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Nel gennaio del 1946 la scrittrice tedesca Marie Luise Kaschnitz pubblica sulla neonata rivista “Die Wandlung” (Il cambiamento) il saggio Von der Schuld (Sulla colpa) nel quale reagisce, a pochi mesi dalla fine della guerra, alle accuse rivolte da più parti ai Tedeschi di aver consentito al nazismo di trascinare il mondo nella tragedia della Seconda Guerra Mondiale. Le pagine della Kaschnitz sono un documento dimenticato del dibattito, ad oggi inconcluso, sul tema della colpa dei Tedeschi che non opposero resistenza al regime di Adolf Hitler: esse non sono recuperate per decidere sulla condanna o sull’assoluzione della scrittrice e di chi con lei si definì ‘vigliacco’ per aver taciuto, bensì per cercare di comprendere le cause dal punto di vista umano del fenomeno della Innere Emigration, causato dal potere paralizzante esercitato dal regime del terrore, che chiuse ai più ogni via di fuga concreta e, soprattutto, la via della coscienza.

Nel contesto dell’orientalismo ottocentesco riveste un ruolo significativo la produzione narrativa dell’egittologo berlinese Georg Ebers (1837-1898), i cui romanzi rientrano nella categoria del Professorenroman. Al confine fra letteratura e storiografia, le opere di ambientazione egizia di Ebers diedero origine ad una vera e propria egittomania e fecero conoscere ad un vasto pubblico di lettori figure, eventi, usi e costumi dell’antica terra del Nilo, a quel tempo oggetto di studio della prima generazione di egittologi tedeschi (Lepsius, Brugsch); ma la trasposizione letteraria dell’antico mondo egizio fu anche occasione per mettere a tema questioni scottanti di natura religiosa, politica e sociale del presente. L’analisi del romanzo Uarda, un successo stampato in migliaia di copie, intende non solo mettere a fuoco la Weltanschauung di Ebers, ma g anche contribuire a riscoprire uno scrittore che, seppur di valore mediocre dal punto di vista letterario, rappresenta un tassello significativo dello Zeitgeist guglielmino.

In the global health crisis unleashed by the COVID-19 pandemic, understanding its multiple impacts on family budgets is emerging as a critical area of research. This study examines the impact of the pandemic on Romanian households, shedding light on how families navigated the economic upheavals caused by this unprecedented situation. Using a comprehensive methodological framework that includes secondary data analysis and opinion surveys, the research closely examines changes in income, expenditure patterns and the resilience strategies adopted by families to withstand the economic strain caused by the pandemic. The research reveals a significant disruption in household incomes and a marked shift towards more conservative spending habits, with an increased focus on essential expenses. It also reveals that families are adopting various adaptation strategies, including budget optimisation and seeking government assistance, to mitigate the economic impact of the pandemic. The results of the study are crucial for understanding the wider socio-economic impact of COVID-19 on family budgets and provide valuable insights for formulating targeted public policies to strengthen household resilience in the face of future crises. By examining the impact of the pandemic on family budgets in Romania, the study contributes to the academic discourse on crisis management and economic resilience. It highlights the need for comprehensive support mechanisms to protect vulnerable populations during global emergencies.

This study investigates the tempering behavior of bainite and martensite in a medium carbon, high silicon steel, with a focus on the microstructural evolution and the attainment of equilibrium, over a temperature range of 200–650 °C. The dissimilarities between the characteristics of the two initial microstructures, both comprising a C-saturated tetragonal ferrite matrix and retained austenite, are reflected in the differences observed in their evolution towards equilibrium as the tempering temperature increases. Therefore, while retained austenite plays a pivotal role in the bainitic microstructure, in the martensitic microstructure it is the ferritic matrix, which is highly dislocated and enriched in carbon, that plays a determinant role. The findings demonstrate that while both bainite and martensite can converge towards the same equilibrium state upon high-temperature tempering (600–650 °C), the pathway to this convergence is markedly different, with bainite exhibiting a slower transformation rate. This path to equilibrium has been characterised by means of high-resolution dilatometry, scanning electron microscopy and detailed X-ray diffraction analysis. This has provided a dynamic and detailed picture of the most relevant microstructural changes and tempering mechanisms in high silicon steels. It has also provided a foundation for tailoring heat treatment processes to optimise the mechanical properties of advanced bainitic and martensitic steels.

Tissue homeostasis, function recovery, and protection mechanisms are boosted by the balanced and timely control of inflammation and oxidative stress. Nowadays, many natural products and bio-derivates exhibit antioxidant and anti-inflammatory activity, supporting medical care and tissue wellness against inflammation, oxidative stress, and inflammaging. Castanea sativa wood distillate (WD) is a bio-derivative used as a corroborant and biofertilizer in agriculture. Based on the safety profile of low concentrations of WD on human cells, the present study aims to assess the anti-inflammatory and antioxidant activity of WD on different cell types in the integumentary system. Human keratinocytes, mucosal epithelium, dermal fibroblasts, and endothelial cells were exposed to WD, and the concentrations devoid of pro-apoptotic potential were profiled. Then, the effect of nontoxic doses of WD revealed an anti-inflammatory effect, observed through the immunodetection of prostanoid cascade markers in experimentally induced inflammation. A reduction in endothelial hyperpermeability was evidenced by the immunofluorescence analysis of cell–cell adhesion proteins, VE-cadherin and ZO-1. In addition, WD buffered the exogenously produced oxidative stress. On the whole, WD showed both anti-inflammatory and antioxidant activities on the various cell types, preserving endothelial barrier integrity. Overall, this study supports the involvement of this bio-derivative in novel exploitable fields, such as therapeutic dermatological applications for human and animal medical care.

Abstract The stigmas of Crocus sativus accumulate the exclusive apocarotenoids crocin and picrocrocin, which are dried and desiccated to make commercial saffron. In addition to providing characteristic organoleptic qualities, saffron apocarotenoids are valuable compounds in the pharmaceutical and health industries. Previously, we developed Desirée potato tubers enriched with these apocarotenoids which also showed increased potential benefits for human health. In the current study, Solanum tuberosum (S. tuberosum) Group Phureja 01H15 which accumulates high levels of zeaxanthin, was engineered to produce saffron apocarotenoids to increase the levels of these metabolites in potato tubers using a construct namely O6, which contains the CsCCD2L, UGT74AD1, and UGT709G1 genes necessary for the biosynthesis of crocin and picrocrocin under the control of the patatin promoter. Here, we obtained transgenic S. tuberosum Group Phureja 01H15 lines with high concentrations of crocins and picrocrocin (up to 3.648 mg/g DW, 2.345 mg/g DW, respectively), which were up to 10 and 3 times higher than those obtained in the Desirée background, respectively. Furthermore, we performed transcriptome analyses of tubers from Desirée and 01H15 wild type and carrying O6 construct. Differentially expressed gene analysis revealed transcript changes not only on tuber carotenoid and apocarotenoid genes but also in other related pathways, suggesting a possible role in isoprenoid metabolism remodeling. Thus, this heterologous system serves as a robust platform for the production of these valuable metabolites.

The COVID-19 pandemic caused global disruption in 2020, throwing the world into an unprecedented health crisis with unpredicted socio-economic consequences. Strikingly, politicians and supranational organizations failed to collaborate and coordinate a united global response. In light of this, this research study explores how the vaccine race may have been used as a weapon of political communication, constantly influenced by international relations and economic interests. This study analyses the US response to the COVID-19 pandemic and how the vaccine development was used to support Trump’s political discourse to gain international political leadership amidst the electoral campaign to become reelected. The core research findings show that President Trump’s administration started politicizing vaccine developments as the country became immersed in the 2020 presidential campaign. Furthermore, the reviewed literature and the empirical evidence suggest that advancements in the country’s pharmaceutical sector and the development of the COVID-19 vaccine were used as a communication weapon to affect Trump’s political campaign and the global COVID-19 vaccine race.

In this work, we provide with an overview of the main theories, metallurgical and microstructural concepts used for the design of carbide free bainitic steels adapted to industrial hot rolling and coiling practices. The selected alloys were cast and tested at pilot plant scale and the obtained good combinations of properties tend to validate the thorough and careful approach undertaken to predict the microstructures during the alloy design process.

The paper discusses the effect of prior martensite on the bainitic transformation of a high Si hypereutectoid steel. The research uses a combination of experimental techniques, high-resolution dilatometry and X-ray diffraction analysis, and theoretical calculations to investigate the impact of martensite on the transformation kinetics and microstructure evolution. The study shows that the presence of martensite, regardless of the amount, accelerates the bainitic transformation, particularly in the early and fastest stages, and at higher isothermal transformation temperatures. At lower temperatures, the preconditioning of the austenite prior to the bainitic transformation is such that its mechanical stability increases to the point where the whole transformation is inhibited. It is also suggested that the formation of cementite due to the tempering of martensite at the isothermal stage controls the final fraction of bainitic ferrite. The findings provide valuable insights into the role of prior martensite in bainitic transformation kinetics and microstructure development.

Abstract Exon junction complexes are deposited at exon-exon junctions during splicing. They are primarily known to activate non-sense mediated degradation of transcripts harbouring premature stop codons before the last intron. According to a popular model, exon-junction complexes accompany mRNAs to the cytoplasm where the first translating ribosome pushes them out. However, they are also removed by uncharacterized, translation-independent mechanisms. Little is known about kinetic and transcript specificity of these processes. Here we tag core subunits of exon-junction complexes with complementary split nanoluciferase fragments to obtain sensitive and quantitative assays for complex formation. Unexpectedly, exon-junction complexes form large stable mRNPs containing stalled ribosomes. Complex assembly and disassembly rates are determined after an arrest in transcription and/or translation. 85% of newly deposited exon-junction complexes are disassembled by a translation-dependent mechanism. However as this process is much faster than the translation-independent one, only 30% of the exon-junction complexes present in cells at steady state require translation for disassembly. Deep RNA sequencing shows a bias of exon-junction complex bound transcripts towards microtubule and centrosome coding ones and demonstrate that the lifetimes of exon-junction complexes are transcript-specific. This study provides a dynamic vision of exon-junction complexes and uncovers their unexpected stable association with ribosomes.

Abstract In the mouse embryo, the transition from the preimplantation to the postimplantation epiblast is governed by changes in the gene regulatory network (GRN) that lead to transcriptional, epigenetic, and functional changes. This transition can be faithfully recapitulated in vitro by the differentiation of mouse embryonic stem cells (mESCs) to epiblast-like cells (EpiLCs), that reside in naïve and formative states of pluripotency, respectively. However, the GRN that drives this conversion is not fully elucidated. Here we demonstrate that the transcription factor OCT6 is a key driver of this process. Firstly, we show that Oct6 is not expressed in mESCs but is rapidly induced as cells exit the naïve pluripotent state. By deleting Oct6 in mESCs, we find that knockout cells fail to acquire the typical morphological changes associated with the formative state when induced to differentiate. Additionally, the key naïve pluripotency TFs Nanog, Klf2, Nr5a2, Prdm14, and Esrrb were expressed at higher levels than in wild-type cells, indicating an incomplete dismantling of the naïve pluripotency GRN. Conversely, premature expression of Oct6 in naïve cells triggered a rapid morphological transformation mirroring differentiation, that was accompanied by the upregulation of the endogenous Oct6 as well as the formative genes Sox3, Zic2/3, Foxp1, Dnmt3A and FGF5. Strikingly, we found that OCT6 represses Nanog in a bistable manner and that this regulation is at the transcriptional level. Moreover, our findings also reveal that Oct6 is repressed by NANOG. Collectively, our results establish OCT6 as a key TF in the dissolution of the naïve pluripotent state and support a model where Oct6 and Nanog form a double negative feedback loop which could act as an important toggle mediating the transition to the formative state.

Abstract Periodically, the European Space Agency (ESA) updates scientific roadmaps in consultation with the scientific community. The ESA SciSpacE Science Community White Paper (SSCWP) 9, “Biology in Space and Analogue Environments”, focusses in 5 main topic areas, aiming to address key community-identified knowledge gaps in Space Biology. Here we present one of the identified topic areas, which is also an unanswered question of life science research in Space: “How to Obtain an Integrated Picture of the Molecular Networks Involved in Adaptation to Microgravity in Different Biological Systems?” The manuscript reports the main gaps of knowledge which have been identified by the community in the above topic area as well as the approach the community indicates to address the gaps not yet bridged. Moreover, the relevance that these research activities might have for the space exploration programs and also for application in industrial and technological fields on Earth is briefly discussed.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Abstract Progress in mechanobiology allowed us to better understand the important role of mechanical forces in the regulation of biological processes. Space research in the field of life sciences clearly showed that gravity plays a crucial role in biological processes. The space environment offers the unique opportunity to carry out experiments without gravity, helping us not only to understand the effects of gravitational alterations on biological systems but also the mechanisms underlying mechanoperception and cell/tissue response to mechanical and gravitational stresses. Despite the progress made so far, for future space exploration programs it is necessary to increase our knowledge on the mechanotransduction processes as well as on the molecular mechanisms underlying microgravity-induced cell and tissue alterations. This white paper reports the suggestions and recommendations of the SciSpacE Science Community for the elaboration of the section of the European Space Agency roadmap “Biology in Space and Analogue Environments” focusing on “How are cells and tissues influenced by gravity and what are the gravity perception mechanisms?” The knowledge gaps that prevent the Science Community from fully answering this question and the activities proposed to fill them are discussed.

Saffron (Crocus sativus L.), a historically significant crop valued for its nutraceutical properties, has been poorly explored from a phytosanitary perspective. This study conducted a thorough examination of viruses affecting saffron samples from Spanish cultivars, using high-throughput sequencing alongside a systematic survey of transcriptomic datasets from Crocus sativus at the Sequence Read Archive. Our analysis unveiled a broad diversity and abundance, identifying 17 viruses across the 52 analyzed libraries, some of which were highly prevalent. This includes known saffron-infecting viruses and previously unreported ones. In addition, we discovered 7 novel viruses from the Alphaflexiviridae, Betaflexiviridae, Potyviridae, Solemoviridae, and Geminiviridae families, with some present in libraries from various locations. These findings indicate that the saffron-associated virome is more complex than previously reported, emphasizing the potential of phytosanitary analysis to enhance saffron productivity.

The application of artificial intelligence to chemistry usually focuses on the identification of good correlations between descriptors and a given property of interest. The descriptors often come from arbitrary sets, with the implicit assumption that the evaluation of a sufficiently wide range of descriptors will lead to a satisfactory choice. Recent work in our group has focused on applying statistical analysis to large amounts of DFT results with the goal of finding optimal descriptor sets for a given property, which we label as hidden descriptors. This article briefly discusses this treatment and the chemical knowledge that has been gained through its application in two different domains: metal-ligand bond strength in transition metal complexes, and energy barriers in bimolecular nucleophilic substitution reactions.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Abstract Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8 + T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.

Abstract Background The exon junction complex (EJC) is involved in most steps of the mRNA life cycle, ranging from splicing to nonsense-mediated mRNA decay (NMD). It is assembled by the splicing machinery onto mRNA in a sequence-independent manner. A fundamental open question is whether the EJC is deposited onto all exon‒exon junctions or only on a subset of them. Several previous studies have made observations supportive of the latter, yet these have been limited by methodological constraints. Results In this study, we sought to overcome these limitations via the integration of two different approaches for transcriptome-wide mapping of EJCs. Our results revealed that nearly all, if not all, internal exons consistently harbor an EJC in Drosophila, demonstrating that EJC presence is an inherent consequence of the splicing reaction. Furthermore, our study underscores the limitations of eCLIP methods in fully elucidating the landscape of RBP binding sites. Our findings highlight how highly specific (low false positive) methodologies can lead to erroneous interpretations due to partial sensitivity (high false negatives). Conclusions This study contributes to our understanding of EJC deposition and its association with pre-mRNA splicing. The universal presence of EJC on internal exons underscores its significance in ensuring proper mRNA processing. Additionally, our observations highlight the need to consider both specificity and sensitivity in RBP mapping methodologies.

Background: The effect of the COVID-19 pandemic on healthcare systems emphasized the need for rapid and effective triage tools to identify patients at risk of severe or fatal infection. Measuring host response markers of inflammation and endothelial activation at clinical presentation may help to inform appropriate triage and care practices in patients with SARS-CoV-2 infection. Methods: We enrolled patients with COVID-19 across five GeoSentinel clinical sites (in Italy, Belgium, Canada, and the United States) from September 2020 to December 2021, and analyzed the association of plasma markers, including soluble urokinase-type plasminogen activator receptor (suPAR), soluble tumor necrosis factor receptor-1 (sTREM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), complement component C5a (C5a), von Willebrand factor (VWF-a2), and interleukin-1 receptor antagonist (IL-1Ra), with 28-day (D28) mortality and 7-day (D7) severity (discharged, hospitalized on ward, or died/admitted to the ICU). Results: Of 193 patients, 8.9% (16 of 180) died by D28. Higher concentrations of suPAR were associated with increased odds of mortality at D28 and severity at D7 in univariable and multivariable regression models. The biomarkers sTREM-1 and IL-1Ra showed bivariate associations with mortality at D28 and severity at D7. IL-6, VWF, C5a, and IL-8 were not as indicative of progression to severe disease or death. Conclusions: Our findings confirm previous studies’ assertions that point-of-care tests for suPAR and sTREM-1 could facilitate the triage of patients with SARS-CoV-2 infection, which may help guide hospital resource allocation.

HEV antibody detection constitutes the main screening test for HEV infection. The aim of this study is to compare the sensitivity and specificity of four techniques: LIAISON® MUREX DiaSorin anti-HEV IgG and anti-HEV IgM assays, Hepatitis E VIRCLIA® IgM and IgG monotests, WANTAI HEV-IgM and IgG ELISA and VIDAS® anti-HEV IgM and IgG tests in five panels of samples configurated according to the immunoblot (RecomLine, Mikrogen, Neuss, Germany). Anti-HEV IgM sensitivity in the acute phase was 100% in all techniques, while sensitivity, including the immediate convalescence phase, was 96.74% for LIAISON®, 83.14% for VIRCLIA®, 84.78% for WANTAI and 88.04% for VIDAS®. Anti-HEV IgM specificity was 100% for both LIAISON® and VIRCLIA®. Anti-HEV IgM WANTAI agreed with VIRCLIA® with a good Kappa coefficient (κ = 0.71). Anti-HEV IgG post-infection sensitivity was 100% for LIAISON®, VIDAS® and VIRCLIA® and 99% for WANTAI. Anti-HEV IgG specificity reached 97.17% for LIAISON and 88.68% for VIRCLIA®. Our results demonstrated a better capacity of LIAISON® MUREX anti-HEV IgM than that of competitors for detecting acute infections as well as accurate anti-HEV IgG results and in how to resolve them.

A set of planar motion mechanism experiments of the Duisburg Test Case Post-Panamax container model executed in a towing tank with shallow depth is applied to train a neural network to analyse the ability of the proposed model to learn the effects of different depth conditions on ship’s manoeuvring capabilities. The motivation of the work presented in this paper is to contribute an alternative and effective approach to model non-linear systems through artificial neural networks that address the manoeuvring simulation of ships in shallow water. The system is developed using the Levenberg–Marquardt backpropagation training algorithm and the resilient backpropagation scheme to demonstrate the correlation between the vessel forces and the respective trajectories and velocities. Sensitivity analyses were performed to identify the number of layers necessary for the proposed model to predict the vessel manoeuvring characteristics in two different depths. The outcomes achieved with the proposed system have shown excellent accuracy and ability in predicting ship manoeuvring with varying depths of shallow water.

Abstract The present white paper concerns the indications and recommendations of the SciSpacE Science Community to make progress in filling the gaps of knowledge that prevent us from answering the question: “How Do Gravity Alterations Affect Animal and Human Systems at a Cellular/Tissue Level?” This is one of the five major scientific issues of the ESA roadmap “Biology in Space and Analogue Environments”. Despite the many studies conducted so far on spaceflight adaptation mechanisms and related pathophysiological alterations observed in astronauts, we are not yet able to elaborate a synthetic integrated model of the many changes occurring at different system and functional levels. Consequently, it is difficult to develop credible models for predicting long-term consequences of human adaptation to the space environment, as well as to implement medical support plans for long-term missions and a strategy for preventing the possible health risks due to prolonged exposure to spaceflight beyond the low Earth orbit (LEO). The research activities suggested by the scientific community have the aim to overcome these problems by striving to connect biological and physiological aspects in a more holistic view of space adaptation effects.

Antecedentes: La sensibilización o alergia a medicamentos antimicrobianos tópicos es un problema conocido. Furacin® representa uno de los fármacos más prescritos en nuestro medio; sus principios activos son: nitrofurazona al 0.2% y polietilenglicol (PEG) como vehículo. Reporte de caso: Paciente masculino de 57 años, sin antecedentes de interés para el padecimiento actual, que inició con erupción cutánea, ampollas y exudado seroso 2 a 3 días después de aplicar Furacin® en una herida cutánea infectada. Se llevaron a cabo pruebas epicutáneas con batería true test, nitrofurantoína al 1% en vaselina, PEG 15000 y 4000 al 1% en vaselina, PEG 400 puro, y PEG monometil éter 350 al 1% en agua, con resultado positivo para nitrofurantoina luego de 96 horas. Conclusión: La nitrofurazona se indica ampliamente como antibiótico tópico, debido a su espectro bactericida; no obstante, debe considerarse (incluidos sus excipientes) en pacientes que manifiestan reacciones adversas después de su aplicación. Palabras clave: Dermatitis de contacto; Nitrofurazona; Antibióticos tópicos.

Antecedentes: Los exantemas cutáneos eritemato-papulares de breve duración sugieren el diagnóstico clínico de urticaria; no obstante, puede tratarse de otro tipo de dermatitis, y para establecer el diagnóstico deben llevarse a cabo exploraciones complementarias. Reporte de caso: Paciente femenina de 53 años, diagnosticada en 2016 con linfoma difuso de células B grandes, en remisión completa. Desde el 2010 manifestó episodios de lesiones eritemato-papulosas, de 24-36 horas de duración. Recibió antihistamínicos, corticoides y omalizumab sin mejoría clínica. La determinación de ANA resultó positiva (1/320), con patrón mitótico nuclear. La biopsia cutánea fue compatible con dermatitis herpetiforme. El estudio de anticuerpos de celiaquía y locus mostró positividad para HLA-DQ2 y DQ2.5 con heterocigosis. Se estableció el diagnosticó de dermatitis herpetiforme. El tratamiento consistió en dieta exenta de gluten y prescripción de dapsona, con resultados satisfactorios. Conclusión: Es importante establecer el diagnóstico diferencial de pacientes con urticaria crónica que no responden al tratamiento de referencia, además de efectuar el examen clínico y la exploración física exhaustivos antes de iniciar el protocolo, y apoyarse de un equipo multidisciplinario para establecer el diagnóstico certero y tratamiento adecuado. Debido a los efectos secundarios de la dapsona, es imprescindible el seguimiento posterior de los pacientes.

Amongst the attendees at Wittgenstein’s lecture to the Heretics Society in November 1929, there was also Alethea Graham, a student in her fourth year at Girton College who attended also his lectures in Lent Term 1930. Excerpts from her diary mentioning the philosopher are here transcribed and commented upon. A sharper focus on the audience of Wittgenstein’s Lecture on Ethics and his first academic class is then added.

Este artículo estudia las evoluciones técnicas y conceptuales del fotograma botánico, desde sus orígenes científicos procedentes de las impresiones del natural y los dibujos fotogénicos, hasta su recuperación en el arte por parte de las vanguardias y las representaciones contemporáneas. Analiza la relación entre imagen y referente en las imágenes de herbarios y cómo éstos han ido evolucionando tanto en propósito como en enfoque. Desde sus inicios, la fotografía anhelaba reproducir la realidad natural de manera precisa como forma de apoyo a la botánica. En un momento de expansión científica sin precedentes, la necesidad de registrar las plantas con rapidez y precisión pareció encontrar en la técnica del fotograma la solución definitiva. Sin embargo, ésta no acabó de cumplir las expectativas de la ciencia, por lo que, a lo largo del siglo XIX, el interés en esta herramienta disminuyó. En la actualidad, este método ha experimentado un renacimiento de la mano de artistas que reinterpretan el fotograma como una forma de explorar la naturaleza y generar contenido en torno a nuestra relación con el mundo vegetal. La química fotográfica se ha convertido en parte del propio proceso generador de contenido de la obra artística, haciéndonos reflexionar sobre temporalidad, materialidad y ecología, alejándose de su función original de mímesis.

Introduction: Emotional Intelligence (EI), defined as the ability to perceive, identify, understand, and regulate emotional states is related to health outcomes. In this line, some studies examined this personal resource in the cancer area and, specifically, in breast cancer. Also, the different models and measures have led to a categorisation considering the various construct-method pairings of EI. Despite the increased number of studies about EI in the breast cancer context, there are no systematic reviews that summarise the results obtained in the different investigations. Objectives: Hence, the present review aims: to identify and describe the measures that have been used for assessing EI within this field, and to summarise the main results regarding EI in terms of its predictors and outcomes, considering the instruments used to assess it. Methods: The PRISMA guidelines were followed. Database search was conducted in WOS, Scopus, Pubmed, and PSYCArticles. Results: A total of 156 articles were found and 21 met the eligibility criteria. On one hand, one of the most used instruments was the TMMS-24 framed within the self-report ability EI, followed by those framed within the self-report mixed EI. None of the studies measured EI by the performance-based ability EI perspective. On the other hand, EI was related to other variables such as psychological well-being, quality of life, resilience, workability, anxiety, and depression. The majority of the studies were cross-sectional, and some of them included an intervention. Conclusions: This review provides a comprehensive overview of the existing studies concerning EI in the context of breast cancer, highlighting some of its characteristics regarding design, participants, used measures, and related variables. Also, the obtained results can improve the clinical practice and the understanding of the EI as an influencing factor in the health and quality of life of breast cancer populations.

Analysing the financial performance of companies involves examining various aspects of a company’s financial activity, including profitability, liquidity, solvency, rate of return, cash flow and debt ratio. Beside the detailed information on the financial situation of a company, the financial performance analysis can help assess a company’s potential, including its ability to meet its financial goals. The present paper performs examining of annual financial reports of three companies from pharmaceutical sector from Romania and analysing key financial indicators during three years: ante-pandemic, pandemic, post-pandemic. The crisis generated by the COVID-19 pandemic has directly influenced all economic sectors worldwide, in most cases in a negative sense. At the opposite pole, the pharmaceutical industry had the opportunity to expand and improve its performance, as a result of the constant market need for medicines and medical devices. The financial performance analysis of the three most important pharmaceutical companies from Romania provides detailed information on financial situation of these companies. The paper underlines the importance of the analysis for making investment, management and strategic decisions, but also to identify trends and risks and assess the companies’ ability to meet their goals, presiding at the same time measures for long-term business expansion in a post-pandemic environment.

Abstract Point of care rapid diagnostic tests (POC-RDT) for Hepatitis C virus (HCV), Human Immunodeficiency virus (HIV) and Hepatitis B virus (HBV), are ideal for screening in non-clinical outreach settings as they can provide immediate results and facilitate diagnosis, allowing high risk population screening. The aim of this study was to compare POC-RDT with laboratory conventional tests. A total of 301 vulnerable evaluable subjects (drug users, migrants and homeless population) were recruited at a mobile screening unit in outreach settings in Madrid. Fingerprick whole blood capillary samples were tested using the SD BIOLINE HCV POC-RDT, Determine HIV Early Detect and Determine HBsAg 2, and the results were assessed against the LIAISON XL HCV, HIV and Murex-HBsAg-Quant, reference assays, respectively. The feasibility and user satisfaction of the POC-RDT were evaluated through a questionnaire. The resolved sensitivity and resolved specificity and their 95% confidence intervals (95% CI) were as follows, respectively: SD-BIOLINE-HCV: 98.8% (95% CI 93.4, 100.0) and 100.0% (95% CI 98.3, 100.0); Determine HIV Early Detect: 100% (95% CI 85.2, 100.0) and 100% (95% CI 98.7, 100); and Determine HBsAg 2: 66.7% (95% CI 9.4, 99.2) and 100.0% (95% CI 98.7, 100.0). As expected, the number of subjects with a confirmed positive result for HBsAg was very low (n = 4). Therefore, the analytical sensitivity has been evaluated in addition: The Determine HBsAg 2 test demonstrated 100% sensitivity for standard concentrations ≥ 0.125 IU/mL. The subject questionnaire yielded positive feedback for most subjects. The POC-RDT fingerprick blood collection method was well received, and the tests demonstrated a comparable clinical performance with conventional tests in outreach settings and vulnerable high-risk populations.

We conducted a prospective cohort study at the IRCCS Sacro Cuore Don Calabria Hospital in Negrar di Valpolicella from 2019 to 2021 to investigate the duration of T. whipplei colonization. In addition, the correlation between persistent colonization and the continent of origin, current treatment regimen, clinical manifestations, and parasite coinfection was evaluated. The cohort included subjects who were tested in a previous study (years 2014–2016) and found to be positive for T. whipplei DNA in fecal samples. Thirty-three subjects were enrolled in a prospective study between 2019 and 2021. Feces, saliva, urine, and blood were collected at baseline and after 12 months. Medical history, current treatment, and symptoms were recorded. Among them, 25% showed persistent intestinal or oral colonization, 50% had no colonization at both visits, and 25% had intermittent colonization. No association was found between persistent T. whipplei colonization and subjects’ continent of origin, current treatment regimen, initial clinical manifestations, and parasite coinfection. The longest duration of persistent T. whipplei intestinal colonization exceeded six years, with 11 subjects presenting persistent positivity for more than three years, including 1 minor. Our research was limited by the lack of a strain-specific identification of T. whipplei that made it impossible to distinguish between persistence of the same T. whipplei strain, reinfection from household exposure, or infection by a new strain. Larger prospective studies are needed to further explore the implications of this persistence and determine the key factors influencing the duration of colonization and its potential health impacts.

The maritime industry faces many pressing challenges due to increasing environmental and safety regulations and crew safety concerns [...]

The United Nations (UN) 2030 Agenda and Sustainable Development highlights the value of the Sustainable Development Goals (SDGs) in enabling societal progress. Contemporary society needs to consider sustainable development in a broader context where equity, diversity, and inclusion are integral to design of educational systems. Education can act as a disruptor that brings change to existing economic growth models misaligned with the needs and demands of modern society. As we transition to economic models that are more attuned to the needs of global society and planet, access to education, natural resources, and human talent is crucial for sustaining development, and allowing societies to continue advancing. However, it is imperative to deliberate on the necessity of adopting an alternative perspective on economic growth and its facilitation while adhering to the principles of sustainability. Inclusive, diverse, and transdisciplinary education can help to enhance quality learning, social equity, and resilience in nations, fostering intellectual empowerment, lifelong learning values, and a cohesive society. The prominence of education and its partners, training, and awareness has been recurrently underscored in UN assemblies, illuminating its capacity to address concerns such as climate change, violations of human rights, and degradation of the environment. Conversely, minimal headway in this realm indicates enduring and formidable hurdles obstructing the progress of education. Broadening the reach of education is fundamental for supporting an improved future. Although the expansion of educational opportunities is applauded, it is insufficient if the requirements of global economies are not considered. A thriving community requires substantial investment, and the capability of world economies to bring about change through capital investment is finite and dependent on access to scarce resources and their level of economic development. In addition, the fact that education has become an unattainable luxury good contributes to the widening gaps and distinctions between wealthier and less affluent nations. As such, there is a need to critically introspect on the role that education plays in driving sustainable development.

European countries need active and proactive educational systems assisted by models that can drive a cultural transformation, which supports sustainable socio-economic and environmental development. In this paper, we reflect on the future of European education by engaging on a critical review of the literature, which informs the further development of a novel pedagogy that we have coined as “Circular Pedagogy.” We offer some insights on how the foundations of a new educational model (ANEM) could be cemented and solidly supported by pillars that acknowledge our societies' rich and diverse cultures. Furthermore, the discussions are framed as part of the European University of Technology's (EUt+) consortium, as we reflect on its future educational model. Technological universities are in need of novel pedagogies that drive change as we “think human first.” European education faces significant challenges derived from the need to enable learning environments guided by equity, diversity, and inclusive frameworks for all categories of diverse learners. We propose a learner-centred, dynamic, and proactive pedagogy that can help us to manage and navigate the inevitable cultural conflict that will emerge as different societies and individuals seek to work together, to enable a better understanding and identification of the triggers that might arise due to potential cultural clashes and detachment.

The world's economies face acute anthropocentric challenges. We are witnessing significant structural disruption, driven by an urgent need to redress a historical focus on unchecked economic growth and unequal access to resources, requiring seismic transformations of our economic, social, and educational systems. Debate about sustainable development is becoming less controversial. Yet, many countries still struggle to commit to action. Whist political leaders engage in commendable discussion on sustainable practices, impacts range from rhetoric to constrained solutions. Our socio-economic and environmental challenges require collective effort, as we witness a contestation of development models that omit environmental preservation, lack inclusivity and compromise future generations. In this context, in which we seek alternative models that are more applicable to reality, education emerges as a driving force for change. Education already plays a role in the design of the socio-political economy. So, thoughtfully designed, it can help to define our understanding of sustainability beyond political and economic selection of goals and self-serving dimensions. Given transformative character, education can help to bridge the need for an inclusive and sustainable economic development model. Through an economic lens, this paper offers critical and reflective insights into how education can contribute to the necessary transformation for the achievement of the UN Sustainable Development Goals (SDGs). We argue that, with the right changes, education and economic development can be synergistic in pursuit of circularity, thereby meeting the requirements for just and equitable access, and preventing the depletion of natural resources needed for a thriving and flourishing humanity.

Research on small and medium-sized enterprises (SMEs) access to bank finance is vital for the euro area economy. SMEs heavily represent the European business sector, employing around 100 million people and accounting for more than half of the Gross Domestic Product. Research studies in the field often rely on the ECB/EC Survey on the Access to Finance of Enterprises (SAFE). Many studies employ probit or logit models with categorical dependent variables derived from SAFE. The research findings show that hardly any study employs the simpler linear probability model (LPM), with a dominant lack of research providing evidence that justifies the model selection process and suitability. However, it is well known that different econometrics models can lack consistency and frequently yield different results. Yet, the literature has no consensus on the best econometric approach. In addition, there is a lack of robustness tests in the literature to ensure model validity, underlining the need for a comprehensive review of the methodological framework that dominates SAFE data use. This paper addresses the identified research gap by introducing a robust methodological framework that helps researchers identify and choose an appropriate categorical model when using SAFE data. The study adds significant value to the extant literature by identifying four criteria that need to be considered when selecting the appropriate model among three common binary dependent models: LPM, probit and logit models. The findings show that the probit model was appropriate is all cases but that the LPM should not be disregarded, as it can be used in two cases: when considering the interaction between monetary policy and debt to assets and monetary policy and innovation. The use of the LPM is justified as a less complex econometric model, allowing for clearer communication of the results. This innovative, robust approach to choosing the appropriate econometric categorical dependent model when employing SAFE data contributes to support policy effectively.

Editorial for this Special Issue.

In this paper, we provide in-depth critical analysis and reflections on how technology, innovation and digital literacy can help to bring awareness on the need for a new dimension and approach to foster a transformational attitude towards education. Learning drives change, and if we aim to make an impact, there is a need to enable collaboration between different disciplines so that new transformative educational models can emerge. At the centre of our analysis, we identify the role of pedagogy and how it can contribute to put forward humans as central and critical actors in using science, technology, and innovations (STIs) to foster human security. We explore the critical role of Higher Education Institutions (HEIs) and their engagement with science, technology, and innovation in the search for educational transformation that supports multicultural, diverse and inclusive learning environments within the tenets of social engagement and cohesion that guide us towards the principles of human security.

TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.

Socially responsible mutual funds (SRMF) and the "antisocially conscious", Vitium Global Fund Barrier Fund (formerly known as the Vice Fund, the term used in this paper) returns, volatility patterns, and causal effects are examined in this study within the context of the lessons learned from the 2008 Global Economic and Financial Crisis (GEFC). In times of a new and unprecedented crisis due to the COVID-19 pandemic, a look back to our recent past reveals that volatility patterns on daily stock returns presented some level of predictability on prices for both types of funds. The research findings are significant as funds' potential predictability could help market players when designing their investment strategies. More specifically, an increase in volatility persistence is found after the GEFC, together with an increase in the Vice Fund's resilience to market shocks. Although all funds, without substantial differences, take time to absorb the shocks. A noteworthy outcome relates to SRMF that was able to achieve higher returns and exhibited lower volatility levels during the crisis period. Whereas the Vice Fund revealed long-run sustainable performance offering fund managers and investors investment opportunities that are endorsed by the fund performance over the period. Furthermore, unidirectional causality was found running from the Vice Fund to the SRMF, exhibiting a clear dominance during the GEFC period. The research findings contribute to the debate on the future of socially responsible investment, indicating that SRMF appears to be driven by "antisocially conscious" funds signaling limited rewards for investors inclined to invest in funds that are considered socially responsible.

Companies that think and tend towards sustainability and sustainable development must register and present certain levels of performance, so as to ensure the sustained support of all the company's stakeholders. The objective of the work is the synthetic presentation of the aspects related to the theories of the performance of companies listed on the stock exchange, the utility of stock indices, it proposes indicators to be taken into account by investors and other stakeholders. Also, specific stock market performance indicators are calculated for two Romanian pharmaceutical companies, emphasizing their role for stakeholders (like Earnings per Share, Dividend per Share, Equity per share or net asset per share, Stock market capitalization, Marketability, etc), starting from the information published in the annual financial statements (submitted to the competent ministry), as well as the stock market quotations. Unfortunately for stakeholders, companies present and publish information favourable to their image, which is sometimes considered unrealistic and superficial. The conclusions of the paper summarize the importance of standardizing the presentation of the performance indicators of the companies, in order to ensure a faithful image of the company, as well as the success of an existing or potential investment.

Corporate governance is gaining interest not only from investors but companies that want to operate in international markets, prompting a more thorough analysis of the field to prioritise stakeholder interests alongside shareholder value. By adopting a holistic approach that considers stakeholders’ diverse needs and expectations, companies can build resilience, foster trust, and create sustainable value for all stakeholders, ensuring long-term success and societal impact. This paper analyses corporate governance principles applied at the international, European, and national levels, emphasising the importance of the field for the stakeholders. The practical approach of the paper analyses the application and compliance of the corporate governance code of 18 companies in the field of financial intermediation and insurance, which are listed on the Bucharest Stock Exchange, underlining the crucial role of transparency of operations in instilling confidence and reassurance in stakeholders. The conclusions present proposals for measures to improve corporate governance practices at the level of companies.

The olive fruit fly (Bactrocera oleae Rossi) is the most dangerous pest of olive fruits and negatively influences the chemical and sensory quality of the oil produced. Organic farms have few tools against this pest and are constantly looking for effective and sustainable products such as geomaterials, i.e., zeolite. Since a particle film covers the canopy, a study was carried out on the olive tree’s responses to zeolite foliar coating. The tested treatments were natural zeolite (NZ), zeolite enriched with ammonium (EZ), and Spintor-Fly® (SF). EZ was associated with higher photosynthetic activity with respect to the other treatments, while no differences were found between SF and NZ. Foliar treatments affect the amount of BVOC produced in both leaves and olives, where 26 and 23 different BVOCs (biogenic volatile organic compounds) were identified but not the type of compounds emitted. Foliar treatment with EZ significantly affected fruit size, and the olive fruit fly more frequently attacked the olives, while treatment with NZ had olives with similar size and attack as those treated with Spintor-Fly®; no difference in oil quantity was detected. Oil produced from olives treated with NZ presented higher values of phenolic content and intensities of bitterness and spiciness than oils from those treated with EZ and SF. According to the results of this study, using zeolite films on an olive tree canopy does not negatively influence plant physiology; it has an impact on BVOC emission and the chemical and sensory characteristics of the oil.

Antecedentes: La quinina es un alcaloide con propiedades antipiréticas, antiinfecciosas y, además, un ingrediente del agua tónica. Se han descrito reacciones adversas con este producto, como fotosensibilidad, vasculitis y dermatitis de contacto. Reporte de caso: Paciente masculino de 31 años, que luego de 3-4 horas de consumir ginebra con agua tónica “Schweppes®” manifestó úlceras en los labios y la cavidad bucal, y una lesión eritematosa fija en la segunda falange de la mano, 24 horas después. Las pruebas cutáneas con aeroalérgenos y alimentos resultaron negativas, y las pruebas epicutáneas de 48 horas positivas (quinina [++] y “Schweppes®” [++]). Con base en los hallazgos de las pruebas, se estableció el diagnóstico de reacción adversa por quinina, contenida en el agua tónica. Conclusión: La quinina puede encontrarse en diferentes alimentos o medicamentos, por lo que es importante establecer el diagnóstico preciso y ofrecer recomendaciones adecuadas por el consumo de este producto.

ABSTRACT SARS-CoV-2 vaccine protection has encountered waning of immune response and breakthrough infections. The hybrid immune response generated by the combination of vaccination and infection was shown to offer higher and broader protection. Here, we present a seroprevalence study of anti-SARS-CoV-2 spike/RBD IgG in 1,121 health care workers immunized with Sputnik V and a follow-up of humoral response at 2 and 24 weeks postvaccination (wpv), including neutralizing antibody response (NAT) against ancestral, Gamma, and Delta variants. The first seroprevalence study showed that among 122 individuals with one dose, 90.2% were seropositive versus 99.7% seropositivity among volunteers with the complete two-dose regimen. At 24 wpv, 98.7% of the volunteers remained seropositive, although antibody levels decreased. IgG levels and NAT were higher in individuals that had acquired COVID-19 previous to vaccination than in naive individuals at 2 and 24 wpv. Antibody levels dropped over time in both groups. In contrast, IgG levels and NAT increased after vaccine breakthrough infection. At 2 wpv, 35/40 naive individuals had detectable NAT against SARS-CoV-2 Gamma and 6/40 against Delta. In turn, 8/9 previously infected individuals developed a neutralizing response against SARS-CoV-2 Gamma and 4/9 against Delta variants. NAT against variants followed a trajectory similar to NAT against ancestral SARS-CoV-2, and breakthrough infection led to an increase in NAT and complete seroconversion against variants. In conclusion, Sputnik V-induced humoral response persisted at 6 months postvaccination, and hybrid immunity induced higher levels of anti-S/RBD antibodies and NAT in previously exposed individuals, boosted the response after vaccination, and conferred wider breadth of protection. IMPORTANCE Since December 2020, Argentina has begun a mass vaccination program. The first vaccine available in our country was Sputnik V, which has been approved for use in 71 countries with a total population of 4 billion people. Despite all the available information, there are fewer published studies on the response induced by Sputnik V vaccination compared to that of other vaccines. Although the global political context has paralyzed the verification by the WHO of the efficacy of this vaccine, our work aims to add new clear and necessary evidence to Sputnik V performance. Our results contribute to general knowledge of the humoral immune response developed by vaccines based on viral vector technology, highlighting the higher immune protection conferred by hybrid immunity and reinforcing the importance of completing vaccination schedules and booster doses to maintain adequate antibody levels.

Sensory-processing sensitivity (SPS) defined, as a personality trait, seems to be characterized by emotional sensitivity, and stronger reactivity to both external and internal stimuli. SPS can represent a risk factor for developing clinical conditions during childhood and adolescence. This personality trait is not to be considered a pathological clinical condition, however, can expose to greater environmental vulnerability. In particular, the recent studies about SPS can be contextualized to social situations that evoke traumatic and stressful emotional responses such as social exclusion. We hypothesize that highly sensitive people (HSP) are more vulnerable to social exclusion and social pain. This hypothesis could help structure new educational and intervention models designed to improve coping strategies and promote HSP’s psychophysical and social well-being.

Similar to other industries, the maritime industry is also facing increasing restrictions on ships regarding pollution control. The research presented in this paper is aimed at studying the pros and cons of alternative fuels followed by a detailed analysis on hydrogen fuel cells (PEMFC) for a particular ship operating in Lisbon, Portugal. Dynamic forces acting on the ship have been studied for a year. Assessing various scenarios based on these results aids ship operators in making informed decisions regarding the future course of action for their existing vessels. These different cases are first: business as usual (diesel engine), second: replacing the diesel engine with a hydrogen hybrid system and, third: replacement of the ship with a new hydrogen hybrid ship. The study is based on the simulation of numerical equations and CFD simulation results. As the result, the second scenario is best suited in both aspects; namely, environmental and economic.

Abstract A better understanding of schizophrenia subtypes is necessary to stratify the patients according to clinical attributes. To explore the genomic architecture of schizophrenia symptomatology, we analyzed blood co-expression modules and their association with clinical data from patients in remission after a first episode of schizophrenia. In total, 91 participants of the 2EPS project were included. Gene expression was assessed using the Clariom S Human Array. Weighted-gene co-expression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its correlation with global functioning, clinical symptomatology, and premorbid adjustment. Among the 25 modules identified, six modules were significantly correlated with clinical data. These modules could be clustered in two groups according to their correlation with clinical data. Hub genes in each group showing overlap with risk genes for schizophrenia were enriched in biological processes related to metabolic processes, regulation of gene expression, cellular localization and protein transport, immune processes, and neurotrophin pathways. Our results indicate that modules with significant associations with clinical data showed overlap with gene sets previously identified in differential gene-expression analysis in brain, indicating that peripheral tissues could reveal pathogenic mechanisms. Hub genes involved in these modules revealed multiple signaling pathways previously related to schizophrenia, which may represent the complex interplay in the pathological mechanisms behind the disease. These genes could represent potential targets for the development of peripheral biomarkers underlying illness traits in clinical remission stages after a first episode of schizophrenia.

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.