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PubMed1987

An evaluation of a computer program to predict the outcome of hyaline membrane disease.

A computerized model was developed to predict the severity of hyaline membrane disease. This study compared the program's predictive ability with that of three neonatologists. Blood gas and respiratory support data of 33 infants were entered into the computer which then predicted the severity of disease. The computer predicted 18 outcomes correctly. The neonatologists, provided with the same data, predicted 24 outcomes correctly. Both sets of predictions--computer and physician--found that patients predicted to have mild outcomes had the shortest oxygen requirements, duration of mechanical ventilation, and length of hospitalization, and infants predicted to have severe outcomes had the greatest oxygen requirements, duration of mechanical ventilation, and length of hospitalization. While actual severity was linked to birth weight, the model did not utilize birth weight in its predictive algorithm. Consequently, although the computer program predicted the outcomes with moderate success, it was less accurate than the neonatologists.

Blood Gas Analysis↗
PubMed2003

Cosmic ray measurements at aircraft altitudes and comparison with predictions of computer codes.

Extensive measurements of dose exposure of aircrew have been carried out in recent years using passive detectors on subsonic and supersonic air routes by DIAS (Dublin Institute for Advanced Studies). Studies were based on measurement of LET spectra using nuclear recoils produced in CR-39 nuclear track detectors by high energy neutrons and protons. The detectors were calibrated using energetic heavy ions. Data obtained were compared with the predictions of the EPCARD and CARI-6 codes. Good agreement has been found between the experimental and theoretical values.

Aircraft↗
PubMed2001

Computational modeling predicts the structure and dynamics of chromatin fiber.

BACKGROUND: The compact form of the chromatin fiber is a critical regulator of fundamental processes such as transcription and replication. These reactions can occur only when the fiber is unraveled and the DNA strands contained within are exposed to interact with nuclear proteins. While progress on identifying the biochemical mechanisms that control localized folding and hence govern access to genetic information continues, the internal structure of the chromatin fiber, let alone the structural pathways for folding and unfolding, remain unknown. RESULTS: To offer structural insights into how this nucleoprotein complex might be organized, we present a macroscopic computer model describing the mechanics of the chromatin fiber on the polymer level. We treat the core particles as electrostatically charged disks linked via charged elastic DNA segments and surrounded by a microionic hydrodynamic solution. Each nucleosome unit is represented by several hundred charges optimized so that the effective Debye-Hückel electrostatic field matches the field predicted by the nonlinear Poisson-Boltzmann equation. On the basis of Brownian dynamics simulations, we show that oligonucleosomes condense and unfold in a salt-dependent manner analogous to the chromatin fiber. CONCLUSIONS: Our predicted chromatin model shows good agreement with experimental diffusion coefficients and small-angle X-ray scattering data. A fiber of width 30 nm, organized in a compact helical zigzag pattern with about 4 nucleosomes per 10 nm, naturally emerges from a repeating nucleosome folding motif. This fiber has a cross-sectional radius of gyration of R(c) = 8.66 nm, in close agreement with corresponding values for rat thymus and chicken erythrocyte chromatin (8.82 and 8.5 nm, respectively).

Algorithms↗
PubMed1993

Molecular identity of a sperm acrosome antigen recognized by HS-63 monoclonal antibody.

The molecular identity of mouse sperm acrosome antigen recognized by HS-63 monoclonal antibody was analyzed by various biochemical, immunological and molecular biological methods. When its cognate antigen, MSA-63 was isolated from mouse testis by immunoaffinity chromatography, a group of protein spots with wide range of molecular sizes and isoelectric points were identified. Through previous studies, it was established that most of these protein spots were actin-like molecules co-purified with MSA-63 protein from mouse testis. To analyze the molecular size heterogeneity of the isolated MSA-63 proteins, rabbit antisera against a computer-predicted antigenic synthetic peptide (amino acid residue No. 160-171) and a recombinant glutathione S-transferase (GST) fusion protein (GST-63) were raised. These two antisera and those raised against the isolated MSA-63 protein were used as the probes in comparative Western blot assay, indirect immunofluorescent assay and enzyme-linked immunosorbent assay (ELISA). Using ELISA, antisera against GST-63 and computer-predicted antigenic synthetic peptides were shown to cross-react with affinity-isolated MSA-63 protein coated on microwells. However, little immunological cross-reactivity was observed between GST-63 fusion protein and the synthetic peptide. By using a Western blot assay, two major protein bands of 22 and 32 kDa, respectively were commonly detected on mouse testis homogenate strips by both anti-MSA-63 and anti-GST-63. In addition, anti-MSA-63 also recognized several protein bands with molecular masses greater than 35 kDa. The results of this study suggested that the molecular heterogeneity of MSA-63 protein isolated from mouse testis and sperm, is due to a series of post-translational modifications on a single gene product. These modifications may include glycosylations, proteolytic digestions and tight non-covalent associations with other testicular cytoskeletal proteins, such as actins.

Acrosome↗
PubMed1992

Blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients: prediction by computer modeling.

To establish a qualitative and quantitative model of blood glucose response to stress hormone exposure, healthy subjects (HS) on and off somatostatin (250 micrograms/h) as well as insulin dependent diabetic patients were infused with either epinephrine (E), glucagon (G), cortisol (F), growth hormone (GH) or with a cocktail of these hormones raising plasma stress hormones to values seen in severe diabetic ketoacidosis. The developed input/output model consists of two submodels interconnected in series plus two additional submodels for correction of gains describing both sensitivity of tissue response and utilisation as well as provision of glucose. It was shown and confirmed experimentally that blood glucose response to stress hormones was essentially nonlinear. Furthermore, the mathematical models for healthy subjects and for insulin dependent diabetic patients proved to be of the same structure and differed only in the values of some typical parameters. The model raises the possibility to describe and in part to predict blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients.

Adult↗
PubMed2004

Antisense-mediated VEGF suppression in bladder and breast cancer cells.

Angiogenesis plays a key role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is one of the major angiogenic factors. In the study we have evaluated the efficiency of antisense oligodeoxynucleotides (AS-ODN) against VEGF selected from computational prediction of VEGF mRNA structure. Twenty-five different AS-ODN in two different tumor cell lines were investigated. Treatment of cell line EJ28 by VEGF723 resulted in a 83.5% suppression of VEGF protein when compared with control-ODN. Three further AS-ODN reduced VEGF protein more than 45% in comparison to control-ODN. This was caused by an antisense-specific downregulation of the VEGF transcript determined by real-time PCR. Furthermore, antisense-mediated inhibition of VEGF was associated by a reduced cell viability. In MCF-7 cells VEGF protein was inhibited more than 45% by two AS-ODN. In conclusion, we found that computational prediction of potential single strand mRNA motifs is a well suitable method to elect effective AS-ODN.

Breast Neoplasms↗
PubMed1975

Pattern recognitiion and structure-activity relationship studies. Computer-assisted prediction of antitumor activity in structurally diverse drugs in an experimental mouse brain tumor system.

This paper reports the application of pattern recognition and substructural analysis to the problem of predicting the antineoplastic activity of 24 test compounds in an experimental mouse brain tumor system based on 138 structurally diverse compounds tested in this tumor system. The molecules were represented by three types of substructural fragments, the augmented atom, the heteropath, and the ring fragments. Of the two pattern recognition methods used to predict the activity of the test compounds the nearest neighbor method predicted 83% correctly while the learning machine method predicted 92% correctly. The test structures and the important substructural fragments used in this study are given and the implications of these results are discussed.

Animals↗
PubMed2005

Long-range oscillation in a periodic DNA sequence motif may influence nucleosome array formation.

We have experimentally examined the characteristics of nucleosome array formation in different regions of mouse liver chromatin, and have computationally analyzed the corresponding genomic DNA sequences. We have shown that the mouse adenosine deaminase (MADA) gene locus is packaged into an exceptionally regular nucleosome array with a shortened repeat, consistent with our computational prediction based on the DNA sequence. A survey of the mouse genome indicates that <10% of 70 kb windows possess a nucleosome-ordering signal, consisting of regular long-range oscillations in the period-10 triplet motif non-T, A/T, G (VWG), which is as strong as the signal in the MADA locus. A strong signal in the center of this locus, confirmed by in vitro chromatin assembly experiments, appears to cooperate with weaker, in-phase signals throughout the locus. In contrast, the mouse odorant receptor (MOR) locus, which lacks locus-wide signals, was representative of approximately 40% of the mouse genomic DNA surveyed. Within this locus, nucleosome arrays were similar to those of bulk chromatin. Genomic DNA sequences which were computationally similar to MADA or MOR resulted in MADA- or MOR-like nucleosome ladders experimentally. Overall, we provide evidence that computationally predictable information in the DNA sequence may affect nucleosome array formation in animal tissue.

Adenosine Deaminase↗
PubMed2006

[Screening and their anti-tumor activity of antisense oligodeoxynucleotides targeting KDR mRNA in breast cancer MCF-7 cells].

OBJECTIVE: To screen the antisense oligodeoxynucleotides (asONs) which could hybridize with KDR (kinase insert domain-containing receptor) mRNA in an effective and specific way and to explore their anti-tumor effects on breast cancer MCF-7 cell line in vitro. METHODS: The asONs were firstly selected using oligodeoxynucleotides library hybridization or computer prediction, then their hybridization ability with KDR mRNA was further tested with oligonucleotide microarray. The asONs with strong hybridization intensity were selected. Their inhibitory effects on MCF-7 cells proliferation and KDR expression were assayed by MTT, RT-PCR and Western blotting assay, respectively. RESULTS: In 13 asONs selected with oligodeoxynucleotides library hybridization, 8 (8/13, 61.5%) showed strong hybridization signals, while such was only 1 in 17 asONs designed by computer prediction. 9 asONs with strong hybridization intensity were selected and synthesized with phosphorothioated modification. All these asONs inhibited the MCF-7 cells proliferation in a dose-dependent manner, in which asON4 and asON7 screened by oligodeoxynucleotides library in combination with oligonucleotide microarray were the most effective, with inhibitory rates of 51.6% and 62.2% at 0.8 micromol/L, respectively. The KDR expression at mRNA and protein levels was reduced by both the two asONs, in a dose-dependent manner. CONCLUSION: asONs screened by oligodeoxynucleotides library hybridization are well consistent with that chosen with oligonucleotide microarray. The combination of oligodeoxynucleotides library with oligonucleotide microarray is an effective approach of asONs screening. The asONs targeting KDR mRNA showed prominent anti-tumor activity on breast cancer MCF-7 cells.

Breast Neoplasms↗
PubMed2001

[The Prediction of the Molecular Biology Characteristics of Recombinant Fusion Exotoxin B7-1-Linker-PE40 and B7-2-Linker-PE40]

In order to confirm the reasonability of designed recombinant exotoxin B7-1-Linker-PE40 and B7-2-Linker-PE40, their molecular biology characteristics, such as flexibility, antigenicity, hydrophilicity, epitope and secondary structure, were predicted by using a computer software GOLDKEY. It had been found that the recombinant fusion exotoxin had kept the epitope characterstics of B7-1, B7-2 and PE40, and had not got new epitope, and the antigenicity in flexible linker was extxemely low. The linker inserted in the recombinant fusion exotoxin had low epitope, low antigenicity and high flexibility. Compared to B7-1, B7-2 and PE40, there are several amino acid residues changes in B7-1-Linker-PE40 and B7-2-Linker-PE40, respectively, which might have some effect on secondary structure of the recombinant fusion exotoxins. Western blot analysis revealed that both B7-1-Linker-PE40 and B7-2-Linker-PE40 could bind specifically with antibodies against B7-1, B7-2 and PE40, respectively. The result of Western blot was consistant with the computer prediction that the recombinant proteins retain the antigenicity and spacial structure of B7 and PE40. It is suggested that both fusion proteins designed and constructed were resonable and computer analysis would be helpful for us to study the biological activity of the recombinant fusion exotoxin B7-1-Linker-PE40 and B7-2-Linker-PE40 and construct other recombinant proteins further.

Journal Article↗
PubMed1989

[Experimental research on the quantitative computed tomographic prediction of the compressive strength of the thoracolumbar vertebrae].

Testing 98 motion segments we investigated the possibility of a prediction of the compressive strength of thoracolumbar vertebrae by QCT. The ultimate compressive strength can be predicted from the density of the trabecular bone and from the size of the endplates--both determined by QCT--with an error of 1 kN. The increase of compressive strength in craniocaudal direction is calculated at approximately 0.3 kN per anatomical level. This variation is due to the increase of the endplate areas.

Adult↗
PubMed2006

Close sequence comparisons are sufficient to identify human cis-regulatory elements.

Cross-species DNA sequence comparison is the primary method used to identify functional noncoding elements in human and other large genomes. However, little is known about the relative merits of evolutionarily close and distant sequence comparisons. To address this problem, we identified evolutionarily conserved noncoding regions in primate, mammalian, and more distant comparisons using a uniform approach (Gumby) that facilitates unbiased assessment of the impact of evolutionary distance on predictive power. We benchmarked computational predictions against previously identified cis-regulatory elements at diverse genomic loci and also tested numerous extremely conserved human-rodent sequences for transcriptional enhancer activity using an in vivo enhancer assay in transgenic mice. Human regulatory elements were identified with acceptable sensitivity (53%-80%) and true-positive rate (27%-67%) by comparison with one to five other eutherian mammals or six other simian primates. More distant comparisons (marsupial, avian, amphibian, and fish) failed to identify many of the empirically defined functional noncoding elements. Our results highlight the practical utility of close sequence comparisons, and the loss of sensitivity entailed by more distant comparisons. We derived an intuitive relationship between ancient and recent noncoding sequence conservation from whole-genome comparative analysis that explains most of the observations from empirical benchmarking. Lastly, we determined that, in addition to strength of conservation, genomic location and/or density of surrounding conserved elements must also be considered in selecting candidate enhancers for in vivo testing at embryonic time points.

Animals↗
PubMed1987

Altered aminoglycoside pharmacokinetics in critically ill patients with sepsis.

The pharmacokinetic disposition of aminoglycosides in critically ill patients with sepsis was studied. In an open-label study of the disposition of gentamicin and tobramycin, individualized pharmacokinetic values of 100 critically ill patients in the surgical intensive-care unit were compared with those of a concurrently monitored group of 100 surgery patients who were not critically ill. The a priori computer-predicted dosage requirements of the critically ill patients were also compared with the dosages derived from their individualized pharmacokinetic values, and intrapatient variation in the critically ill patients was studied. Serum concentration-time data were analyzed using a one-compartment model and the DataMed Clinical Support Services system to provide individualized dosage requirements. Initial dosing guidelines were also generated for the critically ill patients using the a priori model of the DataMed Clinical Support Services program and patient demographic information. The critically ill patients were significantly older, had higher serum creatinine concentrations (SCr), and had lower elimination rate constants (k) and total body clearances (CL) than the surgery patients who were not critically ill. The volume of distribution (V) was not significantly different. The a priori computer predictions for the critically ill patients were significantly lower than the individualized values for V, CL, dose, and amount of drug per 24 hours. The dosing regimen from the a priori model was the same as the individualized regimen in only 2/100 patients. In the 76 critically ill patients who had a second pharmacokinetic analysis performed, there was a significant decrease in k and CL from the first analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2003

Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy.

PURPOSE: To investigate the value of CT-determined tumor perfusion as a predictive factor of local and regional failure and cause-specific survival in head-and-neck cancer treated by radiotherapy. MATERIALS AND METHODS: In 105 patients, the perfusion of a primary head-and-neck squamous cell carcinoma was estimated using dynamic CT. A contrast agent bolus was rapidly injected i.v., while during the first pass a dynamic data acquisition was performed at the level of the largest axial tumor surface. The perfusion in the selected tumor region of interest was calculated by dividing the slope of the tumor-time density curve by the maximal value in arterial density. Primary and nodal tumor volume was calculated from the CT images. All patients were treated by radiotherapy with curative intent; in 15 patients, adjuvant concomitant chemotherapy was administered. Mean follow-up time was 2.2 years. Actuarial (life-table) statistical analysis was done; multivariate analysis was performed using the Cox proportional hazards model. RESULTS: When the patients were stratified according to the median perfusion value (83.5 mL/min/100 g), those with the lower perfusion rate had a significantly higher local failure rate (p < 0.05). In the multivariate analysis, perfusion rate (p = 0.01) and T category (p = 0.03) were found to be the independent predictors of local failure. Perfusion rate had predictive value regarding neither regional control nor cause-specific survival. CONCLUSIONS: CT-determined tumor perfusion rate was found to be an independent predictor of local outcome in irradiated head-and-neck cancer. The results of this study confirm the hypothesis that less-perfused tumors respond poorly to radiotherapy.

Adult↗
PubMed2005

A genomic-scale search for regulatory binding sites in the integration host factor regulon of Escherichia coli K12.

We examined general aspects of the DNA-protein interaction between the integration host factor (IHF) global regulator and its regulatory binding sites in the Escherichia coli K12 genome. Two models were developed with distinct weight matrices for the regulatory binding sites recognized by IHF. Using these matrices we performed a genome scale scan and built a set of computationally predicted binding sites for each of the models. The sites found by the model associated with repetitive sequences had a higher score in the sequence to matrix alignment. They were also more rare than the other sites. The sites not associated with repeats rapidly tended to become undistinguishable from the background as statistical stringency was relaxed. We compared our results to the known sites documented in RegulonDB and found new members of the IHF Regulon. The two models exhibit clearly distinct affinity patterns (scores in the sequence to matrix alignments and in the number of regulatory sites), as we vary the stringency of the statistical confidence parameters. We suggest that these differences may play an important role in the dynamics of the network. We concluded that IHF may regulate two genes encoding ATP-dependent RNA helicases. This interaction is not described in RegulonDB, even as a computational prediction. IHF may also regulate RNA modification processes.

Binding Sites↗
PubMed2005

Protein conformational transitions coupled to binding in molecular recognition of unstructured proteins: deciphering the effect of intermolecular interactions on computational structure prediction of the p27Kip1 protein bound to the cyclin A-cyclin-dependent kinase 2 complex.

The relationship between folding mechanism coupled to binding and structure prediction of the tertiary complexes is studied for the p27(Kip) (1) protein which has an intrinsically disordered unbound form and undergoes a functional folding transition during complex formation with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) binary complex. Hierarchy of p27(Kip1) structural loss determined in our earlier studies from temperature-induced Monte Carlo simulations and subsequent characterization of the transition state ensemble (TSE) for the folding reaction have shown that simultaneous ordering of the p27(Kip1) native intermolecular interface for the beta-hairpin and beta-strand secondary structure elements is critical for nucleating a rapid kinetic transition to the native tertiary complex. In the present study, we investigate the effect of forming specific intermolecular interactions on structure prediction of the p27(Kip1) tertiary complex. By constraining different secondary structure elements of p27(Kip1) in their native bound conformations and conducting multiple simulated annealing simulations, we analyze differences in the success rate of predicting the native structure of p27(Kip1) in the tertiary complex. In accordance with the nucleation-condensation mechanism, we have found that further stabilization of the native intermolecular interface for the beta-hairpin and beta-strand elements of p27(Kip1), that become ordered in the TSE, but are hardly populated in the unbound state, results in a consistent acquisition of the native bound structure. Conversely, the excessive stablization of the local secondary structure elements, which are rarely detected in the TSE, has a detrimental effect on convergence to the native bound structure.

Cell Cycle↗
PubMed1994

Total biventricular volume and total left ventricular volume by ultrafast computed tomography: prediction of left ventricular mass.

Since LV hypertrophy is an independent predictor of increased cardiac mortality, a simple noninvasive measure of LV mass would be a valuable screening tool. A retrospective assessment of 50 UFCT studies was performed. Measurements of LV mass, TBV, and TLV were determined in each case. There was excellent correlation between TBV and LVM (R = 0.93) and between TLV and LV mass (R = 0.92). Also, there was minimal interobserver variability between two independent observers for estimates of both TBV (R = 0.995) and TLV (R = 0.99). Thus these preliminary data indicate that LV mass may be estimated from TBV or TLV and that these tools may assist in the identification of patients potentially at high risk for future coronary events, as indicated by the presence of increased LV mass and coronary atherosclerosis.

Adult↗