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PubMed1999

Clinical, genetic, and pharmacogenetic applications of the Invader assay.

The Invader technology has been developed for the detection of nucleic acids. It is a signal amplification system able to accurately quantify DNA and RNA targets with high sensitivity. Exquisite specificity is achieved by combining hybridization with enzyme recognition, which provides the ability to discriminate mutant from wild-type at ratios greater than 1/1000 (mutant/wt). The technology is isothermal and flexible and incorporates a homogeneous fluorescence readout. It is therefore readily adaptable for use in clinical reference laboratories, as well as high-throughput applications using 96-, 384-, and 1,536-well microtiter plate formats. The molecular mechanism of the system and specific applications for use in clinical and research laboratories are described. These include direct analysis of unamplified human genomic DNA to detect mutations and single-nucleotide polymorphisms associated with factor V Leiden, factor II, cystic fibrosis, and apolipoprotein E, and gene expression assays that quantify messenger RNA levels in cells using direct lysates.

Clinical Laboratory Techniques↗
PubMed1997

Immune responses to the hepatitis C virus NS4A protein are profoundly influenced by the combination of the viral genotype and the host major histocompatibility complex.

The interaction between the host major histocompatibility complex (MHC) and the genotype of the hepatitis C virus (HCV) was analysed using synthetic full-length non-structural (NS) 4A proteins, residues 1658-1712, of genotypes 1b, 2b, 3a, 4a and 5a. Human and murine antibodies specific for the five NS4A genotypes analysed focused on residues 1688-1707. In immunized B10 H-2 congenic mice, the H-2d, H-2f and H-2s haplotypes were good responders to NS4A, irrespective of the viral genotype. In contrast, the H-2k haplotype was a low or non-responder to all NS4A genotypes, except for genotype 2b. Also, H-2f- and H-2s-restricted NS4A genotype 1b-specific T-cells focused on residues 1670-1679 and 1683-1692, respectively, whereas H-2k-restricted NS4A genotype 2b-specific T-cells focused on the carboxy terminus. Interestingly, H-2f-restricted genotype 1b-specific T-cells did not cross-react with T-cell site analogues of seven other genotypes, whereas the H-2s-restricted, genotype 1b-specific T-cells cross-reacted with genotypes 1a, 4a and 5a. Thus the combination of viral genotype and host MHC profoundly influences the ability to mount an HCV NS4A-specific immune response.

Amino Acid Sequence↗
PubMed1994

Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells.

Secondary responses to Ag in vivo are characterized by more rapid kinetics and greatly enhanced magnitude compared with primary responses. For CD4+ T cells, this is in part due to a greater frequency of Ag-specific memory cells, and may also reflect differences in responsiveness of memory vs naive cells to stimulation. To compare activation requirements and the role of accessory cells, naive and memory cells were stimulated with immobilized anti-CD3 in the presence or absence of APC. With anti-CD3 alone, naive cells proliferated slightly but produced no detectable IL-2, whereas memory cells proliferated well with significant IL-2 production. Increasing numbers of T-depleted APC greatly enhanced responses of naive cells to levels equivalent to those of memory cells, whereas for memory cells only IL-2 production increased slightly. The response of naive cells was equivalent in magnitude and kinetics to that of memory cells when low density APC, enriched in dendritic cells and depleted of resting B cells, were used with anti-CD3. To directly compare naive and memory responses in an Ag-specific model, we examined CD4+ cells specific for a peptide of pigeon cytochrome c fragment isolated from TCR-alpha beta transgenic mice. Naive cells were compared with 4-day activated blasts (effectors) and memory cells generated by adoptive transfer of effectors to adult thymectomized bone marrow reconstituted mice, in which the cells return to a resting state but still respond to recall Ag. Naive cells responded to Ag on dendritic cells and activated B cells but not on resting B cells or macrophages. In contrast, both memory cells and effectors were stimulated by all APCs, including resting B cells and macrophage to a limited extent. The ability of memory cells to respond to all APC types was confirmed using Ag-specific cells generated by in vivo priming with keyhole limpet hemocyanin. These results suggest that memory cells are considerably less dependent on accessory cell costimulation than naive cells, but that naive cells can respond equivalently in both magnitude and kinetics if Ag is presented on costimulatory APCs such as dendritic cells. In addition, these studies suggest that the enhanced secondary T cell response is due to a combination of the increased frequency of Ag-specific cells and their ability to react to Ag presented on a wider range of APC types, rather than an inherent capacity of memory T cells to respond better and faster.

Animals↗
PubMed2004

Herbivore-induced plant vaccination. Part II. Array-studies reveal the transience of herbivore-specific transcriptional imprints and a distinct imprint from stress combinations.

Summary Microarray technology has given plant biologists the ability to simultaneously monitor changes in the expression of hundreds of genes, and yet, to date, this technology has not been applied to ecological phenomena. In native tobacco (Nicotiana attenuata), prior attack of sap-feeding mirids (Tupiocoris notatus) results in vaccination of the plant against subsequent attacks by chewing hornworms (Manduca sexta). This vaccination is mediated by a combination of direct and indirect defenses and tolerance responses, which act in concert with the attack preferences of a generalist predator. Here, we use microarrays enriched in herbivore-elicited genes with a principal components analysis (PCA) to characterize transcriptional 'imprints' of single, sequential, or simultaneous attacks by these two main herbivores of N. attenuata. The PCA identified distinctly different imprints left by individual attack from the two species after 24 h, but not after 5 days. Moreover, imprints of sequential or simultaneous attacks differed significantly from those of single attack, suggesting the existence of a distinct gene expression program responsive to the combination of biological stressors. A dissection of the transcriptional imprints revealed responses in direct and indirect defense genes that were well correlated with observed increases in defense metabolites. Attack from both herbivores elicits a switch from growth- to defense-related transcriptional processes, and herbivore-specific changes occur largely in primary metabolism and signaling cascades. PCA of these polygenic transcriptional imprints characterizes the ephemeral changes in the transcriptome that occur during the maturation of ecologically relevant phenotypic responses.

Animals↗
PubMed1984

A method for specific chemical modification of gamma-carboxyglutamic acid residues in proteins.

A method for the chemical modification of gamma-carboxyglutamic acid (Gla) residues in proteins is introduced that has the combined advantages of mildness, a high degree of specificity, and the ability to introduce a radiolabel at modification sites for ease in quantitation. Unlike other Gla modification procedures which are performed in the lyophilized state at 110 degrees C, this procedure is carried out in solution at 37 degrees C. The addition of morpholine and formaldehyde to a slightly acidic solution of bovine prothrombin fragment 1 (residues 1-156) results in the conversion of Gla residues to gamma- methyleneglutamic acid (gamma- MGlu ). The extent of modification is controlled by the relative amounts of modification reagents to protein. A 100-fold molar excess of reagents to fragment 1 produced a protein molecule containing two gamma- MGlu residues, while a modification run at 10,000-fold molar excess of reagents to protein yielded fragment 1 containing eight gamma- MGlu residues per molecule. The specificity of this modification is illustrated by the interaction of native and modified protein with antibody populations directed against fragment 1. Native fragment 1, 8 gamma- MGlu fragment 1, and 2 gamma- MGlu fragment 1 show fairly similar behavior toward whole anti-fragment 1 serum. Differential behavior was exhibited by the native and modified proteins toward a subpopulation of antibodies specific to the calcium ion conformation of fragment 1. Unmodified fragment 1 displayed a strong affinity for these antibodies; however, the 2 gamma- MGlu fragment 1 exhibited a moderate affinity and the 8 gamma- MGlu fragment 1 did not bind to these antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Carboxyglutamic Acid↗
PubMed2005

Characterizing occupational therapy practice in stroke rehabilitation.

UNLABELLED: Richards LG, Latham NK, Jette DU, Rosenberg L, Smout RJ, DeJong G. Characterizing occupational therapy practice in stroke rehabilitation. OBJECTIVES: To describe how occupational therapy (OT) activities during stroke inpatient rehabilitation vary by admission functional status and over time and how time spent in these various activities relates to functional status at discharge. DESIGN: Observational cohort study. SETTING: Six inpatient rehabilitation hospitals in the United States. PARTICIPANTS: People (N=713) receiving 4 to 19 hours of post-stroke OT. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients were categorized by number of 4-hour blocks of OT received and by admission upper-extremity (UE) dressing score on the FIM instrument. In each group, the percentage of time spent in 16 activities and the percentage of patients who received each activity were calculated. The amount of time in activities was compared for those patients scoring 1 or 2 at admission who achieved at least a level of supervision for UE dressing (a score of >or=5) using Wilcoxon 2-sample tests. RESULTS: The majority of OT time was spent in impairment-focused activities (37.5%) or training basic activities of daily living (31.9%). Treatment progressed to more advanced activities over time (eg, less bed mobility, more home management), yet little time was spent on community integration or leisure activities and with very few patients. Successful patients received more higher-level activities, whereas unsuccessful patients received larger amounts of basic-level activities. CONCLUSIONS: OT activities focused on a combination of remediating impairments and retraining specific functional tasks, at the ability level of each individual patient, and provided higher-level activities as patients improved their function. More time in higher-level activities was related to greater success in rehabilitation. However, higher-level activities remain the least common activities provided during inpatient rehabilitation.

Activities of Daily Living↗
PubMed2000

A review of age-related changes in energy regulation and suggested mechanisms.

This review discusses recent studies on possible causes of weight loss in older individuals. Studies of the regulation of food intake suggest that aging is associated with an impairment in the regulation of food intake that inhibits appropriate short-term and long-term compensation for imposed alterations in energy intake. The combination of a reduced ability to regulate energy intake, decreased sensory specific satiety, and adverse social factors such as functional limitations, social isolation and depression, increases the risk of negative energy balance leading to weight loss in older individuals.

Aging↗
PubMed2000

Chemically sensitive high throughput parallel analysis of solid phase supported library members

This paper introduces Fourier transform infrared imaging as a powerful spectroscopic tool for the parallel identification of members of resin-supported combinatorial libraries. This technique combines the chemical specificity and high sensitivity of FTIR with the ability to rapidly analyze multiple supported resin beads simultaneously. It is shown here that the chemical identity of ligands on a variety of supported resin beads can be identified in a single experiment without destroying or otherwise perturbing the system.

Journal Article↗
PubMed1995

A segment of the C-terminal half of the G-protein beta 1 subunit specifies its interaction with the gamma 1 subunit.

The beta and gamma subunits of the heterotrimeric guanine nucleotide binding (G protein) act as a dimer and directly regulate various signal transduction pathways. By using cotransfection assays, we tested the ability of several beta gamma combinations to activate inositol phospholipid-specific phospholipase C (PI-PLC)-beta 2. Our findings indicate that only beta gamma combinations that form dimers will activate PI-PLC-beta 2. Since G beta 1 interacts with G gamma 1, while G beta 2 cannot, chimeras between G beta 1 and G beta 2 were used to identify the regions in beta 1 that determine its specific association with gamma 1. Our evidence demonstrates that a chimera between beta 2 and beta 1 that contains the C-terminal 173 amino acids of beta 1 can interact and activate PI-PLC-beta 2 with gamma 1. Chimeras that contain portions of the beta 1 C-terminal region display a weaker association with gamma 1. Furthermore, the contribution of each of these regions depends on the sequence context of each chimeric protein. However, the segment between residues 210 and 293 of beta 1 consistently plays a critical role in specifying association with gamma 1.

Amino Acid Sequence↗
PubMed2002

Bioengineering of a phytoremediation plant by means of somatic hybridization.

Phytoremediation is a technology that exploits a plant's ability to remove contaminants from the environment or render toxic compounds harmless. An efficient metal phytoremediating plant must combine high biomass production and established cultivation methods with high tolerance to a specific contaminant and ability for root uptake, translocation, and compartmentalization of contaminants in the above-ground biomass. Symmetric and asymmetric somatic hybridizations were used to introduce toxic metal-resistant traits from Thlaspi caerulescens into Brassica juncea. B. juncea hypocotyl protoplasts were fused with T. caerulescens mesophyll protoplasts. The hypocotyl protoplasts of B. juncea were stained with CFDA before fusion and thus fluoresced green under UV, whereas the mesophyll protoplasts of T. caerulescens had red autofluorescense. Heteroplasmic fusion products were identified and selected by flow cytometry and cell sorting. All putative hybrids grown in the greenhouse had morphological characteristics of B. juncea. A Thlaspi-specific repetitive sequence was hybridized to total DNA of plants, including the parental species. All plants from both symmetric and asymmetric fusions showed Thlaspi-specific hybridization patterns while B. juncea did not exhibit any hybridization signal. Hybrid plants, produced by asymmetric somatic hybridization between the two species, demonstrated high metal accumulation potential, tolerance to toxic metals, and good biomass production.

Journal Article↗
PubMed2005

A Bayesian framework for SNP identification.

As evolutionary models for single-nucleotide polymorphisms (SNPs) become available, methods for using them in the context of evolutionary information and expert prior information is a necessity. We formulate a probability model for SNPs as a Bayesian inference problem. Using this framework we compare the individual and combined predictive ability of four evolutionary models of varying levels of specificity on three SNP databases (two specifically targeted at functional SNPs) by calculating posterior probabilities and generating Receiver Operating Characteristic (ROC) curves. We discover that none of the models do exceptionally well, in some cases no better than a random-guess model. However, we demonstrate that several properties of the Bayesian formulation improve the predictability of SNPs in the three databases, specifically the ability to utilize mixtures of evolutionary models and a prior based on the genetic code.

Bayes Theorem↗
PubMed1955

SEROLOGICAL activity of various fractions of culture filtrates of the tubercle bacillus.

As culture filtrates of Mycobacterium tuberculosis have been shown by numerous workers to be antigenically heterogeneous, a series of experiments has been started to identify some of the different antigens likely to be useful in laboratory tests for measuring the antibodies in human blood. The work involves the fractionation of concentrated culture filtrates by various chemical procedures, the chemical analysis of the fractions, and their subsequent testing and cross-testing with various serological procedures.A number of fractions made from filtrates of heated and unheated cultures have been tested for activity in the Middlebrook-Dubos haemagglutination test. As might be expected, the fractions were found to vary in potency, some showing at least a thousand times more erythrocyte-sensitizing activity than others. Cross-inhibition tests made with the most active preparations indicated the existence of at least two different substances responsible for sensitizing erythrocytes to agglutination, one being demonstrable only in certain unheated fractions.Antibodies detected with the tannic acid haemagglutination test have a different serological specificity from those detected by the Middlebrook-Dubos test. Different heated fractions gave strong cross-reactions with each other in the tannic acid haemagglutination procedure, and little difference could be seen between them; in contrast, four active fractions from unheated filtrates were distinct from each other, showing very little cross-reaction.Results obtained with another haemagglutination procedure, consisting of agglutination of normal erythrocytes by antiserum-antigen mixtures, showed that this method detected another antigen, not measured in the tannic acid or Middlebrook-Dubos techniques under the conditions of the tests.The present experiments have shown that the culture filtrates and fractions thereof contain a series of distinct antigens or at least characteristic combinations of antigens that differ in serological specificity and in their ability to react in the different tests. Further experiments are necessary to determine whether the serological differences are of any special significance in relation to tuberculous disease or bacterial type specificity.

Antibodies↗
PubMed1995

Endoscopic evaluation of iron deficiency anemia. A guide to diagnostic strategy in older patients.

Gastrointestinal blood loss is the primary cause of iron deficiency anemia in older adults. Bidirectional endoscopy (combined colonoscopy and esophagogastroduodenoscopy) is highly sensitive and specific in its ability to locate gastro-intestinal lesions resulting in iron deficiency anemia. Although the diagnostic yield of esophagogastroduodenoscopy is higher than that of colonoscopy, the possibility of malignant disease dictates that initial colonoscopy be performed in all but a few cases involving distinct upper gastrointestinal risk factors and symptoms. If neither colonoscopy nor esophagogastroduodenoscopy identifies a source of blood loss, a safe course is to observe the patient and provide supplemental iron. Patients who fail to respond to supplemental iron or who become transfusion-dependent require further evaluation. Small-bowel evaluation has a role in selected patients.

Aged↗
PubMed1998

The contemporary value of pretreatment prostatic acid phosphatase to predict pathological stage and recurrence in radical prostatectomy cases.

PURPOSE: We examine the clinical prognostic value of the currently available simple and inexpensive immunoenzymatic prostatic acid phosphatase (PAP) assay for the staging and prognosis of radical prostatectomy cases. MATERIALS AND METHODS: Between February 1, 1990 and May 3, 1996 pretreatment PAP was measured in 295 patients who underwent radical prostatectomy. From February 1, 1990 to May 17, 1992 the Hybritech Tandem-E assay was used in 75 cases, from May 18, 1992 to February 28, 1993 the Abbott EIA assay was used in 49 and from March 1, 1993 to May 3, 1996 the Abbott IMx assay was used in 171. PAP assays were analyzed individually and the results were combined with pretreatment prostate specific antigen (PSA) values to assess the ability to predict organ confined prostate cancer and serological recurrence after radical prostatectomy. RESULTS: PAP testing was not of value for predicting organ confined disease or positive margins. However, this test was useful for predicting the first serological PSA recurrence in the 3 periods (77 to 85% correct) and overall (82% correct, p < 0.001, odds ratio 6.06). The Kaplan-Meier disease-free survival rate at 4 years was 78.8% for men with PAP less than 3 ng./ml. and 38.8% for those with PAP 3 ng./ml. or greater, which was significant when pretreatment PSA was less than 10 ng./ml. (p = 0.047), 10 ng./ml. or greater (p = 0.012) and overall (p < 0.001). PAP testing added prognostic information to pretreatment PSA values and it was an independent predictor of recurrence. CONCLUSIONS: The widely available and inexpensive PAP assays of the 1990s are predictors of recurrence after radical prostatectomy. They should be included in future studies of prostate cancer recurrence modeling. However, they do not predict pathological stage or margin status.

Acid Phosphatase↗
PubMed1997

The role of the extracellular matrix in arterial remodelling.

The extracellular matrix is now recognized as a biologically active and dynamic composition of structural, adhesive, and counteradhesive fibrous proteins embedded in a hydrated ground substance of glycosaminoglycans and proteoglycans. The ability of resident cells to detect small differences in the specific combination, concentration and distribution of matrix components suggests that perturbation of the homeostatic matrix can lead to remodelling following angioplasty. Recent studies reviewed herein have focused on how alterations of the relative composition of matrix components ultimately leads to changes in cell growth, behaviour and differentiation, all of which can significantly contribute to remodelling of the vascular wall following injury. These cell-matrix interactions may provide novel therapeutic targets in the prevention of unfavourable remodelling that leads to restenosis.

Adaptation, Physiological↗
PubMedDate not supplied

Monoclonal antibody identifies a distinctive epitope expressed by human multiple myeloma cells.

Employing a technology called differential immunization for antigen and antibody discovery (DIAAD), we aimed to generate monoclonal antibodies (mAbs) specific to human multiple myeloma (MM) cells. The fundamental principles of DIAAD rely on the induction of high zone tolerance to the "wild type" (normal) antigen. followed by immunization with the modified (diseased) antigen. Because chronic myelogenic leukemia (CML) cells are derived from a lineage closely related to MM, we immunized mice by contrasting a pool of MM cells with CML cells. Monoclonal antibody VAC69 reacted exclusively with MM cells, identifying a membrane molecule composed of a single-chain glycoprotein with a molecular weight of 78-120 kd. This antigen exhibited narrow tissue specificity and was not found on human cancers such as prostate, breast, or cervical carcinoma; leukemia; or lymphoma, nor was it seen on normal human peripheral lymphocytes or on Epstein-Barr virus-transformed B-cell lines. By immunohistochemistry, mAb VAC69 showed no binding to antigens expressed on normal human ovary, breast, prostate, lung or colon tissue, nor did it bind to human breast or prostate cancer. Conversely, mAb VAC69 bound strongly to human MM, although showing only slight binding to histiocytes or inflamed cells in human lymph nodes and human tumors of the colon, lung, and ovary. Monoclonal antibody VAC69 also triggered cancer-specific cytotoxicity in vitro (in the presence of complement) as well as in vivo using a sever combined immunodeficiency model transplanted with human MM. Further studies showed the ability of mAb VAC69 to be specifically internalized by human MM cells, indicating its potential use for therapeutic intervention in MM by delivering drugs into cancer cells.

Animals↗
PubMed1985

Prediction of fetal lung maturity: inaccuracy of study using conventional ultrasound instruments.

The ability of three ultrasound (US) parameters--echogenicity, texture, and through transmission--to predict fetal lung maturity was tested in 59 patients using currently available clinical US equipment. The chi square test was used to determine whether there was an association between any single parameter and a "mature" lecithin/sphingomyelin (LS) ratio or specific phosphatidycholine (SPC). Multiple linear regression analysis was used to assess the combined ability of these three parameters and gestational age to predict LS ratio and SPC. There was no correlation between fetal lung maturity, as determined by mature LS and SPC indices, and the US parameters tested using unmodified clinical equipment.

Amniocentesis↗
PubMed2006

Site-specific labeling of proteins for single-molecule FRET by combining chemical and enzymatic modification.

An often limiting factor for studying protein folding by single-molecule fluorescence resonance energy transfer (FRET) is the ability to site-specifically introduce a photostable organic FRET donor (D) and a complementary acceptor (A) into a polypeptide chain. Using alternating-laser excitation and chymotrypsin inhibitor 2 as a model, we show that chemical labeling of a unique cysteine, followed by enzymatic modification of a reactive glutamine in an N-terminally appended substrate sequence recognition tag for transglutaminase (TGase) affords stoichiometrically D-/A-labeled protein suitable for single-molecule FRET experiments. Thermodynamic data indicate that neither the presence of the TGase tag nor D/A labeling perturbs protein stability. As the N terminus in proteins is typically solvent accessible, a TGase tag can (in principle) be appended to any protein of interest by genetic engineering. Two-step chemical/enzymatic labeling may thus represent a simple, low-cost, and widely available strategy for D/A labeling of proteins for FRET-based single-molecule protein folding studies, even for non-protein-experts laboratories.

Cysteine↗