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PubMed2026

Genomic and epigenetic regulatory mechanisms in exercise-based rehabilitation processes: Cellular and tissue remodeling, microvascular adaptation, and circulating biomarkers.

While exercise-based rehabilitation is known to positively impact functionally related parameters, the role of genomic and epigenomic responses coordinated with cellular, extracellular matrix (ECM), mitochondrial, and microvascular adaptations remains insufficiently investigated. This narrative review summarizes mechanistic evidence linking exercise-associated mechanical, metabolic, hypoxia-redox, inflammatory, and hemodynamic stimuli with tissue remodeling and clinically relevant biomarkers. Current findings indicate that integrin-focal adhesion kinase (FAK) signaling and Hippo YAP/TAZ pathways contribute to mechanical signal transduction, cytoskeletal regulation, and gene expression, whereas metabolic adaptation, ATP homeostasis, and protein synthesis are regulated through AMPK-PGC-1α, SIRT1, and mTOR-dependent pathways. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulation, further influence cell-specific responses in myofibers, satellite cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and immune cells. In addition, VEGF-VEGFR2, eNOS-NO, and KLF2/KLF4 signaling, together with extracellular matrix turnover and inflammation resolution, contribute to tissue repair and microvascular adaptation during rehabilitation. Importantly, acute exercise-induced molecular responses should not be interpreted as direct evidence of sustained tissue adaptation. Circulating microRNAs, extracellular vesicles, cell-free DNA, collagen-related markers, and vascular proteins represent promising approaches for monitoring rehabilitation-related changes; however, their clinical translation remains limited by challenges related to tissue specificity, biomarker kinetics, analytical variability, and the need for standardized validation alongside structural and functional outcomes.

AMPK–PGC-1α signaling↗

PubMed1997

A novel method for structure-based prediction of ion channel conductance properties.

A rapid and easy-to-use method of predicting the conductance of an ion channel from its three-dimensional structure is presented. The method combines the pore dimensions of the channel as measured in the HOLE program with an Ohmic model of conductance. An empirically based correction factor is then applied. The method yielded good results for six experimental channel structures (none of which were included in the training set) with predictions accurate to within an average factor of 1.62 to the true values. The predictive r2 was equal to 0.90, which is indicative of a good predictive ability. The procedure is used to validate model structures of alamethicin and phospholamban. Two genuine predictions for the conductance of channels with known structure but without reported conductances are given. A modification of the procedure that calculates the expected results for the effect of the addition of nonelectrolyte polymers on conductance is set out. Results for a cholera toxin B-subunit crystal structure agree well with the measured values. The difficulty in interpreting such studies is discussed, with the conclusion that measurements on channels of known structure are required.

Adenosine Triphosphatases↗

PubMed1991

Reassessing the validity and reliability of the MMPI Alexithymia Scale.

In the past decade, alexithymia has emerged as a heuristically useful personality construct used to explain the pathogenesis of a variety of physical illnesses, including classical psychosomatic diseases, somatization disorders, hypochondriasis, and somatoform pain disorders. Unfortunately, research evaluating the alexithymia construct has been conducted with little attention to assessing the psychometric properties of various scales used to measure it. In two separate studies, we examined various scale and item properties as well as the factor structure and validity of the Minnesota Multiphasic Personality Inventory Alexithymia Scale (MMPI-A), one of the most commonly used scales to assess alexithymia. In Study 1, the 22 items that comprise the MMPI-A were extracted from a computerized MMPI data bank which included separate samples of psychiatric inpatients and outpatients. Poor item-to-scale characteristics and only moderate levels of internal reliability were found for both samples. Factor analysis produced factors that were poorly related to the theoretical domains of the alexithymia construct. In Study 2, we found little support for validity of the scale as those patients identified as alexithymic and nonalexithymic by the MMPI-A did not differ on several theoretically relevant scales. These results question seriously the value of the MMPI-A in investigating the alexithymia construct.

Adult↗

PubMed2024

Molecular basis for antibody recognition of multiple drug-peptide/MHC complexes.

The HapImmuneTM platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib-peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the VH and VL domains, binds HLAs in an unconventional, angled way, with VL making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten-peptide conjugates and to adjust its conformation to different HLAs presenting hapten-peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten-peptide antigens, which will inform the development of next-generation therapeutic antibodies.

Humans↗

PubMed1994

Stabilization of beta-ribbon structures in peptides using disulfide bonds.

The effect of a disulfide crosslink between two peptide chains on the stability of beta-ribbon secondary structures formed by these peptides has been investigated. Based on structural principles, we hypothesized that introduction of an unstrained disulfide crosslink at appropriate locations on two peptide chains should have a stabilizing effect on the beta-ribbon structure formed by these two peptide chains. To test this hypothesis, we designed and synthesized two sets of 9-residue peptides incorporating cysteine in one and (S)-alpha-amino-epsilon-mercaptohexanoic acid in the other. Comparison of the CD data clearly show that the dimer containing a disulfide bond between the longer sidechains of (S)-alpha-amino-epsilon-mercaptohexanoic acid shows dramatically higher beta-ribbon character as compared to the dimer with cystine disulfide bond, thus validating our structural hypothesis.

Amino Acid Sequence↗

PubMed1991

Structure-activity relationships of chemical mutagens and carcinogens.

In recent years, octanol-water partition coefficients (P) have been used in toxicology studies to correlate chemical structure and biological activity. Generally, only limited attempts are made to show how a new correlation equation relates to those previously published, especially when different activities are involved. Evidence is presented to show that there is often a high degree of self-consistency between the dependence of activity on hydrophobicity (defined by log P) from different systems. Examples are drawn from nonspecific toxicity, mutagenicity and carcinogenicity. It is suggested that this kind of lateral correlation is an important means for validating structure-activity relationships.

Alcohols↗

PubMed1995

Accurate prediction of protein secondary structural class with fuzzy structural vectors.

The prerequisites for accurate prediction of protein secondary structural class (all-alpha, all-beta, alpha+beta, alpha/beta or multidomain) were studied, and a new similarity-based method is presented for the prediction of the secondary structural class of a protein from its sequence. The new method uses representatives of nuclear families as a learning set. For the sequence to be predicted, the method produces a vector of certainty factors called a fuzzy structural vector. Validation with independent test sets shows that the prediction accuracy of the proposed method has clear dependency on the representativity of the learning set. The representatives obtained from the nuclear families of the Brookhaven Protein Data Bank (PDB) were shown to give accurate predictions for PDB proteins, whilst the amino acid composition-based methods used previously achieve their maximum predictability with relatively limited learning sets, and they remain inaccurate even with highly representative learning sets. The usability of the new method is increased further by the fuzzy structural vectors, which substantially reduce the risk of misclassification and realistically describe vague secondary structural tendencies.

Algorithms↗

PubMed2026

Sperm subpopulations differing in mitochondrial abundance show divergent nuclear allele frequencies.

Mammalian ejaculates contain heterogeneous sperm subpopulations that differ in subcellular architecture and developmental history, despite appearing morphologically uniform. The extent to which this cellular heterogeneity reflects underlying nuclear genomic structure within a sire remains largely unexplored. Mitochondrial architecture in sperm is established during spermatogenesis, with final assembly and organization occurring during spermiogenesis under nuclear genomic control, positioning variation in mitochondrial abundance and organization as a potential phenomic indicator of within-sire allelic segregation. Here, we tested whether sperm subpopulations defined by differing mitochondrial abundance exhibit systematic differences in nuclear allele representation. Boar sperm were resolved into low and high mitochondrial subpopulations using fluorescence-activated cell sorting based on MitoTracker™ Green fluorescence while excluding debris, doublets, and non-viable cells. Epifluorescence microscopy confirmed that high MitoTracker™ Green fluorescence sperm possessed longer mitochondrial sheaths, validating a structural distinction between subpopulations. Whole-genome sequencing of paired mitochondrial subpopulations from three boars was performed, and allelic ratio distortion was evaluated relative to heterozygous baseline populations. Analyses across heterozygous loci genome-wide identified candidate allele frequency shifts between mitochondrial-defined subpopulations, suggesting non-random segregation of alleles within ejaculates. Using a minimum sequencing depth of 30 reads in both sorted fractions, 182 candidate SNPs were identified with evidence of allele-frequency differences between mitochondrial fluorescence-defined subpopulations. These findings suggest that sperm mitochondrial abundance can potentially serve as an indirect, high-throughput marker of nuclear genomic heterogeneity within sires. This proof-of-concept framework establishes a foundation for future studies integrating sperm phenotyping, genome-wide allele-frequency analysis and functional validation to better characterize gamete-level heterogeneity.

Male↗

PubMed1998

Predictive validity of cocaine, sedative, and alcohol dependence diagnoses.

This study examined the predictive validity of Structured Clinical Interview for DSM-III-R (Spitzer, Williams, Gibbon, & First, 1990) based substance dependence diagnoses (i.e., cocaine, sedative, and alcohol) for 518 opioid-dependent outpatients entering methadone maintenance. Patients were followed over 1 year of treatment, which involved daily methadone substitution supplemented by individual and group counseling. Urine specimens were tested randomly 1-4 times per month. Patients diagnosed with current cocaine, sedative, or alcohol dependence were more likely to use these drugs than were patients with past only or no dependence syndrome. Current cocaine dependence predicted early treatment dropout. The results demonstrate the predictive and discriminant validity of several substance dependence diagnoses common among patients in substance abuse or other psychiatric treatment settings.

Adult↗

PubMed1997

The AIMS2-SF: a short form of the Arthritis Impact Measurement Scales 2. French Quality of Life in Rheumatology Group.

OBJECTIVE: To develop a short form of the Arthritis Impact Measurement Scales 2 (AIMS2) questionnaire, preserving content validity as the priority criterion. METHODS: A 2-step reduction procedure was used: 1) Delphi technique, with 1 panel of patients and 1 panel of experts each selecting 1 set of items independently; and 2) nominal group technique, where members of both panels reached consensus on the final selection of items, using information derived from item analysis. Psychometric properties of the AIMS2-Short Form (AIMS2-SF) and AIMS2 were compared using data from a cohort of 127 rheumatoid arthritis patients who completed the AIMS2 twice prior to the initiation of methotrexate (MTX) treatment and 3 months post-initiation of MTX treatment. RESULTS: The 2 panels reached consensus on a 26-item AIMS2-SF (54.4% reduction from the AIMS2). Factor analysis showed preservation of the 5-component structure. Convergent validity (Physical and Symptom components with clinical variables: r = 0.24-0.59), test-retest reproducibility (intraclass correlation coefficient >0.7), and sensitivity to change at 3 months (standardized response mean 0.36-0.8, except Social Interaction component [0.08]) were very close to the values for the original AIMS2. CONCLUSION: The AIMS2-SF is a shorter version of the AIMS2 (i.e., available in 2-page format) and has psychometric properties similar to those of the AIMS2.

Activities of Daily Living↗

PubMed1998

Iditis: protein structure database.

The validation, enrichment and organization of the data stored in PDB files is essential for those data to be used accurately and efficiently for modelling, experimental design and the determination of molecular interactions. The Iditis protein structure database has been designed to allow the widest possible range of queries to be performed across all available protein structures. The Iditis database is the most comprehensive protein structure resource currently available, and contains over 500 fields of information describing all publicly deposited protein structures. A custom-written database engine and graphical user interface provide a natural and simple environment for the construction of searches for complex sequence- and structure-based motifs. Extensions and specialized interfaces allow the data generated by the database to used in conjunction with a wide range of applications.

Database Management Systems↗

PubMed1985

Epidemiology: reflections on testing the validity of psychiatric interviews.

Laboratory tests that validate psychiatric disorder are unavailable. Accordingly, the validity of structured diagnostic interviews such as the Diagnostic Interview Schedule have been assessed through a double-blind test-retest design. This approach compares the Diagnostic Interview Schedule to a clinician's assessment and evaluates its results by three statistics: sensitivity and specificity, for which the clinician's interview serves as the standard, and K, which measures concordance between the two interviews. This design is found wanting on several counts: the reinterview may be answered differently because of clinical change or because of its meaning to the respondent; the clinician's interview may be an erratic standard; and the statistics are affected by both prevalence and severity of disorder. Furthermore, the statistics may not predict the accuracy of prevalence estimates made by the interview or its ability to detect correlates of disorder. Some alternative approaches are suggested.

Clinical Trials as Topic↗

PubMed1978

Wechsler Memory Scale: a selective review of the literature.

Research on the Wechsler Memory Scale (WMS) is reviewed with respect to questions of its reliability, factor structure, construct validity, and utility. The relationship of Memory Quotient to Full Scale IQ is explored and the conditions under which disparity between the two scores may be clinically useful indicated. Despite its numerous limitations, the WMS has been a sensitive test of short-term verbal memory. As such, it may be helpful in identifying impairment of the dominant (left) temporal lobe and its medial hippocampal connections. The test is badly in need of re-standardization, however, and suggestions for improving the instrument are made.

Adult↗

PubMed1996

The effect of concentration on the structure of alpha-crystallin.

Several models have been proposed for arrangement of the subunits in alpha-crystallin. These include the contrasting proposals that subunits are arranged in three layers and that subunits assemble into micelle-like structures. The validity of the micelle model was investigated by examining the effects of variations in protein concentration on the surface tension, conductivity, molecular weight and conformation of alpha-crystallin. The data were compared with those obtained for bovine serum albumin (BSA) and sodium dodecyl sulphate (SDS). Measurements of surface tension were conducted in the range, 10 micrograms ml-1 to 130 mg ml-1, in low and high ionic strength buffers. An apparent point of inflection, independent of ionic strength, was seen in alpha-crystallin's surface tension at around 1.9 mg ml-1 (95 microM). The surface tension did not plateau beyond this point, as is the case with surfactants, but continued to decrease up to 130 mg ml-1. BSA exhibited similar surface tension properties with an apparent inflection at 0.9 mg ml-1 (13 microM). The conductivity of alpha-crystallin and BSA solutions increased smoothly with no sign of any transition up to 96 mg ml-1 and 60 mg ml-1, respectively. In contrast, SDS showed a clear transition in this property at the concentration corresponding to its CMC. The aggregation state of the alpha-crystallin aggregates was examined by comparing molecular masses and Stokes radii. The size of the protein remained uniform over a wide concentration range and was unaffected by variations in ionic strength. Protein conformation, which was monitored by examining the microenvironment of tryptophan residues, was also found to be independent of protein concentration. It is concluded that over the concentration range that was investigated, alpha-crystallin does not exhibit any of the properties associated with classical micelles formed from small amphiphilic molecules.

Animals↗

PubMed1999

Influence of internal dynamics on accuracy of protein NMR structures: derivation of realistic model distance data from a long molecular dynamics trajectory.

In order to study the effect of internal dynamics on the accuracy of NMR structures in detail, we generated NOE distance data from a long molecular dynamics trajectory of BPTI. Cross-relaxation rates were calculated from the trajectory by analysis of the appropriate proton-proton vector autocorrelation functions. A criterion for the convergence of correlation functions was developed, and the analysis was restricted to those correlation functions that had converged within the simulation time. Effective distances were determined from the calculated cross-relaxation rates. Internal dynamics affected the derived distances in a realistic way, since they were subject both to radial averaging (which increases the cross-relaxation rate) and angular averaging (which decreases the cross-relaxation rate). The comparison of the effective distances with average distance between the protons during the trajectory showed that for most the effects of angular and distance averaging essentially cancel out. For these distances, the effective distance derived from an NOE is therefore a very good estimate of the average distance, or the distance in the average structure. However, for about 10% of the distances, the effective distance was more than 10% larger than the average distance, while for about 5%, it was more than 10% smaller, in some cases by more than 2 A. Little correlation is observed between the effects on cross-relaxation rates to different protons of the same residue. The results of this analysis have implications for the way structures are calculated from NOE distance data. For many distances, the assumption of a rigid structure is valid, and large error bounds would result in the loss of too much information content. On the other hand, the error bounds very often employed are not wide enough for some of the effects seen in our study.

Animals↗

PubMed1995

A local lymph-node assay validation study of a structure-activity relationship model for contact allergens.

A structure-activity relationship model for prediction of contact allergenic potential of chemicals had previously been developed. The model had been shown to be able to classify known allergens and nonallergens using data on physicochemical and reactivity parameters of functional groups by discriminant two-value multiple regression analysis. To investigate the model, six selected chemicals which had not been previously investigated for allergenicity were studied with both the model and a murine local lymph-node assay. The same compounds were predicted to be allergens (3-bromo-2-coumaranone, 1-nitrocyclohexene and alpha-acryloyloxy-beta, beta-dimethyl-beta-butyrolactone) and nonallergens (1-carbethoxy-4-piperidone, 6,7-dimethoxy-2-tetralone and 9-acetylanthracene) by both the model and the local lymph-node assay.

Allergens↗

PubMed1989

Effect of neuroleptics on positive and negative symptoms and the deficit state.

The concept of negative symptoms tries to operationalize a deficit syndrome observed in schizophrenia, but also in other disorders. The instruments for the measurement developed so far are unclear in their dimensional structure and validity. Further methodological development is needed. A new scale for measuring negative symptoms was derived from the AMDP-system and applied to results of drug trials with clozapine, fluperlapine, and haloperidol. The three drugs were equally effective on negative symptoms of acute and chronic schizophrenics.

Antipsychotic Agents↗

PubMed1999

[Quality of life. Construct validation and the development of a modular system].

The construct Quality of Life (QoL) is investigated by metaanalysis of eight (inter)nationally validated questionnaires in a multicenter study. Data have been collected in a mentally healthy (n = 479), a depressed (n = 171) and a schizophrenic (n = 139) sample. Conventional psychometric criteria and a facet analytical methodology have been applied. The resulting questionnaire "Modular System for Quality of Life" (MSQoL) consists of a core module with 47 items (one "G-factor" and six subdimensions), which is sufficiently valid for all three samples. Additionally, there are four specific modules (demography, family, partnership, profession). No specific modules can be identified for the psychopathological subgroups. The validated radex structure for subjective QoL offers the opportunity for a cumulative research design and for adaptations to the actual setting.

Adolescent↗