New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Orthotropic Femur Model

<p>Orthotropic Finite Element Femur Model</p> <p> </p> <p>Open-source. Please reference the following publication if you use this model<br>Authors: Diogo M. Geraldes, Luca Modenese and Andrew T. M. Phillips</p> <p>Year: 2015</p> <p>Title: Consideration of multiple load cases is critical in modelling orthotropic bone adaptation in the femur<br>Journal: Biomechanics and Modelling in Mechanobiology<br>DOI: 10.1007/s10237-015-0740-7</p> <p>If you have any questions, please do not hesitate in contacting the corresponding author:</p> <p>geraldes[at]imperial[dot]ac[dot]uk</p> <p> </p

A Parasitic Resistance Extraction Tool Leveraged by Image Processing

Most academic and commercial tri-dimensional (3D) parasitic resistance extraction EDA/CAD tools rely on finite element methods (FEM) and are mainly suited to digital circuitry. In analog and mixed-signal (AMS) circuits, such as power converters and radio-frequency analog front-ends, the layout structures used for the metal interconnections become much more diversified and complex. This paper proposes an EDA/CAD tool, based on an innovative methodology for 3D parasitic resistance extraction, leveraged by image processing techniques and algorithms. Some practical examples are shown to demonstrate the attractiveness of the proposed tool. Moreover, since our tool efficiently works in the domains of 2D image processing, if an extensive database of layouts is provided and enough training is carried out, advanced deep-learning techniques can be straightforwardly employed, speeding up parasitic resistance extraction in highly complex AMS layouts.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Bio-Electronic

Prevalence of metabolic syndrome and its association with educational inequalities among Brazilian adults: a population-based study

The present study estimated the prevalence of metabolic syndrome (MS) according to the criteria established by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and the International Diabetes Federation (IDF) and analyzed the contribution of social factors in an adult urban population in the Southeastern region of Brazil. The sample plan was based on multistage probability sampling according to family head income and educational level. A random sample of 1116 subjects aged 30 to 79 years was studied. Participants answered a questionnaire about socio-demographic variables and medical history. Fasting capillary glucose (FCG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides were determined and all non-diabetic subjects were submitted to the 75-g oral glucose tolerance test. Body mass index (BMI, kg/m²), waist circumference and blood pressure (BP) were determined. Age- and gender-adjusted prevalence of MS was 35.9 and 43.2% according to NCEP-ATPIII and IDF criteria, respectively. Substantial agreement was found between NCEP-ATPIII and IDF definitions. Low HDL-C levels and high BP were the most prevalent MS components according to NCEP-ATPIII criteria (76.3 and 59.2%, respectively). Considering the diagnostic criteria adopted, 13.5% of the subjects had diabetes and 9.7% had FCG ≥100 mg/dL. MS prevalence was significantly associated with age, skin color, BMI, and educational level. This cross-sectional population-based study in the Southeastern region of Brazil indicates that MS is highly prevalent and associated with an important social indicator, i.e., educational level. This result suggests that in developing countries health policy planning to reduce the risk of MS, in particular, should consider improvement in education

Characterization Of A Hexameric Exo-acting Gh51 α-l- Arabinofuranosidase From The Mesophilic Bacillus Subtilis

α-l-Arabinofuranosidases (α-l-Abfases, EC 3.2.1.55) display a broad specificity against distinct glycosyl moieties in branched hemicellulose and recent studies have demonstrated their synergistic use with cellulases and xylanases for biotechnological processes involving plant biomass degradation. In this study, we examined the structural organization of the arabinofuranosidase (GH51 family) from the mesophilic Bacillus subtilis (AbfA) and its implications on function and stability. The recombinant AbfA showed to be active over a broad temperature range with the maximum activity between 35 and 50 C, which is desirable for industrial applications. Functional studies demonstrated that AbfA preferentially cleaves debranched or linear arabinan and is an exo-acting enzyme producing arabinose from arabinoheptaose. The enzyme has a canonical circular dichroism spectrum of α/β proteins and exhibits a hexameric quaternary structure in solution, as expected for GH51 members. Thermal denaturation experiments indicated a melting temperature of 53.5 C, which is in agreement with the temperature-activity curves. The mechanisms associated with the unfolding process were investigated through molecular dynamics simulations evidencing an important contribution of the quaternary arrangement in the stabilization of the β-sandwich accessory domain and other regions involved in the formation of the catalytic interface of hexameric Abfases belonging to GH51 family. © 2013 Springer Science+Business Media New York.553260267Alvira, P., Negro, M.J., Ballesteros, M., Effect of endoxylanase and α-l-arabinofuranosidase supplementation on the enzymatic hydrolysis of steam exploded wheat straw (2011) Bioresource Technology, 102, pp. 4552-4558. , 10.1016/j.biortech.2010.12.112 1:CAS:528:DC%2BC3MXitVWnu70%3DNuman, M., Bhosle, N., α-l-Arabinofuranosidases: The potential applications in biotechnology (2006) Journal of Industrial Microbiology and Biotechnology, 33, pp. 247-260. , 10.1007/s10295-005-0072-1 1:CAS:528:DC%2BD28XitV2qtL8%3DInácio, J.M., Correia, I.L., De Sá-Nogueira, I., Two distinct arabinofuranosidases contribute to arabino-oligosaccharide degradation in Bacillus subtilis (2008) Microbiology, 154, pp. 2719-2729. , 10.1099/mic.0.2008/018978-0Taylor, E.J., Smith, N.L., Turkenburg, J.P., D'Souza, S., Gilbert, H.J., Davies, G.J., Structural insight into the ligand specificity of a thermostable family 51 arabinofuranosidase, Araf51, from Clostridium thermocellum (2006) Biochemical Journal, 395, pp. 31-37. , 10.1042/BJ20051780 1:CAS:528:DC%2BD28XitlSgu70%3DRuller, R., Rosa, J.C., Faça, V.M., Greene, L.J., Ward, R.J., Efficient constitutive expression of Bacillus subtilis xylanase A in Escherichia coli DH5alpha under the control of the Bacillus BsXA promoter (2006) Biotechnology and Applied Biochemistry, 43, pp. 9-15. , 10.1042/BA20050016 1:CAS:528:DC%2BD28Xms1Cisg%3D%3DMiller, G.L., Use of dinitrosalicylic acid reagent for determination of reducing sugar (1959) Analytical Chemistry, 31, pp. 426-428. , 10.1021/ac60147a030 1:CAS:528:DyaG1MXmtFKiuw%3D%3DSantos, C.R., Meza, A.N., Hoffmam, Z.B., Silva, J.C., Alvarez, T.M., Ruller, R., Giesel, G.M., Murakami, M.T., Thermal-induced conformational changes in the product release area drive the enzymatic activity of xylanases 10B: Crystal structure, conformational stability and functional characterization of the xylanase 10B from Thermotoga petrophila RKU-1 (2010) Biochemical and Biophysical Research Communications, 403, pp. 214-219. , 10.1016/j.bbrc.2010.11.010 1:CAS:528:DC%2BC3cXhsFGgs77PFischer, H., De Oliveira Neto, M., Napolitano, H.B., Polikarpov, I., Craievich, A.F., Determination of the molecular weight of proteins in solution from a single small-angle X-ray scattering measurement on a relative scale (2010) Journal of Applied Crystallography, 43, pp. 101-109. , 10.1107/S0021889809043076 1:CAS:528:DC%2BC3cXhtFamu7s%3DYang, Z., Template-based modeling and free modeling by I-TASSER in CASP7 (2007) Proteins, 69 (SUPPL. 8), pp. 108-117Noel, J.K., Whitford, P.C., Sanbonmatsu, K.Y., Onuchic, J.N., SMOG@ctbp: Simplified deployment of structure-based models in GROMACS (2010) Nucleic Acids Research, 38, pp. 657-W661. , 10.1093/nar/gkq498 1:CAS:528:DC%2BC3cXotVSqt7s%3DPetoukhov, M.V., Svergun, D.I., Global rigid body modeling of macromolecular complexes against small-angle scattering data (2005) Biophysical Journal, 89, pp. 1237-1250. , 10.1529/biophysj.105.064154 1:CAS:528:DC%2BD2MXnvVSrs7k%3DVan Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E., Berendsen, H.J.C., GROMACS: Fast, flexible, and free (2005) Journal of Computational Chemistry, 26, pp. 1701-1718. , 10.1002/jcc.20291Whitford, P.C., Noel, J.K., Gosavi, S., Schug, A., Sanbonmatsu, K.Y., Onuchic, J.N., An all-atom structure-based potential for proteins: Bridging minimal models with all-atom empirical forcefields (2009) Proteins: Structure, Function and Bioinformatics, 75, pp. 430-441. , 10.1002/prot.22253 1:CAS:528:DC%2BD1MXjsVahs70%3DClementi, C., Nymeyer, H., Onuchic, J.N., Topological and energetic factors: What determines the structural details of the transition state ensemble and "en-route" intermediates for protein folding? An investigation for small globular proteins (2000) Journal of Molecular Biology, 298, pp. 937-953. , 10.1006/jmbi.2000.3693 1:CAS:528:DC%2BD3cXivFGjt7s%3DMyers, R.H., Montgomery, D.C., (2001) Response Surface Methodology, , 2 Wiley New YorkDelabona, P.D.S., Cota, J., Hoffmam, Z.B., Paixão, D.A.A., Farinas, C.S., Cairo, J.P.L.F., Understanding the cellulolytic system of Trichoderma harzianum P49P11 and enhancing saccharification of pretreated sugarcane bagasse by supplementation with pectinase and α-l-arabinofuranosidase (2013) Bioresource Technology, 131, pp. 500-507Sakamoto, T., Kawasaki, H., Purification and properties of two type-B α-l-arabinofuranosidases produced by Penicillium chrysogenum (2003) Biochimica et Biophysica Acta, 1621, pp. 204-210. , 10.1016/S0304-4165(03)00058-8 1:CAS:528:DC%2BD3sXjtlSks7w%3DBeylot, M.H., McKie, V.A., Voragen, A.G., Doeswijk-Voragen, C.H., Gilbert, H.J., The pseudomonas cellulosa glycoside hydrolase family 51 arabinofuranosidase exhibits wide substrate specificity (2001) Biochemical Journal, 358, pp. 607-614. , 10.1042/0264-6021:3580607 1:CAS:528:DC%2BD3MXntlSgsro%3DSouza, T.A., Santos, C.R., Souza, A.R., Oldiges, D.P., Ruller, R., Prade, R.A., Squina, F.M., Murakami, M.T., Structure of a novel thermostable GH51 α-l-arabinofuranosidase from Thermotoga petrophila RKU-1 (2011) Protein Science, 20, pp. 1632-1637. , 10.1002/pro.693 1:CAS:528:DC%2BC3MXhtVaksLzIDebeche, T., Cummings, N., Connerton, I., Debeire, P., O'Donohue, M.J., Genetic and biochemical characterization of a highly thermostable α-l-arabinofuranosidase from Thermobacillus xylanilyticus (2000) Applied and Environmental Microbiology, 66, pp. 1734-1736. , 10.1128/AEM.66.4.1734-1736.2000 1:CAS:528:DC%2BD3cXisVWlsbc%3DDos Santos, C., Squina, F., Navarro, A., Oldiges, D., Leme, A., Ruller, R., Mort, A., Murakami, M., Functional and biophysical characterization of a hyperthermostable GH51 α-l-arabinofuranosidase from Thermotoga petrophila (2011) Biotechnology Letters, 33, pp. 131-137. , 10.1007/s10529-010-0409-3 1:CAS:528:DC%2BC3cXhsF2gsrrEAmbrish, R., Alper, K., Yang, Z., I-TASSER: A unified platform for automated protein structure and function prediction (2010) Nature Protocols, 5, pp. 725-738. , 10.1038/nprot.2010.5Hovel, K., Shallom, D., Niefind, K., Belakhov, V., Shoham, G., Baasov, T., Shoham, Y., Schomburg, D., Crystal structure and snapshots along the reaction pathway of a family 51 [alpha]-l-arabinofuranosidase (2003) EMBO Journal, 22, pp. 4922-4932. , 10.1093/emboj/cdg49

On Switched Controller Design for Robust Control of Uncertain Polynomial Nonlinear Systems Using Sum of Squares

This manuscript presents a switched control design for robust control of a class of uncertain nonlinear systems. In particular, it is considered a class of nonlinear systems whose dynamics are described by polynomial functions, that depend on the state vector of the system, with uncertain parameters. The design procedure can be represented in terms of sum of squares. The proposed switched control procedure uses a switching law to select at each instant of time a state-feedback polynomial gain, which belongs to a set of gains obtained from the proposed design procedure. The aim of the switching law is to choose a state-feedback polynomial gain that minimizes the time derivative of a polynomial Lyapunov function. A numerical example, using a chaotic Lorenz system with parametric uncertainties, illustrates the validity of the proposed approach.São Paulo State University (UNESP) School of Engineering Department of Electrical Engineering, José Carlos Rossi Ave, 1370Federal Institute of Education Science and Technology of Mato Grosso do Sul (IFMS), Angelo Melão St, 790Federal Institute of Education Science and Technology of Paraná (IFPR), Dr. Tito Ave, Jardim PanoramaSão Paulo State University (UNESP) School of Engineering Department of Electrical Engineering, José Carlos Rossi Ave, 137