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PubMed1999

Interregional connectivity to primary motor cortex revealed using MRI resting state images.

The topographic organization of cortical neurons is traditionally examined using histological procedures. Functional magnetic resonance imaging (fMRI) offers the potential noninvasively to detect interregional connectivity of human brain. In the brain, there is spontaneous firing of neurons even in the resting state. Such spontaneous firing will increase local blood flow, cause MRI signal fluctuations, and affect remotely located neurons through the efferent output. By calculating covariance of each voxel referenced to the time course of a selected brain region, it is possible to detect the neurons connected to the selected region. Using this covariance method, neural connectivity to primary motor cortex was assessed during a resting state in six healthy right-handed volunteers. This interregional connectivity is similar to connectivity established by other anatomical, histochemical, and physiological techniques. This method may offer in vivo noninvasive measurements of neural projections.

Adult↗
PubMed1979

Studies on Chinese hamster ovary mutants showing multiple cross-resistance to oxidative phosphorylation inhibitors.

Several stable Chinese hamster ovary (CHO) mutants were selected after ethylmethane sulfonate mutagenesis for resistance to oligomycin, ruatmycin, venturicidin, or antimycin. These mutants shared a number of common properties. They exhibited cross-resistance to those drugs which act on oxidative phosphorylation, irrespective of the structure and site of action of the drug. All the mutants showed a reduced ability to grow in suspension and to reach high saturation densities. They were also unable to use galactose as a carbon source. The short lag period required for selection (10-15 days), the similarity of the mutation rates for resistance to each of the four drugs, the high variance/mean ratios in fluctuation tests, and the recessive behavior of the resistance marker in hybrids suggest that the mutations responsible for resistance to oxidative phosphorylation inhibitors in CHO cells are coded by nuclear DNA. Segregation experiments indicated no linkage between the oligomycin-resistant marker (OLG) AND Thg (thioguanine resistance). Oxidative phosphorylation, as measured by the rate of respiration coupled to phosphorylation in whole cells remained as sensitive to the drugs in the mutants as in the parental cell line. Glucose transport and the overall Krebs' cycle activities also appeared similar in the mutants and the wild type. All the mutants had an increased rate of lactic acid production (up to twofold), associated with increased specific activities for several glycolytic enzymes when assayed in cell-free extracts.

Animals↗
PubMed2004

Cardiovascular rhythms in the 0.15-Hz band: common origin of identical phenomena in man and dog in the reticular formation of the brain stem?

Selected examples from experiments in humans and dogs with time series of reticular neurons, respiration, arterial blood pressure and cutaneous forehead blood content fluctuations were analysed using multiscaled time-frequency distribution, post-event-scan and pointwise transinformation. We found in both experiments a "0.15-Hz rhythm" exhibiting periods of spindle waves (increasing and decreasing amplitudes), phase synchronized with respiration at 1:2 and 1:1 integer number ratios. At times of wave-epochs and n:m phase synchronization, the 0.15-Hz rhythm appeared in heart rate and arterial blood pressure. As phase synchronization of the 0.15-Hz rhythm with respiration was established at a 1:1 integer number ratio, all cardiovascular-respiratory oscillations were synchronized at 0.15 Hz. Analysis of a canine experiment supplied evidence that the emergence of the 0.15-Hz rhythm and n:m phase synchronization appears to result from a decline in the level of the general activity of the organism associated with a decline in the level of activity of reticular neurons in the lower brainstem network. These findings corroborate the notion of the 0.15-Hz rhythm as a marker of the "trophotropic mode of operation" first introduced by W.R. Hess.

Animals↗
PubMed2005

Kinetic properties of a commercial and a native inoculum for aerobic milk fat degradation.

The aerobic fat biodegradation potential and growth characteristics of a commercial and a native inoculum (activated sludge from a dairy wastewater treatment pond), were evaluated. Batch tests were conducted with a medium based on butter oil, as the sole source of carbon, and mineral salts. Residual fat, biomass and CO(2) production were measured. Overall fat removal values were above 78% for both inocula. The growth kinetics of the commercial and native inocula followed Haldane and Monod models respectively. Both inocula showed a similar behaviour when butter oil concentration was under 360 mg/l; at higher values, the difference between the growth rates increased as a consequence of the inhibition exhibited by the commercial inoculum. The selection of an inoculum for bioaugmentation of bioreactors in the wastewater treatment requires a comprehensive knowledge of their degradation ability and tolerance to fluctuating compounds and of the operational conditions that will be utilized.

Animals↗
PubMed1983

Immunoglobulin surface-binding kinetics studied by total internal reflection with fluorescence correlation spectroscopy.

An experimental application of total internal reflection with fluorescence correlation spectroscopy (TIR/FCS) is presented. TIR/FCS is a new technique for measuring the binding and unbinding rates and surface diffusion coefficient of fluorescent-labeled solute molecules in equilibrium at a surface. A laser beam totally internally reflects at the solid-liquid interface, selectively exciting surface-adsorbed molecules. Fluorescence collected by a microscope from a small, well-defined surface area approximately 5 micron2 spontaneously fluctuates as solute molecules randomly bind to, unbind from, and/or diffuse along the surface in chemical equilibrium. The fluorescence is detected by a photomultiplier and autocorrelated on-line by a minicomputer. The shape of the autocorrelation function depends on the bulk and surface diffusion coefficients, the binding rate constants, and the shape of the illuminated and observed region. The normalized amplitude of the autocorrelation function depends on the average number of molecules bound within the observed area. TIR/FCS requires no spectroscopic or thermodynamic change between dissociated and complexed states and no extrinsic perturbation from equilibrium. Using TIR/FCS, we determine that rhodamine-labeled immunoglobulin and insulin each nonspecifically adsorb to serum albumin-coated fused silica with both reversible and irreversible components. The characteristic time of the most rapidly reversible component measured is approximately 5 ms and is limited by the rate of bulk diffusion. Rhodamine-labeled bivalent antibodies to dinitrophenyl (DNP) bind to DNP-coated fused silica virtually irreversibly. Univalent Fab fragments of these same antibodies appear to specifically bind to DNP-coated fused silica, accompanied by a large amount of nonspecific binding. TIR/FCS is shown to be a feasible technique for measuring absorption/desorption kinetic rates at equilibrium. In suitable systems where nonspecific binding is low, TIR/FCS should prove useful for measuring specific solute-surface kinetic rates.

Animals↗
PubMed1999

Pramipexole--a new dopamine agonist for the treatment of Parkinson's disease.

Although L-DOPA is the current 'gold standard' for treatment of Parkinson's disease, its effectiveness fades rapidly and its use results in serious motor fluctuations (on-off, wearing off, freezing, involuntary movements) for most patients with Parkinson's disease. Pramipexole is an aminothiazole dopamine agonist with selective actions at dopamine receptors belonging to the D2 subfamily, where it possesses full activity similar to dopamine itself. Pramipexole's preferential affinity for the D3 receptor subtype could contribute to efficacy in the treatment of both the motor and psychiatric symptoms of Parkinson's disease. Both in vitro and in vivo studies in animals suggest that pramipexole possesses numerous neuroprotective properties, including dopamine autoreceptor agonist properties, antioxidant properties, ability to block the mitochondrial permeability transition pore and the ability to stimulate the release of trophic factors. Clinical studies have demonstrated that pramipexole has excellent pharmacokinetic properties and that it is an effective monotherapy in treating early Parkinson's disease and an effective adjunctive therapy with L-DOPA in treating late Parkinson's disease. In addition, pramipexole has demonstrated efficacy in a clinical trial for the treatment of major depression. In the early disease studies, pramipexole was able to retard the need for L-DOPA treatment for several years. Thus, a new 'L-DOPA-sparing' paradigm for treating Parkinson's disease may now be possible, whereby patients are initially treated with pramipexole and L-DOPA is added only as necessary.

Animals↗
PubMed1999

A novel acidotropic pH indicator and its potential application in labeling acidic organelles of live cells.

BACKGROUND: Ratio imaging has received intensive attention in the past few decades. The growing potential of ratio imaging is significantly limited, however, by the lack of appropriate fluorescent probes, for acidic organelles in particular. The classic fluorescent dyes (such as fluoresceins, rhodamines and coumarins) are not suitable for studying acidic organelles (such as lysosomes) because their fluorescence is significantly decreased under neutral or acidic conditions. This has motivated us to develop probes that can be used in ratio imaging that are strongly fluorescent even in acidic media. RESULTS: The compound 2-(4-pyridyl)-5-((4-(2-dimethylaminoethyl-aminocarbamoyl) methoxy)phenyl)oxazole (PDMPO) was prepared and characterized as a new acidotropic dual-excitation and dual-emission pH indicator. It emits intense yellow fluorescence at lower pH and gives intense blue fluorescence at higher pH. This unique pH-dependent fluorescence property was readily explored to selectively stain lysosomes and to determine the pH of the organelle in an emission-ratio-imaging mode. PDMPO is selectively localized to lysosomes and exhibits a pH-dependent dual excitation and emission. CONCLUSIONS: PDMPO selectively labels acidic organelles (such as lysosomes) of live cells and the two distinct emission peaks can be used to monitor the pH fluctuations of live cells in ratio measurements. Additionally, the very large Stokes shift and excellent photostability of PDMPO make the compound an ideal fluorescent acidotropic probe. The unique fluorescence properties of PDMPO might give researchers a new tool with which to study acidic organelles of live cells.

Acids↗
PubMed2000

A glimpse of a possible amyloidogenic intermediate of transthyretin.

Studies have indicated that partially unfolded states occur under conditions that favor amyloid formation by transthyretin (TTR), as well as other amyloidogenic proteins. In this study, we used hydrogen exchange measurements to show that there is selective destabilization of one half of the beta-sandwich structure of TTR under such conditions. This provides more direct information about conformational fluctuations than previously available, and will facilitate design of future experiments to probe the intermediates critical to amyloid formation.

Amides↗
PubMed2003

Coevolution in temporally variable environments.

Many potentially mutualistic interactions are conditional, with selection that varies between mutualism and antagonism over space and time. We develop a genetic model of temporally variable coevolution that incorporates stochastic fluctuations between mutualism and antagonism. We use this model to determine conditions necessary for the coevolution of matching traits between a host and a conditional mutualist. Using an analytical approximation, we show that matching traits will coevolve when the geometric mean interaction is mutualistic. When this condition does not hold, polymorphism and trait mismatching are maintained, and coevolutionary cycles may result. Numerical simulations verify this prediction and suggest that it remains robust in the presence of temporal autocorrelation. These results are compared with those from spatial models with unrestricted movement. The comparisons demonstrate that gene flow is unnecessary for generating empirical patterns predicted by the geographic mosaic theory of coevolution.

Animals↗
PubMed2005

Virological profiles in hepatitis B virus inactive carriers: monthly evaluation in 1-year follow-up study.

UNLABELLED: STUDY SUBJECT: We longitudinally evaluated the virological behaviour and the hepatitis B virus (HBV) genomic variability in inactive HBV surface antigen (HBsAg) chronic carriers. PATIENTS AND METHODS: Fourteen HBsAg-positive healthy workers (13 inactive carriers and 1 with active HBV infection) were followed up for 12 months by monthly evaluation of aminotransferase, HBV DNA, and IgM anti HBV core antigen (IgM anti-HBc) values. Moreover, HBV serum isolates from each case were amplified, cloned and sequenced to evaluate the presence of the potentially clinical relevant core-promoter and precore mutations. The same technical procedures were used to examine the S gene of isolates from 3 randomly selected inactive carriers and the patients with active HBV infections. RESULTS: Aminotransferase values were constantly normal in all cases. Viremia levels appear to fluctuate widely over time in each individual case, although the HBV DNA remained below 2 x 10(4) copies/ml in all samples. Only four serum samples from two inactive carriers had IgM anti-HBc values higher than the specific cut-off limit of the assay. Either wild type or core-promoter/precore HBV variants or a mixture of them were detected in the inactive carriers. S gene nucleotide homology among the clones from the three inactive carriers and the subject with active infection was 98.9%, 98.3%, 98.1% and 98.2%, respectively. CONCLUSIONS: The degree of suppression of HBV replication in inactive carriers is variable over time, and the entity and quality of HBV variability is comparable between active and inactive carriers.

Adult↗
PubMed2005

A large, voltage-dependent channel, isolated from mitochondria by water-free chloroform extraction.

We examined ion channels derived from a chloroform extract of isolated, dehydrated rat liver mitochondria. The extraction method was previously used to isolate a channel-forming complex containing poly-3-hydroxybutyrate and calcium polyphosphate from Escherichia coli. This complex is also present in eukaryotic membranes, and is located primarily in mitochondria. Reconstituted channels showed multiple subconductance levels and were voltage-dependent, showing an increased probability of higher conductance states at voltages near zero. In symmetric 150 mM KCl, the maximal conductance of the channel ranged from 350 pS to 750 pS. For voltages >+/-60 mV, conductance fluctuated in the range of approximately 50- approximately 200 pS. In the presence of a 1:3 gradient of KCl, at pH = 7.4, selectivity periodically switched between different states ranging from weakly anion-selective (V(rev) approximately -15 mV) to ideally cation-selective (V(rev) approximately +29 mV), without a significant change in its conductance. Overall, the diverse, but highly reproducible, channel activity most closely resembled the behavior of the permeability transition pore channel seen in patch-clamp experiments on native mitoplasts. We suggest that the isolated complex may represent the ion-conducting module from the permeability transition pore.

Animals↗
PubMed1995

Post-1945 international migration: New Zealand, Australia and Canada compared.

"New Zealand's immigration policies and trends since 1945 are compared with those of Canada and Australia. For most of this period, Australia has pursued the more expansive immigration policy while Canada and New Zealand have tended to link immigration intakes to fluctuations in labor demand. All three countries initially discriminated against non-European immigrants but gradually moved towards nondiscriminatory policies based on similar selection criteria and means of assessment. New Zealand has traditionally been more cautious than both Canada and Australia in terms of how many immigrants it accepted and from what sources, but it has recently followed the other two in raising immigration targets encouraging migration from nontraditional sources, particularly Asian countries. Historical, global and national factors are drawn upon to explain the degree of convergence between these three societies."

Americas↗
PubMed1992

[Laser-Doppler flowmetry].

Laser-Doppler flowmetry (LDF) is a non-invasive technique for measuring the tissue blood flow. It has been shown in the skin that LDF discloses blood flow fluctuations due to vasomotor nerve activity. LDF can give measurements of blood flow at various sites of different tissue. Furthermore, LDF may enable selective measurement of blood flow at different depths within the tissue, when the device and the probe are appropriately chosen. Thus, LDF is available for examining vasomotor responses at various tissue sites. For clinical application, a method for calibrating the LDF signal in absolute units should be established.

Autonomic Nervous System Diseases↗
PubMed1986

Clinical and pharmacokinetic concerns of 24-hour dosing with theophylline.

Selection of the dosing interval for oral theophylline must consider the product's absorption rate, the patient's elimination rate, and the tolerated fluctuation in serum concentration. Attempts to produce formulations with ultra-slow absorption for "once daily" marketing have thus far resulted in incomplete and erratic absorption.

Absorption↗
PubMedDate not supplied

Selective suppression of autoantibody responses in NZB/NZW mice treated with long-term cyclophosphamide.

Autoimmune responses were assayed in 80 cyclophosphamide-treated and control NZB/NZW mice over a period of 1 year. Fluctuation between positive and negative immunofluorescent heterogeneous ANA tests and daily alterations of ANA titers were detected in young mice of both sexes. Although high-dose cyclophosphamide therapy (8 mg/kg/day) failed to prevent the spontaneous appearance of ANA, titered ANA values were partially suppressed in high-dose treated mice. This study permitted sequential comparisons between ANA titers and anti-DNA as useful indices of cyclophosphamide-induced suppression of autoimmune disease. ANA titers were relatively resistant to cyclophosphamide therapy. Antibodies directed specifically against DNA were suppressed mice receiving high-dose cyclophosphamide. In treated animals, decreased anti-DNA levels were associated with protection from severe glomerulonephritis and renal vasculitis. Treatment with low-dose cyclophosphamide (1 mg/kg/day) appeared paradoxically to stimulate autoantibody production and renal disease/vasculitis.

Animals↗
PubMed1994

The occurrence of heritable Mu excisions in starving cells of Escherichia coli.

A strain of Escherichia coli constructed by Shapiro has a segment of Mu bacteriophage DNA inserted between the araC and lacZ genes. Excision events that produce an in-frame fusion of lacZ to araB result in a cell (here designated Ara-Lac+) that can grow on lactose if arabinose is present as an inducer. Whether or not these excision events occur in the absence of selection for the Ara-Lac+ phenotype has figured prominently in the debate of the phenomenon known as 'directed' or 'adaptive' mutation. In an attempt to settle the issue, we have used classic fluctuation tests to show that cells capable of producing a clone of descendants that are phenotypically Ara-Lac+ do, indeed, arise in stationary phase cultures kept starving in depleted minimal medium. We found that Ara-Lac+ progenitors arise rapidly under these conditions, in contrast to the delayed appearance of Ara-Lac+ mutants when cells are incubated on lactose-arabinose minimal plates. Similar results are reported in the accompanying paper by Maenhaut-Michel and Shapiro, who used indirect selection to isolate Ara-Lac+ cells in the absence of selection. However, their sequencing data have introduced a new unexpected complication to the interpretation of all such experiments, and it is no longer clear exactly when the fusions arise.

Arabinose↗
PubMed2006

Characterization of cycA mutants of Escherichia coli. An assay for measuring in vivo mutation rates.

Quantitative assessment of the spontaneous or induced genomic mutation rate, a fundamental evolutionary parameter, usually requires the use of well-characterized mutant selection systems. Although there is a great number of genetic selection schemes available in Escherichia coli, the selection of D-cycloserine resistant mutants is shown here to be particularly useful to yield a general view of mutation rates and spectra. The combination of a well-defined experimental protocol with the Ma-Sandri-Sarkar maximum likelihood method of fluctuation analysis results in reproducible data, adequate for statistical comparisons. The straightforward procedure is based on a simple phenotype-genotype relationship, and detects mutations in the single-copy, chromosomal cycA gene, involved in the uptake of D-cycloserine. In contrast to the widely used rifampicin resistance assay, the procedure selects mutations which are neutral in respect of cell growth. No specific genetic background is needed, and practically the entire mutation spectrum (base substitutions, frameshifts, deletions, insertions) can simultaneously be measured. A systematic analysis of cycA mutations revealed a spontaneous mutation rate of 6.54 x 10(-8) in E. coli K-12 MG1655. The mutation spectrum was dominated by point mutations (base substitutions, frameshifts), spread over the entire gene. IS insertions, caused by IS1, IS2, IS3, IS4, IS5 and IS150, represented 24% of the mutations.

Amino Acid Transport Systems↗
PubMed1997

[Segawa disease].

Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation) is an autosomal dominant, childhood onset, postural dystonia and the first hereditary basal ganglia disorder whose causative enzyme and gene defect were clarified. The initial symptom is unilateral pes equinovarus with marked diurnal fluctuation. Progression becomes slower after mid-teens and stationary after thirties. Postural tremor may occur after 10 years of age, especially after thirties. Parkinsonian resting tremor action and torsion dystonia. and disturbed locomotion do not occur. L-Dopa shows marked and sustained effect without side effects. F-Dopa PET and [11C] raclopride PET of over 20-year-old cases are normal. Deficiency of GTP cyclohydrolase I (GCH-I) was suggested from low CSF biopterin and neopterin. Mutation of GCH-I gene and decreased GCH-I were clarified as etiology. Twenty-five mutations discordant among families have been found. Autopsy of a gene proven case revealed decreased striatal tyrosine hydroxylase (TH) and dopamine (DA) in ventral striatum where direct pathway is predominant. Decreased GCH-I causes decreased tetrahydrobiopterin (BH4), TH and DA in nigrostriatal (NS) terminal. The lowest affinity of BH4 to TH causes selective involvement of DA. Postural dystonia is caused by decreased TH and DA affecting D1-direct pathway. Thalamic ventrolateral and pedunculo-pontine nuclei are spared. Diurnal fluctuation of symptoms is due to diurnal fluctuation of TH and DA at NS-DA terminal. Decreased DA to below 20% of normal, shown by polysomnographical studies, and its physiological age related decremental changes in NS-DA terminal underlies characteristic clinical course. High D2 receptor before early thirties masks D1 related hypertonus and manifest progression before 20 years of age. Other pteridine abnormalities also cause dopa responsive postural dystonia with diurnal fluctuation. A case of juvenile parkinsonism without dystonia showed decreased TH in dorsolateral putamen where indirect pathway is predominant. These suggest that decreased TH due to decreased BH4 involves D1-direct pathway causing dystonia, and decreased TH itself involves D2-indirect pathway causing parkinsonism.

Adolescent↗