Dengue Virus Genome Uncoating Requires Ubiquitination

The process of genome release or uncoating after viral entry is one of the least-studied steps in the flavivirus life cycle. Flaviviruses are mainly arthropod-borne viruses, including emerging and reemerging pathogens such as dengue, Zika, and West Nile viruses. Currently, dengue virus is one of the most significant human viral pathogens transmitted by mosquitoes and is responsible for about 390 million infections every year around the world. Here, we examined for the first time molecular aspects of dengue virus genome uncoating. We followed the fate of the capsid protein and RNA genome early during infection and found that capsid is degraded after viral internalization by the host ubiquitin-proteasome system. However, proteasome activity and capsid degradation were not necessary to free the genome for initial viral translation. Unexpectedly, genome uncoating was blocked by inhibiting ubiquitination. Using different assays to bypass entry and evaluate the first rounds of viral translation, a narrow window of time during infection that requires ubiquitination but not proteasome activity was identified. In this regard, ubiquitin E1-activating enzyme inhibition was sufficient to stabilize the incoming viral genome in the cytoplasm of infected cells, causing its retention in either endosomes or nucleocapsids. Our data support a model in which dengue virus genome uncoating requires a nondegradative ubiquitination step, providing new insights into this crucial but understudied viral process. IMPORTANCE: Dengue is the most significant arthropod-borne viral infection in humans. Although the number of cases increases every year, there are no approved therapeutics available for the treatment of dengue infection, and many basic aspects of the viral biology remain elusive. After entry, the viral membrane must fuse with the endosomal membrane to deliver the viral genome into the cytoplasm for translation and replication. A great deal of information has been obtained in the last decade regarding molecular aspects of the fusion step, but little is known about the events that follow this process, which leads to viral RNA release from the nucleocapsid. Here, we investigated the fate of nucleocapsid components (capsid protein and viral genome) during the infection process and found that capsid is degraded by the ubiquitin-proteasome system. However, in contrast to that observed for other RNA and DNA viruses, dengue virus capsid degradation was not responsible for genome uncoating. Interestingly, we found that dengue virus genome release requires a nondegradative ubiquitination step. These results provide the first insights into dengue virus uncoating and present new opportunities for antiviral intervention.Fil: Byk, Laura Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Iglesias, Nestor Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: de Maio, Federico Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Gebhard, Leopoldo German. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rossi, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Gamarnik, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Epidemiology of chronic obstructive pulmonary disease: Health effects of air pollution

Abstract:  COPD is one of the leading causes of morbidity and mortality in the industrialized and the developing countries. According to the prediction of the World Health Organization, COPD will become the third leading cause of mortality and the fifth cause of disability in 2020 worldwide. In epidemiology, distinct phenotypic entities converge on the term COPD, so that prevalence and mortality data may be inclusive of chronic bronchitis, emphysema and asthma; moreover, the assessment of prevalence rates may change considerably according to the diagnostic tools used. Thus, a considerable problem is to estimate the real prevalence of COPD in the general population. COPD is determined by the action of a number of various risk factors, among which, the most important is cigarette smoking. However, during the last few decades, evidence from epidemiological studies finding consistent associations between air pollution and various outcomes (respiratory symptoms, reduced lung function, chronic bronchitis and mortality), has suggested that outdoor air pollution is a contributing cause of morbidity and mortality. In conclusion, epidemiological studies suggest that air pollution plays a remarkable role in the exacerbation and in the pathogenesis of chronic respiratory diseases. Thus, respiratory physicians, as well as public health professionals, should advocate for a cleaner environment

Gender influence on professional satisfaction and gender issue perception among young oncologists. A survey of the Young Oncologists Working Group of the Italian Association of Medical Oncology (AIOM)

Background: The professional gender gap is increasingly recognised in oncology. We explored gender issues perception and gender influence on professional satisfaction/gratification among young Italian oncologists. Methods: Italian oncologists aged 6440 years and members of the Italian Association of Medical Oncology were invited to participate in an online survey addressing workload/burnout, satisfaction in professional abilities and relations, relevant factors for professional gratification, and gender barriers. \u3c72 test for general association or \u3c72 test for trend was used to analyse the data. Results: 201 young oncologists participated in the survey: 67% female, 71% aged 30-40 years, 41% still in training and 82% without children. Women and men were equally poorly satisfied by the relations with people occupying superior hierarchical positions. There was heterogeneity between women and men in current (p=0.011) and expected future (p=0.007) satisfaction in professional abilities: women were more satisfied by current empathy and relations with colleagues and were more confident in their future managerial and team leader skills. The most important elements for professional gratification indicated by all participants were, in general, work-life balance (36%) and intellectual stimulation/research (32%); specifically for women, work-life balance (48%) and intellectual stimulation/research (20%); and specifically for men, career (29%) and social prestige/recognition (26%). Heterogeneity within the same gender emerged. For example, the elements indicated by men as the most important were intellectual stimulation/research (39%) and work-life balance (21%) in general, versus social prestige/recognition (24%) and career (24%), respectively, specifically for men (p<0.0001). More women versus men perceived gender issue as an actual problem (60% vs 38%, p=0.03); men underestimated gender barriers to women's career (p=0.011). Conclusions: Satisfaction in professional abilities varied by gender. Work-life balance is important for both women and men. Stereotypes about gender issues may be present. Gender issue is an actual problem for young oncologists, mostly perceived by women

How does quality enter into health care purchasing decisions?

A number of employers, business consortia, and public purchasers are promoting value-based purchasing as a way to improve the quality of patient care. Some purchasers are using publicly available information on health plan and provider performance to make their health plan and provider choices, while others are using their market power to drive improvements in patient care and safety. This article examines six key strategies used by purchasers

Hacia un enfoque curricular promotor de la creatividad y la innovación en los estudiantes de ingeniería industrial en el ámbito de industria 4.0

La Industria 4.0 o 4ta. Revolución Industrial es el dominio de los procesos industriales por medios cibernéticos [1]. Esta cibercultura requiere ingenieros competentes técnicamente, creativos, innovadores y capaces de comunicarse de manera compleja [2,3]. Tal formación implica un enfoque de enseñanza acorde. Investigamos: cuáles son los factores que promueven la creatividad y la innovación de los estudiantes de Ingeniería Industrial e impulsan el rol del docente hacia un enfoque curricular promotor de ellos. Se trabajó sobre los docentes, titular y ayudante, y 40 alumnos de la materia Organización Industrial A (80% trabaja) de Ingeniería Industrial de la Universidad de Morón, turno noche, en los períodos lectivos 2018 y 2019. Se aplicó la investigación-acción donde dos observadoras registraron el desarrollo de las clases y a posteriori analizaron con los docentes, elaborando categorías conceptuales: postura del docente frente al alumnado, participación de los alumnos, estrategias, recursos didácticos y evaluación. Dieron lugar a postular un nuevo enfoque para los cursos que se implementó durante 2018 y 2019, pasando de la práctica conductista al modelo ecológico [4]. Los alumnos respondieron positivamente al nuevo enfoque. El nivel de aprobación de trabajos prácticos fue 92,3 % en 2019; lo que dio un incremento de 26 % entre 2017 y 2019

A needle in a haystack? Catching Pop\ III stars in the Epoch of Reionization: I. Pop\ III star forming environments

Despite extensive search efforts, direct observations of the first (Pop III) stars have not yet succeeded. Theoretical studies have suggested that late Pop III star formation (SF) is still possible in pristine clouds of high-mass galaxies, coexisting with Pop II stars, down to the Epoch of Reionization (EoR). Here we reassess this finding by exploring Pop III SF in eight $50h^{-1} ~ \mathrm{cMpc}$ simulations performed with the hydrodynamical code dustyGadget. We find that Pop III SF ($\sim 10^{-3.4} - 10^{-3.2} ~ \mathrm{M_\odot yr^{-1} cMpc^{-3}}$) is still occurring down to $z \sim 6 - 8$, i.e. well within the reach of deep JWST surveys. At these epochs, $\gtrsim 20 - 30 \%$ of galaxies with $M_\star \gtrsim 3 \times 10^9 ~ \mathrm{M_\odot}$ are found to host Pop III stars, although with a Pop III/Pop II mass fraction $\lesssim 0.1 \%$. Regardless of their mass, Pop\ III hosting galaxies are mainly found on the main sequence, at high SFRs, probably induced by accretion of pristine gas. This scenario is also supported by their increasing SF histories and their preferential location in high-density regions of the cosmic web. Pop\ III stars are found both in the outskirts of metal-enriched regions and in isolated, pristine clouds. In the latter case, their signal may be less contaminated by Pop IIs, although its detectability will strongly depend on the specific line-of-sight to the source, due to the complex morphology of the host galaxy and its highly inhomogeneous dust distribution.Comment: Submitted to MNRAS, comments welcom