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Results for “Association and function analysis”

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PubMed1997

Valvular perforation in left-sided infective endocarditis: a prospective echocardiographic evaluation and clinical outcome.

We undertook this study to determine the use of transthoracic and transesophageal echocardiography in detecting valvular perforation and the clinical impact of the latter on the outcome of left-sided infective endocarditis. Transthoracic echocardiography was performed in 58 consecutive patients with infective endocarditis. According to the study protocol, a subgroup of 42 patients also underwent transesophageal echocardiogrophy. At referral, 20 (34%) of 58 patients had echocardiographic evidence of valvular perforation (group A). No valvular perforations were found in the remaining 38 patients (group B). During a follow-up period of 27 +/- 16 months, a major complication occurred in 18 of 20 patients in group A and in 11 of 38 patients in group B (p < 0.0001). Univariate analysis indicated previous infective endocarditis, aortic involvement, and New York Heart Association functional class had a predictive value for valvular perforation (p < 0.001). Stepwise regression analysis confirmed aortic valve perforation as the only independent predictive variable for surgery and death. Valvular perforation is a common complication of infective endocarditis and is associated with an adverse outcome. Transthoracic echocardiography can detect or suggest valvular perforation in infective endocarditis, but transesophageal echocardiography better defines this complication and predicts severe heart failure or the need for early surgical management.

Adult↗

PubMed2006

FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization.

Single nucleotide polymorphism (SNP) prioritization based on the phenotypic risk is essential for association studies. Assessment of the risk requires access to a variety of heterogeneous biological databases and analytical tools. FASTSNP (function analysis and selection tool for single nucleotide polymorphisms) is a web server that allows users to efficiently identify and prioritize high-risk SNPs according to their phenotypic risks and putative functional effects. A unique feature of FASTSNP is that the functional effect information used for SNP prioritization is always up-to-date, because FASTSNP extracts the information from 11 external web servers at query time using a team of web wrapper agents. Moreover, FASTSNP is extendable by simply deploying more Web wrapper agents. To validate the results of our prioritization, we analyzed 1569 SNPs from the SNP500Cancer database. The results show that SNPs with a high predicted risk exhibit low allele frequencies for the minor alleles, consistent with a well-known finding that a strong selective pressure exists for functional polymorphisms. We have been using FASTSNP for 2 years and FASTSNP enables us to discover a novel promoter polymorphism. FASTSNP is available at http://fastsnp.ibms.sinica.edu.tw.

Gene Frequency↗

PubMed2001

Intermediate survival and predictors of death after surgical ventricular restoration.

This study examined the effects of Dor procedure on long-term survival in patients with previous transmural anterior myocardial infarction who were referred to a single experienced center for left ventricular reconstruction by endoventricular patch-plasty repair. Our aim was to evaluate the impact of this procedure on long-term survival and to assess the ability of preoperative, perioperative, and postoperative variables to predict late survival. Major indications for surgery were left ventricular dysfunction, angina, ventricular arrhythmias, or a combination of the three; 20 patients underwent urgent cardiac surgery. The total group was 245 patients, with 8.1% hospital mortality, and 19 patients lost to follow-up [corrected]. The study group comprised 207 patients. Many pre- and postoperative clinical, hemodynamic, and functional variables, as well as operative parameters, were studied by univariate analysis. During a mean follow-up period of 39+/-19 months, 30 end points were observed, including 27 deaths and 3 heart transplants. Event-free survival was 98%+/-1% at 1 year, 95.8%+/-1.4% at 2 years, and 82.1%+/-3.3% at 5 years. Cox regression analysis showed preoperative New York Heart Association functional class, ejection fraction, end systolic volume index, and remote asynergy as independent predictors of mortality. The procedure has a favorable impact on 5-year survival. Independent predictors of late survival are the preoperative functional status and the left ventricular systolic function.

Cardiovascular Surgical Procedures↗

PubMed1988

Discriminant function analysis of clinical laboratory data. Use in alcohol research.

There has been a growing interest in the use of discriminant function analysis of routinely collected laboratory data to differentiate between alcoholic and nonalcoholic individuals. However, no consensus has been reached concerning the validity and reliability of this form of analysis regarding the diagnosis of, or screening for, alcoholism. In addition, this technique may provide important information concerning the multivariate nature of the pathophysiological effects of alcohol. However, this issue is seldom discussed. Because of differences in methodology across studies and the growing confusion regarding conceptual issues associated with this statistical technique, there have been few critical reviews. This chapter is directed at critically evaluating the current literature, particularly with respect to the methodological and conceptual issues associated with the use of discriminant function analysis in alcohol research. As part of this approach we suggest guidelines for future research in this area.

Alcoholism↗

PubMed1995

Molecular cloning, structural analysis and functional expression of the proline-rich focal adhesion and microfilament-associated protein VASP.

The vasodilator-stimulated phosphoprotein (VASP), a substrate for cAMP- and cGMP-dependent protein kinases in vitro and in intact cells, is associated with actin filaments, focal adhesions and dynamic membrane regions. VASP, cloned here from human HL-60 and canine MDCK cells, is organized into three distinct domains. A central proline-rich domain contains a GPPPPP motif as a single copy and as a 3-fold tandem repeat, as well as three conserved phosphorylation sites for cyclic nucleotide-dependent protein kinases. A C-terminal domain contains a repetitive mixed-charge cluster which is predicted to form an alpha-helix. The hydrodynamic properties of purified human VASP together with the calculated molecular mass of cloned VASP suggest that the native protein is a homotetramer with an elongated structure. VASP over-expressed in transiently transfected BHK21 cells was predominantly detected at stress fibres, at focal adhesions and in F-actin-containing cell surface protrusions, whereas truncated VASP lacking the C-terminal domain was no longer concentrated at focal adhesions. These data indicate that the C-terminal domain is required for anchoring VASP at focal adhesion sites, whereas the central domain is suggested to mediate VASP interaction with profilin. Our results provide evidence for the structural basis by which VASP, both a target of the cAMP and cGMP signal transduction pathways and a component of the actin-based cytoskeleton, including the cytoskeleton-membrane interface, may be able to exchange signals between these networks.

Amino Acid Sequence↗

PubMed1997

Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior.

We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans. A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site. Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists. Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors. We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 10.43; P = 0.003).

Adult↗

PubMed1998

Death-associated proteins: from gene identification to the analysis of their apoptotic and tumour suppressive functions.

Aberrations of apoptosis are implicated in many diseases, including cancer, autoimmune disease, cardiovascular disease and neurodegeneration. The cell's apoptotic machinery is, therefore, an important potential target for the development of new therapies. Our laboratory has used a strategy called technical knockout (TKO) to identify novel genes involved in apoptosis. TKO is based on random inactivation of gene expression with antisense cDNA libraries, followed by selection of those cells that survive in the continuous presence of an apoptotic stimulus. Using this approach, we have isolated five novel genes, including a serine/threonine kinase, a nucleotide-binding protein and a homologue of the p220 translation initiation factor. Expression of one of these genes (DAP kinase) is lost in some cancers, and this loss appears to increase the metastatic potential of some tumours.

Animals↗

PubMed2006

Comprehensive analysis of expression and function of 51 sarco(endo)plasmic reticulum Ca2+-ATPase mutants associated with Darier disease.

We examined possible defects of sarco(endo)plasmic reticulum Ca2+-ATPase 2b (SERCA2b) associated with its 51 mutations found in Darier disease (DD) pedigrees, i.e. most of the substitution and deletion mutations of residues reported so far. COS-1 cells were transfected with each of the mutant cDNAs, and the expression and function of the SERCA2b protein was analyzed with microsomes prepared from the cells and compared with those of the wild type. Fifteen mutants showed markedly reduced expression. Among the other 36, 29 mutants exhibited completely abolished or strongly inhibited Ca2+-ATPase activity, whereas the other seven possessed fairly high or normal ATPase activity. In four of the aforementioned seven mutants, Ca2+ transport activity was significantly reduced or almost completely lost, therefore uncoupled from ATP hydrolysis. The other three were exceptional cases as they were seemingly normal in protein expression and Ca2+ transport function, but were found to have abnormalities in the kinetic properties altered by the three mutations, which happened to be in the three DD pedigrees found by us previously (Sato, K., Yamasaki, K., Daiho, T., Miyauchi, Y., Takahashi, H., Ishida-Yamamoto, A., Nakamura, S., Iizuka, H., and Suzuki, H. (2004) J. Biol. Chem. 279, 35595-35603). Collectively, our results indicated that in most cases (48 of 51) DD mutations cause severe disruption of Ca2+ homeostasis by the defects in protein expression and/or transport function and hence DD, but even a slight disturbance of the homeostasis will result in the disease. Our results also provided further insight into the structure-function relationship of SERCAs and revealed critical regions and residues of the enzyme.

Adenosine Triphosphatases↗

PubMed2005

Cloning and functional analysis of the gene encoding the 33- to 36-kilodalton outer membrane protein associated with carbapenem resistance in Acinetobacter baumannii.

We investigated a multiresistant strain of Acinetobacter baumannii isolated in our hospital. Analysis of the N-terminal peptide sequence of the outer membrane proteins (OMPs) purified from the strain allowed us to clone and sequence the nucleotides of the gene encoding the 33- to 36-kDa OMP associated with carbapenem resistance in A. baumannii.

Acinetobacter↗

PubMed1999

Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300.

Human herpesvirus 8/Kaposi sarcoma-associated virus (HHV-8/KSHV) contains, in addition to genes required for viral replication, a unique set of nonstructural genes which may be part of viral mimicry and contribute to viral replication and pathogenesis in vivo. Among these, HHV-8 encodes four open reading frames (ORFs) that showed homology to the transcription factors of the interferon regulatory factor (IRF) family. The ORF K9, viral IRF 1 (vIRF-1), has been cloned, and it was shown that, when overexpressed, it down modulates the interferon-mediated transcriptional activation of the interferon-stimulated gene 15 (ISG 15) promoter, and the role of vIRF-1 in viral mimicry was implied. However, the molecular mechanism of this effect has not been clarified. Here, we extend this observation and show that vIRF-1 also downregulates the transcriptional activity of IFNA gene promoter in infected cells by interfering with the transactivating activity of cellular IRFs, including IRF-1 and IRF-3. We further show that ectopic expression of vIRF-1 in NIH 3T3 cells confers resistance to tumor necrosis factor alpha-induced apoptosis. While vIRF-1 is unable to bind DNA with the same specificity as cellular IRFs, we demonstrate by in vitro binding assay that it can associate with the family of cellular IRFs, such as IRF-1 and the interferon consensus sequence binding protein. vIRF-1 interaction domain was localized between amino acids (aa) 152 and 243. While no binding between the full-size IRF-3 and vIRF-1 could be detected by the same assay, we show that vIRF-1 also targets the carboxy-terminal region (aa 1623 to 2414) of the transcriptional coactivator p300 which could also bind IRF-3 and IRF-1. These results demonstrate that vIRF-1 can modulate the transcription of the IFNA genes by direct heterodimerization with members of the IRF family, as well as by competitive binding with cellular transcription factors to the carboxy-terminal region of p300.

3T3 Cells↗

PubMed1993

[Functional and phenotypic analysis of tumor infiltrating lymphocytes derived from solid tumors and effusion associated lymphocytes in malignant ascites cultured in recombinant interleukin 2].

Tumor infiltrating lymphocytes (TIL) and effusion associated lymphocytes (EAL) were isolated from 7 human solid tumors and 6 malignant ascitic fluids respectively, and cultured in rIL2 (700JRU/ml)-containing medium. Long-term culture (> 14 days) of separated lymphocytes with exponential increase in cell number was achieved in 5 EAL-cultures, whereas in only 2 TIL-cultures. rIL2-expanded TIL and EAL manifested significant cytotoxicity in a 4-hrs chromium release assay. The maximum NK and LAK activity were reached 21 days and 14 days after starting incubation with rIL2 respectively, followed by a rapid decrease in cytolytic potential without declining growth rate of the cells. Phenotypic analysis showed the majority of the freshly isolated TIL and EAL were CD3+ T cells, and CD16+ NK cells were rarely identified in TIL. With induction of LAK cell activity, CD8+ T cells predominantly increased in TIL-cultures, while both CD4+ and CD8+ T cells and CD16+ NK cells were increased in EAL cultures. In activated TIL most cytolytic activity was found in CD8+ T cells, in contrast CD16+ NK cells were responsible for it in activated EAL. These results indicated that EAL and TIL have similar properties in which they coexist with cancer cells at tissue level and were capable of expanding and acquiring LAK cell activity in the presence of rIL2, but apparently differ in their mechanism of rIL2-mediated activation.

Adult↗

PubMed2025

Integrated multi-omics analysis reveals TMEM147 as an immunosuppressive prognostic biomarker in LUAD.

TMEM147, an endoplasmic reticulum (ER) membrane protein, is implicated in lung adenocarcinoma (LUAD) progression, although its precise role remains unclear. To elucidate its function, this study integrated bioinformatics analyses with experimental validation. First, TMEM147 expression was assessed using TCGA and GEO datasets, with validation performed in LUAD cell lines. Survival analysis evaluated its prognostic significance. Subsequently, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and single-sample gene set enrichment analysis (ssGSEA) were employed to identify associated functional pathways and interactions within the tumor immune microenvironment. Transcription factor binding predictions and in vitro functional assays (migration, invasion, proliferation) further characterized TMEM147's role. Results indicated that TMEM147 was significantly upregulated in LUAD and correlated with poor outcomes in patients. FLI1 was predicted as a key transcriptional regulator of TMEM147. Furthermore, TMEM147 expression influenced immune cell infiltration profiles and was associated with pathways involved in ribonucleoprotein biogenesis and oxidative phosphorylation (OXPHOS). Importantly, silencing TMEM147 significantly reduced cancer cell migration, invasion, and proliferation. These findings collectively suggest that TMEM147 promotes LUAD progression and holds potential as both a prognostic biomarker and a therapeutic target.

Bioinformatics analysis↗

PubMed2005

Associating phenotypes with molecular events: recent statistical advances and challenges underpinning microarray experiments.

Progress in mapping the genome and developments in array technologies have provided large amounts of information for delineating the roles of genes involved in complex diseases and quantitative traits. Since complex phenotypes are determined by a network of interrelated biological traits typically involving multiple inter-correlated genetic and environmental factors that interact in a hierarchical fashion, microarrays hold tremendous latent information. The analysis of microarray data is, however, still a bottleneck. In this paper, we review the recent advances in statistical analyses for associating phenotypes with molecular events underpinning microarray experiments. Classical statistical procedures to analyze phenotypes in genetics are reviewed first, followed by descriptions of the statistical procedures for linking molecular events to measured gene expression phenotypes (microarray-based gene expression) and observed phenotypes such as diseases status. These statistical procedures include (1) prior analysis, such as data quality controls, and normalization analyses for minimizing the effects of experimental artifacts and random noise; (2) gene selections and differentiation procedures based on inferential statistics for the class comparisons; (3) dynamic temporal patterns analysis through exploratory statistics such as unsupervised clustering and supervised classification and predictions; (4) assessing the reliability of microarray studies using real-time PCR and the reproducibility issues from many studies and multiple platforms. In addition, the post analysis to associate the discovered patterns of gene expression to pathway and functional analysis for selected genes are also considered in order to increase our understanding of interconnected gene processes.

Algorithms↗

PubMed2003

Factors associated with the wish to hasten death: a study of patients with terminal illness.

BACKGROUND: There is considerable debate regarding the clinical issues surrounding the wish to hasten death (WTHD) in the terminally ill. The clinical factors contributing to the WTHD need further investigation among the terminally ill in order to enhance understanding of the clinical assessment and treatment needs that underlie this problem. A more detailed understanding may assist with the development of appropriate therapeutic interventions. METHOD: A sample of terminally ill cancer patients (N = 256) recruited from an in-patient hospice unit, home palliative care service and a general hospital palliative care consulting service from Brisbane Australia between 1998-2001 completed a questionnaire assessing psychological (depression and anxiety), social (family relationship, social support, level of burden on others) and the impact of physical symptoms. The association between these factors and the WTHD was investigated. RESULTS: A high WTHD was reported by 14 % of patients. A discriminant function analysis revealed that the following variables were associated with a high WTHD (P < 0.001): higher levels of depressive symptoms, being admitted to an in-patient hospice setting, a greater perception of being a burden on others, lower family cohesion, lower levels of social support, higher levels of anxiety and greater impact of physical symptoms. CONCLUSIONS: Psychological and social factors are related to a WTHD among terminally ill cancer patients. Greater attention needs to be paid to the assessment of psychological and social issues in order to provide appropriate therapeutic interventions for terminally ill patients.

Adult↗

PubMed2006

Recent advances in molecular pharmacology of the histamine systems: organic cation transporters as a histamine transporter and histamine metabolism.

Histamine is inactivated by the histamine-metabolizing enzyme histamine N-methyltransferase (HNMT) in bronchus, kidney, and the central nervous system. HNMT seems to be localized in the cytoplasm, but histamine is unable to easily enter the intracellular space. Therefore, two hypotheses can be elicited: one is the plasma membrane hypothesis that HNMT can be translocated to the plasma membrane and function at the cell surface under growth factor stimulation and the other is the transporter hypothesis that organic cation transporter (OCT)-2 and -3 can function as a histamine transporter as well. To investigate the involvement of OCT2, HEK293 cells stably double transfected with C-terminal hemagglutinin (HA)-tagged HNMT cDNA and/or C-terminal myc-tagged rat OCT2 were prepared for analysis of HNMT activity associated with OCT2 function. After 60-min incubation of these cells with PBS including HA (100 microM), N(tau)-methylhistamine (MHA) concentration of the supernatants was determined by the HPLC-fluorometry method. MHA from cells with HNMT plus OCT-2 was produced at about 3-fold higher level than that from cells with HNMT alone, suggesting that OCT-2 could function as a histamine transporter as well and that HNMT function could partly depend on OCT-2 transporter activity. Using OCT-3 knockout (OCT-3-/-) mice, histamine content and survival rates were investigated in lipopolysaccharide (LPS)-induced endotoxemia model. Without LPS stimulation, histamine content was compared between OCT-3-/- and wild mice. Histamine content in the spleen of OCT-3-/- mice was higher than that f wild mice. With LPS stimulation, the survival rate of OCT-3-/- mice was significantly decreased 12 h after LPS (20 mg/kg) stimulation, suggesting that before immunological stimulation, a higher content of histamine in spleen could stimulate histamine receptors in mast cells, macrophages, dendritic cells, as well as T lymphocytes and explaining the decreased survival rate in OCT-3-/- mice possibly due to the functional changes of immunological cells.

Animals↗

PubMed1989

Motor slowing in asymptomatic HIV infection.

To examine neuropsychological deficits associated with the human immunodeficiency virus (HIV), 25 asymptomatic homosexual men and sexual partners of intravenous drug users and 25 seronegative homosexual men and nonhigh-risk heterosexuals were assessed on measures of fine motor control, visual scanning, attention, depression, and global psychological functioning. Analysis suggested that HIV infection is associated with reduced fine motor control. Seropositivity is associated with elevated depression and global psychological maladjustment. When depression and global adjustment were analyzed as covariates, motor slowing was evident in the seropositive group. These findings suggest an association between motor slowing and HIV infection in asymptomatic subjects and point to the necessity of measuring affect at least as a control variable. Further study is needed to determine whether the fine motor deficit evident in this sample is limited to distinct subgrouping of the over-all sample.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Slow-wave activity in the spectral analysis of the electroencephalogram is associated with cortical dysfunctions in patients with Alzheimer's disease.

Cortical functions and slow-wave activity in the spectral analysis of the electroencephalogram (EEG) have been studied in 19 patients with Alzheimer's disease (AD), 18 patients with Parkinson's disease with dementia (PD), and 14 control subjects (C) to determine which functions are explained by their relationship of slow-wave activity. Multiple regression analyses revealed that a variance in visual functions, praxia of the hand, automatic speech, speech understanding, and retrieval from semantic memory were explained by their relationship with slow-wave activity in EEG in the AD group but not in the PD or C groups. The PD and AD groups exhibited equal cortical dysfunctions and mean amplitudes of delta activity in EEG. The cholinergic system, disrupted in AD, has been shown to be important in the regulation of neocortical electrical activity and may be associated with the processing of cortical functions.

Aged↗

PubMed2005

Functional genomic relationships in HIV-1 disease revealed by gene-expression profiling of primary human peripheral blood mononuclear cells.

BACKGROUND: An assessment of biomarkers from an analysis of human peripheral blood mononuclear cell gene-expression profiles was made, to acquire an understanding of transcriptional changes associated with human immunodeficiency virus type 1 (HIV-1) infection in vivo. METHODS: Supervised learning algorithms were used to create signature gene sets that could be used to distinguish seropositive from seronegative samples and delineate changes in disease status during the early stages of infection. Bioinformatic tools were used to classify persons and to functionally characterize groups of differentially expressed genes, to elucidate the impact of viral infection on host cell gene-expression patterns. RESULTS: A 10-gene signature set that could be used to accurately determine the HIV-1 serostatus was identified. A 6-gene signature set was used to distinguish seropositive persons exhibiting differential changes in CD4(+) T cell counts, with 93% accuracy. Functional classification of differentially expressed genes in HIV-1 indicated a preponderance of down-regulated genes with functions related to the immune response and apoptosis. Hierarchical cluster analysis in persons whose CD4(+) T cell counts increased, compared with that in persons whose CD4(+) T cell counts decreased, was characterized by the down-regulation of genes associated with apoptosis, mitochondrial function, protein biosynthesis, and RNA binding. CONCLUSIONS: Gene-expression profile analysis of a complex infectious virus, such as HIV-1, may be useful to elucidate the functional genomic relationships associated with viral infection.

CD4-Positive T-Lymphocytes↗