Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses

<p>Abstract</p> <p>Background</p> <p>Hereditary Hemochromatosis (HH) is a genetic disease associated with iron overload, in which individuals homozygous for the mutant C282Y <it>HFE </it>associated allele are at risk for the development of a range of disorders particularly liver disease. Conformational diseases are a class of disorders associated with the expression of misfolded protein. HFE C282Y is a mutant protein that does not fold correctly and consequently is retained in the Endoplasmic Reticulum (ER). In this context, we sought to identify ER stress signals associated with mutant C282Y HFE protein expression, which may have a role in the molecular pathogenesis of HH.</p> <p>Results</p> <p>Vector constructs of Wild type HFE and Mutant C282Y HFE were made and transfected into HEK293 cell lines. We have shown that expression of C282Y HFE protein triggers both an unfolded protein response (UPR), as revealed by the increased GRP78, ATF6 and CHOP expression, and an ER overload response (EOR), as indicated by NF-κB activation. Furthermore, C282Y HFE protein induced apoptotic responses associated with activation of ER stress. Inhibition studies demonstrated that tauroursodeoxycholic acid, an endogenous bile acid, downregulates these events. Finally, we found that the co-existence of both C282Y HFE and Z alpha 1-antitrypsin protein (the protein associated with the liver disease of Z alpha 1-antitrypsin deficiency) expression on ER stress responses acted as potential disease modifiers with respect to each other.</p> <p>Conclusion</p> <p>Our novel observations suggest that both the ER overload response (EOR) and the unfolded protein response (UPR) are activated by mutant C282Y HFE protein.</p

Ancient chicken remains reveal the origins of virulence in Marek's disease virus

This is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via the DOI in this recordData and materials availability: All MDV sequence data generated have been deposited in GenBank under accession PRJEB64489. Code is available at GitHub (https://github.com/antonisdim/MDV) and archived at Zenodo (https://zenodo.org/records/10022436) (25).The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens.European Research Council (ERC)Wellcome TrustOxford Martin School Pandemic Genomics ProgrammeArts and Humanities Research Council (AHRC)European Union Horizon 2020Biotechnology and Biological Sciences Research Council (BBSRC)Research Foundation–Flanders (Fonds voor Wetenschappelijk Onderzoek

Ancient goat genomes reveal mosaic domestication in the Fertile Crescent

Current genetic data are equivocal as to whether goat domestication occurred multiple times or was a singular process. We generated genomic data from 83 ancient goats (51 with genome-wide coverage) from Paleolithic to Medieval contexts throughout the Near East. Our findings demonstrate that multiple divergent ancient wild goat sources were domesticated in a dispersed process that resulted in genetically and geographically distinct Neolithic goat populations, echoing contemporaneous human divergence across the region. These early goat populations contributed differently to modern goats in Asia, Africa, and Europe. We also detect early selection for pigmentation, stature, reproduction, milking, and response to dietary change, providing 8000-year-old evidence for human agency in molding genome variation within a partner species

Assessment of protein silver nanoparticles toxicity against pathogenic Alternaria solani

Mycogenic synthesis of silver nanoparticles (AgNPs) was carried out in the present investigation using an aqueous extract of endophytic non-pathogenic Alternaria solani F10 (KT721914). The mycosynthesized AgNPs were characterized by means of spectroscopic and microscopic techniques. The surface plasmon resonance found at 430 nm confirmed the formation of stable AgNPs for several weeks at room temperature. Also, the results revealed the formation of spherical and monodispersed AgNPs with an average size of 14.8 +/- 1.2 nm. The FT-IR spectrum suggested that the fungal extracellular proteins and secondary metabolites had the role in Ag reduction and AgNPs capping of which protein Ag nanoconjugates were formed. Furthermore, the mycosynthesized AgNPs exhibited potent antifungal activity against different pathogenic isolates of the same Alternaria solani fungus, the causal pathogen of tomato early blight disease. The antifungal efficiency of the AgNPs at 1, 5 and 10 ppm were evaluated for 8 days after incubation by measuring the inhibition rate of fungal radial growth. The results were further supported by investigating fungal hyphae morphology alteration by scanning and transmission electron microscopy. Treated fungal hyphae showed formation of pits and pores. Also, the mycosynthesized AgNPs were able to pass and distribute throughout the fungal cell area and interact with the cell components.A financial support from European Commission by Erasmus Mundus Scholarship-ACTION 2 WELCOME program is gratefully acknowledged. Work in JAD laboratory was supported by grant BIO2014-54269-R from the Ministerio de Economia y Competividad (Spain).Abdel-Hafez, SII.; Nafady, NA.; Abdel-Rahim, IR.; Shaltout, AM.; Daros Arnau, JA.; Mohamed, MA. (2016). 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Ontology Design for Pharmaceutical Research Outcomes

The network of scholarly publishing involves generating and exchanging ideas, certifying research, publishing in order to disseminate findings, and preserving outputs. Despite enormous efforts in providing support for each of those steps in scholarly communication, identifying knowledge fragments is still a big challenge. This is due to the heterogeneous nature of the scholarly data and the current paradigm of distribution by publishing (mostly document-based) over journal articles, numerous repositories, and libraries. Therefore, transforming this paradigm to knowledge-based representation is expected to reform the knowledge sharing in the scholarly world. Although many movements have been initiated in recent years, non-technical scientific communities suffer from transforming document-based publishing to knowledge-based publishing. In this paper, we present a model (PharmSci) for scholarly publishing in the pharmaceutical research domain with the goal of facilitating knowledge discovery through effective ontology-based data integration. PharmSci provides machine-interpretable information to the knowledge discovery process. The principles and guidelines of the ontological engineering have been followed. Reasoning-based techniques are also presented in the design of the ontology to improve the quality of targeted tasks for data integration. The developed ontology is evaluated with a validation process and also a quality verification method

Ancient chicken remains reveal the origins of virulence in Marek's disease virus.

The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens