Increased mTOR Signaling and Impaired Autophagic Flux Are Hallmarks of SARS-CoV-2 Infection.

The COVID-19 (Coronavirus Disease 2019), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), severely affects mainly individuals with pre-existing comorbidities. Here our aim was to correlate the mTOR (mammalian/mechanistic Target of Rapamycin) and autophagy pathways with the disease severity. Through western blotting and RNA analysis, we found increased mTOR signaling and suppression of genes related to autophagy, lysosome, and vesicle fusion in Vero E6 cells infected with SARS-CoV-2 as well as in transcriptomic data mining of bronchoalveolar epithelial cells from severe COVID-19 patients. Immunofluorescence co-localization assays also indicated that SARS-CoV-2 colocalizes within autophagosomes but not with a lysosomal marker. Our findings indicate that SARS-CoV-2 can benefit from compromised autophagic flux and inhibited exocytosis in individuals with chronic hyperactivation of mTOR signaling.

Association between IL-27 and Tr1 cells in severe form of paracoccidioidomycosis.

Interleukin-27, a cytokine of the IL-12 family, is secreted by antigen-presenting cells such as macrophages and dendritic cells (DCs). Recent studies suggest an anti-inflammatory role for IL-27 by inducing IL-10 producing Tr1 cells capable of inhibiting Th1 and Th17 type responses. Our study aimed to investigate the involvement of IL-27 and Tr1 cells in the immunomodulation of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Brazil. The presence of IL-27 was evaluated in serum and biopsies of patients with PCM by ELISA, immunohistochemistry, and immunofluorescence. The presence of Tr1 in peripheral blood was analyzed by flow cytometry. In vitro assays were performed to verify the ability of P. brasiliensis yeast to induce IL-27 production by DCs and macrophages, as well as the polarization of lymphocytes to the Tr1 phenotype. Patients with the acute form and severe chronic form, the most severe and disseminated forms of PCM, presented higher serum concentrations of IL-27 and higher percentage of Tr1 cells compared to patients with mild chronic form. IL-27 was also detected in lesions of patients with PCM and associated with DCs and macrophages. P. brasiliensis Pb18 yeasts were able to induce IL-27 production by both DCs and macrophages. We found that DCs pulsed with Pb18 were able to induce Tr1 lymphocytes in vitro. Our data suggest that IL-27 and Tr1 cells could contribute to the deficient immune response to P. brasiliensis that leads to severe and disseminated forms of the disease.

Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study.

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.

Perfil de mulheres com câncer de mama tratadas com quimioterapia / Profile of women with breast cancer treated with chemotherapy / El perfil de las mujeres con cáncer de mama tratadas con quimioterapia

Objetivo: caracterizar o perfil sociodemográfico, epidemiológico e clínico de mulheres com câncer de mama tratadas com quimioterapia. Método: estudo descritivo-exploratório, de natureza quantitativa, desenvolvido no hospital universitário com 195 mulheres. Foram coletadas informações do formulário de anotações de enfermagem utilizado no Processo de Enfermagem, dos prontuários e do Sistema de Informação Hospitalar (SIH). Os dados foram digitados em planilha do Excel, empregado o teste Qui-quadrado, considerando significância p < 0,05. Resultados: idade média 54,37 anos; raça branca (69,74%). História ginecológicoobstétrica: (43%) uso de anticoncepcional, (87,69%) tiveram filhos; (15,9%) menarca precoce, (3,58%) menopausa tardia. Hábitos de vida: elevada incidência de sobrepeso e obesidade (45,12%). As variáveis menopausa tardia e obesidade apresentaram significância estatística (p<0,011). Houve predominância de tratamento adjuvante (59%); esquema quimioterápico FAC com (37,43%); estadiamento níveis: IIA (17,43%) e IIIB (17,43%). Conclusão: estudos como este, possibilitam ações de saúde planejadas em todos os níveis de atenção e consequentemente promoção de melhores condições de vida para populações-alvo.(AU)

Objective: to characterize the sociodemographic, clinical and epidemiological profile of women with breast cancer treated with chemotherapy. Method: descriptive-exploratory study, with quantitative approach, developed at the university hospital with 195 women. There was collection of the information from the nursing notes form used in the nursing process, the medical records and the Hospital Information System (HIS). Data were entered in Excel spreadsheet, used the chi-square test, considering p < 0.05. Results: mean age 54.37 years; Caucasians (69.74%). Gynecological and obstetrical history: (43%) contraceptive use, (87.69%) had children; (15.9%) early menarche, (3.58%) late menopause. Living habits: high incidence of overweight and obesity (45.12%). The late menopause and obesity variables were statistically significant (p<0.011). There was a predominance of adjuvant treatment (59%); FAC chemotherapy regimen with (37.43%); staging levels: IIA (17.43%) and IIIB (17.43%). Conclusion: studies like this enable health actions planned at all levels of attention and thus promote better living conditions for the target populations.(AU)

Objetivo: caracterizar el perfil sociodemográfico, clínico y epidemiológico de las mujeres con cáncer de mama tratadas con quimioterapia. Método: estudio exploratorio-descriptivo, cuantitativo, desarrollado en el hospital universitario con 195 mujeres. Fueron recogidas las informaciones del formulario de notas de enfermería utilizado en el proceso de enfermería, los registros médicos y el Sistema de Información Hospitalaria (SIH). Los datos fueron introducidos en la hoja de cálculo Excel, utilizada la prueba de chicuadrado, considerando p < 0,05. Resultados: la edad media 54,37 años; Caucásicos (69,74%). Historia ginecológica y obstétrica: (43%) uso de anticonceptivos, (87,69%) tenían niños; (15,9%) menarquia temprana, (3,58%) menopausia tardía. Hábitos de vida: alta incidencia de sobrepeso y obesidad (45,12%). Las variables de la menopausia tardía y obesidad fueron estadísticamente significativas (p<0,011). Hubo un predominio de tratamiento adyuvante (59%); régimen de quimioterapia FAC con (37.43%); los niveles de estadificación: IIA (17,43%) y IIIB (17,43%). Conclusión: los estudios de este tipo permiten a las acciones de salud previstos en todos los niveles de atención y de este modo promover mejores condiciones de vida para las poblaciones objetivo.(AU)

Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times.

Retinoic acid (RA) is a terpenoid that is synthesized from vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinical and experimental data provide uncontested evidence for the pleiotropic roles of RA signaling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signaling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signaling is exquisitely regulated according to specific phases of cardiac development and that RA signaling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signaling by RA receptors (RARs) in early phases of heart development. This article is part of a Special Issue entitled: Nuclear receptors in animal development.