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What makes ribosome-mediated transcriptional attenuation sensitive to amino acid limitation?

Ribosome-mediated transcriptional attenuation mechanisms are commonly used to control amino acid biosynthetic operons in bacteria. The mRNA leader of such an operon contains an open reading frame with "regulatory" codons, cognate to the amino acid that is synthesized by the enzymes encoded by the operon. When the amino acid is in short supply, translation of the regulatory codons is slow, which allows transcription to continue into the structural genes of the operon. When amino acid supply is in excess, translation of regulatory codons is rapid, which leads to termination of transcription. We use a discrete master equation approach to formulate a probabilistic model for the positioning of the RNA polymerase and the ribosome in the attenuator leader sequence. The model describes how the current rate of amino acid supply compared to the demand in protein synthesis (signal) determines the expression of the amino acid biosynthetic operon (response). The focus of our analysis is on the sensitivity of operon expression to a change in the amino acid supply. We show that attenuation of transcription can be hyper-sensitive for two main reasons. The first is that its response depends on the outcome of a race between two multi-step mechanisms with synchronized starts: transcription of the leader of the operon, and translation of its regulatory codons. The relative change in the probability that transcription is aborted (attenuated) can therefore be much larger than the relative change in the time it takes for the ribosome to read a regulatory codon. The second is that the general usage frequencies of codons of the type used in attenuation control are small. A small percentage decrease in the rate of supply of the controlled amino acid can therefore lead to a much larger percentage decrease in the rate of reading a regulatory codon. We show that high sensitivity further requires a particular choice of regulatory codon among several synonymous codons for the same amino acid. We demonstrate the importance of a high fraction of regulatory codons in the control region. Finally, our integrated model explains how differences in leader sequence design of the trp and his operons of Escherichia coli and Salmonella typhimurium lead to high basal expression and low sensitivity in the former case, and to large dynamic range and high sensitivity in the latter. The model clarifies how mechanistic and systems biological aspects of the attenuation mechanism contribute to its overall sensitivity. It also explains structural differences between the leader sequences of the trp and his operons in terms of their different functions.

Journal Article↗

PhyloGibbs: a Gibbs sampling motif finder that incorporates phylogeny.

A central problem in the bioinformatics of gene regulation is to find the binding sites for regulatory proteins. One of the most promising approaches toward identifying these short and fuzzy sequence patterns is the comparative analysis of orthologous intergenic regions of related species. This analysis is complicated by various factors. First, one needs to take the phylogenetic relationship between the species into account in order to distinguish conservation that is due to the occurrence of functional sites from spurious conservation that is due to evolutionary proximity. Second, one has to deal with the complexities of multiple alignments of orthologous intergenic regions, and one has to consider the possibility that functional sites may occur outside of conserved segments. Here we present a new motif sampling algorithm, PhyloGibbs, that runs on arbitrary collections of multiple local sequence alignments of orthologous sequences. The algorithm searches over all ways in which an arbitrary number of binding sites for an arbitrary number of transcription factors (TFs) can be assigned to the multiple sequence alignments. These binding site configurations are scored by a Bayesian probabilistic model that treats aligned sequences by a model for the evolution of binding sites and "background" intergenic DNA. This model takes the phylogenetic relationship between the species in the alignment explicitly into account. The algorithm uses simulated annealing and Monte Carlo Markov-chain sampling to rigorously assign posterior probabilities to all the binding sites that it reports. In tests on synthetic data and real data from five Saccharomyces species our algorithm performs significantly better than four other motif-finding algorithms, including algorithms that also take phylogeny into account. Our results also show that, in contrast to the other algorithms, PhyloGibbs can make realistic estimates of the reliability of its predictions. Our tests suggest that, running on the five-species multiple alignment of a single gene's upstream region, PhyloGibbs on average recovers over 50% of all binding sites in S. cerevisiae at a specificity of about 50%, and 33% of all binding sites at a specificity of about 85%. We also tested PhyloGibbs on collections of multiple alignments of intergenic regions that were recently annotated, based on ChIP-on-chip data, to contain binding sites for the same TF. We compared PhyloGibbs's results with the previous analysis of these data using six other motif-finding algorithms. For 16 of 21 TFs for which all other motif-finding methods failed to find a significant motif, PhyloGibbs did recover a motif that matches the literature consensus. In 11 cases where there was disagreement in the results we compiled lists of known target genes from the literature, and found that running PhyloGibbs on their regulatory regions yielded a binding motif matching the literature consensus in all but one of the cases. Interestingly, these literature gene lists had little overlap with the targets annotated based on the ChIP-on-chip data. The PhyloGibbs code can be downloaded from http://www.biozentrum.unibas.ch/~nimwegen/cgi-bin/phylogibbs.cgi or http://www.imsc.res.in/~rsidd/phylogibbs. The full set of predicted sites from our tests on yeast are available at http://www.swissregulon.unibas.ch.

Algorithms↗

Seriation in paleontological data using markov chain Monte Carlo methods.

Given a collection of fossil sites with data about the taxa that occur in each site, the task in biochronology is to find good estimates for the ages or ordering of sites. We describe a full probabilistic model for fossil data. The parameters of the model are natural: the ordering of the sites, the origination and extinction times for each taxon, and the probabilities of different types of errors. We show that the posterior distributions of these parameters can be estimated reliably by using Markov chain Monte Carlo techniques. The posterior distributions of the model parameters can be used to answer many different questions about the data, including seriation (finding the best ordering of the sites) and outlier detection. We demonstrate the usefulness of the model and estimation method on synthetic data and on real data on large late Cenozoic mammals. As an example, for the sites with large number of occurrences of common genera, our methods give orderings, whose correlation with geochronologic ages is 0.95.

Animals↗

The framing of drivers' route choices when travel time information is provided under varying degrees of cognitive load.

In two experiments, participants chose between staying on a main route with a certain travel time and diverting to an alternative route that could take a range of travel times. In the first experiment, travel time information was displayed on a sheet of paper to participants seated at a desk. In the second experiment, the same information was displayed in a virtual environment through which participants drove. Overall, participants were risk-averse when the average travel time along the alternative route was shorter than the certain travel time of the main route but risk-seeking when the average travel time of the alternative route was longer than the certain travel time along the main route. In the second experiment, in which cognitive load was higher, participants simplified their decision-making strategies. A simple probabilistic model describes the risk-taking behavior and the load effects. Actual or potential applications of this research include the development of efficient travel time information systems for drivers.

Adult↗

Mapping novel traits by array-assisted bulk segregant analysis in Saccharomyces cerevisiae.

We demonstrate a new method, microarray-assisted bulk segregant analysis, for mapping traits in yeast by genotyping pooled segregants. We apply a probabilistic model to the progeny of a single cross and as little as two microarray hybridizations to reliably map an auxotrophic marker, a Mendelian trait, and a major-effect quantitative trait locus.

Chromosome Mapping↗

Prevalence of heartburn and gastroesophageal reflux disease in the urban Brazilian population.

BACKGROUND: The epidemiological aspects of heartburn and gastroesophageal reflux disease have been object of growing interest in the last decade because of its increasing prevalence and the complications of the disease. AIMS: To evaluate the prevalence of heartburn and gastroesophageal reflux disease as well as their main characteristics in the Brazilian urban population. METHODS: A national inquire enrolling 13,959 adults was conducted in 22 Brazilian cities. The inclusion criteria were the presence of heartburn at least once a week ("heartburn group") and age greater than 16 years old. Individuals with heartburn with frequency of more than once a week were considered as having gastroesophageal reflux disease (GERD group). Factors related to the complaint were asked such as predisposing factors, habits (tobacco, alcohol and coffee intake) and body mass index. In this populational study a probabilistic model was used. RESULTS: The results are presented in absolute and relative frequency, which were ponderated estimates of the respective population figures. The global prevalence of heartburn was 11.9% (1,651 persons). Heartburn once a week was present in 4.6% (637 persons) and GERD in 7.3% (1,014 persons). The average ages of both groups were similar (men: 36.9 +/- 15.0; women: 39.6 +/- 15.1 yrs). Females were more affected in both groups. The occurrence of GERD increased with age and was more prevalent after 55 years old. The body mass index was in the normal range and similar in both groups (men: 24.7 +/- 4.6; women: 25.3 +/- 5.2 kg/m(2)). In both groups the individuals related their symptoms to food intake, fatty and spicy foods (heartburn group: 64.7%, 28.5%, 17.7%; GERD group: 55.0%, 25.9%, 11.7% respectively). In GERD group, stress (24.2%), health problems (22.3%) were more related to the symptoms than in heartburn group (20.0% and 15.0% respectively). CONCLUSIONS: The global prevalence of heartburn (11.9%) is relatively high in the Brazilian urban population, although lower than the reported figure to other countries. Heartburn and GERD have higher prevalence in women and both are related to food intake, fatty and spicy foods; GERD is more prevalent in individuals older than 35 years old.

Adolescent↗

Seroepidemiology of schistosomiasis mansoni.

In population surveys in which the Schistosoma mansoni intensity of infection is low, or in localities where the schistosomiasis control program had success, the parasitologic methods lack in sensitivity. Despite of some limitations, the immunological methods are useful to provide valuable information in such field conditions. Thus, the prevalence of schistosomiasis in untreated population can be determined by the detection of IgG or IgM antibodies, as well as the incidence by the IgA antibodies, employing mainly immunofluorescence (IF) and immunoenzymatic (ELISA), and in some extent hemagglutination (HA) or even skin test. The true prevalence and incidence of schistosomiasis can be estimated using a probabilistic model equation, since knowing before-hand the sensitivity and specificity of employed test. The sensitivity and the specificity of serologic test become higher in low aged group, under 14. The geometric mean IF titers also gives a positive correlation with the intensity of infection. Presently, there are need of serologic tests which are economic and practical in seroepidemiologic inquiries, requiring no specialized personnel to collect population blood or serum samples, and also easily interpret the test results. The reagents for such tests are desired to be stable and reproducible. Moreover, it is expected that the tests can distinguish an active infection.

Adolescent↗

[Essay on the epistemological relationship between probability and scientific method].

In the XIX century, regularities in statistics of events were perceived in Medicine and Human Sciences. These regularities raised the possibility of forecasting what considered to be impredictable, and so, probabilistics laws became an alternative to the strictly-causal laws. This work presents a brief historical review of probability calculus and its applications. Some philosophical thoughs, regarding the use of probabilistics models and decision analysis in Medicine, are also discussed.

Clinical Medicine↗

Probabilistic risk assessment for snails, slugs, and endangered honeycreepers in diphacinone rodenticide baited areas on Hawaii, USA.

Three probabilistic models were developed for characterizing the risk of mortality and subacute coagulopathy to Poouli, an endangered nontarget avian species, in broadcast diphacinone-baited areas on Hawaii, USA. For single-day exposure, the risk of Poouli mortality approaches 0. For 5-d exposure, the mean probability of mortality increased to 3% for adult and 8% for juvenile Poouli populations. For Poouli that consume snails containing diphacinone residues for 14 d, the model predicted increased levels of coagulopathy for 0.42 and 11% of adult and juvenile Poouli populations, respectively. Worst-case deterministic risk characterizations predicted acceptable levels of risk for nonthreatened or endangered species such as northern bobwhite quail and mallards. Also, no acute toxicity was noted for snails and slugs that feed on diphacinone baits.

Animals↗

Environmental mapping based on spatial variability.

Environmental maps show the probable environmental states of different types of land use or development of landscape in a geographic context. Remotely sensed data are particularly efficient for environmental mapping in order to outline major environmental types. Multiple schemes of image classification used in environmental mapping are either traditionally statistical or heuristic. While the former methods do not take account of spatial variability in space and aerial data, the latter ones does not lend themselves to optimal solutions we present. Novel probabilistic models of piecewise-homogeneous images are used in environmental mapping to segment real images. The models consider both an image and a land cover map. Such a pair constitutes an example of a Markov random field specified by a joint Gibbs probability distribution of images and maps. Parameters of the model are estimated by using a stochastic approximation technique. Its convergence to the desired values is studied experimentally. Addition of spatial attributes appears to be necessary in most areas where the differences in spatial data between regions in the image occur. Experiments in generating the pairs of images and environmental maps and in segmenting the simulated as well as real images are discussed.

Environment↗

Economic analysis of on-demand maintenance therapy with proton pump inhibitors in patients with non-erosive reflux disease.

AIM: To evaluate the costs and effectiveness of on-demand maintenance therapy with oral esomeprazole, lansoprazole, omeprazole, pantoprazole or rabeprazole in patients with endoscopy-confirmed non-erosive reflux disease (NERD) in the UK. METHODS: A probabilistic model was developed to compare the costs and effectiveness of five proton pump inhibitors (PPIs) in endoscopy-negative, symptomatic NERD patients who had complete resolution of heartburn symptoms following 4 weeks of open-label acute PPI treatment. The total annual expected costs (euro, 2003 values) and utilities gained per patient were measured over a 1-year horizon from the perspective of the UK NHS. Model uncertainty was addressed by sensitivity analyses. RESULTS: The base-case annual median costs and utilities gained with on-demand PPI therapy were: 123 euro and 0.89 for rabeprazole 10mg; 176 euro and 0.90 for pantoprazole 20mg; 190 euro and 0.89 for esomeprazole 20mg; 195 euro and 0.91 for lansoprazole 15mg; 201 euro and 0.90 for omeprazole 20mg; and 210 euro and 0.91 for omeprazole 10mg. Differences in costs, but not in outcomes, were statistically significant. The results were robust to sensitivity analyses. CONCLUSIONS: In this analysis, on-demand use of rabeprazole for the management of NERD incurred the least cost in comparison with the other PPIs evaluated. Utility gains were comparable for all on-demand PPIs. The place of on-demand PPIs in therapy, however, requires further evaluation.

Anti-Ulcer Agents↗

Economic consequences of epidemiological changes in diabetes in middle-income countries: the Mexican case.

OBJECTIVE: To identify the costs and economic consequences of expected changes in the demand for health care services for type 2 diabetes in the three main public institutions of the Mexican health care system. RESEARCH DESIGN AND METHODS: The cost evaluation method to estimate direct and indirect costs was based on instrumentation and consensus techniques. To estimate the costs and epidemiological changes for 2003-2005, three probabilistic models were constructed according to the Box-Jenkins technique. RESULTS: Comparing the economic impact in 2003 versus 2005 (P < 0.05), there is a 26% increase in financial requirements. The total amount for diabetes in 2005 (in U.S. dollars) will be 317,631,206, dollars including 140,410,816 dollars in direct costs and 177,220,390 dollars in indirect costs. The total direct costs, representing financial requirements to provide health care for expected cases of type 2 diabetes and its main complications in the three main public institutions in Mexico, up to 2005, will be 37,079,587 dollars for the Ministry of Health (or Secretaría de Salud [SSA], serving the uninsured population) and 103,331,235 dollars for the Mexican Social Security Institute, or Instituto Mexicano del Seguro Social (IMSS), and the Institute for Social Security and Services for State Workers, or Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), both of which serve the insured population. CONCLUSIONS: Our data suggest that changes in the demand for health care services for patients with diabetes will continue with an increasing trend, mainly in the insured population. In economic terms, the results of direct and indirect costs are one of the main challenges to be solved to decrease the economic burden that diabetes represents for the population, the health care institutions, and for society as a whole.

Costs and Cost Analysis↗

Is the matching familiar figures test a measure of cognitive style? A warning for users.

A probabilistic model of reflection-impulsivity as measured by the Matching Familiar Figures Test (MFFT) is presented and tested on 77 fourth graders. In testing the model two groups emerged, a random response group (n = 22) and a cognitive response group (n = 55), who use the evaluation process. Correlations among latencies, total errors, initial errors, school-scores, and IQs were compared for our total sample and the two groups. The correlation of MFFT latencies and errors disappeared for the random-response group and new correlations with errors appeared while the cognitive response group kept a statistically significant correlation of latencies with errors and no other error correlation was shown. This last group was classified by Kagan's median-split procedure showing that most reflective subjects kept their classification. Preliminary results suggest a reinterpretation of reflection-impulsivity literature, especially as related to the impulsive style.

Child↗

Study of the hearing losses of industrial workers with occupational noise exposure, using statistical methods for the analysis of qualitative data.

The application of a polychotomous generalization of the linear probabilistic model of Cox is described, which allows the investigation of the effects of different noise levels with various durations of exposure on hearing. If the model assumptions are not rejected, it is possible to separate the effect of noise exposure from the effect of age. The results will thus show to what extent the hearing losses of an industrial worker are due to presbyacusis or to noise exposure. An empirical investigation was based on the evaluation of hearing losses at the audiometric frequencies 1, 2 and 3 kHz in 35 212 industrial workers of both sexes. It was attempted to predict the distribution of hearing losses in the left and the right ear as an additive function of the effect of noise exposure, age and sex. The parameters describing the effect of age increased linearly. Noise levels equal to and above 85 dB(A) have a noxious influence on hearing. Furthermore, hearing loss does not increase continuously with duration of exposure; from 15 years onwards, no essential increase in hearing loss appears which can be attributed to noise at work.

Adolescent↗

A surgeon's risk of AIDS.

A probabilistic model is used to estimate the cumulative risk to surgeons from human immunodeficiency virus (HIV). Recent data suggest that the probability of infection following percutaneous inoculation is about 1 in 250 cases. Several studies suggest that the frequency of percutaneous injury in surgery is at least 1 in 40 cases, for some as high as 1 in 20 cases. Assuming that on the average a surgeon will perform 350 operations per year and will practice for 30 years, the cumulative risk of HIV infection will depend on the prevalence of HIV infection in the surgical population. For HIV prevalences of 1 in 100 to 1 in 10, the cumulative risk per surgeon ranges from 1 in 100 to 1 in 5, respectively. Based on these risk estimates, it is crucial to decrease the frequency of percutaneous injury. The case is made for substantial improvements in barrier protection and modification of surgical technique.

Acquired Immunodeficiency Syndrome↗

A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of quetiapine, olanzapine and valproate semisodium in the treatment of mania associated with bipolar disorder. DATA SOURCES: Electronic databases; industry submissions made to the National Institute for Clinical Excellence. REVIEW METHODS: Randomised trials and economic evaluations that evaluated the effectiveness of quetiapine, olanzapine or valproate semisodium in the treatment of mania associated with bipolar disorder were selected for inclusion. Data were extracted by one reviewer into a Microsoft Access database and checked for quality and accuracy by a second. The quality of the cost-effectiveness studies was assessed using a checklist updated from that developed by Drummond and colleagues. Relative risk and mean difference data were presented as Forest plots but only pooled where this made sense clinically and statistically. Studies were grouped by drug and, within each drug, by comparator used. Chi-squared tests of heterogeneity were performed for the outcomes if pooling was indicated. A probabilistic model was developed to estimate costs from the perspective of the NHS, and health outcomes in terms of response rate, based on an improvement of at least 50% in a patient's baseline manic symptoms derived from an interview-based mania assessment scale. The model evaluated the cost-effectiveness of the alternative drugs when used as part of treatment for the acute manic episode only. RESULTS: Eighteen randomised trials met the inclusion criteria. Aspects of three of the quetiapine studies were commercial-in-confidence. The quality of the included trials was limited and overall, key methodological criteria were not met in most trials. Quetiapine, olanzapine and valproate semisodium appear superior to placebo in reducing manic symptoms, but may cause side-effects. There appears to be little difference between these treatments and lithium in terms of effectiveness, but quetiapine is associated with somnolence and weight gain, whereas lithium is associated with tremor. Olanzapine as adjunct therapy to mood stabilisers may be more effective than placebo in reducing mania and improving global health, but it is associated with more dry mouth, somnolence, weight gain, increased appetite, tremor and speech disorder. There was little difference between these treatments and haloperidol in reducing mania, but haloperidol was associated with more extrapyramidal side-effects and negative implications for health-related quality of life. Intramuscular olanzapine and lorazepam were equally effective and safe in one very short (24 hour) trial. Valproate semisodium and carbamazepine were equally effective and safe in one small trial in children. Olanzapine may be more effective than valproate semisodium in reducing mania, but was associated with more dry mouth, increased appetite, oedema, somnolence, speech disorder, Parkinson-like symptoms and weight gain. Valproate semisodium was associated with more nausea than olanzapine. The results from the base-case analysis demonstrate that choice of optimal strategy is dependent on the maximum that the health service is prepared to pay per additional responder. For a figure of less than 7179 British pounds per additional responder, haloperidol is the optimal decision; for a spend in excess of this, it would be olanzapine. Under the most favourable scenario in relation to the costs of responders and non-responders beyond the 3-week period considered in the base-case analysis, the incremental cost-effectiveness ratio of olanzapine is reduced to 1236 British pounds. CONCLUSIONS: In comparison with placebo, quetiapine, olanzapine and valproate semisodium appear superior in reducing manic symptoms, but all drugs are associated with adverse events. In comparison with lithium, no significant differences were found between the three drugs in terms of effectiveness, and all were associated with adverse events. Several limitations of the cost-effectiveness analysis exist, which inevitably means that the results should be treated with some caution. There remains a need for well-conducted, randomised, double-blind head-to-head comparisons of drugs used in the treatment of mania associated with bipolar disorder and their cost-effectiveness. Participant demographic, diagnostic characteristics, the treatment of mania in children, the use of adjunctive therapy and long-term safety issues in the elderly population, and acute and long-term treatment are also subjects for further study.

Antimanic Agents↗

Analysis of the fluctuating microbial counts in commercial raw milk--a case study.

Microbial counts of raw milk from eight commercial dairy farms recorded over a period of about 2 years were obtained from a processing plant. All the counts formed irregular fluctuating series whose statistical properties were examined. In all eight cases the autocorrelation function indicated that the counts were random and had no underlying periodicity. This suggested that the fluctuations, at least to some extent, reflected the combined effect of numerous factors, some unknown, and that these factors operate randomly and independently. In five out of the eight cases the fluctuating pattern of the record could be described by a probabilistic model based on the assumption that the counts have a lognormal distribution. The validity of the model was confirmed by comparing the calculated frequencies of counts exceeding preselected levels with those actually observed in fresh data. The model enabled ranking the five sources on the basis of anticipated frequencies of excessive counts rather than on the basis of mean performance. Two sequences had clearly identified regions with different statistical characteristics. They were interpreted as a reflection of changes in the sanitary conditions at the corresponding farms. In one case, both the overall magnitudes and the fluctuation amplitude of the counts progressively decreased, a situation for which the described model as formulated was inapplicable.

Animals↗

Sternal acceleration ballistocardiography and arterial pressure wave analysis to determine stroke volume.

OBJECTIVE: To describe a cardiac output measurement using a new method to derive and analyze the long-axis ballistocardiogram that is less invasive than pulmonary artery thermodilution. DESIGN: Prospective physiologic study. SETTING: Intensive care unit of The Halifax Infirmary, a teaching hospital of Dalhousie University, Halifax, NS. PATIENTS: Thirty-nine patients in sinus rhythm with pulmonary artery thermodilution catheters or radial artery catheters in place. The first 30 subjects were the "learning set" and the next 9 were the "test set." INTERVENTIONS: A small (54-g) accelerometer was taped on the patient's chest. OUTCOME MEASURES: Measurements of time and amplitude coordinates of the acceleration and radial artery pressure wavepeaks, as well as anthropometric information. RESULTS: A stroke volume prediction equation was generated (R2 = 0.76) from the learning set. This equation was applied to the test set and correlated with the pulmonary artery thermodilution-derived stroke volumes (R = 0.79). Stroke volumes were compared using a previously described statistical method: a) bias (predicted > thermodilution) = 0.03 mL (95% confidence interval [CI] -4.2 to 4.8 mL); b) lower limit of agreement = -21 mL (95% CI -29 to -13 mL); c) upper limit of agreement = 22 mL (95% CI 14 to 29 mL). Of derived stroke volumes, 82% were within 15 mL of pulmonary artery thermodilution-derived values. CONCLUSIONS: The sternal acceleration ballistocardiogram combined with hemodynamic and demographic data in a probabilistic model shows promise of providing a less invasive measure of cardiac output than thermodilution.

Aged↗