Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells.

Fas (CD95/Apo-1) ligand is a potent inducer of apoptosis and one of the major killing effector mechanisms of cytotoxic T cells. Thus, Fas ligand activity has to be tightly regulated, involving various transcriptional and post-transcriptional processes. For example, preformed Fas ligand is stored in secretory lysosomes of activated T cells, and rapidly released by degranulation upon reactivation. In this study, we analyzed the minimal requirements for activation-induced degranulation of Fas ligand. T cell receptor activation can be mimicked by calcium ionophore and phorbol ester. Unexpectedly, we found that stimulation with phorbol ester alone is sufficient to trigger Fas ligand release, whereas calcium ionophore is neither sufficient nor necessary. The relevance of this process was confirmed in primary CD4(+) and CD8(+) T cells and NK cells. Although the activation of protein kinase(s) was absolutely required for Fas ligand degranulation, protein kinase C or A were not involved. Previous reports have shown that preformed Fas ligand co-localizes with other markers of cytolytic granules. We found, however, that the activation-induced degranulation of Fas ligand has distinct requirements and involves different mechanisms than those of the granule markers CD63 and CD107a/Lamp-1. We conclude that activation-induced degranulation of Fas ligand in cytotoxic lymphocytes is differently regulated than other classical cytotoxic granule proteins.

The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1(G93A) mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP(3))-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP(3) can prompt IP(3) receptor (IP(3)R)-mediated Ca(2+) release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca(2+) signaling that occurs downstream of mGluR5 in hSOD1(G93A)-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in the absence of spontaneous oscillations. The interaction of IP(3)Rs with the anti-apoptotic protein Bcl-X(L) was previously described to prevent cell death by modulating intracellular Ca(2+) signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X(L), fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca(2+) oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1(G93A) mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS.

Phototropism: Translating light into directional growth.

Phototropism allows plants to align their photosynthetic tissues with incoming light. The direction of incident light is sensed by the phototropin family of blue light photoreceptors (phot1 and phot2 in Arabidopsis), which are light-activated protein kinases. The kinase activity of phototropins and phosphorylation of residues in the activation loop of their kinase domains are essential for the phototropic response. These initial steps trigger the formation of the auxin gradient across the hypocotyl that leads to asymmetric growth. The molecular events between photoreceptor activation and the growth response are only starting to be elucidated. In this review, we discuss the major steps leading from light perception to directional growth concentrating on Arabidopsis. In addition, we highlight links that connect these different steps enabling the phototropic response.

Evidence for an overestimated vulnerability of adolescent rats to develop signs of drug addiction

Drug addiction is a multi-etiological disorder to which some individuals are more vulnerable an others. Whereas converging clinical and epidemiological studies report a peak of drug use ring adolescence, many behavioral traits characterizing teenagers have been proposed to contribute to this vulnerability, including a heightened sensation-seeking, an enhanced impulsivity d a larger influence exerted by peers. By many aspects, juvenile rodents display behavioral traits at resemble those of teenagers. However, the concept of increased vulnerability to drug addiction juvenile rats remains in debate. Indeed, only a few studies directly compared juvenile and adult fdents regarding behavioral predictors of drug abuse. Moreover, some key features of drug diction have never been investigated in juvenile rats yet. For this very reason, we conducted a arge-scale behavioral comparison of adult and adolescent rats with the aim of dissecting their espective behavioral traits and vulnerabilities to drug addiction. We first have shown that juvenile rats exhibited an enhanced motor impulsivity, and a loss of control over reward seeking assessed by a persistent reward taking despite adverse consequences mild electric footshocks]. We also report that juvenile rats displayed a higher anxiety profile, ind we discuss why these behaviors might represent key underpinning mechanisms leading to an enhanced vulnerability to drug abuse. Meanwhile, we collected clear cut observations that do not support such an interpretation. In Articular, juvenile and adult rats displayed identical novelty-induced habituation and preference at are considered to represent two potent predictors of cocaine initiation and compulsive intake, "pre strikingly, juvenile rats were less attracted by cues predicting reward in a Pavlovian utoshaping task, suggesting a lower propensity for cues or context to trigger the reinstatement of a^previously extinguished reward seeking behavior. Finally, using a paradigm assessing schedule- ciuced polydipsia, juvenile and adult rats exhibited similar compulsive drinking, under control conditions and following a chronic cocaine treatment as well. Hence, these observations call for a cautious interpretation of adolescent vulnerability to drug use. In particular, we underlined that even the most compulsive young rats did not consume ärger amounts of cocaine than adults, nor exhibited larger efforts in a cue-induced relapse aradigm, despite a transient increased motivation for lever-pressing. And further, despite a higher ensitivity to the behavioral effects of cocaine, juvenile rats did not differ from adults in their ropensity to constantly prefer saccharin over cocaine in a discrete-choice procedure, even after a ?'Id chronic stress procedure. Altogether, our results shape an objective overview of the juvenile rats' behavior in relation to oth drug and non-drug rewards, suggesting a heterogeneous and task-specific profile. Despite elements potentially underlying a real risk for substance use, adolescent rats do not exhibit a ehavioral repertoire suggesting increased vulnerability for compulsive drug abuse. Our conclusions strongly encourage deeper neurobiological investigations of the developing brain, and also open a debate on a possible overestimation of juvenile rats' and teenager's risk to develop aladaptive behaviors and drug addiction. - L'addiction aux drogues est une pathologie d'origine multifactorielle, à laquelle certains individus sont plus vulnérables que d'autres. De nombreuses études cliniques et épidémiologiques suggèrent une consommation excessive de drogues pendant l'adolescence, et plusieurs explications ont été avancées pour justifier cette tendance, parmi lesquelles on note une augmentation de la recherche de sensation, une impulsivité plus marquée et une plus forte influence de l'entourage. Le rat juvénile présente de nombreuses caractéristiques développementales similaires à l'adolescence humaine. En revanche, la vulnérabilité des rats juvéniles à l'abus de drogue est encore sujette à caution. En effet, peu d'études ont directement comparé des traits de comportements pouvant refléter un accroissement du risque d'abus chez les rats juvéniles par comparaison aux rats adultes. En outre, certaines caractéristiques fondamentales de l'addiction chez l'homme n'ont pas encore été étudiées chez le rat adolescent. Ce travail de thèse s'est donc donné pour objectif de comparer le comportement de rats adultes vis-à-vis de celui de rats adolescents, afin d'évaluer dans quelle mesure ces derniers seraient plus vulnérables à l'abus de drogues. Nos résultats indiquent que les rats juvéniles présentent une augmentation des comportements impulsifs, ainsi qu'une plus grande persistance à rechercher de manière compulsive une récompense en dépit de légers chocs électriques. Les rats juvéniles présentent également un profil anxieux plus élevé, ce qui peut constituer une autre source de vulnérabilité. Cependant, certaines caractéristiques comportementales ne suggèrent pas de vulnérabilité chez les rats juvéniles. Aucune différence entre rats adultes et adolescents n'a été trouvée pour l'habituation et la préférence pour la nouveauté, deux traits prédisant l'initiation et la prise compulsive de drogue. De plus, nous avons montré que les rats adolescents attribuent moins d'intérêt à des stimuli prédisant la disponibilité d'une récompense, suggérant une vulnérabilité plus faible à la rechute induite par les stimuli associés à la prise de drogue. Une étude complémentaire des comportements compulsifs indique une absence de différence entre rats adultes et adolescents, à la fois en condition basale ou après un traitement chronique à la cocaïne. L'étude des comportements de prise de drogue ne va pas non plus dans le sens d'une vulnérabilité des rats adolescents. Bien que les rats compulsifs sélectionnés pendant la période juvénile présentent une plus grande motivation à prendre de la cocaïne, ils ne diffèrent ni dans la quantité de cocaïne consommée, ni dans la rechute induite par les stimuli environnementaux. En dépit d'une sensibilisation comportementale plus importante, les rats adolescents présentent la même préférence que les adultes face à un choix entre une drogue et une récompense alternative, suggérant une résilience à la cocaïne comparable à celle des adultes. Enfin, cette résilience pour la cocaïne n'est pas affectée par un stress chronique lors de l'adolescence. En résumé, cette étude dresse un regard objectif sur les comportements en lien avec une vulnérabilité à l'abus de drogues chez le rat juvénile, suggérant que celle-ci est hétérogène et spécifique au protocole utilisé. En dépit de certains éléments de vulnérabilité, les rats adolescents ne présentent pas d'attirance excessive pour la cocaïne, ni de prédisposition à la consommation compulsive de cette drogue. L'ensemble de ces éléments pourra constituer une base solide pour l'investigation neurobiologique du cerveau en développement, et ouvre un débat sur une possible surestimation de la vulnérabilité des rats juvéniles et de leurs homologues humains aux pathologies psychiatriques telles que l'addiction aux drogues.

Lipoxygenase 2 and the early steps of jasmonic acid biosynthesis in "Arabidopsis thaliana"

Résumé Les oxylipines, telles que l'acide jasmonique (AJ ou jasmonate), jouent un rôle central en réponse à la blessure et à la pathogenèse. De nombreuses études ont montré l'importance de la voie canonique du jasmonate lors de la défense des plantes. De plus, un précurseur cyclopentenone de l'AJ, l'acide oxo-phyto-dienoic (OPDA), a été impliqué comme jouant le rôle d'une molécule signal lors de la défense contre certains pathogènes. En utilisant des mutants bloqués dans la biosynthèse de l'acide jasmonique (aos) ou dans sa perception (coi1-1), nous avons cherché à définir dans quelle mesure l'OPDA joue un rôle de signal induisant l'expression génétique en réponse à la blessure chez Arabidopsis. A l'aide de puces à ADN (microarray), nous avons montré que les transcriptomes d'aos et de coi1-1 sont très semblables après blessure, ce qui suggère que les produits d'AOS sont tous perçus via COI1. Pourtant, lorsqu'on analyse les métabolites présents chez ces mutants, une différence est visible, puisque aos n'accumule pas d'AJ, alors que coi1-1 en accumule encore rapidement après blessure. Nous avons étudié la possibilité qu'un mécanisme de régulation post-traductionnelle sur la voie de biosynthèse du jasmonate explique l'accumulation d'AJ chez coi1-1 après blessure. La lipoxygenase 2 (LOX2) est la première enzyme impliquée dans la biosynthèse de l'AJ et est donc une cible potentielle d'un tel mécanisme. Un indice sur la manière dont l'activité LOX pourrait être régulée vient du mutant fou2 (pour fatty acid oxygenation upregcilated 2) dans lequel l'activité LOX ainsi que le niveau d'AJ sont constitutivement élevés. Cette mutation implique un flux de cation dans la régulation de la production de l'AJ. De plus, il a été montré que plusieurs LOXs, dans des organismes autres que des plantes, peuvent lier le calcium. Nous montrons que l'activité LOX requiert l'addition de cations divalents pour être maximale in vitro, et que non seulement le calcium mais aussi le magnésium joue ce rôle. De plus, nous caractérisons un mutant récessif de LOX2 chez Arabidopsis (lox2-1). Ces plantes sont fertiles, et une analyse quantitative montre qu'elles accumulent toujours un peu d'AJ après blessure. Ceci suggère que LOX2 n'est pas la seule LOX impliquée dans la synthèse d'AJ. Aussi les plantes lox2-1 ne sont pas plus sensibles que les plantes de type sauvage lorsqu'elles sont infectées par la moisissure Botrytis cinerea ou lorsqu'elles sont exposées à un détritivore, néanmoins elles sont plus sensibles lorsqu'elles sont offertes en nourriture à un insecte herbivore. Les insectes et les plantes ont co-évolué conjointement, ainsi une plante ne contenant qu'un niveau réduit d'AJ favorise l'insecte. La disponibilité d'un mutant avec un niveau intermédiaire d'AJ va permettre de mieux comprendre pourquoi les plantes produisent autant de jasmonate. Abstract Oxylipins such as jasmonic acid (JA) play central roles in the wound response and during pathogenesis and many studies have confirmed the important role of the canonical jasmonate pathway in plant defense. Moreover, the cyclopentenone precursor of JA, oxo-phytodienoic acid (OPDA), is also thought to function as a signaling molecule in defense towards some pathogens. Its action was reported to depend on a different signal pathway to JA. By using mutants blocked in the biosynthesis (aos) or perception (coil-1) of JA, we investigated to which extend OPDA works as signaling molecule to trigger gene expression in the wound response of Arabidopsis. Using microarrays, we showed that aos and coil-1 transcriptome are similar in response to wounding, suggesting that products of AOS are all perceived by COI1. However, we found a difference between the two mutants at the metobolomic level, since aos is devoid of JA, but coil-1 can still rapidly accumulate JA upon wounding. We investigated the possibility that the post-translational activation of JA biosynthesis could explain the fast accumulation of JA in coil-1 plants upon wounding. Lipoxygenase (LOX) 2 is the first enzyme implicated in JA synthesis and was thus chosen as a potential target for posttranslational regulation. A clue as to how LOX activity might be regulated came from the fatty acid oxygenation upregulated 2 (foul) mutant in which LOX activity and JA levels are elevated. The foul mutant implicates cations flux in the regulation of JA production, and several LOXs in organisms other than plants have been shown to bind calcium. We showed that Arabidopsis LOX requires divalent cations for full activity in vitro, and that not only calcium but also magnesium can play this role. Moreover, a single recessive mutant of AtLOX2 was characterized. These plants are fully fertile. Quantitative oxylipin analysis showed that lox2-1 can still accumulate some JA after wounding, which suggests that LOX2 is not the only LOX involved in JA biosynthesis. lox2-1 plants do not show altered susceptibility to the fungus Botrytis cinerea or to a detritivore, however, they are more susceptible to an insect herbivore. The insect and plants are closely co-evolved and a reduced ability to synthesize JA favors the insect. The availability of a lox2-1 mutant with intermediate JA levels will further help understanding why plants produce elevated JA levels.

Small RNA-dependent expression of secondary metabolism is controlled by Krebs cycle function in Pseudomonas fluorescens.

Pseudomonas fluorescens CHA0, an antagonist of phytopathogenic fungi in the rhizosphere of crop plants, elaborates and excretes several secondary metabolites with antibiotic properties. Their synthesis depends on three small RNAs (RsmX, RsmY, and RsmZ), whose expression is positively controlled by the GacS-GacA two-component system at high cell population densities. To find regulatory links between primary and secondary metabolism in P. fluorescens and in the related species Pseudomonas aeruginosa, we searched for null mutations that affected central carbon metabolism as well as the expression of rsmY-gfp and rsmZ-gfp reporter constructs but without slowing down the growth rate in rich media. Mutation in the pycAB genes (for pyruvate carboxylase) led to down-regulation of rsmXYZ and secondary metabolism, whereas mutation in fumA (for a fumarase isoenzyme) resulted in up-regulation of the three small RNAs and secondary metabolism in the absence of detectable nutrient limitation. These effects required the GacS sensor kinase but not the accessory sensors RetS and LadS. An analysis of intracellular metabolites in P. fluorescens revealed a strong positive correlation between small RNA expression and the pools of 2-oxoglutarate, succinate, and fumarate. We conclude that Krebs cycle intermediates (already known to control GacA-dependent virulence factors in P. aeruginosa) exert a critical trigger function in secondary metabolism via the expression of GacA-dependent small RNAs.

Molecular chaperones as enzymes that catalytically unfold misfolded polypeptides.

Stress-denatured or de novo synthesized and translocated unfolded polypeptides can spontaneously reach their native state without assistance of other proteins. Yet, the pathway to native folding is complex, stress-sensitive and prone to errors. Toxic misfolded and aggregated conformers may accumulate in cells and lead to degenerative diseases. Members of the canonical conserved families of molecular chaperones, Hsp100s, Hsp70/110/40s, Hsp60/CCTs, the small Hsps and probably also Hsp90s, can recognize and bind with high affinity, abnormally exposed hydrophobic surfaces on misfolded and aggregated polypeptides. Binding to Hsp100, Hsp70, Hsp110, Hsp40, Hsp60, CCTs and Trigger factor may cause partial unfolding of the misfolded polypeptide substrates, and ATP hydrolysis can induce further unfolding and release from the chaperone, leading to spontaneous refolding into native proteins with low-affinity for the chaperones. Hence, specific chaperones act as catalytic polypeptide unfolding isomerases, rerouting cytotoxic misfolded and aggregated polypeptides back onto their physiological native refolding pathway, thus averting the onset of protein conformational diseases.

Different antigen-presenting cells differ in their capacity to induce lymphokine production and proliferation of an apo-cytochrome c-specific T cell clone.

The activation of an apo-cytochrome c-specific T cell clone was found to differ, depending on the antigen-presenting cell population. Whereas total syngeneic spleen cells and bone marrow macrophages could be shown to trigger proliferation, IL 2, and MAF production by the T cell clone, a B cell lymphoma only induced MAF secretion. Further studies demonstrated that this effect was not due to a different antigen processing by the B lymphoma or to limiting amounts of Ia and antigen molecules on the B lymphoma cell surface. The dissociation of induction of MAF production from IL-2 production/proliferation found with the different antigen-presenting cells indicates strongly that molecules other than Ia and antigen may be required for the complete functional activation of antigen-specific T cell clones.

Immune and stress responses covary with melanin-based coloration in the barn swallow

Eumelanin and pheomelanin are the main endogenous pigments in animals and melanin-based coloration has multiple functions. Melanization is associated with major life-history traits, including immune and stress response, possibly because of pleiotropic effects of genes that control melanogenesis. The net effects on pheo- versus eumelanization and other life-history traits may depend on the antagonistic effects of the genes that trigger the biosynthesis of either melanin form. Covariation between melanin-based pigmentation and fitness traits enforced by pleiotropic genes has major evolutionary implications particularly for socio-sexual communication. However, evidence from non-model organisms in the wild is limited to very few species. Here, we tested the hypothesis that melanin-based coloration of barn swallow (Hirundo rustica) throat and belly feathers covaries with acquired immunity and activation of the hypothalamic-pituitary-adrenal (HPA) axis, as gauged by corticosterone plasma levels. Individuals of both sexes with darker brownish belly feathers had weaker humoral immune response, while darker males had higher circulating corticosterone levels only when parental workload was experimentally reduced. Because color of belly feathers depends on both eu- and pheomelanin, and its darkness decreases with an increase in the concentration of eu- relative to pheomelanin, these results are consistent with our expectation that relatively more eu- than pheomelanized individuals have better immune response and smaller activation of the HPA-axis. Covariation of immune and stress response arose for belly but not throat feather color, suggesting that any function of color as a signal of individual quality or of alternative life-history strategies depends on plumage region.

Two Cases of Interferon-Alpha-Induced Sarcoidosis Koebnerized along Venous Drainage Lines: New Pathogenic Insights and Review of the Literature of Interferon-Induced Sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder of unknown origin commonly affecting the lung, the lymphoid system and the skin. We report here two cases of cutaneous sarcoidosis in two former intravenous drug users following interferon (IFN)-α and ribavirin therapy for chronic hepatitis C. Both patients developed skin sarcoidosis along venous drainage lines of both forearms, coinciding with the areas of prior drug injections. The unique distribution of the skin lesions suggests that tissue damage induced by repeated percutaneous drug injections represents a trigger for the local skin manifestation of sarcoidosis. Interestingly, skin damage was recently found to induce the local expression IFN-α, a well-known trigger of sarcoidosis in predisposed individuals. Here we review the literature on sarcoidosis elicited in the context of IFN-α therapy and propose a new link between the endogenous expression of IFN-α and the induction of disease manifestations in injured skin. © 2013 S. Karger AG, Basel.

Metabolic adaptation to cancer growth: from the cell to the organism.

Tumour cells proliferate much faster than normal cells; nearly all anticancer treatments are toxic to both cell types, limiting their efficacy. The altered metabolism resulting from cellular transformation and cancer progression supports cellular proliferation and survival, but leaves cancer cells dependent on a continuous supply of energy and nutrients. Hence, many metabolic enzymes have become targets for new cancer therapies. In addition to its well-described roles in cell-cycle progression and cancer, the cyclin/CDK-pRB-E2F1 pathway contributes to lipid synthesis, glucose production, insulin secretion, and glycolytic metabolism, with strong effects on overall metabolism. Notably, these cell-cycle regulators trigger the adaptive "metabolic switch" that underlies proliferation.

Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression.

Wound healing proceeds by the concerted action of a variety of signals that have been well identified. However, the mechanisms integrating them and coordinating their effects are poorly known. Herein, we reveal how PPARbeta/delta (PPAR: peroxisome proliferator-activated receptor) follows a balanced pattern of expression controlled by a crosstalk between inflammatory cytokines and TGF-beta1. Whereas conditions that mimic the initial inflammatory events stimulate PPARbeta/delta expression, TGF-beta1/Smad3 suppresses this inflammation-induced PPARbeta/delta transcription, as seen in the late re-epithelialization/remodeling events. This TGF-beta1/Smad3 action involves an inhibitory effect on AP-1 activity and DNA binding that results in an inhibition of the AP-1-driven induction of the PPARbeta/delta promoter. As expected from these observations, wound biopsies from Smad3-null mice showed sustained PPARbeta expression as compared to those of their wild-type littermates. Together, these findings suggest a mechanism for setting the necessary balance between inflammatory signals, which trigger PPARbeta/delta expression, and TGF-beta1/Smad3 that governs the timely decrease of this expression as wound healing proceeds to completion.

The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity.

Lat(Y136F) knock-in mice harbor a point mutation in Tyr(136) of the linker for activation of T cells and show accumulation of Th2 effector cells and IgG1 and IgE hypergammaglobulinemia. B cell activation is not a direct effect of the mutation on B cells since in the absence of T cells, mutant B cells do not show an activated phenotype. After adoptive transfer of linker for activation of T cell mutant T cells into wild-type, T cell-deficient recipients, recipient B cells become activated. We show in vivo and in vitro that the Lat(Y136F) mutation promotes T cell-dependent B cell activation leading to germinal center, memory, and plasma cell formation even in an MHC class II-independent manner. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses are found. Characterization of the abundant plasmablasts found in secondary lymphoid organs of Lat(Y136F) mice revealed the presence of a previously uncharacterized CD93-expressing subpopulation, whose presence was confirmed in wild-type mice after immunization. In Lat(Y136F) mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally. Although the noncomplement-fixing IgG1 and IgE are the only isotypes significantly increased in Lat(Y136F) serum, we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that Th2 cells developing in Lat(Y136F) mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease.

Targeting endoplasmic reticulum signaling pathways in cancer.

The endoplasmic reticulum (ER) orchestrates the production of membrane-bound and secreted proteins. However, its capacity to process the synthesis and folding of protein is limited. Protein overload and the accumulation of misfolded proteins in the ER trigger an adaptive response known as the ER-stress response that is mediated by specific ER-anchored signaling pathways. This response regulates cell functions aimed at restoring cellular homeostasis or at promoting apoptosis of irreparably damaged cells. Activation or deregulation of ER-signaling pathways has been associated with various diseases including cancer. Here we discuss how tumors engage ER-signaling pathways to promote tumorigenesis and how manipulation of this process by anticancer drugs may contribute to cancer treatment.

Music Performance Anxiety (MPA) : cardiorespiratory activity in high- and low-anxious professional music students before a performance situation

Descriptors: music performance anxiety, respiration, hyperventilation Surveys indicate that high-anxious musicians may suffer from hyperventilation (HV) before or during performance. Reported symptoms include shortness of breath, fast/ deep breathing and thumping heart. However, no study has yet tested if these selfreported symptoms reflect actual cardiorespiratory activity. Themain goal of this study was to determine if MPA is manifested physiologically in specific correlates of cardiorespiratory activity associated with HV.We studied 74 professional music students from Swiss Music Academies. In this study, we compared the most anxious students (highanxious; n 5 20) with the least anxious students (low-anxious; n 5 23) based on their self-reported performance anxiety. We measured cardiorespiratory patterns with the Lifeshirt system, end-tidal CO2 with a capnograph (EtCO2, a good non-invasive estimator of HV), self-perceived physiological activation and affective experience in three situations on different days: baseline, performance without audience, and performance with audience. Comparing measures for the private vs. the public concert, high- compared to low-anxious students showed a significant drop in EtCO2 before the public concert and reported larger increases in anxiety, tension, palpitations and breathing difficulties. In contrast, heart rate, respiratory rate and volume did not differ significantly between groups. The results of this study support the hypothesis thatMPA may be associated with a tendency to hyperventilate and, thus, point to a potential hyperventilation problem in high-anxious music students.