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At least 1,351 records · Page 75Linked to original sources
PubMed2006

Modulation of poliovirus replicative fitness in HeLa cells by deoptimization of synonymous codon usage in the capsid region.

We replaced degenerate codons for nine amino acids within the capsid region of the Sabin type 2 oral poliovirus vaccine strain with corresponding nonpreferred synonymous codons. Codon replacements were introduced into four contiguous intervals spanning 97% of the capsid region. In the capsid region of the most highly modified virus construct, the effective number of codons used (N(C)) fell from 56.2 to 29.8, the number of CG dinucleotides rose from 97 to 302, and the G+C content increased from 48.4% to 56.4%. Replicative fitness in HeLa cells, measured by plaque areas and virus yields in single-step growth experiments, decreased in proportion to the number of replacement codons. Plaque areas decreased over an approximately 10-fold range, and virus yields decreased over an approximately 65-fold range. Perhaps unexpectedly, the synthesis and processing of viral proteins appeared to be largely unaltered by the restriction in codon usage. In contrast, total yields of viral RNA in infected cells were reduced approximately 3-fold and specific infectivities of purified virions (measured by particle/PFU ratios) decreased approximately 18-fold in the most highly modified virus. The replicative fitness of both codon replacement viruses and unmodified viruses increased with the passage number in HeLa cells. After 25 serial passages (approximately 50 replication cycles), most codon replacements were retained, and the relative fitness of the modified viruses remained well below that of the unmodified virus. The increased replicative fitness of high-passage modified virus was associated with the elimination of several CG dinucleotides. Potential applications for the systematic modulation of poliovirus replicative fitness by deoptimization of codon usage are discussed.

Base Sequence↗
PubMed2003

Are medical reports on fitness to drive trustworthy?

PURPOSE: Previous studies have shown that physicians often have poor knowledge of the medical restriction on fitness to drive, or submit poor quality medical reports. To determine the reliability of physicians' reports on fitness to drive, the medical data provided on the standard medical fitness form was compared with the additional data collected on repeated assessment. METHODS: A random sample of 100 applicants for a driver's licence aged more than 49 years who submitted the standard medical form were asked to provide, from their regular family doctor, confirmation of their health status and/or additional medical data in order to make a re-evaluation. RESULTS: The rate of rejection for a licence for medical reasons was 3% on the basis of the standard evaluation and 17% on the basis of the re-evaluation (p<0.001). CONCLUSION: This study shows that the random evaluation of physician assessments of applicants for a driver's licence increases the detection rate of medical problems that can affect fitness to drive. The alarming difference in the rate of rejection between the two assessments may reflect a lackadaisical attitude of medical professionals toward the licence assessment procedure and/or physician unawareness of the medical restrictions on fitness to drive. Results of this study suggest that this subject must be included in medical education programmes.

Aged↗
PubMed2004

Rule fitness and pathology in learning classifier systems.

It has long been known that in some relatively simple reinforcement learning tasks traditional strength-based classifier systems will adapt poorly and show poor generalisation. In contrast, the more recent accuracy-based XCS, appears both to adapt and generalise well. In this work, we attribute the difference to what we call strong over general and fit over general rules. We begin by developing a taxonomy of rule types and considering the conditions under which they may occur. In order to do so an extreme simplification of the classifier system is made, which forces us toward qualitative rather than quantitative analysis. We begin with the basics, considering definitions for correct and incorrect actions, and then correct, incorrect, and overgeneral rules for both strength and accuracy-based fitness. The concept of strong overgeneral rules, which we claim are the Achilles' heel of strength-based classifier systems, are then analysed. It is shown that strong overgenerals depend on what we call biases in the reward function (or, in sequential tasks, the value function). We distinguish between strong and fit overgeneral rules, and show that although strong overgenerals are fit in a strength-based system called SB-XCS, they are not in XCS. Next we show how to design fit overgeneral rules for XCS (but not SB-XCS), by introducing biases in the variance of the reward function, and thus that each system has its own weakness. Finally, we give some consideration to the prevalence of reward and variance function bias, and note that non-trivial sequential tasks have highly biased value functions.

Algorithms↗
PubMed1989

Fitness to plead and psychiatric reports.

The role of the psychiatrist in the determination of fitness to plead is reviewed by reference to 77 pre-trial psychiatric reports prepared on 31 Special Hospital patients detained under the provision of Section 5(1)(c) (Unfit to Plead) of the Criminal Procedure (Insanity) Act 1964. Each psychiatric report was analysed using a standardized checklist which addressed the legal criteria used to determine fitness to plead, the nature of the alleged offence and the clinical diagnosis. The results showed that almost 40% of the reports made no mention of fitness to plead at all and that only one-third of the reports made a statement about fitness to plead which was supported by reference to standard legal criteria. The results of this study support earlier work which has suggested that psychiatrists have a poor understanding of the issues surrounding fitness to plead and criminal responsibility. These findings are discussed in relation to recommendations made by the Report of the Committee on Mentally Abnormal Offenders, 1975 (Butler Report) and legislative changes introduced by the Mental Health Act 1983.

Forensic Psychiatry↗
PubMedDate not supplied

Comparison of initial fixation strength between biodegradable and metallic interference screws and a press-fit fixation technique in a porcine model.

The objective of this study was to evaluate the initial fixation strength of a biodegradable interference screw compared with press-fit fixation and a titanium interference screw in anterior cruciate ligament reconstruction using a bone-patellar tendon-bone graft. Porcine lower limbs were used. The specimens underwent 500 loading cycles between 60 and 250 N. This corresponds to loads in the graft during aggressive rehabilitation. Thereafter, intact specimens were loaded to failure. Failure mode was defined by visual analysis. Under cyclic loads none of the interference screw fixations failed. In the press-fit group (angle between load axis and tunnel axis 80 degrees), five specimens failed. The mean maximal load to failure was 945 N (+/- 87) for the titanium screw, 797 N (+/- 60) for the biodegradable screw, and 708 N (+/- 211) for the five press-fit specimens that did not fail during cyclic loading. With respect to primary fixation strength, biodegradable screws are a reasonable alternative to titanium interference screws. The press-fit fixation did not provide a secure fixation in all cases. Five press-fit specimens failed under cyclic loads comparable with those seen under conditions of accelerated rehabilitation.

Absorbable Implants↗
PubMed1999

Cost savings associated with fitness-to-stand-trial assessments in detention centres: a pilot program.

OBJECTIVE: To determine whether fitness-to-stand-trial assessments "in detention" offer cost benefit over inpatient assessments. METHOD: The development of a pilot "fitness clinic" in a detention centre is described, and the results of 1 year of assessments are presented. The cost benefit of fitness assessments conducted in detention centres is outlined. RESULTS: Significant cost savings were realized by operating fitness clinics in detention centres. CONCLUSION: Fitness clinics in detention centres offer important benefits and are recommended as an adjunct to forensic programs.

Adult↗
PubMed2001

Exploring the technical aspects of "fit" in qualitative research.

The concept of fit and processes of fitting have been largely ignored in qualitative inquiry. In this article, the authors address the technical significance of fit as an analytic process for both data and concepts in the process of theory construction. The ramifications of violating processes of fit and examples of misfits are discussed. Finally, the procedural components and fit as a method of validation are presented.

Evaluation Studies as Topic↗
PubMed2005

Fitness consequences of Anopheles gambiae population hybridization.

BACKGROUND: The use of transgenic mosquitoes with parasite inhibiting genes has been proposed as an integral strategy to control malaria transmission. However, release of exotic transgenic mosquitoes will bring in novel alleles along with parasite-inhibiting genes that may have unknown effects on native populations. Thus it is necessary to study the effects and dynamics of fitness traits in native mosquito populations in response to the introduction of novel genes. This study was designed to evaluate the dynamics of fitness traits in a simulation of introduction of novel alleles under laboratory conditions using two strains of Anopheles gambiae: Mbita strain from western Kenya and Ifakara strain from Tanzania. METHODS: The dynamics of fitness traits were evaluated under laboratory conditions using the two An. gambiae strains. These two geographically different strains were cross-bred and monitored for 20 generations to score fecundity, body size, blood-meal size, larval survival, and adult longevity, all of which are important determinants of the vector's potential in malaria transmission. Traits were analysed using pair-wise analysis of variance (ANOVA) for fecundity, body size, and blood-meal size while survival analysis was performed for larval survival and adult longevity. RESULTS: Fecundity and body size were significantly higher in the progeny up to the 20th generation compared to founder strains. Adult longevity had a significantly higher mean up to the 10th generation and average blood-meal size was significantly larger up to the 5th generation, indicating that hybrids fitness is enhanced over that of the founder strains. CONCLUSION: Hybridization of the two mosquito populations used in this study led to increased performance in the fitness traits studied. Given that the studied traits are important determinants of the vector's potential to transmit malaria, these results suggest the need to release genetically modified mosquitoes that have the same or very similar backgrounds to the native populations.

Animals↗
PubMed2005

A physician fitness program: enhancing the physician as an "exercise" role model for patients.

BACKGROUND: Physically active physicians are more apt to counsel patients about exercise. PURPOSES: The purpose of this study was to determine the effect of a physician fitness program on resident physician cardiovascular fitness, physical activity behavior/stage of change, and physical activity counseling behavior/attitudes. METHODS: A prospective, intervention study with measurements at baseline (before intervention), 3 months (immediately after intervention), and 6 months (3 months after intervention) evaluated a multifaceted exercise program for 48 internal medicine residents. Resident physician cardiovascular fitness, energy expenditure, physical activity stage of change, knowledge, attitudes, and counseling behavior were measured. RESULTS: Resident physician fitness significantly declined over time (baseline VO(2)-170 = 29.1 ml/kg/min, first follow-up VO(2)-170 = 27.3 ml/kg/min, and second follow-up VO(2)-170 = 26.2 ml/kg/min; p = .001). Although there was no change in overall energy expenditure, the number of resident physicians in the precontemplation or contemplation stage of change significantly declined with a corresponding increase in the number in a "higher" stage of change at first (p = .0034) and second follow-up (p = .024). There was a nonsignificant increase in self-reported patient counseling. Resident physician counseling confidence and perceived success significantly improved at first follow-up only (p = .01 and p = .03, respectively). CONCLUSION: Although resident physician fitness and energy expenditure did not improve after intervention, a significant improvement in resident physician physical activity stage of change and attitudes toward patient counseling was noted. Randomized controlled trials are needed to confirm whether these changes are attributable to the intervention.

Attitude of Health Personnel↗
PubMed2000

Parametric mapping of scaled fitting error in dynamic susceptibility contrast enhanced MR perfusion imaging.

The purpose of this study was to examine the benefits of routine generation of a parametric image of scaled curve fitting errors in the analysis of dynamic susceptibility contrast enhanced MR perfusion imaging. We describe the scaled fitting error (SFE), which reflects the magnitude of potential errors in the estimation of perfusion parameters from dynamic susceptibility contrast enhanced studies. The SFE is the root-mean-square error between the observed values in the time course of change of effective transverse relaxation rate (delta R2* (t)) in tissue and the theoretical values derived by gamma variate curve fitting, scaled with a simple function related to the area under the fitted gamma variate curve. The SFE was tested using Monte Carlo simulation and by observations in normal volunteers and patients. This demonstrated that the SFE was linearly related to uncertainties in calculation of the values of relative cerebral blood volume (rCBV) and relative mean transit time (rMTT). High spatial resolution SFE maps were obtained in all volunteers and patients. In normal brain, SFE was consistently higher in white matter than in grey matter. In 54/85 patients with neurodegenerative or vascular brain disease, SFE maps showed focal areas with high values owing to poor signal to noise ratio in delta R2*(t). Increased SFE was also found in 11/54 brain tumours owing to loss of conformance of delta R2*(t) to the gamma variate function. SFE mapping is simple to implement and the computational overhead is negligible. It is concluded that parametric maps of SFE allow visual and quantitative comparison of fitting errors with the theoretical gamma variate model between anatomical regions and provide a quality control device to rapidly assess the reliability of the associated rCBV and rMTT estimations.

Adult↗
PubMed2006

The long-term results of press-fit cemented stems in total knee prostheses.

We evaluated the long-term fixation of 64 press-fit cemented stems of constrained total knee prostheses in 32 young patients with primary malignant bone tumours. Initial stable fixation, especially in rotation, was achieved by precise fit of the stem into the reamed endosteum, before cementation. Complementary fixation, especially in migration and rotation, was obtained by pressurised antibiotic-loaded cement. The mean age at operation was 33 years (13 to 61). No patient was lost to follow-up; 13 patients died and the 19 survivors were examined at a mean follow-up of 12.5 years (4 to 21). Standard revision press-fit cemented stems were used on the side of the joint which was not involved with tumour (26 tibial and six femoral), on this side there was no loosening or osteolysis and stem survival was 100%. On the reconstruction side, custom-made press-fit stems were used and the survival rate, with any cause for revision as an end point, was 88%, but 97% for loosening or osteolysis. This longevity is similar to that achieved at 20 years with the Charnley-Kerboull primary total hip replacement with press-fit cemented femoral components. We recommend this type of fixation when extensive reconstruction of the knee is required. It may also be suitable for older patients requiring revision of a total knee replacement or in difficult situations such as severe deformity and complex articular fractures.

Adolescent↗
PubMed2006

Testing the Rasch model by means of the mixture fit index.

Rudas, Clogg, and Lindsay (RCL) proposed a new index of fit for contingency table analysis. Using the overparametrized two-component mixture, where the first component with weight 1-w represents the model to be tested and the second component with weight w is unstructured, the mixture index of fit was defined to be the smallest w compatible with the saturated two-component mixture. This index of fit, which is insensitive to sample size, is applied to the problem of assessing the fit of the Rasch model. In this application, use is made of the equivalence of the semi-parametric version of the Rasch model to specifically restricted latent class models. Therefore, the Rasch model can be represented by the structured component of the RCL mixture, with this component itself consisting of two or more subcomponents corresponding to the classes, and the unstructured component capturing the discrepancies between the data and the model. An empirical example demonstrates the application of this approach. Based on four-item data, the one- and two-class unrestricted latent class models and the one- to three-class models restricted according to the Rasch model are considered, with respect to both their chi-squared statistics and their mixture fit indices.

Humans↗
PubMed2006

From bad to good: Fitness reversals and the ascent of deleterious mutations.

Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10(-5) of all mutations).

Adaptation, Biological↗
PubMed2026

A genome-wide in vivo screen reveals fitness pathways required for streptococcal infective endocarditis.

Infective endocarditis (IE) is a life-threatening disease most often caused by blood-borne bacteria that infect previously damaged cardiac tissue. Despite the importance of this disease, the genetic basis for IE-associated fitness remains poorly defined. Here, we present the first genome-wide in vivo analysis of bacterial fitness in a vertebrate model of IE. We identified 146 genes in Streptococcus sanguinis required for IE fitness, the majority of which had not previously been linked to endocarditis. These determinants cluster into conserved metabolic, cell envelope, transport, and regulatory pathways, representing a vast reservoir of potential targets for novel antimicrobial intervention. A subset of these genes was examined in Streptococcus mutans; all were found to be essential for IE fitness in this distantly related oral species as well, suggesting broad conservation. Using experimental evolution, we further show that disruption of key fitness pathways triggers reproducible compensatory "bypass" mechanisms. Together, these findings provide a comprehensive, genome-wide map of the bacterial niche-requirements for streptococcal infective endocarditis.

Animals↗
PubMed2026

A novel dimerization site in non-structural protein 5A of hepatitis C virus regulates viral replication fitness.

We previously found that high genome replication fitness of the hepatitis C virus (HCV) was associated with severe disease in immunocompromised patients. Elevated replication fitness was mediated by accumulation of mutations in the replication enhancing domain (ReED) within domain (D) 2 of non-structural protein (NS) 5A. NS5A is a partially unstructured phosphoprotein lacking enzymatic activity but fulfilling a key role in HCV replication due to interacting with various cellular and viral proteins. It can exist in a variety of dimeric and oligomeric conformations mediated by NS5A D1 with clinically approved NS5A inhibitors proposed to exert their antiviral function by fixing these dimers in distinct conformations. In this study, we aimed at elucidating the ReED's mode of action. AlphaFold modelling indicated a so far unrecognized NS5A dimerization site in the ReED. Indeed, split nano luciferase assays revealed a significantly stronger NS5A dimerization of high replicator ReED variants, suggesting that high replication fitness is mediated by enforcement of NS5A self-interaction. This hypothesis was supported by the effect of low dose (1 pM) NS5A inhibitor treatment, increasing replication fitness and phenocopying the effects of ReED mutations. Furthermore, we found that HCV isolate JFH1, replicating with very high efficiency, is completely resistant to the regulatory function of the ReED. Chimeric replicons composed of ReED resistant JFH1 and the ReED sensitive isolate J6 identified NS3 helicase and NS5B polymerase as critical genetic elements mediating ReED sensitivity/resistance. Our data overall suggest that the ReED in NS5A is a negative regulator of HCV replication fitness with dimerization releasing the inhibitory interaction with helicase and/or polymerase, thereby likely facilitating initiation of RNA synthesis.

Viral Nonstructural Proteins↗
PubMed2005

Methods to determine HIV-1 ex vivo fitness.

The fitness of human immunodeficiency virus type-1 (HIV-1) appears to be an important piece of the puzzle in understanding the global HIV-1 epidemic and disease progression in infected individuals. We have developed a dual infection/competition assay followed by a sensitive heteroduplex tracking assay (HTA) to measure the relative fitness of any HIV-1 isolate. Differences in fitness between wild-type and drug-resistant HIV-1 isolates can also be used as indicators of the emergence of drug-resistant isolates. This chapter describes the methods utilized to measure viral fitness (relative replicative capacity) during growth competition experiments. HTA is used to evaluate the production of HIV-1 variants in a competition, which can then be used to estimate ex vivo viral fitness.

Genes, env↗
PubMed2004

Model-based fitting of single-channel dwell-time distributions.

Single-channel recordings provide unprecedented resolutions on kinetics of conformational changes of ion channels. Several approaches exist for analysis of the data, including the dwell-time histogram fittings and the full maximal-likelihood approaches that fit either the idealized dwell-time sequence or more ambitiously the noisy data directly using hidden Markov modeling. Although the full maximum likelihood approaches are statistically advantageous, they can be time-consuming especially for large datasets and/or complex models. We present here an alternative approach for model-based fitting of one-dimensional and two-dimensional dwell-time histograms. To improve performance, we derived analytical expressions for the derivatives of one-dimensional and two-dimensional dwell-time distribution functions and employed the gradient-based variable metric method for fast search of optimal rate constants in a model. The algorithm also has the ability to allow for a first-order correction for the effects of missed events, global fitting across different experimental conditions, and imposition of typical constraints on rate constants including microscopic reversibility. Numerical examples are presented to illustrate the performance of the algorithm, and comparisons with the full maximum likelihood fitting are discussed.

Algorithms↗
PubMed2004

A fast global fitting algorithm for fluorescence lifetime imaging microscopy based on image segmentation.

Global fitting algorithms have been shown to improve effectively the accuracy and precision of the analysis of fluorescence lifetime imaging microscopy data. Global analysis performs better than unconstrained data fitting when prior information exists, such as the spatial invariance of the lifetimes of individual fluorescent species. The highly coupled nature of global analysis often results in a significantly slower convergence of the data fitting algorithm as compared with unconstrained analysis. Convergence speed can be greatly accelerated by providing appropriate initial guesses. Realizing that the image morphology often correlates with fluorophore distribution, a global fitting algorithm has been developed to assign initial guesses throughout an image based on a segmentation analysis. This algorithm was tested on both simulated data sets and time-domain lifetime measurements. We have successfully measured fluorophore distribution in fibroblasts stained with Hoechst and calcein. This method further allows second harmonic generation from collagen and elastin autofluorescence to be differentiated in fluorescence lifetime imaging microscopy images of ex vivo human skin. On our experimental measurement, this algorithm increased convergence speed by over two orders of magnitude and achieved significantly better fits.

Algorithms↗