Sistema de control borroso en lazo cerrado para terapias con insulina en diabetes tipo I

La diabetes mellitus es un trastorno del metabolismo de los carbohidratos producido por la insuficiente o nula producción de insulina o la reducida sensibilidad a esta hormona. Es una enfermedad crónica con una mayor prevalencia en los países desarrollados debido principalmente a la obesidad, la vida sedentaria y disfunciones en el sistema endocrino relacionado con el páncreas. La diabetes Tipo 1 es una enfermedad autoinmune en la que son destruidas las células beta del páncreas, que producen la insulina, y es necesaria la administración de insulina exógena. Un enfermo de diabetes Tipo 1 debe seguir una terapia con insulina administrada por la vía subcutánea que debe estar adaptada a sus necesidades metabólicas y a sus hábitos de vida, esta terapia intenta imitar el perfil insulínico de un páncreas no patológico. La tecnología actual permite abordar el desarrollo del denominado “páncreas endocrino artificial”, que aportaría precisión, eficacia y seguridad para los pacientes, en cuanto a la normalización del control glucémico y reducción del riesgo de hipoglucemias. Permitiría que el paciente no estuviera tan pendiente de su enfermedad. El páncreas artificial consta de un sensor continuo de glucosa, una bomba de infusión de insulina y un algoritmo de control, que calcula la insulina a infusionar usando la glucosa como información principal. Este trabajo presenta un método de control en lazo semi-cerrado mediante un sistema borroso experto basado en reglas. La regulación borrosa se fundamenta en la ambigüedad del lenguaje del ser humano. Esta incertidumbre sirve para la formación de una serie de reglas que representan el pensamiento humano, pero a la vez es el sistema que controla un proceso, en este caso el sistema glucorregulatorio. Este proyecto está enfocado en el diseño de un controlador borroso que haciendo uso de variables como la glucosa, insulina y dieta, sea capaz de restaurar la función endocrina del páncreas de forma tecnológica. La validación del algoritmo se ha realizado principalmente mediante experimentos en simulación utilizando una población de pacientes sintéticos, evaluando los resultados con estadísticos de primer orden y algunos más específicos como el índice de riesgo de Kovatchev, para después comparar estos resultados con los obtenidos por otros métodos de control anteriores. Los resultados demuestran que el control borroso (FBPC) mejora el control glucémico con respecto a un sistema predictivo experto basado en reglas booleanas (pBRES). El FBPC consigue reducir siempre la glucosa máxima y aumentar la mínima respecto del pBRES pero es en terapias desajustadas, donde el FBPC es especialmente robusto, hace descender la glucosa máxima 8,64 mg/dl, el uso de insulina es 3,92 UI menor, aumenta la glucosa mínima 3,32 mg/dl y lleva al rango de glucosa 80 – 110 mg/dl 15,33 muestras más. Por lo tanto se puede concluir que el FBPC realiza un mejor control glucémico que el controlador pBRES haciéndole especialmente efectivo, robusto y seguro en condiciones de desajustes de terapia basal y con gran capacidad de mejora futura. SUMMARY The diabetes mellitus is a metabolic disorder caused by a poor or null insulin secretion or a reduced sensibility to insulin. Diabetes is a chronic disease with a higher prevalence in the industrialized countries, mainly due to obesity, the sedentary life and endocrine disfunctions connected with the pancreas. Type 1 diabetes is a self-immune disease where the beta cells of the pancreas, which are the responsible of secreting insulin, are damaged. Hence, it is necessary an exogenous delivery of insulin. The Type 1 diabetic patient has to follow a therapy with subcutaneous insulin administration which should be adjusted to his/her metabolic needs and life style. This therapy tries to mimic the insulin profile of a non-pathological pancreas. Current technology lets the development of the so-called endocrine artificial pancreas that would provide accuracy, efficiency and safety to patients, in regards to the glycemic control normalization and reduction of the risk of hypoglycemic. In addition, it would help the patient not to be so concerned about his disease. The artificial pancreas has a continuous glucose sensor, an insulin infusion pump and a control algorithm, that calculates the insulin infusion using the glucose as main information. This project presents a method of control in semi-closed-loop, through an expert fuzzy system based on rules. The fuzzy regulation is based on the human language ambiguity. This uncertainty serves for construction of some rules that represent the human language besides it is the system that controls a process, in this case the glucoregulatory system. This project is focus on the design of a fuzzy controller that, using variables like glucose insulin and diet, will be able to restore the pancreas endocrine function with technology. The algorithm assessment has mainly been done through experiments in simulation using a population of synthetic patients, evaluating the results with first order statistical parameters and some other more specific such as the Kovatchev risk index, to compare later these results with the ones obtained in others previous methods of control. The results demonstrate that the fuzzy control (FBPC) improves the glycemic control connected with a predictive expert system based on Booleans rules (pBRES). The FBPC is always able to reduce the maximum level of glucose and increase the minimum level as compared with pBRES but it is in unadjusted therapies where FBPC is especially strong, it manages to decrease the maximum level of glucose and insulin used by 8,64 mg/dl and 3,92 UI respectively, also increases the value of minimum glucose by 3,32 mg/dl, getting 15,33 samples more inside the 80-110 mg/dl glucose rank. Therefore we can conclude that FBPC achieves a better glycemic control than the controller pBRES doing it especially effective, robust and safe in conditions of mismatch basal therapy and with a great capacity for future improvements.

Aerial video geo-registration using terrain models from dense and coherent stereo matching

In the context of aerial imagery, one of the first steps toward a coherent processing of the information contained in multiple images is geo-registration, which consists in assigning geographic 3D coordinates to the pixels of the image. This enables accurate alignment and geo-positioning of multiple images, detection of moving objects and fusion of data acquired from multiple sensors. To solve this problem there are different approaches that require, in addition to a precise characterization of the camera sensor, high resolution referenced images or terrain elevation models, which are usually not publicly available or out of date. Building upon the idea of developing technology that does not need a reference terrain elevation model, we propose a geo-registration technique that applies variational methods to obtain a dense and coherent surface elevation model that is used to replace the reference model. The surface elevation model is built by interpolation of scattered 3D points, which are obtained in a two-step process following a classical stereo pipeline: first, coherent disparity maps between image pairs of a video sequence are estimated and then image point correspondences are back-projected. The proposed variational method enforces continuity of the disparity map not only along epipolar lines (as done by previous geo-registration techniques) but also across them, in the full 2D image domain. In the experiments, aerial images from synthetic video sequences have been used to validate the proposed technique.

Numerical simulation of a synthetic jet with OpenFoam

Numerical simulations of flow surrounding a synthetic jet actuating device are presented. By modifying a dynamic mesh technique available in OpenFoam-a well-documented open-source solver for fluid dynamics, detailed computations of the sinusoidal motion of the synthetic jet diaphragm were possible. Numerical solutions were obtained by solving the two dimensional incompressible viscous N-S equations, with the use of a second order implicit time marching scheme and a central finite volume method for spatial discretization in both streamwise and crossflow directions. A systematic parametric study is reported here, in which the external Reynolds number, the diaphragm amplitude and frequency, and the slot dimensions are varied.

Vision-Based Tracking, Odometry and Control for UAV Autonomy

El principal objetivo de este trabajo es proporcionar una solución en tiempo real basada en visión estéreo o monocular precisa y robusta para que un vehículo aéreo no tripulado (UAV) sea autónomo en varios tipos de aplicaciones UAV, especialmente en entornos abarrotados sin señal GPS. Este trabajo principalmente consiste en tres temas de investigación de UAV basados en técnicas de visión por computador: (I) visual tracking, proporciona soluciones efectivas para localizar visualmente objetos de interés estáticos o en movimiento durante el tiempo que dura el vuelo del UAV mediante una aproximación adaptativa online y una estrategia de múltiple resolución, de este modo superamos los problemas generados por las diferentes situaciones desafiantes, tales como cambios significativos de aspecto, iluminación del entorno variante, fondo del tracking embarullado, oclusión parcial o total de objetos, variaciones rápidas de posición y vibraciones mecánicas a bordo. La solución ha sido utilizada en aterrizajes autónomos, inspección de plataformas mar adentro o tracking de aviones en pleno vuelo para su detección y evasión; (II) odometría visual: proporciona una solución eficiente al UAV para estimar la posición con 6 grados de libertad (6D) usando únicamente la entrada de una cámara estéreo a bordo del UAV. Un método Semi-Global Blocking Matching (SGBM) eficiente basado en una estrategia grueso-a-fino ha sido implementada para una rápida y profunda estimación del plano. Además, la solución toma provecho eficazmente de la información 2D y 3D para estimar la posición 6D, resolviendo de esta manera la limitación de un punto de referencia fijo en la cámara estéreo. Una robusta aproximación volumétrica de mapping basada en el framework Octomap ha sido utilizada para reconstruir entornos cerrados y al aire libre bastante abarrotados en 3D con memoria y errores correlacionados espacialmente o temporalmente; (III) visual control, ofrece soluciones de control prácticas para la navegación de un UAV usando Fuzzy Logic Controller (FLC) con la estimación visual. Y el framework de Cross-Entropy Optimization (CEO) ha sido usado para optimizar el factor de escala y la función de pertenencia en FLC. Todas las soluciones basadas en visión en este trabajo han sido probadas en test reales. Y los conjuntos de datos de imágenes reales grabados en estos test o disponibles para la comunidad pública han sido utilizados para evaluar el rendimiento de estas soluciones basadas en visión con ground truth. Además, las soluciones de visión presentadas han sido comparadas con algoritmos de visión del estado del arte. Los test reales y los resultados de evaluación muestran que las soluciones basadas en visión proporcionadas han obtenido rendimientos en tiempo real precisos y robustos, o han alcanzado un mejor rendimiento que aquellos algoritmos del estado del arte. La estimación basada en visión ha ganado un rol muy importante en controlar un UAV típico para alcanzar autonomía en aplicaciones UAV. ABSTRACT The main objective of this dissertation is providing real-time accurate robust monocular or stereo vision-based solution for Unmanned Aerial Vehicle (UAV) to achieve the autonomy in various types of UAV applications, especially in GPS-denied dynamic cluttered environments. This dissertation mainly consists of three UAV research topics based on computer vision technique: (I) visual tracking, it supplys effective solutions to visually locate interesting static or moving object over time during UAV flight with on-line adaptivity approach and multiple-resolution strategy, thereby overcoming the problems generated by the different challenging situations, such as significant appearance change, variant surrounding illumination, cluttered tracking background, partial or full object occlusion, rapid pose variation and onboard mechanical vibration. The solutions have been utilized in autonomous landing, offshore floating platform inspection and midair aircraft tracking for sense-and-avoid; (II) visual odometry: it provides the efficient solution for UAV to estimate the 6 Degree-of-freedom (6D) pose using only the input of stereo camera onboard UAV. An efficient Semi-Global Blocking Matching (SGBM) method based on a coarse-to-fine strategy has been implemented for fast depth map estimation. In addition, the solution effectively takes advantage of both 2D and 3D information to estimate the 6D pose, thereby solving the limitation of a fixed small baseline in the stereo camera. A robust volumetric occupancy mapping approach based on the Octomap framework has been utilized to reconstruct indoor and outdoor large-scale cluttered environments in 3D with less temporally or spatially correlated measurement errors and memory; (III) visual control, it offers practical control solutions to navigate UAV using Fuzzy Logic Controller (FLC) with the visual estimation. And the Cross-Entropy Optimization (CEO) framework has been used to optimize the scaling factor and the membership function in FLC. All the vision-based solutions in this dissertation have been tested in real tests. And the real image datasets recorded from these tests or available from public community have been utilized to evaluate the performance of these vision-based solutions with ground truth. Additionally, the presented vision solutions have compared with the state-of-art visual algorithms. Real tests and evaluation results show that the provided vision-based solutions have obtained real-time accurate robust performances, or gained better performance than those state-of-art visual algorithms. The vision-based estimation has played a critically important role for controlling a typical UAV to achieve autonomy in the UAV application.

DRC1, DNA replication and checkpoint protein 1, functions with DPB11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae

In addition to DNA polymerase complexes, DNA replication requires the coordinate action of a series of proteins, including regulators Cdc28/Clb and Dbf4/Cdc7 kinases, Orcs, Mcms, Cdc6, Cdc45, and Dpb11. Of these, Dpb11, an essential BRCT repeat protein, has remained particularly enigmatic. The Schizosaccharomyces pombe homolog of DPB11, cut5, has been implicated in the DNA replication checkpoint as has the POL2 gene with which DPB11 genetically interacts. Here we describe a gene, DRC1, isolated as a dosage suppressor of dpb11–1. DRC1 is an essential cell cycle-regulated gene required for DNA replication. We show that both Dpb11 and Drc1 are required for the S-phase checkpoint, including the proper activation of the Rad53 kinase in response to DNA damage and replication blocks. Dpb11 is the second BRCT-repeat protein shown to control Rad53 function, possibly indicating a general function for this class of proteins. DRC1 and DPB11 show synthetic lethality and reciprocal dosage suppression. The Drc1 and Dpb11 proteins physically associate and function together to coordinate DNA replication and the cell cycle.

The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1

The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with Ki = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8–170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

A versatile synthetic dimerizer for the regulation of protein–protein interactions

The use of low molecular weight organic compounds to induce dimerization or oligomerization of engineered proteins has wide-ranging utility in biological research as well as in gene and cell therapies. Chemically induced dimerization can be used to activate intracellular signal transduction pathways or to control the activity of a bipartite transcription factor. Dimerizer systems based on the natural products cyclosporin, FK506, rapamycin, and coumermycin have been described. However, owing to the complexity of these compounds, adjusting their binding or pharmacological properties by chemical modification is difficult. We have investigated several families of readily prepared, totally synthetic, cell-permeable dimerizers composed of ligands for human FKBP12. These molecules have significantly reduced complexity and greater adaptability than natural product dimers. We report here the efficacies of several of these new synthetic compounds in regulating two types of protein dimerization events inside engineered cells—–induction of apoptosis through dimerization of engineered Fas proteins and regulation of transcription through dimerization of transcription factor fusion proteins. One dimerizer in particular, AP1510, proved to be exceptionally potent and versatile in all experimental contexts tested.

Comparative analyses of the secondary structures of synthetic and intracellular yeast MFA2 mRNAs

The overall folded (global) structure of mRNA may be critical to translation and turnover control mechanisms, but it has received little experimental attention. Presented here is a comparative analysis of the basic features of the global secondary structure of a synthetic mRNA and the same intracellular eukaryotic mRNA by dimethyl sulfate (DMS) structure probing. Synthetic MFA2 mRNA of Saccharomyces cerevisiae first was examined by using both enzymes and chemical reagents to determine single-stranded and hybridized regions; RNAs with and without a poly(A) tail were compared. A folding pattern was obtained with the aid of the mfold program package that identified the model that best satisfied the probing data. A long-range structural interaction involving the 5′ and 3′ untranslated regions and causing a juxtaposition of the ends of the RNA, was examined further by a useful technique involving oligo(dT)-cellulose chromatography and antisense oligonucleotides. DMS chemical probing of A and C nucleotides of intracellular MFA2 mRNA was then done. The modification data support a very similar intracellular structure. When low reactivity of A and C residues is found in the synthetic RNA, ≈70% of the same sites are relatively more resistant to DMS modification in vivo. A slightly higher sensitivity to DMS is found in vivo for some of the A and C nucleotides predicted to be hybridized from the synthetic structural model. With this small mRNA, the translation process and mRNA-binding proteins do not block DMS modifications, and all A and C nucleotides are modified the same or more strongly than with the synthetic RNA.

Structure and function in rhodopsin: high level expression of a synthetic bovine opsin gene and its mutants in stable mammalian cell lines.

Stable mammalian cell lines harboring a synthetic bovine opsin gene have been derived from the suspension-adapted HEK293 cell line. The opsin gene is under the control of the immediate-early cytomegalovirus promoter/enhancer in an expression vector that also contains a selectable marker (Neo) governed by a relatively weak promoter. The cell lines expressing the opsin gene at high levels are selected by growth in the presence of high concentrations of the antibiotic geneticin. Under the conditions used for cell growth in suspension, opsin is produced at saturated culture levels of more than 2 mg/liter. After reconstitution with 11-cis-retinal, rhodopsin is purified to homogeneity in a single step by immunoaffinity column chromatography. Rhodopsin thus prepared (> 90% recovery at concentrations of up to 15 microM) is indistinguishable from rhodopsin purified from bovine rod outer segments by the following criteria: (i) UV/Vis absorption spectra in the dark and after photobleaching and the rate of metarhodopsin II decay, (ii) initial rates of transducin activation, and (iii) the rate of phosphorylation by rhodopsin kinase. Although mammalian cell opsin migrates slower than rod outer segment opsin on SDS/polyacrylamide gels, presumably due to a different N-glycosylation pattern, their mobilities after deglycosylation are identical. This method has enabled the preparation of several site-specific mutants of bovine opsin in comparable amounts.

A synthetic random basic copolymer with promiscuous binding to class II major histocompatibility complex molecules inhibits T-cell proliferative responses to major and minor histocompatibility antigens in vitro and confers the capacity to prevent murine graft-versus-host disease in vivo.

Graft-versus-host disease (GVHD) is a T-cell-mediated disease of transplanted donor T cells recognizing host alloantigens. Data presented in this report show, to our knowledge, for the first time that a synthetic copolymer of the amino acids L-Glu, L-Lys, L-Ala, and L-Tyr (molecular ratio, 1.9:6.0:4.7:1.0; Mr, 6000-8500) [corrected], termed GLAT, with promiscuous binding to multiple major histocompatibility complex class II alleles is capable of preventing lethal GVHD in the B10.D2 --> BALB/c model (both H-2d) across minor histocompatibility barriers. Administration of GLAT over a limited time after transplant significantly reduced the incidence, onset, and severity of disease. GLAT also improved long-term survival from lethal GVHD: 14/25 (56%) of experimental mice survived > 140 days after transplant compared to 2/26 of saline-treated or to 1/10 of hen egg lysozyme-treated control mice (P < 0.01). Long-term survivors were documented to be fully chimeric by PCR analysis of a polymorphic microsatellite region in the interleukin 1beta gene. In vitro, GLAT inhibited the mixed lymphocyte culture in a dose-dependent fashion across a variety of major barriers tested. Furthermore, GLAT inhibited the response of nylon wool-enriched T cells to syngeneic antigen-presenting cells presenting minor histocompatibility antigens. Prepulsing of the antigen-presenting cells with GLAT reduced the proliferative response, suggesting that GLAT inhibits antigen presentation.

Induction of intracellular cAMP by a synthetic retroviral envelope peptide: a possible mechanism of immunopathogenesis in retroviral infections.

A synthetic heptadecapeptide, CKS-17, represents the highly conserved amino acid sequences occurring within the transmembrane envelope protein of many animal and human retroviruses. CKS-17 has been demonstrated to exhibit suppressive properties for numerous immune functions. We have recently shown that CKS-17 acts as an immunomodulatory epitope causing an imbalance of human type 1 and type 2 cytokine production and suppression of cell-mediated immunities. cAMP, an intracellular second messenger, plays an important role in regulation of cytokine biosynthesis--i.e., elevation of intracellular cAMP levels selectively inhibits type 1 cytokine production but has no effect or enhances type 2 cytokine production. Here, we demonstrate that CKS-17 induces dramatic rises in the intracellular cAMP levels of a human monocyte cell line and of human peripheral blood mononuclear cells in a time- and dose-dependent manner. A peptide corresponding to the reverse sequence of CKS-17, used as control, has no effect on intracellular cAMP levels. The cAMP-inducing ability of CKS-17 is significantly blocked by SQ-22536, an inhibitor of adenylate cyclase. These results indicate that CKS-17, a highly conserved component of the transmembrane proteins of immunosuppressive retroviruses, induces increased intracellular levels of cAMP via activation of adenylate cyclase and suggest that this retroviral envelope peptide may differentially modulate type 1 and type 2 cytokine production through elevation of intracellular cAMP levels.

Differential modulation of Th1- and Th2-related cytokine mRNA expression by a synthetic peptide homologous to a conserved domain within retroviral envelope protein.

The influence of a synthetic retroviral peptide, CKS-17, on T helper type 1 (Th1)- or Th2-related cytokines was investigated in human blood mononuclear cells. Cells were stimulated with staphylococcal enterotoxin A, anti-CD3 plus anti-CD28 monoclonal antibodies, or lipopolysaccharide to induce cytokine mRNA. mRNA was detected by a reverse transcription-polymerase chain reaction or Northern blot analysis. CKS-17 down-regulated stimulant-induced mRNA accumulation for interferon gamma (IFN-gamma), interleukin (IL)-2, and p40 heavy and p35 light chains of IL-12, a cytokine that mediates development of Th1 response. CKS-17 up-regulated stimulant-induced mRNA accumulation of IL-10 and did not suppress Th2-related cytokine (IL-4, IL-5, IL-6, or IL-13) mRNA expression. A reverse sequence of CKS-17 peptide, used as a control, showed no such action. Anti-human IL-10 monoclonal antibody blocked ability of CKS-17 to inhibit mRNA accumulation for IFN-gamma but not the CKS-17 suppressive activity of IL-12 p40 heavy chain mRNA. Thus, CKS-17-mediated suppression of IFN-gamma mRNA expression is dependent upon augmentation of IL-10 production by CKS-17. This conserved component of several retroviral envelope proteins, CKS-17, may act as an immunomodulatory epitope responsible for cytokine dysregulation that leads to suppression of cellular immunity.

A Performance Evaluation of Surface Normals-Based Descriptors for Recognition of Objects using CAD-Models

This paper describes a study and analysis of surface normal-base descriptors for 3D object recognition. Specifically, we evaluate the behaviour of descriptors in the recognition process using virtual models of objects created from CAD software. Later, we test them in real scenes using synthetic objects created with a 3D printer from the virtual models. In both cases, the same virtual models are used on the matching process to find similarity. The difference between both experiments is in the type of views used in the tests. Our analysis evaluates three subjects: the effectiveness of 3D descriptors depending on the viewpoint of camera, the geometry complexity of the model and the runtime used to do the recognition process and the success rate to recognize a view of object among the models saved in the database.

DES exposure in utero : vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones.

Mode of access: Internet.

Bibliography on synthetic detergents in water and wastes, including analytical methods and physiological effects

Mode of access: Internet.