\u3cem\u3eGargantua \u3c/em\u3eand the New Historiography

One major tenet of much modern Rabelais criticism since Screech and Defaux — and even. in certain ways, since Lefranc — is that the Oeuvres cannot fully be appreciated by the present-day reader until he acquires familiarity with matters known to Rabelais and his intended audience. As shown again most recently by Gerard Defaux, there are codes culturels subtending much of the Oeuvres, codes to which Rabelais most definitely was alluding and of which modern readers must therefore be aware if they are to perceive the meanings that Rabelais knew his own readers, familiar with these codes, would derive from his texts

A Literary Form for Love: Yves Navarre\u27s My Friends Are Gone with the Wind

In My Friends Are Gone with the Wind (Ce sont amis que vent emporte, 1991), one of his last and most innovative texts, Yves Navarre (1940-1994), one of the most important contemporary French novelists to deal significantly and regularly with gay themes, returns to his preoccupation with the dangers that the forms inherent in traditional literary narrative pose for the expression of authentic human experience. The narrator, Roch, wants to capture the reality of his love for David, in part to prove to what he sees as a largely hostile heterosexual world that gays are as capable of loving relationships as straights, in part to show those often inhibited straights how to express their love. He realizes that love\u27s excessive nature requires a literary form that throws off the shackles of traditional order and chronology, so he allows memory to erupt within his manuscript as it occurs, unordered by logic. In the process, Roch accepts that he has to let everything in, even David\u27s infidelities, but that by capturing the truth of love, its impulsive nature, he will convey their love in such a powerful way that it will testify convincingly throughout time to their feelings for each other

A Significant Source for the Madeleine and Other Major Episodes in Combray: Proust\u27s Intertextual Use of Pierre Loti\u27s My Brother Yves

The most famous passage in Marcel Proust’s In Search of Lost Time, and one of the most famous passages in Western literature, is the moment when the narrator sips tea while eating a shell-shaped pastry called a madeleine and suddenly recalls very vividly an apparently long-forgotten scene from his childhood. From this episode Proust developed his theories about involuntary memory and its important role in our emotional welfare. Proust was an avid reader of the French novelist Pierre Loti when he was young. Contemporary accounts show that he was able to recite whole passages from Loti’s work in public from memory. This article demonstrates the extent to which Proust made intertextual use of scenes from Loti’s novel My Brother Yves in constructing the madeleine and other famous passages in Combray, the first section of In Search of Lost Time. It does not attempt to question the originality of Proust’s work. Rather, building on previous studies of intertextuality in Proust, it seeks to show how the author went about creating his work and dialoguing with at least some of his potential contemporary readers

Painting with Words as Painters Paint: Pierre Loti’s Concern with Perspective

Even before he took to creating art with words, French novelist Pierre Loti (1850-1923) was an avid drawer. So much so that, when he did write, he sometimes felt the need to supplement his verbal efforts with visual ones. In one of his autobiographically-based novels, Le Roman d’un enfant (1890), he recounts how, at the age of eight, he and his friend Lucette left absurd and incoherent letters in the street so that they could enjoy the reactions of those who stopped to read them. The narrator..

Calcium/Calmodulin Dependent Protein Kinase Kinase 2 Regulates the Expansion of Tumor-Induced Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy

Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses

Ajuts: R01/R56 NIH Grant AI-52779 (GDT), NIH F31 Fellowship (1F31AI106519-01)(TLP), Center for AIDS Research (P30 AI 64518) i Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, grant number UM1-AI100645-01 (AM)Abstract.Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control

A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies

Background: Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral ftness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in ftness losses. Results: Strongly selected mutations were identifed by analyzing 5′-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was frst detected at day 91 post screening and was fxed in the viral population at day 273 while the synonymous N323tc mutation was frst detected at day 177 and fxed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when ftness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a signifcant ftness loss while the N323tc mutation had little impact on viral ftness. Conclusions: The rapid fxation, the lack of detectable immune responses and the signifcant ftness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodie

Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses

Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called “beneficial” regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control

Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies

Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make bnAbs is a key strategy for immunogen design. Here we study the B cell response in a bnAb-producing individual, and report cooperation between two B cell lineages to drive bnAb development. We isolated an autologous virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization—traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both autologous and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals