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Results for “Association and function analysis”

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PubMed2006

Predicting domain-specific insight of schizophrenia patients from symptomatology, multiple neurocognitive functions, and personality related traits.

This study examines the contribution of various neurocognitive functions, clinical characteristics, and personality traits to the prediction of three insight dimensions. Clinically stable schizophrenia patients (n=107) residing in the community were evaluated using the Positive and Negative Syndrome Scale, the Scale for the Assessment of Unawareness of Mental Disorder, and a comprehensive battery of instruments to measure personality related variables and neurocognitive functioning. Step-wise multivariate regression analysis indicates significant association of variability in insight dimensions with neurocognitive functioning (20-41%), personality related traits (8-18% temperament factors, 4-7% self-constructs, 10-14% coping styles), severity of symptoms (about 7%), illness duration (6%), and education (about 5%). Poor insight was attributed to impairment in visual and movement skills, sustained attention, executive functions, intensity of autistic preoccupations and positive symptoms, as well as increased novelty seeking behavior, task and emotion oriented coping styles, better self-esteem, self-efficacy, and higher education. Better awareness was related to better performance of neurocognitive tasks, reward dependence behavior, avoidant coping style, and longer illness duration. Aside from common indicators for the various insight dimensions, we defined specific indicators for each insight dimension. Thus, insight dimensions in schizophrenia patients residing in the community were attributed to neurocognitive and personality related factors rather than to psychopathological symptoms. The findings enable better understanding of the multifactorial nature of insight and highlight targets for more effective intervention and rehabilitation.

Adaptation, Psychological↗

PubMed2006

Transcriptomic analysis of an in vitro murine model of ovarian carcinoma: functional similarity to the human disease and identification of prospective tumoral markers and targets.

Ovarian cancer is an aggressive disease of poor prognostic when detected at advanced stage. It is widely accepted that the ovarian surface epithelium plays a central role in disease etiology, but little is known about disease progression at the molecular level. To identify genes involved in ovarian tumorigenesis, we carried out a genome-wide transcriptomic analysis of six spontaneously transformed mouse ovarian surface epithelial (MOSE) cell lines, an in vitro model for human ovarian carcinoma. Loess normalization followed by statistical analysis with control of multiple testing resulted in 509 differentially expressed genes using an adjusted P-value < or = 0.05 as cut-off. The top 20 differentially expressed genes included 10 genes (Spp1, Cyp1b1, Btg1, Cfh, Mt1, Mt2, Igfbp5, Gstm1, Gstm2, and Esr1) implicated in various aspects of ovarian carcinomas, and other 3 genes (Gsto1, Lcn7, and Alcam) associated to breast cancer. Upon functional analysis, the majority of alterations affected genes involved in glutathione metabolism and MAPK signaling pathways. Interestingly, over 20% of the aberrantly expressed genes were related to extracellular components, suggestive of potential markers of disease progression. In addition, we identified the genes Pura, Cnn3, Arpc1b, Map4k4, Tgfb1i4, and Crsp2 correlated to in vivo tumorigenic parameters previously reported for these cells. Taken together, our findings support the utility of MOSE cells in studying ovarian cancer biology and as a source of novel diagnostic and therapeutic targets.

Animals↗

PubMed2002

Assessment and treatment of vocal tics associated with Tourette's syndrome.

A functional analysis suggested that a young man's vocal tics were maintained by automatic reinforcement. A preference assessment was conducted to identify stimuli that effectively competed with the occurrence of vocal tics. When used as components of a reinforcement-based intervention, however, these stimuli were ineffective at reducing the occurrence of vocal tics. Observations conducted in a naturalistic context led to the hypothesis that variations in tics were associated with body positioning. Thus, an additional analysis was conducted to determine if vocal tics occurred less when the participant was lying down versus when he was seated upright. Results suggested that a combination of procedures might be useful in developing idiosyncratic interventions for automatically reinforced problem behavior, such as vocal tics.

Adult↗

PubMed2000

Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis.

In this study we describe the identification and structure-function analysis of a novel death-associated protein (DAP) kinase-related protein, DRP-1. DRP-1 is a 42-kDa Ca(2+)/calmodulin (CaM)-regulated serine threonine kinase which shows high degree of homology to DAP kinase. The region of homology spans the catalytic domain and the CaM-regulatory region, whereas the remaining C-terminal part of the protein differs completely from DAP kinase and displays no homology to any known protein. The catalytic domain is also homologous to the recently identified ZIP kinase and to a lesser extent to the catalytic domains of DRAK1 and -2. Thus, DAP kinase DRP-1, ZIP kinase, and DRAK1/2 together form a novel subfamily of serine/threonine kinases. DRP-1 is localized to the cytoplasm, as shown by immunostaining and cellular fractionation assays. It binds to CaM, undergoes autophosphorylation, and phosphorylates an exogenous substrate, the myosin light chain, in a Ca(2+)/CaM-dependent manner. The truncated protein, deleted of the CaM-regulatory domain, was converted into a constitutively active kinase. Ectopically expressed DRP-1 induced apoptosis in various types of cells. Cell killing by DRP-1 was dependent on two features: the status of the catalytic activity, and the presence of the C-terminal 40 amino acids shown to be required for self-dimerization of the kinase. Interestingly, further deletion of the CaM-regulatory region could override the indispensable role of the C-terminal tail in apoptosis and generated a "superkiller" mutant. A dominant negative fragment of DAP kinase encompassing the death domain was found to block apoptosis induced by DRP-1. Conversely, a catalytically inactive mutant of DRP-1, which functioned in a dominant negative manner, was significantly less effective in blocking cell death induced by DAP kinase. Possible functional connections between DAP kinase and DRP-1 are discussed.

Amino Acid Sequence↗

PubMed2001

Depression and self-reported functional status in older primary care patients.

OBJECTIVE: The authors' goal was to examine whether depression is associated with overreporting of functional disability. METHOD: The subjects were 304 patients 60 years old or older who were recruited from primary care settings. Measures included examiner ratings of depression diagnosis and medical burden and self-reported and examiner-rated functional assessments. Multiple regression techniques were used to determine the independent association of depression with self-reported function after examiner-rated function was added to the analysis as a covariate. RESULTS: Depression diagnosis was associated with poorer self-reported role functioning, whether the patient attributed the disability to physical or emotional causes. Depression was not independently associated with poorer self-reported physical functioning. CONCLUSIONS: Clinicians and researchers should recognize that depression can confound the self-reporting and attribution of functional disability.

Activities of Daily Living↗

PubMed2025

FUSE-PhyloTree: linking functions and sequence conservation modules of a protein family through phylogenomic analysis.

SUMMARY: FUSE-PhyloTree is a phylogenomic analysis software for identifying local sequence conservation associated with the different functions of a multi-functional (e.g. paralogous or multi-domain) protein family. FUSE-PhyloTree introduces an original approach that combines advanced sequence analysis with phylogenetic methods. First, local sequence conservation modules within the family are identified using partial local multiple sequence alignment. Next, the evolution of the detected modules and known protein functions is inferred within the family's phylogenetic tree using three-level phylogenetic reconciliation and ancestral state reconstruction. As a result, FUSE-PhyloTree provides a gene tree annotated with both predicted sequence modules and ancestral gene functions, enabling the association of functions with specific sequence regions based on their co-emergence. AVAILABILITY AND IMPLEMENTATION: FUSE-PhyloTree is provided as Docker and Singularity images including all the required software tools. Images, source code, test data, and documentation are available at https://github.com/OcMalde/fuse-phylotree and https://zenodo.org/records/15855068.

Phylogeny↗

PubMed1995

Comparative analysis of ATPase of yeast elongation factor 3 and ATPase associated with Tetrahymena ribosomes.

Elongation factor 3 (EF-3) is a unique and essential requirement of the fungal translational apparatus. The biochemical function of EF-3 has recently been defined. The protein removes deacylated tRNA from the ribosomal exit site (E-site) thus facilitating occupation of the ribosomal A-site by aa-tRNA. A functional homolog of yeast EF-3 has not been identified in non-fungal species. Yeast EF-3 is a ribosome-dependent ATPase that can also accept GTP and ITP as substrates. The function of EF-3 in ribosomal reactions requires ATP hydrolysis. An ATPase activity associated with higher eukaryotic ribosomes has been claimed to be a direct functional homolog of yeast EF-3. Comparative analysis of biochemical, immunological and functional properties of ATPase activity associated with the ribosomes isolated from the ciliated protozoan Tetrahymena pyriformis with that of yeast EF-3 ATPase indicates that these two activities are significantly different. Results reported in this communication strongly suggest that the ribosome associated ATP hydrolytic activity of Tetrahymena pyriformis is not a functional homolog of yeast EF-3.

Adenosine Triphosphatases↗

PubMed2003

Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies.

OBJECTIVE: There is strong evidence for a genetic contribution to schizophrenia, but efforts to identify susceptibility genes have been largely unsuccessful because of the low power of individual studies. The authors' goal was to evaluate the collective evidence for an association between the Val158/108Met polymorphism of the catechol O-methyltransferase (COMT) gene and schizophrenia. METHOD: They performed separate meta-analyses of existing case-control and family-based association studies. RESULTS: Overall, case-control studies showed no indication of an association between either allele and schizophrenia, and family-based studies found modest evidence implicating the Val allele in schizophrenia risk. The pooled analyses of studies from diverse geographical regions may have obscured ethnic differences in patterns of genetic risk for schizophrenia. Stratification of the studies by ethnicity of the subjects yielded evidence for an association with the Val allele in case-control studies of European samples and, especially, in family-based studies of European samples. Case-control and family-based studies of Asian samples produced mixed results and, overall, little evidence for association. CONCLUSIONS: The results of the two types of association studies diverged somewhat, but the evidence from the family-based studies, although based on fewer reports, may be more accurate. The Val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry, but the influence of this polymorphism on risk in Asian populations remains unclear. These results call for more family-based studies to confirm the association between COMT and schizophrenia in European samples and to clarify its contribution to risk in Asian samples. They also suggest that case-control studies should use methods of genomic control to avoid being confounded by population stratification.

Adult↗

PubMed2003

Evaluation of an antibiotic-impregnated shunt system for the treatment of hydrocephalus.

OBJECT: Staphylococcus species are the most common organisms responsible for infection following implantable cerebrospinal fluid (CSF) diversionary procedures. The role of an antibiotic-impregnated shunt (AIS) system in the prevention of shunt infection has remained unclear because no human clinical trial has been reported on thus far. In this study, the authors assess an AIS system with respect to its prevention of shunt infection. METHODS: Patients were prospectively randomized into groups to evaluate the efficacy of an AIS system against an identical control shunt system. The data accrued were subjected to a detailed statistical analysis. Logistic regression analysis was performed to determine the independent association between outcome and predictor variables. Shunt function analysis was also performed to compare the average time to infection between the two groups. One hundred ten patients were recruited; 60 received control shunt systems and 50 received AIS systems. Thirteen shunt infections were recorded (10 in the control group and three in the AIS group). Nine (69%) of 13 infections occurred within 2 months after shunt implantation (eight of 10 in the control group and one of three in the AIS group). Apart from one patient in whom no organism was identified, a total of 14 organisms (12 patients) were cultured from either the CSF (nine) or the shunt apparatus (three). Staphylococcus species accounted for the majority of shunt infections (83%): all 10 control shunts were found to have a positive culture of staphylococci, whereas none of the AISs had any staphylococci (p = 0.038). CONCLUSIONS: The AIS afforded antistaphylococcal protection, especially during the early postoperative period when most shunt infections are known to occur and throughout the follow-up period (median 9 months). The AIS system represents another important tool to enable the neurosurgeon to prevent shunt infections.

Adolescent↗

PubMed2026

Determinants of functional burden pleiotropy and gene dosage responses across human traits.

Pleiotropic and monotonic effects of gene dosage are central to understanding comorbidities in developmental pediatric and psychiatric disorders, yet the underlying biological processes are not well characterized. Here we develop a functional burden analysis to investigate the association of all protein-coding copy-number variants, genome-wide, with 43 complex traits in approximately 500,000 UK Biobank participants. We test variant associations disrupting 172 tissue or cell-type gene sets, finding associations for all traits, which we replicate in the All of Us cohort. Functional burden pleiotropy, defined as the number of traits significantly associated with a gene set, correlates with genetic constraint and is higher for brain than non-brain functions, even after normalizing for genetic constraint. Levels of pleiotropy, measured by burden correlation, are similar in deletions and loss-of-function single-nucleotide variants, and higher than in common variants and duplications. Most gene dosage responses are non-monotonic, with deletions and duplications showing same-direction effects, and monotonic responses decrease with genetic constraint. We observe associations between functional gene sets and traits for either deletions or duplications, but rarely both, with negatively correlated effect sizes. Together, these results link genetic constraint and brain-specific mechanisms to the whole-body multimorbidity of neurodevelopmental and psychiatric conditions.

Humans↗

PubMed2026

Peripheral inflammation and executive function among community samples across the lifespan: A systematic review and meta-analysis.

Higher levels of peripheral inflammatory markers are proposed to disrupt cognitive processes; however, the extent to which this relationship applies to executive functions, specifically, has yet to be systematically evaluated. The current meta-analysis synthesizes all available literature measuring the association between peripheral inflammation and executive functions among community individuals across the lifespan. This systematic review searched Web of Science, PubMed, and PsycINFO for published and unpublished studies, in the English language, that assessed the association between markers of peripheral inflammation and self-report and behavioral measures of executive function. In addition to methodological and demographic information, correlation/beta coefficients were extracted from included studies to quantify the association between inflammation and executive functions. This review included 58 studies, 41 of which were included in the random-effects meta-analysis (N = 255,539). Among community individuals, higher levels of CRP and IL-6 were associated with poorer executive functioning. These results did not differ when models accounted for potential confounding variables. Meta-regressions revealed that the relationship between inflammatory biomarkers and executive function did not differ as a function of age, adiposity, or percentage of the sample who identified as female. Results of the present review indicate that higher levels of specific inflammatory markers are associated with lower performance on executive function measures; however, we observed significant heterogeneity in the study design and measurement of both inflammation and executive functioning, suggesting important considerations for future research.

Humans↗

PubMed1983

Depressive symptoms associated with dexamethasone resistance.

Using split sample discriminant function analysis on a series of 63 consecutive depressed outpatients, the authors identified several items on the Hamilton Depression Rating Scale that were associated with dexamethasone resistance (late and middle insomnia, retardation, somatic and psychic anxiety, and obsessive-compulsive symptoms), and several items that were associated with dexamethasone suppression (genital symptoms, somatic-general symptoms, hypochondriasis, early insomnia, and depersonalization). The accuracy of the classification function was 100% for the index split sample, 84% for the overall sample, and 72% for the other split sample. The implications of these findings are discussed.

Adult↗

PubMed1988

Clinical predictors of electrophysiologic findings in patients with syncope of unknown origin.

Unexplained syncope is a common medical problem. Intracardiac electrophysiologic studies (EPS) have been used to uncover the underlying arrhythmic mechanisms. Electrophysiologic studies are especially helpful in the management of patients with inducible tachyarrhythmias, but is of limited usefulness in those with normal EPS findings. We investigated whether clinical and noninvasive laboratory variables can predict the results of EPS in 89 patients with unexplained syncope. The prevalence of inducible ventricular tachycardia (VT) was 15%; supraventricular tachycardia, 15%; bradyarrhythmias, 41%; and normal EPS, 29%. We used multivariate discriminant function analysis to predict the results of EPS. The variables selected for identification of patients with inducible VT by this analysis include New York Heart Association (NYHA) functional class, gender, digitalis use, nonsustained VT, and atrial fibrillation. Based on our statistical model, performing EPS on 45% of the patients with unexplained syncope would result in a 90% sensitivity in detecting patients with inducible VT. The variables selected for identification of patients with normal EPS findings include: New York Heart Association functional class, heart disease, digitalis use, and intraventricular conduction. Based on this model, it would require that all but 12% of patients with unexplained syncope be studied to achieve a 90% predictive accuracy for identification of patients with normal EPS. During follow-up, recurrence rates for the different EPS categories did not differ significantly. The five-year cumulative survival among the EPS groups were as follows: VT, 37% +/- 28%; SVT, 90% +/- 9%; bradyarrhythmias, 71% +/- 10%; and normal EPS, 96% +/- 4%. Survival of the VT group differed significantly from that of the normal group. In patients with unexplained syncope, EPS findings can be predicted from clinical and noninvasive laboratory data. Mortality during follow-up relates to EPS findings.

Adult↗

PubMed2003

Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation.

Reconstitution of cellular immunity by 3 months after hematopoietic stem cell transplantation (HSCT) is a critical determinant of the long-term success of the transplantation. We analyzed the factors affecting recovery of cytomegalovirus (CMV)-specific CD4+ and CD8+ function at 3 months after HSCT by univariate and multivariable analyses including source of stem cells (bone marrow vs peripheral blood stem cells [PBSCs]), age, sex, graft-versus-host disease (GVHD), steroid use, conditioning regimens, ganciclovir use, HLA matching, circulating CMV antigenemia, absolute CD4+ and CD8+ counts, and donor CMV serology. High-dose steroids and CD4+ count less than 100 x 10(9)/L were significant predictors of impaired CD4+ functional recovery in the multivariable analysis. High-dose steroids, bone marrow as a source of stem cells, and CD8+ count less than 50 x 10(9)/L were associated with impaired CD8+ function in the multivariable analysis. Steroids were found to impair both CD4+ and CD8+ function in a dose-dependent manner. In the absence of high-dose steroids, low-level subclinical CMV antigenemia was found to stimulate both CD4+ and CD8+ functional recovery in recipients of ganciclovir prophylaxis. There was no difference in immune reconstitution between those who received prophylactic ganciclovir versus antigenemia-guided pre-emptive therapy. Thus, absolute CD4+ and CD8+ counts less than 100 x 10(9)/L and 50 x 10(9)/L, respectively; bone marrow as the source of stem cells; and high-dose steroid use all predict delayed recovery of functional T-cell immunity at 3 months after transplantation. Subclinical CMV reactivation while on ganciclovir appears to be a potent stimulator of T-cell function. These findings have implications for vaccination and adoptive-immunotherapy strategies in this population.

Adolescent↗

PubMedDate not supplied

Winter depression and functional impairment among ambulatory primary care patients.

This study of primary care patients sought to estimate the prevalence of and functional impairment associated with winter-seasonal depression. Three hundred three patients visiting a primary care clinic in January or February were assessed for seasonal patterns of health change, current DSM-III-R major depressive disorder (MDD), and current functional status. Approximately 9% of patients met criteria for MDD with winter-seasonal pattern, and an additional 29% reported seasonal mood changes without meeting criteria for current MDD. Multivariate analysis revealed that the functional impairment associated with such winter seasonality exceeded that associated with any of the common chronic medical conditions measured, and that such dysfunction was evident even in the absence of a diagnosable depressive disorder (MDD). Winter-seasonal pain was reported by one quarter of the overall sample and by half of those with current MDD, supporting preliminary reports that pain may be a common presenting symptom in seasonal affective disorder. The findings suggest that efforts at detection and treatment of such syndromes in primary care settings would be justified.

Adolescent↗

PubMed2002

Peptide-specific CD8+ T-cell evolution in vivo: response to peptide vaccination with Melan-A/MART-1.

Monitoring of CD8+ T-cell responses in cancer patients during peptide vaccination is essential to provide useful surrogate markers and to demonstrate vaccine efficacy. We have longitudinally followed CD8+ T-cell responses in 3 melanoma patients who were immunized with peptides derived from Melan-A/MART-1. Recombinant HLA-A2 tetramers loaded with the naturally presented Melan-A/MART-1 nonamer peptide (AAGIGILTV) and the Melan-A/MART-1 analog (ELAGIGILTV) were used in combination with phenotypical analysis for different T-cell subsets including naive T cells, effector T cells, "true memory" T cells and "memory effector" T cells, based on CD45RA/RO and CCR7-expression. At least in a single patient, T cells binding to the AAGIGILTV epitope were detected in naive, precursor (CD45RA+/CCR7+) CD8+ T cells, and CD8+ T cells binding to the analog ELAGIGILTV peptide were identified in the terminally differentiated (CD45RA+/CCR7-) T-cell subset. Molecular and functional analysis of tetramer-binding T cells revealed that the T-cell receptor (TCR) repertoire was oligo/polyclonal in AAGIGILTV-reactive T cells, but different and restricted to a few TCR clonotypes in ELAGIGILTV-reactive T cells prior to vaccination. The TCR repertoire reactive with Melan-A/MART-1 peptide epitopes was broadened during vaccination and exhibited a different profile of cytokine release after specific stimulation: tetramer-binding T cells from 2/3 patients secreted granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon-gamma but not interleukin-2 (IL-2) in response to Melan-A/MART-1 peptides. In the third patient, tetramer-binding T cells secreted IL-2 exclusively. Our results show that T-cell responses to peptide vaccination consist of different T-cell subsets associated with different effector functions. Complementary analysis for TCR CDR3 and cytokine profiles may be useful to define the most effective CD8+ T-cell population induced by peptide vaccination.

ATP-Binding Cassette Transporters↗

PubMed1994

Epstein-Barr virus nuclear protein 2A forms oligomers in vitro and in vivo through a region required for B-cell transformation.

Epstein-Barr virus nuclear antigen 2 (EBNA-2) has been shown to be indispensable for immortalization of latently infected B lymphocytes, and it has been shown that EBNA-2 exists in a high-molecular-weight complex in these cells. In order to study the components of this protein machinery, we have purified baculovirus-expressed EBNA-2 from insect cells to greater than 95% homogeneity. We have shown by both gel filtration and sucrose gradient analysis that the purified material corresponds to a multimer containing eight EBNA-2 subunits. This multimeric complex is stable in 1.0 M NaCl, suggesting that the self-association is quite strong in vitro. By expressing portions of the EBNA-2 open reading frame to generate fusion proteins in yeast cells, we have used the two-hybrid system to demonstrate that this self-association occurs in vivo and is mediated at least in part by a domain of EBNA-2 encompassing amino acids 122 to 344. Mutational analysis of the self-association function suggests that two subdomains that flank amino acid 232 may each play a role in EBNA-2 protein-protein interaction.

Amino Acid Sequence↗

PubMed2003

Selective breeding, quantitative trait locus analysis, and gene arrays identify candidate genes for complex drug-related behaviors.

Acute functional tolerance to ethanol develops during a single exposure to ethanol; it has been suggested to be a predisposing factor for the development of ethanol dependence. Genetic determinants of acute functional tolerance, as well as of ethanol dependence, have been clearly demonstrated. We describe a novel approach that uses a combination of selective breeding (to segregate genes contributing to the phenotype of interest, i.e., acute functional tolerance to the incoordinating effect of ethanol), quantitative trait locus analysis (to define chromosomal regions associated with acute functional tolerance), and DNA microarray technology (to identify differentially expressed genes in the brains of the selected lines of mice) to identify candidate genes for the complex phenotype of ethanol tolerance. The results indicate the importance of a signal transduction cascade that involves the glutamate receptor delta2 protein, the Ephrin B3 ligand, and the NMDA receptor, as well as a transcriptional regulatory protein that may be induced by activation of the NMDA receptor (zinc finger protein 179) and a protein that can modulate downstream responses to NMDA receptor activation (peroxiredoxin), in mediating acute tolerance to the incoordinating effect of ethanol.

Alcohol-Induced Disorders↗