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PubMed1980

Quantitative structure-pharmacokinetic relationships derived on antibacterial sulfonamides in rats and its comparison to quantitative structure-activity relationships.

Quantitative structure-pharmacokinetic relationships have been derived for a series of substituted 2-sulfapyridines. Pharmacokinetic parameters, such as elimination rate constant (ke), clearance (Cl), and protein-binding constant (Kassoc), have been determined in rats. The observed variation is statistically significant, explained by changes in the lipophilic (deltaRm), electronic (pKa), and steric effects (I, ES) of the substituents. The obtained correlations are discussed with respect to the previously derived correlations for the antibacterial activity of these compounds. A scale up of the results opens up the possibility of a rational synthesis of highly active sulfonamides with special pharmacokinetic properties because lipophilicity influences strongly the pharmacokinetic properties, whereas no influence on the degree of antibacterial effect is observed. Steric substituent influence is opposite on specific binding to bacterial enzymes and unspecific binding to serum proteins.

Animals↗

PubMed2006

Mining gene expression data by interpreting principal components.

BACKGROUND: There are many methods for analyzing microarray data that group together genes having similar patterns of expression over all conditions tested. However, in many instances the biologically important goal is to identify relatively small sets of genes that share coherent expression across only some conditions, rather than all or most conditions as required in traditional clustering; e.g. genes that are highly up-regulated and/or down-regulated similarly across only a subset of conditions. Equally important is the need to learn which conditions are the decisive ones in forming such gene sets of interest, and how they relate to diverse conditional covariates, such as disease diagnosis or prognosis. RESULTS: We present a method for automatically identifying such candidate sets of biologically relevant genes using a combination of principal components analysis and information theoretic metrics. To enable easy use of our methods, we have developed a data analysis package that facilitates visualization and subsequent data mining of the independent sources of significant variation present in gene microarray expression datasets (or in any other similarly structured high-dimensional dataset). We applied these tools to two public datasets, and highlight sets of genes most affected by specific subsets of conditions (e.g. tissues, treatments, samples, etc.). Statistically significant associations for highlighted gene sets were shown via global analysis for Gene Ontology term enrichment. Together with covariate associations, the tool provides a basis for building testable hypotheses about the biological or experimental causes of observed variation. CONCLUSION: We provide an unsupervised data mining technique for diverse microarray expression datasets that is distinct from major methods now in routine use. In test uses, this method, based on publicly available gene annotations, appears to identify numerous sets of biologically relevant genes. It has proven especially valuable in instances where there are many diverse conditions (10's to hundreds of different tissues or cell types), a situation in which many clustering and ordering algorithms become problematic. This approach also shows promise in other topic domains such as multi-spectral imaging datasets.

Algorithms↗

PubMed1998

Glucocorticoids induce G1 as well as S-phase lengthening in normal human stimulated lymphocytes: differential effects on cell cycle regulatory proteins.

In order to analyze dexamethasone effects on peripheral blood lymphocyte proliferation, we defined various experimental conditions: dexamethasone introduced (i) at the time of phytohemagglutinin stimulation, (ii) 48 h after the beginning of phytohemagglutinin stimulation, and (iii) on unstimulated lymphocytes. In stimulated lymphocytes, we observed an early G1 accumulation (P < 0.005), a delayed increase in the duration of S-phase (P < 0.03), and a consequent increase in cell-cycle duration. The expression of several cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) was modified. Cyclin D3, CDK4, and CDK6 involved in G1-phase control were significantly decreased under dexamethasone treatment whatever the level of stimulation of lymphocytes (stimulated or unstimulated PBL). Cyclin E and CDK2, acting in G1/ S-phase transition and S-phase regulation, decreased in stimulated lymphocytes before any modification of S-phase (P < 0.002). The expression of CKIs, mainly of p27Kip1, appeared to vary with the degree of cell stimulation: a decrease was observed on treated unstimulated lymphocytes, while p27Kip1 increased in dexamethasone-treated cells during stimulation. Our results indicate sequential modifications of the cell-cycle regulation by dexamethasone starting with an action on G1 followed by S-phase control modifications. The protein analysis pinpoints the major complexes concerned: CDK4 and CDK6/cyclin D are mainly involved in G1-phase modifications, while CDK2 and its partner, cyclin E, might be specifically involved in the lengthening of S-phase. The variations observed for p27Kip1 might amplify the functional effects of dexamethasone on kinasic complexes.

Apoptosis↗

PubMed2004

Bayesian spatial and ecological models for small-area accident and injury analysis.

In this article, recently developed Bayesian spatial and ecological regression models are applied to analyse small-area variation in accident and injury. This study serves to demonstrate how Bayesian modelling techniques can be implemented to assess potential risk factors measured at group (e.g. area) level. Presented here is a unified modelling framework that enables thorough investigations into associations between injury rates and regional characteristics, residual variation and spatial autocorrelation. Using hospital separation data for 83 local health areas in British Columbia (BC), Canada, in 1990-1999, we explore and examine ecological/contextual determinants of motor vehicle accident injury (MVAI) among male children and youth aged 0-24 and for those of six age groups (<1, 1-4, 5-9, 10-14, 15-19 and 20-24). Eighteen local health area characteristics are studied. They include a broad spectrum of socio-economic indicators, residential environment indicators (roads and parks), medical services availability and utilisation, population health, proportion of recent immigrants, crime rates, rates of speeding charge and rates of seatbelt violation. Our study indicates a large regional variation in MVAI in males aged 0-24 in British Columbia, Canada, in 1990-1999, and that adjusting for appropriate risk factors eliminates nearly all the variation observed. Socio-economic influence on MVAI was profoundly apparent in young males of all ages with the injury being more common in communities of lower socio-economic status. High adult male crime rates were significantly associated with high injury rates of boys aged 1-14. Seatbelt violations and excess speeding charges were found to be positively associated with the injury rates of young men aged 20-24. This and similar ecological studies shed light on reasons for regional variations in accident occurrence as well as in the resulting injuries and hospital utilisation. Thereby they are potentially useful in identifying priority areas for injury/accident prevention and in informing regional health planning and policy development.

Accidents↗

PubMed2003

Binding of poly(amido amine) dendrimer to sodium hyaluronate in aqueous NaCl solution.

Binding of poly(amido amine) dendrimer to sodium hyaluronate (NaHA) in aqueous 0.25 M NaCl solution has been investigated by static light scattering. It was observed that the apparent weight-average molecular weight and the radius of gyration increase with the ratio of NH(2) terminal groups in the dendrimer to the carboxylate groups in the NaHA, [NH(2)]/[COO(-)]. Up to [NH(2)]/[COO(-)]=31, the observed variation of molecular weight was reproduced by the "average binding" model, where an average number of dendrimers binds to each NaHA chain. Based on the "critical binding" model, the maximum number, n(max), of dendrimers which can bind to a NaHA chain was calculated to be n(max)=300 for a solution of [NH(2)]/[COO(-)]=56. The obtained value corresponds to the binding of one dendrimer per 1.5 repeating units on a NaHA chain. It is suggested from the observed radius of gyration that, while the dendrimer-NaHA complexes of [NH(2)]/[COO(-)] up to 5 maintain a wormlike character similar to NaHA without bound dendrimers, those of [NH(2)]/[COO(-)] above 10 behave like rigid rods. It is concluded that the hydrogen-bonding interaction, besides the electrostatic interaction, should play an important role in the formation of the NaHA-dendrimer complexes.

Carboxylic Acids↗

PubMed2004

Phenotype-genotype relationships of SULT1A1 in human liver and variations in the IC50 of the SULT1A1 inhibitor quercetin.

Human sulfotransferases catalyze sulfate conjugation and 2 polymorphic genes, SULT1A1 and SULT1A2 in this family of transferases have been identified, encoding for 2 isoenzymes with very similar properties and substrate specificities. In order to test the hypothesis that variability in sulfation is due to genetic polymorphism in SULT1A1, the sulfation rate of 4-nitrophenol, a diagnostic substrate, was measured in 50 human liver samples and the genotype at the SULT1A1 locus was analyzed. The rate of 4-nitrophenol sulfation varied from 473 - 1,405 pmol/min/mg between the 5th and 95th percentiles, with a median and a mean +/- SD of 757 and 807 +/- 292 pmol/min/mg, respectively. The activities detected among the SULT1A1*2/*2 homozygotes (5 cases) were significantly lower than those of the other 2 genotypes, SULTA1*11/*1 and SULT1A1*1/*2 (5 and 40 cases, respectively), whereas there was no significant difference found between the SULT1A1*1/*1 and SULT1A1*1/*2 genotypes. To evaluate the possible influence of SULT1A2 polymorphism, genotype assays were also performed for this locus. No SULT1A2*2/*2 carrier, 26 SULT1A2*1/*1 and 24 SULT1A2*1/*2 were detected in the population sample under study. However, no correlation between the rate of 4-nitrophenol sulfation and the SULT1A2 genotype was detected. These results confirm that the variation in the rate of 4-nitrophenol sulfation in human liver is mainly due to SULT1A. Since SULT1A1*1/*2 polymorphism accounts for no more than 10% of the phenotypic variation seen in this cohort, other factors must also contribute to the variability in the rate of 4-nitrophenol sulfation in human liver. However, on the basis of the data obtained, variations in age, gender and liver function as possible causative factors can be excluded. The IC50 of quercetin, a potent inhibitor of 4-nitrophenol sulfation, was measured in the liver samples and ranged from 4.6 to 17.3 nM between the 5th and 95th percentiles. The median and the mean +/- SD were 7.7 nM and 8.3 +/- 2.5 nM, respectively. There was a weak but significant correlation between the IC50 value and age of the liver donors (r = 0.283, p = 0.046). The observed variation did not correlate with the genotypes at the SULT1A1 and SULT1A2 loci.

Adult↗

PubMed1998

Differential in vitro modulation of Schwann cell proliferation by Mycobacterium leprae and macrophages in the murine strains, Swiss white and C57Bl/6.

The special susceptibility of Schwann cells (SCs) to parasitization by M. leprae and of macrophages to M. leprae-induced defects implicates them in leprous nerve pathogenesis. SC proliferation is an important prerequisite for peripheral nerve regeneration and is regulated by a number of secretory factors. Several of these factors are secreted by SCs themselves as well as by the macrophages which are recruited at the site of lesion to assist in regeneration. SC proliferation, as indicated by 3H-thymidine incorporation, was therefore studied in response to M. leprae infection and in the presence of macrophages in order to determine the role of SC in leprous neuropathy. Cells derived from two strains of mice, Swiss White (SW) and C57Bl/6 were used, as macrophages from these strains have been shown to differ in their response to M. leprae; such differences are similar to those observed in macrophages from lepromatous and tuberculoid leprosy patients, respectively. Infection with M. leprae for a duration of 9 days resulted in reduced proliferation of SCs from SW strain, while SCs from C57Bl/6 remained unaffected. However, in the presence of macrophages, SCs from both strains not only showed enhanced proliferation, but SW SCs also overcame the M. leprae-induced suppression of their proliferation. Altered SC proliferation, therefore, can be implicated as a factor in leprous nerve pathogenesis. The strain variation observed in the response of SCs indicate different nerve damage mechanisms in lepromatous and tuberculoid patients.

Animals↗

PubMed1988

[Variations in protein levels in the hemolymph, hepatopancreas and ovary of Penaeus schmitti during ovarian maturation (Crustacea, Decapoda, Peneidae)].

Variations of protein concentrations in the haemolymph, hepatopancreas and ovaries were studied during the ovarian maturation of the shrimp Penaeus schmitti. The main variations observed during this physiological process are the increase of protein and the decrease of water contents in the ovary, more pronounced at the first stages of gonadosomatic index (GSI:0-4). During ovarian maturation, water content of the ovaries and hepatopancreas decrease from 10.7 and 3.9% respectively. In relative values, protein content increases from about 40.0% in the ovary, 47.5% in the haemolymph and 15.4% in the hepatopancreas. In absolute values, the protein concentrations of the hepatopancreas showed no significant variation. In the opposite, ovary protein content is 14.7 fold higher at the end than the early stages of vitellogenesis. Relations between haemolymph, hepatopancreas and ovary with eventual transfers of protein material are discussed.

Animals↗

PubMed2004

Monitoring of reduced sulfur compounds in the atmosphere of Gosan, Jeju Island during the Spring of 2001.

The atmospheric concentrations of dimethylsulfide (DMS) and carbon disulfide (CS2) were measured concurrently with relevant environmental parameters at Gosan, Jeju Island, Korea during 5-26 April 2001. The mean concentrations for these two compounds were 18.7+/-17.9 and 6.4+/-9.9 pptv, respectively. Results of our analysis indicated that relative temporal variations between DMS and CS2 can be best described by dividing the whole data set into three different periods which reflect the variable transport patterns of air masses into the study area. (Periods I, II, and III denote: 5-10, 10-18, and 19-26 April.) The environmental conditions during those three periods varied greatly. The effects of continental and/or oceanic processes were evident for certain periods, yielding diverse relationships between DMS and CS2 in both absolute and relative terms. Most observed variations were best explained in terms of an interplay between source/sink processes and air mass transport patterns. The sea-to-air flux of DMS, when estimated using our measurement data during this study period, was approximately 4 micromole m(-2)d(-1).

Air Pollutants↗

PubMed2005

Testing species boundaries in the Antrodiaetus unicolor complex (Araneae: Mygalomorphae: Antrodiaetidae): "paraphyly" and cryptic diversity.

The inability to correctly identify species has far reaching implications in nearly all areas of biology, yet few studies investigate methods for delineating species boundaries. Moreover, once these boundaries have been hypothesized, little thought has been given to how these constructs can be further evaluated. We employ a molecular phylogenetic approach using nuclear 28S rRNA and mitochondrial cytochrome c oxidase subunit I genes to test the general efficacy of species boundaries in the Antrodiaetus unicolor spider species complex. Our analyses provide evidence that An. unicolor is "paraphyletic" with respect to An. microunicolor, indicating that morphological criteria used to delineate species boundaries undersplits actual species-level diversity in this group of spiders. These analyses also demonstrate that individuals from geographically proximate populations sometimes exhibit considerable molecular divergence, strongly suggesting that An. unicolor is a cryptic species complex. Finally, this molecular approach has provided the phylogenetic framework that is necessary to begin interpreting the vast amount of morphological variation observed in these spiders based upon findings from previous studies. Our approach using multiple genes appears to be a rigorous method to critically examine species boundaries originally based on traditional morphological approaches to spider taxonomy.

Animals↗

PubMed1994

Evolution of acetylcholinesterase transcripts and molecular forms during development in the central nervous system of the quail.

We studied the expression of acetylcholinesterase (AChE) in the nervous system (cerebellum, optic lobes and neuroretina) of the quail at different stages of development, from embryonic day 10 (E10) to the adult. Analyzing AChE mRNAs and AChE molecular forms, we observed variations in the following: (a) production of multiple mRNA species (4.5 kb, 5.3 kb, and 6 kb); (b) translation and/or stability of the AChE protein; (c) production of active and inactive AChE molecules; (d) production of amphiphilic and nonamphiphilic AChE forms; and (e) proportions of tetrameric G4, dimeric G2, and monomeric G1 forms. The large transcripts present distinct temporal patterns and disappear in the adult, which possesses only the 4.5-kb mRNA; these changes are unlikely to be related to those observed for the AChE protein, because all transcripts seem to encode the same catalytic subunit (type T). In addition, the levels of mRNA and AChE are not correlated in the three regions, especially at the adult stage. The proportion of inactive AChE was found to be markedly higher at the hatching period (E16) than at earlier stages (E10 and E13) or in the adult. The G4 form is predominant already at E10, and in the adult its proportion reaches 80% of the activity in the cerebellum and optic lobes, and 65-70% in the neuroretina. This form is largely nonamphiphilic in embryonic tissues, but it becomes progressively more amphiphilic with development. Thus, the different processing and maturation steps appear to be regulated in an independent manner and potentially correspond to physiologically adaptative mechanisms.

Acetylcholinesterase↗

PubMed2000

MtDNA polymorphism in the Hungarians: comparison to three other Finno-Ugric-speaking populations.

Mitochondrial DNA sequence variation as well as restriction site polymorphisms were examined in 437 individuals from four Finno-Ugric-speaking populations. These included the Hungarians (Budapest region and the Csángós from Hungary and Romania), the Finns and two Saami groups from northeastern Finland (Inari Saami and Skolt Saami), and the Erzas from central Russia. The mtDNA data obtained in this study were combined with our previous data on Y chromosomal variation for eight different loci in these populations. The genetic variation observed among the Hungarians resembled closely that found in other European populations. The Hungarians could not be distinguished from the neighboring populations (e.g., the Austrians) any more than from their Finno-Ugric linguistic relatives.

DNA, Mitochondrial↗

PubMed1992

Fitting genetic models to Carabelli trait data in South Australian twins.

This study aimed to clarify genetic and environmental contributions to Carabelli trait variation on permanent first molar teeth in a large sample of South Australian twins. Estimates of polychoric correlations were obtained between pairs of monozygous (MZ) and dizygous (DZ) twins for Carabelli data and various gene-environment models fitted by a weighted least-squares approach. The favored model included additive genetic effects together with both a general environmental component and an environmental effect specific to each side. An estimate of heritability around 90% indicated a very strong genetic contribution to observed variation. The pattern of correlations for MZ and DZ data suggested that further studies involving other types of relatives would be worthwhile for detection of possible non-additive genetic effects of dominance or epistasis.

Adolescent↗

PubMed2004

Deep brain stimulation for dystonia confirming a somatotopic organization in the globus pallidus internus.

OBJECT: In patients with dystonia, symptoms vary greatly in their extent and severity. The efficacy of pallidal stimulation is now established, but an interindividual variability in the responses to this treatment exists. A retrospective analysis of postoperative magnetic resonance (MR) images demonstrated millimetric variations in the positions of electrode contacts inside the posterolateroventral portion of the globus pallidus internus (GPi). It therefore seemed very likely that there is a somatotopic organization within the GPi. The goal of this study was to examine the positions of specific electrode contacts according to patients' clinical evolution, so that a somatotopic organization within the GPi could be defined. METHODS: This study included 19 patients (17 of whom were right handed) with generalized dystonia who were treated by bilateral stimulation of the GPi. Patients were examined pre- and postoperatively by using the Burke-Fahn-Marsden Dystonia Rating Scale. Dividing the patient's body into three parts--cervicoaxial area, superior limb, and inferior limb--we determined the following: 1) where the dystonic symptoms started; 2) where symptoms predominated at the time of surgery; and 3) where the highest postoperative improvement was observed. Variations in clinical response were correlated to the positions of the electrode contacts. All activated electrode contacts were in the posterolateroventral portion of the GPi (Laitinen target). A correlation between the contact location measured longitudinally and the part of the body in which the highest improvement was observed (three different areas; p = 0.004) showed that a location more anterior for the inferior limb and one more posterior for the superior limb were delineated for the right side, but not for the left side. CONCLUSIONS: Inside the posterolateroventral subvolume of the GPi on the right side, three statistically different locations of electrode contacts were determined to be primary deep brain stimulation treatment sites for particular body parts in cases of dystonia.

Adult↗

PubMed1996

Novel isoforms of synexin in Xenopus laevis: multiple tandem PGQM repeats distinguish mRNAs in specific adult tissues and embryonic stages.

Synexin (annexin VII) is a calcium-dependent, phospholipid-binding and membrane fusion protein in the annexin gene family, which forms calcium channels and may play a role in exocytotic secretion. We report here the cloning and characterization of five novel isoforms of cDNAs encoding Xenopus synexin from brain, oocyte and stage 24 cDNA libraries. The most prevalent Xenopus synexin has 1976 bp of cDNA sequence, which contains a 1539 bp open reading frame of 512 amino acids encoding a 54 kDa protein. This Xenopus protein is 6 kDa larger than the previously reported human and mouse synexins with which it shares approx. 73% identity in the C-terminal region and approx. 44% identity in the N-terminal region. Further studies with PCR revealed the molecular basis of the substantial divergence in the Xenopus synexin's N-terminal domain. The domain equivalent to the mammalian tissue-specific cassette exon occurs at a different position and is variable in size and sequence. The most interesting observation relates to the occurrence of different forms of synexin due to the varying numbers of tandem PGQM repeats that are expressed differently in different adult tissues and embryonic stages. For these reasons we have labelled this set of unique isoforms annexin VIIb, referring to mammalian forms, which lack the PGQM tandem repeats, as annexin VIIa. In spite of these differences from annexin VIIa, the form of recombinant annexin VIIb with three PGQM repeats was found to be catalytically active. We interpret these results to indicate that the actual calcium and phospholipid binding sites are conserved in Xenopus, and that the variations observed between members of the synexin gene family in the regulatory domain clearly point towards the tissue- and stage-specific roles of individual members, possibly involving the exocytotic process.

Amino Acid Sequence↗

PubMed1983

Occurrence and seasonal variation of 19-norcholest-4-en-3-one and 3 beta-monohydroxy sterols in the Californian gorgonian, Muricea californica.

The first natural occurrence of 19-norcholestenone is reported, together with 17 sterols and one other delta 4-3-ketone in the extracts of the Californian gorgonian, Muricea californica (Aurivillius). Six additional demethyl sterols and five additional 4-monomethyl sterols which remain unidentified were also detected. Lipid extracts of M. californica from a winter and summer collection were split by various chromatographic methods into free sterol, steryl ester, and steryl conjugate fractions. Sterol compositions (determined by CG and CG-MS) of each fraction, subsequent to hydrolysis, are tabulated and discussed with respect to plausible origins of observed variations. The possible relationship of the Muricea 19-nor-steroidal ketone to other naturally occurring 19-nor-steroids is discussed.

Animals↗

PubMed1976

Functional adaptation of sarcomere number of normal cat muscle.

1. Physiological and histological data were obtained from soleus and tibialis anterior muscles of normal adult cats to study to what extent fibre length and sarcomere number varied between animals and how this was related to the physiological characteristics of the muscles. 2. For a given muscle, the variation in the sarcomere number of individual muscle fibres between animals was found to be about 25%. These difference could partly be explained by comparing the number of sarcomeres and the length of the fibula, which was chosen as an index of the size of the animal. The average sarcomere number in the tibialis anterior muscle was about 60% greater than in the soleus. The variations between animals and between the anterior tibialis and soleus muscles were significantly greater than the variations observed within the same muscle. 3. The sarcomere length is dependent upon the articular angle, that is to say, the length change imposed on the muscle. These length changes are more extensive in the soleus muscle (100%) than in the tibialis anterior muscle (60%). A very significant correlation was found between articular angle and sarcomere length (for soleus r = 0.98, for tibialis anterior r = 0.94). 4. Although fibre length did vary considerably within a given muscle, the sarcomere length showed only minor variations at any given angle. This suggests that sarcomere number is determined in each individual muscle fibre. Such an adaptation implies a concomitant adaptation of the tendinous part of the fibre. This adaptation, resulting in definite sarcomere length at a definite angle, has obvious physiological implications. 5. Conventional length vs. active tension curves were established for the soleus and the tibialis anterior muscles. It is suggested that the difference between the sarcomere number of the two muscles may result in the difference between the shape of curves of these two muscles. 6. Active torque-angle curves were established for the two muscles in situ. The shapes of the curves for soleus and tibialis anterior are similar in spite of the different mechanical conditions of the two muscles. This fact helps to explain why the two muscles, despite their similar articular range, had very different sarcomere number.

Adaptation, Physiological↗

PubMed2003

Effects of working memory demands on frontal slow waves in time-interval reproduction tasks in humans.

Very few studies have examined the event-related potentials associated with the retention of temporal information for later use. In the present experiment, event-related potentials were recorded during two duration reproduction tasks in which a delay was introduced between the encoding and the reproduction phases. Furthermore, working memory demands were varied during the delay (number of durations to be memorized and degree of manipulation of the durations). These variables had no significant effect on the amplitude of the contingent negative variation observed during duration encoding. By contrast, the amplitude of the slow wave recorded over middle frontal regions during the delay increased with working memory demands, which confirms the key role played by these frontal regions in the cognitive processes engaged during the retention of duration in working memory.

Adult↗