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Results for “functional profiling”

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At least 1,009 records · Page 56Linked to original sources
PubMed2000

Importance of the alanine methyl ester side chain for the biological activity profile of dual-function phenyl phosphate derivatives of bromo-methoxy-zidovudine.

In a systematic search for developing a virucidal spermicide with potent anti-human immunodeficiency virus (HIV) and spermicidal activities, we synthesized and evaluated 14 phosphoramidate derivatives of 5-bromo-6-methoxy-zidovudine (PP-BMZ) with differing amino acid ester side chains and para substitutions on the phenyl moiety. Anti-HIV activity was tested by measuring viral p24 antigen production as a marker of viral replication in HIV-1-infected human peripheral blood mononuclear cells. The effect of various PP-BMZ compounds on human sperm motion kinematics was analysed by computer-assisted sperm analysis. Varying the Ala side chain of the phosphoramidate group to other non-polar amino acids, including the cyclic amino acids proline and tryptophan, led to significant alterations in both anti-HIV and spermicidal activities. Our findings highlight the necessity of the Ala side chain and the presence of an electron-withdrawing para-bromo substituent on the phenyl moiety in addition to the bromo-methoxy functional groups on the thymine ring for the PP-BMZ compounds to be effective virucidal spermicides. These membrane permeable dual-function nucleoside analogues may provide the basis for a new strategy aimed at prevention of the sexual transmission of HIV while providing fertility control for women.

Alanine↗
PubMed2005

MMPI-2 personality profiles of high-functioning adults with autism spectrum disorders.

The Minnesota Multiphasic Personality Inventory-Second Edition was administered to 20 adults with autism spectrum disorders (ASD) who fell in the average to above average range of intelligence and 24 age-, intelligence-, and gender-matched college students. Large group differences, with the ASD group scoring higher, were found on the L validity scale, Clinical Scales 2 (D) and 0 (Si), Content scale Social Discomfort (SOD), Supplementary scale Repression (R), and Personality Psychopathology Five (PSY-5) scale INTR (Introversion). The proportion of ASD adults scoring in the clinical range on these scales was between 25% and 35%. High scores on these scales are consistent with the clinical picture of Asperger syndrome and high-functioning autism in adulthood. Future directions and implications for identifying adults in need of a specialized autism assessment are discussed.

Adolescent↗
PubMed2026

Thrombin concentration shapes endothelial extracellular vesicle profiles with divergent inflammatory functions.

Thrombin, a central enzyme in the coagulation cascade, also regulates diverse cellular processes, including inflammation and vascular barrier function, primarily by activating protease-activated receptor 1. Previous studies demonstrated that thrombin elicits concentration-dependent, opposing effects; low concentrations confer anti-inflammatory and barrier-protective responses, whereas high concentrations promote inflammation and barrier disruption. The underlying mechanisms, however, remain incompletely understood. Here, we showed that thrombin stimulates extracellular vesicle (EV) release from endothelial cells across a broad concentration range and that EVs generated at low vs high thrombin concentrations carry distinct microRNA (miR) cargo. Low-thrombin EVs mediate cytoprotective responses via the transfer of miR-409-5p, which targets ubiquitin-specific protease 7 that promotes inflammation via the NF-kB signaling pathway in recipient cells, whereas high-thrombin EVs disrupt barrier integrity and promote inflammation through delivery of miR-155-5p, a regulator of suppressor of cytokine signaling 1 that acts as a crucial negative regulator of the cytokine signaling pathway. Functional manipulation of these EVs confirmed the causal roles. Incorporation of anti-miR-409-5p abrogated the protective effects of low-thrombin EVs, whereas anti-miR-155-5p suppressed the cytopathic effects of high-thrombin EVs. Moreover, control EVs engineered to carry a miR-409-5p mimic reproduced the anti-inflammatory and barrier-protective phenotype of low-thrombin EVs. Collectively, these findings identified EV-associated miRs as key mediators of the concentration-dependent dual actions of thrombin, which may open the therapeutic potential of EVs engineered to deliver selective miRs or anti-miRs for the treatment of inflammatory vascular diseases.

Thrombin↗
PubMed1994

Profile of chicken macrophage functions after exposure to catecholamines in vitro.

The effects of catecholamines (CA) on various chicken macrophage functions were examined. Macrophage monolayers were exposed to .01, .1, .25, 1, 2, and 5 micrograms/mL of dopamine (DA), norepinephrine (NE) and epinephrine (E) for 1 hr. All CA were toxic for macrophages at 1-5 micrograms dose range resulting in 25-50% cell death. All CA at the .1 and .25 micrograms/mL level increased E. coli and sheep red blood cells (SRBC) phagocytosis by macrophages. The percentage of Fc-receptor positive macrophages increased after CA exposure. Prolonged exposure of macrophages (3 hr) reduced SRBC phagocytosis by DA-treated but not in NE- and E-treated macrophages. However, after 1 hr exposure and 3 hr recovery period, CA-induced changes were reversed in all but DA-treated cultures. Apomorphine and metoclopromide blocked DA whereas propranolol blocked NE and E effects suggesting specificity of the observed effects via catecholaminergic receptors on chicken macrophages. Dopamine and NE (.25 micrograms/mL) did not affect but E exposure enhanced LPS-induced tumoricidal factor production. These findings suggest that CA modulate chicken macrophage effector functions.

Animals↗
PubMed1984

Interpreting the profile of liver-function tests in pediatric liver transplants.

Results of traditional laboratory tests of liver function were correlated with the clinical course in 26 pediatric patients after liver transplantation. On the basis of clinical outcome after transplantation, the patients were divided into two groups: (a) uncomplicated course with short hospital stay, and (b) post-transplantation course complicated by multiple clinical problems. The patterns of results for tests reflecting liver function--bilirubin (total and conjugated), aspartate (EC 2.6.1.1) and alanine (EC 2.6.1.2) aminotransferases, and gamma-glutamyltransferase (gamma GT, EC 2.3.2.2)--were consistent with the clinical findings in these patients. Values for alkaline phosphatase (EC 3.1.3.1), however, were only rarely increased, even when there was clinical evidence of biliary obstruction. Not only was serum gamma GT increased in obstructive jaundice, but this sometimes was the only test giving results outside the normal limits. We suggest that the persistent and marked increases of gamma GT observed in half of the patients may have resulted from immune-mediated damage to the transplanted liver.

Adolescent↗
PubMed1994

Echocardiographic profile of the normally functioning Omnicarbon valve.

Transthoracic echocardiography was performed in 141 patients with 90 Omnicarbon valves in the aortic and 66 in the mitral position. Additionally, 53 of them were investigated by transesophageal echocardiography comparing monoplane and multiplane facilities. The opening direction of the disc and the location of the pivot axis could be correctly determined by transthoracic, monoplane, and multiplane transesophageal echocardiography, respectively, in 100%, 80%, and 100% of the mitral and in 53%, 21%, and 82% of the aortic prostheses. Small regurgitation jets were detected in 90% of the aortic valves (1.6 +/- 0.4 cm2) by transthoracic and in all mitral prostheses (2.3 +/- 0.8 cm2) by transesophageal echocardiography. Based on morphological identification of the pivot points structures, origins of leakage jets were clearly identified as "design-related" in 12% (transthoracic echocardiography of aortic valves) to 100% (multiplane transesophageal echocardiography of mitral valves). In the aortic position, values obtained for transprosthetic forward flow velocity measurements exhibited wide scatter which did not allow a firm separation between valve sizes. No better differentiation was possible by using the calculated Doppler gradients or the velocity time integrals, either. Mean gradients and velocity time integrals showed even smaller differences between groups in the mitral valve patients. It is concluded that the Omnicarbon valve has a suitable design for morphological echocardiographic examination, and multiplane transesophageal technique expands the diagnostic capability. Forward flow measurements do not appear to be suited for detecting a beginning obstruction of this mechanical prosthesis.

Adult↗
PubMed1998

Fibroblast growth factor receptor 4, implicated in progression of islet cell carcinogenesis by its expression profile, does not contribute functionally.

Fibroblast growth factor receptor 4 (FGFR4) gene expression is activated in late-stage beta-cell tumors that develop in transgenic mice harboring SV40 large T antigen (Tag) gene that is under the transcriptional control of the insulin promoter (RIP-Tag). The FGFR4 gene was active in cell lines derived from tumors but not in cells derived from hyperplastic islets. We used both gain-of-function and loss-of-function FGFR4 transgenic mice to determine whether FGFR4 modulates islet cell tumorigenesis and, if so, to identify the nature of the effect. Both types of FGFR4 transgenic mice were viable and fertile and developed islet tumors when crossed with RIP-Tag mice. Remarkably, there was no significant perturbation in the tumorigenesis pathway resulting from either chronic up-regulation or absence of FGFR4 gene expression. Analyses included the incidence and size of tumors, rate of cell proliferation, cell density, and life span. We conclude that FGFR4 gene activation is a marker of but is not causal for beta-cell transformation.

Adenoma, Islet Cell↗
PubMed2003

Identification of functional links between genes using phylogenetic profiles.

MOTIVATION: Genes with identical patterns of occurrence across the phyla tend to function together in the same protein complexes or participate in the same biochemical pathway. However, the requirement that the profiles be identical (i) severely restricts the number of functional links that can be established by such phylogenetic profiling; (ii) limits detection to very strong functional links, failing to capture relations between genes that are not in the same pathway, but nevertheless subserve a common function and (iii) misses relations between analogous genes. Here we present and apply a method for relaxing the restriction, based on the probability that a given arbitrary degree of similarity between two profiles would occur by chance, with no biological pressure. Function is then inferred at any desired level of confidence. RESULTS: We derive an expression for the probability distribution of a given number of chance co-occurrences of a pair of non-homologous orthologs across a set of genomes. The method is applied to 2905 clusters of orthologous genes (COGs) from 44 fully sequenced microbial genomes representing all three domains of life. Among the results are the following. (1) Of the 51 000 annotated intrapathway gene pairs, 8935 are linked at a level of significance of 0.01. This is over 30-fold greater than the 271 intrapathway pairs obtained at the same confidence level when identical profiles are used. (2) Of the 540 000 interpathway genes pairs, some 65 000 are linked at the 0.01 level of significance, some 12 standard deviations beyond the number expected by chance at this confidence level. We speculate that many of these links involve nearest-neighbor path, and discuss some examples. (3) The difference in the percentage of linked interpathway and intrapathway genes is highly significant, consistent with the intuitive expectation that genes in the same pathway are generally under greater selective pressure than those that are not. (4) The method appears to recover well metabolic networks. This is illustrated by the TCA cycle which is recovered as a highly connected, weighted edge network of 30 of its 31 COGs. (5) The fraction of pairs having a common pathway is a symmetric function of the Hamming distance between their profiles. This finding, that the functional correlation between profiles with near maximum Hamming distance is as large as between profiles with near zero Hamming distance, and as statistically significant, is plausibly explained if the former group represents analogous genes.

Algorithms↗
PubMed2001

Renal function: the Cinderella of cardiovascular risk profile.

The presence of an altered renal function in essential hypertension, advanced heart failure (HF) and after a myocardial infarction (MI) is associated with higher cardiovascular morbidity and mortality. Indices of altered renal function (e.g., microalbuminuria, increased serum creatinine concentrations, decrease in estimated creatinine clearance or overt proteinuria) are independent predictors of cardiovascular morbidity and mortality in any of the three clinical situations. These parameters should then be routinely evaluated in clinical practice. These facts have several therapeutic implications. First, although there is no evidence-based information on the level of blood pressure that confers optimal renal protection, levels substantially lower than past recommendations are advisable. Second, hypertensive kidney damage should be prevented by early treatment of hypertensive patients, particularly those with microalbuminuria. Finally, to avoid further aggravation of high cardiovascular risk, antihypertensive agents devoid of unwanted metabolic side effects should be used for the treatment of hypertensive vascular damage. In HF, the combination of an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker seem to be the most renoprotective. Renal outcome is also improved by ACE inhibition after an MI. Finally, renal and cardiovascular outcome seem to run in parallel in all these situations.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Integrative investigation of metabolic and transcriptomic data.

BACKGROUND: New analysis methods are being developed to integrate data from transcriptome, proteome, interactome, metabolome, and other investigative approaches. At the same time, existing methods are being modified to serve the objectives of systems biology and permit the interpretation of the huge datasets currently being generated by high-throughput methods. RESULTS: Transcriptomic and metabolic data from chemostat fermentors were collected with the aim of investigating the relationship between these two data sets. The variation in transcriptome data in response to three physiological or genetic perturbations (medium composition, growth rate, and specific gene deletions) was investigated using linear modelling, and open reading-frames (ORFs) whose expression changed significantly in response to these perturbations were identified. Assuming that the metabolic profile is a function of the transcriptome profile, expression levels of the different ORFs were used to model the metabolic variables via Partial Least Squares (Projection to Latent Structures--PLS) using PLS toolbox in Matlab. CONCLUSION: The experimental design allowed the analyses to discriminate between the effects which the growth medium, dilution rate, and the deletion of specific genes had on the transcriptome and metabolite profiles. Metabolite data were modelled as a function of the transcriptome to determine their congruence. The genes that are involved in central carbon metabolism of yeast cells were found to be the ORFs with the most significant contribution to the model.

Algorithms↗
PubMed2026

Whole metagenome sequencing: not deep enough for complete microbial function recovery.

BACKGROUND: Whole metagenome shotgun sequencing (WMS) is widely used to profile microbial function. However, technical variability in sequencing and analysis often obscures true biological patterns. Large-scale studies are particularly susceptible to batch effects, such as differences in sequencing depth and platform and annotation strategies, as well as sample-to-flow-cell assignments. However, the relative effects of these factors on functional inference in such studies have yet to be systematically evaluated. We analyzed oral-rinse WMS data from 671 Nigerian youths aged 9-18, sequenced on two Illumina platforms. Microbial molecular functionality encoded in these data was annotated using the mi-faser/Fusion pipeline, to capture the broad functional repertoire, and HUMAnN 3/EC numbers pipeline to characterize curated enzymatic activities. We then quantified how technical factors and batch effects shaped the recovery of microbial functionality. RESULTS: Three findings of our work were most salient. First, we observed that the choice of annotation strategy traded off between breadth and specificity of functional coverage. Second, we found that low-prevalence functions were disproportionately lost at shallow sequencing depths, indicating that in, e.g., case-control studies with few representatives of the minor class, sequencing depth could critically impact study resolution. Finally, using our newly developed model relating sequencing depth to functional recovery, we demonstrated that increasing sequencing depth does not directly or proportionally improve functional recall. That is, at as little as 10% of this study's sequencing depth, 30% of the estimated complete microbiome functional repertoire was detectable. However, even at the full depth used in this study, we were only able to recover an estimated 60% of that complete functional repertoire. We further showed that despite biomes differences in functional diversity and host contamination levels (e.g., soil, fecal), incomplete functional recovery at commonly used sequencing depths was consistently observed. CONCLUSIONS: Together, these findings and our depth-to-function mapping framework provide practical guidelines for the design and interpretation of WMS studies. Coordinating sequencing depth planning with annotation strategy, experimental design, and rigorous batch control is thus essential for robust detection of microbial functions and for ensuring reproducible microbiome insights. Video Abstract.

Humans↗
PubMed2006

Utility of biochemical screening in the context of evaluating patients with a presumptive diagnosis of osteoporosis.

The ageing population is expected to increase the burden of osteoporosis on the health care system. Secondary causes of osteoporosis are found in a proportion of patients. There is much controversy regarding the best work-up for patients who have been diagnosed as having osteoporosis based on bone mineral density. It is difficult to decide where interventions should be targeted both from a patient's perspective and for cost effectiveness. We evaluated the utility of a standard panel (full blood count, plasma viscosity, plasma protein, electrophoresis, urine Bence Jones protein, thyroid function test, bone profile, fasting lipids and liver function test) of biochemical investigations in 327 consecutive patients (287 females, 40 males) referred to the new patient osteoporosis clinic from April 1999 to March 2000. Patients were characterised after measurement of spinal/femoral neck bone mineral density after a dual energy X-ray absorptiometry (DEXA) scan. There were 88 patients with osteoporosis, 91 with osteopenia, 130 had normal bone mineral density and 20 who did not have a bone scan. No case of multiple myeloma was found in this cohort of patients. There was no difference in the mean plasma viscosity of patients with and without osteoporosis (P=0.182). There was no significant difference in the abnormal urine calcium/creatinine (Ca/Cr ratio) in patients with osteoporosis and those without osteoporosis (P=0.316). There was no significant difference in the prevalence of hypothyroidism (P=0.213) or thyrotoxicosis (P=0.138) in patients with and without osteoporosis. There was no strong correlation between cholesterol concentrations and osteoporosis (r=0.069). We found no utility in performing a myeloma screen. A small proportion of patients had abnormalities of calcium homeostasis or thyroid disease. We recommend that a screening biochemical evaluation should be restricted to calcium/bone profile and thyroid function tests in patients with a presumptive diagnosis of osteoporosis.

Bone Density↗
PubMed2005

The relation between subjective and objective measures of everyday life activities in persons with multiple sclerosis.

OBJECTIVES: To investigate the relation between subjective and objective performance-based measures of functional status in persons with multiple sclerosis (MS), and to compare their performance with healthy controls. DESIGN: A between-groups design, using a correlational approach to examine the relation between objective and subjective measures of functional capacity. SETTING: Outpatient rehabilitation research institution. PARTICIPANTS: Seventy-four subjects with clinically definite MS and 35 healthy controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Executive Function Performance Test (EFPT), Functional Assessment of Multiple Sclerosis (FAMS), and Functional Behavior Profile (FBP). RESULTS: MS participants reported more difficulties performing functional tasks than did the healthy controls. MS participants also performed significantly worse on the EFPT than healthy controls. However, all correlations between subjective and objective functional measures were nonsignificant. After controlling for depressive symptomatology, EFPT performance was significantly associated with FBP scores, but not FAMS scores. CONCLUSIONS: The lack of association between objective performance-based measures and subjective self-report measures of functional activities is a challenge to outcomes measurement and has implications for assessment of functional performance. Results are discussed in terms of the different dimensions that these tools are measuring and their respective strengths and limitations.

Activities of Daily Living↗