Automated medical diagnosis of alzheimer´s disease using an Efficient Net convolutional neural network

Producción CientíficaAlzheimer's disease (AD) poses an enormous challenge to modern healthcare. Since 2017, researchers have been using deep learning (DL) models for the early detection of AD using neuroimaging biomarkers. In this paper, we implement the EfficietNet-b0 convolutional neural network (CNN) with a novel approach—"fusion of end-to-end and transfer learning"—to classify different stages of AD. 245 T1W MRI scans of cognitively normal (CN) subjects, 229 scans of AD subjects, and 229 scans of subjects with stable mild cognitive impairment (sMCI) were employed. Each scan was preprocessed using a standard pipeline. The proposed models were trained and evaluated using preprocessed scans. For the sMCI vs. AD classification task we obtained 95.29% accuracy and 95.35% area under the curve (AUC) for model training and 93.10% accuracy and 93.00% AUC for model testing. For the multiclass AD vs. CN vs. sMCI classification task we obtained 85.66% accuracy and 86% AUC for model training and 87.38% accuracy and 88.00% AUC for model testing. Based on our experimental results, we conclude that CNN-based DL models can be used to analyze complicated MRI scan features in clinical settings.Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL

Modification of the lignin structure during alkaline delignification of eucalyptus wood by kraft, soda-AQ, and soda-O2 cooking

11 páginas.-- 5 figuras.-- 4 tablas.-- 50 referencias.-- Supporting Information The general conditions for the kraft, soda-AQ, and soda-O2 alkaline cooking of eucalyptus feedstock, are shown in Table S1. The identification and relative molar abundance of the compounds identified in the Py-GC/MS of MWL from eucalyptus wood, and residual and black liquor lignins from kraft, soda-AQ,and soda-O2 pulping at different kappa numbers, are listed in Table S2. This material is available free of charge via the Internet at http://pubs.acs.org/doi/suppl/10.1021/ie401364dThe modification of the lignin structure of an eucalyptus feedstock during alkaline delignification by kraft, soda-AQ, and soda-O2 cooking processes has been investigated by different analytical techniques (size exclusion chromatography (SEC), pyrolysis gas chromatography-mass spectroscopy (Py-GC/MS), 1H-13C two-dimensional nuclear magnetic resonance (2D-NMR), and 31P NMR). The characteristics of the lignins were compared at different pulp kappa levels, and with the native lignin isolated from the wood. The structural differences between the kraft, soda-AQ, and soda-O2 residual lignins were more significant at earlier pulping stages. At the final stages, all the lignin characteristics were similar, with the exception of their phenolic content. Strong differences between lignins from pulps and cooking liquors were observed, including enrichment in guaiacyl units in pulp residual lignin and enrichment in syringyl units in black liquor lignin. A comparison of the alkaline cookings indicate that soda-O2 process produced higher lignin degradation and provided promising results as pretreatment for the deconstruction of eucalyptus feedstocks for subsequent use in lignocellulose biorefineries. © 2013 American Chemical Society.This study has been funded by the EU-Project LIGNODECO (No. KBBE-244362), the Spanish project (No. AGL2011-25379), and the CSIC project (No. 201040E075). Dr. Rencoret thanks the CSIC for a JAE-DOC contract in the program “Junta para la Ampliación de Estudios”, cofinanced by Fondo Social Europeo (FSE). Finally, we thank Suzano Papel e Celulose (Brazil) for providing the pulp and black liquor samples from the alkaline cooking experiments and the corresponding additional data.Peer Reviewe

Lactose binding to human galectin-7 (p53-induced gene 1) induces long-range effects through the protein resulting in increased dimer stability and evidence for positive cooperativity.

16 pags, 11 figs, 3 tabs. -- Supplementary data for this article are available online at: http://glycob.oxfordjournals.org/lookup/suppl/doi:10.1093/glycob/cwt005/-/DC1The product of p53-induced gene 1 is a member of the galectin family, i.e., galectin-7 (Gal-7). To move beyond structural data by X-ray diffraction, we initiated the study of the lectin by nuclear magnetic resonance (NMR) and circular dichroism spectroscopies, and molecular dynamics (MD) simulations. In concert, our results indicate that lactose binding to human Gal-7 induces long-range effects (minor conformational shifts and changes in structural dynamics) throughout the protein that result in stabilization of the dimer state, with evidence for positive cooperativity. Monte Carlo fits of 15N-Gal-7 HSQC titrations with lactose using a two-site model yield K1 = 0.9 ± 0.6 × 103 M−1 and K2 = 3.4 ± 0.8 × 103 M−1. Ligand binding-induced stabilization of the Gal-7 dimer was supported by several lines of evidence: MD-based calculations of interaction energies between ligand-loaded and ligand-free states, gel filtration data and hetero-FRET spectroscopy that indicate a highly reduced tendency for dimer dissociation in the presence of lactose, CD-based thermal denaturation showing that the transition temperature of the lectin is significantly increased in the presence of lactose, and saturation transfer difference (STD) NMR using a molecular probe of the monomer state whose presence is diminished in the presence of lactose. MD simulations with the half-loaded ligand-bound state also provided insight into how allosteric signaling may occur. Overall, our results reveal long-range effects on Gal-7 structure and dynamics, which factor into entropic contributions to ligand binding and allow further comparisons with other members of the galectin family.This work was supported by a research grant from the National Institutes of Health (CA 096090 to K.H.M.), the RAS program “Molecular and Cellular Biology” RFBR grant (No. 12 04 31360 to E.E.), the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 260600 (“GlycoHIT”), grants CTQ2009-08536 and BFU2009-10052 and a FPI PhD fellowship to M.A.B. from the Spanish Ministry of Science and Innovation and the CIBER of Respiratory Diseases (CIBERES), an initiative from the Spanish Institute of Health Carlos III (ISCIII). E.E. was supported by a Travel Grant from the Minnesota Supercomputing Institute (University of Minnesota) during her stay in the research lab of Prof. K.H. Mayo. I.N. was supported in the Mayo lab by National Institutes of Health Hematology Training Grant (HL 07062

Minimizing the entropy penalty for ligand binding: lessons from the molecular recognition of the histo blood-group antigens by human galectin-3

6 p.-5 fig.-2 tab.Ligand conformational entropy plays an important role in carbohydrate recognition events. Glycans are characterized by intrinsic flexibility around the glycosidic linkages, thus in most cases, loss of conformational entropy of the sugar upon complex formation strongly affects the entropy of the binding process. By employing a multidisciplinary approach combining structural, conformational, binding energy, and kinetic information, we investigated the role of conformational entropy in the recognition of the histo blood‐group antigens A and B by human galectin‐3, a lectin of biomedical interest. We show that these rigid natural antigens are pre‐organized ligands for hGal‐3, and that restriction of the conformational flexibility by the branched fucose (Fuc) residue modulates the thermodynamics and kinetics of the binding process. These results highlight the importance of glycan flexibility and provide inspiration for the design of high‐affinity ligands as antagonists for lectins.We thank Agencia Estatal de Investigacion and ISCIII of Spain and the European Research Council for financial support.Peer reviewe

Application and New Developments of NMR Spectroscopy for the Study of Molecular Recognition Processes between Carbohydrates and their Receptors

Tesis doctoral. Universidad Complutense de Madrid. Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular I. Defendida el 20-10-2014Los carbohidratos constituyen uno de los tipos de biomoléculas más complejos y ubicuos, cuyo reconocimiento por parte de receptores proteicos pertenecientes a diversas familias (lectinas, anticuerpos, enzimas y virus) determina una variedad de respuestas relacionadas con procesos fisiológicos y patológicos. El conocimiento, a nivel atómico, de la estructura de los carbohidratos y de sus interacciones con proteínas es esencial para una completa comprensión de muchos procesos vitales, así como abrir la puerta a su modulación. Al mismo tiempo, la gran variabilidad structural y versatilidad funcional de los glicanos impone la necesidad de desarrollar nuevas herramientas que permitan ampliar nuestro conocimiento sobre la estructura de estas moléculas y su reconocimiento por parte de receptores. En esta Tesis se ha hecho un uso exhaustivo de métodos de espectroscopía por resonancia magnética nuclear (RMN) para obtener información estructural sobre procesos de reconocimiento molecular en una serie de sistemas carbohidrato-proteína de interés biomédico. En distintos capítulos, esta Tesis aborda el estudio del reconocimiento molecular entre glicanos y los cuatro tipos principales de receptores de carbohidratos: lectinas, anticuerpos, enzimas y virus.SUMMARY Carbohydrates are among the most ubiquitous and complex types of biomolecules in nature. Their interplay with a number of receptor families including lectins, antibodies, enzymes and viruses, triggers a variety of responses related to physiological and pathological events. Thus, knowledge on the forces that govern these interactions at atomic detail is essential for a thorough understanding of many vital processes and to open the possibility of their modulation. At the same time, the high structural variability and functional versatility of glycans call for developing new tools to probe carbohydrate conformation and recognition features by receptors. In this Thesis, we have made extensive use of NMR spectroscopy methods to gain structural insight into the interactions of a series of protein-carbohydrate systems of biomedical relevance. In addition, we present an innovative approach for conformational characterization of sugars and structural aspects of their recognition by receptors, based on the exploitation of paramagnetic effects arisen from lanthanide-binding carbohydrate conjugates.Para realizar este trabajo, el doctorando ha disfrutado de una Beca FPI del Ministerio de Economía y Competitividad.Peer reviewe

Aplicación y nuevos desarrollos de la espectroscopía por RMN para el estudio de procesos de reconocimiento molecular entre carbohidratos y sus receptores

Los carbohidratos constituyen uno de los tipos de biomoléculas más complejos y ubicuos, cuyo reconocimiento por parte de receptores proteicos pertenecientes a diversas familias (lectinas, anticuerpos, enzimas y virus) determina una variedad de respuestas relacionadas con procesos fisiológicos y patológicos. El conocimiento, a nivel atómico, de la estructura de los carbohidratos y de sus interacciones con proteínas es esencial para una completa comprensión de muchos procesos vitales, así como abrir la puerta a su modulación. Al mismo tiempo, la gran variabilidad estructural y versatilidad funcional de los glicanos impone la necesidad de desarrollar nuevas herramientas que permitan ampliar nuestro conocimiento sobre la estructura de estas moléculas y su reconocimiento por parte de receptores. En esta Tesis se ha hecho un uso exhaustivo de métodos de espectroscopía por resonancia magnética nuclear (RMN) para obtener información estructural sobre procesos de reconocimiento molecular en una serie de sistemas carbohidrato-proteína de interés biomédico. En distintos capítulos, esta Tesis aborda el estudio del reconocimiento molecular entre glicanos y los cuatro tipos principales de receptores de carbohidratos: lectinas, anticuerpos, enzimas y virus

Structure and function of prokaryotic UDP-glucose pyrophosphorylase, a drug target candidate

24 p.-9 fig.UDP-glucose is an essential metabolite for a variety of processes in the cell physiology in all organisms. In prokaryotes, it is involved in the synthesis of trehalose, an osmoprotectant, in galactose utilization via the Leloir pathway and it plays a key role in the synthesis of the components of the bacterial envelope, particularly the lipopolysaccharide and the capsule, which represent necessary virulence factors of many bacterial pathogens. UDP-glucose is synthesized in bacteria by the prokaryotic UDP-glucose pyrophosphorylase (UGP, EC 2.7.7.9), an enzyme belonging to the family of sugar:nucleotidyl transferases. Despite the ubiquitous distribution of UGP activity in all domains of life, prokaryotic UGPs are evolutionarily unrelated to their eukaryotic counterparts. Taken together, these features make of bacterial UGP an attractive target candidate for the discovery and development of new generation antibiotics. This review summarizes the current knowledge on structure and function of bacterial UGPs, underlying their potential as drug target candidates.We thank MINECO for financial support (Grant CTQ 2012-32025, AES12/PI12/01628), EU for funding through the GlycoHit, ITN-Glycopharm, FP7-HEALTH-2012-INNOVATION-1, project number: 305483 and COST actions BM1003 and CM1102, as well as Comunidad de Madrid for the MHit project. MAB acknowledges a FPI fellowship from MINECO.Peer reviewe

(1)H, (13)C, and (15)N backbone and side-chain chemical shift assignments for the 36 proline-containing, full length 29 kDa human chimera-type galectin-3.

9 p.Galectin-3 has a unique trimodular design consisting of the canonical lectin domain, a collagen-like tandem-repeat section and an N-terminal peptide with two sites for Ser phosphorylation. Structural characterization of the full-length protein with its non-lectin part (115 of 250 residues) will help understand the multifunctionality of this potent cellular effector. Here, we report 1H, 13C, and 15N chemical shift assignments as determined by heteronuclear NMR spectroscopy.This work was generously supported by a research grant from the National Cancer Institute (CA-096090) to KHM; EC funding (GlycoHIT, contract no. 260600; GLYCOPHARM, contract no. 217297) to JJB & HJG, and European Research Council funding (ERC AdG °249929) to CW. NMR instrumentation was provided with funds from the National Science Foundation (BIR-961477), the University of Minnesota Medical School, and the Minnesota Medical Foundation.Peer reviewe

End-to-end deep learning architectures using 3D neuroimaging biomarkers for early Alzheimer’s diagnosis

Producción CientíficaThis study uses magnetic resonance imaging (MRI) data to propose end-to-end learning implementing volumetric convolutional neural network (CNN) models for two binary classification tasks: Alzheimer’s disease (AD) vs. cognitively normal (CN) and stable mild cognitive impairment (sMCI) vs. AD. The baseline MP-RAGE T1 MR images of 245 AD patients and 229 with sMCI were obtained from the ADNI dataset, whereas 245 T1 MR images of CN people were obtained from the IXI dataset. All of the images were preprocessed in four steps: N4 bias field correction, denoising, brain extraction, and registration. End-to-end-learning-based deep CNNs were used to discern between different phases of AD. Eight CNN-based architectures were implemented and assessed. The DenseNet264 excelled in both types of classification, with 82.5% accuracy and 87.63% AUC for training and 81.03% accuracy for testing relating to the sMCI vs. AD and 100% accuracy and 100% AUC for training and 99.56% accuracy for testing relating to the AD vs. CN. Deep learning approaches based on CNN and end-to-end learning offer a strong tool for examining minute but complex properties in MR images which could aid in the early detection and prediction of Alzheimer’s disease in clinical settings.Comisión Europea y Ministerio de Industria,Comercio y Turismo - (project AAL-20125036

Trimethylamine N-oxide is a new plant molecule that promotes abiotic stress tolerance

12 p.-6 fig.Trimethylamine N-oxide (TMAO) is a well-known naturally occurring osmolyte in animals that counteracts the effect of different denaturants related to environmental stress and has recently been associated with severe human chronic diseases. In plants, however, the presence of TMAO has not yet been reported. In this study, we demonstrate that plants contain endogenous levels of TMAO, that it is synthesized by flavin-containing mono-oxygenases, and that its levels increase in response to abiotic stress conditions. In addition, our results reveal that TMAO operates as a protective osmolyte in plants, promoting appropriate protein folding and as an activator of abiotic stress–induced gene expression. Consistent with these functions, we show that TMAO enhances plant adaptation to low temperatures, drought, and high salt. We have thus uncovered a previously unidentified plant molecule that positively regulates abiotic stress tolerance.Research in the Salinas laboratory was supported by grants BIO2016-79187-R from AEI/FEDER, UE, and PID2019-106987RB-100/AEI/10.13039/5011033.Peer reviewe