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PubMed1985

Primary and secondary structure of 26S ribosomal RNA of Oenothera mitochondria.

The primary structure of 26S ribosomal RNA from mitochondria of the dicotyledoneous plant Oenothera berteriana is inferred from the sequence of a cloned rDNA restriction fragment. A tentative secondary structure model valid for Oenothera and for the major part of maize mitochondrial 26S rRNA has been constructed in analogy to the refined german model for E. coli L-rRNA (Maly and Brimacombe 1983). The derived structure generally matches the eubacterial model providing further support to the E. coli consensus structure. Some structural features however show eukaryotic characteristics. Possible interactions between L-rRNA, 5S rRNA and initiator-tRNA are discussed.

Base Sequence↗
PubMed2000

Clinical utility, factor analysis, and further validation of the memorial delirium assessment scale in patients with advanced cancer: Assessing delirium in advanced cancer.

BACKGROUND: Delirium is a common neuropsychiatric complication in patients with advanced cancer. The Memorial Delirium Assessment Scale (MDAS) is a recently developed 10-item severity rating instrument. The purpose of the current prospective study was to further assess the clinical utility, factor structure, and validity of the MDAS in a relatively homogeneous population of patients with advanced cancer. METHODS: Study entry of 104 patients occurred on their consecutive admission to a tertiary-level, acute palliative care unit in a university-affiliated teaching hospital. Patients underwent regular cognitive screening using the Mini-Mental State Examination, and serial monitoring of delirium using standardized semistructured interviews and MDAS ratings, up to the study endpoints of either patient discharge or death. RESULTS: Seventy-one patients met Diagnostic and Statistical Manual (of Mental Disorders)-IV criteria for a first episode of delirium. In 15 of 71 (21%) patients with a first episode of delirium, the first MDAS ratings were prorated because of dyspnea, fatigue, or profound delirium. In the remaining 56 patients (79%), the first MDAS ratings were rated fully and therefore evaluable. Correlations among the scale items ranged from moderate to low (correlation coefficient [r] = 0.68-0.02). Analysis of the pattern of factor loadings identified two primary correlated factors: global cognitive (Factor I) and neurobehavioral (Factor II) (r = 0.33). Cronbach alpha coefficients for Factors I and II were 0.8 and 0.66, respectively, indicating a relatively high level of correlation for items within each. The Cronbach alpha coefficient for all 10 items was 0.78, suggesting a general underlying factor. In a larger sample of complete MDAS ratings (n = 330) a cutoff total MDAS score of 7 of 30 yielded the highest sensitivity (98%) and specificity (96%) for delirium diagnosis. The MDAS was correlated moderately with the Mini-Mental State Examination (r = 0.55). CONCLUSIONS: The authors concluded that the MDAS structure is representative of the many features of delirium, broadly grouped as global cognitive and neurobehavioral dimensions. Prorating item scores is necessary in approximately 20% of advanced cancer patients with delirium. This poses potential limitations on the applicability of the MDAS in research. Conversely, the ability to prorate item scores confers a clinical advantage to the instrument when assessing delirium in a patient population with advanced cancer.

Aged↗
PubMed1995

A brief method for assessing social development: structure, reliability, stability, and developmental validity of the Interpersonal Competence Scale.

The Interpersonal Competence Scale (ICS-T) is a set of brief rating scales for teachers and parents. It consists of 18 items that assess social and behavioural characteristics of children and youths. The ICS-T yields three primary factors: AGG (argues, trouble at school, fights), POP (popular with boys, popular with girls, lots of friends), and ACA (spelling, math). Subsidiary factors include AFF (smile, friendly), OLY (appearance, sports, wins), and INT (shyness, sad, worry). The psychometric properties of the scale (internal structure, reliability, long-term stability) are presented and evaluated over successive ages. The scale factors have been linked to contemporaneous observations of behavior and social network membership. Developmental validity of the ICS-T includes the significant prediction of later school dropout and teenage parenthood. The ICS-T scale is described, along with instructions for use and scoring.

Adolescent↗
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↗
PubMed2000

Selecting protein targets for structural genomics of Pyrobaculum aerophilum: validating automated fold assignment methods by using binary hypothesis testing.

Three-dimensional protein folds were assigned to all ORFs of the recently sequenced genome of the hyperthermophilic archaeon Pyrobaculum aerophilum. Binary hypothesis testing was used to estimate a confidence level for each assignment. A separate test was conducted to assign a probability for whether each sequence has a novel fold-i.e., one that is not yet represented in the experimental database of known structures. Of the 2,130 predicted nontransmembrane proteins in this organism, 916 matched a fold at a cumulative 90% confidence level, and 245 could be assigned at a 99% confidence level. Likewise, 286 proteins were predicted to have a previously unobserved fold with a 90% confidence level, and 14 at a 99% confidence level. These statistically based tools are combined with homology searches against the Online Mendelian Inheritance in Man (OMIM) human genetics database and other protein databases for the selection of attractive targets for crystallographic or NMR structure determination. Results of these studies have been collated and placed at http://www.doe-mbi.ucla.edu/people/parag/P A_HOME/, the University of California, Los Angeles-Department of Energy Pyrobaculum aerophilum web site.

Algorithms↗
PubMed2000

[Obtaining samples of the human diaphragm during upper laparotomy. A structural analysis].

UNLABELLED: The diaphragm seems to undergo adaptive structural change in chronic obstructive pulmonary disease. The possibility of obtaining muscle specimens is limited, however, particularly when respiratory function is severely affected. OBJECTIVE: To assess the viability of a new technique for obtaining diaphragm muscle samples appropriate for structural assessment even from patients with severe functional change, and to study the size of fibers in relation to severity of disease. METHODS: Fifteen muscle specimens were obtained from patients (aged 57 +/- 15 years) by abdominal laparotomy. All had undergone full lung function testing. Muscle samples were taken during surgery using a new technique involving formation of a tobacco pouch with dome biopsy. The method had been previously validated in animal models. Later, the biopsies were processed to evaluate fiber proportions and sizes (ATPase dyes at different levels of pH). RESULTS: The 15 patients had a wide range of lung function results (FEV1 22-120% ref); 4 were severely affected (FEV1 < or = 50% ref). Nutritional status was normal in all cases; FEV1/FVC was 67 +/- 13%, RV was 134 +/- 55% ref, maximal mouth pressure (PImmax) was -75 +/- 27 cmH2O, transdiaphragmatic pressure (PIdimax) was 96 +/- 26 cmH2O, DLCO was 87 +/- 26% ref and PaO2 was 89 +/- 14 mmHg. We were able to obtain specimens valid for structural analysis from all patients with no complications. Light type I fibers predominated (54 +/- 9%) and size was normal overall (57 +/- 9 microns minimum diameter [Dm] atrophy index 195 +/- 243, and hypertrophy index 66 +/- 78), with no differences between the two fiber subtypes (Dm 58 +/- 8 microns for type I and 61 +/- 8 microns for type II). Overall size correlated inversely with static volumes (e.g. Dm with RV, r = -0.729, p < 0.01). CONCLUSIONS: The laparoscopic technique described is simple and safe for use in humans to obtain diaphragm muscle specimens that are valid for morphometric analysis, allowing us to enlarge the range of subjects that can be enrolled for this type of study. The fiber muscles studied are smaller when functional involvement is greater in chronic obstructive pulmonary disease.

Adult↗
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↗
PubMed1999

Mother and teacher reports of ADHD symptoms: DSM-IV Questionnaire data.

OBJECTIVE: Diagnosis of attention-deficit/hyperactivity disorder (ADHD) is thought to be best accomplished by a multimodal approach. In many research and clinical settings, such extensive procedures may not be feasible. A screening instrument that could identify children meeting necessary (but not sufficient) criteria would permit selection of subgroups for more resource-intensive diagnostic procedures. METHOD: The Diagnostic Rating Scale (DRS) was completed by the mothers and teachers of 124 children referred to hospital-based clinics and 225 nonreferred children. The authors performed principal components analysis (PCA) on the questionnaire, compared the scores obtained by children from the 2 samples, and examined age and gender effects. Diagnoses derived from the DRS were not validated against structured diagnostic interviews. RESULTS: PCAs replicated the DSM-IV symptom combinations. Children from the referred sample exhibited more symptoms (p < .001) than children from the community sample. Boys were overrepresented among the children who received DRS-derived ADHD diagnoses. Girls were more likely (92%) to receive a diagnosis of ADHD, predominantly inattentive subtype, than other ADHD diagnoses. CONCLUSIONS: The results of this study provide preliminary support for the validity of the parent and teacher DRS as time- and resource-efficient screening instruments for examining symptoms associated with ADHD.

Attention Deficit Disorder with Hyperactivity↗
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&#x2122; Green fluorescence while excluding debris, doublets, and non-viable cells. Epifluorescence microscopy confirmed that high MitoTracker&#x2122; 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↗
PubMed1999

Strategies toward predicting peptide cellular permeability from computed molecular descriptors.

The therapeutic efficacy of an orally administered drug is dictated not only by its pharmacological properties such as potency and selectivity, but also its pharmacokinetic properties such as its access to the site of activity. Thorough evaluation of the physicochemical and biological barriers to drug delivery is essential to the selection and successful development of drug candidates. We have demonstrated previously that cellular permeability, as a primary component of drug delivery, is principally dependent upon the desolvation potential of the polar functionalities in the molecule and, secondarily, upon the solute lipophilicity [Conradi, R.A., Hilgers, A.R., Ho, N.F.H., Burton, P.S. (1992). The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm. Res. 9, 473-479]. Increasingly sophisticated computational methods are becoming available for describing molecular structural features proposed to correlate with such molecular physicochemical determinants of permeability. Herein we examine the relationships of various computationally derived molecular geometric descriptors for a set of peptides and peptidomimetics, in the context of experimentally measured hydrogen-bond potentials and lipophilicities, with their cellular permeabilities. These descriptors include molecular volume, polar and non-polar surface areas and projected molecular cross-sectional areas. Particular attention is paid to the roles of solvation treatments and other computational factors in descriptor generation, deconvolution of cellular transport mechanisms and statistical analyses of the resulting data for the development of valid, structure-based and mechanistically meaningful models of cellular permeability. No significant correlation of cellular permeability with computed descriptors was found. This was primarily because of our inability to identify surrogates for hydrogen-bond desolvation potential for the solutes from among these descriptors.

Adenocarcinoma↗
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↗