HLA Class I alleles associated with HCV polymorphisms and response to antiviral therapy in HCV genotype 1-infected patients

Aims: The adaptive immune response against hepatitis C virus (HCV) is significantly shaped by the host's composition of HLA alleles. Thus, the HLA phenotype is a critical determinant of viral evolution during adaptive immune pressure. Potential associations of HLA class I alleles with polymorphisms of HCV immune escape variants are largely unknown. Methods: Direct sequence analysis of the genes encoding the HCV proteins E2, NS3 and NS5B in a cohort of 159 patients with chronic HCV genotype 1 infection who were treated with pegylated interferon-alfa 2b and ribavirin in a prospective controlled trial for 48 weeks was exhibited. HLA class I genotyping was performed by strand-specific reverse hybridization with the INNO-LiPA line probe assays for HLA-A and HLA-B and by strand-specific PCR-SSP. We analyzed each amino acid position of HCV proteins using an extension of Fisher's exact test for associations with HLA alleles. In addition, associations of specific HLA alleles with inflammatory activity, liver fibrosis, HCV RNA viral load and virologic treatment outcome were investigated. Results: Separate analyses of HCV subtype 1a and 1b isolates revealed substantially different patterns of HLA-restricted polymorphisms between subtypes. Only one polymorphism within NS5B (V2758x) was significantly associated with HLA B*15 in HCV genotype 1b infected patients (adjusted p=0,048). However, a number of HLA class I-restricted polymorphisms within novel putative HCV CD8+ T cell epitopes (genotype 1a: HLA-A*11 GTRTIASPK1086-1094 [NS3], HLA-B*07 WPAPQGARSL1111-1120 [NS3]; genotype 1b: HLA-A*24 HYAPRPCGI488-496 [E2], HLA-B*44 GENETDVLL530-538 [E2], HLA-B*15 RVFTEAMTRY2757-2766 [NS5B]) were observed with high predicted epitope binding scores assessed by the web-based software SYFPEITHI (>21). Most of the identified putative epitopes were overlapping with already otherwise published epitopes, indicating a high immunogenicity of the accordant HCV protein region. In addition, certain HLA class I alleles were associated with inflammatory activity, stage of liver fibrosis, and sustained virologic response to antiviral therapy. Conclusions: HLA class I restricted HCV sequence polymorphisms are rare. HCV polymorphisms identified within putative HCV CD8+ T cell epitopes in the present study differ in their genomic distribution between genotype 1a and 1b isolates, implying divergent adaptation to the host's immune pressure on the HCV subtype level.

Gene expression profiling of human glioblastomas for the identification of predictive factors and characterisation of molecular mechanism implicated in response to therapy and outcome

ABSTRACT Poor outcome for glioblastoma patients is largely due to resistance to chemoradiation therapy. While epigenetic inactivation of MGMT mediated DNA repair is highly predictive for benefit from the alkylating agent therapy Temozolomide, additional mechanisms for resistance associated with molecular alterations exist. Furthermore, new concepts in cancer suggest that resistance to treatment may be linked to cancer stem cells that escape therapy and act as source for tumour recurrence. We determined gene expression signatures associated with outcome in glioblastoma patients enrolled in a phase II and phase III clinical trial establishing the new combination therapy of radiation plus concomitant and adjuvant Temozolomide. Correlating stable gene clusters emerging from unsupervised analysis with survival of 42 treated patients identified a number of biological processes associated with outcome. Most prominent, a gene cluster dominated by HOX genes and comprising PROM1, was associated with resistance. PROM1 encodes CD133, a marker for a subpopulation of tumour cells enriched for glioblastoma stem- like cells. The core of this correlated HOX cluster was comprised in the top genes of a "self-renewal signature" defined in a mouse model for MLL-AF9 initiated leukaemia. The association of the HOX gene cluster with tumour resistance was confirmed in two external data sets of 146 malignant glioma As additional resistance factors we identified over-expression of the epidermal growth factor receptor gene, EGFR, while increased gene expression related to biological features of tumour host interaction, including markers for tumour vascular and cell adhesion, and innate immune response, were associated with better outcome. The "self-renewal" signature associated with resistance to the new combination chemoradiation therapy provides first clinical evidence that glioma stem like cells may implicated in resistance in a uniformly treated cohort of glioblastoma patients. This study underlines the need to target the tumour stem cell compartment, and provides some testable hypothesis for biological mechanisms relevant for malignant behaviour of glioblastoma that may be targeted in new treatment approaches. Résumé Le glioblastome, tumeur cérébrale primaire maligne la plus fréquente, est connue pour son mauvais pronostique. Des avancées chimiothérapeutiques récentes avec des agents alkylants comme le témozolomide (TMZ), ont permis une amélioration notable dans la survie de certains patients. Les bénéficiaires ont la caractéristique commune de présenter une particularité génétique, la methylation du MGMT (methylguanine methyltransferase). Néanmoins, d'autres mécanismes de résistance en fonction des aberrations moléculaires existent. Nous avons établi les profils d'expressions génétiques des patients traités par irradiation et TMZ dans des études cliniques de phase II et III. En combinant des méthodes non-supervisées et supervisées, de l'étude de la cohorte des patients traités nous avons découvert des groupes de gènes associés à la survie. Un ensemble de gènes contenant les gènes Hox semble lié au mécanisme de résistance au traitement. Récemment, les gènes Hox ont été décrits comme faisant partie d"une signature d'autorenouvellement (self-renewal) des cellules souches cancéreuses de la leucémie. L'autorenouvellement est un processus grâce auquel les cellules souches se maintiennent tout au long de la vie. Cette association à la résistance est confirmée dans deux autres études indépendantes. Un autre facteur de résistance au traitement est la surexpression du gène EGFR. D'autre part, deux groupes de gènes associés à la relation entre hôte-tumeur tels que les marqueurs des vaisseaux tumoraux et de la réponse immunitaire innée s'avèrent avoir un effet positif sur la survie des patients traités. La découverte de la signature d'autorenouvellement comme facteur de résistance à la nouvelle chimio-radiothérapie offre une preuve clinique que les cellules souches cancéreuses sont impliquées dans la résistance au traitement. If est donc logique de penser que le traitement ciblé contre des cellules souches cancéreuses va dans l'avenir permettre des thérapies anticancéreuses plus performantes.

" Arabidopsis Thaliana " response to insect feeding : new components controlling defense gene expression and plant resistance

Abstract: Plants cannot run away to escape attacking herbivores, but they defend themselves by producing anti-digestive proteins and toxic compounds (for example glucosinolates). The first goal of this thesis was to study changes in gene expression after insect attack using microarrays. The responses of Arabidopsis thaliana to feeding by the specialist Pieris rapae and the generalist Spodoptera liffora is were compared. We found that the transcript profiles after feeding by the two chewing insects were remarkably similar, although the generalist induced a slightly stronger response. The second goal was to evaluate the implication of the four signals jasmonic acid (JA), salicylic acid (SA), ethylene (ET), and abscisic acid (ABA) in the control of insect-regulated gene expression. Using signaling mutants, we observed that JA was the predominant signal and that ABA modulated defense gene expression. In contrast, SA and ET appeared to control slightly gene expression, but only after feeding by S. litforalis. The third goal was to establish whether plant responses are really effective against insects. In accordance with the transcript profile, both insects were affected by the JA-dependent defenses, as they performed better on the JA-insensitive mutant. S. littoralis also performed better on ABA-deficient mutants, providing evidence for the role of ABA in defense against insects. When testing indole or aliphatic glucosinolate deficient mutants, we found that they were also more susceptible to insect feeding, providing some of the first genetic evidence for the defensive role of glucosinolates in planta. Finally, a glutathione-deficient mutant, pad2-1, was also more susceptible to insect feeding and we could attribute this phenotype to a lowered accumulation of the major indole glucosinolate. In this thesis, we provide a comprehensive list of insect-regulated genes, including many transcription factors that constitute interesting candidate genes for the further study of insect-induced expression changes. Understanding how the plant responses to insects are regulated will provide tools for a better management of insect pest in the field. Résumé: Les plantes ne peuvent s'échapper pour fuir les insectes qui les attaquent, mais elles se défendent en produisant des protéines anti-digestives et des composés toxiques (par exemple des glucosinolates). Le premier but de cette thèse était d'étudier les changements de l'expression génétique lors d'attaque par des insectes en utilisant des puces à ADN. Nous avons comparé la réponse d'Arabidopsis thaliana à deux espèces d'insectes avec des habitudes alimentaires différentes : le spécialiste Pieris rapae et le généraliste Spodoptera littoralis. Nous avons trouvé que les profils de transcription après l'attaque par les deux insectes sont remarquablement similaires, bien que le généraliste induise une réponse légèrement plus forte. Le deuxième but était de déterminer l'implication de quatre signaux dans le contrôle de la réponse :l'acide jasmonique (JA), l'acide salicylique (SA), l'éthylène (ET), et l'acide abscissique (ABA). En utilisant de mutants de signalisation, nous avons montré que l'acide jasmonique était le signal prédominant et que l'acide abscissique modulait l'expression génétique. D'autre part, l'acide salicylique et l'éthylène contrôlent à un degré moindre l'expression génétique, mais seulement après l'attaque par S. littoralís. Le troisième but était d'établir si les réponses des plantes sont efficaces contre les insectes. En accord avec le profil de transcription, les deux espèces d'insectes se sont mieux développées sur un mutant insensible au JA, indiquant que les défenses contrôlées par ce signal sont cruciales pour la plante. De plus, les larves de S. littorales se sont mieux développées sur des mutants déficients en ABA, ce qui fournit une preuve du rôle de l'acide abscissique dans la défense contre les insectes. En testant des mutants déficients en glucosinolates de type indole ou aliphatique, nous avons trouvé qu'ils étaient plus sensibles aux insectes, démontrant ainsi le rôle défensif des glucosinolates in planta. Finalement, le mutant déficient en glutathion pad2-1 était aussi plus sensible à l'attaque des insectes, et nous avons pu attribuer ce phénotype à une plus faible augmentation d'un indole glucosinolate dans ce mutant. Dans cette thèse, nous avons mis en évidence un nombre important de gènes contrôlés par les insectes, comprenant de nombreux facteurs de transcription qui constituent des candidats intéressants pour`étudier plus en détail les changements d'expression génétique induits par les insectes. Une meilleure compréhension de la réponse des plantes contre l'attaque des insectes devrait nous permettre de développer de nouvelles stratégies pour mieux gérer les ravageurs des cultures.

Immune response to HIV.

PURPOSE OF REVIEW: Major advances have been made in the delineation of HIV-specific immune response and in the mechanisms of virus escape. The kinetics of the immunological and virological events occurring during primary HIV infection indicate that the establishment of the latent HIV reservoir, the major obstacle to HIV eradication likely occurs during the very early stages of primary infection, that is, the 'eclipse phase', prior to the development of the HIV-specific immune response which has limited efficacy in the control of the early events of infection. Therefore, the window of opportunity to develop effective interventions either to clear HIV during primary infection or to prevent rebound of HIV in patients successfully treated who stop antiretroviral therapy is very narrow. RECENT FINDINGS: Genetic factors most strongly associated with nonprogressive infection are human leukocyte antigen (HLA) class I alleles and particularly HLA-B5701. CD4 and CD8 T-cell responses with polyfunctional profile are associated with nonprogressive infection. Broader neutralizing antibodies are detected 3-4 years after infection, generated only in 20% of individuals but show no efficacy in the control of HIV replication. SUMMARY: In the present review, we shall discuss the different components of the HIV-specific immune response elicited by the infection, the kinetics of these responses during primary infection and the changes following transition to the chronic phase of infection, and the functional profile of 'effective' versus 'noneffective' HIV-specific immune responses.

The Individualized Genetic Barrier Predicts Treatment Response in a Large Cohort of HIV-1 Infected Patients.

The success of combination antiretroviral therapy is limited by the evolutionary escape dynamics of HIV-1. We used Isotonic Conjunctive Bayesian Networks (I-CBNs), a class of probabilistic graphical models, to describe this process. We employed partial order constraints among viral resistance mutations, which give rise to a limited set of mutational pathways, and we modeled phenotypic drug resistance as monotonically increasing along any escape pathway. Using this model, the individualized genetic barrier (IGB) to each drug is derived as the probability of the virus not acquiring additional mutations that confer resistance. Drug-specific IGBs were combined to obtain the IGB to an entire regimen, which quantifies the virus' genetic potential for developing drug resistance under combination therapy. The IGB was tested as a predictor of therapeutic outcome using between 2,185 and 2,631 treatment change episodes of subtype B infected patients from the Swiss HIV Cohort Study Database, a large observational cohort. Using logistic regression, significant univariate predictors included most of the 18 drugs and single-drug IGBs, the IGB to the entire regimen, the expert rules-based genotypic susceptibility score (GSS), several individual mutations, and the peak viral load before treatment change. In the multivariate analysis, the only genotype-derived variables that remained significantly associated with virological success were GSS and, with 10-fold stronger association, IGB to regimen. When predicting suppression of viral load below 400 cps/ml, IGB outperformed GSS and also improved GSS-containing predictors significantly, but the difference was not significant for suppression below 50 cps/ml. Thus, the IGB to regimen is a novel data-derived predictor of treatment outcome that has potential to improve the interpretation of genotypic drug resistance tests.

Escape in a nonideal electro-mechanical system

In this work a particular system is investigated consisting of a pendulum whose point of support is vibrated along a horizontal guide by a two bar linkage driven from a DC motor, considered as a limited power source. This system is nonideal since the oscillatory motion of the pendulum influences the speed of the motor and vice-versa, reflecting in a more complicated dynamical process. This work comprises the investigation of the phenomena that appear when the frequency of the pendulum draws near a secondary resonance region, due to the existing nonlinear interactions in the system. Also in this domain due to the power limitation of the motor, the frequency of the pendulum can be captured at resonance modifying completely the final response of the system. This behavior is known as Sommerfeld effect and it will be studied here for a nonlinear system.

Differential response to gepirone but not to chlordiazepoxide in malnourished rats subjected to learned helplessness

The learned helplessness (LH) paradigm is characterized by learning deficits resulting from inescapable events. The aims of the present study were to determine if protein-calorie malnutrition (PCM) alters learning deficits induced by LH and if the neurochemical changes induced by malnutrition alter the reactivity to treatment with GABA-ergic and serotonergic drugs during LH. Well-nourished (W) and PCM Wistar rats (61 days old) were exposed or not to inescapable shocks (IS) and treated with gepirone (GEP, 0.0-7.5 mg/kg, intraperitoneally, N = 128) or chlordiazepoxide (0.0-7.5 mg/kg, intraperitoneally, N = 128) 72 h later, 30 min before the test session (30 trials of escape learning). The results showed that rats exposed to IS had higher escape latency than non-exposed rats (12.6 ± 2.2 vs 4.4 ± 0.8 s) and that malnutrition increased learning impairment produced by LH. GEP increased the escape latency of W animals exposed or non-exposed to IS, but did not affect the response of PCM animals, while chlordiazepoxide reduced the escape deficit of both W and PCM rats. The data suggest that PCM animals were more sensitive to the impairment produced by LH and that PCM led to neurochemical changes in the serotonergic system, resulting in hyporeactivity to the anxiogenic effects of GEP in the LH paradigm.

Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas' disease?

Intense immune responses are observed during human or experimental infection with the digenetic protozoan parasite Trypanosoma cruzi. The reasons why such immune responses are unable to completely eliminate the parasites are unknown. The survival of the parasite leads to a parasite-host equilibrium found during the chronic phase of chagasic infection in most individuals. Parasite persistence is recognized as the most likely cause of the chagasic chronic pathologies. Therefore, a key question in Chagas' disease is to understand how this equilibrium is established and maintained for a long period. Understanding the basis for this equilibrium may lead to new approaches to interventions that could help millions of individuals at risk for infection or who are already infected with T. cruzi. Here, we propose that the phenomenon of immunodominance may be significant in terms of regulating the host-parasite equilibrium observed in Chagas' disease. T. cruzi infection restricts the repertoire of specific T cells generating, in some cases, an intense immunodominant phenotype and in others causing a dramatic interference in the response to distinct epitopes. This immune response is sufficiently strong to maintain the host alive during the acute phase carrying them to the chronic phase where transmission usually occurs. At the same time, immunodominance interferes with the development of a higher and broader immune response that could be able to completely eliminate the parasite. Based on this, we discuss how we can interfere with or take advantage of immunodominance in order to provide an immunotherapeutic alternative for chagasic individuals.

Recognition of hepatitis C virus RNA by toll like receptors 7 and 8 : implications for the initiation of innate immune response

Le virus de l’hépatite C (VHC) est un virus à ARN simple brin positif (ssARN) qui se replique dans le foie. Deux cents millions de personnes sont infectées par le virus dans le monde et environ 80% d’entre elles progresseront vers un stade chronique de l’infection. Les thérapies anti-virales actuelles comme l’interféron (IFN) ou la ribavirin sont de plus en plus utilisées mais ne sont efficaces que dans la moitié des individus traités et sont souvent accompagnées d’une toxicité ou d’effets secondaires indésirables. Le système immunitaire inné est essentiel au contrôle des infections virales. Les réponses immunitaires innées sont activées suite à la reconnaissance par les Pathogen Recognition Receptors (PRRs), de motifs macromoléculaires dérivés du virus appelés Pathogen-Associated Molecular Patterns (PAMPs). Bien que l'activation du système immunitaire par l'ARN ou les protéines du VHC ait été largement étudiée, très peu de choses sont actuellement connues concernant la détection du virus par le système immunitaire inné. Et même si l’on peut très rapidement déceler des réponses immunes in vivo après infection par le VHC, l’augmentation progressive et continue de la charge virale met en évidence une incapacité du système immunitaire à contrôler l’infection virale. Une meilleure compréhension des mécanismes d’activation du système immunitaire par le VHC semble, par conséquent, essentielle au développement de stratégies antivirales plus efficaces. Dans le présent travail nous montrons, dans un modèle de cellule primaire, que le génome ARN du VHC contient des séquences riches en GU capables de stimuler spécifiquement les récepteurs de type Toll (TLR) 7 et 8. Cette stimulation a pour conséquence la maturation des cellules dendritiques plasmacytoïdes (pDCs), le production d’interféron de type I (IFN) ainsi que l’induction de chémokines et cytokines inflammatoires par les différentes types de cellules présentatrices d’antigènes (APCs). Les cytokines produites après stimulation de monocytes ou de pDCs par ces séquences ssARN virales, inhibent la production du virus de façon dépendante de l’IFN. En revanche, les cytokines produites après stimulation de cellules dendritiques myéloïdes (mDCs) ou de macrophages par ces mêmes séquences n’ont pas d’effet inhibiteur sur la production virale car les séquences ssARN virales n’induisent pas la production d’IFN par ces cellules. Les cytokines produites après stimulation des TLR 7/8 ont également pour effet de diminuer, de façon indépendante de l’IFN, l’expression du récepteur au VHC (CD81) sur la lignée cellulaire Huh7.5, ce qui pourrait avoir pour conséquence de restreindre l’infection par le VHC. Quoiqu’il en soit, même si les récepteurs au VHC comme le CD81 sont largement exprimés à la surface de différentes sous populations lymphocytaires, les DCs et les monocytes ne répondent pas aux VHC, Nos résultats indiquent que seuls les macrophages sont capables de reconnaître le VHC et de produire des cytokines inflammatoires en réponse à ce dernier. La reconnaissance du VHC par les macrophages est liée à l’expression membranaire de DC-SIGN et l’engagement des TLR 7/8 qui en résulte. Comme d’autres agonistes du TLR 7/8, le VHC stimule la production de cytokines inflammatoires (TNF-α, IL-8, IL-6 et IL-1b) mais n’induit pas la production d’interféron-beta par les macrophages. De manière attendue, la production de cytokines par des macrophages stimulés par les ligands du TLR 7/8 ou les séquences ssARN virales n’inhibent pas la réplication virale. Nos résultats mettent en évidence la capacité des séquences ssARN dérivées du VHC à stimuler les TLR 7/8 dans différentes populations de DC et à initier une réponse immunitaire innée qui aboutit à la suppression de la réplication virale de façon dépendante de l’IFN. Quoiqu’il en soit, le VHC est capable d’échapper à sa reconnaissance par les monocytes et les DCs qui ont le potentiel pour produire de l’IFN et inhiber la réplication virale après engagement des TLR 7/8. Les macrophages possèdent quant à eux la capacité de reconnaître le VHC grâce en partie à l’expression de DC-SIGN à leur surface, mais n’inhibent pas la réplication du virus car ils ne produisent pas d’IFN. L’échappement du VHC aux défenses antivirales pourrait ainsi expliquer l’échec du système immunitaire inné à contrôler l’infection par le VHC. De plus, la production de cytokines inflammatoires observée après stimulation in vitro des macrophages par le VHC suggère leur potentielle contribution dans l’inflammation que l’on retrouve chez les individus infectés par le VHC.

Scanning LDV for vibration measurement of filiform hairs in crickets in response to induced airflow - art. no. 63450E

Cercal hairs represent in cricket a wind sensitive escape system, able to detect the airflow generated from predating species. These sensors have been studied as a biomimetic concept to allow the development of MEMS for biomedical use. In particular, the behaviour of the hairs, including airflow response, resonant frequency and damping, has been investigated up to a frequency of 20 kHz. The microscopic nature of the hairs, the complex vibrations of excited hairs and the high damping of the system suggested that the use of Laser Doppler vibrometry could possibly improve the test performance. Two types of tests were performed: in the first case the hairs were indirectly excited using the signal obtained from a vibrating aluminium plate, whilst in the second case the hairs were directly excited using a white noise chirp. The results from the first experiment indicated that the hairs move in-phase with the exciting signal up to frequencies in the order of 10 kHz, responding to the vibration modes of the plate with a signal attenuation of 12 to 20 dB. The chirp experiment revealed the presence of rotational resonant modes at 6850 and 11300 Hz. No clear effect of hair length was perceivable on the vibration response of the filiform sensors. The obtained results proved promising to support the mechanical and vibration characterisation of the hairs and suggest that scanning Laser vibrometry can be used extensively on highly dampened biological materials.

Relation of pretreatment sequence diversity in NS5A region of HCV genotype 1 with immune response between pegylated-INF/ribavirin therapy outcomes

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific immune responses and the combination of pegylated interferon (INF)-alpha and ribavirin therapy. Major histocompatibility complex class I restricted CD8+ T cells are responsible for the control of viraemia in HCV infection, and several studies suggest protection against viral infection associated with specific HLAs. The reason for low rates of sustained viral response (SVR) in HCV patients remains unknown. Escape mutations in response to cytotoxic T lymphocyte are widely described; however, its influence in the treatment outcome is ill understood. Here, we investigate the differences in CD8 epitopes frequencies from the Los Alamos database between groups of patients that showed distinct response to pegylated alpha-INF with ribavirin therapy and test evidence of natural selection on the virus in those who failed treatment, using five maximum likelihood evolutionary models from PAML package. The group of sustained virological responders showed three epitopes with frequencies higher than Non-responders group, all had statistical support, and we observed evidence of selection pressure in the last group. No escape mutation was observed. Interestingly, the epitope VLSDFKTWL was 100% conserved in SVR group. These results suggest that the response to treatment can be explained by the increase in immune pressure, induced by interferon therapy, and the presence of those epitopes may represent an important factor in determining the outcome of therapy.

Triple- and quadruple-escape peaks in HPGe detectors: Experimental observation and Monte Carlo simulation

The triple- and quadruple-escape peaks of 6.128 MeV photons from the (19)F(p,alpha gamma)(16)O nuclear reaction were observed in an HPGe detector. The experimental peak areas, measured in spectra projected with a restriction function that allows quantitative comparison of data from different multiplicities, are in reasonably good agreement with those predicted by Monte Carlo simulations done with the general-purpose radiation-transport code PENELOPE. The behaviour of the escape intensities was simulated for some gamma-ray energies and detector dimensions; the results obtained can be extended to other energies using an empirical function and statistical properties related to the phenomenon. (C) 2010 Elsevier B.V. All rights reserved.

Hunger suppresses the onset and the freezing component of the antipredator response to conspecific skin extract in pintado catfish

Although the skin of an injured conspecific releases alarm substance in some fish species, it has been shown that such damage induces feeding behaviour rather than an alarm reaction under conditions of food scarcity. We studied chemical communication associated with this paradox in a Brazilian catfish, the pintado (Pseudoplatystoma coruscans). In preliminary tests pintado were confirmed to demonstrate an alarm reaction to conspecific skin extract. In the experiment we investigated whether skin extract of pintado induces either alarm response (panic or alert component) or feeding in hungry conspecifics. Fish feed-deprived for eight days and fed control fish were exposed to either conspecific skin extract or distilled water (as a control). Alarm reaction was restricted to the skin extract treatment and occurred in the fish irrespective of their hunger state, but the components of this response were significantly affected by hungry. Fed fish showed a complete alarm reaction (dashing and freezing behaviours). Feed-deprived fish exhibited only part of this biphasic response, the dashing component. We conclude that chemicals from injured fish elicit an alarm reaction, which is partially inhibited by feeding motivation.

Relation of pretreatment sequence diversity in NS5A region of HCV genotype 1 with immune response between pegylated-INF/ribavirin therapy outcomes

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Escape in a nonideal electro-mechanical system

In this work a particular system is investigated consisting of a pendalum whose point of support is vibrated along a horizontal guide by a two bar linkage driven from a DC motor, considered as a limited power source. This system is nonideal since the oscillatory motion of the pendulum influences the speed of the motor and vice-versa, reflecting in a more complicated dynamical process. This work comprises the investigation of the phenomena that appear when the frequency of the pendulum draws near a secondary resonance region, due to the existing nonlinear interactions in the system. Also in this domain due to the power limitation of the motor, the frequency of the pendulum can be captured at resonance modifying completely the final response of the system. This behavior is known as Sommerfield effect and it will be studied here for a nonlinear system.