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PubMed2003

Clinical features of antidepressant associated manic and hypomanic switches in bipolar disorder.

The present study investigated possible clinical differences between bipolar patients with and without manic or hypomanic switch during antidepressant (AD) treatment. The authors undertook a retrospective assessment of 169 individuals affected by bipolar disorder type I (BP I: n=96) and II (BP II: n=73) who experienced at least one manic or hypomanic episode following depression without any interposed normothymic period ("manic switch") during AD therapy. They were compared with a sex, age (+/-5 years), and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects who have never had manic switches. Only 2 of the 169 patients had had spontaneous switches before the AD-related one. Switched subjects were marginally older (t=-2.65, df=414, P=.008) compared to not switched and less frequently delusional (chi2=13.86, P=.0002). Polarity of the onset episode was more frequently depressive in switched patients (chi2=21.93, P=.00002), which had also less previous manic episodes than not switched (t=3.44, df=332, P=.0006). Those differences were more pronounced in the BP I subsample. Switched patients were more frequently BP I (chi2=29.66; P<.00001). Maintenance with mood stabilizers appears to be a strong protective factor; in fact, of the 124 individuals undertaking a mood stabilizer therapy, 21 had a switch and 103 had no switches (chi2=41.10, P<.000001). In conclusion, some clinical variables, such as the number of manic episodes, the presence of delusions, the polarity of onset episode, and the mood-stabilizing treatment, may be involved in AD-related switches. Further studies are required to investigate the causal relationships between those factors.

Adult↗

PubMed1989

Renin inhibitory peptides: a study of structural modifications in the peptide backbone.

We studied the peptide backbone modifications that improve the metabolic stability of the resulting peptides and yet retain high inhibitory activity against human plasma renin. A systematic investigation of N-alpha-methyl and C-alpha-methyl modifications at the P2 and P3 sites of renin-inhibitory peptides that contain part of the human angiotensinogen sequence led to the discovery of N-alpha-methyl amino acids at the P2 site as a useful structural modification. U-71,038 (11) inhibited human plasma renin with an in vitro potency (IC50) of 2.6 x 10(-10) mol/l. It is highly selective for renin and, as anticipated, resistant to proteolytic degradation. Additional study based on molecular graphic modelling has led us to propose a gamma-lactam conformational constraint at the P2-P3 site. This pseudo-dipeptide has proved useful in the preparation of active renin inhibitors. Compound 18a inhibited human plasma renin with an in vitro potency (IC50) of 2.1 x 10(-9) mol/l. This class of compounds also offers structural features for the study of enzyme-bound conformers.

Amino Acid Sequence↗

PubMed2003

Role of mast cells in gastrointestinal mucosal defense.

The purpose of this review, based on studies from our laboratory as well as from others, is to summarize salient features of mast cell immunobiology and to describe their associations with gastrointestinal mucosal defense. Gastrointestinal mast cells are involved in many pathologic effects, such as food hypersensitivity. On the other hand, they also play a protective role in defense against parasitic and microbial infections. Thus, they have both positive and negative effects, but presently the mechanisms that control the balance of these various effects are poorly known. It has been suggested that stabilization of mast cells may be a key mechanism to protect the gastrointestinal tract from injury. Few molecules are known to possess both mast cell stabilizing and gastrointestinal cytoprotective activity. These include zinc compounds, sodium cromoglycate, FPL 52694, ketotifen, aloe vera, certain flavonoids such as quercetin, some sulfated proteoglycans such as chondroitin sulfate and dehydroleucodine. Dehydroleucodine, a sesquiterpene lactone isolated from Artemisia douglasiana Besser, exhibits anti-inflammatory and gastrointestinal cytoprotective action. The lactone stimulates mucus production, and inhibits histamine and serotonin release from intestinal mast cells. The lactone could act as a selective mast cell stabilizer by releasing cytoprotective factors and inhibiting pro-inflammatory mast cell mediators.

Animals↗

PubMed1999

Nasal dilator strips increase maximum inspiratory flow via nasal wall stabilization.

OBJECTIVE: Inspiratory flow limitation associated with collapse of the nasal vestibular walls is a feature of nasal breathing at high ventilatory levels. We examined whether an external nasal dilator strip (ENDS) device (Breathe Right, CNS Inc., Chanhassen, MN) influences maximum inspiratory and expiratory flow rates. STUDY DESIGN: Prospective, randomized. METHODS: We studied 20 Caucasian subjects (13 female, 7 male; age range, 16-49 y) performing maximum-effort nasal flow-volume loop studies with (ENDS) and without ENDS (control) and following topical nasal decongestant (oxymetazoline hydrochloride, 0.2 mg per nostril). RESULTS: ENDS increased peak inspiratory flow from 2.55+/-0.24 L/s (mean+/-standard error [SE]) to 2.86+/-0.25 L/s and forced inspiratory flow at 50% of vital capacity from 2.23+/-0.24 L/s to 2.53+/-0.24 L/s (both, P<.0001), but had no effect on maximum expiratory flows. Nasal decongestant increased the forced expiratory volume in 1 second from 3.39+/-0.22 L/s to 3.59+/-0.22 L/s and the average forced expiratory flow over 25% to 75% of vital capacity from 3.31+/-0.31 L/s to 3.61+/-0.28 L/s (both, P< or = .008), but had no effect on maximum inspiratory flows. The combination of decongestant and ENDS increased both inspiratory and expiratory maximum flows. CONCLUSION: Since ENDS selectively increases maximum nasal inspiratory flow rates, we conclude that ENDS increases inspiratory nasal patency during maximum inspiratory efforts through the nose by supporting the lateral nasal vestibular walls and making them more resistant to collapse.

Adolescent↗

PubMed2005

Comparison of highly-fluorinated chloroformates as direct aqueous sample derivatizing agents for hydrophilic analytes and drinking-water disinfection by-products.

Four highly-fluorinated alkyl and aryl chloroformates, including 2,2,3,3,4,4,5,5-octafluoro-1-pentyl chloroformate (OFPCF), 2,3,4,5,6-pentafluorobenzyl chloroformate (PFBCF), 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-1-octyl chloroformate (TDFOCF), and 2-(2,3,4,5,6-pentafluorophenoxy)-ethyl chloroformate (PFPECF), were synthesized and tested as reagents for the direct water derivatization of polar and hydrophilic analytes. The goal of this research was to develop an optimal derivatizing agent to aid in the identification of highly polar ozonation drinking water disinfection by-products (DBPs) that are believed to be missed with current analytical procedures. The chemical properties (reactivity, selectivity, derivatization products, and their chromatographic and spectral features) for the four chloroformates were investigated using a set of highly polar standard analytes, including malic and tartaric acids, hydroxylamine, valine, 2-aminoethanol, resorcinol, 1,3,5-trihydroxybenzene, and 2,4-dihydroxybenzoic acid. Upon derivatization, the analytes were extracted from the aqueous solvent and analyzed by gas chromatography (GC)-mass spectrometry (MS) in the electron capture negative ionization (ECNI) mode. Positive chemical ionization (PCI)-MS was used for confirmation of molecular ions that were weak or absent in ECNI mass spectra. Of the four derivatizing reagents tested, OFPCF showed the best performance, with good reaction efficiency, good chromatographic and spectroscopic properties, low detection limits (10-100 fmol), and a linear response more than two orders of magnitude. Further, the entire procedure from raw aqueous sample to ready-to-inject hexane solutions of the derivatives requires less than 10 min. PFBCF showed ideal applicability for derivatizing aminoalcohols and aminoacids. The two chloroformates with the highest intrinsic stability (TDFOCF and PFPECF) failed to derivatize some of the analytes. Finally, the OFPCF derivatizing agent was tested with simulated ozonated drinking water (aqueous fulvic acid treated with ozone), and three highly polar reaction by-products were determined.

Journal Article↗

PubMed2002

Thermotropic phase behavior of monoglyceride-dicetylphosphate dispersions and interactions with proteins: a (2)H and (31)P NMR study.

The phase behavior of a 1-[(2)H(35)]-stearoyl-rac-glycerol ([(2)H(35)]-MSG)/dicetylphosphate (DCP) mixture and its interaction with beta-lactoglobulin and lysozyme were studied by (2)H and (31)P nuclear magnetic resonance (NMR). The behavior of the lipids was monitored by using deuterium-labeled [(2)H(35)]-MSG as a selective probe for (2)H NMR and DCP for (31)P NMR. Both (2)H and (31)P NMR spectra exhibit characteristic features representative of different phases. In the lamellar phases, (31)P NMR spectra of DCP are different from the spectra of natural phospholipids, which is attributable to differences in the intramolecular motions and the orientation of the shielding tensor of DCP compared with phospholipids. The presence of the negatively charged amphiphile DCP has a large effect on the phase behavior of [(2)H(35)]-MSG. At low temperature, the presence of DCP inhibits crystallization of the gel phase into the coagel. Upon increasing the temperature, the gel phase of [(2)H(35)]-MSG transforms in the liquid-crystalline lamellar phase. In the presence of DCP, the gel phase directly transforms into an isotropic phase. The negatively charged beta-lactoglobulin and the positively charged lysozyme completely neutralize the destabilizing effect of DCP on the monoglyceride liquid-crystalline phase and they even stabilize this phase. Without DCP the proteins do not seem to interact with the monoglyceride. These results suggest that interaction is facilitated by electrostatic interactions between the negatively charged DCP and positively charged residues in the proteins. In addition, the nonbilayer-forming DCP creates insertion sites for proteins in the bilayer.

Animals↗

PubMed2003

Molecular features of an alcohol binding site in a neuronal potassium channel.

Aliphatic alcohols (1-alkanols) selectively inhibit the neuronal Shaw2 K(+) channel at an internal binding site. This inhibition is conferred by a sequence of 13 residues that constitutes the S4-S5 loop in the pore-forming subunit. Here, we combined functional and structural approaches to gain insights into the molecular basis of this interaction. To infer the forces that are involved, we employed a fast concentration-clamp method (10-90% exchange time = 800 micros) to examine the kinetics of the interaction of three members of the homologous series of 1-alkanols (ethanol, 1-butanol, and 1-hexanol) with Shaw2 K(+) channels in Xenopus oocyte inside-out patches. As expected for a second-order mechanism involving a receptor site, only the observed association rate constants were linearly dependent on the 1-alkanol concentration. While the alkyl chain length modestly influenced the dissociation rate constants (decreasing only approximately 2-fold between ethanol and 1-hexanol), the second-order association rate constants increased e-fold per carbon atom. Thus, hydrophobic interactions govern the probability of productive collisions at the 1-alkanol binding site, and short-range polar interactions help to stabilize the complex. We also examined the relationship between the energetics of 1-alkanol binding and the structural properties of the S4-S5 loop. Circular dichroism spectroscopy applied to peptides corresponding to the S4-S5 loop of various K(+) channels revealed a correlation between the apparent binding affinity of the 1-alkanol binding site and the alpha-helical propensity of the S4-S5 loop. The data suggest that amphiphilic interactions at the Shaw2 1-alkanol binding site depend on specific structural constraints in the pore-forming subunit of the channel.

Alcohols↗

PubMed1996

Approach to an organo-typical environment for cultured cells and tissues.

If cells or tissues are taken out of an organ and put in culture, normally they lose morphological, physiological and biochemical features. This dedifferentiation process starts during the isolation procedure and continues during the whole culture period. It is caused by the stagnant liquid condition and the inadequate anchorage of cells at the bottom of tissue culture plasticware. The use of filters as basement membrane substitutes and the coating of cultureware with extracellular matrix proteins improve the environmental factors for cultured cells but do not consider the paracrine influence of cytokines or the nutritional needs of individual cell types. To limit cellular dedifferentiation in culture, we constructed a new system, which adapts, as far as possible, cell and tissue cultures to an organo-typical environment. The system is based on a compatible cell carrier arrangement, which allows individual selection of supports for optimal cell anchorage and differentiation. The cell carriers are placed in a newly constructed container, which is permanently perfused with fresh culture medium. The system runs outside an incubator with simple laboratory tools; only a peristaltic pump, a warming table and pH-stabilized media are necessary. Without any subculturing, acute and chronic influences of drugs or the quality of medical implantation grafts can be studied over months.

Cell Adhesion↗

PubMed1990

Stability of computer ECG amplitude measurements in the presence of noise. The CSE Working Party.

An important feature of an ECG analysis program is its ability to provide reliable measurements under various operating conditions, e.g., on noise-free and noisy ECGs. Therefore, within the European cooperative project "Common Standards For Quantitative Electrocardiography" (CSE), the accuracy and stability of ECG measurements obtained by several computer programs has been compared. To investigate the stability of measurements two sets of 10 ECGs with and without seven different high- and low-frequency types of noise--altogether 160 electrocardiograms and 160 vectorcardiograms--have been analyzed by eight electrocardiographic and five vectorcardiographic computer programs. The stability of measurement was tested with respect to results obtained for the noise-free recordings. In a previous paper, the influence of noise on wave boundary recognition has been reported. In the present paper, the effect of noise on amplitude measurements and on problems of waveform definitions within the QRS complex are described. The results indicate that programs analyzing an averaged beat exhibit less variability than programs which measure every complex or a selected beat. Comparability and stability of measurements could be improved if a standardized procedure for amplitude references were to be introduced. In addition, the stability of QRS waveform labelling could be improved if waveforms' minimum amplitude and duration were to be validated against the noise level which itself should be determined by a standardized procedure.

Analog-Digital Conversion↗

PubMed2001

Potent estrogen agonists based on carborane as a hydrophobic skeletal structure. A new medicinal application of boron clusters.

BACKGROUND: Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable thermal stability and exceptional hydrophobicity. Applications of the unique structural and chemical properties offered by icosahedral carboranes in boron neutron capture therapy have received increasing attention over the past 30 years. However, these features of carboranes may allow another application as a hydrophobic pharmacophore in biologically active molecules that interact hydrophobically with receptors. RESULTS: We have designed candidate estrogen-receptor-binding compounds having carborane as a hydrophobic skeletal structure and synthesized them. The most potent compound bearing a carborane cage exhibited activity at least 10-fold greater than that of 17beta-estradiol in the luciferase reporter gene assay. Estrogen receptor-alpha-binding data for the compound were consistent with the results of the luciferase reporter gene assay. The compound also showed potent in vivo effects on the recovery of uterine weight and bone loss in ovariectomized mice. CONCLUSION: Further development of the potent carborane-containing estrogenic agonists described here, having a new skeletal structure and unique characteristics, should yield novel therapeutic agents, especially selective estrogen receptor modulators. Furthermore, the suitability of the spherical carborane cage for binding to the cavity of the estrogen receptor-alpha ligand-binding domain should provide a basis for a similar approach to developing novel ligands for other steroid receptors.

Animals↗

PubMed2006

Synthesis, properties, and NAD+-NADH-type redox ability of 14-substituted 1,3-dimethyl-5,10-methanocycloundeca[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3h)-dionylium tetrafluoroborates and their hydride adducts.

A synthesis of 14-substituted 1,3-dimethyl-5,10-methanocycloundeca[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dionylium tetrafluoroborates 11a,b(+).BF4- was accomplished by the methylation of 5,10-methanocycloundeca[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dione derivatives with MeI and following anion-exchange reaction by treatment with 42% aq HBF(4). Compound 11b(+).BF4- was synthesized alternatively by the reaction of 1,6-methano[11]annulenylium tetrafluoroborate with 6-phenylamino-1,3-dimethyluracil and following oxidative cyclization reaction. Remarkable structural characteristics of 11a,b(+)were clarified on inspection of the UV-vis and NMR spectral data as well as X-ray crystal analyses. The stability of cations 11a,b(+)() is expressed by the pK(R+) values which were determined spectrophotometrically as 9.8 and 9.7, which are smaller by 1.4 and 1.2 pH units than those of the corresponding seven-membered ring cations, respectively; however, the values are larger by 3.6 and 3.5 pH units than that of the parent 1,6-methano[11]annulenylium ion (pK(R+) = 6.2). The feature is rationalized on the basis of the perturbation derived from the bond fixation of the parent cation and the electron-donating ability of pyrrolopyrimidine. The electrochemical reduction of 11a,b(+).BF4- exhibited reduction potential at -0.58 and -0.52 (V vs Ag/AgNO3) upon cyclic voltammetry (CV). Reaction of 11a(+).BF4- with hydride afforded mixures of the C13- and C11-adducts in a ratio with hydride afforded, on the other hand, the C13-adduct as a single product. In both cations, the methano-bridge seemed to control the nucleophilic attack to the C13 favorably with exo-selectivity. The photoinduced autorecycling oxidation reactions of 11a,b(+).BF4- toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 1.1 to 32.2. Furthermore, as an example of the NAD+-NADH models, the reduction of a pyruvate analogue and some carbonyl compounds with the hydride adducts of 11a,b+.BF4- was accomplished for the first time to give the corresponding alcohol derivatives.

Borates↗

PubMed2004

Enhancement of treatment adherence among patients with bipolar disorder.

OBJECTIVE: Because about one-third of persons with bipolar illness take less than 30 percent of their medication and because nonadherence is associated with rehospitalization and suicide, the literature was searched to identify controlled studies of enhancement of treatment adherence among persons with bipolar disorder. METHODS: Studies published up to October 2003 were evaluated. Those selected for review were controlled trials that used samples of adults with a diagnosis of bipolar disorder and that measured adherence to either mood-stabilizing medication or psychotherapy. Information was extracted on the diagnostic composition and size of the study group, the type and duration of the intervention, the method of measuring adherence, and outcomes. RESULTS: Eleven studies met inclusion criteria. Although the literature on enhancing treatment adherence among persons with bipolar disorder is limited, the existing data are promising and demonstrate development over time in our understanding of how best to manage this illness. Interventions that have been shown to be effective include interpersonal group therapy, cognitive-behavioral therapy, group sessions for partners of persons with bipolar disorder, and patient and family psychoeducation. Effective therapies occur in the context of long-term management of illness that incorporates a good understanding of medications and their risks and benefits as well as education about illness awareness and self-management. The majority of effective therapies feature an interactional component between patients and their care providers or therapists. CONCLUSIONS: Adherence to treatment for bipolar disorder may be enhanced by interventions that address issues of appropriately taking medications to manage illness. For optimum outcomes, promotion of adherence must be integrated into the medication management of bipolar illness.

Bipolar Disorder↗

PubMed2004

Watershed segmentation for breast tumor in 2-D sonography.

Automatic contouring for breast tumors using medical ultrasound (US) imaging may assist physicians without relevant experience, in making correct diagnoses. This study integrates the advantages of neural network (NN) classification and morphological watershed segmentation to extract precise contours of breast tumors from US images. Textural analysis is employed to yield inputs to the NN to classify ultrasonic images. Autocovariance coefficients specify texture features to classify breasts imaged by US using a self-organizing map (SOM). After the texture features in sonography have been classified, an adaptive preprocessing procedure is selected by SOM output. Finally, watershed transformation automatically determines the contours of the tumor. In this study, the proposed method was trained and tested using images from 60 patients. The results of computer simulations reveal that the proposed method always identified similar contours and regions-of-interest (ROIs) to those obtained by manual contouring (by an experienced physician) of the breast tumor in ultrasonic images. As US imaging becomes more widespread, a functional automatic contouring method is essential and its clinical application is becoming urgent. Such a method provides robust and fast automatic contouring of US images. This study is not to emphasize that the automatic contouring technique is superior to the one undertaken manually. Both automatic and manual contours did not, after all, necessarily result in the same factual pathologic border. In computer-aided diagnosis (CAD) applications, automatic segmentation can save much of the time required to sketch a precise contour, with very high stability.

Breast Neoplasms↗

PubMed2003

Increased rates of sequence evolution in endosymbiotic bacteria and fungi with small effective population sizes.

Mutualistic, maternally transmitted endosymbiotic microorganisms undergo severe population bottlenecks at each host generation, resulting in a reduction in effective population size (Ne). Previous studies of Buchnera, the primary endosymbiont of aphids, and of several other species of endosymbiotic bacteria have shown that these species exhibit an increase in the rate of substitution of slightly deleterious mutations, among other predicted effects of increased drift due to small Ne, such as reduced codon bias. However, these studies have been limited in taxonomic scope, and it was therefore not clear whether the increase in rate is a general feature of endosymbiont lineages. Here, we test the prediction that a long-term reduction in Ne causes an increase in substitution rate using DNA sequences of the 16S rRNA gene from 13 phylogenetically independent comparisons between taxonomically diverse endosymbiotic microorganisms and their free-living relatives. Maximum likelihood and distance-based methods both indicate a significant increase in substitution rate in a wide range of bacterial and fungal endosymbionts compared to closely related free-living lineages. We use the same data set to test whether 16S genes from endosymbionts display increased A + T content, another indicator of increased genetic drift, and find that there is no significant difference in base composition between endosymbiont and nonendosymbiont 16S genes. However, analysis of an additional data set of whole bacterial genomes demonstrates that, while host-dependent bacteria have significantly increased genomic A + T content, the base content of the 16S gene tends to vary less than that of the whole genome. It is possible that selection for stability of rRNA is strong enough to overcome the effects of drift toward increased A + T content in endosymbiont 16S genes, despite the reduced effective population sizes of these organisms.

Animals↗

PubMed2005

Structural and enzymatic parameters that determine alkyl dehydrogenation/hydroxylation of capsaicinoids by cytochrome p450 enzymes.

Previous studies on the metabolism of capsaicinoids, natural products isolated from chili peppers, demonstrated the production of unique macrocyclic, alkyl dehydrogenated, omega-, and omega-1-hydroxylated products. This study investigated the structural and enzymatic parameters that direct selective alkyl dehydrogenation and hydroxylation of capsaicinoids, using a variety of structurally related capsaicinoid analogs and cytochrome P450 (P450) enzymes. CYP2C9 preferentially catalyzed alkyl dehydrogenation, whereas CYP2E1 and 3A4 catalyzed omega- and omega-1-hydroxylation, respectively. Analysis of incubations containing various P450s and structural variants of capsaicin by liquid chromatography-tandem mass spectrometry demonstrated similarities in the rate of capsaicinoid metabolism, but marked differences in the metabolite profiles. Production of macrocyclic and omega-1-hydroxylated metabolites from the various capsaicinoids was dependent on the structure of the alkyl terminus and P450 enzyme. A tertiary carbon at the omega-1 position, coupled to an adjacent unsaturated bond at the omega-2,3 position, enhanced the formation of the macrocyclic and dehydrogenated metabolites and were requisite structural features for omega-1-hydroxylated product formation. Conversely, substrates lacking these structural features were efficiently oxidized to the omega-hydroxylated metabolite. These data were consistent with our hypothesis that metabolism of the alkyl portion of capsaicinoids was governed, in part, by the stability and propensity to form an intermediate radical and a carbocation, and a direct interaction between the alkyl terminus and the heme of many P450 enzymes. These results provided valuable insights into potential mechanisms by which P450s metabolize capsaicinoids and highlight critical chemical features that may also govern the metabolism of structurally related compounds including fatty acids, monoter-penes, and isoprenoids.

Capsaicin↗

PubMed1986

Spread and arrest of seizures: the importance of layer 4 in laminar interactions during neocortical epileptogenesis.

Much of the past investigation of epileptogenesis has centered on characterizing the paroxysmal depolarization shift (PDS) and postulating its origin. Spatial as well as functional analyses of cortical epileptic foci have been few in number, and in nearly all of them fully evolved drug foci, which were used for their stability, probably obscured differences in the responsivity among constituent neuronal populations at earlier stages of epileptic evolution. Proportionately little attention has been directed at determining where penicillin acts within the cortex. For the past 12 years, we have addressed both issues. Specific questions have included, for both individual neurons and neuronal aggregates: what are the initial abnormalities of responsiveness in an acute epileptic focus; how do these abnormalities evolve as the focus develops; is there a differential susceptibility of various neocortical layers to epileptogenesis; how do the various cortical laminar populations interact during epileptogenesis; how do the resultant response abnormalities propagate within and between cortical columns; and what are the effects of anticonvulsants on the various spatial and temporal features of epileptogenesis? In pursuit of this information, we have recorded the evolution of discrete and temporary epileptic foci in cat striate cortex, which were induced by the microinjection or iontophoresis of penicillin into the different cortical layers. Simultaneous, multilaminar responses of individual neurons and of neuronal aggregates to selective visual stimulation have been characterized before, during, and after focus development using multibarrel micropipettes. Correlations between drug diffusion and these multilaminar recordings were made periodically by using 14C-labeled penicillin. Stages: Using these techniques, new characteristics of focal epilepsy come to light that are not apparent in the spontaneous spiking of the typical established penicillin focus. Three successive stages of penicillin-induced epileptogenic abnormality were noted in the responses of isolated neurons: (a) an initial graded enhancement of the primary latency response to field-specific stimuli into a burst discharge (the EPR burst); (b) the subsequent graded development of a longer latency burst in response to field-specific and nonspecific stimuli (the LR burst); and (c) the evolution of a single stereotyped burst discharge (IIS) as the latency separating EPR and LR bursts declined (PDS or LR discharge). Each type of neuronal burst was accompanied by a local field potential of similar latency, but of progressively increasing amplitude, with each successive stage of epileptogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed2003

Molecular dynamics studies of caspase-3.

Caspase-3 is a fundamental target for pharmaceutical interventions against a variety of diseases involving disregulated apoptosis. The enzyme is active as a dimer with two symmetry-related active sites, each featuring a Cys-His catalytic dyad and a selectivity loop, which recognizes the characteristic DEVD pattern of the substrate. Here, a molecular dynamics study of the enzyme in complex with two pentapeptide substrates DEVDG is presented, which provides a characterization of the dynamic properties of the active form in aqueous solution. The mobility of the substrate and that of the catalytic residues are rather low indicating a distinct preorganization effect of the Michaelis complex. An essential mode analysis permits us to identify coupled motions between the two monomers. In particular, it is found that the motions of the two active site loops are correlated and tend to steer the substrate toward the reactive center, suggesting that dimerization has a distinct effect on the dynamic properties of the active site regions. The selectivity loop of one monomer turns out to be correlated with the N-terminal region of the p12 subunit of the other monomer, an interaction that is also found to play a fundamental role in the electrostatic stabilization of the quaternary structure. To further characterize the specific influence of dimerization on the enzyme essential motions, a molecular dynamics analysis is also performed on the isolated monomer.

Binding Sites↗

PubMed1998

Benzoquinazoline derivatives as substitutes for thymine in nucleic acid complexes. Use of fluorescence emission of benzo[g]quinazoline-2,4-(1H,3H)-dione in probing duplex and triplex formation.

Triple helix formation obeys structural features that do not allow accommodation of every double-stranded sequence; it requires the occurrence of homopurine stretches. A further constraint comes from the weak energy of interaction between the third strand and the double-stranded target. In an attempt to design bases leading to increased stability of triplexes, we explored the ability of modified bases with an extended aromatic domain to increase third strand binding through stacking interactions. We report here the use of benzo[g]- and benzo[f]quinazoline-2,4-dione-(1H,3H)-dione as substitutes for thymine in the canonical TAT triplet. The synthesis and characterization of the beta nucleoside derivatives of benzoquinazolines are described. Triplex-forming oligonucleotides containing these modified bases have been prepared, and their ability to form triplexes has been evaluated by UV absorption-monitored thermal denaturation measurements. Benzo[g]quinazoline and benzo[f]quinazoline formed triple-stranded structures with slightly decreased stabilities. In addition, benzo[g]quinazoline revealed strong fluorescence emission properties which can be used to monitor selectively the formation of triple-helical structures. Annealing of benzo[g]quinazoline to complementary strands did not produce any fluorescence modification. But when it was introduced into the Hoogsteen strand of PyPuPy complexes, the fluorescence intensity was reduced and the emission maximum was shifted to short wavelengths.

DNA↗