Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “virtual screening”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,153 records · Page 64Linked to original sources
PubMed2006

Library design, synthesis, and screening: pyridine dicarbonitriles as potential prion disease therapeutics.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are a family of invariably fatal neurodegenerative disorders, and there are no effective therapeutics currently available. In this paper, we report on the design, synthesis, and screening of a series of pyridine dicarbonitriles as potential novel prion disease therapeutics. A virtual reaction-based library of 1050 compounds was constructed. Docking and evaluation using GOLD scores assisted the initial selection of compounds for synthesis. The selection was augmented with further compounds to increase structural diversity. A total of 45 compounds were synthesized via a one-pot three-component coupling reaction. The mechanism of the three-component coupling reaction was investigated, and it was discovered that chemical oxidation is required for the last step, forming the pyridine ring (aromatization). A total of 19 compounds were identified as binders to one or more forms of prion protein by in vitro screening using surface plasmon resonance (SPR). A selection of compounds were investigated for activity in cells, resulting in the discovery of a new inhibitor of PrP(Sc) formation.

Combinatorial Chemistry Techniques↗
PubMed1993

Binocular vision in a virtual world: visual deficits following the wearing of a head-mounted display.

The short-term effects on binocular stability of wearing a conventional head-mounted display (HMD) to explore a virtual reality environment were examined. Twenty adult subjects (aged 19-29 years) wore a commercially available HMD for 10 min while cycling around a computer generated 3-D world. The twin screen presentations were set to suit the average interpupillary distance of our subject population, to mimic the conditions of public access virtual reality systems. Subjects were examined before and after exposure to the HMD and there were clear signs of induced binocular stress for a number of the subjects. The implications of introducing such HMDs into the workplace and entertainment environments are discussed.

Computer Simulation↗
PubMed2005

GPCALMA: a Grid-based tool for mammographic screening.

OBJECTIVES: The next generation of high energy physics (HEP) experiments requires a GRID approach to a distributed computing system: the key concept is the Virtual ORGANISATION (VO), a group of distributed users with a common goal and the will to share their resources. METHODS: A similar approach, applied to a group of hospitals that joined the GPCALMA project (Grid Platform for Computer Assisted Library for MAmmography), will allow common screening programs for early diagnosis of breast and, in the future, lung cancer. The application code makes use of neural networks for the image analysis and is useful in improving the radiologists' diagnostic performance. GRID services allow remote image analysis and interactive online diagnosis, with a potential for a relevant reduction of the delays presently associated with screening programs. RESULTS AND CONCLUSIONS: A prototype of the system, based on AliEn GRID Services [1], is already available, with a central server running common services [2] and several clients connecting to it. Mammograms can be acquired in any location; the related information required to select and access them at any time is stored in a common service called Data Catalogue, which can be queried by any client. Thanks to the PROOF facility [3], the result of a query can be used as input for analysis algorithms, which are executed on the nodes where the input images are stored,. The selected approach avoids data transfers for all the images with a negative diagnosis and allows an almost real time diagnosis for the set of images with high cancer probability.

Algorithms↗
PubMed2004

Pursuing the leadlikeness concept in pharmaceutical research.

Lipinski and others, through concepts such as drug-likeness, re-focussed drug discovery back to the principles of medicinal chemistry in the high-throughput era as key to reducing attrition. More recently, the need to go further in defining what makes a good lead has been recognised with the concept of leadlikeness. Leadlikeness implies cut-off values in the physico-chemical profile of chemical libraries such that they have reduced complexity (e.g. MW below <400) and other more restricted properties. We examine these concepts in the context of Virtual (theoretically possible), Tangible (chemically feasible) and Real (physically available) worlds of molecules. In a thought experiment, we take the HTS concept to the extreme: screening an estimated 60 million 'Global Collection' on 5000 targets and realising that perhaps millions of drug candidates might be found that could not possibly be handled in reality. Sampling of the Virtual and Tangible worlds is therefore a necessity. We show that the world of Reals is significantly under-sampled as the MW of compounds increases. This supports the design and screening of 'reduced complexity' (leadlike) compound libraries, preferably with synthetic handles available for rapid chemical iteration and detected as interesting by careful screening or biophysical assays.

Carboxylic Acids↗
PubMed2005

Use of an EMG-driven biomechanical model to study virtual injuries.

INTRODUCTION: How the CNS activates muscles to produce coordinated movement is a matter of debate and great interest. We are attempting to answer this question, in part, by investigating how individual muscles and groups of muscles are activated under different physiologic and environmental conditions. We have developed an EMG-driven virtual arm to assist in this endeavor. PURPOSE: To demonstrate how the virtual arm can be used to simulate a neuromuscular injury and to examine whether a virtual injury can evoke a change in muscle activation patterns. METHODS: The virtual arm is a three-dimensional graphical representation and biomechanical model of a human arm including the major flexor and extensor muscles crossing the elbow. The muscles are actuated based on experimentally recorded electromyograms. A Hill-type muscle model was used to predict muscle forces, which in turn were used to move the graphical display of the arm on the screen. Two subjects, one considered highly trained and the other a novice, participated in this study. Virtual movements, before and after simulating an injury were evaluated, and model performance was assessed by comparing the virtual arm-predicted moment and the actual moment generated by the subjects. RESULTS: The highly trained subject was proficient at controlling the virtual arm. For this subject, simulating a neuromuscular injury evoked a different pattern of activation compared to the preinjured state. CONCLUSIONS: The virtual arm may be a useful tool for the study of motor coordination and how muscle activation patterns change in response to injury. Future work involving more subjects and experimental conditions is planned to better assess the efficacy of the virtual arm as a research tool for investigating motor control strategies.

Arm↗
PubMed2001

Detection of novel gene expression in paraffin-embedded tissues by isotopic in situ hybridization in tissue microarrays.

Correlating altered gene expression patterns with particular disease states is a critical step in understanding disease processes and developing treatment strategies. Many thousands of novel gene sequences have recently been annotated in public and private databases and are now available for analysis. Tissue-specific expression patterns of these sequences can be evaluated physically on DNA arrays and other high throughput assays, or virtually by bioinformatics mining of expressed sequence tag (EST) databases. As a secondary screening tool, in situ hybridisation (ISH) not only confirms tissue specificity, but also reveals what is often valuable information about cell-type expression patterns of nov16l sequences. Due to their availability and long-term stability at room temperature, formalin-fixed paraffin-embedded clinical specimens provide an invaluable resource for evaluating expression patterns of novel human genes. We describe a high-throughput approach for identifying and quantifying the expression of novel genes in paraffin-embedded human tissues using isotopic in situ hybridisation and tissue microarrays (TMA).

Blotting, Northern↗
PubMedDate not supplied

Heterogeneity of B cell growth factor (BCGF)-producing T cells in humans. Clonal analysis of BCGF-producing cells within T4+ and T8+ subsets and evidence for the involvement of different growth factors in different BCGF assays.

Human peripheral blood T cells were cloned under conditions allowing the clonal expansion of virtually all T cells. Clones derived from T4+ or T4- (T8+) subsets were screened for their ability to induce B cell proliferation either in the Staphylococcus aureus Cowan-I (SAC)-driven assay or in the costimulation assay based on the use of anti-mu antibodies. BCGF activity in the SAC- and in the anti-mu-driven system was displayed by 13% and 15% T8+ clones, respectively, while 74% and 79% T4+ clones had BCGF activity in the same assay. SN of clones with BCGF activity were further screened for their susceptibility to the inhibition by CM 269 (anti-IL-2 receptor) monoclonal antibody. All clones were inhibited in the SAC assay, whereas several clones were partially or totally resistant to inhibition in the anti-mu assay. Nine of such non-inhibited clones were further analyzed for their ability to produce gamma-IFN (known to act as a BCGF) and IL-2: six of them were found to produce gamma-IFN, while none produced any detectable IL-2 activity.

Cells, Cultured↗
PubMed1999

The Southern Cone Initiative against Chagas disease.

Chagas disease (also known as American trypanosomiasis) is now ranked as the most serious parasitic disease of the Americas, with an economic impact far outranking the combined effects of other parasitic diseases such as malaria, schistosomiasis and leishmaniasis. Although the chronic infection remains virtually incurable, transmission can be halted by eliminating the domestic insect vectors and screening blood donors to avoid transfusional transmission. In line with this strategy, governments of the six Southern Cone countries (Argentina, Bolivia, Brazil, Chile, Paraguay and Uruguay) launched in 1991 an ambitious initiative to control Chagas disease through elimination of the main vector, Triatoma infestans, and large-scale screening of blood donors. Now at its mid-point, the programme has achieved remarkable success, with transmission halted over vast areas of the previously endemic regions. Well over 2 million rural houses have been sprayed to eliminate T. infestans, and the programme has already shown significant economic rates of return in addition to the medical and social benefits.

Animals↗
PubMed2005

Isolation, catalytic properties, and competitive inhibitors of the zinc-dependent murine glutaminyl cyclase.

Murine glutaminyl cyclase (mQC) was identified in the insulinoma cell line beta-TC 3 by determination of enzymatic activity and RT-PCR. The cloned cDNA was expressed in the secretory pathway of the methylotrophic yeast Pichia pastoris and purified after fermentation using a new three-step protocol. mQC converted a set of various substrates with very similar specificity to human QC, indicating a virtually identical catalytic competence. Furthermore, mQC was competitively inhibited by imidazole derivatives. A screen of thiol reagents revealed cysteamine as a competitive inhibitor of mQC bearing a Ki value of 42 +/-2 microM. Substitution of the thiol or the amino group resulted in a drastic loss of inhibitory potency. The pH dependence of catalysis and inhibition support that an uncharged nitrogen of the inhibitors and the substrate is necessary in order to bind to the active site of the enzyme. In contrast to imidazole and cysteamine, the heterocyclic chelators 1,10-phenanthroline, 2,6-dipicolinic acid, and 8-hydroxyquinoline inactivated mQC in a time-dependent manner. In addition, citric acid inactivated the enzyme at pH 5.5. Inhibition by citrate was abolished in the presence of zinc ions. A determination of the metal content by total reflection X-ray fluorescence spectrometry and atomic absorption spectroscopy in mQC revealed stoichiometric amounts of zinc bound to the protein. Metal ion depletion appeared to have no significant effect on protein structure as shown by fluorescence spectroscopy, suggesting a catalytic role of zinc. The results demonstrate that mQC and probably all animal QCs are zinc-dependent catalysts. Apparently, during evolution from an ancestral protease, a switch occurred in the catalytic mechanism which is mainly based on a loss of one metal binding site.

Amino Acid Sequence↗
PubMedDate not supplied

Solvent selection strategies for extractive biocatalysis.

This report follows the development of systematic solvent screening strategies for the identification of superior pure solvents and introduces techniques for the identification of effective coextractants. Specifically, methods to predict the biocompatibility and extractant capability of solvents are discussed. Biocompatibility is predicted by using heuristic data or the correlations between bioactivity and the logarithm of the partition coefficient of the solvent or the concentration of solvent in the cell membrane. A computer program, known as the extractant screening program or ESP, has been developed to effectively predict the behavior of virtually any product in any solvent/aqueous system. It is demonstrated that a biocompatible yet poor solvent can be mixed with a toxic solvent that has better extractant properties to yield a mixture with improved solvent characteristics that is still biocompatible. The fact that solvents do not mix in an ideal manner is exploited by using ESP to identify solvent mixtures that are still biocompatible at relatively high concentrations of toxic solvent.

Animals↗
PubMed2005

Structure-activity models for contact sensitization.

Allergic contact dermatitis (ACD) is a widespread cause of workers' disabilities. Although some substances found in the workplace are rigorously tested, the potential of the vast majority of chemicals to cause skin sensitization remains unknown. At the same time, exhaustive testing of all chemicals in workplaces is costly and raises ethical concerns. New approaches to developing information for risk assessment based on computational (quantitative) structure-activity relationship [(Q)SAR] methods may be complementary to and reduce the need for animal testing. Virtually any number of existing, de novo, and even preconceived compounds can be screened in silico at a fraction of the cost of animal testing. This work investigates the utility of ACD (Q)SAR modeling from the occupational health perspective using two leading software products, DEREK for Windows and TOPKAT, and an original method based on logistic regression methodology. It is found that the correct classification of (Q)SAR predictions for guinea pig data achieves values of 73.3, 82.9, and 87.6% for TOPKAT, DEREK for Windows, and the logistic regression model, respectively. The correct classification using LLNA data equals 73.0 and 83.2% for DEREK for Windows and the logistic regression model, respectively.

Allergens↗
PubMed2005

Digital imaging of haematological morphology.

Microscopic images of haematological cells are now routinely photographed using digital cameras. Advances in technology mean that the quality of such digital images can now approach that viewed through a microscope. At the same time there is an emerging appreciation that such images can be used in many roles: digital images are now being used to construct digital 'virtual slides', or are being employed together with cell recognition systems for morphological screening. Additionally, an Internet-based viewing systems allow access to on-line annotation, as well as real-time data gathering and feedback. The process of viewing digital images differs from the viewing of glass slides through a microscope; however, such images can provide diagnostic equivalence, and have an emerging role in areas such as education, quality control and continuing professional development. This review explores some of the present strengths, weaknesses and future applications of digital imaging in haematology.

Blood Cells↗
PubMed1993

Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. Medical Research Council Working Party on Phenylketonuria.

Efficient neonatal screening for phenylketonuria and the availability of complex diets for lifelong use have virtually eliminated severe mental handicap from the disease. Nevertheless, there remains a high risk of fetal damage in offspring of women with the disease, and the possibility that the diets themselves may be harmful cannot be excluded. Search for a preventive treatment for the disease has been greatly aided by advances in molecular genetics. For example, in mice modified liver cells have been implanted, which have not only corrected the phenylalanine defect but have remained healthy for the normal life span of the animal. Overall, however, prevention and treatment have not progressed as quickly as was hoped, and research and development must be pursued vigorously to take account of contemporary perceptions of the disorder.

Adolescent↗
PubMed2005

Meta-analysis: computed tomographic colonography.

BACKGROUND: Computed tomographic (CT) colonography, also called virtual colonoscopy, is an evolving technology under evaluation as a new method of screening for colorectal cancer. However, its performance as a test has varied widely across studies, and the reasons for these discrepancies are poorly defined. PURPOSE: To systematically review the test performance of CT colonography compared to colonoscopy or surgery and to assess variables that may affect test performance. DATA SOURCES: The PubMed, MEDLINE, and EMBASE databases and the Cochrane Controlled Trials Register were searched for English-language articles published between January 1975 and February 2005. STUDY SELECTION: Prospective studies of adults undergoing CT colonography after full bowel preparation, with colonoscopy or surgery as the gold standard, were selected. Studies had to have used state-of-the-art technology, including at least a single-detector CT scanner with supine and prone positioning, insufflation of the colon with air or carbon dioxide, collimation smaller than 5 mm, and both 2-dimensional and 3-dimensional views during scan interpretation. The evaluators of the colonogram had to be unaware of the findings from use of the gold standard test. Data on sensitivity and specificity overall and for detection of polyps less than 6 mm, 6 to 9 mm, and greater than 9 mm in size were abstracted. Sensitivities and specificities weighted by sample size were calculated, and heterogeneity was explored by using stratified analyses and meta-regression. DATA SYNTHESIS: 33 studies provided data on 6393 patients. The sensitivity of CT colonography was heterogeneous but improved as polyp size increased (48% [95% CI, 25% to 70%] for detection of polyps <6 mm, 70% [CI, 55% to 84%] for polyps 6 to 9 mm, and 85% [CI, 79% to 91%] for polyps >9 mm). Characteristics of the CT colonography scanner, including width of collimation, type of detector, and mode of imaging, explained some of this heterogeneity. In contrast, specificity was homogenous (92% [CI, 89% to 96%] for detection of polyps <6 mm, 93% [CI, 91% to 95%] for polyps 6 to 9 mm, and 97% [CI, 96% to 97%] for polyps >9 mm). LIMITATIONS: The studies differed widely, and the extractable variables explained only a small amount of the heterogeneity. In addition, only a few studies examined the newest CT colonography technology. CONCLUSIONS: Computed tomographic colonography is highly specific, but the range of reported sensitivities is wide. Patient or scanner characteristics do not fully account for this variability, but collimation, type of scanner, and mode of imaging explain some of the discrepancy. This heterogeneity raises concerns about consistency of performance and about technical variability. These issues must be resolved before CT colonography can be advocated for generalized screening for colorectal cancer.

Aged↗
PubMed1979

Diabetes newly diagnosed during pregnancy: A 4-year study at Groote Schuur Hospital.

As a result of active screening for gestational diabetes of the population attending various antenatal clinics in the Cape Peninsula, 127 patients with a repeatedly diabetic glucose tolerance test (GTT) were discovered; in many the GTT was grossly abnormal. The most useful screening factor was repeated glycosuria. Because they had booked late, 22 patients received virtually no treatment, and 1 patient aborted. Treatment of the remaining 104 patients was achieved principally by regulating diet, but when this failed metformin or glibenclamide therapy was instituted. Insulin was used when diet and oral drugs failed. Diabetic control was considered adequate if fasting blood glucose levels remained below 5,5 mmol/l and if postprandial levels were below 7 mmol/l. Most patients (67) were well controlled on a strict dietary regimen, and there were no perinatal deaths in this group. Glibenclamide and metformin, judging from this small series, appear to be safe for use in gestational diabetics. The overall perinatal mortality in treated patients was 10/1 000 as compared with an effective perinatal mortality of 145/1 000 in the 'untreated' group. Neonatal morbidity was similar to that in other reported series. Hypoglycaemia was seldom a problem and 79% of birth weights were between the 10th and the 90th percentiles.

Adolescent↗
PubMedDate not supplied

Characteristics of false-negative smears tested in the normal screening situation.

It is common practice to rescreen false-negative (FN) smears. However, it is inevitable that this is done with some foreknowledge; at least it is known that the test smears contain one or more special cases. Therefore, we decided to test smears in the normal screening situation, when cytotechnologists are completely unaware of being tested. This experiment was done with five FNs and five true-positive (TP) smears. In a third experiment the FNs were tested with the cytotechnologists aware of their presence. Finally, 10 qualities of FNs and TPs were analyzed. In the normal screening situation, only in 1 of 25 tests was the FN recognized as malignant, while all the TPs were detected at the first testing. However, when the cytotechnologists were aware of being tested, the FN was detected in seven of eight tests. The FNs differed from the TPs in 5 of the 10 analyzed characteristics. FNs contained few (if any) large neoplastic epithelial fragments. Detached malignant cells were nearly lacking. The cancer cells had small nuclei that presented little anisokaryosis. The FNs possessed generally hypochromatic nuclei. These features explain why the malignant cells were almost never identified in the normal screening situation. We conclude that FNs and TPs differ and that it seems virtually impossible to avoid all false-negative diagnoses.

Carcinoma↗
PubMed1992

A member of the tetra spans transmembrane protein superfamily is recognized by a monoclonal antibody raised against an HLA class I-deficient, lymphokine-activated killer-susceptible, B lymphocyte line. Cloning and preliminary functional studies.

The IA4 mAb was identified among a series of antibodies raised in BALB/c mice after immunization against a HLA class I-deficient, lymphokine-activated killer (LAK)-susceptible EBV-B lymphocyte line. The IA4 antibody was selected because of its high expression, in the range of 10(5) to 25 x 10(5) sites/cell, on several B lymphocyte lines (EBV-transformed or Burkitt) and monocytic lines such as HL60 and U937, and because its expression was correlated with both target susceptibility to LAK lysis and reduced expression of HLA class I surface Ag on two pairs of EBV-B-transformed cell lines (721/721.134 and MM/10F2). Despite the strategy followed to raise the mAb and the correlation mentioned above, no direct role of the IA4 molecules in LAK susceptibility has been established, since the IA4 molecule is poorly expressed on the sensitive targets Daudi and K562; moreover, the IA4 antibody did not affect reproducibly the in vitro killing of positive target cells by LAK effectors. The IA4 antibody was poorly immunoprecipitating and the surface molecule recognized was identified by gene cloning following an expression strategy using a U937 cDNA library transfected in COS cells, and a screening strategy based on membrane expression of IA4 molecule. The IA4 cDNA is virtually identical to "R2," a mRNA species previously identified in activated human T cells by subtractive hybridization. The IA4 cDNA contains an open reading frame coding for a protein 267 amino acids long with four potential transmembrane domains and one large external hydrophilic domain of about 110 amino acids, possibly glycosylated. The encoded protein belongs to a family of surface molecules, the tetra spans transmembrane protein superfamily, all displaying the four transmembrane domains, expressed on various cell types including lymphocytes (CD9, CD37, CD53, TAPA-1), melanoma cells (ME491), and intestinal cells (CO-029). These molecules have been reported to be involved in cell activation and cell death. Surprisingly, the Schistosoma mansoni Ag Sm23 displays significant homologies with this family. The IA4 molecule is a widely distributed surface marker expressed on circulating lymphocytes and monocytes, newborn thymocytes, and the cell lines mentioned above. The IA4 molecule expression is up-regulated upon cell activation. Weakly expressed on resting peripheral T and B lymphocytes and large granular lymphocytes (NK), its expression roughly doubles after activation by PHA, staphylococcus aureus Cowan I, and IL-2, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

Computed tomographic colonography.

Computed tomographic colonography, also called virtual colonoscopy, is an evolving technology under evaluation as a new method of screening for colorectal cancer. However, its performance as a test has varied widely across studies, and the reasons for these discrepancies are poorly defined. We provide an overview of some potential causes and discuss the available, often indirect, evidence. In addition, several other obstacles that may influence implementation are discussed. Future investigations should demonstrate the influence of these potential factors on sensitivity of computed tomographic colonography. Despite a growing body of evidence, it remains uncertain to what extent patient acceptance, radiation issues, flat lesions, and extracolonic findings will be a stumbling block to using computed tomographic colonography for colorectal cancer screening.

Aged↗