786 research outputs found
Acquisition of functions on the outer capsid surface during evolution of double-stranded RNA fungal viruses
Unlike their counterparts in bacterial and higher eukaryotic hosts, most fungal viruses are transmitted intracellularly and lack an extracellular phase. Here we determined the cryo-EM structure at 3.7 Ă
resolution of Rosellinia necatrix quadrivirus 1 (RnQV1), a fungal double-stranded (ds)RNA virus. RnQV1, the type species of the family Quadriviridae, has a multipartite genome consisting of four monocistronic segments. Whereas most dsRNA virus capsids are based on dimers of a single protein, the ~450-Ă
-diameter, T = 1 RnQV1 capsid is built of P2 and P4 protein heterodimers, each with more than 1000 residues. Despite a lack of sequence similarity between the two proteins, they have a similar α-helical domain, the structural signature shared with the lineage of the dsRNA bluetongue virus-like viruses. Domain insertions in P2 and P4 preferential sites provide additional functions at the capsid outer surface, probably related to enzyme activity. The P2 insertion has a fold similar to that of gelsolin and profilin, two actin-binding proteins with a function in cytoskeleton metabolism, whereas the P4 insertion suggests protease activity involved in cleavage of the P2 383-residue C-terminal region, absent in the mature viral particle. Our results indicate that the intimate virus-fungus partnership has altered the capsid genome-protective and/or receptor-binding functions. Fungal virus evolution has tended to allocate enzyme activities to the virus capsid outer surface
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Jig-less end-effector system for automating exhausting composite fuselage assembly tasks
Collections: Brunel Composite CentreIn this study, the jig-less end-effector system developed to assemble components of a full-scale multifunctional integrated composite thermoplastic lower fuselage section is tested and validated. To offset the environmental impact of higher volume of air transport, the aviation industry wants to design lighter and more environmentally friendly aircraft. To achieve this, there is a need to exploit novel materials and technologies. Advanced thermoplastic composites provide an excellent material option thanks to their weldability, low density, low overall production cost, improved fracture toughness and recyclability. However, to fully appreciate their capabilities and benefits, new manufacturing approaches and techniques are needed. Hence, projects such as TCTool, "innovative tooling, end-effector development and industrialisation for welding of thermoplastic components", aim to develop innovative tooling and end-effector systems for the assembly of a multifunctional thermoplastic fuselage. This study presents the development, operation, and testing of the jig-less end-effector system used in the TCTool project for picking, placing, and temporary welding and fixing fuselage's clips and stringers.This study has received funding from the Clean Sky 2 Joint Undertaking under the European Union's
Horizon 2020 research and innovation program under grant agreement No. 865131 for TCTool Project,
and has been partially funded by the projet â5R â Cervera Network in robotic technologies for intelligent
manufacturingâ, contract number CER-20211007, under âCentros TecnolĂłgicos de Excelencia
Cerveraâ (founded by âThe Centre for the Development of Industrial Technology (CDTI)â). The authors
would like to thank TWI Ltd. for conducting the tensile tests and optical microscopy.
TCTool project partners: GKN-Fokker Aerospace, TWI Ltd., Andalusian Foundation for Aerospace
Development â Advanced Center for Aerospace Technologies, Brunel University London, London
South Bank University, Acroflight Ltd
Cumplimiento, conocimiento y automedicaciĂłn como factores asociados a los resultados clĂnicos negativos de la farmacoterapia
The patient plays a fundamental role in the attainment of good results in pharmacotherapy. Noncompliance,self-medication, or insufficient knowledge of the therapy being employed may provide asource for the causes of these negative clinical outcomes, otherwise known as medicine related problems(MRP). he Dader method was used in the evaluation, identification and classification of MRP. Theassociation of variables was established through the statistical Chi square test. Patient knowledge of themedicine, degree of compliance to therapy and self-medication were studied as causes of the negativeoutcomes encountered. 2556 patients were interviewed throughout the year that the study took place,giving a total of 2261 of valid cases. 33% presented an MRP as the cause of his/her visit to the hospitalemergency ward. Knowledge of the medicine, compliance and self-medication were only studied in thepopulation that presented an MRP and in this work it is demonstrated that these are aspects that areassociated with different dimensions of MRP. It is not possible to establish an association between theexistence or not of negative clinical outcomes in patients with the factors of knowledge of medication,compliance and self-medication. This is due to the fact that these variables are not attributable to thepatient himself, but rather are associated with the characteristics of each medicine.El paciente juega un papel primordial en la consecuciĂłn de los resultados terapĂ©uticos. El incumplimiento,la automedicaciĂłn, o la falta de conocimiento del la farmacoterapia pueden ser causas de esosresultados clĂnicos negativos, denominados en ocasiones problemas relacionados con medicamentos(PRM). El mĂ©todo DĂĄder se utilizĂł para la evaluaciĂłn, identificaciĂłn y clasificaciĂłn de PRM. LaasociaciĂłn de variables se estableciĂł mediante el estadĂstico chi cuadrado. El conocimiento de la medicaciĂłn,el cumplimiento y la automedicaciĂłn fueron estudiados como causa de estos resultados negativosde la medicaciĂłn. Fueron entrevistados 2556 pacientes durante el año de estudio, resultando 2261 casosvĂĄlidos. El 33 % presentaron un PRM como causa de visita a urgencias. El conocimiento de la medicaciĂłn,el cumplimiento y la automedicaciĂłn fueron estudiados solo en la poblaciĂłn que presentĂł unPRM y se demuestra que son aspectos asociados a las distintas dimensiones de PRM. No es posibleestablecer asociaciĂłn entre la existencia o no de resultados clĂnicos negativos en los pacientes con elconocimiento de la medicaciĂłn, el cumplimiento y la automedicaciĂłn, debido a que estas variables noson atributos del paciente sino que estĂĄn asociadas a cada medicamento
The regulatory subunit of PKA-I remains partially structured and undergoes ÎČ-aggregation upon thermal denaturation
Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of ÎČ-structure. A similar αâÎČ transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-ÎČ-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the ÎČ-sandwiches in these domains favors inter-molecular ÎČ-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al
Synthesis and Anti-Diabetic Activity of an 8-Purine Derivative as a Novel DPP-4 Inhibitor in Obese Diabetic Zücker Rats
Meriem Chayah,1â 3 AngĂ©lica Luque-GonzĂĄlez,1 VerĂłnica GĂłmez-PĂ©rez,1 Diego Salagre,4,5 Amjad Al-Shdaifat,6 JoaquĂn MarĂa Campos,1,2 Ana Conejo-GarcĂa,1,2 Ahmad Agil2,4,5 1Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Granada, Spain; 2Biosanitary Institute of Granada (Ibs.granada), SAS-University of Granada, Granada, Spain; 3Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government (GENYO), Granada, Spain; 4Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain; 5Federico Oloriz Neuroscience Institute, University of Granada, Granada, Spain; 6Department of Medicine and Family Medicine, Faculty of Medicine, Hashemite University, Zarqa, JordaniaCorrespondence: Ahmad Agil; Ana Conejo-GarcĂa, Email [email protected]; [email protected]: Type 2 diabetes mellitus (T2DM) is one of the worldâs principal metabolic diseases characterized by chronic hyperglycemia. The gut incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which has been proposed as a new treatment for T2DM, are extensively metabolized by Dipeptidyl peptidase 4 (DPP-4). Inhibitors of DPP-4 block the degradation of GLP-1 and GIP and may increase their natural circulating levels, favoring glycemic control in T2DM. A novel and potent selective inhibitor of DPP-4 with an 8-purine derived structure ( 1) has been developed and tested in vitro and in vivo in ZĂŒcker obese diabetic fatty (ZDF) rats, an experimental model of the metabolic syndrome and T2DM to assess the inhibitory activity using vildagliptin as reference standard. ZDF rats were subdivided into three groups (n = 7/group), control (C-ZDF), and those treated with compound 1 (Compound 1-ZDF) and with vildagliptin (V-ZDF), both at 10 mg/kg/d rat body weight, in their drinking water for 12 weeks, and a group of lean littermates (ZL) was used. ZDF rats developed DM (fasting hyperglycemia, 425 ± 14.8 mg/dL; chronic hyperglycemia, HbA1c 8.5 ± 0.4%), compared to ZL rats. Compound 1 and vildagliptin reduced sustained HbAl1c (14% and 10.6%, P < 0.05, respectively) and fasting hyperglycemia values (24% and 19%, P < 0.05, respectively) compared to C-ZDF group (P < 0.001). Compound 1 and vildagliptin have shown a potent activity with an IC50 value of 4.92 and 3.21 ÎŒM, respectively. These data demonstrate that oral compound 1 administration improves diabetes in ZDF rats by the inhibitory effect on DPP-4, and the potential to be a novel, efficient and tolerable approach for treating diabetes of obesity-related T2DM, in ZDF rats.Keywords: diabetes mellitus type 2, DPP-4 inhibitors, purine derivatives, ZDF rat
Role of Haptoglobin in Polycystic Ovary Syndrome (PCOS), Obesity and Disorders of Glucose Tolerance in Premenopausal Women
alleles of the haptoglobin 뱉chain polymorphism reduce the anti-oxidant properties and increase the pro-inflammatory actions of this acute-phase protein in a gene-dosage fashion. We hypothesized that the haptoglobin polymorphism might contribute to the increased oxidative stress and low-grade chronic inflammation frequently associated with polycystic ovary syndrome, obesity, and abnormalities of glucose tolerance.<0.001), yet no association was found between obesity and haptoglobin genotypes. No differences were observed in haptoglobin levels or genotype frequencies depending on glucose tolerance. Fifty percent of the variation in serum haptoglobin concentrations was explained by the variability in serum C-reactive protein concentrations, BMI, insulin sensitivity and haptoglobin genotypes. alleles suggests that the anti-oxidant and anti-inflammatory properties of haptoglobin may be reduced in these patients
Static and dynamic ionization levels of transition metal-doped zinc chalcogenides
Transition metal (TM) impurities in semiconductors have a considerable effect on the electronic properties and on the lattice vibrations. The unfilled d shell permits the impurity atoms to exist in a variety of charge states. In this work, the static donor and acceptor ionization energies of ZnX:M, with X = S, Se, Te and M:Sc, Ti, V, Fe, Co, Ni are obtained from first principles total energy calculations and compared with experimental results in the literature where they exist. From these results, many of the TM-doped zinc chalogenides have an amphoteric behavior. To analyze the rule of the deep gap levels in both the radiative and non-radiative processes, the dynamic ionization energies are obtained as a function of the inward and outward MâX displacements. In many cases, the changes in the mass and the force constants resulting from the substitution of an impurity center for a lattice atom are small. When the charge or the environment of the impurity changes, the electron population tend to remain compensated. As consequence, the changes in the lattice vibrational modes are small
Efficacy of a strategy for implementing a guideline for the control of cardiovascular risk in a primary healthcare setting: the SIRVA2 study a controlled, blinded community intervention trial randomised by clusters
This work describes the methodology used to assess a strategy for implementing clinical practice guidelines (CPG) for cardiovascular risk control in a health area of Madrid
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Demonstration of the event identification capabilities of the NEXT-White detector
In experiments searching for neutrinoless double-beta decay, the possibility of identifying the two emitted electrons is a powerful tool in rejecting background events and therefore improving the overall sensitivity of the experiment. In this paper we present the first measurement of the efficiency of a cut based on the different event signatures of double and single electron tracks, using the data of the NEXT-White detector, the first detector of the NEXT experiment operating underground. Using a 228Th calibration source to produce signal-like and background-like events with energies near 1.6 MeV, a signal efficiency of 71.6 ± 1.5 stat± 0.3 sys% for a background acceptance of 20.6 ± 0.4 stat± 0.3 sys% is found, in good agreement with Monte Carlo simulations. An extrapolation to the energy region of the neutrinoless double beta decay by means of Monte Carlo simulations is also carried out, and the results obtained show an improvement in background rejection over those obtained at lower energies. [Figure not available: see fulltext.
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