Contribución al conocimiento de AMPK como diana terapéutica a través del descubrimiento de nuevos moduladores

La proteína quinasa activada por AMP (AMPK) es un sensor de la energía celular que, una vez activado, juega un papel fundamental en muchos procesos que tienen lugar en la célula y que están encaminados a restaurar la homeostasis energética. Esta proteína activa e intensifica rutas y procesos catabólicos para generar ATP, como la β-oxidación de ácidos grasos y la autofagia, e inhibe procesos y rutas anabólicas que consumen energía, como la síntesis de ácidos grasos, colesterol y proteínas. Está presente en todos los organismos eucariotas, y en el caso de los humanos, se encuentra en prácticamente todos los tejidos y órganos: hígado, riñón, músculo y músculo esquelético, tejido vascular, neuronas, tejido adiposo, sistema inmunológico. Esta ubicuidad, entre especies, entre tejidos y entre rutas metabólicas la convierte en imprescindible en el correcto funcionamiento celular. Desde su descubrimiento, esta proteína viene concentrando un creciente interés en los campos de la química médica, la farmacología, la biología molecular y la medicina. Esto ha hecho que poco a poco avance nuestro conocimiento sobre las formas en las que esta proteína lleva a cabo su función, sobre sus mecanismos de activación y regulación y sobre la forma en que coordina unos y otros campos de la homeostasis, metabolismo energético, inmunología, crecimiento y ciclo celular, etcétera, para originar una respuesta cohesionada, y por tanto sana, a las situaciones de consumición de las reservas de energía. Además, resulta evidente que una proteína con un papel tan capital como AMPK debe estar involucrada en numerosas enfermedades. Su desregulación o funcionamiento anómalo por cualquier causa están asociados a patologías que pueden afectar a cualquier zona del organismo: desde el cáncer a enfermedades neurodegenerativas, pasando por la diabetes, el síndrome metabólico, la obesidad, el síndrome de Wolff-Parkinson-White y alteraciones vasculares. Y, como pasaba con su funcionamiento en condiciones sanas, cada vez tenemos una información más completa del inmenso abanico de alteraciones en las que AMPK está involucrada, en todas ellas desempeñando un papel importante..

Enantiospecific Synthesis of 1,3-Disubstituted Allenes from Propargylic Carbonates through a Borylation-1,2-Elimination Process

An array of enantioenriched vinyl boronates bearing an allylic carbonate moiety have been prepared through selective hydroboration of propargyl carbonates. Treatment of these vinyl boronates with TBAF in THF affords enantioenriched 1,3- disubstituted allenes through a novel 1,2-anti elimination in good yields and high enantiospecificitiesWe thank MINECO (CTQ2016-78779-R) and MICINN (PID2019-107380GB I00) for financial suppor

Study of a Waste Kaolin as Raw Material for Mullite Ceramics and Mullite Refractories by Reaction Sintering

A deposit of raw kaolin, located in West Andalusia (Spain), was studied in this work using a representative sample. The methods of characterization were X-ray diffraction (XRD), X-ray fluorescence (XRF), particle size analysis by sieving and sedimentation, and thermal analysis. The ceramic properties were determined. A sample of commercial kaolin from Burela (Lugo, Spain), with applications in the ceramic industry, was used in some determinations for comparison purposes. The kaolin deposit has been produced by alteration of feldspar-rich rocks. This raw kaolin was applied as an additive in local manufactures of ceramics and refractories. However, there is not previous studies concerning its characteristics and firing properties. Thus, the meaning of this investigation was to conduct a scientific study on this subject and to evaluate the possibilities of application. The raw kaolin was washed for the beneficiation of the rock using water to increase the kaolinite content of the resultant material. The results indicated that the kaolinite content of the raw material was 20 wt % as determined by XRD, showing ~23 wt % of particles lower than 63 µm. The kaolinite content of the fraction lower than 63 µm was 50 wt %. Thus, an improvement of the kaolinite content of this raw kaolin was produced by wet separation. However, the kaolin was considered as a waste kaolin, with microcline, muscovite and quartz identified by XRD. Thermal analyses by Thermo-Dilatometry (TD), Differential Thermal Analysis (DTA) and Thermo-Gravimetry (TG) allowed observe kaolinite thermal decomposition, quartz phase transition and sintering effects. Pressed samples of this raw kaolin, the fraction lower than 63 µm obtained by water washing and the raw kaolin ground using a hammer mill were fired at several temperatures in the range 1000–1500 °C for 2 h. The ceramic properties of all these samples were determined and compared. The results showed the progressive linear firing shrinkage by sintering in these samples, with a maximum value of ~9% in the fraction lower than 63 µm. In general, water absorption capacity of the fired samples showed a decrease from ~18–20% at 1050 °C up to almost zero after firing at 1300 °C, followed by an increase of the experimental values. The open porosity was almost zero after firing at 1350 °C for 2 h and the bulk density reached a maximum value of 2.40 g/cm3 as observed in the ground raw kaolin sample. The XRD examination of fired samples indicated that they are composed by mullite, from kaolinite thermal decomposition, and quartz, present in the raw sample, as main crystalline phases besides a vitreous phase. Fully-densified or vitrified materials were obtained by firing at 1300–1350 °C for 2 h. In a second step of this research, it was examined the promising application of the previous study to increase the amount of mullite by incorporation of alumina (α-alumina) to this kaolin sample. Firing of mixtures, prepared using this kaolin and α-alumina under wet processing conditions, produced the increase of mullite in relative proportion by reaction sintering at temperatures higher than 1500 °C for 2 h. Consequently, a mullite refractory can be prepared using this kaolin. This processing of high-alumina refractories is favoured by a previous size separation, which increases the kaolinite content, or better a grinding treatment of the raw kaolin

First results of the140ce(N,ү)141ce cross-section measurement at n_tof

An accurate measurement of the140Ce(n,ү) energy-dependent cross-section was performed at the n_TOF facility at CERN. This cross-section is of great importance because it represents a bottleneck for the s-process nucleosynthesis and determines to a large extent the cerium abundance in stars. The measurement was motivated by the significant difference between the cerium abundance measured in globular clusters and the value predicted by theoretical stellar models. This discrepancy can be ascribed to an overestimation of the140Ce capture cross-section due to a lack of accurate nuclear data. For this measurement, we used a sample of cerium oxide enriched in140Ce to 99.4%. The experimental apparatus consisted of four deuterated benzene liquid scintillator detectors, which allowed us to overcome the difficulties present in the previous measurements, thanks to their very low neutron sensitivity. The accurate analysis of the p-wave resonances and the calculation of their average parameters are fundamental to improve the evaluation of the140Ce Maxwellian-averaged cross-section. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

First Results of the 140^{140}Ce(n,γ)141^{141}Ce Cross-Section Measurement at n_TOF

An accurate measurement of the $^{140}$Ce(n,γ) energy-dependent cross-section was performed at the n_TOF facility at CERN. This cross-section is of great importance because it represents a bottleneck for the s-process nucleosynthesis and determines to a large extent the cerium abundance in stars. The measurement was motivated by the significant difference between the cerium abundance measured in globular clusters and the value predicted by theoretical stellar models. This discrepancy can be ascribed to an overestimation of the $^{140}$Ce capture cross-section due to a lack of accurate nuclear data. For this measurement, we used a sample of cerium oxide enriched in $^{140}$Ce to 99.4%. The experimental apparatus consisted of four deuterated benzene liquid scintillator detectors, which allowed us to overcome the difficulties present in the previous measurements, thanks to their very low neutron sensitivity. The accurate analysis of the p-wave resonances and the calculation of their average parameters are fundamental to improve the evaluation of the $^{140}$Ce Maxwellian-averaged cross-section

First Results of the 140^{140}Ce(n,γ)141^{141}Ce Cross-Section Measurement at n_TOF

An accurate measurement of the $^{140}$Ce(n,γ) energy-dependent cross-section was performed at the n_TOF facility at CERN. This cross-section is of great importance because it represents a bottleneck for the s-process nucleosynthesis and determines to a large extent the cerium abundance in stars. The measurement was motivated by the significant difference between the cerium abundance measured in globular clusters and the value predicted by theoretical stellar models. This discrepancy can be ascribed to an overestimation of the $^{140}$Ce capture cross-section due to a lack of accurate nuclear data. For this measurement, we used a sample of cerium oxide enriched in $^{140}$Ce to 99.4%. The experimental apparatus consisted of four deuterated benzene liquid scintillator detectors, which allowed us to overcome the difficulties present in the previous measurements, thanks to their very low neutron sensitivity. The accurate analysis of the p-wave resonances and the calculation of their average parameters are fundamental to improve the evaluation of the $^{140}$Ce Maxwellian-averaged cross-section

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

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 &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;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 &lt;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&lt;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&lt;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