Glycans in melanoma: Drivers of tumour progression but sweet targets to exploit for immunotherapy.

Aberrant glycosylation recently emerged as an unmissable hallmark of cancer progression in many cancers. In melanoma, there is growing evidence that the tumour 'glycocode' plays a major role in promoting cell proliferation, invasion, migration, but also dictates the nature of the immune infiltrate, which strongly affects immune cell function, and clinical outcome. Aberrant glycosylation patterns dismantle anti-tumour defence through interactions with lectins on immune cells, which are crucial to shape anti-tumour immunity but also to trigger immune evasion. The glycan/lectin axis represents a new immune subversion pathway that is exploited by melanoma to hijack immune cells and escape from immune control. In this review, we describe the glycosylation features of melanoma tumour cells, and further gather findings related to the role of glycosylation in melanoma tumour progression, deciphering in detail its impact on immunity. We also depict glycan-based strategies aiming at restoring a functional anti-tumour response in melanoma patients. Glycans/lectins emerge as key immune checkpoints with promising translational properties. Exploitation of these pathways could reshape potent anti-tumour immunity while impeding immunosuppressive circuits triggered by aberrant tumour glycosylation patterns, holding great promise for cancer therapy.

Determinants of bacterial survival and proliferation in blood.

Bloodstream infection is a major public health concern associated with high mortality and high healthcare costs worldwide. Bacteremia can trigger fatal sepsis whose prevention, diagnosis, and management have been recognized as a global health priority by the World Health Organization. Additionally, infection control is increasingly threatened by antimicrobial resistance, which is the focus of global action plans in the framework of a One Health response. In-depth knowledge of the infection process is needed to develop efficient preventive and therapeutic measures. The pathogenesis of bloodstream infection is a dynamic process resulting from the invasion of the vascular system by bacteria, which finely regulate their metabolic pathways and virulence factors to overcome the blood immune defenses and proliferate. In this review, we highlight our current understanding of determinants of bacterial survival and proliferation in the bloodstream and discuss their interactions with the molecular and cellular components of blood.

Interdisciplinary studies on Coxiella burnetii: From molecular to cellular, to host, to one health research.

The Q-GAPS (Q fever GermAn interdisciplinary Program for reSearch) consortium was launched in 2017 as a German consortium of more than 20 scientists with exceptional expertise, competence, and substantial knowledge in the field of the Q fever pathogen Coxiella (C.) burnetii. C. burnetii exemplifies as a zoonotic pathogen the challenges of zoonotic disease control and prophylaxis in human, animal, and environmental settings in a One Health approach. An interdisciplinary approach to studying the pathogen is essential to address unresolved questions about the epidemiology, immunology, pathogenesis, surveillance, and control of C. burnetii. In more than five years, Q-GAPS has provided new insights into pathogenicity and interaction with host defense mechanisms. The consortium has also investigated vaccine efficacy and application in animal reservoirs and identified expanded phenotypic and genotypic characteristics of C. burnetii and their epidemiological significance. In addition, conceptual principles for controlling, surveilling, and preventing zoonotic Q fever infections were developed and prepared for specific target groups. All findings have been continuously integrated into a Web-based, interactive, freely accessible knowledge and information platform (www.q-gaps.de), which also contains Q fever guidelines to support public health institutions in controlling and preventing Q fever. In this review, we will summarize our results and show an example of how an interdisciplinary consortium provides knowledge and better tools to control a zoonotic pathogen at the national level.

Immune responses to Tilapia lake virus infection: what we know and what we don't know.

Tilapia lake virus (TiLV) is a novel contagious pathogen associated with a lethal disease affecting and decimating tilapia populations on several continents across the globe. Fish viral diseases, such as Tilapia lake virus disease (TiLVD), represent a serious threat to tilapia aquaculture. Therefore, a better understanding of the innate immune responses involved in establishing an antiviral state can help shed light on TiLV disease pathogenesis. Moreover, understanding the adaptive immune mechanisms involved in mounting protection against TiLV could greatly assist in the development of vaccination strategies aimed at controlling TiLVD. This review summarizes the current state of knowledge on the immune responses following TiLV infection. After describing the main pathological findings associated with TiLVD, both the innate and adaptive immune responses and mechanisms to TiLV infection are discussed, in both disease infection models and in vitro studies. In addition, our work, highlights research questions, knowledge gaps and research areas in the immunology of TiLV infection where further studies are needed to better understand how disease protection against TiLV is established.

Dendritic Cell Subsets in Melanoma: Pathophysiology, Clinical Prognosis and Therapeutic Exploitation.

Evasion from immunity is a hallmark of cancer development. Dendritic cells (DCs) are strategic immune cells shaping anti-tumor immune responses, but tumor cells exploit DC versatility to subvert their functions. Unveiling the puzzling role of DCs in the control of tumor development and mechanisms of tumor-induced DC hijacking is critical to optimize current therapies and to design future efficient immunotherapies for melanoma. Dendritic cells, crucially positioned at the center of anti-tumor immunity, represent attractive targets to develop new therapeutic approaches. Harnessing the potencies of each DC subset to trigger appropriate immune responses while avoiding their subversion is a challenging yet promising step to achieve tumor immune control. This review focuses on advances regarding the diversity of DC subsets, their pathophysiology and impact on clinical outcome in melanoma patients. We provide insights into the regulation mechanisms of DCs by the tumor, and overview DC-based therapeutic developments for melanoma. Further insights into DCs' diversity, features, networking, regulation and shaping by the tumor microenvironment will allow designing novel effective cancer therapies. The DCs deserve to be positioned in the current melanoma immunotherapeutic landscape. Recent discoveries strongly motivate exploitation of the exceptional potential of DCs to drive robust anti-tumor immunity, offering promising tracks for clinical successes.

The melanoma tumor glyco-code impacts human dendritic cells' functionality and dictates clinical outcomes.

Subversion of immunity is a hallmark of cancer development. Dendritic cells (DCs) are strategic immune cells triggering anti-tumor immune responses, but tumor cells exploit their versatility to subvert their functions. Tumor cells harbor unusual glycosylation patterns, which can be sensed through glycan-binding receptors (lectins) expressed by immune cells that are crucial for DCs to shape and orientate antitumor immunity. Yet, the global tumor glyco-code and its impact on immunity has not been explored in melanoma. To decrypt the potential link between aberrant glycosylation patterns and immune evasion in melanoma, we investigated the melanoma tumor glyco-code through the GLYcoPROFILE™ methodology (lectin arrays), and depicted its impact on patients' clinical outcome and DC subsets' functionality. Specific glycan patterns correlated with clinical outcome of melanoma patients, GlcNAc, NeuAc, TF-Ag and Fuc motifs being associated with poor outcome, whereas Man and Glc residues elicited better survival. Strikingly, tumor cells differentially impacting cytokine production by DCs harbored distinct glyco-profiles. GlcNAc exhibited a negative influence on cDC2s, whereas Fuc and Gal displayed inhibitory impacts on cDC1s and pDCs. We further identified potential booster glycans for cDC1s and pDCs. Targeting specific glycans on melanoma tumor cells restored DCs' functionality. The tumor glyco-code was also linked to the nature of the immune infiltrate. This study unveils the impact of melanoma glycan patterns on immunity, and paves the way for innovative therapeutic options. Glycans/lectins interactions arise as promising immune checkpoints to rescue DCs from tumor' hijacking to reshape antitumor immunity and inhibit immunosuppressive circuits triggered by aberrant tumor glycosylation.

Group A streptococci induce stronger M protein-fibronectin interaction when specific human antibodies are bound.

Group A streptococcus (GAS) is a highly adapted, human-specific pathogen that is known to manipulate the immune system through various mechanisms. GAS' M protein constitutes a primary target of the immune system due to its spatial configuration and dominance on the bacterial surface. Antibody responses targeting the M protein have been shown to favor the conserved C region. Such antibodies (Abs) circumvent antigenic escape and efficiently bind to various M types. The ability of GAS to bind to fibronectin (Fn), a high molecular weight glycoprotein of the extracellular matrix, has long been known to be essential for the pathogen's evolutionary success and fitness. However, some strains lack the ability to efficiently bind Fn. Instead, they have been found to additionally bind Fn via the A-B domains of their M proteins. Here, we show that human Abs can induce increased Fn-binding affinity in M proteins, likely by enhancing the weak A-B domain binding. We found that this enhanced Fn binding leads to a reduction in Ab-mediated phagocytosis, indicating that this constitutes a GAS immune escape mechanism. We could show that the Fc domain of Abs is necessary to trigger this phenomenon and that Ab flexibility may also play a key role. We, moreover, saw that our Abs could enhance Fn binding in 3 out of 5 emm type strains tested, belonging to different clades, making it likely that this is a more generalizable phenomenon. Together our results suggest a novel synergistic interplay of GAS and host proteins which ultimately benefits the bacterium.

Listeria InlB Expedites Vacuole Escape and Intracellular Proliferation by Promoting Rab7 Recruitment via Vps34.

Rapid phagosomal escape mediated by listeriolysin O (LLO) is a prerequisite for Listeria monocytogenes intracellular replication and pathogenesis. Escape takes place within minutes after internalization from vacuoles that are negative to the early endosomal Rab5 GTPase and positive to the late endosomal Rab7. Using mutant analysis, we found that the listerial invasin InlB was required for optimal intracellular proliferation of L. monocytogenes. Starting from this observation, we determined in HeLa cells that InlB promotes early phagosomal escape and efficient Rab7 acquisition by the Listeria-containing vacuole (LCV). Recruitment of the class III phosphoinositide 3-kinase (PI3K) Vps34 to the LCV and accumulation of its lipid product, phosphatidylinositol 3-phosphate (PI3P), two key endosomal maturation mediators, were also dependent on InlB. Small interfering RNA (siRNA) knockdown experiments showed that Vps34 was required for Rab7 recruitment and early (LLO-mediated) escape and supported InlB-dependent intracellular proliferation. Together, our data indicate that InlB accelerates LCV conversion into an escape-favorable Rab7 late phagosome via subversion of class III PI3K/Vps34 signaling. Our findings uncover a new function for the InlB invasin in Listeria pathogenesis as an intracellular proliferation-promoting virulence factor. IMPORTANCE Avoidance of lysosomal killing by manipulation of the endosomal compartment is a virulence mechanism assumed to be largely restricted to intravacuolar intracellular pathogens. Our findings are important because they show that cytosolic pathogens like L. monocytogenes, which rapidly escape the phagosome after internalization, can also extensively subvert endocytic trafficking as part of their survival strategy. They also clarify that, instead of delaying phagosome maturation (to allow time for LLO-dependent disruption, as currently thought), via InlB L. monocytogenes appears to facilitate the rapid conversion of the phagocytic vacuole into an escape-conducive late phagosome. Our data highlight the multifunctionality of bacterial virulence factors. At the cell surface, the InlB invasin induces receptor-mediated phagocytosis via class I PI3K activation, whereas after internalization it exploits class III PI3K (Vsp34) to promote intracellular survival. Systematically elucidating the mechanisms by which Listeria interferes with PI3K signaling all along the endocytic pathway may lead to novel anti-infective therapies.

TGF-ß/IFN-γ Antagonism in Subversion and Self-Defense of Phase II Coxiella burnetii-Infected Dendritic Cells.

Dendritic cells (DCs) belong to the first line of innate defense and come into early contact with invading pathogens, including the zoonotic bacterium Coxiella burnetii, the causative agent of Q fever. However, the pathogen-host cell interactions in C. burnetii-infected DCs, particularly the role of mechanisms of immune subversion beyond virulent phase I lipopolysaccharide (LPS), as well as the contribution of cellular self-defense strategies, are not understood. Using phase II Coxiella-infected DCs, we show that impairment of DC maturation and MHC I downregulation is caused by autocrine release and action of immunosuppressive transforming growth factor-ß (TGF-ß). Our study demonstrates that IFN-γ reverses TGF-ß impairment of maturation/MHC I presentation in infected DCs and activates bacterial elimination, predominantly by inducing iNOS/NO. Induced NO synthesis strongly affects bacterial growth and infectivity. Moreover, our studies hint that Coxiella-infected DCs might be able to protect themselves from mitotoxic NO by switching from oxidative phosphorylation to glycolysis, thus ensuring survival in self-defense against C. burnetii. Our results provide new insights into DC subversion by Coxiella and the IFN-γ-mediated targeting of C. burnetii during early steps in the innate immune response.

Resistencia, re-existencia y juvenicidio: tres metáforas para comprender la Colombia del levantamiento popular / Resistance, re-existence and youthcide: three metaphors for understanding the popular uprising in Colombia / Resistência, re-existência e juvenilicídio: três metáforas para entender a Colômbia da revolta popular

Resumen (analítico) El artículo analiza las modalidades de resistencia y re-existencia producidas en el contexto del levantamiento popular de 2021, en sus relaciones con el juvenicidio. Metodológicamente, se optó por el análisis de narrativas de experiencias de jóvenes de tres ciudades, así como el análisis de un corpus de imágenes relacionado con estos acontecimientos. En resultados, la categoría salir del cerco evidenció que el levantamiento está imbricado con el juvenicidio, desde la precarización y la violencia estatal en pandemia y la existencia de opresiones cruzadas. En la categoría subvertir, se observó la presencia de estrategias de confrontación y deslegitimación simbólica al sistema dominante. En la categoría estéticas populares sobresalen la autorrepresentación y la curación simbólica. La categoría educación popular evidenció la implementación de prácticas fomentadoras del interaprendizaje y la cocreación para buenos vivires.

Abstract (analytical) This article analyzes the modalities of resistance and re-existence that occurred in the context of the Colombian popular uprising in 2021 and relates them with the practice of youthcide. At a methodological level, the article analyses narratives of experiences of young people from three cities, as well as a corpus of images related to the popular uprising. The results identify a category of getting off the fence, which shows that the uprising is related to acts of youthcide. The protests were a response to precariousness and state violence during pandemic, as well as the existence of multiple forms of oppression of the youth population. In the subversion category, confrontation strategies and symbolic delegitimization of the dominant system were observed. In the popular aesthetic category, self-representation and symbolic healing were evident. In the popular education category, the implementation of practices that promote mutual learning and co-creation for good living were identified.

Resumo (analítico) O artigo analisa as modalidades de resistência e reexistência ocorridas durante a revolta popular de 2021, em suas relações com a juvenilicídio. Metodologicamente, utilizou-se a análise de narrativas de experiências de jovens de três cidades, bem como a análise de imagens relacionadas a esses eventos. Nos resultados, a categoria de sair da cerca mostrou que a revolta está entrelaçada com a juvenilicídio, a partir do aprofundamento da precariedade e da violência estatal e para-estatal. Na categoria subverter, observou-se a implementação de estratégias de enfrentamento e deslegitimação simbólica do sistema dominante. Na categoria estética popular, destacam-se a autorrepresentação e a cura simbólica. E na categoria educação popular foram desveladas práticas que promovem o aprendizado mútuo para o bem viver.

Unique CLR expression patterns on circulating and tumor-infiltrating DC subsets correlated with clinical outcome in melanoma patients.

Subversion of immunity by tumors is a crucial step for their development. Dendritic cells (DCs) are strategic immune cells that orchestrate anti-tumor immune responses but display altered functions in cancer. The bases for such DCs' hijacking are not fully understood. Tumor cells harbor unusual glycosylation patterns of surface glycoproteins and glycolipids. DCs express glycan-binding receptors, named C-type lectin receptors (CLR), allowing them to sense changes in glycan signature of their environment, and subsequently trigger a response. Recognition of tumor glycans by CLRs is crucial for DCs to shape antitumor immunity, and decisive in the orientation of the response. Yet the status of the CLR machinery on DCs in cancer, especially melanoma, remained largely unknown. We explored CLR expression patterns on circulating and tumor-infiltrating cDC1s, cDC2s, and pDCs of melanoma patients, assessed their clinical relevance, and further depicted the correlations between CLR expression profiles and DCs' features. For the first time, we highlighted that the CLR repertoire of circulating and tumor-infiltrating cDC1s, cDC2s, and pDCs was strongly perturbed in melanoma patients, with modulation of DCIR, CLEC-12α and NKp44 on circulating DCs, and perturbation of Dectin-1, CD206, DEC205, DC-SIGN and CLEC-9α on tumor-infiltrating DCs. Furthermore, melanoma tumor cells directly altered CLR expression profiles of healthy DC subsets, and this was associated with specific glycan patterns (Man, Fuc, GlcNAc) that may interact with DCs through CLR molecules. Notably, specific CLR expression profiles on DC subsets correlated with unique DCs' activation status and functionality and were associated with clinical outcome of melanoma patients. Higher proportions of DCIR-, DEC205-, CLEC-12α-expressing cDCs were linked with a better survival, whereas elevated proportions of CD206-, Dectin1-expressing cDCs and NKp44-expressing pDCs were associated with a poor outcome. Thus, melanoma tumor may shape DCs' features by exploiting the plasticity of the CLR machinery. Our study revealed that melanoma manipulates CLR pathways to hijack DC subsets and escape from immune control. It further paved the way to exploit glycan-lectin interactions for the design of innovative therapeutic strategies, which exploit DCs' potentialities while avoiding hijacking by tumor, to properly reshape anti-tumor immunity by manipulating the CLR machinery.

Coxsackievirus Protease 2A Targets Host Protease ATG4A to Impair Autophagy.

Enteroviruses (EVs) are medically important RNA viruses that cause a broad spectrum of human illnesses for which limited therapy exists. Although EVs have been shown to usurp the cellular recycling process of autophagy for pro-viral functions, the precise manner by which this is accomplished remains to be elucidated. In the current manuscript, we sought to address the mechanism by which EVs subvert the autophagy pathway using Coxsackievirus B3 (CVB3) as a model. We showed that CVB3 infection selectively degrades the autophagy cysteine protease ATG4A but not other isoforms. Exogenous expression of an N-terminally Flag-labeled ATG4A demonstrated the emergence of a 43-kDa cleavage fragment following CVB3 infection. Furthermore, bioinformatics analysis coupled with site-directed mutagenesis and in vitro cleavage assays revealed that CVB3 protease 2A cleaves ATG4A before glycine 374. Using a combination of genetic silencing and overexpression studies, we demonstrated a novel pro-viral function for the autophagy protease ATG4A. Additionally, cleavage of ATG4A was associated with a loss of autophagy function of the truncated cleavage fragment. Collectively, our study identified ATG4A as a novel substrate of CVB3 protease, leading to disrupted host cellular function and sheds further light on viral mechanisms of autophagy dysregulation.

Entre a Dor e a Alegria: Repercussões Subjetivas no Ser Palhaço(a) / Between Pain and Happiness: Subjective Repercussions in the Being Clown / Entre el Dolor y la Alegría: Repercusiones Subjetivas de Ser Payaso(a)

Investigou-se como a dor e a alegria podem influenciar a construção do ser palhaço(a) com o objetivo de compreender melhor a construção da sua subjetividade. Foram realizadas entrevistas com dez palhaços(as). Utilizou-se como método a análise de conteúdo e o software NVivo® para sistematizar as informações presentes nos discursos dos(as) participantes em doze categorias, agrupadas em dois eixos temáticos e analisadas a partir de sua pertinência na construção do entendimento de ser palhaço(a). Os resultados indicaram que a dor diante de perdas afetivas no processo de ser palhaço(a) passa pela transformação do trágico à comicidade, não para minimizá-la, mas para lidar com a finitude humana por meio da ética, poética e estética de afirmação da vida. A transgressão da palhaçaria permite superar dificuldades e transformá-las criativamente em riso. Conclui-se que o ser palhaço(a) torna-se a vitrine das condições humanas apresentadas por meio do cômico, do trágico, do ridículo, do perder, do político, do rústico e do ser-no-mundo.

It was investigated how pain and joy can influence the construction of being a clown in order to better understand the construction of their subjectivity. Interviews were conducted with ten clowns. Content analysis and the NVivo® software were used as a method to systematize the information present in the participants' speeches into twelve categories, grouped into two thematic axes and analyzed based on its pertinence in the construction of the understanding of being a clown. The results indicated that the pain in the face of affective losses in the process of being a clown goes through the transformation from the tragic to the comic, not to minimize it, but to deal with human finitude through ethics, poetics and life-affirming aesthetics. The transgression of clowning allows you to overcome difficulties and creatively transform them into laughter. It is concluded that being a clown becomes the showcase of human conditions presented through the comic, the tragic, the ridiculous, the losing, the political, the rustic and the being-in-the-world.

Se investigó cómo el dolor y la alegría pueden influir en la construcción del payaso, con el objetivo de comprender mejor la construcción de su subjetividad. Se realizaron entrevistas con diez payasos. El análisis de contenido y el software NVivo® se utilizaron como método para sistematizar la información presente en los discursos de los participantes, en doce categorías, agrupadas en dos ejes temáticos, y analizadas desde la pertinencia en la construcción de la comprensión del payaso. Los resultados indicaron que el dolor ante pérdidas afectivas en el proceso de ser payaso sufre una transformación de lo trágico a lo cómico, no para minimizar el dolor, sino para lidiar con la finitud humana a través de la ética, la poética y la estética afirmadora de la vida. La transgresión del clown te permite superar las dificultades y transformarlas creativamente en risa. Se concluye que ser payaso se convierte en el escaparate de las condiciones humanas que se presentan a través de lo cómico, lo trágico, lo ridículo, lo perdedor, lo político, lo rústico y el ser-en-el-mundo.

Diversification of circulating and tumor-infiltrating plasmacytoid DCs towards the P3 (CD80+ PDL1-)-pDC subset negatively correlated with clinical outcomes in melanoma patients.

Objectives: Plasmacytoid DCs (pDCs) play a critical yet enigmatic role in antitumor immunity through their pleiotropic immunomodulatory functions. Despite proof of pDC diversity in several physiological or pathological contexts, pDCs have been studied as a whole population so far in cancer. The assessment of individual pDC subsets is needed to fully grasp their involvement in cancer immunity, especially in melanoma where pDC subsets are largely unknown and remain to be uncovered. Methods: We explored for the first time the features of diverse circulating and tumor-infiltrating pDC subsets in melanoma patients using multi-parametric flow cytometry, and assessed their clinical relevance. Based on CD80, PDL1, CD2, LAG3 and Axl markers, we provided an integrated overview of the frequency, basal activation status and functional features of pDC subsets in melanoma patients together with their relationship to clinical outcome. Results: Strikingly, we demonstrated that P3-pDCs (CD80+PDL1-) accumulated within the tumor of melanoma patients and negatively correlated with clinical outcomes. The basal activation status, diversification towards P1-/P2-/P3-pDCs and functionality of several pDC subsets upon TLR7/TLR9 triggering were perturbed in melanoma patients, and were differentially linked to clinical outcome. Conclusion: Our study shed light for the first time on the phenotypic and functional heterogeneity of pDCs in the blood and tumor of melanoma patients and their potential involvement in shaping clinical outcomes. Such novelty brightens our understanding of pDC complexity, and prompts the further deciphering of pDCs' features to better apprehend and exploit these potent immune players. It highlights the importance of considering pDC diversity when developing pDC-based therapeutic strategies to ensure optimal clinical success.

Violencia intrafamiliar, abusos sexuales y discapacidad intelectual: un estudio de caso único desde una mirada narrativa / Domestic Violence, Sexual Abuse and Intellectual Disability: A Single Case Study from a Narrative Perspective

Se presentan los resultados de un estudio parcial de caso único a través de la perspectiva biográfico-narrativa. Teniendo en cuenta un trabajo de campo previo más amplio, para este texto hemos realizado una entrevista semiestructurada y dos en profundidad para abordar de manera focal un caso de violación y abuso sexual a Teresa, persona diagnosticada con Discapacidad Intelectual (PCDI). De las entrevistas emergen diferentes categorías inductivas (violencia intrafamiliar –abusos sexuales, insultos, agresiones–, identidad como persona con discapacidad) que se abordan en la discusión en dos ejes interpretativos que se corresponden con dos etapas diferenciadas de la vida de la participante (la naturalización de la violencia y el inicio del cambio como forma de lucha). Como resultados más destacables encontramos hechos, en una primera etapa, que nos hablan de la repetición en el tiempo de dos tipos de abusos (físico, emocional) por parte de sus familiares, entre los que reluce la condición de discapacidad, y, una segunda etapa, presentamos su proceso de subversión personal sobre el que Teresa pudo reconducir esta situación. Como parte de las conclusiones, entendimos las medidas preventivas y de respeto a la diversidad como elementos esenciales para erradicar la violencia hacia las PCDI. (AU)

The results of a partial single-case study are presented through the bio-graphical-narrative perspective. Taking into account a broader previous field work, for this text we have conducted a semi-structured interview and two in depth to address in a focal way a case of rape and sexual abuse of Teresa, a person diagnosed with Intellectual Disability (PDID). From the interviews emerge different categories of inductive (do-mestic violence –sexual abuse, insults, assaults–, identity as a person with disabilities) that are addressed in the discussion in two interpretative axes that correspond to two distinct stages of the participant’s life (the naturalization of violence and the beginning of change as a form of struggle). As most noteworthy results we find facts, in a first stage, that tell us about the repetition over time of two types of abuses (physical, emo-tional) by their relatives, among which shines the condition of disability status, and, a second stage, we presented her process of personal subversion on which Teresa was able to reconnect this situation. As part of the conclusions, we understood preventive and diversity-respect measures as essential elements for eradicating violence against PCDI. (AU)

Violence, Suffering and Subversion: Notes From a Qualitative Study About Schooling Trajectories of Brazilian Young Homosexuals.

The objective of this article was to analyze the schooling trajectories of young homosexuals, as well as to verify situations that caused psychological distress in formal education environments. Three men who self-identified as homosexual participated in the research. Semi-structured, reflexive and group interviews were used as data collection methods and data were analyzed through Thematic Analysis. The participants' accounts revealed four key themes. 1) It was evident that the participants experienced multiple forms of violence and discrimination and that they suffered psychological distress in educational environments. As a result, 2) participants tended to hide their sexual identities in the school environment, reinforcing psychological distress. A key explanatory theme in the young people's accounts was 3) institutional neglect that centered on omissions and silences in the school context, thus reinscribing their invisibility. However, despite the detrimental environment and psychological distress, homosexual young men also 4) find ways to subvert and destabilize heteronormativity.

"Temos que devolver o jogo ao(à) jogador(a)": as dimensões éticas e morais da pedagogia dos esportes coletivos a partir de abordagens baseadas no jogo / "We have to give back the game to the player": ethical and moral dimensions of collective sports pedagogy from game-based approaches / "Tenemos que devolver el juego al/la jugador/a": dimensiones éticas y morales de la pedagogía de los deportes colectivos desde enfoques basados en el juego

Partimos da crítica à tendência utilitarista das abordagens baseadas no jogo (GBAs) com o objetivo de analisar como as dimensões éticas e morais se revelam no "ato de jogar" a partir da prática pedagógica do(a) treinador(a) dos esportes coletivos. Sustentados nos conceitos do "jogar" ético e do "esportear" moral, defendemos 1) a primazia do jogar sobre o esportear, 2) a necessidade de que os sentimentos éticos, manifestos pelo estado de jogo, passem pelo crivo da norma, representada pela atitude lusória e 3) que atitudes transgressoras e subversivas à regra sejam analisadas em função de sua fonte: amor a si ou resistência aos impasses promovidos pelas regras. Concluímos que o ato de jogar revela por si mesmo o plano ético-moral inerente ao jogo/esporte, sendo a instrumentalização do jogo com um comprometimento exclusivamente voltado à dimensão moral normativa um risco à dimensão ética inerente ao papel do(a) jogador(a). (AU)

We start from the critique of the utilitarian tendency of game-based approaches (GBAs) with the objective of analyzing how the ethical and moral dimensions are revealed in the "act of playing" from the coaches' pedagogical practice. Through the concepts of ethical "to play" and moral "to sport", we support 1) the primacy of playing over sporting, 2) the need for ethical feelings, manifested by the "state of play", to pass through the scrutiny of the "lusory attitude" and 3) that transgressive and subversive attitudes to the rule are considerable depending on their source: self-love or resistance to the impasses promoted by the rules. We conclude that the "act of playing" reveals by itself the ethical-moral plan inherent to the game/sport, and the instrumentalization of the game with a commitment exclusively focused on the normative moral dimension is a risk to the ethical dimension inherent to the role of the player.(AU)

Partimos de la crítica a la tendencia utilitarista de los enfoques basados en el juego (GBAs) con el objetivo de analizar cómo se revelan las dimensiones éticas y morales en el "acto de jugar" a partir de la práctica pedagógica del/la entrenador/a de deportes colectivos. A partir de los conceptos del "jugar" ético y del "deportear" moral, defendemos 1) la primacía del jugar sobre el "deportear," 2) la necesidad de que los sentimientos éticos, puestos de manifiesto por el estado de juego, pasen por el tamiz de la norma, representada por la actitud lusoria y 3) que las actitudes transgresoras y subversivas a la regla sean analizadas según su origen: amor propio o resistencia a los impasses promovidos por las reglas. Concluimos que el acto de jugar revela por sí mismo el plano ético-moral inherente al juego/deporte, y la instrumentalización del juego con un compromiso centrado exclusivamente en la dimensión moral normativa es un riesgo para la dimensión ética inherente al rol del jugador.(AU)

Leitura de textos literários como subversão à linguagem do poder / Literary text reading like subversion of the language of power

Este ensaio propõe apontamentos sobre as especificidades da leitura de textos literários como experiência potencialmente formadora de novos sentidos para o leitor e subversiva à linguagem do poder, com seus discursos normatizados e normatizadores do cotidiano. Foi realizada uma revisão narrativa de literatura sobre a temática, e dividiu-se este texto em quatro eixos centrais: o primeiro, em que se apresenta algumas concepções sobre literatura, texto literário e leitura literária; o segundo, em que se discorre sobre a leitura individual e de escuta, partindo do pressuposto de que tal modalidade possibilita ao leitor uma experiência criativa e crítica a partir da produção de sentidos derivada do encontro com o texto. Este ponto encontra-se intimamente relacionado ao terceiro, a leitura literária como experiência; e por fim, apresentam-se interpretações sobre a leitura literária como experiência de subversão à palavra de ordem e à linguagem do poder. Tal diálogo nos levou a concluir que a leitura literária pode representar uma resistência às naturalizações do instituído cotidiano, uma vez que ela se revela como um âmbito de produção de singularidades, instigando no leitor a interrogação sobre o mundo concreto ao seu redor e seus discursos hegemônicos.(AU)

This essay proposes notes on the specificities of reading literary texts as an experience, potentially forming new meanings for the reader, and subversive to the language of power, with its normative and normative discourses of daily life. To this end we conducted a narrative literature review on the subject, and divided this text into four central axes: in the first, we present some conceptions about literature, literary text and literary reading; in the second, we discuss about individual and listening reading, assuming that such modality allows the reader a creative and critical experience from the production of meanings derived from the encounter with the text. This point is closely related to the third, literary reading as an experience; and finally, we present interpretations about literary reading as an experience of subversion of the watchword and the language of power. This dialogue led us to conclude that literary reading may represent a resistance to the naturalizations of the daily institute, because it reveals itself as a scope for the production of singularities, prompting the reader to question the concrete world around him and his hegemonic discourses.(AU)

Este ensayo propone notas sobre las especificidades de la lectura de textos literarios como una experiencia que potencialmente forma nuevos significados para el lector y que es subversiva al lenguaje del poder, un lenguage con discursos normalizados y normalizadores de la vida cotidiana. Se realizó una revisión de la literatura narrativa sobre el tema, y ​​este texto se dividió en cuatro ejes centrales: el primero, en el que se presentan algunas concepciones sobre la literatura, el texto literario y la lectura literaria; el segundo, en que se discute la lectura y la escucha individual, a partir de la suposición de que esta modalidad permite al lector una experiencia creativa y crítica a partir de la producción de significados derivados de su encuentro con el texto. Este punto está muy relacionado con el tercero, la lectura literaria como experiencia; y finalmente, las interpretaciones de la lectura literaria se presentan como una experiencia de subversión a la orden y al lenguaje del poder. Este diálogo nos llevó a concluir que la lectura literaria puede representar una resistencia a las naturalizaciones en el cotidiano, pues se revela como un ámbito de producción de singularidades, e instiga al lector a cuestionar el mundo concreto que le rodea y sus discursos hegemónicos.(AU)

Dysfunctional BTN3A together with deregulated immune checkpoints and type I/II IFN dictate defective interplay between pDCs and γδ T cells in melanoma patients, which impacts clinical outcomes.

OBJECTIVES: pDCs and γδ T cells emerge as potent immune players participating in the pathophysiology of cancers, yet still remaining enigmatic while harbouring a promising potential for clinical translations. Despite strategic and closed missions, crosstalk between pDCs and γδ T cells has not been deciphered yet in cancers, especially in melanoma where the long-term control of the tumor still remains a challenge. METHODS: This prompted us to explore the interplay between pDCs and γδ T cells in the context of melanoma, investigating the reciprocal features of pDCs or γδ T cells, the underlying molecular mechanisms and its impact on clinical outcomes. RESULTS: TLRL-activated pDCs from the blood and tumor infiltrate of melanoma patients displayed an impaired ability to activate, to modulate immune checkpoints and trigger the functionality of γδ T cells. Conversely, γδ T cells from the blood or tumor infiltrate of melanoma patients activated by PAg were defective in triggering pDCs' activation and modulation of immune checkpoints, and failed to elicit the functionality of pDCs. Reversion of the dysfunctional cross-talks could be achieved by specific cytokine administration and immune checkpoint targeting. Strikingly, we revealed an increased expression of BTN3A on circulating and tumor-infiltrating pDCs and γδ T cells from melanoma patients, but stressed out the potential impairment of this molecule. CONCLUSION: Our study uncovered that melanoma hijacked the bidirectional interplay between pDCs and γδ T cells to escape from immune control, and revealed BTN3A dysfunction. Such understanding will help harness and synergise the power of these potent immune cells to design new therapeutic approaches exploiting their antitumor potential while counteracting their skewing by tumors to improve patient outcomes.