A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection.

COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.

The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response.

Rationale: Viral infections are complex processes based on an intricate network of molecular interactions. The infectious agent hijacks components of the cellular machinery for its profit, circumventing the natural defense mechanisms triggered by the infected cell. The successful completion of the replicative viral cycle within a cell depends on the function of viral components versus the cellular defenses. Non-coding RNAs (ncRNAs) are important cellular modulators, either promoting or preventing the progression of viral infections. Among these ncRNAs, the long non-coding RNA (lncRNA) family is especially relevant due to their intrinsic functional properties and ubiquitous biological roles. Specific lncRNAs have been recently characterized as modulators of the cellular response during infection of human host cells by single stranded RNA viruses. However, the role of host lncRNAs in the infection by human RNA coronaviruses such as SARS-CoV-2 remains uncharacterized. Methods: In the present work, we have performed a transcriptomic study of a cohort of patients with different SARS-CoV-2 viral load and analyzed the involvement of lncRNAs in supporting regulatory networks based on their interaction with RNA-binding proteins (RBPs). Results: Our results revealed the existence of a SARS-CoV-2 infection-dependent pattern of transcriptional up-regulation in which specific lncRNAs are an integral component. To determine the role of these lncRNAs, we performed a functional correlation analysis complemented with the study of the validated interactions between lncRNAs and RBPs. This combination of in silico functional association studies and experimental evidence allowed us to identify a lncRNA signature composed of six elements - NRIR, BISPR, MIR155HG, FMR1-IT1, USP30-AS1, and U62317.2 - associated with the regulation of SARS-CoV-2 infection. Conclusions: We propose a competition mechanism between the viral RNA genome and the regulatory lncRNAs in the sequestering of specific RBPs that modulates the interferon response and the regulation of RNA surveillance by nonsense-mediated decay (NMD).

Machine learning prediction of side effects for drugs in clinical trials.

Early and accurate detection of side effects is critical for the clinical success of drugs under development. Here, we aim to predict unknown side effects for drugs with a small number of side effects identified in randomized controlled clinical trials. Our machine learning framework, the geometric self-expressive model (GSEM), learns globally optimal self-representations for drugs and side effects from pharmacological graph networks. We show the usefulness of the GSEM on 505 therapeutically diverse drugs and 904 side effects from multiple human physiological systems. Here, we also show a data integration strategy that could be adopted to improve the ability of side effect prediction models to identify unknown side effects that might only appear after the drug enters the market.

Machine learning and network medicine approaches for drug repositioning for COVID-19.

We present two machine learning approaches for drug repurposing. While we have developed them for COVID-19, they are disease-agnostic. The two methodologies are complementary, targeting SARS-CoV-2 and host factors, respectively. Our first approach consists of a matrix factorization algorithm to rank broad-spectrum antivirals. Our second approach, based on network medicine, uses graph kernels to rank drugs according to the perturbation they induce on a subnetwork of the human interactome that is crucial for SARS-CoV-2 infection/replication. Our experiments show that our top predicted broad-spectrum antivirals include drugs indicated for compassionate use in COVID-19 patients; and that the ranking obtained by our kernel-based approach aligns with experimental data. Finally, we present the COVID-19 repositioning explorer (CoREx), an interactive online tool to explore the interplay between drugs and SARS-CoV-2 host proteins in the context of biological networks, protein function, drug clinical use, and Connectivity Map. CoREx is freely available at: https://paccanarolab.org/corex/.

Role of miR-2392 in driving SARS-CoV-2 infection.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans.

The Great Deceiver: miR-2392's Hidden Role in Driving SARS-CoV-2 Infection.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.

Dosimetry in Digital Breast Tomosynthesis Evaluated by Monte Carlo Technique.

ABSTRACT: The influence of the angular deviation of the tube during digital breast tomosynthesis (DBT) acquisition to the dose in the examined breast and in other organs and tissues is not well known. In this work, the Monte Carlo method was used with an adult female virtual anthropomorphic phantom to investigate the impact of this angular variation on the breast dose. The absorbed dose in the examined breast was normalized by the air kerma, which resulted in an absorbed dose coefficient (DT/Kair) for the breast. The absorbed dose in each organ was normalized by the glandular dose in the breast, resulting in the relative organ dose (ROD). An adult female virtual anthropomorphic phantom (FSTA_M50_H50) was incorporated into a scenario containing tomosynthesis equipment with Mo/Mo, Mo/Rh, and W/Rh target/filter combinations and tube voltages of 28 kV. The comparison between the results of the simulations considering digital mammography (DM) and DBT data showed that the DT/Kair values for the examined breast obtained with the DBT parameters were up to 24 times higher than with the DT/Kair obtained with DM parameters. A DT/Kair of 0.97 × 10-1 mGy mGy-1 was obtained in a DBT exam of the right breast. Considering the other organs, the highest ROD values were observed in the thyroid (6.45 × 10-4), eyes (3.87 × 10-4), liver (1.95 × 10-5), and eye lenses (3.21 × 10-3). A variation in the absorbed dose values for the breast and other organs was observed for all projections different from 0°.

Predicting the frequencies of drug side effects.

A central issue in drug risk-benefit assessment is identifying frequencies of side effects in humans. Currently, frequencies are experimentally determined in randomised controlled clinical trials. We present a machine learning framework for computationally predicting frequencies of drug side effects. Our matrix decomposition algorithm learns latent signatures of drugs and side effects that are both reproducible and biologically interpretable. We show the usefulness of our approach on 759 structurally and therapeutically diverse drugs and 994 side effects from all human physiological systems. Our approach can be applied to any drug for which a small number of side effect frequencies have been identified, in order to predict the frequencies of further, yet unidentified, side effects. We show that our model is informative of the biology underlying drug activity: individual components of the drug signatures are related to the distinct anatomical categories of the drugs and to the specific drug routes of administration.

Las violencias desde el espectador de fútbol: habitus del aficionado, el hincha y el barrista / Violence from the point of view of the spectator: habitus of the amateur, the fan and the supporter

El fútbol espectáculo sigue teniendo entre sus desafíos las violencias tanto en los estadios como fuera de ellos. Este deporte tiene distintos tipos de espectadores aquí nombrados como aficionado, hincha y barrista, yendo desde la aproximación netamente estética hacia el fútbol, pasando por la preferencia de un equipo hasta la participación en grupos de apoyo. En este trabajo, desde el concepto de habitus de Pierre Bourdieu, se pudo identificar, a partir de un análisis del discurso, un habitus aficionado, un habitus hincha y un habitus barrista, todos relacionados de distinta manera con las violencias dentro del campo del fútbol espectáculo. Se concluye que el habitus violento no es una condición individual sino una disposición construida con base en la interacción y producida por la valoración contextual de dichos actos

The soccer as show still has among its challenges the violences both in the stadiums and out-side them. This sport has different types of spectators here named as amateur, fans and sup-porters, ranging from the purely aesthetic approach to soccer, through the preference of a team to participation in support groups. In this work, from Pierre Bourdieu's concept of habitus, it was possible to identify, from an analysis of the discourse, an amateur habitus, a fan habitus and a supporter habitus, all related in different ways to the violence within the field of show soccer. It is concluded that the violent habitus is not an individual condition but a disposition built on interaction and produced by the contextual evaluation of these acts

Occupational exposures during abdominal fluoroscopically guided interventional procedures for different patient sizes - A Monte Carlo approach.

In this study we evaluated the occupational exposures during an abdominal fluoroscopically guided interventional radiology procedure. We investigated the relation between the Body Mass Index (BMI), of the patient, and the conversion coefficient values (CC) for a set of dosimetric quantities, used to assess the exposure risks of medical radiation workers. The study was performed using a set of male and female virtual anthropomorphic phantoms, of different body weights and sizes. In addition to these phantoms, a female and a male phantom, named FASH3 and MASH3 (reference virtual anthropomorphic phantoms), were also used to represent the medical radiation workers. The CC values, obtained as a function of the dose area product, were calculated for 87 exposure scenarios. In each exposure scenario, three phantoms, implemented in the MCNPX 2.7.0 code, were simultaneously used. These phantoms were utilized to represent a patient and medical radiation workers. The results showed that increasing the BMI of the patient, adjusted for each patient protocol, the CC values for medical radiation workers decrease. It is important to note that these results were obtained with fixed exposure parameters.

Polícia, antropometria e datiloscopia: história transnacional dos sistemas de identificação, do rio da Prata ao Brasil / Police, anthropometry, and fingerprinting: the transnational history of identification systems from Rio de la Plata to Brazil

Resumo O artigo estuda a circulação transnacional de métodos de identificação de pessoas na América do Sul. Analisa a implementação do sistema antropométrico nas polícias de Argentina, Uruguai e Brasil a partir da última década do século XIX e as críticas que esse sistema recebeu no momento de consolidação da datiloscopia na região, no início do século XX. Em um contexto de intenso trânsito mundial de ideias, especialistas e tecnologias policiais, o bertillonage foi discutido e hibridado na América Latina. A história do sistema antropométrico nas repúblicas do rio da Prata e do Brasil envolveu diversas viagens de médicos, juristas e policiais a Paris, debates sobre sua adequação às realidades locais e a constituição de uma aberta polêmica sobre as técnicas de identificação.

Abstract The article explores the transnational circulation of methods for identifying people in South America. It analyzes both the implementation of the anthropometric system at police departments in Argentina, Uruguay, and Brazil starting in the 1890s, as well as the criticisms that were aimed at this method when fingerprinting took hold in the region in the early twentieth century. In a context of a heavy worldwide flow of ideas, experts, and technologies in policing, “bertillonage” was discussed and underwent hybridization in Latin America. The history of the anthropometric system in these three countries involved many travels by physicians, jurists, and police agents to Paris, debates over its suitability to local contexts, and an open controversy about identification techniques.

Police, anthropometry, and fingerprinting: the transnational history of identification systems from Rio de la Plata to Brazil. / Polícia, antropometria e datiloscopia: história transnacional dos sistemas de identificação, do rio da Prata ao Brasil.

The article explores the transnational circulation of methods for identifying people in South America. It analyzes both the implementation of the anthropometric system at police departments in Argentina, Uruguay, and Brazil starting in the 1890s, as well as the criticisms that were aimed at this method when fingerprinting took hold in the region in the early twentieth century. In a context of a heavy worldwide flow of ideas, experts, and technologies in policing, "bertillonage" was discussed and underwent hybridization in Latin America. The history of the anthropometric system in these three countries involved many travels by physicians, jurists, and police agents to Paris, debates over its suitability to local contexts, and an open controversy about identification techniques.

Structural divergence of plant TCTPs.

The Translationally Controlled Tumor Protein (TCTP) is a highly conserved protein at the level of sequence, considered to play an essential role in the regulation of growth and development in eukaryotes. However, this function has been inferred from studies in a few model systems, such as mice and mammalian cell lines, Drosophila and Arabidopsis. Thus, the knowledge regarding this protein is far from complete. In the present study bioinformatic analysis showed the presence of one or more TCTP genes per genome in plants with highly conserved signatures and subtle variations at the level of primary structure but with more noticeable differences at the level of predicted three-dimensional structures. These structures show differences in the "pocket" region close to the center of the protein and in its flexible loop domain. In fact, all predictive TCTP structures can be divided into two groups: (1) AtTCTP1-like and (2) CmTCTP-like, based on the predicted structures of an Arabidopsis TCTP and a Cucurbita maxima TCTP; according to this classification we propose that their probable function in plants may be inferred in principle. Thus, different TCTP genes in a single organism may have different functions; additionally, in those species harboring a single TCTP gene this could carry multiple functions. On the other hand, in silico analysis of AtTCTP1-like and CmTCTP-like promoters suggest that these share common motifs but with different abundance, which may underscore differences in their gene expression patterns. Finally, the absence of TCTP genes in most chlorophytes with the exception of Coccomyxa subellipsoidea, indicates that other proteins perform the roles played by TCTP or the pathways regulated by TCTP occur through alternative routes. These findings provide insight into the evolution of this gene family in plants.

Muertes por violencias en Argentina: dos estudios de caso en los Municipios de Venado Tuerto y San Rafael / Violence-related deaths in Argentina: two case studies in the cities of Venado Tuerto and San Rafael

Este artículo ofrece los resultados de un estudio comparado de dos municipios: Venado Tuerto y San Rafael de la República Argentina, que presentaron tendencias diferentes en relación a las tasas de homicidios por armas de fuego. La metodología combinó dos estrategias de análisis: por un lado, entrevistas semi-estructuradas con informantes clave (funcionarios municipales y provinciales en distintas áreas de la gestión, y referentes de organizaciones no gubernamentales) y, por el otro, grupos focales con actores vinculados a la atención médica, la educación y las instituciones religiosas. Los resultados sugieren una distancia muy corta entre las ciudades en las cuales las tasas han aumentado y aquellas en las que han disminuido. La diferencia más significativa es que en Venado Tuerto se encontró una mayor fragilidad en las instituciones públicas, por la falta de articulación entre las mismas. En tanto en San Rafael, los actores entrevistados atribuyen el bajo nivel de conflictividad a una red de prevención de violencias en la cual se coordinan agencias provinciales y municipales. Sin tratarse, ni Venado Tuerto, ni San Rafael, de ciudades violentas en los niveles latinoamericanos más truculentos, ambas muestran resultados diferentes que apuntan directamente a la posibilidad de juntar a las instituciones en un entramado de conversaciones, acuerdos y políticas en conjunto.

This article presents the results of a comparative study of two Argentinian cities, namely Venado Tuerto and San Rafael, which revealed different trends in the rates of firearm-related homicides. The methodology combined two strategies of analysis: semi-structured interviews with key informants (municipal and provincial government agents in different areas of management, as well as members of non-governmental organizations) and focus groups with actors involved in medical care, education, and religious institutions. The results suggest little difference between cities in which rates have increased and those in which rates have decreased. The most significant difference was that in Venado Tuerto a greater fragility of public institutions was observed due to the lack of articulation between such institutions. In San Rafael, the actors interviewed attribute the low level of conflict to a violence prevention network in which provincial and municipal agencies interact. Although neither city is violent at the most critical Latin American levels, the different results shown in Venado Tuerco and San Rafael indicate the possibility of bringing institutions together in a joint framework of conversations, agreements and policies.

[Violence-related deaths in Argentina: two case studies in the cities of Venado Tuerto and San Rafael]. / Muertes por violencias en Argentina: dos estudios de caso en los Municipios de Venado Tuerto y San Rafael.

This article presents the results of a comparative study of two Argentinian cities, namely Venado Tuerto and San Rafael, which revealed different trends in the rates of firearm-related homicides. The methodology combined two strategies of analysis: semi-structured interviews with key informants (municipal and provincial government agents in different areas of management, as well as members of non-governmental organizations) and focus groups with actors involved in medical care, education, and religious institutions. The results suggest little difference between cities in which rates have increased and those in which rates have decreased. The most significant difference was that in Venado Tuerto a greater fragility of public institutions was observed due to the lack of articulation between such institutions. In San Rafael, the actors interviewed attribute the low level of conflict to a violence prevention network in which provincial and municipal agencies interact. Although neither city is violent at the most critical Latin American levels, the different results shown in Venado Tuerco and San Rafael indicate the possibility of bringing institutions together in a joint framework of conversations, agreements and policies.

Juan César García y el movimiento latinoamericano de medicina social: notas sobre una trayectoria de vida / Juan César García and the Latin American social medicine movement: notes on a life trajectory

Este artículo analiza la trayectoria de Juan César García, uno de los referentes del movimiento latinoamericano de medicina social. La pregunta que desencadenó este trabajo buscó indagar el momento y las circunstancias en que García incorporó para sí la matriz del marxismo para pensar los problemas de salud. De esta manera, siguiendo los lineamientos metodológicos propuestos por Pierre Bourdieu, utilizamos la noción de "trayectoria de vida" para reconstruir un recorrido vital que se bifurca en varias rutas: de su Necochea natal a la ciudad de La Plata, desde allí hasta Santiago de Chile y, finalmente, sus innumerables viajes desde Washington hacia gran parte de América Latina. Para ello, realizamos entrevistas semiestructuradas con informantes clave: familiares, amigos y colegas de Argentina, Brasil, Ecuador y Cuba. Asimismo, analizamos los títulos de su biblioteca personal, donada a la fundación internacional que lleva su nombre, y documentos de distintos archivos particulares.

This article analyzes the trajectory of Juan César García, one of the referential figures of the Latin American social medicine movement. The question that inspired this work sought to uncover in what moment and in what circumstances García incorporated a Marxist framework into his way of thinking about health problems. Following the methodological guidelines proposed by Pierre Bourdieu, we used the concept of "life trajectories" to reconstruct a life path that divides in various directions: from his birthplace in Necochea to the city of La Plata, from there to Santiago de Chile and, finally, his numerous trips from Washington DC to a large part of Latin America. In order to trace these paths, we carried out semi-structured interviews with key informants: family members, friends, and colleagues from Argentina, Brazil, Ecuador and Cuba. We also analyzed the books included in his personal library, donated after his death to the international foundation that carries his name, and documents from different personal archives.

Médicos y policías durante la epidemia de fiebre amarilla (Buenos Aires, 1871) / Police officers and medical doctors during the yellow fever epidemic (Buenos Aires, 1871)

Este trabajo analiza la actuación de médicos y policías durante la epidemia de fiebre amarilla que tuvo lugar en la ciudad de Buenos Aires en 1871. Aunque las embestidas de enfermedades infectocontagiosas fueron recurrentes durante el siglo XIX, la epidemia de fiebre amarilla constituye un quiebre, no solo por sus dimensiones cuantitativas y por los efectos materiales sobre la ciudad, sino también por las querellas que suscitó entre discursos en pugna. En particular, se intenta mostrar aquí cómo las figuras de los médicos y los policías fueron posicionadas en relación al tema del héroe y del sacrificado en cumplimiento del deber.

This paper examines the action of medical doctors and policemen during the yellow fever epidemic in Buenos Aires (1871). Even though during the XIX century epidemics were frequent, the yellow fever one constitutes a break, not only because of its scope and material effects on the city, but also because it opened a crisis of hegemonic discourses. In particular, the paper scrutinizes the effects of the yellow fever epidemics on the figures of doctors and policemen, who were redesigned in light of tropes of heroism and sacrifice.

Mens sana in corpore sano: José M. Ramos Mejía and the medicalization of the argentine society / Mens sana in corpore sano: José M. Ramos Mejía and the medicalization of the argentine society

Este artículo trata sobre un período de la historia argentina en el cual la "mirada médica", a través de un grupo de prestigiosos intelectuales, se convirtió en una clave de interpretación de la sociedad argentina. El análisis gira en torno a la obra de uno de los médicos higienistas más influyentes, José María Ramos Mejía, deteniéndose especialmente en su libro más famoso: Las multitudes argentinas (1899). La hipótesis principal que recorre el texto es la siguiente: la medicalización de la sociedad, acentuada luego de las epidemias de cólera y fiebre amarilla de mediados del siglo XIX, ofreció a las elites públicas la posibilidad de construir dominios legítimos de intervención estatal. Intromisiones del Estado en la vida privada que, además de ser algo resistidas por la población, entraban en tensión con los principios teóricos del liberalismo que los propios miembros de la elite defendían...

Mens sana in corpore sano: José M. Ramos Mejía and the medicalization of the argentine society / Mens sana in corpore sano: José M. Ramos Mejía and the medicalization of the argentine society

Este artículo trata sobre un período de la historia argentina en el cual la "mirada médica", a través de un grupo de prestigiosos intelectuales, se convirtió en una clave de interpretación de la sociedad argentina. El análisis gira en torno a la obra de uno de los médicos higienistas más influyentes, José María Ramos Mejía, deteniéndose especialmente en su libro más famoso: Las multitudes argentinas (1899). La hipótesis principal que recorre el texto es la siguiente: la medicalización de la sociedad, acentuada luego de las epidemias de cólera y fiebre amarilla de mediados del siglo XIX, ofreció a las elites públicas la posibilidad de construir dominios legítimos de intervención estatal. Intromisiones del Estado en la vida privada que, además de ser algo resistidas por la población, entraban en tensión con los principios teóricos del liberalismo que los propios miembros de la elite defendían...(AU)