Oncogenic RET Kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans

To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation

Super star cluster feedback driving ionization, shocks and outflows in the halo of the nearby starburst ESO 338-IG04

Stellar feedback strongly affects the interstellar medium (ISM) of galaxies. Stellar feedback in the first galaxies likely plays a major role in enabling the escape of LyC photons, which contribute to the re-ionization of the Universe. Nearby starburst galaxies serve as local analogues allowing for a spatially resolved assessment of the feedback processes in these galaxies. We characterize the feedback effects from the star clusters in the local high-redshift analogue ESO 338-IG04 on the ISM and compare the results with the properties of the most massive clusters. We use high quality VLT/MUSE optical integral field data to derive the physical properties of the ISM such as ionization, density, shocks, and perform new fitting of the spectral energy distributions of the brightest clusters in ESO 338-IG04 from HST imaging. ESO 338-IG04 has a large ionized halo which we detect to a distance of 9 kpc. We identify 4 Wolf-Rayet (WR) clusters based on the blue and red WR bump. We follow previously identified ionization cones and find that the ionization of the halo increases with distance. Analysis of the galaxy kinematics shows two complex outflows driven by the numerous young clusters in the galaxy. We find a ring of shocked emission traced by an enhanced [OI]/H$\alpha$ ratio surrounding the starburst and at the end of the outflow. Finally we detect nitrogen enriched gas associated with the outflow, likely caused by the WR stars in the massive star clusters. Photo-ionization dominates the central starburst and sets the ionization structure of the entire halo, resulting in a density bounded halo, facilitating the escape of LyC photons. Outside the central starburst, shocks triggered by an expanding super bubble become important. The shocks at the end of the outflow suggest interaction between the hot outflowing material and the more quiescent halo gas.Comment: Accepted for publication in Astronomy and Astrophysics, 22 pages, 15 figure

Experiencias sobre producción ecológica de huevos de gallina en la Comunidad Valenciana

Desde el año 1999 se han criado diferentes lotes de gallinas en tres granjas, de razas de puesta tanto autóctonas como híbridas, en producción ecológica. Las razas híbridas han mostrado mejor nivel de puesta y menor consumo de pienso, justificando la conveniencia económica de utilizar estas razas en producción ecológica. Sin embargo, algunas razas autóctonas presentan suficiente potencial para hacerlas competitivas tras una selección adecuada. Las razas autóctonas también pueden presentar interés en sistemas de producción basados en piensos de baja calidad proteica

Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients

Aims: To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results: One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion: Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix

Vagal afferents contribute to sympathoexcitation-driven metabolic dysfunctions

Multiple crosstalk between peripheral organs and the nervous system are required to maintain physiological and metabolic homeostasis. Using Vav3-deficient mice as a model for chronic sympathoexcitation-associated disorders, we report here that afferent fibers of the hepatic branch of the vagus nerve are needed for the development of the peripheral sympathoexcitation, tachycardia, tachypnea, insulin resistance, liver steatosis and adipose tissue thermogenesis present in those mice. This neuronal pathway contributes to proper activity of the rostral ventrolateral medulla, a sympathoregulatory brainstem center hyperactive in Vav3−/− mice. Vagal afferent inputs are also required for the development of additional pathophysiological conditions associated with deregulated rostral ventrolateral medulla activity. By contrast, they are dispensable for other peripheral sympathoexcitation-associated disorders sparing metabolic alterations in liver.X R B is supported by grants from the Castilla-León Government (CSI252P18, CLC-2017-01), the Spanish Ministry of Science, Innovation and Universities (MSIU) (SAF2015-64556-R), Worldwide Cancer Research (14-1248), the Ramón Areces Foundation, and the Spanish Association against Cancer (GC16173472GARC). X R B’s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Ministry of Education of the Castilla-León Government (CLC-2017-01). S R-F and L F L-M contracts have been supported by funding from the MISIU (BES-2013-063573) and the Spanish Ministry of Education, Culture and Sports (L F L-M, FPU13/02923), respectively. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund

An open building information modelling based co-simulation architecture to model building energy and environmental life cycle assessment: A case study on two buildings in the United Kingdom and Luxembourg

Given the complexity and interconnection of different aspects involved in building evaluation, one of the most relevant, and challenging, research topics is the integration of different domain models (such as thermal comfort, indoor environmental quality and occupant comfort) to effectively describe and inform improvement strategies for the behaviour and performance of a building and building stock. Currently, this problem is unsolved with only one study attempting to integrate building energy simulation and life cycle assessments (separately, both practices are utilised to facilitate the design and management of buildings, traditionally consultancies offer building energy simulation services – most commonly for regulatory purposes – and more recently life cycle impact assessments), whilst no work has attempted this integration in a dynamic manner. This study addresses this gap by developing a dynamic, open building information modelling based co-simulation architecture. This architecture is the first to tightly couple and integrate EnergyPlus and Brightway2, in a way that does not rely upon heuristics or simplified tools. Furthermore, it is the first building energy simulation and life cycle assessment co-simulation to enable time-differentiated (dynamic) results and the first to be enabled only by open technologies. The architecture has been validated against two case-study non-domestic buildings located in the United Kingdom and Luxembourg, demonstrating its applicability to the construction and operational life cycle phases of buildings. The work presented in this paper has shown how a time-differentiated co-simulation approach across energy and lifecycle domains enables a more holistic analysis of whole buildings with greater accuracy and granularity

Immunosuppression-independent role of regulatory T cells against hypertension-driven renal dysfunctions

Hypertension-associated cardiorenal diseases represent one of the heaviest burdens for current health systems. In addition to hemodynamic damage, recent results have revealed that hematopoietic cells contribute to the development of these diseases by generating proinflammatory and profibrotic environments in the heart and kidney. However, the cell subtypes involved remain poorly characterized. Here we report that CD39+ regulatory T (TREG) cells utilize an immunosuppression-independent mechanism to counteract renal and possibly cardiac damage during angiotensin II (AngII)-dependent hypertension. This mechanism relies on the direct apoptosis of tissue-resident neutrophils by the ecto-ATP diphosphohydrolase activity of CD39. In agreement with this, experimental and genetic alterations in TREG/TH cell ratios have a direct impact on tissue-resident neutrophil numbers, cardiomyocyte hypertrophy, cardiorenal fibrosis, and, to a lesser extent, arterial pressure elevation during AngII-driven hypertension. These results indicate that TREG cells constitute a first protective barrier against hypertension-driven tissue fibrosis and, in addition, suggest new therapeutic avenues to prevent hypertension-linked cardiorenal diseases.This work has been supported by grants from the Castilla-León Autonomous Government (CSI101U13), the Spanish Ministry of Economy and Competitiveness (SAF2012-31371, RD12/0036/0002), Worldwide Cancer Research, the Solórzano Foundation, and the Ramón Areces Foundation to X.R.B. P.M. is funded by the Spanish Ministry of Economy and Competitiveness (SAF2011-27330). S.F., M.M.-M., J.R.-V., and A.M.-M. were supported by the Spanish Ministry of Economy and Competitiveness through BES-2010-031386, CSIC JAE-Doc, Juan de la Cierva, and BES-2009-016103 contracts, respectively. Spanish government-sponsored funding to X.R.B. is partially supported by the European Regional Development Fund.Peer Reviewe