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PubMed1991

Effects of ritanserin on aversive classical conditioning in humans.

According to one formulation of the behavioural functions of 5HT, aversive conditioned stimuli mediate their behavioural and emotional effects through activation of 5HT projections from dorsal raphe nucleus to receptors of the 5HT2 family in amygdala and elsewhere. To test this theory in humans, groups of ten normal volunteers received placebo, the 5HT2 lc antagonist ritanserin (10 mg PO) and no pill. Ritanserin had no effect on skin conductance level, variability (spontaneous fluctuations) or habituation to a sequence of ten neutral tones. After a conditioning trial in which tone 11 was followed by an aversive white noise, skin conductance responses to a further ten tones were enhanced. This effect was abolished by ritanserin. The results indicate a selective involvement of 5HT2/lc receptors in modulating aversively conditioned skin conductance responses.

Adult↗
PubMed2005

Low-dose tacrolimus for two cases of myasthenia gravis with invasive thymoma that relapsed shortly after thymectomy.

Two patients with myasthenia gravis (Ossermann IIb) involving invasive thymoma who underwent extensive thymectomy manifested myasthenic crisis shortly after the procedure; however, both patients were treated with intravenous immunoglobulin and recovered from myasthenic crisis that had been deteriorating for about 1 week. Subsequently, the patients were administered a low-dose of tacrolimus (3 mg/day) in addition to prednisolone. Several months later, tacrolimus continued to control fluctuations of myasthenic symptoms and maintained remission in these patients. The serum titer of anti-Ach-receptor antibodies decreased in parallel with clinical improvement due to tacrolimus, and we accordingly reduced the dosage of prednisolone. Tacrolimus is a new immunosuppressive agent acting through the selective inhibition of helper-T-cell activation that can be reduced dosage of steroids and can maintain remission of myasthenia gravis with invasive thymoma.

Adult↗
PubMed2004

Mapping backbone dynamics in solution with site-directed spin labeling: GCN4-58 bZip free and bound to DNA.

In site-directed spin labeling, a nitroxide-containing side chain is introduced at selected sites in a protein. The EPR spectrum of the labeled protein encodes information about the motion of the nitroxide on the nanosecond time scale, which has contributions from the rotary diffusion of the protein, from internal motions in the side chain, and from backbone fluctuations. In the simplest model for the motion of noninteracting (surface) side chains, the contribution from the internal motion is sequence independent, as is that from protein rotary diffusion. Hence, differences in backbone motions should be revealed by comparing the sequence-dependent motions of nitroxides at structurally homologous sites. To examine this model, nitroxide side chains were introduced, one at a time, along the GCN4-58 bZip sequence, for which NMR (15)N relaxation experiments have identified a striking gradient of backbone mobility along the DNA-binding region [Bracken et al. (1999) J. Mol. Biol. 285, 2133]. Spectral simulation techniques and a simple line width measure were used to extract dynamical parameters from the EPR spectra, and the results reveal a mobility gradient similar to that observed in NMR relaxation, indicating that side chain motions mirror backbone motions. In addition, the sequence-dependent side chain dynamics were analyzed in the DNA/protein complex, which has not been previously investigated by NMR relaxation methods. As anticipated, the backbone motions are damped in the DNA-bound state, although a gradient of motion persists with residues at the DNA-binding site being the most highly ordered, similar to those of helices on globular proteins.

DNA↗
PubMed2004

Proton field-cycling nuclear magnetic resonance relaxometry in the smectic A mesophase of thermotropic cyanobiphenyls: Effects of sonication.

Proton field-cycling nuclear magnetic resonance relaxometry is used to study the spin-lattice relaxation dispersion of selected standard smectic A liquid crystals at different temperatures. Relaxation features at both, in the presence and absence of a monochromatic ultrasonic field are considered. We show that the laboratory-frame spin-lattice relaxation time is mainly governed by translational diffusion. Order director fluctuations (ODF) are less important while rotational diffusion seems to be only relevant near the clearing point. Our study suggests that sonication enhances the ODF contribution in the SmA mesophase. Within the framework of the approach we have outlined, different features associated with the ODF mechanism can be investigated.

Journal Article↗
PubMed1985

Uptake and disposition of mirex in hepatocytes and subcellular fractions in CD1 mouse liver.

In vivo uptake and disposition of [14C]mirex by CD1 mouse liver subcellular fractions and cells of different nuclear ploidy were examined following single or multiple doses of mirex injected intraperitoneally. Significant amounts of mirex were rapidly taken up by liver (21-29%), suggesting that liver is one of the primary sites of accumulation of the chemical. Among subcellular fractions, mirex was predominantly distributed in mitochondria and microsomes in the irreversibly bound form (about 20%), although its levels fluctuated considerably with time. Mirex was completely dissociated with trichloroacetic acid treatment from both nuclear and plasma membrane fractions, although the total uptake by these fractions was markedly high. The time course of uptake and concentration-dependent disposition of mirex revealed that polyploid hepatocytes selectively accumulated higher amounts of the chemical (two to three times) compared to diploid hepatocytes. The increased affinity of polyploid cells to mirex may indicate a greater susceptibility of this cell type to the chemical insult and also may suggest a possible early involvement of polyploids in the tumorigenic process in rodent livers.

Animals↗
PubMed1993

Chloride channels activated by osmotic stress in T lymphocytes.

We have used whole-cell and perforated-patch recording techniques to characterize volume-sensitive Cl- channels in T and B lymphocytes. Positive transmembrane osmotic pressure (intracellular osmolality > extracellular osmolality) triggers the slow induction of a Cl- conductance. Membrane stretch caused by cellular swelling may underlie the activation mechanism, as moderate suction applied to the pipette interior can reversibly oppose the induction of Cl- current by an osmotic stimulus. Intracellular ATP is required for sustaining the Cl- current. With ATP-free internal solutions, the inducibility of Cl- current declines within minutes of whole-cell recording, while in whole-cell recordings with ATP or in perforated-patch experiments, the current can be activated for at least 30 min. The channels are anion selective with a permeability sequence of I- > SCN- > NO3-, Br- > Cl- > MeSO3- > acetate, propionate > ascorbate > aspartate and gluconate. GCl does not show voltage- and time-dependent gating behavior at potentials between -100 and +100 mV, but exhibits moderate outward rectification in symmetrical Cl- solutions. Fluctuation analysis indicates a unitary chord conductance of approximately 2 pS at -80 mV in the presence of symmetrical 160 mM Cl-. The relationship of mean current to current variance during the osmotic activation of Cl- current implies that each cell contains on the order of 10(4) activatable Cl- channels, making it the most abundant ion channel in lymphocytes yet described. The current is blocked in a voltage-dependent manner by DIDS and SITS (Ki = 17 and 89 microM, respectively, at +40 mV), the degree of blockade increasing with membrane depolarization. The biophysical and pharmacological properties of this Cl- channel are consistent with a role in triggering volume regulation in lymphocytes exposed to hyposmotic conditions.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

Evaluation of whether accelerated protein evolution in chordates has occurred before, after, or simultaneously with gene duplication.

Gene duplication and loss are predicted to be at least of the order of the substitution rate and are key contributors to the development of novel gene function and overall genome evolution. Although it has been established that proteins evolve more rapidly after gene duplication, we were interested in testing to what extent this reflects causation or association. Therefore, we investigated the rate of evolution prior to gene duplication in chordates. Two patterns emerged; firstly, branches, which are both preceded by a duplication and followed by a duplication, display an elevated rate of amino acid replacement. This is reflected in the ratio of nonsynonymous to synonymous substitution (mean nonsynonymous to synonymous nucleotide substitution rate ratio [Ka:Ks]) of 0.44 compared with branches preceded by and followed by a speciation (mean Ka:Ks of 0.23). The observed patterns suggest that there can be simultaneous alteration in the selection pressures on both gene duplication and amino acid replacement, which may be consistent with co-occurring increases in positive selection, or alternatively with concurrent relaxation of purifying selection. The pattern is largely, but perhaps not completely, explained by the existence of certain families that have elevated rates of both gene duplication and amino acid replacement. Secondly, we observed accelerated amino acid replacement prior to duplication (mean Ka:Ks for postspeciation preduplication branches was 0.27). In some cases, this could reflect adaptive changes in protein function precipitating a gene duplication event. In conclusion, the circumstances surrounding the birth of new proteins may frequently involve a simultaneous change in selection pressures on both gene-copy number and amino acid replacement. More precise modeling of the relative importance of preduplication, postduplication, and simultaneous amino acid replacement will require larger and denser genomic data sets from multiple species, allowing simultaneous estimation of lineage-specific fluctuations in mutation rates and adaptive constraints.

Amino Acid Substitution↗
PubMed1982

Changing patterns of single-stranded-DNA-binding proteins in differentiating brain cortex and cerebellar neurons.

Single-stranded-DNA-binding proteins were analyzed in nuclei of differentiating rat cortex and cerebellar neurons. The developmental period investigated ranged from gestational day 19 (i.e. 3 days before term) to postnatal day 30. During this time both types of neurons undergo transition from proliferating, undifferentiated precursor cells to non-proliferating, terminally differentiated neurons. For comparison, nuclei from mature cortex glia and liver were also examined. Nuclei were isolated according to cell type, the proteins were 14C-labeled in vitro by reductive methylation and were fractionated by affinity chromatography on tandemly arranged columns of double-stranded and single-stranded DNA-cellulose. The columns were uncoupled and the proteins adsorbed to the single-stranded DNA were eluted with salt. They were then analyzed by high resolution two-dimensional gel electrophoresis followed by fluorography. This strategy ensured the selective detection of proteins that recognize single-stranded DNA specifically, and eliminated interference by proteins binding to DNA by simple ionic interaction as well as by proteins with affinity for double-stranded DNA. Many single-stranded-DNA-binding proteins showed conspicuous developmental fluctuations. In cortex neurons these took place around the time of birth and the first postnatal week, whereas in cerebellar neurons they occurred later and in a more protracted fashion. Thus, in both cortex and cerebellar neurons the protein changes followed a time course closely paralleling the arrest of cell division and the beginning of terminal differentiation. It is suggested that this approach may lead to the detection of putative regulatory proteins of the cell nucleus.

Animals↗
PubMed2004

Differential expression of the mechanosensitive potassium channel TREK-1 in epicardial and endocardial myocytes in rat ventricle.

Mechanoelectric feedback (MEF) is the process by which mechanical forces on the myocardium induce electrical responses. It is thought that MEF is important in controlling the beat to beat force of contraction in the ventricle, in response to fluctuations in load, and it may also play a role in controlling the dispersion of repolarization. The transduction mechanism for MEF is via stretch sensitive ion channels in the surface membrane of myocytes. Two types of stretch sensitive channels have been described; a non-selective cation channel, and a potassium selective channel. TREK-1 is a member of the recently cloned tandem pore potassium channels that has been shown to be mechanosensitive and to be expressed in rat heart. Here we report that the gene expression level of TREK-1, quantified using real-time RT-PCR against glyceraldehyde phosphate dehydrogenase (GAPDH) as a comparator gene, was found to be 0.34 +/- 0.14 in endocardial cells compared to 0.02 +/- 0.02 in epicardial cells (P < 0.05). To confirm that this is reflected in a different current density, whole cell TREK-1 currents, activated by chloroform, were recorded with patch clamp techniques in epicardial and endocardial cells. TREK-1 current density in epicardial and endocardial cells was 0.21 +/- 0.06 pA/pF and 0.8 +/- 0.27 pA/pF, respectively (P</= 0.05). We discuss the implications of this differential expression of TREK-1 for controlling action potential repolarization when the myocardium is stretched. We hypothesize that the gene expression of TREK-1 is controlled by the different amounts of stretch experienced by muscle cells across the ventricular wall.

Animals↗
PubMed2000

Genetic diversity among Arthrobacter species collected across a heterogeneous series of terrestrial deep-subsurface sediments as determined on the basis of 16S rRNA and recA gene sequences.

This study was undertaken in an effort to understand how the population structure of bacteria within terrestrial deep-subsurface environments correlates with the physical and chemical structure of their environment. Phylogenetic analysis was performed on strains of Arthrobacter that were collected from various depths, which included a number of different sedimentary units from the Yakima Barricade borehole at the U.S. Department of Energy's Hanford site, Washington, in August 1992. At the same time that bacteria were isolated, detailed information on the physical, chemical, and microbiological characteristics of the sediments was collected. Phylogenetic trees were prepared from the 39 deep-subsurface Arthrobacter isolates (as well as 17 related type strains) based on 16S rRNA and recA gene sequences. Analyses based on each gene independently were in general agreement. These analyses showed that, for all but one of the strata (sedimentary layers characterized by their own unifying lithologic composition), the deep-subsurface isolates from the same stratum are largely monophyletic. Notably, the layers for which this is true were composed of impermeable sediments. This suggests that the populations within each of these strata have remained isolated under constant, uniform conditions, which have selected for a particular dominant genotype in each stratum. Conversely, the few strains isolated from a gravel-rich layer appeared along several lineages. This suggests that the higher-permeability gravel decreases the degree of isolation of this population (through greater groundwater flow), creating fluctuations in environmental conditions or allowing migration, such that a dominant population has not been established. No correlation was seen between the relationship of the strains and any particular chemical or physical characteristics of the sediments. Thus, this work suggests that within sedimentary deep-subsurface environments, permeability of the deposits plays a major role in determining the genetic structure of resident bacterial populations.

Arthrobacter↗
PubMed1998

Sensitivity of condition indices to changing density in a white-tailed deer population.

The ways in which comprehensive condition profiles, incorporating morphometric, histologic, physiologic, and diet quality indices, responded to changes in density of a white-tailed deer (Odocoileus virginianus) population were examined. Changes in these condition indices were monitored in a northeastern Oklahoma deer herd as density declined from peaks of 80 and 72 deer/km2 in 1989 and 1990 (high-density) to lows of 39 and 41 deer/km2 in 1991 and 1992 (reduced-density), respectively. Compared to a reference population (6 deer/km2), deer sampled during high-density exhibited classic signs of nutritional stress such as low body and visceral organ masses (except elevated adrenal gland mass), low fecal nitrogen levels, reduced concentrations of serum albumin, elevated serum creatinine concentrations, and a high prevalence of parasitic infections. Although density declined by one half over the 4-yr study, gross indices of condition (in particular body mass and size) remained largely unchanged. However, selected organ masses, serum albumin and non-protein nitrogen constituents, and fecal nitrogen indices reflected improvements in nutritional status with reductions in density. Many commonly used indices of deer condition (fat reserves, hematocrit, total serum protein, and blood urea nitrogen) were not responsive to fluctuations in density.

Adrenal Glands↗
PubMed2000

Pulsatile parathyroid hormone secretion in health and disease.

In humans plasma parathyroid hormone (PTH) fluctuates episodically at a frequency of 6-7 bursts per hour. Approximately 30% of circulating PTH is attributable to pulsatile secretion and 70% to tonic secretion. PTH release is tightly controlled by Ca2+. Acute hypocalcaemia elicits a biphasic wave of PTH release, with an initial selective amplification and acceleration of the pulsatile component followed by proportionate stimulation of pulsatile and tonic secretion. Acute hypercalcaemia submaximally suppresses the frequency and mass of PTH bursts as well as tonic PTH release. Patients with primary hyperparathyroidism exhibit proportionate increases in pulsatile and tonic secretion, with no change in pulse frequency. In secondary hyperparathyroidism due to renal insufficiency, tonic secretion and pulsatile burst mass are also proportionately amplified, and burst frequency is increased. Moreover, the hypocalcaemia-induced increase in burst frequency and mass as well as their suppression during hypercalcaemia is diminished, suggesting partial uncoupling of hyperplastic parathyroids from physiological regulatory mechanisms. While the secretory pattern of PTH and its dysregulation in disease states is now well defined, the functional significance of pulsatile PTH signalling for target tissues is still largely unexplored. Preliminary work indicates that intermittent, in contrast to continuous, PTH administration stimulates bone formation. Cell culture studies suggest PTH receptor down-regulation with tonic exposure.

Bone Diseases↗
PubMed1986

Evaluating the applications of the spatially adaptive program (SAPRO) in clinical perimetry: Part I.

Some clinical application possibilities of a spatially adaptive program (SAPRO) are presented and analyzed. Due to the ability of the program to adapt operationally to the visual field situation that is encountered, useful clinical findings can be obtained, even in patients with complicated visual field disturbances. The spatially adaptive detection mechanism, as well as a simplified bracketing strategy, make it possible to keep the cost/benefit ratio down. Short- and long-term fluctuations, especially when these are large, may compromise the validity of the examination results or place them in doubt. Their effects can be diminished using data reduction methods (averaging). In cases where averaging cannot be applied, one can nevertheless achieve useful results by the appropriate selection of the perimetric visual fields (or portions thereof) that are measured.

Adult↗
PubMed1994

Immunocytochemical detection of cyclin A and cyclin D in formalin-fixed, paraffin-embedded tissues: novel, pertinent markers of cell proliferation.

Cyclin proteins in association with cyclin-dependent protein kinase subunits represent a new class of potentially oncogenic serine/threonine protein kinases that function to execute critical cell cycle transitions in all eukaryotic cells. Characterized by dramatic fluctuations in abundance, which occur in accordance with the periodicity of the cell cycle, the expression patterns of specific cyclins provide a unique and relevant indicator of cellular activation and cell cycle progression. In this study, we introduce a series of monospecific antibodies that are selective for human cyclin A and cyclin D, respectively, and we assess the feasibility of utilizing these reagents for immunocytochemical analyses. Conditions were optimized for detecting cyclin A and cyclin D in formalin-fixed, paraffin-embedded sections of the postnatal human palatine tonsil, in which normal cell proliferation is well characterized. Subsequent studies demonstrated the performance of these antibodies in the examination of pediatric bone tumors, in which decalcification methods are additionally performed. In both cases, the proliferative status of individual cells was monitored with an exceedingly high degree of resolution. Taken together with the available biochemical data, the results of these studies reveal a novel means of characterizing the proliferative status of normal as well as neoplastic tissues. The demonstrated utility of these immunochemical reagents will potentially facilitate retrospective studies aimed at examining cell proliferation in a wide variety of archival histopathologic specimens.

Antibodies↗
PubMed1979

Single-step selection of clones of a mouse hepatoma line deficient in aryl hydrocarbon hydroxylase.

The mouse hepatoma line Hepa-1 has high and inducible aryl hydrocarbon (benzo[a]pyrene) hydroxylase[benzo[a]pyrene, reduced-flavoprotein:oxygen oxidoreductase (3-hydroxylating), EC 1.14.14.2] activity. Fourteen subclones of a clonal derivative of Hepa-1 were isolated and shown not to display heterogeneity in aryl hydrocarbon hydroxylase activity beyond what could be ascribed to experimental error. Hepa-1 was found to be very sensitive to benzo[a]pyrene (BaP) toxicity and a single-step selection procedure for isolating clones resistant to BaP at 4 microgram/ml was designed. Those BaP-resistant variants tested had much reduced aryl hydrocarbon hydroxylase activities under both inducing and noninducing conditions and they retained their resistance to BaP and low aryl hydrocarbon hydroxylase activities over considerable periods of time of culture in the absence of BaP. The spontaneous rate of origin of the BaP-resistant clones was estimated, by Luria-Delbrück fluctuation analysis, to be 2 X 10(-7) events per cell per generation. It is concluded that the properties of the variants are consistent with the notion that they are mutational in origin and that this system is a promising one for carrying out a somatic cell genetic analysis of aryl hydrocarbon hydroxylase.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Accelerated exchange of a buried water molecule in selectively disulfide-reduced bovine pancreatic trypsin inhibitor.

Using magnetic relaxation dispersion (MRD), we have previously shown that the four internal water molecules in bovine pancreatic trypsin inhibitor (BPTI) exchange with bulk water on time scales between 10(-8) and 10(-4) s at room temperature. Because this exchange is controlled by the protein structure, internal water molecules can be used to probe rare conformational fluctuations. Here, we report (2)H and (17)O MRD data at three temperatures for wild-type BPTI and two BPTI variants where the 14-38 disulfide bond has been cleaved by a double Cys --> Ser mutation or by disulfide reduction and carboxamidomethylation. The MRD data show that the internal water molecules are conserved on disulfide cleavage. However, the exchange rate of the water molecule buried near the disulfide bond is enhanced by 2-4 orders of magnitude. The relation of water exchange to other dynamic processes in BPTI is discussed.

Animals↗
PubMed2005

Reciprocal interactions between oscillatory activities of different frequencies in the subthalamic region of patients with Parkinson's disease.

Synchronization of neuronal activity evident in the local field potential (LFP) recorded in the subthalamic region of patients with Parkinson's disease occurs at low frequencies (< 30 Hz) and, in some patients following treatment with levodopa, at high frequencies between 65 and 85 Hz. Here we investigate the functional relationship between these different activities by determining whether spontaneous fluctuations in their strength are correlated across time. To this end, we analysed recordings of LFPs from macroelectrodes inserted in the subthalamic area of 16 patients with Parkinson's disease, after treatment with anti-parkinsonian medication. Time-evolving autospectra of LFPs with significant 65-85 Hz peaks (from 21 sides) were computed and correlations between frequency components determined over time. LFP activity in the 5-32 Hz band was significantly negatively correlated with that in the 65-85 Hz band in data averaged across all 21 sides, as well as in 15 (71%) of the individual records. Negative correlations were relatively selective for interactions between these frequency bands and occurred over time epochs of as little as 40 s. They occurred about 50 min after levodopa and were recorded concurrently with contralateral levodopa-induced dyskinesias in all but four cases. Positive correlations were not seen between activities in the 5-32 Hz and 65-85 Hz bands. The spontaneous negative correlations suggest a reciprocal relationship between population synchrony in the high- and low-frequency ranges, and raise the possibility that spontaneous fluctuations in the balance between these activities may contribute to levodopa-induced dyskinesias.

Action Potentials↗
PubMed2000

Presence of antinucleosome autoantibodies in a restricted set of connective tissue diseases: antinucleosome antibodies of the IgG3 subclass are markers of renal pathogenicity in systemic lupus erythematosus.

OBJECTIVE: To study the frequency and disease specificity of antinucleosome antibody reactivity in diverse connective tissue diseases (CTD), and to determine factors, such as antibody subclass, that may influence the pathogenicity of these antibodies in relation to disease activity. METHODS: IgG and IgM antinucleosome activities on nucleosome core particles from 496 patients with 13 different CTD and 100 patients with hepatitis C were measured by enzyme-linked immunosorbent assay (ELISA). Of the patients with CTD, 120 had systemic lupus erythematosus (SLE), 37 had scleroderma (systemic sclerosis; SSc), 20 had mixed connective tissue disease (MCTD), and 319 had other CTD, including Sjögren's syndrome, inflammatory myopathy, rheumatoid arthritis, primary antiphospholipid syndrome, Wegener's granulomatosis, Takayasu arteritis, giant cell arteritis, relapsing polychondritis, Behçet's syndrome, and sarcoidosis. Antinucleosome-positive sera were further analyzed, by isotype-specific ELISA, for antinucleosome and anti-double-stranded DNA (anti-dsDNA) IgG subclasses. RESULTS: SLE, SSc, and MCTD were the only 3 CTD in which antinucleosome IgG were detected (71.7%, 45.9%, and 45.0% of patients, respectively). Antinucleosomes of the IgG3 subclass were present at high levels in patients with active SLE and were virtually absent in those with SSc, MCTD, or inactive SLE, and their levels showed a positive correlation with SLE disease activity. Of note, an increase in levels of antinucleosome of the IgG3 isotype was observed during SLE flares, and this increase was found to be closely associated with active nephritis. Levels of antinucleosome of the IgG1 subclass showed a trend toward an inverse correlation with SLE disease activity. No significant fluctuation in the anti-dsDNA isotype profile was observed in relation to SLE severity or clinical signs. CONCLUSION: Our data suggest that IgG antinucleosome is a new marker that may help in the differential diagnosis of CTD; antinucleosome of the IgG3 isotype might constitute a selective biologic marker of active SLE, in particular, of lupus nephritis.

Antibodies, Antinuclear↗