Home About us Contact
|
Home About us Contact | ||
|
|
||
Secondary Responses (secondary + response)
Selected AbstractsBroad-Complex, E74, and E75 early genes control DNA puff BhC4-1 expression in prepupal salivary glandsGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 11 2006L.R. Basso Jr. Abstract The DNA puff BhC4-1 gene of the sciarid Bradysia hygida is induced in salivary glands prior to the pupal molt as a secondary response to the increase in ecdysone titers. Previous studies demonstrated that the BhC4-1 promoter is activated in transgenic Drosophila melanogaster salivary glands as a late response to the ecdysone peak that triggers metamorphosis, revealing that this aspect of BhC4-1 transcriptional regulation is conserved in the Drosophila background. To identify regulators of BhC4-1 expression, we utilized a candidate gene approach and tested the roles of the ecdysone-induced genes BR-C, E74, and E75. Our results reveal that the BR-C Z3 isoform is essential for BhC4-1-lacZ induction in prepupal salivary glands and constitute the first demonstration of the participation of early genes products on DNA puff genes regulation. genesis 44:505,514, 2006. © 2006 Wiley-Liss, Inc. [source] On removing the primary field from fixed-wing time-domain airborne electromagnetic data: some consequences for quantitative modelling, estimating bird position and detecting perfect conductorsGEOPHYSICAL PROSPECTING, Issue 4 2001Richard Smith In the process of removing the primary field from fixed-wing time-domain airborne EM data, the response is decomposed into two parts, which are referred to here as the time-domain ,in-phase' and ,quadrature' components. The time-domain in-phase component is dominated by the primary field, which varies significantly as the transmitter,receiver separation changes. The time-domain quadrature component comes solely from the secondary response associated with currents induced in the ground and this is the component that has traditionally been used in the interpretation of data from fixed-wing towed-bird time-domain EM systems. In the off-time, the quadrature response is very similar to the total secondary response. However, there are large differences in the on-time and even some small differences in the off-time.One consequence of these differences is that when airborne EM data are to be interpreted using a synthetic mathematical model, the synthetic data calculated should also be the quadrature component. A second consequence relates to the time-domain in-phase component which is sometimes used to estimate the receiver-sensor (bird) position. The bird-position estimation process assumes there is no secondary field in the in-phase component. If the ground is resistive, the secondary contained in the in-phase component is small, so the bird-position estimate is accurate to about 30 cm, but in highly conductive areas the secondary contribution can be large and the position estimate can be out by as much as 5 m. A third consequence arises for highly conductive bodies, the response of which is predominantly in-phase. This means that any response from these types of body is lost in the component that has been removed in the primary-field extraction procedure. However, if the bird position is measured very accurately, the actual free-space primary field can be estimated. If this is then subtracted from the estimated primary (actually free-space primary plus secondary in-phase response), then the residual is the secondary in-phase response of the ground. Using this methodology, very conductive ore bodies could be detected. However, a sensitivity analysis shows that detection of a large vertically dipping very conductive body at 150 m depth would require that the bird position be measured to an accuracy of about 1.4 cm and the aircraft attitude to within about 0.01°. Such tolerances are very stringent and not easily attainable with current technology. [source] Generation, persistence and plasticity of CD4 T-cell memoriesIMMUNOLOGY, Issue 4 2010Jason R. Lees Summary The development of immune memory mediated by T lymphocytes is central to durable, long-lasting protective immunity. A key issue in the field is how to direct the generation and persistence of memory T cells to elicit the appropriate secondary response to provide protection to a specific pathogen. Two prevailing views have emerged; that cellular and molecular regulators control the lineage fate and functional capacities of memory T cells early after priming, or alternatively, that populations of memory T cells are inherently plastic and subject to alterations in function and/or survival at many stages during their long-term maintenance. Here, we will review current findings in CD4 T-cell memory that suggest inherent plasticity in populations of memory CD4 T cells at all stages of their development , originating with their generation from multiple types of primed CD4 T cells, during their persistence and homeostatic turnover in response to T-cell receptor signals, and also following secondary challenge. These multiple aspects of memory CD4 T-cell flexibility contrast the more defined lineages and functions ascribed to memory CD8 T cells, suggesting a dynamic nature to memory CD4 T-cell populations and responses. The flexible attributes of CD4 T-cell memory suggest opportunities and mechanisms for therapeutic manipulation at all phases of immune memory development, maintenance and recall. [source] Popliteal lymph node assay: facts and perspectivesJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2005Guillaume Ravel Abstract The popliteal lymph node assay (PLNA) derives from the hypothesis that some supposedly immunemediated adverse effects induced by certain pharmaceuticals involve a mechanism resembling a graft-versus-host reaction. The injection of many but not all of these compounds into the footpad of mice or rats produces an increase in the weight and/or cellularity of the popliteal lymph node in the treated limb (direct PLNA). Some of the compounds known to cause these adverse effects in humans, however, failed to induce a positive PLNA response, leading to refinements of the technique to include pretreatment with enzyme inducers, depletion of CD4+ T cells or additional endpoints such as histological examination, lymphocyte subset analysis and cytokine fingerprinting. Alternative approaches have been used to improve further the predictability of the assay. In the secondary PLNA, the test compound is injected twice in order to illicit a greater secondary response, thus suggesting a memory-specific T cell response. In the adoptive PLNA, popliteal lymph node cells from treated mice are injected into the footpad of naive mice; a marked response to a subsequent footpad challenge demonstrates the involvement of T cells. Finally, the reporter antigens TNP-Ficoll and TNP-ovalbumin are used to differentiate compounds that induce responses involving neo-antigen help or co-stimulatory signals (modified PLNA). The PLNA is increasingly considered as a tool for detection of the potential to induce both sensitization and autoimmune reactions. A major current limitation is validation. A small inter-laboratory validation study of the direct PLNA found consistent results. No such study has been performed using an alternative protocol. Other issues include selection of the optimal protocol for an improved prediction of sensitization vs autoimmunity, and the elimination of false-positive responses due to primary irritation. Finally, a better understanding of underlying mechanisms is essential to determine the most relevant endpoints. The confusion resulting from use of the PLNA to predict autoimmune-like reactions as well as sensitization should be clarified. Interestingly, most drugs that were positive in the direct PLNA are also known to cause drug hypersensitivity syndrome in treated patients. This observation is expected to open new avenues of research. Copyright © 2005 John Wiley & Sons, Ltd. [source] Soluble, insoluble and geometric signals sculpt the architecture of mineralized tissuesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2004U. Ripamonti Abstract Bone morphogenetic and osteogenic proteins (BMPs/OPs), members of the transforming growth factor-, (TGF-,) superfamily, are soluble mediators of tissue morphogenesis and induce de novo endochondral bone formation in heterotopic extraskeletal sites as a recapitulation of embryonic development. In the primate Papio ursinus, the induction of bone formation has been extended to the TGF-, isoforms per se. In the primate and in the primate only, the TGF-, isoforms are initiators of endochondral bone formation by induction and act in a species-, site- and tissue-specific mode with robust endochondral bone induction in heterotopic sites but with limited new bone formation in orthotopic bone defects. The limited inductive capacity orthotopically of TGF-, isoforms is associated with expression of the inhibitory Smads, Smad6 and Smad7. In primates, bone formation can also be induced using biomimetic crystalline hydroxyapatite matrices with a specific surface geometry and without the exogenous application of osteogenic proteins of the TGF-, superfamily, even when the biomimetic matrices are implanted heterotopically in the rectus abdominis muscle. The sequence of events that directs new bone formation upon the implantation of highly crystalline biomimetic matrices initiates with vascular invasion, mesenchymal cell migration, attachment and differentiation of osteoblast-like cells attached to the substratum, expression and synthesis of osteogenic proteins of the TGF-, superfamily resulting in the induction of bone as a secondary response. The above findings in the primate indicate enormous potential for the bioengineering industry. Of particular interest is that biomimetic matrices with intrinsic osteoinductivity would be an affordable option in the local context. [source] Post-European settlement response gradients of river sensitivity and recovery across the upper Hunter catchment, AustraliaEARTH SURFACE PROCESSES AND LANDFORMS, Issue 7 2009Kirstie Fryirs Abstract Most analyses of river adjustment have focused on parts of catchments where metamorphosis has occurred. This provides a non-representative view of river responses to human-disturbance. Although many rivers have been subjected to systematic land-use change and disturbance, significant variability is evident in the form, extent and consequences of adjustment. This study documents the catchment-wide distribution of river sensitivity and adjustment in the upper Hunter catchment, New South Wales, Australia in the period since European settlement. The spatial distribution and timing of lateral, vertical and wholesale river adjustments are used to assess river sensitivity to change. The type and pattern of rivers, influenced largely by valley setting, have induced a fragmented pattern of river adjustment in the upper Hunter catchment. Adjustments have been largely non-uniform and localized, reflecting the predominance of bedrock-controlled rivers which have limited capacity to adjust and are resilient to change. Less than 20% of river courses have experienced metamorphosis. Phases of reach-scale geomorphic adjustment to human disturbance are characterized as a gradient of primary, secondary and tertiary responses. In general terms, primary responses such as cutoffs or straightening were followed by secondary responses such as channel expansion. These secondary responses occurred between 50,70 years after initial disturbance. A subsequent tertiary phase of river recovery, denoted as a transition from predominantly erosional to predominantly depositional geomorphic processes such as channel contraction, occurred around 70,120 years after initial disturbance. Such responses are ongoing across much of the upper Hunter catchment. Copyright © 2009 John Wiley & Sons, Ltd. [source] Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis -specific CD4+ memory T lymphocyte populationsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2007Natalie Abstract In the search for effective vaccines against intracellular pathogens such as HIV, tuberculosis and malaria, recombinant viral vectors are increasingly being used to boost previously primed T cell responses. Published data have shown prime-boost vaccination with BCG-MVA85A (modified vaccinia virus Ankara expressing antigen 85A) to be highly immunogenic in humans as measured by ex vivo IFN-, ELISPOT. Here, we used polychromatic flow cytometry to investigate the phenotypic and functional profile of these vaccine-induced Mycobacterium tuberculosis (M.tb) antigen 85A-specific responses in greater detail. Promisingly, antigen 85A-specific CD4+ T cells were found to be highly polyfunctional, producing IFN-,, TNF-,, IL-2 and MIP-1,. Surface staining showed the responding CD4+ T cells to be relatively immature (CD45RO+ CD27intCD57,); this observation was supported by the robust proliferative responses observed following antigenic stimulation. Furthermore, these phenotypic and functional properties were independent of clonotypic composition and epitope specificity, which was maintained through the different phases of the vaccine-induced immune response. Overall, these data strongly support the use of MVA85A in humans as a boosting agent to expand polyfunctional M.tb -specific CD4+ T cells capable of significant secondary responses. [source] Intrinsic properties of human and murine memory B cellsIMMUNOLOGICAL REVIEWS, Issue 1 2006Shannon M. Anderson Summary:, The central question of how the immune system responds in a qualitatively and quantitatively better way upon re-exposure to a pathogen is largely unanswered. Both the increased frequency of antigen-specific memory cells and the intrinsic properties that memory cells acquire after antigen experience could contribute to the faster and more robust responses seen after repeated exposure to antigen. In the case of the memory B-cell response, it has been difficult to discern the individual contributions of these two effects. However, because of recent advances in identifying memory B cells, there is an increasing understanding of the intrinsic properties of these cells. The current insights into the unique properties of memory B cells and the progress that has been made in understanding how these affect secondary responses in both the human and the mouse systems are discussed. In addition, we compare the various advantages and disadvantages inherent in each of these systems, in terms of studying the intrinsic properties of memory B cells, and introduce the details of the system that we have developed using conventional heavy chain transgenic (Tgic) mice, which addresses some of the drawbacks of traditional memory models. [source] Differential CD4+ T-cell memory responses induced by two subsets of human monocyte-derived dendritic cellsIMMUNOLOGY, Issue 3 2007Sandra Bajaña Summary Dendritic cells (DC) are powerful inducers of primary T-cell responses, but their role in secondary responses has not been extensively analysed. Here, we address the role of two DC subsets derived from human CD16+ (16+ mDC) or CD16, (16, mDC) monocytes on the reactivation of memory responses. CD4+ CD45RA, memory T cells were obtained from adult blood donors, and central (TCM) and effector (TEM) memory T cells were isolated by fluorescence-activated cell sorting with anti-CCR7 antibodies. The 16+ mDC and 16, mDC were cocultured with autologous lymphocytes, either unpulsed or loaded with purified protein derivatives of Mycobacterium tuberculosis (PPD) or tetanus toxoid (TT), and were analysed for up to 8 days. Over a range of doses, 16+ mDC drove stronger T-cell proliferative responses against both antigens. Overall, antigen-specific memory cells tended to acquire a phenotype of TEM at later time-points in the culture, whereas cells that had completed fewer cycles of division were similar to TCM. The 16+ mDC induced higher rates of proliferation on both TCM and TEM lymphocytes than 16, mDC. This phenomenon was not related to the ability of both DC to induce CD25 expression on T cells, to lower secretion of interleukin-2, or to raise production of interleukin-10 during T-cell/16, mDC cocultures. The induction of TCM effector capacity in terms of interferon-, production was faster and more pronounced with 16+ mDC, whereas both DC had similar abilities with TEM. In conclusion, these data might reveal new potentials in vaccination protocols with 16+ mDC aimed at inducing strong responses on central memory T cells. [source] Retinoic acid regulates the expression of PBX1, PBX2, and PBX3 in P19 cells both transcriptionally and post-translationallyJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Pu Qin Abstract Pre-B cell leukemia transcription factors (PBXs) are important co-factors for the transcriptional regulation mediated by a number of Hox proteins during embryonic development. It was previously shown that the expression of several Pbx genes is elevated in mouse embryo limb buds and embryonal carcinoma P19 cells upon retinoic acid (RA) treatment although the mechanism of this induction is not well understood. In this report, we demonstrate that PBX1a, PBX1b, PBX2, and PBX3 mRNAs and PBX1/2/3 proteins are induced during endodermal and neuronal differentiation of P19 cells in a RAR-dependent subtype-unspecific manner following RA treatment. The increases in both PBX1 mRNA and PBX3 mRNA levels are secondary responses to RA treatment requiring new proteins synthesis while the increase in PBX2 mRNA is a primary response. The RA-dependent increases in PBX1 mRNA, PBX2 mRNA, and PBX3 mRNA levels are likely to be transcriptionally regulated since the stability of these mRNAs does not change. In addition, the half-lives of PBX1/2/3 proteins are significantly extended by RA treatment. Two possible mechanisms could contribute to the stabilization of PBX proteins: PBX proteins associate with RA-dependent increased levels of MEIS proteins, and RA may decrease the proteasome dependent degradation of PBX proteins. © 2004 Wiley-Liss, Inc. [source] Principles of pharmacodynamics and their applications in veterinary pharmacologyJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2004P. LEES Pharmacodynamics (PDs) is the science of drug action on the body or on microorganisms and other parasites within or on the body. It may be studied at many organizational levels , sub-molecular, molecular, cellular, tissue/organ and whole body , using in vivo, ex vivo and in vitro methods and utilizing a wide range of techniques. A few drugs owe their PD properties to some physico-chemical property or action and, in such cases, detailed molecular drug structure plays little or no role in the response elicited. For the great majority of drugs, however, action on the body is crucially dependent on chemical structure, so that a very small change, e.g. substitution of a proton by a methyl group, can markedly alter the potency of the drug, even to the point of loss of activity. In the late 19th century and first half of the 20th century recognition of these facts by Langley, Ehrlich, Dale, Clarke and others provided the foundation for the receptor site hypothesis of drug action. According to these early ideas the drug, in order to elicit its effect, had to first combine with a specific ,target molecule' on either the cell surface or an intracellular organelle. It was soon realized that the ,right' chemical structure was required for drug,target site interaction (and the subsequent pharmacological response). In addition, from this requirement, for specificity of chemical structure requirement, developed not only the modern science of pharmacology but also that of toxicology. In relation to drug actions on microbes and parasites, for example, the early work of Ehrlich led to the introduction of molecules selectively toxic for them and relatively safe for the animal host. In the whole animal drugs may act on many target molecules in many tissues. These actions may lead to primary responses which, in turn, may induce secondary responses, that may either enhance or diminish the primary response. Therefore, it is common to investigate drug pharmacodynamics (PDs) in the first instance at molecular, cellular and tissue levels in vitro, so that the primary effects can be better understood without interference from the complexities involved in whole animal studies. When a drug, hormone or neurotransmitter combines with a target molecule, it is described as a ligand. Ligands are classified into two groups, agonists (which initiate a chain of reactions leading, usually via the release or formation of secondary messengers, to the response) and antagonists (which fail to initiate the transduction pathways but nevertheless compete with agonists for occupancy of receptor sites and thereby inhibit their actions). The parameters which characterize drug receptor interaction are affinity, efficacy, potency and sensitivity, each of which can be elucidated quantitatively for a particular drug acting on a particular receptor in a particular tissue. The most fundamental objective of PDs is to use the derived numerical values for these parameters to classify and sub-classify receptors and to compare and classify drugs on the basis of their affinity, efficacy, potency and sensitivity. This review introduces and summarizes the principles of PDs and illustrates them with examples drawn from both basic and veterinary pharmacology. Drugs acting on adrenoceptors and cardiovascular, non-steroidal anti-inflammatory and antimicrobial drugs are considered briefly to provide a foundation for subsequent reviews in this issue which deal with pharmacokinetic (PK),PD modelling and integration of these drug classes. Drug action on receptors has many features in common with enzyme kinetics and gas adsorption onto surfaces, as defined by Michaelis,Menten and Langmuir absorption equations, respectively. These and other derived equations are outlined in this review. There is, however, no single theory which adequately explains all aspects of drug,receptor interaction. The early ,occupation' and ,rate' theories each explain some, but not all, experimental observations. From these basic theories the operational model and the two-state theory have been developed. For a discussion of more advanced theories see Kenakin (1997). [source] Effects of FSH receptor deletion on epididymal tubules and sperm morphology, numbers, and motilityMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 2 2005Amit Grover Abstract Follicle stimulating hormone (FSH) interacts with its cognate receptor (R) on Sertoli cells within the testis and plays an important role in the maintenance of spermatogenesis. Male FSH-R knockout (FORKO) mice show fewer Sertoli cells and many that are structurally abnormal and as a consequence fewer germ cells. Lower levels of serum testosterone (T) and androgen binding protein (ABP) also occur, along with reduced fertility. To assess the effects of FSH-R depletion as an outcome of testicular abnormalities, sperm from the cauda epididymidis were counted and examined ultrastructurally. As reduced fertility may also reflect changes to the epididymis, the secondary responses of the epididymis to lower T and ABP levels were also examined by comparing differences in sizes of epididymal tubules in various regions of FORKO and wild type (WT) mice. Sperm motility was evaluated in FORKO mice and compared to that of WT mice by computer assisted sperm analysis (CASA). Quantitatively, the data revealed that epithelial areas of the caput and corpus epididymidis were significantly smaller in FORKO mice compared to WT mice. Cauda epididymal sperm counts in FORKO mice were also much lower than in WT mice. This resulted in changes to 9 out of 14 sperm motility parameters, related mostly to velocity measures, which were significantly lower in the FORKO mice. The greatest change was observed relative to the percent static sperm, which was elevated by 20% in FORKO mice compared to controls. EM analyses revealed major changes to the structure of the heads and tails of cauda luminal sperm in FORKO mice. Taken together these data suggest a key role for the FSH receptor in maintaining Sertoli cells to sustain normal sperm numbers and proper shapes of their heads and tails. In addition, the shrinkage in epididymal epithelial areas observed in FORKO mice likely reflect direct and/or indirect changes in the functions of these cells and their role in promoting sperm motility, which is noticeably altered in FORKO mice. Mol. Reprod. Dev. © 2005 Wiley-Liss, Inc. [source] Ex vivo Inhibition of NF-,B Signaling in Alloreactive T-cells Prevents Graft-Versus-Host DiseaseAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009M. J. O'Shaughnessy The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the graft-versus-host disease (GVHD) capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-,B pathway in alloreactive T-cells, which is critical for T-cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-,B activation, can induce T-cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control or PS1145-treated MLR cells in syngeneic Rag,/, recipients resulted in intact contact hypersensitivity (CHS) responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-,B pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early posttransplant GVHD lethality but that also permits donor T-cell responses to recover after a period of lymphopenic expansion. [source] | ||||||||||||||||