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Results for “Association and function analysis”

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PubMed2004

Functional analysis in serum from atypical Hemolytic Uremic Syndrome patients reveals impaired protection of host cells associated with mutations in factor H.

A subgroup of patients with the most severe form of the Hemolytic Uremic Syndrome (HUS) presents mutations in the complement regulatory protein factor H. The functional analyses of the factor H mutant proteins purified from some of these patients have shown a specific defect in the capacity to control complement activation on cellular surfaces. Here, we show that these factor H-related complement regulatory defects can be detected in the patients' serum with a simple hemolytic assay. Data obtained from HUS patients and control individuals indicate that this assay is a useful tool for the molecular diagnosis of factor H-related HUS.

Animals↗

PubMedDate not supplied

Preliminary validation of a patient-based self-assessment measure of severity of illness in type 2 diabetes: results from the pilot phase of the Veterans Health Study.

Measures of case mix are needed to control for patients' clinical status in studies assessing the process and outcomes of care. The Veterans Health Study (VHS) is a longitudinal study of determinants of health outcomes in ambulatory veterans. This study assessed the validity of a case-mix measure developed to quantify severity of illness in ambulatory type 2 diabetic patients. As part of the pilot phase of the VHS, 245 veterans using 4 primary care clinics in Boston were screened for diabetes and 5 other chronic illnesses when they presented for care. Subjects screening positive for diabetes returned to complete severity of illness and outcome measures. The variables for the diabetes case-mix module were chosen based upon the principles of parsimony, duration of follow-up, and clinical validity and credibility. Variables were selected to predict function, as measured by the Medical Outcomes Study Short-Form 36 (SF-36). The diabetic patients in this study had a heavy burden of chronic illness, with an average of 3.9 comorbid conditions and a mean general health perceptions score of 48 on the SF-36 (scored from 0 to 100, with 100 indicating best health). A summary variable called DMSEV was created for "diabetes severity". This included atherosclerotic complications(stroke, transient ischemic attack or myocardial infarction; chest pain frequency; and claudication), plus any history of eye, foot, or neuropathic symptoms. DMSEV correlated with all 8 outcome scales of the SF-36, and in particular was highly associated with physical function (r=0.49, P=.0001). Least squares linear regression analysis controlling for age and comorbidity confirmed the association of DMSEV with all 8 SF-36 scales. The correlation with physical function remained highly significant (P<.0001), with an R of 0.31. This patient-based self-assessment questionnaire and the summary variable DMSEV appear to be valid measures of severity of illness in ambulatory diabetic veterans with multiple comorbidities. After further testing, this case-mix measure may be suitable for controlling for severity of illness in ambulatory-based studies of diabetic patients with multiple chronic illnesses.

Aged↗

PubMed2001

Distinct functions of the ATP binding cassettes of transporters associated with antigen processing: a mutational analysis of Walker A and B sequences.

The transporters associated with antigen processing (TAP1/TAP2) provide peptides to MHC class I molecules in the endoplasmic reticulum. Like other ATP-binding cassette proteins, TAP uses ATP hydrolysis to power transport. We have studied peptide binding to as well as translocation by TAP proteins with mutations in the Walker A and B sequences that are known to mediate ATP binding and hydrolysis. We show that a mutation in the TAP1 Walker B sequence reported to abrogate class I expression by a lung tumor does not affect ATP binding affinity, suggesting a defect restricted to ATP hydrolysis. This mutation reduces peptide transport by only 50%, suggesting that TAP function can be highly limiting for antigen presentation in non-lymphoid cells. Single substitutions in Walker A sequences (TAP1K544A, TAP2K509A), or their complete replacements, abrogate nucleotide binding to each subunit. Although all of these mutations abrogate peptide transport, they reveal distinct roles for nucleotide binding to the two transporter subunits in TAP folding and in regulation of peptide substrate affinity, respectively. Alteration of the TAP1 Walker A motif can have strong effects on TAP1 and thereby TAP complex folding. However, TAP1 Walker A mutations compatible with correct folding do not affect peptide binding. In contrast, abrogation of the TAP2 nucleotide binding capacity has little or no effect on TAP folding but eliminates peptide binding to TAP at 37 degrees C in the presence of nucleotides. Thus, nucleotide binding to TAP2 but not to TAP1 is a prerequisite for peptide binding to TAP. Based on these results, we propose a model in which nucleotide and peptide release from TAP are coupled and followed by ATP binding to TAP2, which induces high peptide affinity and initiates the transport cycle.

ATP-Binding Cassette Transporters↗

PubMed2001

Depressive symptoms and risk of functional decline and death in patients with heart failure.

OBJECTIVES: We sought to examine whether depressive symptoms are associated with poorer prognosis in patients with heart failure. BACKGROUND: Depression is an established risk factor for poor outcome in patients with coronary heart disease (CHD). Little is known of its role in patients with heart failure. METHODS: We prospectively followed 391 patients > or =50 years of age who met criteria for decompensated heart failure on hospital admission. The outcome of the study was death or decline in activities of daily living (ADL) at six months, relative to baseline. Depressive symptoms were measured at baseline by means of the Geriatric Depression Scale, Short-Form, with 6 to 7 symptoms, 8 to 10 symptoms and > or =11 symptoms indicating mild, moderate and severe levels of depressive symptoms, respectively. RESULTS: There was a strong and graded association between the severity of depressive symptoms at baseline and the rate of the combined end point of either functional decline or death at six months. After adjustment for demographic factors, medical history, baseline functional status and clinical severity, patients with > or =11 depressive symptoms, compared with those with <6 depressive symptoms, had an 82% higher risk of either functional decline or death, whereas the intermediate levels of depressive symptoms showed intermediate risk (p = 0.003 for trend). A similar graded association was found for functional decline and death separately; however, after multivariate analysis, the association with mortality was less strong and no longer statistically significant. CONCLUSIONS: An increasing number of depressive symptoms is a negative prognostic factor for patients with heart failure, just as it is for patients with CHD.

Aged↗

PubMed1995

Oligoclonal banding of IgG in CSF, blood-brain barrier function, and MRI findings in patients with sarcoidosis, systemic lupus erythematosus, and Behçet's disease involving the nervous system.

A retrospective study of CSF and serum analysis from a total of 43 patients with sarcoidosis, 20 with systemic lupus erythematosus, and 12 with Behçet's disease with neurological involvement found local synthesis of oligoclonal IgG using isoelectric focusing and immunoblotting in 51%, 25%, and 8% respectively at some stage in their disease. Blood-brain barrier breakdown, when assessed with an albumin ratio found 47% of patients with sarcoidosis, 30% of those with systemic lupus erythematosus, and 42% of patients with Behçet's disease exhibiting abnormal barrier function at some time. Serial CSF analysis showed that clinical relapses were associated with worsening barrier function and in some patients the development of local oligoclonal IgG synthesis; conversely steroid treatment led to a statistically significant improvement in barrier function, and in two patients a loss of oligoclonal IgG bands. A higher proportion of patients had MRI abnormalities than oligoclonal IgG or blood-brain barrier breakdown, MRI being abnormal in 16 of 19 patients with sarcoidosis, three of four patients with systemic lupus erythematosus, and seven of nine patients with Behçet's disease, although this may have been due to temporal factors. In the differential diagnosis of chronic neurological disorders, locally synthesised oligoclonal IgG cannot distinguish between diseases, but the loss of bands seen in two patients contrasts with what is seen in multiple sclerosis, and thus may be a useful diagnostic clue.

Behcet Syndrome↗

PubMed1998

Functional analysis by site-directed mutagenesis of the complex polymorphism in rat transporter associated with antigen processing.

The transporter associated with Ag processing, TAP, is an endoplasmic reticulum resident heterodimeric member of the ATP-binding cassette transporter family. TAP transports short peptides from cytosol to the endoplasmic reticulum lumen for loading into recently synthesized class I MHC molecules. In the rat, two alleles of the TAP2 chain differ in their permissiveness to the transport of peptides with small hydrophobic, polar, or charged amino acids at the C terminus, and this correlates with differences between the peptide sets loaded into certain class I molecules in vivo. We have used segmental exchanges and site-directed mutagenesis to identify the residues in rat TAP2 responsible for differential transport between the two alleles of peptides terminating above all in the positively charged residue, arginine. Of the 25 residues by which the two functional TAP2 alleles differ, we have localized differential transport of peptides with a C-terminal arginine to two adjacent clusters of exchanges in the membrane domain involving a total of five amino acids. Each cluster, transferred by site-directed mutagenesis from the permissive to the restrictive sequence, can independently confer on TAP a partial ability to transport peptides with arginine at the C terminus. The results suggest that the permissive TAP2-A allele evolved in at least two steps, each partially permissive for peptides with charged C termini.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Proteins with class alpha/beta fold have high-level participation in fusion events.

Now that complete genome sequences are available for a variety of organisms, the elucidation of potential gene products function is a central goal in the post-genome era. Domain fusion analysis has been proposed recently to infer the functional association of the component proteins. Here, we took a new approach to the analysis of the structural features of the proteins involved in fusion events. An exhaustive survey of fusion events within 30 completely sequenced genomes and subsequent structure annotations to the component proteins at a SCOP superfamily level with hidden Markov models was carried out. A domain fusion map was then constructed. The results revealed that proteins with the class alpha/beta fold are frequently involved in fusion events, around 86% of the total 676 assigned single-domain fusion pairs including at least one component protein belonging to the alpha/beta fold class. Moreover, the domain fusion map in our work may offer an attractive framework for designing chimeric enzymes following Nature's lead, and may give useful hints for exploring the evolutionary history of proteins. (c) 2002 Elsevier Science Ltd.

Archaeal Proteins↗

PubMed2006

Discovering semantic features in the literature: a foundation for building functional associations.

BACKGROUND: Experimental techniques such as DNA microarray, serial analysis of gene expression (SAGE) and mass spectrometry proteomics, among others, are generating large amounts of data related to genes and proteins at different levels. As in any other experimental approach, it is necessary to analyze these data in the context of previously known information about the biological entities under study. The literature is a particularly valuable source of information for experiment validation and interpretation. Therefore, the development of automated text mining tools to assist in such interpretation is one of the main challenges in current bioinformatics research. RESULTS: We present a method to create literature profiles for large sets of genes or proteins based on common semantic features extracted from a corpus of relevant documents. These profiles can be used to establish pair-wise similarities among genes, utilized in gene/protein classification or can be even combined with experimental measurements. Semantic features can be used by researchers to facilitate the understanding of the commonalities indicated by experimental results. Our approach is based on non-negative matrix factorization (NMF), a machine-learning algorithm for data analysis, capable of identifying local patterns that characterize a subset of the data. The literature is thus used to establish putative relationships among subsets of genes or proteins and to provide coherent justification for this clustering into subsets. We demonstrate the utility of the method by applying it to two independent and vastly different sets of genes. CONCLUSION: The presented method can create literature profiles from documents relevant to sets of genes. The representation of genes as additive linear combinations of semantic features allows for the exploration of functional associations as well as for clustering, suggesting a valuable methodology for the validation and interpretation of high-throughput experimental data.

Abstracting and Indexing↗

PubMed2006

Nutritional status at 2 years in former infants with bronchopulmonary dysplasia influences nutrition and pulmonary outcomes during childhood.

Improved survival rates for extreme prematurity have been accompanied by an increase in the incidence of bronchopulmonary dysplasia (BPD). The objective of this study was to assess factors associated with long-term nutritional and pulmonary function outcomes. The study was a cross-sectional study of 52 children who had been born prematurely, had experienced BPD, and were 4-8 y old at the time of the study. Undernutrition was defined as a Z score for weight-for-height of <-2 SD. Body composition and lung function were evaluated. Resting energy expenditure (REE) was measured using indirect calorimetry. Stepwise logistic regression was used to test for factors associated with undernutrition and pulmonary function. Eighteen children (35%) with BPD, predominantly girls, were undernourished. Undernutrition occurred within the first months of life and was associated with high REE. Multivariate analysis showed that factors significantly associated with undernutrition were female sex and undernutrition at age 2 y. Thirty-one children (60%) had abnormal lung function tests. Multivariate analysis showed that undernutrition at age 2 y was the only factor associated with the risk of developing distension of the airways. Nutritional status at age 2 y in children who had BPD in infancy influences nutritional and pulmonary outcomes in childhood.

Bronchopulmonary Dysplasia↗

PubMed1993

Lymphocytes isolated from the peritoneal fluid of women with advanced ovarian carcinoma differ significantly from autologous peripheral blood lymphocytes.

The phenotypic and functional analysis of ovarian carcinoma-associated lymphocytes (OCAL), obtained from a group of patients with neoplastic carcinosis, reveals major differences between OCAL and peripheral blood lymphocytes (PBL). Virtually all of the OCAL belong to the T cell lineage, whereas both B and natural killer (NK) cells are virtually absent. NK activity is also significantly lower than that exerted by PBL. Following treatment with rIL-2, lymphokine-activated killer cell activity is poorly inducible in OCAL. In addition, in vitro stimulated OCAL produce low amounts of lymphokines. Clonal analyses reveal a low clonal efficiency, which indicates a severe proliferative defect. T cell clones obtained show peculiar features: the percentage of CD4 and CD8 clones varies greatly in the different samples. Both CD8 and a significant proportion of proliferating CD4+ clones are cytotoxic in a lectin-dependent cytolytic assay. These findings, together with the results obtained from comparative analyses of the peripheral blood of the same group of patients, demonstrate the unique characteristics of OCAL and should be considered in the preparation of protocols for the locoregional immunotherapy of ovarian carcinoma.

Adenocarcinoma↗

PubMed2000

Transmembrane proteins of tight junctions.

Tight junctions from a morphological and functional boundary between the apical and basolateral cell surface domains of epithelia and endothelia, and regulate selective diffusion along the paracellular space. Two types of four-span transmembrane proteins, occludin and claudins, as well as the single-span protein JAM are associated with tight junctions. The functional analysis of these proteins starts to reveal how they are involved in the functions of tight junctions, which of their domains are important for these functions, and how they interact with each other to form the junctional diffusion barriers.

Animals↗

PubMed2005

Augmentation index in heart disease.

New techniques for the evaluation of specific components of blood pressure waveforms have been shown to have broad applications in cardiology. One of the more useful parameters of pressure wave analysis is the augmentation index (AI), which measures the interaction of the forward pressure wave with reflected waves from the distal circulation. Analysis of AI and associated wave functions show differences related to cardiac risk, the presence of disease, and the effects of drug administration. The AI can provide useful additional information in the evaluation of high-risk populations and is a useful research tool in evaluating drug and treatment effects. New techniques have allowed AI to become more widely available and current measurements are convenient and reliable.

Aging↗

PubMed2024

Pangenomes of human gut microbiota uncover links between genetic diversity and stress response.

The genetic diversity of the gut microbiota has a central role in host health. Here, we created pangenomes for 728 human gut prokaryotic species, quadrupling the genes of strain-specific genomes. Each of these species has a core set of a thousand genes, differing even between closely related species, and an accessory set of genes unique to the different strains. Functional analysis shows high strain variability associates with sporulation, whereas low variability is linked with antibiotic resistance. We further map the antibiotic resistome across the human gut population and find 237 cases of extreme resistance even to last-resort antibiotics, with a predominance among Enterobacteriaceae. Lastly, the presence of specific genes in the microbiota relates to host age and sex. Our study underscores the genetic complexity of the human gut microbiota, emphasizing its significant implications for host health. The pangenomes and antibiotic resistance map constitute a valuable resource for further research.

Humans↗

PubMed2004

HLA haplotypes associated with type 1 diabetes mellitus in North Indian children.

Human leukocyte antigen (HLA) encoded susceptibility to develop type 1 diabetes mellitus (T1DM) has been investigated in children from North India. The results revealed significantly increased prevalence of HLA-A26, -B8, and -B50 among patients and strong positive association of the disease with DRB1*0301 (82.1% vs 13.9%, chi2=71.3, odds ratio [OR]=28.3) and a negative association with DRB1*02 (chi2=12.2, PF=38.5). HLA-DQB1*0201 occurred in 96.4% of the patients, whereas the heterodimer DQA1*0501-DQB1*0201 was present in 82.1% of patients (60.7% in single dose and 21.4% in double dose) and revealed significant deviation from the healthy controls (chi2=74.1, pc=6.0E-10). In addition to DRB1*03, positive association was also observed with DRB1*09 (14.3% vs 1.3%, chi2=13.4) and DRB1*04 (39.3% vs 15.6%, chi2=8.39). No HLA association was observed in relation to residual pancreatic beta-cell function or associated thyroid autoimmunity. Family analysis revealed involvement of multiple DR3+ve haplotypes with T1DM in North Indian children with A26-B8-DRB1*03 (25% vs 3.5%, chi2=16.9, p=3.96E-05) and Ax-B50-DRB1*03 (25% vs 0.7%, chi2=44.7, p=9.88E-11) being the most frequent haplotypes encountered among patients. The classical Caucasian haplotype A1-B8-DRB1*03 was infrequent (7.2%) among the diabetic children. The study highlights the race specificity of HLA association and disease associated HLA haplotypes in T1DM among North Indian children.

Adolescent↗

PubMed2002

Utility of history, physical examination, electrocardiogram, and chest radiograph for differentiating normal from decreased systolic function in patients with heart failure.

To determine whether clinical parameters alone can differentiate normal versus decreased systolic left ventricular function in patients with heart failure. Detailed clinical data were collected prospectively from 225 consecutive patients who were hospitalized with heart failure. Findings in patients with normal (ejection fraction > or =45%) or decreased (ejection fraction <45%) left ventricular function were compared. Systolic function was normal in 104 patients (46%) and decreased in 121 patients (54%). Patients with normal function were older (mean [+/- SD] age, 59 +/- 13 years vs. 54 +/- 13 years, P = 0.007) and more likely to be female (56% vs. 35%, P = 0.001), obese (body mass index > or =30 kg/m(2), 62% vs. 48%, P = 0.04), have marked systolic (> or =160 mm Hg, 50% vs. 27%, P <0.001) and diastolic (> or =110 mm Hg, 25% vs. 13%, P = 0.02) hypertension, and use calcium antagonists (34% vs. 14%, P = 0.001). Patients with decreased function were more likely to use alcohol (37% vs. 20%, P = 0.007), angiotensin-converting enzyme (ACE) inhibitors (85% vs. 62%, P <0.001), and digoxin (57% vs. 27%, P <0.001); and more likely to have tachycardia (51% vs. 32%, P = 0.004), rales (89% vs. 80%, P = 0.05), electrocardiographic left ventricular hypertrophy (42% vs. 22%, P = 0.002), left atrial abnormality (52% vs. 22%, P <0.001), or flow cephalization on chest radiograph (91% vs. 79%, P = 0.02). Only sex, tachycardia, and use of digoxin and ACE inhibitors were associated with ventricular function in multivariable analysis. However, the sensitivity, specificity, and predictive values for all clinical variables were low. Differences in clinical parameters in heart failure patients with decreased versus normal systolic function cannot predict systolic function in these patients, supporting recommendations that heart failure patients should undergo specialized testing to measure ventricular function.

Aged↗

PubMed1968

Nonsteady-state three compartment tracer kinetics. I. Theory.

A set of differential equations is derived which describes the four unidirectional fluxes of a substance across the boundaries of the central compartment of a serially arranged three compartment system, and the amount of this substance present in the central compartment. An analytic solution is obtained which yields all of these quantities as functions of time. The analysis is associated with a defined set of repetitive experiments from which the necessary data are obtained and during which the two outer compartments must be subject to experimental control. The solution is applicable to both the initial steady state and a transient, time-dependent state created by making a step change in the initial conditions. It describes the fluxes and compartment size without assuming that constant kinetic coefficients relate the fluxes to compartmental quantities but is limited by the requirement that the response of the system be repeatable in time.

Biophysical Phenomena↗

PubMed1997

Mutagenesis of an immunodominant T cell epitope can affect recognition of different T and B determinants within the same antigen.

The effects of mutagenesis of residues of a major T cell epitope were investigated in order to expand knowledge from synthetic peptides to the naturally processed antigen. The impact of substitutions within the core of the immunodominant p61-80/PT19 mycobacterial epitope was ascertained in respect of this epitope per se, or of a C-terminal (140-159) overlapping T/B epitope and of a conformational B epitope. The core substitution A71L impaired T immunogenicity of the target epitope within the protein, but not in the peptide, whereas the N73A substitution impaired the responses in both instances. Notably, each of these single amino acid mutations abrogated the T but not the B immunogenicity of the C-terminal epitope. Furthermore, mutation of five core residues (71-76) also ablated expression of a monoclonal antibody defined conformational B epitope. In conclusion, immunological analysis of mutated proteins revealed functional associations between topographically distinct antigenic determinants which may account for the previously observed differences in the specificity of immune responses between immunised and infected hosts.

Animals↗

PubMed2000

Right lower prefronto-parietal cortical dysfunction in akinetic catatonia: a combined study of neuropsychology and regional cerebral blood flow.

BACKGROUND: Catatonia is a psychomotor syndrome that can be characterized by behavioural, affective and motor abnormalities. In order to reveal further underlying pathophysiological mechanisms of psychomotor disturbances in catatonia we investigated neuropsychological function and regional cerebral perfusion (r-CBF) in a combined study. METHODS: Ten catatonic patients were investigated with Tc-99mECD brain SPECT and compared with 10 psychiatric (similar age, sex, medication and underlying psychiatric diagnosis but without catatonic syndrome) and 20 healthy controls. Neuropsychological measures included tests for general intelligence, attention, executive functions and right parietal visual-spatial abilities. Correlational analyses were performed between neuropsychological measures, catatonic symptoms and r-CBF. RESULTS: Catatonic patients showed a significant decrease of r-CBF in right lower and middle prefrontal and parietal cortex compared with psychiatric and healthy controls as well as significantly poorer performance in visual-spatial abilities associated with right parietal function. Correlational analysis revealed significant correlations between visual-spatial abilities and right parietal r-CBF only in psychiatric and healthy controls but not in catatonic patients. In contrast, attentional measures correlated significantly with motor symptoms, visual-spatial abilities and right parietal r-CBF in catatonia only but not in psychiatric or in healthy controls. CONCLUSION: Findings are preliminary but suggest right lower prefronto-parietal cortical dysfunction in catatonia, which may be closely related to psychomotor disturbances.

Adult↗