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PubMed1994

Analysis of the genetic requirements for inducible multiple-antibiotic resistance associated with the mar locus in Escherichia coli.

A series of novel genetic constructs derived from the marRAB operon was used to determine the role of this gene cluster in salicylate-inducible multiple-antibiotic resistance in Escherichia coli. Our findings indicate that regulated antibiotic resistance associated with this locus requires only the products of marR and marA, without any neighboring genes.

Bacterial Proteins↗

PubMed2026

Diverse haplotypes at a complex Solanum americanum locus confer resistance to Phytophthora infestans and P. capsici.

Plants encounter diverse pathogens and have evolved a two-layered innate immune system to detect pathogen molecules and activate defense mechanisms that restrict infection. Most cloned plant Resistance (R) genes encode NLR immune receptors. NLR genes are often found in clusters of paralogs with sequence and copy number variation; whether these NLR clusters evolve in response to single or multiple pathogens has been unclear. We report here the isolation of a Phytophthora capsici resistance gene, Rpc2, along with a novel P. infestans resistance gene, Rpi-amr5, from two Solanum americanum accessions. These orthologous genes reside in the Rpi-amr1 cluster, which has previously been associated with resistance to P. infestans. By screening RXLR effector libraries of P. infestans and P. capsici, we identified multiple effectors recognised by both NLRs. Our findings highlight the complexity of NLR clusters and evolution driven by interactions with multiple pathogens. This work will underpin efforts to elevate resistance against Phytophthora pathogens and enhances our understanding of NLR evolution.

Journal Article↗

PubMed2004

Hypercapnic exposure in congenital central hypoventilation syndrome reveals CNS respiratory control mechanisms.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses and loss of breathlessness to hypercapnia, yet arouse from sleep to high CO2, suggesting intact chemoreceptor afferents. The syndrome provides a means to differentiate brain areas controlling aspects of breathing. We used functional magnetic resonance imaging to determine brain structures responding to inspired 5% CO2-95% O2 in 14 CCHS patients and 14 controls. Global signal changes induced by the challenge were removed on a voxel-by-voxel basis. A priori-defined volume-of-interest time trends (assessed with repeated measures ANOVA) and cluster analysis based on modeling each subject to a step function (individual model parameter estimates evaluated with t-test, corrected for multiple comparisons) revealed three large response clusters to hypercapnia distinguishing the two groups, extending from the 1) posterior thalamus through the medial midbrain to the dorsolateral pons, 2) right caudate nucleus, ventrolaterally through the putamen and ventral insula to the mid-hippocampus, and 3) deep cerebellar nuclei to the dorsolateral cerebellar cortex bilaterally. Smaller clusters and defined areas of group signal differences in the midline dorsal medulla, amygdala bilaterally, right dorsal-posterior temporal cortex, and left anterior insula also emerged. In most sites, early transient or sustained responses developed in controls, with little, or inverse change in CCHS subjects. Limbic and medullary structures regulating responses to hypercapnia differed from those previously shown to mediate loaded breathing ventilatory response processing. The findings show the significant roles of cerebellar and basal ganglia sites in responding to hypercapnia and the thalamic and midbrain participation in breathing control.

Adolescent↗

PubMed1979

Follow-up study of chronic gastric erosions.

Chronic gastric erosions were detected with a frequency of 4.4% in 8,468 patients over the six year period from 1971 to 1977. The lesions were usually multiple, chain-like or clustered, along the greater curvature. The age group most often afflicted was the 50-60 year olds, and male predominance were three to one. In one-third of the cases, chronic erosions were found in combination with gastric or duodenal ulceration. Longterm observation of 64 patients over a period of four and a half years revealed no change in the condition in 50%, increase, decrease or complete disappearance of the lesions were found in the remaining 50%. In 10% chain-like multiple erosions developed into a persisting fold in the gastric mucosa. No evidence suggesting that erosive lesions lead to chronic ulceration or development of either polyps or malignancy within 4 1/2 years was recorded, nor was there any association with gastric protein loss.

Adolescent↗

PubMed2006

Gene expression alterations in immune system pathways following exposure to immunosuppressive chemicals.

Exposure to environmental agents can affect a number of adverse immunological outcomes, including changes in the incidence of infectious disease. Diethylstilbestrol (DES), dexamethasone (DEX), cyclophosphamide, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are immunosuppressive chemicals that can induce similar pathophysiological end points in the thymus; however, the mechanism of toxicity is different for each compound. We examined differential gene expression in the spleen and thymus following chemical exposure and correlated these changes with alterations in functional immune end points and our knowledge of the known mechanisms of action. RNA from the spleen and thymus has been analyzed using Illumina Sentrix arrays and BeadStudio software. Preliminary data suggest that DES induced the greatest number of gene changes in the spleen, while DEX induced the most changes in the thymus. In both spleen and thymus, genomic analysis revealed gene expression changes that were common to multiple chemicals and that may be associated with xenobiotic-induced immune system perturbations, including alterations in genes associated with apoptosis, antigen processing and presentation, and response to biotic stimulus. This was particularly evident in the thymus, where there were many similarities in the expression profiles, as well as gene alterations unique to a single compound. In contrast, expression profiles in spleen were more distinct. The category of genes most profoundly affected by all four chemicals was response to biotic stimulus: there were both clusters of genes modulated by multiple chemicals and genes altered by a single chemical. The distinct gene profiles may specifically relate to cellular targets and mechanism of action.

Animals↗

PubMed2006

Multiscale spatial Monte Carlo simulations: multigriding, computational singular perturbation, and hierarchical stochastic closures.

Monte Carlo (MC) simulation of most spatially distributed systems is plagued by several problems, namely, execution of one process at a time, large separation of time scales of various processes, and large length scales. Recently, a coarse-grained Monte Carlo (CGMC) method was introduced that can capture large length scales at reasonable computational times. An inherent assumption in this CGMC method revolves around a mean-field closure invoked in each coarse cell that is inaccurate for short-ranged interactions. Two new approaches are explored to improve upon this closure. The first employs the local quasichemical approximation, which is applicable to first nearest-neighbor interactions. The second, termed multiscale CGMC method, employs singular perturbation ideas on multiple grids to capture the entire cluster probability distribution function via short microscopic MC simulations on small, fine-grid lattices by taking advantage of the time scale separation of multiple processes. Computational strategies for coupling the fast process at small length scales (fine grid) with the slow processes at large length scales (coarse grid) are discussed. Finally, the binomial tau-leap method is combined with the multiscale CGMC method to execute multiple processes over the entire lattice and provide additional computational acceleration. Numerical simulations demonstrate that in the presence of fast diffusion and slow adsorption and desorption processes the two new approaches provide more accurate solutions in comparison to the previously introduced CGMC method.

Algorithms↗

PubMed2005

Double-quantum filtered 1H MAS NMR spectra.

It is shown that straightforward double-quantum filtered (1)H MAS NMR experiments yield spectral lineshapes that permit to estimate the minimum number of (1)H spins in a cluster. The approach may offer an alternative to multiple-quantum experiments for the characterisation of (1)H spin clusters of moderate size. The duration of the double-quantum excitation period has to be chosen suitably, it is necessary to find a practical compromise between optimum double-quantum filtration efficiency and optimum information content of the spectral lineshapes. Some (1)H MAS NMR experiments on partially deuterated maleic acid are reported as well as numerical simulations.

Algorithms↗

PubMed2004

An epidemiologic critique of current microbial risk assessment practices: the importance of prevalence and test accuracy data.

Data deficiencies are impeding the development and validation of microbial risk assessment models. One such deficiency is the failure to adjust test-based (apparent) prevalence estimates to true prevalence estimates by correcting for the imperfect accuracy of tests that are used. Such adjustments will facilitate comparability of data from different populations and from the same population over time as tests change and the unbiased quantification of effects of mitigation strategies. True prevalence can be estimated from apparent prevalence using frequentist and Bayesian methods, but the latter are more flexible and can incorporate uncertainty in test accuracy and prior prevalence data. Both approaches can be used for single or multiple populations, but the Bayesian approach can better deal with clustered data, inferences for rare events, and uncertainty in multiple variables. Examples of prevalence inferences based on results of Salmonella culture are presented. The opportunity to adjust test-based prevalence estimates is predicated on the availability of sensitivity and specificity estimates. These estimates can be obtained from studies using archived gold standard (reference) samples, by screening with the new test and follow-up of test-positive and test-negative samples with a gold standard test, and by use of latent class methods, which make no assumptions about the true status of each sampling unit. Latent class analysis can be done with maximum likelihood and Bayesian methods, and an example of their use in the evaluation of tests for Toxoplasma gondii in pigs is presented. Guidelines are proposed for more transparent incorporation of test data into microbial risk assessments.

Bayes Theorem↗

PubMed2004

Biosphere: the interoperation of web services in microarray cluster analysis.

UNLABELLED: The growing use of DNA microarrays in biomedical research has led to the proliferation of analysis tools. These software programs address different aspects of analysis (e.g. normalisation and clustering within and across individual arrays) as well as extended analysis methods (e.g. clustering, annotation and mining of multiple datasets). Therefore, microarray data analysis typically requires the interoperability of multiple software programs involving different analysis types and methods. Such interoperation is often hampered by the heterogeneity inherent in the software tools (which may function by implementing different interfaces and using different programming languages). To address this problem, we employed the simple object access protocol (SOAP)-based web service approach that provides a uniform programmatic interface to these heterogeneous software components. To demonstrate this approach in the microarray context, we created a web server application, Biosphere, which interoperates a number of web services that are geographically widely distributed. These web services include a clustering web service, which is a suite of different clustering algorithms for analysing microarray data; XEMBL, developed at the European Bioinformatics Institute (EBI) for retrieving EMBL Nucleotide Sequence Database sequence data; and three gene annotation web services: GetGO, GetHAPI and GetUMLS. GetGO allows retrieval of Gene Ontology (GO) annotation, and the other two web services retrieve annotation from the biomedical literature that is indexed based on the Medical Subject Headings (MeSH) terms. With these web services, Biosphere allows the users to do the following: (i) cluster gene expression data using seven different algorithms; (ii) visualise the clustering results that are grouped statistically in colour; and (iii) retrieve sequence, annotation and citation data for the genes of interest. AVAILABILITY: Biosphere and its web services described in Web Service Description Language (WSDL) can be accessed at http://rook.cecid.hku.hk:8280/BiosphereServer.

Cluster Analysis↗

PubMed2005

Phospholipase C isozymes are differentially distributed in the rat adrenal medulla.

Immunohistochemistry has been used to examine the distribution of selected phospholipase C (PLC) isozymes within the adrenal medulla of the rat. PLCbeta isozymes were expressed at moderate levels in the chromaffin cells but more strongly in association with ganglion cell clusters. PLCbeta2 and PLCbeta3 staining of clusters did not overlap suggesting selective PLC isozyme expression in two distinct ganglionic types. The distribution of PLCbeta4 immunoreactivity was very similar to PLCbeta3 with the strongest staining observed in the same cell clusters. Antibodies to PLCbeta1 labelled multiple bands on Western blots and were not therefore used for immunohistochemistry. The chromaffin cells were also immunoreactive for PLCgamma1, although the strongest staining with this antibody was seen in cells surrounding large sinus vessels. PLCdelta1 and PLCdelta2 had quite distinct distributions, with the former selectively localized to an endothelial cell population surrounding the chromaffin cells. This observation was supported by experiments on isolated bovine adrenal medullary cells where PLCdelta1 expression was lost when the cell preparation was enriched for chromaffin cells. Antibodies to PLCdelta2 labelled a network of nerve fibres throughout the medulla and clusters of ganglion cells located primarily at the medullary-cortical boundary. PLCdelta2 immunoreactivity was also present in nerve fibres within the adrenal capsule where it appeared to be co-localized with PLCbeta4 staining.

Adrenal Medulla↗

PubMed1997

The role of long-range interactions in defining the secondary structure of proteins is overestimated.

MOTIVATION: Secondary structure predictions based on the properties of individual residues, and sometimes on local interactions, usually fail to exceed 65% efficiency. Therefore, non-local, long-range interactions seem to be a significant cause of this limitation. RESULTS: In this paper, we apply approaches to localize highly interacting residues and clusters of residues involved in multiple non-local interactions, and test various secondary structure predictions on this separate subset to assess the effect of long-range interactions on the prediction efficiencies. It was found that only a marginal part of the failure of secondary structure predictions results from the presence of long-range interactions. Alternative possibilities are also discussed.

Algorithms↗

PubMed2000

Tobacco, alcohol, and caffeine use and cessation in early pregnancy.

OBJECTIVES: Little is known about what happens when individuals attempt to make multiple behavior changes simultaneously. Pregnant women in particular are often in the position of needing to change several behaviors at once, including giving up more than one pleasurable substance. We investigated the success of pregnant women in spontaneously quitting tobacco, alcohol, or caffeine, alone or in combination. METHODS: Pregnant women (n = 7489) were identified in the practices of large health maintenance organizations in Seattle and Minneapolis and were interviewed by telephone. Analyses examined the patterns of using and quitting more than one substance, and the extent to which using more than one substance predicts ability to quit other substances. RESULTS: Use of the three substances tended to cluster within individuals. Users of multiple substances were less likely to quit each substance than users of single substances. However, in the subgroup of multiple substance users who had quit one substance, having quit a second substance was more, rather than less, common. In multivariate analyses predicting quitting, demographic variables, and not having been pregnant previously were significant predictors of quitting each substance; being a nonsmoker predicted quitting alcohol, and being a nonsmoker and nondrinker predicted quitting caffeine. CONCLUSIONS: The reasons for difficulty in quitting more than one substance are unknown but may include the difficulty of formulating appropriate behavioral strategies or less concern about healthy behavior in pregnancy. Many women in the study successfully quit using two substances, however, and counseling should focus on achieving that outcome.

Adult↗

PubMed1999

Multiple alignment and sorting of peptides derived from phage-displayed random peptide libraries with polyclonal sera allows discrimination of relevant phagotopes.

Biopanning of phage-displayed random peptide libraries is a powerful technique for identifying peptides that mimic epitopes (mimotopes) for monoclonal antibodies (mAbs). However, peptides derived using polyclonal antisera may represent epitopes for a diverse range of antibodies. Hence following screening of phage libraries with polyclonal antisera, including autoimmune disease sera, a procedure is required to distinguish relevant from irrelevant phagotopes. We therefore applied the multiple sequence alignment algorithm PILEUP together with a matrix for scoring amino acid substitutions based on physicochemical properties to generate guide trees depicting relatedness of selected peptides. A random heptapeptide library was biopanned nine times using no selecting antibodies, immunoglobulin G (IgG) from sera of subjects with autoimmune diseases (primary biliary cirrhosis (PBC) and type 1 diabetes) and three murine ascites fluids that contained mAbs to overlapping epitope(s) on the Ross River Virus envelope protein 2. Peptides randomly sampled from the library were distributed throughout the guide tree of the total set of peptides whilst many of the peptides derived in the absence of selecting antibody aligned to a single cluster. Moreover peptides selected by different sources of IgG aligned to separate clusters, each with a different amino acid motif. These alignments were validated by testing all of the 53 phagotopes derived using IgG from PBC sera for reactivity by capture ELISA with antibodies affinity purified on the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major autoantigen in PBC: only those phagotopes that aligned to PBC-associated clusters were reactive. Hence the multiple sequence alignment procedure discriminates relevant from irrelevant phagotopes and thus a major difficulty with biopanning phage-displayed random peptide libraries with polyclonal antibodies is surmounted.

Algorithms↗

PubMed2006

Effect of spatial smoothing on t-maps: arguments for going back from t-maps to masked contrast images.

Voxelwise statistical analysis has become popular in explorative functional brain mapping with fMRI or PET. Usually, results are presented as voxelwise levels of significance (t-maps), and for clusters that survive correction for multiple testing the coordinates of the maximum t-value are reported. Before calculating a voxelwise statistical test, spatial smoothing is required to achieve a reasonable statistical power. Little attention is being given to the fact that smoothing has a nonlinear effect on the voxel variances and thus the local characteristics of a t-map, which becomes most evident after smoothing over different types of tissue. We investigated the related artifacts, for example, white matter peaks whose position depend on the relative variance (variance over contrast) of the surrounding regions, and suggest improving spatial precision with 'masked contrast images': color-codes are attributed to the voxelwise contrast, and significant clusters (e.g., detected with statistical parametric mapping, SPM) are enlarged by including contiguous pixels with a contrast above the mean contrast in the original cluster, provided they satisfy P < 0.05. The potential benefit is demonstrated with simulations and data from a [11C]Carfentanil PET study. We conclude that spatial smoothing may lead to critical, sometimes-counterintuitive artifacts in t-maps, especially in subcortical brain regions. If significant clusters are detected, for example, with SPM, the suggested method is one way to improve spatial precision and may give the investigator a more direct sense of the underlying data. Its simplicity and the fact that no further assumptions are needed make it a useful complement for standard methods of statistical mapping.

Algorithms↗

PubMed2005

Bayesian analysis of clustered interval-censored data.

The recording of multiple interval-censored failure times is common in dental research. Modeling multilevel data has been a difficult task. This paper aims to use the Bayesian approach to analyze a set of multilevel clustered interval-censored data from a clinical study to investigate the effectiveness of silver diamine fluoride and sodium fluoride varnish in arresting active dentin caries in Chinese pre-school children. The time to arrest dentin caries on a surface was measured. A three-level random-effects Weibull regression model was used. Analysis was performed with WinBUGS. Results revealed a strong positive correlation (0.596) among the caries lesions' arrest times on different surfaces from the same child. The software WinBUGS made the above complicated estimation simple. In conclusion, the annual application of silver diamine fluoride on caries lesions, and caries removal before the application, were found to shorten the arrest time.

Bayes Theorem↗

PubMed2002

Time-dependent changes in ARE-driven gene expression by use of a noise-filtering process for microarray data.

The current study was designed to identify the time-dependent gene expression profiles of antioxidant responsive element (ARE)-driven genes induced by tert-butylhydroquinone (tBHQ). A set of simple noise-filtering methods was introduced to evaluate and minimize the variance of microarray datasets. Gene expression induced by tBHQ (10 microM) in IMR-32 human neuroblastoma cells was analyzed by means of large-scale oligonucleotide microarray. Rank analysis was used to determine the acceptable number of independent samples necessary to eliminate false positives from the dataset. A dramatic reduction in the number of genes passing the rank analysis was achieved by using a 3 x 3 matrix comparison. Reproducibility was evaluated based on the coefficient of variation for average difference change. Completion of these analyses revealed that 101 of the 9,670 genes examined showed dynamic changes with treatment ranging from 4 h to 48 h. Since certain ARE-driven genes have been already identified, gene clustering would presumably group them together based on similar regulation. Self-organizing map grouped the genes induced by tBHQ into 12 (4x3) distinct clusters. Those previously identified ARE-driven genes were shown to group into different clusters. Since all potential ARE-driven genes did not cluster together, we speculate that multiple transcription factors and/or multiple signal transduction pathways contribute to transcriptional activation of the ARE. In conclusion, many novel potential ARE-driven genes were identified in this study. They function in detoxification and antioxidant defense, neuronal proliferation and differentiation, and signal transduction. The noise-filtering process applied to these microarray data, therefore, has proven to be very useful in identification of the time-dependent changes in ARE-drive gene expression.

Animals↗

PubMed2005

Multiple risk behaviour and its association with head and neck injuries: a national analysis of young Canadians.

BACKGROUND: Among adolescents, risk behaviors often cluster together and lead to risk behaviour syndromes. Multiple risk behaviors in turn become important determinants of health outcomes, including injuries. METHODS: A national sample (n = 11,415) of Canadian youth aged 11-15 years was examined from the 1997-1998 Health Behaviour in School-Aged Children Survey. Principal components analyses were used to characterize how adolescent risk behaviors cluster together into factors. Associations between these behavioral factors and injury outcomes were explored via multiple logistic regression analyses. RESULTS: Two factors of risk behaviors emerged: lifestyle risks and psychological risks. Strong associations between the lifestyle risk scale and the occurrence of head and neck injuries were identified (P < 0.001 for trend). The relative odds for the highest quintile versus the lowest quintile were 6.96 (95% CI: 3.95-12.26). Similar injury risks were not identified in association with the psychological risk scale. CONCLUSIONS: The findings provide novel information about potential causes of injury to young people and provide a reliable method by which researchers can quantify two determinants of health. These are helpful for injury control research in that they provided a means by which health risk behaviors can be measured and then related to the injury experiences of young people.

Adolescent↗

PubMed2003

Conserved residue clustering and protein structure prediction.

Protein residues that are critical for structure and function are expected to be conserved throughout evolution. Here, we investigate the extent to which these conserved residues are clustered in three-dimensional protein structures. In 92% of the proteins in a data set of 79 proteins, the most conserved positions in multiple sequence alignments are significantly more clustered than randomly selected sets of positions. The comparison to random subsets is not necessarily appropriate, however, because the signal could be the result of differences in the amino acid composition of sets of conserved residues compared to random subsets (hydrophobic residues tend to be close together in the protein core), or differences in sequence separation of the residues in the different sets. In order to overcome these limits, we compare the degree of clustering of the conserved positions on the native structure and on alternative conformations generated by the de novo structure prediction method Rosetta. For 65% of the 79 proteins, the conserved residues are significantly more clustered in the native structure than in the alternative conformations, indicating that the clustering of conserved residues in protein structures goes beyond that expected purely from sequence locality and composition effects. The differences in the spatial distribution of conserved residues can be utilized in de novo protein structure prediction: We find that for 79% of the proteins, selection of the Rosetta generated conformations with the greatest clustering of the conserved residues significantly enriches the fraction of close-to-native structures.

Acyl Coenzyme A↗