SeqHound: biological sequence and structure database as a platform for bioinformatics research

BACKGROUND: SeqHound has been developed as an integrated biological sequence, taxonomy, annotation and 3-D structure database system. It provides a high-performance server platform for bioinformatics research in a locally-hosted environment. RESULTS: SeqHound is based on the National Center for Biotechnology Information data model and programming tools. It offers daily updated contents of all Entrez sequence databases in addition to 3-D structural data and information about sequence redundancies, sequence neighbours, taxonomy, complete genomes, functional annotation including Gene Ontology terms and literature links to PubMed. SeqHound is accessible via a web server through a Perl, C or C++ remote API or an optimized local API. It provides functionality necessary to retrieve specialized subsets of sequences, structures and structural domains. Sequences may be retrieved in FASTA, GenBank, ASN.1 and XML formats. Structures are available in ASN.1, XML and PDB formats. Emphasis has been placed on complete genomes, taxonomy, domain and functional annotation as well as 3-D structural functionality in the API, while fielded text indexing functionality remains under development. SeqHound also offers a streamlined WWW interface for simple web-user queries. CONCLUSIONS: The system has proven useful in several published bioinformatics projects such as the BIND database and offers a cost-effective infrastructure for research. SeqHound will continue to develop and be provided as a service of the Blueprint Initiative at the Samuel Lunenfeld Research Institute. The source code and examples are available under the terms of the GNU public license at the Sourceforge site http://sourceforge.net/projects/slritools/ in the SLRI Toolkit

Rapid increase in clearance of phenobarbital in neonates on extracorporeal membrane oxygenation: A pilot retrospective population pharmacokinetic analysis

Objectives: This study characterizes the changes in the pharmacokinetics of phenobarbital associated with extracorporeal membrane oxygenation treatment in neonates, to illustrate our findings and provide guidance on dosing.Design: Retrospective pilot population pharmacokinetic analysis.Setting: Neonatal ICU.Patients: Thirteen critically ill neonates (birth body weight, 3.21kg [2.65-3.72 kg]; postnatal age at start of treatment: 2 d [0-7 d]; gestational age: 38wk [38-41 wk]) receiving venovenous or venoarterial extracorporeal membrane oxygenation.Interventions: Phenobarbital administered in a loading dose of 7.5mg/kg (8.5-16mg/kg) and maintenance dose of 6.9mg/kg/d (4.5-8.5mg/kg/d).Measurements and Main Results: Therapeutic drug monitoring data were available, yielding 5, 31, and 19 phenobarbital concentrations before, during, and after extracorporeal membrane oxygenation, respectively. Population pharmacokinetic analysis was performed using NONMEM 7.3.0 (ICON Development Solutions, Ellicott City, MD). Maturation functions for clearance and volume of distribution were obtained from literature. In a one-compartment model, clearance and volume of distribution for a typical neonate off extracorporeal membrane oxygenation and with a median birth body weight (3.21kg) at median postnatal age (2 d) were 0.0096L/hr (relative se = 11%)) and 2.72L (16%), respectively. During extracorporeal membrane oxygenation, clearance was found to linearly increase with time. Upon decannulation, phenobarbital clearance initially decreased and subsequently increased slowly driven by maturation. Extracorporeal membrane oxygenation-related changes in volume of distribution could not be identified, possibly due to sparse data collection shortly after extracorporeal membrane oxygenation start. According to the model, target attainment is achieved in the first 12 days of extracorporeal membrane oxygenation with a regimen of a loading dose of 20mg/kg and a maintenance dose of 4mg/kg/d divided in two doses with an increase of 0.25mg/kg every 12 hours during extracorporeal membrane oxygenation treatment.Conclusions: We found a time-dependent increase in phenobarbital clearance during the first 12 days of extracorporeal membrane oxygenation treatment in neonates, which results in continuously decreasing phenobarbital exposure and increases the risk of therapeutic failure over time. Due to high unexplained variability, frequent and repeated therapeutic drug monitoring should be considered even with the model-derived regimen.Pharmacolog

BIRCH: A user-oriented, locally-customizable, bioinformatics system

BACKGROUND: Molecular biologists need sophisticated analytical tools which often demand extensive computational resources. While finding, installing, and using these tools can be challenging, pipelining data from one program to the next is particularly awkward, especially when using web-based programs. At the same time, system administrators tasked with maintaining these tools do not always appreciate the needs of research biologists. RESULTS: BIRCH (Biological Research Computing Hierarchy) is an organizational framework for delivering bioinformatics resources to a user group, scaling from a single lab to a large institution. The BIRCH core distribution includes many popular bioinformatics programs, unified within the GDE (Genetic Data Environment) graphic interface. Of equal importance, BIRCH provides the system administrator with tools that simplify the job of managing a multiuser bioinformatics system across different platforms and operating systems. These include tools for integrating locally-installed programs and databases into BIRCH, and for customizing the local BIRCH system to meet the needs of the user base. BIRCH can also act as a front end to provide a unified view of already-existing collections of bioinformatics software. Documentation for the BIRCH and locally-added programs is merged in a hierarchical set of web pages. In addition to manual pages for individual programs, BIRCH tutorials employ step by step examples, with screen shots and sample files, to illustrate both the important theoretical and practical considerations behind complex analytical tasks. CONCLUSION: BIRCH provides a versatile organizational framework for managing software and databases, and making these accessible to a user base. Because of its network-centric design, BIRCH makes it possible for any user to do any task from anywhere

PROMPT: a protein mapping and comparison tool

BACKGROUND: Comparison of large protein datasets has become a standard task in bioinformatics. Typically researchers wish to know whether one group of proteins is significantly enriched in certain annotation attributes or sequence properties compared to another group, and whether this enrichment is statistically significant. In order to conduct such comparisons it is often required to integrate molecular sequence data and experimental information from disparate incompatible sources. While many specialized programs exist for comparisons of this kind in individual problem domains, such as expression data analysis, no generic software solution capable of addressing a wide spectrum of routine tasks in comparative proteomics is currently available. RESULTS: PROMPT is a comprehensive bioinformatics software environment which enables the user to compare arbitrary protein sequence sets, revealing statistically significant differences in their annotation features. It allows automatic retrieval and integration of data from a multitude of molecular biological databases as well as from a custom XML format. Similarity-based mapping of sequence IDs makes it possible to link experimental information obtained from different sources despite discrepancies in gene identifiers and minor sequence variation. PROMPT provides a full set of statistical procedures to address the following four use cases: i) comparison of the frequencies of categorical annotations between two sets, ii) enrichment of nominal features in one set with respect to another one, iii) comparison of numeric distributions, and iv) correlation of numeric variables. Analysis results can be visualized in the form of plots and spreadsheets and exported in various formats, including Microsoft Excel. CONCLUSION: PROMPT is a versatile, platform-independent, easily expandable, stand-alone application designed to be a practical workhorse in analysing and mining protein sequences and associated annotation. The availability of the Java Application Programming Interface and scripting capabilities on one hand, and the intuitive Graphical User Interface with context-sensitive help system on the other, make it equally accessible to professional bioinformaticians and biologically-oriented users. PROMPT is freely available for academic users from

International Society of Sports Nutrition Position Stand: Probiotics.

Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population

Population pharmacokinetics of riociguat and its metabolite in patients with chronic thromboembolic pulmonary hypertension from routine clinical practice

Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials.Pharmacolog

PreBIND and Textomy – mining the biomedical literature for protein-protein interactions using a support vector machine

<p>Abstract</p> <p>Background</p> <p>The majority of experimentally verified molecular interaction and biological pathway data are present in the unstructured text of biomedical journal articles where they are inaccessible to computational methods. The Biomolecular interaction network database (BIND) seeks to capture these data in a machine-readable format. We hypothesized that the formidable task-size of backfilling the database could be reduced by using Support Vector Machine technology to first locate interaction information in the literature. We present an information extraction system that was designed to locate protein-protein interaction data in the literature and present these data to curators and the public for review and entry into BIND.</p> <p>Results</p> <p>Cross-validation estimated the support vector machine's test-set precision, accuracy and recall for classifying abstracts describing interaction information was 92%, 90% and 92% respectively. We estimated that the system would be able to recall up to 60% of all non-high throughput interactions present in another yeast-protein interaction database. Finally, this system was applied to a real-world curation problem and its use was found to reduce the task duration by 70% thus saving 176 days.</p> <p>Conclusions</p> <p>Machine learning methods are useful as tools to direct interaction and pathway database back-filling; however, this potential can only be realized if these techniques are coupled with human review and entry into a factual database such as BIND. The PreBIND system described here is available to the public at <url>http://bind.ca</url>. Current capabilities allow searching for human, mouse and yeast protein-interaction information.</p