ns-R diffusion. These data suggested that hydration dependent diffusional differences could be a function of relative probe location along the bilayer normal. In this communication, we have addressed the relative effect of the rhodamine substituent on Ns-R diffusion complex by examining the diffusional dynamics of free rhodamine B under the same conditions used to evaluate Ns-R complex and phospholipid diffusion. X-ray diffraction studies were performed to determine the Ns-R location in the membrane and model the CSL lipid bilayer profile structure to give a rationale for the differences in probe diffusional dynamics as a function of interbilayer water space.

Animals↗

PubMed1993

Transient kinetics of the interaction of actin with myosin subfragment-1 in the absence of nucleotide.

The kinetics of the association of actin with myosin subfragment-1 (S1) has been studied by using S1 labeled at the sulfhydryl group SH1 with 5-(iodoacetamido)fluorescein (S1-AF). Upon rapid mixing in a stopped-flow apparatus, the fluorescence intensity of the fluorescein moiety increased by 50%, followed by a slower increase that was well resolved. This slow phase of the fluorescence change could not be fitted to either a monoexponential or a biexponential function, but it could be fitted to a sum of three exponential terms yielding three observed first-order rate constants (lambda i). The dissociation of acto.-(S1-AF) was studied by displacement of S1-AF from the complex with native S1. The dissociation kinetics was characterized by a single rate constant (approximately 0.012 s-1 at 20 degrees C), and this constant was independent of S1 concentration. Together with previous equilibrium data that were obtained under identified conditions for formation of acto-subfragment-1 (Lin, S.-H., and H. C. Cheung. 1991. Biochemistry. 30:4317-4323), a six-state two-pathway model is proposed as a minimum kinetic scheme for formation of rigor acto.S1. In this model, unbound subfragment-1 exists in two conformational states (S1' and S1) which are in equilibrium with each other, one corresponding to the previously established low-temperature state and the other to the high-temperature state. Each subfragment-1 state can interact with actin to form a collision complex, followed by two isomerizations to form two acto-subfragment-1 states (A.S1' and A.S1). Both isomerizations were visible in stopped-flow experiments. Two special cases of the model were considered: 1) a rapid pre-equilibration of the initial collision complex with actin and S1, and 2) trace accumulation of the collision complex. The first case required that the three combinations of the three observed rate constants be independent of actin concentration. The data were incompatible with this approximation. The other special case required that the sum of the lambda i vary linearly with actin concentration and the other two combinations of lambda i vary with actin concentration in a quadratic fashion. The present data were in agreement with the second case. At 20 degrees C and in 60 mM KCl, 2 mM MgCl2, 30 mM 2-([-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino)ethanesulfonic acid, and pH 7.5, the biomolecular association rate constants for the interaction of actin with S1' and S1 were 8.58 x 10(5) and 1.11 x 10(6) M-1 s-1, respectively.

Actins↗

PubMed2003

The what and where in visual masking.

A metacontrast mask suppresses the visibility of, without influencing the reaction time (RT) to, the target. We investigated whether this dissociation results from a sensori-motor pathway immune to masking effects or from the characteristics of stimulus timing in mutually inhibitory sustained and transient channels. For target visibility, para- and metacontrast yielded the usual U-shaped functions. Peak paracontrast occurred at stimulus onset asynchronies (SOAs) of -150 to -100 ms. RTs were relatively low for metacontrast and did not show a systematic change as a function of SOA. The RT contribution from contour-masking was greatest at an SOA of -150 ms (paracontrast) and declined to near zero in the metacontrast regime. The dissociation between visibility and RT seen in metacontrast did not occur in paracontrast, rejecting the theory that RTs are elicited by a single sensori-motor pathway immune to masking. The dependence of the dissociation on stimulus timing can be explained by RECOD, a dual-pathway model wherein fast and slow activities interact.

Contrast Sensitivity↗

PubMed1999

Approaches to anti-aging intervention: the promises and the uncertainties.

Humans have long sought the elixir to long life. Today, although advances in our understanding of the aging process have given gerontologists new insights in potential anti-aging interventions, public demand for these interventions is outpacing our current knowledge. My presentation begins with a brief historical background that outlines some of the past and present approaches to anti-aging interventions. Using the dietary restriction paradigm as a prototype, discussions center on a three-pathway model that provides the bases to design effective interventions: (1) retardation of biological aging, (2) suppression of age-related disease, and (3) modulation of cross talk between (1) and (2). One other concept useful for discussion in relation to interventions is the enhancement of an organism's resistance to deter vulnerability to aging and disease. These models are best used to explain the efficacy of currently popular interventions such as antioxidant supplementation and hormone therapies. This presentation further highlights the promises that antioxidant supplements hold in warding off oxidative damage as well as their inherent problems and biological limitations. Also discussed here are the promises and uncertainties of anti-aging interventions by genetic manipulation, as seen in animal model studies, and prophylactic treatments targeted against disease, such as hormonal approaches using estrogen and DHEA, as well as other intervening measures.

Aging↗

PubMed2000

Gonadal development in mammals at the cellular and molecular levels.

In mammals, although sex is determined chromosomally, gonads in both sexes begin development as similar structures. Until recently it was widely held that female development constituted a "default" pathway of development, which would occur in the absence of a testis-determining gene. This master gene on the Y chromosome, SRY in the human and Sry in the mouse, is thought to act in a cell-autonomous fashion to determine that cells in the gonadal somatic population develop as pre-Sertoli cells. Triggering of somatic cell differentiation along the Sertoli cell pathway is therefore a key event; it was thought that further steps in gonadal differentiation would follow in a developmental cascade. In the absence of Sertoli cells, the lack of anti-Mullerian hormone would allow development of the female Mullerian duct and absence of Leydig cells would prevent maintenance of the Wolffian duct. Recent findings that female signals not only maintain the Mullerian duct and repress the Wolffian duct but also suppress the development of Leydig cells and maintain meiotic germ cells, together with the finding that an X-linked gene is required for ovarian development and must be silenced in the male, have shown that the female default pathway model is an oversimplification. Morphological steps in gonadal differentiation can be correlated with emerging evidence of molecular mechanisms; growth factors, cell adhesion, and signaling molecules interact together, often acting within short time windows via reciprocal control relationships.

Animals↗

PubMed2003

On the origin of size-dependent tortuosity for permeation of hydrophilic solutes across the stratum corneum.

Due to their low skin permeabilities, transdermal transport of hydrophilic solutes is poorly understood. In this study, we sought to determine the dependence of solute tortuosity on solute size and stratum corneum (SC) porosity. With porous pathway model, transdermal transport of hydrophilic solutes through the SC was modeled as diffusion through imperfections/defects that occur between/within the lipid lamellar organization of the SC. In order to seek an analytical solution, we assumed that the pores in the SC were cylindrical and organized in a cubical pattern. The proposed theoretical model describing the dependence of solute tortuosity on solute size and SC porosity is in agreement with prior experimentally derived tortuosity values.

Epithelium↗

PubMed2002

Human epidermal membrane constant conductance iontophoresis: alternating current to obtain reproducible enhanced permeation and reduced lag times of a nonionic polar permeant.

An experimental protocol, using an initial 1 min direct current (DC) applied potential of 4 V followed by alternating current (AC), was established to: (a) increase conductance and permeability and decrease lag time for human epidermal membrane (HEM) relative to unaltered HEM and; (b) maintain constant conductance and permeability during flux studies. The protocol allowed specific permeation parameters of the membrane to be characterized under electrically enhanced, constant flux conditions. The permeability, lag time, and effective membrane thickness were determined using a nonionic polar permeant, urea, while the enhanced conductance was maintained at a constant level with AC. A tortuous pore pathway model was employed to analyze the data. The AC protocol increased membrane permeability, and decreased lag time and effective membrane thickness relative to similar parameters obtained in previous studies from unaltered HEM. Lag times ranged from 32.0 to 105.5 min, and permeability coefficients calculated from steady state fluxes ranged from 1.68 to 6.03x10(-7) cm/s for HEM samples with electrical resistance values during transport of 2.3-8.0 kOmega x cm2. Effective membrane thicknesses were calculated to range from 0.34 to 0.61 cm during AC iontophoresis. Significant additional results were obtained when the protocol was applied for two consecutive runs using the same HEM sample, with time for the HEM sample to recover between runs. During the second run, the applied potential was adjusted to reproduce the conductance obtained on the first run. Under these conditions, the consecutive runs yielded essentially the same lag time, permeability and effective membrane thickness values. These results suggest that constant fluxes can be achieved by keeping HEM electrical conductance constant during AC iontophoresis.

Electric Stimulation↗

PubMed2003

Proteomic approach to apoptotic thymus maturation.

Apoptosis is an essential process for selection of T lymphocytes specific for foreign antigen in the process of mammalian thymus maturation. Proteomics, a comprehensive study of proteins expressed in a cell, will facilitate the systematic analysis of protein molecules related to such a complicated biological system. Protein expression profiles including information about protein signatures, localization and their quantitative changes with extracellular stimulations are extremely useful to construct intracellular pathway models resulting in the apoptotic cell death.

Apoptosis↗

PubMed2006

A conceptual model of water's role as a reservoir in Helicobacter pylori transmission: a review of the evidence.

Helicobacter pylori infection plays a role in the development of chronic gastritis, peptic ulcer and gastric cancer, yet the route of transmission into susceptible hosts remains unknown. Studies employing microbiological techniques have demonstrated that H. pylori has the ability to survive when introduced into water and that H. pylori is present in water and other environmental samples all over the world. Epidemiological studies have shown that water source and exposures related to water supply, including factors related to sewage disposal and exposure to animals, are risk factors for infection. This review describes the microbiological and epidemiological evidence for, and proposes a model of, waterborne H. pylori transmission outlining important features in the transmission cycle. In the model, humans and animals shed the bacteria in their faeces and the mechanisms for entry into water, and for survival, ingestion and infection are dependent upon a range of environmental influences. Verification of the proposed model pathways has important implications for public-health prevention strategies.

Animals↗

PubMed2002

Probing Src homology 2 domain ligand interactions by differential line broadening.

Few techniques for probing the role of individual amino acids in interactions of a protein with ligands are available. Chemical shift perturbations in NMR spectra provide qualitative information about the response of individual amino acids of a protein to its interactions with ligands. Line shapes derived from (15)N-HSQC spectra recorded for different steps of a ligand titration yield both kinetic constants and insight into mechanisms by which the ligand binds. Here we have analyzed line shapes for 37 signals of amino acids of the N-terminal src homology 2 domain (N-SH2) of the 85 kDa subunit of phosphatidylinositol 3-kinase (PI3-K) upon binding of phosphotyrosine (ptyr)-containing peptides. Kinetic rates at individual amino acids of the SH2 varied throughout the structure. For a subset of SH2 residues, the fine structure of the NMR line shapes indicated slow motions induced by the presence of small amounts of the ligand. These complex line shapes require one or more additional conformational states on the kinetic pathway. Modeling of the observed ligand interactions suggests a quasi-allosteric initial binding step. N-SH2 mutants with altered ligand affinity or specificity were also examined. Analysis of their line shapes revealed three distinct classes of mutants with different kinetic behaviors.

Isoleucine↗

PubMed2004

Mutagenesis study of the 2Fe-2S center and the FAD binding site of the Na(+)-translocating NADH:ubiquinone oxidoreductase from Vibrio cholerae.

Many marine and pathogenic bacteria have a unique sodium-translocating NADH:ubiquinone oxidoreductase (Na(+)-NQR), which generates an electrochemical Na(+) gradient during aerobic respiration. Na(+)-NQR consists of six subunits (NqrA-F) and contains five known redox cofactors: two covalently bound FMNs, one noncovalently bound FAD, one riboflavin, and one 2Fe-2S center. A stable neutral flavin-semiquinone radical is observed in the air-oxidized enzyme, while the NADH- or dithionite-reduced enzyme exhibits a stable anionic flavin-semiquinone radical. The NqrF subunit has been implicated in binding of both the 2Fe-2S cluster and the FAD. Four conserved cysteines (C70, C76, C79, and C111) in NqrF match the canonical 2Fe-2S motif, and three conserved residues (R210, Y212, S246) have been predicted to be part of a flavin binding domain. In this work, these two motifs have been altered by site-directed mutagenesis of individual residues and are confirmed to be essential for binding, respectively, the 2Fe-2S cluster and FAD. EPR spectra of the FAD-deficient mutants in the oxidized and reduced forms exhibit neutral and anionic flavo-semiquinone radical signals, respectively, demonstrating that the FAD in NqrF is not the source of either radical signal. In both the FAD and 2Fe-2S center mutants the line widths of the neutral and anionic flavo-semiquinone EPR signals are unchanged from the wild-type enzyme, indicating that neither of these centers is nearby or coupled to the radicals. Measurements of steady-state turnover using NADH, Q-1, and the artificial electron acceptor ferricyanide strongly support an electron transport pathway model in which the noncovalently bound FAD in the NqrF subunit is the initial electron acceptor and electrons then flow to the 2Fe-2S center.

Amino Acid Sequence↗

PubMed2003

Reactivity of the organometallic fac-[(CO)3ReI(H2O)3]+ aquaion. Kinetic and thermodynamic properties of H2O substitution.

The water exchange process on [(CO)(3)Re(H(2)O)(3)](+) (1) was kinetically investigated by (17)O NMR. The acidity dependence of the observed rate constant k(obs) was analyzed with a two pathways model in which k(ex) (k(ex)(298) = (6.3 +/- 0.1) x 10(-3) s(-1)) and k(OH) (k(OH)(298)= 27 +/- 1 s(-1)) denote the water exchange rate constants on 1 and on the monohydroxo species [(CO)(3)Re(I)(H(2)O)(2)(OH)], respectively. The kinetic contribution of the basic form was proved to be significant only at [H(+)] < 3 x 10(-3) M. Above this limiting [H(+)] concentration, kinetic investigations can be unambiguously conducted on the triaqua cation (1). The variable temperature study has led to the determination of the activation parameters Delta H(++)(ex) = 90 +/- 3 kJ mol(-1), Delta S(++)(ex) = +14 +/- 10 J K(-1) mol(-1), the latter being indicative of a dissociative activation mode for the water exchange process. To support this assumption, water substitution reaction on 1 has been followed by (17)O/(1)H/(13)C/(19)F NMR with ligands of various nucleophilicities (TFA, Br(-), CH(3)CN, Hbipy(+), Hphen(+), DMS, TU). With unidentate ligands, except Br(-), the mono-, bi-, and tricomplexes were formed by water substitution. With bidentate ligands, bipy and phen, the chelate complexes [(CO)(3)Re(H(2)O)(bipy)]CF(3)SO(3) (2) and [(CO)(3)Re(H(2)O)(phen)](NO(3))(0.5)(CF(3)SO(3))(0.5).H(2)O (3) were isolated and X-ray characterized. For each ligand, the calculated interchange rate constants k'(i) (2.9 x 10(-3) (TFA) < k'(I) < 41.5 x 10(-3) (TU) s(-1)) were found in the same order as the water exchange rate constant k(ex), the S-donor ligands being slightly more reactive. This result is indicative of I(d) mechanism for water exchange and complex formation, since larger variations of k'(i) are expected for an associatively activated mechanism.

Journal Article↗

PubMed2006

Water-exchange study revealed unexpected substitution behavior of [(CO)2(NO)Re(H2O)3]2+ in aqueous media.

The pH-dependent water-exchange rates of [(CO)2(NO)Re(H2O(cis))2(H2O(trans))]2+ (1) in aqueous media were investigated by means of 17O NMR spectroscopy at 298 K. Because of the low pK(a) value found for 1 (pK(a) = 1.4 +/- 0.3), the water-exchange rate constant k(obs)(H2O(trans/cis)) was analyzed with a two-pathway model in which k(Re)(H2O(trans/cis)) and k(ReOH)(H2O)(trans/cis)) denote the water-exchange rate constants in trans or cis position to the nitrosyl ligand on 1 and on the monohydroxo species [(CO)2(NO)Re(H2O)2(OH)]+ (2), respectively. Whereas the rate constants k(ReOH)(H2O)(trans)) and k(ReOH)(H2O)(cis)) were determined as (4.2 +/- 2) x 10(-3) s(-1) and (5.8 +/- 2) x 10(-4) s(-1), respectively, k(Re)(H2O)(trans)) and k(Re)(H2O)(cis)) were too small to be determined in the presence of the much more reactive species 2. Apart from the water exchange, an unexpectedly fast C identical with 16O --> C identical withO exchange was also observed via NMR and IR spectroscopy. It was found to proceed through 1 and 2, with rate constants k(Re)(CO) and k(ReOH)(CO) of (19 +/- 4) x 10(-3) s(-1) and (4 +/- 3) x 10(-3) s(-1), respectively. On the other hand, N identical with 16O --> N identical with *O exchange was not observed.

Carbon Monoxide↗

PubMed1998

Pathways for electron tunneling in cytochrome c oxidase.

Warburg showed in 1929 that the photochemical action spectrum for CO dissociation from cytochrome c oxidase is that of a heme protein. Keilin had shown that cytochrome a does not react with oxygen, so he did not accept Warburg's view until 1939, when he discovered cytochrome a3. The dinuclear cytochrome a3-CuB unit was found by EPR in 1967, whereas the dinuclear nature of the CuA site was not universally accepted until oxidase crystal structures were published in 1995. There are negative redox interactions between cytochrome a and the other redox sites in the oxidase, so that the reduction potential of a particular site depends on the redox states of the other sites. Calculated electron-tunneling pathways for internal electron transfer in the oxidase indicate that the coupling-limited rates are 9 x 10(5) (CuA-->a) and 7 x 10(6) s(-1) (a-->a3); these calculations are in reasonable agreement with experimental rates, after corrections are made for driving force and reorganization energy. The best CuA-a pathway starts from the ligand His204 and not from the bridging sulfur of Cys196, and an efficient a-a3 path involves the heme ligands His378 and His376 as well as the intervening Phe377 residue. All direct paths from CuA to a3 are poor, indicating that direct CuA-->a3 electron transfer is much slower than the CuA-->a reaction. The pathways model suggests a means for gating the electron flow in redox-linked proton pumps.

Animals↗

PubMed1997

Induction of ornithine decarboxylase by IL-3 is mediated by sequential c-Myc-independent and c-Myc-dependent pathways.

Enforced c-Myc expression promotes continuous, growth factor-independent, cell cycle progression and activates expression of the ornithine decarboxylase (ODC) gene and its promoter. c-Myc-responsiveness of murine ODC is mediated by two conserved c-Myc:Max E-boxes in ODC intron 1. c-Myc and ODC are both required for cell growth and their expression is sequentially induced in G0/G1 cells stimulated with mitogens, yet their expression is not modulated by the cell cycle in proliferating cells. Here we demonstrate that regulation of ODC and its promoter by Interleukin-3 (IL-3) in murine myeloid cells is mediated in part by c-Myc, c-Myc induced ODC through the same transcription start site as IL-3 and, in asynchronously growing cells, maximal activity of the ODC promoter required the intronic c-Myc binding sites. However, induction of ODC following IL-3 stimulation of quiescent cells is mediated by at least two pathways. The first phase of this response was independent of the intronic c-Myc:Max E-boxes and de novo protein synthesis. Sustained induction of the ODC promoter however required the c-Myc:Max binding sites and protein synthesis. Accumulation of c-Myc following stimulation of quiescent cells with IL-3 correlated with the delayed phase of the response. Consistent with a two pathway model of ODC regulation, inducible overexpression of dominant negative form of c-Myc (In373-Myc), which specifically inhibits the c-Myc-Max network, inhibited the delayed, but not immediate, induction of ODC promoter activity in response to IL-3. Dominant negative c-Myc protein also effectively suppressed induction of the endogenous ODC gene by IL-3. Therefore, c-Myc functions as a direct and required-regulator of ODC. These results also suggest a model whereby c-Myc's role in regulating its targets may be to convert a transient, immediate-early, activation event into the persistent induction of gene expression.

Animals↗