Abstract
Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, there remain few clinically effective drugs to complement ...vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS-CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side effect. One alternative, with structural similarities to heparin, is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated, and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective in inhibiting cell infection than low-molecular-weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.
The interferon‐induced transmembrane proteins (IFITM) are implicated in several biological processes, including antiviral defense, but their modes of action remain debated. Here, taking advantage of ...pseudotyped viral entry assays and replicating viruses, we uncover the requirement of host co‐factors for endosomal antiviral inhibition through high‐throughput proteomics and lipidomics in cellular models of IFITM restriction. Unlike plasma membrane (PM)‐localized IFITM restriction that targets infectious SARS‐CoV2 and other PM‐fusing viral envelopes, inhibition of endosomal viral entry depends on lysines within the conserved IFITM intracellular loop. These residues recruit Phosphatidylinositol 3,4,5‐trisphosphate (PIP3) that we show here to be required for endosomal IFITM activity. We identify PIP3 as an interferon‐inducible phospholipid that acts as a rheostat for endosomal antiviral immunity. PIP3 levels correlated with the potency of endosomal IFITM restriction and exogenous PIP3 enhanced inhibition of endocytic viruses, including the recent SARS‐CoV2 Omicron variant. Together, our results identify PIP3 as a critical regulator of endosomal IFITM restriction linking it to the Pi3K/Akt/mTORC pathway and elucidate cell‐compartment‐specific antiviral mechanisms with potential relevance for the development of broadly acting antiviral strategies.
Synopsis
The interferon‐induced transmembrane proteins (IFITM) can restrict entry of multiple viruses through mechanisms that are still elusive. This work shows that IFITM3‐dependent endosomal restriction of viral entry requires phosphatidylinositol (3,4,5)‐trisphosphate (PIP3) binding.
Inhibition of endosomal viral entry depends on the interaction of lysines within the conserved IFITM3 intracellular loop with PIP3.
PIP3 is an interferon‐inducible phospholipid that acts as a rheostat for endosomal innate immunity.
An interferon‐dependent increase in PIP3 is regulated by the PI3K/Akt/mTOR pathway in a cell‐type dependent manner.
Exogenous PIP3 delivery enhances inhibition of endocytic viral entry, including that of the recent SARS‐CoV2 Omicron variant.
Phosphatidylinositol (3,4,5)‐trisphosphate enhances inhibition of endocytic viral entry via binding to the intracellular loop of interferon‐induced transmembrane protein 3.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
ZIKV is an enveloped, arthropod-borne (arbovirus) virus characterized by a single positive-stranded RNA genome. ZIKV was firstly isolated in 1948 from a sentinel monkey that was monitored for the ...infection by Yellow fever virus in the Zika forest of Uganda (Dick et al., 1952). The virus belongs to the family of Flaviviridae and it is closely related to other members of the family, mainly Dengue, Yellow fever, West Nile and Japanese Encephalitis Viruses.
We investigated the potential anti-HIV-1 activity of the candidate microbicide 5-hydroxytyrosol (5-HT) both in primary human cervical tissue explants (CTE), established from tissues of women ...undergoing histerectomy, and in endometrium-associated leukocytes (EAL). CTE were exposed to either the laboratory-adapted HIV-1BaL or to primary viral isolates in the presence or absence of 5-HT or 3TC/lamivudine as control and were then monitored for 12 days in terms of HIV-1 p24 Gag antigen production in culture supernatants. HIV-1BaL replication was also evaluated in EAL by reverse transcriptase (RT) activity. The highest nontoxic concentrations of 5-HT (200 and 100 μM for CTE and EAL, respectively) exerted a significant inhibitory effect on virus replication in both primary cell systems. 5-HT did not cause significant alterations of the activation profile of CD4+ and CD8+ T cells, in terms of CD4, CCR5, CD25, CD69 and HLA-DR expression, although it decreased the percentage of CD38+CD8+ T cells. Thus, 5-HT deserves consideration as a potential candidate microbicide for preventing HIV-1 transmission or curtailing its replication in the female reproductive tract.
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•5-HT was tested as candidate anti-HIV microbicide to prevent or limit HIV-1 replication in primary human CTE and EAL.•Nontoxic concentrations of 5-HT (<200 μM) inhibited R5 HIV-1 replication in both CTE and EAL.•5-HT also decreased the levels of CD4+ and CD8+ T lymphocytes infiltrating the CTE and coexpressing CD38.•5-HT should be tested either alone or in combination with other anti-HIV microbicides to prevent sexual HIV transmission.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fueled the COVID-19 pandemic with its enduring medical and socioeconomic challenges because of subsequent waves and ...long-term consequences of great concern. Here, we chart the molecular basis of COVID-19 pathogenesis by analyzing patients' immune responses at single-cell resolution across disease course and severity. This approach confirms cell subpopulation-specific dysregulation in COVID-19 across disease course and severity and identifies a severity-associated activation of the receptor for advanced glycation endproducts (RAGE) pathway in monocytes. In vitro THP1-based experiments indicate that monocytes bind the SARS-CoV-2 S1-receptor binding domain (RBD) via RAGE, pointing to RAGE-Spike interaction enabling monocyte infection. Thus, our results demonstrate that RAGE is a functional receptor of SARS-CoV-2 contributing to COVID-19 severity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
El presente arti?culo describe, en forma sucinta, resultados de investigaciones en el a?mbito de la Educacio?n Superior, desarrollados por docentes investigadores de la UCU- Argentina y UCLV- Cuba, ...cuya caracteri?stica principal es el trabajo bajo la modalidad “en li?nea”, en tanto, la distancia entre ambas universidades difiere por ma?s de 6000 km. Iniciado los intercambios hace un poco ma?s de dos an?os, y una vez acordado los temas de intere?s se planteo? desarrollar el primer trabajo de investigacio?n sobre estilos docentes y grupos de investigacio?n en li?nea. Durante su implementacio?n, y tal como sucede en los caminos de la investigacio?n, surgen nuevas preguntas, otros problemas, que permitieron plantear otros temas referidos por un lado a la Orientacio?n Educativa y las estrategias de aprendizaje en el contexto universitario y las buenas pra?cticas en la docencia del nivel superior.
Sendos trabajos se plantean desde un enfoque cualitativo, por considerar que el mismo permite la comprensio?n del feno?meno que se desea estudiar desde una perspectiva holi?stica, “desde adentro”, involucrando a los diferentes actores del contexto estudiado.
PALABRAS CLAVES: Investigacio?n- Educacio?n Superior- Orientacio?n Educativa- Buenas Pra?cticas
Abstract
This article describes, succinctly, the research results in the field of Higher Education, developed by researchers of the UCU-Argentina and UCLV-Cuba whose main characteristic is the blender learning used by both universities that are distanced more than 6000 km. The exchanges started a little over two years ago, and once the topics of interest were agreed upon, the first research work on teaching styles and online research groups was proposed. During its implementation, and as it happens in the ways of the investigation, new questions arose, other problems, that allowed to raise other subjects referred on the one hand to the Educational Orientation and the strategies of learning in the university context and, on the other hand, the good practices in the superior level teaching.
The two works are proposed from a qualitative perspective, considering that it allows the understanding of the phenomenon that one wishes to study from a holistic perspective, "from within", involving the different actors of the studied context.
KEYWORDS: Research - Higher Education - Educational Guidance - Good Practices.
Resumo
O presente artigo descreve, de forma breve, os resultados de pesquisas no a?mbito da Educac?a?o Superior, desenvolvido por docentes pesquisadores da UCU – Argentina e UCLV- Cuba, cuja caracteri?stica principal e? o trabalho sob a modalidade “em linha”, uma vez que a dista?ncia entre as duas universidades e? de mais de 6000 km. Os interca?mbios foram iniciados ha? pouco mais de dois anos, e uma vez estabelecido de comum acordo os temas de interesse, se propuseram a desenvolver o primeiro trabalho de pesquisa sobre estilos docentes e grupos de pesquisa em linha. Durante a sua implementac?a?o, e como se passa nos caminhos da pesquisa, surgem novas perguntas, outros problemas, que permitiram propor outros temas referidos por um lado a? Orientac?a?o Educativa e a?s estrate?gias de aprendizagem no contexto universita?rio e as boas pra?ticas na doce?ncia de ni?vel superior.
Ambos os trabalhos se desenvolvem desde um enfoque qualitativo, por considerarmos que o mesmo permite a compreensa?o do feno?meno que se deseja estudar desde uma perspectiva holi?stica, “desde dentro”, envolvendo os diferentes atores do contexto estudado.
PALAVRAS CHAVE: Pesquisa- Educac?a?o Superior- Orientac?a?o Educativa- Boas Pra?ticas.
El presente arti?culo describe, en forma sucinta, resultados de investigaciones en el a?mbito de la Educacio?n Superior, desarrollados por docentes investigadores de la UCU- Argentina y UCLV- Cuba, cuya caracteri?stica principal es el trabajo bajo la modalidad “en li?nea”, en tanto, la distancia entre ambas universidades difiere por ma?s de 6000 km. Iniciado los intercambios hace un poco ma?s de dos an?os, y una vez acordado los temas de intere?s se planteo? desarrollar el primer trabajo de investigacio?n sobre estilos docentes y grupos de investigacio?n en li?nea. Durante su implementacio?n, y tal como sucede en los caminos de la investigacio?n, surgen nuevas preguntas, otros problemas, que permitieron plantear otros temas referidos por un lado a la Orientacio?n Educativa y las estrategias de aprendizaje en el contexto universitario y las buenas pra?cticas en la docencia del nivel superior.
Sendos trabajos se plantean desde un enfoque cualitativo, por considerar que el mismo permite la comprensio?n del feno?meno que se desea estudiar desde una perspectiva holi?stica, “desde adentro”, involucrando a los diferentes actores del contexto estudiado.
PALABRAS CLAVES: Investigacio?n- Educacio?n Superior- Orientacio?n Educativa- Buenas Pra?cticas
Abstract
This article describes, succinctly, the research results in the field of Higher Education, developed by researchers of the UCU-Argentina and UCLV-Cuba whose main characteristic is the blender learning used by both universities that are distanced more than 6000 km. The exchanges started a little over two years ago, and once the topics of interest were agreed upon, the first research work on teaching styles and online research groups was proposed. During its implementation, and as it happens in the ways of the investigation, new questions arose, other problems, that allowed to raise other subjects referred on the one hand to the Educational Orientation and the strategies of learning in the university context and, on the other hand, the good practices in the superior level teaching.
The two works are proposed from a qualitative perspective, considering that it allows the understanding of the phenomenon that one wishes to study from a holistic perspective, "from within", involving the different actors of the studied context.
KEYWORDS: Research - Higher Education - Educational Guidance - Good Practices.
Resumo
O presente artigo descreve, de forma breve, os resultados de pesquisas no a?mbito da Educac?a?o Superior, desenvolvido por docentes pesquisadores da UCU – Argentina e UCLV- Cuba, cuja caracteri?stica principal e? o trabalho sob a modalidade “em linha”, uma vez que a dista?ncia entre as duas universidades e? de mais de 6000 km. Os interca?mbios foram iniciados ha? pouco mais de dois anos, e uma vez estabelecido de comum acordo os temas de interesse, se propuseram a desenvolver o primeiro trabalho de pesquisa sobre estilos docentes e grupos de pesquisa em linha. Durante a sua implementac?a?o, e como se passa nos caminhos da pesquisa, surgem novas perguntas, outros problemas, que permitiram propor outros temas referidos por um lado a? Orientac?a?o Educativa e a?s estrate?gias de aprendizagem no contexto universita?rio e as boas pra?ticas na doce?ncia de ni?vel superior.
Ambos os trabalhos se desenvolvem desde um enfoque qualitativo, por considerarmos que o mesmo permite a compreensa?o do feno?meno que se deseja estudar desde uma perspectiva holi?stica, “desde dentro”, envolvendo os diferentes atores do contexto estudado.
PALAVRAS CHAVE: Pesquisa- Educac?a?o Superior- Orientac?a?o Educativa- Boas Pra?ticas.
Recibido: Diciembre 21 de 2017 Aceptado: Abril 3 de 2018
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