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Combining high-performance computing and networking for advanced 3-D cardiac imaging.

This paper deals with the integration of a powerful parallel computer-based image analysis and visualization system for cardiology into a hospital information system. Further services are remote access to the hospital Web server through an internet network. The visualization system includes dynamic three-dimensional representation of two types of medical images (e.g., magnetic resonance and nuclear medicine) as well as two images in the same modality (e.g., basal versus stress images). A series of software tools for quantitative image analysis developed for supporting diagnosis of cardiac disease are also available, including automated image segmentation and quantitative time evaluation of left ventricular volumes and related indices during cardiac cycle, myocardial mass, and myocardial perfusion indices. The system has been tested both at a specialized cardiologic center and for remote consultation in diagnosis of cardiac disease by using anatomical and perfusion magnetic resonance images.

Cardiac Output↗

PipTools: a computational toolkit to annotate and analyze pairwise comparisons of genomic sequences.

Sequence conservation between species is useful both for locating coding regions of genes and for identifying functional noncoding segments. Hence interspecies alignment of genomic sequences is an important computational technique. However, its utility is limited without extensive annotation. We describe a suite of software tools, PipTools, and related programs that facilitate the annotation of genes and putative regulatory elements in pairwise alignments. The alignment server PipMaker uses the output of these tools to display detailed information needed to interpret alignments. These programs are provided in a portable format for use on common desktop computers and both the toolkit and the PipMaker server can be found at our Web site (http://bio.cse.psu.edu/). We illustrate the utility of the toolkit using annotation of a pairwise comparison of the mouse MHC class II and class III regions with orthologous human sequences and subsequently identify conserved, noncoding sequences that are DNase I hypersensitive sites in chromatin of mouse cells.

Animals↗

MetaCyc and AraCyc. Metabolic pathway databases for plant research.

MetaCyc (http://metacyc.org) contains experimentally determined biochemical pathways to be used as a reference database for metabolism. In conjunction with the Pathway Tools software, MetaCyc can be used to computationally predict the metabolic pathway complement of an annotated genome. To increase the breadth of pathways and enzymes, more than 60 plant-specific pathways have been added or updated in MetaCyc recently. In contrast to MetaCyc, which contains metabolic data for a wide range of organisms, AraCyc is a species-specific database containing only enzymes and pathways found in the model plant Arabidopsis (Arabidopsis thaliana). AraCyc (http://arabidopsis.org/tools/aracyc/) was the first computationally predicted plant metabolism database derived from MetaCyc. Since its initial computational build, AraCyc has been under continued curation to enhance data quality and to increase breadth of pathway coverage. Twenty-eight pathways have been manually curated from the literature recently. Pathway predictions in AraCyc have also been recently updated with the latest functional annotations of Arabidopsis genes that use controlled vocabulary and literature evidence. AraCyc currently features 1,418 unique genes mapped onto 204 pathways with 1,156 literature citations. The Omics Viewer, a user data visualization and analysis tool, allows a list of genes, enzymes, or metabolites with experimental values to be painted on a diagram of the full pathway map of AraCyc. Other recent enhancements to both MetaCyc and AraCyc include implementation of an evidence ontology, which has been used to provide information on data quality, expansion of the secondary metabolism node of the pathway ontology to accommodate curation of secondary metabolic pathways, and enhancement of the cellular component ontology for storing and displaying enzyme and pathway locations within subcellular compartments.

4-Hydroxyphenylpyruvate Dioxygenase↗

A dose delivery verification method for conventional and intensity-modulated radiation therapy using measured field fluence distributions.

Treatment verification has been a weak link in external beam radiation therapy. As new and more complicated treatment techniques, such as intensity-modulated radiation therapy (IMRT), are implemented into clinical practice, verifying the accuracy of treatment delivery becomes increasingly important. Existing methods for treatment verification are highly labor intensive. We have developed a method for verifying the delivery of external beam radiotherapy and implemented the methodology into a system consisting of both hardware and software components. The system uses grayscale images acquired on the treatment machine from the planned treatment beams. From these images, the photon fluence distribution of each beam is derived. These measured photon fluence maps are then used as input to a separate dose calculation engine to compute the delivered absolute dose and the dose distribution in the same patient, assuming that the patient is set up as required by the treatment plan. The dose distribution generated from the measured fluence maps can then be compared to that of the treatment plan. Software tools, such as overlaying isodose curves generated with this method on those imported from the plan, dose difference maps, dose difference volume histograms, and three-dimensional perspective views of the dose differences, have also been developed. The system thus provides a means to verify the dose, the dose prescription, and the monitor units applied. The potential exists with a suitable electronic portal imaging system to reduce the quality assurance efforts, especially for IMRT.

Algorithms↗

A dedicated caller for DUX4 rearrangements from whole-genome sequencing data.

Rearrangements involving the DUX4 gene (DUX4-r) define a subtype of paediatric and adult acute lymphoblastic leukaemia (ALL) with a favourable outcome. Currently, there is no 'standard of care' diagnostic method for their confident identification. Here, we present an open-source software tool designed to detect DUX4-r from short-read, whole-genome sequencing (WGS) data. Evaluation on a cohort of 210 paediatric ALL cases showed that our method detects all known, as well as previously unidentified, cases of IGH::DUX4 and rearrangements with other partner genes. These findings demonstrate the possibility of robustly detecting DUX4-r using WGS in the routine clinical setting.

Humans↗

Understanding flux in plant metabolic networks.

The revolutionary growth in our ability to identify the 'parts list' of cellular infrastructure in plants in detail, and to alter it with precision, challenges us to develop methods to quantify how these parts function. For components of metabolism, this means mapping fluxes at the level of metabolic networks. Advances in experimental, analytical and software tools for metabolic flux analysis now allow maps of the fluxes through central metabolism to be obtained from the results of stable-isotope-labeling experiments. Such maps have led to notable successes in understanding and engineering metabolic function in microorganisms. Recent studies in plants are giving insight into particular fluxes, such as those of the pentose phosphate pathway, and into general phenomena, such as substrate- or futile-cycles and compartmentation. The importance of experimental design and statistical analysis have been illustrated, and analyses of fluxes in heterotrophic plant tissues have been carried out recently.

Brassica napus↗

X window system based user interface in radiology.

A teleradiology system was designed for image transfer between two hospitals. One of the main challenges of the work was the user interface, which was to be easy to operate and to learn, and was equipped with useful functions for image manipulation and diagnosing. The software tools used were the Unix operating system (HP-UX v.7.0), C programming language and the X Window System (or simply X). The graphical user interface (GUI) was based on OSF-Motif standard, and it was developed by using the HP-Interface Architect. Both OSF-Motif and HP-Interface Architect are based on X. The results of the development project were installed for clinical use in the Turku University Central Hospital. The work demonstrates, that the X Window System has useful and advantageous features for radiology department's computer network environment.

Computer Communication Networks↗

GLYCOSCIENCES.de: an Internet portal to support glycomics and glycobiology research.

The development of glycan-related databases and bioinformatics applications is considerably lagging behind compared with the wealth of available data and software tools in genomics and proteomics. Because the encoding of glycan structures is more complex, most of the bioinformatics approaches cannot be applied to glycan structures. No standard procedures exist where glycan structures found in various species, organs, tissues or cells can be routinely deposited. In this article the concepts of the GLYCOSCIENCES.de portal are described. It is demonstrated how an efficient structure-based cross-linking of various glycan-related data originating from different resources can be accomplished using a single user interface. The structure oriented retrieval options-exact structure, substructure, motif, composition and sugar components-are discussed. The types of available data-references, composition, spatial structures, nuclear magnetic resonance (NMR) shifts (experimental and estimated), theoretically calculated fragments and Protein Database (PDB) entries-are exemplified for Man(3.) The free availability and unrestricted use of glycan-related data is an absolute prerequisite to efficiently share distributed resources. Additionally, there is an urgent need to agree to a generally accepted exchange format as well as to a common software interface. An open access repository for glyco-related experimental data will secure that the loss of primary data will be considerably reduced.

Computational Biology↗

Hopper: software for automating data tracking and flow in DNA sequencing.

MOTIVATION: Genome-scale DNA sequencing is a multistep process in which large numbers of small template clones are propagated, purified, sequenced and analyzed on acrylamide gels. A significant challenge to these projects is the scale at which the data handling must be done. Hence, large-scale sequencing facilities will benefit from tracking template DNA information (purification methods, reaction and electrophoresis conditions) in a systematic fashion. A lack of software tools that support automated sample entry, and automatic data storage, retrieval and analysis are a major hindrance to recording and using laboratory workflow information to monitor the overall quality of data production. RESULTS: The UNIX file system has been used to prototype automation of the flow of data from the ABI sequencer to a data repository. Data are automatically processed by a central Perl program, Hopper, which runs a series of programs that analyze data quality (read length estimate, fraction of indeterminate bases, and number of contaminating and repetitive sequences), assemble shotgun sequence data, and generates simple reports describing the results.

Database Management Systems↗

Comparison of MLR, PLS and GA-MLR in QSAR analysis.

The use of the internet has evolved in quantitative structure-activity relationship (QSAR) over the past decade with the development of web based activities like the availability of numerous public domain software tools for descriptor calculation and chemometric toolboxes. The importance of chemometrics in QSAR has accelerated in recent years for processing the enormous amount of information in form of predictive mathematical models for large datasets of molecules. With the availability of huge numbers of physicochemical and structural parameters, variable selection became crucial in deriving interpretable and predictive QSAR models. Among several approaches to address this problem, the principle component regression (PCR) and partial least squares (PLS) analyses provide highly predictive QSAR models but being more abstract, they are difficult to understand and interpret. Genetic algorithm (GA) is a stochastic method well suited to the problem of variable selection and to solve optimization problems. Consequently the hybrid approach (GA-MLR) combining GA with multiple linear regression (MLR) may be useful in derivation of highly predictive and interpretable QSAR models. In view of the above, a comparative study of stepwise-MLR, PLS and GA-MLR in deriving QSAR models for datasets of alpha1-adrenoreceptor antagonists and beta3-adrenoreceptor agonists has been carried out using the public domain software Dragon for computing descriptors and free Matlab codes for data modeling.

Adrenergic alpha-Agonists↗

PieceMaker: selection of DNA fragments for selector-guided multiplex amplification.

We describe PieceMaker, a software tool for the design of applications of selector probes-oligonucleotide probes that direct circularization of target nucleic acid molecules. Such probes can be combined in parallel to circularize a selection of fragments from restriction digested total genomic DNA. These fragments can then be amplified in a single PCR using a common primer pair, yielding substrates for subsequent analyses, such as parallel genotyping or sequencing. However, designing multiplex selector assays is a laborious task. The PieceMaker program alleviates this problem by selecting restriction enzymes to generate suitable fragments for selection, and generating the output data required to design the selector probes.

Computational Biology↗

A modular framework for development and interlaboratory sharing and validation of diffusion tensor tractography algorithms.

This Technical Note describes a novel modular framework for development and interlaboratory distribution and validation of 3D tractography algorithms based on in vivo diffusion tensor imaging (DTI) measurements. The proposed framework allows individual MRI research centers to benefit from new tractography algorithms developed at other independent centers by "plugging" new tractography modules directly into their own custom DTI software tools, such as existing graphical user interfaces (GUI) for visualizing brain white matter pathways. The proposed framework is based on the Java 3D programming platform, which provides an object-oriented programming (OOP) model and independence of computer hardware configuration and operating system. To demonstrate the utility of the proposed approach, a complete GUI for interactive DTI tractography was developed, along with two separate and interchangeable modules that implement two different tractography algorithms. Although the application discussed here relates to DTI tractography, the programming concepts presented here should be of interest to anyone who wishes to develop platform-independent GUI applications for interactive 3D visualization.

Algorithms↗

[Computer-assisted interactive didactic system in radiology].

A computer-assisted didactic interactive system for radiology is described; it was implemented on a widely available, cost-effective personal computer with advanced graphic features. A set of suitable CT images was selected and digitized with a specific software that also allowed to process the acquired images. After adding graphic and textual comments, the images were ready to be put in the tutorial. A second software tool was used to manage the image display and to control the correct sequence of the interactive steps of the tutorial. A series of computer-driven multiple-choice questions was prepared to provide the user with a tool improving his/her knowledge of the topics covered by the system, in a simple and unconventional way. The tutorial was designed so that both the absolute number and the percentage of correct answers can be displayed and the critical evaluation of incorrect answers is automatically performed; in the end, the system goes back to the first screen and the tutorial can be run again. The system performance is good with standard hardware; it can be markedly improved with the integration of peripherals--i.e. hard disk. In the next future, the commercial availability of more advanced storage media (videodisks and optical disks) will dramatically improve the archiving capacity and will reduce access times.

Computer-Assisted Instruction↗

Mapping of phase response properties of monopolar ECG voltages.

In the present investigation an attempt has been made to study the phase response properties of monopolar chest lead ECG voltages. Using a generator model of the heart an equivalent circuit of ECG network has been developed. The equivalent impedance between WCT and probe electrode has been determined by reduction techniques. From this equivalent impedance the phaser characteristics of monopolar ECG voltages have been analysed for change in probe electrode locations. The source of the generated voltage, i.e., the heart, will develop a different voltage for its different condition. There will also be a change in impedances. Thus for the normal subject the distribution of the phaser of the ECG voltages will be different from that of the abnormal one. A software tool has been developed to evaluate the relative phase response of ECG voltages. The data acquisition of monopolar ECG records of chest leads V1 to V6 from chart recorder has been done with the help of AutoCAD application package. The harmonic constituents of ECG voltages have been evaluated at each harmonic plane and the phase characteristics have been studied in polar coordinate for normal subjects as well as for a typical case. An interesting result has been observed in typical cases which are indicated in the paper.

Algorithms↗

BiQ Analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing.

SUMMARY: Manual processing of DNA methylation data from bisulfite sequencing is a tedious and error-prone task. Here we present an interactive software tool that provides start-to-end support for this process. In an easy-to-use manner, the tool helps the user to import the sequence files from the sequencer, to align them, to exclude or correct critical sequences, to document the experiment, to perform basic statistics and to produce publication-quality diagrams. Emphasis is put on quality control: The program automatically assesses data quality and provides warnings and suggestions for dealing with critical sequences. The BiQ Analyzer program is implemented in the Java programming language and runs on any platform for which a recent Java virtual machine is available. AVAILABILITY: The program is available without charge for non-commercial users and can be downloaded from http://biq-analyzer.bioinf.mpi-inf.mpg.de/

DNA↗

ARB: a software environment for sequence data.

The ARB (from Latin arbor, tree) project was initiated almost 10 years ago. The ARB program package comprises a variety of directly interacting software tools for sequence database maintenance and analysis which are controlled by a common graphical user interface. Although it was initially designed for ribosomal RNA data, it can be used for any nucleic and amino acid sequence data as well. A central database contains processed (aligned) primary structure data. Any additional descriptive data can be stored in database fields assigned to the individual sequences or linked via local or worldwide networks. A phylogenetic tree visualized in the main window can be used for data access and visualization. The package comprises additional tools for data import and export, sequence alignment, primary and secondary structure editing, profile and filter calculation, phylogenetic analyses, specific hybridization probe design and evaluation and other components for data analysis. Currently, the package is used by numerous working groups worldwide.

Data Display↗

PPD - Proteome Profile Database.

With the complete sequencing of multiple genomes, there have been extensions in the methods of sequence analysis from single gene/protein-based to analyzing multiple genes and proteins simultaneously. Therefore, there is a demand of user-friendly software tools that will allow mining of these enormous datasets. PPD is a WWW-based database for comparative analysis of protein lengths in completely sequenced prokaryotic and eukaryotic genomes. PPD's core objective is to create protein classification tables based on the lengths of proteins by specifying a set of organisms and parameters. The interface can also generate information on changes in proteins of specific length distributions. This feature is of importance when the user's interest is focused on some evolutionarily related organisms or on organisms with similar or related tissue specificity or life-style. PPD is available at: PPD Home.

Animals↗

Tri-nucleotide threading for parallel amplification of minute amounts of genomic DNA.

Efforts to correlate genetic variations with phenotypic differences are intensifying due to the availability of high-density maps of single nucleotide polymorphisms (SNPs) and the development of high throughput scoring methods. These recent advances have led to an increased interest for improved multiplex preparations of genetic material to facilitate such whole genome analyses. Here we propose a strategy for the parallel amplification of polymorphic loci based on a reduced set of nucleotides. The technique denoted Tri-nucleotide Threading (TnT), allows SNPs to be amplified via controlled linear amplification followed by complete removal of the target material and subsequent amplification with a pair of universal primers. A dedicated software tool was developed for this purpose and variable positions in genes associated with different forms of cancer were analyzed using sub-nanogram amounts of starting material. The amplified fragments were then successfully scored using a microarray-based PrASE technique. The results of this study, in which 75 SNPs were analyzed, show that the TnT technique circumvents potential problems associated with multiplex amplification of SNPs from minute amounts of material. The technique is specific, sensitive and can be readily adapted to equipment and genotyping techniques used in other research laboratories without requiring changes to the preferred typing method.

Cytidine Triphosphate↗