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PubMed1983

Induction of differences in the circadian profiles of DNA synthesis between normal and neoplastic cell populations by hydroxyurea without perturbation of the normal circadian rhythms.

This paper presents data which support a previously stated hypothesis that differences in phasing can be induced in the rhythms of DNA synthetic activity (DNA-SA) between normal and neoplastic cell populations in the same animal. The drug used was hydroxyurea (HU). Mice were standardized to a light-dark cycle with light from 06.00 to 18.00 h. Minimal disruption of the normal circadian pattern in DNA-SA in tongue, esophagus, and rectum occurred when 500 mg/kg HU was given at 17.00 h. The same dose of HU given at 05.00 h resulted in significant perturbation of the normal circadian pattern of DNA-SA in these organs. 500 mg/kg HU at 17.00 h did, however, significantly perturb DNA-SA in the Ehrlich's ascites cardinoma (EAC). To study this phenomenon further the following experiments were done in EAC bearing mice: (A) 500 mg/kg HU given at 09.00, 13.00 and 17.00 h; (B) 500 mg/kg HU given at 21.00, 01.00 and 05.00 h, and (C) 3,000 mg/kg given at 17.00 h. In general, the response of the normal organs to HU varied depending on the circadian time of treatment with HU, whereas the response of the EAC was more uniform regardless of when the HU was given. By plotting the data obtained from the 3 normal organs and the EAC on the same graph specific points could be identified when: (a) maximal DNA-SA occurred in the EAC and at the same time minimal DNA-SA occurred in tongue, esophagus, and rectum, or (b) various levels of DNA-SA occurred in the EAC, but, at the same time maximal or peak levels of DNA-SA occurred in the normal organs.

Animals↗
PubMedDate not supplied

Use of pruned computational neural networks for processing the response of oscillating chemical reactions with a view to analyzing nonlinear multicomponent mixtures.

The suitability of pruned computational neural networks (CNNs) for resolving nonlinear multicomponent systems involving synergistic effects by use of oscillating chemical reaction-based methods implemented using the analyte pulse perturbation technique is demonstrated. The CNN input data used for this purpose are estimates provided by the Levenberg-Marquardt method in the form of a three-parameter Gaussian curve associated with the singular profile obtained when the oscillating system is perturbed by an analyte mixture. The performance of the proposed method was assessed by applying it to the resolution of mixtures of pyrogallol and gallic acid based on their perturbating effect on a classical oscillating chemical system, viz. the Belousov-Zhabotinskyi reaction. A straightforward network topology (3:3:2, with 18 connections after pruning) allowed the resolution of mixtures of the two analytes in concentration ratios from 1:7 to 6:2 with a standard error of prediction for the testing set of 4.01 and 8.98% for pyrogallol and gallic acid, respectively. The reduced dimensions of the selected CNN architecture allowed a mathematical transformation of the input vector into the output one that can be easily implemented via software. Finally, the suitability of response surface analysis as an alternative to CNNs was also tested. The results were poor (relative errors were high), which confirms that properly selected pruned CNNs are effective tools for solving the analytical problem addressed in this work.

Journal Article↗
PubMed1986

Myocardial energetics after thermally graded hyperkalemic crystalloid cardioplegic arrest.

Previous studies assessing the efficacy of myoprotective regimens have compared preischemic and postischemic myocardial oxygen consumption within a limited range of cardiac performance. However, recent data suggest that ischemia-induced perturbations in myocardial energetics may occur only when the left ventricle develops physiologic pressures. Therefore, in canine hearts supported by cardiopulmonary bypass, myocardial oxygen consumption (ml oxygen X 10(-2)/beat/100 gm left ventricular weight) was determined during incremental isovolumic pressure-volume loading before and 30 minutes after 2 hours of cardioplegic arrest. The ischemic insult was graded by maintaining myocardial temperature at 12 degrees C (Group I, n = 6), 20 degrees C (Group II, n = 7), or 28 degrees C (Group III, n = 6). Postischemic Starling curves were unchanged in Groups I and II but depressed 53% in Group III hearts (p less than 0.005). In Group I, postischemic myocardial oxygen consumption at specific peak developed pressures was similar to preischemic oxygen consumption. In contrast, postischemic Group II and III hearts consumed 39% more oxygen than preischemically when peak developed pressure exceeded 75 mm Hg (p less than 0.01). Postischemic hearts demonstrated reciprocal changes in arteriovenous oxygen content difference (24%, 30%, and 34% lower than preischemic values for Groups I, II, and III, respectively) and coronary blood flow (156%, 195%, and 192% higher than preischemic values for Groups I, II, and III, respectively). Only in Group II and III hearts did the increased coronary blood flow offset the defect in oxygen extraction such that myocardial oxygen consumption was increased. These data suggest that inefficient utilization of oxygen when the heart is developing physiologic pressures is a sensitive marker for myocardial injury after crystalloid cardioplegic arrest.

Animals↗
PubMed1993

Thermotropic behavior of phosphatidylcholine-glucosyl ceramide mixtures: effects of phospholipid acyl chain composition and interaction with water.

The thermotropic behavior of multilamellar vesicles composed of mixtures of dimyristoyl phosphatidylcholine-glucosyl ceramide and of egg phosphatidylcholine-glucosyl ceramide was investigated using differential scanning calorimetry. Macroscopic demixing of the lipid components occurred when multilamellar vesicles were prepared from mixtures of glucosyl ceramide and egg phosphatidylcholine by conventional methods. This problem was overcome by a technique based on spray drying of the lipid mixture. The results obtained for the two systems are compared with data available for dipalmitoyl phosphatidylcholine-glucosyl ceramide mixtures (Biochemistry 22 (1983) 3497-3501). All three phosphatidylcholines perturb the complex thermotropic behavior of glucosyl ceramide. The data suggest that the interference with intermolecular interactions among glycosyl ceramide molecules by phospholipid molecules is related to the molecular miscibility of the two components. This is strongly dependent on the acyl chain composition of the phosphatidylcholine and the water activity of the ambient aqueous phase.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Characterization of a 12-mer duplex d(GGCGGAGTTAGG).d(CCTAACTCCGCC) containing a highly reactive (+)-CC-1065 sequence by 1H and 31P NMR, hydroxyl-radical footprinting, and NOESY restrained molecular dynamics calculations.

The solution structure of the GC-rich non-self-complementary DNA 12-mer duplex (I), which contains a (+)-CC-1065 highly reactive bonding sequence 5'AGTTA* (where * denotes the [formula: see text] covalent modification site), has been examined thoroughly by one- and two-dimensional proton and phosphorus NMR spectroscopy, hydroxyl-radical footprinting, and NOESY restrained molecular mechanics and dynamics calculations. The assignments of the nonexchangeable proton resonances (except some of the H5' and H5" protons due to severe resonance overlap), phosphorus resonances, and the exchangeable resonances (except amino protons of adenosine and guanosine) of this 12-mer duplex have been made. The results show that this 12-mer duplex maintains an overall B-form DNA with all anti base orientation throughout in aqueous solution at room temperature. Hydroxyl-radical footprinting experiments on a 21-mer sequence that contains this 12-mer duplex used for NMR studies showed that the minor groove is somewhat narrowed at the 7G-8T and 17A-18C steps, as indicated by the inhibition of cleavage at these locations. Although both high-field NMR and hydroxyl-radical footprinting experiments supported a bent-like structure for this 12-mer duplex, nondenaturing gel electrophoresis on the ligated 21-mer sequence that contains this 12-mer duplex did not show the abnormally slow migration characteristic of a bent DNA duplex. Analysis of the NMR data sets reveals several local structural perturbations similar to those found on an (A)n tract DNA duplex. For example, the existence of a propeller twist was detected within the A.T-rich region for both the 12-mer and the (A)n tract DNA duplexes. The 18CH5 aromatic resonance that is directly adjacent to the 3' side of the 5'TAA segment was significantly shifted upfield with a chemical shift of 5.10 ppm, which is almost within the region normally associated with sugar H3' protons. The sugar geometries for 18C and 7G, which are located to the 3' side of the 5'TAA segment, are proposed to be in the neighborhood of C3'-endo and O1'-endo in equilibrium C3'-endo, respectively. We propose that this unusually upfield-shifted resonance signal for 18CH5 and the average C3'-endo sugar geometry for 18C nucleotide on the 12-mer duplex is connected with the peculiar conformation, possibly a transient kink, within the 5'AC/GT step. The results of the NOESY restrained molecular mechanics and dynamics calculations on the 12-mer sequence reveal two kinks, which are located on either side of the 18C nucleotide that has an average C3'-endo sugar geometry.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1996

Direct tubulin polymerization perturbation contributes significantly to the induction of micronuclei in vivo.

The computational analysis data presented indicate a significant mechanistic association between the ability of a chemical to cause tubulin polymerization perturbation (TPP), via direct interaction with the protein, and the in vivo induction of micronuclei (MN). Since it is known that TPP is not a genotoxic event, the analyses suggest that the induction of MN by a non-genotoxic mechanism is a significant alternate pathway.

Algorithms↗
PubMed1992

Postural responses to lateral perturbation in healthy subjects and ankle sprain patients.

The purpose of this study was to investigate postural responses of healthy subjects and patients with recent ankle sprains following a perturbation that created sway in the frontal plane. EMG data were taken from the posterior tibialis (PT) (not monitored in patients), peroneal longus (PL), and tibialis anterior muscles (TA). Subjects stood on a platform that provided a rotational perturbation (approximately 70 degrees.s-1) in the frontal plane. This perturbation had the effect of everting and loading one limb while inverting and unloading the contralateral limb. An initial response in the PT of the loaded limb and the PL of the unloaded limb was noted at approximately 50 ms following the perturbation. This was followed by a bilateral response in the TA at 60 ms. The amplitude of the TA muscle was significantly greater in the loaded limb. For ankle sprain patients a bilateral TA response and a PL response in the unloaded limb was noted at approximately 65 ms. TA response amplitude ratios between the loaded and unloaded limbs were similar to that of the healthy subjects. These data suggest that ankle sprain patients use a modified postural response following lateral perturbation as a compensation for the injury.

Adult↗
PubMed1994

N-cadherin in normal and abnormal brain development.

The brain relies upon numerous morphoregulatory molecules to control cell-cell interactions, cell migration and neurite extension. N-cadherin, a calcium-dependent cell adhesion molecule, is essential for normal CNS development. Homophilic binding of N-cadherin depends upon a specific conformation assumed by the molecule when it binds calcium. N-cadherin is a substrate for a specific zinc-dependent protease that may be involved in the regulation of N-cadherin at the cell surface. The reliance of N-cadherin on two cations for proper function makes it a potential target for toxicants which act by replacing or modifying calcium or zinc at ion-binding sites. Exposure of the developing brain to lead, an ubiquitous toxicant known to interact with calcium, disturbs neural tube closure and subsequent maturation of the nervous system. Preliminary data indicates that lead may induce these effects by direct interaction with N-cadherin. Numerous common toxicants, including metals and solvents, also perturb cadherins and cause defective CNS development. These data indicate that changes in the spatio-temporal expression of cadherin can result in profound alterations in neural structure and function, and may underlie CNS malformations caused by numerous toxic agents.

Animals↗
PubMed1990

Analysis of EMG activity and temporal components of gait during recovery from perturbation.

In ten able-bodied adults, gait was unexpectedly displaced in order to induce rapid dorsiflexion at heelstrike. Electromyographic (EMG) data were collected bilaterally from the tibialis anterior (TA) and gastrocnemius (G) muscles, and electrogoniometric data monitored joint angle changes in the ankle. Analysis of the data indicated initial EMG responses in the G of the perturbed limb and the TA of the contralateral limb at latencies of approximately 100 msec. It appeared that G activity served to decelerate the dorsiflexion of the ankle of the perturbed limb, whereas the TA accelerated dorsiflexion in the swing limb. Analysis of later EMG activity and foot-ground contact indicated that recovery after perturbation was easily completed during stance of the perturbed limb. Because of the comparatively minimal degree and velocity of displacement, further study with similar protocols might be considered appropriate to study balance problems in clinical populations.

Accidental Falls↗
PubMed2005

Genomic analysis of metabolic pathway gene expression in mice.

BACKGROUND: A segregating population of (C57BL/6J x DBA/2J)F2 intercross mice was studied for obesity-related traits and for global gene expression in liver. Quantitative trait locus analyses were applied to the subcutaneous fat-mass trait and all gene-expression data. These data were then used to identify gene sets that are differentially perturbed in lean and obese mice. RESULTS: We integrated global gene-expression data with phenotypic and genetic segregation analyses to evaluate metabolic pathways associated with obesity. Using two approaches we identified 13 metabolic pathways whose genes are coordinately regulated in association with obesity. Four genomic regions on chromosomes 3, 6, 16, and 19 were found to control the coordinated expression of these pathways. Using criteria that included trait correlation, differential gene expression, and linkage to genomic regions, we identified novel genes potentially associated with the identified pathways. CONCLUSION: This study demonstrates that genetic and gene-expression data can be integrated to identify pathways associated with clinical traits and their underlying genetic determinants.

Adipose Tissue↗
PubMedDate not supplied

Response of the olfactory bulb antioxidant system following diethyldithiocarbamate (DDTC) administration in rats.

This study was designed in order to evaluate alterations in the reactive oxygen species (ROS) scavenging system in olfactory bulb, dorsal neocortex and cerebellum for 6 weeks following a single subcutaneous dose (600 mg kg-1) of diethyldithiocarbamate (DDTC) to rats. A single dose of DDTC caused substantial damage to the olfactory epithelium and degeneration within the olfactory bulb. The epithelium regenerates, followed by regeneration in the olfactory bulb. The mean olfactory bulb weight decreased significantly 3 days after DDTC administration and gradually recovered to control values in 6 weeks. The DDTC-induced lesion of the olfactory nerve resulted in significant changes in glutathione (GSH) and antioxidant enzyme activities in olfactory bulb. In contrast, no significant changes were found in either cerebellum or dorsal neocortex. These observations indicate that a single dose of DDTC selectively affected the ROS scavenging system of the olfactory bulb. Moreover, these changes persisted for at least 6 weeks, which includes regeneration and synaptogenesis. Olfactory bulb GSH concentrations decreased significantly by 47 +/- 4%, glutathione reductase activity decreased by 18 +/- 3% and catalase activity increased by 27 +/- 7% over the 6 weeks. Superoxide dismutase activity decreased significantly in olfactory bulb of rats by 32 +/- 6% at 3 days following the lesion and then recovered and increased by 38 +/- 3% at 3 weeks. Olfactory bulb malondialdehyde concentrations were elevated (298 +/- 67%) throughout the post-lesion survival period, although this change did not reach the stringent statistical significance level required in this study. These data suggest that increased ROS flux perturbs the olfactory bulb antioxidant defense system during olfactory nerve regeneration.

Animals↗
PubMed2000

Expression patterns of E-cadherin, involucrin, and connexin gap junction proteins in the lining epithelia of inflamed gingiva.

The structural integrity and functional differentiation of the lining epithelium were studied in relation to inflammatory changes associated with destructive periodontitis. In the different regions of lining epithelia from clinically healthy gingiva and periodontitis, comparisons were made of the expression patterns of E-cadherin, which is critical in intercellular adhesion; of proteins associated with gap junction communication channels; and of involucrin, which is a key marker of differentiation in stratified epithelia. Filamentous actin (F-actin), which is important in cell structural integrity, attachment, and migration, was also examined. Semiquantitative immunohistochemical analysis revealed that in both clinically healthy gingiva and lesions of advanced periodontitis, expression patterns of E-cadherin, involucrin, and connexins 26 and 43 were similar, with a statistically significant reduction in staining intensity from the external oral epithelium, through the gingival sulcus, to the junctional epithelium or pocket epithelium, respectively. Furthermore, there was a striking reduction in staining for E-cadherin, involucrin, and both connexins in the pathological lining epithelium of the periodontal pocket. These changes were associated with marked alterations of filamentous actin expression, collectively indicating profound perturbation of the epithelial structure. The data reported support the concept that the ability of the pathological lining epithelium to function as an effective barrier against the ingress of microbial products into the tissues is severely compromised.

Actins↗
PubMed2001

Modulation of cyclin D1 and its signaling components by the phorbol ester TPA and the tyrosine phosphatase inhibitor vanadate.

The mechanism by which 12-O-tetradecanoylphorbol-13-acetate (TPA) triggers cell-cycle progression at G1 phase in mouse embryonic fibroblast C3H 10T1/2 cells was examined. TPA treatment resulted in a temporary induction of cyclin D1 peaking at 9 h post stimulation. PD98059 (10 microM), the specific inhibitor of MAPK kinase, completely blocked TPA-stimulated cyclin D1 induction and DNA synthesis, confirming that MAPK activation plays an essential role in TPA-stimulated cell-cycle progression. Although both PKCalpha and PKCepsilon are expressed in C3H 10T1/2 cells, inhibitor studies suggest that PKCepsilon activation is required for the activation of MEK/MAPK signal transduction cascade. p70s6K, an important kinase involved in the regulation of protein synthesis and cell-cycle progression, has been reported to be activated through a PKC-dependent pathway (TPA-activatable) in addition to a PI3K-dependent pathway. Here, we demonstrate for the first time that TPA-stimulated MAPK activation is essential for the phosphorylation of several key residues involved in the activation of p70s6K, namely, thr389, thr421, and ser424. Vanadate, the tyrosine phosphatase inhibitor, triggered a sustained elevation of the level of active MAPK. However, corresponding to a rapid loss of cyclin D1 protein, vanadate treatment resulted in a significant shut out of 3H-thymidine incorporation into DNA regardless of TPA cotreatment. Vanadate treatment also led to the increase of active MEK, increased phosphorylation of p70s6K at thr389, thr421, and ser424 yet without activation of PKB. These data suggest that vanadate can selectively perturb the activation of signaling components which raises the interesting issue as to how vanadate downregulates the cyclin D1 level.

Animals↗
PubMed1992

Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5-fluorouracil.

We determined the effects of organ environment on the response of murine CT-26 colon carcinoma cells to 2 structurally and pharmacologically distinct chemotherapeutic agents. CT-26 cells were injected i.v. (to produce lung lesions), s.c., into the cecal wall, and into the spleen (to produce spleen and liver lesions). Doxorubicin (DXR) at 10 mg/kg, 5-fluorouracil (5-FU) at 20 mg/kg, or saline (control) was injected intravenously on different schedules after tumor-cell implantation. The in vivo responses of the tumors growing in the cecum, spleen, liver, lung and subcutis were compared. Colon carcinomas growing in the subcutis were most sensitive to DXR. Tumors growing in the spleen and cecum were most sensitive to 5-FU and less so to DXR. Tumors in the liver were highly resistant to both drugs, whereas experimental lung metastases were sensitive to 5-FU but resistant to DXR. The differential responses of the tumors to the drugs were not due to drug distribution. The level of protein-kinase-C activity was elevated in the spleen, liver and cecum tumors as compared with s.c. tumors and correlated with the in vivo DXR resistance of the tumor cells. This correlation suggested that organ environment may modulate the chemosensitivity of tumor cells, at least in part, by perturbing signal transduction pathways. Collectively, the data indicate that the organ environment has profound effects on the response of tumor cells to chemotherapy. A molecular understanding of this phenomenon should facilitate the design of more effective systemic chemotherapy for cancer metastases.

Animals↗
PubMed1994

Effects of truncated activin and FGF receptors and of follistatin on the inducing activities of BVg1 and activin: does activin play a role in mesoderm induction?

Activin and Vg1, two members of the TGF-beta family, are believed to play roles in mesoderm induction and axis formation in the amphibian embryo. Both molecules are provided maternally, either as protein (activin) or as RNA and protein (Vg1), and experiments with a truncated form of a type IIB activin receptor have led to the conclusion that activin is required for induction of mesoderm in vivo. In this paper we first show that truncated versions of two different Xenopus activin receptors also have severe effects on the activity of the mature region of Vg1, suggesting that such receptors may block the function of several members of the TGF-beta family. We go on to demonstrate that follistatin, a secreted protein which binds activin and blocks its activity, does not interfere with Vg1 signalling. Furthermore, overexpression of follistatin mRNA in Xenopus embryos does not perturb mesoderm formation. Taken together, our data show that the effects of truncated activin receptors on Xenopus development can be explained by the inhibition of Vg1 activity, while the lack of effect of follistatin argues against a function for activin in mesoderm induction.

Activin Receptors↗
PubMed1999

Isoform-specific interactions between halothane and the ryanodine receptor Ca(2+)-release channel: implications for malignant hyperthermia and the protein theory of anaesthetic action.

General anaesthetics exhibit a relatively close relationship between their pharmacological potency and their lipid solubility and may thus act by non-specific perturbation of biomembranes. However, more recent data on anaesthetic action suggests that inhalational drugs such as halothane bind directly to hydrophobic protein domains, thereby modulating important receptor functions. In support of this protein theory of anaesthetic action our native gel analysis presented here shows that halothane induces oligomerization of the skeletal muscle ryanodine receptor (RyR) 1 Ca(2+)-release channel, but not its cardiac RyR-2 isoform. Thus, inhalational anaesthetics are not only able to influence protein-protein interactions directly but also appear to differentiate between protein isoforms and/or configurations. This suggests that distinct peptide binding sites exist for these pharmacological agents. In addition, similar mutations in the RyR-2 isoform, which would trigger an episode of malignant hyperthermia in skeletal muscle fibres via abnormal RyR-1 isoforms, would probably not induce an increase in cardiac Ca(2+)-release upon administration of halothane.

Anesthesia, Inhalation↗
PubMed2004

Mathematical modelling of corneal swelling.

This paper presents a differential model of the corneal transport system capable of modelling thickness changes in response to osmotic perturbations applied to either limiting membrane. The work is directed towards understanding corneal behaviour in vivo. The model considers the coupled viscous flows within the corneal stroma and across the epithelial and endothelial membranes. The flows within the stroma are established based on transport theory in porous media, while the flows across the membranes are described using the phenomenological equations of irreversible thermodynamics. The ability of the numerical model to reproduce corneal thickness changes in response to endothelial perturbations was tested against available experimental data. The sensitivity of the model to changes in stromal and membrane transport coefficients was examined.

Cell Membrane Permeability↗
PubMed1982

Mutations induced by a hormonal imbalance in Drosophila melanogaster.

Pterin treatment of chrysalids in diapause modified the juvenile hormone- ecdysone ratio. The treatment of Drosophila donor mutant with a mixture of reduced folic acid, pterins and extract of Pierides chrysalids in diapause induced the formation of short sequences, by the intermediary of variations in hormonal balance. The effect of this variation was seen in the germinal lines especially at the gonial stage, where recessive, visible or lethal mutations were induced in the form of clusters. Genetically active fractions were found in the 4S-8S and 18S-28S sedimentation zones after saccharose gradient ultracentrifugation. The short DNA sequences coded for tRNA and rRNA. Consequently, it is there DNA sequences from the Drosophila donor mutant that altered the genetic information of the host. 2 types of recessive visible mutation appeared: those affecting the differentiation of the imaginal discs and those affecting the pigment biosynthetic chain. Recessive lethals were induced by treatment. 3 hypothesis are proposed: the first suggests the formation of a short DNA sequence complexing at a specific locus in the acceptor. The second involves transposable factors belonging to the acceptor itself, behaving as a particular transposable factor. The third supposes the induction of alterations at loci of rRNA and tRNA synthesis at the origin of perturbations in protein synthesis. The present data do not allow us to choose between the 3 hypotheses. In conclusion, it seems that a "hormonal imbalance" can have grave consequences not only for the individual itself but also for its descendants.

Animals↗