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Results for “differential selection”

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PubMed2006

Evidence of differential selection of HIV-1 variants carrying drug-resistant mutations in seroconverters.

OBJECTIVES: To estimate the relative efficiency of transmission of different HIV-1 drug-resistance mutations from patients failing treatment, considered as potential transmitters (PTs), to seroconverters (SCs). DESIGN: Ecological cross-sectional study. METHODS: HIV-1 protease and reverse transcriptase (RT) sequence data, obtained from 155 SCs and 2,690 PTs at the Department of Molecular Biology of the University of Siena, Italy, in the period 1997-2004 were used. The efficiency of transmission was studied by odds ratio (OR) analysis and evaluation of 95% confidence intervals (95% CIs). For mutations not detected in viruses from SCs, a binomial probability model was used, assuming P-values <0.05 as indicative of a negative selection at transmission. RESULTS: The overall prevalence of drug mutations associated with nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PIs) was 13.2%, 4.6% and 2.0% in SCs, and 69.9%, 27.6% and 33.7% in PTs, respectively. Among RT mutations present both in PTs and SCs, M1841/V and T215F/Y had the lowest relative efficiency of transmission, whereas V1181, Y181C/I and K219E/Q showed the highest relative efficiency. Of the three major protease mutations that could be evaluated by this approach, M46l/L had a lower rate of transmission than 184V and L90M. Among the mutations not detected in viruses from SCs, the RT E44D, V1081, Q151M and Y188C/H/L, and the protease D30N, G48V and V82A/F/S/T substitutions appeared to be negatively selected. CONCLUSIONS: The transmission rate of drug-resistant HIV-1 variants may be differentially affected by the mutational pattern. The binomial model enabled to evaluate the negative selection against specific substitutions. Given the low prevalence of some resistance mutations in SCs, very large data sets are required to evaluate the potential selection of such mutations.

Anti-HIV Agents↗
PubMed1999

Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate.

A series of hydroxamates, which are not metalloprotease inhibitors, have been found to be selectively toxic to a range of transformed and human tumour cells without killing normal cells (fibroblasts, melanocytes) at the same concentrations. Within 24 h of treatment, drug action is characterized by morphological reversion of tumour cells to a more normal phenotype (dendritic morphology), and rapid and reversible acetylation of histone H4 in both tumour and normal cells. Two hydroxamates inhibited growth of xenografts of human melanoma cells in nude mice; resistance did not develop in vivo or in vitro. A third hydroxamate, trichostatin A, was active in vitro but became inactivated and had no anti-tumour activity in vivo. Development of dendritic morphology was found to be dependent upon phosphatase activity, RNA and protein synthesis. Proliferating hybrid clones of sensitive and resistant cells remained sensitive to ABHA, indicating a dominant-negative mechanism of sensitivity. Histone H4 hyperacetylation suggests that these agents act at the chromatin level. This work may lead to new drugs that are potent, and selective anti-tumour agents with low toxicity to normal cells.

Animals↗
PubMed2006

Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: selectivity of anagrelide for the megakaryocytic lineage.

Anagrelide (ANA) and hydroxycarbamide (HC) are two distinct pharmacological agents used to treat thrombocythaemia associated with myeloproliferative disorders. Although both drugs have been in clinical use for a number of years, comparative studies of their selectivity and mode of action are still lacking. Here, we have evaluated the activities of ANA and HC on the growth and differentiation of human haematopoietic progenitor cells in liquid culture. Both drugs inhibited thrombopoietin-induced megakaryocytopoiesis in a dose-dependent manner, but with strikingly different potencies (IC(50)=26 nM for ANA and 30 muM for HC) and modes of action. Whereas HC inhibited cell proliferation, ANA acted primarily on the differentiation process. At doses that abrogated megakaryocytopoiesis, HC also inhibited the expansion of CD34(+) cells stimulated by stem cell factor, interleukin-3 and Flt-3 ligand and also induced apoptosis. Furthermore, HC inhibited erythroid and myelomonocytic cell growth, induced by erythropoietin or granulocyte-macrophage colony-stimulating factor, respectively. In contrast, ANA showed none of these additional effects. Taken together, these results demonstrate that ANA is a potent and selective inhibitor of megakaryocytopoiesis, having no significant activity against haematopoietic progenitor cell expansion or differentiation into other lineages. In contrast, the anti-megakaryocytopoietic activity of HC cannot be dissociated from its more general cytoreductive and cytotoxic actions.

Antigens, CD34↗
PubMed2002

Functional effects of agents differentially selective to noradrenergic or serotonergic systems.

BACKGROUND: The diversity of pharmacological actions of antidepressants suggests that they may bring about their clinical effects by different functional means. METHODS: Twenty healthy volunteers were randomized in a cross-over design to receive 2 weeks of a clinical dose of both reboxetine and sertraline. Baseline assessments of personality were made using the Cloninger Tridimensional Personality Questionnaire and the Karolinska Scales of Personality. Daily and weekly ratings of mood (POMS and PANAS) and quality of life (SASS) were undertaken. RESULTS: Reboxetine and sertraline differed in their effects on the SASS as well as on measures of mood. Reboxetine appeared more likely to be energy enhancing; the effects of sertraline were more difficult to quantify. Personality factors, such as harm avoidance predicted the preference of subjects for these effects and the effect of being on a preferred drug had a significant impact on SASS, and ratings of moods as well as on self-assessments of personality. CONCLUSIONS: The differences reported here are consistent with the original thinking that led to the development of the SSRIs. The findings point to the need for further research on possible differential functional effects of psychotropic agents selective to different brain systems. The findings also have implications for clinical practice, in particular for maintenance treatment with antidepressants.

Adrenergic Uptake Inhibitors↗
PubMed1993

Selective differentiation of CD4+ T helper cell subsets.

During the past year significant advances have been made in our understanding of the factors contributing to the differentiation of CD4 T helper cell subsets. These have been driven, in part, by the realization that signals (cytokines) from the innate immune response are critical in T cell subset differentiation. In addition, several studies have also elucidated how the antigen-presenting cell, the antigenic epitope and the antigen concentration may contribute to the selective development of a particular T helper cell subset.

Animals↗
PubMed1977

An attempt to differentiate selection and amplification in hormone receptor development: the unicellular model.

Earlier experiments demonstrated that a membrane pattern of Protozoa behaves as a receptor with respect to hormones of higher organisms. This raised the possibility that some selection or strengthening of this unspecific patter is involved in the evolution of the specific membrane patterns of the individual cells of higher organisms. In the present experiments, as a result of continual histamine treatment, the phagocytotic ability of a population of Tetrahymena was increased more intensely than after a single histamine treatment. The phagocytotic rate remained high for some time after the animals were returned from histamine-containing to normal medium. Thus, from the experimental data, it appears likely that as the hormone appears, selection becomes involved in the proliferation of cells possessing receptors. This observation might not only be of phylogenetic interest, but could also be relevant in receptor maturation as manifested in ontogenetic membrane differentiation.

Animals↗
PubMed2000

Do discrepancies between microsatellite and allozyme variation reveal differential selection between sea and lagoon in the sea bass (Dicentrarchus labrax)?

In the present study the genetic structure of Dicentrarchus labrax (14 samples from the Mediterranean) was analysed at six microsatellite loci, in order to test the hypothesis that some enzymatic loci undergo selection between marine and lagoon habitat. Eight of the 14 samples were analysed at both microsatellite and allozyme markers. The analysis of the genetic variation among the Mediterranean samples showed that (i) &Fcirc;ST values obtained with the six microsatellite loci were much smaller than those obtained with the 28 allozymes and (ii) microsatellite loci seemed to reflect more the geographical proximity than an ecological one. Thirteen enzymatic loci exhibited moderate to high values compared with microsatellites. This was interpreted as evidence that these allozymes are non-neutral. However, only six loci seemed to be implicated in differentiation between marine and lagoon samples, the causes of selection being unknown for the others. A possible scenario of population dynamics of the sea bass between marine and lagoon habitat is suggested.

Adaptation, Physiological↗
PubMed1997

CD86 (B7-2) on human B cells. A functional role in proliferation and selective differentiation into IgE- and IgG4-producing cells.

Immunoglobulin (Ig) E production by B cells requires two primary signals provided by T cells, interleukin (IL)-4 or IL-13 and CD40 ligand (CD40L). In addition, costimulatory signals, such as CD23-CD21 interaction, contribute further ensuring a selective control over this production. Recently, CD28, expressed on T cells, has been reported to be involved in this process. The CD28 ligands, CD80 (B7-1) and CD86 (B7-2), are expressed on human tonsillar B cells, and their expression is up-regulated by IL-4, IL-13, and/or an anti-CD40 monoclonal antibody (mAb). We have investigated whether signaling via the B7 molecules affects IgE synthesis. Human B cells were stimulated by IL-4 plus anti-CD40 mAb in the presence of different anti-B7 mAbs. Cross-linking of CD86 with IT2.2 potentiated IgE and IgG4 production and epsilon transcripts expression. The production of the other isotypes was not modulated. Conversely, the anti-CD80 and the other anti-CD86 mAbs tested had no effect. The increase of IgE and IgG4 production induced by IT2.2 was accompanied by an increase in proliferation, in cell surface density of CD23, and in CD23 binding to CD21-expressing B cells. In contrast, the expression of other B cell surface molecules such as CD11a, CD30, and CD58 remained unaffected. Since IT2.2 favors CD23-CD21 pairing, we tested whether blocking this interaction affected IT2.2-increased IgE production. The neutralizing anti-CD23 mAb, Mab 25, caused a dose-dependent inhibition of the effect of IT2.2 on IgE synthesis. Finally, IT2.2 potentiation on B cell proliferation and IgE production required the two primary signals, IL-4 and anti-CD40 mAb, since IT2.2 alone or in combination with only one of these stimuli did not show any effect on B cells. This study is the first demonstration of a signaling role for CD86. Together with IL-4 or IL-13 and CD40L, CD86 favors CD23-CD21 pairing and consequently functions as a selective and potent costimulus for human IgE and IgG4 synthesis.

Antibodies, Monoclonal↗
PubMed2004

A selective differential medium for Enterobacter sakazakii, a preliminary study.

Enterobacter sakazakii can cause fatal invasive infection of neonates associated with the presence of this organism in powdered infant milk formula. A new chromogenic medium (Druggan-Forsythe-Iversen agar, DFI) is described for the selective detection of this emergent pathogen. The medium is based on the alpha-glucosidase reaction which is detected using 5-bromo-4-chloro-3-indolyl-alpha,D-glucopyranoside (XalphaGlc). Ent. sakazakii hydrolyses this substrate to an indigo pigment, producing blue-green colonies on this medium. DFI was compared with the current method of detection on violet red bile glucose agar (VRBGA) followed by pigment production on tryptone soy agar (TSA) after 48-72 h at 25 degrees C and subsequent biochemical profile determination using Biomerieux API20E. Ninety-five clinical and food strains of Ent. sakazakii were detected on the DFI chromogenic medium 2 days sooner than the alternative method. The characteristics of 148 strains representing 17 genera of non-Ent. sakazakii Enterobacteriaceae were compared using the two methods. Only 16/18 Escherichia vulneris strains, 2/3 strains of Pantoea spp. and 1/8 Citrobacter koseri strains gave false positive results on DFI agar. Eight alpha-glucosidase positive strains were identified as Pantoea using their API20E biochemical profile, but had higher percentage identification as Ent. sakazakii using ID32E. Therefore the DFI medium enables the detection of Ent. sakazakii within mixed cultures of Enterobacteriaceae, whereas the organism could be missed when using VRBGA since the latter is a general Enterobacteriaceae selective medium. In addition, the common use of API20E to check yellow pigmented colonies on TSA may lead to false negative results and consequently the acceptance of a batch of infant formula milk (IFM) that contains Ent. sakazakii.

Colony Count, Microbial↗
PubMed2004

Basal B-cell receptor signaling in B lymphocytes: mechanisms of regulation and role in positive selection, differentiation, and peripheral survival.

B-cell development is a highly ordered multistep process dependent upon signals generated by the pre-B and B-cell antigen receptor (BCR). BCR signals drive maturation of the B cell by integrating a number of parallel and sequential biological processes that result in generation of fully immunocompetent B cells. Among these biological processes are positive selection through several developmental checkpoints, negative selection of potentially self-reactive B cells, and activation of the mature B cell. In addition, recent studies have shown that developing and mature B cells rely on the constant activity of the BCR for their continued survival. Ligand (antigen)-dependent and -independent mechanisms of BCR signaling have been proposed, but their specific contributions to B-cell maturation and differentiation in the bone marrow and periphery are not completely clear. We discuss here a model, whereby ligand-independent basal BCR activity would be sufficient to trigger B-cell development through to the mature stage. However, long-term survival and formation of specific mature B-cell populations may be dependent on ligand-receptor interactions.

Animals↗
PubMed2003

Selecting differentially expressed genes from microarray experiments.

High throughput technologies, such as gene expression arrays and protein mass spectrometry, allow one to simultaneously evaluate thousands of potential biomarkers that could distinguish different tissue types. Of particular interest here is distinguishing between cancerous and normal organ tissues. We consider statistical methods to rank genes (or proteins) in regards to differential expression between tissues. Various statistical measures are considered, and we argue that two measures related to the Receiver Operating Characteristic Curve are particularly suitable for this purpose. We also propose that sampling variability in the gene rankings be quantified, and suggest using the "selection probability function," the probability distribution of rankings for each gene. This is estimated via the bootstrap. A real dataset, derived from gene expression arrays of 23 normal and 30 ovarian cancer tissues, is analyzed. Simulation studies are also used to assess the relative performance of different statistical gene ranking measures and our quantification of sampling variability. Our approach leads naturally to a procedure for sample-size calculations, appropriate for exploratory studies that seek to identify differentially expressed genes.

Biomarkers, Tumor↗
PubMed2005

Differential selection and mutation between dsDNA and ssDNA phages shape the evolution of their genomic AT percentage.

BACKGROUND: Bacterial genomes differ dramatically in AT%. We have developed a model to show that the genomic AT% in rapidly replicating bacterial species can be used as an index of the availability of nucleotides A and T for DNA replication in cellular medium. This index is then used to (1) study the evolution and adaptation of the bacteriophage genomic AT% in response to the differential nucleotide availability of the host and (2) test the prediction that double-stranded DNA (dsDNA) phage should exhibit better adaptation than single-stranded DNA (ssDNA) phage because the rate of spontaneous deamination, which leads to C-->T or C-->U mutations depending on whether C is methylated or not, is about 100-fold greater in ssDNA than in dsDNA. RESULTS: We retrieved 79 dsDNA phage and 27 ssDNA phage genomes together with their host genomic sequences. The dsDNA phages have their genomic AT% better adapted to the host genomic AT% than ssDNA phage. The poorer adaptation of the ssDNA phage can be partially accounted for by the C-->T(U) mutations mediated by the spontaneous deamination. For ssDNA phage, the genomic A% is more strongly correlated with their host genomic AT% than the genomic T%. CONCLUSION: A significant fraction of variation in the genomic AT% in the dsDNA phage, and that in the genomic A% and T% of the ssDNA phage, can be explained by the difference in selection and mutation between them.

Bacteriophages↗
PubMed2001

Microarray data analysis: a practical approach for selecting differentially expressed genes.

BACKGROUND: The biomedical community is rapidly developing new methods of data analysis for microarray experiments, with the goal of establishing new standards to objectively process the massive datasets produced from functional genomic experiments. Each microarray experiment measures thousands of genes simultaneously producing an unprecedented amount of biological information across increasingly numerous experiments; however, in general, only a very small percentage of the genes present on any given array are identified as differentially regulated. The challenge then is to process this information objectively and efficiently in order to obtain knowledge of the biological system under study and by which to compare information gained across multiple experiments. In this context, systematic and objective mathematical approaches, which are simple to apply across a large number of experimental designs, become fundamental to correctly handle the mass of data and to understand the true complexity of the biological systems under study. RESULTS: The present report develops a method of extracting differentially expressed genes across any number of experimental samples by first evaluating the maximum fold change (FC) across all experimental parameters and across the entire range of absolute expression levels. The model developed works by first evaluating the FC across the entire range of absolute expression levels in any number of experimental conditions. The selection of those genes within the top X% of highest FCs observed within absolute expression bins was evaluated both with and without the use of replicates. Lastly, the FC model was validated by both real time polymerase chain reaction (RT-PCR) and variance data. Semi-quantitative RT-PCR analysis demonstrated 73% concordance with the microarray data from Mu11K Affymetrix GeneChips. Furthermore, 94.1% of those genes selected by the 5% FC model were found to lie above measurement variability using a SDwithin confidence level of 99.9%. CONCLUSION: As evidenced by the high rate of validation, the FC model has the potential to minimize the number of required replicates in expensive microarray experiments by extracting information on gene expression patterns (e.g. characterizing biological and/or measurement variance) within an experiment. The simplicity of the overall process allows the analyst to easily select model limits which best describe the data. The genes selected by this process can be compared between experiments and are shown to objectively extract information which is biologically & statistically significant.

Animals↗
PubMed1997

V(H) repertoire maturation during B cell development in vitro: differential selection of Ig heavy chains by fetal and adult B cell progenitors.

B cell development is characterized by marked changes in Ig repertoire, which include shifts in the pattern of V(H) segment usage. B cell precursors characteristically utilize a restricted set of V(H) segments, while mature B cell populations use a wide range of V(H) segments. V(H)81x is an example of a V(H) segment that is highly utilized in B cell precursors, but is rarely utilized in mature B cells. To dissect the molecular and cellular requirements for Ig repertoire maturation, we have examined V(H)81x usage in an in vitro model of B cell development. We find that primary fetal or adult B cell progenitors differentiating in vitro mimic progenitors differentiating in vivo with respect to V(H)81x overusage and subsequent decline in V(H)81x usage, showing that neither of these events is dependent on the intact architecture of the primary lymphoid organ or contact with stromal cells. The relative decline in V(H)81x usage in cultures initiated with adult progenitors was associated with a decrease in the ratio of productive/nonproductive V(H)81x-DJ(H) rearrangements; however, an increase in this ratio was observed in identical cultures initiated with fetal progenitors. This result indicates a difference in selection of V(H)81x-encoded heavy chains that is intrinsic to fetal and adult B cell progenitors. Thus, while the relative decline in V(H)81x usage during adult development can be at least partially explained by selection against cells bearing V(H)81x-encoded heavy chains, other mechanisms must be postulated to explain the decline in V(H)81x usage during fetal development.

Age Factors↗
PubMed1992

[Differential selection of anti-anginal drugs in stable stenocardia in relation to the data of central and intracardiac hemodynamics].

Rheography and echocardiography were used to study central and intracardiac hemodynamic parameters in 196 patients with Functional Classes I-II from the screening of the main antianginal drugs during an acute pharmacological test under bicycle ergometric monitoring. It was established that the hemodynamic type of circulation and left ventricular end-diastolic and end-systolic volumes may be used as criteria for the differential choice of antianginal agents. The values of these parameters are given for sustac, propranolol, verapamil, nifedipine and sustac plus propranolol.

Adult↗
PubMed1992

Differential selection of malathion resistance in Anopheles culicifacies A and B (Diptera: Culicidae) in Haryana State, India.

In November 1989, for the first time after the introduction of malathion spray in 1982, increased densities of Anopheles culicifacies Giles s.l. were observed in Chhatera and Barota, two villages in Halalpur block in Sonepat District, Haryana State, India. In bioassay tests against the diagnostic dose of malathion (5% for 1 h), 41-47% of mosquitoes survived. An culicifacies populations in this area comprise two sibling species, A and B. Differential malathion resistance was observed; in species A it was 2-9% and in species B 62-66%. Likewise, species A was found to be more susceptible to DDT than was species B. The possible use of DDT spray to delay the onset of malathion resistance is discussed.

Animals↗
PubMed2006

Astrocyte differentiation selectively upregulates CCL2/monocyte chemoattractant protein-1 in cultured human brain-derived progenitor cells.

Chemokines (chemoattractant cytokines) and their receptors are present in the brain and may play roles in both neurodevelopment and neuropathology. Increased brain levels of monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, are found in patients with human immunodeficiency virus type 1 (HIV-1)-associated dementia and other acute and chronic neurologic diseases. Although the function of CCL2 in the brain is unclear, it is believed that upregulation of this chemokine during neuropathologic or neuroinflammatory conditions leads to recruitment of activated monocytes into the brain, where they differentiate into macrophages producing neurotoxic and inflammatory molecules. We recently showed that human fetal brain-derived progenitor cells are susceptible to HIV-1 and JC virus infection, and that differentiation toward an astrocyte phenotype increased virus production from these cells. In the current study, we found that in the absence of infection, progenitors produced moderate levels of CCL2 (5.6 ng per million cells). Astrocyte differentiation over 3 weeks increased CCL2 protein levels 30-fold in a biphasic manner, whereas neuronal differentiation decreased production 20-fold. Electromobility shift assays (EMSAs) demonstrated increased nuclear NF-kappaB levels within 2 h of initiating astrocyte differentiation, and inhibitors of NF-kappaB activation partially blocked the CCL2 increase in differentiating astrocytes. Transfection of progenitors with mutated CCL2 promoter/CAT reporter constructs showed that the distal promoter region, containing NF-kappaB and NF-I binding sites, is important for differentiation-induced CCL2 upregulation. Together these results suggest that the transcription factor NF-kappaB, and possibly NF-I, contribute to the upregulation of CCL2 chemokine production during the differentiation of human progenitor cells toward an astrocyte phenotype.

AIDS Dementia Complex↗
PubMed1998

Differential selectivity of cardiac neurons in separate intrathoracic autonomic ganglia.

Analyses of activity generated by neurons in middle cervical or stellate ganglia versus intrinsic cardiac ganglia were performed to determine how neurons in different intrathoracic ganglia, which are involved in cardiac regulation, interact. Discharges of 19% of intrathoracic extracardiac neurons and 32% of intrinsic cardiac neurons were related to cardiodynamics. Epicardial touch increased the activity generated by approximately 80% of intrinsic cardiac neurons and approximately 60% of extracardiac neurons. Both populations responded similarly to epicardial chemical stimuli. Activity generated by neurons in intrinsic cardiac ganglia demonstrated no consistent short-term relationships to neurons in extracardiac ganglia. Myocardial ischemia influenced extracardiac and intrinsic cardiac neurons similarly. Carotid artery baroreceptors influenced neurons in ipsilateral extracardiac ganglia. After decentralization from the central nervous system, intrinsic cardiac neurons received afferent inputs primarily from cardiac chemosensitive neurites, whereas middle cervical ganglion neurons received afferent inputs primarily from cardiac mechanosensory neurites. It is concluded that the populations of neurons in different intrathoracic ganglia can display differential reflex control of cardiac function. Their redundancy in function and noncoupled behavior minimizes cardiac dependency on a single population of intrathoracic neurons.

Animals↗