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Different Phenotypes (different + phenotype)
Selected Abstractsc-Rel phenocopies PKC, but not Bcl-10 in regulating CD8+ T-cell activation versus tolerance,EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2010Elissa K. Deenick Abstract Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKC, results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-,B plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-,B act downstream of PKC, to alter CD8+ T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-,B1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKC,-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKC,-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-,B, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKC, in controlling CD8+ T-cell anergy induction. [source] Differences in multidrug resistance phenotype and matrix metalloproteinases activity between endothelial cells from normal brain and gliomaJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Anthony Régina Abstract Endothelial cells (ECs) are new targets for tumor therapy. In this work, we purified endothelial cells from intracerebral and subcutaneous experimental gliomas as well as from normal brain in order to define some of the phenotypical differences between angiogenic and quiescent brain vasculature. We show that the multidrug resistance genes encoding drug efflux pumps at the brain endothelium are expressed differently in normal and tumoral vasculature. We also show that ECs from gliomas present increased activity of gelatinase B (MMP9), key enzyme in the angiogenic process. Importantly, we observe a different phenotype between ECs in the intracerebral and subcutaneous models. Our results provide molecular evidence of phenotypic distinction between tumoral and normal brain vasculature and indicate that the EC phenotype depends on interactions both with tumor cells and also with the microenvironment. [source] Two epithelial cell invasion-related loci of the oral pathogen Actinobacillus actinomycetemcomitansMOLECULAR ORAL MICROBIOLOGY, Issue 1 2004L. Li Two invasion-related loci, apiA and the two-gene operon apiBC, were isolated from the oral pathogen Actinobacillus actinomycetemcomitans UT32. apiA encodes a 32.5 kDa protein that migrates on SDS-PAGE as a 101 kDa protein as detected by Western blot analysis or silver staining of an outer membrane-enriched fraction of Escherichia coli transformants. E. coli expressing ApiA have a different phenotype than the host vector, in broth and on solid media, and a colony morphology that resembles that of fresh A. actinomycetemcomitans isolates. These E. coli transformants bound to chicken collagen type II, human collagen type II, III, V and fibronectin. apiB and apiC encode proteins of 130.1 and 70.6 kDa, respectively. ApiBC conferred on E. coli a slightly enhanced ability to bind to collagen type III. ApiA- and ApiB-deficient mutants were constructed in A. actinomycetemcomitans. The ApiB-mutant had 4-fold diminished invasion of KB cells; the ApiA-mutant had increased invasion. Both loci were found in all A. actinomycetemcomitans strains, although polymorphism was detected only for apiBC. The deduced sequences of these invasion-related proteins are homologous to members of the YadA adhesin/invasin family. [source] Organotypic culture of human bone marrow adipose tissuePATHOLOGY INTERNATIONAL, Issue 4 2010Kazuyoshi Uchihashi The precise role of bone marrow adipose tissue (BMAT) in the marrow remains unknown. The purpose of the present study was therefore to describe a novel method for studying BMAT using 3-D collagen gel culture of BMAT fragments, immunohistochemistry, ELISA and real-time reverse transcription,polymerase chain reaction. Mature adipocytes and CD45+ leukocytes were retained for >3 weeks. Bone marrow stromal cells (BMSC) including a small number of lipid-laden preadipocytes and CD44+/CD105+ mesenchymal stem cell (MSC)-like cells, developed from BMAT. Dexamethasone (10 µmol/L), but not insulin (20 mU/mL), significantly increased the number of preadipocytes. Dexamethasone and insulin also promoted leptin production and gene expression in BMAT. Adiponectin production by BMAT was <0.8 ng/mL under all culture conditions. Dexamethasone promoted adiponectin gene expression, while insulin inhibited it. This finding suggests that dexamethasone, but not insulin, may serve as a powerful adipogenic factor for BMAT, in which adiponectin protein secretion is normally very low, and that BMAT may exhibit a different phenotype from that of the visceral and subcutaneous adipose tissues. BMAT,osteoblast interactions were also examined, and it was found that osteoblasts inhibited the development of BMSC and reduced leptin production, while BMAT inhibited the growth and differentiation of osteoblasts. The present novel method proved to be useful for the study of BMAT biology. [source] Peroxiredoxin Q of Arabidopsis thaliana is attached to the thylakoids and functions in context of photosynthesis,THE PLANT JOURNAL, Issue 6 2006Petra Lamkemeyer Summary Peroxiredoxin Q (Prx Q) is one out of 10 peroxiredoxins encoded in the genome of Arabidopsis thaliana, and one out of four that are targeted to plastids. Peroxiredoxin Q functions as a monomeric protein and represents about 0.3% of chloroplast proteins. It attaches to the thylakoid membrane and is detected in preparations enriched in photosystem II complexes. Peroxiredoxin Q decomposes peroxides using thioredoxin as an electron donor with a substrate preference of H2O2 > cumene hydroperoxide , butyl hydroperoxide , linoleoyl hydroperoxide and insignificant affinity towards complex phospholipid hydroperoxide. Plants with decreased levels of Prx Q did not have an apparently different phenotype from wildtype at the plant level. However, similar to antisense 2-cysteine (2-Cys) Prx plants [Baier, M. et al. (2000)Plant Physiol., 124, 823,832], Prx Q-deficient plants had a decreased sensitivity to oxidants in a leaf slice test as indicated by chlorophyll a fluorescence measurements. Increased fluorescence ratios of photosystem II to I at 77 K and modified transcript levels of plastid- and nuclear-encoded proteins show that regulatory mechanisms are at work to compensate for the lack of Prx Q. Apparently Prx Q attaches to photosystem II and has a specific function distinct from 2-Cys peroxiredoxin in protecting photosynthesis. Its absence causes metabolic changes that are sensed and trigger appropriate compensatory responses. [source] PAN,DR-Binding Hsp60 self epitopes induce an interleukin-10,mediated immune response in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 7 2009Huib de Jong Objective Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60-directed responses in RA, it is necessary to study such responses at the molecular, epitope-specific level. This study was undertaken to characterize the disease specificity and function of pan,DR-binding Hsp60,derived epitopes as possible modulators of autoimmune inflammation in RA. Methods Lymphocyte proliferation assays (using 3H-thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls. Results A disease (RA),specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor , (TNF,), interleukin-1, (IL-1,), and IL-10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4+ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5,10-fold higher IL-10:TNF, ratio, compared with that of the microbial peptides. Conclusion These results suggest a disease-specific immune-modulatory role of epitope-specific T cells in the inflammatory processes of RA. Therefore, these pan,DR-binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy. [source] CD3 expression distinguishes two ,,T cell receptor subsets with different phenotype and effector function in tuberculous pleurisyCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009N. Yokobori Summary Tuberculous pleurisy is a naturally occurring site of Mycobacterium tuberculosis (Mtb) infection. Herein, we describe the expression of activation, natural killer (NK) and cell migration markers, as well as effector functions from ,,T cells in peripheral blood (PB) and pleural effusion (PE) from tuberculosis patients (TB). We observed a decreased percentage of circulating ,,T from TB patients and differential expression of NK as well as of chemokine receptors on PB and PE. Two subsets of ,,T cells were differentiated by the CD3/,,T cell receptor (,,TCR) complex. The ,,TCRlow subset had a higher CD3 to TCR ratio and was enriched in V,2+ cells, whereas most V,1+ cells belonged to the ,,TCRhigh subset. In PB from TB, most ,,TCRhigh were CD45RA+CCR7 - and ,,TCRlow were CD45RA+/,CCR7+CXCR3+. In the pleural space the proportion of CD45RA - CCR7+CXCR3+ cells was higher. Neither spontaneous nor Mtb -induced interferon (IFN)-, production was observed in PB-,,T cells from TB; however, PE-,,T cells showed a strong response. Both PB- and PE-,, T cells expressed surface CD107a upon stimulation with Mtb. Notably, PE-,,TCRlow cells were the most potent effector cells. Thus, ,,T cells from PB would acquire a further activated phenotype within the site of Mtb infection and exert full effector functions. As ,,T cells produce IFN-, within the pleural space, they would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a T helper type 1 profile. [source] Craniorachischisis and Heterotaxia with Heart Disease in Twins: Link or Change Nature?CONGENITAL HEART DISEASE, Issue 5 2010Sebastiano Bianca MD ABSTRACT Craniorachischisis is a rare neural tube defect in which both acrania and a complete schisis of the vertebral column are present. Heterotaxy results from failure to establish normal left,right asymmetry during embryonic development and is characterized by a variable group of congenital anomalies that include complex cardiac malformations and situs inversus or situs ambiguous. We report a diamniotic twin pregnancy with two malformed fetuses affected one by craniorachischisis and the other by heterotaxya with paired right-sided viscera, asplenia, and complex congenital heart disease. The occurrence of severe congenital anomalies in both members of the twin pair implies a strong influence of genetic factors. At present, the genetic basis determining the different phenotypes observed in our twins is unknown. Our case with the simultaneous presence of both midline and laterality defects in twins supports the hypothesis that the midline plays a critical role in establishing left,right asymmetry in the body and that a mutation in a gene responsible for both heterotaxy and midline defects may be strongly supposed. [source] Phenotypic plasticity in number of glomeruli and sensory innervation of the antennal lobe in leaf-cutting ant workers (A. vollenweideri)DEVELOPMENTAL NEUROBIOLOGY, Issue 4 2010Christina Kelber Abstract In the leaf-cutting ant Atta vollenweideri, the worker caste exhibits a pronounced size-polymorphism, and division of labor is dependent on worker size (alloethism). Behavior is largely guided by olfaction, and the olfactory system is highly developed. In a recent study, two different phenotypes of the antennal lobe of Atta vollenweideri workers were found: MG- and RG-phenotype (with/without a macroglomerulus). Here we ask whether the glomerular numbers are related to worker size. We found that the antennal lobes of small workers contain ,390 glomeruli (low-number; LN-phenotype), and in large workers we found a substantially higher number of ,440 glomeruli (high-number; HN-phenotype). All LN-phenotype workers and some small HN-phenotype workers do not possess an MG (LN-RG-phenotype and HN-RG-phenotype), and the remaining majority of HN-phenotype workers do possess an MG (HN-MG-phenotype). Using mass-staining of antennal olfactory receptor neurons we found that the sensory tracts divide the antennal lobe into six clusters of glomeruli (T1,T6). In LN-phenotype workers, ,50 glomeruli are missing in the T4-cluster. Selective staining of single sensilla and their associated receptor neurons revealed that T4-glomeruli are innervated by receptor neurons from the main type of olfactory sensilla, the Sensilla trichodea curvata. The other type of olfactory sensilla (Sensilla basiconica) exclusively innervates T6-glomeruli. Quantitative analyses of differently sized workers revealed that the volume of T6 glomeruli scales with the power of 2.54 to the number of Sensilla basiconica. The results suggest that developmental plasticity leading to antennal-lobe phenotypes promotes differences in olfactory-guided behavior and may underlie task specialization within ant colonies. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 70: 222,234, 2010. [source] Effects of Social Structure on the Behaviour and Performance of Alternative Reproductive Phenotypes in Male Rock Shrimp, Rhynchocinetes typusETHOLOGY, Issue 4 2008Stefan Dennenmoser Males that adopt alternative mating tactics within a conditional strategy often undergo costly morphological changes when switching to the next phenotype during ontogeny. Whether costs of changing to a subsequent reproductive phenotype are outweighed by a higher mating probability may depend on the frequencies of different phenotypes in a group of competitors. Benefits and costs associated with different phenotype frequencies depend on interactions within and between alternative phenotypes, but the underlying behavioural mechanisms have rarely been studied. Herein, we used the rock shrimp Rhynchocinetes typus as a model: ontogenetic male stages of this species differ in morphological and behavioural traits that indicate alternative reproductive phenotypes. The small, subordinate, male stage (typus) develops via several intermediate stages (intermedius) to the dominant male stage (robustus): in competitive interactions the typus males usually employ the sneaking tactic, while the robustus males invariably employ the monopolizing fighter tactic. In laboratory experiments, we manipulated phenotype frequencies to examine whether there are frequency-dependent effects on searching behaviour, aggressiveness and mating probability. With increasing frequency of robustus males, the rate of aggressive interactions among them increased. Furthermore, robustus males increased walking velocity when more than one robustus male was present. In contrast, typus males did not adjust their searching or aggressive behaviour. The increase of aggressive interactions among robustus males provided more opportunities for typus males to seize a temporarily unguarded female. While typus males exploit fights among robustus males that produce mating opportunities for them, robustus males benefit from typus males, which reveal the presence of receptive females. We suggest that each phenotype benefits from the presence of the other phenotype and suffers costly interference among individuals of the same phenotype. Whether frequency-dependent effects on the mating probability of subordinates also affect their ontogenetic switchpoint should be examined in future studies. [source] Myotonic dystrophy type 2EUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2002J. Finsterer Myotonic dystrophy type 2 (DM2) is a clinically but not genetically heterogeneous, multisystem disorder, that is clinically similar to, but distinct from myotonic dystrophy type 1 (DM1). Initially, different phenotypes of DM2 were described by Ricker (proximal myotonic myopathy, PROMM), Ranum (myotonic dystrophy 2, DM2) and Udd (proximal myotonic dystrophy, PDM). Clinical features these three phenotypes had in common were diffuse, proximal or distal weakness, wasting, myotonia, cataract, cerebral, endocrine and cardiac abnormalities. Initially, the clinical differences between DM1 and PROMM seemed unmistakable, but meanwhile it has become apparent that the clinical differences between these entities are blurring. In 1999, Day et al., Meola et al. and Ricker et al. mapped the mutated gene of all three phenotypes to chromosome 3q. In 2001, the three different phenotypes were found to rely on the same mutation in the ZNF9 gene on chromosome 3q21.3. Although DM2 may be clinically heterogeneous, it is by result of a mutation in a single gene. The mutation responsible for DM2 is a CCTG-repeat expansion of 75,11 000 repeats in intron 1 of the ZNF9 gene on chromosome 3q21.3. Because of the clinical heterogeneity, the diagnosis of DM2 should rely on DNA analysis alone. [source] A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytesEXPERIMENTAL DERMATOLOGY, Issue 9 2009Clio Dessinioti Abstract:, Inherited diseases of pigmentation were among the first traits studied in humans because of their easy recognition. The discovery of genes that regulate melanocytic development and function and the identification of disease-causative mutations have greatly improved our understanding of the molecular basis of pigmentary genodermatoses and their underlying pathogenetic mechanisms. Pigmentation mutants can account for hypo-/amelanosis, with or without altered melanocyte number, resulting in different phenotypes, such as Waardenburg syndrome, piebaldism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, oculocutaneous albinism and Griscelli syndrome. In this review, we summarize the basic concepts of melanocyte biology and discuss how molecular defects in melanocyte development and function can result in the development of hypopigmentary hereditary skin diseases. [source] The transcarboxylase domain of pyruvate carboxylase is essential for assembly of the peroxisomal flavoenzyme alcohol oxidaseFEMS YEAST RESEARCH, Issue 7 2007Paulina Z. Ozimek Abstract Pyruvate carboxylase (Pyc1p) has multiple functions in methylotrophic yeast species. Besides its function as an enzyme, Pyc1p is required for assembly of peroxisomal alcohol oxidase (AO). Hence, Pyc1p-deficient cells share aspartate auxotrophy (Asp,) with a defect in growth on methanol as sole carbon source (Mut,). To identify regions in Hansenula polymorpha Pyc1p that are required for the function of HpPyc1p in AO assembly, a series of random mutations was generated in the HpPYC1 gene by transposon mutagenesis. Upon introduction of 18 mutant genes into the H. polymorpha PYC1 deletion strain (pyc1), four different phenotypes were obtained, namely Asp, Mut,, Asp, Mut+, Asp+ Mut,, and Asp+ Mut+. One mutant showed an Asp+ Mut, phenotype. This mutant produced HpPyc1p containing a pentapeptide insertion in the region that links the conserved N-terminal biotin carboxylation domain (BC) with the central transcarboxylation (TC) domain. Three mutants that were Asp, Mut, contained insertions in the TC domain, suggesting that this domain is important for both functions of Pyc1p. Analysis of a series of constructed C-terminal and N-terminal truncated versions of HpPyc1p showed that the TC domain of Pyc1p, including the region linking this domain to the BC domain, is essential for AO assembly. [source] Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations,HUMAN MUTATION, Issue 1 2010Alessandra Pangrazio Abstract The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis. © 2009 Wiley-Liss, Inc. [source] A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot,,HUMAN MUTATION, Issue 3 2006Georges Nemer Abstract In vertebrates, heart formation which integrates different structures and cell types is a complex process that involves a network of genes regulated by transcription factors. Proper spatiotemporal expression of these factors ensure the highly needed tight control of each step in organogenesis. A mistake at any step from cell-commitment to valve formation will have a major impact on heart morphogenesis and function leading to congenital heart disease (CHD). Cardiac abnormalities occur with an incidence of one per 100 live births and represent 25% of all congenital malformations. As an alternative approach to linkage-analysis of familial cases of CHD, we started screening familial and sporadic cases of CHDs in a highly consanguineous population for mutations in genes encoding cardiac-enriched transcription factors. The evolutionarily conserved role of these proteins in cardiac development suggested a role in CHD. In this study, we report a mutation in the gene encoding GATA4, one of the earliest markers of heart development. This mutation was found in two out of 26 patients with Tetralogy of Fallot (TOF), and in none of the 94 patients with different phenotypes included in the study, nor in 223 healthy individuals. The heterozygous mutation results in an amino acid substitution in the first zinc finger of GATA4 that reduced its transcriptional activation of downstream target genes, without affecting GATA4 ability to bind DNA, nor its interaction with ZFPM2. © 2006 Wiley-Liss, Inc. [source] Genetic diversity and structure of the West Balkan Pramenka sheep types as revealed by microsatellite and mitochondrial DNA analysisJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 6 2008inkulov Summary Several different phenotypes of the native Pramenka sheep have been developed in the Balkan region for different environmental and socio-cultural conditions. Animals from seven West Balkan Pramenka sheep types were analysed for 15 microsatellite markers and for mitochondrial DNA (mtDNA) and the results were used to assess genetic variation within and among the types and to infer the genetic population structure of the Pramenka sheep. Mean expected heterozygosity and allelic richness over the microsatellite loci and sheep types were 0.78 and 7.9, respectively. A Bayesian statistical method for estimating hidden genetic structure suggested that a core of the largest panmictic population was formed by Serbian, Kosovan, Bosnian, Montenegrin and Albanian types, while Croatian and Macedonian types comprised two other main populations, respectively. Mitochondrial DNA analysis revealed two mtDNA haplogroups in the Pramenka sheep, B and A, with a frequency of 93.7% and 6.3%, respectively. A total of 60 mtDNA haplotypes were found in 64 animals sequenced, and the mean nucleotide and haplotypic diversities over the types were 0.013 and 0.945, respectively. Molecular analysis suggests that the West Balkan Pramenka sheep types have their origins in two distinct maternal lineages of domestic sheep and different Pramenka phenotypes tend to form few panmictic populations. The Pramenka sheep represents a valuable resource of genetic diversity in sheep. [source] A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell,microenvironment interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Robert D. Loberg Abstract The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics. © 2005 Wiley-Liss, Inc. [source] CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxineJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2006M. E. E. Shams PhD Summary Background:, Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O -desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N -desmethylvenlafaxine (NDV). Objectives:, The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. Method:, In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. Results:, There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1·8 and the 10th and 90th percentiles 0·3 and 5·2, respectively. Individuals with ODV/V ratios below 0·3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5·2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1·1 ± 0·8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4·8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0·3 had more side effects (P < 0·005) and reduced serum concentrations of sodium (P < 0·05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. Conclusion:, The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects. [source] Effects of NGF on different phenotypes and genotypes of cholinergic murine SN56 cellsJOURNAL OF NEUROCHEMISTRY, Issue 2003H. Bielarczyk Nerve growth factor (NGF) is important for differentiation and maintenance of septal cholinergic neurons. It caused concentration-dependent increase of choline acetyltransferase (ChAT) activity ([EC50%] 1 ng/mL), acetylcholine (ACh) content and morphologic maturation of SN56TrkA(+)p75(+) but not TrkA(,)p75(+) cells. NGF added with cyclic AMP altered significantly differential effects of the latter neither in TrkA(,) nor TrkA(+). However, when cyclic AMP-predifferentiated cells were treated with NGF alone, it caused suppression of the cholinergic phenotype in both cell lines. Anti-p75 antibodies totally reversed inhibitory effects of NGF on ChAT activity. Differentiation was accompanied by increase whereas its reversal by decrease of intracellular Ca content. These data indicate that NGF may exert opposite effects on phenotype of cholinergic neurons by p75 receptor signaling pathways and changes in intracellular Ca. Acknowledgement: Supported by KBN project 6P05A 01020. [source] Variation in Reproductive Behaviour within a Sex:Neural Systems and Endocrine ActivationJOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2002T. Rhen Abstract Intrasexual variation in reproductive behaviour, morphology and physiology is taxonomically widespread in vertebrates, and is as biologically and ecologically significant as the differences between the sexes. In this review, we examine the diverse patterns of intrasexual variation in reproductive behaviours within vertebrates. By illustrating the genetic, cellular, hormonal and/or neural mechanisms underlying behavioural variation in a number of species, another level of complexity is added to studies of brain organization and function. Such information increases our understanding of the unique and conserved mechanisms underlying sex and individual differences in behaviour in vertebrates as a whole. Here, we show that intrasexual variation in behaviour may be discrete or continuous in nature. Moreover, this variation may be due to polymorphism at a single genetic locus or many loci, or may even be the result of phenotypic plasticity. Phenotypic plasticity simply refers to cases where a single genotype (or individual) can produce (or display) different phenotypes. Defined in this way, plasticity subsumes many different types of behavioural variation. For example, some behavioural phenotypes are established by environmental factors during early ontogeny, others are the result of developmental transitions from one phenotype early in life to another later in life, and still other strategies are facultative with different behaviours displayed in different social contexts. [source] Differential Expression of Vasoactive Intestinal Polypeptide Receptor 1 and 2 mRNA in Murine Intestinal T Lymphocyte SubtypesJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2001B.-F. Qian Abstract Neuropeptides may exert a variety of effects on the immune cells at both systemic and mucosal immune sites. The immunoregulatory properties refer to the ability of physiological signals and pathways to influence various immune functions. Vasoactive intestinal polypeptide (VIP), a neuropeptide present in high concentration in gut, was studied for its production and receptor expression in intraepithelial and lamina propria T lymphocytes of mouse intestine. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, it was demonstrated that VIP receptor 1 (VIPR1) was constantly expressed in intraepithelial and lamina propria T lymphocytes from both small and large intestine. In contrast, VIPR2 was identified only in T cells from small intestine. Further studies on purified subpopulations of T lymphocytes indicated the existence of VIPR2 in CD8+ T cells, but not CD4+ and CD4CD8 double negative T cells, although all these three subpopulations displayed VIPR1. In addition, VIPR1 mRNA was detected in splenic T lymphocytes, but no signal was obtained for VIPR2 mRNA, even after stimulation of the cells with anti-CD3,-chain mAb, phorbol 12-myristate 13-acetate (PMA) and/or VIP. The presence of VIP receptor(s) on intestinal T lymphocytes was supported by the detection of VIP on the cell surface using dual colour immunoflowcytometry. In-vitro treatment with VIP resulted in a tendency towards an increased size of the VIP immunoreactive T cell population and significantly enhanced the average immunofluorescence intensity of the surface labelling. This indicates that the receptors are partially occupied by locally produced VIP in vivo and that more peptide molecules can be bound on the lymphocytes when needed, released and accumulated in higher concentration at the action sites. We failed to detect the expression of VIP mRNA in T lymphocytes, from either intestine or spleen. These observations support that VIP may be an important immune modulator in gut acting through specific receptors on T lymphocytes. The differential mRNA expression of VIP receptor subtypes in cells with different phenotypes and in different immune compartments may suggest diverse regulatory roles of the neuropeptide in immune responses. [source] Convergence, Degeneracy, and ControlLANGUAGE LEARNING, Issue 2006David W. Green Understanding the neural representation and control of language in normal bilingual speakers provides insights into the factors that constrain the acquisition of another language, insights into the nature of language expertise, and an understanding of the brain as an adaptive system. We illustrate both functional and structural brain changes associated with acquiring other languages and discuss the value of neuroimaging data in identifying individual differences and different phenotypes. Understanding normal variety is vital too if we are to understand the consequences of brain damage in bilingual and polyglot speakers. [source] Bladder control, urgency, and urge incontinence: Evidence from functional brain imaging,NEUROUROLOGY AND URODYNAMICS, Issue 6 2008Derek Griffiths Abstract Aim To review brain imaging studies of bladder control in subjects with normal control and urge incontinence; to define a simple model of supraspinal bladder control; and to propose a neural correlate of urgency and possible origins of urge incontinence. Methods Review of published reports of brain imaging relevant to urine storage, and secondary analyses of our own recent observations. Results In a simple model of normal urine storage, bladder and urethral afferents received in the periaqueductal gray (PAG) are mapped in the insula, forming the basis of sensation; the anterior cingulate gyrus (ACG) provides monitoring and control; the prefrontal cortex makes voiding decisions. The net result, as the bladder fills, is inhibition of the pontine micturition center (PMC) and of voiding, together with gradual increase in insular response, corresponding to increasing desire to void. In urge-incontinent subjects, brain responses differ. At large bladder volumes and strong sensation, but without detrusor overactivity (DO), most cortical responses become exaggerated, especially in ACG. This may be both a learned reaction to previous incontinence episodes and the neural correlate of urgency. The neural signature of DO itself seems to be prefrontal deactivation. Possible causes of urge incontinence include dysfunction of prefrontal cortex or limbic system, suggested by weak responses and/or deactivation, as well as abnormal afferent signals or re-emergence of infantile reflexes. Conclusions Bladder control depends on an extensive network of brain regions. Dysfunction in various parts may contribute to urge incontinence, suggesting that there are different phenotypes requiring different treatments. Neurourol. Urodynam. 27:466,474, 2008. © 2007 Wiley-Liss, Inc. [source] Exhaled nitric oxide and exercise-induced bronchoconstriction in young wheezy children , interactions with atopyPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 7 2009L. Pekka Malmberg The association between exercise-induced bronchoconstriction (EIB) and exhaled nitric oxide (FENO) has not been investigated in young children with atopic or non-atopic wheeze, two different phenotypes of asthma in the early childhood. Steroid naďve 3- to 7-yr-old children with recent wheeze (n = 84) and age-matched control subjects without respiratory symptoms (n = 71) underwent exercise challenge test, measurement of FENO and skin prick testing (SPT). EIB was assessed by using impulse oscillometry, and FENO by standard online technique. Although FENO levels were highest in atopic patients with EIB, both atopic and non-atopic wheezy children with EIB showed higher FENO than atopic and non-atopic control subjects, respectively. In atopic wheezy children, a significant relationship between FENO and the severity of EIB was found (r = 0.44, p = 0.0004), and FENO was significantly predictive of EIB. No clear association between FENO and EIB or predictive value was found in non-atopic wheezy children. Both atopic and non-atopic young wheezy children with EIB show increased FENO levels. However, the association between the severity of EIB and FENO is present and FENO significantly predictive of EIB only in atopic subjects, suggesting different interaction between bronchial responsiveness and airway inflammation in non-atopic wheeze. [source] Cuticular hydrocarbons in a termite: phenotypes and a neighbour,stranger effectPHYSIOLOGICAL ENTOMOLOGY, Issue 3 2002Manfred Kaib Abstract The composition of cuticular hydrocarbons of different colonies of the fungus-growing termite Macrotermes falciger shows considerable intercolonial variation. Ordination, as well as cluster analyses, separate profiles into three distinct chemical phenotypes. Behavioural tests with major workers reveal no alarm behaviour or mortality in pairings of workers from the same colony but a full range from no alarm to overt aggression, with associated death, when individuals were paired from different colonies. The level of mortality increases with differences in the composition of cuticular hydrocarbons between colonies. However, no mortality occurs in pairings of individuals from neighbouring colonies belonging to different phenotypes. The data thus provide evidence for a ,neighbour,stranger' effect (so-called ,dear-enemy' phenomenon) in termites. [source] Ciliary biology: Understanding the cellular and genetic basis of human ciliopathies,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 4 2009Magdalena Cardenas-Rodriguez Abstract Motile cilia have long been known to play a role in processes such as cell locomotion and fluid movement whereas the functions of primary cilia have remained obscure until recent years. To date, ciliary dysfunction has been shown to be causally linked to a number of clinical manifestations that characterize the group of human disorders known as ciliopathies. This classification reflects a common or shared cellular basis and implies that it is possible to associate a series of different human conditions with ciliary dysfunction, which allows gaining insight into the cellular defect in disorders of unknown etiology solely based on phenotypic observations. Furthermore, to date we know that the cilium participates in a number of biological processes ranging from chemo- and mechanosensation to the transduction of a growing list of paracrine signaling cascades that are critical for the development and maintenance of different tissues and organs. Consequently, the primary cilium has been identified as a key structure necessary to regulate and maintain cellular and tissue homeostasis and thus its study is providing significant information to understand the pathogenesis of the different phenotypes that characterize these human conditions. Finally, the similarities between different ciliopathies at the phenotypic level are proving to be due to their shared cellular defect and also their common genetic basis. To this end, recent studies are showing that mutations in a given ciliary gene often appear involved in the pathogenesis of more than one clinical entity, complicating their genetic dissection, and hindering our ability to generate accurate genotype,phenotype correlations. © 2009 Wiley-Liss, Inc. [source] Understanding dendritic cell biology and its role in immunological disorders through proteomic profilingPROTEOMICS - CLINICAL APPLICATIONS, Issue 2 2010Gabriela Bomfim Ferreira Abstract Dendritic cells (DC) have always been present on the bright spot of immune research. They have been extensively studied for the last 35 years, and much is known about their different phenotypes, stimulatory capacity, and role in the immune system. During the last 15 years, great attention has been given to studies on global gene and protein expression profiles during the differentiation and maturation processes of these cells. It is well understood that studying the proteome, together with information on the role of protein post-translational modifications (PTM), will reveal the real dynamics of a living cell. The rapid increase of proteomic studies during the last decade describing the differentiation and maturation process in DCs, as well as modifications brought by the use of different compounds that either increase or decrease their immunogenicity, reflects the importance of understanding the molecular processes behind the functional properties of these cells. In the present review, we will give an overview of proteomic studies focusing on DCs. Thereby we will concentrate on the importance of these studies in understanding DC behavior from a molecular point of view and how these findings have aided in understanding the differences in functional properties of these cells. [source] Genetics of atrioventricular conduction disease in humansTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 2 2004D. Woodrow Benson Abstract Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV block has unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with disease gene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics. © 2004 Wiley-Liss, Inc. [source] Phenotypes of obstructive lung diseaseTHE CLINICAL RESPIRATORY JOURNAL, Issue 2008C. Janson Abstract Recently, there has been much emphasis on the fact that there are many different phenotypes in asthma and chronic obstructive pulmonary disease (COPD). The aim of this review is to investigate some aspects of phenotyping in these two diseases. Epidemiological studies show a quite different risk factor pattern in allergic and non-allergic asthma. Several studies also indicated that there are pathophysiological differences between these two types of asthma: such as eosinophil inflammation in allergic and neutrophil predominance in non-allergic asthma. Neutrophil inflammation may also be a marker of severe asthma. At least one study indicates that non-allergic asthmatics are less responsive to inhaled corticosteroids than allergic asthmatics. Recently, it has been emphasized that COPD also has manifestations other than lung function decline and that this also needs to be taken into account in severity characterisation. Dyspnea, weight loss, psychological status and co-morbidity are factors that seem to be of large prognostic importance independently of the level of airflow obstruction in COPD. Progress has been made in understanding how asthma develops, but effective measures for primary preventions is still lacking. Better phenotyping in asthma will hopefully enable us to make progress in this area. Phenotyping is also important for assessment of prognosis in both asthma and COPD. Please cite this paper as: Janson C. Phenotypes of obstructive lung disease. The Clinical Respiratory Journal 2008; 2: 88,91. [source] Two-dimensional gel electrophoresis-based proteomic analysis of the Medicago truncatula,rust (Uromyces striatus) interactionANNALS OF APPLIED BIOLOGY, Issue 2 2010M.Á. Castillejo A two-dimensional gel electrophoresis (2-DE) based proteomic approach has been used to study the Medicago truncatula,Uromyces striatus interaction. The 2-DE leaf protein profile of three M. truncatula genotypes displaying different phenotypes (susceptible and showing prehaustorial and posthaustorial resistance) in both noninoculated and inoculated plants have been compared. Multivariate statistical analysis identified 63 differential protein spots under the experimental conditions (genotypes/treatments). Variable spots were subjected to tandem mass spectrometry (MS, matrix-assisted laser desorption ionisation time of flight, MALDI-TOF/TOF) analysis to identify their possible functions. A total of 27 proteins were identified using a combination of peptide mass fingerprinting (PMF) and MSMS fragmentation. Most of these observed changes correspond to enzymes involved in photosynthesis, energy metabolic pathways and stress related, whose pattern expression was different in relation to susceptibility/resistance of the genotypes studied. Results obtained in this work suggest that differences observed could be related to efficiency in energy utilisation and the induction of proteins involved in defence mechanism operating during early stages of infection. [source] | |||||||||||||||||||||||||||||||