Multiobjective RBFNNs Designer for Function Approximation: An Application for Mineral Reduction

Radial Basis Function Neural Networks (RBFNNs) are well known because, among other applications, they present a good perfor- mance when approximating functions. The function approximation prob- lem arises in the construction of a control system to optimize the process of the mineral reduction. In order to regulate the temperature of the ovens and other parameters, it is necessary a module to predict the ¯nal concentration of mineral that will be obtained from the source materials. This module can be formed by an RBFNN that predicts the output and by the algorithm that designs the RBFNN dynamically as more data is obtained. The design of RBFNNs is a very complex task where many parameters have to be determined, therefore, a genetic algorithm that determines all of them has been developed. This algorithm provides sat- isfactory results since the networks it generates are able to predict quite precisely the ¯nal concentration of mineral.Spanish CICYT Project TIN2004-01419European Commission's Research Infrastructures RII3-CT-2003-506079 (HPC-Europa

Golgi Oncoprotein GOLPH3 Gene Expression is Regulated by Functional E2F and CREB/ATF Promoter Elements

The Golgi organelle duplicates its protein and lipid content to segregate evenly between two daughter cells after mitosis. However, how Golgi biogenesis is regulated during interphase remains largely unknown. Here we show that messenger RNA (mRNA) expression of GOLPH3 and GOLGA2, two genes encoding Golgi proteins, is induced specifically in G1 phase, suggesting a link between cell cycle regulation and Golgi growth. We have examined the role of E2F transcription factors, critical regulators of G1 to S progression of the cell cycle, in the expression of Golgi proteins during interphase. We show that promoter activity for GOLPH3, a Golgi protein that is also oncogenic, is induced by E2F1-3 and repressed by E2F7. Mutation of the E2F motifs present in the GOLPH3 promoter region abrogates E2F1-mediated induction of a GOLPH3 luciferase reporter construct. Furthermore, we identify a critical CREB/ATF element in the GOLPH3 promoter that is required for its steady state and ATF2-induced expression. Interestingly, depletion of GOLPH3 with small interfering RNA (siRNA) delays the G1 to S transition in synchronized U2OS cells. Taken together, our results reveal a link between cell cycle regulation and Golgi function, and suggest that E2F-mediated regulation of Golgi genes is required for the timely progression of the cell cycle.This work was supported by grants from the Spanish Ministry (SAF2015-67562-R, co-financed by Feder funds, and SAF2014-57791-REDC) and the Basque Government (IT634-13) to AMZ. B.P.-G. is recipient of a Spanish Ministry FPI fellowship for graduate studies; J.V.R. was recipient of a UPV/EHU fellowship for graduate studies; G.M. was recipient of a Spanish Ministry FPU fellowship for graduate studies

Golgi Oncoprotein GOLPH3 Gene Expression is Regulated by Functional E2F and CREB/ATF Promoter Elements

The Golgi organelle duplicates its protein and lipid content to segregate evenly between two daughter cells after mitosis. However, how Golgi biogenesis is regulated during interphase remains largely unknown. Here we show that messenger RNA (mRNA) expression of GOLPH3 and GOLGA2, two genes encoding Golgi proteins, is induced specifically in G1 phase, suggesting a link between cell cycle regulation and Golgi growth. We have examined the role of E2F transcription factors, critical regulators of G1 to S progression of the cell cycle, in the expression of Golgi proteins during interphase. We show that promoter activity for GOLPH3, a Golgi protein that is also oncogenic, is induced by E2F1-3 and repressed by E2F7. Mutation of the E2F motifs present in the GOLPH3 promoter region abrogates E2F1-mediated induction of a GOLPH3 luciferase reporter construct. Furthermore, we identify a critical CREB/ATF element in the GOLPH3 promoter that is required for its steady state and ATF2-induced expression. Interestingly, depletion of GOLPH3 with small interfering RNA (siRNA) delays the G1 to S transition in synchronized U2OS cells. Taken together, our results reveal a link between cell cycle regulation and Golgi function, and suggest that E2F-mediated regulation of Golgi genes is required for the timely progression of the cell cycle.This work was supported by grants from the Spanish Ministry (SAF2015-67562-R, co-financed by Feder funds, and SAF2014-57791-REDC) and the Basque Government (IT634-13) to AMZ. B.P.-G. is recipient of a Spanish Ministry FPI fellowship for graduate studies; J.V.R. was recipient of a UPV/EHU fellowship for graduate studies; G.M. was recipient of a Spanish Ministry FPU fellowship for graduate studies

La hoja de ruta de la ingeniería de computadores al final de la ley de Moore y el escalado de Dennard

En el presente trabajo se hace una revisión sobre la situación de la ingeniería de computadores al inicio de la década de los 2020 con objeto de perfilar algunos de los cambios que deberían establecerse en la enseñanza superior de esta disciplina. Se considera la gran relevancia del control del consumo energético y de las aplicaciones relacionadas con clasificación y optimización que requieren cantidades ingentes de datos (big data) y tiempos de respuesta difícilmente alcanzables utilizando las técnicas tradicionales de la ingeniería de computadores, y dada la reducción del ritmo que marca la ley de Moore y el final del escalado de Dennard. El artículo proporciona referencias bibliográficas recientes sobre la situación de la ingeniería de computadores, e identifica los nuevos requisitos de las interfaces presentes en la jerarquía de capas propia de los sistemas de cómputo, fundamentalmente los relacionados con la seguridad, el consumo energético, y el aprovechamiento del paralelismo heterogéneo. También se reflexiona sobre los límites teóricos que se pueden establecer para la computación y las expectativas que ofrece la computación cuántica.This paper reviews the state of Computer Engineering at the beginning of the 2020s in order to outline some of the changes that should be established in higher education in this discipline. It is considered the great relevance of controlling energy consumption and applications related to classification and optimization that require huge amounts of data (big data) and response times difficult to achieve using traditional techniques of computer engineering, and given the reduction of the improvement rate set by Moore's law and the end of Dennard scaling. The article also provides recent bibliographical references on the situation of Computer Engineering, and identifies the new requirements of the interfaces present in the hierarchy of layers of computer systems, mainly those related to security, energy consumption, and the use of heterogeneous parallelism. It also reflects on the theoretical limits that can be established for computation and the expectations that quantum computation offers.Universidad de Granada: Departamento de Arquitectura y Tecnología de Computadore

Genomic mutation profile in progressive chronic lymphocytic leukemia patients prior to first-line chemoimmunotherapy with FCR and rituximab maintenance (REM)

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment

A bacterial antirepressor with SH3 domain topology mimics operator DNA in sequestering the repressor DNA recognition helix

Direct targeting of critical DNA-binding elements of a repressor by its cognate antirepressor is an effective means to sequester the repressor and remove a transcription initiation block. Structural descriptions for this, though often proposed for bacterial and phage repressor–antirepressor systems, are unavailable. Here, we describe the structural and functional basis of how the Myxococcus xanthus CarS antirepressor recognizes and neutralizes its cognate repressors to turn on a photo-inducible promoter. CarA and CarH repress the carB operon in the dark. CarS, produced in the light, physically interacts with the MerR-type winged-helix DNA-binding domain of these repressors leading to activation of carB. The NMR structure of CarS1, a functional CarS variant, reveals a five-stranded, antiparallel β-sheet fold resembling SH3 domains, protein–protein interaction modules prevalent in eukaryotes but rare in prokaryotes. NMR studies and analysis of site-directed mutants in vivo and in vitro unveil a solvent-exposed hydrophobic pocket lined by acidic residues in CarS, where the CarA DNA recognition helix docks with high affinity in an atypical ligand-recognition mode for SH3 domains. Our findings uncover an unprecedented use of the SH3 domain-like fold for protein–protein recognition whereby an antirepressor mimics operator DNA in sequestering the repressor DNA recognition helix to activate transcription

Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVE: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare