Documentos para la historia de Ronda, Marbella y Gaucín en el archivo parroquial de San Vicente Mártir de Tocina (Sevilla). 1496-1504

En este breve trabajo se editan cinco documentos que se custodian en el Archivo Parroquial de Tocina, antigua encomienda de la Orden de Malta, y en el archivo particular de Julio Liñán Naranjo (Tocina – Sevilla). Se trata de documentos emitidos por las cancillerías del príncipe Juan, de los Reyes Católicos y del rey Carlos I. Es posible que formaran parte de un juicio de residencia a Ruy Gutiérrez de Escalante, corregidor de Ronda, Marbella y Gaucín, quien mandó cortar las orejas a Diego Sánchez, vecino de Málaga, por una deuda contra Juan de Sevilla, carnicero.In this paper five documents are edited. These documents are to be found in the Parish Records of Tocina, a former encomienda of the Order of Malta, and in the private archive of Julián Liñán Naranjo in Tocina. The documents were issued by the chancelleries of Prince Juan, the Catholic Kings, Fernando and Isabel, and King Carlos I. It is possible that they formed part of an action taken against Ruy Gutiérrez de Escalante, corregidor of Ronda, Marbella and Gaucín, who ordered that Diego Sánchez, who lived in Málaga, should have his ears cut off because of a debt he had incurred with Juan de Sevilla, a butcher

Transcription Factor Activity Inference in Systemic Lupus Erythematosus

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE. Methods: In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples. Results: TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets—one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE. Conclusions: These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets.Innovative Medicines Initiative 2 Joint Undertaking (JU) - 831434 (3TR)European Union’s Horizon 2020 research and innovation program and EFPIANIH AR69572 and NIH RO-1 grant AR06957

Differential Treatments Based on Drug-induced Gene Expression Signatures and Longitudinal Systemic Lupus Erythematosus Stratification

Daniel Toro is at present supported by structural funds to MEAR from the Fundación Pública Andaluza Progreso y Salud of the Junta de AndalucíaSupplementary information is available for this paper at https://doi.org/10.1038/s41598-019-51616-9.Systemic lupus erythematosus (SLE) is a heterogeneous disease with unpredictable patterns of activity. Patients with similar activity levels may have different prognosis and molecular abnormalities. In this study, we aimed to measure the main differences in drug-induced gene expression signatures across SLE patients and to evaluate the potential for clinical data to build a machine learning classifier able to predict the SLE subset for individual patients. SLE transcriptomic data from two cohorts were compared with drug-induced gene signatures from the CLUE database to compute a connectivity score that reflects the capability of a drug to revert the patient signatures. Patient stratification based on drug connectivity scores revealed robust clusters of SLE patients identical to the clusters previously obtained through longitudinal gene expression data, implying that differential treatment depends on the cluster to which patients belongs. The best drug candidates found, mTOR inhibitors or those reducing oxidative stress, showed stronger cluster specificity. We report that drug patterns for reverting disease gene expression follow the cell-specificity of the disease clusters. We used 2 cohorts to train and test a logistic regression model that we employed to classify patients from 3 independent cohorts into the SLE subsets and provide a clinically useful model to predict subset assignment and drug efficacy.This work has been partially supported by Junta de Andalucía through grant PI-0173–2017. The Hopkins Lupus Cohort is supported by NIH AR RO1069572

A one-transistor-synapse strategy for electrically-programmable massively-parallel analog array processors

This paper presents a linear, four-quadrants, electrically-programmable, one-transistor synapse strategy applicable to the implementation of general massively-parallel analog processors in CMOS technology. It is specially suited for translationally-invariant processing arrays with local connectivity, and results in a significant reduction in area occupation and power dissipation of the basic processing units. This allows higher integration densities and therefore, permits the integration of larger arrays on a single chip.Comisión Interministerial de Ciencia y Tecnología TIC96- 1392-C02-0

CMOS optical-sensor array with high output current levels and automatic signal-range centring

A CMOS compatible photosensor with high output current levels, and an area-efficient scheme for automatic signal-range centring according to illumination conditions are presented. The high output current levels allow the use of these devices in continuoustime asynchronous imagers, as well as in high-sampling-frequency applications

Robust symmetric multiplication for programmable analog VLSI array processing

This paper presents an electrically programmable analog multiplier. The circuit performs the multiplication between an input variable and an electrically selectable scaling factor. The multiplier is divided in several blocks: a linearized transconductor, binary weighted current mirrors and a differential to single-ended current adder. This paper shows the advantages introduced using a linearized OTA-based multiplier. The circuit presented renders higher linearity and symmetry in the output current than a previously reported single-transistor multiplier. Its inclusion in an array processor based on CNN allows for a more accurate implementation of the processing model and a more robust weight distribution scheme than those found in previous designs.Office of Naval Research (USA) N-00014- 02-1-0884Ministerio de Ciencia y Tecnología TIC2003-09817-C02-0

Weight-control strategy for programmable CNN chips

This paper describes a hybrid weight-control strategy for the VLSI realization of programmable CNNs, based on automatic adaptation of analog control signals to levels specified by digital words. This approach merges the advantages of digital and analog programmability, achieving low areas and reduced number of control lines, simplifying the control and storage of the weight values, and eliminating their dependency on global process-parameter variations

Hybrid-control of synapse circuits for programmable cellular neural networks

This paper describes a hybrid weight-control strategy for VLSI realizations of programmable Cellular Neural Networks (CNNs), based on auto-tuning of analog control signals to digitally specified values. The approach merges the advantages of digital and analog programmability, achieving low areas and reduced number of control lines, simplifying the control and storage of weight values, and eliminating their dependency on global process-parameter variations

Four-quadrant one-transistor-synapse for high-density CNN implementations

Presents a linear four-quadrants, electrically-programmable, one-transistor synapse strategy applicable to the implementation of general massively-parallel analog processors in CMOS technology. It is specially suited for translationally-invariant processing arrays with local connectivity, and results in a significant reduction in area occupation and power dissipation of the basic processing units. This allows higher integration densities and therefore, permits the integration of larger arrays on a single chip.Comisión Interministerial de Ciencia y Tecnología TIC96-1392-C02-0

A Focal-Plane Image Processor for Low Power Adaptive Capture and Analysis of the Visual Stimulus

Portable applications of artificial vision are limited by the fact that conventional processing schemes fail to meet the specifications under a tight power budget. A bio-inspired approach, based in the goal-directed organization of sensory organs found in nature, has been employed to implement a focal-plane image processor for low power vision applications. The prototype contains a multi-layered CNN structure concurrent with 32times32 photosensors with locally programmable integration time for adaptive image capture with on-chip local and global adaptation mechanisms. A more robust and linear multiplier block has been employed to reduce irregular analog wave propagation ought to asymmetric synapses. The predicted computing power per power consumption, 142MOPS/mW, is orders of magnitude above what rendered by conventional architectures