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PubMedDate not supplied

Integrated homology modelling and X-ray study of herpes simplex virus I thymidine kinase: a case study.

Knowledge-based homology modelling together with site-directed mutagenesis, epitope and conformational mapping is an approach to predict the structures of proteins and for the rational design of new drugs. In this study we present how this procedure has been applied to model the structure of herpes simplex virus type 1 thymidine kinase (HSV1 TK, HSV1 ATP-thymidine-5'-phosphotransferase, EC 2.7.1.21). We have used, and evaluated, several secondary structure prediction methods, such as the classical one based on Chou and Fastman algorithm, neural networks using the Kabsch and Sander classification, and the PRISM method. We have validated the algorithms by applying them to the porcine adenylate kinase (ADK), whose three-dimensional structure is known and that has been used for the alignment of the TKs as well. The resulting first model of HSV1-TK consisted of the first beta-strand connected to the phosphate binding loop and its subsequent alpha-helix, the fourth beta-strand connected to the conserved FDRH sequence and two alpha-helix with basic amino acids. The 3D structure was built using the X-ray structure of ADK as template and following the general procedure for homology modelling. We extended the model by means of COMPOSER, an automatic process for protein modelling. Site-directed mutagenesis was used to experimentally verify the predicted active-site model of HSV1-TK. The data measured in our lab and by others support the suggestion that the FDRH motif is part of the active site and plays an important role in the phosphorylation of substrates. The structure of HSV1 TK, recently solved in collaboration with Prof. G. Schulz at 2.7 A resolution, includes 284 of 343 residues of the N-terminal truncated TK. The secondary structures could be clearly assigned and fitted to the density. The comparison between crystallographically determined structure and the model shows that nearly 70% of the HSV1 TK structure has been correctly modelled by the described integrated approach to knowledge based ligand protein complex structure prediction. This indicate that computer assisted methods, combined with "manual" correction both for alignment and 3D construction are useful and can be successful.

Crystallography, X-Ray↗
PubMed1994

Critical care nursing research: opportunities and resources.

BACKGROUND: As patient needs become more complex in the critical care setting, nurses with increased clinical expertise are needed to expand the research knowledge base and apply existing knowledge in practice settings. PURPOSE: To review opportunities and resources that are available to facilitate nurses' involvement in critical care research: opportunities for participation in research, sources of ideas, human and financial resources, and ideas for the dissemination of research findings. CONCLUSIONS: Opportunities and resources available for critical care research are numerous, varied, and widely available. They should be used to advance the scientific bases for critical care practice.

Clinical Nursing Research↗
PubMed1994

A model for structured data entry based on explicit descriptional knowledge.

Clinical narratives in patient records are usually recorded in free text, limiting the use of this information for research, quality assessment, and decision support. This study focuses on the capture of clinical narratives in a structured format by supporting physicans with structured data entry (SDE). We analyzed and made explicit which requirements SDE should meet to be acceptable for the physician on the one hand, and generate unambiguous patient data on the other. Starting from these requirements, we found that in order to support SDE, the knowledge on which it is based needs to be made explicit: we refer to this knowledge as descriptional knowledge. We articulate the nature of this knowledge, and propose a model in which it can be formally represented. The model allows the construction of specific knowledge bases, each representing the knowledge needed to support SDE within a circumscribed domain. Data entry is made possible through a general entry program, of which the behavior is determined by a combination of user input and the content of the applicable domain knowledge base. We clarify how descriptional knowledge is represented, modeled, and used for data entry to achieve SDE, which meets the proposed requirements.

Artificial Intelligence↗
PubMed1992

Detection of native-like models for amino acid sequences of unknown three-dimensional structure in a data base of known protein conformations.

We present an approach which can be used to identify native-like folds in a data base of protein conformations in the absence of any sequence homology to proteins in the data base. The method is based on a knowledge-based force field derived from a set of known protein conformations. A given sequence is mounted on all conformations in the data base and the associated energies are calculated. Using several conformations and sequences from the globin family we show that the native conformation is identified correctly. In fact the resolution of the force field is high enough to discriminate between a native fold and several closely related conformations. We then apply the procedure to several globins of known sequence but unknown three dimensional structure. The homology of these sequences to globins of known structures in the data base ranges from 49 to 17%. With one exception we find that for all globin sequences one of the known globin folds is identified as the most favorable conformation. These results are obtained using a force field derived from a data base devoid of globins of known structure. We briefly discuss useful applications in protein structural research and future development of our approach.

Algorithms↗
PubMed2004

CSHM: Web-based safety and health monitoring system for construction management.

INTRODUCTION: This paper describes a web-based system for monitoring and assessing construction safety and health performance, entitled the Construction Safety and Health Monitoring (CSHM) system. METHOD: The design and development of CSHM is an integration of internet and database systems, with the intent to create a total automated safety and health management tool. A list of safety and health performance parameters was devised for the management of safety and health in construction. A conceptual framework of the four key components of CSHM is presented: (a) Web-based Interface (templates); (b) Knowledge Base; (c) Output Data; and (d) Benchmark Group. RESULTS: The combined effect of these components results in a system that enables speedy performance assessment of safety and health activities on construction sites. With the CSHM's built-in functions, important management decisions can theoretically be made and corrective actions can be taken before potential hazards turn into fatal or injurious occupational accidents. IMPACT ON INDUSTRY: As such, the CSHM system will accelerate the monitoring and assessing of performance safety and health management tasks.

Benchmarking↗
PubMed2026

Margin Adequacy in Phyllodes Tumors Revisited: Reappraisal of the Evidence Base and Knowledge Gaps.

The optimal surgical margin for minimizing local recurrence (LR) and distant metastasis in phyllodes tumors (PTs) remains controversial. Despite multiple observational cohorts, variation among studies limits the interpretation of margin-outcome associations. We therefore performed a structured critical interpretative synthesis (CIS) to evaluate whether the current evidence supports specific margin thresholds. The CIS incorporated a systematic review, random-effects meta-analysis, an appraisal of existing meta-analyses and guidelines, and an expert interpretative analysis of 40 single-cohort studies from 2015 to 2025 evaluating surgical margin width and outcomes in PTs. Authors' recommendations regarding margin adequacy were extracted as interpretative "author conclusions." In parallel, LR and distant metastasis outcomes were pooled by tumor grade using random-effects models with prediction intervals. Final margin recommendations were derived by integrating CIS findings and multidisciplinary expert judgment. Current management guidelines do not recommend re-excision for positive or close margins in benign PTs. Contemporary guidelines are also concordant in advising negative margins for borderline and malignant PTs, although the specified margin width ranges from 1 to 10 mm. Within this range, no association has been established between increasing margin width and the risk of LR or malignant transformation upon LR. The estimated LR rates are 12.5% for borderline and 16.5% for malignant PTs. Malignant transformation on recurrence occurred in only 1% and 3% of all benign and borderline PTs, respectively. Approximately 14% of malignant PT metastasize, often without LR. Current heterogeneous evidence does not show lower recurrence with margins wider than a negative (≥1 mm) margin in PTs. For borderline and malignant PTs, a mandatory 10-mm threshold is insufficiently supported, as narrower negative margins may be adequate in selected cases. However, an optimal margin threshold cannot be defined from current data. These conclusions are practice-supporting rather than guideline-defining and reinforce the need for high-quality evidence to establish harmonized, grade-specific margin recommendations.

Humans↗
PubMed2005

Ionizing radiation and genetic risks XIV. Potential research directions in the post-genome era based on knowledge of repair of radiation-induced DNA double-strand breaks in mammalian somatic cells and the origin of deletions associated with human genomic disorders.

Recent estimates of genetic risks from exposure of human populations to ionizing radiation are those presented in the 2001 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). These estimates incorporate two important concepts, namely, the following: (1) most radiation-induced mutations are DNA deletions, often encompassing multiple genes, but only a small proportion of the induced deletions is compatible with offspring viability; and (2) the viability-compatible deletions induced in germ cells are more likely to manifest themselves as multi-system developmental anomalies rather than as single gene disorders. This paper: (a) pursues these concepts further in the light of knowledge of mechanisms of origin of deletions and other rearrangements from two fields of contemporary research: repair of radiation-induced DNA double-strand breaks (DSBs) in mammalian somatic cells and human molecular genetics; and (b) extends them to deletions induced in the germ cell stages of importance for radiation risk estimation, namely, stem cell spermatogonia in males and oocytes in females. DSB repair studies in somatic cells have elucidated the roles of two mechanistically distinct pathways, namely, homologous recombination repair (HRR) that utilizes extensive sequence homology and non-homologous end-joining (NHEJ) that requires little or no homology at the junctions. A third process, single-strand annealing (SSA), which utilizes short direct repeat sequences, is considered a variant of HRR. HRR is most efficient in late S and G2 phases of the cell cycle and is a high fidelity mechanism. NHEJ operates in all cell cycle phases, but is especially important in G1. In the context of radiation-induced DSBs, NHEJ is error-prone. SSA is also an error-prone mechanism and its role is presumably similar to that of HRR. Studies in human molecular genetics have demonstrated that the occurrence of large deletions, duplications or other rearrangements in certain regions of the genome is related to the presence of large segments of repetitive DNA called segmental duplications (also called duplicons or low copy repeats, LCRs) in such regions. The mechanism that is envisaged for the origin of deletions and other rearrangements involves misalignment of region-specific LCRs of homologous chromosomes in meiosis followed by unequal crossing-over (i.e., non-allelic homologous recombination, NAHR). We hypothesize that: (a) in spermatogonial stem cells, NHEJ is probably the principal mechanism underlying the origin of radiation-induced deletions, although SSA and NAHR may also be involved to some extent, especially at low doses; and (b) in irradiated oocytes, NAHR is likely to be the main mechanism for generating deletions. We suggest future research possibilities, including the development of models for identifying regions of the genome that are susceptible to radiation-induced deletions. Such efforts may have particular significance in the context of the estimation of genetic risks of radiation exposure of human females, a problem that is still with us.

Animals↗
PubMed2005

Optimum design and operation of primary sludge fermentation schemes for volatile fatty acids production.

This paper presents a model-knowledge based algorithm for optimising the primary sludge fermentation process design and operation. This is a recently used method to obtain the volatile fatty acids (VFA), needed to improve biological nutrient removal processes, directly from the raw wastewater. The proposed algorithm consists in a heuristic reasoning algorithm based on the expert knowledge of the process. Only effluent VFA and the sludge blanket height (SBH) have to be set as design criteria, and the optimisation algorithm obtains the minimum return sludge and waste sludge flow rates which fulfil those design criteria. A pilot plant fed with municipal raw wastewater was operated in order to obtain experimental results supporting the developed algorithm groundwork. The experimental results indicate that when SBH was increased, higher solids retention time was obtained in the settler and VFA production increased. Higher recirculation flow-rates resulted in higher VFA production too. Finally, the developed algorithm has been tested by simulating different design conditions with very good results. It has been able to find the optimal operation conditions in all cases on which preset design conditions could be achieved. Furthermore, this is a general algorithm that can be applied to any fermentation-elutriation scheme with or without fermentation reactor.

Algorithms↗
PubMed1998

Worldwide prevention of cancer and other chronic diseases based on knowledge of mechanisms.

International research, particularly as part of US/Japan programs, has led to major advances in knowledge of causes of heart disease, stroke, many types of cancer and diabetes, showing that individual lifestyle is associated with these diseases. In Japan, a major health problem is high blood pressure and stroke, and cancer of the stomach, from excessive use of salt and salted, pickled foods, and the relative low intake of protective fruits and vegetables. We identified a likely gastric carcinogen, 2-chloro-4-methylthiobutanoate, in salted, pickled fish. In the Western world, heart disease and cancer of the breast, colon, rectum, prostate, pancreas, ovary and endometrium relate to a nutritional tradition too high in total fat and fried or broiled meats, and too low in fiber, vegetables and fruits. The cooked meats contain genotoxic chemicals, heterocyclic amines, causative elements in heart disease and the nutritionally linked cancers. Decreasing total fat intake, from 40 to 20% of calories and a greater use of starches such as rice, pasta, potatoes and whole grain bread, as well as daily intake of five to nine vegetables and fruits would be beneficial. Adults should consume 2.5 l of fluids per day. Green or black tea and fruit juices have health promoting properties. Regular exercise contributes to good health, and to the avoidance of obesity, a major problem in the USA and of increasing importance in Japan. Avoidance of a risky lifestyle would likely prevent diseases important not only for the individual and his family, but with major impact in lowering medical care costs. Tobacco and cigarette use, particularly on a Western diet, involve a high risk of heart attacks, and cancers of the lung, pancreas, kidney, urinary bladder, and cervix, accounting for 35% of medical care expenditures.

Alcohol Drinking↗
PubMed1997

Quantitative study of ductal breast cancer--patient targeted prognosis: an exploration of case base reasoning.

Current analytic methodologies allow the extraction, even from small tumor masses, of extensive information on the biologic characteristics of malignant lesions, such as tumor aggressivity, metastatic potential, drug resistance, and host interactions. Clinical practice now offers a wide range of therapeutic strategies. Information technological advances offer the opportunity to refer to very large data bases of patient anamnestic data, response to treatment and clinical outcome. There is a need to formulate therapy and prognosis for each individual case. Case based reasoning is a knowledge based methodology where the outcome for complex situations can be predicted by referring to a large data base of cases of known outcomes. The preliminary data obtained from this study suggest that case based reasoning may offer a promising approach to individual targeted prognosis.

Breast Neoplasms↗
PubMedDate not supplied

Automatic segmentation of non-enhancing brain tumors in magnetic resonance images.

Tumor segmentation from magnetic resonance (MR) images may aid in tumor treatment by tracking the progress of tumor growth and/or shrinkage. In this paper we present the first automatic segmentation method which separates non-enhancing brain tumors from healthy tissues in MR images to aid in the task of tracking tumor size over time. The MR feature images used for the segmentation consist of three weighted images (T1, T2 and proton density (PD)) for each axial slice through the head. An initial segmentation is computed using an unsupervised fuzzy clustering algorithm. Then, integrated domain knowledge and image processing techniques contribute to the final tumor segmentation. They are applied under the control of a knowledge-based system. The system knowledge was acquired by training on two patient volumes (14 images). Testing has shown successful tumor segmentations on four patient volumes (31 images). Our results show that we detected all six non-enhancing brain tumors, located tumor tissue in 35 of the 36 ground truth (radiologist labeled) slices containing tumor and successfully separated tumor regions from physically connected CSF regions in all the nine slices. Quantitative measurements are promising as correspondence ratios between ground truth and segmented tumor regions ranged between 0.368 and 0.871 per volume, with percent match ranging between 0.530 and 0.909 per volume.

Astrocytoma↗
PubMed1999

Design and synthesis of a globin fold.

We propose a simple method to find an amino acid sequence that is foldable into a globular protein with a desired structure based on a knowledge-based 3D-1D compatibility function. An asymmetric alpha-helical single-domain structure of sperm whale myoglobin consisting of 153 amino acid residues was chosen for the design target. The optimal sequence to fit the main-chain framework has been searched by recursive generation of the protein 3D profile. The heme-binding site was designed by fixing His64 and His93 at the distal and proximal positions, respectively, and by penalizing residues that protrude into the space with a repulsive function. The apparent bumps among side chains in the computer model of the converged, self-consistent sequence were removed by replacing some of the bumping residues with smaller ones according to the final 3D profile. The finally obtained sequence shares 26% of sequence with the natural myoglobin. The designed globin-1 (DG1) with the artificial sequence was obtained by expression of the synthetic gene in Escherichia coli. Analyses using size-exclusion chromatography, circular dichroism spectroscopy, and solution X-ray scattering showed that DG1 folds into a monomeric, compact, highly helical, and globular form with an overall molecular shape similar to the target structure in an aqueous solution. Furthermore, it binds a single heme per protein molecule, which exhibited well-defined spectroscopic properties. The radius of gyration of DG1 was determined to be 20.6 A, slightly larger than that of natural apoMb, and decreased to 19.5 A upon heme binding based on X-ray scattering analysis. However, the heme-bound DG1 did not stably bind molecular oxygen as natural globins do, possibly due to high conformational diversity of side-chain structures observed in the NMR and denaturation experiments. These results give insight into the relationship between the sequence selection and the structural uniqueness of natural proteins to achieve biological functions.

Amino Acid Sequence↗
PubMed2000

Redesign of artificial globins: effects of residue replacements at hydrophobic sites on the structural properties.

Artificial sequences of the 153 amino acids have been designed to fit the main-chain framework of the sperm whale myoglobin (Mb) structure based on a knowledge-based 3D-1D compatibility method. The previously designed artificial globin (DG1) folded into a monomeric, compact, highly helical and globular form with overall dimensions similar to those of the target structure, but it lacked structural uniqueness at the side-chain level [Isogai, Y., Ota, M., Fujisawa, T. , Izuno, H., Mukai, M., Nakamura, H., Iizuka, T., and Nishikawa, K. (1999) Biochemistry 38, 7431-7443]. In this study, we redesigned hydrophobic sites of DG1 to improve the structural specificity. Several Leu and Met residues in DG1 were replaced with beta-branched amino acids, Ile and Val, referring to the 3D profile of DG1 to produce three redesigned globins, DG2-4. These residue replacements resulted in no significant changes of their compactness and alpha-helical contents in the absence of denaturant, whereas they significantly affected the dependence of the secondary structure on the concentration of guanidine hydrochloride. The analyses of the denaturation curves revealed higher global stabilities of the designed globins than that of natural apoMb. Among DG1-4, DG3, in which 11 Leu residues of DG1 are replaced with seven Ile and four Val residues, and one Met residue is replaced with Val, displayed the lowest stability but the most cooperative folding-unfolding transition and the most dispersed NMR spectrum with the smallest line width. The present results indicate that the replacements of Leu (Met) with the beta-branched amino acids at appropriate sites reduce the freedom of side-chain conformation and improve the structural specificity at the expense of stability.

Amino Acid Sequence↗
PubMed2000

Endocrine disruptors and male reproductive function--a short review.

Semen quality has decline in many countries over the last few decades. There has been an increase in the incidence of testicular cancer world-wide. The incidences of cryptorchidism and hypospadias have also increased in many countries. A biological plausible hypothesis has suggested that man-made chemicals act as endocrine disruptors resulting in altered development of the reproductive tract causing the observed effects. Endocrine disruptors include natural products, pharmaceuticals, industrial products and environmental pollutants. There are limitations in the current in vivo and in vitro assays for the assessment of endocrine disruptors. Epidemiological human studies are necessary to fill in the gap of knowledge. Based on the current knowledge, the impact of endocrine disruptors on the male reproductive function remain to be appreciated.

Cryptorchidism↗
PubMed2001

A model for potential tumor immunotherapy based on knowledge of immune mechanisms responsible for spontaneous abortion.

Attempts to treat various cancers by immunotherapy have been tried for about 50 years. Most studies have focused on improving cytotoxic T lymphocyte (CTL) responses against various tumors. Immunotherapy has been both active and passive, and results have been modest at best. Spontaneous abortion (SAB) of pregnancies could in some ways resemble remission of a tumor. Both tumors and conceptusses are faced with a similar problem -- how to grow in a host in a vascular rich area, and yet escape immune surveillance despite both entities being an allogenic stimulus. In general, the fetus is far more immunogenic than a spontaneous tumor, and yet abortuses seem to avoid CTL responses but are sometimes invaded by natural killer (NK) cells. There are data suggesting that SAB will occur if there is inhibition of production of an immunosuppressive protein called progesterone-induced blocking factor (PIBF). This protein inhibits NK cell cytolysis and influences TH2 cytokine dominance over TH1. If some tumors avoid NK cell destruction through a PIBF mechanism, perhaps an active rejection of these tumors could be achieved by inhibiting PIBF production by treating with a progesterone receptor antagonist. Passive immunization could also be considered by conjugative radionuclide or toxic chemical to a PIBF antibody which may be tumor specific since PIBF is not produced in normal tissue. The first step should be to see if PIBF can be detected in the peripheral circulation in patients with certain tumors.

Abortion, Spontaneous↗
PubMed1999

Avoidance of lithium intoxication: advice based on knowledge about the renal lithium clearance under various circumstances.

To avoid lithium intoxications, clinicians should counteract conditions under which lithium clearance changes. If that is not possible, the lithium dosage should be adjusted to the lithium clearance. Lithium clearance is usually 20-30 per cent of the glomerular filtration rate and varies with it, for example during pregnancy and kidney disease. Lithium clearance may also change independently of the glomerular filtration rate. It decreases for example during dehydration (water deficiency) and low sodium intake, pathological conditions with edema formation, treatment with diuretics, anti-hypertensive drugs, or non-steroid anti-inflammatory drugs. It increases during treatment with some vasodilating drugs. Precautionary measures against lithium intoxication are suggested for each of these situations.

Antimanic Agents↗