Krüppel-like factor 6 regulates transforming growth factor-β gene expression during human respiratory syncytial virus infection

<p>Abstract</p> <p>Background</p> <p>Human respiratory syncytial virus (RSV) infection is associated with airway remodeling and subsequent asthma development. Transforming growth factor-beta (TGF) plays a crucial role in asthma development. The mechanism regulating TGF gene expression during RSV infection is not known. Kruppel-like factor family of transcription factors are critical regulators of cellular/tissue homeostasis. Previous studies have shown that Kruppel-like factor 6 (KLF6) could function as a trans-activator of TGF gene; however, whether KLF members play a role during infection is unknown. In the current study we have evaluated the role of KLF6 during TGF expression in RSV infected cells.</p> <p>Findings</p> <p>Silencing KLF6 expression by shRNA led to drastic inhibition in TGF production during RSV infection, as assessed by ELISA analysis of medium supernatants. RT-PCR analysis revealed loss of TGF expression in KLF6 silenced cells. Chromatin-immunoprecipitation assay conducted with RSV infected cells showed binding of KLF6 protein to the TGF promoter during RSV infection. We further observed reduced RSV infectivity in KLF6 silenced cells and in cells incubated with TGF neutralizing antibody. In contrast, enhanced RSV infection was noted in cells incubated with purified TGF.</p> <p>Conclusion</p> <p>We have identified KLF6 as a key transcription factor required for trans-activation of TGF gene during RSV infection. Moreover, TGF production is required for efficient RSV infection and thus, KLF6 is also required for efficient RSV infection by virtue of KLF6 dependent TGF production during infection.</p

How does managerial experience predict the internationalization type of a young firm?

This study aims to find out how useful managers' past general and export experience is in predicting whether young manufacturing firms become fast internationalizers. Extant literature about the role of managerial experience in determining young firms' internationalization type is scant. This paper fills this gap by providing systematic evidence on which kinds of general and export experience can be used for accurate predictions of two firm types: born globals and general fast internationalizers. Our dataset encompasses information about managerial experience of the whole population of young Estonian manufacturing firms. Based on using four different prediction methods (logistic regression, rough sets, decision tree, neural networks) and a large variety of variables reflecting managers' past experience, the results indicate that in prediction models, export experience variables are more valuable than general experience variables. Born globals can be predicted with an accuracy of at least 90% in case of all applied machine learning methods, while the precision is lower in case of general fast internationalizers. The study leads to important implications for international business theory and practice

La sindicalización de los trabajadores del campo

El movimiento obrero sindical se inicia como una expresión del sentimiento de rebeldía de la clase trabajadora por la situación, a todas luces injustas, que prevalecía en la época en que se iniciaba el desarrollo industrial. El comienzo de l a industrialización fué un golpe decisivo, un golpe de muerte al régimen agrícola , que en e se entonces reinaba; dundo paso así a un nuevo sistema económico 11 "Capitalismo", régimen éste, que se fundamentó en la filosofía del individualismo y del liberalismo económico, sustentando el principio "Dejar Hacer, Dejar Pasar"

Recreational Drugs and the Risk of Hepatocellular Carcinoma

Hepatocellular carcinoma represents an important contributor to the global cancer-related burden, and liver cirrhosis is the main risk factor for its development. Conventional or illegal drug consumption is a potential but infrequent cause of cirrhosis. However, the causal relationship between recreational drugs and the risk of developing liver cancer has not been studied in detail thus far. The aim of this review is to synthesize the available published evidence on legal and illegal recreational drug use and the risk of hepatocellular carcinoma and other liver tumors. Expanding our knowledge about the contributions of these substances to the appearance of liver cancers is important for combatting this preventable cause of cancer. Abstract Recreational or aesthetic drug use is a distinctive behavior of humans, principally attested in the last century. It is known that recreational and illegal drugs are major contributors to the universal morbidity rate worldwide. Many of these substances have a well-established hepatotoxic potential, causing acute or chronic liver injury, liver fibrosis and cirrhosis, but their implications for hepatocellular carcinoma or other varieties of liver tumors are little known. In this article, we perform an extensive literature review, aiming to provide updated information about recreational drug use and the risk of developing liver tumors. Khat use and pyrrolizidine alkaloid consumption (present in some natural plants) have been linked to liver cirrhosis. Kava intake is associated with different liver tumors in animal models but not in humans. Cannabis’ potential to accelerate liver fibrosis in chronic hepatitis is controversial according to the existing data. Cigarette smoking is an important contributor to hepatocellular carcinoma, and anabolic androgen steroids are well-defined causes of a variety of liver cancers and other hepatic tumors. (...)This research was supported by grants from Instituto de Salud Carlos III, cofounded by the Fondo Europeo de Desarrollo Regional—FEDER (contract numbers: FIS 21_01248; PI18/00901; UMA18-FEDERJA-193). CIBEREHD is funded by the Instituto de Salud Carlos III (ISCIII). All authors are members of the COST ACTION “CA-17112”, Prospective European Drug-Induced Liver Injury Network, supported by COST (European Cooperation in Science and Technology), www.cost.eu. JMPB holds a Rio Hortega contract from ISCIII. ASZ holds a Jaume Bosch Training Action 2022 from CIBEREHD (ISCIII)

Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions

Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifes- tations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps.Instituto de Salud Carlos III: PI18/01804 Instituto de Salud Carlos III: PI19-00883; Instituto de Salud Carlos III: PT 20/00127; Instituto de Salud Carlos III: UMA18-FEDERJA-194; Instituto de Salud Carlos III: PY18-3364; Consejería de Salud de Andalucía: PI-0310-2018, PEMP-0127-2020; Instituto de Salud Carlos III: Rio Hortega CM17/00243; Instituto de Salud Carlos III: Sara Borrell CD20/00083; Instituto de Salud Carlos III: Sara Borrell CD21/00198

Quaternary ice sheets and sea level regression drove divergence in a marine gastropod along Eastern and Western coasts of South America

The southern coastline of South America is a remarkable area to evaluate how Quaternary glacial processes impacted the demography of the near-shore marine biota. Here we present new phylogeographic analyses in the pulmonate Siphonaria lessonii across its distribution, from northern Chile in the Pacific to Uruguay in the Atlantic. Contrary to our expectations, populations from the southwestern Atlantic, an area that was less impacted by ice during glacial maxima, showed low genetic diversity and evidence of recent expansion, similar to the patterns recorded in this study across heavily ice-impacted areas in the Pacific Magellan margin. We propose that Atlantic and Pacific shallow marine hard-substrate benthic species were both affected during the Quaternary in South America, but by different processes. At higher latitudes of the southeast Pacific, ice-scouring drastically affected S. lessonii populations compared to non-glaciated areas along the Chile-Peru province where the species was resilient. In the southwest Atlantic, S. lessonii populations would have been dramatically impacted by the reduction of near-shore rocky habitat availability as a consequence of glacio-eustatic movements. The increase of gravelly and rocky shore substrates in the southwest Atlantic supports a hypothesis of glacial refugia from where the species recolonized lower latitudes across the Atlantic and Pacific margins. Our results suggest that current patterns of genetic diversity and structure in near-shore marine benthic species do not solely depend on the impact of Quaternary glacial ice expansions but also on the availability of suitable habitats and life-history traits, including developmental mode, bathymetry and the likelihood of dispersal by rafting.Fil: Fernandez Iriarte, Pedro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: González Wevar, C. A.. Universidad de Chile; Chile. Universidad Austral de Chile.Instituto de Ciencias Marinas y Limnológicas; ChileFil: Segovia, N. I.. Universidad Católica del Norte; Chile. Universidad de Chile; ChileFil: Rosenfeld, S.. Universidad de Magallanes; ChileFil: Hüne, M.. Universidad de Chile; ChileFil: Fainburg, Leandro Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Nuñez, Jesus Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Haye, P. A.. Universidad Católica del Norte; ChileFil: Poulin, E.. Universidad de Chile; Chil

Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that pre- scription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical hu- man in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.This work was supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional-FEDER (contract numbers: PI18/01804, PI19-00883, PT20/00127, UMA18-FEDERJA-194, PY18-3364, Spain) and grants of Consejería de Salud de Andalucía cofounded by FEDER (contract number: PEMP-0127-2020, Spain). M.V.P. holds a Sara Borrell (CD21/00198, Spain) research contract from ISCIII and Consejería de Salud de Andalucía. C.L.G. holds a Juan de la Cierva Incorporación (IJCI-2017-31466, Spain) research contract from Ministerio de Ciencia del Gobierno de España. SCReN and CIBERehd are funded by ISCIII (Spain). This publication is based upon work from COST Action “CA17112dProspective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu. The figures in this review were created with Biorender.com

Developing capacity in health informatics in a resource poor setting: lessons from Peru

The public sectors of developing countries require strengthened capacity in health informatics. In Peru, where formal university graduate degrees in biomedical and health informatics were lacking until recently, the AMAUTA Global Informatics Research and Training Program has provided research and training for health professionals in the region since 1999. The Fogarty International Center supports the program as a collaborative partnership between Universidad Peruana Cayetano Heredia in Peru and the University of Washington in the United States of America. The program aims to train core professionals in health informatics and to strengthen the health information resource capabilities and accessibility in Peru. The program has achieved considerable success in the development and institutionalization of informatics research and training programs in Peru. Projects supported by this program are leading to the development of sustainable training opportunities for informatics and eight of ten Peruvian fellows trained at the University of Washington are now developing informatics programs and an information infrastructure in Peru. In 2007, Universidad Peruana Cayetano Heredia started offering the first graduate diploma program in biomedical informatics in Peru