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Abstract Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL–based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies.

“Beyond the threshold of war, there seemed to be no reality and no past” (Hoffman 13). In her celebrated book After Such Knowledge: A Meditation on the Aftermath of the Holocaust (2004), Hoffman discusses the pervading presence of the Shoah in Jewish culture and memory, its psychological, emotional, and the historical reverberations of such catastrophe but, above all, she analyzes the effects this has had on the survivors’ descendants. Also described by Hirsch, members of the second generation—like Hoffman and herself—established a strong relationship to “the personal, collective, and cultural trauma of those who came before” so much so that their parents’ memories “constitute memories in their own right” (Hirsch 5). This has had such a powerful influence on later generations who have grown up with such inherited memories of catastrophe and trauma, that many of them have started questioning some of these accounts. One such writer is the Jewish American author Nathan Englander who, in his critically acclaimed short story collection What We Talk About When We Talk Anne Frank (2012), engages in a discussion regarding postmemory and its influence on the creation of both a Jewish cultural narrative and collective memory, and how this affects the characters’ lives on many different levels, as well as the voices of third generation authors indirectly. In his work, Englander addresses the discussion of the memory of the Shoah and its later rewritings in quite a provocative way: by means of humor which, as scholars such as Rosenberg and Krijnen maintain, seems to constitute one of the main characteristics of contemporary Jewish writing (Rosenberg 2015; Krijnen 2016). Therefore, it is the aim of this article to analyze Englander’s use of such technique to provide new insights on what it means to be Jewish American today and the effects of the Shoah and its inherited memory on third-generation Jewish American intellectuals.

Abstract Background Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment. Methods HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry. Results HCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNβ-treated RRMS patients but not in HCMV(−) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNβ. Considering the B cell functional profile, HCMV(−) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001). Conclusions Our study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS.

Des de principis del segle xxi, una nova fornada d’estudis sobre la història del cooperativisme s’ha interessat per la influència d’aquest moviment d’emancipació en la configuració dels barris populars. Des d’una perspectiva urbana i microhistò- rica, la recerca sobre cooperatives i cooperativistes ha nodrit l’anàlisi de les relacions entre cooperativisme, obrerisme i associacionisme popular. L’estudi de la trajectòria de Celestí Ventura Raballí (1892-1969) en el sindicalisme i el cooperativisme, i la seva dedicació a la cooperativa La Fraternitat de la Barceloneta (Barcelona) per- met aprofundir en aquestes relacions de dues maneres. En primer lloc, examinant el rol de les cooperatives com a rereguarda del moviment obrer i, de forma més general, les mútues influències entre lluites obreres i expansió del cooperativisme. En segon lloc, i atenent a la participació de Ventura en les estructures sindicalistes, cooperativistes i mutualistes, explorant la multiplicitat de funcions que caracteritzà l’associacionisme obrerista a Catalunya durant bona part del segle xx.

Epstein Barr virus (EBV) causes a highly prevalent and lifelong infection contributing to the development of some malignancies. In addition to the key role played by T cells in controlling this pathogen, NK cells mediate cytotoxicity and IFNγ production in response to EBV-infected B cells in lytic cycle, both directly and through antibody (Ab)-dependent activation. We recently described that EBV-specific Ab-dependent NK cell interaction with viral particles (VP) bound to B cells triggered degranulation and TNFα secretion but not B cell lysis nor IFNγ production. In this report we show that NK cell activation under these conditions reduced B cell transformation by EBV. NK cells eliminated VP from the surface of B cells through a specific and active process which required tyrosine kinase activation, actin polymerization and Ca2+, being independent of proteolysis and perforin. VP were displayed at the NK cell surface before being internalized and partially shuttled to early endosomes and lysosomes. VP transfer was encompassed by a trogocytosis process including the EBV receptor CD21, together with CD19 and CD20. Our study reveals a novel facet of the antibody-dependent NK cell mediated response to this viral infection.

An accumulated rainfall of around 100 mm favoured the productivity of the specialist Moustached Warbler Acrocephalus melanopogon, but temperature had a negative effect. By contrast, temperature had a positive effect on the productivity of the generalist Reed Warbler Acrocephalus scirpaceus, whereas rainfall had almost no effect, although productivity also peaked when rainfall approached 100 mm. Understanding the extent to which climate and geography are driving the negative trend of Moustached Warbler productivity, and the stable trend of Reed Warbler productivity. Using data from a breeding bird monitoring ringing scheme in Spain (PASER; 1995 – 2021), we investigated the effects of seasonal rainfall and temperature patterns on the productivity of two sympatric warblers: the resident/short-distance migrant Moustached Warbler (occurring at nine ringing stations from a total of 129), and the generalist long-distance migrant Reed Warbler (57 out of 129 ringing stations). Analyses were performed using multi-adaptive regression splines (MARS). Between 1995 and 2021 geographical and site-specific factors drove annual productivity for both species, combined with rainfall and temperature. For the Moustached Warbler, geographical and site-related variables, together with the temporal changes (year), were more important than rainfall and temperature. For the Reed Warbler, temperature was more important than year but less than site and longitude. Warmer temperatures and a higher frequency of torrential rainfall events may compromise the conservation of the vulnerable Moustached Warbler in Spain due to the adverse effect on productivity. In contrast, increasing temperatures across Spain may benefit the widely distributed Reed Warbler. Thus, Moustached Warbler populations are likely to decrease, whereas Reed Warbler populations might increase. However, further research is needed to establish the impact of climate change on survival, and its implications for the population trends and dynamics of these two sympatric warblers. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(–), and PLZF(–) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(–) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(–) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-β therapy was associated with lower proportions of FcRγ(–) CD56dim NK cells in HCMV(+) and increased PLZF(–) CD56bright NK cells in HCMV(–) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(–) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS.

The following article offers a study and reassessment of the controversial figure of Alexander Crummell, an African American leader whose influence has been neglected by most scholars. His postbellum ideas on the advancement of black people influenced some of his contemporaries like Booker T. Washington and even later leaders such as W. E. B. DuBois. The article also offers an interpretation of two of Crummell’s most famous speeches on the future of his race, which suggest possible solutions to the tensions and problems experienced by his people after the end of the Civil War.

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This study describes the grammar-related behaviours of three experienced non-native teachers of English working in state secondary schools in Catalonia and investigates what beliefs may explain, from the teachers' point of view, these behaviours; it also examines what factors in their turn determine these beliefs. The results uncover three essentially different approaches to metatalk, which have their origins in complex and varied relationships between cognitive, experiential and contextual factors. (Contains 6 notes.)

La autora presenta en este texto la experiencia que lleva a cabo dentro del programa Todo lo que me gusta es ilegal, inmoral o engorda, en el que los organizadores invitan a un artista a compartir con el público asistente aspectos relacionados con sus procesos de trabajo. Encerrarse en una librería para imaginar secciones, que tuvo lugar en la librería Múltiplos -que dirige la autora-, se concretó en una serie de sesiones de trabajo enfocadas al tema de los libros y sus sistemas de clasificación. En este marco de reflexión, asistimos al relato, contado en primera persona, de la experiencia de encerrarse durante tres días en la librería Múltiplos con dos objetivos: leer todos los libros, y construir una clasificación que diera lugar a una librería con secciones. Un experimento que carecía de guión, y cuya formalización se concretaría en el transcurso de ese fin de semana. Tras llevar a cabo ese proyecto, la autora se enfrenta a la fragilidad de todo sistema de clasificación, por arbitrario, relativo y cambiante. Una fragilidad que es a la vez tan sólida en su potencial como productora de sub- jetividad. A partir de una misma colección de libros se pueden generar múltiples y quizás infinitas librerías con secciones. Y, más allá de sus connotaciones pragmáticas e incluso estéticas, la experiencia hará ver cómo cual- quier clasificación puede ser, sobre todo, una excusa para articular el pensamiento, tan ne- cesaria como lo es la escritura.

Roger Sordé1,2, Albert Pahissa1,2, Jordi Rello3,41Department of Infectious Diseases, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; 2Spanish Network for Research in Infectious Diseases (REIPI), Spain; 3Department of Critical Care, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; 4CIBER Enfermedades Respiratorias (CIBERES), SpainAbstract: Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations. The main cause of death in CF patients is respiratory failure resulting from chronic pulmonary infection. Pseudomonas aeruginosa is the most prevalent organism in the airway colonization of CF patients, and its persistence in the airways has been related to greater morbidity with a more rapid deterioration in lung function. P. aeruginosa has enormous genetic and metabolic flexibility that allows it to adapt and persist within the airways of CF patients, and it has the ability to easily acquire antimicrobial resistance. For these reasons, the management of infections and chronic colonization by P. aeruginosa remains a challenge for physicians. This article reviews the current and future antibacterial chemotherapy options for respiratory pseudomonal infection in CF patients.Keywords: cystic fibrosis, Pseudomonas aeruginosa, respiratory infection, antimicrobial treatment