643 research outputs found
Molecular dynamics simulations of iron- and aluminum-loaded serum transferrin: Protonation of tyr188 is necessary to prompt metal release
Serum transferrin (sTf) carries iron in blood serum and delivers it into cells by receptor-mediated endocytosis. The protein can also bind other metals, including aluminum. The crystal structures of the metal-free and metal-loaded protein indicate that the metal release process involves an opening of the protein. In this process, Lys206 and Lys296 lying in the proximity of each other form the dilysine pair or, so-called, dilysine trigger. It was suggested that the conformational change takes place due to variations of the protonation state of the dilysine trigger at the acidic endosomal pH. In 2003, Rinaldo and Field (Biophys. J. 85, 3485-3501) proposed that the dilysine trigger alone can not explain the opening and that the protonation of Tyr188 is required to prompt the conformational change. However, no evidence was supplied to support this hypothesis. Here, we present several 60 ns molecular dynamics simulations considering various protonation states to investigate the complexes formed by sTf with Fe(III) and Al(III). The calculations demonstrate that only in those systems where Tyr188 has been protonated does the protein undergo the conformational change and that the dilysine trigger alone does not lead to the opening. The simulations also indicate that the metal release process is a stepwise mechanism, where the hinge-bending motion is followed by the hinge-twisting step. Therefore, the study demonstrates for the first time that the protonation of Tyr188 is required for the release of metal from the metal loaded sTf and provides valuable information about the whole process
Un modelo basado en agentes para el análisis de la segregación étnica espacial urbana
Se pretende analizar la segregación étnica espacial urbana mediante un modelo basado en agentes. Con dicho propósito, se ha estudiado el efecto de variables como la densidad de la población, el nivel de intolerancia hacia grupos étnicos diferentes al propio, el grado de heterogeneidad cultural, el tamaño del vecindario y el tamaño de las minorías en la segregación étnica espacial urbana (medida a través del índice de disimilaridad). En particular, se han realizado una serie de experimentos virtuales con un modelo basado en agentes construido a partir del modelo de Schelling, pero con presupuestos sobre el comportamiento de los individuos más realistas. Los resultados de los experimentos virtuales podrían ayudar a diseñar políticas sociales dirigidas a reducir la segregación étnica espacial urbana en sociedades multiétnicas.
This work attempts to analyse the urban spatial ethnic segregation through an agent-based model. For that purpose, it studies the effect of variables as the density of population, the level of intolerance towards different ethnic groups, the level of cultural diversity, the size of neighbourhood and the size of minorities on the urban spatial ethnic segregation (measured by the index of dissimilarity). In particular, it carries out virtual experiments with an agent-based model building from Schelling''s model, but with assumptions about the behaviour of individuals more realistic. The results of virtual experiments could help to design social policies in order to reduce the urban spatial ethnic segregation in multiethnic societies
Rendimientos productivos y calidad de la canal de hembras, machos castrados quirurgicamente y machos inmunocastrados procedentes de líneas paternas duroc y pietrain
Tradicionalmente la castración quirúrgica ha sido la práctica más habitual en la producción de cerdo blanco destinado a la industria de productos cárnicos curados. La castración quirúrgica conlleva un empeoramiento de los rendimientos productivos y penaliza el bienestar animal. Como alternativa ha surgido la inmunización de los cerdos contra el factor de liberación de la gonadotropina (GnRH) (Fàbrega et al., 2010). La inmunocastración suprime la función testicular (Zamaratskaia et al., 2008) y reduce la producción de androsterona (Dunshea et al., 2001) y escatol (Matthews et al., 2000) así como la agresividad (Jaros et al., 2005). Por tanto, la inmunocastración puede ser una alternativa a la castración física en situaciones comerciales. Por otro lado, para la obtención de productos curados se precisan canales con más grasa y mayor proporción de partes nobles que para productos frescos, por lo que se utilizan estrategias como aumentar el peso al sacrificio o el cruce con líneas paternas específicas. El objetivo de este estudio fue evaluar el rendimiento productivo y la calidad de la canal de hembras enteras (HE), machos castrados (MC) y machos inmunocastrados (MI) procedentes de genéticas paternas Duroc (DU) y Pietrain (PI) con un peso al sacrificio de 134 kg
Evaluating anemometer drift: A statistical approach to correct biases in wind speed measurement
Recent studies on observed wind variability have revealed a decline (termed “stilling”) of near-surface wind speed during the last 30–50 years over many mid-latitude terrestrial regions, particularly in the Northern Hemisphere. The well-known impact of cup anemometer drift (i.e., wear on the bearings) on the observed weakening of wind speed has been mentioned as a potential contributor to the declining trend. However, to date, no research has quantified its contribution to stilling based on measurements, which is most likely due to lack of quantification of the ageing effect. In this study, a 3-year field experiment (2014–2016) with 10-minute paired wind speed measurements from one new and one malfunctioned (i.e., old bearings) SEAC SV5 cup anemometer which has been used by the Spanish Meteorological Agency in automatic weather stations since mid-1980s, was developed for assessing for the first time the role of anemometer drift on wind speed measurement. The results showed a statistical significant impact of anemometer drift on wind speed measurements, with the old anemometer measuring lower wind speeds than the new one. Biases show a marked temporal pattern and clear dependency on wind speed, with both weak and strong winds causing significant biases. This pioneering quantification of biases has allowed us to define two regression models that correct up to 37% of the artificial bias in wind speed due to measurement with an old anemometer
Efecto de la densidad en cebo sobre el rendimiento productivo, la composición de la carne y el perfil de ácidos grasos de cerdos sacrificados con 110 kg de peso
El número de cerdos por cuadra y la densidad influyen sobre el rendimiento productivo
(Edmons et al., 1998). Además, la densidad de cría puede afectar a la calidad de la canal y
de la carne (Estevez et al., 2003), ya que una reducción del espacio disponible da lugar a
peleas y mordeduras de colas. Sin embargo, la producción de carne por m
2
aumenta con la
densidad con un mejor aprovechamiento de la superficie disponible. Por otro lado, la
densidad podría afectar de distinto modo a hembras (HE) y a machos castrados (MC)
debido posiblemente al menor consumo voluntario de pienso de las HE. A este particular,
Hamilton et al. (2003) observaron que a altas densidades de cría las HE fueron
relativamente más magras mientras que los MC eran relativamente más grasos. Cambios en
la densidad de cría, pueden afectar a la composición en ácidos grasos de la canal debido a
cambios en el consumo y a la utilización del alimento (Nürnberg et al., 1998). El objetivo de
este estudio fue comparar el efecto de la densidad de cebo de HE y MC con alto potencial
de crecimiento, sobre el rendimiento productivo y la composición de la carne y el perfil de
ácidos grasos en cerdos de 19 a 109 kg PV
Time resolved amplified FRET identifies protein kinase B activation state as a marker for poor prognosis in clear cell renal cell carcinoma
Purpose
Clear cell Renal Cell Carcinomas (ccRCC), the largest group of renal tumours, are resistant to classical therapies. The determination of the functional state of actionable biomarkers for the assessment of these adenocarcinomas is essential. The dysregulation of the oncoprotein, PKB/Akt has been linked with poor prognoses in human cancers.
Material & methods
We analysed the status of the PKB/Akt pathway in a representative tumour tissue microarray obtained from the primary tumours and their metastases in 60 ccRCC with long term follow up. We sought to define the evolution of this pathway from the primary tumour to the metastatic event and to know the impact of its functional state in tumour aggressiveness and patient survival. Two-site time resolved amplified FRET (A-FRET) was utilised for assessing the activation state of PKB/Akt and this was compared to conventional immunohistochemistry measurements.
Results
Activation state of PKB/Akt in primary tumours defined by A-FRET correlated with poorer overall survival (hazard ratio 0.228; p = 0.002). Whereas, increased protein expression of phosphoPKB/Akt, identified using classical immunohistochemistry, yielded no significant difference (hazard ratio 1.390; p = 0.548).
Conclusions
Quantitative determination of PKB/Akt activation in ccRCC primary tumours alongside other diagnostics tools could prove key in taking oncologists closer to an efficient personalised therapy in ccRCC patients.
General significance
The quantitative imaging technology based on Amplified-FRET can rapidly analyse protein activation states and molecular interactions. It could be used for prognosis and assess drug function during the early cycles of chemotherapy. It enables evaluation of clinical efficiency of personalised cancer treatment
Immunogenicity of variable regions of hepatitis C virus proteins: selection and modification of peptide epitopes to assess hepatitis C virus genotypes by ELISA
The immunogenicity of variable regions of hepatitis C virus (HCV) proteins was studied by ELISA by using 543 synthetic peptides from 120 variable regions and 90 sera from HCV-infected patients. Some regions from certain genotypes were less immunogenic, or even non-immunogenic, compared with their equivalents in other genotypes. However, the mean recognition of all peptides from genotypes 1a, 1b and 3 by sera infected with genotypes 1a, 1b and 3, respectively, showed no significant differences, suggesting a similar overall immunogenicity of variable regions from these genotypes. Proteins NS4a, NS4b and NS5a were found to be the most immunogenic. Recognition of individual peptides by the sera of infected patients showed that the humoral response against HCV is patient-dependent. The work shows that 15-mer peptides may encompass several B-cell epitopes. These epitopes may lie in slightly different positions in different genotypes. Thirty-one percent of the 543 peptides were recognized by some of the 35 healthy donors. This may be a reflection of the large number of antigens to which they had been exposed, but it may also reflect a strategy of HCV to respond to immune pressure. After selection and modification, a set of 40 peptides was used to assess genotypes 1a, 1b, 1, 2 and 3 in the sera of HCV-infected patients, with sensitivities of 34.1, 48.5, 68.8, 58.3 and 48.9% and specificities of 100, 99.1, 97.1, 99.5 and 99%, respectively. The overall sensitivity and specificity for the assessment of genotypes 1, 2 and 3 were 64 and 98%, respectively
Analysis of Fine Motor Skills in Essential Tremor: Combining Neuroimaging and Handwriting Biomarkers for Early Management
Essential tremor (ET) is a highly prevalent neurological disorder characterized by action-induced tremors involving the hand, voice, head, and/or face. Importantly, hand tremor is present in nearly all forms of ET, resulting in impaired fine motor skills and diminished quality of life. To advance early diagnostic approaches for ET, automated handwriting tasks and magnetic resonance imaging (MRI) offer an opportunity to develop early essential clinical biomarkers. In this study, we present a novel approach for the early clinical diagnosis and monitoring of ET based on integrating handwriting and neuroimaging analysis. We demonstrate how the analysis of fine motor skills, as measured by an automated Archimedes’ spiral task, is correlated with neuroimaging biomarkers for ET. Together, we present a novel modeling approach that can serve as a complementary and promising support tool for the clinical diagnosis of ET and a large range of tremors.This work was supported in part by the Universidad del País Vasco/Euskal Herriko Unibertsitatea, the University of Cambridge, PPG 17/51 and GIU 092/19, the Basque government (Saiotek SA-2010/00028, ELEKIN, Engineering and Society and Bioengineering Research Groups, GIC18/136, and ELKARTEK 18/99, 20/81), ‘‘Ministerio de Ciencia e Innovación’’ (SAF201677758R), FEDER funds, DomusVi Foundation (FP18/76), and the government of Gipuzkoa (HELENA, SABRINA, DG18/14-23, DG19/29, DG20/25 projects). This work is also based upon the work from COST Actions CA18106 and CA15225, supported by COST (European Cooperation in Science and Technology)
Galaxy and Mass Assembly (GAMA): A WISE study of the activity of emission-line systems in G23
We present a detailed study of emission-line systems in the Galaxy And Mass Assembly (GAMA) G23 region, making use of Wide-field Infrared Survey Explorer (WISE) photometry that includes carefully measured resolved sources. After applying several cuts to the initial catalog of. 41,000 galaxies, we extract a sample of 9809 galaxies. We then compare the spectral diagnostic Baldwin, Philips & Terlevich (BPT) classification of 1154 emission-line galaxies (38% resolved in W1) to their location in the WISE color-color diagram, leading to the creation of a new zone for mid-infrared warm galaxies located 2μm above the star-forming sequence, below the standard WISE active galactic nucleus (AGN) region. We find that the BPT and WISE diagrams agree on the classification for 85% and 8% of the galaxies as non-AGN (star-forming = SF) and AGN, respectively, and disagree on. 7% of the entire classified sample. Thirty-nine percent of the AGNs (all types) are broad-line systems for which the [N II] and [Hα] fluxes can barely be disentangled, giving in most cases spurious [N II]/[Hα] flux ratios. However, several optical AGNs appear to be completely consistent with SF in WISE. We argue that these could be low-power AGNs, or systems whose hosts dominate the IR emission. Alternatively, given the sometimes high [O III] luminosity in these galaxies, the emission lines may be generated by shocks coming from super-winds associated with SF rather than AGN activity. Based on our findings, we have created a new diagnostic: [W1 - W2] versus [N II]/[Hα], which has the virtue of separating SF from AGNs and high-excitation sources. It classifies 3 to ∼5 times more galaxies than the classic BPT
Thermodynamics of an Anyon System
We examine the thermal behavior of a relativistic anyon system, dynamically
realized by coupling a charged massive spin-1 field to a Chern-Simons gauge
field. We calculate the free energy (to the next leading order), from which all
thermodynamic quantities can be determined. As examples, the dependence of
particle density on the anyon statistics and the anyon anti-anyon interference
in the ideal gas are exhibited. We also calculate two and three-point
correlation functions, and uncover certain physical features of the system in
thermal equilibrium.Comment: 18 pages; in latex; to be published in Phys. Rev.
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