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PubMed2003

Comparing performance of computational tools for combinatorial library design.

In using computational tools for library design it is necessary to understand the performance and limitations of available methods. This letter reports systematic comparisons of applying ligand-based and structure-based tools across therapeutic project-derived data sets. Included are assessments of performance in real-world iterative design applications and the utility of target structural information. The results suggest that combining screening and target structure information is robust; further, a well-designed screening library can compensate for lacking structural information.

CDC2-CDC28 Kinases↗
PubMed1988

Human pancreatic secretory trypsin inhibitor (PSTI) produced in active form and secreted from Escherichia coli.

As a basis for a protein design project, we decided to produce the human pancreatic secretory trypsin inhibitor (PSTI) in its active form. Total gene synthesis was carried out efficiently by (i) computer design of the gene fragments, (ii) synthesis of the oligodeoxynucleotides by the segmental support method, and (iii) assembly of double strands under optimized ligation conditions. Fusion to the ompA gene signal peptide led to secretion of processed PSTI in various constructions, with or without additional amino acids (aa) at the N-terminus. The secreted proteins (56 to 63 aa) were biologically active, suggesting that the three cysteine bridges were correctly formed. Surprisingly, after induction the product was found almost exclusively in the culture medium. Variants of PSTI with Asp or Asn at aa positions 21 and 29 [sequences published by Greene et al., Methods Enzymol. (1976) 813-825, and by Yamamoto et al., Biochem. Biophys. Res. Commun. (1985) 605-612] showed the same Ki for both human and porcine trypsin.

Amino Acid Sequence↗
PubMed2005

Implant stability measurements for implants placed at the time of extraction: a cohort, prospective clinical trial.

BACKGROUND: Studies indicate that implants placed at the time of extraction have high success rates. Implants must be stable at the time of insertion. Presently there are no data indicating the degree of implant stability when implants are placed at the time of extraction. This study evaluated changes in stability of implants from implant placement to abutment connection utilizing resonance frequency analysis (RFA). The unit of measurement was the international stability quotient (ISQ). METHODS: Prior to treatment, patients were given medical history and dental evaluations. Periapical and panogram radiographs were taken. Fifty-two patients requiring extraction of one or two teeth and implant placement immediately after extraction were enrolled in this study. Under conscious sedation and local anesthesia or local anesthesia alone, teeth were atraumatically removed and the extraction sockets were debrided. A total of 73 dental implants (57 in the maxilla, 16 in the mandible) were placed. Using a one-stage approach, all implants were placed within the patient's alveolar envelope and were never placed directly into extraction sockets. All implants were placed into contained extraction sites. Bone augmentation procedures were not performed. After implant insertion, the RFA electronic transducer was attached to the head of the implant with the retaining screw. The device was attached to a computer designed to register RFA scores in ISQ units. RFA measurements were taken at implant placement and abutment connection. Bone qualities, quantity, implant length and width as well as site of placement were recorded. RESULTS: The average interval between implant insertion and abutment connection was 5.6 months (SD 2.05). Two implants were lost between implant insertion and 1 year. At 2 to 3 years, the cumulative survival was 97.2%. Resonance frequency measurements at implant placement showed a mean primary stability of 62.0 (SE 1.1; range 43 to 83 ISQ) and a mean secondary stability after 1 year of 64.0 (SE 1.2; range 40 to 98 ISQ) for all implants. The increase was marginally significant (generalized estimating equation z-statistic = 1.79; P value = 0.07). CONCLUSIONS: Implants placed at the time of extraction and inserted into native bone and not directly into extractions sockets have a high degree of initial stability as evidenced by RFA measurements. Implants with initial high ISQ levels revealed a slight drop in levels over time, while implants with levels lower than 60 had increases in levels between implant insertion and abutment connection. At 2 to 3 years the cumulative survival rate was 97.2%.

Bone Density↗
PubMed2002

Exploring the boundaries of plausibility: empirical study of a key problem in the design of computer-based clinical simulations.

All clinical simulation designers face the problem of identifying the plausible diagnostic and management options to include in their simulation models. This study explores the number of plausible diagnoses that exist for a given case, and how many subjects must work up a case before all plausible diagnoses are identified. Data derive from 144 residents and faculty physicians from 3 medical centers, each of whom worked 9 diagnostically challenging cases selected from a set of 36. Each subject generated up to 6 diagnostic hypotheses for each case, and each hypothesis was rated for plausibility by a clinician panel. Of the 2091 diagnoses generated, 399 (19.1%), an average of 11 per case, were considered plausible by study criteria. The distribution of plausibility ratings was found to be statistically case dependent. Averaged across cases, the final plausible diagnosis was generated by the 28th clinician (sd = 8) who worked the case. The results illustrate the richness and diversity of human cognition and the challenges these pose for creation of realistic simulations in biomedical domains.

Computer Simulation↗
PubMed1991

Mixed oligo designer (MOD), a computer program to aid planning of automated, mixed oligodeoxyribonucleotide synthesis for mutagenesis experiments.

A computer program, MOD (mixed oligo designer), which aids in planning site-directed mutagenesis experiments using highly substituted oligodeoxyribonucleotides (oligos), is described. The program calculates the relationship between the degree of oligo substitution and the mutation frequency, in order to achieve an optimal level of mutagenesis. The program can be used on a wide variety of computers and runs under a number of different operating systems.

Algorithms↗
PubMed1987

Computer-assisted instruction: design and content in neuroscience nursing.

Computer-assisted instruction (CAI) includes games, tutorials, simulations, and drills. Computer simulation exercises can be used to simulate patient care and promote diagnostic reasoning skills in nursing. Computer simulation exercises (CSEs) based on case studies of patients with head injury, spinal cord injury, epilepsy, febrile seizures and meningitis have been developed and implemented at the University of Washington School of Nursing, Department of Physiological Nursing, in conjunction with the Health Sciences Center for Educational Resources. These simulations provide a realistic, constantly changing scenerio in which the nurse-learner collects data, analyzes it, and makes decisions about the patient's nursing care. The patient's condition may change dramatically as a result of the decisions made by the nurse-learner.

Computer Simulation↗
PubMed1987

Computer-aided drug design.

Progress in genetic engineering has increased the need for, while advances in computational hardware have removed barriers impeding, the development of appropriate computational tools to assist in the understanding of molecular interactions. Advancements both in techniques and in broadening application have been clearly demonstrated. Further development requires progress in the fundamental aspects of theoretical chemistry as well as an increased base of experience in choosing the appropriate set of assumptions for a particular problem. Computer-aided drug design is a current reality, but one that, at its best, supplements an incomplete methodology with the traditional insight and wisdom of an experienced medicinal chemist. In the next few years progress in developing a sound theoretical foundation will make molecular design a realistic aid to the medicinal chemist and protein engineer.

Chemistry, Pharmaceutical↗
PubMed2004

Anatomical considerations for the spread of odontogenic infection originating from the pericoronitis of impacted mandibular third molar: computed tomographic analyses.

OBJECTIVES: The aims of the present study were to clarify the anatomy of impacted mandibular third molars in relation to surrounding structures and to investigate the pathway of infection originating from pericoronitis of this tooth. STUDY DESIGN: Computed tomography (CT) images were evaluated in 87 patients with uninfected mandibular third molar impaction and in 12 patients with infection originating from an impacted mandibular third molar. In uninfected patients, bony features around the impacted crown were investigated together with the relationship between the crown and surrounding muscles. In infected patients, involvements of bony and soft tissue structures were evaluated according to the disappearance of cortices and lateral asymmetry of density and shape in the spaces and muscles. RESULTS: In uninfected patients, the disappearance of the lingual cortical plate was observed in 48 (35.3%) impacted molars, while only in 11 (8.1%) teeth for buccal cortices. The cortical thickness was thinner on the lingual side than the buccal side. Sixty-five percent of the masseter muscle horizontally overlapped the crown, while almost all of the medial pterygoid muscle was posteriorly situated apart from the crown. The mylohyoid muscle horizontally overlapped the crown at below or intermediate vertical positions. In infected patients, the involvement of lingual structures was more frequently observed than that of buccal structures. The mylohyoid muscle was involved in 10 (83.3%) of 12 patients. Among them, 8 showed submandibular space involvement. CONCLUSION: CT findings supported the clinical observations of infection spread in patients with pericoronitis of the impacted mandibular third molar. CT appeared to be an effective tool for investigating the pathway of infection originating from the pericoronitis of impacted mandibular third molars.

Absorptiometry, Photon↗
PubMed2002

Long-range interactions stabilize the fold of a non-natural oligomer.

Toward designing nonbiological polymers that fold into predictable tertiary structures, we report a "beta-oligomer" composed of beta-amino acids that adopts a cooperatively folded structure. We have computationally designed a C(2)-symmetrical pair of interacting 14-helical beta-oligomers stabilized via long-range interhelical interactions and stapled together by a disulfide bond. The reduced (BHBred) and oxidized (BHBox) forms of the synthetic beta-oligomer represent the individual isolated helices and the two-helix bundle, respectively. We also prepared a third monomeric synthetic beta-oligomer (BHBmon) to avoid inadvertent disulfide formation during characterization. Circular dichroism spectroscopy revealed that BHBox showed a 2-fold increase in secondary structure, relative to the monohelical controls, BHBred and BHBmon. Further, BHBox showed a sigmoidal thermal unfolding curve with a per-residue van't Hoff enthalpy of approximately 0.7 kcal/(mol.residue), analogous to folded proteins. In contrast, BHBmon shows a broad thermal transition, typical of multistate unfolding for monomeric helices. Also, analytical ultracentrifugation showed that BHBmon and BHBox were monomeric at concentrations < or =800 and 280 microM, respectively. Therefore, the enhanced helicity of BHBox could be attributed to intramolecular helix-helix interactions.

Aminobutyrates↗
PubMed2005

Design of lambda Cro fold: solution structure of a monomeric variant of the de novo protein.

One of the classical DNA-binding proteins, bacteriophage lambda Cro, forms a homodimer with a unique fold of alpha-helices and beta-sheets. We have computationally designed an artificial sequence of 60 amino acid residues to stabilize the backbone tertiary structure of the lambda Cro dimer by simulated annealing using knowledge-based structure-sequence compatibility functions. The designed amino acid sequence has 25% identity with that of natural lambda Cro and preserves Phe58, which is important for formation of the stably folded structure of lambda Cro. The designed dimer protein and its monomeric variant, which was redesigned by the insertion of a beta-hairpin sequence at the C-terminal region to prevent dimerization, were synthesized and biochemically characterized to be well folded. The designed protein was monomeric under a wide range of protein concentrations and its solution structure was determined by NMR spectroscopy. The solved structure is similar to that of a monomeric variant of natural lambda Cro with a root-mean-square deviation of the polypeptide backbones at 2.1A and has a well-packed protein core. Thus, our knowledge-based functions provide approximate but essential relationships between amino acid sequences and protein structures, and are useful for finding novel sequences that are foldable into a given target structure.

Amino Acid Sequence↗
PubMed1998

Cost effectiveness of shortening screening interval or extending age range of NHS breast screening programme: computer simulation study.

OBJECTIVE: To compare the cost effectiveness of two possible modifications to the current UK screening programme: shortening the screening interval from three to two years and extending the age of invitation to a final screen from 64 to 69. DESIGN: Computer simulation model which first simulates life histories for women in the absence of a screening programme for breast cancer and then assesses how these life histories would be changed by introducing different screening policies. The model was informed by screening and cost data from the NHS breast screening programme. SETTING: North West region of England. MAIN OUTCOME MEASURES: Numbers of deaths prevented, life years gained, and costs. RESULTS: Compared with the current breast screening programme both modifications would increase the number of deaths prevented and the number of life years saved. The current screening policy costs 2522 pounds per life year gained; extending the age range of the programme would cost 2612 pounds and shortening the interval 2709 pounds per life year gained. The marginal cost per life year gained of extending the age range of the screening programme is 2990 pounds and of shortening the screening interval is 3545 pounds. CONCLUSIONS: If the budget for the NHS breast screening programme were to allow for two more invitations per woman, substantial mortality reductions would follow from extending the age range screened or reducing the screening interval. The difference between the two policies is so small that either could be chosen.

Age Factors↗
PubMed1999

The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study.

In conjunction with pharmacologic therapy, pacing has been proposed as a potential treatment to decrease symptoms in patients with moderate-to-severe congestive heart failure (CHF). Uncontrolled studies of pacing therapy for CHF dealing with different pacing sites, modes of pacing, and atrioventricular delays have reported mixed outcomes. The Pacing Therapies in Congestive Heart Failure (PATH-CHF) study is a single-blind, randomized, crossover, controlled trial designed to evaluate the effects of pacing on acute hemodynamic function and to assess chronic clinical benefit in patients with moderate-to-severe CHF. The effect of pacing on oxygen consumption at peak exercise and at anaerobic threshold during cardiopulmonary exercise tests, and on 6-minute walk distance, have been selected as primary endpoints of the study. Secondary endpoints of the trial were changes in New York Heart Association (NYHA) functional class, quality-of-life as assessed by the Minnesota Living with Heart Failure questionnaire, and hospitalization frequency. Finally, changes in ejection fraction, cardiac output, and filling pattern were assessed by echocardiography. The trial was planned to include 53 patients from 7 centers in Europe over a period of 3 years. The study was divided into 2 parts: acute testing and chronic follow-up. The acute study, performed during the pacemaker implantation, involved extensive testing using a custom-designed computer (FLEXSTIM) and a unique burst pacing protocol (FLEXSTIM protocol) to determine the best ventricular pacing sites and the most appropriate atrioventricular delays. The chronic phase consisted of a crossover study designed to test in each patient the best univentricular pacing site and biventricular pacing as assessed by the acute hemodynamic study. The study started with the first implant in 1995 and has, to date, included 42 patients. The study is expected to be completed by the end of 1998. The results of a first interim analysis showed trends toward improvement in all primary and secondary endpoints during the pacing periods compared with no pacing.

Adult↗
PubMed2026

Generative artificial intelligence for enzyme design and biocatalysis.

Sparked by innovations in generative artificial intelligence (AI), the field of protein design has undergone a paradigm shift with an explosion of new models for optimizing existing enzymes or creating them from scratch. After more than one decade of low success rates for computationally designed enzymes, generative AI models are now frequently used for designing proficient enzymes. Here, we provide a comprehensive overview and classification of generative AI models for enzyme design, highlighting models with experimental validation relevant to real-world settings and outlining their respective limitations. We argue that generative AI models now have the maturity to create and optimize enzymes for industrial applications. Wider adoption of generative AI models with experimental feedback loops can speed up the development of biocatalysts and serve as a community assessment to inform the next generation of models.

Biocatalysis↗
PubMed1979

A computer-assisted personnel data system for a hospital department of dietetics. I. Development of the data base.

A data base was developed for a computer-assisted personnel data system for a university hospital department of dietetics which would store data on employees' employment, personnel information, attendance records, and termination. Development of the data base required designing computer programs and files, coding directions and forms for card input, and forms and procedures for on-line transmission. A program was written to compute accrued vacation, sick leave, and holiday time, and to generate historical records.

Computers↗
PubMedDate not supplied

Evaluation of eccentric occlusal contacts in complete dentures.

Three edentulous patients were evaluated using the kinesiograph and a specially designed computer program to identify the length of eccentric contacts between their dentures when masticating test foods. Three different interchangeable occlusal arrangements were constructed and tested. Results of the evaluation of more than 1,400 chewing cycles showed that while 25% of masticatory contacts were eccentric, the great majority of contacts were within a distance of 1 mm from centric occlusion. More eccentric contacts occurred in the opening phase than might be expected. Posterior tooth form did not appear to affect the range of eccentric contacts.

Aged↗
PubMed2006

Shape similarity measures for the design of small RNA switches.

Conformational switching in the secondary structure of RNAs has recently attracted considerable attention, fostered by the discovery of 'riboswitches' in living organisms. These are genetic control elements that were found in bacteria and offer a unique regulation mechanism based on switching between two highly stable states, separated by an energy barrier between them. In riboswitches, the energy barrier is crossed by direct metabolite binding, which facilitates regulation by allosteric means. However, other event triggers can cause switching to occur, such as single-point mutations and slight variations in temperature. Examples of switches with these event triggers have already been reported experimentally in the past. Here, the goal is to computationally design small RNA switches that rely on these triggers. Towards this end, our computer simulations utilize a variety of different similarity measures to assess the distances between an initial state and triggered states, based on the topology of the secondary structure itself. We describe these combined similarity measures that rely on both coarse-grained and fine-grained graph representations of the RNA secondary structure. As a result of our simulations, we provide some candidate sequences of approximately 30-50 nt, along with the exact triggers that drive the switching. The event triggers under consideration can be modelled by Zuker's mfold or the Vienna package. The proposed methodology that rely on shape measures can further be used to computationally generate more candidates by simulating various event triggers and calculating their effect on the shape.

Nucleic Acid Conformation↗
PubMed2001

Bone volume after secondary bone grafting in unilateral and bilateral clefts determined by computed tomography scans.

OBJECTIVE: The purpose of this study was to evaluate the outcome of bone grafts in cleft palate patients, thus assessing the amount of bone necessary to facilitate eruption-especially in the buccopalatal direction-of the permanent canine into the bone graft. STUDY DESIGN: Computed tomography scans taken immediately postoperatively and 1 year postoperatively of 42 unilateral and of 8 bilateral cleft lip and palate patients who underwent surgery at the age of 9 years (early secondary bone graft) or 12 years (late secondary bone graft) were compared. Three slices from the computed tomography scans taken immediately after the surgery were selected from the center of the bone graft and were then compared with corresponding slices from the 1-year postoperative computed tomography scans. Statistical analysis was performed by using the Wilcoxon 2-sample rank sum test. RESULTS: In the unilateral cleft group, 70% of the transplanted bone remained in the cleft area after 1 year, whereas in the bilateral cleft group, only 45% of the initial bone graft remained after 1 year. CONCLUSION: No statistically significant difference was found between early secondary bone grafting and late secondary bone grafting. In most cases, a sufficient amount of bone was present in the target area to facilitate eruption of the permanent canine.

Age Factors↗
PubMed1998

Non-radiological technique for 3D imaging of intestinal endoscopes: computerised graphical 3D representation of endoscope and skeleton.

Colorectal cancer is a common malignancy but as yet there is no agreement regarding the optimal method for screening. Colonoscopy is theoretically the investigation of choice. The examination can, however, be difficult to perform and the average trainee requires at least 200 supervised examinations to become proficient. Colonoscopy takes on average about half an hour per patient and sedation is normally required because of painful instrument looping. The authors previously developed a non-radiological method of visualising the path of the endoscope using magnetic drive coils under the patient and a chain of sensors in the biopsy channel of the instrument. The computer-generated grey-scale images produced in real time were deemed unsatisfactory and the anatomical markers confusing. A new computer graphics system is described in which a much more realistic endoscope and, if necessary, skeleton can be produced. The wire-frame octagonal representation should help in the detailed analysis of colonoscopy using existing endoscopes and aid in future computer design and testing of novel instruments incorporating worm or snake-like properties.

Colonoscopy↗