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At least 577 records · Page 32Linked to original sources
PubMed1994

Deformation of swollen erythrocytes provides a model of sickling-induced leak pathways, including a novel bromide-sensitive component.

Deoxygenation-induced red blood cell (RBC) sickling probably activates multiple cation leak pathways. In an attempt to model this, we examined the net passive K efflux ("K leak") from normal and sickle RBCs undergoing elliptical deformation in hypotonic media (200 mOsmol/L). This hypotonic deformation activates two deformation-dependent K leak pathways that are not detectable during the balanced leak (Kefflux = Nainflux) resulting from deformation of RBCs in isotonic medium. These are (1) a calcium-dependent leak component and (2) a novel leak pathway that is inhibited by substitution of bromide (but not sulfamate) for chloride, which converts the unbalanced K leak (Kefflux > Nainflux) of hypotonic deformation to a residual balanced leak. This dramatic effect of hypotonic deformation is reversible, is detected in both normal and sickle RBCs, and is inhibited significantly by 4,4'-diisothiocyano-2,2'-stilbene disulfonate. Remarkably, bromide also inhibits by 55% the K leak resulting from authentic deoxygenation-induced RBC sickling and, thereby, blunts the imbalance of accompanying monovalent cation leaks. The unique effect of bromide is not readily explainable on the basis of known behaviors of known ion leak/transport pathways. The mechanical threshold for triggering K leak during hypotonic deformation is at applied shear stress of 164 dyne/cm2, a value similar to the abnormal susceptibility we previously found for oxygenated sickle RBCs during isotonic deformation. These data suggest that membrane stretch accompanying hypotonic deformation activates the same multiple leak pathways that contribute to net K leak during authentic RBC sickling, including a previously unknown bromide-sensitive leak.

Anemia, Sickle Cell↗
PubMed1986

METAMOD: software for steady-state modelling and control analysis of metabolic pathways on the BBC microcomputer.

METAMOD, a BBC microcomputer-based software package for steady-state modelling and control analysis of model metabolic pathways, is described, The package consists of two programs. METADEF allows the user to define the pathway in terms of reactions, rate equations and initial concentrations of metabolites. METACAL uses one of two algorithms to calculate the steady-state concentrations and fluxes. One algorithm uses the current ratio of production and consumption rates of variable metabolites to adjust iteratively their concentrations in such a way that they converge towards the steady state. The other algorithm solves the roots of the system equations by means of a quasi-Newtonian procedure. Control analysis allows the calculation of elasticity, control and response coefficients, by means of finite difference approximation. METAMOD is interactive and easy to use, and suitable for teaching and research purposes.

Algorithms↗
PubMed2003

Childhood onset generalised dystonia can be modelled by increased gain in the indirect basal ganglia pathway.

Clinical experience suggests an important role of the indirect basal ganglia pathway in the genesis of childhood onset generalised dystonia, but it has been difficult to reconcile the increased muscle activity in dystonia with the current model of basal ganglia function in which the indirect pathway is considered primarily inhibitory. The aim of this study was to present a modification of the direct-indirect pathway model, in which the indirect pathway is inverting rather than purely inhibitory, so that while high signals are inhibited, low signals are amplified. As the basal ganglia may be a feedback loop that modifies cortical activity, instability from excessive gain in this feedback loop could explain features of dystonia. A detailed mathematical model is provided, together with simulations of cortical cell population spiking behaviour when connected through a basal ganglia loop. The simulations show that increased gain in the indirect pathway relative to the direct pathway can lead to unstable uncontrolled synchronous oscillations in cortex and basal ganglia. This behaviour could result in dystonia. The model provides a consistent explanation for the association of dystonia with parkinsonism and disorders characterised by dopamine depletion, the ability to treat some dystonias with dopamine, the ability of neuroleptic drug treatment to cause an acute dystonic reaction treatable with anticholinergic drugs, and the ability of pallidotomy or deep brain stimulation of the internal pallidum to alleviate symptoms of generalised dystonia.

Basal Ganglia↗
PubMed1993

Transthoracic defibrillation: effect of dual-pathway sequential pulse shocks and single-pathway biphasic pulse shocks in a canine model.

To determine whether dual-pathway sequential shocks and single-pathway biphasic shocks improved the efficacy of transthoracic defibrillation, we delivered single or sequential truncated waveform shocks of variable duration, voltage, and direction (polarity) to three groups of closed-chest dogs. Dual-pathway sequential shocks were assessed in group 1 (eight animals), biphasic shocks with a single pathway were compared in 11 dogs (group 2), and the effect of varying the duration of the biphasic shocks was assessed in group 3 (four animals). There was no improvement in success rates of the intervention shocks compared with a standard single "control" shock at any energy level. In this experimental model unidirectional or biphasic sequential shocks given over single or dual pathways were not superior to standard single-pulse transthoracic defibrillation.

Analysis of Variance↗
PubMed1999

Biochemical analysis of myelin lipids and proteins in a model of methyl donor pathway deficit: effect of S-adenosylmethionine.

S-Adenosylmethionine (SAMe) is the methyl donor to numerous acceptor molecules. We used cycloleucine (CL), which prevents the conversion of methionine to SAMe by inhibiting ATP-l-methionine-adenosyltransferase (MAT), to characterize the lipid and protein changes induced in peripheral nerve and brain myelin in rats during development. We also investigated the effect of exogenous SAMe by administering SAMe-1,4-butane disulfonate (SAMe-SD4). CL was given on days 7, 8, 12, and 13 and SAMe-SD4 was given daily from day 7; the animals were killed on day 18. CL accumulates in the brain reaching a concentration within 24 h compatible with its ID(50) in vitro and interacting with methionine metabolism; brain MAT activity and SAMe levels were lower and methionine levels higher than in controls. CL significantly reduced brain and nerve weight gains, brain myelin content, proteins, phospholipids, and galactolipids. Among phospholipids in nerve and brain, only sphingomyelin was significantly increased, by 35-50%. Sciatic nerve protein analyses showed some significant changes: protein zero in sciatic nerve remained unchanged but the 14.0- and 18.5-kDa isoforms of myelin basic protein showed a dramatic increase. Among the main proteins, in purified brain myelin, the proteolipid protein and dimer-20 isoform decreased after CL. SAMe-SD4 highlights some sensitive parameters by counteracting, at least partially, some alterations of PL--particularly galactolipids and sphingomyelins--and proteins induced by CL. The partial beneficial effects might also be explained by the age-related limited bioavailability of exogenous SAMe, a finding, to our knowledge, not yet reported elsewhere. This study demonstrates that availability of methyl donors is closely related to the formation of myelin components.

Animals↗
PubMed1992

Heme biosynthesis pathway regulation in a model of hepatocarcinogenesis pre-initiation.

1. Heme regulation before the appearance of hyperplastic nodules was investigated in mice models of hepatocarcinogenesis. 2. With this aim 5-aminolaevulinate synthetase (ALA-S), microsomal heme-oxygenase (MHO), mitochondrial and cytoplasmic rhodanese activities were examined throughout a period of 35 days in animals exposed to dietary p-dimethylaminoazobenzene (DAB). 3. ALA-S activity was significantly diminished (50%) on day 14, then showing a sharply rising profile from day 28 onwards, and reaching 350% on day 35. 4. A similar profile was observed for mitochondrial rhodanese activity. 5. Changes in MHO and cytoplasmic rhodanese activities were almost the opposite to those observed for ALA-S. 6. The distinctive alteration in mitochondrial and cytoplasmic rhodanese would suggest that it plays a subtle role in ALA-S regulation during carcinogenesis initiation through a mechanism that appears to involve subcellular localization controls perhaps by means of the breakage of cystine trisulphide postulated to act as an ALA-S activator. 7. Taking into account the present results, we suggest a probable mechanism for the onset of hepatocarcinogenesis that includes a primary activating liver status, provoking biochemical aberration leading to the stage of initiation of hepatocarcinogenesis involving the whole organ.

5-Aminolevulinate Synthetase↗
PubMed1993

Kynurenine pathway enzymes in a rat model of chronic epilepsy: immunohistochemical study of activated glial cells.

The kynurenine pathway metabolites quinolinic acid and kynurenic acid have been hypothetically linked to the occurrence of seizure phenomena. The present immunohistochemical study reports the activation of astrocytes containing three enzymes responsible for the metabolism of quinolinic acid and kynurenic acid in a rat model of chronic epilepsy. Rats received 90 min of patterned electrical stimulation through a bipolar electrode stereotaxically positioned in one hippocampus. This treatment induces non-convulsive limbic status epilepticus that leads to chronic, spontaneous, recurrent seizures. One month after the status epilepticus, the rats showed neuronal loss and gliosis in the piriform cortex, thalamus, and hippocampus, particularly on the side contralateral to the stimulation. Astrocytes containing the kynurenic acid biosynthetic enzyme (kynurenine aminotransferase) and the enzymes for the biosynthesis and degradation of quinolinic acid (3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase, respectively) became highly hypertrophied in brain areas where neurodegeneration occurred. Detailed qualitative and quantitative analyses were performed in the hippocampus. In CA1 and CA3 regions, the immunostained surface area of reactive astrocytes increased up to five-fold as compared to controls. Enlarged cells containing the three enzymes were mainly observed in the stratum radiatum, whereas the stratum pyramidale, in which neuronal somata degenerated, showed relatively fewer reactive glial cells. Hypertrophied kynurenine aminotransferase- and 3-hydroxyanthranilic acid oxygenase-immunoreactive cells were comparable in their morphology and distribution pattern. In contrast, reactive quinolinic acid phosphoribosyl transferase-positive glial cells displayed diversified sizes and shapes. Some very large quinolinic acid phosphoribosyl transferase-immunoreactive cells were noticed in the molecular layer of the dentate gyrus. In the hippocampus, the number of immunoreactive glial cells increased in parallel to the hypertrophic responses. In addition, pronounced increases in immunoreactivities, associated with hypertrophied astrocytes, occurred around lesioned sites in the thalamus and piriform cortex. These findings indicate that kynurenine metabolites derived from glial cells may play a role in chronic epileptogenesis.

3-Hydroxyanthranilate 3,4-Dioxygenase↗
PubMed2006

Analysis of Nedd8-associated polypeptides: a model for deciphering the pathway for ubiquitin-like modifications.

Ubiquitin-like proteins modify target proteins, altering their activities or causing them to be slated for degradation. These modifications are used to efficiently regulate key events in the cell. To explore the set of proteins modified by a small ubiquitin-like protein, we have developed a proteomic approach. Affinity purification of an epitope-tagged Nedd8 allowed the identification of the majority of proteins known to be involved with the neddylation pathway. This purification not only isolated the known targets of neddylation but also the constellation of enzymes and complexes known to regulate neddylation and deneddylation, including the COP9 signalosome, Nub1, and enzymes in the neddylation cascade. This purification scheme can be applied to other small ubiquitin-like proteins, especially those with limited protein targets such as the SUMOs (1, 2, and 3), Isg15, or FAT10.

COP9 Signalosome Complex↗
PubMed2001

A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase.

The protein p27Kip1 is an inhibitor of cell division. An increase in p27 causes proliferating cells to exit from the cell cycle, and a decrease in p27 is necessary for quiescent cells to resume division. Abnormally low amounts of p27 are associated with pathological states of excessive cell proliferation, especially cancers. In normal and tumour cells, p27 is regulated primarily at the level of translation and protein turnover. Phosphorylation of p27 on threonine 187 (T187) by cyclin-dependent kinase 2 (Cdk2) is thought to initiate the major pathway for p27 proteolysis. To critically test the importance of this pathway in vivo, we replaced the murine p27 gene with one that encoded alanine instead of threonine at position 187 (p27T187A). Here we show that cells expressing p27T187A were unable to downregulate p27 during the S and G2 phases of the cell cycle, but that this had a surprisingly modest effect on cell proliferation both in vitro and in vivo. Our efforts to explain this unexpected result led to the discovery of a second proteolytic pathway for controlling p27, one that is activated by mitogens and degrades p27 exclusively during G1.

Animals↗
PubMed1998

Potential role of the peroxynitrate-poly(ADP-ribose) synthetase pathway in a rat model of severe hemorrhagic shock.

Peroxynitrite (a potent oxidant produced by nitric oxide and superoxide) and hydroxyl radical, reactive oxidants produced during hemorrhagic shock, are potent triggers of DNA single-strand breakage. DNA injury triggers the activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS), which contributes to cellular injury. Hemorrhagic shock is associated with early vasomotor paralysis as well as with early derangements in the cellular metabolic status. Here we have tested whether activation of PARS contributes to the vasodilatation and early mortality in a rat model of severe hemorrhagic shock. In anesthetized rats hemorrhaged to a mean arterial blood pressure of 35 mmHg, pretreatment with the PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone significantly improved survival rate. Furthermore, an inhibitor of nitric oxide biosynthesis (NG-methyl-L-arginine) and the cell-permeable superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin also offered a significant protection in terms of hypotension and acute mortality. However, the selective inhibitor of the inducible nitric oxide synthase, mercaptoethylguanidine, failed to affect blood pressure or mortality. The present data suggest that PARS activation plays a role in the pathophysiology of hemorrhagic shock. Early production of peroxynitrite (produced by nitric oxide from constitutive nitric oxide synthase) and hydroxyl radical may induce DNA single-strand breakage, which is the immediate trigger of PARS activation.

Animals↗
PubMed2006

Neurodevelopmental pathways to aggression: a model to understand and target treatment in youth.

The authors describe a neurodevelopmentally relevant, clinically derived model for understanding and treating aggressive behavior in youth. Based on case experience and literature review, the authors divide aggressive behavior into five symptomatic domains with respective neurobiological/neurodevelopmental underpinnings. These five symptom domains (impulsivity, affective instability, anxious/hyperarousal, cognitive disorganization, and predatory aggression) emerge as logical and clinically useful targets for treatment. The authors aim to establish a relationship between these symptom domains and brain structure and function that offers a clinically relevant approach to the complexities of understanding aggression and its treatment.

Adolescent↗
PubMedDate not supplied

A structural model of the substance use pathways among minority youth.

OBJECTIVE: To evaluate the substance use pathways of minority adolescents with a structural equation modeling (SEM) based on the social ecological model. METHOD: Seven hundred ninety adolescents completed the baseline survey questionnaire for the Center for Substance Abuse Prevention's Mentoring and Family Strengthening Initiative. The exogenous variables were family supervision, family involvement, and social support, whereas self-control, school connectedness, and substance use served as the endogenous variables. RESULTS: The following significant direct effects were found: family involvement to self-control; self-control and social support to school connectedness; school connectedness to substance use. CONCLUSIONS: These findings provide empirical evidence that family protective factors can significantly influence adolescents' substance use and should be adopted into substance use prevention interventions.

Adolescent↗
PubMed2002

Platelet aging in vivo is associated with activation of apoptotic pathways: studies in a model of suppressed thrombopoiesis in dogs.

The mechanism(s) involved in the clearance of senescent platelets are largely unknown. We have recently demonstrated that platelet aging in vivo is associated with loss of membrane phospholipid asymmetry, a universal phenomenon in cells undergoing apoptosis. Thus, we postulated that senescent platelets may exhibit programmed cell death changes. which may trigger their removal from circulation. Since platelets contain the apoptosis machinery as well as mitochondria, a key organelle in the regulation of apoptosis, we studied the appearance of apoptotic-like changes during platelet aging in vivo. To investigate this, we assessed changes in mitochondrial membrane potential (deltapsi) in circulating canine platelets during decline in platelet count after suppression of thrombopoiesis by estradiol injection, a validated model to obtain circulating platelets of increasing mean age. Phosphatidylserine (PS) exposure was determined by flow cytometry by binding of FITC-labeled annexin V. Mitochondrial deltapsi was studied with the cationic lipophilic dye DIOC6 (3) and the J-aggregate-forming cation JC-1 and analysis by flow cytometry. The proportion of platelets with exposed PS rose significantly with age, from 2.88% before to 6.7%, 8 days after estradiol injection. By flow cytometry it was demonstrated a significant decreased in DIOC6 (3) fluorescence (median fluorescence intensity 791+/-98 vs 567+/-102 day 0 vs day 8 post injection of estradiol, respectively; n: 11; p <0.01), consistent with mitochondrial deltapsi collapse. JC-1 has the unique property of forming J-aggregates under high mitochondrial deltapsi (red fluorescence, FL2) whereas the monomeric form fluoresces in green (FL1). Aged platelets in vivo, loaded with JC-1, exhibited a significant increase in FL1/FL2 ratio (2.5+/-1.7 vs 4.7+/-1.6, day 0 vs day 8 post injection of estradiol, respectively; n: 13; p <0.05), confirming the mitochondrial deltapsi alteration. The results show that platelet aging in vivo is associated with a decrease in mitochondrial deltapsi and PS exposure. In conclusion, our data provide for the first time, evidence that platelet senescence is associated with changes characteristics of apoptosis, which may promote their removal from circulation.

Animals↗
PubMed1992

Analysis of a kinetic model for melanin biosynthesis pathway.

The kinetic behavior of the melanin biosynthesis pathway from L-tyrosine up to dopachrome has been studied from experimental and simulation assays. The reaction mechanism proposed is based on a single active site of tyrosinase. The diphenolase and monophenolase activities of tyrosinase involve one single (oxidase) and two overlapped (hydroxylase and oxidase) catalytic cycles, respectively. The stoichiometry of the pathway implies that one molecule of tyrosinase must accomplish two turnovers in the hydroxylase cycle for each one in the oxidase cycle. Furthermore, the steady-state rates of dopachrome production and O2 consumption from tyrosine and L-dopa, also fulfill the stoichiometry of the pathway: VO2T/VDCT = 1.5 and VO2T/VDCD = 1.0, where T represents L-tyrosine, DC represents dopachrome, and D represents L-dopa. It has been ascertained by high performance liquid chromatography that in the steady-state, a quantity of dopa is accumulated ([D]ss) which fulfills the constant ratio [D]ss = R[T]0. Taking this ratio into account, an analytical expression has been deduced for the monophenolase activity of tyrosinase. In this expression kcatT congruent to (2/3)k3(K1/K2)R, revealing that kcatT is not a true catalytic constant, since it also depends on equilibrium constants and on the experimental R = 0.057. This low value explains the lower catalytic efficiency of tyrosinase on tyrosine than on dopa, (VmaxT/KmT)/(VmaxD/KmD) congruent to (2/3)R, since a significant portion of tyrosinase is scavenged from the catalytic turnover as dead-end complex EmetT in the steady-state of the monophenolase activity of tyrosinase.

Basidiomycota↗
PubMed1998

Prediction of permeability-surface area product data by continuous-distribution pore models.

OBJECTIVE: To investigate the ability of continuous-distribution pore models to accurately predict permeability-surface area product (PS) experimental data in skeletal muscle. METHODS: Models having a water-only (WO) pathway and continuous distributions of microvascular transport-pathway sizes were fit to solute reflection-coefficient (sigma) experimental data (approximately 0.5-16 nm Stokes radii) obtained from skeletal muscle to determine optimal parameter values. Without further modification, these models were used to predict experimental PS values obtained from the literature for small solutes ranging in size from NaCl to inulin and for three proteins, alpha-lactalbumin, ovalbumin, and albumin (approximately 0.23-3.7 nm radii). The protein PSs were determined from fluorescent tracer-diffusion curves and a nonlinear model of tracer diffusion in the cat hindlimb preparation. The model's PS predictions were compared to those of a discrete-pore model previously developed and a fiber-matrix (FM) model. RESULTS: A log-normal (LN) continuous pore-size distribution plus WO-pathway model (three free parameters) fit the sigma data to within the 95% confidence intervals of each of eight solutes spanning a 32-fold size range and was nearly as close to the data as was the two discrete-pore plus WO-pathway model (four free parameters). Both models closely described the PS data for nine solutes spanning a 14-fold size range. The fit of a fiber-matrix plus WO-pathway model (three free parameters) to the sigma data was much poorer than for the other models. CONCLUSIONS: The LN and two-discrete-pore models accurately describe sigma and PS experimental data in cat and human skeletal muscle. Therefore, experimental data resulting from complex microvascular transport processes are well characterized by simple pore models.

Albumins↗