Altered Synaptic Membrane Retrieval after Strong Stimulation of Cerebellar Granule Neurons in Cyclic GMP-Dependent Protein Kinase II (cGKII) Knockout Mice

The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (cGK) signaling pathway regulates the clustering and the recruitment of proteins and vesicles to the synapse, thereby adjusting the exoendocytic cycle to the intensity of activity. Accordingly, this pathway can accelerate endocytosis following large-scale exocytosis, and pre-synaptic cGK type II (cGKII) plays a major role in this process, controlling the homeostatic balance of vesicle exocytosis and endocytosis. We have studied synaptic vesicle recycling in cerebellar granule cells from mice lacking cGKII under strong and sustained stimulation, combining imaging techniques and ultrastructural analyses. The ultrastructure of synapses in the adult mouse cerebellar cortex was also examined in these animals. The lack of cGKII provokes structural changes to synapses in cultured cells and in the cerebellar cortex. Moreover, endocytosis is slowed down in a subset of boutons in these cells when they are stimulated strongly. In addition, from the results obtained with the selective inhibitor of cGKs, KT5823, it can be concluded that cGKI also regulates some aspects of vesicle cycling. Overall, these results confirm the importance of the cGMP pathway in the regulation of vesicle cycling following strong stimulation of cerebellar granule cells

Investigar para educar en una conyuntura de crisis

Esta publicación pretende hacer visible el trabajo de los docentes investigadores de la Facultad de Educación (FED) de la Universidad Nacional de Cuyo, unidad académica que forma a formadores y que investiga para ofrecer respuestas a problemas educativos actuales. Es una recopilación de conocimientos evaluados por pares, quienes, de modo creativo y fundamentado, ofrecen al lector diversas respuestas que predisponen al diálogo, sin presentar sus posturas como verdades absolutas. La Facultad de Educación, como educadora de futuros profesores, acoge asignaturas y profesionales de múltiples áreas, desde la lingüística o la matemática hasta las ciencias naturales y sociales, pasando por muchas otras disciplinas, tales como: antropología, didáctica, pedagogía o ética; así, los docentes-investigadores de la FED realizan estudios muy diversos, lo cual se ve reflejado en los trabajos que se presentan

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Çédille, revista de estudios franceses

Presentació

Cuentos de nunca acabar. Aproximaciones desde la interculturalidad

Cuentos de nunca acabar. Aproximaciones desde la interculturalidad, surge después de la pandemia y su imposibilidad de socializar “en persona” con los compañeros de eventuales encuentros, porque la Comprensión Lectora tenía que reinventarse para su nueva reflexión cognitiva, adaptación contextual y reconstrucción del conocimiento. Este renovado enfoque de la realidad postpandemia, concebido en el marco de la educación intercultural comunitaria, busca potencializar los entornos naturales, sociales y culturales como recursos de aprendizaje multidisciplinario a través del lenguaje animado de los cuentos. En este marco, había que dinamizar la asignatura de Comunicación Oral y Escrita, que se dicta en los Primeros Niveles de los Centros de Apoyo de Otavalo, Cayambe, Latacunga y Riobamba, mediante un eje transversal donde los estudiantes escriban fundamentados en valores de la cosmovisión andina, considerando que provienen de varios lugares de la sierra y amazonía ecuatoriana. Todo surgió del encuentro presencial de un sábado cualquiera donde los estudiantes realizaban ejercicios narrativos, logrando una apreciable respuesta de imaginación, más emotiva que la clásica tarea de las Unidades, tanto así que, pasados unos días, seguían llegando sus escritos a mi correo. Entonces nos pusimos manos a la obra, cada estudiante tendría dos opciones como Actividad Integradora, la primera consistía en escribir un cuento de su propia inspiración, y la segunda analizar un clásico para comentar sus valores y antivalores. La mayor parte de estudiantes decidió escribir su propio cuento, de donde se escogieron algunas participaciones que podrían considerarse originales, para una edición que, respetando la transcripción de la tradición oral que prima en los sectores comunitarios, nos concretamos en revisar la puntuación y ortografía para publicarlos. Con esto buscamos innovar la Actividad Integradora, por algo más práctico y operativo para configurar los Objetos de Aprendizaje que buscamos. Así nació, en medio del camino, este libro de Cuentos de nunca acabar. Aproximaciones desde la interculturalidad, que ponemos en sus manos. Hernán Hermosa Mantilla Quito, junio de 202

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Non-additive potentiation of glutamate release by phorbol esters and metabotropic mGlu7 receptor in cerebrocortical nerve terminals

We recently showed that prolonged activation of metabotropic glutamate receptor 7 (mGlu7) potentiates glutamate release. This signalling involves phospholipase C activation via a pertussis toxin insensitive G protein and the subsequent hydrolysis of phosphatidylinositol (4,5)-bisphosphate. Release potentiation is independent of protein kinase C activation but it is dependent on the downstream release machinery, as reflected by the concomitant translocation of active zone Munc13-1 protein from the soluble to particulate fractions. Here we show that phorbol ester and mGlu7 receptor-dependent facilitation of neurotransmitter release is not additive, suggesting they share a common signalling mechanism. However, release potentiation is restricted to release sites that express N-type Ca2+ channels, because phorbol ester and mGlu7 receptor-mediated release potentiation are absent in nerve terminals from mice lacking N-type Ca2+ channels. In addition, phorbol esters but not mGlu7 receptors potentiate release at nerve terminals with P/Q-type Ca2+ channels, although only under restricted conditions of Ca2+ influx. The differential effect of phorbol esters at nerve terminals with either N- or P/Q-type Ca2+ channels seems to be unrelated to the type Munc13 isoform expressed, and it is more likely dependent on other properties of the release machinery.Ministerio de Educación y Ciencia (BFU2007-64154/BFI; BFU2010/16947)Instituto de Salud Carlos IIIComunidad de Madrid (S-BIO-0179/2006)Depto. de Bioquímica y Biología MolecularFac. de VeterinariaTRUEpu

Partial compensation for N-type Ca2+ channel loss by P/Q-type Ca2+ channels underlines the differential release properties supported by these channels at cerebrocortical nerve terminals

N-type and P/Q-type Ca2+ channels support glutamate release at central synapses. To determine whether the glutamate release mediated by these channels exhibits distinct properties, we have isolated each release component in cerebrocortical nerve terminals from wild-type mice by specifically blocking N-type Ca2+ channels with ω-conotoxin-GVIA and P/Q-type Ca 2+ channels with ω-agatoxin-IVA. In addition, we have determined the release properties at terminals from mice lacking the α1B subunit of N-type channels (Cav 2.2) to test the possibility that P/Q-type channels can compensate for the loss of N-type Ca2+ channels. We recently demonstrated that, while evoked glutamate release depends on P/Q- and N-type channels in wild-type nerve terminals, only P/Q-type channels participate in these knockout mice. Moreover, in nerve terminals expressing solely P/Q-type channels, metabotropic glutamate receptor 7 (mGluR7) fails to inhibit the evoked Ca2+ influx and glutamate release. Here, we show that the failure of mGluR7 to modulate evoked glutamate release is not due to a lack of receptors, as nerve terminals from mice lacking N-type Ca2+ channels express mGluR7. Indeed, we show that other receptor responses, such as the inhibition of forskolin-induced release, are preserved in these knockout mice. N-type channels are more loosely coupled to release than P/Q-type channels in nerve terminals from wild-type mice, as reflected by the tighter coupling of release in knockout nerve terminals. We conclude that the glutamate release supported by N- and P/Q-type channels exhibits distinct properties, and that P/Q-type channels cannot fully compensate for the loss of N-type channels. © 2009 Federation of European Neuroscience Societies and Blackwell.Ministerio de Educación y Ciencia (MEC). EspañaInstituto de Salud Carlos IIIComunidad de MadridFondo Social EuropeoDepto. de Bioquímica y Biología MolecularFac. de VeterinariaTRUEpu