PI3Kα inhibition reduces obesity in mice

Partial inhibition of PI3K is one of the best-validated and evolutionary conserved manipulations to extend longevity. The best known health beneficial effects of reduced PI3K are related to metabolism and include increased energy expenditure, reduced nutrient storage, and protection from obesity. We have previously shown that a dual chemical inhibitor of the alpha and delta PI3K isoforms (CNIO-PI3Ki) reduces obesity in mice and monkeys, without evident toxic effects after long-term treatment. Here, we dissect the role of the alpha and delta PI3K isoforms by making use of selective inhibitors against PI3Kα (BYL-719 also known as alpelisib) or PI3Kδ (GS-9820 also known as acalisib). Treatment of mice with the above mentioned inhibitors indicated that BYL-719 increases energy expenditure in normal mice and efficiently reduces body weight in obese (ob/ob) mice, whereas these effects were not observed with GS-9820. Of note, the dose of BYL-719 required to reduce obesity was 10x higher than the equivalent dose of CNIO-PI3Ki, which could suggest that simultaneous inhibition of PI3K alpha and delta is more beneficial than single inhibition of the alpha isoform. In summary, we conclude that inhibition of PI3Kα is sufficient to increase energy expenditure and reduce obesity, and suggest that concomitant PI3Kα inhibition could play an auxiliary role

Applications of telemedicine in the integral management of chronic obstructive pulmonary disease: systematic review

Resumen: Introducción. La enfermedad pulmonar obstructiva crónica es una enfermedad común, prevenible y tratable. Constitu- ye en la actualidad la 4a causa de mortalidad a nivel mundial con tendencia ascendente. Es una entidad muy infradiag- nosticada, que supone un elevado gasto a la Sanidad Pública y una importante pérdida de calidad de vida de las perso- nas que la padecen. En la actualidad no existe un programa de cribado eficaz y el seguimiento de los pacientes es una tarea difícil. Material y métodos. Se ha realizado una búsqueda sistemática de artículos relacionados con el manejo de la EPOC basado en el uso de las tecnologías. Las bases de datos utilizadas han sido: MEDLINE, Web of Science y Cochrane Library, además de las páginas web de organismos como WHO, SEPAR y GOLD. Se han incluido un total de 12 ar- tículos. Resultados. Del total de 12 artículos, 7 encontraron beneficios estadísticamente significativos de la aplicación de estas intervenciones en comparación con la asistencia sanitaria habitual. Entre los beneficios observados se encuentran un aumento de la adherencia a los tratamientos, un aumento de la calidad de vida, un mejor control sintomático y una re- ducción del número de exacerbaciones agudas. Conclusiones. La telemedicina es una herramienta potente que ofrece un amplio abanico de posibilidades para el mane- jo de la EPOC: telemonitorización, coaching electrónico, prevención temprana de las exacerbaciones, screening, tele- rehabilitación... Sin embargo, las evidencias existentes son insuficientes por lo que se requieren estudios potentes para poder extraer conclusiones firmes. Palabras clave: telemedicina; EPOC; telemonitorización; telerehabilitación. Abstract: Introduction. Chronic Obstructive Pulmonary Disease is a common, preventable and treatable disease. It is currently the 4th cause of mortality worldwide with an upward trend. It is a underdiagnosed entity, which implies a high cost to Public Health, and a huge loss of quality of life for the people who suffer it. Currently, there is no effective screening program, and follow-up is a difficult task. Material and methods. A systematic review was made of articles related to the management of COPD based on the use of the technologies. The databases used were: MEDLINE, Web of Science and Cochrane Library in addition to the websites of organizations such as WHO, SEPAR and GOLD. A total of 12 articles have been included. Results. Of the total of 12 articles, 7 found statistically significant benefits of the application of these interventions in comparison with the usual healthcare. Among the benefits there is an increase in treatment adherence, an increase in quality of life, better control of their symptoms and a reduction in the number of accute exacerbations. Conclusions. Telemedicine is a powerful tool that offers a wide range of possibilities for the management of COPD: telemonitoring, electronic coaching, early prevention of exacerbations, screening, telerehabilitation... However, the existing evidence is weak so it is required the development of powerful studies in order to establish firm conclusions. Keywords: telemedicine; COPD; telemonitoring; telerehabilitation

p21(Cip1) plays a critical role in the physiological adaptation to fasting through activation of PPARα.

Fasting is a physiological stress that elicits well-known metabolic adaptations, however, little is known about the role of stress-responsive tumor suppressors in fasting. Here, we have examined the expression of several tumor suppressors upon fasting in mice. Interestingly, p21 mRNA is uniquely induced in all the tissues tested, particularly in liver and muscle (>10 fold), and this upregulation is independent of p53. Remarkably, in contrast to wild-type mice, p21-null mice become severely morbid after prolonged fasting. The defective adaptation to fasting of p21-null mice is associated to elevated energy expenditure, accelerated depletion of fat stores, and premature activation of protein catabolism in the muscle. Analysis of the liver transcriptome and cell-based assays revealed that the absence of p21 partially impairs the transcriptional program of PPARα, a key regulator of fasting metabolism. Finally, treatment of p21-null mice with a PPARα agonist substantially protects them from their accelerated loss of fat upon fasting. We conclude that p21 plays a relevant role in fasting adaptation through the positive regulation of PPARα

Perisylvian white matter connectivity in the human right hemisphere

Background By using diffusion tensor magnetic resonance imaging (DTI) and subsequent tractography, a perisylvian language network in the human left hemisphere recently has been identified connecting Brocas's and Wernicke's areas directly (arcuate fasciculus) and indirectly by a pathway through the inferior parietal cortex. Results Applying DTI tractography in the present study, we found a similar three-way pathway in the right hemisphere of 12 healthy individuals: a direct connection between the superior temporal and lateral frontal cortex running in parallel with an indirect connection. The latter composed of a posterior segment connecting the superior temporal with the inferior parietal cortex and an anterior segment running from the inferior parietal to the lateral frontal cortex. Conclusion The present DTI findings suggest that the perisylvian inferior parietal, superior temporal, and lateral frontal corticies are tightly connected not only in the human left but also in the human right hemisphere

The Neglected Tropical Diseases of Latin America and the Caribbean: A Review of Disease Burden and Distribution and a Roadmap for Control and Elimination

The neglected tropical diseases (NTDs) represent some of the most common infections of the poorest people living in the Latin American and Caribbean region (LAC). Because they primarily afflict the disenfranchised poor as well as selected indigenous populations and people of African descent, the NTDs in LAC are largely forgotten diseases even though their collective disease burden may exceed better known conditions such as of HIV/AIDS, tuberculosis, or malaria. Based on their prevalence and healthy life years lost from disability, hookworm infection, other soil-transmitted helminth infections, and Chagas disease are the most important NTDs in LAC, followed by dengue, schistosomiasis, leishmaniasis, trachoma, leprosy, and lymphatic filariasis. On the other hand, for some important NTDs, such as leptospirosis and cysticercosis, complete disease burden estimates are not available. The NTDs in LAC geographically concentrate in 11 different sub-regions, each with a distinctive human and environmental ecology. In the coming years, schistosomiasis could be eliminated in the Caribbean and transmission of lymphatic filariasis and onchocerciasis could be eliminated in Latin America. However, the highest disease burden NTDs, such as Chagas disease, soil-transmitted helminth infections, and hookworm and schistosomiasis co-infections, may first require scale-up of existing resources or the development of new control tools in order to achieve control or elimination. Ultimately, the roadmap for the control and elimination of the more widespread NTDs will require an inter-sectoral approach that bridges public health, social services, and environmental interventions

A protein functionalization platform based on selective reactions at methionine residues.

Nature has a remarkable ability to carry out site-selective post-translational modification of proteins, therefore enabling a marked increase in their functional diversity1. Inspired by this, chemical tools have been developed for the synthetic manipulation of protein structure and function, and have become essential to the continued advancement of chemical biology, molecular biology and medicine. However, the number of chemical transformations that are suitable for effective protein functionalization is limited, because the stringent demands inherent to biological systems preclude the applicability of many potential processes2. These chemical transformations often need to be selective at a single site on a protein, proceed with very fast reaction rates, operate under biologically ambient conditions and should provide homogeneous products with near-perfect conversion2-7. Although many bioconjugation methods exist at cysteine, lysine and tyrosine, a method targeting a less-explored amino acid would considerably expand the protein functionalization toolbox. Here we report the development of a multifaceted approach to protein functionalization based on chemoselective labelling at methionine residues. By exploiting the electrophilic reactivity of a bespoke hypervalent iodine reagent, the S-Me group in the side chain of methionine can be targeted. The bioconjugation reaction is fast, selective, operates at low-micromolar concentrations and is complementary to existing bioconjugation strategies. Moreover, it produces a protein conjugate that is itself a high-energy intermediate with reactive properties and can serve as a platform for the development of secondary, visible-light-mediated bioorthogonal protein functionalization processes. The merger of these approaches provides a versatile platform for the development of distinct transformations that deliver information-rich protein conjugates directly from the native biomacromolecules