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Background: COVID-19 causes significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. It remains unclear which host factors determine disease severity and survival. Given the propensity of clonal hematopoiesis (CH) to promote inflammation in healthy individuals, we investigated its effect on COVID-19 outcomes. Method(s): We performed a multi-omics interrogation of the genome, epigenome, transcriptome, and proteome of peripheral blood mononuclear cells from COVID-19 patients (n=227). We obtained clinical data, laboratory studies, and survival outcomes. We determined CH status and TET2-related DNA methylation. We performed single-cell proteogenomics to understand clonal composition in relation to cell phenotype. We interrogated single-cell gene expression in isolation and in conjunction with DNA accessibility. We integrated these multi-omics data to understand the effect of CH on clonal composition, gene expression, methylation of cis-regulatory elements, and lineage commitment in COVID-19 patients. We performed shRNA knockdowns to validate the effect of one candidate transcription factor in myeloid cell lines. Result(s): The presence of CH was strongly associated with COVID-19 severity and all-cause mortality, independent of age (HR 3.48, 95% CI 1.45-8.36, p=0.005). Differential methylation of promoters and enhancers was prevalent in TET2-mutant, but not DNMT3A-mutant CH. TET2- mutant CH was associated with enhanced classical/intermediate monocytosis and single-cell proteogenomics confirmed an enrichment of TET2 mutations in these cell types. We identified celltype specific gene expression changes associated with TET2 mutations in 102,072 single cells (n=34). Single-cell RNA-seq confirmed the skewing of hematopoiesis towards classical and intermediate monocytes and demonstrated the downregulation of EGR1 (a transcription factor important for monocyte differentiation) along with up-regulation of the lncRNA MALAT1 in monocytes. Combined scRNA-/scATAC-seq in 43,160 single cells (n=18) confirmed the skewing of hematopoiesis and up-regulation of MALAT1 in monocytes along with decreased accessibility of EGR1 motifs in known cis-regulatory elements. Using myeloid cell lines for functional validation, shRNA knockdowns of EGR1 confirmed the up-regulation of MALAT1 (in comparison to wildtype controls). Conclusion(s): CH is an independent prognostic factor in COVID-19 and skews hematopoiesis towards monocytosis. TET2-mutant CH is characterized by differential methylation and accessibility of enhancers binding myeloid transcriptions factors including EGR1. The ensuing loss of EGR1 expression in monocytes causes MALAT1 overexpression, a factor known to promote monocyte differentiation and inflammation. These data provide a mechanistic insight to the adverse prognostic impact of CH in COVID-19.
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Background: The pandemic of Coronavirus disease 19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), has become a global challenge in the last two years. SARS-CoV- 2 enters the cells of the infected subjects through angiotensin converting enzyme 2 (ACE-2), leading to its depletion on cell surface. ACE-2 activity is involved in the catabolism of des-Arg( 9)-bradykinin and increases the expression of angiotensin converting enzyme (ACE) in animal models. ACE in turn inactivates bradykinin. The infection has therefore the potential to cause a deregulation of the contact system and its pro-inflammatory activity, which could also contribute to the pathogenesis of COVID-19. Since bradykinin-mediated angioedema is generally thought to be the result of a poorly regulated contact system, it has been speculated that these patients are prone to severe SARS-CoV- 2 infection and that COVID-19 can in turn elicit angioedema attacks. We examined these hypotheses in a large group of bradykinin-mediated angioedema patients. Method(s): W e c onducted a m ulticenter r etrospective s tudy t argeting all the patients with hereditary angioedema (HAE) or acquired angioedema due to C1 inhibitor deficiency followed up by the centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). All accessible patients underwent a telephone interview between January 1st and March 31st 2021;we collected data about demographic and angioedema features, the occurrence of SARS-CoV- 2 positivity and COVID-19 outcomes from the beginning of the pandemic until March 31st 2021. A digital diary of attacks developed by ITACA helped us to collect attacks data. 15 centers participated in the survey. Result(s): 677 patients were included;52/677 reported SARS-CoV- 2 positivity (48 with hereditary and 4 with acquired C1 inhibitor deficiency). The incidence was 7.68% (confidence interval 5,79-9,95%), similar to the general population (6.04%). 4/52 patients (7.7%) reported severe COVID-19;the median disease duration was 15 days. One patient suffered a pulmonary thromboembolism;no deaths were reported. 27/52 patients (51,9%) had angioedema attacks during the infection, with a median of 1 attack per patient;severity of COVID-19 predicted more frequent and more severe angioedema attacks in a multivariate analysis (p < 0.001). Conclusion(s): COVID-19 does not seem more severe in bradykinin-mediated angioedema than in the general population. SARS-CoV- 2 infection can elicit angioedema attacks.
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Los retos a los que se enfrenta la Unión Europea crean en ocasiones situaciones de tensión, en las que la organización debe responder al mismo tiempo a la protección y garantía de los derechos fundamentales de su ciudadanía, y a necesidades de índole global que excepcionalmente requieren la suspensión de esos mismos derechos por un bien mayor. Este fue el caso durante la pandemia de 2020, en el que la Unión Europea y los Estados miembros decretaron cuarentenas en contra de la libertad de movimiento, para restringir los contactos e intentar contener los contagios. En este contexto se produjo también una implementación de políticas digitales para afrontar la gestión de la crisis, en concreto nos referimos a las aplicaciones covid de rastreo y vigilancia de los contactos entre individuos. Estas aplicaciones estaban sujetas a los requisitos y garantías del marco legislativo comunitario, que hemos visto evolucionar en los últimos dos años, para hacer frente a la creciente digitalización de los servicios públicos. El caso de las aplicaciones covid es paradigmático para observar cómo se ha producido esa adaptación. La injerencia de los estados de forma excepcional durante la crisis, pero regulada hoy en instrumentos de coordinación comunitarios, ha creado nuevos marcos de navegación en internet. Los usuarios cuentan ahora con un nuevo nivel de protección de sus datos personales y su derecho a la privacidad, que si bien venía garantizada por el Reglamento de Protección de Datos (679/2016), ha dado un importante paso adelante con la aceleración de la digitalización de la administración durante la pandemia. Además, a través de una crítica desde la teoría contractual, podemos ver cómo la Unión Europea ha respondido a las dinámicas globales a nivel de normativa digital, priorizando hoy un sistema de contrapesos y límites tanto a las empresas como a las administraciones públicas, en su intercambio con los usuarios en internet. Las aplicaciones covid materializan esas limitaciones y garantías de protección de los usuarios (esencialmente de su privacidad y derechos fundamentales), que nos llevan a plantear la creación de un nuevo contrato social digital, igual que se ha transformado en otras ocasiones para responder a cuestiones como la clase, el género, la raza y la ecología.Alternate :The challenges facing the European Union (EU) can sometimes create tensions, in which the organization must answer both to the protection and guarantee of the fundamental rights of its citizens, and to global needs that exceptionally require the suspension of those same rights for the greater good. In its liberal political tradition that believes in the existence of a public and a private sphere, it has established systems of checks and balances, rule of law and stable institutions to protect the rights and freedoms of its citizens.Yet sometimes these must be suspended in cases of exceptionality for their own preservation. This was the case during the 2020 pandemic, when the European Union and its member States decreed quarantines against the consolidated and fundamental freedom of movement of persons, to restrict contacts and try to contain contagions. In this context, digital policies were also implemented to deal with crisis management, like Covid applications for tracing and monitoring contacts between individuals. This invasion of the private sphere of citizens had to be accompanied by a set of limitations and guarantees, to protect this inherent and private individual's right. These applications were subject to the requirements of the European legislative framework (the commonly known acquis communautaire), which included several legal instruments laid out by the EU to create a framework to guide the performance of its member-state Governments on this matter. Apart from the GDPR and the ePrivacy Directive, we underline the importance of Recommendation (EU) 2020/518 that connects health rights, health management and data protection;and also, the importance of Communication 2020/C 124 I/01 th t set a series of ideal elements to guide apps functions, and established the importance that it is Government agencies that manage digital apps, so there is a guarantee of the protection of citizens' rights. Through the comparative study of how apps were managed when they first appeared in 2020 throughout most of 2021, and how apps evolved (both in management and use) in 2021 and throughout 2022, we can address the evolution of EU policy on digital matters, which have meant to create new frameworks for internet navigation. At first, there were 24 different apps for the 24 out of 27 Member States who decided to create and promote the use of these instruments among their citizens. Most of them were managed by national authorities (except for Austria and Romania who were managed by Red Cross and a local NGO respectively), and were developed by a public-private collaboration, or only public agencies.At the end of the crisis, at least politically since societal weariness and the economic crisis rendered it difficult to keep up the restrictions introduced in the spring of 2020, in June 2021 the EU created its GreenPass or vaccination passport.This policy was implemented in most countries and even though 24 different national health services were still in place, they all used the EU passport, available to citizens via their national health websites or apps. Even though the exceptionality of the pandemic has ended, one of the outcomes has been the establishment of a system of data gathering, storage and management for public means, managed by National Authorities, which has technically created a digital contract where the State guarantees citizens' digital rights. This is even more important as we attend to an increase in the digitalization of public services, especially since 2020.The changes were thus promoted in a state of exception during the crisis to regulate Government interference in the citizen's private sphere but have laid a roadmap for the development of the digital framework, which may lead to the conclusion of a digital social contract. The social contract appears in the EU's liberal tradition as a metaphor of the relation between the State and the individual, it defines the notion of sovereignty as the set of rights possessed by the citizen that may be subject to special protection. Hence, the social contract serves as the basis for creating modern societies, yet it is not permanent and can (and will) change when societies change accordingly. Several critiques have been made to the original social contract, creating new and developed contracts, including the class critique (from worker's movements and Marxism during the 19th Century to Piketty's present denouncing of social inequalities), the gender critique (as Carole Pateman's Sexual Contract puts it, the social contract institutionalized patriarchy), the racial critique (where Charles W. Mills develops the gender critique from a racial point of view where the social contract created a system of domination by the Western world) and finally the environmental critique (where its advocates claim for an eco-social contract or a nature social contract that shifts the approach to a bio-centric system). Therefore, the contract serves as a theoretical framework that can be changed, and in this case, it challenges the evolution towards a digital social contract. The evolution of internet and tech structures that support the web and its processes has been marked by three stages: its birth in the 80s by the hand of the State and linked to military research;its deregulation during the 90s and the privatization of the main telecommunications enterprises (in the case of the EU, the digital policy followed this trend);and the consolidation of a digital sphere in the 21st century, where the EU has taken a step back and created a set of instruments to guarantee the protection and freedom of its citizens when they navigate the internet. We can see how the EU has responded to global dynamics at the level of digital regulation, prioritizing today a multistakeholder system with s veral actors, and counterweights and limits for both companies and public administrations in their exchange with users on the internet. With the emergence of new spaces for social relations such as in the digital sphere, new types of sovereignty must be considered in order to guarantee the rights and privacy of users (we must not forget the importance of the separation between spheres, as fear liberalism reminds us, and of limiting exceptionality to those circumstances that really appear as such). Once the foundations on which the model of digital guarantees can be developed have been laid, the next step can be the creation of a real digital contract between users and the state on the internet. However, the contract is but an idea of reason for understanding politics and institutions, which begs the question of what digital politics we aspire to as societies.
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La vocación de este artículo es, desde el materialismo histórico, proponer respuestas a la crisis sanitaria de la covid-19. Para ello, planteamos cinco objetivos: plantear la estructura epidémica de la contemporaneidad;reflexionar en torno a las analogías entre cólera morbo, gripe y la covid-19;describir el proceso de fundación de la OMS, el papel de China y las transformaciones del nuevo orden mundial;analizar las consecuencias de la Revolución Ganadera;interpretar el virus chino, desde el contexto de renacimiento de los nacionalismos de estado y relacionarlo con la pandemia de covid-19. Hemos situado el punto de partida en el análisis la estructura epidémica que determina la contemporaneidad desde el cólera morbo (1817-34), la gripe española (1918-20) y la covid-19 (2020-22), es decir, se trata una exploración diacrónica de las diferentes construcciones sociales en torno a las pandemias, desde 1817 hasta 2020. Como tesis central del trabajo, trazamos una aproximación a las consecuencias de la Revolución Ganadera y el cambio climático por causas antropogénicas, y su relación con la salud humana, para desembocar en una posible conexión con la pandemia de covid-19. Pero esta tesis necesita de un análisis histórico en el que se establecen diferentes contextos que se desarrollan desde 1970: el papel de China y sus políticas de apertura a la economía de mercado, que suponen más de mil millones de nuevos consumidores, a partir de los años noventa. Esta nueva situación supondrá la explosión de la demanda de alimentos, así como la consecuente ruptura de muchos ecosistemas, de modo que, a partir de los años noventa, los argumentos ecológicos se convierten en una de las nuevas contradicciones entre el Norte y el Sur. Por otra parte, tratamos de ubicar la pandemia en su contexto más inmediato: el Tratado de Libre Comercio de América del Norte (1993) que firman Canadá, Estados Unidos y México;la desaparición de modelo de pequeñas o medianas granjas en beneficio de explotaciones verticales de millones de cerdos y aves de corral;la evolución de la Organización Mundial de la Salud (OMS), desde 1948, orientada a la cooperación y desarrollo, como factor de equilibrio Norte-Sur hasta su papel durante la pandemia, y, por último, la consolidación de las políticas económicas neoliberales (Hayek-Friedman), que fundamentan la globalización y reconstrucción del nuevo orden mundial. Además, este artículo se ocupa de los efectos que ha producido el estallido y propagación inesperada de la pandemia desde marzo de 2020 en las formas de comunicación política (oficial) de contenidos etnocéntricos y nacionalistas. Ante un problema global de dramáticas consecuencias, la respuesta de los gobiernos se concreta en tácticas populistas cuyo objetivo ha sido la exoneración de sus responsabilidades políticas, económicas, sociales y sanitarias. Tendrá que ser la OMS la que considere imprescindible establecer criterios científicos para referirse a las mutaciones del virus con el fin de acabar con la estigmatización política. La OMS tomará la iniciativa en la denominación de las variantes de interés (VOI) y variantes preocupantes (VOC) neutrales y fáciles de manejar desde el punto de vista de la información.Alternate :From a historical, sociological, and political science perspective, and inspired by the paradigm of historical materialism, this article proposes an approach to the different contexts that circumscribe the outbreak of the Covid-19 pandemic through two types of sources: on the one hand, the bibliography, of a historiographical, sociological and epidemiological nature, in which the collection of articles published in 2020 by Rob Wallace, under the title Big farms, big flus, stands outAgro-industries and infectious diseases, and on the other hand, the primary sources, that is, the work of analysis of the press, especially El País or El Mundo, the Resolutions and communications of the WHO, as well as other diverse documents, located on the internet. This macro-sche atic approach defines our starting point: a reflection on questions such as: What has happened to us? What is happening to us? How can international relations be interpreted? What value does the nationalist shift occupy at the moment? And even, why have we suffered a pandemic with dramatic consequences? With this in mind, the article proposes five objectives: to analyze the epidemic structure of contemporary times, to observe the analogies between cholera morbo, influenza and Covid-19, to describe the founding process of the WHO, the role of China and the transformations of the new world order and finally, to interpret the Chinese virus, from the context of the rebirth of nationalisms and to relate this interpretation to the Covid-19 pandemic. To develop these objectives, we propose a diachronic analysis of the different social constructions around pandemics from 1832 to 2020, likewise, we also intend to establish analogies between the different pandemics and the international relations that developed over three moments: he Asian morbid cholera (1817-34), the Spanish flu (1918-20) and Covid-19 (2020-22). In short, we will define the epidemic structure of contemporaneity. Next, as the central thesis of the work, we propose an approach to the consequences of the Livestock Revolution and climate change due to anthropogenic causes, and its relationship with human health to lead to a possible connection with the Covid-19 pandemic. This thesis needs a historical analysis in which different conditions that develop since 1970, during the third Industrial Revolution, are established. After the demographic explosion of the 1970s, during which time industrial livestock farming has been dominant in the United States, the production model soon spread to Latin America, Asia and Europe in such a way that a gradual relocation is set in motion that will accelerate during the l990s.That is, when Eastern Europe (just like Asia or Latin America) joins the international market and offers attractive deregulation scenarios for international food industries. For this we mainly use the hypotheses of Rob Wallace and K. Shortridge: it is essential to take into account relocation tactics, industrial strategies related to the mass production of poultry meat, and the appearance of new epidemic outbreaks that affect the population since at least 1997 -as well as the origin of typical pneumonia, known as SARS (Severe Acute Respiratory Syndrome) and its relationship with the coronavirus. In addition, the study of this specific context (1970-2020) allows us to understand five vital aspects to interpret the emergence of Covid-19: the decisive role of China and its policies of opening up to the market economy between 1980 and 1985, which accounted for more than one billion new consumers. In the face of this explosion in the demand for food and raw materials, millions of hectares are cleared to establish crop fields, and a large part of the planets ecosystems are destroyed. That is why ecological arguments become one of the new contradictions in the North-South dialectic;the process of collapse of the Soviet Union supposes the rebirth of nationalisms in Europe. From 1990 to 2007, nationalisms are consolidated, grow and evolve towards populist content, useful for the different governments during the financial crisis;the signing of the North American Free Trade Agreement in 1993 between Canada, the United States and Mexico will imply the practical disappearance of the traditional model of small or medium farms in the United States and Mexico, to the benefit of vertical operations of millions of pigs and poultry. In 1998, the first outbreak of swine flu was declared in North Carolina and, later, in Veracruz;the consolidation of neoliberal economic policies (Hayek-Friedman), which support globalization and reconstruction of the new world order;and lastly, the evolution of the functions of the WHO (World Health Organization) since its foundation in 1948. This was oriented towards the cooperation and development of great health campaigns in the third world an as a factor of North-South balance until the shift presented by the secretary General Halfdan T Mahler, who would define the goal of health for all by the year 2000. From this chronological and plot line, we lead to the financial crisis of 2007 to find the specific context in which the pandemic is declared in March 2020. On the other hand, this article deals with the effects that the outbreak and unexpected spread of a new virus has produced in the forms of (official) political communication of ethnocentric and nationalist content.These speeches raised xenophobic markings based on the rapid growth in morbidity and mortality statistics due to the new virus. So the concept of the Chinese virus, a social construction launched by Donald Trump, has configured a biased vision, successful until now, for the benefit of the West. Faced with a global problem with dramatic consequences, the response of governments will take the form of populist tactics whose objective will be the exoneration of their political, economic, social and health responsibilities. Given this situation, it will have to be the WHO that considers it essential to establish scientific criteria to refer to the mutations of the virus in order to end political stigmatization. The WHO will take the lead in naming information-neutral and information-friendly variants of interest (VOI) and variants of concern (VOC), renamed with letters of the Greek alphabet. In short, it is convenient to take into account the populist response of the different governments (United States, Brazil, France or Germany) centered on collective emotions typical of a language of war.
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A personal learning environment (PLE) is known as a crucial support for educators who lead learners through the process of collection, creation, and organization of personalized learning tools. In this manner, the learner can interpret a variety of new tools in their own interest, which makes the learning process easier. The PLE approach represents a considerable movement away from traditional learning, where learners are considered consumers of information through isolated channels, particularly learning management systems (LMSs), to a model where learners draw significant connections from numerous resources that they choose. Thus, educational settings have implemented LMSs fully into their respective learning contexts. In this sense, LMS is identified as a learning platform that helps learners and educators submit assignments, share ideas, and communicate through web-based systems with numerous benefits. Under these circumstances, self-regulation is addressed as a significant component that explains how learners build and manage PLEs and come up with more choices;they take ownership of their own learning and enhance self-regulated learning (SRL) practices. On this occasion, there is a belief that teachers can utilize LMSs to shift from passive to active learning and to improve self-reflection (SR). Therefore, considering all the above issues, the current study examines integrating a third-generation LMS to enhance learners’SR. This study considered PLEs by utilizing Zimmerman’s SRL model to investigate the integration of the third-generation LMS. SR is applied in this study in the form of a pretest and posttest following the involvement of the PLE course, which was designed and applied during the COVID-19 pandemic. Finally, the experimental findings of the current study formulated a model of SR factors in PLEs through the LMS platform with partial least squares structural equation modeling (SEM) before and after the intervention. Author
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The pervasiveness of live-streaming, especially in the period of Covid-19, has brought ample monetizing opportunities for content creators through viewers' donation. Given that donation is commonly driven by the gained benefits to the donors, voluntary donation in live-streaming is still unstable due to the lack of constraints. Drawing on the dedication-constraint framework, we examined how streamer-viewer interactions, motivational feedback and self-regulation deficiency affect viewers' donation intention in live-streaming. A survey was conducted among live-streaming users in Taiwan, and the collected data were analyzed by partial least squares. The findings show that the motivational feedback (dedication-based mechanism) has a stronger influence than self-regulation deficiency (constraint-based mechanism) in determining viewers' donation intention. Responsiveness is proven as the most important interaction-based antecedent of motivation feedback and self-regulation deficiency, beside personalization and entertainment. In sum, our empirical findings have significant implications for research and practice to deepen the understanding of donation, encourage viewers to donate and maintain the relationship with content creators in live-streaming communities. © 2022 International Consortium for Electronic Business. All rights reserved.
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High volatility in deregulated electricity markets is that characteristic that exposes its participants to higher risks. Volatility is due to many, and most of the times unpredictable, factors, ranging from fuel prices, production from renewable energy sources, electricity demand to Covid-19 and energy crisis. This article describes the initial stages of the work that combines signalling with market conditions in order to analyse the factors affecting the clearing prices of the day ahead market in view of enhancing the forecasting of these prices. The proposed forecasting methodology is based on the extreme learning machine (ELM) and it is tested on the German and Finnish markets. © 2022 IEEE.
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This study sought to establish the corporal deregulation that is seen in the bodies of students using digital devices like Instagram. The methodology used was comprised of a visual analysis, literary review and thematic interviews. The conclusions revealed the joining of human and non-human bodies in an organized regime, a governmentality, in which techniques and stereotypes of gender and race circulate, from which bodies are molded and reproduced through the digital de-vice;a government without governing bodies in the context of the social distancing of the Covid-19 pandemic and the crisis of bodily touch. © 2022, Global Knowledge Academics. All rights reserved.
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For most of people, the burden caused by COVID-19 is not only physical, but also spiritual. Several research studies have shown that the negative emotions caused by COVID-19 have increased significantly worldwide, but there are not effective emotional interventions for people in most countries. Therefore, this negative emotional trend is likely to expand further and cause more adverse effects, such as pathological depression. By applying python to crawl the posts of depressed patients on Chinese social media platforms, and using natural language processing to quantitatively analyze the words with high frequency, this paper summarizes the text characteristics and depression degrees of depressives' posts on Chinese social media platforms, so as to present a preliminary psychological intervention mode. Then, the paper proposes a more targeted psychological intervention mode for depressives with different characteristics based on the paradigm of human-computer interaction and the results of the questionnaire. The study finds that the patients with sufficient self-regulation abilities and the patients without self-regulation abilities do not meet the high-frequency word extraction results, while patients with insufficient self-regulation abilities do. Additionally, for these three types of patients, different psychological intervention modes can be established based on different interaction paradigms. © 2022 SPIE.
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Purpose>Air connectivity is one of the most important aspects of tourism development, especially for island state destinations (ISD) which rely on air travel for accessibility. The complexity of the tourism industry necessitates close interaction among involved stakeholders to ensure successful policy implementation of air transportation operations that facilitate tourism mobility at a destination.Design/methodology/approach>In this paper self-administered questionnaires in a structured format were distributed to 200 managers. Additionally, seven unstructured follow-up interviews were conducted to enrich the content and better support the conclusions.Findings>The results of the study suggest that air transportation and connectivity are not fully integrated with tourism policy and strategy planning. Yet it is crucial that a stakeholder approach is adopted that accounts for the needs of diverse stakeholders and airline strategies, along with a diversified tourism policy that can establish Cyprus as year-round destination.Originality/value>The role of the airline industry in overall tourism strategy and policy is examined and the unique problems and challenges ISDs like Cyprus face in developing as a tourism destination and overcoming tourism seasonality are underlined.
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Purpose>Reflecting on recent empirical developments as well as insights from regulatory state theory, the paper considers directions in which the regulatory state could develop in the post-COVID-19 era.Design/methodology/approach>This is a de-contextualised analysis of regulatory developments drawing on the prior regulatory state literature and literature on post-crisis responses. Taking into account recent empirical developments related to the COVID-19 pandemic, the paper sets out, in a comparative context, scenarios for the future development of the regulatory state.Findings>Predicting the direction in which the regulatory state will develop is challenging, particularly at this early stage. Yet, we provide a conceptual framework for thinking about possible futures of the regulatory state and how domestic and international factors might mediate these futures.Originality/value>The paper provides a structured approach to the analysis of the regulatory state bringing together insights from the literature on the regulatory state, public management reform, and global regulatory shifts.
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Speed read Legislative changes in Brazil have ‘weakened environmental regulations’ Legal deregulation peaked at the height of the COVID-19 pandemic, study found Brazilian society, scientists and media may have mitigated the damage Environmental progress in Brazil looks set to be one of the casualties of COVID-19, with harmful changes to the law being pushed through while attention is diverted by the global pandemic, a study warns. Since January 2019, the Brazilian government approved 57 pieces of legislation that effectively weaken national environmental laws, the study published in Biological Conservation found. Researchers also analysed monthly deforestation rates provided by the National Institute for Space Research (INPE) of Brazil, and fines associated with illegal deforestation, issued by the Brazilian Institute of Environment and Renewable Natural Resources (IBAMA). According to INPE, deforestation in the Amazon was 9.5 per cent higher between August 2019 and July 2020 than between August 2018 and July 2019 – making it the highest level of annual deforestation since 2008.
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SARS-CoV-2 is the causative agent of COVID-19 and infects the respiratory tract, blood cells, gastrointestinal tract, kidneys, liver, heart, brain and other organs. The ability of SARS-CoV-2 to escape from immune surveillance leads to deregulation of the immune response, cytokine storm and extensive tissue damage to infected organs. It is assumed that the pathogenesis of the deterioration of the course of COVID-19 is much more complicated and one of the mechanisms for the escape of SARS-Cov-2 from the influence of innate immunity is the inhibition of signaling pathways for the production and action of interferon (IFN). This review summarizes the role of the IFN system in SARS-CoV-2 infection and discusses the sophisticated mechanisms that coronaviruses have developed over the course of evolution to evade immune surveillance and suppress IFN responses. The IFN-related issues of counteraction to SARS-Cov-2 infection and the IFN-dependent adverse course of COVID-19 is also discussed.
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Introduction: The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARSCoV2) is the causative agent responsible for the COVID-19 pandemic and has resulted in devastating impacts on global public health. The nucleocapsid (N) protein of other coronaviruses, such as SARS-CoV-1, have been previously implicated in the deregulation of the host cell cycle through interactions with cell cycle checkpoint proteins, Cyclin-Dependent Kinases (CDKs) or cyclins. In this study, we highlight the role of SARS-CoV-2 N-protein in modulating CDK expression, thereby, deregulating the host cell cycle. Methods: A549 cells were transfected with pCMV plasmids, harbouring the SARS-CoV-2 N-protein. Protein extracts of control and Nprotein transfected cells were electrophoresed on SDS-PAGE, transferred onto a nitrocellulose membrane and incubated with CDK2 and CDK4 antibodies. The blots were visualized and protein quantification was performed using ImageJ analysis. Results: Transfection of SARS-CoV-2 N resulted in differential expression of CDK2 and CDK4, which are key regulators that drive cell cycle progression through G0 or G1 phase into S phase. Notably, preliminary findings also demonstrate that N protein results in decreased CDK2 and CDK4 expression. Conclusion: The differential expression of CDKs caused by SARS-CoV-2 N-protein suggests its role in inducing cell cycle arrest at the S phase to facilitate SARS-CoV-2 replication. The results from this research may aid in future characterisation of the mechanisms for SARS-CoV-2-mediated cell cycle arrest, and contribute towards the development of novel antiviral strategies and therapies.
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The proceedings contain 32 papers. The topics discussed include: molecular pathogenesis and prognostic stratification: acute myeloid leukemia;molecular pathogenesis and prognostic stratification of myelodysplastic syndromes;extracellular vesicles and their role in tumor microenvironment;new genomic, transcriptomic and cellular risk factors in multiple myeloma;drivers of progression in MPNS;SARS-COV2 coagulopathy: an intricated puzzle;role of the microenvironment in the pathogenesis of myelodysplastic syndromes;the tumor microenvironment in Hodgkin lymphoma: clinical implications;CRISPR/CAS9-based genome editing to model the anti-leukemia immune response and identify its molecular players;and deregulation of the transforming growth factor-B pathway in low-risk MDS patients SF3B1 mutated.
ABSTRACT
Background: SARS-CoV-2 primarily infects the lung but may also damage other organs including the brain, heart, kidney, and intestine. Central nervous system (CNS) disorders include loss of smell and taste, headache, delirium, acute psychosis, seizures, and stroke. Pathological loss of gray matter occurs in SARS-CoV-2 infection but it is unclear whether this is due to direct viral infection, indirect effects associated with systemic inflammation, or both. Methods: We used iPSC-derived brain organoids and primary human astrocytes from cerebral cortex to study direct SARS-CoV-2 infection, as confirmed by Spike and Nucleocapsid immunostaining and RT-qPCR. siRNAs, blocking antibodies, and small molecule inhibitors were used to assess SARS-CoV-2 receptor candidates. Bulk RNA-seq, DNA methylation seq, and Nanostring GeoMx digital spatial profiling were utilized to identify virus-induced changes in host gene expression. Results: Astrocytes were robustly infected by SARS-CoV-2 in brain organoids while neurons and neuroprogenitor cells supported only low-level infection. Based on siRNA knockdowns, Neuropilin-1, not ACE2, functioned as the primary receptor for SARS-CoV-2 in astrocytes. The endolysosomal two-pore channel protein, TPC, also facilitated infection likely through its regulatory effects on endocytosis. Other alternative receptors, including the AXL tyrosine kinase, CD147, and dipeptidyl protease 4 (DPP4), did not function as SARS-CoV-2 receptors in astrocytes. SARS-CoV-2 infection dynamically induced type I, II, and III interferons, and genes involved in Toll-like receptor signaling, MDA5 and RIG-I sensing of double-stranded RNA, and production of inflammatory cytokines. Genes activating apoptosis were also increased. Down-regulated genes included those involved in water, ion and lipid transport, synaptic transmission, and formation of cell junctions. Epigenetic analyses revealed transcriptional changes related to DNA methylation states, particularly decreased DNA methylation in interferon-related genes. Long-term viral infection of brain organoids resulted in progressive neuronal degeneration and death. Conclusion: Our findings support a model where SARS-CoV-2 infection of astrocytes produces a panoply of changes in the expression of genes regulating innate immune signaling and inflammatory responses. Deregulation of these genes in astrocytes produces a microenvironment within the CNS that ultimately disrupts normal neuron function, promoting neuronal cell death and CNS deficits.
ABSTRACT
Background: Coronavirus disease 2019 (COVID19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has varied clinical presentations from mild subclinical to severe disease with high mortality. Our aim was to determine whether examining immune-related gene expression early in infection could predict progression to severe disease. Methods: In subjects of the All Ireland Infectious Diseases Cohort study, we analysed expression of 579 genes with the NanoString nCounter Immunology panel in peripheral blood mononuclear cells in those with confirmed SARS-CoV-2 infection collected within 5 days of symptom onset and matched SARS-CoV-2 negative controls with respiratory infection. Subsequent maximum COVID19 disease severity was classified as mild or severe. Read counts were normalized using panel housekeeping genes. Expression changes in severity groups were estimated against control baseline. Results: Between April and July of 2020, we recruited 120 subjects, 62 with COVID19 and 58 controls, with average age 59 y.o. (IQR 34-88), 66% males and 69% Caucasian ethnicity. Maximal disease severity was used to separate COVID19 cases into mild (n=31) and severe (n=31). We identified 20 significantly deregulated genes between those with COVID19 and controls (;log2 fold;>0.5, p<0.05, Benjamin-Yekutieli p-adjustment). Function of 12 of these genes related to cytokine signaling, 9 upregulated genes to type I interferon signaling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1), while 7 downregulated genes mapped to innate immune function (IRF7, ICAM2, SERPING1, IFI16, BST2, FCER1A, PTK2). Expression in the severe group showed downregulation of FCER1A (innate immunity regulation), IL1B and TNF (inflammatory cytokines), and PTGS2 (inflammatory mediator) and greater upregulation of TNFSF4 (cytokine signaling) and PTK2 (innate immunity). Mild cases presented higher upregulation of IFIT2 (type I interferon signaling). Conclusion: Observed early downregulation of regulators and mediators of inflammation in those who developed severe COVID19, suggested dysregulation of inflammation. Specifically, IFIT2 upregulation in mild cases and FCER1A downregulation in severe cases, points to early differences in host responses centered on deregulation of the interferon and inflammation responses. Whether these patterns reflect delayed interferon involvement in pathways to control the infection and contribute to pathological inflammation and cytokine storms observed in severe COVID19 requires further research.
ABSTRACT
Since the beginning of the COVID-19 pandemic, many countries have adopted online education as an alternative to face-to-face courses. This has increased awareness of the importance of analyzing learning data left by students to improve and evaluate the learning process. This article presents a new tool, named TaBAT, created to work with different LMSs in the form of dashboards accessible online and allowing teachers to monitor the progress of their learners and at the same time and allow teachers to track the progress of their learners, while allowing learners to develop self-regulation skills and visualize their learning process. The results of a study conducted show that TaBAT helped learners to increase their progress and spend more time in the online course. © 2022 IEEE.
ABSTRACT
The world has paid increasing attention to energy efficiency projects since the Paris agreement and UN climate summit. Recently, the COVID-19 pandemic accelerated the process of the green energy transition, which has attracted considerable attention from economists, environmentalists, and international organizations and has led to significant research in energy. This study addresses the importance of green energy practices in the post-COVID-19 era to deal with environmental deregulation using bibliometric analysis. Data were extracted from the Scopus database from 2020 to 2022. Results indicate that China gained a prominent place in publishing topic-related articles. However, Italy stands at the top position in total and average article citations. Sustainability is the most productive journal, followed by Energies and the Journal of Cleaner Production. Nazarbayev University and the University of Cambridge are the most contributing research institutes. In general, the cooperation of authors, institutes, and countries strengthens research;however, collaboration at the author level across the nation was lower than in others. The study highlights three research streams and four themes by systematically conducting a bibliometric coupling and co-occurrence network that anticipates and significantly segregates literature. Bibliometric coupling identifies three research streams of sustainable green business strategies, green infrastructure requirements, and green solutions and opportunities from COVID-19. Furthermore, the co-occurrence network proposes four main themes related to green innovation in the epidemic era, security and sustainable development goals with green practices, public health protection and green finance, and investment and risk management. The results provide insights into current research in the field of energy and will assist future work promoting environmentally friendly projects.
ABSTRACT
Intro: Deregulated protein synthesis is a common trait across solid and hematologic malignancies and an attractive target for cancer therapy. Rocaglates compounds that inhibit eukaryotic initiation factor 4A1 (eIF4A1), the essential DEAD-box RNA helicase that resolves mRNA 5'UTR secondary structures during cap-dependent translation initiation. Rocaglates' unique mechanism of action causes sequence-selective mRNA binding by eIF4A1, clamping the inactive helicase onto the transcript. This suppresses translation globally and affects many oncogenic and pro-survival transcripts in particular. Zotatifin, the first-in class synthetic rocaglate, is currently in Phase I clinical trials for the treatment of solid tumors and as an antiviral against SARS-CoV2. Currently, eIF4A1 and DDX3 are the only reported targets of rocaglate-mediated RNA clamping. Employing unbiased proteomic approaches, we have discovered that rocaglates, thought to act as pure eIF4A/translation inhibitors, extensively remodel the translation machinery and translatome. Additionally, mass-spec interrogation for proteins interacting with specific RNA sequences reveals novel targets of rocaglate-mediated, sequence-specific RNA clamping. Methods: We conducted original mass-spectrometry analyses of translational reprogramming by rocaglates. TMT-pSILAC assessed acute changes in protein production, while MATRIX, which captures high-resolution profiles of the translation machinery, revealed translation factors that drive reprogramming in response to rocaglate exposure. We validated results biochemically, in cellulo, and in vivo using patient-derived xenograft (PDX) mouse models. To probe existing and novel rocaglate RNA-clamping targets, we developed unbiased “clampome” assays - in cellulo protein-RNA-pull downs followed by mass-spec analysis of proteins with increased binding to RNA in the presence of rocaglates. Results: We find rocaglates, including zotatifin, have effects far more complex than simple “translational inhibition” as currently defined. Indeed, translatome analysis by TMT-pSILAC revealed myriad up-regulated proteins that drive hitherto unrecognized cytotoxic mechanisms. The GEF-H1 guanine exchange factor, for example, drives anti-survival RHOA/JNK activation, suggesting novel candidate biomarkers of rocaglate clinical outcomes. Translation-machinery analysis by MATRIX identifed rocaglate-induced dependence on specific translation factors including eEF1ϵ1 that drive remodeling. Novel rocaglate RNA-binding targets revealed by clampome studies remain under detailed evaluation as mediators of drug activities. Discussion: Our original proteome-level interrogation revealed that the complete cellular response to these historical “translation inhibitors” is mediated by comprehensive translational landscape remodeling. Effects on a broader suite of RNA binding proteins than eIF4A1 alone we suggest mediate the potent antitumor activities of these unique compounds, elucidation of which permits development of novel precision approaches to targeted translational deregulation in cancer.