Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states

Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states

Advanced solar dynamic space power systems perspectives, requirements and technology needs

Projected NASA, Civil, Commercial, and Military missions will require space power systems of increased versatility and power levels. The Advanced Solar Dynamic (ASD) Power systems offer the potential for efficient, lightweight, survivable, relatively compact, long-lived space power systems applicable to a wide range of power levels (3 to 300 kWe), and a wide variety of orbits. The successful development of these systems could satisfy the power needs for a wide variety of these projected missions. Thus, the NASA Lewis Research Center has embarked upon an aggressive ASD reserach project under the direction of NASA's Office of Aeronautics and Space Technology (DAST). The project is being implemented through a combination of in-house and contracted efforts. Key elements of this project are missions analysis to determine the power systems requirements, systems analysis to identify the most attractive ASD power systems to meet these requirements, and to guide the technology development efforts, and technology development of key components

Total nutritional therapy : a nutrition education program for physicians

Objetivo: Casi la mitad de todos los pacientes hospitalizados se encuentran desnutridos y los médicos tienen muy poco conocimiento o apenas utilizan el soporte nutricional1. Para corregir este problema, la Federación Latinoamericana de Nutrición Parenteral y Enteral (FELANPE) ideó un curso introductorio de nutrición clínica para médicos de dos días, con el apoyo de los Laboratorios Abbott. El objetivo del tratamiento nutricional total (TNT) es ayudar al médico a aprovechar sus conocimientos de nutrición para incrementar la conciencia sobre malnutrición y aplicación del tratamiento nutricional. Desde 1997, más de 8.000 médicos han completado el curso TNT en 16 países latinoamericanos. Métodos y procedimientos experimentales: Durante 1999 y 2000, 675 participantes respondieron, seis meses después de haber terminado el curso TNT, a una encuesta en la que se pretendía averiguar la repercusión que había tenido el curso en el uso de la evaluación nutricional, los equipos de apoyo nutricional o las consultas sobre nutrición en la práctica clínica y si habían participado en alguna asociación o conferencia de nutrición. Resultados: La mayoría de los médicos que rellenaron la encuesta había aumentado el uso de las herramientas de evaluación nutricional y el tiempo dedicado a este tratamiento; asimismo, había aumentado el número de pacientes que recibieron tratamiento nutricional. Conclusiones: El curso TNT ha resultado un modelo eficiente para la educación de los médicos generales en nutrición clínica. Este curso debería integrarse en la formación de los médicos residentes.Q4Q3Objective: Almost half of all hospitalized patients are malnourished with low physician awareness or implementation of nutrition support1. To address this problem, a 2-day immersion course in clinical nutrition for physicians was developed by the Latin American Federation of Parenteral and Enteral Nutrition (FELANPE) with support from Abbott Laboratories. The goal of Total Nutritional Therapy (TNT) is to help physicians utilize this nutrition knowledge to increase their awareness of malnutrition and implementation of nutritional therapy. Since 1997, over 8,000 physicians have completed the TNT course in 16 Latin American countries. Research Methods & Procedures: During 1999 and 2000, 675 participants responded to a survey 6 months after having completed the TNT course to determine what impact the course had on the use of nutrition assessment, nutrition support teams, or nutrition consultations in their clinical practice, and if they had participated in any nutrition association or conferences. Results: The majority of physicians who completed the survey increased their use of nutrition assessment and time dedicated to nutrition therapy, and increased the number of their patients placed on nutrition therapy. Conclusions: The TNT course has been shown to be an efficient model of clinical nutrition education for general physicians. The course should be considered as part of the training of medical residents.https://orcid.org/0000-0003-0401-0743N/

Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor

Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in non-hematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP)). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects

Abnormal Ocular Pneumoplethysmographic Results in Unilateral Neovascular Glaucoma.

Little is known about the predictive value of ocular pneumoplethysmography in patients with ophthalmic disease. We evaluated eight patients with unilateral increased intraocular pressure due to neovascular glaucoma who did not have evidence of severe extracranial carotid stenosis by duplex scanning and continuous-wave Doppler ultrasound. The ophthalmic systolic pressure measured by ocular pneumoplethysmography was decreased in the affected eye of all eight patients, indicating that neovascular glaucoma may be a cause of abnormal ocular pneumoplethysmographic results. Patients with neovascular glaucoma tended to have larger interocular ophthalmic systolic pressure differences than other patients with false-positive ocular pneumoplethysmographic results by noninvasive criteria

Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice

PMCID: PMC3579848This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited