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At least 397 records · Page 22Linked to original sources

PubMed2003

Experimental and numerical validation for the novel configuration of an arthroscopic indentation instrument.

Softening of articular cartilage, mainly attributable to deterioration of superficial collagen network and depletion of proteoglycans, is a sign of incipient osteoarthrosis. Early diagnosis of osteoarthrosis is essential to prevent the further destruction of the tissue. During the past decade, a few arthroscopic instruments have been introduced for the measurement of cartilage stiffness; these can be used to provide a sensitive measure of cartilage status. Ease of use, accuracy and reproducibility of the measurements as well as a low risk of damaging cartilage are the main qualities needed in any clinically applicable instrument. In this study, we have modified a commercially available arthroscopic indentation instrument to better fulfil these requirements when measuring cartilage stiffness in joints with thin cartilage. Our novel configuration was validated by experimental testing as well as by finite element (FE) modelling. Experimental and numerical tests indicated that it would be better to use a smaller reference plate and a lower pressing force (3 N) than those used in the original instrument (7-10 N). The reproducibility (CV = 5.0%) of the in situ indentation measurements was improved over that of the original instrument (CV = 7.6%), and the effect of material thickness on the indentation response was smaller than that obtained with the original instrument. The novel configuration showed a significant linear correlation between the indenter force and the reference dynamic modulus of cartilage in uncontined compression, especially in soft tissue (r = 0.893, p < 0.001, n = 16). FE analyses with a transversely isotropic poroelastic model indicated that the instrument was suitable for detecting the degeneration of superficial cartilage. In summary, the instrument presented in this study allows easy and reproducible measurement of cartilage stiffness, also in thin cartilage, and therefore represents a technical improvement for the early diagnosis of osteoarthrosis during arthroscopy.

Animals↗

PubMed1997

The validation of three human reliability quantification techniques--THERP, HEART and JHEDI: Part III--Practical aspects of the usage of the techniques.

This is the third paper in a series of three dealing with the detailed investigation of the empirical validity of three human reliability assessment (HRA) techniques. The first paper introduced the need for validation and specified the three techniques most requiring validation. The second paper detailed the results of an extensive independent validation experiment. This experimental validation involved 30 UK assessors using the techniques THERP, HEART and JHEDI (10 assessors per technique) to estimate the human error probabilities (HEPs) for 30 nuclear power and reprocessing (NP&R) tasks. The results for all three techniques were positive in terms of significant correlations, and general precision levels of 72% of all HEP estimates within a factor of 10 of the true value (unknown to the assessors). These results lend support to the empirical validity of these techniques in particular, and to HRA in general. However, the results were not all positive. In particular the consistency of usage of the techniques was variable. Additionally, subjects were generally not good at knowing their own uncertainty, i.e. they were not able to accurately predict when they were accurate nor when they were inaccurate. This desirable parameter is known as calibration, and the results from the validation suggested that subjects were not well-calibrated. This paper aims to determine how consistency of usage can be improved and to discern whether certain task types are, in practice, not well-assessed by the techniques, and hence are effectively currently beyond these techniques' abilities. Such information is aimed at aiding the HRA practitioner, or the ergonomist, interested in using these techniques. Recommendations for improving calibration are also discussed in this paper. A subsidiary but important focus of this paper is of a more fundamental nature, and of more general interest to the ergonomist. It concerns the validity of the techniques from an error reduction perspective. Currently these techniques may be used to identify how to reduce error probability, which is generally (in the qualitative sense) within the domain of ergonomics. One major mechanism for HRA-based error reduction is the utilisation of Performance Shaping Factor (PSF) information. This paper considers the validity of these PSF as ergonomics constructs. Drawing results from the validation exercise, it is seen how different PSF can be applied to the same scenario and can result in the same error probability, but will result in different error reduction guidance. It is therefore recommended that error reduction guidance must be based on a composite analysis of the results of the task, error identification and quantification analyses, with most weighting given to the qualitative analyses.

Evaluation Studies as Topic↗

PubMedDate not supplied

The logical structure and validity of experimental designs in pharmacokinetics and clinical pharmacology.

Much of the literature on research design in clinical pharmacology and pharmacokinetics emphasizes statistical concerns, thus suggesting that a primary ingredient of a valid research design is an appropriate plan for statistical analysis of data. However, statistical validity is only one of several ways to evaluate an experimental study. The present paper reviews the underlying logic and sources of invalidity of experimental drug research suggesting influences and factors which may deceive or lure an experimenter into erroneous conclusions.

Models, Biological↗

PubMed2003

Burst fracture in the metastatically involved spine: development, validation, and parametric analysis of a three-dimensional poroelastic finite-element model.

STUDY DESIGN: A finite-element study and in vitro experimental validation was performed for a parametric investigation of features that contribute to burst fracture risk in the metastatically involved spine. OBJECTIVES: To develop and validate a three-dimensional poroelastic model of a metastatically compromised vertebral segment, to evaluate the effect of lytic lesions on vertebral strains and pressures, and to determine the influence of loading and motion segment status (bone density, pedicle involvement, disc degeneration, and tumor size) on the relative risk of burst fracture initiation. SUMMARY OF BACKGROUND DATA: Finite-element analysis has been used successfully to predict failure loads and fracture patterns for bone. Although models for vertebra affected with tumors have been presented, these have not been thoroughly validated experimentally. Consequently, their predictive capabilities remain uncertain. METHODS: A three-dimensional poroelastic finite-element model of the first lumbar vertebra and adjacent intervertebral discs, including a tumor of variable size, was developed. To validate the model, 12 cadaver spinal motion segments were tested in axial compression, in intact condition, and with simulated osteolytic defects. Features of the validated model were parametrically varied to investigate the effects of tumor size, trabecular bone density, pedicle involvement, applied loads, loading rates, and disc degeneration using outcome variables of vertebral bulge and vertebral axial deformation. RESULTS: Consistent trends between the experimental data and model predictions were observed. Overall, the model results suggest that tumor size contributes most toward the risk of initiating burst fracture, followed by the applied load magnitude and bone density. CONCLUSIONS: The parametric analysis suggests that the principal factors affecting the initiation of burst fracture in metastatically affected vertebrae are tumor size, magnitude of spinal loading, and bone density. Consequently, patient-specific measures of these factors should be factored into decisions regarding clinical prophylaxis. Pedicle involvement or disc degeneration was less important according to the outcome measures in this study.

Adult↗

PubMed2003

Microarray analysis of nonhuman primates: validation of experimental models in neurological disorders.

Nonhuman primates (NHPs) have provided robust experimental animal models for many human-related diseases due to their similar physiologies. Nonetheless, profound differences remain in the acquisition, progression, and outcome of important diseases such as AIDS and Alzheimer's, for which the underlying basis remains obscure. We explored the utility of human high-density oligonucleotide arrays to survey the transcription profile of NHP genomes. Total RNA from prefrontal cortices of human (Homo sapiens), common chimpanzee (Pan troglodytes), cynomolgous macaque (Macaca fascicularis), and common marmoset (Callithrix jacchus) was labeled and hybridized to Affymetrix U95A GeneChip probe arrays. Corresponding data obtained previously from common chimpanzee and orangutan (Pongo pygmaeus) were added for comparison. Qualitative (present or not detected) and quantitative (expression level) analysis indicated that many genes known to be involved in human neurological disorders were present and regulated in NHPs. A gene involved in dopamine metabolism (catechol-O-methyltransferase) was absent in macaque and marmoset. Glutamate receptor 2 was up-regulated, and transcription-associated genes were down-regulated in NHPs compared with humans. We demonstrate that transcript profiling of NHPs could provide comparative genomic data to validate and better focus experimental animal models of human neurological disorders.

Adult↗

PubMed2026

Teleost lincRNAs: Functional roles, regulatory mechanisms, and future applications in aquaculture.

Long intergenic non-coding RNAs (lincRNAs) regulate gene expression across vertebrate physiological systems, yet their functional roles in teleost fish remain incompletely synthesized. This review systematically integrates current evidence through PRISMA-guided searches across PubMed, Web of Science, and Scopus, identifying ten lincRNA-focused functional studies with genetic, mechanistic, or developmental validation, complemented by twenty two supplementary contextual references. Findings span development, immunity, environmental adaptation, reproduction, regeneration, and toxicology, with each association graded as experimentally validated, bioinformatically predicted, correlational, or speculative. This synthesis offers three core contributions. First, it shows that cis-acting regulation on neighboring genes, mediated through Wnt, NF-κB, and AHR signaling, is the dominant validated lincRNA mechanism across teleost physiological domains. Second, it demonstrates that direct experimental validation, primarily via CRISPR-Cas9 and chromatin-capture assays, remains concentrated in zebrafish, whereas aquaculture-species associations remain largely correlational. Third, it identifies two findings that challenge current lincRNA classification: unexpected regulatory directionality at the slincR-sox9b locus, and micropeptide-encoding potential within annotated lincRNAs. Together, these contributions establish an evidence-graded foundation for future mechanistic studies and translational aquaculture applications.

Aquaculture↗

PubMed1990

Optimization and simulation of continuous affinity-recycle extraction (care).

Simulation and optimization of continuous affinity recycle extraction (CARE), a protein purification unit operation based on protein adsorption to solid phase adsorbents, is described in this paper. Rather than packing conventional adsorbent particles in a fixed bed (column), solid/liquid contact is carried out in well-mixed reactors. Continuous operation is achieved by recirculation of the adsorbent particles between two or more contactors. The feasibility of this purification scheme was established with the recovery and isolation of the enzyme beta-galactosidase from E.coli, using the affinity support PABTG/Agarose. A mathematical model describing system performance was developed. The mathematical model was used to optimize several facets of the system design and operation. The base two-stage contractor design was modified by the addition of an intermediate wash stage as well as the incorporation of multiple adsorption stages. These design modifications serve to increase purification, concentration and recovery while utilizing the same amount of adsorbent. The methodology for defining and optimizing objective functions was developed and experimentally validated. Finally, optimum system start-up protocols, minimizing the time required to reach steady-state operation, were developed and experimentally validated. The impact of early introduction of adsorptive purification in a downstream processing sequence, with CARE, was evaluated and is described. Through the early introduction of a highly specific adsorptive step, significant purification is achieved simultaneously with clarification and concentration. In addition, purification performance in CARE was contrasted with that achievable in conventional column chromatography.

Chromatography, Affinity↗

PubMed2026

Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden.

BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these variants frequently remain classified as of uncertain significance (VUS) due to limited predictive power and lack of transcript-level evidence, constraining genetic yield and clinical management. Our study aimed to determine the functional impact of SAVs in ACM genes and refine their classification using ACMG/AMP and ClinGen SVI criteria. METHODS: SAVs identified in 200 ACM probands underwent SpliceAI prediction, GTEx cardiac exon-usage annotation, and functional assessment using pSPL3-based minigene assays. Aberrant transcripts were quantified using Percent Splicing Alteration (PSA). Segregation data and ACMG/AMP criteria refined by ClinGen SVI were applied to integrate functional and clinical evidence for classification. RESULTS: Aberrant splicing was confirmed in 9/20 variants (45%), including synonymous, missense, and non-canonical intronic changes. SpliceAI scores correlated strongly with PSA values (R²=0.86). Case-control burden testing revealed significant enrichment of splice-altering variants in DSP, DSG2, DSC2 and FLNC. Integrating predictive algorithms with experimental validation and segregation analysis markedly enhances reclassification of 16/20 variants (80%). CONCLUSION: Splicing defects beyond canonical sites significantly shape ACM genetic landscape. Integrating predictive models with experimental validation clarifies uncertain variants bridging the gap between genomic uncertainty and clinical decision-making.

Humans↗

PubMed2006

A search algorithm for fixed-composition protein design.

We present a computational protein design algorithm for finding low-energy sequences of fixed amino acid composition. The search algorithms used in protein design typically do not restrict amino acid composition. However, the random energy model of Shakhnovich suggests that the use of fixed-composition sequences may circumvent defects in the modeling of the denatured state. Our algorithm, FC_FASTER, links fixed-composition versions of Monte Carlo and the FASTER algorithm. As proof of principle, FC_FASTER was tested on an experimentally validated, full-sequence design of the beta1 domain of protein G. For the wild-type composition, FC_FASTER found a lower energy sequence than the experimentally validated sequence. Also, for a different composition, FC_FASTER found the hypothetical lowest-energy sequence in 14 out of 32 trials.

Algorithms↗

PubMed2006

Detection of divergent genes in microbial aCGH experiments.

BACKGROUND: Array-based comparative genome hybridization (aCGH) is a tool for rapid comparison of genomes from different bacterial strains. The purpose of such analysis is to detect highly divergent or absent genes in a sample strain compared to an index strain. Development of methods for analyzing aCGH data has primarily focused on copy number abberations in cancer research. In microbial aCGH analyses, genes are typically ranked by log-ratios, and classification into divergent or present is done by choosing a cutoff log-ratio, either manually or by statistics calculated from the log-ratio distribution. As experimental settings vary considerably, it is not possible to develop a classical discriminant or statistical learning approach. METHODS: We introduce a more efficient method for analyzing microbial aCGH data using a finite mixture model and a data rotation scheme. Using the average posterior probabilities from the model fitted to log-ratios before and after rotation, we get a score for each gene, and demonstrate its advantages for ranking and detecting divergent genes with enlarged specificity and sensitivity. RESULTS: The procedure is tested and compared to other approaches on simulated data sets, as well as on four experimental validation data sets for aCGH analysis on fully sequenced strains of Staphylococcus aureus and Streptococcus pneumoniae. CONCLUSION: When tested on simulated data as well as on four different experimental validation data sets from experiments with only fully sequenced strains, our procedure out-competes the standard procedures of using a simple log-ratio cutoff for classification into present and divergent genes.

Computational Biology↗

PubMed1998

External validity and experimental design: the sensitive phase for song learning.

In the past decade there has been widespread acceptance of the idea that the use of live, socially interactive tutors in song learning experiments produces results that differ dramatically from, and are more valid than, results obtained with tape tutors. The influential series of experiments by Baptista & Petrinovich (1984, Animal Behaviour, 32, 172-181, 1986, Animal Behaviour, 34, 1359-1371; Petrinovich & Baptista 1987, Animal Behaviour, 35, 961-974) have promoted this view, and their results have been widely accepted. Baptista & Petrinovich's results have led them and others to question whether there are age-limited sensitive phases for song learning, as Marler's (1970, Journal of Comparative Physiology and Psychology Monographs, 711-25) early studies on the white-crowned sparrow, Zonotrichia leucophrys, suggested, and led them to argue that interactive tutoring produces essentially open-ended learning. I argue here that this view is mistaken, and that the sensitive phase for song learning in the white-crowned sparrow is identical for live and tape tutors and is restricted to the first few months of life. Baptista & Petrinovich presented live and tape tutors for different periods to their subjects. Type of tutor (live versus tape) is confounded with duration of exposure to tutors. As a consequence, their experiments confound two different forms of song learning that occur at different ages, and give the mistaken appearance of an extended sensitive phase when live tutors are used. Copyright 1998 The Association for the Study of Animal Behaviour

Journal Article↗

PubMed1996

Finite-element models of the human head.

A review is presented of the existing finite-element (FE) models for the biomechanics of human head injury. Finite element analysis can be an important tool in describing the injury biomechanics of the human head. Complex geometric and material properties pose challenges to FE modelling. Various assumptions and simplifications are made in model development that require experimental validation. More recent models incorporate anatomic details with higher precision. The cervical vertebral column and spinal cord are included. Model results have been more qualitative than quantitative owing to the lack of adequate experimental validation. Advances include transient stress distribution in the brain tissue, frequency responses, effects of boundary conditions, pressure release mechanism of the foramen magnum and the spinal cord, verification of rotation and cavitation theories of brain injury, and protective effects of helmets. These theoretical results provide a basic understanding of the internal biomechanical responses of the head under various dynamic loading conditions. Basic experimental research is still needed to be determine more accurate material properties and injury tolerance criteria, so that FE models can fully exercise their analytical and predictive power for the study and prevention of human head injury.

Biomechanical Phenomena↗

PubMed2006

Monomorphism of human cytochrome c.

Cytochrome c (Cyt c) has key roles in both mitochondrial electron transfer and apoptosis onset and is therefore likely undergoing a strong selective pressure against amino acid variation. Nevertheless, a phylogenetically fast amino acid replacement rate in the Cyt c of species of the anthropoid primate lineage was recently reported. We therefore looked for the presence of nonsynonymous single nucleotide polymorphisms (nsSNPs) in the human Cyt c (HGNC approved gene symbol: CYCS), which, given its cellular constraints, could have important functional consequences, and found a large number of putative nsSNPs reported in the dbSNP database. We then subjected these putative SNPs to experimental validation by sequencing the Cyt c gene in a panel of 95 individuals assumed as a standard reference of the human population diversity. Surprisingly, none of the putative SNPs survived experimental validation. We conclude that non-rare allelic variants of the Cyt c protein are absent in the human populations analyzed in this study.

Alleles↗

PubMed2000

The effects of dynamic optical properties during interstitial laser photocoagulation.

A nonlinear mathematical model was developed and experimentally validated to investigate the effects of changes in optical properties during interstitial laser photocoagulation (ILP). The effects of dynamic optical properties were calculated using the Arrhenius damage model, resulting in a nonlinear optothermal response. This response was experimentally validated by measuring the temperature rise in albumen and polyacrylamide phantoms. A theoretical study of ILP in liver was conducted constraining the peak temperatures below the vaporization threshold. The temperature predictions varied considerably between the static and dynamic scenarios, and were confirmed experimentally in phantoms. This suggests that the Arrhenius model can be used to predict dynamic changes in optical and thermal fields. An increase in temperature rise due to a decrease in light penetration within the coagulated region during ILP of the liver was also demonstrated. The kinetics of ILP are complex and nonlinear due to coagulation, which changes the tissue properties during treatment. These complex effects can be adequately modelled using an Arrhenius damage formulation.

Acrylic Resins↗

PubMed2025

In silico prediction method for plant Nucleotide-binding leucine-rich repeat- and pathogen effector interactions.

Plant Nucleotide-binding leucine-rich repeat (NLR) proteins play a crucial role in effector recognition and activation of Effector triggered immunity following pathogen infection. Genome sequencing advancements have led to the identification of a myriad of NLRs in numerous agriculturally important plant species. However, deciphering which NLRs recognize specific pathogen effectors remains challenging. Predicting NLR-effector interactions in silico will provide a more targeted approach for experimental validation, critical for elucidating function, and advancing our understanding of NLR-triggered immunity. In this study, NLR-effector protein complex structures were predicted using AlphaFold2-Multimer for all experimentally validated NLR-effector interactions reported in literature. Binding affinities- and energies were predicted using 97 machine learning models from Area-Affinity. We show that AlphaFold2-Multimer predicted structures have acceptable accuracy and can be used to investigate NLR-effector interactions in silico. Binding affinities for 58 NLR-effector complexes ranged between -8.5 and -10.6 log(K), and binding energies between -11.8 and -14.4 kcal/mol-1, depending on the Area-Affinity model used. For 2427 "forced" NLR-effector complexes, these estimates showed larger variability, enabling identification of novel NLR-effector interactions with 99% accuracy using an Ensemble machine learning model. The narrow range of binding energies- and affinities for "true" interactions suggest a specific change in Gibbs free energy, and thus conformational change, is required for NLR activation. This is the first study to provide a method for predicting NLR-effector interactions, applicable to all pathosystems. Finally, the NLR-Effector Interaction Classification (NEIC) resource can streamline research efforts by identifying NLRs important for plant-pathogen resistance, advancing our understanding of plant immunity.

Plant Proteins↗

PubMed1983

The validity of experimental pain measures.

Forty subjects served in a study investigating the characteristics of experimental pain measures. Subjects indicated when their pain threshold and tolerance levels had been reached with each of three stressors: cold, pressure, and electrical shock. Using the multitrait-multimethod matrix procedure, the measures of threshold and tolerance were found to show both generality and discriminant validity across stressors. Threshold judgements, which emphasize discrimination of nociceptive quality, and tolerance decisions, which indicate an unwillingness to receive more intense stimuli, are not equivalent measures of responsiveness. Both should be obtained in studies involving experimental pain. Stressors, while related, are also not equivalent. Minimum method variance was associated with the discomfort produced by electrical pulse trains.

Adolescent↗

PubMed2005

Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies.

With a draft genome-sequence assembly for the chimpanzee available, it is now possible to perform genome-wide analyses to identify, at a submicroscopic level, structural rearrangements that have occurred between chimpanzees and humans. The goal of this study was to investigate chromosomal regions that are inverted between the chimpanzee and human genomes. Using the net alignments for the builds of the human and chimpanzee genome assemblies, we identified a total of 1,576 putative regions of inverted orientation, covering more than 154 mega-bases of DNA. The DNA segments are distributed throughout the genome and range from 23 base pairs to 62 mega-bases in length. For the 66 inversions more than 25 kilobases (kb) in length, 75% were flanked on one or both sides by (often unrelated) segmental duplications. Using PCR and fluorescence in situ hybridization we experimentally validated 23 of 27 (85%) semi-randomly chosen regions; the largest novel inversion confirmed was 4.3 mega-bases at human Chromosome 7p14. Gorilla was used as an out-group to assign ancestral status to the variants. All experimentally validated inversion regions were then assayed against a panel of human samples and three of the 23 (13%) regions were found to be polymorphic in the human genome. These polymorphic inversions include 730 kb (at 7p22), 13 kb (at 7q11), and 1 kb (at 16q24) fragments with a 5%, 30%, and 48% minor allele frequency, respectively. Our results suggest that inversions are an important source of variation in primate genome evolution. The finding of at least three novel inversion polymorphisms in humans indicates this type of structural variation may be a more common feature of our genome than previously realized.

Animals↗

PubMed2026

ZBTB16-associated NK cell alterations reveal shared immunometabolic signatures linking primary Sjögren's syndrome and type 1 diabetes mellitus.

BACKGROUND: Primary Sjögren's syndrome (pSS) and type 1 diabetes mellitus (T1DM) share immune-inflammatory features, yet conserved pathogenic signatures linking these autoimmune disorders remain incompletely understood. The present research sought to uncover common molecular markers and dissect the underlying immune-metabolic cross-talk underlying pSS and T1DM. METHODS: Gene expression profiles of patients with pSS and T1DM were retrieved from the Gene Expression Omnibus database, normalized, and corrected for batch effects prior to downstream analyses. Overlapping potential biomarkers were screened by integrating differential expression analysis, weighted gene co-expression network analysis and least absolute shrinkage and selection operator regression. Functional enrichment based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases was implemented to interpret gene biological properties, and a protein-protein interaction network was further established afterwards. Diagnostic performance was evaluated using receiver operating characteristic analysis. Experimental validation was conducted in non-obese diabetic (NOD) mice using quantitative PCR, immunohistochemistry, and flow cytometry. The CIBERSORT algorithm was adopted to quantify immune cell infiltration levels. RESULTS: ZBTB16 was identified as a shared hub biomarker in both pSS and T1DM and exhibited favorable diagnostic performance. Experimental validation confirmed significantly reduced ZBTB16 expression in peripheral blood mononuclear cells, salivary gland tissues, and pancreatic tissues of NOD mice. Gene Set Enrichment Analysis indicated that ZBTB16-associated signatures were enriched in mitochondrial-related processes, neuroactive ligand-receptor interactions, and ribosome-related pathways. Immune infiltration analysis revealed that resting natural killer (NK) cells were positively correlated with ZBTB16 expression in both diseases. Flow cytometric analysis further confirmed a reduced proportion of resting NK cells in peripheral blood of NOD mice, consistent with the CIBERSORT-based prediction. CONCLUSION: This study identifies ZBTB16 as a shared biomarker linking pSS and T1DM. Reduced resting NK-cell abundance was consistently observed in both computational and experimental analyses, and bioinformatic correlation analysis suggested a positive association with ZBTB16 expression. These findings provide evidence for shared molecular and immunological signatures underlying the two autoimmune disorders and support further investigation of the biological role and diagnostic value of ZBTB16 in pSS and T1DM.

Sjogren's Syndrome↗