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Sample records for adaptive cellular response

  1. Glycerol stress in Saccharomyces cerevisiae: Cellular responses and evolved adaptations.

    PubMed

    Mattenberger, Florian; Sabater-Muñoz, Beatriz; Hallsworth, John E; Fares, Mario A

    2017-03-01

    Glycerol synthesis is key to central metabolism and stress biology in Saccharomyces cerevisiae, yet the cellular adjustments needed to respond and adapt to glycerol stress are little understood. Here, we determined impacts of acute and chronic exposures to glycerol stress in S. cerevisiae. Glycerol stress can result from an increase of glycerol concentration in the medium due to the S. cerevisiae fermenting activity or other metabolic activities. Acute glycerol-stress led to a 50% decline in growth rate and altered transcription of more than 40% of genes. The increased genetic diversity in S. cerevisiae population, which had evolved in the standard nutrient medium for hundreds of generations, led to an increase in growth rate and altered transcriptome when such population was transferred to stressful media containing a high concentration of glycerol; 0.41 M (0.990 water activity). Evolution of S. cerevisiae populations during a 10-day period in the glycerol-containing medium led to transcriptome changes and readjustments to improve control of glycerol flux across the membrane, regulation of cell cycle, and more robust stress response; and a remarkable increase of growth rate under glycerol stress. Most of the observed regulatory changes arose in duplicated genes. These findings elucidate the physiological mechanisms, which underlie glycerol-stress response, and longer-term adaptations, in S. cerevisiae; they also have implications for enigmatic aspects of the ecology of this otherwise well-characterized yeast.

  2. The Inhibitor of Apoptosis (IAPs) in Adaptive Response to Cellular Stress

    PubMed Central

    Marivin, Arthur; Berthelet, Jean; Plenchette, Stéphanie; Dubrez, Laurence

    2012-01-01

    Cells are constantly exposed to endogenous and exogenous cellular injuries. They cope with stressful stimuli by adapting their metabolism and activating various “guardian molecules.” These pro-survival factors protect essential cell constituents, prevent cell death, and possibly repair cellular damages. The Inhibitor of Apoptosis (IAPs) proteins display both anti-apoptotic and pro-survival properties and their expression can be induced by a variety of cellular stress such as hypoxia, endoplasmic reticular stress and DNA damage. Thus, IAPs can confer tolerance to cellular stress. This review presents the anti-apoptotic and survival functions of IAPs and their role in the adaptive response to cellular stress. The involvement of IAPs in human physiology and diseases in connection with a breakdown of cellular homeostasis will be discussed. PMID:24710527

  3. Genetic screening of new genes responsible for cellular adaptation to hypoxia using a genome-wide shRNA library.

    PubMed

    Yoshino, Seiko; Hara, Toshiro; Weng, Jane S; Takahashi, Yuka; Seiki, Motoharu; Sakamoto, Takeharu

    2012-01-01

    Oxygen is a vital requirement for multi-cellular organisms to generate energy and cells have developed multiple compensatory mechanisms to adapt to stressful hypoxic conditions. Such adaptive mechanisms are intricately interconnected with other signaling pathways that regulate cellular functions such as cell growth. However, our understanding of the overall system governing the cellular response to the availability of oxygen remains limited. To identify new genes involved in the response to hypoxic stress, we have performed a genome-wide gene knockdown analysis in human lung carcinoma PC8 cells using an shRNA library carried by a lentiviral vector. The knockdown analysis was performed under both normoxic and hypoxic conditions to identify shRNA sequences enriched or lost in the resulting selected cell populations. Consequently, we identified 56 candidate genes that might contribute to the cellular response to hypoxia. Subsequent individual knockdown of each gene demonstrated that 13 of these have a significant effect upon oxygen-sensitive cell growth. The identification of BCL2L1, which encodes a Bcl-2 family protein that plays a role in cell survival by preventing apoptosis, validates the successful design of our screen. The other selected genes have not previously been directly implicated in the cellular response to hypoxia. Interestingly, hypoxia did not directly enhance the expression of any of the identified genes, suggesting that we have identified a new class of genes that have been missed by conventional gene expression analyses to identify hypoxia response genes. Thus, our genetic screening method using a genome-wide shRNA library and the newly-identified genes represent useful tools to analyze the cellular systems that respond to hypoxic stress.

  4. Cellular, physiological, and molecular adaptive responses of Erwinia amylovora to starvation.

    PubMed

    Santander, Ricardo D; Oliver, James D; Biosca, Elena G

    2014-05-01

    Erwinia amylovora causes fire blight, a destructive disease of rosaceous plants distributed worldwide. This bacterium is a nonobligate pathogen able to survive outside the host under starvation conditions, allowing its spread by various means such as rainwater. We studied E. amylovora responses to starvation using water microcosms to mimic natural oligotrophy. Initially, survivability under optimal (28 °C) and suboptimal (20 °C) growth temperatures was compared. Starvation induced a loss of culturability much more pronounced at 28 °C than at 20 °C. Natural water microcosms at 20 °C were then used to characterize cellular, physiological, and molecular starvation responses of E. amylovora. Challenged cells developed starvation-survival and viable but nonculturable responses, reduced their size, acquired rounded shapes and developed surface vesicles. Starved cells lost motility in a few days, but a fraction retained flagella. The expression of genes related to starvation, oxidative stress, motility, pathogenicity, and virulence was detected during the entire experimental period with different regulation patterns observed during the first 24 h. Further, starved cells remained as virulent as nonstressed cells. Overall, these results provide new knowledge on the biology of E. amylovora under conditions prevailing in nature, which could contribute to a better understanding of the life cycle of this pathogen.

  5. Adaptive Posttranslational Control in Cellular Stress Response Pathways and Its Relationship to Toxicity Testing and Safety Assessment

    PubMed Central

    Zhang, Qiang; Bhattacharya, Sudin; Pi, Jingbo; Clewell, Rebecca A.; Carmichael, Paul L.; Andersen, Melvin E.

    2015-01-01

    Although transcriptional induction of stress genes constitutes a major cellular defense program against a variety of stressors, posttranslational control directly regulating the activities of preexisting stress proteins provides a faster-acting alternative response. We propose that posttranslational control is a general adaptive mechanism operating in many stress pathways. Here with the aid of computational models, we first show that posttranslational control fulfills two roles: (1) handling small, transient stresses quickly and (2) stabilizing the negative feedback transcriptional network. We then review the posttranslational control pathways for major stress responses—oxidative stress, metal stress, hyperosmotic stress, DNA damage, heat shock, and hypoxia. Posttranslational regulation of stress protein activities occurs by reversible covalent modifications, allosteric or non-allosteric enzymatic regulations, and physically induced protein structural changes. Acting in feedback or feedforward networks, posttranslational control may establish a threshold level of cellular stress. Sub-threshold stresses are handled adequately by posttranslational control without invoking gene transcription. With supra-threshold stress levels, cellular homeostasis cannot be maintained and transcriptional induction of stress genes and other gene programs, eg, those regulating cell metabolism, proliferation, and apoptosis, takes place. The loss of homeostasis with consequent changes in cellular function may lead to adverse cellular outcomes. Overall, posttranslational and transcriptional control pathways constitute a stratified cellular defense system, handling stresses coherently across time and intensity. As cell-based assays become a focus for chemical testing anchored on toxicity pathways, examination of proteomic and metabolomic changes as a result of posttranslational control occurring in the absence of transcriptomic alterations deserves more attention. PMID:26408567

  6. Adaptive Cellular Interactions in the Immune System: The Tunable Activation Threshold and the Significance of Subthreshold Responses

    NASA Astrophysics Data System (ADS)

    Grossman, Zvi; Paul, William E.

    1992-11-01

    A major challenge for immunologists is to explain how the immune system adjusts its responses to the microenvironmental context in which antigens are recognized. We propose that lymphocytes achieve this by tuning and updating their responsiveness to recurrent signals. In particular, cellular anergy in vivo is a dynamic state in which the threshold for a stereotypic mode of activation has been elevated. Anergy is associated with other forms of cellular activity, not paralysis. Cells engaged in such subthreshold interactions mediate functions such as maintenance of immunological memory and control of infections. In such interactions, patterns of signals are recognized and classified and evoke selective responses. The robust mechanism proposed for segregation of suprathreshold and subthreshold immune responses allows lymphocytes to use recognition of self-antigens in executing physiological functions. Autoreactivity is allowed where it is dissociated from uncontrolled aggression.

  7. Adaptive response modelling

    NASA Astrophysics Data System (ADS)

    Campa, Alessandro; Esposito, Giuseppe; Belli, Mauro

    Cellular response to radiation is often modified by a previous delivery of a small "priming" dose: a smaller amount of damage, defined by the end point being investigated, is observed, and for this reason the effect is called adaptive response. An improved understanding of this effect is essential (as much as for the case of the bystander effect) for a reliable radiation risk assessment when low dose irradiations are involved. Experiments on adaptive response have shown that there are a number of factors that strongly influence the occurrence (and the level) of the adaptation. In particular, priming doses and dose rates have to fall in defined ranges; the same is true for the time interval between the delivery of the small priming dose and the irradiation with the main, larger, dose (called in this case challenging dose). Different hypotheses can be formulated on the main mechanism(s) determining the adaptive response: an increased efficiency of DNA repair, an increased level of antioxidant enzymes, an alteration of cell cycle progression, a chromatin conformation change. An experimental clearcut evidence going definitely in the direction of one of these explanations is not yet available. Modelling can be done at different levels. Simple models, relating the amount of damage, through elementary differential equations, to the dose and dose rate experienced by the cell, are relatively easy to handle, and they can be modified to account for the priming irradiation. However, this can hardly be of decisive help in the explanation of the mechanisms, since each parameter of these models often incorporates in an effective way several cellular processes related to the response to radiation. In this presentation we show our attempts to describe adaptive response with models that explicitly contain, as a dynamical variable, the inducible adaptive agent. At a price of a more difficult treatment, this approach is probably more prone to give support to the experimental studies

  8. A comparative systems analysis of polysaccharide-elicited responses in Neurospora crassa reveals carbon source-specific cellular adaptations

    PubMed Central

    Benz, J. Philipp; Chau, Bryant H.; Zheng, Diana; Bauer, Stefan; Glass, N. Louise; Somerville, Chris R.

    2014-01-01

    Summary Filamentous fungi are powerful producers of hydrolytic enzymes for the deconstruction of plant cell wall polysaccharides. However, the central question of how these sugars are perceived in the context of the complex cell wall matrix remains largely elusive. To address this question in a systematic fashion we performed an extensive comparative systems analysis of how the model filamentous fungus Neurospora crassa responds to the three main cell wall polysaccharides: pectin, hemicellulose and cellulose. We found the pectic response to be largely independent of the cellulolytic one with some overlap to hemicellulose, and in its extent surprisingly high, suggesting advantages for the fungus beyond being a mere carbon source. Our approach furthermore allowed us to identify carbon source-specific adaptations, such as the induction of the unfolded protein response on cellulose, and a commonly induced set of 29 genes likely involved in carbon scouting. Moreover, by hierarchical clustering we generated a co-expression matrix useful for the discovery of new components involved in polysaccharide utilization. This is exemplified by the identification of lat-1, which we demonstrate to encode for the physiologically relevant arabinose transporter in Neurospora. The analyses presented here are an important step towards understanding fungal degradation processes of complex biomass. PMID:24224966

  9. Hormesis and adaptive cellular control systems

    EPA Science Inventory

    Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from...

  10. Powerful Complex Immunoadjuvant Based on Synergistic Effect of Combined TLR4 and NOD2 Activation Significantly Enhances Magnitude of Humoral and Cellular Adaptive Immune Responses

    PubMed Central

    Dzharullaeva, Alina S.; Tukhvatulina, Natalia M.; Shcheblyakov, Dmitry V.; Shmarov, Maxim M.; Dolzhikova, Inna V.; Stanhope-Baker, Patricia; Naroditsky, Boris S.; Gudkov, Andrei V.; Logunov, Denis Y.; Gintsburg, Alexander L.

    2016-01-01

    Binding of pattern recognition receptors (PRRs) by pathogen-associated molecular patterns (PAMPs) activates innate immune responses and contributes to development of adaptive immunity. Simultaneous stimulation of different types of PRRs can have synergistic immunostimulatory effects resulting in enhanced production of molecules that mediate innate immunity such as inflammatory cytokines, antimicrobial peptides, etc. Here, we evaluated the impact of combined stimulation of PRRs from different families on adaptive immunity by generating alum-based vaccine formulations with ovalbumin as a model antigen and the Toll-like receptor 4 (TLR4) agonist MPLA and the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist MDP adsorbed individually or together on the alum-ovalbumin particles. Multiple in vitro and in vivo readouts of immune system activation all showed that while individual PRR agonists increased the immunogenicity of vaccines compared to alum alone, the combination of both PRR agonists was significantly more effective. Combined stimulation of TLR4 and NOD2 results in a stronger and broader transcriptional response in THP-1 cells compared to individual PRR stimulation. Immunostimulatory composition containing both PRR agonists (MPLA and MDP) in the context of the alum-based ovalbumin vaccine also enhanced uptake of vaccine particles by bone marrow derived dendritic cells (BMDCs) and promoted maturation (up-regulation of expression of CD80, CD86, MHCII) and activation (production of cytokines) of BMDCs. Finally, immunization of mice with vaccine particles containing both PRR agonists resulted in enhanced cellular immunity as indicated by increased proliferation and activation (IFN-γ production) of splenic CD4+ and CD8+ T cells following in vitro restimulation with ovalbumin and enhanced humoral immunity as indicated by higher titers of ovalbumin-specific IgG antibodies. These results indicate that combined stimulation of TLR4 and NOD2

  11. Powerful Complex Immunoadjuvant Based on Synergistic Effect of Combined TLR4 and NOD2 Activation Significantly Enhances Magnitude of Humoral and Cellular Adaptive Immune Responses.

    PubMed

    Tukhvatulin, Amir I; Dzharullaeva, Alina S; Tukhvatulina, Natalia M; Shcheblyakov, Dmitry V; Shmarov, Maxim M; Dolzhikova, Inna V; Stanhope-Baker, Patricia; Naroditsky, Boris S; Gudkov, Andrei V; Logunov, Denis Y; Gintsburg, Alexander L

    2016-01-01

    Binding of pattern recognition receptors (PRRs) by pathogen-associated molecular patterns (PAMPs) activates innate immune responses and contributes to development of adaptive immunity. Simultaneous stimulation of different types of PRRs can have synergistic immunostimulatory effects resulting in enhanced production of molecules that mediate innate immunity such as inflammatory cytokines, antimicrobial peptides, etc. Here, we evaluated the impact of combined stimulation of PRRs from different families on adaptive immunity by generating alum-based vaccine formulations with ovalbumin as a model antigen and the Toll-like receptor 4 (TLR4) agonist MPLA and the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist MDP adsorbed individually or together on the alum-ovalbumin particles. Multiple in vitro and in vivo readouts of immune system activation all showed that while individual PRR agonists increased the immunogenicity of vaccines compared to alum alone, the combination of both PRR agonists was significantly more effective. Combined stimulation of TLR4 and NOD2 results in a stronger and broader transcriptional response in THP-1 cells compared to individual PRR stimulation. Immunostimulatory composition containing both PRR agonists (MPLA and MDP) in the context of the alum-based ovalbumin vaccine also enhanced uptake of vaccine particles by bone marrow derived dendritic cells (BMDCs) and promoted maturation (up-regulation of expression of CD80, CD86, MHCII) and activation (production of cytokines) of BMDCs. Finally, immunization of mice with vaccine particles containing both PRR agonists resulted in enhanced cellular immunity as indicated by increased proliferation and activation (IFN-γ production) of splenic CD4+ and CD8+ T cells following in vitro restimulation with ovalbumin and enhanced humoral immunity as indicated by higher titers of ovalbumin-specific IgG antibodies. These results indicate that combined stimulation of TLR4 and NOD2

  12. Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation

    PubMed Central

    Day, Judy D.; Metes, Diana M.; Vodovotz, Yoram

    2015-01-01

    A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient’s (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well-tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression. PMID:26441988

  13. Cellular immune responses to HIV

    NASA Astrophysics Data System (ADS)

    McMichael, Andrew J.; Rowland-Jones, Sarah L.

    2001-04-01

    The cellular immune response to the human immunodeficiency virus, mediated by T lymphocytes, seems strong but fails to control the infection completely. In most virus infections, T cells either eliminate the virus or suppress it indefinitely as a harmless, persisting infection. But the human immunodeficiency virus undermines this control by infecting key immune cells, thereby impairing the response of both the infected CD4+ T cells and the uninfected CD8+ T cells. The failure of the latter to function efficiently facilitates the escape of virus from immune control and the collapse of the whole immune system.

  14. Cellular Adaptation Facilitates Sparse and Reliable Coding in Sensory Pathways

    PubMed Central

    Farkhooi, Farzad; Froese, Anja; Muller, Eilif; Menzel, Randolf; Nawrot, Martin P.

    2013-01-01

    Most neurons in peripheral sensory pathways initially respond vigorously when a preferred stimulus is presented, but adapt as stimulation continues. It is unclear how this phenomenon affects stimulus coding in the later stages of sensory processing. Here, we show that a temporally sparse and reliable stimulus representation develops naturally in sequential stages of a sensory network with adapting neurons. As a modeling framework we employ a mean-field approach together with an adaptive population density treatment, accompanied by numerical simulations of spiking neural networks. We find that cellular adaptation plays a critical role in the dynamic reduction of the trial-by-trial variability of cortical spike responses by transiently suppressing self-generated fast fluctuations in the cortical balanced network. This provides an explanation for a widespread cortical phenomenon by a simple mechanism. We further show that in the insect olfactory system cellular adaptation is sufficient to explain the emergence of the temporally sparse and reliable stimulus representation in the mushroom body. Our results reveal a generic, biophysically plausible mechanism that can explain the emergence of a temporally sparse and reliable stimulus representation within a sequential processing architecture. PMID:24098101

  15. Cellular modes of adaptation to environmental changes

    NASA Astrophysics Data System (ADS)

    Huckle, William R.

    2001-10-01

    Eukaryotic cells are remarkably adaptable entities. Whether embedded in solid tissues or freely suspended in blood or other fluids, cells principally exist in an aqueous environment but maintain a hydrophobic barrier, the plasma membrane, across which changes in the environment are detected. Utilizing specialized macromolecular components, cells can sense changes in temperature, hydrostatic pressure, oxygen tension, shear, shape, osmolarity, pH, electrical potential, electromagnetic radiation, and the concentrations of specific chemical compounds. Modes of response are equally varied, ranging from rapid secretion of stored substances to irreversible functional differentiation to self-destruction. Recent research has elucidated many of the enzymatic and genetic programs that accomplish these adaptations and suggests novel targets for therapeutic intervention.

  16. Complex cellular responses to reactive oxygen species.

    PubMed

    Temple, Mark D; Perrone, Gabriel G; Dawes, Ian W

    2005-06-01

    Genome-wide analyses of yeast provide insight into cellular responses to reactive oxygen species (ROS). Many deletion mutants are sensitive to at least one ROS, but no one oxidant is representative of 'oxidative stress' despite the widespread use of a single compound such as H(2)O(2). This has major implications for studies of pathological situations. Cells have a range of mechanisms for maintaining resistance that involves either induction or repression of many genes and extensive remodeling of the transcriptome. Cells have constitutive defense systems that are largely unique to each oxidant, but overlapping, inducible repair systems. The pattern of the transcriptional response to a particular ROS depends on its concentration, and 'classical' antioxidant systems that are induced by high concentrations of ROS can be repressed when cells adapt to low concentrations of ROS.

  17. Mechanisms of cellular adaptation to quantum dots--the role of glutathione and transcription factor EB.

    PubMed

    Neibert, Kevin D; Maysinger, Dusica

    2012-05-01

    Cellular adaptation is the dynamic response of a cell to adverse changes in its intra/extra cellular environment. The aims of this study were to investigate the role of: (i) the glutathione antioxidant system, and (ii) the transcription factor EB (TFEB), a newly revealed master regulator of lysosome biogenesis, in cellular adaptation to nanoparticle-induced oxidative stress. Intracellular concentrations of glutathione species and activation of TFEB were assessed in rat pheochromocytoma (PC12) cells following treatment with uncapped CdTe quantum dots (QDs), using biochemical, live cell fluorescence and immunocytochemical techniques. Exposure to toxic concentrations of QDs resulted in a significant enhancement of intracellular glutathione concentrations, redistribution of glutathione species and a progressive translocation and activation of TFEB. These changes were associated with an enlargement of the cellular lysosomal compartment. Together, these processes appear to have an adaptive character, and thereby participate in the adaptive cellular response to toxic nanoparticles.

  18. Cellular and molecular aspects of plant adaptation to microgravity

    NASA Astrophysics Data System (ADS)

    Kordyum, Elizabeth; Kozeko, Liudmyla

    2016-07-01

    Elucidation of the range and mechanisms of the biological effects of microgravity is one of the urgent fundamental tasks of space and gravitational biology. The absence of forbidding on plant growth and development in orbital flight allows studying different aspects of plant adaptation to this factor that is directly connected with development of the technologies of bioregenerative life-support systems. Microgravity belongs to the environmental factors which cause adaptive reactions at the cellular and molecular levels in the range of physiological responses in the framework of genetically determined program of ontogenesis. It is known that cells of a multicellular organism not only take part in reactions of the organism but also carry out processes that maintain their integrity. In light of these principles, the problem of identification of biochemical, physiological and structural patterns that can have adaptive significance at the cellular and molecular levels in real and simulated microgravity is considered. It is pointed that plant cell responses in microgravity and under clinorotation vary according to growth phase, physiological state, and taxonomic position of the object. At the same time, the responses have, to some degree, a similar character reflecting the changes in the cell organelle functional load. The maintenance of the plasmalemma fluidity at the certain level, an activation of both the antioxidant system and expression of HSP genes, especially HSP70, under increasing reactive oxygen species, lipid peroxidation intensity and alteration in protein homeostasis, are a strategic paradigm of rapid (primary) cell adaptation to microgravity. In this sense, biological membranes, especially plasmalemma, and their properties and functions may be considered as the most sensitive indicators of the influence of gravity or altered gravity on a cell. The plasmalemma lipid bilayer is a border between the cell internal content and environment, so it is a mediator

  19. Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

    PubMed Central

    2009-01-01

    Background Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements. Results We first present a new method for globally optimizing nonlinear models of metabolic pathways that are based on the Generalized Mass Action (GMA) representation. The optimization task is posed as a nonconvex nonlinear programming (NLP) problem that is solved by an outer-approximation algorithm. This method relies on solving iteratively reduced NLP slave subproblems and mixed-integer linear programming (MILP) master problems that provide valid upper and lower bounds, respectively, on the global solution to the original NLP. The capabilities of this method are illustrated through its application to the anaerobic fermentation pathway in Saccharomyces cerevisiae. We next introduce a method to identify the feasibility parametric regions that allow a system to meet a set of physiological constraints that can be represented in mathematical terms through algebraic equations. This technique is based on applying the outer-approximation based algorithm iteratively over a reduced search space in order to identify regions that contain feasible solutions to the problem and discard others in which no feasible solution exists. As an example, we characterize the feasible enzyme activity changes that are compatible with an appropriate adaptive response of yeast Saccharomyces cerevisiae to heat shock Conclusion Our results show the utility of the

  20. A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxia.

    PubMed

    Bouquet, Fanny; Ousset, Marielle; Biard, Denis; Fallone, Frédérique; Dauvillier, Stéphanie; Frit, Philippe; Salles, Bernard; Muller, Catherine

    2011-06-01

    DNA-dependent protein kinase (DNA-PK) is involved in DNA double-strand break (DSB) signalling and repair. We report that DNA-PK is activated by mild hypoxia conditions (0.1-1% O₂) as shown by (1) its autophosphorylation on Ser2056, and (2) its mobilisation from a soluble nucleoplasmic compartment to a less extractable nuclear fraction. The recruitment of DNA-PK was not followed by activation and recruitment of the XRCC4-DNA-ligase-IV complex, suggesting that DSBs are not responsible for activation of DNA-PK. To unravel the mechanism of DNA-PK activation, we show that exposure of cells to trichostatin A, a histone deacetylase inhibitor, leads to DNA-PK autophosphorylation and relocalisation to DNA. Histone acetylation (mainly H3K14) is increased in hypoxic cells and treatment with anacardic acid, an inhibitor of histone acetyl transferase, prevented both histone modifications and DNA-PK activation in hypoxic conditions. Importantly, in using either silenced DNA-PK cells or cells exposed to a specific DNA-PK inhibitor (NU7026), we demonstrated that hypoxic DNA-PK activation positively regulates the key transcription factor HIF-1 and one subsequent target gene, GLUT1. Our results show that hypoxia initiates chromatin modification and consequently DNA-PK activation, which positively regulate cellular oxygen-sensing and oxygen-signalling pathways.

  1. Cellular immune response experiment MA-031

    NASA Technical Reports Server (NTRS)

    Criswell, B. S.

    1976-01-01

    Significant changes in phytohemagglutinin (PHA) lymphocytic responsiveness occurred in the cellular immune response of three astronauts during the 9 day flight of the Apollo Soyuz Test Project. Parameters studied were white blood cell concentrations, lymphocyte numbers, B- and T-lymphocyte distributions in peripheral blood, and lymphocyte responsiveness to PHA, pokeweed mitogen, Concanavalin A, and influenza virus antigen.

  2. Cellular responses to environmental DNA damage

    SciTech Connect

    Not Available

    1994-08-01

    This volume contains the proceedings of the conference entitled Cellular Responses to Environmental DNA Damage held in Banff,Alberta December 1--6, 1991. The conference addresses various aspects of DNA repair in sessions titled DNA repair; Basic Mechanisms; Lesions; Systems; Inducible Responses; Mutagenesis; Human Population Response Heterogeneity; Intragenomic DNA Repair Heterogeneity; DNA Repair Gene Cloning; Aging; Human Genetic Disease; and Carcinogenesis. Individual papers are represented as abstracts of about one page in length.

  3. Cellular and developmental adaptations to hypoxia: a Drosophila perspective.

    PubMed

    Romero, Nuria Magdalena; Dekanty, Andrés; Wappner, Pablo

    2007-01-01

    The fruit fly Drosophila melanogaster, a widely utilized genetic model, is highly resistant to oxygen starvation and is beginning to be used for studying physiological, developmental, and cellular adaptations to hypoxia. The Drosophila respiratory (tracheal) system has features in common with the mammalian circulatory system so that an angiogenesis-like response occurs upon exposure of Drosophila larvae to hypoxia. A hypoxia-responsive system homologous to mammalian hypoxia-inducible factor (HIF) has been described in the fruit fly, where Fatiga is a Drosophila oxygen-dependent HIF prolyl hydroxylase, and the basic helix-loop-helix Per/ARNT/Sim (bHLH-PAS) proteins Sima and Tango are, respectively, the Drosophila homologues of mammalian HIF-alpha (alpha) and HIF-beta (beta). Tango is constitutively expressed regardless of oxygen tension and, like in mammalian cells, Sima is controlled at the level of protein degradation and subcellular localization. Sima is critically required for development in hypoxia, but, unlike mammalian model systems, it is dispensable for development in normoxia. In contrast, fatiga mutant alleles are all lethal; however, strikingly, viability to adulthood is restored in fatiga sima double mutants, although these double mutants are not entirely normal, suggesting that Fatiga has Sima-independent functions in fly development. Studies in cell culture and in vivo have revealed that Sima is activated by the insulin receptor (InR) and target-of-rapamycin (TOR) pathways. Paradoxically, Sima is a negative regulator of growth. This suggests that Sima is engaged in a negative feedback loop that limits growth upon stimulation of InR/TOR pathways.

  4. Adaptive immune responses to Candida albicans infection

    PubMed Central

    Richardson, Jonathan P; Moyes, David L

    2015-01-01

    Fungal infections are becoming increasingly prevalent in the human population and contribute to morbidity and mortality in healthy and immunocompromised individuals respectively. Candida albicans is the most commonly encountered fungal pathogen of humans, and is frequently found on the mucosal surfaces of the body. Host defense against C. albicans is dependent upon a finely tuned implementation of innate and adaptive immune responses, enabling the host to neutralise the invading fungus. Central to this protection are the adaptive Th1 and Th17 cellular responses, which are considered paramount to successful immune defense against C. albicans infections, and enable tissue homeostasis to be maintained in the presence of colonising fungi. This review will highlight the recent advances in our understanding of adaptive immunity to Candida albicans infections. PMID:25607781

  5. The adaptive cruise control vehicles in the cellular automata model

    NASA Astrophysics Data System (ADS)

    Jiang, Rui; Wu, Qing-Song

    2006-11-01

    This Letter presented a cellular automata model where the adaptive cruise control vehicles are modelled. In this model, the constant time headway policy is adopted. The fundamental diagram is presented. The simulation results are in good agreement with the analytical ones. The mixture of ACC vehicles with manually driven vehicles is investigated. It is shown that with the introduction of ACC vehicles, the jam can be suppressed.

  6. Effect of cellular mobility on immune response

    NASA Astrophysics Data System (ADS)

    Pandey, R. B.; Mannion, R.; Ruskin, H. J.

    2000-08-01

    Mobility of cell types in our HIV immune response model is subject to an intrinsic mobility and an explicit directed mobility, which is governed by Pmob. We investigate how restricting the explicit mobility, while maintaining the innate mobility of a viral-infected cell, affects the model's results. We find that increasing the explicit mobility of the immune system cells leads to viral dominance for certain levels of viral mutation. We conclude that increasing immune system cellular mobility indirectly increases the virus’ inherent mobility.

  7. Cellular immune response in intraventricular experimental neurocysticercosis.

    PubMed

    Moura, Vania B L; Lima, Sarah B; Matos-Silva, Hidelberto; Vinaud, Marina C; Loyola, Patricia R A N; Lino, Ruy S

    2016-03-01

    Neurocysticercosis (NCC) is considered a neglected parasitic infection of the human central nervous system. Its pathogenesis is due to the host immune response, stage of evolution and location of the parasite. The aim of this study was to evaluate the in situ and systemic immune response through cytokines dosage (IL-4, IL-10, IL-17 and IFN-γ) as well as the local inflammatory response of the experimental NCC with Taenia crassiceps. The in situ and systemic cellular and inflammatory immune response were evaluated through the cytokines quantification at 7, 30, 60 and 90 days after inoculation and histopathological analysis. All cysticerci were found within the cerebral ventricles. There was a discrete intensity of inflammatory cells of mixed immune profile, polymorphonuclear and mononuclear cells, at the beginning of the infection and predominance of mononuclear cells at the end. The systemic immune response showed a significant increase in all the analysed cytokines and predominance of the Th2 immune profile cytokines at the end of the infection. These results indicate that the location of the cysticerci may lead to ventriculomegaly. The acute phase of the infection showed a mixed Th1/Th17 profile accompanied by high levels of IL-10 while the late phase showed a Th2 immune profile.

  8. Endothelial Cellular Responses to Biodegradable Metal Zinc.

    PubMed

    Ma, Jun; Zhao, Nan; Zhu, Donghui

    Biodegradable zinc (Zn) metals, a new generation of biomaterials, have attracted much attention due to their excellent biodegradability, bioabsorbability, and adaptability to tissue regeneration. Compared with magnesium (Mg) and iron (Fe), Zn exhibits better corrosion and mechanical behaviors in orthopedic and stent applications. After implantation, Zn containing material will slowly degrade, and Zn ions (Zn(2+)) will be released to the surrounding tissue. For stent applications, the local Zn(2+)concentration near endothelial tissue/cells could be high. However, it is unclear how endothelia will respond to such high concentrations of Zn(2+), which is pivotal to vascular remodeling and regeneration. Here, we evaluated the short-term cellular behaviors of primary human coronary artery endothelial cells (HCECs) exposed to a concentration gradient (0-140 μM) of extracellular Zn(2+). Zn(2+) had an interesting biphasic effect on cell viability, proliferation, spreading, and migration. Generally, low concentrations of Zn(2+) promoted viability, proliferation, adhesion, and migration, while high concentrations of Zn(2+) had opposite effects. For gene expression profiles, the most affected functional genes were related to cell adhesion, cell injury, cell growth, angiogenesis, inflammation, vessel tone, and coagulation. These results provide helpful information and guidance for Zn-based alloy design as well as the controlled release of Zn(2+)in stent and other related medical applications.

  9. Cellular immune responses towards regulatory cells.

    PubMed

    Larsen, Stine Kiær

    2016-01-01

    This thesis describes the results from two published papers identifying spontaneous cellular immune responses against the transcription factors Foxp3 and Foxo3. The tumor microenvironment is infiltrated by cells that hinder effective tumor immunity from developing. Two of these cell types, which have been linked to a bad prognosis for patients, are regulatory T cells (Treg) and tolerogenic dendritic cells (DC). Tregs inhibit effector T cells from attacking the tumor through various mechanisms, including secreted factors and cell-to-cell contact. Tregs express the transcription factor Foxp3, which is necessary for their development and suppressive activities. Tolerogenic DCs participate in creating an environment in the tumor where effector T cells become tolerant towards the tumor instead of attacking it. The transcription factor Foxo3 was recently described to be highly expressed by tolerogenic DCs and to programme their tolerogenic influence. This thesis describes for the first time the existence of spontaneous cellular immune responses against peptides derived from Foxp3 and Foxo3. We have detected the presence of cytotoxic T cells that recognise these peptides in an HLA-A2 restricted manner in cancer patients and for Foxp3 in healthy donors as well. In addition, we have demonstrated that the Foxp3- and Foxo3-specific CTLs recognize Foxp3- and Foxo3-expressing cancer cell lines and importantly, suppressive immune cells, namely Tregs and in vitro generated DCs. Cancer immunotherapy is recently emerging as an important treatment modality improving the survival of selected patients. The current progress is largely owing to targeting of the immune suppressive milieu that is dominating the tumor microenvironment. This is being done through immune checkpoint blockade with CTLA-4 and PD-1/PD-L1 antibodies and through lymphodepleting conditioning of patients and ex vivo activation of TILs in adoptive cell transfer. Several strategies are being explored for depletion of

  10. Chiral hexagonal cellular sandwich structures: dynamic response

    NASA Astrophysics Data System (ADS)

    Spadoni, A.; Ruzzene, M.; Scarpa, F.

    2005-05-01

    Periodic cellular configurations with negative Poisson's ratio have attracted the attention of several researchers because of their superior dynamic characteristics. Among the geometries featuring a negative Poisson's ratio, the chiral topology possesses a geometric complexity that guarantees unique deformed configurations when excited at one of its natural frequencies. Specifically, localized deformations have been observed even at relatively low excitation frequencies. This is of particular importance as resonance can be exploited to minimize the power required for the appearance of localized deformations, thus giving practicality to the concept. The particular nature of these deformed configurations and the authority provided by the chiral geometry, suggest the application of the proposed structural configuration for the design of innovative lifting bodies, such as helicopter rotor blades or airplane wings. The dynamic characteristics of chiral structures are here investigated through a numerical model and experimental investigations. The numerical formulation uses dynamic shape functions to accurately describe the behavior of the considered structural assembly over a wide frequency range. The model is used to predict frequency response functions, and to investigate the occurrence of localized deformations. Experimental tests are also performed to demonstrate the accuracy of the model and to illustrate the peculiarities of the behavior of the considered chiral structures.

  11. Aggresomes: A Cellular Response to Misfolded Proteins

    PubMed Central

    Johnston, Jennifer A.; Ward, Cristina L.; Kopito, Ron R.

    1998-01-01

    Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins. PMID:9864362

  12. Mechano-biological Coupling of Cellular Responses to Microgravity

    NASA Astrophysics Data System (ADS)

    Long, Mian; Wang, Yuren; Zheng, Huiqiong; Shang, Peng; Duan, Enkui; Lü, Dongyuan

    2015-11-01

    Cellular response to microgravity is a basic issue in space biological sciences as well as space physiology and medicine. It is crucial to elucidate the mechano-biological coupling mechanisms of various biological organisms, since, from the principle of adaptability, all species evolved on the earth must possess the structure and function that adapts their living environment. As a basic element of an organism, a cell usually undergoes mechanical and chemical remodeling to sense, transmit, transduce, and respond to the alteration of gravitational signals. In the past decades, new computational platforms and experimental methods/techniques/devices are developed to mimic the biological effects of microgravity environment from the viewpoint of biomechanical approaches. Mechanobiology of plant gravisensing in the responses of statolith movements along the gravity vector and the relevant signal transduction and molecular regulatory mechanisms are investigated at gene, transcription, and protein levels. Mechanotransduction of bone or immune cell responses and stem cell development and tissue histogenesis are elucidated under microgravity. In this review, several important issues are briefly discussed. Future issues on gravisensing and mechanotransducing mechanisms are also proposed for ground-based studies as well as space missions.

  13. BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

    EPA Science Inventory

    Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-Dose
    Cancer Responses
    .
    There has been a concerted effort in the field of radiation biology to better understand cellular
    responses
    that could have an impact on the estin1ation of cancer...

  14. Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: focus on the nervous system.

    PubMed

    Lee, Jaewon; Jo, Dong-Gyu; Park, Daeui; Chung, Hae Young; Mattson, Mark P

    2014-07-01

    During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for the latter mechanism is grounded in the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examplesof such pathways include those involving the transcription factors nuclear factor erythroid 2-related factor 2, nuclear factor-κB, hypoxia-inducible factor 1α, peroxisome proliferator-activated receptor γ, and forkhead box subgroup O, as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against tissue injury and disease. Because neurons are particularly sensitive to potentially noxious phytochemicals, we focus on the nervous system but also include findings from other cell types in which actions of phytochemicals on specific signal transduction pathways have been more thoroughly studied.

  15. Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

    PubMed Central

    Jo, Dong-Gyu; Park, Daeui; Chung, Hae Young

    2014-01-01

    During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for the latter mechanism is grounded in the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examplesof such pathways include those involving the transcription factors nuclear factor erythroid 2-related factor 2, nuclear factor-κB, hypoxia-inducible factor 1α, peroxisome proliferator-activated receptor γ, and forkhead box subgroup O, as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against tissue injury and disease. Because neurons are particularly sensitive to potentially noxious phytochemicals, we focus on the nervous system but also include findings from other cell types in which actions of phytochemicals on specific signal transduction pathways have been more thoroughly studied. PMID:24958636

  16. Untranslated regions (UTRs) orchestrate translation reprogramming in cellular stress responses.

    PubMed

    Sajjanar, Basavaraj; Deb, Rajib; Raina, Susheel Kumar; Pawar, Sachin; Brahmane, Manoj P; Nirmale, Avinash V; Kurade, Nitin P; Manjunathareddy, Gundallahalli B; Bal, Santanu Kumar; Singh, Narendra Pratap

    2017-04-01

    Stress is the result of an organism's interaction with environmental challenges. Regulations of gene expression including translation modulations are critical for adaptation and survival under stress. Untranslated regions (UTRs) of the transcripts play significant roles in translation regulation and continue to raise many intriguing questions in our understanding of cellular stress physiology. IRES (Internal ribosome entry site) and uORF (upstream open reading frame) mediated alternative translation initiations are emerging as unique mechanisms. Recent studies have revealed novel means of mRNAs stabilization in stress granules and their reversible modifications. Differential regulation of select transcripts is possible by the interplay between the adenine/uridine-rich elements (AREs) in 3'UTR with their binding proteins (AUBP) and by microRNA-mediated effects. Coordination of these various mechanisms control translation and thereby enables appropriate responses to environmental stress. In this review, we focus on the role of sequence signatures both at 5' and 3'UTRs in translation reprogramming during cellular stress responses.

  17. Plant Cell Adaptive Responses to Microgravity

    NASA Astrophysics Data System (ADS)

    Kordyum, Elizabeth; Kozeko, Liudmyla; Talalaev, Alexandr

    simulated microgravity and temperature elevation have different effects on the small HSP genes belonging to subfamilies with different subcellular localization: cytosol/nucleus - PsHSP17.1-СІІ and PsHSP18.1-СІ, cloroplasts - PsHSP26.2-Cl, endoplasmatic reticulum - PsHSP22.7-ER and mitochondria - PsHSP22.9-M: unlike high temperature, clinorotation does not cause denaturation of cell proteins, that confirms the sHSP chaperone function. Dynamics of investigated gene expression in pea seedlings growing 5 days after seed germination under clinorotation was similar to that in the stationary control. Similar patterns in dynamics of sHSP gene expression in the stationary control and under clinorotation may be one of mechanisms providing plant adaptation to simulated microgravity. It is pointed that plant cell responses in microgravity and under clinorotation vary according to growth phase, physiological state, and taxonomic position of the object. At the same time, the responses have, to some degree, a similar character reflecting the changes in cell organelle functional load. Thus, next certain changes in the structure and function of plant cells may be considered as adaptive: 1) an increase in the unsaturated fatty acid content in the plasmalemma, 2) rearrangements of organelle ultrastructure and an increase in their functional load, 3) an increase in cortical F-actin under destabilization of tubulin microtubules, 4) the level of gene expression and synthesis of heat shock proteins, 5) alterations of the enzyme and antioxidant system activity. The dynamics of these patterns demonstrated that the adaptation occurs on the principle of self-regulating systems in the limits of physiological norm reaction. The very importance of changed expression of genes involved in different cellular processes, especially HSP genes, in cell adaptation to altered gravity is discussed.

  18. Adaptive responses to antibody based therapy.

    PubMed

    Rodems, Tamara S; Iida, Mari; Brand, Toni M; Pearson, Hannah E; Orbuch, Rachel A; Flanigan, Bailey G; Wheeler, Deric L

    2016-02-01

    Receptor tyrosine kinases (RTKs) represent a large class of protein kinases that span the cellular membrane. There are 58 human RTKs identified which are grouped into 20 distinct families based upon their ligand binding, sequence homology and structure. They are controlled by ligand binding which activates intrinsic tyrosine-kinase activity. This activity leads to the phosphorylation of distinct tyrosines on the cytoplasmic tail, leading to the activation of cell signaling cascades. These signaling cascades ultimately regulate cellular proliferation, apoptosis, migration, survival and homeostasis of the cell. The vast majority of RTKs have been directly tied to the etiology and progression of cancer. Thus, using antibodies to target RTKs as a cancer therapeutic strategy has been intensely pursued. Although antibodies against the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) have shown promise in the clinical arena, the development of both intrinsic and acquired resistance to antibody-based therapies is now well appreciated. In this review we provide an overview of the RTK family, the biology of EGFR and HER2, as well as an in-depth review of the adaptive responses undertaken by cells in response to antibody based therapies directed against these receptors. A greater understanding of these mechanisms and their relevance in human models will lead to molecular insights in overcoming and circumventing resistance to antibody based therapy.

  19. Impaired Adaptive Response to Mechanical Overloading in Dystrophic Skeletal Muscle

    PubMed Central

    Joanne, Pierre; Hourdé, Christophe; Ochala, Julien; Caudéran, Yvain; Medja, Fadia; Vignaud, Alban; Mouisel, Etienne; Hadj-Said, Wahiba; Arandel, Ludovic; Garcia, Luis; Goyenvalle, Aurélie; Mounier, Rémi; Zibroba, Daria; Sakamato, Kei; Butler-Browne, Gillian; Agbulut, Onnik; Ferry, Arnaud

    2012-01-01

    Dystrophin contributes to force transmission and has a protein-scaffolding role for a variety of signaling complexes in skeletal muscle. In the present study, we tested the hypothesis that the muscle adaptive response following mechanical overloading (ML) would be decreased in MDX dystrophic muscle lacking dystrophin. We found that the gains in muscle maximal force production and fatigue resistance in response to ML were both reduced in MDX mice as compared to healthy mice. MDX muscle also exhibited decreased cellular and molecular muscle remodeling (hypertrophy and promotion of slower/oxidative fiber type) in response to ML, and altered intracellular signalings involved in muscle growth and maintenance (mTOR, myostatin, follistatin, AMPKα1, REDD1, atrogin-1, Bnip3). Moreover, dystrophin rescue via exon skipping restored the adaptive response to ML. Therefore our results demonstrate that the adaptive response in response to ML is impaired in dystrophic MDX muscle, most likely because of the dystrophin crucial role. PMID:22511986

  20. Cellular Stress Response to Engineered Nanoparticles: Effect of Size, Surface Coating, and Cellular Uptake

    EPA Science Inventory

    CELLULAR STRESS RESPONSE TO ENGINEERED NANOPARTICLES: EFFECT OF SIZE, SURFACE COATING, AND CELLULAR UPTAKE RY Prasad 1, JK McGee2, MG Killius1 D Ackerman2, CF Blackman2 DM DeMarini2 , SO Simmons2 1 Student Services Contractor, US EPA, RTP, NC 2 US EPA, RTP, NC The num...

  1. Thermal adaptation of cellular membranes in natural populations of Drosophila melanogaster.

    PubMed

    Cooper, Brandon S; Hammad, Loubna A; Montooth, Kristi L

    2014-08-01

    Changes in temperature disrupt the fluidity of cellular membranes, which can negatively impact membrane integrity and cellular processes. Many ectotherms, including Drosophila melanogaster (Meigen), adjust the glycerophospholipid composition of their membranes to restore optimal fluidity when temperatures change, a type of trait plasticity termed homeoviscous adaptation.Existing data suggest that plasticity in the relative abundances of the glycerophospholipids phosphatidylethanolamine (PE) and phosphatidylcholine (PC) underlies cellular adaptation to temporal variability in the thermal environment. For example, laboratory populations of D. melanogaster evolved in the presence of temporally variable temperatures have greater developmental plasticity of the ratio of PE to PC (PE/PC) and greater fecundity than do populations evolved at constant temperatures.Here, we extend this work to natural populations of D. melanogaster by evaluating thermal plasticity of glycerophospholipid composition at different life stages, in genotypes isolated from Vermont, Indiana and North Carolina, USA. We also quantify the covariance between developmental and adult (reversible) plasticity, and between adult responses of the membrane to cool and warm thermal shifts.As predicted by physiological models of homeoviscous adaptation, flies from all populations decrease PE/PC and the degree of lipid unsaturation in response to warm temperatures. Furthermore, these populations have diverged in their degree of membrane plasticity. Flies from the most variable thermal environment (Vermont, USA) decrease PE/PC to a greater extent than do other populations when developed at a warm temperature, a pattern that matches our previous observation in laboratory-evolved populations. We also find that developmental plasticity and adult plasticity of PE/PC covary across genotypes, but that adult responses to cool and warm thermal shifts do not.When combined with our previous observations of laboratory

  2. Reversible and Noisy Progression towards a Commitment Point Enables Adaptable and Reliable Cellular Decision-Making

    PubMed Central

    Garcia-Ojalvo, Jordi; Süel, Gürol M.

    2011-01-01

    Cells must make reliable decisions under fluctuating extracellular conditions, but also be flexible enough to adapt to such changes. How cells reconcile these seemingly contradictory requirements through the dynamics of cellular decision-making is poorly understood. To study this issue we quantitatively measured gene expression and protein localization in single cells of the model organism Bacillus subtilis during the progression to spore formation. We found that sporulation proceeded through noisy and reversible steps towards an irreversible, all-or-none commitment point. Specifically, we observed cell-autonomous and spontaneous bursts of gene expression and transient protein localization events during sporulation. Based on these measurements we developed mathematical population models to investigate how the degree of reversibility affects cellular decision-making. In particular, we evaluated the effect of reversibility on the 1) reliability in the progression to sporulation, and 2) adaptability under changing extracellular stress conditions. Results show that reversible progression allows cells to remain responsive to long-term environmental fluctuations. In contrast, the irreversible commitment point supports reliable execution of cell fate choice that is robust against short-term reductions in stress. This combination of opposite dynamic behaviors (reversible and irreversible) thus maximizes both adaptable and reliable decision-making over a broad range of changes in environmental conditions. These results suggest that decision-making systems might employ a general hybrid strategy to cope with unpredictably fluctuating environmental conditions. PMID:22102806

  3. Adaptive Responses Limited by Intrinsic Noise.

    PubMed

    Shankar, Prabhat; Nishikawa, Masatoshi; Shibata, Tatsuo

    2015-01-01

    Sensory systems have mechanisms to respond to the external environment and adapt to them. Such adaptive responses are effective for a wide dynamic range of sensing and perception of temporal change in stimulus. However, noise generated by the adaptation system itself as well as extrinsic noise in sensory inputs may impose a limit on the ability of adaptation systems. The relation between response and noise is well understood for equilibrium systems in the form of fluctuation response relation. However, the relation for nonequilibrium systems, including adaptive systems, are poorly understood. Here, we systematically explore such a relation between response and fluctuation in adaptation systems. We study the two network motifs, incoherent feedforward loops (iFFL) and negative feedback loops (nFBL), that can achieve perfect adaptation. We find that the response magnitude in adaption systems is limited by its intrinsic noise, implying that higher response would have higher noise component as well. Comparing the relation of response and noise in iFFL and nFBL, we show that whereas iFFL exhibits adaptation over a wider parameter range, nFBL offers higher response to noise ratio than iFFL. We also identify the condition that yields the upper limit of response for both network motifs. These results may explain the reason of why nFBL seems to be more abundant in nature for the implementation of adaption systems.

  4. Adaptive Responses Limited by Intrinsic Noise

    PubMed Central

    Shankar, Prabhat; Nishikawa, Masatoshi; Shibata, Tatsuo

    2015-01-01

    Sensory systems have mechanisms to respond to the external environment and adapt to them. Such adaptive responses are effective for a wide dynamic range of sensing and perception of temporal change in stimulus. However, noise generated by the adaptation system itself as well as extrinsic noise in sensory inputs may impose a limit on the ability of adaptation systems. The relation between response and noise is well understood for equilibrium systems in the form of fluctuation response relation. However, the relation for nonequilibrium systems, including adaptive systems, are poorly understood. Here, we systematically explore such a relation between response and fluctuation in adaptation systems. We study the two network motifs, incoherent feedforward loops (iFFL) and negative feedback loops (nFBL), that can achieve perfect adaptation. We find that the response magnitude in adaption systems is limited by its intrinsic noise, implying that higher response would have higher noise component as well. Comparing the relation of response and noise in iFFL and nFBL, we show that whereas iFFL exhibits adaptation over a wider parameter range, nFBL offers higher response to noise ratio than iFFL. We also identify the condition that yields the upper limit of response for both network motifs. These results may explain the reason of why nFBL seems to be more abundant in nature for the implementation of adaption systems. PMID:26305221

  5. Oxidative stress, radiation-adaptive responses, and aging.

    PubMed

    Miura, Yuri

    2004-09-01

    Organisms living in an aerobic environment were forced to evolve effective cellular strategies to detoxify reactive oxygen species. Besides diverse antioxidant enzymes and compounds, DNA repair enzymes, and disassembly systems, which remove damaged proteins, regulation systems that control transcription, translation, and activation have also been developed. The adaptive responses, especially those to radiation, are defensive regulation mechanisms by which oxidative stress (conditioning irradiation) elicits a response against damage because of subsequent stress (challenging irradiation). Although many researchers have investigated these molecular mechanisms, they remain obscure because of their complex signaling pathways and the involvement of various proteins. This article reviews the factors concerned with radiation-adaptive response, the signaling pathways activated by conditioning irradiation, and the effects of aging on radiation-adaptive response. The proteomics approach is also introduced, which is a useful method for studying stress response in cells.

  6. Characterizing early molecular biomarkers of zinc-induced adaptive and adverseoxidative stress responses in human bronchial epithelial cells

    EPA Science Inventory

    Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure. A pharmacokinetic...

  7. Dynamic involvement of ATG5 in cellular stress responses

    PubMed Central

    Lin, H H; Lin, S-M; Chung, Y; Vonderfecht, S; Camden, J M; Flodby, P; Borok, Z; Limesand, K H; Mizushima, N; Ann, D K

    2014-01-01

    Autophagy maintains cell and tissue homeostasis through catabolic degradation. To better delineate the in vivo function for autophagy in adaptive responses to tissue injury, we examined the impact of compromised autophagy in mouse submandibular glands (SMGs) subjected to main excretory duct ligation. Blocking outflow from exocrine glands causes glandular atrophy by increased ductal pressure. Atg5f/−;Aqp5-Cre mice with salivary acinar-specific knockout (KO) of autophagy essential gene Atg5 were generated. While duct ligation induced autophagy and the expression of inflammatory mediators, SMGs in Atg5f/−;Aqp5-Cre mice, before ligation, already expressed higher levels of proinflammatory cytokine and Cdkn1a/p21 messages. Extended ligation period resulted in the caspase-3 activation and acinar cell death, which was delayed by Atg5 knockout. Moreover, expression of a set of senescence-associated secretory phenotype (SASP) factors was elevated in the post-ligated glands. Dysregulation of cell-cycle inhibitor CDKN1A/p21 and activation of senescence-associated β-galactosidase were detected in the stressed SMG duct cells. These senescence markers peaked at day 3 after ligation and partially resolved by day 7 in post-ligated SMGs of wild-type (WT) mice, but not in KO mice. The role of autophagy-related 5 (ATG5)-dependent autophagy in regulating the tempo, duration and magnitude of cellular stress responses in vivo was corroborated by in vitro studies using MEFs lacking ATG5 or autophagy-related 7 (ATG7) and autophagy inhibitors. Collectively, our results highlight the role of ATG5 in the dynamic regulation of ligation-induced cellular senescence and apoptosis, and suggest the involvement of autophagy resolution in salivary repair. PMID:25341032

  8. Heterogeneity-mediated cellular adaptation and its trade-off: searching for the general principles of diseases.

    PubMed

    Heng, Henry H

    2016-07-15

    Big-data-omics have promised the success of precision medicine. However, most common diseases belong to adaptive systems where the precision is all but difficult to achieve. In this commentary, I propose a heterogeneity-mediated cellular adaptive model to search for the general model of diseases, which also illustrates why in most non-infectious non-Mendelian diseases the involvement of cellular evolution is less predictable when gene profiles are used. This synthesis is based on the following new observations/concepts: 1) the gene only codes "parts inheritance" while the genome codes "system inheritance" or the entire blueprint; 2) the nature of somatic genetic coding is fuzzy rather than precise, and genetic alterations are not just the results of genetic error but are in fact generated from internal adaptive mechanisms in response to environmental dynamics; 3) stress-response is less specific within cellular evolutionary context when compared to known biochemical specificities; and 4) most medical interventions have their unavoidable uncertainties and often can function as negative harmful stresses as trade-offs. The acknowledgment of diseases as adaptive systems calls for the action to integrate genome- (not simply individual gene-) mediated cellular evolution into molecular medicine.

  9. Adaptive array antenna for satellite cellular and direct broadcast communications

    NASA Technical Reports Server (NTRS)

    Horton, Charles R.; Abend, Kenneth

    1993-01-01

    Adaptive phased-array antennas provide cost-effective implementation of large, light weight apertures with high directivity and precise beamshape control. Adaptive self-calibration allows for relaxation of all mechanical tolerances across the aperture and electrical component tolerances, providing high performance with a low-cost, lightweight array, even in the presence of large physical distortions. Beam-shape is programmable and adaptable to changes in technical and operational requirements. Adaptive digital beam-forming eliminates uplink contention by allowing a single electronically steerable antenna to service a large number of receivers with beams which adaptively focus on one source while eliminating interference from others. A large, adaptively calibrated and fully programmable aperture can also provide precise beam shape control for power-efficient direct broadcast from space. Advanced adaptive digital beamforming technologies are described for: (1) electronic compensation of aperture distortion, (2) multiple receiver adaptive space-time processing, and (3) downlink beam-shape control. Cost considerations for space-based array applications are also discussed.

  10. Immune Responses: Getting Close to Experimental Results with Cellular Automata Models

    NASA Astrophysics Data System (ADS)

    Dos Santos, Rita Maria Zorzenon

    Cellular automata approaches are powerful tools to model local and nonlocal interactions generating cooperative behavior. In the last decade, the question of whether cellular automata could embed realistic assumptions about the interactions among cells and molecules of the immune system was quite controversial. Recent results have shown that it is possible to use cellular automata approaches to describe realistically the interactions between the elements of the immune system. The first models using cellular automata approaches, boolean and threshold or window automata, were based on experimental evidence and were mainly used to understand the logic of global immune responses like immunization, tolerance, paralysis, etc. Recently, new classes of cellular automata models which include time delay, stochasticity or adaptation have lead to results that can be compared with in vivo experimental data.

  11. Cellular Mechanisms of Gravitropic Response in Higher Plants

    NASA Astrophysics Data System (ADS)

    Medvedev, Sergei; Smolikova, Galina; Pozhvanov, Gregory; Suslov, Dmitry

    The evolutionary success of land plants in adaptation to the vectorial environmental factors was based mainly on the development of polarity systems. In result, normal plant ontogenesis is based on the positional information. Polarity is a tool by which the developing plant organs and tissues are mapped and the specific three-dimensional structure of the organism is created. It is due to their polar organization plants are able to orient themselves relative to the gravity vector and different vectorial cues, and to respond adequately to various stimuli. Gravitation is one of the most important polarized environmental factor that guides the development of plant organisms in space. Every plant can "estimate" its position relative to the gravity vector and correct it, if necessary, by means of polarized growth. The direction and the magnitude of gravitational stimulus are constant during the whole plant ontogenesis. The key plant response to the action of gravity is gravitropism, i.e. the directed growth of organs with respect to the gravity vector. This response is a very convenient model to study the mechanisms of plant orientation in space. The present report is focused on the main cellular mechanisms responsible for graviropic bending in higher plants. These mechanisms and structures include electric polarization of plant cells, Ca ({2+) }gradients, cytoskeleton, G-proteins, phosphoinositides and the machinery responsible for asymmetric auxin distribution. Those mechanisms tightly interact demonstrating some hierarchy and multiple feedbacks. The Ca (2+) gradients provide the primary physiological basis of polarity in plant cells. Calcium ions influence on the bioelectric potentials, the organization of actin cytoskeleton, the activity of Ca (2+) -binding proteins and Ca (2+) -dependent protein kinases. Protein kinases modulate transcription factors activity thereby regulating the gene expression and switching the developmental programs. Actin cytoskeleton affects

  12. Innate cellular responses to rotavirus infection.

    PubMed

    Holloway, Gavan; Coulson, Barbara S

    2013-06-01

    Rotavirus is a leading cause of severe dehydrating diarrhoea in infants and young children. Following rotavirus infection in the intestine an innate immune response is rapidly triggered. This response leads to the induction of type I and type III interferons (IFNs) and other cytokines, resulting in a reduction in viral replication. Here we review the current literature describing the detection of rotavirus infection by pattern recognition receptors within host cells, the subsequent molecular mechanisms leading to IFN and cytokine production, and the processes leading to reduced rotavirus replication and the development of protective immunity. Rotavirus countermeasures against innate responses, and their roles in modulating rotavirus replication in mice, also are discussed. By linking these different aspects of innate immunity, we provide a comprehensive overview of the host's first line of defence against rotavirus infection. Understanding these processes is expected to be of benefit in improving strategies to combat rotavirus disease.

  13. Linear ubiquitination signals in adaptive immune responses.

    PubMed

    Ikeda, Fumiyo

    2015-07-01

    Ubiquitin can form eight different linkage types of chains using the intrinsic Met 1 residue or one of the seven intrinsic Lys residues. Each linkage type of ubiquitin chain has a distinct three-dimensional topology, functioning as a tag to attract specific signaling molecules, which are so-called ubiquitin readers, and regulates various biological functions. Ubiquitin chains linked via Met 1 in a head-to-tail manner are called linear ubiquitin chains. Linear ubiquitination plays an important role in the regulation of cellular signaling, including the best-characterized tumor necrosis factor (TNF)-induced canonical nuclear factor-κB (NF-κB) pathway. Linear ubiquitin chains are specifically generated by an E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) and hydrolyzed by a deubiquitinase (DUB) called ovarian tumor (OTU) DUB with linear linkage specificity (OTULIN). LUBAC linearly ubiquitinates critical molecules in the TNF pathway, such as NEMO and RIPK1. The linear ubiquitin chains are then recognized by the ubiquitin readers, including NEMO, which control the TNF pathway. Accumulating evidence indicates an importance of the LUBAC complex in the regulation of apoptosis, development, and inflammation in mice. In this article, I focus on the role of linear ubiquitin chains in adaptive immune responses with an emphasis on the TNF-induced signaling pathways.

  14. In vivo cellular visualization of the human retina using optical coherence tomography and adaptive optics

    SciTech Connect

    Olivier, S S; Jones, S M; Chen, D C; Zawadzki, R J; Choi, S S; Laut, S P; Werner, J S

    2006-01-05

    Optical coherence tomography (OCT) sees the human retina sharply with adaptive optics. In vivo cellular visualization of the human retina at micrometer-scale resolution is possible by enhancing Fourier-domain optical-coherence tomography with adaptive optics, which compensate for the eye's optical aberrations.

  15. Interferon regulatory factor 3 in adaptive immune responses.

    PubMed

    Ysebrant de Lendonck, Laure; Martinet, Valerie; Goriely, Stanislas

    2014-10-01

    Interferon regulatory factor (IRF) 3 plays a key role in innate responses against viruses. Indeed, activation of this transcription factor triggers the expression of type I interferons and downstream interferon-stimulated genes in infected cells. Recent evidences indicate that this pathway also modulates adaptive immune responses. This review focuses on the different mechanisms that are implicated in this process. We discuss the role of IRF3 within antigen-presenting cells and T lymphocytes in the polarization of the cellular immune response and its implication in the pathogenesis of immune disorders.

  16. Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease.

    PubMed

    Gilbert, Penney M; Weaver, Valerie M

    2016-09-15

    Human tissues are remarkably adaptable and robust, harboring the collective ability to detect and respond to external stresses while maintaining tissue integrity. Following injury, many tissues have the capacity to repair the damage - and restore form and function - by deploying cellular and molecular mechanisms reminiscent of developmental programs. Indeed, it is increasingly clear that cancer and chronic conditions that develop with age arise as a result of cells and tissues re-implementing and deregulating a selection of developmental programs. Therefore, understanding the fundamental molecular mechanisms that drive cell and tissue responses is a necessity when designing therapies to treat human conditions. Extracellular matrix stiffness synergizes with chemical cues to drive single cell and collective cell behavior in culture and acts to establish and maintain tissue homeostasis in the body. This review will highlight recent advances that elucidate the impact of matrix mechanics on cell behavior and fate across these length scales during times of homeostasis and in disease states.

  17. Functional and cellular adaptations of rodent skeletal muscle to weightlessness

    NASA Technical Reports Server (NTRS)

    Caiozzo, Vincent J.; Haddad, Fadia; Baker, Michael J.; Baldwin, Kenneth M.

    1995-01-01

    This paper describes the affects of microgravity upon three key cellular levels (functional, protein, and mRNA) that are linked to one another. It is clear that at each of these levels, microgravity produces rapid and substantial alterations. One of the key challenges facing the life science community is the development of effective countermeasures that prevent the loss of muscle function as described in this paper. The development of optimal countermeasures, however, awaits a clearer understanding of events occurring at the levels of transcription, translation, and degradation.

  18. Molecular and cellular adaptations to chronic myotendinous strain injury in mdx mice expressing a truncated dystrophin.

    PubMed

    Banks, Glen B; Combs, Ariana C; Chamberlain, Joel R; Chamberlain, Jeffrey S

    2008-12-15

    Myotendinous strain injury is the most common injury of human skeletal muscles because the majority of muscle forces are transmitted through this region. Although the immediate response to strain injury is well characterized, the chronic response to myotendinous strain injury is less clear. Here we examined the molecular and cellular adaptations to chronic myotendinous strain injury in mdx mice expressing a microdystrophin transgene (microdystrophin(DeltaR4-R23)). We found that muscles with myotendinous strain injury had an increased expression of utrophin and alpha7-integrin together with the dramatic restructuring of peripheral myofibrils into concentric rings. The sarcolemma of the microdystrophin(DeltaR4-R23)/mdx gastrocnemius muscles was highly protected from experimental lengthening contractions, better than wild-type muscles. We also found a positive correlation between myotendinous strain injury and ringed fibers in the HSA(LR) (human skeletal actin, long repeat) mouse model of myotonic dystrophy. We suggest that changes in protein expression and the formation of rings are adaptations to myotendinous strain injury that help to prevent muscle necrosis and retain the function of necessary muscles during injury, ageing and disease.

  19. Electrical Stimulation of Cellular Response: Responses and Mechanisms.

    DTIC Science & Technology

    1986-10-01

    frequencies using this new method. This should provide invaluable information regarding the kinetics of the electrochemical transductive coupling at...provide invaluable information regarding the kinetics of the electrochemical transductive coupling at the plasma membrane. Thus far, the installation of...dependence with the kinetics of known cellular processes may provide insight to the putative mechanisms of energy transduction. II.b Methods Connective

  20. Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms

    NASA Technical Reports Server (NTRS)

    Baldwin, Kenneth M.; Haddad, Fadia

    2002-01-01

    The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

  1. Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms.

    PubMed

    Baldwin, Kenneth M; Haddad, Fadia

    2002-11-01

    The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

  2. miRNA modulation of the cellular stress response.

    PubMed

    Babar, Imran A; Slack, Frank J; Weidhaas, Joanne B

    2008-04-01

    Cellular stress responses are potent and dynamic, allowing cells to effectively counteract diverse stresses. These pathways are crucial not only for maintaining normal cellular homeostasis, but also for protecting cells from what would otherwise lead to their demise. A novel class of genes, termed miRNAs, has recently been implicated in the cellular stress response. For example, it has been demonstrated that a cardiac-specific miRNA that is not required for normal development is requisite for a normal cardiac stress response in mice. In addition, we have found that a miRNA family is able to modulate the cellular response to cytotoxic cancer treatment both in vitro and in vivo. In this review, we will discuss these and other important developments in the field. In particular, we will focus on studies that have linked miRNAs to the genotoxic stress response and will suggest how this connection may be both important for our understanding of biology and pertinent for the development of novel cancer therapies.

  3. Global relationships in fluctuation and response in adaptive evolution

    PubMed Central

    Furusawa, Chikara; Kaneko, Kunihiko

    2015-01-01

    Cells change their internal state to adapt to environmental changes, and evolve in response to the new conditions. The phenotype changes first via adaptation in response to environmental changes, and then through mutational changes in the genomic sequence, followed by selection in evolution. Here, we analysed simulated adaptive evolution using a simple cell model consisting of thousands of intracellular components, and found that the changes in their concentrations by adaptation are proportional to those by evolution across all the components, where the proportion coefficient between the two agreed well with the change in the growth rate of a cell. Furthermore, we demonstrate that the phenotypic variance in concentrations of cellular components due to (non-genetic) noise and to genomic alternations is proportional across all components. This implies that the specific phenotypes that are highly evolvable were already given by non-genetic fluctuations. These global relationships in cellular states were also supported by phenomenological theory based on steady reproduction and transcriptome analysis of laboratory evolution in Escherichia coli. These findings demonstrate that a possible evolutionary change in phenotypic state is highly restricted. Our results provide a basis for the development of a quantitative theory of plasticity and robustness in phenotypic evolution. PMID:26202686

  4. Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses

    PubMed Central

    Bhattacharya, Sudin; Conolly, Rory B.; Clewell, Harvey J.; Kaminski, Norbert E.; Andersen, Melvin E.

    2014-01-01

    Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays. Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a

  5. Simulating Quantitative Cellular Responses Using Asynchronous Threshold Boolean Network Ensembles

    EPA Science Inventory

    With increasing knowledge about the potential mechanisms underlying cellular functions, it is becoming feasible to predict the response of biological systems to genetic and environmental perturbations. Due to the lack of homogeneity in living tissues it is difficult to estimate t...

  6. Functional and cellular adaptation to weightlessness in primates

    NASA Technical Reports Server (NTRS)

    Bodine-Fowler, Sue C.; Pierotti, David J.; Talmadge, Robert J.

    1995-01-01

    Considerable data has been collected on the response of hindlimb muscles to unloading due to both spaceflight and hindlimb suspension. One generalized response to a reduction in load is muscle fiber atrophy, although not all muscles respond the same. Our understanding of how muscles respond to microgravity, however, has come primarily from the examination of hindlimb muscles in the unrestrained rate in space. The non-human primate spaceflight paradigm differs considerably from the rodent paradigm in that the monkeys are restrained, usually in a sitting position, while in space. Recently, we examined the effects of microgravity on muscles of the Rhesus monkey by taking biopsies of selected hindlimb muscles prior to and following spaceflights of 14 and 12 day durations (Cosmos 2044 and 2229). Our results revealed that the monkey's response to microgravity differs from that of the rat. The apparent differences in the atrophic response of the hindlimb muscles of the monkey and rat to spaceflight may be attributed to the following: (1) a species difference; (2) a difference in the manner in which the animals were maintained during the flight (i.e., chair restraint or 'free-floating'); and/or (3) an ability of the monkeys to counteract the effects of spaceflight with resistive exercise.

  7. Cellular and molecular regulation of innate inflammatory responses

    PubMed Central

    Liu, Juan; Cao, Xuetao

    2016-01-01

    Innate sensing of pathogens by pattern-recognition receptors (PRRs) plays essential roles in the innate discrimination between self and non-self components, leading to the generation of innate immune defense and inflammatory responses. The initiation, activation and resolution of innate inflammatory response are mediated by a complex network of interactions among the numerous cellular and molecular components of immune and non-immune system. While a controlled and beneficial innate inflammatory response is critical for the elimination of pathogens and maintenance of tissue homeostasis, dysregulated or sustained inflammation leads to pathological conditions such as chronic infection, inflammatory autoimmune diseases. In this review, we discuss some of the recent advances in our understanding of the cellular and molecular mechanisms for the establishment and regulation of innate immunity and inflammatory responses. PMID:27818489

  8. Adaptation or Malignant Transformation: The Two Faces of Epigenetically Mediated Response to Stress

    PubMed Central

    Zoldoš, Vlatka

    2013-01-01

    Adaptive response to stress is a fundamental property of living systems. At the cellular level, many different types of stress elicit an essentially limited repertoire of adaptive responses. Epigenetic changes are the main mechanism for medium- to long-term adaptation to accumulated (intense, long-term, or repeated) stress. We propose the adaptive deregulation of the epigenome in response to stress (ADERS) hypothesis which assumes that the unspecific adaptive stress response grows stronger with the increasing stress level, epigenetically activating response gene clusters while progressively deregulating other cellular processes. The balance between the unspecific adaptive response and the general epigenetic deregulation is critical because a strong response can lead to pathology, particularly to malignant transformation. The main idea of our hypothesis is the continuum traversed by a cell subjected to accumulated stress, which lies between an unspecific adaptive response and pathological deregulation—the two extremes sharing the same underlying cause, which is a manifestation of a unified epigenetically mediated adaptive response to stress. The evolutionary potential of epigenetic regulation in multigenerational adaptation is speculatively discussed in the light of neo-Lamarckism. Finally, an approach to testing the proposed hypothesis is presented, relying on either the publicly available datasets or on conducting new experiments. PMID:24187667

  9. Adaptation or malignant transformation: the two faces of epigenetically mediated response to stress.

    PubMed

    Vojta, Aleksandar; Zoldoš, Vlatka

    2013-01-01

    Adaptive response to stress is a fundamental property of living systems. At the cellular level, many different types of stress elicit an essentially limited repertoire of adaptive responses. Epigenetic changes are the main mechanism for medium- to long-term adaptation to accumulated (intense, long-term, or repeated) stress. We propose the adaptive deregulation of the epigenome in response to stress (ADERS) hypothesis which assumes that the unspecific adaptive stress response grows stronger with the increasing stress level, epigenetically activating response gene clusters while progressively deregulating other cellular processes. The balance between the unspecific adaptive response and the general epigenetic deregulation is critical because a strong response can lead to pathology, particularly to malignant transformation. The main idea of our hypothesis is the continuum traversed by a cell subjected to accumulated stress, which lies between an unspecific adaptive response and pathological deregulation--the two extremes sharing the same underlying cause, which is a manifestation of a unified epigenetically mediated adaptive response to stress. The evolutionary potential of epigenetic regulation in multigenerational adaptation is speculatively discussed in the light of neo-Lamarckism. Finally, an approach to testing the proposed hypothesis is presented, relying on either the publicly available datasets or on conducting new experiments.

  10. Adaptive tracking of narrowband HF channel response

    NASA Astrophysics Data System (ADS)

    Arikan, F.; Arikan, O.

    2003-12-01

    Estimation of channel impulse response constitutes a first step in computation of scattering function, channel equalization, elimination of multipath, and optimum detection and identification of transmitted signals through the HF channel. Due to spatial and temporal variations, HF channel impulse response has to be estimated adaptively. Based on developed state-space and measurement models, an adaptive Kalman filter is proposed to track the HF channel variation in time. Robust methods of initialization and adaptively adjusting the noise covariance in the system dynamics are proposed. In simulated examples under good, moderate and poor ionospheric conditions, it is observed that the adaptive Kalman filter based channel estimator provides reliable channel estimates and can track the variation of the channel in time with high accuracy.

  11. When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage.

    PubMed

    Serrano, Diego; D'Amours, Damien

    2014-09-01

    The drive to proliferate and the need to maintain genome integrity are two of the most powerful forces acting on biological systems. When these forces enter in conflict, such as in the case of cells experiencing DNA damage, feedback mechanisms are activated to ensure that cellular proliferation is stopped and no further damage is introduced while cells repair their chromosomal lesions. In this circumstance, the DNA damage response dominates over the biological drive to proliferate, and may even result in programmed cell death if the damage cannot be repaired efficiently. Interestingly, the drive to proliferate can under specific conditions overcome the DNA damage response and lead to a reactivation of the proliferative program in checkpoint-arrested cells. This phenomenon is known as adaptation to DNA damage and is observed in all eukaryotic species where the process has been studied, including normal and cancer cells in humans. Polo-like kinases (PLKs) are critical regulators of the adaptation response to DNA damage and they play key roles at the interface of cell cycle and checkpoint-related decisions in cells. Here, we review recent progress in defining the specific roles of PLKs in the adaptation process and how this conserved family of eukaryotic kinases can integrate the fundamental need to preserve genomic integrity with effective cellular proliferation.

  12. Circadian Clock Control of the Cellular Response to DNA Damage

    PubMed Central

    Sancar, Aziz; Lindsey-Boltz, Laura A.; Kang, Tae-Hong; Reardon, Joyce T.; Lee, Jin Hyup; Ozturk, Nuri

    2010-01-01

    Mammalian cells possess a cell-autonomous molecular clock which controls the timing of many biochemical reactions and hence the cellular response to environmental stimuli including genotoxic stress. The clock consists of an autoregulatory transcription-translation feedback loop made up of four genes/proteins, BMal1, Clock, Cryptochrome, and Period. The circadian clock has an intrinsic period of about 24 hours, and it dictates the rates of many biochemical reactions as a function of the time of the day. Recently, it has become apparent that the circadian clock plays an important role in determining the strengths of cellular responses to DNA damage including repair, checkpoints, and apoptosis. These new insights are expected to guide development of novel mechanism-based chemotherapeutic regimens. PMID:20227409

  13. Micro-thermocouple probe for measurement of cellular thermal responses.

    PubMed

    Watanabe, M; Kakuta, N; Mabuchi, K; Yamada, Y

    2005-01-01

    We have produced micro-thermocouple probes for the measurement of cellular thermal responses. Cells generate heat with their metabolisms and more heat with reactions to a certain physical or chemical stimulation. Therefore, the analysis of the cellular thermal responses would provide new physiological information. However, a real-time thermal measurement technique on a target of a single cell has not been established. In this study, glass micropipettes, which are widely used in bioengineering and medicine, are used for the base of the thermocouple probes. Using microfabrication techniques, the junction of two different metal films is formed at the micropipette tip with a diameter of 1 μm. This probe can inject a chemical substance into a cell and to detect its subsequent temperature changes simultaneously.

  14. Adaptive neural control of aeroelastic response

    NASA Astrophysics Data System (ADS)

    Lichtenwalner, Peter F.; Little, Gerald R.; Scott, Robert C.

    1996-05-01

    The Adaptive Neural Control of Aeroelastic Response (ANCAR) program is a joint research and development effort conducted by McDonnell Douglas Aerospace (MDA) and the National Aeronautics and Space Administration, Langley Research Center (NASA LaRC) under a Memorandum of Agreement (MOA). The purpose of the MOA is to cooperatively develop the smart structure technologies necessary for alleviating undesirable vibration and aeroelastic response associated with highly flexible structures. Adaptive control can reduce aeroelastic response associated with buffet and atmospheric turbulence, it can increase flutter margins, and it may be able to reduce response associated with nonlinear phenomenon like limit cycle oscillations. By reducing vibration levels and loads, aircraft structures can have lower acquisition cost, reduced maintenance, and extended lifetimes. Phase I of the ANCAR program involved development and demonstration of a neural network-based semi-adaptive flutter suppression system which used a neural network for scheduling control laws as a function of Mach number and dynamic pressure. This controller was tested along with a robust fixed-gain control law in NASA's Transonic Dynamics Tunnel (TDT) utilizing the Benchmark Active Controls Testing (BACT) wing. During Phase II, a fully adaptive on-line learning neural network control system has been developed for flutter suppression which will be tested in 1996. This paper presents the results of Phase I testing as well as the development progress of Phase II.

  15. Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

    PubMed Central

    Cornelius, Carolin; Dinkova-Kostova, Albena T.; Calabrese, Edward J.; Mattson, Mark P.

    2010-01-01

    Abstract Despite the capacity of chaperones and other homeostatic components to restore folding equilibrium, cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This article introduces the concept of hormesis and its applications to the field of neuroprotection. It is argued that the hormetic dose response provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose–response relationships, their mechanistic foundations, and their relationship to the concept of biological plasticity, as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This article describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including sirtuin and Nrf2 and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. Particular attention is given to the emerging role of nitric oxide, carbon monoxide, and hydrogen sulfide gases in hormetic-based neuroprotection and their relationship to membrane radical dynamics and mitochondrial redox signaling. Antioxid. Redox Signal. 13, 1763–1811. PMID:20446769

  16. Microfluidic Device for Studying Controllable Hydrodynamic Flow Induced Cellular Responses.

    PubMed

    Zheng, Chunhong; Zhang, Xiannian; Li, Chunmei; Pang, Yuhong; Huang, Yanyi

    2017-03-07

    Hydrodynamic flow is an essential stimulus in many cellular functions, regulating many mechanical sensitive pathways and closely associating with human health status and diseases. The flow pattern of blood in vessels is the key factor in causing atherosclerosis. Hemodynamics has great effect on endothelial cells' gene expression and biological functions. There are various tools that can be used for studying flow-induced cellular responses but most of them are either bulky or lack precise controllability. We develop an integrated microfluidic device that can precisely generate different flow patterns to human endothelial cells cultured on-chip. We monitored cell morphology and used small-input RNA-seq technology to depict the transcriptome profiles of human umbilical vein endothelial cells under uni- or bidirectional flow. Such integrated and miniatured device has greatly facilitated our understanding of endothelial functions with shear stimulus, not only providing new data on the transcriptomic scale but also building the connection between cell phenotypic changes and expression alternations.

  17. HSV-I and the cellular DNA damage response.

    PubMed

    Smith, Samantha; Weller, Sandra K

    2015-04-01

    Peter Wildy first observed genetic recombination between strains of HSV in 1955. At the time, knowledge of DNA repair mechanisms was limited, and it has only been in the last decade that particular DNA damage response (DDR) pathways have been examined in the context of viral infections. One of the first reports addressing the interaction between a cellular DDR protein and HSV-1 was the observation by Lees-Miller et al. that DNA-dependent protein kinase catalytic subunit levels were depleted in an ICP0-dependent manner during Herpes simplex virus 1 infection. Since then, there have been numerous reports describing the interactions between HSV infection and cellular DDR pathways. Due to space limitations, this review will focus predominantly on the most recent observations regarding how HSV navigates a potentially hostile environment to replicate its genome.

  18. Antioxidant responses and cellular adjustments to oxidative stress.

    PubMed

    Espinosa-Diez, Cristina; Miguel, Verónica; Mennerich, Daniela; Kietzmann, Thomas; Sánchez-Pérez, Patricia; Cadenas, Susana; Lamas, Santiago

    2015-12-01

    Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases.

  19. Antioxidant responses and cellular adjustments to oxidative stress

    PubMed Central

    Espinosa-Diez, Cristina; Miguel, Verónica; Mennerich, Daniela; Kietzmann, Thomas; Sánchez-Pérez, Patricia; Cadenas, Susana; Lamas, Santiago

    2015-01-01

    Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases. PMID:26233704

  20. Cellular stress response pathways and ageing: intricate molecular relationships.

    PubMed

    Kourtis, Nikos; Tavernarakis, Nektarios

    2011-05-17

    Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, senescent decline and ageing is broadly influenced by genetic and extrinsic factors. Numerous gene mutations and treatments have been shown to extend the lifespan of diverse organisms ranging from the unicellular Saccharomyces cerevisiae to primates. It is becoming increasingly apparent that most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to effectively cope with both intrinsic and extrinsic stress. Here, we survey the molecular mechanisms that link ageing to main stress response pathways, and mediate age-related changes in the effectiveness of the response to stress. We also discuss how each pathway contributes to modulate the ageing process. A better understanding of the dynamics and reciprocal interplay between stress responses and ageing is critical for the development of novel therapeutic strategies that exploit endogenous stress combat pathways against age-associated pathologies.

  1. ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression.

    PubMed

    Fallone, F; Britton, S; Nieto, L; Salles, B; Muller, C

    2013-09-12

    Tumor cells adaptation to severe oxygen deprivation (hypoxia) plays a major role in tumor progression. The transcription factor HIF-1 (hypoxia-inducible factor 1), whose α-subunit is stabilized under hypoxic conditions is a key component of this process. Recent studies showed that two members of the phosphoinositide 3-kinase-related kinases (PIKKs) family, ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), regulate the hypoxic-dependent accumulation of HIF-1. These proteins initiate cellular stress responses when DNA damage occurs. In addition, it has been demonstrated that extreme hypoxia induces a replicative stress resulting in regions of single-stranded DNA at stalled replication forks and the activation of ATR (ataxia telangiectasia and Rad3 related protein), another member of the PIKKs family. Here, we show that even less severe hypoxia (0.1% O2) also induces activation of ATR through replicative stress. Importantly, in using either transiently silenced ATR cells, cells expressing an inactive form of ATR or cells exposed to an ATR inhibitor (CGK733), we demonstrate that hypoxic ATR activation positively regulates the key transcription factor HIF-1 independently of the checkpoint kinase Chk1. We show that ATR kinase activity regulates HIF-1α at the translational level and we find that the elements necessary for the regulation of HIF-1α translation are located within the coding region of HIF-1α mRNA. Finally, by using three independent cellular models, we clearly show that the loss of ATR expression and/or kinase activity results in the decrease of HIF-1 DNA binding under hypoxia and consequently affects protein expression levels of two HIF-1 target genes, GLUT-1 and CAIX. Taken together, our data show a new function for ATR in cellular adaptation to hypoxia through regulation of HIF-1α translation. Our work offers new prospect for cancer therapy using ATR inhibitors with the potential to decrease cellular adaptation in hypoxic

  2. Individual differences in response conflict adaptations

    PubMed Central

    Keye, Doris; Wilhelm, Oliver; Oberauer, Klaus; Stürmer, Birgit

    2013-01-01

    Conflict-monitoring theory argues for a general cognitive mechanism that monitors for conflicts in information-processing. If that mechanism detects conflict, it engages cognitive control to resolve it. A slow-down in response to incongruent trials (conflict effect), and a modulation of the conflict effect by the congruence of the preceding trial (Gratton or context effect) have been taken as indicators of such a monitoring system. The present study (N = 157) investigated individual differences in the conflict and the context effect in a horizontal and a vertical Simon task, and their correlation with working memory capacity (WMC). Strength of conflict was varied by proportion of congruent trials. Coherent factors could be formed representing individual differences in speeded performance, conflict adaptation, and context adaptation. Conflict and context factors were not associated with each other. Contrary to theories assuming a close relation between working memory and cognitive control, WMC showed no relation with any factors representing adaptation to conflict. PMID:24385971

  3. Immunogenetic aspects of the cellular immune response of Drosophilia against parasitoids.

    PubMed

    Carton, Y; Nappi, A J

    2001-01-01

    Host-parasite relationships represent integrating adaptations of considerable complexity involving the host's immune capacity to both recognize and destroy the parasite, and the latter's ability to successfully invade the host and to circumvent its immune response. Compatibility in Drosophila-parasitic wasp (parasitoid) associations has been shown to have a genetic basis, and to be both species and strain specific. Studies using resistant and susceptible strains of Drosophila melanogaster infected with virulent and avirulent strains of the wasp Leptopilina boulardi demonstrate that the success of the host cellular immune response depends on the genetic status of both host and parasitoid. Immunological, physiological, biochemical, and genetic data form the bases of a two-component model proposed here to account for the observed specificity and complexity of two coevolved adaptations, host nonself recognition and parasitoid virulence.

  4. Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture.

    PubMed

    Harak, Christian; Meyrath, Max; Romero-Brey, Inés; Schenk, Christian; Gondeau, Claire; Schult, Philipp; Esser-Nobis, Katharina; Saeed, Mohsan; Neddermann, Petra; Schnitzler, Paul; Gotthardt, Daniel; Perez-Del-Pulgar, Sofia; Neumann-Haefelin, Christoph; Thimme, Robert; Meuleman, Philip; Vondran, Florian W R; Francesco, Raffaele De; Rice, Charles M; Bartenschlager, Ralf; Lohmann, Volker

    2016-12-19

    With a single exception, all isolates of hepatitis C virus (HCV) require adaptive mutations to replicate efficiently in cell culture. Here, we show that a major class of adaptive mutations regulates the activity of a cellular lipid kinase, phosphatidylinositol 4-kinase IIIα (PI4KA). HCV needs to stimulate PI4KA to create a permissive phosphatidylinositol 4-phosphate-enriched membrane microenvironment in the liver and in primary human hepatocytes (PHHs). In contrast, in Huh7 hepatoma cells, the virus must acquire loss-of-function mutations that prevent PI4KA overactivation. This adaptive mechanism is necessitated by increased PI4KA levels in Huh7 cells compared with PHHs, and is conserved across HCV genotypes. PI4KA-specific inhibitors promote replication of unadapted viral isolates and allow efficient replication of patient-derived virus in cell culture. In summary, this study has uncovered a long-sought mechanism of HCV cell-culture adaptation and demonstrates how a virus can adapt to changes in a cellular environment associated with tumorigenesis.

  5. Green light signaling and adaptive response.

    PubMed

    Zhang, Tingting; Folta, Kevin M

    2012-01-01

    To a plant, the sun's light is not exclusively energy for photosynthesis, it also provides information about time and prevailing conditions. The plant's surroundings may dampen or filter solar energies, presenting plants with different spectral profiles of their light environment. Plants use this information to adjust form and physiology, tailoring gene expression to best match ambient conditions. Extensive literature exists on how blue, red and far-red light contribute to plant adaptive responses. A growing body of work identifies effects of green light (500-565 nm) that also shape plant biology. Green light responses are known to be either mediated through, or independent of, the cryptochrome blue light receptors. Responses to green light share a general tendency to oppose blue- or red-light-induced responses, including stem growth rate inhibition, anthocyanin accumulation and chloroplast gene expression. Recent evidence demonstrates a role for green light in sensing a shaded environment, independent from far-red shade responses.

  6. The Adaptive Calibration Model of stress responsivity

    PubMed Central

    Ellis, Bruce J.; Shirtcliff, Elizabeth A.

    2010-01-01

    This paper presents the Adaptive Calibration Model (ACM), an evolutionary-developmental theory of individual differences in the functioning of the stress response system. The stress response system has three main biological functions: (1) to coordinate the organism’s allostatic response to physical and psychosocial challenges; (2) to encode and filter information about the organism’s social and physical environment, mediating the organism’s openness to environmental inputs; and (3) to regulate the organism’s physiology and behavior in a broad range of fitness-relevant areas including defensive behaviors, competitive risk-taking, learning, attachment, affiliation and reproductive functioning. The information encoded by the system during development feeds back on the long-term calibration of the system itself, resulting in adaptive patterns of responsivity and individual differences in behavior. Drawing on evolutionary life history theory, we build a model of the development of stress responsivity across life stages, describe four prototypical responsivity patterns, and discuss the emergence and meaning of sex differences. The ACM extends the theory of biological sensitivity to context (BSC) and provides an integrative framework for future research in the field. PMID:21145350

  7. Intraspecific variation in cellular and biochemical heat response strategies of Mediterranean Xeropicta derbentina [Pulmonata, Hygromiidae].

    PubMed

    Troschinski, Sandra; Di Lellis, Maddalena A; Sereda, Sergej; Hauffe, Torsten; Wilke, Thomas; Triebskorn, Rita; Köhler, Heinz-R

    2014-01-01

    Dry and hot environments challenge the survival of terrestrial snails. To minimize overheating and desiccation, physiological and biochemical adaptations are of high importance for these animals. In the present study, seven populations of the Mediterranean land snail species Xeropicta derbentina were sampled from their natural habitat in order to investigate the intraspecific variation of cellular and biochemical mechanisms, which are assigned to contribute to heat resistance. Furthermore, we tested whether genetic parameters are correlated with these physiological heat stress response patterns. Specimens of each population were individually exposed to elevated temperatures (25 to 52°C) for 8 h in the laboratory. After exposure, the health condition of the snails' hepatopancreas was examined by means of qualitative description and semi-quantitative assessment of histopathological effects. In addition, the heat-shock protein 70 level (Hsp70) was determined. Generally, calcium cells of the hepatopancreas were more heat resistant than digestive cells - this phenomenon was associated with elevated Hsp70 levels at 40°C.We observed considerable variation in the snails' heat response strategy: Individuals from three populations invested much energy in producing a highly elevated Hsp70 level, whereas three other populations invested energy in moderate stress protein levels - both strategies were in association with cellular functionality. Furthermore, one population kept cellular condition stable despite a low Hsp70 level until 40°C exposure, whereas prominent cellular reactions were observed above this thermal limit. Genetic diversity (mitochondrial cytochrome c oxidase subunit I gene) within populations was low. Nevertheless, when using genetic indices as explanatory variables in a multivariate regression tree (MRT) analysis, population structure explained mean differences in cellular and biochemical heat stress responses, especially in the group exposed to 40°C. Our

  8. Intraspecific Variation in Cellular and Biochemical Heat Response Strategies of Mediterranean Xeropicta derbentina [Pulmonata, Hygromiidae

    PubMed Central

    Troschinski, Sandra; Di Lellis, Maddalena A.; Sereda, Sergej; Hauffe, Torsten; Wilke, Thomas; Triebskorn, Rita; Köhler, Heinz-R.

    2014-01-01

    Dry and hot environments challenge the survival of terrestrial snails. To minimize overheating and desiccation, physiological and biochemical adaptations are of high importance for these animals. In the present study, seven populations of the Mediterranean land snail species Xeropicta derbentina were sampled from their natural habitat in order to investigate the intraspecific variation of cellular and biochemical mechanisms, which are assigned to contribute to heat resistance. Furthermore, we tested whether genetic parameters are correlated with these physiological heat stress response patterns. Specimens of each population were individually exposed to elevated temperatures (25 to 52°C) for 8 h in the laboratory. After exposure, the health condition of the snails' hepatopancreas was examined by means of qualitative description and semi-quantitative assessment of histopathological effects. In addition, the heat-shock protein 70 level (Hsp70) was determined. Generally, calcium cells of the hepatopancreas were more heat resistant than digestive cells - this phenomenon was associated with elevated Hsp70 levels at 40°C.We observed considerable variation in the snails' heat response strategy: Individuals from three populations invested much energy in producing a highly elevated Hsp70 level, whereas three other populations invested energy in moderate stress protein levels - both strategies were in association with cellular functionality. Furthermore, one population kept cellular condition stable despite a low Hsp70 level until 40°C exposure, whereas prominent cellular reactions were observed above this thermal limit. Genetic diversity (mitochondrial cytochrome c oxidase subunit I gene) within populations was low. Nevertheless, when using genetic indices as explanatory variables in a multivariate regression tree (MRT) analysis, population structure explained mean differences in cellular and biochemical heat stress responses, especially in the group exposed to 40°C. Our

  9. Durable response of intracranial cellular hemangioma to bevacizumab and temozolomide.

    PubMed

    Yeo, Kee Kiat; Puscasiu, Elena; Keating, Robert F; Rood, Brian R

    2013-06-01

    Cellular hemangioma is a subtype of hemangioma that is associated with cellular immaturity and the potential for recurrence. Intracranial location of these lesions is extremely rare, and definitive treatment often requires radical neurosurgical resection. The authors report a case of a 12-year-old boy with a subtemporal cellular hemangioma. He underwent gross-total resection of the tumor, but within 1.5 months the tumor recurred, necessitating a second resection. Because of its proximity to vascular structures, only subtotal resection was possible. Repeat MRI 1 month after the second surgery showed significant tumor recurrence. Given the tumor's demonstrated capacity for recurrence and its proximity to the vein of Labbé and sigmoid sinus, further resection was not indicated. In an effort to limit radiation therapy for this young patient, treatment with bevacizumab and temozolomide was chosen and achieved a complete response that has proven durable for 36 months after cessation of therapy. This is the first report of the successful use of chemotherapy to treat an intracranial hemangioma, a rare condition with limited therapeutic options.

  10. Cellular Bases of Light-regulated Gravity Responses

    NASA Technical Reports Server (NTRS)

    Roux, Stanley J.

    2003-01-01

    This report summarizes the most significant research accomplished in our NAG2-1347 project on the cellular bases of light-regulated gravity responses, It elaborates mainly on our discovery of the role of calcium currents in gravity-directed polar development in single germinating spore cells of the fern Ceratopteris, our development of RNA silencing as a viable method of suppressing the expression of specific genes in Ceratopteris, and on the structure, expression and distribution of members of the annexin family in flowering plants, especially Arabidopsis.

  11. Adaptive immune responses to Acanthamoeba cysts.

    PubMed

    McClellan, Kathy; Howard, Kevin; Mayhew, Elizabeth; Niederkorn, Jerry; Alizadeh, Hassan

    2002-09-01

    Acanthamoeba cysts are not eliminated from the corneas of human subjects or experimentally infected animals. The persistence of Acanthamoeba cysts in the cornea indicates that either the cysts escape immunological elimination or are not recognized by the host's immunological elements. The aim of this study was to determine the immunogenicity and antigenicity of the Acanthamoeba cyst. Mice were immunized intraperitoneally and serum anti-Acanthamoeba IgG was measured by ELISA. Lymphoproliferative assay and delayed type hypersensitivity (DTH) responses to Acanthamoeba castellanii cyst and trophozoite antigens were used to determine the cell mediated immune responses against Acanthamoeba cysts. A. castellanii cysts were both immunogenic and antigenic, producing anti-Acanthamoeba serum IgG, T lymphocyte proliferation, and delayed type hypersensitivity responses. These results indicate that Acanthamoeba cysts are recognized by the immune system. The persistence of the organism in the human cornea means that these adaptive immune responses fail to kill Acanthamoeba cysts.

  12. Real-Time Molecular Monitoring of Chemical Environment in ObligateAnaerobes during Oxygen Adaptive Response

    SciTech Connect

    Holman, Hoi-Ying N.; Wozei, Eleanor; Lin, Zhang; Comolli, Luis R.; Ball, David. A.; Borglin, Sharon; Fields, Matthew W.; Hazen, Terry C.; Downing, Kenneth H.

    2009-02-25

    Determining the transient chemical properties of the intracellular environment canelucidate the paths through which a biological system adapts to changes in its environment, for example, the mechanisms which enable some obligate anaerobic bacteria to survive a sudden exposure to oxygen. Here we used high-resolution Fourier Transform Infrared (FTIR) spectromicroscopy to continuously follow cellular chemistry within living obligate anaerobes by monitoring hydrogen bonding in their cellular water. We observed a sequence of wellorchestrated molecular events that correspond to changes in cellular processes in those cells that survive, but only accumulation of radicals in those that do not. We thereby can interpret the adaptive response in terms of transient intracellular chemistry and link it to oxygen stress and survival. This ability to monitor chemical changes at the molecular level can yield important insights into a wide range of adaptive responses.

  13. Engineering Cellular Response Using Nanopatterned Bulk Metallic Glass

    PubMed Central

    2015-01-01

    Nanopatterning of biomaterials is rapidly emerging as a tool to engineer cell function. Bulk metallic glasses (BMGs), a class of biocompatible materials, are uniquely suited to study nanopattern–cell interactions as they allow for versatile fabrication of nanopatterns through thermoplastic forming. Work presented here employs nanopatterned BMG substrates to explore detection of nanopattern feature sizes by various cell types, including cells that are associated with foreign body response, pathology, and tissue repair. Fibroblasts decreased in cell area as the nanopattern feature size increased, and fibroblasts could detect nanopatterns as small as 55 nm in size. Macrophages failed to detect nanopatterns of 150 nm or smaller in size, but responded to a feature size of 200 nm, resulting in larger and more elongated cell morphology. Endothelial cells responded to nanopatterns of 100 nm or larger in size by a significant decrease in cell size and elongation. On the basis of these observations, nondimensional analysis was employed to correlate cellular morphology and substrate nanotopography. Analysis of the molecular pathways that induce cytoskeletal remodeling, in conjunction with quantifying cell traction forces with nanoscale precision using a unique FIB-SEM technique, enabled the characterization of underlying biomechanical cues. Nanopatterns altered serum protein adsorption and effective substrate stiffness, leading to changes in focal adhesion density and compromised activation of Rho-A GTPase in fibroblasts. As a consequence, cells displayed restricted cell spreading and decreased collagen production. These observations suggest that topography on the nanoscale can be designed to engineer cellular responses to biomaterials. PMID:24724817

  14. Nutritional strategies to modulate the adaptive response to endurance training.

    PubMed

    Hawley, John A

    2013-01-01

    In recent years, advances in molecular biology have allowed scientists to elucidate how endurance exercise training stimulates skeletal muscle remodeling (i.e. promotes mitochondrial biogenesis). A growing field of interest directly arising from our understanding of the molecular bases of training adaptation is how nutrient availability can alter the regulation of many contraction-induced events in muscle in response to endurance exercise. Acutely manipulating substrate availability can exert profound effects on muscle energy stores and patterns of fuel metabolism during exercise, as well as many processes activating gene expression and cell signaling. Accordingly, such interventions when repeated over weeks and months have the potential to modulate numerous adaptive processes in skeletal muscle that ultimately drive the phenotype-specific characteristics observed in highly trained athletes. In this review, the molecular and cellular events that occur in skeletal muscle during and after endurance exercise are discussed and evidence provided to demonstrate that nutrient availability plays an important role in modulating many of the adaptive responses to training. Emphasis is on human studies that have determined the regulatory role of muscle glycogen availability on cell metabolism, endurance training capacity and performance.

  15. Cellular properties and chemosensory responses of the human carotid body

    PubMed Central

    Ortega-Sáenz, Patricia; Pardal, Ricardo; Levitsky, Konstantin; Villadiego, Javier; Muñoz-Manchado, Ana Belén; Durán, Rocío; Bonilla-Henao, Victoria; Arias-Mayenco, Ignacio; Sobrino, Verónica; Ordóñez, Antonio; Oliver, María; Toledo-Aral, Juan José; López-Barneo, José

    2013-01-01

    The carotid body (CB) is the major peripheral arterial chemoreceptor in mammals that mediates the acute hyperventilatory response to hypoxia. The CB grows in response to sustained hypoxia and also participates in acclimatisation to chronic hypoxaemia. Knowledge of CB physiology at the cellular level has increased considerably in recent times thanks to studies performed on lower mammals, and rodents in particular. However, the functional characteristics of human CB cells remain practically unknown. Herein, we use tissue slices or enzymatically dispersed cells to determine the characteristics of human CB cells. The adult human CB parenchyma contains clusters of chemosensitive glomus (type I) and sustentacular (type II) cells as well as nestin-positive progenitor cells. This organ also expresses high levels of the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF). We found that GDNF production and the number of progenitor and glomus cells were preserved in the CBs of human subjects of advanced age. Moreover, glomus cells exhibited voltage-dependent Na+, Ca2+ and K+ currents that were qualitatively similar to those reported in lower mammals. These cells responded to hypoxia with an external Ca2+-dependent increase of cytosolic Ca2+ and quantal catecholamine secretion, as reported for other mammalian species. Interestingly, human glomus cells are also responsive to hypoglycaemia and together these two stimuli can potentiate each other's effects. The chemosensory responses of glomus cells are also preserved at an advanced age. These new data on the cellular and molecular physiology of the CB pave the way for future pathophysiological studies involving this organ in humans. PMID:24167224

  16. Adaptive immune cells temper initial innate responses

    PubMed Central

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2008-01-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells1–4. Lymphocytedeficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1–deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25−Foxp3− or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses. PMID:17891146

  17. Adaptive immune cells temper initial innate responses.

    PubMed

    Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong; Yang, Xuanming; Du, Peishuang; Tang, Hong; Fu, Yang-Xin

    2007-10-01

    Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25-Foxp3- or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.

  18. Cellular pulse-coupled neural network with adaptive weights for image segmentation and its VLSI implementation

    NASA Astrophysics Data System (ADS)

    Schreiter, Juerg; Ramacher, Ulrich; Heittmann, Arne; Matolin, Daniel; Schuffny, Rene

    2004-05-01

    We present a cellular pulse coupled neural network with adaptive weights and its analog VLSI implementation. The neural network operates on a scalar image feature, such as grey scale or the output of a spatial filter. It detects segments and marks them with synchronous pulses of the corresponding neurons. The network consists of integrate-and-fire neurons, which are coupled to their nearest neighbors via adaptive synaptic weights. Adaptation follows either one of two empirical rules. Both rules lead to spike grouping in wave like patterns. This synchronous activity binds groups of neurons and labels the corresponding image segments. Applications of the network also include feature preserving noise removal, image smoothing, and detection of bright and dark spots. The adaptation rules are insensitive for parameter deviations, mismatch and non-ideal approximation of the implied functions. That makes an analog VLSI implementation feasible. Simulations showed no significant differences in the synchronization properties between networks using the ideal adaptation rules and networks resembling implementation properties such as randomly distributed parameters and roughly implemented adaptation functions. A prototype is currently being designed and fabricated using an Infineon 130nm technology. It comprises a 128 × 128 neuron array, analog image memory, and an address event representation pulse output.

  19. Molecular and cellular bases of adaptation to a changing environment in microorganisms

    PubMed Central

    Bleuven, Clara

    2016-01-01

    Environmental heterogeneity constitutes an evolutionary challenge for organisms. While evolutionary dynamics under variable conditions has been explored for decades, we still know relatively little about the cellular and molecular mechanisms involved. It is of paramount importance to examine these molecular bases because they may play an important role in shaping the course of evolution. In this review, we examine the diversity of adaptive mechanisms in the face of environmental changes. We exploit the recent literature on microbial systems because those have benefited the most from the recent emergence of genetic engineering and experimental evolution followed by genome sequencing. We identify four emerging trends: (i) an adaptive molecular change in a pathway often results in fitness trade-off in alternative environments but the effects are dependent on a mutation's genetic background; (ii) adaptive changes often modify transcriptional and signalling pathways; (iii) several adaptive changes may occur within the same molecular pathway but be associated with pleiotropy of different signs across environments; (iv) because of their large associated costs, macromolecular changes such as gene amplification and aneuploidy may be a rapid mechanism of adaptation in the short-term only. The course of adaptation in a variable environment, therefore, depends on the complexity of the environment but also on the molecular relationships among the genes involved and between the genes and the phenotypes under selection. PMID:27798299

  20. Molecular and cellular bases of adaptation to a changing environment in microorganisms.

    PubMed

    Bleuven, Clara; Landry, Christian R

    2016-10-26

    Environmental heterogeneity constitutes an evolutionary challenge for organisms. While evolutionary dynamics under variable conditions has been explored for decades, we still know relatively little about the cellular and molecular mechanisms involved. It is of paramount importance to examine these molecular bases because they may play an important role in shaping the course of evolution. In this review, we examine the diversity of adaptive mechanisms in the face of environmental changes. We exploit the recent literature on microbial systems because those have benefited the most from the recent emergence of genetic engineering and experimental evolution followed by genome sequencing. We identify four emerging trends: (i) an adaptive molecular change in a pathway often results in fitness trade-off in alternative environments but the effects are dependent on a mutation's genetic background; (ii) adaptive changes often modify transcriptional and signalling pathways; (iii) several adaptive changes may occur within the same molecular pathway but be associated with pleiotropy of different signs across environments; (iv) because of their large associated costs, macromolecular changes such as gene amplification and aneuploidy may be a rapid mechanism of adaptation in the short-term only. The course of adaptation in a variable environment, therefore, depends on the complexity of the environment but also on the molecular relationships among the genes involved and between the genes and the phenotypes under selection.

  1. Adaptation of the Black Yeast Wangiella dermatitidis to Ionizing Radiation: Molecular and Cellular Mechanisms

    PubMed Central

    Robertson, Kelly L.; Mostaghim, Anahita; Cuomo, Christina A.; Soto, Carissa M.; Lebedev, Nikolai; Bailey, Robert F.; Wang, Zheng

    2012-01-01

    Observations of enhanced growth of melanized fungi under low-dose ionizing radiation in the laboratory and in the damaged Chernobyl nuclear reactor suggest they have adapted the ability to survive or even benefit from exposure to ionizing radiation. However, the cellular and molecular mechanism of fungal responses to such radiation remains poorly understood. Using the black yeast Wangiella dermatitidis as a model, we confirmed that ionizing radiation enhanced cell growth by increasing cell division and cell size. Using RNA-seq technology, we compared the transcriptomic profiles of the wild type and the melanin-deficient wdpks1 mutant under irradiation and non-irradiation conditions. It was found that more than 3000 genes were differentially expressed when these two strains were constantly exposed to a low dose of ionizing radiation and that half were regulated at least two fold in either direction. Functional analysis indicated that many genes for amino acid and carbohydrate metabolism and cell cycle progression were down-regulated and that a number of antioxidant genes and genes affecting membrane fluidity were up-regulated in both irradiated strains. However, the expression of ribosomal biogenesis genes was significantly up-regulated in the irradiated wild-type strain but not in the irradiated wdpks1 mutant, implying that melanin might help to contribute radiation energy for protein translation. Furthermore, we demonstrated that long-term exposure to low doses of radiation significantly increased survivability of both the wild-type and the wdpks1 mutant, which was correlated with reduced levels of reactive oxygen species (ROS), increased production of carotenoid and induced expression of genes encoding translesion DNA synthesis. Our results represent the first functional genomic study of how melanized fungal cells respond to low dose ionizing radiation and provide clues for the identification of biological processes, molecular pathways and individual genes

  2. Resistance Training: Physiological Responses and Adaptations (Part 3 of 4).

    ERIC Educational Resources Information Center

    Fleck, Steven J.; Kraemer, William J.

    1988-01-01

    The physiological responses and adaptations which occur as a result of resistance training, such as cardiovascular responses, serum lipid count, body composition, and neural adaptations are discussed. Changes in the endocrine system are also described. (JL)

  3. The adaptive immune response in celiac disease.

    PubMed

    Qiao, Shuo-Wang; Iversen, Rasmus; Ráki, Melinda; Sollid, Ludvig M

    2012-07-01

    Compared to other human leukocyte antigen (HLA)-associated diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, fundamental aspects of the pathogenesis in celiac disease are relatively well understood. This is mostly because the causative antigen in celiac disease-cereal gluten proteins-is known and the culprit HLA molecules are well defined. This has facilitated the dissection of the disease-relevant CD4+ T cells interacting with the disease-associated HLA molecules. In addition, celiac disease has distinct antibody responses to gluten and the autoantigen transglutaminase 2, which give strong handles to understand all sides of the adaptive immune response leading to disease. Here we review recent developments in the understanding of the role of T cells, B cells, and antigen-presenting cells in the pathogenic immune response of this instructive disorder.

  4. The Cellular Bases of Antibody Responses during Dengue Virus Infection.

    PubMed

    Yam-Puc, Juan Carlos; Cedillo-Barrón, Leticia; Aguilar-Medina, Elsa Maribel; Ramos-Payán, Rosalío; Escobar-Gutiérrez, Alejandro; Flores-Romo, Leopoldo

    2016-01-01

    Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and can cause from an asymptomatic disease to mild undifferentiated fever, classical dengue, and severe dengue. Neutralizing memory antibody (Ab) responses are one of the most important mechanisms that counteract reinfections and are therefore the main aim of vaccination. However, it has also been proposed that in dengue, some of these class-switched (IgG) memory Abs might worsen the disease. Although these memory Abs derive from B cells by T-cell-dependent processes, we know rather little about the (acute, chronic, or memory) B cell responses and the complex cellular mechanisms generating these Abs during DENV infections. This review aims to provide an updated and comprehensive perspective of the B cell responses during DENV infection, starting since the very early events such as the cutaneous DENV entrance and the arrival into draining lymph nodes, to the putative B cell activation, proliferation, and germinal centers (GCs) formation (the source of affinity-matured class-switched memory Abs), till the outcome of GC reactions such as the generation of plasmablasts, Ab-secreting plasma cells, and memory B cells. We discuss topics very poorly explored such as the possibility of B cell infection by DENV or even activation-induced B cell death. The current information about the nature of the Ab responses to DENV is also illustrated.

  5. Systematic quantitative characterization of cellular responses induced by multiple signals

    PubMed Central

    2011-01-01

    Background Cells constantly sense many internal and environmental signals and respond through their complex signaling network, leading to particular biological outcomes. However, a systematic characterization and optimization of multi-signal responses remains a pressing challenge to traditional experimental approaches due to the arising complexity associated with the increasing number of signals and their intensities. Results We established and validated a data-driven mathematical approach to systematically characterize signal-response relationships. Our results demonstrate how mathematical learning algorithms can enable systematic characterization of multi-signal induced biological activities. The proposed approach enables identification of input combinations that can result in desired biological responses. In retrospect, the results show that, unlike a single drug, a properly chosen combination of drugs can lead to a significant difference in the responses of different cell types, increasing the differential targeting of certain combinations. The successful validation of identified combinations demonstrates the power of this approach. Moreover, the approach enables examining the efficacy of all lower order mixtures of the tested signals. The approach also enables identification of system-level signaling interactions between the applied signals. Many of the signaling interactions identified were consistent with the literature, and other unknown interactions emerged. Conclusions This approach can facilitate development of systems biology and optimal drug combination therapies for cancer and other diseases and for understanding key interactions within the cellular network upon treatment with multiple signals. PMID:21624115

  6. Bronchopulmonary Cellular Response to Aluminum and Zirconium Salts

    PubMed Central

    Stankus, Richard P.; Schuyler, Mark R.; D'Amato, Robert A.; Salvaggio, John E.

    1978-01-01

    The bronchopulmonary cellular immunological response to repeated intratracheal inoculation of aluminum chlorhydrate, sodium zirconium lactate, and zirconium aluminum glycine was examined in rabbits. Results of a dose-response experiment using 0.1, 1.0, and 10.0-mg intratracheal inoculations of each metallic salt demonstrated significant bronchopulmonary histopathology in the 10.0-mg dose-response groups only. Acute lesions were histologically characterized by an inflammatory response centered around respiratory bronchioles. Although epithelioid cell formation was evident in 10.0 mg of aluminum salt (aluminum chlorhydrate and zirconium aluminum glycine) -injected animals, no well-defined granulomas characterized by an orderly arrangement of epithelioid cells, lymphocytes, and giant cells were evident in any of the experimental groups employed. All three metallic salts induced “activated” bronchopulmonary macrophages as determined by an in vitro phagocytic assay. This activation was likely nonimmunological since no measurable differences were observed in metallic salt-induced delayed skin reactivity or migration inhibition factor production between inoculated and uninoculated rabbits. The above observations suggest that aluminum and zirconium salts administered in comparatively high dosage via the respiratory tract route can induce respiratory bronchiolitis and activation of alveolar macrophages in the absence of demonstrable delayed hypersensitivity. Images PMID:352963

  7. The Cellular Bases of Antibody Responses during Dengue Virus Infection

    PubMed Central

    Yam-Puc, Juan Carlos; Cedillo-Barrón, Leticia; Aguilar-Medina, Elsa Maribel; Ramos-Payán, Rosalío; Escobar-Gutiérrez, Alejandro; Flores-Romo, Leopoldo

    2016-01-01

    Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and can cause from an asymptomatic disease to mild undifferentiated fever, classical dengue, and severe dengue. Neutralizing memory antibody (Ab) responses are one of the most important mechanisms that counteract reinfections and are therefore the main aim of vaccination. However, it has also been proposed that in dengue, some of these class-switched (IgG) memory Abs might worsen the disease. Although these memory Abs derive from B cells by T-cell-dependent processes, we know rather little about the (acute, chronic, or memory) B cell responses and the complex cellular mechanisms generating these Abs during DENV infections. This review aims to provide an updated and comprehensive perspective of the B cell responses during DENV infection, starting since the very early events such as the cutaneous DENV entrance and the arrival into draining lymph nodes, to the putative B cell activation, proliferation, and germinal centers (GCs) formation (the source of affinity-matured class-switched memory Abs), till the outcome of GC reactions such as the generation of plasmablasts, Ab-secreting plasma cells, and memory B cells. We discuss topics very poorly explored such as the possibility of B cell infection by DENV or even activation-induced B cell death. The current information about the nature of the Ab responses to DENV is also illustrated. PMID:27375618

  8. The DNA damage response in viral-induced cellular transformation.

    PubMed

    Nikitin, P A; Luftig, M A

    2012-01-31

    The DNA damage response (DDR) has emerged as a critical tumour suppressor pathway responding to cellular DNA replicative stress downstream of aberrant oncogene over-expression. Recent studies have now implicated the DDR as a sensor of oncogenic virus infection. In this review, we discuss the mechanisms by which tumour viruses activate and also suppress the host DDR. The mechanism of tumour virus induction of the DDR is intrinsically linked to the need for these viruses to promote an S-phase environment to replicate their nucleic acid during infection. However, inappropriate expression of viral oncoproteins can also activate the DDR through various mechanisms including replicative stress, direct interaction with DDR components and induction of reactive oxygen species. Given the growth-suppressive consequences of activating the DDR, tumour viruses have also evolved mechanisms to attenuate these pathways. Aberrant expression of viral oncoproteins may therefore promote tumourigenesis through increased somatic mutation and aneuploidy due to DDR inactivation. This review will focus on the interplay between oncogenic viruses and the DDR with respect to cellular checkpoint control and transformation.

  9. Humoral and Cellular Immune Response in Canine Hypothyroidism.

    PubMed

    Miller, J; Popiel, J; Chełmońska-Soyta, A

    2015-07-01

    Hypothyroidism is one of the most common endocrine diseases in dogs and is generally considered to be autoimmune in nature. In human hypothyroidism, the thyroid gland is destroyed by both cellular (i.e. autoreactive helper and cytotoxic T lymphocytes) and humoral (i.e. autoantibodies specific for thyroglobulin, thyroxine and triiodothyronine) effector mechanisms. Other suggested factors include impaired peripheral immune suppression (i.e. the malfunction of regulatory T cells) or an additional pro-inflammatory effect of T helper 17 lymphocytes. The aim of this study was to evaluate immunological changes in canine hypothyroidism. Twenty-eight clinically healthy dogs, 25 hypothyroid dogs without thyroglobulin antibodies and eight hypothyroid dogs with these autoantibodies were enrolled into the study. There were alterations in serum proteins in hypothyroid dogs compared with healthy controls (i.e. raised concentrations of α-globulins, β2- and γ-globulins) as well as higher concentration of acute phase proteins and circulating immune complexes. Hypothyroid animals had a lower CD4:CD8 ratio in peripheral blood compared with control dogs and diseased dogs also had higher expression of interferon γ (gene and protein expression) and CD28 (gene expression). Similar findings were found in both groups of hypothyroid dogs. Canine hypothyroidism is therefore characterized by systemic inflammation with dominance of a cellular immune response.

  10. Marine Bivalve Cellular Responses to Beta Blocker Exposures ...

    EPA Pesticide Factsheets

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent binding of agonists such as catecholamines to β adrenoceptors. In the absence of agonist induced activation of the receptor, adenylate cyclase is not activated which in turn limits cAMP production and protein kinase A activation, preventing increases in blood pressure and arrhythmias. After being taken therapeutically, commonly prescribed β blockers may make their way to coastal habitats via discharge from waste water treatment plants (WWTP) posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular responses of three commercially important marine bivalves - Eastern oysters, blue mussels and hard clams - upon exposure to two β blocker drugs, propranolol and metoprolol, and to find molecular initiating events (MIEs) indicative of the exposure. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas (HP) tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug. Tissues were bathed in 30 parts per thousand (ppt) filtered seawater, antibiotic mix, Leibovitz nutrient media, and the test drug. Exposures were conducted for 24 hours and samples were saved for cellular biomarker assays. A lysosomal destabilization assay, which is a marker of membrane damage, was also performed at the end of each exposure.

  11. Investigation of cellular responses upon interaction with silver nanoparticles

    PubMed Central

    Subbiah, Ramesh; Jeon, Seong Beom; Park, Kwideok; Ahn, Sang Jung; Yun, Kyusik

    2015-01-01

    In order for nanoparticles (NPs) to be applied in the biomedical field, a thorough investigation of their interactions with biological systems is required. Although this is a growing area of research, there is a paucity of comprehensive data in cell-based studies. To address this, we analyzed the physicomechanical responses of human alveolar epithelial cells (A549), mouse fibroblasts (NIH3T3), and human bone marrow stromal cells (HS-5), following their interaction with silver nanoparticles (AgNPs). When compared with kanamycin, AgNPs exhibited moderate antibacterial activity. Cell viability ranged from ≤80% at a high AgNPs dose (40 µg/mL) to >95% at a low dose (10 µg/mL). We also used atomic force microscopy-coupled force spectroscopy to evaluate the biophysical and biomechanical properties of cells. This revealed that AgNPs treatment increased the surface roughness (P<0.001) and stiffness (P<0.001) of cells. Certain cellular changes are likely due to interaction of the AgNPs with the cell surface. The degree to which cellular morphology was altered directly proportional to the level of AgNP-induced cytotoxicity. Together, these data suggest that atomic force microscopy can be used as a potential tool to develop a biomechanics-based biomarker for the evaluation of NP-dependent cytotoxicity and cytopathology. PMID:26346562

  12. Improving Adaptive Learning Technology through the Use of Response Times

    ERIC Educational Resources Information Center

    Mettler, Everett; Massey, Christine M.; Kellman, Philip J.

    2011-01-01

    Adaptive learning techniques have typically scheduled practice using learners' accuracy and item presentation history. We describe an adaptive learning system (Adaptive Response Time Based Sequencing--ARTS) that uses both accuracy and response time (RT) as direct inputs into sequencing. Response times are used to assess learning strength and…

  13. Cellular response to titanium discs coated with polyelectrolyte multilayer films

    NASA Astrophysics Data System (ADS)

    Zhan, Jing; Luo, Qiao-jie; Huang, Ying; Li, Xiao-dong

    2014-09-01

    The purpose of this study was to investigate the effects of polyelectrolyte multilayer (PEM) coatings on the biological behavior of titanium (Ti) substrates. Collagen type Ι/hyaluronic acid (Col/HA) and chitosan/hyaluronic acid (Chi/HA) multilayer PEM coatings were introduced onto Ti substrates using layer-by-layer assembly. Contact angle instruments and quartz crystal microbalance were used for film characterization. The results obtained showed that both Col/HA and Chi/HA surfaces had high hydrophilicity and promoted cell adhesion in MC3T3-E1 pre-osteoblast and human gingival fibroblast cells. In addition, the synthesis of function-related proteins and gene expression levels in both MC3T3-E1 and fibroblast cells was higher for the Col/HA coating compared with the Chi/HA coating, indicating better cellular response to the Col/HA coating.

  14. Cellular response of titanium and its alloys as implants.

    PubMed

    Bhola, Rahul; Bhola, Shaily M; Mishra, Brajendra; Ayers, Reed; Olson, David L; Ohno, Timothy

    2011-08-01

    The cellular response of osteocytes to commercially pure titanium (α) and its alloys (α + β and β) has been tested in a culture media, and the results have been supplemented by analyses from various techniques such as inductively coupled plasma atomic emission spectroscopic (ICP-AES) analysis, X-ray photoemission spectroscopy (XPS), scanning electron microscopy (SEM), metallography, and electrochemical measurements. These results have been correlated with respect to the presence of various alloying elements in these alloys to qualify them for human application. The newer β alloys have been examined for their potential use as implants. These results serve as a preliminary baseline to characterize the best alloy system for a comprehensive long-term investigation.

  15. Reduced cellular immune response in social insect lineages

    PubMed Central

    Sconiers, Warren B.; Frank, Steven D.; Dunn, Robert R.; Tarpy, David R.

    2016-01-01

    Social living poses challenges for individual fitness because of the increased risk of disease transmission among conspecifics. Despite this challenge, sociality is an evolutionarily successful lifestyle, occurring in the most abundant and diverse group of organisms on earth—the social insects. Two contrasting hypotheses predict the evolutionary consequences of sociality on immune systems. The social group hypothesis posits that sociality leads to stronger individual immune systems because of the higher risk of disease transmission in social species. By contrast, the relaxed selection hypothesis proposes that social species have evolved behavioural immune defences that lower disease risk within the group, resulting in lower immunity at the individual level. We tested these hypotheses by measuring the encapsulation response in 11 eusocial and non-eusocial insect lineages. We built phylogenetic mixed linear models to investigate the effect of behaviour, colony size and body size on cellular immune response. We found a significantly negative effect of colony size on encapsulation response (Markov chain Monte Carlo generalized linear mixed model (mcmcGLMM) p < 0.05; phylogenetic generalized least squares (PGLS) p < 0.05). Our findings suggest that insects living in large societies may rely more on behavioural mechanisms, such as hygienic behaviours, than on immune function to reduce the risk of disease transmission among nest-mates. PMID:26961895

  16. MOF maintains transcriptional programs regulating cellular stress response.

    PubMed

    Sheikh, B N; Bechtel-Walz, W; Lucci, J; Karpiuk, O; Hild, I; Hartleben, B; Vornweg, J; Helmstädter, M; Sahyoun, A H; Bhardwaj, V; Stehle, T; Diehl, S; Kretz, O; Voss, A K; Thomas, T; Manke, T; Huber, T B; Akhtar, A

    2016-05-01

    MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions. However, in response to injury, MOF is absolutely critical for podocyte maintenance in vivo. Consistently, we detect defective nuclear, endoplasmic reticulum and Golgi structures, as well as presence of multivesicular bodies in vivo in podocytes lacking Mof following injury. Undertaking genome-wide expression analysis of podocytes, we uncover several MOF-regulated pathways required for stress response. We find that MOF, along with the members of the non-specific lethal but not the male-specific lethal complex, directly binds to genes encoding the lysosome, endocytosis and vacuole pathways, which are known regulators of podocyte maintenance. Thus, our work identifies MOF as a key regulator of cellular stress response in glomerular podocytes.

  17. Biophysical responses upon the interaction of nanomaterials with cellular interfaces.

    PubMed

    Wu, Yun-Long; Putcha, Nirupama; Ng, Kee Woei; Leong, David Tai; Lim, Chwee Teck; Loo, Say Chye Joachim; Chen, Xiaodong

    2013-03-19

    The explosion of study of nanomaterials in biological applications (the nano-bio interface) can be ascribed to nanomaterials' growing importance in diagnostics, therapeutics, theranostics (therapeutic diagnostics), and targeted modulation of cellular processes. However, a growing number of critics have raised concerns over the potential risks of nanomaterials to human health and safety. It is essential to understand nanomaterials' potential toxicity before they are tested in humans. These risks are complicated to unravel, however, because of the complexity of cells and their nanoscale macromolecular components, which enable cells to sense and respond to environmental cues, including nanomaterials. In this Account, we explore these risks from the perspective of the biophysical interactions between nanomaterials and cells. Biophysical responses to the uptake of nanomaterials can include conformational changes in biomolecules like DNA and proteins, and changes to the cellular membrane and the cytoskeleton. Changes to the latter two, in particular, can induce changes in cell elasticity, morphology, motility, adhesion, and invasion. This Account reviews what is known about cells' biophysical responses to the uptake of the most widely studied and used nanoparticles, such as carbon-based, metal, metal-oxide, and semiconductor nanomaterials. We postulate that the biophysical structure impairment induced by nanomaterials is one of the key causes of nanotoxicity. The disruption of cellular structures is affected by the size, shape, and chemical composition of nanomaterials, which are also determining factors of nanotoxicity. Currently, popular nanotoxicity characterizations, such as the MTT and lactate dehydrogenase (LDH) assays, only provide end-point results through chemical reactions. Focusing on biophysical structural changes induced by nanomaterials, possibly in real-time, could deepen our understanding of the normal and altered states of subcellular structures and

  18. TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress.

    PubMed

    Raben, Nina; Puertollano, Rosa

    2016-10-06

    In recent years, our vision of lysosomes has drastically changed. Formerly considered to be mere degradative compartments, they are now recognized as key players in many cellular processes. The ability of lysosomes to respond to different stimuli revealed a complex and coordinated regulation of lysosomal gene expression. This review discusses the participation of the transcription factors TFEB and TFE3 in the regulation of lysosomal function and biogenesis, as well as the role of the lysosomal pathway in cellular adaptation to a variety of stress conditions, including nutrient deprivation, mitochondrial dysfunction, protein misfolding, and pathogen infection. We also describe how cancer cells make use of TFEB and TFE3 to promote their own survival and highlight the potential of these transcription factors as therapeutic targets for the treatment of neurological and lysosomal diseases.

  19. Ethanol Cellular Defense Induce Unfolded Protein Response in Yeast

    PubMed Central

    Pérez-Torrado, Roberto

    2016-01-01

    Ethanol is a valuable industrial product and a common metabolite used by many cell types. However, this molecule produces high levels of cytotoxicity affecting cellular performance at several levels. In the presence of ethanol, cells must adjust some of their components, such as the membrane lipids to maintain homeostasis. In the case of microorganism as Saccharomyces cerevisiae, ethanol is one of the principal products of their metabolism and is the main stress factor during fermentation. Although, many efforts have been made, mechanisms of ethanol tolerance are not fully understood and very little evidence is available to date for specific signaling by ethanol in the cell. This work studied two S. cerevisiae strains, CECT10094, and Temohaya-MI26, isolated from flor wine and agave fermentation (a traditional fermentation from Mexico) respectively, which differ in ethanol tolerance, in order to understand the molecular mechanisms underlying the ethanol stress response and the reasons for different ethanol tolerance. The transcriptome was analyzed after ethanol stress and, among others, an increased activation of genes related with the unfolded protein response (UPR) and its transcription factor, Hac1p, was observed in the tolerant strain CECT10094. We observed that this strain also resist more UPR agents than Temohaya-MI26 and the UPR-ethanol stress correlation was corroborated observing growth of 15 more strains and discarding UPR correlation with other stresses as thermal or oxidative stress. Furthermore, higher activation of UPR pathway in the tolerant strain CECT10094 was observed using a UPR mCherry reporter. Finally, we observed UPR activation in response to ethanol stress in other S. cerevisiae ethanol tolerant strains as the wine strains T73 and EC1118. This work demonstrates that the UPR pathway is activated under ethanol stress occurring in a standard fermentation and links this response to an enhanced ethanol tolerance. Thus, our data suggest that there

  20. Local adaptation in transgenerational responses to predators

    PubMed Central

    Walsh, Matthew R.; Castoe, Todd; Holmes, Julian; Packer, Michelle; Biles, Kelsey; Walsh, Melissa; Munch, Stephan B.; Post, David M.

    2016-01-01

    Environmental signals can induce phenotypic changes that span multiple generations. Along with phenotypic responses that occur during development (i.e. ‘within-generation’ plasticity), such ‘transgenerational plasticity’ (TGP) has been documented in a diverse array of taxa spanning many environmental perturbations. New theory predicts that temporal stability is a key driver of the evolution of TGP. We tested this prediction using natural populations of zooplankton from lakes in Connecticut that span a large gradient in the temporal dynamics of predator-induced mortality. We reared more than 120 clones of Daphnia ambigua from nine lakes for multiple generations in the presence/absence of predator cues. We found that temporal variation in mortality selects for within-generation plasticity while consistently strong (or weak) mortality selects for increased TGP. Such results provide us the first evidence for local adaptation in TGP and argue that divergent ecological conditions select for phenotypic responses within and across generations. PMID:26817775

  1. Transcription Factors in the Cellular Response to Charged Particle Exposure

    PubMed Central

    Hellweg, Christine E.; Spitta, Luis F.; Henschenmacher, Bernd; Diegeler, Sebastian; Baumstark-Khan, Christa

    2016-01-01

    Charged particles, such as carbon ions, bear the promise of a more effective cancer therapy. In human spaceflight, exposure to charged particles represents an important risk factor for chronic and late effects such as cancer. Biological effects elicited by charged particle exposure depend on their characteristics, e.g., on linear energy transfer (LET). For diverse outcomes (cell death, mutation, transformation, and cell-cycle arrest), an LET dependency of the effect size was observed. These outcomes result from activation of a complex network of signaling pathways in the DNA damage response, which result in cell-protective (DNA repair and cell-cycle arrest) or cell-destructive (cell death) reactions. Triggering of these pathways converges among others in the activation of transcription factors, such as p53, nuclear factor κB (NF-κB), activated protein 1 (AP-1), nuclear erythroid-derived 2-related factor 2 (Nrf2), and cAMP responsive element binding protein (CREB). Depending on dose, radiation quality, and tissue, p53 induces apoptosis or cell-cycle arrest. In low LET radiation therapy, p53 mutations are often associated with therapy resistance, while the outcome of carbon ion therapy seems to be independent of the tumor’s p53 status. NF-κB is a central transcription factor in the immune system and exhibits pro-survival effects. Both p53 and NF-κB are activated after ionizing radiation exposure in an ataxia telangiectasia mutated (ATM)-dependent manner. The NF-κB activation was shown to strongly depend on charged particles’ LET, with a maximal activation in the LET range of 90–300 keV/μm. AP-1 controls proliferation, senescence, differentiation, and apoptosis. Nrf2 can induce cellular antioxidant defense systems, CREB might also be involved in survival responses. The extent of activation of these transcription factors by charged particles and their interaction in the cellular radiation response greatly influences the destiny of the irradiated and also

  2. Formation and Regulation of Adaptive Response in Nematode Caenorhabditis elegans

    PubMed Central

    Zhao, Y.-L.; Wang, D.-Y.

    2012-01-01

    All organisms respond to environmental stresses (e.g., heavy metal, heat, UV irradiation, hyperoxia, food limitation, etc.) with coordinated adjustments in order to deal with the consequences and/or injuries caused by the severe stress. The nematode Caenorhabditis elegans often exerts adaptive responses if preconditioned with low concentrations of agents or stressor. In C. elegans, three types of adaptive responses can be formed: hormesis, cross-adaptation, and dietary restriction. Several factors influence the formation of adaptive responses in nematodes, and some mechanisms can explain their response formation. In particular, antioxidation system, heat-shock proteins, metallothioneins, glutathione, signaling transduction, and metabolic signals may play important roles in regulating the formation of adaptive responses. In this paper, we summarize the published evidence demonstrating that several types of adaptive responses have converged in C. elegans and discussed some possible alternative theories explaining the adaptive response control. PMID:22997543

  3. Dichotomy of protective cellular immune responses to human visceral leishmaniasis.

    PubMed

    Khalil, E A G; Ayed, N B; Musa, A M; Ibrahim, M E; Mukhtar, M M; Zijlstra, E E; Elhassan, I M; Smith, P G; Kieny, P M; Ghalib, H W; Zicker, F; Modabber, F; Elhassan, A M

    2005-05-01

    cellular immune responses to human VL are dichotomatous, and that IFN-gamma production and the LST response are not in a causal relationship. Following vaccination and probably cure of VL infection, the IFN-gamma response declines with time while the LST response persists. LST is a simple test that can be used to assess candidate vaccine efficacy.

  4. Pairing of heterochromatin in response to cellular stress

    SciTech Connect

    Abdel-Halim, H.I.; Mullenders, L.H.F. . E-mail: L.Mullenders@lumc.nl; Boei, J.J.W.A.

    2006-07-01

    We previously reported that exposure of human cells to DNA-damaging agents (X-rays and mitomycin C (MMC)) induces pairing of the homologous paracentromeric heterochromatin of chromosome 9 (9q12-13). Here, we show that UV irradiation and also heat shock treatment of human cells lead to similar effects. Since the various agents induce very different types and frequencies of damage to cellular constituents, the data suggest a general stress response as the underlying mechanism. Moreover, local UV irradiation experiments revealed that pairing of heterochromatin is an event that can be triggered without induction of DNA damage in the heterochromatic sequences. The repair deficient xeroderma pigmentosum cells (group F) previously shown to fail pairing after MMC displayed elevated pairing after heat shock treatment but not after UV exposure. Taken together, the present results indicate that pairing of heterochromatin following exposure to DNA-damaging agents is initiated by a general stress response and that the sensing of stress or the maintenance of the paired status of the heterochromatin might be dependent on DNA repair.

  5. Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

    PubMed Central

    Roth, Hanna; Magg, Vera; Uch, Fabian; Mutz, Pascal; Klein, Philipp; Haneke, Katharina; Lohmann, Volker; Bartenschlager, Ralf; Fackler, Oliver T.; Locker, Nicolas; Stoecklin, Georg

    2017-01-01

    ABSTRACT As obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells also synthesize antiviral proteins to limit virus infection. Modulation of host cell translation therefore represents a frequent strategy by which viruses optimize their replication and spread. Here we sought to define how host cell translation is regulated during infection of human cells with dengue virus (DENV) and Zika virus (ZIKV), two positive-strand RNA flaviviruses. Polysome profiling and analysis of de novo protein synthesis revealed that flavivirus infection causes potent repression of host cell translation, while synthesis of viral proteins remains efficient. Selective repression of host cell translation was mediated by the DENV polyprotein at the level of translation initiation. In addition, DENV and ZIKV infection suppressed host cell stress responses such as the formation of stress granules and phosphorylation of the translation initiation factor eIF2α (α subunit of eukaryotic initiation factor 2). Mechanistic analyses revealed that translation repression was uncoupled from the disruption of stress granule formation and eIF2α signaling. Rather, DENV infection induced p38-Mnk1 signaling that resulted in the phosphorylation of the eukaryotic translation initiation factor eIF4E and was essential for the efficient production of virus particles. Together, these results identify the uncoupling of translation suppression from the cellular stress responses as a conserved strategy by which flaviviruses ensure efficient replication in human cells. PMID:28074025

  6. Cellular Response of Campylobacter jejuni to Trisodium Phosphate

    PubMed Central

    Riedel, Charlotte Tandrup; Cohn, Marianne Thorup; Stabler, Richard A.; Wren, Brendan

    2012-01-01

    The highly alkaline compound trisodium phosphate (TSP) is used as an intervention to reduce the load of Campylobacter on poultry meat in U.S. poultry slaughter plants. The aim of the present study was to investigate the cellular responses of Campylobacter jejuni NCTC11168 when exposed to sublethal concentrations of TSP. Preexposure of C. jejuni to TSP resulted in a significant increase in heat sensitivity, suggesting that a combined heat and TSP treatment may increase reduction of C. jejuni. A microarray analysis identified a limited number of genes that were differently expressed after sublethal TSP exposure; however, the response was mainly associated with ion transport processes. C. jejuni NCTC11168 nhaA1 (Cj1655c) and nhaA2 (Cj1654c), which encode orthologues to the Escherichia coli NhaA cation/proton antiporter, were able to partially restore TSP, alkaline, and sodium resistance phenotypes to an E. coli cation/proton antiporter mutant. In addition, inhibition of resistance-nodulation-cell division (RND) multidrug efflux pumps by the inhibitor PaβN (Phe-Arg β-naphthylamide dihydrochloride) decreased tolerance to sublethal TSP. Therefore, we propose that NhaA1/NhaA2 cation/proton antiporters and RND multidrug efflux pumps function in tolerance to sublethal TSP exposure in C. jejuni. PMID:22194296

  7. Adaptive cellular protection against UVA-1-induced lipid peroxidation in human dermal fibroblasts shows donor-to-donor variability and is glutathione dependent.

    PubMed

    Schneider, Lars Alexander; Dissemond, Joachim; Brenneisen, Peter; Hainzl, Adelheid; Briviba, Karlis; Wlaschek, Meinhard; Scharffetter-Kochanek, Karin

    2006-01-01

    Photo-oxidative stress and subsequent lipid peroxidation (LPO) is one of the major mechanisms of UVA-related skin pathology. The skin's protection system against photo-oxidative stress involves low molecular scavengers as well as highly specialised antioxidant enzymes like glutathione peroxidase (GPX). Against repetitive UVA-1 exposures in vitro it is partly adaptive, as recent studies have shown exemplarily for antioxidant enzymes. We now investigated in vitro by repetitively irradiating human dermal fibroblasts with UVA-1 whether this adaptive response might reflect itself in reduced cellular membrane damage, that is, LPO. Our experiments show that the degree of cellular protection against LPO and the adaptive potential of the cells against a repetitive UVA-1 exposure varies from donor-to-donor and depends highly on glutathione.

  8. Adaptive acidification tolerance response of Salmonella typhimurium.

    PubMed

    Foster, J W; Hall, H K

    1990-02-01

    Salmonella typhimurium can encounter a wide variety of environments during its life cycle. One component of the environment which will fluctuate widely is pH. In nature, S. typhimurium can experience and survive dramatic acid stresses that occur in diverse ecological niches ranging from pond water to phagolysosomes. However, in vitro the organism is very sensitive to acid. To provide an explanation for how this organism survives acid in natural environments, the adaptive ability of S. typhimurium to become acid tolerant was tested. Logarithmically grown cells (pH 7.6) shifted to mild acid (pH 5.8) for one doubling as an adaptive procedure were 100 to 1,000 times more resistant to subsequent strong acid challenge (pH 3.3) than were unadapted cells shifted directly from pH 7.6 to 3.3. This acidification tolerance response required protein synthesis and appears to be a specific defense mechanism for acid. No cross protection was noted for hydrogen peroxide, SOS, or heat shock. Two-dimensional polyacrylamide gel electrophoretic analysis of acid-regulated polypeptides revealed 18 proteins with altered expression, 6 of which were repressed while 12 were induced by mild acid shifts. An avirulent phoP mutant was 1,000-fold more sensitive to acid than its virulent phoP+ parent, suggesting a correlation between acid tolerance and virulence. The Mg2(+)-dependent proton-translocating ATPase was also found to play an important role in acid tolerance. Mutants (unc) lacking this activity were unable to mount an acid tolerance response and were extremely acid sensitive. In contrast to these acid-sensitive mutants, a constitutively acid-tolerant mutant (atr) was isolated from wild-type LT2 after prolonged acid exposure. This mutant overexpressed several acidification tolerance response polypeptides. The data presented reveal an important acidification defense modulon with broad significance toward survival in biologically hostile environments.

  9. Cellular Response of Sinorhizobium sp. Strain A2 during Arsenite Oxidation

    PubMed Central

    Fukushima, Koh; Huang, He; Hamamura, Natsuko

    2015-01-01

    Arsenic (As) is a widely distributed toxic element in the environment and microorganisms have developed resistance mechanisms in order to tolerate it. The cellular response of the chemoorganotrophic arsenite (As[III])-oxidizing α-Proteobacteria, Sinorhizobium sp. strain A2, to arsenic was examined in the present study. Several proteins associated with arsenite oxidase and As resistance were shown to be accumulated in the presence of As(III). A shift in central carbon metabolism from the tricarboxylic acid pathway to glyoxylate pathway was also observed in response to oxidative stress. Our results revealed the strategy of the As(III)-oxidizing Sinorhizobium strain to mitigate arsenic toxicity and oxidative damage by multiple metabolic adaptations. PMID:26477790

  10. Radio-Adaptive Responses of Mouse Myocardiocytes

    NASA Technical Reports Server (NTRS)

    Seawright, John W.; Westby, Christian M.

    2011-01-01

    One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) Cs-137 gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Pro-apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value . 0.003) 4hr after H, but not after 4hr LH when compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive

  11. New insights into the cellular response to radiation using microbeams

    NASA Astrophysics Data System (ADS)

    Folkard, Melvyn; Prise, Kevin; Schettino, Giuseppe; Shao, Chunlin; Gilchrist, Stuart; Vojnovic, Boris

    2005-04-01

    Micro-irradiation techniques continue to be highly relevant to a number of radiobiological studies, due to their ability to deliver precise doses of radiation to selected individual cells (or sub-cellular targets) in vitro. The Gray cancer institute (GCI) ion microbeam uses a 1 μm diameter bore glass capillary to vertically collimate protons, or helium ions accelerated by a 4 MV Van de Graaff. Using 3He2+ ions, 99% of cells are targeted with an accuracy of ±2 μm, and with a particle counting accuracy >99%. Using automated cell finding and irradiation procedures, up to 10,000 cells per hour can be individually irradiated. Microbeams are now being used to study a number of novel 'non-targeted' responses that do not follow the standard radiation model based on direct DNA damage and are now known to occur when living cells and tissues are irradiated. One such response is the so-called 'bystander effect' where unirradiated cells are damaged through signalling pathways initiated by a nearby irradiated cell. This effect predominates at low doses and profoundly challenges our understanding of environmental radiation risk. Furthermore, we now have evidence that simple molecules (such as nitric oxide) are involved in the signalling process, such that it may be possible to chemically influence the bystander response. If so, then this could eventually lead to improvements in the treatment of cancer by radiotherapy. Other studies have shown that the bystander effect is induced with equal effectiveness if either the nucleus or the cytoplasm of a cell is targeted.

  12. A Computational Model of Cellular Response to Modulated Radiation Fields

    SciTech Connect

    McMahon, Stephen J.; Butterworth, Karl T.; McGarry, Conor K.; Trainor, Colman; O'Sullivan, Joe M.; Hounsell, Alan R.; Prise, Kevin M.

    2012-09-01

    Purpose: To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies. Materials and Methods: A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields. Results: The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses. Conclusions: The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2 Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable in vivo.

  13. Cellular basis for the olfactory response to nicotine.

    PubMed

    Bryant, Bruce; Xu, Jiang; Audige, Valery; Lischka, Fritz W; Rawson, Nancy E

    2010-03-17

    Smokers regulate their smoking behavior on the basis of sensory stimuli independently of the pharmacological effects of nicotine (Rose J. E., et al. (1993) Pharmacol., Biochem. Behav.44 (4), 891-900). A better understanding of sensory mechanisms underlying smoking behavior may help to develop more effective smoking alternatives. Olfactory stimulation by nicotine makes up a considerable part of the flavor of tobacco smoke, yet our understanding of the cellular mechanisms responsible for olfactory detection of nicotine remains incomplete. We used biophysical methods to characterize the nicotine sensitivity and response mechanisms of neurons from olfactory epithelium. In view of substantial differences in the olfactory receptor repertoire between rodent and human (Mombaerts P. (1999) Annu. Rev. Neurosci.22, 487-509), we studied biopsied human olfactory sensory neurons (OSNs), cultured human olfactory cells (Gomez G., et al. (2000) J. Neurosci. Res.62 (5), 737-749), and rat olfactory neurons. Rat and human OSNs responded to S(-)-nicotine with a concentration dependent influx of calcium and activation of adenylate cyclase. Some rat OSNs displayed some stereoselectivity, with neurons responding to either enantiomer alone or to both. Freshly biopsied and primary cultured human olfactory neurons were less stereoselective. Nicotinic cholinergic antagonists had no effect on the responses of rat or human OSNs to nicotine. Patch clamp recording of rat OSNs revealed a nicotine-activated, calcium-sensitive nonspecific cation channel. These results indicate that nicotine activates a canonical olfactory receptor pathway rather than nicotinic cholinergic receptors on OSNs. Further, because the nicotine-sensitive mechanisms of rodents appear generally similar to those of humans, this animal model is an appropriate one for studies of nicotine sensation.

  14. Cellular unfolded protein response against viruses used in gene therapy

    PubMed Central

    Sen, Dwaipayan; Balakrishnan, Balaji; Jayandharan, Giridhara R.

    2014-01-01

    Viruses are excellent vehicles for gene therapy due to their natural ability to infect and deliver the cargo to specific tissues with high efficiency. Although such vectors are usually “gutted” and are replication defective, they are subjected to clearance by the host cells by immune recognition and destruction. Unfolded protein response (UPR) is a naturally evolved cyto-protective signaling pathway which is triggered due to endoplasmic reticulum (ER) stress caused by accumulation of unfolded/misfolded proteins in its lumen. The UPR signaling consists of three signaling pathways, namely PKR-like ER kinase, activating transcription factor 6, and inositol-requiring protein-1. Once activated, UPR triggers the production of ER molecular chaperones and stress response proteins to help reduce the protein load within the ER. This occurs by degradation of the misfolded proteins and ensues in the arrest of protein translation machinery. If the burden of protein load in ER is beyond its processing capacity, UPR can activate pro-apoptotic pathways or autophagy leading to cell death. Viruses are naturally evolved in hijacking the host cellular translation machinery to generate a large amount of proteins. This phenomenon disrupts ER homeostasis and leads to ER stress. Alternatively, in the case of gutted vectors used in gene therapy, the excess load of recombinant vectors administered and encountered by the cell can trigger UPR. Thus, in the context of gene therapy, UPR becomes a major roadblock that can potentially trigger inflammatory responses against the vectors and reduce the efficiency of gene transfer. PMID:24904562

  15. Chlamydia trachomatis: Protective Adaptive Responses and Prospects for a Vaccine.

    PubMed

    Poston, Taylor B; Darville, Toni

    2016-04-01

    Chlamydia trachomatis is the most common cause of sexually transmitted bacterial infection globally. These infections translate to a significant public health burden, particularly women's healthcare costs due to serious disease sequelae such as pelvic inflammatory disease (PID), tubal factor infertility, chronic pelvic pain, and ectopic pregnancy. There is no evidence that natural immunity can provide complete, long-term protection necessary to prevent chronic pathology, making human vaccine development critical. Vaccine design will require careful consideration of protective versus pathological host-response mechanisms in concert with elucidation of optimal antigens and adjuvants. Evidence suggests that a Th1 response, facilitated by IFN-γ-producing CD4 T cells, will be instrumental in generating long-term, sterilizing immunity. Although the role of antibodies is not completely understood, they have exhibited a protective effect by enhancing chlamydial clearance. Future work will require investigation of broadly neutralizing antibodies and antibody-augmented cellular immunity to successfully design a vaccine that potently elicits both arms of the immune response. Sterilizing immunity is the ultimate goal. However, vaccine-induced partial immunity that prevents upper genital tract infection and inflammation would be cost-effective compared to current screening and treatment strategies. In this chapter, we examine evidence from animal and human studies demonstrating protective adaptive immune responses to Chlamydia and discuss future challenges and prospects for vaccine development.

  16. Extreme cellular adaptations and cell differentiation required by a cyanobacterium for carbonate excavation.

    PubMed

    Guida, Brandon Scott; Garcia-Pichel, Ferran

    2016-05-17

    Some cyanobacteria, known as euendoliths, excavate and grow into calcium carbonates, with their activity leading to significant marine and terrestrial carbonate erosion and to deleterious effects on coral reef and bivalve ecology. Despite their environmental relevance, the mechanisms by which they can bore have remained elusive and paradoxical, in that, as oxygenic phototrophs, cyanobacteria tend to alkalinize their surroundings, which will encourage carbonate precipitation, not dissolution. Therefore, cyanobacteria must rely on unique adaptations to bore. Studies with the filamentous euendolith, Mastigocoleus testarum, indicated that excavation requires both cellular energy and transcellular calcium transport, mediated by P-type ATPases, but the cellular basis for this phenomenon remains obscure. We present evidence that excavation in M. testarum involves two unique cellular adaptations. Long-range calcium transport is based on active pumping at multiple cells along boring filaments, orchestrated by the preferential localization of calcium ATPases at one cell pole, in a ring pattern, facing the cross-walls, and by repeating this placement and polarity, a pattern that breaks at branching and apical cells. In addition, M. testarum differentiates specialized cells we call calcicytes, that which accumulate calcium at concentrations more than 500-fold those found in other cyanobacteria, concomitantly and drastically lowering photosynthetic pigments and enduring severe cytoplasmatic alkalinization. Calcicytes occur commonly, but not exclusively, in apical parts of the filaments distal to the excavation front. We suggest that calcicytes allow for fast calcium flow at low, nontoxic concentrations through undifferentiated cells by providing buffering storage for excess calcium before final excretion to the outside medium.

  17. Extreme cellular adaptations and cell differentiation required by a cyanobacterium for carbonate excavation

    PubMed Central

    Guida, Brandon Scott; Garcia-Pichel, Ferran

    2016-01-01

    Some cyanobacteria, known as euendoliths, excavate and grow into calcium carbonates, with their activity leading to significant marine and terrestrial carbonate erosion and to deleterious effects on coral reef and bivalve ecology. Despite their environmental relevance, the mechanisms by which they can bore have remained elusive and paradoxical, in that, as oxygenic phototrophs, cyanobacteria tend to alkalinize their surroundings, which will encourage carbonate precipitation, not dissolution. Therefore, cyanobacteria must rely on unique adaptations to bore. Studies with the filamentous euendolith, Mastigocoleus testarum, indicated that excavation requires both cellular energy and transcellular calcium transport, mediated by P-type ATPases, but the cellular basis for this phenomenon remains obscure. We present evidence that excavation in M. testarum involves two unique cellular adaptations. Long-range calcium transport is based on active pumping at multiple cells along boring filaments, orchestrated by the preferential localization of calcium ATPases at one cell pole, in a ring pattern, facing the cross-walls, and by repeating this placement and polarity, a pattern that breaks at branching and apical cells. In addition, M. testarum differentiates specialized cells we call calcicytes, that which accumulate calcium at concentrations more than 500-fold those found in other cyanobacteria, concomitantly and drastically lowering photosynthetic pigments and enduring severe cytoplasmatic alkalinization. Calcicytes occur commonly, but not exclusively, in apical parts of the filaments distal to the excavation front. We suggest that calcicytes allow for fast calcium flow at low, nontoxic concentrations through undifferentiated cells by providing buffering storage for excess calcium before final excretion to the outside medium. PMID:27140633

  18. Global cellular response to chemotherapy-induced apoptosis

    PubMed Central

    Wiita, Arun P; Ziv, Etay; Wiita, Paul J; Urisman, Anatoly; Julien, Olivier; Burlingame, Alma L; Weissman, Jonathan S; Wells, James A

    2013-01-01

    How cancer cells globally struggle with a chemotherapeutic insult before succumbing to apoptosis is largely unknown. Here we use an integrated systems-level examination of transcription, translation, and proteolysis to understand these events central to cancer treatment. As a model we study myeloma cells exposed to the proteasome inhibitor bortezomib, a first-line therapy. Despite robust transcriptional changes, unbiased quantitative proteomics detects production of only a few critical anti-apoptotic proteins against a background of general translation inhibition. Simultaneous ribosome profiling further reveals potential translational regulation of stress response genes. Once the apoptotic machinery is engaged, degradation by caspases is largely independent of upstream bortezomib effects. Moreover, previously uncharacterized non-caspase proteolytic events also participate in cellular deconstruction. Our systems-level data also support co-targeting the anti-apoptotic regulator HSF1 to promote cell death by bortezomib. This integrated approach offers unique, in-depth insight into apoptotic dynamics that may prove important to preclinical evaluation of any anti-cancer compound. DOI: http://dx.doi.org/10.7554/eLife.01236.001 PMID:24171104

  19. From Cellular Attractor Selection to Adaptive Signal Control for Traffic Networks

    PubMed Central

    Tian, Daxin; Zhou, Jianshan; Sheng, Zhengguo; Wang, Yunpeng; Ma, Jianming

    2016-01-01

    The management of varying traffic flows essentially depends on signal controls at intersections. However, design an optimal control that considers the dynamic nature of a traffic network and coordinates all intersections simultaneously in a centralized manner is computationally challenging. Inspired by the stable gene expressions of Escherichia coli in response to environmental changes, we explore the robustness and adaptability performance of signalized intersections by incorporating a biological mechanism in their control policies, specifically, the evolution of each intersection is induced by the dynamics governing an adaptive attractor selection in cells. We employ a mathematical model to capture such biological attractor selection and derive a generic, adaptive and distributed control algorithm which is capable of dynamically adapting signal operations for the entire dynamical traffic network. We show that the proposed scheme based on attractor selection can not only promote the balance of traffic loads on each link of the network but also allows the global network to accommodate dynamical traffic demands. Our work demonstrates the potential of bio-inspired intelligence emerging from cells and provides a deep understanding of adaptive attractor selection-based control formation that is useful to support the designs of adaptive optimization and control in other domains. PMID:26972968

  20. From Cellular Attractor Selection to Adaptive Signal Control for Traffic Networks

    NASA Astrophysics Data System (ADS)

    Tian, Daxin; Zhou, Jianshan; Sheng, Zhengguo; Wang, Yunpeng; Ma, Jianming

    2016-03-01

    The management of varying traffic flows essentially depends on signal controls at intersections. However, design an optimal control that considers the dynamic nature of a traffic network and coordinates all intersections simultaneously in a centralized manner is computationally challenging. Inspired by the stable gene expressions of Escherichia coli in response to environmental changes, we explore the robustness and adaptability performance of signalized intersections by incorporating a biological mechanism in their control policies, specifically, the evolution of each intersection is induced by the dynamics governing an adaptive attractor selection in cells. We employ a mathematical model to capture such biological attractor selection and derive a generic, adaptive and distributed control algorithm which is capable of dynamically adapting signal operations for the entire dynamical traffic network. We show that the proposed scheme based on attractor selection can not only promote the balance of traffic loads on each link of the network but also allows the global network to accommodate dynamical traffic demands. Our work demonstrates the potential of bio-inspired intelligence emerging from cells and provides a deep understanding of adaptive attractor selection-based control formation that is useful to support the designs of adaptive optimization and control in other domains.

  1. The adaptive response in radiobiology: evolving insights and implications.

    PubMed Central

    Wolff, S

    1998-01-01

    The first of the regularly reproducible experiments to show that very low doses of ionizing radiation, like very low doses of chemical agents, could induce mechanisms whereby cells become better fit to cope with subsequent exposures to high doses were carried out on the induction of chromosome aberrations in cultures of human lymphocytes. If cells that had been exposed to a very low dose (1 cGy) of X rays were subsequently exposed to a relatively high dose (1 Gy), approximately half as many chromosome breaks were induced. Subsequent experiments showed that this adaptive response to low doses requires a certain minimal dose before it becomes active; occurs only within a relatively small window of dose; is dose-rate dependent; and depends on the genetic constitution of the people or animals exposed, with some being unresponsive. It was further shown that the response to the low-dose preexposure was not instantaneous but took approximately 4 to 6 hr to become fully active, and could be prevented if during this period protein synthesis was inhibited, i.e., a necessary protein (enzyme) was being induced. In fact, subsequent experiments with two-dimensional gel electrophoresis showed new proteins in cells irradiated with 1 to 2 cGy. The adaptation induced by low doses of radiation was therefore attributed to the induction of a novel efficient chromosome break repair mechanism that if active at the time of challenge with high doses would lead to less residual damage. This hypothesis was strengthened by a series of experiments in which it was found that inhibitors of poly(ADP-ribose)polymerase, an enzyme implicated in DNA strand break rejoining, could prevent the adaptive response. Although the phenomenon is well established in cellular systems, it is still problematical as to whether or not it will have any utility in establishing risks of ionizing radiation to humans. Newer experiments have now been carried out on the mechanisms underlying the effect and whether or not

  2. The cellular immune response plays an important role in protecting against dengue virus in the mouse encephalitis model.

    PubMed

    Gil, Lázaro; López, Carlos; Blanco, Aracelys; Lazo, Laura; Martín, Jorge; Valdés, Iris; Romero, Yaremis; Figueroa, Yassel; Guillén, Gerardo; Hermida, Lisset

    2009-02-01

    For several years, researchers have known that the generation of neutralizing antibodies is a prerequisite for attaining adequate protection against dengue virus. Nevertheless, the cellular immune response is the principal arm of the adaptive immune system against non-cytopathic viruses such as dengue, as once the virus enters into the cell it is necessary to destroy it to eliminate the virus. To define the role of the cellular immune response in the protection against dengue, we selected the mouse encephalitis model. Mice were immunized with a single dose of infective dengue 2 virus and different markers of both branches of the induced adaptive immunity were measured. Animals elicited a broad antibody response against the four dengue virus serotypes, but neutralizing activity was only detected against the homologous serotype. On the other hand, the splenocytes of the infected animals strongly proliferated after in vitro stimulation with the homologous virus, and specifically the CD8 T-cell subset was responsible for the secretion of the cytokine IFN-gamma. Finally, to define the role of T cells in in vivo protection, groups of animals were inoculated with the depleting monoclonal antibodies anti-CD4 or anti-CD8. Only depletion with anti-CD8 decreased to 50% the level of protection reached in the non-depleted mice. The present work constitutes the first report defining the role of the cellular immune response in protection against dengue virus in the mouse model.

  3. Differential influenza H1N1-specific humoral and cellular response kinetics in kidney transplant patients.

    PubMed

    Rambal, Vinay; Müller, Karin; Dang-Heine, Chantip; Sattler, Arne; Dziubianau, Mikalai; Weist, Benjamin; Luu, Si-Hong; Stoyanova, Alexandra; Nickel, Peter; Thiel, Andreas; Neumann, Avidan; Schweiger, Brunhilde; Reinke, Petra; Babel, Nina

    2014-02-01

    Renal transplant recipients (RTR) are considered at high risk for influenza-associated complications due to immunosuppression. The efficacy of standard influenza vaccination in RTRs is unclear. Hence, we evaluated activation of the adaptive immunity by the pandemic influenza A(H1N1) 2009 (A(H1N1)pdm09) vaccine in RTRs as compared to healthy controls. To determine cross-reactivity and/or bystander activation, seasonal trivalent influenza vaccine and tetanus/diphteria toxoid (TT/DT) vaccine-specific T cells along with allospecific T cells were quantified before and after A(H1N1)pdm09 vaccination. Vaccination-induced alloimmunity was additionally determined by quantifying serum creatinine and proinflammatory protein IP-10. Contrary to healthy controls, RTRs required a booster vaccination to achieve seroconversion (13.3 % day 21; 90 % day 90). In contrast to humoral immunity, sufficient A(H1N1)pdm09-specific T-cell responses were mounted in RTRs already after the first immunization with a magnitude comparable with healthy controls. Interestingly, vaccination simultaneously boosted T cells reacting to seasonal flu but not to TT/DT, suggesting cross-activation. No alloimmune effects were recorded. In conclusion, protective antibody responses required booster vaccination. However, sufficient cellular immunity is established already after the first vaccination, demonstrating differential kinetics of humoral and cellular immunity.

  4. ROS-triggered phosphorylation of complex II by Fgr kinase regulates cellular adaptation to fuel use.

    PubMed

    Acín-Pérez, Rebeca; Carrascoso, Isabel; Baixauli, Francesc; Roche-Molina, Marta; Latorre-Pellicer, Ana; Fernández-Silva, Patricio; Mittelbrunn, María; Sanchez-Madrid, Francisco; Pérez-Martos, Acisclo; Lowell, Clifford A; Manfredi, Giovanni; Enríquez, José Antonio

    2014-06-03

    Electron flux in the mitochondrial electron transport chain is determined by the superassembly of mitochondrial respiratory complexes. Different superassemblies are dedicated to receive electrons derived from NADH or FADH2, allowing cells to adapt to the particular NADH/FADH2 ratio generated from available fuel sources. When several fuels are available, cells adapt to the fuel best suited to their type or functional status (e.g., quiescent versus proliferative). We show that an appropriate proportion of superassemblies can be achieved by increasing CII activity through phosphorylation of the complex II catalytic subunit FpSDH. This phosphorylation is mediated by the tyrosine-kinase Fgr, which is activated by hydrogen peroxide. Ablation of Fgr or mutation of the FpSDH target tyrosine abolishes the capacity of mitochondria to adjust metabolism upon nutrient restriction, hypoxia/reoxygenation, and T cell activation, demonstrating the physiological relevance of this adaptive response.

  5. Cellular Response of Shewanella oneidensis to StrontiumStress

    SciTech Connect

    Brown, Steven D.; Martin, Madhavi; Deshpande, Sameer; Seal,Sudipta; Huang, Katherine; Alm, Eric; Yang, Yunfeng; Wu, Liyou; Yan,Tengfen; Liu, Xueduan; Arkin, Adam; Chourey, Karuna; Zhou, Jizhong; Thompson, Dorothea K.

    2007-03-30

    The physiology and transcriptome dynamics of the metalion-reducing bacterium Shewanella oneidensis strain MR-1 in response tononradioactive strontium (Sr) exposure were investigated. Studiesindicated that MR-1 was able to grow aerobically in complex medium in thepresence of 180 mMSrCl2 but showed severe growth inhibition at levelsabove that concentration. Temporal gene expression profiles weregenerated from aerobically grown, mid-exponential-phase MR-1 cellsshocked with 180 mM SrCl2 and analyzed for significant differences inmRNA abundance with reference to data for nonstressed MR-1 cells. Geneswith annotated functions in siderophore biosynthesis and iron transportwere among the most highly induced (>100-fold [P<0.05]) openreading frames in response to acute Sr stress, and a mutant(SO3032::pKNOCK) defective in siderophore production was found to behypersensitive to SrCl2 exposure, compared to parental and wild-typestrains. Transcripts encoding multidrug and heavy metal efflux pumps,proteins involved in osmotic adaptation, sulfate ABC transporters, andassimilative sulfur metabolism enzymes also were differentially expressedfollowing Sr exposure but at levels that were several orders of magnitudelower than those for iron transport genes. Precipitate formation wasobserved during aerobic growth of MR-1 in broth cultures amended with 50,100, or 150 mM SrCl2 but not in cultures of the SO3032::pKNOCK mutant orin the abiotic control. Chemical analysis of this precipitate usinglaser-induced breakdown spectroscopy and static secondary ion massspectrometry indicated extracellular solid-phase sequestration of Sr,with at least a portion of the heavy metal associated with carbonatephases.

  6. Thioredoxin-dependent Redox Regulation of Cellular Signaling and Stress Response through Reversible Oxidation of Methionines

    SciTech Connect

    Bigelow, Diana J.; Squier, Thomas C.

    2011-06-01

    Generation of reactive oxygen species (ROS) is a common feature of many forms of stress to which plants are exposed. Successful adaptation to changing environmental conditions requires sensitive sensors of ROS such as protein-bound methionines that are converted to their corresponding methionine sulfoxides, which in turn can influence cellular signaling pathways. Such a signaling protein is calmodulin, which represents an early and central point in calcium signaling pathways important to stress response in plants. We describe recent work elucidating fundamental mechanisms of reversible methionine oxidation within calmodulin, including the sensitivity of individual methionines within plant and animal calmodulin to ROS, the structural and functional consequences of their oxidation, and the interactions of oxidized calmodulin with methionine sulfoxide reductase enzymes.

  7. The primary cilium is a self-adaptable, integrating nexus for mechanical stimuli and cellular signaling.

    PubMed

    Nguyen, An M; Young, Y-N; Jacobs, Christopher R

    2015-11-24

    Mechanosensation is crucial for cells to sense and respond to mechanical signals within their local environment. While adaptation allows a sensor to be conditioned by stimuli within the environment and enables its operation in a wide range of stimuli intensities, the mechanisms behind adaptation remain controversial in even the most extensively studied mechanosensor, bacterial mechanosensitive channels. Primary cilia are ubiquitous sensory organelles. They have emerged as mechanosensors across diverse tissues, including kidney, liver and the embryonic node, and deflect with mechanical stimuli. Here, we show that both mechanical and chemical stimuli can alter cilium stiffness. We found that exposure to flow stiffens the cilium, which deflects less in response to subsequent exposures to flow. We also found that through a process involving acetylation, the cell can biochemically regulate cilium stiffness. Finally, we show that this altered stiffness directly affects the responsiveness of the cell to mechanical signals. These results demonstrate a potential mechanism through which the cell can regulate its mechanosensing apparatus.

  8. Motion adaptive vertical handoff in cellular/WLAN heterogeneous wireless network.

    PubMed

    Li, Limin; Ma, Lin; Xu, Yubin; Fu, Yunhai

    2014-01-01

    In heterogeneous wireless network, vertical handoff plays an important role for guaranteeing quality of service and overall performance of network. Conventional vertical handoff trigger schemes are mostly developed from horizontal handoff in homogeneous cellular network. Basically, they can be summarized as hysteresis-based and dwelling-timer-based algorithms, which are reliable on avoiding unnecessary handoff caused by the terminals dwelling at the edge of WLAN coverage. However, the coverage of WLAN is much smaller compared with cellular network, while the motion types of terminals can be various in a typical outdoor scenario. As a result, traditional algorithms are less effective in avoiding unnecessary handoff triggered by vehicle-borne terminals with various speeds. Besides that, hysteresis and dwelling-timer thresholds usually need to be modified to satisfy different channel environments. For solving this problem, a vertical handoff algorithm based on Q-learning is proposed in this paper. Q-learning can provide the decider with self-adaptive ability for handling the terminals' handoff requests with different motion types and channel conditions. Meanwhile, Neural Fuzzy Inference System (NFIS) is embedded to retain a continuous perception of the state space. Simulation results verify that the proposed algorithm can achieve lower unnecessary handoff probability compared with the other two conventional algorithms.

  9. Motion Adaptive Vertical Handoff in Cellular/WLAN Heterogeneous Wireless Network

    PubMed Central

    Ma, Lin; Xu, Yubin; Fu, Yunhai

    2014-01-01

    In heterogeneous wireless network, vertical handoff plays an important role for guaranteeing quality of service and overall performance of network. Conventional vertical handoff trigger schemes are mostly developed from horizontal handoff in homogeneous cellular network. Basically, they can be summarized as hysteresis-based and dwelling-timer-based algorithms, which are reliable on avoiding unnecessary handoff caused by the terminals dwelling at the edge of WLAN coverage. However, the coverage of WLAN is much smaller compared with cellular network, while the motion types of terminals can be various in a typical outdoor scenario. As a result, traditional algorithms are less effective in avoiding unnecessary handoff triggered by vehicle-borne terminals with various speeds. Besides that, hysteresis and dwelling-timer thresholds usually need to be modified to satisfy different channel environments. For solving this problem, a vertical handoff algorithm based on Q-learning is proposed in this paper. Q-learning can provide the decider with self-adaptive ability for handling the terminals' handoff requests with different motion types and channel conditions. Meanwhile, Neural Fuzzy Inference System (NFIS) is embedded to retain a continuous perception of the state space. Simulation results verify that the proposed algorithm can achieve lower unnecessary handoff probability compared with the other two conventional algorithms. PMID:24741347

  10. 7th International Workshop on Microbeam Probes of Cellular Radiation Response

    SciTech Connect

    Brenner, David J.

    2009-07-21

    The extended abstracts that follow present a summary of the Proceedings of the 7th International Workshop: Microbeam Probes of Cellular Radiation Response, held at Columbia University’s Kellogg Center in New York City on March 15–17, 2006. These International Workshops on Microbeam Probes of Cellular Radiation Response have been held regularly since 1993 (1–5). Since the first workshop, there has been a rapid growth (see Fig. 1) in the number of centers developing microbeams for radiobiological research, and worldwide there are currently about 30 microbeams in operation or under development. Single-cell/single-particle microbeam systems can deliver beams of different ionizing radiations with a spatial resolution of a few micrometers down to a few tenths of a micrometer. Microbeams can be used to addressquestions relating to the effects of low doses of radiation (a single radiation track traversing a cell or group of cells), to probe subcellular targets (e.g. nucleus or cytoplasm), and to address questions regarding the propagation of information about DNA damage (for example, the radiation-induced bystander effect). Much of the recent research using microbeams has been to study low-dose effects and ‘‘non-targeted’’ responses such as bystander effects, genomic instability and adaptive responses. This Workshop provided a forum to assess the current state of microbeam technology and current biological applications and to discuss future directions for development, both technological and biological. Over 100 participants reviewed the current state of microbeam research worldwide and reported on new technological developments in the fields of both physics and biology.

  11. A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

    PubMed Central

    Leonard, Bobby E.

    2008-01-01

    Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type 125I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

  12. Reprogramming cellular behavior with RNA controllers responsive to endogenous proteins.

    PubMed

    Culler, Stephanie J; Hoff, Kevin G; Smolke, Christina D

    2010-11-26

    Synthetic genetic devices that interface with native cellular pathways can be used to change natural networks to implement new forms of control and behavior. The engineering of gene networks has been limited by an inability to interface with native components. We describe a class of RNA control devices that overcome these limitations by coupling increased abundance of particular proteins to targeted gene expression events through the regulation of alternative RNA splicing. We engineered RNA devices that detect signaling through the nuclear factor κB and Wnt signaling pathways in human cells and rewire these pathways to produce new behaviors, thereby linking disease markers to noninvasive sensing and reprogrammed cellular fates. Our work provides a genetic platform that can build programmable sensing-actuation devices enabling autonomous control over cellular behavior.

  13. How Language Supports Adaptive Teaching through a Responsive Learning Culture

    ERIC Educational Resources Information Center

    Johnston, Peter; Dozier, Cheryl; Smit, Julie

    2016-01-01

    For students to learn optimally, teachers must design classrooms that are responsive to the full range of student development. The teacher must be adaptive, but so must each student and the learning culture itself. In other words, adaptive teaching means constructing a responsive learning culture that accommodates and even capitalizes on diversity…

  14. Using partial least squares regression to analyze cellular response data.

    PubMed

    Kreeger, Pamela K

    2013-04-16

    This Teaching Resource provides lecture notes, slides, and a problem set for a lecture introducing the mathematical concepts and interpretation of partial least squares regression (PLSR) that were part of a course entitled "Systems Biology: Mammalian Signaling Networks." PLSR is a multivariate regression technique commonly applied to analyze relationships between signaling or transcriptional data and cellular behavior.

  15. [Mechanism of cytogenetic adaptive response induced by low dose radiation].

    PubMed

    Cai, L; Liu, S

    1990-11-01

    Cytogenetic observation on human lymphocytes indicated that pre-exposure of 10, 50 and 75 mGy X-rays could induced the adaptive response. Experimental results with different temperature treatment showed that the adaptive response induced by low dose radiation could be enhanced by 41 degrees C and 43 degrees C, but inhibited by 4 degrees C in addition the treatment by 41 degrees C for one hour could also cause the adaptive response as did low dose radiation. Results showed that adaptive response induced by low dose radiation (10 or 50 mGy X-rays) could be eliminated by the protein synthesis inhibitor, implying that the adaptive response is related with the metabolism of cells, especially with the production of certain protective proteins.

  16. Adaptive response in animals exposed to non-ionizing radiofrequency fields: some underlying mechanisms.

    PubMed

    Cao, Yi; Tong, Jian

    2014-04-22

    During the last few years, our research group has been investigating the phenomenon of adaptive response in animals exposed to non-ionizing radiofrequency fields. The results from several separate studies indicated a significant increase in survival, decreases in genetic damage as well as oxidative damage and, alterations in several cellular processes in mice pre-exposed to radiofrequency fields and subsequently subjected to sub-lethal or lethal doses of γ-radiation or injected with bleomycin, a radiomimetic chemical mutagen. These observations indicated the induction of adaptive response providing the animals the ability to resist subsequent damage. Similar studies conducted by independent researchers in mice and rats have supported our observation on increased survival. In this paper, we have presented a brief review of all of our own and other independent investigations on radiofrequency fields-induced adaptive response and some underlying mechanisms discussed.

  17. FBXW7 modulates cellular stress response and metastatic potential via HSF1 post-translational modification

    PubMed Central

    Aranda-Orgilles, Beatriz; Lui, Kevin; Aydin, Iraz T.; Trimarchi, Thomas; Darvishian, Farbod; Salvaggio, Christine; Zhong, Judy; Bhatt, Kamala; Chen, Emily I.; Celebi, Julide T.; Lazaris, Charalampos; Tsirigos, Aristotelis; Osman, Iman; Hernando, Eva; Aifantis, Iannis

    2015-01-01

    Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7 α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer. PMID:25720964

  18. Cellular Responses to Beta Blocker Exposures in Marine ...

    EPA Pesticide Factsheets

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent activation of adenylate cyclase and increases in blood pressure by limiting cAMP production and protein kinase A activation. After being taken therapeutically, β blockers may make their way to coastal habitats via discharge from waste water treatment plants, posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular biomarkers of β blocker exposure using two drugs, propranolol and metoprolol, in three commercially important marine bivalves -Crassostrea virginica, Mytilus edulis and Mercenaria mercenaria. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug for 24 hours. Samples were preserved for cellular biomarker assays. Elevated cellular damage and changes in enzymatic activities were noted at environmentally relevant concentrations, and M. mercenaria was found to be the most sensitive bivalve out of the three species tested. These studies enhance our understanding of the potential impacts of commonly used prescription medication on organisms in coastal ecosystems, and demonstrate that filter feeders such as marine bivalves may serve as good model organisms to examine the effects of water soluble drugs. Evaluating a suite of biomarkers

  19. Light-adaptation in the photophobic response by Stentor coeruleus.

    PubMed

    Hong, C B; Prusti, R K; Song, P S

    1987-03-01

    Effects of preillumination on photophobic response (light-adaptation) and recovery of the photophobic sensitivity in the dark (dark-adaptation) in Stentor coeruleus were examined. When the cells were preilluminated with white light of 7.80 W/m2 for 2 min, the fluence-rate response curve of photophobic response was shifted toward higher light intensities by half an order of magnitude compared to the one without preillumination. Preillumination with a higher light intensity resulted in a further shift of the fluence-rate response curve. An action spectrum for light-adaptation showed a primary peak at 610 nm and secondary peaks at 540 and 480 nm which are almost identical to the peaks observed in the photophobic action spectrum. The light-adapted cells showed a recovery of their photophobic sensing ability following dark treatment. Dark-adaptation resulted in total recovery of photophobic sensing ability in 8 minutes for the most cases examined.

  20. Epigenetic memory for stress response and adaptation in plants.

    PubMed

    Kinoshita, Tetsu; Seki, Motoaki

    2014-11-01

    In contrast to the majority of animal species, plants are sessile organisms and are, therefore, constantly challenged by environmental perturbations. Over the past few decades, our knowledge of how plants perceive environmental stimuli has increased considerably, e.g. the mechanisms for transducing environmental stress stimuli into cellular signaling cascades and gene transcription networks. In addition, it has recently been shown that plants can remember past environmental events and can use these memories to aid responses when these events recur. In this mini review, we focus on recent progress in determination of the epigenetic mechanisms used by plants under various environmental stresses. Epigenetic mechanisms are now known to play a vital role in the control of gene expression through small RNAs, histone modifications and DNA methylation. These are inherited through mitotic cell divisions and, in some cases, can be transmitted to the next generation. They therefore offer a possible mechanism for stress memories in plants. Recent studies have yielded evidence indicating that epigenetic mechanisms are indeed essential for stress memories and adaptation in plants.

  1. Analysis of differential immune responses induced by innate and adaptive immunity following transplantation

    PubMed Central

    He, Hongzhen; Stone, James R; Perkins, David L

    2003-01-01

    The roles of innate and adaptive immunity in allograft rejection remain incompletely understood. Previous studies analysing lymphocyte deficient or syngeneic graft recipients have identified subsets of inflammatory chemokines and cytokines induced by antigen independent mechanisms. In the current study, we analysed a panel of 60 inflammatory parameters including serum cytokines, intragraft chemokines and cytokines, receptors, and cellular markers. Our results confirmed the up-regulation of a subset of markers by innate mechanisms and also identified a subset of parameters up-regulated only in the context of an adaptive response. Thus, we successfully differentiated markers of the innate and adaptive phases of rejection. Current paradigms emphasize that innate signals can promote a subsequent adaptive response. Interestingly, in our studies, expression of the markers induced by innate mechanisms was markedly amplified in the allogeneic, but not syngeneic or lymphocyte deficient, recipients. These results suggest that inflammatory mediators can have functional overlap between the innate and adaptive responses, and that the adaptive component of the rejection process amplifies the innate response by positive feedback regulation. PMID:12757613

  2. PACS—Realization of an adaptive concept using pressure actuated cellular structures

    NASA Astrophysics Data System (ADS)

    Gramüller, B.; Boblenz, J.; Hühne, C.

    2014-10-01

    A biologically inspired concept is investigated which can be utilized to develop energy efficient, lightweight and applicational flexible adaptive structures. Building a real life morphing unit is an ambitious task as the numerous works in the particular field show. Summarizing fundamental demands and barriers regarding shape changing structures, the basic challenges of designing morphing structures are listed. The concept of Pressure Actuated Cellular Structures (PACS) is arranged within the recent morphing activities and it is shown that it complies with the underlying demands. Systematically divided into energy-related and structural subcomponents the working principle is illuminated and relationships between basic design parameters are expressed. The analytical background describing the physical mechanisms of PACS is presented in concentrated manner. This work focuses on the procedure of dimensioning, realizing and experimental testing of a single cell and a single row cantilever made of PACS. The experimental outcomes as well as the results from the FEM computations are used for evaluating the analytical methods. The functionality of the basic principle is thus validated and open issues are determined pointing the way ahead.

  3. An Adaptive Control Method for Ros-Drill Cellular Microinjector with Low-Resolution Encoder

    PubMed Central

    Zhang, Zhenyu; Olgac, Nejat

    2013-01-01

    A novel control methodology which uses a low-resolution encoder is presented for a cellular microinjection technology called the Ros-Drill (rotationally oscillating drill). It is developed primarily for ICSI (intracytoplasmic sperm injection) operations, with the objective of generating a desired oscillatory motion at the tip of a micro glass pipette. It is an inexpensive setup, which creates high-frequency (higher than 500 Hz) and small-amplitude (around 0.2 deg) rotational oscillations at the tip of an injection pipette. These rotational oscillations enable the pipette to drill into cell membranes with minimum biological damage. Such a motion control procedure presents no particular difficulty when it uses sufficiently precise motion sensors. However, size, costs, and accessibility of technology to the hardware components severely constrain the sensory capabilities. Consequently, the control mission and the trajectory tracking are adversely affected. This paper presents two contributions: (a) a dedicated novel adaptive feedback control method to achieve a satisfactory trajectory tracking capability. We demonstrate via experiments that the tracking of the harmonic rotational motion is achieved with desirable fidelity; (b) some important analytical features and related observations associated with the controlled harmonic motion which is created by the low-resolution feedback control structure. PMID:27006914

  4. How biochemical constraints of cellular growth shape evolutionary adaptations in metabolism.

    PubMed

    Berkhout, Jan; Bosdriesz, Evert; Nikerel, Emrah; Molenaar, Douwe; de Ridder, Dick; Teusink, Bas; Bruggeman, Frank J

    2013-06-01

    Evolutionary adaptations in metabolic networks are fundamental to evolution of microbial growth. Studies on unneeded-protein synthesis indicate reductions in fitness upon nonfunctional protein synthesis, showing that cell growth is limited by constraints acting on cellular protein content. Here, we present a theory for optimal metabolic enzyme activity when cells are selected for maximal growth rate given such growth-limiting biochemical constraints. We show how optimal enzyme levels can be understood to result from an enzyme benefit minus cost optimization. The constraints we consider originate from different biochemical aspects of microbial growth, such as competition for limiting amounts of ribosomes or RNA polymerases, or limitations in available energy. Enzyme benefit is related to its kinetics and its importance for fitness, while enzyme cost expresses to what extent resource consumption reduces fitness through constraint-induced reductions of other enzyme levels. A metabolic fitness landscape is introduced to define the fitness potential of an enzyme. This concept is related to the selection coefficient of the enzyme and can be expressed in terms of its fitness benefit and cost.

  5. Marine molluscs in environmental monitoring. I. Cellular and molecular responses

    NASA Astrophysics Data System (ADS)

    Bresler, Vladimir; Abelson, Avigdor; Fishelson, Lev; Feldstein, Tamar; Rosenfeld, Michael; Mokady, Ofer

    2003-10-01

    The study reported here is part of an ongoing effort to establish sensitive and reliable biomonitoring markers for probing the coastal marine environment. Here, we report comparative measurements of a range of histological, cellular and sub-cellular parameters in molluscs sampled in polluted and reference sites along the Mediterranean coast of Israel and in the northern tip of the Gulf of Aqaba, Red Sea. Available species enabled an examination of conditions in two environmental 'compartments': benthic (Donax trunculus) and intertidal (Brachidontes pharaonis, Patella caerulea) in the Mediterranean; pelagic (Pteria aegyptia) and intertidal (Cellana rota) in the Red Sea. The methodology used provides rapid results by combining specialized fluorescent probes and contact microscopy, by which all parameters are measured in unprocessed animal tissue. The research focused on three interconnected levels. First, antixenobiotic defence mechanisms aimed at keeping hazardous agents outside the cell. Paracellular permeability was 70-100% higher in polluted sites, and membrane pumps (MXRtr and SATOA) activity was up to 65% higher in polluted compared to reference sites. Second, intracellular defence mechanisms that act to minimize potential damage by agents having penetrated the first line of defence. Metallothionein expression and EROD activity were 160-520% higher in polluted sites, and lysosomal functional activity (as measured by neutral red accumulation) was 25-50% lower. Third, damage caused by agents not sufficiently eliminated by the above mechanisms (e.g. single-stranded DNA breaks, chromosome damage and other pathological alterations). At this level, the most striking differences were observed in the rate of micronuclei formation and DNA breaks (up to 150% and 400% higher in polluted sites, respectively). The different mollusc species used feature very similar trends between polluted and reference sites in all measured parameters. Concentrating on relatively basic

  6. p53-Mediated Cellular Response to DNA Damage in Cells with Replicative Hepatitis B Virus

    NASA Astrophysics Data System (ADS)

    Puisieux, Alain; Ji, Jingwei; Guillot, Celine; Legros, Yann; Soussi, Thierry; Isselbacher, Kurt; Ozturk, Mehmet

    1995-02-01

    Wild-type p53 acts as a tumor suppressor gene by protecting cells from deleterious effects of genotoxic agents through the induction of a G_1/S arrest or apoptosis as a response to DNA damage. Transforming proteins of several oncogenic DNA viruses inactivate tumor suppressor activity of p53 by blocking this cellular response. To test whether hepatitis B virus displays a similar effect, we studied the p53-mediated cellular response to DNA damage in 2215 hepatoma cells with replicative hepatitis B virus. We demonstrate that hepatitis B virus replication does not interfere with known cellular functions of p53 protein.

  7. Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease.

    PubMed

    Li, Hui; Satriano, Joseph; Thomas, Joanna L; Miyamoto, Satoshi; Sharma, Kumar; Pastor-Soler, Núria M; Hallows, Kenneth R; Singh, Prabhleen

    2015-09-01

    Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.

  8. Genome-wide transcriptional responses to a lipid hydroperoxide: adaptation occurs without induction of oxidant defenses.

    PubMed

    Alic, Nazif; Felder, Thomas; Temple, Mark D; Gloeckner, Christian; Higgins, Vincent J; Briza, Peter; Dawes, Ian W

    2004-07-01

    Free radicals can initiate the oxidation of polyunsaturated fatty acids in cells through the process of lipid peroxidation. The genome-wide transcriptional changes in Saccharomyces cerevisiae after treatment with the toxic lipid peroxidation product linoleic acid hydroperoxide (LoaOOH) were identified. High-dose treatment led to a switch in transcription from biosynthetic to protective functions. This response encompassed a set of genes stimulated predominantly by LoaOOH, and not by other oxidants or heat shock, which contained components of the pleiotropic drug resistance system. The dose dependence of the transcriptional response revealed that large and widespread changes occur only in response to higher doses. Pretreatment of cells with sublethal doses of LoaOOH induces resistance to an otherwise lethal dose through the process of adaptation. Adaptive doses elicited a more subtle transcriptional response affecting metabolic functions, including an increase in the capacity for detoxification and downregulation of the rate of protein synthesis. Surprisingly, the cellular response to adaptive doses did not include induction of oxidative-stress defense enzymes nor of transcripts involved in general cellular defense systems.

  9. Activation of cellular immune response in acute pancreatitis.

    PubMed Central

    Mora, A; Pérez-Mateo, M; Viedma, J A; Carballo, F; Sánchez-Payá, J; Liras, G

    1997-01-01

    BACKGROUND: Inflammatory mediators have recently been implicated as potential markers of severity in acute pancreatitis. AIMS: To determine the value of neopterin and polymorphonuclear (PMN) elastase as markers of activation of cellular immunity and as early predictors of disease severity. PATIENTS: Fifty two non-consecutive patients classified according to their clinical outcome into mild (n = 26) and severe pancreatitis (n = 26). METHODS: Neopterin in serum and the PMN elastase/A1PI complex in plasma were measured during the first three days of hospital stay. RESULTS: Within three days after the onset of acute pancreatitis, PMN elastase was significantly higher in the severe pancreatitis group. Patients with severe disease also showed significantly higher values of neopterin on days 1 and 2 but not on day 3 compared with patients with mild disease. There was a significant correlation between PMN elastase and neopterin values on days 1 and 2. PMN elastase on day 1 predicted disease severity with a sensitivity of 76.7% and a specificity of 91.6%. Neopterin did not surpass PMN elastase in the probability of predicting disease severity. CONCLUSIONS: These data show that activation of cellular immunity is implicated in the pathogenesis of acute pancreatitis and may be a main contributory factor to disease severity. Neopterin was not superior to PMN elastase in the prediction of severity. PMID:9245935

  10. Systematic identification of genes and transduction pathways involved in radio-adaptive response

    SciTech Connect

    Wu, Honglu

    2015-05-22

    Low doses of radiation have been shown to protect against the biological effects of later exposure to toxic levels of radiation. In this study, we propose to identify the molecular mechanisms of this adaptive response by systematically identifying the genes that play a role in radio-protection. In the original proposal, a human cell line that is well-documented to exhibit the radio-adaptive effect was to be used. In this revised study plan, we will use a mouse model, C57BL/6, which has also been well investigated for radio-adaptation. The goal of the proposed study is to enhance our understanding of cellular responses to low doses of radiation exposure at the molecular level.

  11. A Sharing Item Response Theory Model for Computerized Adaptive Testing

    ERIC Educational Resources Information Center

    Segall, Daniel O.

    2004-01-01

    A new sharing item response theory (SIRT) model is presented that explicitly models the effects of sharing item content between informants and test takers. This model is used to construct adaptive item selection and scoring rules that provide increased precision and reduced score gains in instances where sharing occurs. The adaptive item selection…

  12. Responsiveness-to-Intervention: A "Systems" Approach to Instructional Adaptation

    ERIC Educational Resources Information Center

    Fuchs, Douglas; Fuchs, Lynn S.

    2016-01-01

    Classroom research on adaptive teaching indicates few teachers modify instruction for at-risk students in a manner that benefits them. Responsiveness-To-Intervention, with its tiers of increasingly intensive instruction, represents an alternative approach to adaptive instruction that may prove more workable in today's schools.

  13. Response of MICROTOX organisms to leachates of autoclaved cellular concrete

    SciTech Connect

    Latona, M.C.; Neufeld, R.D.; Hu, W.; Kelly, C.; Vallejo, L.E.

    1997-08-01

    The MICROTOX bioassay, a toxicity test involving bioluminescent microorganisms, was conducted on aqueous leachates derived from a construction material made using coal fly ash as the key siliceous ingredient. The material is known as autoclaved cellular concrete (ACC). The test indicated an absence of toxic effects attributable to soluble species, which included the priority heavy metals in the filtered leachates. Toxic or inhibitive effects on the test bacteria were observed for the toxicity characteristic leaching procedure (TCLP) leachates, but this was probably due to acetic acid in the extractant rather than the solubilized metals. The ASTM (distilled-deionized water extractant) and simulated acid rain leachates, by comparison, produced a repeatable stimulative effect. Stimulation observed in the form of enhanced light output may be a manifestation of hormesis, a phenomenon reportedly caused by exposure to extremely low concentrations (part-per-billion range) of otherwise toxic agents such as heavy metals.

  14. Development of second generation peptides modulating cellular adiponectin receptor responses

    NASA Astrophysics Data System (ADS)

    Otvos, Laszlo; Knappe, Daniel; Hoffmann, Ralf; Kovalszky, Ilona; Olah, Julia; Hewitson, Tim; Stawikowska, Roma; Stawikowski, Maciej; Cudic, Predrag; Lin, Feng; Wade, John; Surmacz, Eva; Lovas, Sandor

    2014-10-01

    The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including adiponectin. Recently we developed and characterized a first-in-class peptide-based adiponectin receptor agonist by using in vitro and in vivo models of glioblastoma and breast cancer (BC). In the current study, we further explored the effects of peptide ADP355 in additional cellular models and found that ADP355 inhibited chronic myeloid leukemia (CML) cell proliferation and renal myofibroblast differentiation with mid-nanomolar IC50 values. According to molecular modeling calculations, ADP355 was remarkably flexible in the global minimum with a turn present in the middle of the peptide. Considering these structural features of ADP355 and the fact that adiponectin normally circulates as multimeric complexes, we developed and tested the activity of a linear branched dimer (ADP399). The dimer exhibited approximately 20-fold improved cellular activity inhibiting K562 CML and MCF-7 cell growth with high pM - low nM relative IC50 values. Biodistribution studies suggested superior tissue dissemination of both peptides after subcutaneous administration relative to intraperitoneal inoculation. After screening of a 397-member adiponectin active site library, a novel octapeptide (ADP400) was designed that counteracted 10-1000 nM ADP355- and ADP399-mediated effects on CML and BC cell growth at nanomolar concentrations. ADP400 induced mitogenic effects in MCF-7 BC cells perhaps due to antagonizing endogenous adiponectin actions or acting as an inverse agonist. While the linear dimer agonist ADP399 meets pharmacological criteria of a contemporary peptide drug lead, the peptide showing antagonist activity (ADP400) at similar concentrations will be an important target validation tool to study adiponectin functions.

  15. Transcriptome and Proteome Dynamics of the Cellular Response of Shewanella oneidensis to Chromium Stress

    SciTech Connect

    Thompson, D.K.

    2005-04-18

    The overall goal of this DOE NABIR project is to characterize the molecular basis and regulation of hexavalent chromium [Cr(VI)] stress response and reduction by Shewanella oneidensis strain MR-1. Temporal genomic profiling and mass spectrometry-based proteomic analysis were employed to characterize the dynamic molecular response of S. oneidensis MR-1 to both acute and chronic Cr(VI) exposure. The acute stress response of aerobic, mid-exponential phase cells shocked to a final concentration of 1 mM potassium chromate (K2CrO4) was examined at post-exposure time intervals of 5, 30, 60, and 90 min relative to untreated cells. The transcriptome of mid-exponential cultures was also analyzed 30 min after shock doses of 0.3, 0.5, or 1 mM K{sub 2}CrO{sub 4}. The tonB1-exbB1-exbD1 genes comprising the TonB1 iron transport system were some of the most highly induced coding sequences (CDSs) after 90 min (up to {approx}240 fold), followed by other genes involved in heme transport, sulfate transport, and sulfur assimilation pathways. In addition, transcript levels for CDSs with annotated functions in DNA repair (dinP, recX, recA, recN) and detoxification processes (so3585, so3586) were substantially increased in Cr(VI)-exposed cells compared to untreated cells. By contrast, genes predicted to encode hydrogenases (HydA, HydB), oxidoreductases (SO0902-03-04, SO1911), iron-sulfur cluster binding proteins (SO4404), decaheme cytochrome c proteins (MtrA, OmcA, OmcB), and a number of LysR or TetR family transcriptional regulators were some of the most highly repressed CDSs following the 90-min shock period. Transcriptome profiles generated from MR-1 cells adapted to 0.3 mM Cr(VI) differed significantly from those characterizing cells exposed to acute Cr(VI) stress without adaptation. Parallel proteomic characterization of soluble protein and membrane protein fractions extracted from Cr(VI)-shocked and Cr(VI)-adapted MR-1 cells was performed using multidimensional HPLC-ESI-MS/MS (both

  16. Cellular evaluation of the toxicity of combustion derived particulate matter: influence of particle grinding and washing on cellular response.

    PubMed

    Katterman, Matthew E; Birchard, Stephanie; Seraphin, Supapan; Riley, Mark R

    2007-01-01

    There is increasing interest in continual monitoring of air for the presence of inhalation health hazards, such as particulate matter, produced through combustion of fossil fuels. Currently there are no means to rapidly evaluate the relative toxicity of materials or to reliably predict potential health impact due to the complexity of the composition, size, and physical properties of particulate matter. This research evaluates the feasibility of utilizing cell cultures as the biological recognition element of an inhalation health monitoring system. The response of rat lung type II epithelial (RLE-6TN) cells to a variety of combustion derived particulates and their components has been evaluated. The focus of the current work is an evaluation of how particles are delivered to a cellular sensing array and to what degree does washing or grinding of the particles impacts the cellular response. There were significant differences in the response of these lung cells to PM's of varying sources. Mechanical grinding or washing was found to alter the toxicity of some of these particulates; however these effects were strongly dependent on the fuel source. Washing reduced toxicity of oil PM's, but had little effect on those from diesel or coal. Mechanical grinding could significantly increase the toxicity of coal PM's, but not for oil or diesel.

  17. Exposure to stressful environments - Strategy of adaptive responses

    NASA Technical Reports Server (NTRS)

    Farhi, Leon E.

    1991-01-01

    Stresses such as hypoxia, water lack, and heat exposure can produce strains in more than a single organ system, in turn stimulating the body to adapt in multiple ways. Nevertheless, a general strategy of the various adaptive responses emerges when the challenges are divided into three groups: (1) conditions that affect the supply of essential molecules, (2) stresses that prevent the body from regulating properly the output of waste products such as CO2 and heat, and (3) environments that disrupt body transport systems. Problems may arise when there is a conflict between two stresses requiring conflicting adaptive changes. An alternative to adaptation, creation of microenvironment, is often favored by the animal.

  18. Cellular immune responses to methylcholanthrene-induced fibrosarcoma in BALB/c mice

    PubMed Central

    1975-01-01

    Several in vitro parameters of cellular immunity were examined in BALB/c mice with an experimentally induced fibrosarcoma tumor. The results of capillary migration of spleen cells in high tumor cell dose inoculated mice show appearance of cellular immune response in the early stages of the tumor growth. As the tumor progresses, the cellular response declines and rapidly disappears, culminating in stimulation values near the time of the death of these mice. The blastogenic studies also show early cellular recognition of tumor antigen by mouse spleen cells and whole blood (Z24 h). After the 2nd day following tumor injection, no blast transformation is noted. However, the results obtained with a lower inoculating tumor cell dose demonstrate an initial cellular recognition on the 7th day. This response gradually disappears by the 19th day and remains negative up to the time of the death of these mice. This cellular immunity was confirmed by the cytotoxic experiments showing that the primary cells responsible for this cellular reactivity were the immune cells. An interesting finding was the presence of a factor(s) capable of blocking the cytotoxic effect. The nature and mechanism of this blocking factor(s) is now under investigation. PMID:1185107

  19. Cellular and Molecular Responses to Mechanical Expansion of Tissue

    PubMed Central

    Razzak, Muhammad Abdur; Hossain, Md. Sanower; Radzi, Zamri Bin; Yahya, Noor Azlin B.; Czernuszka, Jan; Rahman, Mohammad T.

    2016-01-01

    The increased use of tissue expander in the past decades and its potential market values in near future give enough reasons to sum up the consequences of tissue expansion. Furthermore, the patients have the right to know underlying mechanisms of adaptation of inserted biomimetic, its bioinspired materials and probable complications. The mechanical strains during tissue expansion are related to several biological phenomena. Tissue remodeling during the expansion is highly regulated and depends on the signal transduction. Any alteration may lead to tumor formation, necrosis and/or apoptosis. In this review, stretch induced cell proliferation, apoptosis, the roles of growth factors, stretch induced ion channels, and roles of second messengers are organized. It is expected that readers from any background can understand and make a decision about tissue expansion. PMID:27899897

  20. Adaptive response of human melanoma cells to methylglyoxal injury.

    PubMed

    Amicarelli, F; Bucciarelli, T; Poma, A; Aimola, P; Di Ilio, C; Ragnelli, A M; Miranda, M

    1998-03-01

    The effects of methylglyoxal on the growth of a line of human melanoma cells are investigated. Methylglyoxal inhibits cell growth in a dose-dependent manner and causes an increase in glyceraldehyde 3-phosphate dehydrogenase, and glyoxalase 1 and glyoxalase 2 specific activities. The cellular response to increasing concentrations of methylglyoxal in the culture medium is also studied by measuring L-lactate production, reduced-oxidized glutathione levels and apoptotic cell death. Methylglyoxal seems to promote a change of cell population phenotypic repertoire toward a more monomorphic phenotype. In conclusion, methylglyoxal seems to induce an enzymatic cellular response that lowers methylglyoxal levels and selects the most resistant cells.

  1. Cellular responses to egg-oil (charismon©).

    PubMed

    Bereiter-Hahn, Jürgen; Bernd, August; Beschmann, Heike; Eberle, Irina; Kippenberger, Stefan; Rossberg, Maila; Strecker, Valentina; Zöller, Nadja

    2014-01-01

    Egg-oil (Charismon©) is known for its beneficial action in wound healing and other skin irritancies and its antibacterial activity. The physiological basis for these actions has been investigated using cells in culture: HaCaT-cells (immortalized human keratinocytes), human endothelial cells in culture (HUVEC), peripheral blood mononuclear lymphocytes (PBML) and a full thickness human skin model (FTSM). Emphasis was on the influence of egg-oil on cell migration and IL-8 production in HaCaT cells, respiration, mitochondrial membrane potential, reactive oxygen (ROS) production and proliferation in HUVEC and HaCaT cells, cytokine and interleukin production in PBML and UV-light induced damage of FTSM. IL-8 production by HaCaT cells is stimulated by egg-oil whilst in phythemagglutin in-activated PBMLs production of the interleukins IL-2, IL-6, IL-10 and IFN-γ and TFN-α is reduced. ROS-production after H(2)O(2) stimulation first is enhanced but later on reduced. Respiration becomes activated due to partial uncoupling of the mitochondrial respiratory chain and proliferation of HaCaT and HUVEC is reduced. Recovery of human epidermis cells in FTSM after UV-irradiation is strongly supported by egg-oil. These results support the view that egg-oil acts through reduction of inflammatory processes and ROS production. Both these processes are equally important in cellular aging as in healing of chronic wounds.

  2. fMRI study of the role of glutamate NMDA receptor in the olfactory adaptation in rats: Insights into cellular and molecular mechanisms of olfactory adaptation.

    PubMed

    Zhao, Fuqiang; Wang, Xiaohai; Zariwala, Hatim A; Uslaner, Jason M; Houghton, Andrea K; Evelhoch, Jeffrey L; Hostetler, Eric; Winkelmann, Christopher T; Hines, Catherine D G

    2017-02-03

    Olfactory adaptation, characterized by attenuation of response to repeated odor stimulations or continuous odor exposure, is an intrinsic feature of olfactory processing. Adaptation can be induced by either "synaptic depression" due to depletion of neurotransmitters, or "enhanced inhibition" onto principle neurons by local inhibitory interneurons in olfactory structures. It is not clear which mechanism plays a major role in olfactory adaptation. More importantly, molecular sources of enhanced inhibition have not been identified. In this study, olfactory responses to either repeated 40-s stimulations with interstimulus intervals (ISI) of 140-s or 30-min, or a single prolonged 200-s stimulus were measured by fMRI in different naïve rats. Olfactory adaptations in the olfactory bulb (OB), anterior olfactory nucleus (AON), and piriform cortex (PC) were observed only with repeated 40-s odor stimulations, and no olfactory adaptations were detected during the prolonged 200-s stimulation. Interestingly, in responses to repeated 40-s odor stimulations in the PC, the first odor stimulation induced positive activations, and odor stimulations under adapted condition induced negative activations. The negative activations suggest that "sparse coding" and "global inhibition" are the characteristics of olfactory processing in PC, and the global inhibition manifests only under an adapted condition, not a naïve condition. Further, we found that these adaptations were NMDA receptor dependent; an NMDA receptor antagonist (MK801) blocked the adaptations. Based on the mechanism that glutamate NMDA receptor plays a role in the inhibition onto principle neurons by interneurons, our data suggest that the olfactory adaptations are caused by enhanced inhibition from interneurons. Combined with the necessity of the interruption of odor stimulation to observe the adaptations, the molecular source for the enhanced inhibition is most likely an increased glutamate release from presynaptic

  3. RNA-seq analyses of cellular responses to elevated body temperature in the high Antarctic cryopelagic nototheniid fish Pagothenia borchgrevinki.

    PubMed

    Bilyk, Kevin T; Cheng, C-H Christina

    2014-12-01

    Through evolution in the isolated, freezing (-1.9°C) Southern Ocean, Antarctic notothenioid fish have become cold-adapted as well as cold-specialized. Notothenioid cold specialization is most evident in their limited tolerance to heat challenge, and an apparent loss of the near universal inducible heat shock (HSP70) response. Beyond these it remains unclear how broadly cold specialization pervades the underlying tissue-wide cellular responses. We report the first analysis of massively parallel RNA sequencing (RNA-seq) to identify gene expression changes in the liver in response to elevated body temperature of a high-latitude Antarctic nototheniid, the highly cold-adapted and cold-specialized cryopelagic bald notothen, Pagothenia borchgrevinki. From a large (14,873) mapped set of qualified, annotated liver transcripts, we identified hundreds of significantly differentially expressed genes following two and four days of 4°C exposure, suggesting substantial transcriptional reorganization in the liver when body temperature was raised 5°C above native water temperature. Most notably, and in sharp contrast to heat stressed non-polar fish species, was a widespread down-regulation of nearly all classes of molecular chaperones including HSP70, as well as polyubiquitins that are associated with proteosomal degradation of damaged proteins. In parallel, genes involved in the cell cycle were down-regulated by day two of 4°C exposure, signifying slowing cellular proliferation; by day four, genes associated with transcriptional and translational machineries were down-regulated, signifying general slowing of protein biosynthesis. The log2 fold differential transcriptional changes are generally of small magnitudes but significant, and in total portray a broad down turn of cellular activities in response to four days of elevated body temperature in the cold-specialized bald notothen.

  4. MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation

    PubMed Central

    Pang, Keliang; You, He; Chen, Yanbo; Chu, Pengcheng; Hu, Meiqin; Shen, Jianying; Guo, Wei; Xie, Can; Lu, Bai

    2017-01-01

    Magnetic manipulation of cell activity offers advantages over optical manipulation but an ideal tool remains elusive. The MagR protein was found through its interaction with cryptochrome (Cry) and the protein in solution appeared to respond to magnetic stimulation (MS). After we initiated an investigation on the specific role of MagR in cellular response to MS, a subsequent study claimed that MagR expression alone could achieve cellular activation by MS. Here we report that despite systematically testing different ways of measuring intracellular calcium and different MS protocols, it was not possible to detect any cellular or neuronal responses to MS in MagR-expressing HEK cells or primary neurons from the dorsal root ganglion and the hippocampus. By contrast, in neurons co-expressing MagR and channelrhodopin, optical but not MS increased calcium influx in hippocampal neurons. Our results indicate that MagR alone is not sufficient to confer cellular magnetic responses. PMID:28360843

  5. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

    PubMed Central

    Liliensiek, Birgit; Weigand, Markus A.; Bierhaus, Angelika; Nicklas, Werner; Kasper, Michael; Hofer, Stefan; Plachky, Jens; Gröne, Herman-Josef; Kurschus, Florian C.; Schmidt, Ann Marie; Yan, Shi Du; Martin, Eike; Schleicher, Erwin; Stern, David M.; Hämmerling, Günter J.; Nawroth, Peter P.; Arnold, Bernd

    2004-01-01

    While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation. PMID:15173891

  6. A cascade reaction network mimicking the basic functional steps of adaptive immune response

    NASA Astrophysics Data System (ADS)

    Han, Da; Wu, Cuichen; You, Mingxu; Zhang, Tao; Wan, Shuo; Chen, Tao; Qiu, Liping; Zheng, Zheng; Liang, Hao; Tan, Weihong

    2015-10-01

    Biological systems use complex ‘information-processing cores’ composed of molecular networks to coordinate their external environment and internal states. An example of this is the acquired, or adaptive, immune system (AIS), which is composed of both humoral and cell-mediated components. Here we report the step-by-step construction of a prototype mimic of the AIS that we call an adaptive immune response simulator (AIRS). DNA and enzymes are used as simple artificial analogues of the components of the AIS to create a system that responds to specific molecular stimuli in vitro. We show that this network of reactions can function in a manner that is superficially similar to the most basic responses of the vertebrate AIS, including reaction sequences that mimic both humoral and cellular responses. As such, AIRS provides guidelines for the design and engineering of artificial reaction networks and molecular devices.

  7. Regulation of Cellular Immune Responses in Sepsis by Histone Modifications.

    PubMed

    Carson, W F; Kunkel, S L

    2017-01-01

    Severe sepsis, septic shock, and related inflammatory syndromes are driven by the aberrant expression of proinflammatory mediators by immune cells. During the acute phase of sepsis, overexpression of chemokines and cytokines drives physiological stress leading to organ failure and mortality. Following recovery from sepsis, the immune system exhibits profound immunosuppression, evidenced by an inability to produce the same proinflammatory mediators that are required for normal responses to infectious microorganisms. Gene expression in inflammatory responses is influenced by the transcriptional accessibility of the chromatin, with histone posttranslational modifications determining whether inflammatory gene loci are set to transcriptionally active, repressed, or poised states. Experimental evidence indicates that histone modifications play a central role in governing the cytokine storm of severe sepsis, and that aberrant chromatin modifications induced during the acute phase of sepsis may mediate chronic immunosuppression in sepsis survivors. This review will focus on the role of histone modifications in governing immune responses in severe sepsis, with an emphasis on specific leukocyte subsets and the histone modifications observed in these cells during chronic stages of sepsis. Additionally, the expression and function of chromatin-modifying enzymes (CMEs) will be discussed in the context of severe sepsis, as potential mediators of epigenetic regulation of gene expression in sepsis responses. In summary, this review will argue for the use of chromatin modifications and CME expression in leukocytes as potential biomarkers of immunosuppression in patients with severe sepsis.

  8. Bioenergetic adaptation in response to autophagy regulators during rotenone exposure

    PubMed Central

    Giordano, Samantha; Dodson, Matthew; Ravi, Saranya; Redmann, Matthew; Ouyang, Xiaosen; Usmar, Victor M Darley; Zhang, Jianhua

    2015-01-01

    Parkinson’s disease (PD) is the second most common neurodegenerative disorder with both mitochondrial dysfunction and insufficient autophagy playing a key role in its pathogenesis. Among the risk factors, exposure to the environmental neurotoxin rotenone increases the probability of developing PD. We previously reported that in differentiated SH-SY5Y cells, rotenone-induced cell death is directly related to inhibition of mitochondrial function. How rotenone at nM concentrations inhibits mitochondrial function, and whether it can engage the autophagy pathway necessary to remove damaged proteins and organelles, is unknown. We tested the hypothesis that autophagy plays a protective role against rotenone toxicity in primary neurons. We found that rotenone (10–100 nM) immediately inhibited cellular bioenergetics. Concentrations that decreased mitochondrial function at 2 hr, caused cell death at 24 hr with an LD50 of 10 nM. Overall autophagic flux was decreased by 10 nM rotenone at both 2 and 24 hr, but surprisingly mitophagy, or autophagy of the mitochondria, was increased at 24 hr, suggesting that a mitochondrial-specific lysosomal degradation pathway may be activated. Upregulation of autophagy by rapamycin protected against cell death while inhibition of autophagy by 3-methyladenine (3-MA) exacerbated cell death. Interestingly, while 3-MA exacerbated the rotenone-dependent effects on bioenergetics, rapamycin did not prevent rotenone-induced mitochondrial dysfunction, but caused reprogramming of mitochondrial substrate usage associated with both complex I and complex II activities. Taken together, these data demonstrate that autophagy can play a protective role in primary neuron survival in response to rotenone; moreover, surviving neurons exhibit bioenergetic adaptations to this metabolic stressor. PMID:25081478

  9. Endoplasmic reticulum stress as a novel cellular response to di (2-ethylhexyl) phthalate exposure.

    PubMed

    Peropadre, Ana; Fernández Freire, Paloma; Pérez Martín, José Manuel; Herrero, Óscar; Hazen, María José

    2015-12-25

    Di (2-ethylhexyl) phthalate is a high-production chemical widely used as a plasticizer for polyvinyl chloride products. Due to its ubiquitous presence in environmental compartments and the constant exposure of the general population through ingestion, inhalation, and dermal absorption, this compound has been subjected to extensive in vivo and in vitro toxicological studies. Despite the available information, research on the cytotoxicity of di (2-ethylhexyl) phthalate in mammalian cells is relatively limited.In this paper, an in vitro multi-parametric approach was used to provide further mechanistic data on the toxic activity of this chemical in Vero and HaCaT cells. Our results reveal that a 24 h exposure to di (2-ethylhexyl) phthalate causes, in both cell lines, an inhibition of cell proliferation that was linked to cell cycle delay at the G1 phase. Concomitantly, the tested compound induces mild endoplasmic reticulum stress which leads to an adaptive rather than a pro-apoptotic response in mammalian cells. These findings demonstrate that there are multiple potential cellular targets of di (2-ethylhexyl) phthalate-induced toxicity and the need to develop further experimental studies for the risk assessment of this ubiquitous plasticizer.

  10. Cellular Stress Response Gene Expression During Upper and Lower Body High Intensity Exercises

    PubMed Central

    Kochanowicz, Andrzej; Sawczyn, Stanisław; Niespodziński, Bartłomiej; Mieszkowski, Jan; Kochanowicz, Kazimierz

    2017-01-01

    Objectives The aim was to compare the effect of upper and lower body high-intensity exercise on chosen genes expression in athletes and non-athletes. Method Fourteen elite male artistic gymnasts (EAG) aged 20.6 ± 3.3 years and 14 physically active men (PAM) aged 19.9 ± 1.0 years performed lower and upper body 30 s Wingate Tests. Blood samples were collected before, 5 and 30 minutes after each effort to assess gene expression via PCR. Results Significantly higher mechanical parameters after lower body exercise was observed in both groups, for relative power (8.7 ± 1.2 W/kg in gymnasts, 7.2 ± 1.2 W/kg in controls, p = 0.01) and mean power (6.7 ± 0.7 W/kg in gymnasts, 5.4 ± 0.8 W/kg in controls, p = 0.01). No differences in lower versus upper body gene expression were detected for all tested genes as well as between gymnasts and physical active man. For IL-6 m-RNA time-dependent effect was observed. Conclusions Because of no significant differences in expression of genes associated with cellular stress response the similar adaptive effect to exercise may be obtained so by lower and upper body exercise. PMID:28141870

  11. Modeling Light Adaptation in Circadian Clock: Prediction of the Response That Stabilizes Entrainment

    PubMed Central

    Yoshinaga, Tetsuya; Aihara, Kazuyuki

    2011-01-01

    Periods of biological clocks are close to but often different from the rotation period of the earth. Thus, the clocks of organisms must be adjusted to synchronize with day-night cycles. The primary signal that adjusts the clocks is light. In Neurospora, light transiently up-regulates the expression of specific clock genes. This molecular response to light is called light adaptation. Does light adaptation occur in other organisms? Using published experimental data, we first estimated the time course of the up-regulation rate of gene expression by light. Intriguingly, the estimated up-regulation rate was transient during light period in mice as well as Neurospora. Next, we constructed a computational model to consider how light adaptation had an effect on the entrainment of circadian oscillation to 24-h light-dark cycles. We found that cellular oscillations are more likely to be destabilized without light adaption especially when light intensity is very high. From the present results, we predict that the instability of circadian oscillations under 24-h light-dark cycles can be experimentally observed if light adaptation is altered. We conclude that the functional consequence of light adaptation is to increase the adjustability to 24-h light-dark cycles and then adapt to fluctuating environments in nature. PMID:21698191

  12. Cellular responses to endogenous electrochemical gradients in morphological development

    NASA Technical Reports Server (NTRS)

    Desrosiers, M. F.

    1996-01-01

    Endogenous electric fields give vectorial direction to morphological development in Zea mays (sweet corn) in response to gravity. Endogenous electrical fields are important because of their ability to influence: (1) intercellular organization and development through their effects on the membrane potential, (2) direct effects such as electrophoresis of membrane components, and (3) both intracellular and extracellular transport of charged compounds. Their primary influence is in providing a vectorial dimension to the progression of one physiological state to another. Gravity perception and transduction in the mesocotyl of vascular plants is a complex interplay of electrical and chemical gradients which ultimately provide the driving force for the resulting growth curvature called gravitropism. Among the earliest events in gravitropism are changes in impedance, voltage, and conductance between the vascular stele and the growth tissues, the cortex, in the mesocotyl of corn shoots. In response to gravistimulation: (1) a potential develops which is vectorial and of sufficient magnitude to be a driving force for transport between the vascular stele and cortex, (2) the ionic conductance changes within seconds showing altered transport between the tissues, and (3) the impedance shows a transient biphasic response which indicates that the mobility of charges is altered following gravistimulation and is possibly the triggering event for the cascade of actions which leads to growth curvature.

  13. Incorporating adaptive responses into future projections of coral bleaching.

    PubMed

    Logan, Cheryl A; Dunne, John P; Eakin, C Mark; Donner, Simon D

    2014-01-01

    Climate warming threatens to increase mass coral bleaching events, and several studies have projected the demise of tropical coral reefs this century. However, recent evidence indicates corals may be able to respond to thermal stress though adaptive processes (e.g., genetic adaptation, acclimatization, and symbiont shuffling). How these mechanisms might influence warming-induced bleaching remains largely unknown. This study compared how different adaptive processes could affect coral bleaching projections. We used the latest bias-corrected global sea surface temperature (SST) output from the NOAA/GFDL Earth System Model 2 (ESM2M) for the preindustrial period through 2100 to project coral bleaching trajectories. Initial results showed that, in the absence of adaptive processes, application of a preindustrial climatology to the NOAA Coral Reef Watch bleaching prediction method overpredicts the present-day bleaching frequency. This suggests that corals may have already responded adaptively to some warming over the industrial period. We then modified the prediction method so that the bleaching threshold either permanently increased in response to thermal history (e.g., simulating directional genetic selection) or temporarily increased for 2-10 years in response to a bleaching event (e.g., simulating symbiont shuffling). A bleaching threshold that changes relative to the preceding 60 years of thermal history reduced the frequency of mass bleaching events by 20-80% compared with the 'no adaptive response' prediction model by 2100, depending on the emissions scenario. When both types of adaptive responses were applied, up to 14% more reef cells avoided high-frequency bleaching by 2100. However, temporary increases in bleaching thresholds alone only delayed the occurrence of high-frequency bleaching by ca. 10 years in all but the lowest emissions scenario. Future research should test the rate and limit of different adaptive responses for coral species across latitudes and

  14. Cellular specificity of the gravitropic motor response in roots

    NASA Technical Reports Server (NTRS)

    Evans, M. L.; Ishikawa, H.

    1997-01-01

    A number of features of the gravitropic response of roots are not readily accounted for by the classical Cholodny-Went theory. These include the observations that (i) in the later stages of the response the growth gradient is reversed with no evident reversal of the auxin gradient; (ii) a major component of the acceleration of growth along the upper side occurs in the distal elongation zone (DEZ), a group of cells located between the meristem and the main elongation, not within the central elongation zone; and (iii) the initiation of differential growth in the DEZ appears to be independent of the establishment of auxin asymmetry. Alternative candidates for mediation of differential growth in the DEZ include calcium ions and protons. Gravi-induced curvature is accompanied by polar movement of calcium toward the lower side of the maize root tip and the DEZ is shown to be particularly sensitive to growth inhibition by calcium. Also, gravistimulation of maize roots causes enhanced acid efflux from the upper side of the DEZ. Evidence for gravi-induced modification of ion movements in the root tip includes changes in intracellular potentials and current flow. It is clear that there is more than one motor region in the root with regard to gravitropic responses and there is evidence that the DEZ itself consists of more than one class of responding cells. In order to gain a more complete understanding of the mechanism of gravitropic curvature, the physiological properties of the sub-zones of the root apex need to be thoroughly characterized with regard to their sensitivity to hormones, calcium, acid pH and electrical perturbations.

  15. Genetic variation in the cellular response of Daphnia magna (Crustacea: Cladocera) to its bacterial parasite

    PubMed Central

    Auld, Stuart K. J. R.; Scholefield, Jennifer A.; Little, Tom J.

    2010-01-01

    Linking measures of immune function with infection, and ultimately, host and parasite fitness is a major goal in the field of ecological immunology. In this study, we tested for the presence and timing of a cellular immune response in the crustacean Daphnia magna following exposure to its sterilizing endoparasite Pasteuria ramosa. We found that D. magna possesses two cell types circulating in the haemolymph: a spherical one, which we call a granulocyte and an irregular-shaped amoeboid cell first described by Metchnikoff over 125 years ago. Daphnia magna mounts a strong cellular response (of the amoeboid cells) just a few hours after parasite exposure. We further tested for, and found, considerable genetic variation for the magnitude of this cellular response. These data fostered a heuristic model of resistance in this naturally coevolving host–parasite interaction. Specifically, the strongest cellular responses were found in the most susceptible hosts, indicating resistance is not always borne from a response that destroys invading parasites, but rather stems from mechanisms that prevent their initial entry. Thus, D. magna may have a two-stage defence—a genetically determined barrier to parasite establishment and a cellular response once establishment has begun. PMID:20534618

  16. Exposure to Stressful Environments: Strategy of Adaptive Responses

    NASA Technical Reports Server (NTRS)

    Farhi, Leon E.

    1991-01-01

    Any new natural environment may generate a number of stresses (such as hypoxia, water lack, and heat exposure), each of which can produce strains in more than a single organ system. Every strain may in turn stimulate the body to adapt in multiple ways. Nevertheless, a general strategy of the various adaptive responses emerges when the challenges are divided into three groups. The first category includes conditions that affect the supply of essential molecules, while the second is made up by those stresses that prevent the body from regulating properly the output of waste products, such as CO2 and heat. In both classes, there is a small number of responses, similar in principle, regardless of the specific situation. The third unit is created by environments that disrupt body transport systems. Problems may arise when there is a conflict between two stresses requiring conflicting adaptive changes. An alternative to adaptation, creation of micro-environment, is often favored by the animal.

  17. Urokinase receptor modulates cellular and angiogenic responses in obstructive nephropathy.

    PubMed

    Zhang, Guoqiang; Kim, Heungsoo; Cai, Xiaohe; Lopez-Guisa, Jesus M; Carmeliet, Peter; Eddy, Allison A

    2003-05-01

    Interstitial cells have been implicated in the pathogenesis of renal fibrosis. Given that the urokinase receptor (uPAR) is known to play a role in cell adhesion, migration, and angiogenesis, the present study was designed to evaluate the role of uPAR in the regulation of the phenotypic composition of interstitial cells (macrophages, myofibroblasts, capillaries) in response to chronic renal injury. Groups of uPAR wild-type (+/+) and knockout (-/-) mice were investigated between 3 and 14 d after unilateral ureteral obstruction (UUO) or sham surgery (n = 8 mice per group). The density of F4/80+ interstitial macrophages (Mphi) was significantly lower in the -/- mice (3.3 +/- 0.4 versus 6.9 +/- 1.7% area at day 3 UUO; 10.8 +/- 1.6 versus 15.7 +/- 1.0% at day 14 UUO; -/- versus +/+). In contrast, in the -/- mice there were significantly more alpha smooth muscle actin (alphaSMA)-positive cells (12.9 +/- 3.2 versus 7.8 +/- 1.5% area at day 3 UUO; 21.0 +/- 4.7 versus 9.7 +/- 1.9% at day 14 UUO) and CD34-positive endothelial cells (8.4 +/- 1.9 versus 4.0 +/- 1.1% area at day 14 UUO). These differences were associated with significantly more interstitial fibrosis in the -/- mice based on Sirius red staining (4.6 +/- 0.9 versus 2.3 +/- 0.9% area at 14 d UUO). Absence of the uPAR scavenger receptor was associated with significantly greater accumulation of plasminogen activator inhibitor-1 protein (PAI-1) (20.5 +/- 3.5 versus 9.1 +/- 2.9% area, day 14 UUO) and vitronectin protein (2.4 +/- 1.1 versus 0.9 +/- 0.4% area, day 14 UUO). By immunostaining alphaSMA+ cells, CD34+ cells, vitronectin and PAI-1 co-localized to the same tubulointerstitial area. The number of apoptotic cells increased in response to UUO but was significantly higher in the -/- mice (2.0 +/- 0.2 versus 1.2 +/- 0.2 per 100 tubulointerstitial cells, day 14 UUO) while the number of proliferating cells was significantly lower in the uPAR-/- mice. These data suggest that uPAR deficiency suppresses renal Mphi

  18. Tuning the Poisson's Ratio of Biomaterials for Investigating Cellular Response

    PubMed Central

    Meggs, Kyle; Qu, Xin; Chen, Shaochen

    2013-01-01

    Cells sense and respond to mechanical forces, regardless of whether the source is from a normal tissue matrix, an adjacent cell or a synthetic substrate. In recent years, cell response to surface rigidity has been extensively studied by modulating the elastic modulus of poly(ethylene glycol) (PEG)-based hydrogels. In the context of biomaterials, Poisson's ratio, another fundamental material property parameter has not been explored, primarily because of challenges involved in tuning the Poisson's ratio in biological scaffolds. Two-photon polymerization is used to fabricate suspended web structures that exhibit positive and negative Poisson's ratio (NPR), based on analytical models. NPR webs demonstrate biaxial expansion/compression behavior, as one or multiple cells apply local forces and move the structures. Unusual cell division on NPR structures is also demonstrated. This methodology can be used to tune the Poisson's ratio of several photocurable biomaterials and could have potential implications in the field of mechanobiology. PMID:24076754

  19. Adaptive cellular structures and devices with internal features for enhanced structural performance

    NASA Astrophysics Data System (ADS)

    Pontecorvo, Michael Eugene

    This dissertation aims to develop a family of cellular and repeatable devices that exhibit a variety of force-displacement behaviors. It is envisioned that these cellular structures might be used either as stand-alone elements, or combined and repeated to create multiple types of structures (i.e. buildings, ship hulls, vehicle subfloors, etc.) with the ability to passively or actively perform multiple functions (harmonic energy dissipation, impact mitigation, modulus change) over a range of loading types, amplitudes, and frequencies. To accomplish this goal, this work combines repeatable structural frameworks, such as that provided by a hexagonal cellular structure, with internal structural elements such as springs, viscous dampers, buckling plates, bi-stable von Mises trusses (VMTs), and pneumatic artificial muscles (PAMs). The repeatable framework serves to position damping and load carrying elements throughout the structure, and the configuration of the internal elements allow each cell to be tuned to exhibit a desired force-displacement response. Therefore, gradient structures or structures with variable load paths can be created for an optimal global response to a range of loads. This dissertation focuses on the development of cellular structures for three functions: combined load-carrying capability with harmonic energy dissipation, impact mitigation, and cell modulus variation. One or more conceptual designs are presented for devices that can perform each of these functions, and both experimental measurements and simulations are used to gain a fundamental understanding of each device. Chapter 2 begins with a presentation of a VMT model that is the basis for many of the elements. The equations of motion for the VMT are derived and the static and dynamic behavior of the VMT are discussed in detail. Next, two metrics for the energy dissipation of the VMT - hysteresis loop area and loss factor - are presented. The responses of the VMT to harmonic displacement

  20. Manganese superoxide dismutase interacts with a large scale of cellular and mitochondrial proteins in low dose radiation-induced adaptive radioprotection

    PubMed Central

    Eldridge, Angela; Fan, Ming; Woloschak, Gayle; Grdina, David J.; Chromy, Brett A.; Li, Jian Jian

    2012-01-01

    Cellular adaptive response to certain low level genotoxic stresses including the exposure to low dose ionizing radiation (LDIR) shows promise as a tool to enhance radioprotection in normal cells but not in tumor cells. Manganese superoxide dismutase (MnSOD), a fundamental mitochondrial antioxidant in mammalian cells plays a key role in LDIR-induced adaptive response. In this study, we aim to elucidate the signaling network associated with the MnSOD-induced radiation protection. A MnSOD-interacting protein profile was established in LDIR-treated human skin cells. Human skin keratinocytes (HK18) were irradiated with a single dose LDIR (10 cGy x-ray) and the cell lysates were immunoprecipitated using α-MnSOD and applied to two different gel-based proteomics followed by mass spectrometry for protein identification. Analysis of the profiles of MnSOD interacting partners before and after LDIR detected different patterns of MnSOD protein-protein interactions in response to LDIR. Interestingly, many of the MnSOD interacting proteins are known to have functions related to mitochondrial regulations on cell metabolism, apoptosis and DNA repair. These results provide the evidence indicating that in addition to the enzymatic action detoxifying superoxide, the antioxidant MnSOD may function as a signaling regulator in stress induced adaptive protection through cell survival pathways. PMID:23000060

  1. {sub p}53-Dependent Adaptive Responses in Human Cells Exposed to Space Radiations

    SciTech Connect

    Takahashi, Akihisa; Su Xiaoming; Suzuki, Hiromi; Omori, Katsunori; Seki, Masaya; Hashizume, Toko; Shimazu, Toru; Ishioka, Noriaki; Iwasaki, Toshiyasu; Ohnishi, Takeo

    2010-11-15

    Purpose: It has been reported that priming irradiation or conditioning irradiation with a low dose of X-rays in the range of 0.02-0.1 Gy induces a p53-dependent adaptive response in mammalian cells. The aim of the present study was to clarify the effect of space radiations on the adaptive response. Methods and Materials: Two human lymphoblastoid cell lines were used; one cell line bears a wild-type p53 (wtp53) gene, and another cell line bears a mutated p53 (mp53) gene. The cells were frozen during transportation on the space shuttle and while in orbit in the International Space Station freezer for 133 days between November 15, 2008 and March 29, 2009. After the frozen samples were returned to Earth, the cells were cultured for 6 h and then exposed to a challenging X-ray-irradiation (2 Gy). Cellular sensitivity, apoptosis, and chromosome aberrations were scored using dye-exclusion assays, Hoechst33342 staining assays, and chromosomal banding techniques, respectively. Results: In cells exposed to space radiations, adaptive responses such as the induction of radioresistance and the depression of radiation-induced apoptosis and chromosome aberrations were observed in wtp53 cells but not in mp53 cells. Conclusion: These results have confirmed the hypothesis that p53-dependent adaptive responses are apparently induced by space radiations within a specific range of low doses. The cells exhibited this effect owing to space radiations exposure, even though the doses in space were very low.

  2. Transcriptomic Analysis Reveals Adaptive Responses of an Enterobacteriaceae Strain LSJC7 to Arsenic Exposure

    PubMed Central

    Zhang, Yingjiao; Chen, Songcan; Hao, Xiuli; Su, Jian-Qiang; Xue, Ximei; Yan, Yu; Zhu, Yong-Guan; Ye, Jun

    2016-01-01

    Arsenic (As) resistance determinant ars operon is present in many bacteria and has been demonstrated to enhance As(V) resistance of bacteria. However, whole molecular mechanism adaptations of bacteria in response to As(V) stress remain largely unknown. In this study, transcriptional profiles of Enterobacteriaceae strain LSJC7 responding to As(V) stress were analyzed using RNA-seq and qRT-PCR. As expected, genes involved in As(V) uptake were down-regulated, those involved in As(V) reduction and As(III) efflux were up-regulated, which avoided cellular As accumulation. Reactive oxygen species and nitric oxide (NO) were induced, which caused cellular damages including DNA, protein, and Fe–S cluster damage in LSJC7. The expression of specific genes encoding transcriptional regulators, such as nsrR and soxRS were also induced. NsrR and SoxRS modulated many critical metabolic activities in As(V) stressed LSJC7 cells, including reactive species scavenging and repairing damaged DNA, proteins, and Fe–S clusters. Therefore, besides As uptake, reduction, and efflux; oxidative stress defense and damage repair were the main cellular adaptive responses of LSJC7 to As(V) stress. PMID:27199962

  3. Transcriptomic Analysis Reveals Adaptive Responses of an Enterobacteriaceae Strain LSJC7 to Arsenic Exposure.

    PubMed

    Zhang, Yingjiao; Chen, Songcan; Hao, Xiuli; Su, Jian-Qiang; Xue, Ximei; Yan, Yu; Zhu, Yong-Guan; Ye, Jun

    2016-01-01

    Arsenic (As) resistance determinant ars operon is present in many bacteria and has been demonstrated to enhance As(V) resistance of bacteria. However, whole molecular mechanism adaptations of bacteria in response to As(V) stress remain largely unknown. In this study, transcriptional profiles of Enterobacteriaceae strain LSJC7 responding to As(V) stress were analyzed using RNA-seq and qRT-PCR. As expected, genes involved in As(V) uptake were down-regulated, those involved in As(V) reduction and As(III) efflux were up-regulated, which avoided cellular As accumulation. Reactive oxygen species and nitric oxide (NO) were induced, which caused cellular damages including DNA, protein, and Fe-S cluster damage in LSJC7. The expression of specific genes encoding transcriptional regulators, such as nsrR and soxRS were also induced. NsrR and SoxRS modulated many critical metabolic activities in As(V) stressed LSJC7 cells, including reactive species scavenging and repairing damaged DNA, proteins, and Fe-S clusters. Therefore, besides As uptake, reduction, and efflux; oxidative stress defense and damage repair were the main cellular adaptive responses of LSJC7 to As(V) stress.

  4. Space experiment "Cellular Responses to Radiation in Space (CELLRAD)": Hardware and biological system tests

    NASA Astrophysics Data System (ADS)

    Hellweg, Christine E.; Dilruba, Shahana; Adrian, Astrid; Feles, Sebastian; Schmitz, Claudia; Berger, Thomas; Przybyla, Bartos; Briganti, Luca; Franz, Markus; Segerer, Jürgen; Spitta, Luis F.; Henschenmacher, Bernd; Konda, Bikash; Diegeler, Sebastian; Baumstark-Khan, Christa; Panitz, Corinna; Reitz, Günther

    2015-11-01

    One factor contributing to the high uncertainty in radiation risk assessment for long-term space missions is the insufficient knowledge about possible interactions of radiation with other spaceflight environmental factors. Such factors, e.g. microgravity, have to be considered as possibly additive or even synergistic factors in cancerogenesis. Regarding the effects of microgravity on signal transduction, it cannot be excluded that microgravity alters the cellular response to cosmic radiation, which comprises a complex network of signaling pathways. The purpose of the experiment ;Cellular Responses to Radiation in Space; (CELLRAD, formerly CERASP) is to study the effects of combined exposure to microgravity, radiation and general space flight conditions on mammalian cells, in particular Human Embryonic Kidney (HEK) cells that are stably transfected with different plasmids allowing monitoring of proliferation and the Nuclear Factor κB (NF-κB) pathway by means of fluorescent proteins. The cells will be seeded on ground in multiwell plate units (MPUs), transported to the ISS, and irradiated by an artificial radiation source after an adaptation period at 0 × g and 1 × g. After different incubation periods, the cells will be fixed by pumping a formaldehyde solution into the MPUs. Ground control samples will be treated in the same way. For implementation of CELLRAD in the Biolab on the International Space Station (ISS), tests of the hardware and the biological systems were performed. The sequence of different steps in MPU fabrication (cutting, drilling, cleaning, growth surface coating, and sterilization) was optimized in order to reach full biocompatibility. Different coatings of the foil used as growth surface revealed that coating with 0.1 mg/ml poly-D-lysine supports cell attachment better than collagen type I. The tests of prototype hardware (Science Model) proved its full functionality for automated medium change, irradiation and fixation of cells. Exposure of

  5. Space experiment "Cellular Responses to Radiation in Space (CellRad)": Hardware and biological system tests.

    PubMed

    Hellweg, Christine E; Dilruba, Shahana; Adrian, Astrid; Feles, Sebastian; Schmitz, Claudia; Berger, Thomas; Przybyla, Bartos; Briganti, Luca; Franz, Markus; Segerer, Jürgen; Spitta, Luis F; Henschenmacher, Bernd; Konda, Bikash; Diegeler, Sebastian; Baumstark-Khan, Christa; Panitz, Corinna; Reitz, Günther

    2015-11-01

    One factor contributing to the high uncertainty in radiation risk assessment for long-term space missions is the insufficient knowledge about possible interactions of radiation with other spaceflight environmental factors. Such factors, e.g. microgravity, have to be considered as possibly additive or even synergistic factors in cancerogenesis. Regarding the effects of microgravity on signal transduction, it cannot be excluded that microgravity alters the cellular response to cosmic radiation, which comprises a complex network of signaling pathways. The purpose of the experiment "Cellular Responses to Radiation in Space" (CellRad, formerly CERASP) is to study the effects of combined exposure to microgravity, radiation and general space flight conditions on mammalian cells, in particular Human Embryonic Kidney (HEK) cells that are stably transfected with different plasmids allowing monitoring of proliferation and the Nuclear Factor κB (NF-κB) pathway by means of fluorescent proteins. The cells will be seeded on ground in multiwell plate units (MPUs), transported to the ISS, and irradiated by an artificial radiation source after an adaptation period at 0 × g and 1 × g. After different incubation periods, the cells will be fixed by pumping a formaldehyde solution into the MPUs. Ground control samples will be treated in the same way. For implementation of CellRad in the Biolab on the International Space Station (ISS), tests of the hardware and the biological systems were performed. The sequence of different steps in MPU fabrication (cutting, drilling, cleaning, growth surface coating, and sterilization) was optimized in order to reach full biocompatibility. Different coatings of the foil used as growth surface revealed that coating with 0.1 mg/ml poly-D-lysine supports cell attachment better than collagen type I. The tests of prototype hardware (Science Model) proved its full functionality for automated medium change, irradiation and fixation of cells. Exposure of

  6. Durum Wheat Roots Adapt to Salinity Remodeling the Cellular Content of Nitrogen Metabolites and Sucrose

    PubMed Central

    Annunziata, Maria Grazia; Ciarmiello, Loredana F.; Woodrow, Pasqualina; Maximova, Eugenia; Fuggi, Amodio; Carillo, Petronia

    2017-01-01

    Plants are currently experiencing increasing salinity problems due to irrigation with brackish water. Moreover, in fields, roots can grow in soils which show spatial variation in water content and salt concentration, also because of the type of irrigation. Salinity impairs crop growth and productivity by inhibiting many physiological and metabolic processes, in particular nitrate uptake, translocation, and assimilation. Salinity determines an increase of sap osmolality from about 305 mOsmol kg−1 in control roots to about 530 mOsmol kg−1 in roots under salinity. Root cells adapt to salinity by sequestering sodium in the vacuole, as a cheap osmoticum, and showing a rearrangement of few nitrogen-containing metabolites and sucrose in the cytosol, both for osmotic adjustment and oxidative stress protection, thus providing plant viability even at low nitrate levels. Mainly glycine betaine and sucrose at low nitrate concentration, and glycine betaine, asparagine and proline at high nitrate levels can be assumed responsible for the osmotic adjustment of the cytosol, the assimilation of the excess of ammonium and the scavenging of ROS under salinity. High nitrate plants with half of the root system under salinity accumulate proline and glutamine in both control and salt stressed split roots, revealing that osmotic adjustment is not a regional effect in plants. The expression level and enzymatic activities of asparagine synthetase and Δ1-pyrroline-5-carboxylate synthetase, as well as other enzymatic activities of nitrogen and carbon metabolism, are analyzed. PMID:28119716

  7. Cellular response of freshwater green algae to perfluorooctanoic acid toxicity.

    PubMed

    Xu, Dongmei; Li, Chandan; Chen, Hong; Shao, Bo

    2013-02-01

    Perfluorooctanoic acid (PFOA) is a kind of persistent organic pollutants and its aquatic eco-toxicity has attracted wide attention; however, the mechanism involved in its toxicity as well as the cell response against PFOA have not been well established. Herein, using single-celled green algae Chlorella pyrenoidosa and Selenastrum capricornutum at the logarithmic growth stage as test organisms, we studied the toxic effects of PFOA on the cell permeability, The 96 h-EC(50) values of PFOA for C. pyrenoidosa and S. capricornutum were 207.46 mg L(-1) and 190.99 mg L(-1), respectively, lower than the 96 h-EC(50) values reported in the literatures. After 96 h of PFOA exposure, the permeability of the cell membranes of both algae was significantly decreased, and the chlorophyll concentration mirrored the trends of algal growth. In both algal species, after a 192-h exposure to a low concentration of PFOA, the activities of superoxide dismutase and catalase were greater than those of the control. At higher concentrations of PFOA, activities of superoxide dismutase and catalase were strongly inhibited. These results indicate that long-term exposure to low levels of PFOA may induce excessive generation of reactive oxygen species in algal cells, causing oxidative damage to cells.

  8. Proteomic-based mechanistic investigation of low-dose radiation-induced cellular responses/effects

    SciTech Connect

    Chen, Xian

    2013-10-23

    The goal of our project is to apply our unique systems investigation strategy to reveal the molecular mechanisms underlying the radiation induction and transmission of oxidative damage, adaptive response, and bystander effect at low-doses. Beginning with simple in vitro systems such as fibroblast or epithelial pure culture, our amino acid-coded mass tagging (AACT) comparative proteomic platform will be used to measure quantitatively proteomic changes at high- or low-dose level with respect to their endogenous damage levels respectively, in which a broad range of unique regulated proteins sensitive to low-dose IR will be distinguished. To zoom in how these regulated proteins interact with other in the form of networks in induction/transmission pathways, these regulated proteins will be selected as baits for making a series of fibroblast cell lines that stably express each of them. Using our newly developed method of ?dual-tagging? quantitative proteomics that integrate the capabilities of natural complex expression/formation, simple epitope affinity isolation (not through tandem affinity purification or TAP), and ?in-spectra? AACT quantitative measurements using mass spectrometry (MS), we will be able to distinguish systematically interacting proteins with each bait in real time. Further, in addition to both proteome-wide (global differentially expressed proteins) and pathway-scale (bait-specific) profiling information, we will perform a computational network analysis to elucidate a global pathway/mechanisms underlying cellular responses to real-time low-dose IR. Similarly, we will extend our scheme to investigate systematically those induction/transmission pathways occurring in a fibroblast-epithelial interacting model in which the bystander cell (fibroblast) monitor the IR damage to the target cell (epithelial cell). The results will provide the proteome base (molecular mechanisms/pathways for signaling) for the low dose radiation-induced essential tissue

  9. Evolution of a Cellular Immune Response in Drosophila: A Phenotypic and Genomic Comparative Analysis

    PubMed Central

    Salazar-Jaramillo, Laura; Paspati, Angeliki; van de Zande, Louis; Vermeulen, Cornelis Joseph; Schwander, Tanja; Wertheim, Bregje

    2014-01-01

    Understanding the genomic basis of evolutionary adaptation requires insight into the molecular basis underlying phenotypic variation. However, even changes in molecular pathways associated with extreme variation, gains and losses of specific phenotypes, remain largely uncharacterized. Here, we investigate the large interspecific differences in the ability to survive infection by parasitoids across 11 Drosophila species and identify genomic changes associated with gains and losses of parasitoid resistance. We show that a cellular immune defense, encapsulation, and the production of a specialized blood cell, lamellocytes, are restricted to a sublineage of Drosophila, but that encapsulation is absent in one species of this sublineage, Drosophila sechellia. Our comparative analyses of hemopoiesis pathway genes and of genes differentially expressed during the encapsulation response revealed that hemopoiesis-associated genes are highly conserved and present in all species independently of their resistance. In contrast, 11 genes that are differentially expressed during the response to parasitoids are novel genes, specific to the Drosophila sublineage capable of lamellocyte-mediated encapsulation. These novel genes, which are predominantly expressed in hemocytes, arose via duplications, whereby five of them also showed signatures of positive selection, as expected if they were recruited for new functions. Three of these novel genes further showed large-scale and presumably loss-of-function sequence changes in D. sechellia, consistent with the loss of resistance in this species. In combination, these convergent lines of evidence suggest that co-option of duplicated genes in existing pathways and subsequent neofunctionalization are likely to have contributed to the evolution of the lamellocyte-mediated encapsulation in Drosophila. PMID:24443439

  10. Transgenic mouse model for imaging of ATF4 translational activation-related cellular stress responses in vivo

    PubMed Central

    Iwawaki, Takao; Akai, Ryoko; Toyoshima, Takae; Takeda, Naoki; Ishikawa, Tomo-o; Yamamura, Ken-ichi

    2017-01-01

    Activating transcription factor 4 (ATF4) is a translationally activated protein that plays a role in cellular adaptation to several stresses. Because these stresses are associated with various diseases, the translational control of ATF4 needs to be evaluated from the physiological and pathological points of view. We have developed a transgenic mouse model to monitor the translational activation of ATF4 in response to cellular stress. By using this mouse model, we were able to detect nutrient starvation response, antivirus response, endoplasmic reticulum (ER) stress response, and oxidative stress in vitro and ex vivo, as well as in vivo. The reporter system introduced into our mouse model was also shown to work in a stress intensity-dependent manner and a stress duration-dependent manner. The mouse model is therefore a useful tool for imaging ATF4 translational activation at various levels, from cell cultures to whole bodies, and it has a range of useful applications in investigations on the physiological and pathological roles of ATF4-related stress and in the development of clinical drugs for treating ATF4-associated diseases. PMID:28387317

  11. Aldehyde Dehydrogenases in Cellular Responses to Oxidative/electrophilic Stress

    PubMed Central

    Singh, Surendra; Brocker, Chad; Koppaka, Vindhya; Ying, Chen; Jackson, Brian; Matsumoto, Akiko; Thompson, David C.; Vasiliou, Vasilis

    2013-01-01

    Reactive oxygen species (ROS) are continuously generated within living systems and the inability to manage ROS load leads to elevated oxidative stress and cell damage. Oxidative stress is coupled to the oxidative degradation of lipid membranes, also known as lipid peroxidation. This process generates over 200 types of aldehydes, many of which are highly reactive and toxic. Aldehyde dehydrogenases (ALDHs) metabolize endogenous and exogenous aldehydes and thereby mitigate oxidative/electrophilic stress in prokaryotic and eukaryotic organisms. ALDHs are found throughout the evolutionary gamut, from single celled organisms to complex multicellular species. Not surprisingly, many ALDHs in evolutionarily distant, and seemingly unrelated, species perform similar functions, including protection against a variety of environmental stressors like dehydration and ultraviolet radiation. The ability to act as an ‘aldehyde scavenger’ during lipid peroxidation is another ostensibly universal ALDH function found across species. Up-regulation of ALDHs is a stress response in bacteria (environmental and chemical stress), plants (dehydration, salinity and oxidative stress), yeast (ethanol exposure and oxidative stress), Caenorhabditis elegans (lipid peroxidation) and mammals (oxidative stress and lipid peroxidation). Recent studies have also identified ALDH activity as an important feature of cancer stem cells. In these cells, ALDH expression helps abrogate oxidative stress and imparts resistance against chemotherapeutic agents such as oxazaphosphorine, taxane and platinum drugs. The ALDH superfamily represents a fundamentally important class of enzymes that significantly contributes to the management of electrophilic/oxidative stress within living systems. Mutations in various ALDHs are associated with a variety of pathological conditions in humans, underscoring the fundamental importance of these enzymes in physiological and pathological processes. PMID:23195683

  12. Mast cells in allergy: innate instructors of adaptive responses.

    PubMed

    Stelekati, Erietta; Orinska, Zane; Bulfone-Paus, Silvia

    2007-01-01

    The function of mast cells as effector cells in allergy has been extensively studied. However, increasing insight into mast cell physiology has revealed new mast cell functions and has introduced mast cells as key players in the regulation of innate as well as adaptive immunity. For example, mast cells have recently been found to express Toll-like receptors (TLRs), which enable them to participate in the innate immune response against pathogens. Furthermore, mast cells have been reported to interact with B cells, dendritic cells and T cells and thereby modulate the direction of an adaptive immune response. Finally, recent documentation that mast cells express functional MHC class II and costimulatory molecules and release immunologically active exosomes, has raised the possibility that mast cells also engage in (as yet) poorly understood antigen presentation functions. In this review, we explore the hypothesis that mast cells serve as central mediators between innate and adaptive immunity, rather as pure effector cells, during allergic innate responses.

  13. Readapting the adaptive immune response - therapeutic strategies for atherosclerosis.

    PubMed

    Sage, Andrew P; Mallat, Ziad

    2017-01-04

    Cardiovascular diseases remain a major global health issue, with the development of atherosclerosis as a major underlying cause. Our treatment of cardiovascular disease has improved greatly over the past three decades, but much remains to be done reduce disease burden. Current priorities include reducing atherosclerosis advancement to clinically significant stages and preventing plaque rupture or erosion. Inflammation and involvement of the adaptive immune system influences all these aspects and therefore is one focus for future therapeutic development. The atherosclerotic vascular wall is now recognized to be invaded from both sides (arterial lumen and adventitia), for better or worse, by the adaptive immune system. Atherosclerosis is also affected at several stages by adaptive immune responses, overall providing many opportunities to target these responses and to reduce disease progression. Protective influences that may be defective in diseased individuals include humoral responses to modified LDL and regulatory T cell responses. There are many strategies in development to boost these pathways in humans, including vaccine-based therapies. The effects of various existing adaptive immune targeting therapies, such as blocking critical co-stimulatory pathways or B cell depletion, on cardiovascular disease are beginning to emerge with important consequences for both autoimmune disease patients and the potential for wider use of such therapies. Entering the translation phase for adaptive immune targeting therapies is an exciting and promising prospect.

  14. Adaptive shaping of cortical response selectivity in the vibrissa pathway

    PubMed Central

    Zheng, He J. V.; Wang, Qi

    2015-01-01

    One embodiment of context-dependent sensory processing is bottom-up adaptation, where persistent stimuli decrease neuronal firing rate over hundreds of milliseconds. Adaptation is not, however, simply the fatigue of the sensory pathway, but shapes the information flow and selectivity to stimulus features. Adaptation enhances spatial discriminability (distinguishing stimulus location) while degrading detectability (reporting presence of the stimulus), for both the ideal observer of the cortex and awake, behaving animals. However, how the dynamics of the adaptation shape the cortical response and this detection and discrimination tradeoff is unknown, as is to what degree this phenomenon occurs on a continuum as opposed to a switching of processing modes. Using voltage-sensitive dye imaging in anesthetized rats to capture the temporal and spatial characteristics of the cortical response to tactile inputs, we showed that the suppression of the cortical response, in both magnitude and spatial spread, is continuously modulated by the increasing amount of energy in the adapting stimulus, which is nonuniquely determined by its frequency and velocity. Single-trial ideal observer analysis demonstrated a tradeoff between detectability and spatial discriminability up to a moderate amount of adaptation, which corresponds to the frequency range in natural whisking. This was accompanied by a decrease in both detectability and discriminability with high-energy adaptation, which indicates a more complex coupling between detection and discrimination than a simple switching of modes. Taken together, the results suggest that adaptation operates on a continuum and modulates the tradeoff between detectability and discriminability that has implications for information processing in ethological contexts. PMID:25787959

  15. Linking physiological and cellular responses to thermal stress: β-adrenergic blockade reduces the heat shock response in fish.

    PubMed

    Templeman, Nicole M; LeBlanc, Sacha; Perry, Steve F; Currie, Suzanne

    2014-08-01

    When faced with stress, animals use physiological and cellular strategies to preserve homeostasis. We were interested in how these high-level stress responses are integrated at the level of the whole animal. Here, we investigated the capacity of the physiological stress response, and specifically the β-adrenergic response, to affect the induction of the cellular heat shock proteins, HSPs, following a thermal stress in vivo. We predicted that blocking β-adrenergic stimulation during an acute heat stress in the whole animal would result in reduced levels of HSPs in red blood cells (RBCs) of rainbow trout compared to animals where adrenergic signaling remained intact. We first determined that a 1 h heat shock at 25 °C in trout acclimated to 13 °C resulted in RBC adrenergic stimulation as determined by a significant increase in cell swelling, a hallmark of the β-adrenergic response. A whole animal injection with the β2-adrenergic antagonist, ICI-118,551, successfully reduced this heat-induced RBC swelling. The acute heat shock caused a significant induction of HSP70 in RBCs of 13 °C-acclimated trout as well as a significant increase in plasma catecholamines. When heat-shocked fish were treated with ICI-118,551, we observed a significant attenuation of the HSP70 response. We conclude that circulating catecholamines influence the cellular heat shock response in rainbow trout RBCs, demonstrating physiological/hormonal control of the cellular stress response.

  16. Adaptation responses of crops to climate change

    SciTech Connect

    Seino, Hiroshi

    1993-12-31

    Appreciable global climatic responses to increasing levels of atmospheric CO{sub 2} and other trace gases are expected to take place over the next 50 to 80 years. Increasing atmospheric concentrations of carbon dioxide and other greenhouse gases are producing or will produce changes in the climate of the Earth. In particular, numerous efforts of climate modeling project very substantial increase of surface air temperature. In addition to a general warming of the atmosphere, the possibility of increased summer dryness in the continental mid-latitudes has been suggested on the basis of both historical analogues and some General Circulation Model (GCM) studies. There are three types of effect of climatic change on agriculture: (1) the physiological (direct) effect of elevated levels of atmospheric CO{sub 2} on crop plants and weeds, (2) the effect of changes in parameters of climate (e.g., temperature, precipitation, and solar radiation) on plants and animals, and (3) the effects of climate-related rises in sea-level on land use. The direct effects of elevated CO{sub 2} are on photosynthesis and respiration and thereby on growth, and there are additional effects of increased CO{sub 2} on development, yield quality and stomatal aperture and water use. A doubling of CO{sub 2} increases the instantaneous photosynthetic rate by 30% to 100%, depending on the other environmental conditions, and reduce water requirements of plants by reducing transpiration (per unit leaf area) through reductions in stomatal aperture. A doubling of CO{sub 2} causes partial stomatal closure on both C{sub 3} and C{sub 4} plants (approximately a 40% decrease in aperture). In many experiments this results in reductions of transpiration of about 23% to 46%. However. there is considerable uncertainty over the magnitude of this in natural conditions.

  17. Topology optimization of adaptive fluid-actuated cellular structures with arbitrary polygonal motor cells

    NASA Astrophysics Data System (ADS)

    Lv, Jun; Tang, Liang; Li, Wenbo; Liu, Lei; Zhang, Hongwu

    2016-05-01

    This paper mainly focuses on the fast and efficient design method for plant bioinspired fluidic cellular materials and structures composed of polygonal motor cells. Here we developed a novel structural optimization method with arbitrary polygonal coarse-grid elements based on multiscale finite element frameworks. The fluidic cellular structures are meshed with irregular polygonal coarse-grid elements according to their natural size and the shape of the imbedded motor cells. The multiscale base functions of solid displacement and hydraulic pressure are then constructed to bring the small-scale information of the irregular motor cells to the large-scale simulations on the polygonal coarse-grid elements. On this basis, a new topology optimization method based on the resulting polygonal coarse-grid elements is proposed to determine the optimal distributions or number of motor cells in the smart cellular structures. Three types of optimization problems are solved according to the usages of the fluidic cellular structures. Firstly, the proposed optimization method is utilized to minimize the system compliance of the load-bearing fluidic cellular structures. Second, the method is further extended to design biomimetic compliant actuators of the fluidic cellular materials due to the fact that non-uniform volume expansions of fluid in the cells can induce elastic action. Third, the optimization problem focuses on the weight minimization of the cellular structure under the constraints for the compliance of the whole system. Several representative examples are investigated to validate the effectiveness of the proposed polygon-based topology optimization method of the smart materials.

  18. Examining the limits of cellular adaptation bursting mechanisms in biologically-based excitatory networks of the hippocampus.

    PubMed

    Ferguson, K A; Njap, F; Nicola, W; Skinner, F K; Campbell, S A

    2015-12-01

    Determining the biological details and mechanisms that are essential for the generation of population rhythms in the mammalian brain is a challenging problem. This problem cannot be addressed either by experimental or computational studies in isolation. Here we show that computational models that are carefully linked with experiment provide insight into this problem. Using the experimental context of a whole hippocampus preparation in vitro that spontaneously expresses theta frequency (3-12 Hz) population bursts in the CA1 region, we create excitatory network models to examine whether cellular adaptation bursting mechanisms could critically contribute to the generation of this rhythm. We use biologically-based cellular models of CA1 pyramidal cells and network sizes and connectivities that correspond to the experimental context. By expanding our mean field analyses to networks with heterogeneity and non all-to-all coupling, we allow closer correspondence with experiment, and use these analyses to greatly extend the range of parameter values that are explored. We find that our model excitatory networks can produce theta frequency population bursts in a robust fashion.Thus, even though our networks are limited by not including inhibition at present, our results indicate that cellular adaptation in pyramidal cells could be an important aspect for the occurrence of theta frequency population bursting in the hippocampus. These models serve as a starting framework for the inclusion of inhibitory cells and for the consideration of additional experimental features not captured in our present network models.

  19. Stimuli-Responsive Mechanically Adaptive Polymer Nanocomposites

    PubMed Central

    Shanmuganathan, Kadhiravan; Capadona, Jeffrey R.; Rowan, Stuart J.; Weder, Christoph

    2010-01-01

    A new series of biomimetic stimuli-responsive nanocomposites, which change their mechanical properties upon exposure to physiological conditions, was prepared and investigated. The materials were produced by introducing percolating networks of cellulose nanofibers or “whiskers” derived from tunicates into poly(vinyl acetate) (PVAc), poly(butyl methacrylate) (PBMA), and blends of these polymers, with the objective of determining how the hydrophobicity and glass-transition temperature (Tg) of the polymer matrix affect the water-induced mechanically dynamic behavior. Below the Tg (~60–70 °C), the incorporation of whiskers (15.1 – 16.5% v/v) modestly increased the tensile storage moduli (E′) of the neat polymers from 0.6 to 3.8 GPa (PBMA) and from 2 to 5.2 GPa (PVAc). The reinforcement was much more dramatic above Tg, where E′ increased from 1.2 to 690 MPa (PVAc) and ~1 to 1.1 GPa (PBMA). Upon exposure to physiological conditions (immersion in artificial cerebrospinal fluid, ACSF, at 37 °C) all materials displayed a decrease of E′. The most significant contrast was seen in PVAc; for example the E′ of a 16.5% v/v PVAc/whisker nanocomposite decreased from 5.2 GPa to 12.7 MPa. Only a modest modulus decrease was measured for PBMA/whisker nanocomposite; here the E′ of a 15.1% v/v PBMA/whisker nanocomposite decreased from 3.8 to 1.2 GPa. A systematic investigation revealed that the magnitude of the mechanical contrast was related to the degree of swelling with ACSF, which was shown to increase with whisker content, temperature, and polarity of the matrix (PVAc > PBMA). The mechanical morphing of the new materials can be described in the framework of both the percolation and Halpin-Kardos models for nanocomposite reinforcement, and is the result of changing interactions among the nanoparticles and plasticization of the matrix upon swelling. PMID:20305827

  20. Genetic erosion impedes adaptive responses to stressful environments

    PubMed Central

    Bijlsma, R; Loeschcke, Volker

    2012-01-01

    Biodiversity is increasingly subjected to human-induced changes of the environment. To persist, populations continually have to adapt to these often stressful changes including pollution and climate change. Genetic erosion in small populations, owing to fragmentation of natural habitats, is expected to obstruct such adaptive responses: (i) genetic drift will cause a decrease in the level of adaptive genetic variation, thereby limiting evolutionary responses; (ii) inbreeding and the concomitant inbreeding depression will reduce individual fitness and, consequently, the tolerance of populations to environmental stress. Importantly, inbreeding generally increases the sensitivity of a population to stress, thereby increasing the amount of inbreeding depression. As adaptation to stress is most often accompanied by increased mortality (cost of selection), the increase in the ‘cost of inbreeding’ under stress is expected to severely hamper evolutionary adaptive processes. Inbreeding thus plays a pivotal role in this process and is expected to limit the probability of genetically eroded populations to successfully adapt to stressful environmental conditions. Consequently, the dynamics of small fragmented populations may differ considerably from large nonfragmented populations. The resilience of fragmented populations to changing and deteriorating environments is expected to be greatly decreased. Alleviating inbreeding depression, therefore, is crucial to ensure population persistence. PMID:25568035

  1. Immune system - part I. Fundamentals of innate immunity with emphasis on molecular and cellular mechanisms of inflammatory response.

    PubMed

    Cruvinel, Wilson de Melo; Mesquita, Danilo; Araújo, Júlio Antônio Pereira; Catelan, Tânia Tieko Takao; de Souza, Alexandre Wagner Silva; da Silva, Neusa Pereira; Andrade, Luís Eduardo Coelho

    2010-01-01

    The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the body's homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.

  2. The role of thiols in cellular response to radiation and drugs

    SciTech Connect

    Biaglow, J.E.; Varnes, M.E.; Clark, E.P.; Epp, E.R.

    1983-09-01

    Cellular nonprotein thiols (NPSH) consist of glutathione (GSH) and other low molecular weight species such as cysteine, cysteamine, and coenzyme A. GSH is usually less than the total cellular NPSH, and with thiol reactive agents, such as diethyl maleate (DEM), its rate of depletion is in part dependent upon the cellular capacity for its resynthesis. If resynthesis is blocked by buthionine-S,R-sulfoximine(BSO), the NPSH, including GSH, is depleted more rapidly, Cellular thiol depletion by diamide, N-ethylmaleimide, and BSO may render oxygenated cells more sensitive to radiation. These cells may or may not show a reduction in the oxygen enhancement ratio (OER). Human A549 lung carcinoma cells depleted of their NPSH either by prolonged culture or by BSO treatment do not show a reduced OER but do show increased aerobic responses to radiation. Some nitroheterocyclic radiosensitizing drugs also deplete cellular thiols under aerobic conditions. Such reactivity may be the reason that they show anomalous radiation sensitization (i.e., better than predicted on the basis of electron affinity). Other nitrocompounds, such as misonidazole, are activated under hypoxic conditions to radical intermediates. When cellular thiols are depleted peroxide is formed. Under hypoxic conditions thiols are depleted because metabolically reduced intermediates react with GSH instead of oxygen. Thiol depletion, under hypoxic conditions, may be the reason that misonidazole and other nitrocompounds show an extra enhancement ratio with hypoxic cells. Thiol depletion by DEM or BSO alters the radiation response of hypoxic cells to misonidazole.

  3. Adaptation responses to climate change differ between global megacities

    NASA Astrophysics Data System (ADS)

    Georgeson, Lucien; Maslin, Mark; Poessinouw, Martyn; Howard, Steve

    2016-06-01

    Urban areas are increasingly at risk from climate change, with negative impacts predicted for human health, the economy and ecosystems. These risks require responses from cities to improve their resilience. Policymakers need to understand current adaptation spend to plan comprehensively and effectively. Through the measurement of spend in the newly defined `adaptation economy', we analyse current climate change adaptation efforts in ten megacities. In all cases, the adaptation economy remains a small part of the overall economy, representing a maximum of 0.33% of a city's gross domestic product (here referred to as GDPc). Differences in total spend are significant between cities in developed, emerging and developing countries, ranging from #15 million to #1,600 million. Comparing key subsectors, we demonstrate the differences in adaptation profiles. Developing cities have higher proportional spend on health and agriculture, whereas developed cities have higher spend on energy and water. Spend per capita and percentage of GDPc comparisons more clearly show disparities between cities. Developing country cities spend half the proportion of GDPc and significantly less per capita, suggesting that adaptation spend is driven by wealth rather than the number of vulnerable people. This indicates that current adaptation activities are insufficient in major population centres in developing and emerging economies.

  4. Replicated evolution of integrated plastic responses during early adaptive divergence.

    PubMed

    Parsons, Kevin J; Robinson, Beren W

    2006-04-01

    Colonization of a novel environment is expected to result in adaptive divergence from the ancestral population when selection favors a new phenotypic optimum. Local adaptation in the new environment occurs through the accumulation and integration of character states that positively affect fitness. The role played by plastic traits in adaptation to a novel environment has generally been ignored, except for variable environments. We propose that if conditions in a relatively stable but novel environment induce phenotypically plastic responses in many traits, and if genetic variation exists in the form of those responses, then selection may initially favor the accumulation and integration of functionally useful plastic responses. Early divergence between ancestral and colonist forms will then occur with respect to their plastic responses across the gradient bounded by ancestral and novel environmental conditions. To test this, we compared the magnitude, integration, and pattern of plastic character responses in external body form induced by shallow versus open water conditions between two sunfish ecomorphs that coexist in four postglacial lakes. The novel sunfish ecomorph is present in the deeper open water habitat, whereas the ancestral ecomorph inhabits the shallow waters along the lake margin. Plastic responses by open water ecomorphs were more correlated than those of their local shallow water ecomorph in two of the populations, whereas equal levels of correlated plastic character responses occurred between ecomorphs in the other two populations. Small but persistent differences occurred between ecomorph pairs in the pattern of their character responses, suggesting a recent divergence. Open water ecomorphs shared some similarities in the covariance among plastic responses to rearing environment. Replication in the form of correlated plastic responses among populations of open water ecomorphs suggests that plastic character states may evolve under selection

  5. Beyond Adapting to Climate Change: Embedding Adaptation in Responses to Multiple Threats and Stresses

    SciTech Connect

    Wilbanks, Thomas J; Kates, Dr. Robert W.

    2010-01-01

    Climate change impacts are already being experienced in every region of the United States and every part of the world most severely in Arctic regions and adaptation is needed now. Although climate change adaptation research is still in its infancy, significant adaptation planning in the United States has already begun in a number of localities. This article seeks to broaden the adaptation effort by integrating it with broader frameworks of hazards research, sustainability science, and community and regional resilience. To extend the range of experience, we draw from ongoing case studies in the Southeastern United States and the environmental history of New Orleans to consider the multiple threats and stresses that all communities and regions experience. Embedding climate adaptation in responses to multiple threats and stresses helps us to understand climate change impacts, themselves often products of multiple stresses, to achieve community acceptance of needed adaptations as co-benefits of addressing multiple threats, and to mainstream the process of climate adaptation through the larger envelope of social relationships, communication channels, and broad-based awareness of needs for risk management that accompany community resilience.

  6. Sex as a response to oxidative stress: a twofold increase in cellular reactive oxygen species activates sex genes.

    PubMed

    Nedelcu, Aurora M; Marcu, Oana; Michod, Richard E

    2004-08-07

    Organisms are constantly subjected to factors that can alter the cellular redox balance and result in the formation of a series of highly reactive molecules known as reactive oxygen species (ROS). As ROS can be damaging to biological structures, cells evolved a series of mechanisms (e.g. cell-cycle arrest, programmed cell death) to respond to high levels of ROS (i.e. oxidative stress). Recently, we presented evidence that in a facultatively sexual lineage--the multicellular green alga Volvox carteri--sex is an additional response to increased levels of stress, and probably ROS and DNA damage. Here we show that, in V. carteri, (i) sex is triggered by an approximately twofold increase in the level of cellular ROS (induced either by the natural sex-inducing stress, namely heat, or by blocking the mitochondrial electron transport chain with antimycin A), and (ii) ROS are responsible for the activation of sex genes. As most types of stress result in the overproduction of ROS, we believe that our findings will prove to extend to other facultatively sexual lineages, which could be indicative of the ancestral role of sex as an adaptive response to stress and ROS-induced DNA damage.

  7. Heterogeneity in cellular and humoral immune responses against Toxoplasma gondii antigen in humans

    PubMed Central

    FATOOHI, A F; COZON, G J N; GONZALO, P; MAYENCON, M; GREENLAND, T; PICOT, S; PEYRON, F

    2004-01-01

    Protection against Toxoplasma gondii in infected patients is mainly attributed to cellular immunity. We here attempt to improve the characterization of the proteins that induce cellular immunity in naturally infected patients. Cellular immunity was evaluated by flow cytometry after 7 days of blood culture from 31 chronically T. gondii infected and 8 noninfected pregnant women, in the presence of soluble T. gondii antigen (ST-Ag) or fractionated proteins from ST-Ag, separated by sodium dodecyl sulphate polyacrylamide gel electrophoresis. Blood cultures from infected patients with ST-Ag induced 39·5 ± 12·7% of activated (CD25+) CD4+ T cells using flow cytometry. This contrasts with the absence of activated CD4+ T cells after either culture with PBS or in blood cultures from noninfected women. The protein fraction between 21 and 41·9 kD induced the highest response (14·7 ± 10·0%). Blood samples from 20 infected and 5 uninfected women were cultured in presence of 12 protein subfractions of 2–208 kD. The highest frequencies of response among infected patients were seen with fractions (Fr) 26–31·9 kD (C.I. 85–100%) and Fr 32–36·9 kD (C.I. 77–100%). Although we note a good concordance between cellular and humoral response, Western blot analysis of ST-Ag does not completely predict the panel of proteins recognized by cellular immunity. Two-dimensional separation of the ST-Ag revealed more than 200 protein spots in these fractions. However, only two proteins in the 20–40 kD range induced a significant humoral response. Further studies are necessary to determine which proteins in the Fr 26–31·9 kD and 32–36·9 kD are superior immunogens for cellular responses. PMID:15147357

  8. Heterogeneity in cellular and humoral immune responses against Toxoplasma gondii antigen in humans.

    PubMed

    Fatoohi, A F; Cozon, G J N; Gonzalo, P; Mayencon, M; Greenland, T; Picot, S; Peyron, F

    2004-06-01

    Protection against Toxoplasma gondii in infected patients is mainly attributed to cellular immunity. We here attempt to improve the characterization of the proteins that induce cellular immunity in naturally infected patients. Cellular immunity was evaluated by flow cytometry after 7 days of blood culture from 31 chronically T. gondii infected and 8 noninfected pregnant women, in the presence of soluble T. gondii antigen (ST-Ag) or fractionated proteins from ST-Ag, separated by sodium dodecyl sulphate polyacrylamide gel electrophoresis. Blood cultures from infected patients with ST-Ag induced 39.5 +/- 12.7% of activated (CD25+) CD4+ T cells using flow cytometry. This contrasts with the absence of activated CD4+ T cells after either culture with PBS or in blood cultures from noninfected women. The protein fraction between 21 and 41.9 kD induced the highest response (14.7 +/- 10.0%). Blood samples from 20 infected and 5 uninfected women were cultured in presence of 12 protein subfractions of 2-208 kD. The highest frequencies of response among infected patients were seen with fractions (Fr) 26-31.9 kD (C.I. 85-100%) and Fr 32-36.9 kD (C.I. 77-100%). Although we note a good concordance between cellular and humoral response, Western blot analysis of ST-Ag does not completely predict the panel of proteins recognized by cellular immunity. Two-dimensional separation of the ST-Ag revealed more than 200 protein spots in these fractions. However, only two proteins in the 20-40 kD range induced a significant humoral response. Further studies are necessary to determine which proteins in the Fr 26-31.9 kD and 32-36.9 kD are superior immunogens for cellular responses.

  9. Dynamics of cellular immune responses in the acute phase of dengue virus infection.

    PubMed

    Yoshida, Tomoyuki; Omatsu, Tsutomu; Saito, Akatsuki; Katakai, Yuko; Iwasaki, Yuki; Kurosawa, Terue; Hamano, Masataka; Higashino, Atsunori; Nakamura, Shinichiro; Takasaki, Tomohiko; Yasutomi, Yasuhiro; Kurane, Ichiro; Akari, Hirofumi

    2013-06-01

    In this study, we examined the dynamics of cellular immune responses in the acute phase of dengue virus (DENV) infection in a marmoset model. Here, we found that DENV infection in marmosets greatly induced responses of CD4/CD8 central memory T and NKT cells. Interestingly, the strength of the immune response was greater in animals infected with a dengue fever strain than in those infected with a dengue hemorrhagic fever strain of DENV. In contrast, when animals were re-challenged with the same DENV strain used for primary infection, the neutralizing antibody induced appeared to play a critical role in sterilizing inhibition against viral replication, resulting in strong but delayed responses of CD4/CD8 central memory T and NKT cells. The results in this study may help to better understand the dynamics of cellular and humoral immune responses in the control of DENV infection.

  10. Neural Basis of Adaptive Response Time Adjustment during Saccade Countermanding

    PubMed Central

    Pouget, Pierre; Logan, Gordon D.; Palmeri, Thomas J.; Boucher, Leanne; Paré, Martin; Schall, Jeffrey D.

    2011-01-01

    Humans and macaque monkeys adjust their response time adaptively in stop signal (countermanding) tasks, responding slower after stop-signal trials than after control trials with no stop signal. We investigated the neural mechanism underlying this adaptive response time adjustment in macaque monkeys performing a saccade countermanding task. Earlier research showed that movements are initiated when the random accumulation of presaccadic movement-related activity reaches a fixed threshold. We found that a systematic delay in response time after stop signal trials was accomplished not through a change of threshold, baseline, or accumulation rate, but instead through a change in the time when activity first began to accumulate. The neurons underlying movement initiation have been identified with mathematical accumulator models of response time performance. Therefore, this new result provides surprising new insights into the neural instantiation of stochastic accumulator models and the mechanisms through which executive control can be exerted. PMID:21880921

  11. Role of thiols in cellular response to radiation and drugs. Symposium: thiols

    SciTech Connect

    Biaglow, J.E.; Varnes, M.E.; Clark, E.P.; Epp, E.R.

    1983-09-01

    Cellular nonprotein thiols (NPSH) consist of glutathione (GSH) and other low molecular weight species such as cysteine, cysteamine, and coenzyme. A GSH is usually less than the total cellular NPSH, and with thiol reactive agents, such as diethyl maleate (DEM), its rate of depletion is in part dependent upon the cellular capacity for its resynthesis. If resynthesis is blocked by buthionine-S,R-sulfoximine(BSO), the NPSH, including GSH, is depleted more rapidly, Cellular thiol depletion by diamide, N-ethylmaleimide, and BSO may render oxygenated cells more sensitive to radiation. These cells may or may not show a reduction in the oxygen enhancement ratio (OER). Human A549 lung carcinoma cells depleted of their NPSH either by prolonged culture or by BSO treatment do not show a reduced OER but do show increased aerobic responses to radiation. Other nitrocompounds, such as misonidazole, are activated under hypoxic conditions to radical intermediates. When cellular thiols are depleted peroxide is formed. Under hypoxic conditions thiols are depleted because metabolically reduced intermediates react with GSH instead of oxygen. Thiol depletion, under hypoxic conditions, may be the reason that misonidazole and other nitrocompounds show an extra enhancement ratio with hypoxic cells. Thiol depletion by DEM or BSO alters the radiation response of hypoxic cells to misonidazole. In conclusion, we propose an altered thiol model which includes a mechanism for thiol involvement in the aerobic radiation response of cells.

  12. Cellular adaptation to nutrient deprivation: crosstalk between the mTORC1 and eIF2α signaling pathways and implications for autophagy.

    PubMed

    Wengrod, Jordan C; Gardner, Lawrence B

    2015-01-01

    The hostile tumor microenvironment results in the generation of intracellular stresses including hypoxia and nutrient deprivation. In order to adapt to such conditions, the cell utilizes several stress-response mechanisms, including the attenuation of protein synthesis, the inhibition of cellular proliferation, and induction of autophagy. Autophagy leads to the degradation of cellular contents, including damaged organelles and mutant proteins, which the cell can then use as an alternate energy source. Two integral changes to the signaling milieu to promote such a response include inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of eIF2α. This review will describe how conditions found in the tumor microenvironment regulate mTORC1 as well as eIF2α, the downstream impact of these modifications, and the implications in tumorigenesis. We will then discuss the remarkable similarities and overlapping function of these 2 signaling pathways, focusing on the response to amino acid deprivation, and present a new model involving crosstalk between them based on our recent work.

  13. Adaptive Patterns of Stress Responsivity: A Preliminary Investigation

    ERIC Educational Resources Information Center

    Del Giudice, Marco; Hinnant, J. Benjamin; Ellis, Bruce J.; El-Sheikh, Mona

    2012-01-01

    The adaptive calibration model (ACM) is an evolutionary-developmental theory of individual differences in stress responsivity. In this article, we tested some key predictions of the ACM in a middle childhood sample (N = 256). Measures of autonomic nervous system activity across the sympathetic and parasympathetic branches validated the 4-pattern…

  14. Compensatory structural adaptive modifications of vagina in response to functional demand in goat.

    PubMed

    Hussin, Amer M; Zaid, Nazih W; Hussain, S O

    2014-01-01

    Vaginal biopsies and smears were collected from ten adult local healthy goats. Routine histological methods were carried out on vaginal biopsies and then stained with PAS stain. The smears were stained with Methylene blue. All samples were inspected under light microscope. The present study found that many constituents of the wall of the vagina, which have an important functional role, were absent; among these were the vaginal glands, goblet cells, muscularis mucosa, and lymphatic nodules. On the other hand, vagina showed special compensatory histological mechanisms, namely, the deep epithelial folds, the well-developed germinated stratum basale, the apparent basement membrane, and the profuse defensive cells, such as neutrophils, macrophages, lymphocytes, plasma cells, and mast cells. The general stains of this study could not recognize dendritic cells although they play an important functional role. Moreover, the herein study declared also that the vaginal smears showing many adaptive cellular mechanisms among these were, the keratinization, the process of sheet formation that lines the vaginal lumen, the process of metachromasia which is related to the cellular activity in protein synthesis, keratin, and finally the presence of endogenous microorganisms. It was concluded that all the above cellular compensatory adaptive mechanisms may compensate the lacking vaginal constituents and act to raise the immune response of the vagina.

  15. Imaging the cellular response to transient shear stress using time-resolved digital holography

    NASA Astrophysics Data System (ADS)

    Arita, Yoshihiko; Antkowiak, Maciej; Gunn-Moore, Frank; Dholakia, Kishan

    2014-02-01

    Shear stress has been recognized as one of the biophysical methods by which to permeabilize plasma membranes of cells. In particular, high pressure transient hydrodynamic flows created by laser-induced cavitation have been shown to lead to the uptake of fluorophores and plasmid DNA. While the mechanism and dynamics of cavitation have been extensively studied using a variety of time-resolved imaging techniques, the cellular response to the cavitation bubble and cavitation induced transient hydrodynamic flows has never been shown in detail. We use time-resolved quantitative phase microscopy to study cellular response to laser-induced cavitation bubbles. Laser-induced breakdown of an optically trapped polystyrene nanoparticle (500nm in diameter) irradiated with a single nanosecond laser pulse at 532nm creates transient shear stress to surrounding cells without causing cell lysis. A bi-directional transient displacement of cytoplasm is observed during expansion and collapse of the cavitation bubble. In some cases, cell deformation is only observable at the microsecond time scale without any permanent change in cell shape or optical thickness. On a time scale of seconds, the cellular response to shear stress and cytoplasm deformation typically leads to retraction of the cellular edge most exposed to the flow, rounding of the cell body and, in some cases, loss of cellular dry mass. These results give a new insight into the cellular response to laser-induced shear stress and related plasma membrane permeabilization. This study also demonstrates that laser-induced breakdown of an optically trapped nanoparticle offers localized cavitation (70 μm in diameter), which interacts with a single cell.

  16. Performance of an adaptive coding scheme in a fixed wireless cellular system working in millimeter-wave bands

    NASA Astrophysics Data System (ADS)

    Farahvash, Shayan; Akhavan, Koorosh; Kavehrad, Mohsen

    1999-12-01

    This paper presents a solution to problem of providing bit- error rate performance guarantees in a fixed millimeter-wave wireless system, such as local multi-point distribution system in line-of-sight or nearly line-of-sight applications. The basic concept is to take advantage of slow-fading behavior of fixed wireless channel by changing the transmission code rate. Rate compatible punctured convolutional codes are used to implement adaptive coding. Cochannel interference analysis is carried out for downlink direction; from base station to subscriber premises. Cochannel interference is treated as a noise-like random process with a power equal to the sum of the power from finite number of interfering base stations. Two different cellular architectures based on using single or dual polarizations are investigated. Average spectral efficiency of the proposed adaptive rate system is found to be at least 3 times larger than a fixed rate system with similar outage requirements.

  17. An asymmetric image cryptosystem based on the adaptive synchronization of an uncertain unified chaotic system and a cellular neural network

    NASA Astrophysics Data System (ADS)

    Cheng, Chao-Jung; Cheng, Chi-Bin

    2013-10-01

    Chaotic dynamics provide a fast and simple means to create an excellent image cryptosystem, because it is extremely sensitive to initial conditions and system parameters, pseudorandomness, and non-periodicity. However, most chaos-based image encryption schemes are symmetric cryptographic techniques, which have been proven to be more vulnerable, compared to an asymmetric cryptosystem. This paper develops an asymmetric image cryptosystem, based on the adaptive synchronization of two different chaotic systems, namely a unified chaotic system and a cellular neural network. An adaptive controller with parameter update laws is formulated, using the Lyapunov stability theory, to asymptotically synchronize the two chaotic systems. The synchronization controller is embedded in the image cryptosystem and generates a pair of asymmetric keys, for image encryption and decryption. Using numerical simulations, three sets of experiments are conducted to evaluate the feasibility and reliability of the proposed chaos-based image cryptosystem.

  18. Bayesian optimal response-adaptive design for binary responses using stopping rule.

    PubMed

    Komaki, Fumiyasu; Biswas, Atanu

    2016-05-02

    Response-adaptive designs are used in phase III clinical trials to allocate a larger number of patients to the better treatment arm. Optimal designs are explored in the recent years in the context of response-adaptive designs, in the frequentist view point only. In the present paper, we propose some response-adaptive designs for two treatments based on Bayesian prediction for phase III clinical trials. Some properties are studied and numerically compared with some existing competitors. A real data set is used to illustrate the applicability of the proposed methodology where we redesign the experiment using parameters derived from the data set.

  19. Role of p53 in the cellular response following oleic acid accumulation in Chang liver cells.

    PubMed

    Park, Eun-Jung; Lee, Ah Young; Chang, Seung-Hee; Yu, Kyeong-Nam; Kim, Jae-Ho; Cho, Myung-Haing

    2014-01-03

    Abnormal accumulation of fatty acids triggers the harmful cellular response called lipotoxicity. In this study, we investigated the cellular response following accumulation of oleic acid (OA), a monounsaturated fatty acid, in human Chang liver cells. OA droplets were distributed freely in the cytoplasm and/or degraded within lysosomes. OA exposure increased ATP production and concomitantly dilated mitochondria. At 24h after OA exposure, cell viability decreased slightly and was coupled with a reduction in mitochondrial Ca(2+) concentration, the alteration in cell viability was also associated with the generation of reactive oxygen species and changes in the cell cycle. Moreover, OA treatment increased the expression of autophagy- and apoptotic cell death-related proteins in a dose-dependent manner. Furthermore, we investigated the role of p53, a tumor suppressor protein, in the cellular response elicited by OA accumulation. OA-induced changes in cell viability and ATP production were rescued to control levels when cells were pretreated with pifithrin-alpha (PTA), a p53 inhibitor. By contrast, the expressions of LC3-II and perilipin, proteins required for lipophagy, were down-regulated by PTA pretreatment. Taken together, our results suggest that p53 plays a key role in the cellular response elicited by OA accumulation in Chang liver cells.

  20. Cellular and humoral local immune responses in sheep experimentally infected with Oestrus ovis (Diptera: Oestridae).

    PubMed

    Tabouret, Guillaume; Lacroux, Caroline; Andreoletti, Olivier; Bergeaud, Jean Paul; Hailu-Tolosa, Yacob; Hoste, Hervé; Prevot, Françoise; Grisez, Christelle; Dorchies, Philippe; Jacquiet, Philippe

    2003-01-01

    Cellular and humoral local responses were investigated following repetitive artificial Oestrus ovis infections in lambs. The presence of larvae induced a huge local recruitment of either leucocytes (T and B lymphocytes, macrophages) or granulocytes (eosinophils, mast cells and globule leucocytes). This cellular response was more pronounced in the ethmoid and sinus (development sites of second and third instar larvae) than in the septum or turbinates where first instar larvae migrate. Infected lambs produced Oestrus ovis specific IgG and IgA antibodies in their mucus. This local humoral response was mainly directed against larval salivary gland antigens and not against larval digestive tract antigens. Compared to the control animals, the sinusal mucosa of infected animals was extremely thickened and the epithelium exhibited hyperplasia, metaplasia and eosinophilic exocytosis. The possible roles of these local immune responses in the regulation of O. ovis larvae populations in sheep are discussed.

  1. Transforming growth factor-beta1 mediates cellular response to DNA damage in situ

    NASA Technical Reports Server (NTRS)

    Ewan, Kenneth B.; Henshall-Powell, Rhonda L.; Ravani, Shraddha A.; Pajares, Maria Jose; Arteaga, Carlos; Warters, Ray; Akhurst, Rosemary J.; Barcellos-Hoff, Mary Helen

    2002-01-01

    Transforming growth factor (TGF)-beta1 is rapidly activated after ionizing radiation, but its specific role in cellular responses to DNA damage is not known. Here we use Tgfbeta1 knockout mice to show that radiation-induced apoptotic response is TGF-beta1 dependent in the mammary epithelium, and that both apoptosis and inhibition of proliferation in response to DNA damage decrease as a function of TGF-beta1 gene dose in embryonic epithelial tissues. Because apoptosis in these tissues has been shown previously to be p53 dependent, we then examined p53 protein activation. TGF-beta1 depletion, by either gene knockout or by using TGF-beta neutralizing antibodies, resulted in decreased p53 Ser-18 phosphorylation in irradiated mammary gland. These data indicate that TGF-beta1 is essential for rapid p53-mediated cellular responses that mediate cell fate decisions in situ.

  2. A threshold of endogenous stress is required to engage cellular response to protect against mutagenesis

    PubMed Central

    Saintigny, Yannick; Chevalier, François; Bravard, Anne; Dardillac, Elodie; Laurent, David; Hem, Sonia; Dépagne, Jordane; Radicella, J. Pablo; Lopez, Bernard S.

    2016-01-01

    Endogenous stress represents a major source of genome instability, but is in essence difficult to apprehend. Incorporation of labeled radionuclides into DNA constitutes a tractable model to analyze cellular responses to endogenous attacks. Here we show that incorporation of [3H]thymidine into CHO cells generates oxidative-induced mutagenesis, but, with a peak at low doses. Proteomic analysis showed that the cellular response differs between low and high levels of endogenous stress. In particular, these results confirmed the involvement of proteins implicated in redox homeostasis and DNA damage signaling pathways. Induced-mutagenesis was abolished by the anti-oxidant N-acetyl cysteine and plateaued, at high doses, upon exposure to L-buthionine sulfoximine, which represses cellular detoxification. The [3H]thymidine-induced mutation spectrum revealed mostly base substitutions, exhibiting a signature specific for low doses (GC > CG and AT > CG). Consistently, the enzymatic activity of the base excision repair protein APE-1 is induced at only medium or high doses. Collectively, the data reveal that a threshold of endogenous stress must be reached to trigger cellular detoxification and DNA repair programs; below this threshold, the consequences of endogenous stress escape cellular surveillance, leading to high levels of mutagenesis. Therefore, low doses of endogenous local stress can jeopardize genome integrity more efficiently than higher doses. PMID:27406380

  3. The Dose Window for Radiation-Induced Protective Adaptive Responses

    PubMed Central

    Mitchel, Ronald E. J.

    2009-01-01

    Adaptive responses to low doses of low LET radiation occur in all organisms thus far examined, from single cell lower eukaryotes to mammals. These responses reduce the deleterious consequences of DNA damaging events, including radiation-induced or spontaneous cancer and non-cancer diseases in mice. The adaptive response in mammalian cells and mammals operates within a certain window that can be defined by upper and lower dose thresholds, typically between about 1 and 100 mGy for a single low dose rate exposure. However, these thresholds for protection are not a fixed function of total dose, but also vary with dose rate, additional radiation or non-radiation stressors, tissue type and p53 functional status. Exposures above the upper threshold are generally detrimental, while exposures below the lower threshold may or may not increase either cancer or non-cancer disease risk. PMID:20585438

  4. The Influence of Innate and Adaptive Immune Responses on Atherosclerosis

    PubMed Central

    Witztum, Joseph L.; Lichtman, Andrew H.

    2014-01-01

    Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. PMID:23937439

  5. The stringent response regulates adaptation to darkness in the cyanobacterium Synechococcus elongatus

    PubMed Central

    Hood, Rachel D.; Higgins, Sean A.; Flamholz, Avi; Nichols, Robert J.

    2016-01-01

    The cyanobacterium Synechococcus elongatus relies upon photosynthesis to drive metabolism and growth. During darkness, Synechococcus stops growing, derives energy from its glycogen stores, and greatly decreases rates of macromolecular synthesis via unknown mechanisms. Here, we show that the stringent response, a stress response pathway whose genes are conserved across bacteria and plant plastids, contributes to this dark adaptation. Levels of the stringent response alarmone guanosine 3′-diphosphate 5′-diphosphate (ppGpp) rise after a shift from light to dark, indicating that darkness triggers the same response in cyanobacteria as starvation in heterotrophic bacteria. High levels of ppGpp are sufficient to stop growth and dramatically alter many aspects of cellular physiology, including levels of photosynthetic pigments and polyphosphate, DNA content, and the rate of translation. Cells unable to synthesize ppGpp display pronounced growth defects after exposure to darkness. The stringent response regulates expression of a number of genes in Synechococcus, including ribosomal hibernation promoting factor (hpf), which causes ribosomes to dimerize in the dark and may contribute to decreased translation. Although the metabolism of Synechococcus differentiates it from other model bacterial systems, the logic of the stringent response remains remarkably conserved, while at the same time having adapted to the unique stresses of the photosynthetic lifestyle. PMID:27486247

  6. Immune and stress responses in oysters with insights on adaptation.

    PubMed

    Guo, Ximing; He, Yan; Zhang, Linlin; Lelong, Christophe; Jouaux, Aude

    2015-09-01

    Oysters are representative bivalve molluscs that are widely distributed in world oceans. As successful colonizers of estuaries and intertidal zones, oysters are remarkably resilient against harsh environmental conditions including wide fluctuations in temperature and salinity as well as prolonged air exposure. Oysters have no adaptive immunity but can thrive in microbe-rich estuaries as filter-feeders. These unique adaptations make oysters interesting models to study the evolution of host-defense systems. Recent advances in genomic studies including sequencing of the oyster genome have provided insights into oyster's immune and stress responses underlying their amazing resilience. Studies show that the oyster genomes are highly polymorphic and complex, which may be key to their resilience. The oyster genome has a large gene repertoire that is enriched for immune and stress response genes. Thousands of genes are involved in oyster's immune and stress responses, through complex interactions, with many gene families expanded showing high sequence, structural and functional diversity. The high diversity of immune receptors and effectors may provide oysters with enhanced specificity in immune recognition and response to cope with diverse pathogens in the absence of adaptive immunity. Some members of expanded immune gene families have diverged to function at different temperatures and salinities or assumed new roles in abiotic stress response. Most canonical innate immunity pathways are conserved in oysters and supported by a large number of diverse and often novel genes. The great diversity in immune and stress response genes exhibited by expanded gene families as well as high sequence and structural polymorphisms may be central to oyster's adaptation to highly stressful and widely changing environments.

  7. [The cellular mechanisms of exercise adaptation from the perspective of skeletal muscle plasticity].

    PubMed

    Sun, Yi; Ding, Shu-Zhe

    2014-10-01

    As highly plastic tissue, skeletal muscle adapts to stressors such as exercise. Reasonable amount of exercise is known to play a role in the prevention of cardiovascular diseases, diabetes and cancer. However, in the field of Exercise Physiology, the debate has been on for a while as to which kind of exercise is more effective in health promotion. In this review, the authors contrast and compare the signaling pathways mediated by different types of exercise, and boldly speculate the intrinsic similarities and discrepancies among them, hoping to enrich the theoretical frames of exercise adaptation, as well as provide effective exercise regimen to the public.

  8. Adaptive optics and phase diversity imaging for responsive space applications.

    SciTech Connect

    Smith, Mark William; Wick, David Victor

    2004-11-01

    The combination of phase diversity and adaptive optics offers great flexibility. Phase diverse images can be used to diagnose aberrations and then provide feedback control to the optics to correct the aberrations. Alternatively, phase diversity can be used to partially compensate for aberrations during post-detection image processing. The adaptive optic can produce simple defocus or more complex types of phase diversity. This report presents an analysis, based on numerical simulations, of the efficiency of different modes of phase diversity with respect to compensating for specific aberrations during post-processing. It also comments on the efficiency of post-processing versus direct aberration correction. The construction of a bench top optical system that uses a membrane mirror as an active optic is described. The results of characterization tests performed on the bench top optical system are presented. The work described in this report was conducted to explore the use of adaptive optics and phase diversity imaging for responsive space applications.

  9. Cellular localization and adaptive changes of the cardiac delta opioid receptor system in an experimental model of heart failure in rats.

    PubMed

    Treskatsch, Sascha; Feldheiser, Aarne; Shaqura, Mohammed; Dehe, Lukas; Habazettl, Helmut; Röpke, Torsten K; Shakibaei, Mehdi; Schäfer, Michael; Spies, Claudia D; Mousa, Shaaban A

    2016-02-01

    The role of the cardiac opioid system in congestive heart failure (CHF) is not fully understood. Therefore, this project investigated the cellular localization of delta opioid receptors (DOR) in left ventricle (LV) myocardium and adaptive changes in DOR and its endogenous ligand, the precursor peptide proenkephalin (PENK), during CHF. Following IRB approval, DOR localization was determined by radioligand binding using [H(3)]Naltrindole and by double immunofluorescence confocal analysis in the LV of male Wistar rats. Additionally, 28 days following an infrarenal aortocaval fistula (ACF) the extent of CHF and adaptions in left ventricular DOR and PENK expression were examined by hemodynamic measurements, RT-PCR, and Western blot. DOR specific membrane binding sites were identified in LV myocardium. DOR were colocalized with L-type Ca(2+)-channels (Cav1.2) as well as with intracellular ryanodine receptors (RyR) of the sarcoplasmatic reticulum. Following ACF severe congestive heart failure developed in all rats and was accompanied by up-regulation of DOR and PENK on mRNA as well as receptor proteins representing consecutive adaptations. These findings might suggest that the cardiac delta opioid system possesses the ability to play a regulatory role in the cardiomyocyte calcium homeostasis, especially in response to heart failure.

  10. The adaptive response of jaw muscles to varying functional demands.

    PubMed

    Grünheid, Thorsten; Langenbach, Geerling E J; Korfage, Joannes A M; Zentner, Andrej; van Eijden, Theo M G J

    2009-12-01

    Jaw muscles are versatile entities that are able to adapt their anatomical characteristics, such as size, cross-sectional area, and fibre properties, to altered functional demands. The dynamic nature of muscle fibres allows them to change their phenotype to optimize the required contractile function while minimizing energy use. Changes in these anatomical parameters are associated with changes in neuromuscular activity as the pattern of muscle activation by the central nervous system plays an important role in the modulation of muscle properties. This review summarizes the adaptive response of jaw muscles to various stimuli or perturbations in the orofacial system and addresses general changes in muscles as they adapt, specific adaptive changes in jaw muscles under various physiologic and pathologic conditions, and their adaptive response to non-surgical and surgical therapeutic interventions. Although the jaw muscles are used concertedly in the masticatory system, their adaptive changes are not always uniform and vary with the nature, intensity, and duration of the stimulus. In general, stretch, increases neuromuscular activity, and resistance training result in hypertrophy, elicits increases in mitochondrial content and cross-sectional area of the fibres, and may change the fibre-type composition of the muscle towards a larger percentage of slow-type fibres. In contrast, changes in the opposite direction occur when neuromuscular activity is reduced, the muscle is immobilized in a shortened position, or paralysed. The broad range of stimuli that affect the properties of jaw muscles might help explain the large variability in the anatomical and physiological characteristics found among individuals, muscles, and muscle portions.

  11. Seed Pubescence and Shape Modulate Adaptive Responses to Fire Cues.

    PubMed

    Gómez-González, Susana; Ojeda, Fernando; Torres-Morales, Patricio; Palma, Jazmín E

    2016-01-01

    Post-fire recruitment by seeds is regarded as an adaptive response in fire-prone ecosystems. Nevertheless, little is known about which heritable seed traits are functional to the main signals of fire (heat and smoke), thus having the potential to evolve. Here, we explored whether three seed traits (pubescence, dormancy and shape) and fire regime modulate seed response to fire cues(heat and smoke). As a model study system, we used Helenium aromaticum (Asteraceae), a native annual forb from the Chilean matorral, where fires are anthropogenic. We related seed trait values with fitness responses (germination and survival) after exposure to heat-shock and smoke experimental treatments on seeds from 10 H. aromaticum wild populations. We performed a phenotypic selection experiment to examine the relationship of seed traits with post-treatment fitness within a population (adaptive hypothesis). We then explored whether fire frequency in natural habitats was associated with trait expression across populations, and with germination and survival responses to experimental fire-cues. We found that populations subjected to higher fire frequency had, in average, more rounded and pubescent seeds than populations from rarely burned areas. Populations with more rounded and pubescent seeds were more resistant to 80°C heat-shock and smoke treatments.There was correlated selection on seed traits: pubescent-rounded or glabrouscent-elongated seeds had the highest probability of germinating after heat-shock treatments. Seed pubescence and shape in H. aromaticum are heritable traits that modulate adaptive responses to fire. Our results provide new insights into the process of plant adaptation to fire and highlight the relevance of human-made fires as a strong evolutionary agent in the Anthropocene.

  12. Adaptive thermoregulation in endotherms may alter responses to climate change.

    PubMed

    Boyles, Justin G; Seebacher, Frank; Smit, Ben; McKechnie, Andrew E

    2011-11-01

    Climate change is one of the major issues facing natural populations and thus a focus of recent research has been to predict the responses of organisms to these changes. Models are becoming more complex and now commonly include physiological traits of the organisms of interest. However, endothermic species have received less attention than have ectotherms in these mechanistic models. Further, it is not clear whether responses of endotherms to climate change are modified by variation in thermoregulatory characteristics associated with phenotypic plasticity and/or adaptation to past selective pressures. Here, we review the empirical data on thermal adaptation and acclimatization in endotherms and discuss how those factors may be important in models of responses to climate change. We begin with a discussion of why thermoregulation and thermal sensitivity at high body temperatures should be co-adapted. Importantly, we show that there is, in fact, considerable variation in the ability of endotherms to tolerate high body temperatures and/or high environmental temperatures, but a better understanding of this variation will likely be critical for predicting responses to future climatic scenarios. Next, we discuss why variation in thermoregulatory characteristics should be considered when modeling the effects of climate change on heterothermic endotherms. Finally, we review some biophysical and biochemical factors that will limit adaptation and acclimation in endotherms. We consider both long-term, directional climate change and short-term (but increasingly common) anomalies in climate such as extreme heat waves and we suggest areas of important future research relating to both our basic understanding of endothermic thermoregulation and the responses of endotherms to climate change.

  13. Seed Pubescence and Shape Modulate Adaptive Responses to Fire Cues

    PubMed Central

    Gómez-González, Susana; Ojeda, Fernando; Torres-Morales, Patricio; Palma, Jazmín E.

    2016-01-01

    Post-fire recruitment by seeds is regarded as an adaptive response in fire-prone ecosystems. Nevertheless, little is known about which heritable seed traits are functional to the main signals of fire (heat and smoke), thus having the potential to evolve. Here, we explored whether three seed traits (pubescence, dormancy and shape) and fire regime modulate seed response to fire cues(heat and smoke). As a model study system, we used Helenium aromaticum (Asteraceae), a native annual forb from the Chilean matorral, where fires are anthropogenic. We related seed trait values with fitness responses (germination and survival) after exposure to heat-shock and smoke experimental treatments on seeds from 10 H. aromaticum wild populations. We performed a phenotypic selection experiment to examine the relationship of seed traits with post-treatment fitness within a population (adaptive hypothesis). We then explored whether fire frequency in natural habitats was associated with trait expression across populations, and with germination and survival responses to experimental fire-cues. We found that populations subjected to higher fire frequency had, in average, more rounded and pubescent seeds than populations from rarely burned areas. Populations with more rounded and pubescent seeds were more resistant to 80°C heat-shock and smoke treatments.There was correlated selection on seed traits: pubescent-rounded or glabrouscent-elongated seeds had the highest probability of germinating after heat-shock treatments. Seed pubescence and shape in H. aromaticum are heritable traits that modulate adaptive responses to fire. Our results provide new insights into the process of plant adaptation to fire and highlight the relevance of human-made fires as a strong evolutionary agent in the Anthropocene. PMID:27438267

  14. Silver Nanoparticle-Mediated Cellular Responses in Various Cell Lines: An in Vitro Model

    PubMed Central

    Zhang, Xi-Feng; Shen, Wei; Gurunathan, Sangiliyandi

    2016-01-01

    Silver nanoparticles (AgNPs) have attracted increased interest and are currently used in various industries including medicine, cosmetics, textiles, electronics, and pharmaceuticals, owing to their unique physical and chemical properties, particularly as antimicrobial and anticancer agents. Recently, several studies have reported both beneficial and toxic effects of AgNPs on various prokaryotic and eukaryotic systems. To develop nanoparticles for mediated therapy, several laboratories have used a variety of cell lines under in vitro conditions to evaluate the properties, mode of action, differential responses, and mechanisms of action of AgNPs. In vitro models are simple, cost-effective, rapid, and can be used to easily assess efficacy and performance. The cytotoxicity, genotoxicity, and biocompatibility of AgNPs depend on many factors such as size, shape, surface charge, surface coating, solubility, concentration, surface functionalization, distribution of particles, mode of entry, mode of action, growth media, exposure time, and cell type. Cellular responses to AgNPs are different in each cell type and depend on the physical and chemical nature of AgNPs. This review evaluates significant contributions to the literature on biological applications of AgNPs. It begins with an introduction to AgNPs, with particular attention to their overall impact on cellular effects. The main objective of this review is to elucidate the reasons for different cell types exhibiting differential responses to nanoparticles even when they possess similar size, shape, and other parameters. Firstly, we discuss the cellular effects of AgNPs on a variety of cell lines; Secondly, we discuss the mechanisms of action of AgNPs in various cellular systems, and try to elucidate how AgNPs interact with different mammalian cell lines and produce significant effects; Finally, we discuss the cellular activation of various signaling molecules in response to AgNPs, and conclude with future perspectives

  15. TC1 (C8orf4) is upregulated by cellular stress and mediates heat shock response.

    PubMed

    Park, Juhee; Jung, Yusun; Kim, Jungtae; Kim, Ka-Young; Ahn, Sang-Gun; Song, Kyuyoung; Lee, Inchul

    2007-08-24

    TC1 (C8orf4) is associated with aggressive behavior and poor survival in cancer. We have recently reported that it is a target gene of NF-kappaB and regulates the Wnt/beta-catenin pathway. Here, we show that TC1 is upregulated by various cellular stresses and mediates heat shock response. Heat shock and other cellular stresses including H2O2, 12-O-tetradecanoylphorbol 13-acetate (TPA), lipopolysaccharide (LPS), and UV enhance TC1 transcription in HeLa, KATO-III, HEK293T, and HK cells. TC1 protein then moves into the nuclei independently of NF-kappaB activation. TC1 upregulates heat shock proteins, and TC1-knockdown inhibits stress-induced downstream regulation significantly. Heat shock factor 1(HSF1) and TC1 upregulate each other, suggesting a potential positive feedback in the heat shock response regulation. Our data suggest that TC1 is a novel heat shock response regulator.

  16. Cellular Senescence, Radiation Damage to Mitochondria, and the Compensatory Response in Ripening Pear Fruits 1

    PubMed Central

    Romani, Roger J.; Yu, Ida K.; Ku, Lily L.; Fisher, L. Karl; Dehgan, Nancy

    1968-01-01

    A compensatory response, viz. in vivo recovery from radiation damage to mitochondria, occurs in preclimacteric pear fruits (Pyrus communis L.) treated with ionizing radiation. The compensatory response is absent or markedly impaired in senescent fruits irradiated at or near the climacteric peak. Senescent cells failed to recover from harmful effects of radiation on: 1) mitochondrial yield, 2) in vivo incorporation of amino acids into mitochondrial protein, and 3) mitochondrial respiratory control and ADP/O. A diminished response to “split-dose” irradiation and a delayed rate of recovery confirmed the degeneracy and loss of compensatory power with cell age. A loss of restorative activity, especially in mitochondria that supply the cell with essential energy, may underlie the more obvious signs of cumulative stress that accompany cellular senescence. Use of ionizing radiation as an investigative tool and the molecular implications of radiation damage, recovery, and cellular senescence are discussed. PMID:16656887

  17. Cellular immune responses in multiple sclerosis patients treated with interferon-beta

    PubMed Central

    Bustamante, M. F.; Rio, J.; Castro, Z.; Sánchez, A.; Montalban, X.; Comabella, M.

    2013-01-01

    Summary We investigated cellular immune responses at baseline in peripheral blood mononuclear cells (PBMC) of patients with multiple sclerosis (MS) treated with interferon (IFN)-β and classified into responders and non-responders according to clinical response criteria. Levels for IFN-γ, interleukin (IL)-17A, IL-17F, IL-10 and IL-4 were determined in activated PBMC of 10 responders, 10 non-responders and 10 healthy controls by cytometric bead arrays. Cytokine levels in cell culture supernatants were similar between responders and non-responders, and comparable to those obtained in healthy controls. These findings do not support differential cellular immune responses in PBMC at baseline between IFN-β responders and non-responders. PMID:23379429

  18. Membrane vesicle production by Chlamydia trachomatis as an adaptive response

    PubMed Central

    Frohlich, Kyla M.; Hua, Ziyu; Quayle, Alison J.; Wang, Jin; Lewis, Maria E.; Chou, Chau-wen; Luo, Miao; Buckner, Lyndsey R.; Shen, Li

    2014-01-01

    Bacteria have evolved specific adaptive responses to cope with changing environments. These adaptations include stress response phenotypes with dynamic modifications of the bacterial cell envelope and generation of membrane vesicles (MVs). The obligate intracellular bacterium, Chlamydia trachomatis, typically has a biphasic lifestyle, but can enter into an altered growth state typified by morphologically aberrant chlamydial forms, termed persistent growth forms, when induced by stress in vitro. How C. trachomatis can adapt to a persistent growth state in host epithelial cells in vivo is not well understood, but is an important question, since it extends the host-bacterial relationship in vitro and has thus been indicated as a survival mechanism in chronic chlamydial infections. Here, we review recent findings on the mechanistic aspects of bacterial adaptation to stress with a focus on how C. trachomatis remodels its envelope, produces MVs, and the potential important consequences of MV production with respect to host-pathogen interactions. Emerging data suggest that the generation of MVs may be an important mechanism for C. trachomatis intracellular survival of stress, and thus may aid in the establishment of a chronic infection in human genital epithelial cells. PMID:24959424

  19. Higher Plants in Space: Microgravity Perception, Response, and Adaptation

    NASA Astrophysics Data System (ADS)

    Zheng, Hui Qiong; Han, Fei; Le, Jie

    2015-11-01

    Microgravity is a major abiotic stress in space. Its effects on plants may depend on the duration of exposure. We focused on two different phases of microgravity responses in space. When higher plants are exposed to short-term (seconds to hours) microgravity, such as on board parabolic flights and sounding rockets, their cells usually exhibit abiotic stress responses. For example, Ca 2+-, lipid-, and pH-signaling are rapidly enhanced, then the production of reactive oxygen species and other radicals increase dramatically along with changes in metabolism and auxin signaling. Under long-term (days to months) microgravity exposure, plants acclimatize to the stress by changing their metabolism and oxidative response and by enhancing other tropic responses. We conclude by suggesting that a systematic analysis of regulatory networks at the molecular level of higher plants is needed to understand the molecular signals in the distinct phases of the microgravity response and adaptation.

  20. Adaptation.

    PubMed

    Broom, Donald M

    2006-01-01

    welfare can be very good when it is occurring. Other adaptation is difficult and may involve lower or higher level emergency physiological responses or abnormal behaviour, often with bad feelings such as pain or fear. In that case, welfare is poor or very poor even if complete adaptation eventually occurs and there is no long-term threat to the life of the individual. In some circumstances, adaptation may be unsuccessful, the individual is not able to cope, stress occurs and welfare is ultimately very poor.

  1. Landowner response to wildfire risk: Adaptation, mitigation or doing nothing.

    PubMed

    Gan, Jianbang; Jarrett, Adam; Johnson Gaither, Cassandra

    2015-08-15

    Wildfire has brought about ecological, economic, and social consequences that engender human responses in many parts of the world. How to respond to wildfire risk is a common challenge across the globe particularly in areas where lands are controlled by many small private owners because effective wildfire prevention and protection require coordinated efforts of neighboring stakeholders. We explore (i) wildfire response strategies adopted by family forestland owners in the southern United States, one of the most important and productive forest regions in the world, through a landowner survey; and (ii) linkages between the responses of these landowners and their characteristics via multinomial logistic regression. We find that landowners used diverse strategies to respond to wildfire risk, with the most popular responses being "doing nothing" and combined adaptation and mitigation, followed by adaptation or mitigation alone. Landowners who had lost properties to wildfire, lived on their forestlands, had a forest management plan, and were better educated were more likely to proactively respond to wildfire risk. Our results indicate the possibility to enhance the effectiveness of collective action of wildfire risk response by private forestland owners and to coordinate wildfire response with forest conservation and certification efforts. These findings shed new light on engaging private landowners in wildfire management in the study region and beyond.

  2. Bioanalytical evidence that chemicals in tattoo ink can induce adaptive stress responses.

    PubMed

    Neale, Peta A; Stalter, Daniel; Tang, Janet Y M; Escher, Beate I

    2015-10-15

    Tattooing is becoming increasingly popular, particularly amongst young people. However, tattoo inks contain a complex mixture of chemical impurities that may pose a long-term risk for human health. As a first step towards the risk assessment of these complex mixtures we propose to assess the toxicological hazard potential of tattoo ink chemicals with cell-based bioassays. Targeted modes of toxic action and cellular endpoints included cytotoxicity, genotoxicity and adaptive stress response pathways. The studied tattoo inks, which were extracted with hexane as a proxy for the bioavailable fraction, caused effects in all bioassays, with the red and yellow tattoo inks having the greatest response, particularly inducing genotoxicity and oxidative stress response endpoints. Chemical analysis revealed the presence of polycyclic aromatic hydrocarbons in the tested black tattoo ink at concentrations twice the recommended level. The detected polycyclic aromatic hydrocarbons only explained 0.06% of the oxidative stress response of the black tattoo ink, thus the majority of the effect was caused by unidentified components. The study indicates that currently available tattoo inks contain components that induce adaptive stress response pathways, but to evaluate the risk to human health further work is required to understand the toxicokinetics of tattoo ink chemicals in the body.

  3. Adaptive Responses to Tissue Injury: Role of Heme Oxygenase-1

    PubMed Central

    Agarwal, Anupam; Bolisetty, Subhashini

    2013-01-01

    Tissue injury may result as a consequence of a physical, chemical, or biological insult. Such injury recruits an adaptive response to restore homeostasis and protect against further injury. One of the most prompt protective and adaptive responses by all tissues is the robust activation of the highly inducible, anti-inflammatory, anti-oxidant, and anti-apoptotic protein, heme oxygenase-1 (HO-1). HO-1, a microsomal enzyme, catalyzes the breakdown of pro-oxidant heme, which is released from heme proteins to equimolar quantities of iron, carbon monoxide, and biliverdin. Biliverdin is converted to bilirubin by biliverdin reductase. The beneficial effects of HO-1 expression are not merely due to heme degradation but are also attributed to the cytoprotective properties of the byproducts of the reaction. Manipulation of this enzymatic system in a myriad of disease models has provided substantial evidence to support its role as a cytoprotective enzyme and is therefore an emerging therapeutic molecule. PMID:23874015

  4. Adaptation of the Black Yeast Wangiella dermatitidis to Ionizing Radiation: Molecular and Cellular Mechanisms

    DTIC Science & Technology

    2012-11-01

    laboratory and in the damaged Chernobyl nuclear reactor suggest they have adapted the ability to survive or even benefit from exposure to ionizing...damaged nuclear reactor at Chernobyl , which are constantly exposed to ionizing radiation, harbor large of amounts of microorganisms, including fungal...species [3,4]. Furthermore, Zhdanova et al. reported that beta and gamma radiation promoted directional growth of fungi isolated from the Chernobyl

  5. Adaptive Redox Response of Mesenchymal Stromal Cells to Stimulation with Lipopolysaccharide Inflammagen: Mechanisms of Remodeling of Tissue Barriers in Sepsis

    DTIC Science & Technology

    2013-03-08

    Mechanisms of Remodeling of Tissue Barriers in Sepsis Nikolai V. Gorbunov1*, Bradley R. Garrison1, Dennis P. McDaniel2, Min Zhai1, Pei-Jyun Liao1... sepsis [2, 5]. This problem leads to the searching for other potential mechanisms that could produce adverse effects on host metabolome resulting...understanding of the basic cellular mechanisms implicated in redox adaptive responses in 16 tissue barriers. This particular area of the molecular

  6. Biological Bases for Radiation Adaptive Responses in the Lung

    SciTech Connect

    Scott, Bobby R.; Lin, Yong; Wilder, Julie; Belinsky, Steven

    2015-03-01

    Our main research objective was to determine the biological bases for low-dose, radiation-induced adaptive responses in the lung and use the knowledge gained to produce an improved risk model for radiation-induced lung cancer that accounts for activated natural protection, genetic influences, and the role of epigenetic regulation (epiregulation). Currently, low-dose radiation risk assessment is based on the linear-no-threshold hypothesis which now is known to be unsupported by a large volume of data.

  7. Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases

    SciTech Connect

    Balajee, A.S.; Meador, J.A.; Su, Y.

    2011-03-24

    It is increasingly realized that human exposure either to an acute low dose or multiple chronic low doses of low LET radiation has the potential to cause different types of cancer. Therefore, the central theme of research for DOE and NASA is focused on understanding the molecular mechanisms and pathways responsible for the cellular response to low dose radiation which would not only improve the accuracy of estimating health risks but also help in the development of predictive assays for low dose radiation risks associated with tissue degeneration and cancer. The working hypothesis for this proposal is that the cellular mechanisms in terms of DNA damage signaling, repair and cell cycle checkpoint regulation are different for low and high doses of low LET radiation and that the mode of action of phosphatidylinositol-3 kinase like kinases (PIKK: ATM, ATR and DNA-PK) determines the dose dependent cellular responses. The hypothesis will be tested at two levels: (I) Evaluation of the role of ATM, ATR and DNA-PK in cellular response to low and high doses of low LET radiation in simple in vitro human cell systems and (II) Determination of radiation responses in complex cell microenvironments such as human EpiDerm tissue constructs. Cellular responses to low and high doses of low LET radiation will be assessed from the view points of DNA damage signaling, DNA double strand break repair and cell cycle checkpoint regulation by analyzing the activities (i.e. post-translational modifications and kinetics of protein-protein interactions) of the key target proteins for PI-3 kinase like kinases both at the intra-cellular and molecular levels. The proteins chosen for this proposal are placed under three categories: (I) sensors/initiators include ATM ser1981, ATR, 53BP1, gamma-H2AX, MDC1, MRE11, Rad50 and Nbs1; (II) signal transducers include Chk1, Chk2, FANCD2 and SMC1; and (III) effectors include p53, CDC25A and CDC25C. The primary goal of this proposal is to elucidate the

  8. Innate and adaptive cellular immunity in flavivirus-naïve human recipients of a live-attenuated dengue serotype 3 vaccine produced in Vero cells (VDV3).

    PubMed

    Sanchez, Violette; Gimenez, Sophie; Tomlinson, Brian; Chan, Paul K S; Thomas, G Neil; Forrat, Remi; Chambonneau, Laurent; Deauvieau, Florence; Lang, Jean; Guy, Bruno

    2006-06-05

    VDV3, a clonal derivative of the Mahidol live-attenuated dengue 3 vaccine was prepared in Vero cells. Despite satisfactory preclinical evaluation, VDV3 was reactogenic in humans. We explored whether immunological mechanisms contributed to this outcome by monitoring innate and adaptive cellular immune responses for 28 days after vaccination. While no variations were seen in serum IL12 or TNFalpha levels, a high IFNgamma secretion was detected from Day 8, concomitant to IFNalpha, followed by IL10. Specific Th1 and CD8 responses were detected on Day 28, with high IFNgamma/TNFalpha ratios. Vaccinees exhibited very homogeneous class I HLA profiles, and a new HLA B60-restricted CD8 epitope was identified in NS3. We propose that, among other factors, adaptive immunity may have contributed to reactogenicity, even after this primary vaccination. In addition, the unexpected discordance observed between preclinical results and clinical outcome in humans led us to reconsider some of our preclinical acceptance criteria. Lessons learned from these results will help us to pursue the development of safe and immunogenic vaccines.

  9. Activating adaptive cellular mechanisms of resistance following sublethal cytotoxic chemotherapy: implications for diagnostic microdosing.

    PubMed

    Wurz, Gregory T; DeGregorio, Michael W

    2015-04-01

    As Phase 0 studies have proven to be reasonably predictive of therapeutic dose pharmacokinetics, the application of microdosing has expanded into metabolism, drug-drug interactions and now diagnostics. One potentially serious issue with this application of microdosing that has not been previously discussed is the possibility of activating cellular mechanisms of drug resistance. Here, we provide an overview of Phase 0 microdosing and drug resistance, with an emphasis on cisplatin resistance, followed by a discussion of the potential for inducing acquired resistance to platinum-based or other types of chemotherapy in cancer patients participating in Phase 0 diagnostic microdosing studies. A number of alternative approaches to diagnostic microdosing, such as the human tumor cloning assay and the use of peripheral blood mononuclear cells as a surrogate for measuring DNA adducts, are discussed that would avoid exposing cancer patients to low doses of first-line chemotherapy and the possible risk of triggering cellular mechanisms of acquired resistance. Until it has been established that diagnostic microdosing in cancer patients poses no risk of acquired drug resistance, such studies should be approached with caution.

  10. Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells

    PubMed Central

    Currier, Jenna M.; Cheng, Wan-Yun; Menendez, Daniel; Conolly, Rory; Chorley, Brian N.

    2016-01-01

    Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 2–10 μM Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p < 0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the

  11. Adaptive response of bacteria: Multiple hurdles, cross-tolerance and tools to illustrate underlying mechanisms

    NASA Astrophysics Data System (ADS)

    Paramythiotis, Spyridon; Skandamis, Panagiotis N.

    2015-01-01

    A basic principle in the bacterial resistance against lethal stresses is that exposure of microbial cells to a sublethal hurdle (e.g., pH 5.0, 3% NaCl, or 48°C) may induce resistance to lethal level of the same or different stress. The latter is called "cross-tolerance" and the bacteria experiencing such situations are termed "stress-hardened". The majority of scientific reports on the adaptive responses of bacteria to stresses have recently addressed the need to elucidate the underlying mechanisms controlling bacterial stress response. This in turn, will assist in the efficient application of the multiple hurdle approach, e.g., by selecting specific sanitizers, combining stress treatments or antimicrobials, especially in mild processing, against specific cellular targets, eliminating the possibility of the development of stress adapted cells. Common scientific approaches for studying the link between phenotype (e.g., inactivation, survival, or growth) and physiology is the assessment of global transcriptional changes (up- or down-regulation) or those of certain genes, as well as of proteins involved in certain metabolic pathways, occurring during exposure to stress. This may also be performed in parallel to comparative evaluation of the phenotypic response of wild and mutant strains. The post-genomics research on foodborne pathogens has extended our knowledge beyond their phenotypic behavior and may offer mechanistic insights in the following: (i) the top-down approach (induction), which is the search of the underlying mechanisms (low level) responsible for a specific phenotype based on "-omic" studies; and (ii) the bottom-up approach (deduction), which starts from intracellular level and forms a mechanistic (functional) basis for the cellular response. All these may eventually enable the development of mechanistic microbial models and efficient strategies for controlling survival and growth of pathogens in foods.

  12. Interplay between Cellular Methyl Metabolism and Adaptive Efflux during Oncogenic Transformation from Chronic Arsenic Exposure in Human Cells*S⃞

    PubMed Central

    Coppin, Jean-François; Qu, Wei; Waalkes, Michael P.

    2008-01-01

    After protracted low level arsenic exposure, the normal human prostate epithelial cell line RWPE-1 acquires a malignant phenotype with DNA hypomethylation, indicative of disrupted methyl metabolism, and shows arsenic adaptation involving glutathione overproduction and enhanced arsenic efflux. Thus, the interplay between methyl and glutathione metabolism during this progressive arsenic adaptation was studied. Arsenic-treated cells showed a time-dependent increase in LC50 and a marked increase in homocysteine (Hcy) levels. A marked suppression of S-adenosylmethionine (SAM) levels occurred with decreased methionine adenosyltransferase 2A (converts methionine to SAM) expression and increased negative regulator methionine adenosyltransferase B, suggesting reduced conversion of Hcy to SAM. Consistent with Hcy overproduction, activity and expression of S-adenosylhomocysteine hydrolase (converts S-adenosylhomocysteine to Hcy) were both increased. Expression of cystathionine β-synthase, a key gene in the transsulfuration pathway, and various glutathione production genes were increased, resulting in a 5-fold increase in glutathione. Arsenic efflux increased along with expression of ATP-binding cassette protein C1, which effluxes arsenic as a glutathione conjugate. Evidence of genomic DNA hypomethylation was observed during early arsenic exposure, indicating that the disruption in methyl metabolism had a potential impact related to oncogenesis. Thus, cellular arsenic adaptation is a dynamic, progressive process that involves decreased SAM recycling and concurrent accumulation of Hcy, which is channeled via transsulfuration to increase glutathione and enhance arsenic efflux but may also impact the carcinogenic process. PMID:18487201

  13. A signature microRNA expression profile for the cellular response to thermal stress

    NASA Astrophysics Data System (ADS)

    Wilmink, Gerald J.; Roth, Caleb C.; Ketchum, Norma; Ibey, Bennett L.; Waterworth, Angela; Suarez, Maria; Roach, William P.

    2009-02-01

    Recently, an extensive layer of intra-cellular signals was discovered that was previously undetected by genetic radar. It is now known that this layer consists primarily of a class of short noncoding RNA species that are referred to as microRNAs (miRNAs). MiRNAs regulate protein synthesis at the post-transcriptional level, and studies have shown that they are involved in many fundamental cellular processes. In this study, we hypothesized that miRNAs may be involved in cellular stress response mechanisms, and that cells exposed to thermal stress may exhibit a signature miRNA expression profile indicative of their functional involvement in such mechanisms. To test our hypothesis, human dermal fibroblasts were exposed to an established hyperthermic protocol, and the ensuing miRNA expression levels were evaluated 4 hr post-exposure using microRNA microarray gene chips. The microarray data shows that 123 miRNAs were differentially expressed in cells exposed to thermal stress. We collectively refer to these miRNAs as thermalregulated microRNAs (TRMs). Since miRNA research is in its infancy, it is interesting to note that only 27 of the 123 TRMs are currently annotated in the Sanger miRNA registry. Prior to publication, we plan to submit the remaining novel 96 miRNA gene sequences for proper naming. Computational and thermodynamic modeling algorithms were employed to identify putative mRNA targets for the TRMs, and these studies predict that TRMs regulate the mRNA expression of various proteins that are involved in the cellular stress response. Future empirical studies will be conducted to validate these theoretical predictions, and to further examine the specific role that TRMs play in the cellular stress response.

  14. Development of a micro cell compression stimulator for evaluating real-time cellular responses

    NASA Astrophysics Data System (ADS)

    Nakashima, Y.; Yang, Y.; Minami, K.

    2012-05-01

    This paper presents a micro cell compression stimulator for evaluating real-time cellular responses to compression stimuli. The device was produced by a micro three-dimensional structure fabrication process using multiple exposures to the photoresist. The device consists of a pressure inlet port, cell inlet ports, a gasket, microchannels, cell culture chambers, and a diaphragm on the culture chamber for applying compressive pressure to cells. Compression stimuli applied to the cells can be controlled by regulating the expansion of the diaphragm via a pressure control. The device permits the observation of cellular responses to compressive pressure in real time because it is made of transparent materials and stimulates the cells without deforming the cell culture surface, when observed by optical microscopy. We demonstrated the validity of the fabrication process, evaluated the performance of the fabricated device, and compared the experimental results with the FEM structural analysis results. We found through operational testing that the diaphragm was deformed quickly by applying negative/positive pressure and that the diaphragm displacement became larger with increasing applied pressure. These results indicate that this device can be used to control the intensity and the cell stimulus profile by regulating the applied pressure. In all cases, the cellular deformation during compression stimulus was successfully observed in real time using an optical microscope. The device is expected to facilitate the control of stem cell differentiation and the clarification of cellular mechanoreceptor mechanisms and signal transduction pathways.

  15. Protein O-GlcNAcylation: A critical regulator of the cellular response to stress

    PubMed Central

    Chatham, John C.; Marchase, Richard B.

    2012-01-01

    The post-translational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide ß-N-acetyl-glucosamine (O-GlcNAc) is a highly dynamic and ubiquitous protein modification that plays a critical role in regulating numerous biological processes. Much of our understanding of the mechanisms underlying the role of O-GlcNAc on cellular function has been in the context of chronic disease processes. However, there is increasing evidence that O-GlcNAc levels are increased in response to stress and that acute augmentation of this response is cytoprotective, at least in the short term. Conversely, a reduction in O-GlcNAc levels appears to be associated with decreased cell survival in response to an acute stress. Here we summarize our current understanding of protein O-GlcNAcylation on the cellular response to stress and in mediating cellular protective mechanisms focusing primarily on the cardiovascular system as an example. We consider the potential link between O-GlcNAcylation and cardiomyocyte calcium homeostasis and explore the parallels between O-GlcNAc signaling and redox signaling. We also discuss the apparent paradox between the reported adverse effects of increased O-GlcNAcylation with its recently reported role in mediating cell survival mechanisms. PMID:22308107

  16. Modeling Cellular Noise Underlying Heterogeneous Cell Responses in the Epidermal Growth Factor Signaling Pathway

    PubMed Central

    Iwamoto, Kazunari; Shindo, Yuki; Takahashi, Koichi

    2016-01-01

    Cellular heterogeneity, which plays an essential role in biological phenomena, such as drug resistance and migration, is considered to arise from intrinsic (i.e., reaction kinetics) and extrinsic (i.e., protein variability) noise in the cell. However, the mechanistic effects of these types of noise to determine the heterogeneity of signal responses have not been elucidated. Here, we report that the output of epidermal growth factor (EGF) signaling activity is modulated by cellular noise, particularly by extrinsic noise of particular signaling components in the pathway. We developed a mathematical model of the EGF signaling pathway incorporating regulation between extracellular signal-regulated kinase (ERK) and nuclear pore complex (NPC), which is necessary for switch-like activation of the nuclear ERK response. As the threshold of switch-like behavior is more sensitive to perturbations than the graded response, the effect of biological noise is potentially critical for cell fate decision. Our simulation analysis indicated that extrinsic noise, but not intrinsic noise, contributes to cell-to-cell heterogeneity of nuclear ERK. In addition, we accurately estimated variations in abundance of the signal proteins between individual cells by direct comparison of experimental data with simulation results using Apparent Measurement Error (AME). AME was constant regardless of whether the protein levels varied in a correlated manner, while covariation among proteins influenced cell-to-cell heterogeneity of nuclear ERK, suppressing the variation. Simulations using the estimated protein abundances showed that each protein species has different effects on cell-to-cell variation in the nuclear ERK response. In particular, variability of EGF receptor, Ras, Raf, and MEK strongly influenced cellular heterogeneity, while others did not. Overall, our results indicated that cellular heterogeneity in response to EGF is strongly driven by extrinsic noise, and that such heterogeneity

  17. Adaptive immune response during hepatitis C virus infection.

    PubMed

    Larrubia, Juan Ramón; Moreno-Cubero, Elia; Lokhande, Megha Uttam; García-Garzón, Silvia; Lázaro, Alicia; Miquel, Joaquín; Perna, Cristian; Sanz-de-Villalobos, Eduardo

    2014-04-07

    Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

  18. Respiratory Syncytial Virus and Cellular Stress Responses: Impact on Replication and Physiopathology

    PubMed Central

    Cervantes-Ortiz, Sandra L.; Zamorano Cuervo, Natalia; Grandvaux, Nathalie

    2016-01-01

    Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is a major cause of severe acute lower respiratory tract infection in infants, elderly and immunocompromised adults. Despite decades of research, a complete integrated picture of RSV-host interaction is still missing. Several cellular responses to stress are involved in the host-response to many virus infections. The endoplasmic reticulum stress induced by altered endoplasmic reticulum (ER) function leads to activation of the unfolded-protein response (UPR) to restore homeostasis. Formation of cytoplasmic stress granules containing translationally stalled mRNAs is a means to control protein translation. Production of reactive oxygen species is balanced by an antioxidant response to prevent oxidative stress and the resulting damages. In recent years, ongoing research has started to unveil specific regulatory interactions of RSV with these host cellular stress responses. Here, we discuss the latest findings regarding the mechanisms evolved by RSV to induce, subvert or manipulate the ER stress, the stress granule and oxidative stress responses. We summarize the evidence linking these stress responses with the regulation of RSV replication and the associated pathogenesis. PMID:27187445

  19. Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

    PubMed Central

    Kamal, Sanaa M.; Amin, Ashraf; Madwar, Mohamed; Graham, Camilla S.; He, Qi; Al Tawil, Ahmed; Rasenack, Jens; Nakano, Tatsunori; Robertson, Betty; Ismail, Alaa; Koziel, Margaret James

    2004-01-01

    Acute hepatitis C virus (HCV) is typically defined as new viremia and antibody seroconversion. Rates and immunologic correlates of hepatitis C clearance have therefore been based on clearance of viremia only in individuals who initially had an antibody response. We sought to characterize the immunological correlates of clearance in patients with acute hepatitis C and their sexual contacts. We prospectively determined CD4+ and CD8+ cytotoxic T-lymphocyte responses in index patients with acute HCV and their sexual contacts who developed acute infection, either with or without spontaneous clearance, as well as those contacts who never developed viremia. Responses were measured using proliferation and ELISpot assays for CD4+ and CD8+ responses. We demonstrate in this prospective study that cellular immune responses can develop in exposed but persistently aviremic and antibody-negative individuals as well as those individuals with spontaneous clearance of acute HCV. These findings lend further credence to the importance of cellular immune responses in recovery from HCV and suggest that low exposure to HCV may lead to development of HCV-specific immune responses without ongoing HCV replication. This finding has important implications for HCV vaccine and therapeutic development. PMID:15507612

  20. Adaptive call admission control and resource allocation in multi server wireless/cellular network

    NASA Astrophysics Data System (ADS)

    Jain, Madhu; Mittal, Ragini

    2016-11-01

    The ever increasing demand of the subscribers has put pressure on the capacity of wireless networks around the world. To utilize the scare resources, in the present paper we propose an optimal allocation scheme for an integrated wireless/cellular model with handoff priority and handoff guarantee services. The suggested algorithm optimally allocates the resources in each cell and dynamically adjust threshold to control the admission. To give the priority to handoff calls over the new calls, the provision of guard channels and subrating scheme is taken into consideration. The handoff voice call may balk and renege from the system while waiting in the buffer. An iterative algorithm is implemented to generate the arrival rate of the handoff calls in each cell. Various performance indices are established in term of steady state probabilities. The sensitivity analysis has also been carried out to examine the tractability of algorithms and to explore the effects of system descriptors on the performance indices.

  1. Cellular mechanisms of adaptive myelination: bridging the gap between animal studies and human cognition.

    PubMed

    Bujalka, Helena; Emery, Ben

    2017-04-01

    Voelker and colleagues propose that we may illuminate learning-associated phenomena such as generalization by considering white matter plasticity. Consistent with this idea, human neuroimaging studies reveal learning-induced changes in adult white matter. Animal studies reveal that some forms of learning induce, and are dependent on, generation of new oligodendrocytes. Nevertheless, it remains unclear which alterations to myelin structure are most relevant to learning, and humans and rodents may profoundly differ in their capacity for oligodendrogenesis in adulthood. A full understanding of these issues will be critical to appreciating the role of adaptive myelination in human neuroplasticity.

  2. A cellular automaton model adapted to sandboxes to simulate the transport of solutes

    NASA Astrophysics Data System (ADS)

    Lora, Boris; Donado, Leonardo; Castro, Eduardo; Bayuelo, Alfredo

    2016-04-01

    The increasingly use of groundwater sources for human consumption and the growth of the levels of these hydric sources contamination make imperative to reach a deeper understanding how the contaminants are transported by the water, in particular through a heterogeneous porous medium. Accordingly, the present research aims to design a model, which simulates the transport of solutes through a heterogeneous porous medium, using cellular automata. Cellular automata (CA) are a class of spatially (pixels) and temporally discrete mathematical systems characterized by local interaction (neighborhoods). The pixel size and the CA neighborhood were determined in order to reproduce accurately the solute behavior (Ilachinski, 2001). For the design and corresponding validation of the CA model were developed different conservative tracer tests using a sandbox packed heterogeneously with a coarse sand (size # 20 grain diameter 0,85 to 0,6 mm) and clay. We use Uranine and a saline solution with NaCl as a tracer which were measured taking snapshots each 20 seconds. A calibration curve (pixel intensity Vs Concentration) was used to obtain concentration maps. The sandbox was constructed of acrylic (caliber 0,8 cms) with 70 x 45 x 4 cms of dimensions. The "sandbox" had a grid of 35 transversal holes with a diameter of 4 mm each and an uniform separation from one to another of 10 cms. To validate the CA-model it was used a metric consisting in rating the number of correctly predicted pixels over the total per image throughout the entire test run. The CA-model shows that calibrations of pixels and neighborhoods allow reaching results over the 60 % of correctly predictions usually. This makes possible to think that the application of the CA- model could be useful in further researches regarding the transport of contaminants in hydrogeology.

  3. Cellular Dysfunction in Diabetes as Maladaptive Response to Mitochondrial Oxidative Stress

    PubMed Central

    Naudi, Alba; Jove, Mariona; Ayala, Victoria; Cassanye, Anna; Serrano, Jose; Gonzalo, Hugo; Boada, Jordi; Prat, Joan; Portero-Otin, Manuel; Pamplona, Reinald

    2012-01-01

    Oxidative stress has been implicated in diabetes long-term complications. In this paper, we summarize the growing evidence suggesting that hyperglycemia-induced overproduction of superoxide by mitochondrial electron transport chain triggers a maladaptive response by affecting several metabolic and signaling pathways involved in the pathophysiology of cellular dysfunction and diabetic complications. In particular, it is our goal to describe physiological mechanisms underlying the mitochondrial free radical production and regulation to explain the oxidative stress derived from a high intracellular glucose concentration and the resulting maladaptive response that leads to a cellular dysfunction and pathological state. Finally, we outline potential therapies for diabetes focused to the prevention of mitochondrial oxidative damage. PMID:22253615

  4. Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures

    PubMed Central

    Lee, Anna Y.; St.Onge, Robert P.; Proctor, Michael J.; Wallace, Iain M.; Nile, Aaron H.; Spagnuolo, Paul A.; Jitkova, Yulia; Gronda, Marcela; Wu, Yan; Kim, Moshe K.; Cheung-Ong, Kahlin; Torres, Nikko P.; Spear, Eric D.; Han, Mitchell K. L.; Schlecht, Ulrich; Suresh, Sundari; Duby, Geoffrey; Heisler, Lawrence E.; Surendra, Anuradha; Fung, Eula; Urbanus, Malene L.; Gebbia, Marinella; Lissina, Elena; Miranda, Molly; Chiang, Jennifer H.; Aparicio, Ana Maria; Zeghouf, Mahel; Davis, Ronald W.; Cherfils, Jacqueline; Boutry, Marc; Kaiser, Chris A.; Cummins, Carolyn L.; Trimble, William S.; Brown, Grant W.; Schimmer, Aaron D.; Bankaitis, Vytas A.; Nislow, Corey; Bader, Gary D.; Giaever, Guri

    2014-01-01

    Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small molecules affects biology and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compound in vivo to profile 3250 small molecules in a systematic and unbiased manner. We identified 317 compounds that specifically perturb the function of 121 genes and characterized the mechanism of specific compounds. Global analysis revealed that the cellular response to small molecules is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chemicals, and biological processes. PMID:24723613

  5. JAK/STAT signaling in Drosophila muscles controls the cellular immune response against parasitoid infection.

    PubMed

    Yang, Hairu; Kronhamn, Jesper; Ekström, Jens-Ola; Korkut, Gül Gizem; Hultmark, Dan

    2015-12-01

    The role of JAK/STAT signaling in the cellular immune response of Drosophila is not well understood. Here, we show that parasitoid wasp infection activates JAK/STAT signaling in somatic muscles of the Drosophila larva, triggered by secretion of the cytokines Upd2 and Upd3 from circulating hemocytes. Deletion of upd2 or upd3, but not the related os (upd1) gene, reduced the cellular immune response, and suppression of the JAK/STAT pathway in muscle cells reduced the encapsulation of wasp eggs and the number of circulating lamellocyte effector cells. These results suggest that JAK/STAT signaling in muscles participates in a systemic immune defense against wasp infection.

  6. Elucidating the molecular mechanisms underlying cellular response to biophysical cues using synthetic biology approaches.

    PubMed

    Denning, Denise; Roos, Wouter H

    2016-09-02

    The use of synthetic surfaces and materials to influence and study cell behavior has vastly progressed our understanding of the underlying molecular mechanisms involved in cellular response to physicochemical and biophysical cues. Reconstituting cytoskeletal proteins and interfacing them with a defined microenvironment has also garnered deep insight into the engineering mechanisms existing within the cell. This review presents recent experimental findings on the influence of several parameters of the extracellular environment on cell behavior and fate, such as substrate topography, stiffness, chemistry and charge. In addition, the use of synthetic environments to measure physical properties of the reconstituted cytoskeleton and their interaction with intracellular proteins such as molecular motors is discussed, which is relevant for understanding cell migration, division and structural integrity, as well as intracellular transport. Insight is provided regarding the next steps to be taken in this interdisciplinary field, in order to achieve the global aim of artificially directing cellular response.

  7. The Regulation of Cellular Responses to Mechanical Cues by Rho GTPases

    PubMed Central

    Hoon, Jing Ling; Tan, Mei Hua; Koh, Cheng-Gee

    2016-01-01

    The Rho GTPases regulate many cellular signaling cascades that modulate cell motility, migration, morphology and cell division. A large body of work has now delineated the biochemical cues and pathways, which stimulate the GTPases and their downstream effectors. However, cells also respond exquisitely to biophysical and mechanical cues such as stiffness and topography of the extracellular matrix that profoundly influence cell migration, proliferation and differentiation. As these cellular responses are mediated by the actin cytoskeleton, an involvement of Rho GTPases in the transduction of such cues is not unexpected. In this review, we discuss an emerging role of Rho GTPase proteins in the regulation of the responses elicited by biophysical and mechanical stimuli. PMID:27058559

  8. Cytokine, antibody and proliferative cellular responses elicited by Taenia solium calreticulin upon experimental infection in hamsters.

    PubMed

    Mendlovic, Fela; Cruz-Rivera, Mayra; Ávila, Guillermina; Vaughan, Gilberto; Flisser, Ana

    2015-01-01

    Taenia solium causes two diseases in humans, cysticercosis and taeniosis. Tapeworm carriers are the main risk factor for neurocysticercosis. Limited information is available about the immune response elicited by the adult parasite, particularly the induction of Th2 responses, frequently associated to helminth infections. Calreticulin is a ubiquitous, multifunctional protein involved in cellular calcium homeostasis, which has been suggested to play a role in the regulation of immune responses. In this work, we assessed the effect of recombinant T. solium calreticulin (rTsCRT) on the cytokine, humoral and cellular responses upon experimental infection in Syrian Golden hamsters (Mesocricetus auratus). Animals were infected with T. solium cysticerci and euthanized at different times after infection. Specific serum antibodies, proliferative responses in mesenteric lymph nodes and spleen cells, as well as cytokines messenger RNA (mRNA) were analyzed. The results showed that one third of the infected animals elicited anti-rTsCRT IgG antibodies. Interestingly, mesenteric lymph node (MLN) cells from either infected or non-infected animals did not proliferate upon in vitro stimulation with rTsCRT. Additionally, stimulation with a tapeworm crude extract resulted in increased expression of IL-4 and IL-5 mRNA. Upon stimulation, rTsCRT increased the expression levels of IL-10 in spleen and MLN cells from uninfected and infected hamsters. The results showed that rTsCRT favors a Th2-biased immune response characterized by the induction of IL-10 in mucosal and systemic lymphoid organs. Here we provide the first data on the cytokine, antibody and cellular responses to rTsCRT upon in vitro stimulation during taeniasis.

  9. Cytokine, Antibody and Proliferative Cellular Responses Elicited by Taenia solium Calreticulin upon Experimental Infection in Hamsters

    PubMed Central

    Mendlovic, Fela; Cruz-Rivera, Mayra; Ávila, Guillermina; Vaughan, Gilberto; Flisser, Ana

    2015-01-01

    Taenia solium causes two diseases in humans, cysticercosis and taeniosis. Tapeworm carriers are the main risk factor for neurocysticercosis. Limited information is available about the immune response elicited by the adult parasite, particularly the induction of Th2 responses, frequently associated to helminth infections. Calreticulin is a ubiquitous, multifunctional protein involved in cellular calcium homeostasis, which has been suggested to play a role in the regulation of immune responses. In this work, we assessed the effect of recombinant T. solium calreticulin (rTsCRT) on the cytokine, humoral and cellular responses upon experimental infection in Syrian Golden hamsters (Mesocricetus auratus). Animals were infected with T. solium cysticerci and euthanized at different times after infection. Specific serum antibodies, proliferative responses in mesenteric lymph nodes and spleen cells, as well as cytokines messenger RNA (mRNA) were analyzed. The results showed that one third of the infected animals elicited anti-rTsCRT IgG antibodies. Interestingly, mesenteric lymph node (MLN) cells from either infected or non-infected animals did not proliferate upon in vitro stimulation with rTsCRT. Additionally, stimulation with a tapeworm crude extract resulted in increased expression of IL-4 and IL-5 mRNA. Upon stimulation, rTsCRT increased the expression levels of IL-10 in spleen and MLN cells from uninfected and infected hamsters. The results showed that rTsCRT favors a Th2-biased immune response characterized by the induction of IL-10 in mucosal and systemic lymphoid organs. Here we provide the first data on the cytokine, antibody and cellular responses to rTsCRT upon in vitro stimulation during taeniasis. PMID:25811778

  10. Opt2 mediates the exposure of phospholipids during cellular adaptation to altered lipid asymmetry.

    PubMed

    Yamauchi, Saori; Obara, Keisuke; Uchibori, Kenya; Kamimura, Akiko; Azumi, Kaoru; Kihara, Akio

    2015-01-01

    Plasma membrane lipid asymmetry is important for various membrane-associated functions and is regulated by membrane proteins termed flippases and floppases. The Rim101 pathway senses altered lipid asymmetry in the yeast plasma membrane. The mutant lem3Δ cells, in which lipid asymmetry is disturbed owing to the inactivation of the plasma membrane flippases, showed a severe growth defect when the Rim101 pathway was impaired. To identify factors involved in the Rim101-pathway-dependent adaptation to altered lipid asymmetry, we performed DNA microarray analysis and found that Opt2 induced by the Rim101 pathway plays an important role in the adaptation to altered lipid asymmetry. Biochemical investigation of Opt2 revealed its localization to the plasma membrane and the Golgi, and provided several lines of evidence for the Opt2-mediated exposure of phospholipids. In addition, Opt2 was found to be required for the maintenance of vacuolar morphology and polarized cell growth. These results suggest that Opt2 is a novel factor involved in cell homeostasis by regulating lipid asymmetry.

  11. Universal response-adaptation relation in bacterial chemotaxis.

    PubMed

    Krembel, Anna K; Neumann, Silke; Sourjik, Victor

    2015-01-01

    The bacterial strategy of chemotaxis relies on temporal comparisons of chemical concentrations, where the probability of maintaining the current direction of swimming is modulated by changes in stimulation experienced during the recent past. A short-term memory required for such comparisons is provided by the adaptation system, which operates through the activity-dependent methylation of chemotaxis receptors. Previous theoretical studies have suggested that efficient navigation in gradients requires a well-defined adaptation rate, because the memory time scale needs to match the duration of straight runs made by bacteria. Here we demonstrate that the chemotaxis pathway of Escherichia coli does indeed exhibit a universal relation between the response magnitude and adaptation time which does not depend on the type of chemical ligand. Our results suggest that this alignment of adaptation rates for different ligands is achieved through cooperative interactions among chemoreceptors rather than through fine-tuning of methylation rates for individual receptors. This observation illustrates a yet-unrecognized function of receptor clustering in bacterial chemotaxis.

  12. Stress and adaptation responses to repeated acute acceleration.

    NASA Technical Reports Server (NTRS)

    Burton, R. R.; Smith, A. H.

    1972-01-01

    Study in which groups of adult male chickens (single-comb white leghorn) were exposed daily to acceleration (centrifugation) of 2 or 3 G for 10 min, 1, 4, 8, 12, 16, and 24 hr (continuously), or 0 time (controls). After approximately five months of this intermittent treatment (training), the birds were exposed to continuous accelerations of the same G force (intensity). The degree of stress and adaptation of each bird was determined by survival and relative lymphocyte count criteria. Intermittent training exposures of 2 G developed levels of adaptation in birds directly proportional to the duration of their daily exposure. Intermittent training periods at 3 G, however, produced a physiological deterioration in birds receiving daily exposures of 8 hr or more. Adaptive benefits were found only in the 1- and 4-hr-daily intermittent 3-G exposure groups. Exposure to 3 G produced an immediate stress response as indicated by a low relative lymphocyte count which returned to control (preexposed) values prior to the next daily acceleration period in the 10-min, 1-hr, and 4-hr groups. This daily recovery period from stress appeared to be necessary for adaptation as opposed to deterioration for the more severe environmental (3 G) alteration.

  13. Bayesian response-adaptive designs for basket trials.

    PubMed

    Ventz, Steffen; Barry, William T; Parmigiani, Giovanni; Trippa, Lorenzo

    2017-02-17

    We develop a general class of response-adaptive Bayesian designs using hierarchical models, and provide open source software to implement them. Our work is motivated by recent master protocols in oncology, where several treatments are investigated simultaneously in one or multiple disease types, and treatment efficacy is expected to vary across biomarker-defined subpopulations. Adaptive trials such as I-SPY-2 (Barker et al., 2009) and BATTLE (Zhou et al., 2008) are special cases within our framework. We discuss the application of our adaptive scheme to two distinct research goals. The first is to identify a biomarker subpopulation for which a therapy shows evidence of treatment efficacy, and to exclude other subpopulations for which such evidence does not exist. This leads to a subpopulation-finding design. The second is to identify, within biomarker-defined subpopulations, a set of cancer types for which an experimental therapy is superior to the standard-of-care. This goal leads to a subpopulation-stratified design. Using simulations constructed to faithfully represent ongoing cancer sequencing projects, we quantify the potential gains of our proposed designs relative to conventional non-adaptive designs.

  14. A nonstandard finite difference scheme for a basic model of cellular immune response to viral infection

    NASA Astrophysics Data System (ADS)

    Korpusik, Adam

    2017-02-01

    We present a nonstandard finite difference scheme for a basic model of cellular immune response to viral infection. The main advantage of this approach is that it preserves the essential qualitative features of the original continuous model (non-negativity and boundedness of the solution, equilibria and their stability conditions), while being easy to implement. All of the qualitative features are preserved independently of the chosen step-size. Numerical simulations of our approach and comparison with other conventional simulation methods are presented.

  15. Cellular Neural Network Models of Growth and Immune of Effector Cells Response to Cancer

    NASA Astrophysics Data System (ADS)

    Su, Yongmei; Min, Lequan

    Four reaction-diffusion cellular neural network (R-D CNN) models are set up based on the differential equation models for the growths of effector cells and cancer cells, and the model of the immune response to cancer proposed by Allison et al. The CNN models have different reaction-diffusion coefficients and coupling parameters. The R-D CNN models may provide possible quantitative interpretations, and are good in agreement with the in vitro experiment data reported by Allison et al.

  16. Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors

    EPA Science Inventory

    Dose response and time-course (DRTC) are, along with exposure, the major determinants of health risk. Adaptive changes within exposed organisms in response to environmental stress are common, and alter DRTC behaviors to minimize the effects caused by stressors. In this project, ...

  17. An integrated systems approach for understanding cellular responses to gamma radiation.

    PubMed

    Whitehead, Kenia; Kish, Adrienne; Pan, Min; Kaur, Amardeep; Reiss, David J; King, Nichole; Hohmann, Laura; DiRuggiero, Jocelyne; Baliga, Nitin S

    2006-01-01

    Cellular response to stress entails complex mRNA and protein abundance changes, which translate into physiological adjustments to maintain homeostasis as well as to repair and minimize damage to cellular components. We have characterized the response of the halophilic archaeon Halobacterium salinarum NRC-1 to (60)Co ionizing gamma radiation in an effort to understand the correlation between genetic information processing and physiological change. The physiological response model we have constructed is based on integrated analysis of temporal changes in global mRNA and protein abundance along with protein-DNA interactions and evolutionarily conserved functional associations. This systems view reveals cooperation among several cellular processes including DNA repair, increased protein turnover, apparent shifts in metabolism to favor nucleotide biosynthesis and an overall effort to repair oxidative damage. Further, we demonstrate the importance of time dimension while correlating mRNA and protein levels and suggest that steady-state comparisons may be misleading while assessing dynamics of genetic information processing across transcription and translation.

  18. Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt.

    PubMed

    Mukai, Akiko; Yamamoto-Hino, Miki; Awano, Wakae; Watanabe, Wakako; Komada, Masayuki; Goto, Satoshi

    2010-07-07

    Wingless (Wg)/Wnt has been proposed to exert various functions as a morphogen depending on the levels of its signalling. Therefore, not just the concentration of Wg/Wnt, but also the responsiveness of Wg/Wnt-target cells to the ligand, must have a crucial function in controlling cellular outputs. Here, we show that a balance of ubiquitylation and deubiquitylation of the Wg/Wnt receptor Frizzled determines the cellular responsiveness to Wg/Wnt both in mammalian cells and in Drosophila, and that the cell surface level of Frizzled is regulated by deubiquitylating enzyme UBPY/ubiquitin-specific protease 8 (USP8). Although ubiquitylated Frizzled underwent lysosomal trafficking and degradation, UBPY/USP8-dependent deubiquitylation led to recycling of Frizzled to the plasma membrane, thereby elevating its surface level. Importantly, a gain and loss of UBPY/USP8 function led to up- and down-regulation, respectively, of canonical Wg/Wnt signalling. These results unveil a novel mechanism that regulates the cellular responsiveness to Wg/Wnt by controlling the cell surface level of Frizzled.

  19. In vivo and in vitro cellular response to PEG-based hydrogels for wound repair

    NASA Astrophysics Data System (ADS)

    Waldeck, Heather

    Biomaterials are continuously being explored as a means to support, improve, or influence wound healing processes. Understanding the determining factors controlling the host response to biomaterials is crucial in developing strategies to employ materials for biomedical uses. In order to evaluate the host response to poly(ethylene glycol) (PEG)-based hydrogels, both in vivo and in vitro studies were performed to determine its efficacy as a dermal wound treatment and to investigate the mechanisms controlling cell-material interaction, respectively. The results of an in vivo study using a full thickness wound in a rat model demonstrated that both soluble and immobilized bioactive factors could be incorporated into a PEG-based semi-interpenetrating network (sIPN) to enhance the rate and the quality of dermal wound healing. To gain a better understanding of the results observed in vivo, in vitro studies were then conducted to examine the dynamics and mechanisms of the cell-material interaction. Degradation of the sIPN was explored as an influential factor in both mediating cellular response and controlling solute transport from the material. As degradation through gelatin dissolution could be influenced by simple alterations to the material formulation, these results provide facile guidelines to control the delivery of high molecular weight compounds. Further investigation of the cellular response to PEG-based biomaterials focused on key factors influencing cell-material interaction. Specifically, the role of the beta1 integrin subunit and several serum proteins (TGF-aalpha, IL-1beta and PDGF-BB) in mediating cellular response was explored. As cell-material interactions are based on commonly occurring interfaces between cells and molecules of the native extracellular environment, these studies provided insight into the mechanisms controlling the observed cellular response. Finally, the inflammatory response of primary monocytes to biomaterials was examined. Monocytes

  20. Stress Response and Perinatal Reprogramming: Unraveling (Mal)adaptive Strategies

    PubMed Central

    Musazzi, Laura; Marrocco, Jordan

    2016-01-01

    Environmental stressors induce coping strategies in the majority of individuals. The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders. Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (mal)adaptations. Indeed, adverse experiences in early life are known to induce long-term stress-related neuropsychiatric disorders in vulnerable individuals. Here, we discuss recent findings about stress remodeling of excitatory neurotransmission and brain morphology in animal models of behavioral stress. These changes are likely driven by epigenetic factors that lie at the core of the stress-response reprogramming in individuals with a history of perinatal stress. We propose that reprogramming mechanisms may underlie the reorganization of excitatory neurotransmission in the short- and long-term response to stressful stimuli. PMID:27057367

  1. Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma

    PubMed Central

    Loilome, Watcharin; Kadsanit, Sasithorn; Muisook, Kanha; Yongvanit, Puangrat; Namwat, Nisana; Techasen, Anchalee; Puapairoj, Anucha; Khuntikeo, Narong; Phonjit, Pichai

    2017-01-01

    The adaptive response of the genome protection mechanism occurs in cells when exposed to genotoxic stress due to the overproduction of free radicals via inflammation and infection. In such circumstances, cells attempt to maintain health via several genome protection mechanisms. However, evidence is increasing that this adaptive response may have deleterious effect; a reduction of antioxidant enzymes and/or imbalance in the DNA repair system generates microsatellite instability (MSI), which has procarcinogenic implications. Therefore, the present study hypothesized that MSI caused by imbalanced responses of antioxidant enzymes and/or DNA repair enzymes as a result of oxidative/nitrative stress arising from the inflammatory response is involved in liver fluke-associated cholangiocarcinogenesis. The present study investigated this hypothesis by identifying the expression patterns of antioxidant enzymes, including superoxide dismutase 2 (SOD2) and catalase (CAT), and DNA repair enzymes, including alkyladenine DNA glycosylase (AAG), apurinic endonuclease (APE) and DNA polymerase β (DNA pol β). In addition, the activities of the antioxidant enzymes, SOD2 and CAT, were examined in human cholangiocarcinoma (CCA) tissues using immunohistochemical staining. MSI was also analyzed in human CCA tissues. The resulting data demonstrated that the expression levels of the SOD2 and CAT enzymes decreased. The activities of SOD2 and CAT decreased significantly in the CCA tissues, compared with the hepatic tissue of cadaveric donors. In the DNA repairing enzymes, it was found that the expression levels of AAG and DNA pol β enzymes increased, whereas the expression of APE decreased. In addition, it was found that MSI-high was present in 69% of patients, whereas MSI-low was present in 31% of patients, with no patients classified as having microsatellite stability. In the patients, a MSI-high was correlated with poor prognosis, indicated by a shorter survival rate. These results

  2. Knowledge-Based Intelligent Software Support of Cellular Adaptation to Microgravity Investigations

    NASA Technical Reports Server (NTRS)

    Groleau, Nick; Grymes, Rosalind A.; Alizadeh, Babak; Friedland, Peter (Technical Monitor)

    1994-01-01

    One of the most significant new opportunities that the Space Station affords cell biologists is the ability to do long-term cultivation of cells in the space environment. This facility is essential for investigations that are primarily focused on effects requiring a longer timeline of observation than that provided by the STS (Space Transportation System) platform. Such work requires both very strong laboratory skills to properly and quickly interact with the hardware hosting the culture and deep knowledge of the cell biology domain in order to optimally react to unanticipated scientific developments. Such work can be enabled by advanced automation techniques that have recently been used in the STS-based Spacelab, and that are being readied for the Space Station. In this paper, we describe the adaptation of PI-in-a-Box, the first interactive space science assistant system, to the study of the effects of space flight on cell cycle progression and proliferation.

  3. Response and adaptation of bone cells to simulated microgravity

    NASA Astrophysics Data System (ADS)

    Hu, Lifang; Li, Runzhi; Su, Peihong; Arfat, Yasir; Zhang, Ge; Shang, Peng; Qian, Airong

    2014-11-01

    Bone loss induced by microgravity during space flight is one of the most deleterious factors on astronaut's health and is mainly attributed to an unbalance in the process of bone remodeling. Studies from the space microgravity have demonstrated that the disruption of bone remodeling is associated with the changes of four main functional bone cells, including osteoblast, osteoclast, osteocyte, and mesenchymal stem cells. For the limited availability, expensive costs and confined experiment conditions for conducting space microgravity studies, the mechanism of bone cells response and adaptation to microgravity is still unclear. Therefore, some ground-based simulated microgravity methods have been developed to investigate the bioeffects of microgravity and the mechanisms. Here, based on our studies and others, we review how bone cells (osteoblasts, osteoclasts, osteocytes and mesenchymal stem cells) respond and adapt to simulated microgravity.

  4. Complex dynamics of selection and cellular memory in adaptation to a changing environment

    NASA Astrophysics Data System (ADS)

    Kussell, Edo; Lin, Wei-Hsiang

    We study a synthetic evolutionary system in bacteria in which an antibiotic resistance gene is controlled by a stochastic on/off switching promoter. At the population level, this system displays all the basic ingredients for evolutionary selection, including diversity, fitness differences, and heritability. At the single cell level, physiological processes can modulate the ability of selection to act. We expose the stochastic switching strains to pulses of antibiotics of different durations in periodically changing environments using microfluidics. Small populations are tracked over a large number of periods at single cell resolution, allowing the visualization and quantification of selective sweeps and counter-sweeps at the population level, as well as detailed single cell analysis. A simple model is introduced to predict long-term population growth rates from single cell measurements, and reveals unexpected aspects of population dynamics, including cellular memory that acts on a fast timescale to modulate growth rates. This work is supported by NIH Grant No. R01-GM097356.

  5. Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation

    PubMed Central

    Petrovska, Ivana; Nüske, Elisabeth; Munder, Matthias C; Kulasegaran, Gayathrie; Malinovska, Liliana; Kroschwald, Sonja; Richter, Doris; Fahmy, Karim; Gibson, Kimberley; Verbavatz, Jean-Marc; Alberti, Simon

    2014-01-01

    One of the key questions in biology is how the metabolism of a cell responds to changes in the environment. In budding yeast, starvation causes a drop in intracellular pH, but the functional role of this pH change is not well understood. Here, we show that the enzyme glutamine synthetase (Gln1) forms filaments at low pH and that filament formation leads to enzymatic inactivation. Filament formation by Gln1 is a highly cooperative process, strongly dependent on macromolecular crowding, and involves back-to-back stacking of cylindrical homo-decamers into filaments that associate laterally to form higher order fibrils. Other metabolic enzymes also assemble into filaments at low pH. Hence, we propose that filament formation is a general mechanism to inactivate and store key metabolic enzymes during a state of advanced cellular starvation. These findings have broad implications for understanding the interplay between nutritional stress, the metabolism and the physical organization of a cell. DOI: http://dx.doi.org/10.7554/eLife.02409.001 PMID:24771766

  6. Role for zinc in a cellular response mediated by protein kinase C in human B lymphocytes

    SciTech Connect

    Forbes, I.J.; Zalewski, P.D.; Giannakis, C. )

    1991-07-01

    Recent studies have suggested a role for Zn{sup 2+}, distinct from that of CA{sup 2+}, in the subcellular distribution and activation of protein kinase C (PKC). Here the author show that Zn{sup 2+} is required for a cellular response mediated by PKC, the rapid loss of expression of a human B cell receptor MER, detected by resetting with mouse erythrocytes. Zn{sup 2+}, in the presence of the Zn{sup 2+} ionophore pyrithione, caused rapid inhibition of MER rosetting at concentrations which induce the translocation and activation of PKC. This required cellular uptake of Zn{sup 2+} and was blocked by 1,10-phenanthroline and TPEN which chelate Zn{sup 2+} but not Ca{sup 2+}. Gold, a metal with similar properties, also induced translocation of PKC and inhibition of MER. Phenanthroline and TPEN also blocked the inhibition of MER induced by the PKC activators phorbol ester and sodium fluoride, suggesting that endogenous cellular Zn{sup 2+} is required. They propose that some cellular actions of PKC require a Zn{sup 2+}-dependent event and that these may be a target for gold during chrysotherapy in rheumatoid arthritis.

  7. The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis

    PubMed Central

    Knippschild, Uwe; Krüger, Marc; Richter, Julia; Xu, Pengfei; García-Reyes, Balbina; Peifer, Christian; Halekotte, Jakob; Bakulev, Vasiliy; Bischof, Joachim

    2014-01-01

    Members of the highly conserved and ubiquitously expressed pleiotropic CK1 family play major regulatory roles in many cellular processes including DNA-processing and repair, proliferation, cytoskeleton dynamics, vesicular trafficking, apoptosis, and cell differentiation. As a consequence of cellular stress conditions, interaction of CK1 with the mitotic spindle is manifold increased pointing to regulatory functions at the mitotic checkpoint. Furthermore, CK1 is able to alter the activity of key proteins in signal transduction and signal integration molecules. In line with this notion, CK1 is tightly connected to the regulation and degradation of β-catenin, p53, and MDM2. Considering the importance of CK1 for accurate cell division and regulation of tumor suppressor functions, it is not surprising that mutations and alterations in the expression and/or activity of CK1 isoforms are often detected in various tumor entities including cancer of the kidney, choriocarcinomas, breast carcinomas, oral cancer, adenocarcinomas of the pancreas, and ovarian cancer. Therefore, scientific effort has enormously increased (i) to understand the regulation of CK1 and its involvement in tumorigenesis- and tumor progression-related signal transduction pathways and (ii) to develop CK1-specific inhibitors for the use in personalized therapy concepts. In this review, we summarize the current knowledge regarding CK1 regulation, function, and interaction with cellular proteins playing central roles in cellular stress-responses and carcinogenesis. PMID:24904820

  8. Adaptive Patterns of Stress Responsivity: A Preliminary Investigation

    PubMed Central

    Del Giudice, Marco; Hinnant, J. Benjamin; Ellis, Bruce J.; El-Sheikh, Mona

    2014-01-01

    The adaptive calibration model (ACM) is an evolutionary–developmental theory of individual differences in stress responsivity. In this article, we tested some key predictions of the ACM in a middle childhood sample (N = 256). Measures of autonomic nervous system activity across the sympathetic and parasympathetic branches validated the 4-pattern taxonomy of the ACM via finite mixture modeling. Moreover, the 4 patterns of responsivity showed the predicted associations with family stress levels but no association with measures of ecological stress. Our hypotheses concerning sex differences in responsivity were only partly confirmed. This preliminary study provides initial support for the key predictions of the ACM and highlights some of the methodological challenges that will need to be considered in future research on this topic. PMID:22148947

  9. scFv from Antibody That Mimics gp43 Modulates the Cellular and Humoral Immune Responses during Experimental Paracoccidioidomycosis

    PubMed Central

    Jannuzzi, Grasielle Pereira; Tavares, Aldo Henrique F. P.; Kaihami, Gilberto Hideo; de Almeida, José Roberto Fogaça; de Almeida, Sandro Rogério; Ferreira, Karen Spadari

    2015-01-01

    Paracoccidioidomycosis (PCM), caused by Paracoccidioides species is a prevalent systemic and progressive mycosis that occurs in Latin America. It is caused by Paracoccidioides species. Immunization with dendritic cells transfected with a plasmid encoding the scFv (pMAC/PS-scFv) that mimics the main antigen of P. brasiliensis (gp43) confers protection in experimental PCM. DCs link innate and adaptive immunity by recognizing invading pathogens and selecting the type of effector T cell to mediate the immune response. Here, we showed that DC-pMAC/PS-scFv induces the activation of CD4+ and CD8+ T cells. Moreover, our results demonstrated that BALB/c mice infected with P. brasiliensis and treated with DC-pMAC/PS-scFv showed the induction of specific IgG production against gp43 and IFN-γ, IL-12 and IL-4 cytokines. Analysis of regional lymph nodes revealed increases in the expression of clec7a, myd88, tlr2, gata3 and tbx21, which are involved in the immune response. Taken together, our results indicate that the scFv modulates the humoral and cellular immune responses and presents epitopes to CD4+ and CD8+ T cells. PMID:26091522

  10. Plant adaptation to low atmospheric pressures: potential molecular responses.

    PubMed

    Ferl, Robert J; Schuerger, Andrew C; Paul, Anna-Lisa; Gurley, William B; Corey, Kenneth; Bucklin, Ray

    2002-01-01

    There is an increasing realization that it may be impossible to attain Earth normal atmospheric pressures in orbital, lunar, or Martian greenhouses, simply because the construction materials do not exist to meet the extraordinary constraints imposed by balancing high engineering requirements against high lift costs. This equation essentially dictates that NASA have in place the capability to grow plants at reduced atmospheric pressure. Yet current understanding of plant growth at low pressures is limited to just a few experiments and relatively rudimentary assessments of plant vigor and growth. The tools now exist, however, to make rapid progress toward understanding the fundamental nature of plant responses and adaptations to low pressures, and to develop strategies for mitigating detrimental effects by engineering the growth conditions or by engineering the plants themselves. The genomes of rice and the model plant Arabidopsis thaliana have recently been sequenced in their entirety, and public sector and commercial DNA chips are becoming available such that thousands of genes can be assayed at once. A fundamental understanding of plant responses and adaptation to low pressures can now be approached and translated into procedures and engineering considerations to enhance plant growth at low atmospheric pressures. In anticipation of such studies, we present here the background arguments supporting these contentions, as well as informed speculation about the kinds of molecular physiological responses that might be expected of plants in low-pressure environments.

  11. Plant adaptation to low atmospheric pressures: potential molecular responses

    NASA Technical Reports Server (NTRS)

    Ferl, Robert J.; Schuerger, Andrew C.; Paul, Anna-Lisa; Gurley, William B.; Corey, Kenneth; Bucklin, Ray

    2002-01-01

    There is an increasing realization that it may be impossible to attain Earth normal atmospheric pressures in orbital, lunar, or Martian greenhouses, simply because the construction materials do not exist to meet the extraordinary constraints imposed by balancing high engineering requirements against high lift costs. This equation essentially dictates that NASA have in place the capability to grow plants at reduced atmospheric pressure. Yet current understanding of plant growth at low pressures is limited to just a few experiments and relatively rudimentary assessments of plant vigor and growth. The tools now exist, however, to make rapid progress toward understanding the fundamental nature of plant responses and adaptations to low pressures, and to develop strategies for mitigating detrimental effects by engineering the growth conditions or by engineering the plants themselves. The genomes of rice and the model plant Arabidopsis thaliana have recently been sequenced in their entirety, and public sector and commercial DNA chips are becoming available such that thousands of genes can be assayed at once. A fundamental understanding of plant responses and adaptation to low pressures can now be approached and translated into procedures and engineering considerations to enhance plant growth at low atmospheric pressures. In anticipation of such studies, we present here the background arguments supporting these contentions, as well as informed speculation about the kinds of molecular physiological responses that might be expected of plants in low-pressure environments.

  12. Deriving urban dynamic evolution rules from self-adaptive cellular automata with multi-temporal remote sensing images

    NASA Astrophysics Data System (ADS)

    He, Yingqing; Ai, Bin; Yao, Yao; Zhong, Fajun

    2015-06-01

    Cellular automata (CA) have proven to be very effective for simulating and predicting the spatio-temporal evolution of complex geographical phenomena. Traditional methods generally pose problems in determining the structure and parameters of CA for a large, complex region or a long-term simulation. This study presents a self-adaptive CA model integrated with an artificial immune system to discover dynamic transition rules automatically. The model's parameters are allowed to be self-modified with the application of multi-temporal remote sensing images: that is, the CA can adapt itself to the changed and complex environment. Therefore, urban dynamic evolution rules over time can be efficiently retrieved by using this integrated model. The proposed AIS-based CA model was then used to simulate the rural-urban land conversion of Guangzhou city, located in the core of China's Pearl River Delta. The initial urban land was directly classified from TM satellite image in the year 1990. Urban land in the years 1995, 2000, 2005, 2009 and 2012 was correspondingly used as the observed data to calibrate the model's parameters. With the quantitative index figure of merit (FoM) and pattern similarity, the comparison was further performed between the AIS-based model and a Logistic CA model. The results indicate that the AIS-based CA model can perform better and with higher precision in simulating urban evolution, and the simulated spatial pattern is closer to the actual development situation.

  13. Cell Edge Capacity Improvement by Using Adaptive Base Station Cooperation in Cellular Networks with Fractional Frequency Reuse

    NASA Astrophysics Data System (ADS)

    Xu, Liang; Yamamoto, Koji; Murata, Hidekazu; Yoshida, Susumu

    The present paper focuses on the application of the base station cooperation (BSC) technique in fractional frequency reuse (FFR) networks. Fractional frequency reuse is considered to be a promising scheme for avoiding the inter-cell interference problem in OFDMA cellular systems, such as WiMAX, in which the edge mobile stations (MSs) of adjacent cells use different subchannels for separate transmission. However, the problem of FFR is that the cell edge spectral efficiency (SE) is much lower than that of the cell center. The BSC technique, in which adjacent BSs perform cooperative transmission for one cell edge MS with the same channel, may improve the cell edge SE. However, since more BSs transmit signals for one cell edge MS, the use of BSC can also increase the inter-cell interference, which might degrade the network performance. In this paper, with a focus on this tradeoff, we propose an adaptive BSC scheme in which BSC is only performed for the cell edge MSs that can achieve a significant capacity increase with only a slight increase in inter-cell interference. Moreover, a channel reallocation scheme is proposed in order to further improve the performance of the adaptive BSC scheme. The simulation results reveal that, compared to the conventional FFR scheme, the proposed schemes are effective for improving the performance of FFR networks.

  14. AMP-activated protein kinase regulates L-arginine mediated cellular responses

    PubMed Central

    2013-01-01

    Background Our prior study revealed the loss in short-term L-Arginine (ARG) therapeutic efficacy after continuous exposure; resulting in tolerance development, mediated by endothelial nitric oxide synthase (eNOS) down-regulation, secondary to oxidative stress and induced glucose accumulation. However, the potential factor regulating ARG cellular response is presently unknown. Method Human umbilical vein endothelial cells were incubated with 100 μM ARG for 2 h in buffer (short-term or acute), or for 7 days in culture medium and challenged for 2 h in buffer (continuous or chronic), in the presence or absence of other agents. eNOS activity was determined by analyzing cellular nitrite/nitrate (NO2–/NO3–), and AMP-activated protein kinase (AMPK) activity was assayed using SAMS peptide. 13C6 glucose was added to medium to measure glucose uptake during cellular treatments, which were determined by LC-MS/MS. Cellular glucose was identified by o-toluidine method. Superoxide (O2•–) was identified by EPR-spin-trap, and peroxynitrite (ONOO–) was measured by flow-cytometer using aminophenyl fluorescein dye. Results Short-term incubation of cells with 100 μM ARG in the presence or absence of 30 μM L-NG-Nitroarginine methyl ester (L-NAME) or 30 μM AMPK inhibitor (compound C, CMP-C) increased cellular oxidative stress and overall glucose accumulation with no variation in glucose transporter-1 (GLUT-1), or AMPK activity from control. The increase in total NO2–/NO3– after 2 h 100 μM ARG exposure, was suppressed in cells co-incubated with 30 μM CMP-C or L-NAME. Long-term exposure of ARG with or without CMP-C or L-NAME suppressed NO2–/NO3–, glucose uptake, GLUT-1, AMPK expression and activity below control, and increased overall cellular glucose, O2•– and ONOO–. Gluconeogenesis inhibition with 30 μM 5-Chloro-2-N-2,5-dichlorobenzenesulfonamido-benzoxazole (CDB) during ARG exposure for 2 h maintained overall cellular glucose to control, but increased

  15. Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef

    SciTech Connect

    Jia, Xiaofei; Singh, Rajendra; Homann, Stefanie; Yang, Haitao; Guatelli, John; Xiong, Yong

    2012-10-24

    The HIV-1 protein Nef inhibits antigen presentation by class I major histocompatibility complex (MHC-I). We determined the mechanism of this activity by solving the crystal structure of a protein complex comprising Nef, the MHC-I cytoplasmic domain (MHC-I CD) and the {mu}1 subunit of the clathrin adaptor protein complex 1. A ternary, cooperative interaction clamps the MHC-I CD into a narrow binding groove at the Nef-{mu}1 interface, which encompasses the cargo-recognition site of {mu}1 and the proline-rich strand of Nef. The Nef C terminus induces a previously unobserved conformational change in {mu}1, whereas the N terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on {mu}1 recognize acidic clusters in Nef and MHC-I. The structure shows how Nef functions as a clathrin-associated sorting protein to alter the specificity of host membrane trafficking and enable viral evasion of adaptive immunity.

  16. Aeroelastic Response of the Adaptive Compliant Trailing Edge Transtition Section

    NASA Technical Reports Server (NTRS)

    Herrera, Claudia Y.; Spivey, Natalie D.; Lung, Shun-fat

    2016-01-01

    The Adaptive Compliant Trailing Edge demonstrator was a joint task under the Environmentally Responsible Aviation Project in partnership with the Air Force Research Laboratory and FlexSys, Inc. (Ann Arbor, Michigan), chartered by the National Aeronautics and Space Administration to develop advanced technologies that enable environmentally friendly aircraft, such as continuous mold-line technologies. The Adaptive Compliant Trailing Edge demonstrator encompassed replacing the Fowler flaps on the SubsoniC Aircraft Testbed, a Gulfstream III (Gulfstream Aerospace, Savannah, Georgia) aircraft, with control surfaces developed by FlexSys, Inc., a pair of uniquely-designed, unconventional flaps to be used as lifting surfaces during flight-testing to substantiate their structural effectiveness. The unconventional flaps consisted of a main flap section and two transition sections, inboard and outboard, which demonstrated the continuous mold-line technology. Unique characteristics of the transition sections provided a challenge to the airworthiness assessment for this part of the structure. A series of build-up tests and analyses were conducted to ensure the data required to support the airworthiness assessment were acquired and applied accurately. The transition sections were analyzed both as individual components and as part of the flight-test article assembly. Instrumentation was installed in the transition sections based on the analysis to best capture the in-flight aeroelastic response. Flight-testing was conducted and flight data were acquired to validate the analyses. This paper documents the details of the aeroelastic assessment and in-flight response of the transition sections of the unconventional Adaptive Compliant Trailing Edge flaps.

  17. Peroxisomes are platforms for cytomegalovirus’ evasion from the cellular immune response

    PubMed Central

    Magalhães, Ana Cristina; Ferreira, Ana Rita; Gomes, Sílvia; Vieira, Marta; Gouveia, Ana; Valença, Isabel; Islinger, Markus; Nascimento, Rute; Schrader, Michael; Kagan, Jonathan C.; Ribeiro, Daniela

    2016-01-01

    The human cytomegalovirus developed distinct evasion mechanisms from the cellular antiviral response involving vMIA, a virally-encoded protein that is not only able to prevent cellular apoptosis but also to inhibit signalling downstream from mitochondrial MAVS. vMIA has been shown to localize at mitochondria and to trigger their fragmentation, a phenomenon proven to be essential for the signalling inhibition. Here, we demonstrate that vMIA is also localized at peroxisomes, induces their fragmentation and inhibits the peroxisomal-dependent antiviral signalling pathway. Importantly, we demonstrate that peroxisomal fragmentation is not essential for vMIA to specifically inhibit signalling downstream the peroxisomal MAVS. We also show that vMIA interacts with the cytoplasmic chaperone Pex19, suggesting that the virus has developed a strategy to highjack the peroxisomal membrane proteins’ transport machinery. Furthermore, we show that vMIA is able to specifically interact with the peroxisomal MAVS. Our results demonstrate that peroxisomes constitute a platform for evasion of the cellular antiviral response and that the human cytomegalovirus has developed a mechanism by which it is able to specifically evade the peroxisomal MAVS-dependent antiviral signalling. PMID:27181750

  18. The cellular magnetic response and biocompatibility of biogenic zinc- and cobalt-doped magnetite nanoparticles

    PubMed Central

    Moise, Sandhya; Céspedes, Eva; Soukup, Dalibor; Byrne, James M.; El Haj, Alicia J.; Telling, Neil D.

    2017-01-01

    The magnetic moment and anisotropy of magnetite nanoparticles can be optimised by doping with transition metal cations, enabling their properties to be tuned for different biomedical applications. In this study, we assessed the suitability of bacterially synthesized zinc- and cobalt-doped magnetite nanoparticles for biomedical applications. To do this we measured cellular viability and activity in primary human bone marrow-derived mesenchymal stem cells and human osteosarcoma-derived cells. Using AC susceptibility we studied doping induced changes in the magnetic response of the nanoparticles both as stable aqueous suspensions and when associated with cells. Our findings show that the magnetic response of the particles was altered after cellular interaction with a reduction in their mobility. In particular, the strongest AC susceptibility signal measured in vitro was from cells containing high-moment zinc-doped particles, whilst no signal was observed in cells containing the high-anisotropy cobalt-doped particles. For both particle types we found that the moderate dopant levels required for optimum magnetic properties did not alter their cytotoxicity or affect osteogenic differentiation of the stem cells. Thus, despite the known cytotoxicity of cobalt and zinc ions, these results suggest that iron oxide nanoparticles can be doped to sufficiently tailor their magnetic properties without compromising cellular biocompatibility. PMID:28045082

  19. Cellular Proteomes Drive Tissue-Specific Regulation of the Heat Shock Response

    PubMed Central

    Ma, Jian; Grant, Christopher E.; Plagens, Rosemary N.; Barrett, Lindsey N.; Guisbert, Karen S. Kim; Guisbert, Eric

    2017-01-01

    The heat shock response (HSR) is a cellular stress response that senses protein misfolding and restores protein folding homeostasis, or proteostasis. We previously identified an HSR regulatory network in Caenorhabditis elegans consisting of highly conserved genes that have important cellular roles in maintaining proteostasis. Unexpectedly, the effects of these genes on the HSR are distinctly tissue-specific. Here, we explore this apparent discrepancy and find that muscle-specific regulation of the HSR by the TRiC/CCT chaperonin is not driven by an enrichment of TRiC/CCT in muscle, but rather by the levels of one of its most abundant substrates, actin. Knockdown of actin subunits reduces induction of the HSR in muscle upon TRiC/CCT knockdown; conversely, overexpression of an actin subunit sensitizes the intestine so that it induces the HSR upon TRiC/CCT knockdown. Similarly, intestine-specific HSR regulation by the signal recognition particle (SRP), a component of the secretory pathway, is driven by the vitellogenins, some of the most abundant secretory proteins. Together, these data indicate that the specific protein folding requirements from the unique cellular proteomes sensitizes each tissue to disruption of distinct subsets of the proteostasis network. These findings are relevant for tissue-specific, HSR-associated human diseases such as cancer and neurodegenerative diseases. Additionally, we characterize organismal phenotypes of actin overexpression including a shortened lifespan, supporting a recent hypothesis that maintenance of the actin cytoskeleton is an important factor for longevity. PMID:28143946

  20. Characterization of the cellular response triggered by gold nanoparticle-mediated laser manipulation

    NASA Astrophysics Data System (ADS)

    Kalies, Stefan; Keil, Sebastian; Sender, Sina; Hammer, Susanne C.; Antonopoulos, Georgios C.; Schomaker, Markus; Ripken, Tammo; Escobar, Hugo Murua; Meyer, Heiko; Heinemann, Dag

    2015-11-01

    Laser-based transfection techniques have proven high applicability in several cell biologic applications. The delivery of different molecules using these techniques has been extensively investigated. In particular, new high-throughput approaches such as gold nanoparticle-mediated laser transfection allow efficient delivery of antisense molecules or proteins into cells preserving high cell viabilities. However, the cellular response to the perforation procedure is not well understood. We herein analyzed the perforation kinetics of single cells during resonant gold nanoparticle-mediated laser manipulation with an 850-ps laser system at a wavelength of 532 nm. Inflow velocity of propidium iodide into manipulated cells reached a maximum within a few seconds. Experiments based on the inflow of FM4-64 indicated that the membrane remains permeable for a few minutes for small molecules. To further characterize the cellular response postmanipulation, we analyzed levels of oxidative heat or general stress. Although we observed an increased formation of reactive oxygen species by an increase of dichlorofluorescein fluorescence, heat shock protein 70 was not upregulated in laser-treated cells. Additionally, no evidence of stress granule formation was visible by immunofluorescence staining. The data provided in this study help to identify the cellular reactions to gold nanoparticle-mediated laser manipulation.

  1. Transient expression of protein tyrosine phosphatases encoded in Cotesia plutellae bracovirus inhibits insect cellular immune responses

    NASA Astrophysics Data System (ADS)

    Ibrahim, Ahmed M. A.; Kim, Yonggyun

    2008-01-01

    Several immunosuppressive factors are associated with parasitism of an endoparasitoid wasp, Cotesia plutellae, on the diamondback moth, Plutella xylostella. C. plutellae bracovirus (CpBV) encodes a large number of putative protein tyrosine phosphatases (PTPs), which may play a role in inhibiting host cellular immunity. To address this inhibitory hypothesis of CpBV-PTPs, we performed transient expression of individual CpBV-PTPs in hemocytes of the beet armyworm, Spodoptera exigua, and analyzed their cellular immune responses. Two different forms of CpBV-PTPs were chosen and cloned into a eukaryotic expression vector under the control of the p10 promoter of baculovirus: one with the normal cysteine active site (CpBV-PTP1) and the other with a mutated active site (CpBV-PTP5). The hemocytes transfected with CpBV-PTP1 significantly increased in PTP activity compared to control hemocytes, but those with CpBV-PTP5 exhibited a significant decrease in the PTP activity. All transfected hemocytes exhibited a significant reduction in both cell spreading and encapsulation activities compared to control hemocytes. Co-transfection of CpBV-PTP1 together with its double-stranded RNA reduced the messenger RNA (mRNA) level of CpBV-PTP1 and resulted in recovery of both hemocyte behaviors. This is the first report demonstrating that the polydnaviral PTPs can manipulate PTP activity of the hemocytes to interrupt cellular immune responses.

  2. The cellular magnetic response and biocompatibility of biogenic zinc- and cobalt-doped magnetite nanoparticles

    NASA Astrophysics Data System (ADS)

    Moise, Sandhya; Céspedes, Eva; Soukup, Dalibor; Byrne, James M.; El Haj, Alicia J.; Telling, Neil D.

    2017-01-01

    The magnetic moment and anisotropy of magnetite nanoparticles can be optimised by doping with transition metal cations, enabling their properties to be tuned for different biomedical applications. In this study, we assessed the suitability of bacterially synthesized zinc- and cobalt-doped magnetite nanoparticles for biomedical applications. To do this we measured cellular viability and activity in primary human bone marrow-derived mesenchymal stem cells and human osteosarcoma-derived cells. Using AC susceptibility we studied doping induced changes in the magnetic response of the nanoparticles both as stable aqueous suspensions and when associated with cells. Our findings show that the magnetic response of the particles was altered after cellular interaction with a reduction in their mobility. In particular, the strongest AC susceptibility signal measured in vitro was from cells containing high-moment zinc-doped particles, whilst no signal was observed in cells containing the high-anisotropy cobalt-doped particles. For both particle types we found that the moderate dopant levels required for optimum magnetic properties did not alter their cytotoxicity or affect osteogenic differentiation of the stem cells. Thus, despite the known cytotoxicity of cobalt and zinc ions, these results suggest that iron oxide nanoparticles can be doped to sufficiently tailor their magnetic properties without compromising cellular biocompatibility.

  3. A Review on Hemeoxygenase-2: Focus on Cellular Protection and Oxygen Response

    PubMed Central

    Muñoz-Sánchez, Jorge; Chánez-Cárdenas, María Elena

    2014-01-01

    Hemeoxygenase (HO) system is responsible for cellular heme degradation to biliverdin, iron, and carbon monoxide. Two isoforms have been reported to date. Homologous HO-1 and HO-2 are microsomal proteins with more than 45% residue identity, share a similar fold and catalyze the same reaction. However, important differences between isoforms also exist. HO-1 isoform has been extensively studied mainly by its ability to respond to cellular stresses such as hemin, nitric oxide donors, oxidative damage, hypoxia, hyperthermia, and heavy metals, between others. On the contrary, due to its apparently constitutive nature, HO-2 has been less studied. Nevertheless, its abundance in tissues such as testis, endothelial cells, and particularly in brain, has pointed the relevance of HO-2 function. HO-2 presents particular characteristics that made it a unique protein in the HO system. Since attractive results on HO-2 have been arisen in later years, we focused this review in the second isoform. We summarize information on gene description, protein structure, and catalytic activity of HO-2 and particular facts such as its cellular impact and activity regulation. Finally, we call attention on the role of HO-2 in oxygen sensing, discussing proposed hypothesis on heme binding motifs and redox/thiol switches that participate in oxygen sensing as well as evidences of HO-2 response to hypoxia. PMID:25136403

  4. Induction of a Cellular DNA Damage Response by Porcine Circovirus Type 2 Facilitates Viral Replication and Mediates Apoptotic Responses

    PubMed Central

    Wei, Li; Zhu, Shanshan; Wang, Jing; Quan, Rong; Yan, Xu; Li, Zixue; Hou, Lei; Wang, Naidong; Yang, Yi; Jiang, Haijun; Liu, Jue

    2016-01-01

    Cellular DNA damage response (DDR) triggered by infection of DNA viruses mediate cell cycle checkpoint activation, DNA repair, or apoptosis induction. In the present study, infection of porcine circovirus type 2 (PCV2), which serves as a major etiological agent of PCV2-associated diseases (PCVAD), was found to elicit a DNA damage response (DDR) as observed by the phosphorylation of H2AX and RPA32 following infection. The response requires active viral replication, and all the ATM (ataxia telangiectasia-mutated kinase), ATR (ATM- and Rad3-related kinase), and DNA-PK (DNA-dependent protein kinase) are the transducers of the DDR signaling events in the PCV2-infected cells as demonstrated by the phosphorylation of ATM, ATR, and DNA-PK signalings as well as reductions in their activations after treatment with specific kinase inhibitors. Inhibitions of ATM, ATR, and DNA-PK activations block viral replication and prevent apoptotic responses as observed by decreases in cleaved poly-ADP ribose polymerase (PARP) and caspase-3 as well as fragmented DNA following PCV2 infection. These results reveal that PCV2 is able to exploit the cellular DNA damage response machinery for its own efficient replication and for apoptosis induction, further extending our understanding for the molecular mechanism of PCV2 infection. PMID:27982097

  5. Protein phosphorylation and regulation of adaptive responses in bacteria.

    PubMed Central

    Stock, J B; Ninfa, A J; Stock, A M

    1989-01-01

    Bacteria continuously adapt to changes in their environment. Responses are largely controlled by signal transduction systems that contain two central enzymatic components, a protein kinase that uses adenosine triphosphate to phosphorylate itself at a histidine residue and a response regulator that accepts phosphoryl groups from the kinase. This conserved phosphotransfer chemistry is found in a wide range of bacterial species and operates in diverse systems to provide different regulatory outputs. The histidine kinases are frequently membrane receptor proteins that respond to environmental signals and phosphorylate response regulators that control transcription. Four specific regulatory systems are discussed in detail: chemotaxis in response to attractant and repellent stimuli (Che), regulation of gene expression in response to nitrogen deprivation (Ntr), control of the expression of enzymes and transport systems that assimilate phosphorus (Pho), and regulation of outer membrane porin expression in response to osmolarity and other culture conditions (Omp). Several additional systems are also examined, including systems that control complex developmental processes such as sporulation and fruiting-body formation, systems required for virulent infections of plant or animal host tissues, and systems that regulate transport and metabolism. Finally, an attempt is made to understand how cross-talk between parallel phosphotransfer pathways can provide a global regulatory curcuitry. PMID:2556636

  6. Biological and Theoretical Studies of Adaptive Networks: The Conditioned Response.

    DTIC Science & Technology

    1992-06-30

    Eichenbaum , H. and Butter, C.M., The role of frontalcortex-reticular interactions in performance and extinction of Recordings of multiple-unit activity in...such a way that they are appropriate to the ’task demands’ imposed by training parameters (Levey and Martin , 1968). The main evidence for this adaptive...8217 Science 237, 1445-1452. 12. Levey, A. B. and Martin , I. (1968) ’Shape of the conditioned eyelid response,’ Psychological Review 75, 398-408. 13. Millenson

  7. Deciphering the Adaptive Immune Response to Ovarian Cancer

    DTIC Science & Technology

    2014-10-01

    Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The Cancer Genome Atlas Pan-Cancer analysis...Holt, Ph.D., John Webb Ph.D., Peter Watson, M.D. Title of Project: Deciphering the Adaptive Immune Response to Ovarian Cancer INTRODUCTION...Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER

  8. Influence of pathological progression on the balance between cellular and humoral immune responses in bovine tuberculosis

    PubMed Central

    Welsh, Michael D; Cunningham, Rodat T; Corbett, David M; Girvin, R Martyn; McNair, James; Skuce, Robin A; Bryson, David G; Pollock, John M

    2005-01-01

    Studies of tuberculosis have suggested a shift in dominance from a T helper type 1 (Th1) towards a Th2 immune response that is associated with suppressed cell-mediated immune (CMI) responses and increased humoral responses as the disease progresses. In this study a natural host disease model was used to investigate the balance of the evolving immune response towards Mycobacterium bovis infection in cattle with respect to pathogenesis. Cytokine analysis of CD4 T-cell clones derived from M. bovis-infected animals gave some indication that there was a possible relationship between enhanced pathogenesis and an increased ratio of Th0 [interleukin-4-positive/interferon-γ-positive (IL-4+/IFN-γ+)] clones to Th1 (IFN-γ+) clones. All animals developed strong antimycobacterial CMI responses, but depressed cellular responses were evident as the disease progressed, with the IFN-γ test failing to give consistently positive results in the latter stages. Furthermore, a stronger Th0 immune bias, depressed in vitro CMI responses, elevated levels of IL-10 expression and enhanced humoral responses were also associated with increased pathology. In minimal disease, however, a strong Th1 immune bias was maintained and an anti-M. bovis humoral response failed to develop. It was also seen that the level of the anti-M. bovis immunoglobulin G1 (IgG1) isotype antibody responses correlated with the pathology scores, whereas CMI responses did not have as strong a relationship with the development of pathology. Therefore, the development and maintenance of a Th1 IFN-γ response is associated with a greater control of M. bovis infection. Animals progressing from a Th1-biased to a Th0-biased immune response developed more extensive pathology and performed less well in CMI-based diagnostic tests but developed strong IgG1 humoral responses. PMID:15606800

  9. Innate and Adaptive Immune Response to Apoptotic Cells

    PubMed Central

    Peng, YuFeng; Martin, David A; Kenkel, Justin; Zhang, Kang; Ogden, Carol Anne; Elkon, Keith B.

    2007-01-01

    The immune system is constantly exposed to dying cells, most of which arise during central tolerance and from effete circulating immune cells. Under homeostatic conditions, phagocytes (predominantly macrophages and dendritic cells) belonging to the innate immune system, rapidly ingest cells and their debris. Apoptotic cell removal requires recognition of altered self on the apoptotic membrane, a process which is facilitated by natural antibodies and serum opsonins. Recognition, may be site and context specific. Uptake and ingestion of apoptotic cells promotes an immunosuppressive environment that avoids inflammatory responses to self antigens. However, it does not preclude a T cell response and it is likely that constant exposure to self antigen, particularly by immature dendritic cells, leads to T cell tolerance. Tolerance occurs by several different mechanisms including anergy and deletion (for CD8+ T cells) and induction of T regulatory cells (for CD4+ T cells). Failed apoptotic cell clearance promotes immune responses to self antigens, especially when the cellular contents are leaked from the cell (necrosis). Inflammatory responses may be induced by nucleic acid stimulation of toll like receptors and other immune sensors, specific intracellular proteins and non protein (uric acid) stimulation of inflammasomes. PMID:17888627

  10. On the effects of geometry, defects, and material asymmetry on the mechanical response of shape memory alloy cellular lattice structures

    NASA Astrophysics Data System (ADS)

    Karamooz Ravari, M. R.; Nasr Esfahani, S.; Taheri Andani, M.; Kadkhodaei, M.; Ghaei, A.; Karaca, H.; Elahinia, M.

    2016-02-01

    Shape memory alloy (such as NiTi) cellular lattice structures are a new class of advanced materials with many potential applications. The cost of fabrication of these structures however is high. It is therefore necessary to develop modeling methods to predict the functional behavior of these alloys before fabrication. The main aim of the present study is to assess the effects of geometry, microstructural imperfections and material asymmetric response of dense shape memory alloys on the mechanical response of cellular structures. To this end, several cellular and dense NiTi samples are fabricated using a selective laser melting process. Both cellular and dense specimens were tested in compression in order to obtain their stress-strain response. For modeling purposes, a three -dimensional (3D) constitutive model based on microplane theory which is able to describe the material asymmetry was employed. Five finite element models based on unit cell and multi-cell methods were generated to predict the mechanical response of cellular lattices. The results show the considerable effects of the microstructural imperfections on the mechanical response of the cellular lattice structures. The asymmetric material response of the bulk material also affects the mechanical response of the corresponding cellular structure.

  11. Stress-induced cellular responses and cell death mechanisms during inflammatory cholangiopathies.

    PubMed

    Sasaki, Motoko; Nakanuma, Yasuni

    2017-03-01

    Various cellular responses including apoptosis, necrosis, autophagy and cellular senescence are involved in the pathogenesis of inflammatory cholangiopathies, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and biliary atresia (BA). For example, dysregulated autophagy may play a role in abnormal expression of mitochondrial antigens and following autoimmune pathogenesis in bile duct lesions in PBC. Recently, new types of regulated cell death including necroptosis, parthanatos, pyroptosis, immunogenic cell death are the subject of numerous reports and they may play roles in pathogenesis of liver diseases, such as nonalcoholic steatohepatitis. Although there have been few studies on these new types of regulated cell death in inflammatory cholangiopathies, so far, they may play important roles in the pathophysiology of inflammatory cholangiopathies. Further studies on new types of regulated cell death are mandatory, since they could be targets of new therapeutic approaches for these diseases.

  12. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases.

    PubMed

    Cuenca, Nicolás; Fernández-Sánchez, Laura; Campello, Laura; Maneu, Victoria; De la Villa, Pedro; Lax, Pedro; Pinilla, Isabel

    2014-11-01

    Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.

  13. The transition between immune and disease states in a cellular automaton model of clonal immune response

    NASA Astrophysics Data System (ADS)

    Bezzi, Michele; Celada, Franco; Ruffo, Stefano; Seiden, Philip E.

    1997-02-01

    In this paper we extend the Celada-Seiden (CS) model of the humoral immune response to include infections virus and killer T cells (cellular response). The model represents molecules and cells with bitstrings. The response of the system to virus involves a competition between the ability of the virus to kill the host cells and the host's ability to eliminate the virus. We find two basins of attraction in the dynamics of this system, one is identified with disease and the other with the immune state. There is also an oscillating state that exists on the border of these two stable states. Fluctuations in the population of virus or antibody can end the oscillation and drive the system into one of the stable states. The introduction of mechanisms of cross-regulation between the two responses can bias the system towards one of them. We also study a mean field model, based on coupled maps, to investigate virus-like infections. This simple model reproduces the attractors for average populations observed in the cellular automaton. All the dynamical behavior connected to spatial extension is lost, as is the oscillating feature. Thus the mean field approximation introduced with coupled maps destroys oscillations.

  14. Implication of diethylcarbamazine induced morbidity and the role of cellular responses associated with bancroftian filariasis pathologies.

    PubMed

    Makunde, W H; Kamugisha, M L; Makunde, R A; Malecela-Lazaro, M N; Kitua, A Y

    2006-01-01

    Pre and post-diethylcarbamazine treatment clinical expression, microfilaraemia prevalence and cellular responses were investigated in individuals in Tanga, Tanzania. Fifty-seven male individuals (aged = 15 years old) were identified for further studies on IL-4, IL-6, IL-8. IFN-gamma, IL-beta, TNF-alpha and nitric oxide in plasma and hydrocoele fluid. Microfilarial prevalence in the examined individuals was 12% with a geometric mean intensity (GMI) of 838 mff/ml in a community with a population of 1018 individuals. Microfilaraemic hydrocoele stage II and III were the most frequent pathologies observed with prevalence of 17.5% and 42. 1 %, respectively. All study individuals treated with diethylcarbamazine (DEC) standard dose of 6 mg/kg experienced post-treatment adverse events. There was no direct relationship between elevated IL-6 and the occurrence and severity of clinical adverse effects post-treatment. The findings from this study suggests that, blood elevated cytokine profile is not the main etiological factor in the inflammatory responses developing after treatment of bancroftian filariasis infections and pathology with DEC. Plasma levels of cellular (cytokines) responses during treatment revealed a proportion of symptomatic patients. Prior to treatment, patients with hydroecoele had high levels of IL-6 than those without the pathology. In conclusion these findings do not support the hypothesis that pro-inflammatory cytokines are directly responsible for adverse events to DEC chemotherapy in bancroftian filariasis infections and pathologies such as hydrocoele, lymphoedema and elephantiasis.

  15. Impact of Heat Stress on Cellular and Transcriptional Adaptation of Mammary Epithelial Cells in Riverine Buffalo (Bubalus Bubalis)

    PubMed Central

    Kapila, Neha; Sharma, Ankita; Kishore, Amit; Sodhi, Monika; Tripathi, Pawan K.; Mohanty, Ashok K.

    2016-01-01

    The present study aims to identify the heat responsive genes and biological pathways in heat stressed buffalo mammary epithelial cells (MECs). The primary mammary epithelial cells of riverine buffalo were exposed to thermal stress at 42°C for one hour. The cells were subsequently allowed to recover at 37°C and harvested at different time intervals (30 min to 48 h) along with control samples (un-stressed). In order to assess the impact of heat stress in buffalo MECs, several in-vitro cellular parameters (lactate dehydrogenase activity, cell proliferation assay, cellular viability, cell death and apoptosis) and transcriptional studies were conducted. The heat stress resulted in overall decrease in cell viability and cell proliferation of MECs while induction of cellular apoptosis and necrosis. The transcriptomic profile of heat stressed MECs was generated using Agilent 44 K bovine oligonucleotide array and at cutoff criteria of ≥3-or ≤3 fold change, a total of 153 genes were observed to be upregulated while 8 genes were down regulated across all time points post heat stress. The genes that were specifically up-regulated or down-regulated were identified as heat responsive genes. The upregulated genes in heat stressed MECs belonged to heat shock family viz., HSPA6, HSPB8, DNAJB2, HSPA1A. Along with HSPs, genes like BOLA, MRPL55, PFKFB3, PSMC2, ENDODD1, ARID5A, and SENP3 were also upregulated. Microarray data revealed that the heat responsive genes belonged to different functional classes viz., chaperons; immune responsive; cell proliferation and metabolism related. Gene ontology analysis revealed enrichment of several biological processes like; cellular process, metabolic process, response to stimulus, biological regulation, immune system processes and signaling. The transcriptome analysis data was further validated by RT-qPCR studies. Several HSP (HSP40, HSP60, HSP70, HSP90, and HSPB1), apoptotic (Bax and Bcl2), immune (IL6, TNFα and NF-kβ) and oxidative

  16. Impact of Heat Stress on Cellular and Transcriptional Adaptation of Mammary Epithelial Cells in Riverine Buffalo (Bubalus Bubalis).

    PubMed

    Kapila, Neha; Sharma, Ankita; Kishore, Amit; Sodhi, Monika; Tripathi, Pawan K; Mohanty, Ashok K; Mukesh, Manishi

    The present study aims to identify the heat responsive genes and biological pathways in heat stressed buffalo mammary epithelial cells (MECs). The primary mammary epithelial cells of riverine buffalo were exposed to thermal stress at 42°C for one hour. The cells were subsequently allowed to recover at 37°C and harvested at different time intervals (30 min to 48 h) along with control samples (un-stressed). In order to assess the impact of heat stress in buffalo MECs, several in-vitro cellular parameters (lactate dehydrogenase activity, cell proliferation assay, cellular viability, cell death and apoptosis) and transcriptional studies were conducted. The heat stress resulted in overall decrease in cell viability and cell proliferation of MECs while induction of cellular apoptosis and necrosis. The transcriptomic profile of heat stressed MECs was generated using Agilent 44 K bovine oligonucleotide array and at cutoff criteria of ≥3-or ≤3 fold change, a total of 153 genes were observed to be upregulated while 8 genes were down regulated across all time points post heat stress. The genes that were specifically up-regulated or down-regulated were identified as heat responsive genes. The upregulated genes in heat stressed MECs belonged to heat shock family viz., HSPA6, HSPB8, DNAJB2, HSPA1A. Along with HSPs, genes like BOLA, MRPL55, PFKFB3, PSMC2, ENDODD1, ARID5A, and SENP3 were also upregulated. Microarray data revealed that the heat responsive genes belonged to different functional classes viz., chaperons; immune responsive; cell proliferation and metabolism related. Gene ontology analysis revealed enrichment of several biological processes like; cellular process, metabolic process, response to stimulus, biological regulation, immune system processes and signaling. The transcriptome analysis data was further validated by RT-qPCR studies. Several HSP (HSP40, HSP60, HSP70, HSP90, and HSPB1), apoptotic (Bax and Bcl2), immune (IL6, TNFα and NF-kβ) and oxidative

  17. Cellular responses of osteoblast-like cells to 17 elemental metals.

    PubMed

    Zhang, Dongmei; Wong, Cynthia S; Wen, Cuie; Li, Yuncang

    2017-01-01

    Elemental metals have been widely used to alloy metallic orthopedic implants. However, there is still insufficient research data elucidating the cell responses of osteoblastic cells to alloying elemental metals, which impedes the development of new metallic implant materials. In this study, the cellular responses of osteoblast-like cells (SaOS2) to 17 pure alloying elemental metals, that is, titanium (Ti), zirconium (Zr), hafnium (Hf), vanadium (V), niobium (Nb), tantalum (Ta), chromium (Cr), molybdenum (Mo), manganese (Mn), iron (Fe), ruthenium (Ru), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), silicon (Si), and tin (Sn) were comparatively investigated in vitro. Cellular responses including intracellular total protein synthesis and collagen content, cell adhesion, cell proliferation, and alkaline phosphatase (ALP) activity on these elemental metals were systematically assessed and compared. It was found that these elemental metals could be categorized into three groups based on the cellular functions on them. Group 1, including Ti, Zr, Hf, Nb, Ta, Cr, Ru, and Si, showed excellent cell proliferation and varied ALP activity for SaOS2 cells. Cells exposed to Group 2, including Mo and Sn, although initially attached and grew, did not proliferate over time. In contrast, Group 3, including V, Mn, Fe, Co, Ni, Cu, and Zn, showed severe cytotoxicity toward SaOS2 cells. It is vital to consider the cell responses to the elemental metals when designing a new metallic implant material and the findings of this study provide insights into the biological performance of the elemental metals. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 148-158, 2017.

  18. Different Candida parapsilosis clinical isolates and lipase deficient strain trigger an altered cellular immune response

    PubMed Central

    Tóth, Renáta; Alonso, Maria F.; Bain, Judith M.; Vágvölgyi, Csaba; Erwig, Lars-Peter; Gácser, Attila

    2015-01-01

    Numerous human diseases can be associated with fungal infections either as potential causative agents or as a result of changed immune status due to a primary disease. Fungal infections caused by Candida species can vary from mild to severe dependent upon the site of infection, length of exposure, and past medical history. Patients with impaired immune status are at increased risk for chronic fungal infections. Recent epidemiologic studies have revealed the increasing incidence of candidiasis caused by non-albicans species such as Candida parapsilosis. Due to its increasing relevance we chose two distinct C. parapsilosis strains, to describe the cellular innate immune response toward this species. In the first section of our study we compared the interaction of CLIB 214 and GA1 cells with murine and human macrophages. Both strains are commonly used to investigate C. parapsilosis virulence properties. CLIB 214 is a rapidly pseudohyphae-forming strain and GA1 is an isolate that mainly exists in a yeast form. Our results showed, that the phagocyte response was similar in terms of overall uptake, however differences were observed in macrophage migration and engulfment of fungal cells. As C. parapsilosis releases extracellular lipases in order to promote host invasion we further investigated the role of these secreted components during the distinct stages of the phagocytic process. Using a secreted lipase deficient mutant strain and the parental strain GA1 individually and simultaneously, we confirmed that fungal secreted lipases influence the fungi's virulence by detecting altered innate cellular responses. In this study we report that two isolates of a single species can trigger markedly distinct host responses and that lipase secretion plays a role on the cellular level of host–pathogen interactions. PMID:26528256

  19. Transcriptional regulatory networks in cellular responses and tolerance to dehydration and cold stresses.

    PubMed

    Yamaguchi-Shinozaki, Kazuko; Shinozaki, Kazuo

    2006-01-01

    Plant growth and productivity are greatly affected by environmental stresses such as drought, high salinity, and low temperature. Expression of a variety of genes is induced by these stresses in various plants. The products of these genes function not only in stress tolerance but also in stress response. In the signal transduction network from perception of stress signals to stress-responsive gene expression, various transcription factors and cis-acting elements in the stress-responsive promoters function for plant adaptation to environmental stresses. Recent progress has been made in analyzing the complex cascades of gene expression in drought and cold stress responses, especially in identifying specificity and cross talk in stress signaling. In this review article, we highlight transcriptional regulation of gene expression in response to drought and cold stresses, with particular emphasis on the role of transcription factors and cis-acting elements in stress-inducible promoters.

  20. Deciphering the acute cellular phosphoproteome response to irradiation with X-rays, protons and carbon ions.

    PubMed

    Winter, Martin; Dokic, Ivana; Schlegel, Julian; Warnken, Uwe; Debus, Jürgen; Abdollahi, Amir; Schnölzer, Martina

    2017-03-16

    Radiotherapy is a cornerstone of cancer therapy. The recently established particle therapy with raster-scanning protons and carbon ions landmarks a new era in the field of high-precision cancer medicine. However, molecular mechanisms governing radiation induced intracellular signaling remain elusive. Here, we present the first comprehensive proteomic and phosphoproteomic study applying stable isotope labeling by amino acids in cell culture (SILAC) in combination with high-resolution mass spectrometry to decipher cellular response to irradiation with X-rays, protons and carbon ions. At protein expression level limited alterations were observed 2h post irradiation of human lung adenocarcinoma cells. In contrast, 181 phosphorylation sites were found to be differentially regulated out of which 151 sites were not hitherto attributed to radiation response as revealed by crosscheck with the PhosphoSitePlus database. Radiation-induced phosphorylation of the p(S/T)Q motif was the prevailing regulation pattern affecting proteins involved in DNA damage response signaling. Since radiation doses were selected to produce same level of cell kill and DNA double-strand breakage for each radiation quality, DNA damage responsive phosphorylation sites were regulated to same extent. However, differential phosphorylation between radiation qualities was observed for 55 phosphorylation sites indicating the existence of distinct signaling circuitries induced by X-ray versus particle (proton/carbon) irradiation beyond the canonical DNA damage response. This unexpected finding was confirmed in targeted spike-in experiments using synthetic isotope labeled phosphopeptides. Herewith, we successfully validated uniform DNA damage response signaling coexisting with altered signaling involved in apoptosis and metabolic processes induced by X-ray and particle based treatments. In summary, the comprehensive insight into the radiation-induced phosphoproteome landscape is instructive for the design of

  1. In Vivo Delivery of Antigens by Adenovirus Dodecahedron Induces Cellular and Humoral Immune Responses to Elicit Antitumor Immunity

    PubMed Central

    Villegas-Mendez, Ana; Garin, Marina I; Pineda-Molina, Estela; Veratti, Eugenia; Bueren, Juan A; Fender, Pascal; Lenormand, Jean-Luc

    2010-01-01

    Cancer vaccines based on virus-like particles (VLPs) vectors may offer many advantages over other antigen-delivery systems and represent an alternative to the ex vivo cell therapy approach. In this study, we describe the use of penton-dodecahedron (Pt-Dd) VLPs from human adenovirus type 3 (Ad3) as cancer vaccine vehicle for specific antigens, based on its unique cellular internalization properties. WW domains from the ubiquitin ligase Nedd4 serve as an adapter to bind the antigen to Pt-Dd. By engineering fusion partners of WW with the model antigen ovalbumin (OVA), Pt-Dd can efficiently deliver WW-OVA in vitro and the Pt-Dd/WW complex can be readily internalized by dendritic cells (DCs). Immunization with WW-OVA/Pt-Dd results in 90% protection against B16-OVA melanoma implantation in syngeneic mice. This high level of protection correlates with the development of OVA-specific CD8+ T cells. Moreover, vaccination with WW-OVA Pt-Dd induces robust humoral responses in mice as shown by the high levels of anti-OVA antibodies (Abs) detected in serum. Importantly, treatment of mice bearing B16-OVA tumors with WW-OVA/Pt-Dd results in complete tumor regression in 100% of cases. Thus, our data supports a dual role of Pt-Dd as antigen-delivery vector and natural adjuvant, able to generate integrated cellular and humoral responses of broad immunogenic complexity to elicit specific antitumor immunity. Antigen delivery by Pt-Dd vector is a promising novel strategy for development of cancer vaccines with important clinical applications. PMID:20179681

  2. In vivo delivery of antigens by adenovirus dodecahedron induces cellular and humoral immune responses to elicit antitumor immunity.

    PubMed

    Villegas-Mendez, Ana; Garin, Marina I; Pineda-Molina, Estela; Veratti, Eugenia; Bueren, Juan A; Fender, Pascal; Lenormand, Jean-Luc

    2010-05-01

    Cancer vaccines based on virus-like particles (VLPs) vectors may offer many advantages over other antigen-delivery systems and represent an alternative to the ex vivo cell therapy approach. In this study, we describe the use of penton-dodecahedron (Pt-Dd) VLPs from human adenovirus type 3 (Ad3) as cancer vaccine vehicle for specific antigens, based on its unique cellular internalization properties. WW domains from the ubiquitin ligase Nedd4 serve as an adapter to bind the antigen to Pt-Dd. By engineering fusion partners of WW with the model antigen ovalbumin (OVA), Pt-Dd can efficiently deliver WW-OVA in vitro and the Pt-Dd/WW complex can be readily internalized by dendritic cells (DCs). Immunization with WW-OVA/Pt-Dd results in 90% protection against B16-OVA melanoma implantation in syngeneic mice. This high level of protection correlates with the development of OVA-specific CD8(+) T cells. Moreover, vaccination with WW-OVA Pt-Dd induces robust humoral responses in mice as shown by the high levels of anti-OVA antibodies (Abs) detected in serum. Importantly, treatment of mice bearing B16-OVA tumors with WW-OVA/Pt-Dd results in complete tumor regression in 100% of cases. Thus, our data supports a dual role of Pt-Dd as antigen-delivery vector and natural adjuvant, able to generate integrated cellular and humoral responses of broad immunogenic complexity to elicit specific antitumor immunity. Antigen delivery by Pt-Dd vector is a promising novel strategy for development of cancer vaccines with important clinical applications.

  3. Durable antitumor responses to CD47 blockade require adaptive immune stimulation

    PubMed Central

    Sockolosky, Jonathan T.; Dougan, Michael; Ingram, Jessica R.; Ho, Chia Chi M.; Kauke, Monique J.; Almo, Steven C.; Ploegh, Hidde L.; Garcia, K. Christopher

    2016-01-01

    Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47–SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy. PMID:27091975

  4. Durable antitumor responses to CD47 blockade require adaptive immune stimulation.

    PubMed

    Sockolosky, Jonathan T; Dougan, Michael; Ingram, Jessica R; Ho, Chia Chi M; Kauke, Monique J; Almo, Steven C; Ploegh, Hidde L; Garcia, K Christopher

    2016-05-10

    Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47-SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.

  5. Glassy Dynamics in the Adaptive Immune Response Prevents Autoimmune Disease

    NASA Astrophysics Data System (ADS)

    Sun, Jun; Earl, David J.; Deem, Michael W.

    2005-09-01

    The immune system normally protects the human host against death by infection. However, when an immune response is mistakenly directed at self-antigens, autoimmune disease can occur. We describe a model of protein evolution to simulate the dynamics of the adaptive immune response to antigens. Computer simulations of the dynamics of antibody evolution show that different evolutionary mechanisms, namely, gene segment swapping and point mutation, lead to different evolved antibody binding affinities. Although a combination of gene segment swapping and point mutation can yield a greater affinity to a specific antigen than point mutation alone, the antibodies so evolved are highly cross reactive and would cause autoimmune disease, and this is not the chosen dynamics of the immune system. We suggest that in the immune system’s search for antibodies, a balance has evolved between binding affinity and specificity.

  6. Innate and adaptive immune responses in neurodegeneration and repair.

    PubMed

    Amor, Sandra; Woodroofe, M Nicola

    2014-03-01

    Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer's disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases.

  7. Cellular Mechanisms Underlying Bone-Forming Cell Proliferative Response to Hypergravity

    NASA Technical Reports Server (NTRS)

    Vercoutere, W.; Parra, M.; DaCosta, M.; Wing, A.; Roden, C.; Damsky, C.; Holton, E.; Searby, N.; Globus, R.; Almeida, E.

    2004-01-01

    Life on Earth has evolved under the continuous influence of gravity (1-g). As humans explore and develop space, however, we must learn to adapt to an environment with little or no gravity. Studies indicate that lack of weightbearing for vertebrates occurring with immobilization, paralysis, or in a microgravity environment may cause muscle and bone atrophy through cellular and subcellular level mechanisms. We hypothesize that gravity is needed for the efficient transduction of cell growth and survival signals from the extra-cellular matrix (ECM) (consisting of molecules such as collagen, fibronectin, and laminin) in mechanosensitive tissues. We test for the presence of gravity-sensitive pathways in bone-forming cells (osteoblasts) using hypergravity applied by a cell culture centrifuge. Stimulation of 50 times gravity (50-g) increased proliferation in primary rat osteoblasts for cells grown on collagen Type I and fibronectin, but not on laminin or uncoated surfaces. Survival was also enhanced during hypergravity stimulation by the presence of ECM. Bromodeoxyuridine incorporation in proliferating cells showed an increase in the number of actively dividing cells from about 60% at 1-g to over 90% at 25-g. Reverse transcription-polymerase chain reaction was used to test for all possible integrins. Our combined results indicate that beta1 and/or beta3 integrin subunits may be involved. These data indicate that gravity mechanostimulation of osteoblast proliferation involves specific matrix-integrin signalling pathways which are sensitive to g-level. Further research to define the mechanisms involved will provide direction so that we may better adapt and counteract bone atrophy caused by the lack of weightbearing.

  8. Adaptive antioxidant response protects dermal fibroblasts from UVA-induced phototoxicity.

    PubMed

    Meewes, C; Brenneisen, P; Wenk, J; Kuhr, L; Ma, W; Alikoski, J; Poswig, A; Krieg, T; Scharffetter-Kochanek, K

    2001-02-01

    In response to the attack of reactive oxygen species (ROS) produced upon UV irradiation, the skin has developed a complex antioxidant defense system. Here we report that, in addition to the previously published induction of manganese superoxide dismutase (MnSOD) activity, single and, to a higher extent, repetitive low-dose UVA irradiation also leads to a substantial upregulation of glutathione peroxidase (GPx) activity. This concomitant adaptive response of two antioxidant enzymes acting in the same detoxification pathway coincided with the protection from high-UVA-dose-induced cytotoxicity conferred by low-dose UVA preirradiation. Whereas an interval of 24 h did not, an interval of 12 h did lead to the induction of MnSOD activity and, under selenium-supplemented conditions, of GPx activity as well, conferring definite cellular protection from UVA-induced phototoxicity. Moreover, under selenium-deficient conditions, which abrogate the UVA-mediated induction of GPx activity, adaptive protection against the cytotoxic effects of high UVA doses was significantly lower compared with selenium supplementation. Isolated 4.6-fold overexpression of MnSOD activity in stably transfected fibroblasts led to specific resistance from UVA-mediated phototoxicity under selenium-deficient conditions. Collectively, these data indicate that the concomitant induction of MnSOD and GPx activity is related to the optimal adaptive protection from photooxidative damage. This adaptive antioxidant protection clearly depends on the irradiation interval and a sufficient selenium concentration, findings that may have important implications for the improvement of photoprotective and phototherapeutic strategies in medicine.

  9. The nociception genes painless and Piezo are required for the cellular immune response of Drosophila larvae to wasp parasitization.

    PubMed

    Tokusumi, Yumiko; Tokusumi, Tsuyoshi; Schulz, Robert A

    2017-03-22

    In vertebrates, interaction between the nervous system and immune system is important to protect a challenged host from stress inputs from external sources. In this study, we demonstrate that sensory neurons are involved in the cellular immune response elicited by wasp infestation of Drosophila larvae. Multidendritic class IV neurons sense contacts from external stimuli and induce avoidance behaviors for host defense. Our findings show that inactivation of these sensory neurons impairs the cellular response against wasp parasitization. We also demonstrate that the nociception genes encoding the mechanosensory receptors Painless and Piezo, both expressed in class IV neurons, are essential for the normal cellular immune response to parasite challenge.

  10. Innate and Adaptive Immune Response to Fungal Products and Allergens.

    PubMed

    Williams, P Brock; Barnes, Charles S; Portnoy, Jay M

    2016-01-01

    Exposure to fungi and their products is practically ubiquitous, yet most of this is of little consequence to most healthy individuals. This is because there are a number of elaborate mechanisms to deal with these exposures. Most of these mechanisms are designed to recognize and neutralize such exposures. However, in understanding these mechanisms it has become clear that many of them overlap with our ability to respond to disruptions in tissue function caused by trauma or deterioration. These responses involve the innate and adaptive immune systems usually through the activation of nuclear factor kappa B and the production of cytokines that are considered inflammatory accompanied by other factors that can moderate these reactivities. Depending on different genetic backgrounds and the extent of activation of these mechanisms, various pathologies with resulting symptoms can ensue. Complicating this is the fact that these mechanisms can bias toward type 2 innate and adaptive immune responses. Thus, to understand what we refer to as allergens from fungal sources, we must first understand how they influence these innate mechanisms. In doing so it has become clear that many of the proteins that are described as fungal allergens are essentially homologues of our own proteins that signal or cause tissue disruptions.

  11. Autophagy is an adaptive response in desmin-related cardiomyopathy

    PubMed Central

    Tannous, Paul; Zhu, Hongxin; Johnstone, Janet L.; Shelton, John M.; Rajasekaran, Namakkal S.; Benjamin, Ivor J.; Nguyen, Lan; Gerard, Robert D.; Levine, Beth; Rothermel, Beverly A.; Hill, Joseph A.

    2008-01-01

    A missense mutation in the αB-crystallin (CryAB) gene triggers a severe form of desmin-related cardiomyopathy (DRCM) characterized by accumulation of misfolded proteins. We hypothesized that autophagy increases in response to protein aggregates and that this autophagic activity is adaptive. Mutant CryAB (CryABR120G) triggered a >2-fold increase in cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate accumulation and the abundance of insoluble CryABR120G-associated aggregates. Cardiomyocyte-restricted overexpression of CryABR120G in mice induced intracellular aggregate accumulation and systolic heart failure by 12 months. As early as 2 months (well before the earliest declines in cardiac function), we detected robust autophagic activity. To test the functional significance of autophagic activation, we crossed CryABR120G mice with animals harboring heterozygous inactivation of beclin 1, a gene required for autophagy. Blunting autophagy in vivo dramatically hastened heart failure progression with a 3-fold increase in interstitial fibrosis, greater accumulation of polyubiquitinated proteins, larger and more extensive intracellular aggregates, accelerated ventricular dysfunction, and early mortality. This study reports activation of autophagy in DRCM. Further, our findings point to autophagy as an adaptive response in this proteotoxic form of heart disease. PMID:18621691

  12. Cellular Response to Bleomycin-Induced DNA Damage in Human Fibroblast Cells in Space

    NASA Technical Reports Server (NTRS)

    Lu, Tao; Zhang, Ye; Wong, Michael; Stodieck, Louis; Karouia, Fathi; Wu, Honglu

    2015-01-01

    Living organisms are constantly exposed to space radiation that consists of energetic protons and other heavier charged particles. Whether spaceflight factors, microgravity in particular, affects on the cellular response to DNA damage induced by exposures to radiation or other toxic chemicals will have an impact on the radiation risks for the astronauts, as well as on the mutation rate in microorganisms, is still an open question. Although the possible synergistic effects of space radiation and other spaceflight factors have been investigated since the early days of the human space program, the published results were mostly conflicting and inconsistent. To investigate the effects of spaceflight on the cellular response to DNA damages, human fibroblast cells flown to the International Space Station (ISS) were treated with bleomycin for three hours in the true microgravity environment, which induces DNA damages including the double strand breaks (DSB) similar to the ionizing radiation. Damage in the DNA was measured by the phosphorylation of a histone protein H2AX (-H2AX), which showed slightly more foci in the cells on ISS than in the ground control. The expression of genes involved in the DNA damage response was also analyzed using the PCR array. Although a number of the genes, including CDKN1A and PCNA, were significantly altered in the cells after bleomycin treatment, no significant difference in the expression profile of DNA damage response genes was found between the flight and ground samples. At the time of the bleomycin treatment, the cells on the ISS were found to be proliferating faster than the ground control as measured by the percentage of cells containing positive Ti-67 signals. Our results suggested that the difference in -H2AX between flight and ground was due to the faster growth rate of the cells in space, but spaceflight did not affect the response of the DNA damage response genes to bleomycin treatment.

  13. Cellular Response to Bleomycin-Induced DNA Damage in Human Fibroblast Cells in Space

    NASA Technical Reports Server (NTRS)

    Lu, Tao; Zhang, Ye; Wong, Michael; Stodieck, Louis; Karouia, Fathi; Wu, Honglu

    2015-01-01

    Outside the protection of the geomagnetic field, astronauts and other living organisms are constantly exposed to space radiation that consists of energetic protons and other heavier charged particles. Whether spaceflight factors, microgravity in particular, have effects on cellular responses to DNA damage induced by exposure to radiation or cytotoxic chemicals is still unknown, as is their impact on the radiation risks for astronauts and on the mutation rate in microorganisms. Although possible synergistic effects of space radiation and other spaceflight factors have been investigated since the early days of the human space program, the published results were mostly conflicting and inconsistent. To investigate effects of spaceflight on cellular responses to DNA damages, human fibroblast cells flown to the International Space Station (ISS) were treated with bleomycin for three hours in the true microgravity environment, which induced DNA damages including double-strand breaks (DSB) similar to the ionizing radiation. Damages in the DNA were measured by the phosphorylation of a histone protein H2AX (g-H2AX), which showed slightly more foci in the cells on ISS than in the ground control. The expression of genes involved in DNA damage response was also analyzed using the PCR array. Although a number of the genes, including CDKN1A and PCNA, were significantly altered in the cells after bleomycin treatment, no significant difference in the expression profile of DNA damage response genes was found between the flight and ground samples. At the time of the bleomycin treatment, the cells on the ISS were found to be proliferating faster than the ground control as measured by the percentage of cells containing positive Ki-67 signals. Our results suggested that the difference in g-H2AX focus counts between flight and ground was due to the faster growth rate of the cells in space, but spaceflight did not affect initial transcriptional responses of the DNA damage response genes to

  14. Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes.

    PubMed

    Lin, Miaoxin; Wang, Xiaoyong; Zhu, Jianhui; Fan, Damin; Zhang, Yangmiao; Zhang, Junfeng; Guo, Zijian

    2011-03-01

    Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH₃)₂Cl]₂L¹}(NO₃)₂ (1) and {[cis-Pt(NH₃)₂Cl]₂L²}(NO₃)₂ (2) (L¹ = α,α'-diamino-p-xylene, L² = 4,4'-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.

  15. Psychedelics Recruit Multiple Cellular Types and Produce Complex Transcriptional Responses Within the Brain.

    PubMed

    Martin, David A; Nichols, Charles D

    2016-09-01

    There has recently been a resurgence of interest in psychedelics, substances that profoundly alter perception and cognition and have recently demonstrated therapeutic efficacy to treat anxiety, depression, and addiction in the clinic. The receptor mechanisms that drive their molecular and behavioral effects involve activation of cortical serotonin 5-HT2A receptors, but the responses of specific cellular populations remain unknown. Here, we provide evidence that a small subset of 5-HT2A-expressing excitatory neurons is directly activated by psychedelics and subsequently recruits other select cell types including subpopulations of inhibitory somatostatin and parvalbumin GABAergic interneurons, as well as astrocytes, to produce distinct and regional responses. To gather data regarding the response of specific neuronal populations, we developed methodology for fluorescence-activated cell sorting (FACS) to segregate and enrich specific cellular subtypes in the brain. These methods allow for robust neuronal sorting based on cytoplasmic epitopes followed by downstream nucleic acid analysis, expanding the utility of FACS in neuroscience research.

  16. Cellular and humoral responses in coeliac disease. 1. Wheat protein fractions.

    PubMed

    Penttila, I A; Devery, J M; Gibson, C E; LaBrooy, J T; Skerritt, J H

    1991-12-31

    The humoral and cellular immune response of coeliac individuals to various wheat protein fractions was studied using serum antibody ELISA assays and the indirect leucocyte migration inhibition factor (LMIF) assays. Greater migration inhibition factor activity was seen in coeliacs on a gluten-free-diet having low serum antibody titres, and using purified T-cells instead of total peripheral blood mononucleocytes. Gliadin was the most active fraction in both assays. Raised antibodies to low-molecular weight and high-molecular weight glutenin polypeptides was observed, though these proteins had little migration inhibition factor activity. No cellular or humoral response was seen to albumins or globulins. Proteins associated with the granules of well-washed wheat starch are distinct from gluten proteins and had little T-cell activity, correlating with clinical observations that properly prepared wheat starch is devoid of coeliac toxicity. The greater specificity of the humoral response for individual wheat protein fractions in this study, compared with the earlier reports, likely results from cross-contamination in the earlier work of each fraction with gliadin.

  17. A novel cellular stress response characterised by a rapid reorganisation of membranes of the endoplasmic reticulum

    PubMed Central

    Varadarajan, S; Bampton, E T W; Smalley, J L; Tanaka, K; Caves, R E; Butterworth, M; Wei, J; Pellecchia, M; Mitcheson, J; Gant, T W; Dinsdale, D; Cohen, G M

    2012-01-01

    Canonical endoplasmic reticulum (ER) stress, which occurs in many physiological and disease processes, results in activation of the unfolded protein response (UPR). We now describe a new, evolutionarily conserved cellular stress response characterised by a striking, but reversible, reorganisation of ER membranes that occurs independently of the UPR, resulting in impaired ER transport and function. This reorganisation is characterised by a dramatic redistribution and clustering of ER membrane proteins. ER membrane aggregation is regulated, in part, by anti-apoptotic BCL-2 family members, particularly MCL-1. Using connectivity mapping, we report the widespread occurrence of this stress response by identifying several structurally diverse chemicals from different pharmacological classes, including antihistamines, antimalarials and antipsychotics, which induce ER membrane reorganisation. Furthermore, we demonstrate the potential of ER membrane aggregation to result in pathological consequences, such as the long-QT syndrome, a cardiac arrhythmic abnormality, arising because of a novel trafficking defect of the human ether-a-go-go-related channel protein from the ER to the plasma membrane. Thus, ER membrane reorganisation is a feature of a new cellular stress pathway, clearly distinct from the UPR, with important consequences affecting the normal functioning of the ER. PMID:22955944

  18. Sparse feature selection methods identify unexpected global cellular response to strontium-containing materials.

    PubMed

    Autefage, Hélène; Gentleman, Eileen; Littmann, Elena; Hedegaard, Martin A B; Von Erlach, Thomas; O'Donnell, Matthew; Burden, Frank R; Winkler, David A; Stevens, Molly M

    2015-04-07

    Despite the increasing sophistication of biomaterials design and functional characterization studies, little is known regarding cells' global response to biomaterials. Here, we combined nontargeted holistic biological and physical science techniques to evaluate how simple strontium ion incorporation within the well-described biomaterial 45S5 bioactive glass (BG) influences the global response of human mesenchymal stem cells. Our objective analyses of whole gene-expression profiles, confirmed by standard molecular biology techniques, revealed that strontium-substituted BG up-regulated the isoprenoid pathway, suggesting an influence on both sterol metabolite synthesis and protein prenylation processes. This up-regulation was accompanied by increases in cellular and membrane cholesterol and lipid raft contents as determined by Raman spectroscopy mapping and total internal reflection fluorescence microscopy analyses and by an increase in cellular content of phosphorylated myosin II light chain. Our unexpected findings of this strong metabolic pathway regulation as a response to biomaterial composition highlight the benefits of discovery-driven nonreductionist approaches to gain a deeper understanding of global cell-material interactions and suggest alternative research routes for evaluating biomaterials to improve their design.

  19. Cellular response in the dermis of common wombats (Vombatus ursinus) infected with Sarcoptes scabiei var. wombati.

    PubMed

    Skerratt, Lee F

    2003-01-01

    The cellular response in the dermis of common wombats (Vombatus ursinus) with sarcoptic mange exhibited some typical aspects of an immune response to Sarcoptes scabiei. There was an induction phase for wombats experimentally infected with S. scabiei represented by absence of a dermal inflammatory infiltrate for at least 12 days after infection. T lymphocytes, plasma cells, mast cells, and neutrophils then entered the dermis, consistent with a type IV (delayed) hypersensitivity response. In free-living wombats with severe parakeratotic sarcoptic mange eosinophils were also present in the dermis suggesting that a type I (immediate) hypersensitivity response may develop after a type IV hypersensitivity response. Absence of plasma cells and B lymphocytes in free-living wombats with severe parakeratotic sarcoptic mange compared with their presence in wombats experimentally infected with S. scabiei suggested that some immune tolerance may develop with severe infections. A large proportion of cells in the dermal response were not identified but were possibly cells of connective tissue. The thickness of the epidermis increased within 4 days in response to S. scabiei infection. Some antibodies raised against human leucocyte antigens CD3, CD5, HLA-DP, DQ, DR, and CD79b cross-reacted with leucocyte antigens of common wombats and were used to identify cell types in inflammatory infiltrates using immunohistochemistry.

  20. Insights into the cellular response triggered by silver nanoparticles using quantitative proteomics.

    PubMed

    Verano-Braga, Thiago; Miethling-Graff, Rona; Wojdyla, Katarzyna; Rogowska-Wrzesinska, Adelina; Brewer, Jonathan R; Erdmann, Helmut; Kjeldsen, Frank

    2014-03-25

    The use of nanoparticles in foods, materials, and clinical treatments has increased dramatically in the past decade. Because of the possibility of human exposure to nanoparticles, there is an urgent need to investigate the molecular mechanisms underlying the cellular responses that might be triggered. Such information is necessary to assess potential health risks arising from the use of nanoparticles, and for developing new formulations of next generation nanoparticles for clinical treatments. Using mass spectrometry-based proteomic technologies and complementary techniques (e.g., Western blotting and confocal laser scanning microscopy), we present insights into the silver nanoparticle-protein interaction in the human LoVo cell line. Our data indicate that some unique cellular processes are driven by the size. The 100 nm nanoparticles exerted indirect effects via serine/threonine protein kinase (PAK), mitogen-activated protein kinase (MAPK), and phosphatase 2A pathways, and the 20 nm nanoparticles induced direct effects on cellular stress, including generation of reactive oxygen species and protein carbonylation. In addition, we report that proteins involved in SUMOylation were up-regulated after exposure to 20 nm silver nanoparticles. These results were further substantiated by the observation of silver nanoparticles entering the cells; however, data indicate that this was determined by the size of the nanoparticles, since 20 nm particles entered the cells while 100 nm particles did not.

  1. A Stochastic Cellular Automata Approach to Population Dynamics of Cells in a HIV Immune Response Model

    NASA Astrophysics Data System (ADS)

    Pandey, Ras B.

    1998-03-01

    A stochastic cellular automata (SCA) approach is introduced to study the growth and decay of cellular population in an immune response model relevant to HIV. Four cell types are considered: macrophages (M), helper cells (H), cytotoxic cells (C), and viral infected cells (V). Mobility of the cells is introduced and viral mutation is considered probabilistically. In absence of mutation, the population of the host cells, helper (N_H) and cytotxic (N_C) cells in particular, dominates over the viral population (N_V), i.e., N_H, NC > N_V, the immune system wins over the viral infection. Variation of cellular population with time exhibits oscillations. The amplitude of oscillations in variation of N_H, NC and NV with time decreases at high mobility even at low viral mutation; the rate of viral growth is nonmonotonic with NV > N_H, NC in the long time regime. The viral population is much higher than that of the host cells at higher mutation rate, a possible cause of AIDS.

  2. Serine and SAM Responsive Complex SESAME Regulates Histone Modification Crosstalk by Sensing Cellular Metabolism.

    PubMed

    Li, Shanshan; Swanson, Selene K; Gogol, Madelaine; Florens, Laurence; Washburn, Michael P; Workman, Jerry L; Suganuma, Tamaki

    2015-11-05

    Pyruvate kinase M2 (PKM2) is a key enzyme for glycolysis and catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, which supplies cellular energy. PKM2 also phosphorylates histone H3 threonine 11 (H3T11); however, it is largely unknown how PKM2 links cellular metabolism to chromatin regulation. Here, we show that the yeast PKM2 homolog, Pyk1, is a part of a novel protein complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex), which contains serine metabolic enzymes, SAM (S-adenosylmethionine) synthetases, and an acetyl-CoA synthetase. SESAME interacts with the Set1 H3K4 methyltransferase complex, which requires SAM synthesized from SESAME, and recruits SESAME to target genes, resulting in phosphorylation of H3T11. SESAME regulates the crosstalk between H3K4 methylation and H3T11 phosphorylation by sensing glycolysis and glucose-derived serine metabolism. This leads to auto-regulation of PYK1 expression. Thus, our study provides insights into the mechanism of regulating gene expression, responding to cellular metabolism via chromatin modifications.

  3. Role of cytoskeleton and elastic moduli in cellular response to nanosecond pulsed electric fields

    NASA Astrophysics Data System (ADS)

    Thompson, Gary L.; Roth, Caleb; Tolstykh, Gleb; Kuipers, Marjorie; Ibey, Bennett L.

    2013-02-01

    Nanosecond pulsed electric fields (nsPEFs) are known to increase cell membrane permeability to small molecules in accordance with dosages. As previous work has focused on nsPEF exposures in whole cells, electrodeformation may contribute to this induced-permeabilization in addition to other biological mechanisms. Here, we hypothesize that cellular elasticity, based upon the cytoskeleton, affects nsPEF-induced decrease in cellular viability. Young's moduli of various types of cells have been calculated from atomic force microscopy (AFM) force curve data, showing that CHO cells are stiffer than non-adherent U937 and Jurkat cells, which are more susceptible to nsPEF exposure. To distinguish any cytoskeletal foundation for these observations, various cytoskeletal reagents were applied. Inhibiting actin polymerization significantly decreased membrane integrity, as determined by relative propidium uptake and phosphatidylserine externalization, upon exposure at 150 kV/cm with 100 pulses of 10 ns pulse width. Exposure in the presence of other drugs resulted in insignificant changes in membrane integrity and 24-hour viability. However, Jurkat cells showed greater lethality than latrunculin-treated CHO cells of comparable elasticity. From these results, it is postulated that cellular elasticity rooted in actin-membrane interaction is only a minor contributor to the differing responses of adherent and non-adherent cells to nsPEF insults.

  4. Functional recognition imaging using artificial neural networks: applications to rapid cellular identification via broadband electromechanical response

    NASA Astrophysics Data System (ADS)

    Nikiforov, M. P.; Reukov, V. V.; Thompson, G. L.; Vertegel, A. A.; Guo, S.; Kalinin, S. V.; Jesse, S.

    2009-10-01

    Functional recognition imaging in scanning probe microscopy (SPM) using artificial neural network identification is demonstrated. This approach utilizes statistical analysis of complex SPM responses at a single spatial location to identify the target behavior, which is reminiscent of associative thinking in the human brain, obviating the need for analytical models. We demonstrate, as an example of recognition imaging, rapid identification of cellular organisms using the difference in electromechanical activity over a broad frequency range. Single-pixel identification of model Micrococcus lysodeikticus and Pseudomonas fluorescens bacteria is achieved, demonstrating the viability of the method.

  5. Use of /sup 51/Cr-labeled mononuclear cells for measuring the cellular immune response in mouse lungs

    SciTech Connect

    Zarkower, A.; Scheuchenzuber, W.J.; Ferguson, F.G.

    1981-02-01

    Spleen cells labeled with /sup 51/Cr were used in sensitized syngeneic mice to measure the degree of mononuclear cell infiltration into antigen-challenged tissues. With this method, increased cellular infiltration was found after footpad challenge of mice sensitized with sheep erythrocyte, Escherichia coli, and BCG antigens. Cellular response also was determined by using this technique in the lungs of mice sensitized with sheep erythrocytes and BCG. This procedure offers the opportunity to measure cellular infiltration, whether due to cellular or humoral influences, in tissues not easily accessible to conventional immunological manipulation.

  6. Use of 51Cr-labeled mononuclear cells for measuring the cellular immune response in mouse lungs

    SciTech Connect

    Zarkower, A.; Scheuchenzuber, W.J.; Ferguson, F.G.

    1981-02-01

    Spleen cells labeled with 51Cr were used in sensitized syngeneic mice to measure the degree of mononuclear cell infiltration into antigen-challenged tissues. With this method, increased cellular infiltration was found after footpad challenge of mice sensitized with sheep erythrocyte, Escherichia coli, and BCG antigens. Cellular response also was determined by using this technique in the lungs of mice sensitized with sheep erythrocytes and BCG. This procedure offers the opportunity to measure cellular infiltration, whether due to cellular or humoral influences, in tissues not easily accessible to conventional immunological manipulation.

  7. The Fungal Quorum-Sensing Molecule Farnesol Activates Innate Immune Cells but Suppresses Cellular Adaptive Immunity

    PubMed Central

    Leonhardt, Ines; Spielberg, Steffi; Weber, Michael; Albrecht-Eckardt, Daniela; Bläss, Markus; Claus, Ralf; Barz, Dagmar; Scherlach, Kirstin; Hertweck, Christian; Löffler, Jürgen; Hünniger, Kerstin

    2015-01-01

    ABSTRACT Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α] and macrophage inflammatory protein 1 alpha [MIP-1α]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance. PMID:25784697

  8. Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer.

    PubMed

    Eritja, Núria; Chen, Bo-Juen; Rodríguez-Barrueco, Ruth; Santacana, Maria; Gatius, Sònia; Vidal, August; Martí, Maria Dolores; Ponce, Jordi; Bergadà, Laura; Yeramian, Andree; Encinas, Mario; Ribera, Joan; Reventós, Jaume; Boyd, Jeff; Villanueva, Alberto; Matias-Guiu, Xavier; Dolcet, Xavier; Llobet-Navàs, David

    2017-01-05

    Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.

  9. PD-1 blockade induces responses by inhibiting adaptive immune resistance

    PubMed Central

    Tumeh, Paul C.; Harview, Christina L.; Yearley, Jennifer H.; Shintaku, I. Peter; Taylor, Emma J. M.; Robert, Lidia; Chmielowski, Bartosz; Spasic, Marko; Henry, Gina; Ciobanu, Voicu; West, Alisha N.; Carmona, Manuel; Kivork, Christine; Seja, Elizabeth; Cherry, Grace; Gutierrez, Antonio; Grogan, Tristan R.; Mateus, Christine; Tomasic, Gorana; Glaspy, John A.; Emerson, Ryan O.; Robins, Harlan; Pierce, Robert H.; Elashoff, David A.; Robert, Caroline; Ribas, Antoni

    2014-01-01

    Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.1–5 One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8 T-cells (termed adaptive immune resistance).6,7 Here we show that pre-existing CD8 T-cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR). In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance. PMID:25428505

  10. Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

    PubMed Central

    Eritja, Núria; Chen, Bo-Juen; Rodríguez-Barrueco, Ruth; Santacana, Maria; Gatius, Sònia; Vidal, August; Martí, Maria Dolores; Ponce, Jordi; Bergadà, Laura; Yeramian, Andree; Encinas, Mario; Ribera, Joan; Reventós, Jaume; Boyd, Jeff; Villanueva, Alberto; Matias-Guiu, Xavier; Dolcet, Xavier

    2017-01-01

    ABSTRACT Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC. PMID:28055301

  11. Innate and adaptive immune responses against Staphylococcus aureus skin infections.

    PubMed

    Krishna, Sheila; Miller, Lloyd S

    2012-03-01

    Staphylococcus aureus is an important human pathogen that is responsible for the vast majority of bacterial skin and soft tissue infections in humans. S. aureus can also become more invasive and cause life-threatening infections such as bacteremia, pneumonia, abscesses of various organs, meningitis, osteomyelitis, endocarditis, and sepsis. These infections represent a major public health threat due to the enormous numbers of these infections and the widespread emergence of methicillin-resistant S. aureus (MRSA) strains. MSRA is endemic in hospitals worldwide and is rapidly spreading throughout the normal human population in the community. The increasing frequency of MRSA infections has complicated treatment as these strains are more virulent and are increasingly becoming resistant to multiple different classes of antibiotics. The important role of the immune response against S. aureus infections cannot be overemphasized as humans with certain genetic and acquired immunodeficiency disorders are at an increased risk for infection. Understanding the cutaneous immune responses against S. aureus is essential as most of these infections occur or originate from a site of infection or colonization of the skin and mucosa. This review will summarize the innate immune responses against S. aureus skin infections, including antimicrobial peptides that have direct antimicrobial activity against S. aureus as well as pattern recognition receptors and proinflammatory cytokines that promote neutrophil abscess formation in the skin, which is required for bacterial clearance. Finally, we will discuss the recent discoveries involving IL-17-mediated responses, which provide a key link between cutaneous innate and adaptive immune responses against S. aureus skin infections.

  12. The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes.

    PubMed

    Hooper, Philip L; Balogh, Gabor; Rivas, Eric; Kavanagh, Kylie; Vigh, Laszlo

    2014-07-01

    Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease.

  13. Human leukocyte antigens and cellular immune responses to anthrax vaccine adsorbed.

    PubMed

    Ovsyannikova, Inna G; Pankratz, V Shane; Vierkant, Robert A; Pajewski, Nicholas M; Quinn, Conrad P; Kaslow, Richard A; Jacobson, Robert M; Poland, Gregory A

    2013-07-01

    Interindividual variations in vaccine-induced immune responses are in part due to host genetic polymorphisms in the human leukocyte antigen (HLA) and other gene families. This study examined associations between HLA genotypes, haplotypes, and homozygosity and protective antigen (PA)-specific cellular immune responses in healthy subjects following immunization with Anthrax Vaccine Adsorbed (AVA). While limited associations were observed between individual HLA alleles or haplotypes and variable lymphocyte proliferative (LP) responses to AVA, analyses of homozygosity supported the hypothesis of a "heterozygote advantage." Individuals who were homozygous for any HLA locus demonstrated significantly lower PA-specific LP than subjects who were heterozygous at all eight loci (median stimulation indices [SI], 1.84 versus 2.95, P = 0.009). Similarly, we found that class I (HLA-A) and class II (HLA-DQA1 and HLA-DQB1) homozygosity was significantly associated with an overall decrease in LP compared with heterozygosity at those three loci. Specifically, individuals who were homozygous at these loci had significantly lower PA-specific LP than subjects heterozygous for HLA-A (median SI, 1.48 versus 2.13, P = 0.005), HLA-DQA1 (median SI, 1.75 versus 2.11, P = 0.007), and HLA-DQB1 (median SI, 1.48 versus 2.13, P = 0.002) loci, respectively. Finally, homozygosity at an increasing number (≥ 4) of HLA loci was significantly correlated with a reduction in LP response (P < 0.001) in a dose-dependent manner. Additional studies are needed to reproduce these findings and determine whether HLA-heterozygous individuals generate stronger cellular immune response to other virulence factors (Bacillus anthracis LF and EF) than HLA-homozygous subjects.

  14. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

    PubMed

    Calabrese, Edward J; Bachmann, Kenneth A; Bailer, A John; Bolger, P Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M George; Chiueh, Chuang C; Clarkson, Thomas W; Cook, Ralph R; Diamond, David M; Doolittle, David J; Dorato, Michael A; Duke, Stephen O; Feinendegen, Ludwig; Gardner, Donald E; Hart, Ronald W; Hastings, Kenneth L; Hayes, A Wallace; Hoffmann, George R; Ives, John A; Jaworowski, Zbigniew; Johnson, Thomas E; Jonas, Wayne B; Kaminski, Norbert E; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  15. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework

    SciTech Connect

    Calabrese, Edward J. . E-mail: edwardc@schoolph.umass.edu; Bachmann, Kenneth A.; Bailer, A. John; Bolger, P. Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M. George; Chiueh, Chuang C.; Clarkson, Thomas W.; Cook, Ralph R.; Diamond, David M.; Doolittle, David J.; Dorato, Michael A.; Duke, Stephen O.; Feinendegen, Ludwig; Gardner, Donald E.; Hart, Ronald W.; Hastings, Kenneth L.; Hayes, A. Wallace; Hoffmann, George R.; Ives, John A.; Jaworowski, Zbigniew; Johnson, Thomas E.; Jonas, Wayne B.; Kaminski, Norbert E.

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  16. A role for nematocytes in the cellular immune response of the Drosophilid Zaprionus indianus

    PubMed Central

    Kacsoh, Balint Z.; Bozler, Julianna; Schlenke, Todd A.

    2015-01-01

    SUMMARY The melanotic encapsulation response mounted by Drosophila melanogaster against macroparasites, which is based on haemocyte binding to foreign objects, is poorly characterized relative to its humoral immune response against microbes, and appears to be variable across insect lineages. The genus Zaprionus is a diverse clade of flies embedded within the genus Drosophila. Here we characterize the immune response of Zaprionus indianus against endoparasitoid wasp eggs, which elicit the melanotic encapsulation response in D. melanogaster. We find that Z. indianus is highly resistant to diverse wasp species. Although Z. indianus mounts the canonical melanotic encapsulation response against some wasps, it can also potentially fight off wasp infection using two other mechanisms: encapsulation without melanization and a non-cellular form of wasp killing. Zaprionus indianus produces a large number of haemocytes including nematocytes, which are large fusiform haemocytes absent in D. melanogaster, but which we found in several other species in the subgenus Drosophila. Several lines of evidence suggest these nematocytes are involved in anti-wasp immunity in Z. indianus and in particular in the encapsulation of wasp eggs. Altogether, our data show that the canonical anti-wasp immune response and haemocyte make-up of the model organism D. melanogaster vary across the genus Drosophila. PMID:24476764

  17. Microbial Degradation of Cellular Kinases Impairs Innate Immune Signaling and Paracrine TNFα Responses.

    PubMed

    Barth, Kenneth; Genco, Caroline Attardo

    2016-10-04

    The NFκB and MAPK signaling pathways are critical components of innate immunity that orchestrate appropriate immune responses to control and eradicate pathogens. Their activation results in the induction of proinflammatory mediators, such as TNFα a potent bioactive molecule commonly secreted by recruited inflammatory cells, allowing for paracrine signaling at the site of an infection. In this study we identified a novel mechanism by which the opportunistic pathogen Porphyromonas gingivalis dampens innate immune responses by disruption of kinase signaling and degradation of inflammatory mediators. The intracellular immune kinases RIPK1, TAK1, and AKT were selectively degraded by the P. gingivalis lysine-specific gingipain (Kgp) in human endothelial cells, which correlated with dysregulated innate immune signaling. Kgp was also observed to attenuate endothelial responsiveness to TNFα, resulting in a reduction in signal flux through AKT, ERK and NFκB pathways, as well as a decrease in downstream proinflammatory mRNA induction of cytokines, chemokines and adhesion molecules. A deficiency in Kgp activity negated decreases to host cell kinase protein levels and responsiveness to TNFα. Given the essential role of kinase signaling in immune responses, these findings highlight a unique mechanism of pathogen-induced immune dysregulation through inhibition of cell activation, paracrine signaling, and dampened cellular proinflammatory responses.

  18. Microbial Degradation of Cellular Kinases Impairs Innate Immune Signaling and Paracrine TNFα Responses

    PubMed Central

    Barth, Kenneth; Genco, Caroline Attardo

    2016-01-01

    The NFκB and MAPK signaling pathways are critical components of innate immunity that orchestrate appropriate immune responses to control and eradicate pathogens. Their activation results in the induction of proinflammatory mediators, such as TNFα a potent bioactive molecule commonly secreted by recruited inflammatory cells, allowing for paracrine signaling at the site of an infection. In this study we identified a novel mechanism by which the opportunistic pathogen Porphyromonas gingivalis dampens innate immune responses by disruption of kinase signaling and degradation of inflammatory mediators. The intracellular immune kinases RIPK1, TAK1, and AKT were selectively degraded by the P. gingivalis lysine-specific gingipain (Kgp) in human endothelial cells, which correlated with dysregulated innate immune signaling. Kgp was also observed to attenuate endothelial responsiveness to TNFα, resulting in a reduction in signal flux through AKT, ERK and NFκB pathways, as well as a decrease in downstream proinflammatory mRNA induction of cytokines, chemokines and adhesion molecules. A deficiency in Kgp activity negated decreases to host cell kinase protein levels and responsiveness to TNFα. Given the essential role of kinase signaling in immune responses, these findings highlight a unique mechanism of pathogen-induced immune dysregulation through inhibition of cell activation, paracrine signaling, and dampened cellular proinflammatory responses. PMID:27698456

  19. Development and Standardization of the Diagnostic Adaptive Behavior Scale: Application of Item Response Theory to the Assessment of Adaptive Behavior

    ERIC Educational Resources Information Center

    Tassé, Marc J.; Schalock, Robert L.; Thissen, David; Balboni, Giulia; Bersani, Henry, Jr.; Borthwick-Duffy, Sharon A.; Spreat, Scott; Widaman, Keith F.; Zhang, Dalun; Navas, Patricia

    2016-01-01

    The Diagnostic Adaptive Behavior Scale (DABS) was developed using item response theory (IRT) methods and was constructed to provide the most precise and valid adaptive behavior information at or near the cutoff point of making a decision regarding a diagnosis of intellectual disability. The DABS initial item pool consisted of 260 items. Using IRT…

  20. Cellular responses and disease expression in oysters (Crassostrea virginica) exposed to suspended field contaminated sediments.

    PubMed

    Chu, Fu-Lin E; Volety, Aswani K; Hale, Robert C; Huang, Yongqin

    2002-02-01

    Exposure of oysters to water soluble fractions derived from field-contaminated sediments (FCS) containing predominantly lower molecular weight organic aromatic compounds, has been previously demonstrated to enhance pre-existing infections caused by the protozoan parasite, Perkinsus marinus (Dermo), and the prevalence of experimentally induced infections. To further explore the role of pollution on the onset and progression of disease, effects of suspended FCS from an estuarine creek in Virginia, USA, dominated by higher molecular weight polycyclic aromatic hydrocarbons (PAHs) on cellular responses and Dermo disease expression in oysters (Crassostrea virginica) were examined. Sediments were collected from a PAH polluted estuarine creek in Virginia, USA. To test effects on cellular response, oysters from Maine were exposed daily to 0, 1.0, 1.5, or 2.0 g suspended FCS (corresponding to 0, 70.2, 105, or 140 microg PAHs, respectively) for 5, 10, 20, and 40 days. Hemocyte activities and plasma lipid, protein and lactate dehydrogenase (LDH) levels were then measured. Exposure stimulated neutral red uptake, MTT reduction, and 3H-leucine incorporation in oyster hemocytes at various exposure times, but did not affect the plasma protein, lipid and LDH levels. To test effects on Dermo expression, oysters from a Dermo enzootic area, with an initial estimated infection prevalence of 39%, were exposed daily to 0, 1.0, 1.5, or 2.0 g suspended FCS (corresponding to 0, 75.0, 113, or 150 microg PAHs, respectively) for 30 days. Exposure enhanced disease expression in oysters. However, no significant change was noted in any measured cellular or humoral parameters.

  1. Molecular Mechanism for Cellular Response to β-Escin and Its Therapeutic Implications

    PubMed Central

    Perzanowska, Anna; Dutkiewicz, Malgorzata; Kowalewska, Magdalena; Grabowska, Iwona; Maciejko, Dorota; Fogtman, Anna; Dadlez, Michal; Koziak, Katarzyna

    2016-01-01

    β-escin is a mixture of triterpene saponins isolated from the horse chestnut seeds (Aesculus hippocastanum L.). The anti-edematous, anti-inflammatory and venotonic properties of β-escin have been the most extensively clinically investigated effects of this plant-based drug and randomized controlled trials have proved the efficacy of β-escin for the treatment of chronic venous insufficiency. However, despite the clinical recognition of the drug its pharmacological mechanism of action still remains largely elusive. To determine the cellular and molecular basis for the therapeutic effectiveness of β-escin we performed discovery and targeted proteomic analyses and in vitro evaluation of cellular and molecular responses in human endothelial cells under inflammatory conditions. Our results demonstrate that in endothelial cells β-escin potently induces cholesterol synthesis which is rapidly followed with marked fall in actin cytoskeleton integrity. The concomitant changes in cell functioning result in a significantly diminished responses to TNF-α stimulation. These include reduced migration, alleviated endothelial monolayer permeability, and inhibition of NFκB signal transduction leading to down-expression of TNF-α—induced effector proteins. Moreover, the study provides evidence for novel therapeutic potential of β-escin beyond the current vascular indications. PMID:27727329

  2. Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light

    SciTech Connect

    Lehmann, A.R.; Arlett, C.F.; Broughton, B.C.; Harcourt, S.A.; Steingrimsdottir, H.; Stefanini, M.; Malcolm, A.; Taylor, R.; Natarajan, A.T.; Green, S.

    1988-11-01

    Trichothiodystrophy (TTD) is an autosomal recessive disorder characterized by brittle hair with reduced sulfur content, ichthyosis, peculiar face, and mental and physical retardation. Some patients are photosensitive. A previous study by Stefanini et al. showed that cells from four photosensitive patients with TTD had a molecular defect in DNA repair, which was not complemented by cells from xeroderma pigmentosum, complementation group D. In a detailed molecular and cellular study of the effects of UV light on cells cultured from three further TTD patients who did not exhibit photosensitivity we have found an array of different responses. In cells from the first patient, survival, excision repair, and DNA and RNA synthesis following UV irradiation were all normal, whereas in cells from the second patient all these responses were similar to those of excision-defective xeroderma pigmentosum (group D) cells. With the third patient, cell survival measured by colony-forming ability was normal following UV irradiation, even though repair synthesis was only 50% of normal and RNA synthesis was severely reduced. The excision-repair defect in these cells was not complemented by other TTD cell strains. These cellular characteristics of patient 3 have not been described previously for any other cell line. The normal survival may be attributed to the finding that the deficiency in excision-repair is confined to early times after irradiation. Our results pose a number of questions about the relationship between the molecular defect in DNA repair and the clinical symptoms of xeroderma pigmentosum and TTD.

  3. Clot Formation in the Sipunculid Worm Themiste petricola: A Haemostatic and Immune Cellular Response

    PubMed Central

    Lombardo, Tomás; Blanco, Guillermo A.

    2012-01-01

    Clot formation in the sipunculid Themiste petricola, a coelomate nonsegmented marine worm without a circulatory system, is a cellular response that creates a haemostatic mass upon activation with sea water. The mass with sealing properties is brought about by homotypic aggregation of granular leukocytes present in the coelomic fluid that undergo a rapid process of fusion and cell death forming a homogenous clot or mass. The clot structure appears to be stabilized by abundant F-actin that creates a fibrous scaffold retaining cell-derived components. Since preservation of fluid within the coelom is vital for the worm, clotting contributes to rapidly seal the body wall and entrap pathogens upon injury, creating a matrix where wound healing can take place in a second stage. During formation of the clot, microbes or small particles are entrapped. Phagocytosis of self and non-self particles shed from the clot occurs at the clot neighbourhood, demonstrating that clotting is the initial phase of a well-orchestrated dual haemostatic and immune cellular response. PMID:22550489

  4. Hormesis, cellular stress response and neuroinflammation in schizophrenia: Early onset versus late onset state.

    PubMed

    Calabrese, Vittorio; Giordano, James; Crupi, Rosalia; Di Paola, Rosanna; Ruggieri, Martino; Bianchini, Rio; Ontario, Maria Laura; Cuzzocrea, Salvatore; Calabrese, Edward J

    2017-05-01

    Abnormal redox homeostasis and oxidative stress have been proposed to play a role in the etiology of several neuropsychiatric spectrum disorders. Emerging interest has recently focused on markers of oxidative stress and neuroinflammation in schizophrenic spectrum disorders, at least in particular subgroups of patients. Altered expression of genes related to oxidative stress, oxidative damage to DNA, protein and lipids, as well as reduced glutathione levels in central and peripheral tissues could act synergistically, and contribute to the course of the disease.  Herein, we discuss cellular mechanisms that may be operative in neuroinflammation and contributory to schizophrenia. We address modulation of endogenous cellular defense mechanisms as a potentially innovative approach to therapeutics for schizophrenia, and other neuropsychiatric conditions that are associated with neuroinflammation. Specifically, we discuss the emerging role of heme oxygenase as prominent member of neuroprotective network in redox stress responsive mechanisms, as well as the importance of glutathione relevant in schizophrenia pathophysiology. Finally we introduce the hormetic dose response concept as relevant and important to neuroprotection, and review hormetic mechanisms as possible approaches to manipulation of neuroinflammatory targets that may be viable for treating schizophrenia spectrum disorders. © 2016 Wiley Periodicals, Inc.

  5. Lengthening our perspective: morphological, cellular, and molecular responses to eccentric exercise.

    PubMed

    Hyldahl, Robert D; Hubal, Monica J

    2014-02-01

    The response of skeletal muscle to unaccustomed eccentric exercise has been studied widely, yet it is incompletely understood. This review is intended to provide an up-to-date overview of our understanding of how skeletal muscle responds to eccentric actions, with particular emphasis on the underlying molecular and cellular mechanisms of damage and recovery. This review begins by addressing the question of whether eccentric actions result in physical damage to muscle fibers and/or connective tissue. We next review the symptomatic manifestations of eccentric exercise (i.e., indirect damage markers, such as delayed onset muscle soreness), with emphasis on their relatively poorly understood molecular underpinnings. We then highlight factors that potentially modify the muscle damage response following eccentric exercise. Finally, we explore the utility of using eccentric training to improve muscle function in populations of healthy and aging individuals, as well as those living with neuromuscular disorders.

  6. Interferon-Stimulated Gene 15 in the Control of Cellular Responses to Genotoxic Stress

    PubMed Central

    Jeon, Young Joo; Park, Jong Ho; Chung, Chin Ha

    2017-01-01

    Error-free replication and repair of DNA are pivotal to organisms for faithful transmission of their genetic information. Cells orchestrate complex signaling networks that sense and resolve DNA damage. Post-translational protein modifications by ubiquitin and ubiquitin-like proteins, including SUMO and NEDD8, are critically involved in DNA damage response (DDR) and DNA damage tolerance (DDT). The expression of interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, has recently been shown to be induced under various DNA damage conditions, such as exposure to UV, camptothecin, and doxorubicin. Here we overview the recent findings on the role of ISG15 and its conjugation to target proteins (e.g., p53, ΔNp63α, and PCNA) in the control of cellular responses to genotoxic stress, such as the inhibition of cell growth and tumorigenesis. PMID:28241406

  7. An improved sample loading technique for cellular metabolic response monitoring under pressure

    NASA Astrophysics Data System (ADS)

    Gikunda, Millicent Nkirote

    To monitor cellular metabolism under pressure, a pressure chamber designed around a simple-to-construct capillary-based spectroscopic chamber coupled to a microliter-flow perfusion system is used in the laboratory. Although cyanide-induced metabolic responses from Saccharomyces cerevisiae (baker's yeast) could be controllably induced and monitored under pressure, previously used sample loading technique was not well controlled. An improved cell-loading technique which is based on use of a secondary inner capillary into which the sample is loaded then inserted into the capillary pressure chamber, has been developed. As validation, we demonstrate the ability to measure the chemically-induced metabolic responses at pressures of up to 500 bars. This technique is shown to be less prone to sample loss due to perfusive flow than the previous techniques used.

  8. Dynamic deformation and fragmentation response of maraging steel linear cellular alloy

    NASA Astrophysics Data System (ADS)

    Jakus, Adam E.; Fredenberg, David A.; McCoy, Tammy; Thadhani, Naresh; Cochran, Joe K.

    2012-03-01

    The dynamic deformation and fragmentation response of 25% dense 9-cell linear cellular alloy (LCA) made of unaged 250 maraging steel, fabricated using a direct reduction and extrusion technique, is investigated. Explicit finite element simulations were implemented using AUTODYN finite element code. The maraging steel properties were defined using a Johnson-Cook strength model with previously validated parameters. Rod-on-anvil impact tests were performed using the 7.6mm helium gas gun and the transient deformation and fragmentation response was recorded with highspeed imaging. Analysis of observed deformation states of specimens and finite element simulations reveal that in the case of the 9-cell LCA, dissipation of stress and strain occurs along the interior cell wells resulting in significant and ubiquitous buckling prior to confined fragmentation.

  9. Early detection of disease program: Evaluation of the cellular immune response

    NASA Technical Reports Server (NTRS)

    Criswell, B. S.; Knight, V.; Martin, R. R.; Kasel, J. A.

    1974-01-01

    The early cellular responses of specific components of the leukocyte and epithelial cell populations to foreign challenges of both an infectious and noninfectious character were evaluated. Procedures for screening potential flight crews were developed, documented, and tested on a control population. Methods for preparing suitable populations of lymphocytes, polymorphonuclear leukocytes, macrophages, and epithelial cells were first established and evaluated. Epithelial cells from viral infected individuals were screened with a number of anti-viral antisera. This procedure showed the earliest indication of disease as well as providing a specific diagnosis to the physicians. Both macrophages and polymorphonuclear leukocytes were studied from normal individuals, smokers, and patients with viral infections. Newer techniques enabling better definition of lymphocyte subpopulations were then developed, namely the E and EAC rosette procedures for recognition of T (thymus-derived) and B (bone-marrow-derived) lymphocyte subpopulations. Lymphocyte and lymphocyte subpopulation response to multiple mitogens have been evaluated.

  10. Enteropathogenic Escherichia coli Tir recruits cellular SHP-2 through ITIM motifs to suppress host immune response.

    PubMed

    Yan, Dapeng; Quan, Heming; Wang, Lin; Liu, Feng; Liu, Haipeng; Chen, Jianxia; Cao, Xuetao; Ge, Baoxue

    2013-09-01

    Immune responses to pathogens are regulated by immune receptors containing either an immunoreceptor tyrosine-based activation motif (ITAM) or an immunoreceptor tyrosine-based inhibitory motif (ITIM). The important diarrheal pathogen enteropathogenic Escherichia coli (EPEC) require delivery and insertion of the bacterial translocated intimin receptor (Tir) into the host plasma membrane for pedestal formation. The C-terminal region of Tir, encompassing Y483 and Y511, shares sequence similarity with cellular ITIMs. Here, we show that EPEC Tir suppresses the production of inflammatory cytokines by recruitment of SHP-2 and subsequent deubiquitination of TRAF6 in an ITIM dependent manner. Our findings revealed a novel mechanism by which the EPEC utilize its ITIM motifs to suppress and evade the host innate immune response, which could lead to the development of novel therapeutics to prevent bacterial infection.

  11. Cellular-automaton model with velocity adaptation in the framework of Kerner's three-phase traffic theory.

    PubMed

    Gao, Kun; Jiang, Rui; Hu, Shou-Xin; Wang, Bing-Hong; Wu, Qing-Song

    2007-08-01

    In this paper, we propose a cellular automata (CA) model for traffic flow in the framework of Kerner's three-phase traffic theory. We mainly consider the velocity-difference effect on the randomization of vehicles. The presented model is equivalent to a combination of two CA models, i.e., the Kerner-Klenov-Wolf (KKW) CA model and the Nagel-Schreckenberg (NS) CA model with slow-to-start effect. With a given probability, vehicle dynamical rules are changed over time randomly between the rules of the NS model and the rules of the KKW model. Due to the rules of the KKW model, the speed adaptation effect of three-phase traffic theory is automatically taken into account and our model can show synchronized flow. Due to the rules of the NS model, our model can show wide moving jams. The effect of "switching" from the rules of the KKW model to the rules of the NS model provides equivalent effects to the "acceleration noise" in the KKW model. Numerical simulations are performed for both periodic and open boundaries conditions. The results are consistent with the well-known results of the three-phase traffic theory published before.

  12. Impaired cellular immune response to tetanus toxoid but not to cytomegalovirus in effectively HAART-treated HIV-infected children.

    PubMed

    Alsina, Laia; Noguera-Julian, Antoni; Fortuny, Clàudia

    2013-05-07

    Despite of highly active antiretroviral therapy, the response to vaccines in HIV-infected children is poor and short-lived, probably due to a defect in cellular immune responses. We compared the cellular immune response (assessed in terms of IFN-γ production) to tetanus toxoid and to cytomegalovirus in a series of 13 HIV-perinatally-infected children and adolescents with optimal immunovirological response to first line antiretroviral therapy, implemented during chronic infection. A stronger cellular response to cytomegalovirus (11 out of 13 patients) was observed, as compared to tetanus toxoid (1 out of 13; p=0.003). These results suggest that the repeated exposition to CMV, as opposed to the past exposition to TT, is able to maintain an effective antigen-specific immune response in stable HIV-infected pediatric patients and strengthen current recommendations on immunization practices in these children.

  13. Growth responses and adaptations of Fraxinus pennsylvanica seedlings to flooding

    SciTech Connect

    Sena Gomes, A.R.; Kozlowski, T.T.

    1980-01-01

    Flooding induced several physiological and morphological changes in Fraxinus pennsylvanica seedlings, with stomatal closure among the earliest responses. Subsequent changes included: reduction in dry weight increment of roots, stems, and leaves; formation of hypertrophied lenticles and production of adventitious roots on submerged portions of the stem above the soil line; leaf necrosis; and leaf abscission. After 15 days of stomatal closure as a results of flooding, stomata began to reopen progressively until stomata aperture was similar in flooded and unflooded plants. Adventitious roots began to form at about the time stomatal reopening began. As more adventitious roots formed, elongated, and branched, the stomata opened further. The formation of adventitious roots was in important adaptation for flooding tolerance as shown by the high efficiency of adventitious roots in absorption of water and in high correlation between the production of adventitious roots and stomatal reopening. 6 figures, 2 tables.

  14. Humoral and cellular immune responses to matrix protein of measles virus in subacute sclerosing panencephalitis.

    PubMed Central

    Dhib-Jalbut, S; McFarland, H F; Mingioli, E S; Sever, J L; McFarlin, D E

    1988-01-01

    The immune response to matrix (M) protein of measles virus was examined in patients with subacute sclerosing panencephalitis (SSPE) and controls. Antibodies specific for M and nucleocapsid (NC) proteins in 11 serum and 8 cerebrospinal fluid (CSF) samples from patients with SSPE were quantitated by enzyme-linked immunosorbent assay by using affinity-purified measles virus proteins. Geometric mean anti-NC antibody titers were higher in the serum (6.58 +/- 0.98 [mean +/- standard deviation]) and CSF (4.38 +/- 0.74) of SSPE patients compared with controls. Anti-M antibodies were present in the serum and CSF of all SSPE samples tested but in titers lower than those of anti-NC antibodies. Geometric mean anti-M antibody titer was 3.35 +/- 0.53 in sera from patients with SSPE compared with 3.05 +/- 0.66 in sera from patients with other neurological diseases and 3.12 +/- 0.74 in sera from healthy individuals. Geometric mean anti-M antibody titer was 2.59 +/- 0.86 in the CSF of eight patients with SSPE compared with a mean less than 1.00 for patients with other neurological disease (controls). Intrathecal synthesis of anti-M or anti-NC antibodies was established in four patients with SSPE. The cellular immune responses to M, F, HA, and NC proteins were examined in four of the patients with SSPE by lymphoproliferation and were not significantly different from those in five healthy controls. The results demonstrate humoral and cellular immune responses to M protein in patients with SSPE and indicate that it is unlikely that a defect in the immune response to this virus component accounts for the disease process in the patients studied. Images PMID:3373575

  15. Development and Standardization of the Diagnostic Adaptive Behavior Scale: Application of Item Response Theory to the Assessment of Adaptive Behavior.

    PubMed

    Tassé, Marc J; Schalock, Robert L; Thissen, David; Balboni, Giulia; Bersani, Henry Hank; Borthwick-Duffy, Sharon A; Spreat, Scott; Widaman, Keith F; Zhang, Dalun; Navas, Patricia

    2016-03-01

    The Diagnostic Adaptive Behavior Scale (DABS) was developed using item response theory (IRT) methods and was constructed to provide the most precise and valid adaptive behavior information at or near the cutoff point of making a decision regarding a diagnosis of intellectual disability. The DABS initial item pool consisted of 260 items. Using IRT modeling and a nationally representative standardization sample, the item set was reduced to 75 items that provide the most precise adaptive behavior information at the cutoff area determining the presence or not of significant adaptive behavior deficits across conceptual, social, and practical skills. The standardization of the DABS is described and discussed.

  16. Writ large: Genomic Dissection of the Effect of Cellular Environment on Immune Response

    PubMed Central

    Yosef, Nir; Regev, Aviv

    2016-01-01

    Cells of the immune system routinely respond to cues from their local environment and feedback to their surrounding through transient responses, choice of differentiation trajectories, plastic changes in cell state, and malleable adaptation to their tissue of residence. Genomic approaches have opened the way for comprehensive interrogation of such orchestrated responses. Focusing on genomic profiling of transcriptional and epigenetic cell state, we discuss how they are applied to investigate immune cells faced with various environmental cues. We highlight some of the emerging principles, on the role of dense regulatory circuitry, epigenetic memory, cell type fluidity, and reuse of regulatory modules, in achieving and maintaining appropriate responses to a changing environment. These provide a first step toward a systematic understanding of molecular circuits in complex tissues. PMID:27846493

  17. Multiplexed Fluid Flow Device to Study Cellular Response to Tunable Shear Stress Gradients.

    PubMed

    Ostrowski, Maggie A; Huang, Eva Y; Surya, Vinay N; Poplawski, Charlotte; Barakat, Joseph M; Lin, Gigi L; Fuller, Gerald G; Dunn, Alexander R

    2016-07-01

    Endothelial cells (ECs) line the interior of blood and lymphatic vessels and experience spatially varying wall shear stress (WSS) as an intrinsic part of their physiological function. How ECs, and mammalian cells generally, sense spatially varying WSS remains poorly understood, due in part to a lack of convenient tools for exposing cells to spatially varying flow patterns. We built a multiplexed device, termed a 6-well impinging flow chamber, that imparts controlled WSS gradients to a six-well tissue culture plate. Using this device, we investigated the migratory response of lymphatic microvascular ECs, umbilical vein ECs, primary fibroblasts, and epithelial cells to WSS gradients on hours to days timescales. We observed that lymphatic microvascular ECs migrate upstream, against the direction of flow, a response that was unique among all the cells types investigated here. Time-lapse, live cell imaging revealed that the microtubule organizing center relocated to the upstream side of the nucleus in response to the applied WSS gradient. To further demonstrate the utility of our device, we screened for the involvement of canonical signaling pathways in mediating this upstream migratory response. These data highlight the importance of WSS magnitude and WSS spatial gradients in dictating the cellular response to fluid flow.

  18. Maize Prolamins Could Induce a Gluten-Like Cellular Immune Response in Some Celiac Disease Patients

    PubMed Central

    Ortiz-Sánchez, Juan P.; Cabrera-Chávez, Francisco; Calderón de la Barca, Ana M.

    2013-01-01

    Celiac disease (CD) is an autoimmune-mediated enteropathy triggered by dietary gluten in genetically prone individuals. The current treatment for CD is a strict lifelong gluten-free diet. However, in some CD patients following a strict gluten-free diet, the symptoms do not remit. These cases may be refractory CD or due to gluten contamination; however, the lack of response could be related to other dietary ingredients, such as maize, which is one of the most common alternatives to wheat used in the gluten-free diet. In some CD patients, as a rare event, peptides from maize prolamins could induce a celiac-like immune response by similar or alternative pathogenic mechanisms to those used by wheat gluten peptides. This is supported by several shared features between wheat and maize prolamins and by some experimental results. Given that gluten peptides induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides from maize prolamins could also be tested to determine whether they also induce a cellular immune response. Hypothetically, maize prolamins could be harmful for a very limited subgroup of CD patients, especially those that are non-responsive, and if it is confirmed, they should follow, in addition to a gluten-free, a maize-free diet. PMID:24152750

  19. Investigating the Cellular and Metabolic Responses of World-Class Canoeists Training: A Sportomics Approach

    PubMed Central

    Coelho, Wagner Santos; Viveiros de Castro, Luis; Deane, Elizabeth; Magno-França, Alexandre; Bassini, Adriana; Cameron, Luiz-Claudio

    2016-01-01

    (1) Background: We have been using the Sportomics approach to evaluate biochemical and hematological changes in response to exercise. The aim of this study was to evaluate the metabolic and hematologic responses of world-class canoeists during a training session; (2) Methods: Blood samples were taken at different points and analyzed for their hematological properties, activities of selected enzymes, hormones, and metabolites; (3) Results: Muscle stress biomarkers were elevated in response to exercise which correlated with modifications in the profile of white blood cells, where a leukocyte rise was observed after the canoe session. These results were accompanied by an increase in other exercise intensity parameters such as lactatemia and ammonemia. Adrenocorticotropic hormone and cortisol increased during the exercise sessions. The acute rise in both erythrocytes and white blood profile were probably due to muscle cell damage, rather than hepatocyte integrity impairment; (4) Conclusion: The cellular and metabolic responses found here, together with effective nutrition support, are crucial to understanding the effects of exercise in order to assist in the creation of new training and recovery planning. Also we show that Sportomics is a primal tool for training management and performance improvement, as well as to the understanding of metabolic response to exercise. PMID:27845704

  20. Maize prolamins could induce a gluten-like cellular immune response in some celiac disease patients.

    PubMed

    Ortiz-Sánchez, Juan P; Cabrera-Chávez, Francisco; de la Barca, Ana M Calderón

    2013-10-21

    Celiac disease (CD) is an autoimmune-mediated enteropathy triggered by dietary gluten in genetically prone individuals. The current treatment for CD is a strict lifelong gluten-free diet. However, in some CD patients following a strict gluten-free diet, the symptoms do not remit. These cases may be refractory CD or due to gluten contamination; however, the lack of response could be related to other dietary ingredients, such as maize, which is one of the most common alternatives to wheat used in the gluten-free diet. In some CD patients, as a rare event, peptides from maize prolamins could induce a celiac-like immune response by similar or alternative pathogenic mechanisms to those used by wheat gluten peptides. This is supported by several shared features between wheat and maize prolamins and by some experimental results. Given that gluten peptides induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides from maize prolamins could also be tested to determine whether they also induce a cellular immune response. Hypothetically, maize prolamins could be harmful for a very limited subgroup of CD patients, especially those that are non-responsive, and if it is confirmed, they should follow, in addition to a gluten-free, a maize-free diet.

  1. Cellular adaptation to anthrax lethal toxin-induced mitochondrial cholesterol enrichment, hyperpolarization, and reactive oxygen species generation through downregulating MLN64 in macrophages.

    PubMed

    Ha, Soon-Duck; Park, Sangwook; Han, Chae Young; Nguyen, Marilyn L; Kim, Sung Ouk

    2012-12-01

    Cellular adaptation to different stresses related to survival and function has been demonstrated in several cell types. Anthrax lethal toxin (LeTx) induces rapid cell death, termed "pyroptosis," by activating NLRP1b/caspase-1 in murine macrophages. We and others (S. D. Ha et al., J. Biol. Chem. 282:26275-26283, 2007; I. I. Salles et al., Proc. Natl. Acad. Sci. U. S. A. 100:12426 -12431, 2003) have shown that RAW264.7 cells preexposed to sublethal doses of LeTx become resistant to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). To date, the cellular mechanisms of pyroptosis and TIR are largely unknown. We found that LeTx caused NLRP1b/caspase-1-dependent mitochondrial dysfunction, including hyperpolarization and generation of reactive oxygen species, which was distinct from that induced by stimuli such as NLRP3-activating ATP. In TIR cells, these mitochondrial events were not detected, although caspase-1 was activated, in response to LeTx. We identified that downregulation of the late endosomal cholesterol-transferring protein MLN64 in TIR cells was involved in TIR. The downregulation of MLN64 in TIR cells was at least in part due to DNA methyltransferase 1-mediated DNA methylation. In wild-type RAW264.7 cells and primary bone marrow-derived macrophages, LeTx caused NLRP1b/caspase-1-dependent mitochondrial translocation of MLN64, resulting in cholesterol enrichment, membrane hyperpolarization, reactive oxygen species (ROS) generation, and depletion of free glutathione (GSH). This study demonstrates for the first time that MLN64 plays a key role in LeTx/caspase-1-induced mitochondrial dysfunction.

  2. Gain of cellular adaptation due to prolonged p53 impairment leads to functional switchover from p53 to p73 during DNA damage in acute myeloid leukemia cells.

    PubMed

    Chakraborty, Juni; Banerjee, Shuvomoy; Ray, Pallab; Hossain, Dewan Md Sakib; Bhattacharyya, Sankar; Adhikary, Arghya; Chattopadhyay, Sreya; Das, Tanya; Sa, Gaurisankar

    2010-10-22

    Tumor suppressor p53 plays the central role in regulating apoptosis in response to genotoxic stress. From an evolutionary perspective, the activity of p53 has to be backed up by other protein(s) in case of any functional impairment of this protein, to trigger DNA damage-induced apoptosis in cancer cells. We adopted multiple experimental approaches to demonstrate that in p53-impaired cancer cells, DNA damage caused accumulation of p53 paralogue p73 via Chk-1 that strongly impacted Bax expression and p53-independent apoptosis. On the contrary, when p53 function was restored by ectopic expression, Chk-2 induced p53 accumulation that in turn overshadowed p73 activity, suggesting an antagonistic interaction between p53 family members. To understand such interaction better, p53-expressing cells were impaired differentially for p53 activity. In wild-type p53-expressing cancer cells that were silenced for p53 for several generations, p73 was activated, whereas no such trend was observed when p53 was transiently silenced. Prolonged p53 interference, even in functional p53 settings, therefore, leads to the "gain of cellular adaptation" in a way that alters the cellular microenvironment in favor of p73 activation by altering p73-regulatory proteins, e.g. Chk1 activation and dominant negative p73 down-regulation. These findings not only unveil a hitherto unexplained mechanism underlying the functional switchover from p53 to p73, but also validate p73 as a promising and potential target for cancer therapy in the absence of functional p53.

  3. Humoral and cellular immune responses after influenza vaccination in patients with postcancer fatigue

    PubMed Central

    Prinsen, Hetty; van Laarhoven, Hanneke WM; Pots, Jeanette M; Duiveman-de Boer, Tjitske; Mulder, Sasja F; van Herpen, Carla ML; Jacobs, Joannes FM; Leer, Jan Willem H; Bleijenberg, Gijs; Stelma, Foekje F; Torensma, Ruurd; de Vries, I Jolanda M

    2015-01-01

    The aim of this study was to compare humoral and cellular immune responses to influenza vaccination in cancer survivors with and without severe symptoms of fatigue. Severely fatigued (n = 15) and non-fatigued (n = 12) disease-free cancer survivors were vaccinated against seasonal influenza. Humoral immunity was evaluated at baseline and post-vaccination by a hemagglutination inhibition assay. Cellular immunity was evaluated at baseline and post-vaccination by lymphocyte proliferation and activation assays. Regulatory T cells were measured at baseline by flow cytometry and heat-shock protein 90 alpha levels by ELISA. Comparable humoral immune responses were observed in fatigued and non-fatigued patients, both pre- and post-vaccination. At baseline, fatigued patients showed a significantly diminished cellular proliferation upon virus stimulation with strain H3N2 (1414 ± 1201 counts), and a trend in a similar direction with strain H1N1 (3025 ± 2339 counts), compared to non-fatigued patients (3099 ± 2401 and 5877 ± 4604 counts, respectively). The percentage of regulatory T lymphocytes was significantly increased (4.4 ± 2.1% versus 2.4 ± 0.8%) and significantly lower amounts of interleukin 2 were detected prior to vaccination in fatigued compared to non-fatigued patients (36.3 ± 44.3 pg/ml vs. 94.0 ± 45.4 pg/ml with strain H3N2 and 28.4 ± 44.0 pg/ml versus 74.5 ± 56.1 pg/ml with strain H1N1). Pre-vaccination heat-shock protein 90 alpha concentrations, post-vaccination cellular proliferation, and post-vaccination cytokine concentrations did not differ between both groups. In conclusion, influenza vaccination is favorable for severely fatigued cancer survivors and should be recommended when indicated. However, compared to non-fatigued cancer survivors, fatigued cancer survivors showed several significant differences in immunological reactivity at baseline, which warrants further investigation. PMID:25996472

  4. Humoral and cellular immune responses after influenza vaccination in patients with postcancer fatigue.

    PubMed

    Prinsen, Hetty; van Laarhoven, Hanneke W M; Pots, Jeanette M; Duiveman-de Boer, Tjitske; Mulder, Sasja F; van Herpen, Carla M L; Jacobs, Joannes F M; Leer, Jan Willem H; Bleijenberg, Gijs; Stelma, Foekje F; Torensma, Ruurd; de Vries, I Jolanda M

    2015-01-01

    The aim of this study was to compare humoral and cellular immune responses to influenza vaccination in cancer survivors with and without severe symptoms of fatigue. Severely fatigued (n = 15) and non-fatigued (n = 12) disease-free cancer survivors were vaccinated against seasonal influenza. Humoral immunity was evaluated at baseline and post-vaccination by a hemagglutination inhibition assay. Cellular immunity was evaluated at baseline and post-vaccination by lymphocyte proliferation and activation assays. Regulatory T cells were measured at baseline by flow cytometry and heat-shock protein 90 alpha levels by ELISA. Comparable humoral immune responses were observed in fatigued and non-fatigued patients, both pre- and post-vaccination. At baseline, fatigued patients showed a significantly diminished cellular proliferation upon virus stimulation with strain H3N2 (1414 ± 1201 counts), and a trend in a similar direction with strain H1N1 (3025 ± 2339 counts), compared to non-fatigued patients (3099 ± 2401 and 5877 ± 4604 counts, respectively). The percentage of regulatory T lymphocytes was significantly increased (4.4 ± 2.1% versus 2.4 ± 0.8%) and significantly lower amounts of interleukin 2 were detected prior to vaccination in fatigued compared to non-fatigued patients (36.3 ± 44.3 pg/ml vs. 94.0 ± 45.4 pg/ml with strain H3N2 and 28.4 ± 44.0 pg/ml versus 74.5 ± 56.1 pg/ml with strain H1N1). Pre-vaccination heat-shock protein 90 alpha concentrations, post-vaccination cellular proliferation, and post-vaccination cytokine concentrations did not differ between both groups. In conclusion, influenza vaccination is favorable for severely fatigued cancer survivors and should be recommended when indicated. However, compared to non-fatigued cancer survivors, fatigued cancer survivors showed several significant differences in immunological reactivity at baseline, which warrants further investigation.

  5. Engineering Cellular Microenvironments with Photo- and Enzymatically Responsive Hydrogels: Toward Biomimetic 3D Cell Culture Models.

    PubMed

    Tam, Roger Y; Smith, Laura J; Shoichet, Molly S

    2017-03-27

    Conventional cell culture techniques using 2D polystyrene or glass have provided great insight into key biochemical mechanisms responsible for cellular events such as cell proliferation, differentiation, and cell-cell interactions. However, the physical and chemical properties of 2D culture in vitro are dramatically different than those found in the native cellular microenvironment in vivo. Cells grown on 2D substrates differ significantly from those grown in vivo, and this explains, in part, why many promising drug candidates discovered through in vitro drug screening assays fail when they are translated to in vivo animal or human models. To overcome this obstacle, 3D cell culture using biomimetic hydrogels has emerged as an alternative strategy to recapitulate native cell growth in vitro. Hydrogels, which are water-swollen polymers, can be synthetic or naturally derived. Many methods have been developed to control the physical and chemical properties of the hydrogels to match those found in specific tissues. Compared to 2D culture, cells cultured in 3D gels with the appropriate physicochemical cues can behave more like they naturally do in vivo. While conventional hydrogels involve modifications to the bulk material to mimic the static aspects of the cellular microenvironment, recent progress has focused on using more dynamic hydrogels, the chemical and physical properties of which can be altered with external stimuli to better mimic the dynamics of the native cellular microenvironment found in vivo. In this Account, we describe our progress in designing stimuli-responsive, optically transparent hydrogels that can be used as biomimetic extracellular matrices (ECMs) to study cell differentiation and migration in the context of modeling the nervous system and cancer. Specifically, we developed photosensitive agarose and hyaluronic acid hydrogels that are activated by single or two-photon irradiation for biomolecule immobilization at specific volumes within the 3D

  6. Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

    PubMed Central

    Narise, Kosuke; Okuda, Kensuke; Enomoto, Yukihiro; Hirayama, Tasuku; Nagasawa, Hideko

    2014-01-01

    Adaptive cellular responses resulting from multiple microenvironmental stresses, such as hypoxia and nutrient deprivation, are potential novel drug targets for cancer treatment. Accordingly, we focused on developing anticancer agents targeting the tumor microenvironment (TME). In this study, to search for selective antitumor agents blocking adaptive responses in the TME, thirteen new compounds, designed and synthesized on the basis of the arylmethylbiguanide scaffold of phenformin, were used in structure activity relationship studies of inhibition of hypoxia inducible factor (HIF)-1 and unfolded protein response (UPR) activation and of selective cytotoxicity under glucose-deprived stress conditions, using HT29 cells. We conducted luciferase reporter assays using stable cell lines expressing either an HIF-1-responsive reporter gene or a glucose-regulated protein 78 promoter-reporter gene, which were induced by hypoxia and glucose deprivation stress, respectively, to screen for TME-targeting antitumor drugs. The guanidine analog (compound 2), obtained by bioisosteric replacement of the biguanide group, had activities comparable with those of phenformin (compound 1). Introduction of various substituents on the phenyl ring significantly affected the activities. In particular, the o-methylphenyl analog compound 7 and the o-chlorophenyl analog compound 12 showed considerably more potent inhibitory effects on HIF-1 and UPR activation than did phenformin, and excellent selective cytotoxicity under glucose deprivation. These compounds, therefore, represent an improvement over phenformin. They also suppressed HIF-1- and UPR-related protein expression and secretion of vascular endothelial growth factor-A. Moreover, these compounds exhibited significant antiangiogenic effects in the chick chorioallantoic membrane assay. Our structural development studies of biguanide derivatives provided promising candidates for a novel anticancer agent targeting the TME for selective cancer

  7. Cellular responses to HSV-1 infection are linked to specific types of alterations in the host transcriptome

    PubMed Central

    Hu, Benxia; Li, Xin; Huo, Yongxia; Yu, Yafen; Zhang, Qiuping; Chen, Guijun; Zhang, Yaping; Fraser, Nigel W.; Wu, Dongdong; Zhou, Jumin

    2016-01-01

    Pathogen invasion triggers a number of cellular responses and alters the host transcriptome. Here we report that the type of changes to cellular transcriptome is related to the type of cellular functions affected by lytic infection of Herpes Simplex Virus type I in Human primary fibroblasts. Specifically, genes involved in stress responses and nuclear transport exhibited mostly changes in alternative polyadenylation (APA), cell cycle genes showed mostly alternative splicing (AS) changes, while genes in neurogenesis, rarely underwent these changes. Transcriptome wide, the infection resulted in 1,032 cases of AS, 161 incidences of APA, 1,827 events of isoform changes, and up regulation of 596 genes and down regulations of 61 genes compared to uninfected cells. Thus, these findings provided important and specific links between cellular responses to HSV-1 infection and the type of alterations to the host transcriptome, highlighting important roles of RNA processing in virus-host interactions. PMID:27354008

  8. Cellular Immune Responses against Simian T-Lymphotropic Virus Type 1 Target Tax in Infected Baboons

    PubMed Central

    Castro, Iris; Giret, Teresa M.; Magnani, Diogo M.; Maxwell, Helen S.; Umland, Oliver; Perry, Jessica K.; Pecotte, Jerilyn K.; Brasky, Kathleen M.; Barber, Glen N.; Desrosiers, Ronald C.

    2016-01-01

    ABSTRACT There are currently 5 million to 10 million human T-lymphotropic virus type 1 (HTLV-1)-infected people, and many of them will develop severe complications resulting from this infection. A vaccine is urgently needed in areas where HTLV-1 is endemic. Many vaccines are best tested in nonhuman primate animal models. As a first step in designing an effective HTLV-1 vaccine, we defined the CD8+ and CD4+ T cell response against simian T-lymphotropic virus type 1 (STLV-1), a virus closely related to HTLV-1, in olive baboons (Papio anubis). Consistent with persistent antigenic exposure, we observed that STLV-1-specific CD8+ T cells displayed an effector memory phenotype and usually expressed CD107a, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α). To assess the viral targets of the cellular immune response in STLV-1-infected animals, we used intracellular cytokine staining to detect responses against overlapping peptides covering the entire STLV-1 proteome. Our results show that, similarly to humans, the baboon CD8+ T cell response narrowly targeted the Tax protein. Our findings suggest that the STLV-1-infected baboon model may recapitulate some of the important aspects of the human response against HTLV-1 and could be an important tool for the development of immune-based therapy and prophylaxis. IMPORTANCE HTLV-1 infection can lead to many different and often fatal conditions. A vaccine deployed in areas of high prevalence might reduce the incidence of HTLV-1-induced disease. Unfortunately, there are very few animal models of HTLV-1 infection useful for testing vaccine approaches. Here we describe cellular immune responses in baboons against a closely related virus, STLV-1. We show for the first time that the immune response against STLV-1 in naturally infected baboons is largely directed against the Tax protein. Similar findings in humans and the sequence similarity between the human and baboon viruses suggest that the STLV-1-infected baboon

  9. Cellular immune responses and occult infection in seronegative heterosexual partners of chronic hepatitis C patients.

    PubMed

    Roque-Cuéllar, M C; Sánchez, B; García-Lozano, J R; Praena-Fernández, J M; Núñez-Roldán, A; Aguilar-Reina, J

    2011-10-01

    It is unknown whether hepatitis C virus (HCV)-specific cellular immune responses can develop in seronegative sexual partners of chronically HCV-infected patients and whether they have occult infection. Thirty-one heterosexual partners of patients with chronic HCV were studied, fifteen of them with HCV transmission risks. Ten healthy individuals and 17 anti-HCV seropositive patients, without viremia, were used as controls. Virus-specific CD4+ and CD8+ T-cell responses were measured by flow cytometry against six HCV peptides, situated within the nonstructural (NS) proteins NS3, NS4 and NS5, through intracellular detection of gamma interferon (IFN-γ) or interleukin 4 (IL-4) production and CD69 expression. Sexual partners had a higher production of IFN-γ and IL-4 by CD4+ cells against NS3-p124 (P = 0.003), NS5b-p257 (P = 0.005) and NS5b-p294 (P = 0.012), and CD8+ cells against NS3-p124 (P = 0.002), NS4b-p177 (P = 0.001) and NS3-p294 (P = 0.004) as compared with healthy controls. We observed elevated IFN-γ production by CD4+ T cells against NS5b-p257 (P = 0.042) and NS5b-p294 (P = 0.009) in the sexual partners with HCV transmission risks (sexual, professional and familial altogether) than in those without risks. RNA was extracted from peripheral blood mononuclear cells (PBMC), and detection of HCV-RNA positive and replicative (negative) strands was performed by strand-specific real-time PCR. In four sexual partners, the presence of positive and negative HCV- RNA strands in PBMC was confirmed. Hence, we found an HCV-specific cellular immune response as well as occult HCV infection in seronegative and aviremic sexual partners of chronically HCV-infected patients.

  10. Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages

    PubMed Central

    Kozlowski, Michael; Bryniarski, Pawel; Strobel, Spencer; Bryk, Agata; Myszka, Michal; Tyszka, Anna; Kuszmiersz, Piotr; Nowakowski, Jaroslaw; Filipczak-Bryniarska, Iwona

    2016-01-01

    Depression is associated with an altered immune response, which could be normalized by antidepressant drugs. However, little is known about the influence of antidepressants on the peripheral immune response and function of macrophages in individuals not suffering from depression. Our studies were aimed at determining the influence of antidepressant drugs on the humoral and cellular immune response in mice. Mice were treated intraperitoneally with imipramine, fluoxetine, venlafaxine, or moclobemide and contact immunized with trinitrophenyl hapten followed by elicitation and measurement of contact sensitivity by ear swelling response. Peritoneal macrophages from drug-treated mice were either pulsed with sheep erythrocytes or conjugated with trinitrophenyl and transferred into naive recipients to induce humoral or contact sensitivity response, respectively. Secretion of reactive oxygen intermediates, nitric oxide, and cytokines by macrophages from drug-treated mice was assessed, respectively, in chemiluminometry, Griess-based colorimetry and enzyme-linked immunosorbent assay, and the expression of macrophage surface markers was analyzed cytometrically. Treatment of mice with fluoxetine, venlafaxine, and moclobemide results in suppression of humoral and cell-mediated immunity with a reduction of the release of macrophage proinflammatory mediators and the expression of antigen-presentation markers. In contrast, treatment with imipramine enhanced the humoral immune response and macrophage secretory activity but slightly suppressed active contact sensitivity. Our studies demonstrated that systemically delivered antidepressant drugs modulate the peripheral humoral and cell-mediated immune responses, mostly through their action on macrophages. Imipramine was rather proinflammatory, whereas other tested drugs expressed immunosuppressive potential. Current observations may be applied to new therapeutic strategies dedicated to various disorders associated with excessive

  11. Glassy Dynamics in the Adaptive Immune Response Prevents Autoimmune Disease

    NASA Astrophysics Data System (ADS)

    Sun, Jun; Deem, Michael

    2006-03-01

    The immune system normally protects the human host against death by infection. However, when an immune response is mistakenly directed at self antigens, autoimmune disease can occur. We describe a model of protein evolution to simulate the dynamics of the adaptive immune response to antigens. Computer simulations of the dynamics of antibody evolution show that different evolutionary mechanisms, namely gene segment swapping and point mutation, lead to different evolved antibody binding affinities. Although a combination of gene segment swapping and point mutation can yield a greater affinity to a specific antigen than point mutation alone, the antibodies so evolved are highly cross-reactive and would cause autoimmune disease, and this is not the chosen dynamics of the immune system. We suggest that in the immune system a balance has evolved between binding affinity and specificity in the mechanism for searching the amino acid sequence space of antibodies. Our model predicts that chronic infection may lead to autoimmune disease as well due to cross-reactivity and suggests a broad distribution for the time of onset of autoimmune disease due to chronic exposure. The slow search of antibody sequence space by point mutation leads to the broad of distribution times.

  12. Cellular Immune Responses of Preterm Infants after Vaccination with Whole-Cell or Acellular Pertussis Vaccines▿

    PubMed Central

    Vermeulen, Françoise; Verscheure, Virginie; Damis, Eliane; Vermeylen, Danièle; Leloux, Gaëlle; Dirix, Violette; Locht, Camille; Mascart, Françoise

    2010-01-01

    Based on studies reporting specific antibody titers, it is recommended to vaccinate preterm infants against Bordetella pertussis according to their chronological age. However, as specific T-cell responses also are involved in the protection against B. pertussis, we have determined whether highly preterm infants (<31 weeks) are able to mount these immune responses during vaccination. Forty-eight premature infants were vaccinated at 2, 3, and 4 months of their chronological age with an acellular (Pa; n = 24) or a whole-cell (Pw; n = 24) tetravalent diphtheria-tetanus-pertussis-polio vaccine, and blood samples were collected at 2, 3, and 6 months of age. Most of the Pa- and Pw-vaccinated infants developed at 3 or 6 months of age a gamma interferon (IFN-γ) response to the B. pertussis antigens, accompanied by an interleukin-5 (IL-5) and IL-13 secretion for the Pa-vaccinated infants. No association was found between a very low infant birth weight, the occurrence of severe infections, and corticosteroid treatment or the administration of gammaglobulins with a low level of antigen-induced IFN-γ secretion. We conclude that like full-term infants, most preterm infants are able to mount a specific cellular immune response to the administration of the first doses of an acellular or a whole-cell pertussis vaccine. PMID:20016042

  13. Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals

    PubMed Central

    Mckenzie, Grahame; Ward, George; Stallwood, Yvette; Briend, Emmanuel; Papadia, Sofia; Lennard, Andrew; Turner, Martin; Champion, Brian; Hardingham, Giles E

    2006-01-01

    Background Notch plays a wide-ranging role in controlling cell fate, differentiation and development. The PI3K-Akt pathway is a similarly conserved signalling pathway which regulates processes such as differentiation, proliferation and survival. Mice with disrupted Notch and PI3K signalling show phenotypic similarities during haematopoietic cell development, suggesting functional interaction between these pathways. Results We show that cellular responsiveness to Notch signals depends on the activity of the PI3K-Akt pathway in cells as diverse as CHO cells, primary T-cells and hippocampal neurons. Induction of the endogenous PI3K-Akt pathway in CHO cells (by the insulin pathway), in T-cells (via TCR activation) or in neurons (via TrKB activation) potentiates Notch-dependent responses. We propose that the PI3K-Akt pathway exerts its influence on Notch primarily via inhibition of GSK3-beta, a kinase known to phosphorylate and regulate Notch signals. Conclusion The PI3K-Akt pathway acts as a "gain control" for Notch signal responses. Since physiological levels of intracellular Notch are often low, coincidence with PI3K-activation may be crucial for induction of Notch-dependent responses. PMID:16507111

  14. Lysophosphatidic acid receptor-5 negatively regulates cellular responses in mouse fibroblast 3T3 cells

    SciTech Connect

    Dong, Yan; Hirane, Miku; Araki, Mutsumi; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

    2014-04-04

    Highlights: • LPA{sub 5} inhibits the cell growth and motile activities of 3T3 cells. • LPA{sub 5} suppresses the cell motile activities stimulated by hydrogen peroxide in 3T3 cells. • Enhancement of LPA{sub 5} on the cell motile activities inhibited by LPA{sub 1} in 3T3 cells. • The expression and activation of Mmp-9 were inhibited by LPA{sub 5} in 3T3 cells. • LPA signaling via LPA{sub 5} acts as a negative regulator of cellular responses in 3T3 cells. - Abstract: Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors (LPA{sub 1}–LPA{sub 6}) mediates a variety of biological functions, including cell migration. Recently, we have reported that LPA{sub 1} inhibited the cell motile activities of mouse fibroblast 3T3 cells. In the present study, to evaluate a role of LPA{sub 5} in cellular responses, Lpar5 knockdown (3T3-L5) cells were generated from 3T3 cells. In cell proliferation assays, LPA markedly stimulated the cell proliferation activities of 3T3-L5 cells, compared with control cells. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3-L5 cells were significantly higher than those of control cells. The activity levels of matrix metalloproteinases (MMPs) were measured by gelatin zymography. 3T3-L5 cells stimulated the activation of Mmp-2, correlating with the expression levels of Mmp-2 gene. Moreover, to assess the co-effects of LPA{sub 1} and LPA{sub 5} on cell motile activities, Lpar5 knockdown (3T3a1-L5) cells were also established from Lpar1 over-expressing (3T3a1) cells. 3T3a1-L5 cells increased the cell motile activities of 3T3a1 cells, while the cell motile activities of 3T3a1 cells were significantly lower than those of control cells. These results suggest that LPA{sub 5} may act as a negative regulator of cellular responses in mouse fibroblast 3T3 cells, similar to the case for LPA{sub 1}.

  15. Extratropical Transitions in Atlantic Canada: Impacts and Adaptive Responses

    NASA Astrophysics Data System (ADS)

    Masson, Athena; Catto, Norm

    2013-04-01

    . Storm surge damage occurred along the north shore of the Bonavista Peninsula. Similar effects, differing only in the size of the affected areas, have resulted from several extratropical transitions which have impacted Atlantic Canada since July 1989. Extratropical transition "Leslie" impacted Newfoundland on 10-11 September 2012. Although the area affected was comparable to "Igor", wind velocities and rainfall totals were less, fortunately limiting damage. Preparation, advance warning to the population, proaction, and response efforts all showed significant improvement, however, indicating that the experience gained from coping with "Igor" had been successfully applied in adaptation to "Leslie". Extratropical transitions pose a significantly different set of challenges for adaptation in comparison to purely tropical hurricanes, and responses and adaptation strategies should be tailored to address these specific events. Calculating the frequency, magnitude and intensity of potential shifts is important for accurate forecasting and public awareness, safety management, preparedness, and adaptation. Available data indicate an increase in extratropical frequency and severity in Atlantic Canada since 1991, but there are difficulties in establishing the extent and nature of transition for previous storm events. A cautionary policy would assume no significant changes in extratropical transition frequency for Atlantic Canada, but would also acknowledge that large events remain probable.

  16. Cellular response to empty and palladium-conjugated amino-polystyrene nanospheres uptake: a proteomic study.

    PubMed

    Pietrovito, Laura; Cano-Cortés, Victoria; Gamberi, Tania; Magherini, Francesca; Bianchi, Laura; Bini, Luca; Sánchez-Martín, Rosario M; Fasano, Mauro; Modesti, Alessandra

    2015-01-01

    Amino polystyrene nanospheres are shown to be efficient and controllable delivery devices, capable of transporting several bioactive cargoes. Recently, the design of a new device for prodrug activation, using these nanospheres with palladium encapsulated onto them, has been developed successfully. To study the influence of the cellular uptake of these nanodevices, we investigated the cellular response of human embryonic kidney cells (HEK-293T) and murine fibroblasts (L929) treated with empty or palladium-conjugated amino polystyrene nanospheres. To identify differentially expressed proteins, we performed an exhaustive proteomic analysis. In accordance with genomic data previously obtained, the uptake of the empty nanospheres did not induce significant variation in protein expression levels. Following the treatment with palladium-conjugated nanospheres, some changes in protein profiles in both cell lines were observed; these alterations affect proteins involved in cell metabolism and intracellular transport. No key regulator of the cell cycle result was differentially expressed after the treatment, confirming that these innovative drug delivery systems are harmless and well tolerated by the cells.

  17. Bioabsorbable zinc ion induced biphasic cellular responses in vascular smooth muscle cells

    PubMed Central

    Ma, Jun; Zhao, Nan; Zhu, Donghui

    2016-01-01

    Bioabsorbable metal zinc (Zn) is a promising new generation of implantable scaffold for cardiovascular and orthopedic applications. In cardiovascular stent applications, zinc ion (Zn2+) will be gradually released into the surrounding vascular tissues from such Zn-containing scaffolds after implantation. However, the interactions between vascular cells and Zn2+ are still largely unknown. We explored the short-term effects of extracellular Zn2+ on human smooth muscle cells (SMCs) up to 24 h, and an interesting biphasic effect of Zn2+ was observed. Lower concentrations (<80 μM) of Zn2+ had no adverse effects on cell viability but promoted cell adhesion, cell spreading, cell proliferation, cell migration, and enhanced the expression of F-actin and vinculin. Cells treated with such lower concentrations of Zn2+ displayed an elongated shape compared to controls without any treatment. In contrast, cells treated with higher Zn2+ concentrations (80–120 μM) had opposite cellular responses and behaviors. Gene expression profiles revealed that the most affected functional genes were related to angiogenesis, inflammation, cell adhesion, vessel tone, and platelet aggregation. Results indicated that Zn has interesting concentration-dependent biphasic effects on SMCs with low concentrations being beneficial to cellular functions. PMID:27248371

  18. Comparison of cellular responses induced by low level light in different cell types

    NASA Astrophysics Data System (ADS)

    Huang, Ying-Ying; Chen, Aaron C.-H.; Sharma, Sulbha K.; Wu, Qiuhe; Hamblin, Michael R.

    2010-02-01

    Discoveries are rapidly being made in multiple laboratories that shed "light" on the fundamental molecular and cellular mechanisms underlying the use of low level light therapy (LLLT) in vitro, in animal models and in clinical practice. Increases in cellular levels of respiration, in cytochrome c oxidase activity, in ATP levels and in cyclic AMP have been found. Increased expression of reactive oxygen species and release of nitric oxide have also been shown. In order for these molecular changes to have a major effect on cell behavior, it is likely that various transcription factors will be activated, possibly via different signal transduction pathways. In this report we compare and contrast the effects of LLLT in vitro on murine embryonic fibroblasts, primary cortical neurons, cardiomyocytes and bone-marrow derived dendritic cells. We also examined two human cell lines, HeLa cancer cells and HaCaT keratinocytes. The effects of 810-nm near-infra-red light delivered at low and high fluences were addressed. Reactive oxygen species generation, transcription factor activation and ATP increases are reported. The data has led to the hypothesis that cells with a high level of mitochondrial activity (mitochondrial membrane potential) have a higher response to light than cells with low mitochondrial activity.

  19. Effect of drought and rewatering on the cellular status and antioxidant response of Medicago truncatula plants

    PubMed Central

    Filippou, Panagiota; Antoniou, Chrystalla

    2011-01-01

    Effects of water stress on plants have been well-documented. However, the combined responses to drought and rewatering and their underlying mechanisms are relatively unknown. The present study attempts to describe spatiotemporal alterations in the physiology and cellular status of Medicago truncatula tissues that result from and subsequently follow a period of moderate water deficit. Physiological processes and cellular damage levels were monitored in roots and leaves by determining lipid peroxidation levels, as well as nitric oxide and hydrogen peroxide content, further supported by stomatal conductance and chlorophyll fluorescence measurements in leaves. During water stress, cells in both organs displayed increased damage levels and reactive oxygen and nitrogen species content, while leaves showed reduced stomatal conductance. Furthermore, both tissues demonstrated increased proline content. Upon rewatering, plants recovered displaying readings similar to pre-stress control conditions. Furthermore, molecular analysis of antioxidant gene expression by quantitative real-time RT-PCR revealed differential spatiotemporal regulation in a number of genes examined (including catalase, cytosolic ascorbate peroxidase, copper/zinc and iron superoxide dismutase and alternative oxidase). Overall, M. truncatula plants demonstrated increased sensitivity to drought-induced oxidative damage; however, this was reversed following rewatering indicating a great elasticity in the plant's capacity to cope with free oxygen and nitrogen radicals. PMID:21330785

  20. Cellular mechanisms for response heterogeneity among L2/3 pyramidal cells in whisker somatosensory cortex.

    PubMed

    Elstrott, Justin; Clancy, Kelly B; Jafri, Haani; Akimenko, Igor; Feldman, Daniel E

    2014-07-15

    Whisker deflection evokes sparse, low-probability spiking among L2/3 pyramidal cells in rodent somatosensory cortex (S1), with spiking distributed nonuniformly between more and less responsive cells. The cellular and local circuit factors that determine whisker responsiveness across neurons are unclear. To identify these factors, we used two-photon calcium imaging and loose-seal recording to identify more and less responsive L2/3 neurons in S1 slices in vitro, during feedforward recruitment of the L2/3 network by L4 stimulation. We observed a broad gradient of spike recruitment thresholds within local L2/3 populations, with low- and high-threshold cells intermixed. This recruitment gradient was significantly correlated across different L4 stimulation sites, and between L4-evoked and whisker-evoked responses in vivo, indicating that a substantial component of responsiveness is independent of tuning to specific feedforward inputs. Low- and high-threshold L2/3 pyramidal cells differed in L4-evoked excitatory synaptic conductance and intrinsic excitability, including spike threshold and the likelihood of doublet spike bursts. A gradient of intrinsic excitability was observed across neurons. Cells that spiked most readily to L4 stimulation received the most synaptic excitation but had the lowest intrinsic excitability. Low- and high-threshold cells did not differ in dendritic morphology, passive membrane properties, or L4-evoked inhibitory conductance. Thus multiple gradients of physiological properties exist across L2/3 pyramidal cells, with excitatory synaptic input strength best predicting overall spiking responsiveness during network recruitment.

  1. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

    PubMed Central

    Maier, Patrick; Hartmann, Linda; Wenz, Frederik; Herskind, Carsten

    2016-01-01

    During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization. PMID:26784176

  2. Improvement influenza HA2 DNA vaccine cellular and humoral immune responses with Mx bio adjuvant.

    PubMed

    Soleimani, Sina; Shahsavandi, Shahla; Maddadgar, Omid

    2017-03-01

    Immunization with DNA vaccines as a novel alternative to conventional vaccination strategy requires adjuvant for improving vaccine efficacy. The conserved immunogenic HA2 subunit, which harbors neutralizing epitopes is a promising vaccine candidate against influenza viruses. In this study, for the first time we explore the idea of using host interferon inducible Mx protein to increase the immunogenicity of HA2 H9N2 influenza DNA vaccine. The potency and safety of the Mx adjuvanted-HA2 vaccine was evaluated in BALB/c mice by different prime-boost strategies. To assess the effect of the vaccination on the virus clearance rate, mice were challenged with homologous influenza virus. Administration of the adjuvanted vaccine and boosting with the same regimen could effectively enhance both humoral and cellular immune responses in treated mice. These data demonstrated that Mx as host defense peptide can be potentiated for improving influenza vaccine efficacy.

  3. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.

    PubMed

    Maier, Patrick; Hartmann, Linda; Wenz, Frederik; Herskind, Carsten

    2016-01-14

    During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  4. Cellular and molecular mechanisms for the bone response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Bloomfield, S. A.

    2001-01-01

    To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

  5. Cellular responses evoked by different surface characteristics of intraosseous titanium implants.

    PubMed

    Feller, Liviu; Jadwat, Yusuf; Khammissa, Razia A G; Meyerov, Robin; Schechter, Israel; Lemmer, Johan

    2015-01-01

    The properties of biomaterials, including their surface microstructural topography and their surface chemistry or surface energy/wettability, affect cellular responses such as cell adhesion, proliferation, and migration. The nanotopography of moderately rough implant surfaces enhances the production of biological mediators in the peri-implant microenvironment with consequent recruitment of differentiating osteogenic cells to the implant surface and stimulates osteogenic maturation. Implant surfaces with moderately rough topography and with high surface energy promote osteogenesis, increase the ratio of bone-to-implant contact, and increase the bonding strength of the bone to the implant at the interface. Certain features of implant surface chemistry are also important in enhancing peri-implant bone wound healing. It is the purpose of this paper to review some of the more important features of titanium implant surfaces which have an impact on osseointegration.

  6. Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche.

    PubMed

    Van Doorslaer, Koenraad; DeSalle, Rob; Einstein, Mark H; Burk, Robert D

    2015-06-01

    In order to complete their life cycle, papillomaviruses have evolved to manipulate a plethora of cellular pathways. The products of the human Alphapapillomavirus E6 proteins specifically interact with and target PDZ containing proteins for degradation. This viral phenotype has been suggested to play a role in viral oncogenesis. To analyze the association of HPV E6 mediated PDZ-protein degradation with cervical oncogenesis, a high-throughput cell culture assay was developed. Degradation of an epitope tagged human MAGI1 isoform was visualized by immunoblot. The correlation between HPV E6-induced degradation of hMAGI1 and epidemiologically determined HPV oncogenicity was evaluated using a Bayesian approach within a phylogenetic context. All tested oncogenic types degraded the PDZ-containing protein hMAGI1d; however, E6 proteins isolated from several related albeit non-oncogenic viral types were equally efficient at degrading hMAGI1. The relationship between both traits (oncogenicity and PDZ degradation potential) is best explained by a model in which the potential to degrade PDZ proteins was acquired prior to the oncogenic phenotype. This analysis provides evidence that the ancestor of both oncogenic and non-oncogenic HPVs acquired the potential to degrade human PDZ-containing proteins. This suggests that HPV E6 directed degradation of PDZ-proteins represents an ancient ecological niche adaptation. Phylogenetic modeling indicates that this phenotype is not specifically correlated with oncogenic risk, but may act as an enabling phenotype. The role of PDZ protein degradation in HPV fitness and oncogenesis needs to be interpreted in the context of Alphapapillomavirus evolution.

  7. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression

    PubMed Central

    DeNardo, David G; Coussens, Lisa M

    2007-01-01

    Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed that immune cells functionally regulate epithelial cancer development and progression. Moreover, accumulated clinical and experimental data indicate that the outcome of an immune response toward an evolving breast neoplasm is largely determined by the type of immune response elicited. Acute tumor-directed immune responses involving cytolytic T lymphocytes appear to protect against tumor development, whereas immune responses involving chronic activation of humoral immunity, infiltration by Th2 cells, and protumor-polarized innate inflammatory cells result in the promotion of tumor development and disease progression. Herein we review this body of literature and summarize important new findings revealing the paradoxical role of innate and adaptive leukocytes as regulators of breast carcinogenesis. PMID:17705880

  8. Lysophosphatidic acid receptor-5 negatively regulates cellular responses in mouse fibroblast 3T3 cells.

    PubMed

    Dong, Yan; Hirane, Miku; Araki, Mutsumi; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

    2014-04-04

    Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors (LPA1-LPA6) mediates a variety of biological functions, including cell migration. Recently, we have reported that LPA1 inhibited the cell motile activities of mouse fibroblast 3T3 cells. In the present study, to evaluate a role of LPA5 in cellular responses, Lpar5 knockdown (3T3-L5) cells were generated from 3T3 cells. In cell proliferation assays, LPA markedly stimulated the cell proliferation activities of 3T3-L5 cells, compared with control cells. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3-L5 cells were significantly higher than those of control cells. The activity levels of matrix metalloproteinases (MMPs) were measured by gelatin zymography. 3T3-L5 cells stimulated the activation of Mmp-2, correlating with the expression levels of Mmp-2 gene. Moreover, to assess the co-effects of LPA1 and LPA5 on cell motile activities, Lpar5 knockdown (3T3a1-L5) cells were also established from Lpar1 over-expressing (3T3a1) cells. 3T3a1-L5 cells increased the cell motile activities of 3T3a1 cells, while the cell motile activities of 3T3a1 cells were significantly lower than those of control cells. These results suggest that LPA5 may act as a negative regulator of cellular responses in mouse fibroblast 3T3 cells, similar to the case for LPA1.

  9. 3D scaffold alters cellular response to graphene in a polymer composite for orthopedic applications.

    PubMed

    Kumar, Sachin; Azam, Dilkash; Raj, Shammy; Kolanthai, Elayaraja; Vasu, K S; Sood, A K; Chatterjee, Kaushik

    2016-05-01

    Graphene-based polymer nanocomposites are being studied for biomedical applications. Polymer nanocomposites can be processed differently to generate planar two-dimensional (2D) substrates and porous three-dimensional (3D) scaffolds. The objective of this work was to investigate potential differences in biological response to graphene in polymer composites in the form of 2D substrates and 3D scaffolds. Polycaprolactone (PCL) nanocomposites were prepared by incorporating 1% of graphene oxide (GO) and reduced graphene oxide (RGO). GO increased modulus and strength of PCL by 44 and 22% respectively, whereas RGO increased modulus and strength by 22 and 16%, respectively. RGO increased the water contact angle of PCL from 81° to 87° whereas GO decreased it to 77°. In 2D, osteoblast proliferated 15% more on GO composites than on PCL whereas RGO composite showed 17% decrease in cell proliferation, which may be attributed to differences in water wettability. In 3D, initial cell proliferation was markedly retarded in both GO (36% lower) and RGO (55% lower) composites owing to increased roughness due to the presence of the protruding nanoparticles. Cells organized into aggregates in 3D in contrast to spread and randomly distributed cells on 2D discs due to the macro-porous architecture of the scaffolds. Increased cell-cell contact and altered cellular morphology led to significantly higher mineralization in 3D. This study demonstrates that the cellular response to nanoparticles in composites can change markedly by varying the processing route and has implications for designing orthopedic implants such as resorbable fracture fixation devices and tissue scaffolds using such nanocomposites.

  10. In situ CUTANEOUS CELLULAR IMMUNE RESPONSE IN DOGS NATURALLY AFFECTED BY VISCERAL LEISHMANIASIS

    PubMed Central

    ROSSI, Claudio Nazaretian; TOMOKANE, Thaise Yumie; BATISTA, Luis Fábio da Silva; MARCONDES, Mary; LARSSON, Carlos Eduardo; LAURENTI, Márcia Dalastra

    2016-01-01

    SUMMARY Thirty-eight dogs naturally affected by visceral leishmaniasis were recruited in Araçatuba, São Paulo State, Brazil - an endemic area for visceral leishmaniasis. The animals were distributed into one of two groups, according to their clinical and laboratory features, as either symptomatic or asymptomatic dogs. Correlations between clinical features and inflammatory patterns, cellular immune responses, and parasitism in the macroscopically uninjured skin of the ear were investigated. Histological skin patterns were similar in both groups, and were generally characterized by a mild to intense inflammatory infiltrate in the dermis, mainly consisting of mononuclear cells. There was no difference in the number of parasites in the skin (amastigotes/mm²) between the two groups. Concerning the characterization of the cellular immune response, the number of positive inducible nitric oxide synthase (iNOS+) cells was higher in the dermis of symptomatic than in asymptomatic dogs (p = 0.0368). A positive correlation between parasite density and macrophages density (p = 0.031), CD4+ T-cells (p = 0.015), and CD8+ T-cells (p = 0.023) was observed. Furthermore, a positive correlation between density of iNOS+ cells and CD3+ T-cells (p = 0.005), CD4+ T-cells (p = 0.001), and CD8+ T-cells (p = 0.0001) was also found. The results showed the existence of a non-specific chronic inflammatory infiltrate in the dermis of dogs affected by visceral leishmaniasis, characterized by the presence of activated macrophages and T-lymphocytes, associated to cutaneous parasitism, independent of clinical status. PMID:27410908

  11. Transcriptional and cellular responses of the green alga Chlamydomonas reinhardtii to perfluoroalkyl phosphonic acids.

    PubMed

    Sanchez, David; Houde, Magali; Douville, Mélanie; De Silva, Amila O; Spencer, Christine; Verreault, Jonathan

    2015-03-01

    Perfluoroalkyl phosphonic acids (PFPAs), a new class of perfluoroalkyl substances used primarily in the industrial sector as surfactants, were recently detected in surface water and wastewater treatment plant effluents. Toxicological effects of PFPAs have as yet not been investigated in aquatic organisms. The objective of the present study was to evaluate the effects of perfluorooctylphosphonic acid (C8-PFPA) and perfluorodecylphosphonic acid (C10-PFPA) exposure (31-250μg/L) on Chlamydomonas reinhardtii using genomic (qRT-PCR), biochemical (reactive oxygen species production (ROS) and lipid peroxidation), and physiological (cellular viability) indicators. After 72h of exposure, no differences were observed in cellular viability for any of the two perfluorochemicals. However, increase in ROS concentrations (36% and 25.6% at 125 and 250μg/L, respectively) and lipid peroxidation (35.5% and 35.7% at 125 and 250μg/L, respectively) was observed following exposure to C10-PFPA. C8-PFPA exposure did not impact ROS production and lipid peroxidation in algae. To get insights into the molecular response and modes of action of PFPA toxicity, qRT-PCR-based assays were performed to analyze the transcription of genes related to antioxidant responses including superoxide dismutase (SOD-1), glutathione peroxidase (GPX), catalase (CAT), glutathione S-transferase (GST), and ascorbate peroxidase (APX I). Genomic analyses revealed that the transcription of CAT and APX I was up-regulated for all the C10-PFPA concentrations. In addition, PFPAs were quantified in St. Lawrence River surface water samples and detected at concentrations ranging from 250 to 850pg/L for C8-PFPA and 380 to 650pg/L for C10-PFPA. This study supports the prevalence of PFPAs in the aquatic environment and suggests potential impacts of PFPA exposure on the antioxidant defensive system in C. reinhardtii.

  12. Radiation-quality dependent cellular response in mutation induction in normal human cells.

    PubMed

    Suzuki, Masao; Tsuruoka, Chizuru; Uchihori, Yukio; Kitamura, Hisashi; Liu, Cui Hua

    2009-09-01

    We studied cellular responses in normal human fibroblasts induced with low-dose (rate) or low-fluence irradiations of different radiation types, such as gamma rays, neutrons and high linear energy transfer (LET) heavy ions. The cells were pretreated with low-dose (rate) or low-fluence irradiations (approximately 1 mGy/7-8 h) of 137Cs gamma rays, 241Am-Be neutrons, helium, carbon and iron ions before irradiations with an X-ray challenging dose (1.5 Gy). Helium (LET = 2.3 keV/microm), carbon (LET = 13.3 keV/microm) and iron (LET = 200 keV/microm) ions were produced by the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. No difference in cell-killing effect, measured by a colony forming assay, was observed among the pretreatment with different radiation types. In mutation induction, which was detected in the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus to measure 6-thioguanine resistant clones, there was no difference in mutation frequency induced by the X-ray challenging dose between unpretreated and gamma-ray pretreated cells. In the case of the pretreatment of heavy ions, X-ray-induced mutation was around 1.8 times higher in helium-ion pretreated and 4.0 times higher in carbon-ion pretreated cells than in unpretreated cells (X-ray challenging dose alone). However, the mutation frequency in cells pretreated with iron ions was the same level as either unpretreated or gamma-ray pretreated cells. In contrast, it was reduced at 0.15 times in cells pretreated with neutrons when compared to unpretreated cells. The results show that cellular responses caused by the influence of hprt mutation induced in cells pretreated with low-dose-rate or low-fluence irradiations of different radiation types were radiation-quality dependent manner.

  13. Dynamic Deformation and Fragmentation Response of Maraging Steel Linear Cellular Alloy

    NASA Astrophysics Data System (ADS)

    Jakus, Adam; Fredenburg, D. A.; McCoy, T.; Thadhani, N. N.; Cochran, J.

    2011-06-01

    The dynamic deformation and fragmentation response of 25% dense 9-cell linear cellular alloy (LCA) made of unaged 250 maraging steel, fabricated using a direct reduction and extrusion technique, is investigated. Explicit finite element simulations were implemented using AUTODYN. The maraging steel properties were defined using a Johnson-Cook strength model with previously validated parameters. Rod-on-anvil impact tests were performed using the 7.6 mm helium gas gun and the transient deformation and fragmentation response was recorded with high-speed imaging. For purpose of comparison, the response of 25% dense hollow cylinders of same density as the 9-cell LCA was also studied. Analysis of observed states of specimens and finite element simulations reveal that in the case of the 9-cell LCA, dissipation of stress and strain occurs along the interior cell wells resulting in significant and ubiquitous buckling prior to confined fragmentation. In comparison, the simple hollow cylinder undergoes significant radial lipping, eventually producing larger sized, external fragments. DTRA Grant No. HDTRA1-07-1-0018 and NDSEG Fellowship Program.

  14. Cellular Stress Response and Immune Signaling in Retinal Ischemia–Reperfusion Injury

    PubMed Central

    Minhas, Gillipsie; Sharma, Jyoti; Khan, Nooruddin

    2016-01-01

    Ischemia–reperfusion injury is a well-known pathological hallmark associated with diabetic retinopathy, glaucoma, and other related retinopathies that ultimately can lead to visual impairment and vision loss. Retinal ischemia pathogenesis involves a cascade of detrimental events that include energy failure, excitotoxic damage, calcium imbalance, oxidative stress, and eventually cell death. Retina for a long time has been known to be an immune privileged site; however, recent investigations reveal that retina, as well as the central nervous system, elicits immunological responses during various stress cues. Stress condition, such as reperfusion of blood supply post-ischemia results in the sequestration of different immune cells, inflammatory mediators including cytokines, chemokines, etc., to the ischemic region, which in turn facilitates induction of inflammatory conditions in these tissues. The immunological activation during injury or stress per se is beneficial for repair and maintenance of cellular homeostasis, but whether the associated inflammation is good or bad, during ischemia–reperfusion injury, hitherto remains to be explored. Keeping all these notions in mind, the current review tries to address the immune response and host stress response mechanisms involved in ischemia–reperfusion injury with the focus on the retina. PMID:27822213

  15. Gene Expression Profiling Reveals Early Cellular Responses to Intracellular Magnetic Labeling with Superparamagnetic Iron Oxide Nanoparticles

    PubMed Central

    Kedziorek, Dorota A.; Muja, Naser; Walczak, Piotr; Ruiz-Cabello, Jesus; Gilad, Assaf A.; Jie, Chunfa C.; Bulte, Jeff W. M.

    2010-01-01

    With MRI (stem) cell tracking having entered the clinic, studies on the cellular genomic response toward labeling are warranted. Gene expression profiling was applied to C17.2 neural stem cells following superparamagnetic iron oxide/PLL (poly-L-lysine) labeling over the course of 1 week. Relative to unlabeled cells, less than 1% of genes (49 total) exhibited greater than 2-fold difference in expression in response to superparamagnetic iron oxide/PLL labeling. In particular, transferrin receptor 1 (Tfrc) and heme oxygenase 1 (Hmox1) expression was downregulated early, whereas genes involved in lysosomal function (Sulf1) and detoxification (Clu, Cp, Gstm2, Mgst1) were upregulated at later time points. Relative to cells treated with PLL only, cells labeled with superparamagnetic iron oxide/PLL complexes exhibited differential expression of 1399 genes. Though these differentially expressed genes exhibited altered expression over time, the overall extent was limited. Gene ontology analysis of differentially expressed genes showed that genes encoding zinc-binding proteins are enriched after superparamagnetic iron oxide/PLL labeling relative to PLL only treatment, whereas members of the apoptosis/ programmed cell death pathway did not display increased expression. Overexpression of the differentially expressed genes Rnf138 and Abcc4 were confirmed by quantitative real-time polymerase chain reaction. These results demonstrate that, although early reactions responsible for iron homeostasis are induced, overall neural stem cell gene expression remains largely unaltered following superparamagnetic iron oxide/PLL labeling. PMID:20373404

  16. A mathematical model representing cellular immune development and response to Salmonella of chicken intestinal tissue.

    PubMed

    Schokker, D; Bannink, A; Smits, M A; Rebel, J M J

    2013-08-07

    The aim of this study was to create a dynamic mathematical model of the development of the cellular branch of the intestinal immune system of poultry during the first 42 days of life and of its response towards an oral infection with Salmonella enterica serovar Enteritidis. The system elements were grouped in five important classes consisting of intra- and extracellular S. Enteritidis bacteria, macrophages, CD4+, and CD8+ cells. Twelve model variables were described by ordinary differential equations, including 50 parameters. Parameter values were estimated from literature or from own immunohistochemistry data. The model described the immune development in non-infected birds with an average R² of 0.87. The model showed less accuracy in reproducing the immune response to S. Enteritidis infection, with an average R² of 0.51, although model response did follow observed trends in time. Evaluation of the model against independent data derived from several infection trials showed strong/significant deviations from observed values. Nevertheless, it was shown that the model could be used to simulate the effect of varying input parameters on system elements response, such as the number of immune cells at hatch. Model simulations allowed one to study the sensitivity of the model outcome for varying model inputs. The initial number of immune cells at hatch was shown to have a profound impact on the predicted development in the number of systemic S. Enteritidis bacteria after infection. The theoretical contribution of this work is the identification of responses in system elements of the developing intestinal immune system of poultry obtaining a mathematical representation which allows one to explore the relationships between these elements under contrasting environmental conditions during different stages of intestinal development.

  17. Perturbation of gut bacteria induces a coordinated cellular immune response in the purple sea urchin larva

    PubMed Central

    CH Ho, Eric; Buckley, Katherine M; Schrankel, Catherine S; Schuh, Nicholas W; Hibino, Taku; Solek, Cynthia M; Bae, Koeun; Wang, Guizhi; Rast, Jonathan P

    2016-01-01

    The purple sea urchin (Strongylocentrotus purpuratus) genome sequence contains a complex repertoire of genes encoding innate immune recognition proteins and homologs of important vertebrate immune regulatory factors. To characterize how this immune system is deployed within an experimentally tractable, intact animal, we investigate the immune capability of the larval stage. Sea urchin embryos and larvae are morphologically simple and transparent, providing an organism-wide model to view immune response at cellular resolution. Here we present evidence for immune function in five mesenchymal cell types based on morphology, behavior and gene expression. Two cell types are phagocytic; the others interact at sites of microbial detection or injury. We characterize immune-associated gene markers for three cell types, including a perforin-like molecule, a scavenger receptor, a complement-like thioester-containing protein and the echinoderm-specific immune response factor 185/333. We elicit larval immune responses by (1) bacterial injection into the blastocoel and (2) seawater exposure to the marine bacterium Vibrio diazotrophicus to perturb immune state in the gut. Exposure at the epithelium induces a strong response in which pigment cells (one type of immune cell) migrate from the ectoderm to interact with the gut epithelium. Bacteria that accumulate in the gut later invade the blastocoel, where they are cleared by phagocytic and granular immune cells. The complexity of this coordinated, dynamic inflammatory program within the simple larval morphology provides a system in which to characterize processes that direct both aspects of the echinoderm-specific immune response as well as those that are shared with other deuterostomes, including vertebrates. PMID:27192936

  18. Perturbation of gut bacteria induces a coordinated cellular immune response in the purple sea urchin larva.

    PubMed

    Ch Ho, Eric; Buckley, Katherine M; Schrankel, Catherine S; Schuh, Nicholas W; Hibino, Taku; Solek, Cynthia M; Bae, Koeun; Wang, Guizhi; Rast, Jonathan P

    2016-10-01

    The purple sea urchin (Strongylocentrotus purpuratus) genome sequence contains a complex repertoire of genes encoding innate immune recognition proteins and homologs of important vertebrate immune regulatory factors. To characterize how this immune system is deployed within an experimentally tractable, intact animal, we investigate the immune capability of the larval stage. Sea urchin embryos and larvae are morphologically simple and transparent, providing an organism-wide model to view immune response at cellular resolution. Here we present evidence for immune function in five mesenchymal cell types based on morphology, behavior and gene expression. Two cell types are phagocytic; the others interact at sites of microbial detection or injury. We characterize immune-associated gene markers for three cell types, including a perforin-like molecule, a scavenger receptor, a complement-like thioester-containing protein and the echinoderm-specific immune response factor 185/333. We elicit larval immune responses by (1) bacterial injection into the blastocoel and (2) seawater exposure to the marine bacterium Vibrio diazotrophicus to perturb immune state in the gut. Exposure at the epithelium induces a strong response in which pigment cells (one type of immune cell) migrate from the ectoderm to interact with the gut epithelium. Bacteria that accumulate in the gut later invade the blastocoel, where they are cleared by phagocytic and granular immune cells. The complexity of this coordinated, dynamic inflammatory program within the simple larval morphology provides a system in which to characterize processes that direct both aspects of the echinoderm-specific immune response as well as those that are shared with other deuterostomes, including vertebrates.

  19. Adaptation and inhibition underlie responses to time-varying interaural phase cues in a model of inferior colliculus neurons.

    PubMed

    Borisyuk, Alla; Semple, Malcolm N; Rinzel, John

    2002-10-01

    A mathematical model was developed for exploring the sensitivity of low-frequency inferior colliculus (IC) neurons to interaural phase disparity (IPD). The formulation involves a firing-rate-type model that does not include spikes per se. The model IC neuron receives IPD-tuned excitatory and inhibitory inputs (viewed as the output of a collection of cells in the medial superior olive). The model cell possesses cellular properties of firing rate adaptation and postinhibitory rebound (PIR). The descriptions of these mechanisms are biophysically reasonable, but only semi-quantitative. We seek to explain within a minimal model the experimentally observed mismatch between responses to IPD stimuli delivered dynamically and those delivered statically (McAlpine et al. 2000; Spitzer and Semple 1993). The model reproduces many features of the responses to static IPD presentations, binaural beat, and partial range sweep stimuli. These features include differences in responses to a stimulus presented in static or dynamic context: sharper tuning and phase shifts in response to binaural beats, and hysteresis and "rise-from-nowhere" in response to partial range sweeps. Our results suggest that dynamic response features are due to the structure of inputs and the presence of firing rate adaptation and PIR mechanism in IC cells, but do not depend on a specific biophysical mechanism. We demonstrate how the model's various components contribute to shaping the observed phenomena. For example, adaptation, PIR, and transmission delay shape phase advances and delays in responses to binaural beats, adaptation and PIR shape hysteresis in different ranges of IPD, and tuned inhibition underlies asymmetry in dynamic tuning properties. We also suggest experiments to test our modeling predictions: in vitro simulation of the binaural beat (phase advance at low beat frequencies, its dependence on firing rate), in vivo partial range sweep experiments (dependence of the hysteresis curve on

  20. Role of toll-like receptors 3, 4 and 7 in cellular uptake and response to titanium dioxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Chen, Peng; Kanehira, Koki; Taniguchi, Akiyoshi

    2013-02-01

    Innate immune response is believed to be among the earliest provisional cellular responses, and mediates the interactions between microbes and cells. Toll-like receptors (TLRs) are critical to these interactions. We hypothesize that TLRs also play an important role in interactions between nanoparticles (NPs) and cells, although little information has been reported concerning such an interaction. In this study, we investigated the role of TLR3, TLR4 and TLR7 in cellular uptake of titanium dioxide NP (TiO2 NP) agglomerates and the resulting inflammatory responses to these NPs. Our data indicate that TLR4 is involved in the uptake of TiO2 NPs and promotes the associated inflammatory responses. The data also suggest that TLR3, which has a subcellular location distinct from that of TLR4, inhibits the denaturation of cellular protein caused by TiO2 NPs. In contrast, the unique cellular localization of TLR7 has middle-ground functional roles in cellular response after TiO2 NP exposure. These findings are important for understanding the molecular interaction mechanisms between NPs and cells.

  1. Humoral and cellular immune responses to influenza vaccination in children with cancer receiving chemotherapy

    PubMed Central

    WONG-CHEW, ROSA MARÍA; FRÍAS, MARGARITA NAVA; GARCÍA-LEÓN, MIGUEL LEONARDO; ARRIAGA-PIZANO, LOURDES; SANSON, AURORA MEDINA; LOPEZ-MACÍAS, CONSTANTINO; ISIBASI, ARMANDO; SANTOS-PRECIADO, JOSÉ IGNACIO

    2012-01-01

    The immune response to influenza vaccination in children with cancer is controversial. The objective of this study was to characterize the cellular and humoral immune responses to an influenza vaccine in children with cancer who were receiving chemotherapy. In this study, children with cancer, who were not previously immunized, received an influenza vaccine via intramuscular injection. Blood samples were obtained prior to and at 4 weeks after immunization. Antibodies were measured using a hemagglutination inhibition (HI) assay. Cell-mediated immunity was measured by specific lymphoproliferation with 3H-thymidine incorporation and by measuring cell frequencies following staining with monoclonal antibodies (CD8, CD4, CD19, CD45RA and CD27) using flow cytometry following incubation with the influenza antigen for 5 days. Geometric mean titers (GMT), mean counts per minute (cpm), cell frequencies prior to and following vaccination and percentage patient responses were compared using the Mann-Whitney non-parametric U and Chi-square tests; where p<0.05 was considered to indicate a statistically significant result. A total of 56 children were included. Their mean age was 6.64±3.61 years. Acute lymphoblastic leukemia (ALL) was diagnosed in 75, solid tumors in 23 and lymphoma in 2% of the children. Subjects with titers ≥40 hemagglutination units (HU) increased from 43% prior to vaccination to 73% following vaccination (p=0.01), whereas the GMT increased from 31.35 [95% confidence interval (CI), 29–111] to 143.45 HU (95% CI, 284–640) following vaccination (p<0.001). An increase in CD45RA expression in CD8+ T cells was observed following vaccination (p=0.01). An increase in CD27 expression was observed in the CD4/8-negative cell population stimulated with the influenza antigen following vaccination (p<0.05). No serious adverse effects were observed. An increase in the seropositivity rate and GMT values following influenza vaccination were also observed. Influenza

  2. Cellular responses in the Malpighian tubules of Scaptotrigona postica (Latreille, 1807) exposed to low doses of fipronil and boric acid.

    PubMed

    Ferreira, Rafael Alexandre Costa; Silva Zacarin, Elaine Cristina Mathias; Malaspina, Osmar; Bueno, Odair Correa; Tomotake, Maria Eliza Miyoko; Pereira, Andrigo Monroe

    2013-03-01

    Studies of sub-lethal effects of pesticide residues on stingless bees are scarce and morphological analysis of organs would add information to toxicological analysis in order to clarify the continuous exposure of Scaptotrigona postica to insecticides. The aim of this study was to evaluate the morphology and histochemistry of the Malpighian tubules (excretory organ) of S. postica exposed to fipronil or boric acid to detect cellular responses that indicate toxicity or adaptative mechanisms to stress induced by exposure of worker bees to low doses of these chemical compounds. Newly emerged bees were submitted to toxicological bioassays and morphological analyses by optical microscopy and Transmission Electron Microscopy, as well as histochemical methods, were performed to detect proteins and glycoconjugates. Additionally, immunohistochemical detection of DNA fragmentation and HSP70 (70-kDa Heat shock protein) were performed to detect cell death and stress response, respectively. Statistical analysis, for the bioassays conducted with ingestion of contaminated diet with boric acid at 0.75% (w/w) or with fipronil at 0.1μg/kg of food, showed that the survival of bees that ingested the contaminated diets were significantly different to the survival rate presented by the control group (P<0.0001). Although some characteristics indicative of initiation of cell death were observed, the cells remained metabolically active in the processes of excretion and inactivation of chemical compounds. The data from this study reinforce the importance of research on sublethal effects of low doses of pesticides on bees in an attempt to assess a possible realistic dose and evaluate the risk assessment of stingless bee S. postica foraging in the vicinity of cultivated fields and/or in green urban areas.

  3. Distributed adaptive diagnosis of sensor faults using structural response data

    NASA Astrophysics Data System (ADS)

    Dragos, Kosmas; Smarsly, Kay

    2016-10-01

    The reliability and consistency of wireless structural health monitoring (SHM) systems can be compromised by sensor faults, leading to miscalibrations, corrupted data, or even data loss. Several research approaches towards fault diagnosis, referred to as ‘analytical redundancy’, have been proposed that analyze the correlations between different sensor outputs. In wireless SHM, most analytical redundancy approaches require centralized data storage on a server for data analysis, while other approaches exploit the on-board computing capabilities of wireless sensor nodes, analyzing the raw sensor data directly on board. However, using raw sensor data poses an operational constraint due to the limited power resources of wireless sensor nodes. In this paper, a new distributed autonomous approach towards sensor fault diagnosis based on processed structural response data is presented. The inherent correlations among Fourier amplitudes of acceleration response data, at peaks corresponding to the eigenfrequencies of the structure, are used for diagnosis of abnormal sensor outputs at a given structural condition. Representing an entirely data-driven analytical redundancy approach that does not require any a priori knowledge of the monitored structure or of the SHM system, artificial neural networks (ANN) are embedded into the sensor nodes enabling cooperative fault diagnosis in a fully decentralized manner. The distributed analytical redundancy approach is implemented into a wireless SHM system and validated in laboratory experiments, demonstrating the ability of wireless sensor nodes to self-diagnose sensor faults accurately and efficiently with minimal data traffic. Besides enabling distributed autonomous fault diagnosis, the embedded ANNs are able to adapt to the actual condition of the structure, thus ensuring accurate and efficient fault diagnosis even in case of structural changes.

  4. Adaptation responses in C4 photosynthesis of maize under salinity.

    PubMed

    Omoto, Eiji; Taniguchi, Mitsutaka; Miyake, Hiroshi

    2012-03-15

    The effect of salinity on C(4) photosynthesis was examined in leaves of maize, a NADP-malic enzyme (NADP-ME) type C(4) species. Potted plants with the fourth leaf blade fully developed were treated with 3% NaCl solution for 5d. Under salt treatment, the activities of pyruvate orthophosphate dikinase (PPDK), phosphoenolpyruvate carboxylase (PEPCase), NADP-dependent malate dehydrogenase (NADP-MDH) and NAD-dependent malate dehydrogenase (NAD-MDH), which are derived mainly from mesophyll cells, increased, whereas those of NADP-ME and ribulose-1,5-bisphosphate carboxylase, which are derived mainly from bundle sheath cells (BSCs), decreased. Immunocytochemical studies by electron microscopy revealed that PPDK protein increased, while the content of ribulose-1,5-bisphosphate carboxylase/oxygenase protein decreased under salinity. In salt-treated plants, the photosynthetic metabolites malate, pyruvate and starch decreased by 40, 89 and 81%, respectively. Gas-exchange analysis revealed that the net photosynthetic rate, the transpiration rate, stomatal conductance (g(s)) and the intercellular CO(2) concentration decreased strongly in salt-treated plants. The carbon isotope ratio (δ(13)C) in these plants was significantly lower than that in control. These findings suggest that the decrease in photosynthetic metabolites under salinity was induced by a reduction in gas-exchange. Moreover, in addition to the decrease in g(s), the decrease in enzyme activities in BSCs was responsible for the decline of C(4) photosynthesis. The increase of PPDK, PEPCase, NADP-MDH, and NAD-MDH activities and the decrease of NADP-ME activity are interpreted as adaptation responses to salinity.

  5. REM Sleep Rebound as an Adaptive Response to Stressful Situations

    PubMed Central

    Suchecki, Deborah; Tiba, Paula Ayako; Machado, Ricardo Borges

    2011-01-01

    Stress and sleep are related to each other in a bidirectional way. If on one hand poor or inadequate sleep exacerbates emotional, behavioral, and stress-related responses, on the other hand acute stress induces sleep rebound, most likely as a way to cope with the adverse stimuli. Chronic, as opposed to acute, stress impairs sleep and has been claimed to be one of the triggering factors of emotional-related sleep disorders, such as insomnia, depressive- and anxiety-disorders. These outcomes are dependent on individual psychobiological characteristics, conferring even more complexity to the stress-sleep relationship. Its neurobiology has only recently begun to be explored, through animal models, which are also valuable for the development of potential therapeutic agents and preventive actions. This review seeks to present data on the effects of stress on sleep and the different approaches used to study this relationship as well as possible neurobiological underpinnings and mechanisms involved. The results of numerous studies in humans and animals indicate that increased sleep, especially the rapid eye movement phase, following a stressful situation is an important adaptive behavior for recovery. However, this endogenous advantage appears to be impaired in human beings and rodent strains that exhibit high levels of anxiety and anxiety-like behavior. PMID:22485105

  6. Cardiac adaptations of bullfrog tadpoles in response to chytrid infection.

    PubMed

    Salla, Raquel Fernanda; Gamero, Fernando Urban; Ribeiro, Larissa Rodrigues; Rizzi, Gisele Miglioranza; Medico, Samuel Espinosa Dal; Rissoli, Rafael Zanelli; Vieira, Conrado Augusto; Silva-Zacarin, Elaine Cristina Mathias; Leite, Domingos Silva; Abdalla, Fábio Camargo; Toledo, Luis Felipe; Costa, Monica Jones

    2015-08-01

    The chytrid fungus Batrachochytrium dendrobatidis (Bd) can result in heart failure in Bd-susceptible species. Since Bd infection generally does not cause mortality in North American bullfrogs, the aim of this work was to verify whether this species presents any cardiac adaptation that could improve the tolerance to the fungus. Thus, we analyzed tadpoles' activity level, relative ventricular mass, ventricle morphology, in loco heart frequency, and in vitro cardiac function. The results indicate that infected animals present an increase in both ventricular relative mass and in myofibrils' incidence, which accompanied the increase in myocytes' diameter. Such morphological alterations enabled an increase in the in vitro twitch force that, in vivo, would result in elevation of the cardiac stroke volume. This response requires much less energy expenditure than an elevation in heart frequency, but still enables the heart to pump a higher volume of blood per minute (i.e., an increase in cardiac output). As a consequence, the energy saved in the regulation of the cardiac function of Bd-infected tadpoles can be employed in other homeostatic adjustments to avoid the lethal effect of the fungus. Whether other species present this ability, and to what extent, remains uncertain, but such possible interspecific variability might explain different mortality rates among different species of Bd-infected amphibians.

  7. Mitochondrial role in adaptive response to stress conditions in preeclampsia

    PubMed Central

    Vishnyakova, Polina A.; Volodina, Maria A.; Tarasova, Nadezhda V.; Marey, Maria V.; Tsvirkun, Daria V.; Vavina, Olga V.; Khodzhaeva, Zulfiya S.; Kan, Natalya E.; Menon, Ramkumar; Vysokikh, Mikhail Yu.; Sukhikh, Gennady T.

    2016-01-01

    Preeclampsia (PE) is a pregnancy-specific syndrome, characterized in general by hypertension with proteinuria or other systemic disturbances. PE is the major cause of maternal and fetal morbidity and mortality worldwide. However, the etiology of PE still remains unclear. Our study involved 38 patients: 14 with uncomplicated pregnancy; 13 with early-onset PE (eoPE); and 11 with late-onset PE (loPE). We characterized the immunophenotype of cells isolated from the placenta and all biopsy samples were stained positive for Cytokeratin 7, SOX2, Nestin, Vimentin, and CD44. We obtained a significant increase in OPA1 mRNA and protein expression in the eoPE placentas. Moreover, TFAM expression was down-regulated in comparison to the control (p < 0.01). Mitochondrial DNA copy number in eoPE placentas was significantly higher than in samples from normal pregnancies. We observed an increase of maximum coupled state 3 respiration rate in mitochondria isolated from the placenta in the presence of complex I substrates in the eoPE group and an increase of P/O ratio, citrate synthase activity and decrease of Ca2+-induced depolarization rate in both PE groups. Our results suggest an essential role of mitochondrial activity changes in an adaptive response to the development of PE. PMID:27573305

  8. Distributed reinforcement learning for adaptive and robust network intrusion response

    NASA Astrophysics Data System (ADS)

    Malialis, Kleanthis; Devlin, Sam; Kudenko, Daniel

    2015-07-01

    Distributed denial of service (DDoS) attacks constitute a rapidly evolving threat in the current Internet. Multiagent Router Throttling is a novel approach to defend against DDoS attacks where multiple reinforcement learning agents are installed on a set of routers and learn to rate-limit or throttle traffic towards a victim server. The focus of this paper is on online learning and scalability. We propose an approach that incorporates task decomposition, team rewards and a form of reward shaping called difference rewards. One of the novel characteristics of the proposed system is that it provides a decentralised coordinated response to the DDoS problem, thus being resilient to DDoS attacks themselves. The proposed system learns remarkably fast, thus being suitable for online learning. Furthermore, its scalability is successfully demonstrated in experiments involving 1000 learning agents. We compare our approach against a baseline and a popular state-of-the-art throttling technique from the network security literature and show that the proposed approach is more effective, adaptive to sophisticated attack rate dynamics and robust to agent failures.

  9. Only signaling modules that discriminate sharply between stimulatory and nonstimulatory inputs require basal signaling for fast cellular responses

    NASA Astrophysics Data System (ADS)

    Artomov, Mykyta; Kardar, Mehran; Chakraborty, Arup K.

    2010-09-01

    In many types of cells, binding of molecules to their receptors enables cascades of intracellular chemical reactions to take place (signaling). However, a low level of signaling also occurs in most unstimulated cells. Such basal signaling in resting cells can have many functions, one of which is that it is thought to be required for fast cellular responses to external stimuli. A mechanistic understanding of why this is true and which features of cellular signaling networks make basal signaling necessary for fast responses is unknown. We address this issue by obtaining the time required for activation of common types of cell signaling modules with and without basal signaling. Our results show that the absence of basal signaling does not have any dramatic effects on the response time for signaling modules that exhibit a graded response to increasing stimulus levels. In sharp contrast, signaling modules that exhibit sharp dose-response curves which discriminate sensitively between stimuli to which the cell needs to respond and low-grade inputs (or stochastic noise) require basal signaling for fast cellular responses. In such cases, we find that an optimal level of basal signaling balances the requirements for fast cellular responses while minimizing spurious activation without appropriate stimulation.

  10. Perinatal Exposure to a Low Dose of Bisphenol A Impaired Systemic Cellular Immune Response and Predisposes Young Rats to Intestinal Parasitic Infection

    PubMed Central

    Ménard, Sandrine; Guzylack-Piriou, Laurence; Lencina, Corinne; Leveque, Mathilde; Naturel, Manon; Sekkal, Soraya; Harkat, Cherryl; Gaultier, Eric; Olier, Maïwenn; Garcia-Villar, Raphael; Theodorou, Vassilia; Houdeau, Eric

    2014-01-01

    Perinatal exposure to the food contaminant bisphenol A (BPA) in rats induces long lasting adverse effects on intestinal immune homeostasis. This study was aimed at examining the immune response to dietary antigens and the clearance of parasites in young rats at the end of perinatal exposure to a low dose of BPA. Female rats were fed with BPA [5 µg/kg of body weight/day] or vehicle from gestational day 15 to pup weaning. Juvenile female offspring (day (D)25) were used to analyze immune cell populations, humoral and cellular responses after oral tolerance or immunization protocol to ovalbumin (OVA), and susceptibility to infection by the intestinal nematode Nippostrongylus brasiliensis (N. brasiliensis). Anti-OVA IgG titers following either oral tolerance or immunization were not affected after BPA perinatal exposure, while a sharp decrease in OVA-induced IFNγ secretion occurred in spleen and mesenteric lymph nodes (MLN) of OVA-immunized rats. These results are consistent with a decreased number of helper T cells, regulatory T cells and dendritic cells in spleen and MLN of BPA-exposed rats. The lack of cellular response to antigens questioned the ability of BPA-exposed rats to clear intestinal infections. A 1.5-fold increase in N. brasiliensis living larvae was observed in the intestine of BPA-exposed rats compared to controls due to an inappropriate Th1/Th2 cytokine production in infected jejunal tissues. These results show that perinatal BPA exposure impairs cellular response to food antigens, and increases susceptibility to intestinal parasitic infection in the juveniles. This emphasized the maturing immune system during perinatal period highly sensitive to low dose exposure to BPA, altering innate and adaptative immune response capacities in early life. PMID:25415191

  11. On the synthesis of a bio-inspired dual-cellular fluidic flexible matrix composite adaptive structure based on a non-dimensional dynamics model

    NASA Astrophysics Data System (ADS)

    Li, Suyi; Wang, K. W.

    2013-01-01

    A recent study investigated the dynamic characteristics of an adaptive structure concept featuring dual fluidic flexible matrix composite (F2MC) cells inspired by the configuration of plant cells and cell walls. This novel bio-inspired system consists of two F2MC cells with different fiber angles connected through internal fluid circuits. It was discovered that the dual F2MC cellular structure can be characterized as a two degree of freedom damped mass-spring oscillator, and can be utilized as a vibration absorber or an enhanced actuator under different operation conditions. These results demonstrated that the concept is promising and further investigations are needed to develop methodologies for synthesizing future multi-cellular F2MC structural systems. While interesting, the previous study focused on specific case studies and analysis. That is, the outcome did not provide insight that could be generalized, or tools for synthesizing a multiple F2MC cellular structure. This paper attempts to address this important issue by developing a non-dimensional dynamic model, which reveals good physical insights as well as identifying crucial constitutive parameters for F2MC cellular design. Working with these parameters, rather than physical variables, can greatly simplify the mathematics involved in the study. A synthesis tool is then developed for the dual-cellular structure, and it is found that for each set of achievable target poles and zero, there exist multiple F2MC cellular designs, forming a design space. The presented physical insights and synthesis tool for the dual-cellular structure will be the building blocks for future investigation on cellular structures with a larger number of cells.

  12. Positron emission tomography in the quantification of cellular and biochemical responses to intrapulmonary particulates

    SciTech Connect

    Jones, Hazel A. . E-mail: hazel.jones@imperial.ac.uk; Hamacher, Kurt; Clark, John C.; Schofield, John B.; Krausz, Thomas; Haslett, Christopher; Boobis, Alan R.

    2005-09-01

    Inhaled mineral dusts and fibres can cause chronic pulmonary inflammation, often leading to permanent scarring with loss of function, but the mechanisms involved remain obscure. There are currently no good methods for monitoring inflammatory processes in situ. Positron emission tomography (PET) of suitable intravenously injected radiolabelled markers provides non-invasive and repeatable methods of quantifying biochemical and cellular responses. We have developed animal models of fibrotic and non-fibrotic pulmonary response to particulate instillation and characterised these by histology. Different components of the inflammatory response have been investigated by PET: (1) [{sup 18}F]-labelled fluoro-deoxyglucose, a positron emitting glucose analogue, accumulates in cells in proportion to their glucose uptake; ex vivo microautoradiography indicates that neutrophils are the cells responsible for an increased signal during pulmonary inflammation; a persistently high uptake is associated with lung scarring. (2) The radioligand [{sup 11}C]-R-PK11195 binds to benzodiazepine-like receptors abundant in macrophages; following particulate instillation, the [{sup 11}C]-R-PK11195 PET signal tracks with lung macrophage accumulation and also localises to regions consistent with macrophage clearance; poor macrophage clearance is associated with fibrosis. (3) [{sup 18}F]-fluoroproline is likely a substrate for extracellular matrix production, especially proline-rich collagen; during active scarring, the rate of lung uptake of fluoroproline is elevated. Localisation of radioactivity in the lung has been validated ex vivo by microautoradiography of tritium analogues of each of the positron emitting tracers. The use of PET to monitor different inflammatory processes by repeated scanning of the same animal or individual is helping to identify key events in the fibrotic process.

  13. Regional Differences in the Cellular Immune Response to Experimental Cutaneous or Visceral Infection with Leishmania donovani

    PubMed Central

    Melby, Peter C.; Yang, Yan-Zhu; Cheng, Jun; Zhao, Weiguo

    1998-01-01

    Infection with the protozoan Leishmania donovani can cause serious visceral disease or subclinical infection in humans. To better understand the pathogenesis of this dichotomy, we have investigated the host cellular immune response to cutaneous or visceral infection in a murine model. Mice infected in the skin developed no detectable visceral parasitism, whereas intravenous inoculation resulted in hepatosplenomegaly and an increasing visceral parasite burden. Spleen cells from mice with locally controlled cutaneous infection showed strong parasite-specific proliferative and gamma interferon (IFN-γ) responses, but spleen cells from systemically infected mice were unresponsive to parasite antigens. The in situ expression of IFN-γ, interleukin-4 (IL-4), IL-10, IL-12, and inducible nitric oxide synthase (iNOS) mRNAs was determined in the spleen, draining lymph node (LN), and cutaneous site of inoculation. There was considerably greater expression of IFN-γ and IL-12 p40 mRNAs in the LN draining a locally controlled cutaneous infection than in the spleen following systemic infection. Similarly, there was a high level of IFN-γ production by LN cells following subcutaneous infection but no IFN-γ production by spleen cells following systemic infection. Splenic IL-4 expression was transiently increased early after systemic infection, but splenic IL-10 transcripts increased throughout the course of visceral infection. IL-4 and IL-10 mRNAs were also increased in the LN following cutaneous infection. iNOS mRNA was detected earlier in the LN draining a cutaneous site of infection compared to the spleen following systemic challenge. Thus, locally controlled cutaneous infection was associated with antigen-specific spleen cell responsiveness and markedly increased levels of IFN-γ, IL-12, and iNOS mRNA in the draining LN. Progressive splenic parasitism was associated with an early IL-4 response, markedly increased IL-10 but minimal IL-12 expression, and delayed expression of i

  14. DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis.

    PubMed

    Schmitt, Estelle; Paquet, Claudie; Beauchemin, Myriam; Bertrand, Richard

    2007-06-01

    Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senescence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving "sensor" proteins that sense the damage, and transmit signals to "transducer" proteins, which, in turn, convey the signals to numerous "effector" proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.

  15. Cellular-mediated immune responses in the liver tissue of patients with severe Plasmodium falciparum malaria.

    PubMed

    Punsawadl, Chuchard; Setthapramote, Chayanee; Viriyavejakul, Parnpen

    2014-09-01

    The immune responses against Plasmodiumfalciparum malaria infections are complex and poorly understood. No published studies have yet reported the lymphocyte subsets involved in the human liver tissue of P. falciparum malaria patients. To understand the cellular-mediated immune responses in the liver during malaria infection, we determined the numbers of the various lymphocyte subsets in tissue samples obtained at autopsy from patients who died with P. falciparum malaria infection. All the liver tissue specimens had been stored at the Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Thailand. On the basis of total bilirubin (TB) levels prior to death, patients were divided into 2 groups: those with hyperbilirubinemia [total bilirubin (TB) > or =51.3 micromol/l) (n = 9)] and those without hyperbilirubinemia (TB < 51.3 micromol/l) (n = 12). Normal liver specimens (n = 10) were used as controls. An immunohistochemistry method was used to analyze the types and numbers of lymphocytes (T and B lymphocytes), and Kupffer cells, using specific antibodies against CD3+, CD4+, CD8+, CD20+, and CD68+. Our findings reveal the numbers of T lymphocytes (CD3+ T-cells) and their subsets (CD4+ and CD8+ T-cells) were significantly greater in the portal tracts and sinusoids of liver tissue obtained from P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia or controls. CD8+ T-cells were the major lymphocyte subset in the liver tissue of patients with severe falciparum malaria. A significant positive correlation was seen between the numbers of CD4+ and CD8+ T-cells and the liver enzyme levels among P. falciparum malaria patients. The number of CD68+ cells (Kupffer cells) was significantly greater in the liver sinusoids of P. falciparum malaria cases with hyperbilirubinemia than those without hyperbilirubinemia. These findings suggest T-cells, especially CD8+ T-cells and Kupffer cells are an important part of the

  16. Cellular Interactions and Immune Response of Spherical Nucleic Acid (SNA) Nanoconjugates

    NASA Astrophysics Data System (ADS)

    Massich, Matthew David

    Spherical nucleic acid (SNA) nanoconjugates consist of a densely packed monolayer shell of highly-oriented oligonucleotides covalently bound to a gold nanoparticle core. The nanoconjugates exhibit several important qualities, which make them useful for various biological applications, such as antisense gene regulation strategies and the intracellular detection of biomolecules. The focus of this thesis was to characterize the nanoconjugates interaction with cultured cells and specifically the immune response to their intracellular presence. The immune response of macrophage cells to internalized nanoconjugates was studied, and due to the dense functionalization of oligonucleotides on the surface of the nanoparticle and the resulting high localized salt concentration the innate immune response to the nanoconjugates is ˜25-fold less when compared to a lipoplex carrying the same sequence. Additionally, genome-wide expression profiling was used to study the biological response of cultured cells to the nanoconjugates. The biological response of HeLa cells to gold nanoparticles stabilized by weakly bound ligands was significant, yet when these same nanoparticles were stably functionalized with covalently attached oligonucleotides the cells showed no measurable response. In human keratinocytes, the oligonucleotide sequences caused 427 genes to be differentially expressed when complexed with Dharmafect, but when the oligonucleotides were conjugated to nanoparticles only 7 genes were differentially expressed. Beyond characterizing the cellular interactions and immune response of the nanoconjugates, the optimal length of siRNA (from 19--34 base pairs) that induces the most gene knockdown while maintaining limited immune activation was determined to be 24 base pairs. Further, the SNAs were shown to be useful as a potential antiviral gene therapy by demonstrating approximately 50% knockdown of the Ebola VP35 gene. Lastly, a scanning probe-enabled method was used to rapidly

  17. Transcription factor ATF3 links host adaptive response to breast cancer metastasis

    PubMed Central

    Wolford, Chris C.; McConoughey, Stephen J.; Jalgaonkar, Swati P.; Leon, Marino; Merchant, Anand S.; Dominick, Johnna L.; Yin, Xin; Chang, Yiseok; Zmuda, Erik J.; O’Toole, Sandra A.; Millar, Ewan K.A.; Roller, Stephanie L.; Shapiro, Charles L.; Ostrowski, Michael C.; Sutherland, Robert L.; Hai, Tsonwin

    2013-01-01

    Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell–selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes. PMID:23921126

  18. Cellular responses to disruption of the permeability barrier in a three-dimensional organotypic epidermal model

    SciTech Connect

    Ajani, Gati; Sato, Nobuyuki; Mack, Judith A.; Maytin, Edward V. . E-mail: maytine@ccf.org

    2007-08-15

    Repeated injury to the stratum corneum of mammalian skin (caused by friction, soaps, or organic solvents) elicits hyperkeratosis and epidermal thickening. Functionally, these changes serve to restore the cutaneous barrier and protect the organism. To better understand the molecular and cellular basis of this response, we have engineered an in vitro model of acetone-induced injury using organotypic epidermal cultures. Rat epidermal keratinocytes (REKs), grown on a collagen raft in the absence of any feeder fibroblasts, developed all the hallmarks of a true epidermis including a well-formed cornified layer. To induce barrier injury, REK cultures were treated with intermittent 30-s exposures to acetone then were fixed and paraffin-sectioned. After two exposures, increased proliferation (Ki67 and BrdU staining) was observed in basal and suprabasal layers. After three exposures, proliferation became confined to localized buds in the basal layer and increased terminal differentiation was observed (compact hyperkeratosis of the stratum corneum, elevated levels of K10 and filaggrin, and heightened transglutaminase activity). Thus, barrier disruption causes epidermal hyperplasia and/or enhances differentiation, depending upon the extent and duration of injury. Given that no fibroblasts are present in the model, the ability to mount a hyperplastic response to barrier injury is an inherent property of keratinocytes.

  19. Studies on the cellular bystander response after exposure to high LET irradiation

    NASA Astrophysics Data System (ADS)

    Fournier, C.; Becker, D.; Heiss, M.; Barberet, P.; Topsch, J.; Winter, M.; Ritter, S.; Taucher-Scholz, G.

    In this study various cellular responses of non-targeted cells following heavy ion exposure of human fibroblasts were investigated Heavy ions are an excellent tool to elucidate the impact of ionisation density on the occurrence of bystander effects An improved understanding of bystander responses is important with respect to risk estimation for accidental or therapeutical radiation exposure Human fibroblasts were exposed to low fluences of heavy ions C Ar and U with LETs in the range of 170 to 15000 keV 956 m traversing only a few cells by a particle For selected endpoints targeted irradiation of single cells was performed using a heavy ion microbeam A medium transfer technique was applied to study the transmission of signals limited to soluble factors At several time intervals after exposure the cell cycle progression FACS the expression of CDKN1A and other cycle regulators Western blot immuno-fluorescence and the amount of intracellular reactive oxygen species ROS DCF fluorescence were assessed In addition the frequencies of sister chromatid exchanges SCE and the number of cells containing micronuclei MN were determined 3 days after exposure as indicators for changes or damage on chromosomal level in bystander cells An overall induction of CDKN1A but no distinct clusters of cells bearing an elevated expression level in the direct neighbourhood of the hit cells were observed several hours after exposure This effect was accompanied by a transient delay in the initial G1 phase after exposure The question was addressed whether the cell

  20. Quantitative analysis of the cellular inflammatory response against biofilm bacteria in chronic wounds.

    PubMed

    Fazli, Mustafa; Bjarnsholt, Thomas; Kirketerp-Møller, Klaus; Jørgensen, Anne; Andersen, Claus Bøgelund; Givskov, Michael; Tolker-Nielsen, Tim

    2011-01-01

    Chronic wounds are an important problem worldwide. These wounds are characterized by a persistent inflammatory stage associated with excessive accumulation and elevated cell activity of neutrophils, suggesting that there must be a persistent stimulus that attracts and recruits neutrophils to the wound. One such stimulus might be the presence of bacterial biofilms in chronic wounds. In the present study, biopsy specimens from chronic venous leg ulcers were investigated for the detection of bacteria using peptide nucleic acid-based fluorescence in situ hybridization (PNA-FISH) and confocal laser scanning microscopy. The bacteria in the wounds were often situated in large aggregates. To obtain a measure of the cellular inflammatory response against the bacteria in the chronic wounds, the amount of neutrophils accumulated at the site of infection was evaluated through differential neutrophil counting on the tissue sections from wounds containing either Pseudomonas aeruginosa or Staphylococcus aureus. The P. aeruginosa-containing wounds had significantly higher numbers of neutrophils accumulated compared with the S. aureus-containing wounds. These results are discussed in relation to the hypothesis that the presence of P. aeruginosa biofilms in chronic wounds may be one of the main factors leading to a persistent inflammatory response and impaired wound healing.

  1. Cleavage of Interferon Regulatory Factor 7 by Enterovirus 71 3C Suppresses Cellular Responses

    PubMed Central

    Lei, Xiaobo; Xiao, Xia; Xue, Qinghua; Jin, Qi

    2013-01-01

    Enterovirus 71 (EV71) is a positive-stranded RNA virus which is capable of inhibiting innate immunity. Among virus-encoded proteins, the 3C protein compromises the type I interferon (IFN-I) response mediated by retinoid acid-inducible gene-I (RIG-I) or Toll-like receptor 3 that activates interferon regulatory 3 (IRF3) and IRF7. In the present study, we report that enterovirus 71 downregulates IRF7 through the 3C protein, which inhibits the function of IRF7. When expressed in mammalian cells, the 3C protein mediates cleavage of IRF7 rather than that of IRF3. This process is insensitive to inhibitors of caspase, proteasome, lysosome, and autophagy. H40D substitution in the 3C active site abolishes its activity, whereas R84Q or V154S substitution in the RNA binding motif has no effect. Furthermore, 3C-mediated cleavage occurs at the Q189-S190 junction within the constitutive activation domain of IRF7, resulting in two cleaved IRF7 fragments that are incapable of activating IFN expression. Ectopic expression of wild-type IRF7 limits EV71 replication. On the other hand, expression of the amino-terminal domain of IRF7 enhances EV71 infection, which correlates with its ability to interact with and inhibit IRF3. These results suggest that control of IRF7 by the 3C protein may represent a viral mechanism to escape cellular responses. PMID:23175366

  2. Cellular responses to disruption of the permeability barrier in a three-dimensional organotypic epidermal model.

    PubMed

    Ajani, Gati; Sato, Nobuyuki; Mack, Judith A; Maytin, Edward V

    2007-08-15

    Repeated injury to the stratum corneum of mammalian skin (caused by friction, soaps, or organic solvents) elicits hyperkeratosis and epidermal thickening. Functionally, these changes serve to restore the cutaneous barrier and protect the organism. To better understand the molecular and cellular basis of this response, we have engineered an in vitro model of acetone-induced injury using organotypic epidermal cultures. Rat epidermal keratinocytes (REKs), grown on a collagen raft in the absence of any feeder fibroblasts, developed all the hallmarks of a true epidermis including a well-formed cornified layer. To induce barrier injury, REK cultures were treated with intermittent 30-s exposures to acetone then were fixed and paraffin-sectioned. After two exposures, increased proliferation (Ki67 and BrdU staining) was observed in basal and suprabasal layers. After three exposures, proliferation became confined to localized buds in the basal layer and increased terminal differentiation was observed (compact hyperkeratosis of the stratum corneum, elevated levels of K10 and filaggrin, and heightened transglutaminase activity). Thus, barrier disruption causes epidermal hyperplasia and/or enhances differentiation, depending upon the extent and duration of injury. Given that no fibroblasts are present in the model, the ability to mount a hyperplastic response to barrier injury is an inherent property of keratinocytes.

  3. Rab3 is involved in cellular immune responses of the cotton bollworm, Helicoverpa armigera.

    PubMed

    Li, Jie; Song, Cai-Xia; Li, Yu-Ping; Li, Li; Wei, Xiu-Hong; Wang, Jia-Lin; Liu, Xu-Sheng

    2015-06-01

    Rab3, a member of the Rab GTPase family, has been found to be involved in innate immunity. However, the precise function of this GTPase in innate immunity remains unknown. In this study, we identified a Rab3 gene (Ha-Rab3) from the cotton bollworm, Helicoverpa armigera and studied its roles in innate immune responses. Expression of Ha-Rab3 was upregulated in the hemocytes of H. armigera larvae after the injection of Escherichia coli or chromatography beads. The dsRNA-mediated knockdown of Ha-Rab3 gene in H. armigera larval hemocytes led to significant reduction in the phagocytosis and nodulation activities of hemocytes against E. coli, significant increase in the bacterial load in larval hemolymph, and significant reduction in the encapsulation activities of hemocytes toward invading chromatography beads. Furthermore, Ha-Rab3 knockdown significantly suppressed spreading of plasmatocytes. These results suggest that Ha-Rab3 plays important roles in H. armigera cellular immune responses, possibly by mediating spreading of hemocytes.

  4. Metal oxide nanoparticles interact with immune cells and activate different cellular responses

    PubMed Central

    Simón-Vázquez, Rosana; Lozano-Fernández, Tamara; Dávila-Grana, Angela; González-Fernández, Africa

    2016-01-01

    Besides cell death, nanoparticles (Nps) can induce other cellular responses such as inflammation. The potential immune response mediated by the exposure of human lymphoid cells to metal oxide Nps (moNps) was characterized using four different moNps (CeO2, TiO2, Al2O3, and ZnO) to study the three most relevant mitogen-activated protein kinase subfamilies and the nuclear factor kappa-light-chain-enhancer of the activated B-cell inhibitor, IκBα, as well as the expression of several genes by immune cells incubated with these Nps. The moNps activated different signaling pathways and altered the gene expression in human lymphocyte cells. The ZnO Nps were the most active and the release of Zn2+ ions was the main mechanism of toxicity. CeO2 Nps induced the smallest changes in gene expression and in the IκBα protein. The effects of the particles were strongly dependent on the type and concentration of the Nps and on the cell activation status prior to Np exposure. PMID:27695324

  5. Lysosomal recruitment of TSC2 is a universal response to cellular stress

    PubMed Central

    Demetriades, Constantinos; Plescher, Monika; Teleman, Aurelio A.

    2016-01-01

    mTORC1 promotes cell growth and is therefore inactivated upon unfavourable growth conditions. Signalling pathways downstream of most cellular stresses converge on TSC1/2, which serves as an integration point that inhibits mTORC1. The TSC1/2 complex was shown to translocate to lysosomes to inactivate mTORC1 in response to two stresses: amino-acid starvation and growth factor removal. Whether other stresses also regulate TSC2 localization is not known. How TSC2 localization responds to combinations of stresses and other stimuli is also unknown. We show that both amino acids and growth factors are required simultaneously to maintain TSC2 cytoplasmic; when one of the two is missing, TSC2 relocalizes to lysosomes. Furthermore, multiple different stresses that inhibit mTORC1 also drive TSC2 lysosomal accumulation. Our findings indicate that lysosomal recruitment of TSC2 is a universal response to stimuli that inactivate mTORC1, and that the presence of any single stress is sufficient to cause TSC2 lysosomal localization. PMID:26868506

  6. Cellular and Humoral Antibody Responses of Normal Pastel and Sapphire Mink to Goat Erythrocytes

    PubMed Central

    Lodmell, D. L.; Bergman, R. K.; Hadlow, W. J.; Munoz, J. J.

    1971-01-01

    This study was undertaken to determine whether normal sapphire and royal pastel mink differ immunologically at the cellular and humoral levels. Two days after primary intraperitoneal (ip) inoculation of goat erythrocytes (GE), essentially no 19 or 7S plaque-forming cells (PFC) per 106 cells were detected in spleen or in abdominal and peripheral lymph nodes of either color phase. On the 4th day, more 19S PFC were detected in pastel than in sapphire tissues; pastel tissues also contained 7S PFC, whereas essentially none was present in sapphires until the 6th day. After an ip booster inoculation, the number of PFC was markedly different between the two color phases. Th