Functional Characterization Of Trib1, A Gene Associated With Multiple Cardiometabolic Traits

Genetic variants near the TRIB1 gene are significantly associated with plasma lipid traits and coronary artery disease. While data suggest TRIB1 is the causal gene for these traits, the mechanisms by which TRIB1 affects plasma lipids are not fully understood. In these studies, I sought to elucidate the physiological and molecular mechanism by which TRIB1 affects plasma lipids. Using a Trib1 hepatocyte specific deletion mouse model (Trib1Δhep), I demonstrated that Trib1Δhep mice have significantly increased plasma total cholesterol, HDL cholesterol, non-HDL cholesterol, LDL cholesterol and apoB protein levels, as well as impaired postprandial triglyceride clearance. I also showed that Trib1Δhep mice have markedly delayed catabolism of LDL-apoB and VLDL-apoB due to significantly decreased Ldlr mRNA and protein expression. Since TRIB1’s most studied molecular function is the COP1-mediated ubiquitination and proteasomal degradation the transcription factor CEBPa, I explored if this interaction is responsible for TRIB1 effects on plasma lipids and LDLR. I demonstrated that hepatic deletion of Cebpa in Trib1Δhep mice eliminated the effects on plasma lipids, apoB catabolism and hepatic LDLR regulation. Additionally, I identified the Activating Transcription Factor 3 (Atf3) as a possible novel mechanism linking TRIB1 to the regulation of LDLR in a CEBPa dependent manner. We also discovered that Trib1 whole body deletion (Trib1 KO) on a pure C57BL/6 background leads to a highly penetrant neonatal lethal phenotype, with less than 5% of Trib1 KO mice making to weaning stages. Our studies determined that Trib1 KO perish between day 0 and day 1 after birth likely due to severely low blood glucose levels. I also determined that about adult Trib1 KO mouse have decreased fasting glucose levels, and improved glucose and insulin tolerance. Overall, my studies stablish Trib1 and its regulation of CEBPa as critical factors in the regulation of multiple metabolic pathways affecting plasma lipids, as well as novel regulators of the LDLR and glucose metabolism

Lineage A betacoronavirus NS2 proteins and the homologous torovirus Berne pp1a carboxy-terminal domain are phosphodiesterases that antagonize activation of RNase L

Viruses in the family Coronaviridae, within the order Nidovirales, are etiologic agents of a range of human and animal diseases, including both mild and severe respiratory diseases in humans. These viruses encode conserved replicase and structural proteins as well as more diverse accessory proteins, encoded in the 3′ ends of their genomes, that often act as host cell antagonists. We previously showed that 2′,5′-phosphodiesterases (2′,5′-PDEs) encoded by the prototypical Betacoronavirus, mouse hepatitis virus (MHV), and by Middle East respiratory syndrome-associated coronavirus antagonize the oligoadenylate-RNase L (OAS-RNase L) pathway. Here we report that additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses infecting both humans and animals, encode 2′,5′-PDEs capable of antagonizing RNase L. We used a chimeric MHV system (MHV(Mut)) in which exogenous PDEs were expressed from an MHV backbone lacking the gene for a functional NS2 protein, the endogenous RNase L antagonist. With this system, we found that 2′,5′-PDEs encoded by the human coronavirus HCoV-OC43 (OC43; an agent of the common cold), human enteric coronavirus (HECoV), equine coronavirus (ECoV), and equine torovirus Berne (BEV) are enzymatically active, rescue replication of MHV(Mut) in bone marrow-derived macrophages, and inhibit RNase L-mediated rRNA degradation in these cells. Additionally, PDEs encoded by OC43 and BEV rescue MHV(Mut) replication and restore pathogenesis in wild-type (WT) B6 mice. This finding expands the range of viruses known to encode antagonists of the potent OAS-RNase L antiviral pathway, highlighting its importance in a range of species as well as the selective pressures exerted on viruses to antagonize it. IMPORTANCE Viruses in the family Coronaviridae include important human and animal pathogens, including the recently emerged viruses severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome-associated coronavirus (MERS-CoV). We showed previously that two viruses within the genus Betacoronavirus, mouse hepatitis virus (MHV) and MERS-CoV, encode 2′,5′-phosphodiesterases (2′,5′-PDEs) that antagonize the OAS-RNase L pathway, and we report here that these proteins are furthermore conserved among additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses, suggesting that they may play critical roles in pathogenesis. As there are no licensed vaccines or effective antivirals against human coronaviruses and few against those infecting animals, identifying viral proteins contributing to virulence can inform therapeutic development. Thus, this work demonstrates that a potent antagonist of host antiviral defenses is encoded by multiple and diverse viruses within the family Coronaviridae, presenting a possible broad-spectrum therapeutic target

Functional Characterization of TRIB1, a Gene Associated with Multiple Cardiometabolic Traits

Genetic variants near the TRIB1 gene are significantly associated with plasma lipid traits and coronary artery disease. While data suggest TRIB1 is the causal gene for these traits, the mechanisms by which TRIB1 affects plasma lipids are not fully understood. In these studies, I sought to elucidate the physiological and molecular mechanism by which TRIB1 affects plasma lipids. Using a Trib1 hepatocyte specific deletion mouse model (Trib1Δhep), I demonstrated that Trib1Δhep mice have significantly increased plasma total cholesterol, HDL cholesterol, non-HDL cholesterol, LDL cholesterol and apoB protein levels, as well as impaired postprandial triglyceride clearance. I also showed that Trib1Δhep mice have markedly delayed catabolism of LDL-apoB and VLDL-apoB due to significantly decreased Ldlr mRNA and protein expression. Since TRIB1’s most studied molecular function is the COP1-mediated ubiquitination and proteasomal degradation the transcription factor CEBPa, I explored if this interaction is responsible for TRIB1 effects on plasma lipids and LDLR. I demonstrated that hepatic deletion of Cebpa in Trib1Δhep mice eliminated the effects on plasma lipids, apoB catabolism and hepatic LDLR regulation. Additionally, I identified the Activating Transcription Factor 3 (Atf3) as a possible novel mechanism linking TRIB1 to the regulation of LDLR in a CEBPa dependent manner. We also discovered that Trib1 whole body deletion (Trib1 KO) on a pure C57BL/6 background leads to a highly penetrant neonatal lethal phenotype, with less than 5% of Trib1 KO mice making to weaning stages. Our studies determined that Trib1 KO perish between day 0 and day 1 after birth likely due to severely low blood glucose levels. I also determined that about adult Trib1 KO mouse have decreased fasting glucose levels, and improved glucose and insulin tolerance. Overall, my studies stablish Trib1 and its regulation of CEBPa as critical factors in the regulation of multiple metabolic pathways affecting plasma lipids, as well as novel regulators of the LDLR and glucose metabolism

Los desafíos de la gestión del cuidado de los profesionales de enfermería

Objective: To describe the challenges of care management of nursing professionals. Methodology: This research work is developed from a quantitative approach with a descriptive methodology with non-experimental design, which is supported by documentary-bibliographic analysis. A research process was organized in which the study population was based primarily on written documents such as theses, peer-reviewed journals and scientific articles. In conclusion: The challenges faced by nursing professionals in the management of care at this time involve economic, social and political aspects in a world in constant change, where technology plays a great role in improving inter-hospital services as a communication network, improvements in working conditions, incorporation of new human talent and reducing the deficiency worldwide, strengthening and rethinking of training plans and nursing studies.Objetivo: Describir los desafíos de la gestión del cuidado de los profesionales de enfermería. Metodología: El presente trabajo investigativo se desarrolla desde un enfoque cuantitativo con una metodología descriptiva con diseño no experimental, la cual se apoya en el análisis documental–bibliográfico. Se organizó un proceso investigativo en donde la población de estudio, se basó primordialmente en documentos escritos como tesis, revistas arbitradas y artículos científicos. En conclusión: Los desafíos a los que se enfrentan los profesionales de enfermería en la gestión del cuidado, en esta época involucran los aspectos económicos, social, político en un mundo en constantes cambio, en donde la tecnología juega un gran papel que permite mejorar los servicios inter hospitalarios como red de comunicación, mejoras en las condiciones laborales, incorporación de nuevo talento humano y disminuir la deficiencia a nivel mundial, fortalecimiento y replanteamiento de los planes de formación y estudio de enfermería

A genomic catalog of Earth’s microbiomes

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth’s continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes.</p