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At least 433 records · Page 24Linked to original sources
PubMed1984

Removable high intensity iridium-192 brain implants. Technique and in vivo measurements in canine brain.

A preclinical evaluation of the technical details and dosimetry for temporary high intensity 192Ir brain implants is presented. The canine brain was used for this quality assurance study in which direct in vivo dose measurements were done by thermoluminescent dosimetry (TLD rods). Precise and reproducible positioning of the TLD rods and 192Ir ribbons were assured by simple accessories which can be utilized in the clinical situation. The neurosurgical procedure for this non-routine interstitial implant of the brain, suitability of type and size of afterloading cannulas and facility for firmly anchoring them to the scalp, and comparison of measured doses with computer-predicted values are details assured by the canine study. Agreement between the in vivo determination and computer-generated doses was consistently in the range 2-5%. Data derived from this preclinical evaluation are currently used in both stereotactic and non-stereotactic brain implants at our institution. Details are presented for the implant procedure, dose measurements and brachytherapy planning for multiple ribbons. The latter incorporates direct interaction on computed tomography (CT) images for a hypothetical patient case.

Animals↗
PubMed2006

In silico pharmacogenetics of warfarin metabolism.

Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index and a large variation in individual dosing. After quantification of warfarin and nine of its metabolites in plasma from 13 inbred mouse strains, we correlated strain-specific differences in 7-hydroxywarfarin accumulation with genetic variation within a chromosomal region encoding cytochrome P450 2C (Cyp2c) enzymes. This computational prediction was experimentally confirmed by showing that the rate-limiting step in biotransformation of warfarin to its 7-hydroxylated metabolite was inhibited by tolbutamide, a Cyp2c isoform-specific substrate, and that this transformation was mediated by expressed recombinant Cyp2c29. We show that genetic variants responsible for interindividual pharmacokinetic differences in drug metabolism can be identified by computational genetic analysis in mice.

Animals↗
PubMed2000

Prediction of exact boundaries of exons.

It is known that while the programs used to predict genes are good at determining coding nucleotides, there are considerable inaccuracies in the determination of the gene structural elements. Among them, the most notable is that of the exact boundaries of exons. In order to assess this, we had earlier reviewed various programs that predict potential splice sites and exons. The results led to the following two observations: (i) a high proportion of false positive splice sites from computational predictions occur in the vicinity of real splice sites; and (ii) current algorithms are misled to predict wrong splice sites more often when the coding potential ends within +/-25 nucleotides from real sites than when it ends at farther positions. In this report, we review decision tree models for human splice sites and the resultant software tool, namely SpliceProximalCheck, that discriminates such'proximal' false positives from real splice sites. Further presented is an integrated system (MZEF-SPC) with Splice ProximalCheck (SPC) as a front-end tool operating on the results of Michael Zhang's exon finder program. Examination of the output of the integrated program on an illustrative gene set revealed that as much as 61 of 93 MZEF-predicted false positive exons could be eliminated by SPC for a loss of only 3 out of 33 MZEF-predicted true positive exons.

Algorithms↗
PubMed1994

Z-DNA-forming sequences at a putative duplication site in the human annexin VI-encoding gene.

We report here the presence of five stretches of alternating purine/pyrimidine (APP) intronic sequence close to the 5' end of the first exon in the C-terminal half of the human annexin VI-encoding gene (ANX VI). ANX VI, which comprises eight conserved repeats, is considered to have arisen by duplication of a hypothetical four repeat Anx; the location of the duplication would be predicted to occur within the intron where the APP sequences have been identified. The APP sequences have, by computer prediction, been identified as having significant potential to form Z-DNA. We discuss the significance of these potential Z-DNA-forming sequences being located in a region predicted to be the site of duplication which gave rise to the human ANX VI gene.

Animals↗
PubMed1996

Computational studies of protein folding.

This review describes computational approaches to the determination of protein structure from sequence. The emphasis is on reduced protein models that are sufficiently accurate to represent protein structure at low resolution, yet are computationally efficient enough to allow the extensive search of phase space required to locate the global minimum from an unfolded state. A discussion of both potential functions and algorithmic simulation strategies for such models are presented, along with a number of specific models that have been developed and successfully applied to proteins as large as myoglobin. The results indicate that significant progress is being made in understanding the requirements for computational prediction of protein structure.

Algorithms↗
PubMed2004

A Bayesian method for identifying missing enzymes in predicted metabolic pathway databases.

BACKGROUND: The PathoLogic program constructs Pathway/Genome databases by using a genome's annotation to predict the set of metabolic pathways present in an organism. PathoLogic determines the set of reactions composing those pathways from the enzymes annotated in the organism's genome. Most annotation efforts fail to assign function to 40-60% of sequences. In addition, large numbers of sequences may have non-specific annotations (e.g., thiolase family protein). Pathway holes occur when a genome appears to lack the enzymes needed to catalyze reactions in a pathway. If a protein has not been assigned a specific function during the annotation process, any reaction catalyzed by that protein will appear as a missing enzyme or pathway hole in a Pathway/Genome database. RESULTS: We have developed a method that efficiently combines homology and pathway-based evidence to identify candidates for filling pathway holes in Pathway/Genome databases. Our program not only identifies potential candidate sequences for pathway holes, but combines data from multiple, heterogeneous sources to assess the likelihood that a candidate has the required function. Our algorithm emulates the manual sequence annotation process, considering not only evidence from homology searches, but also considering evidence from genomic context (i.e., is the gene part of an operon?) and functional context (e.g., are there functionally-related genes nearby in the genome?) to determine the posterior belief that a candidate has the required function. The method can be applied across an entire metabolic pathway network and is generally applicable to any pathway database. The program uses a set of sequences encoding the required activity in other genomes to identify candidate proteins in the genome of interest, and then evaluates each candidate by using a simple Bayes classifier to determine the probability that the candidate has the desired function. We achieved 71% precision at a probability threshold of 0.9 during cross-validation using known reactions in computationally-predicted pathway databases. After applying our method to 513 pathway holes in 333 pathways from three Pathway/Genome databases, we increased the number of complete pathways by 42%. We made putative assignments to 46% of the holes, including annotation of 17 sequences of previously unknown function. CONCLUSIONS: Our pathway hole filler can be used not only to increase the utility of Pathway/Genome databases to both experimental and computational researchers, but also to improve predictions of protein function.

Amino Acid Oxidoreductases↗
PubMed2000

Purification, cloning, and three-dimensional structure prediction of Micrococcus luteus FAD-containing tyramine oxidase.

The FAD-containing tyramine oxidase enzyme and gene from the Gram (+) bacterium Micrococcus luteus were isolated, and computer prediction was used to propose a preliminary 3D model of the protein. A 2.8-kb Sau3AI fragment containing the structural gene of tyramine oxidase was cloned from a M. luteus genomic DNA library. The 1332 bp gene encodes a protein of 443 amino acids, with a calculated molecular mass of 49.1 kDa. The enzyme was found to be a homodimer with a molecular weight of 49,000. It oxidizes tyramine, adrenaline, 3-hydroxytyramine, dopamine, and noradrenaline, and was reversibly inhibited by FAD-containing monoamine oxidase A and B specific inhibitors. Sequence comparison show that tyramine oxidase is smaller than other FAD-amine oxidases but that it contains well-conserved amino acid residues reported in all other FAD-amine oxidases. A hypothetical three-dimensional structure of tyramine oxidase has also been proposed based on secondary structure predictions, threading, and comparative modeling.

Amino Acid Sequence↗
PubMed1961

Predictions of the growth model for normal chicken growth.

The model of growth control advanced by Weiss and Kavanau has been further evaluated with an I.B.M. 7090 computer. Predictions for the concentration of growth-inhibiting substances and their quantitative distribution in the animal are in good agreement with known developmental changes. Results are being used to predict the course of compensatory organ growth in the immature animal.

Animals↗
PubMed2005

Proteomic analysis of the porcine interphotoreceptor matrix.

The interphotoreceptor matrix (IPM) is located between photoreceptors and pigment epithelium in the retina and is involved in fundamental functions of the visual cycle. These include visual pigment chromophore exchange, retinal adhesion, metabolite trafficking, and growth factor presentation. In general, IPM preparations are contaminated with intracellular proteins, as has also been described for other body fluids. This study aimed at identifying new components of the IPM by discriminating between truly secreted proteins and proteins that are part of the IPM for secondary reasons. "Soluble" porcine IPM was extracted from retina and pigment epithelium with PBS by two different procedures, followed by extraction with water alone that released "insoluble" IPM matrix sheets. Samples from all preparations were separated by 2-DE and a total of 140 protein spots were identified by MALDI-TOF and/or CapLC Q-TOF MS. Although identified proteins included several already known in the IPM, the majority had not been previously described in this structure. Gene ontology classifications allocated the identified proteins into nine different functional networks. The IPM preparations also included intracellular proteins from cells adjacent to the IPM, which may have resulted from cell disruption. This underlines the experimental difficulties of a biochemical analysis of the IPM as an intact compartment. We show here a strategy for predicting the probability of identified IPM proteins occurring in vivo by combined high-resolution protein separation methods with computational prediction methods. Thus, a set of potentially neuroprotective proteins could be extracted, including PEA-15, peroxiredoxin 5, alpha-B-crystallin, macrophage migration inhibitory factor, 78 kDa glucose-regulated protein (GRP78), protein disulfide-isomerase, and PEP-19, which have not been previously associated with the IPM. Furthermore, with immunohistochemical staining we could confirm the localization of GRP78 in the IPM on porcine eye sections, thus validating the proposed prediction method.

Animals↗
PubMed2005

SayaMatcher: genome scale organization and systematic analysis of nuclear receptor response elements.

The availability of genome sequences enables us to make experiments in silico to find biological features encoded in the genome. In order to study gene expression regulation network by nuclear receptors that function as ligand-activated transcription, nuclear receptor response elements (NREs) in genomes were computationally explored by integration of computational prediction and experimental data. Dealing with expansion of available genome sequences and continuous update of these genomic sequences, the computation needed for these searches is organized to form a 'pipeline', called SayaMatcher. The information of genomic position for those NREs is served using the Distributed Annotation System (DAS) to be shown in Ensembl genome browser. Utilizing the SayaMatcher system, binding activity in vivo was studied for androgen response elements in human.

Animals↗
PubMed2003

NYX (nyctalopin on chromosome X), the gene mutated in congenital stationary night blindness, encodes a cell surface protein.

PURPOSE: The complete type of X-linked congenital stationary night blindness (CSNB1) in human and mouse is caused by mutations in the NYX gene. The human NYX protein has been predicted to contain an N-terminal endoplasmic reticulum (ER) signaling sequence and a C-terminal glycosylphosphatidylinositol (GPI) anchor. In the current study, these computer predictions were verified experimentally by expression of domain-specific cDNA constructs in COS-7 and HeLa cells. Moreover, computer-based analysis of the orthologue mouse amino acid sequence did not reveal a GPI anchor, which may result in a different protein localization compared with human NYX. Therefore, the cellular localization for the mouse Nyx protein was also examined. METHODS: A new method was established that differentially visualizes both the protein at the surface of the living cell and subsequently in intracellular compartments. The localization of the human and mouse V5-tagged wild-type and mutant NYX protein were studied. RESULTS: Human and mouse V5-NYX proteins were dispersed in the form of speckles over the entire cell surface. Subsequent staining of the same cells after detergent extraction revealed that V5-NYX located to the ER and Golgi apparatus. Deletion of the GPI anchor domain of NYX resulted in a time-dependent loss of V5-NYX from the surface of living cells and accumulation of this truncated protein in the ER and Golgi apparatus. Deletion of the ER signal sequence in Nyx delocalized the intracellular V5-Nyx protein and caused its dispersion in the cytosol. Furthermore, mutations introduced in the leucine-rich repeat (LRR)-region, which has been described as a pathogenic variant of NYX, had no effect on subcellular localization of the protein. CONCLUSIONS: These data provide evidence that human and mouse nyctalopin are membrane-bound extracellular proteins and are functionally conserved.

Animals↗
PubMed2003

Prediction of protein subcellular locations by support vector machines using compositions of amino acids and amino acid pairs.

MOTIVATION: The subcellular location of a protein is closely correlated to its function. Thus, computational prediction of subcellular locations from the amino acid sequence information would help annotation and functional prediction of protein coding genes in complete genomes. We have developed a method based on support vector machines (SVMs). RESULTS: We considered 12 subcellular locations in eukaryotic cells: chloroplast, cytoplasm, cytoskeleton, endoplasmic reticulum, extracellular medium, Golgi apparatus, lysosome, mitochondrion, nucleus, peroxisome, plasma membrane, and vacuole. We constructed a data set of proteins with known locations from the SWISS-PROT database. A set of SVMs was trained to predict the subcellular location of a given protein based on its amino acid, amino acid pair, and gapped amino acid pair compositions. The predictors based on these different compositions were then combined using a voting scheme. Results obtained through 5-fold cross-validation tests showed an improvement in prediction accuracy over the algorithm based on the amino acid composition only. This prediction method is available via the Internet.

Algorithms↗
PubMedDate not supplied

Conversion from intravenous aminophylline to sustained-release theophylline: computer simulation versus in vivo results.

The accuracy of computer-predicted theophylline serum concentrations compared with actual serum concentrations in patients whose drug therapy was being converted from aminophylline infusions to an oral sustained-release theophylline product (Theo-Dur) was measured. The SIMKIN computer program was used to simulate theophylline serum-concentration curves in nine patients receiving an initial dose of sustained-release theophylline at the time their maintenance aminophylline infusions were discontinued. The sustained-release theophylline doses were calculated using individual patient theophylline clearance values to produce mean theophylline serum concentrations in the normal therapeutic range. Pharmacokinetic variables used in the SIMKIN program were derived from individual patients' serum concentrations and average literature values. Theophylline serum concentrations were measured before the initial dose of the sustained-release product and periodically for 12 hours. Mean SIMKIN-predicted serum theophylline concentrations were within 10% of actual measurements 39% of the time, but data from individual patients varied considerably. Two patients had prolonged absorption lag times that could not be explained. Computer-simulation programs using population-based pharmacokinetic variables to predict theophylline serum concentrations must be tested against in vivo measurements to verify their accuracy.

Adult↗
PubMed2001

Computational analysis of human disease-associated genes and their protein products.

The complete genome sequences for human, Drosophila melanogaster and Arabidopsis thaliana have been reported recently. With the availability of complete sequences for many bacteria and archaea, and five eukaryotes, comparative genomics and sequence analysis are enabling us to identify counterparts of many human disease genes in model organisms, which in turn should accelerate the pace of research and drug development to combat human diseases. Continuous improvement of specialized protein databases, together with sensitive computational tools, have enhanced the power and reliability of computational prediction of protein function.

Animals↗
PubMed2003

Assessing the impact of predictive biosimulation on drug discovery and development.

Systems biology is creating a context for interpreting the vast amounts of genomic and proteomic data being produced by pharmaceutical companies in support of drug development. While major data collection efforts capitalize on technical advances in miniaturization and automation and represent an industrialization of existing laboratory research, the transition from mental models to predictive computer simulations is setting the pace for advances in this field. This article addresses current approaches to the mathematical modeling of biological systems and assesses the potential impact of predictive biosimulation on drug discovery and development.

Animals↗
PubMed2004

An improved prediction of chloroplast proteins reveals diversities and commonalities in the chloroplast proteomes of Arabidopsis and rice.

Proteins that form part of the chloroplast proteome can be identified by computational prediction of the N-terminal presequences (chloroplast transit peptides, cTPs) of their cytoplasmic precursor proteins. The accuracy of four different cTP predictors has been evaluated on a test set of 4500 proteins whose subcellular localization is known, and was found to be substantially lower than previously reported. A combination of cTP prediction programs was superior to any one of the predictors alone. This combination was employed to estimate the size and composition of the chloroplast proteomes of Arabidopsis and rice, and about 2100 (Arabidopsis thaliana) and 4800 (Oryza sativa) different chloroplast proteins with a cTP are predicted to be encoded by their nuclear genomes. A subset of around 900 chloroplast proteins, predominantly derived from the cyanobacterial endosymbiont and with functions mostly related to metabolism, energy and transcription, is shared by the two species. This points to the existence of both conserved nucleus-encoded chloroplast proteins that are predominantly of prokaryotic origin, and a large fraction of taxon-specific chloroplast-targeted proteins, in flowering plants.

Arabidopsis↗
PubMed2024

PredIL13: Stacking a variety of machine and deep learning methods with ESM-2 language model for identifying IL13-inducing peptides.

Interleukin (IL)-13 has emerged as one of the recently identified cytokine. Since IL-13 causes the severity of COVID-19 and alters crucial biological processes, it is urgent to explore novel molecules or peptides capable of including IL-13. Computational prediction has received attention as a complementary method to in-vivo and in-vitro experimental identification of IL-13 inducing peptides, because experimental identification is time-consuming, laborious, and expensive. A few computational tools have been presented, including the IL13Pred and iIL13Pred. To increase prediction capability, we have developed PredIL13, a cutting-edge ensemble learning method with the latest ESM-2 protein language model. This method stacked the probability scores outputted by 168 single-feature machine/deep learning models, and then trained a logistic regression-based meta-classifier with the stacked probability score vectors. The key technology was to implement ESM-2 and to select the optimal single-feature models according to their absolute weight coefficient for logistic regression (AWCLR), an indicator of the importance of each single-feature model. Especially, the sequential deletion of single-feature models based on the iterative AWCLR ranking (SDIWC) method constructed the meta-classifier consisting of the top 16 single-feature models, named PredIL13, while considering the model's accuracy. The PredIL13 greatly outperformed the-state-of-the-art predictors, thus is an invaluable tool for accelerating the detection of IL13-inducing peptide within the human genome.

Humans↗
PubMed1997

Predicting premorbid neuropsychological functioning following pediatric traumatic brain injury.

This study examined the prediction of premorbid neuropsychological functioning using data from an ongoing prospective study of traumatic brain injuries (TBI) in children ages 6 to 12 years. Prediction equations were derived based on 80 children with orthopedic injuries (OI), who served as a comparison group for the children with TBI. Collectively, parent ratings of premorbid school performance, maternal ethnicity, family socioeconomic status, and children's word recognition skill predicted from 13% to 45% of the variance in three measures of neuropsychological functioning. The regression equations were used to compute predicted scores among 109 children with TBI. Actual scores fell significantly below predicted scores among children with TBI, and the magnitude of the deficits was correlated with injury severity. Premorbid neuropsychological functioning can be predicted in children with TBI, but with less precision than would be desirable for clinical purposes.

Brain Injuries↗