"Who Fears Death" di Nnedi Okorafor, una proposta di traduzione

This dissertaton deals with the translation of selected chapters from Nnedi Okorafor’s novel Who Fears Death. The novel, set in a post-apocalyptic Africa ravaged by inter-ethnic violence, narrates the tale of Onyesonwu, an Ewu, a half-breed born of rape, facing the rejection of her community. Growing up Onyesonwu realizes that the color of her skin is not the only thing that sets her apart from the other inhabitants of Jwahir, as she starts to manifest magical powers, and during an unintentional visit to the spirit realms she finds out that her biological father, a very powerful sorcerer, wants to kill her. At this point the only option left to her is to learn the secret arts of magic under the guidance of Aro, the sorcerer, and then embark on a journey to put and end to the menace posed by her biological father, stop the massacres between the Okeke and Nuru people, and rewrite history. This work is structured in five chapters. The first presents a brief retelling of the author’s life and works. The second chapter constitutes the theoretical frame according to which the novel will be described, and illustrates an analysis on the function of sci-fi literature. The third chapter introduces the novel itself, dealing with its setting and cultural peculiarities, the literary genre to which it belongs, and analysing the themes deemed most relevant, among which the racial and gender issues. The fourth chapter consists of the translation of some chapters from the novel Who Fears Death, and the fifth of a comment on the translation, presenting both a textual analysis, and notes on the choices deemed most interesting or challenging in a translation process perspective.

Targeting neuronal populations by AAV-mediated gene transfer for studying the endocannabinoid system

The cannabinoid type 1 (CB1) receptor is involved in a plethora of physiological functions and heterogeneously expressed on different neuronal populations. Several conditional loss-of-function studies revealed distinct effects of CB1 receptor signaling on glutamatergic and GABAergic neurons, respectively. To gain a comprehensive picture of CB1 receptor-mediated effects, the present study aimed at developing a gain-of-function approach, which complements conditional loss-of-function studies. Therefore, adeno-associated virus (AAV)-mediated gene delivery and Cre-mediated recombination were combined to recreate an innovative method, which ensures region- and cell type-specific transgene expression in the brain. This method was used to overexpress the CB1 receptor in glutamatergic pyramidal neurons of the mouse hippocampus. Enhanced CB1 receptor activity at glutamatergic terminals caused impairment in hippocampus-dependent memory performance. On the other hand, elevated CB1 receptor levels provoked an increased protection against kainic acid-induced seizures and against excitotoxic neuronal cell death. This finding indicates the protective role of CB1 receptor on hippocampal glutamatergic terminals as a molecular stout guard in controlling excessive neuronal network activity. Hence, CB1 receptor on glutamatergic hippocampal neurons may represent a target for novel agents to restrain excitotoxic events and to treat neurodegenerative diseases. Endocannabinoid synthesizing and degrading enzymes tightly regulate endocannabinoid signaling, and thus, represent a promising therapeutic target. To further elucidate the precise function of the 2-AG degrading enzyme monoacylglycerol lipase (MAGL), MAGL was overexpressed specifically in hippocampal pyramidal neurons. This genetic modification resulted in highly increased MAGL activity accompanied by a 50 % decrease in 2-AG levels without affecting the content of arachidonic acid and anandamide. Elevated MAGL protein levels at glutamatergic terminals eliminated depolarization-induced suppression of excitation (DSE), while depolarization-induced suppression of inhibition (DSI) was unchanged. This result indicates that the on-demand availability of the endocannabinoid 2-AG is crucial for short-term plasticity at glutamatergic synapses in the hippocampus. Mice overexpressing MAGL exhibited elevated corticosterone levels under basal conditions and an increase in anxiety-like behavior, but surprisingly, showed no changes in aversive memory formation and in seizure susceptibility. This finding suggests that 2 AG-mediated hippocampal DSE is essential for adapting to aversive situations, but is not required to form aversive memory and to protect against kainic acid-induced seizures. Thus, specific inhibition of MAGL expressed in hippocampal pyramidal neurons may represent a potential treatment strategy for anxiety and stress disorders. Finally, the method of AAV-mediated cell type-specific transgene expression was advanced to allow drug-inducible and reversible transgene expression. Therefore, elements of the tetracycline-controlled gene expression system were incorporated in our “conditional” AAV vector. This approach showed that transgene expression is switched on after drug application and that background activity in the uninduced state was only detectable in scattered cells of the hippocampus. Thus, this AAV vector will proof useful for future research applications and gene therapy approaches.

TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF-kappaB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.