IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions

The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.

Past and future evolution of Abies alba forests in Europe - comparison of a dynamic vegetation model with palaeo data and observations

Information on how species distributions and ecosystem services are impacted by anthropogenic climate change is important for adaptation planning. Palaeo data suggest that Abies alba formed forests under significantly warmer-than-present conditions in Europe and might be a native substitute for widespread drought-sensitive temperate and boreal tree species such as beech (Fagus sylvatica) and spruce (Picea abies) under future global warming conditions. Here, we combine pollen and macrofossil data, modern observations, and results from transient simulations with the LPX-Bern dynamic global vegetation model to assess past and future distributions of A. alba in Europe. LPX-Bern is forced with climate anomalies from a run over the past 21 000 years with the Community Earth System Model, modern climatology, and with 21st-century multimodel ensemble results for the high-emission RCP8.5 and the stringent mitigation RCP2.6 pathway. The simulated distribution for present climate encompasses the modern range of A. alba, with the model exceeding the present distribution in north-western and southern Europe. Mid-Holocene pollen data and model results agree for southern Europe, suggesting that at present, human impacts suppress the distribution in southern Europe. Pollen and model results both show range expansion starting during the Bølling–Allerød warm period, interrupted by the Younger Dryas cold, and resuming during the Holocene. The distribution of A. alba expands to the north-east in all future scenarios, whereas the potential (currently unrealized) range would be substantially reduced in southern Europe under RCP8.5. A. alba maintains its current range in central Europe despite competition by other thermophilous tree species. Our combined palaeoecological and model evidence suggest that A. alba may ensure important ecosystem services including stand and slope stability, infrastructure protection, and carbon sequestration under significantly warmer-than-present conditions in central Europe.

Data from PhD thesis

The ocean quahog, Arctica islandica is the longest-lived non-colonial animal known to science. A maximum individual age of this bivalve of 405 years has been found in a population off the north western coast of Iceland. Conspicuously shorter maximum lifespan potentials (MLSPs) were recorded from other populations of A. islandica in European waters (e.g. Kiel Bay: 30 years, German Bight: 150 years) which experience wider temperature and salinity fluctuations than the clams from Iceland. The aim of my thesis was to identify possible life-prolonging physiological strategies in A. islandica and to examine the modulating effects of extrinsic factors (e.g. seawater temperature, food availability) and intrinsic factors (e.g. species-specific behavior) on these strategies. Burrowing behavior and metabolic rate depression (MRD), tissue-specific antioxidant and anaerobic capacities as well as cell-turnover (= apoptosis and proliferation) rates were investigated in A. islandica from Iceland and the German Bight. An inter-species comparison of the quahog with the epibenthic scallop Aequipecten opercularis (MLSP = 8-10 years) was carried out in order to determine whether bivalves with short lifespans and different lifestyles also feature a different pattern in cellular maintenance and repair. The combined effects of a low-metabolic lifestyle, low oxidative damage accumulation, and constant investment into cellular protection and tissue maintenance, appear to slow-down the process of physiological aging in A. islandica and to afford the extraordinarily long MLSP in this species. Standard metabolic rates were lower in A. islandica when compared to the shorter-lived A. opercularis. Furthermore, A. islandica regulate mantle cavity water PO2 to mean values < 5 kPa, a PO2 at which the formation of reactive oxygen species (ROS) in isolated gill tissues of the clams was found to be 10 times lower than at normoxic conditions (21 kPa). Burrowing and metabolic rate depression (MRD) in Icelandic specimens were more pronounced in winter, possibly supported by low seawater temperature and food availability, and seem to be key energy-saving and life-prolonging parameters in A. islandica. The signaling molecule nitric oxide (NO) may play an important role during the onset of MRD in the ocean quahog by directly inhibiting cytochome-c-oxidase at low internal oxygenation upon shell closure. In laboratory experiments, respiration of isolated A. islandica gills was completely inhibited by chemically produced NO at low experimental PO2 <= 10 kPa. During shell closure, mantle cavity water PO2 decreased to 0 kPa for longer than 24 h, a state in which ROS production is supposed to subside. Compared to other mollusk species, onset of anaerobic metabolism is late in A. islandica in the metabolically reduced state. Increased accumulation of the anaerobic metabolite succinate was initially detected in the adductor muscle of the clams after 3.5 days under anoxic incubation or in burrowed specimens. A ROS-burst was absent in isolated gill tissue of the clams following hypoxia (5 kPa)-reoxygenation (21 kPa). Accordingly, neither the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), nor the specific content of the ROS-scavenger glutathione (GSH) was enhanced in different tissues of the ocean quahog after 3.5 days of self-induced or forced hypoxia/anoxia to prepare for an oxidative burst. While reduced ROS formation compared to routine levels lowers oxidative stress during MRD and also during surfacing, the general preservation of high cellular defense and the efficient removal and replacement of damaged cells over lifetime seem to be of crucial importance in decelerating the senescent decline in tissues of A. islandica. Along with stable antioxidant protection over 200 years of age, proliferation rates and apoptosis intensities in most investigated tissues of the ocean quahog were low, but constant over 140 years of age. Accordingly, age-dependent accumulations of protein and lipid oxidation products are lower in A. islandica tissues when compared to the shorter-lived bivalve A. opercularis. The short-lived swimming scallop is a model bivalve species representing the opposite life and aging strategy to A. islandica. In this species permanently high energy throughput, reduced investment into antioxidant defense with age, and higher accumulation of oxidation products are met by higher cell turnover rates than in the ocean quahog. The only symptoms of physiological change over age ever found in A. islandica were decreasing cell turnover rates in the heart muscle over a lifetime of 140 years. This may either indicate higher damage levels and possibly ongoing loss of functioning in the heart of aging clams, or, the opposite, lower rates of cell damage and a reduced need for cell renewal in the heart tissue of A. islandica over lifetime. Basic physiological capacities of different A. islandica populations, measured at controlled laboratory conditions, could not explain considerable discrepancies in population specific MLSPs. For example, levels of tissue-specific antioxidant capacities and cell turnover rates were similarly high in individuals from the German Bight and from Iceland. Rather than genetic differences, the local impacts of environmental conditions on behavioral and physiological traits in the ocean quahog seem to be responsible for differences in population-specific MLSPs.

Side-Channel Attack Protection Techniques in FPGA Systems using Enhanced Dual-Rail Solutions

Esta tesis doctoral se centra principalmente en técnicas de ataque y contramedidas relacionadas con ataques de canal lateral (SCA por sus siglas en inglés), que han sido propuestas dentro del campo de investigación académica desde hace 17 años. Las investigaciones relacionadas han experimentado un notable crecimiento en las últimas décadas, mientras que los diseños enfocados en la protección sólida y eficaz contra dichos ataques aún se mantienen como un tema de investigación abierto, en el que se necesitan iniciativas más confiables para la protección de la información persona de empresa y de datos nacionales. El primer uso documentado de codificación secreta se remonta a alrededor de 1700 B.C., cuando los jeroglíficos del antiguo Egipto eran descritos en las inscripciones. La seguridad de la información siempre ha supuesto un factor clave en la transmisión de datos relacionados con inteligencia diplomática o militar. Debido a la evolución rápida de las técnicas modernas de comunicación, soluciones de cifrado se incorporaron por primera vez para garantizar la seguridad, integridad y confidencialidad de los contextos de transmisión a través de cables sin seguridad o medios inalámbricos. Debido a las restricciones de potencia de cálculo antes de la era del ordenador, la técnica de cifrado simple era un método más que suficiente para ocultar la información. Sin embargo, algunas vulnerabilidades algorítmicas pueden ser explotadas para restaurar la regla de codificación sin mucho esfuerzo. Esto ha motivado nuevas investigaciones en el área de la criptografía, con el fin de proteger el sistema de información ante sofisticados algoritmos. Con la invención de los ordenadores se ha acelerado en gran medida la implementación de criptografía segura, que ofrece resistencia eficiente encaminada a obtener mayores capacidades de computación altamente reforzadas. Igualmente, sofisticados cripto-análisis han impulsado las tecnologías de computación. Hoy en día, el mundo de la información ha estado involucrado con el campo de la criptografía, enfocada a proteger cualquier campo a través de diversas soluciones de cifrado. Estos enfoques se han fortalecido debido a la unificación optimizada de teorías matemáticas modernas y prácticas eficaces de hardware, siendo posible su implementación en varias plataformas (microprocesador, ASIC, FPGA, etc.). Las necesidades y requisitos de seguridad en la industria son las principales métricas de conducción en el diseño electrónico, con el objetivo de promover la fabricación de productos de gran alcance sin sacrificar la seguridad de los clientes. Sin embargo, una vulnerabilidad en la implementación práctica encontrada por el Prof. Paul Kocher, et al en 1996 implica que un circuito digital es inherentemente vulnerable a un ataque no convencional, lo cual fue nombrado posteriormente como ataque de canal lateral, debido a su fuente de análisis. Sin embargo, algunas críticas sobre los algoritmos criptográficos teóricamente seguros surgieron casi inmediatamente después de este descubrimiento. En este sentido, los circuitos digitales consisten típicamente en un gran número de celdas lógicas fundamentales (como MOS - Metal Oxide Semiconductor), construido sobre un sustrato de silicio durante la fabricación. La lógica de los circuitos se realiza en función de las innumerables conmutaciones de estas células. Este mecanismo provoca inevitablemente cierta emanación física especial que puede ser medida y correlacionada con el comportamiento interno del circuito. SCA se puede utilizar para revelar datos confidenciales (por ejemplo, la criptografía de claves), analizar la arquitectura lógica, el tiempo e incluso inyectar fallos malintencionados a los circuitos que se implementan en sistemas embebidos, como FPGAs, ASICs, o tarjetas inteligentes. Mediante el uso de la comparación de correlación entre la cantidad de fuga estimada y las fugas medidas de forma real, información confidencial puede ser reconstruida en mucho menos tiempo y computación. Para ser precisos, SCA básicamente cubre una amplia gama de tipos de ataques, como los análisis de consumo de energía y radiación ElectroMagnética (EM). Ambos se basan en análisis estadístico y, por lo tanto, requieren numerosas muestras. Los algoritmos de cifrado no están intrínsecamente preparados para ser resistentes ante SCA. Es por ello que se hace necesario durante la implementación de circuitos integrar medidas que permitan camuflar las fugas a través de "canales laterales". Las medidas contra SCA están evolucionando junto con el desarrollo de nuevas técnicas de ataque, así como la continua mejora de los dispositivos electrónicos. Las características físicas requieren contramedidas sobre la capa física, que generalmente se pueden clasificar en soluciones intrínsecas y extrínsecas. Contramedidas extrínsecas se ejecutan para confundir la fuente de ataque mediante la integración de ruido o mala alineación de la actividad interna. Comparativamente, las contramedidas intrínsecas están integradas en el propio algoritmo, para modificar la aplicación con el fin de minimizar las fugas medibles, o incluso hacer que dichas fugas no puedan ser medibles. Ocultación y Enmascaramiento son dos técnicas típicas incluidas en esta categoría. Concretamente, el enmascaramiento se aplica a nivel algorítmico, para alterar los datos intermedios sensibles con una máscara de manera reversible. A diferencia del enmascaramiento lineal, las operaciones no lineales que ampliamente existen en criptografías modernas son difíciles de enmascarar. Dicho método de ocultación, que ha sido verificado como una solución efectiva, comprende principalmente la codificación en doble carril, que está ideado especialmente para aplanar o eliminar la fuga dependiente de dato en potencia o en EM. En esta tesis doctoral, además de la descripción de las metodologías de ataque, se han dedicado grandes esfuerzos sobre la estructura del prototipo de la lógica propuesta, con el fin de realizar investigaciones enfocadas a la seguridad sobre contramedidas de arquitectura a nivel lógico. Una característica de SCA reside en el formato de las fuentes de fugas. Un típico ataque de canal lateral se refiere al análisis basado en la potencia, donde la capacidad fundamental del transistor MOS y otras capacidades parásitas son las fuentes esenciales de fugas. Por lo tanto, una lógica robusta resistente a SCA debe eliminar o mitigar las fugas de estas micro-unidades, como las puertas lógicas básicas, los puertos I/O y las rutas. Las herramientas EDA proporcionadas por los vendedores manipulan la lógica desde un nivel más alto, en lugar de realizarlo desde el nivel de puerta, donde las fugas de canal lateral se manifiestan. Por lo tanto, las implementaciones clásicas apenas satisfacen estas necesidades e inevitablemente atrofian el prototipo. Por todo ello, la implementación de un esquema de diseño personalizado y flexible ha de ser tomado en cuenta. En esta tesis se presenta el diseño y la implementación de una lógica innovadora para contrarrestar SCA, en la que se abordan 3 aspectos fundamentales: I. Se basa en ocultar la estrategia sobre el circuito en doble carril a nivel de puerta para obtener dinámicamente el equilibrio de las fugas en las capas inferiores; II. Esta lógica explota las características de la arquitectura de las FPGAs, para reducir al mínimo el gasto de recursos en la implementación; III. Se apoya en un conjunto de herramientas asistentes personalizadas, incorporadas al flujo genérico de diseño sobre FPGAs, con el fin de manipular los circuitos de forma automática. El kit de herramientas de diseño automático es compatible con la lógica de doble carril propuesta, para facilitar la aplicación práctica sobre la familia de FPGA del fabricante Xilinx. En este sentido, la metodología y las herramientas son flexibles para ser extendido a una amplia gama de aplicaciones en las que se desean obtener restricciones mucho más rígidas y sofisticadas a nivel de puerta o rutado. En esta tesis se realiza un gran esfuerzo para facilitar el proceso de implementación y reparación de lógica de doble carril genérica. La viabilidad de las soluciones propuestas es validada mediante la selección de algoritmos criptográficos ampliamente utilizados, y su evaluación exhaustiva en comparación con soluciones anteriores. Todas las propuestas están respaldadas eficazmente a través de ataques experimentales con el fin de validar las ventajas de seguridad del sistema. El presente trabajo de investigación tiene la intención de cerrar la brecha entre las barreras de implementación y la aplicación efectiva de lógica de doble carril. En esencia, a lo largo de esta tesis se describirá un conjunto de herramientas de implementación para FPGAs que se han desarrollado para trabajar junto con el flujo de diseño genérico de las mismas, con el fin de lograr crear de forma innovadora la lógica de doble carril. Un nuevo enfoque en el ámbito de la seguridad en el cifrado se propone para obtener personalización, automatización y flexibilidad en el prototipo de circuito de bajo nivel con granularidad fina. Las principales contribuciones del presente trabajo de investigación se resumen brevemente a continuación: Lógica de Precharge Absorbed-DPL logic: El uso de la conversión de netlist para reservar LUTs libres para ejecutar la señal de precharge y Ex en una lógica DPL. Posicionamiento entrelazado Row-crossed con pares idénticos de rutado en redes de doble carril, lo que ayuda a aumentar la resistencia frente a la medición EM selectiva y mitigar los impactos de las variaciones de proceso. Ejecución personalizada y herramientas de conversión automática para la generación de redes idénticas para la lógica de doble carril propuesta. (a) Para detectar y reparar conflictos en las conexiones; (b) Detectar y reparar las rutas asimétricas. (c) Para ser utilizado en otras lógicas donde se requiere un control estricto de las interconexiones en aplicaciones basadas en Xilinx. Plataforma CPA de pruebas personalizadas para el análisis de EM y potencia, incluyendo la construcción de dicha plataforma, el método de medición y análisis de los ataques. Análisis de tiempos para cuantificar los niveles de seguridad. División de Seguridad en la conversión parcial de un sistema de cifrado complejo para reducir los costes de la protección. Prueba de concepto de un sistema de calefacción auto-adaptativo para mitigar los impactos eléctricos debido a la variación del proceso de silicio de manera dinámica. La presente tesis doctoral se encuentra organizada tal y como se detalla a continuación: En el capítulo 1 se abordan los fundamentos de los ataques de canal lateral, que abarca desde conceptos básicos de teoría de modelos de análisis, además de la implementación de la plataforma y la ejecución de los ataques. En el capítulo 2 se incluyen las estrategias de resistencia SCA contra los ataques de potencia diferencial y de EM. Además de ello, en este capítulo se propone una lógica en doble carril compacta y segura como contribución de gran relevancia, así como también se presentará la transformación lógica basada en un diseño a nivel de puerta. Por otra parte, en el Capítulo 3 se abordan los desafíos relacionados con la implementación de lógica en doble carril genérica. Así mismo, se describirá un flujo de diseño personalizado para resolver los problemas de aplicación junto con una herramienta de desarrollo automático de aplicaciones propuesta, para mitigar las barreras de diseño y facilitar los procesos. En el capítulo 4 se describe de forma detallada la elaboración e implementación de las herramientas propuestas. Por otra parte, la verificación y validaciones de seguridad de la lógica propuesta, así como un sofisticado experimento de verificación de la seguridad del rutado, se describen en el capítulo 5. Por último, un resumen de las conclusiones de la tesis y las perspectivas como líneas futuras se incluyen en el capítulo 6. Con el fin de profundizar en el contenido de la tesis doctoral, cada capítulo se describe de forma más detallada a continuación: En el capítulo 1 se introduce plataforma de implementación hardware además las teorías básicas de ataque de canal lateral, y contiene principalmente: (a) La arquitectura genérica y las características de la FPGA a utilizar, en particular la Xilinx Virtex-5; (b) El algoritmo de cifrado seleccionado (un módulo comercial Advanced Encryption Standard (AES)); (c) Los elementos esenciales de los métodos de canal lateral, que permiten revelar las fugas de disipación correlacionadas con los comportamientos internos; y el método para recuperar esta relación entre las fluctuaciones físicas en los rastros de canal lateral y los datos internos procesados; (d) Las configuraciones de las plataformas de pruebas de potencia / EM abarcadas dentro de la presente tesis. El contenido de esta tesis se amplia y profundiza a partir del capítulo 2, en el cual se abordan varios aspectos claves. En primer lugar, el principio de protección de la compensación dinámica de la lógica genérica de precarga de doble carril (Dual-rail Precharge Logic-DPL) se explica mediante la descripción de los elementos compensados a nivel de puerta. En segundo lugar, la lógica PA-DPL es propuesta como aportación original, detallando el protocolo de la lógica y un caso de aplicación. En tercer lugar, dos flujos de diseño personalizados se muestran para realizar la conversión de doble carril. Junto con ello, se aclaran las definiciones técnicas relacionadas con la manipulación por encima de la netlist a nivel de LUT. Finalmente, una breve discusión sobre el proceso global se aborda en la parte final del capítulo. El Capítulo 3 estudia los principales retos durante la implementación de DPLs en FPGAs. El nivel de seguridad de las soluciones de resistencia a SCA encontradas en el estado del arte se ha degenerado debido a las barreras de implantación a través de herramientas EDA convencionales. En el escenario de la arquitectura FPGA estudiada, se discuten los problemas de los formatos de doble carril, impactos parásitos, sesgo tecnológico y la viabilidad de implementación. De acuerdo con estas elaboraciones, se plantean dos problemas: Cómo implementar la lógica propuesta sin penalizar los niveles de seguridad, y cómo manipular un gran número de celdas y automatizar el proceso. El PA-DPL propuesto en el capítulo 2 se valida con una serie de iniciativas, desde características estructurales como doble carril entrelazado o redes de rutado clonadas, hasta los métodos de aplicación tales como las herramientas de personalización y automatización de EDA. Por otra parte, un sistema de calefacción auto-adaptativo es representado y aplicado a una lógica de doble núcleo, con el fin de ajustar alternativamente la temperatura local para equilibrar los impactos negativos de la variación del proceso durante la operación en tiempo real. El capítulo 4 se centra en los detalles de la implementación del kit de herramientas. Desarrollado sobre una API third-party, el kit de herramientas personalizado es capaz de manipular los elementos de la lógica de circuito post P&R ncd (una versión binaria ilegible del xdl) convertido al formato XDL Xilinx. El mecanismo y razón de ser del conjunto de instrumentos propuestos son cuidadosamente descritos, que cubre la detección de enrutamiento y los enfoques para la reparación. El conjunto de herramientas desarrollado tiene como objetivo lograr redes de enrutamiento estrictamente idénticos para la lógica de doble carril, tanto para posicionamiento separado como para el entrelazado. Este capítulo particularmente especifica las bases técnicas para apoyar las implementaciones en los dispositivos de Xilinx y su flexibilidad para ser utilizado sobre otras aplicaciones. El capítulo 5 se enfoca en la aplicación de los casos de estudio para la validación de los grados de seguridad de la lógica propuesta. Se discuten los problemas técnicos detallados durante la ejecución y algunas nuevas técnicas de implementación. (a) Se discute el impacto en el proceso de posicionamiento de la lógica utilizando el kit de herramientas propuesto. Diferentes esquemas de implementación, tomando en cuenta la optimización global en seguridad y coste, se verifican con los experimentos con el fin de encontrar los planes de posicionamiento y reparación optimizados; (b) las validaciones de seguridad se realizan con los métodos de correlación y análisis de tiempo; (c) Una táctica asintótica se aplica a un núcleo AES sobre BCDL estructurado para validar de forma sofisticada el impacto de enrutamiento sobre métricas de seguridad; (d) Los resultados preliminares utilizando el sistema de calefacción auto-adaptativa sobre la variación del proceso son mostrados; (e) Se introduce una aplicación práctica de las herramientas para un diseño de cifrado completa. Capítulo 6 incluye el resumen general del trabajo presentado dentro de esta tesis doctoral. Por último, una breve perspectiva del trabajo futuro se expone, lo que puede ampliar el potencial de utilización de las contribuciones de esta tesis a un alcance más allá de los dominios de la criptografía en FPGAs. ABSTRACT This PhD thesis mainly concentrates on countermeasure techniques related to the Side Channel Attack (SCA), which has been put forward to academic exploitations since 17 years ago. The related research has seen a remarkable growth in the past decades, while the design of solid and efficient protection still curiously remain as an open research topic where more reliable initiatives are required for personal information privacy, enterprise and national data protections. The earliest documented usage of secret code can be traced back to around 1700 B.C., when the hieroglyphs in ancient Egypt are scribed in inscriptions. Information security always gained serious attention from diplomatic or military intelligence transmission. Due to the rapid evolvement of modern communication technique, crypto solution was first incorporated by electronic signal to ensure the confidentiality, integrity, availability, authenticity and non-repudiation of the transmitted contexts over unsecure cable or wireless channels. Restricted to the computation power before computer era, simple encryption tricks were practically sufficient to conceal information. However, algorithmic vulnerabilities can be excavated to restore the encoding rules with affordable efforts. This fact motivated the development of modern cryptography, aiming at guarding information system by complex and advanced algorithms. The appearance of computers has greatly pushed forward the invention of robust cryptographies, which efficiently offers resistance relying on highly strengthened computing capabilities. Likewise, advanced cryptanalysis has greatly driven the computing technologies in turn. Nowadays, the information world has been involved into a crypto world, protecting any fields by pervasive crypto solutions. These approaches are strong because of the optimized mergence between modern mathematical theories and effective hardware practices, being capable of implement crypto theories into various platforms (microprocessor, ASIC, FPGA, etc). Security needs from industries are actually the major driving metrics in electronic design, aiming at promoting the construction of systems with high performance without sacrificing security. Yet a vulnerability in practical implementation found by Prof. Paul Kocher, et al in 1996 implies that modern digital circuits are inherently vulnerable to an unconventional attack approach, which was named as side-channel attack since then from its analysis source. Critical suspicions to theoretically sound modern crypto algorithms surfaced almost immediately after this discovery. To be specifically, digital circuits typically consist of a great number of essential logic elements (as MOS - Metal Oxide Semiconductor), built upon a silicon substrate during the fabrication. Circuit logic is realized relying on the countless switch actions of these cells. This mechanism inevitably results in featured physical emanation that can be properly measured and correlated with internal circuit behaviors. SCAs can be used to reveal the confidential data (e.g. crypto-key), analyze the logic architecture, timing and even inject malicious faults to the circuits that are implemented in hardware system, like FPGA, ASIC, smart Card. Using various comparison solutions between the predicted leakage quantity and the measured leakage, secrets can be reconstructed at much less expense of time and computation. To be precisely, SCA basically encloses a wide range of attack types, typically as the analyses of power consumption or electromagnetic (EM) radiation. Both of them rely on statistical analyses, and hence require a number of samples. The crypto algorithms are not intrinsically fortified with SCA-resistance. Because of the severity, much attention has to be taken into the implementation so as to assemble countermeasures to camouflage the leakages via "side channels". Countermeasures against SCA are evolving along with the development of attack techniques. The physical characteristics requires countermeasures over physical layer, which can be generally classified into intrinsic and extrinsic vectors. Extrinsic countermeasures are executed to confuse the attacker by integrating noise, misalignment to the intra activities. Comparatively, intrinsic countermeasures are built into the algorithm itself, to modify the implementation for minimizing the measurable leakage, or making them not sensitive any more. Hiding and Masking are two typical techniques in this category. Concretely, masking applies to the algorithmic level, to alter the sensitive intermediate values with a mask in reversible ways. Unlike the linear masking, non-linear operations that widely exist in modern cryptographies are difficult to be masked. Approved to be an effective counter solution, hiding method mainly mentions dual-rail logic, which is specially devised for flattening or removing the data-dependent leakage in power or EM signatures. In this thesis, apart from the context describing the attack methodologies, efforts have also been dedicated to logic prototype, to mount extensive security investigations to countermeasures on logic-level. A characteristic of SCA resides on the format of leak sources. Typical side-channel attack concerns the power based analysis, where the fundamental capacitance from MOS transistors and other parasitic capacitances are the essential leak sources. Hence, a robust SCA-resistant logic must eliminate or mitigate the leakages from these micro units, such as basic logic gates, I/O ports and routings. The vendor provided EDA tools manipulate the logic from a higher behavioral-level, rather than the lower gate-level where side-channel leakage is generated. So, the classical implementations barely satisfy these needs and inevitably stunt the prototype. In this case, a customized and flexible design scheme is appealing to be devised. This thesis profiles an innovative logic style to counter SCA, which mainly addresses three major aspects: I. The proposed logic is based on the hiding strategy over gate-level dual-rail style to dynamically overbalance side-channel leakage from lower circuit layer; II. This logic exploits architectural features of modern FPGAs, to minimize the implementation expenses; III. It is supported by a set of assistant custom tools, incorporated by the generic FPGA design flow, to have circuit manipulations in an automatic manner. The automatic design toolkit supports the proposed dual-rail logic, facilitating the practical implementation on Xilinx FPGA families. While the methodologies and the tools are flexible to be expanded to a wide range of applications where rigid and sophisticated gate- or routing- constraints are desired. In this thesis a great effort is done to streamline the implementation workflow of generic dual-rail logic. The feasibility of the proposed solutions is validated by selected and widely used crypto algorithm, for thorough and fair evaluation w.r.t. prior solutions. All the proposals are effectively verified by security experiments. The presented research work attempts to solve the implementation troubles. The essence that will be formalized along this thesis is that a customized execution toolkit for modern FPGA systems is developed to work together with the generic FPGA design flow for creating innovative dual-rail logic. A method in crypto security area is constructed to obtain customization, automation and flexibility in low-level circuit prototype with fine-granularity in intractable routings. Main contributions of the presented work are summarized next: Precharge Absorbed-DPL logic: Using the netlist conversion to reserve free LUT inputs to execute the Precharge and Ex signal in a dual-rail logic style. A row-crossed interleaved placement method with identical routing pairs in dual-rail networks, which helps to increase the resistance against selective EM measurement and mitigate the impacts from process variations. Customized execution and automatic transformation tools for producing identical networks for the proposed dual-rail logic. (a) To detect and repair the conflict nets; (b) To detect and repair the asymmetric nets. (c) To be used in other logics where strict network control is required in Xilinx scenario. Customized correlation analysis testbed for EM and power attacks, including the platform construction, measurement method and attack analysis. A timing analysis based method for quantifying the security grades. A methodology of security partitions of complex crypto systems for reducing the protection cost. A proof-of-concept self-adaptive heating system to mitigate electrical impacts over process variations in dynamic dual-rail compensation manner. The thesis chapters are organized as follows: Chapter 1 discusses the side-channel attack fundamentals, which covers from theoretic basics to analysis models, and further to platform setup and attack execution. Chapter 2 centers to SCA-resistant strategies against generic power and EM attacks. In this chapter, a major contribution, a compact and secure dual-rail logic style, will be originally proposed. The logic transformation based on bottom-layer design will be presented. Chapter 3 is scheduled to elaborate the implementation challenges of generic dual-rail styles. A customized design flow to solve the implementation problems will be described along with a self-developed automatic implementation toolkit, for mitigating the design barriers and facilitating the processes. Chapter 4 will originally elaborate the tool specifics and construction details. The implementation case studies and security validations for the proposed logic style, as well as a sophisticated routing verification experiment, will be described in Chapter 5. Finally, a summary of thesis conclusions and perspectives for future work are included in Chapter 5. To better exhibit the thesis contents, each chapter is further described next: Chapter 1 provides the introduction of hardware implementation testbed and side-channel attack fundamentals, and mainly contains: (a) The FPGA generic architecture and device features, particularly of Virtex-5 FPGA; (b) The selected crypto algorithm - a commercially and extensively used Advanced Encryption Standard (AES) module - is detailed; (c) The essentials of Side-Channel methods are profiled. It reveals the correlated dissipation leakage to the internal behaviors, and the method to recover this relationship between the physical fluctuations in side-channel traces and the intra processed data; (d) The setups of the power/EM testing platforms enclosed inside the thesis work are given. The content of this thesis is expanded and deepened from chapter 2, which is divided into several aspects. First, the protection principle of dynamic compensation of the generic dual-rail precharge logic is explained by describing the compensated gate-level elements. Second, the novel DPL is originally proposed by detailing the logic protocol and an implementation case study. Third, a couple of custom workflows are shown next for realizing the rail conversion. Meanwhile, the technical definitions that are about to be manipulated above LUT-level netlist are clarified. A brief discussion about the batched process is given in the final part. Chapter 3 studies the implementation challenges of DPLs in FPGAs. The security level of state-of-the-art SCA-resistant solutions are decreased due to the implementation barriers using conventional EDA tools. In the studied FPGA scenario, problems are discussed from dual-rail format, parasitic impact, technological bias and implementation feasibility. According to these elaborations, two problems arise: How to implement the proposed logic without crippling the security level; and How to manipulate a large number of cells and automate the transformation. The proposed PA-DPL in chapter 2 is legalized with a series of initiatives, from structures to implementation methods. Furthermore, a self-adaptive heating system is depicted and implemented to a dual-core logic, assumed to alternatively adjust local temperature for balancing the negative impacts from silicon technological biases on real-time. Chapter 4 centers to the toolkit system. Built upon a third-party Application Program Interface (API) library, the customized toolkit is able to manipulate the logic elements from post P&R circuit (an unreadable binary version of the xdl one) converted to Xilinx xdl format. The mechanism and rationale of the proposed toolkit are carefully convoyed, covering the routing detection and repairing approaches. The developed toolkit aims to achieve very strictly identical routing networks for dual-rail logic both for separate and interleaved placement. This chapter particularly specifies the technical essentials to support the implementations in Xilinx devices and the flexibility to be expanded to other applications. Chapter 5 focuses on the implementation of the case studies for validating the security grades of the proposed logic style from the proposed toolkit. Comprehensive implementation techniques are discussed. (a) The placement impacts using the proposed toolkit are discussed. Different execution schemes, considering the global optimization in security and cost, are verified with experiments so as to find the optimized placement and repair schemes; (b) Security validations are realized with correlation, timing methods; (c) A systematic method is applied to a BCDL structured module to validate the routing impact over security metric; (d) The preliminary results using the self-adaptive heating system over process variation is given; (e) A practical implementation of the proposed toolkit to a large design is introduced. Chapter 6 includes the general summary of the complete work presented inside this thesis. Finally, a brief perspective for the future work is drawn which might expand the potential utilization of the thesis contributions to a wider range of implementation domains beyond cryptography on FPGAs.

Licensing patterns for Linked Data

Rights expression languages declare the permitted and prohibited actions to be performed on a resource. Along this work, six rights expression languages are compared, abstracting their commonalities and outlining their underlying pattern. Linked Data, which can be object of protection by the intellectual property laws or its access be restricted by an access control system, can be the asset in rights expressions. The requirements for a pattern for licensing Linked Data resources are listed.

Linked Data Rights 2.0: extension of ODRL for Licensing Linked Data

Linked Data assets (RDF triples, graphs, datasets, mappings...) can be object of protection by the intellectual property law, the database law or its access or publication be restricted by other legal reasons (personal data pro- tection, security reasons, etc.). Publishing a rights expression along with the digital asset, allows the rightsholder waiving some or all of the IP and database rights (leaving the work in the public domain), permitting some operations if certain conditions are satisfied (like giving attribution to the author) or simply reminding the audience that some rights are reserved.

Definition of amide protection factors for early kinetic intermediates in protein folding

Hydrogen–deuterium exchange experiments have been used previously to investigate the structures of well defined states of a given protein. These include the native state, the unfolded state, and any intermediates that can be stably populated at equilibrium. More recently, the hydrogen–deuterium exchange technique has been applied in kinetic labeling experiments to probe the structures of transiently formed intermediates on the kinetic folding pathway of a given protein. From these equilibrium and nonequilibrium studies, protection factors are usually obtained. These protection factors are defined as the ratio of the rate of exchange of a given backbone amide when it is in a fully solvent-exposed state (usually obtained from model peptides) to the rate of exchange of that amide in some state of the protein or in some intermediate on the folding pathway of the protein. This definition is straightforward for the case of equilibrium studies; however, it is less clear-cut for the case of transient kinetic intermediates. To clarify the concept for the case of burst-phase intermediates, we have introduced and mathematically defined two different types of protection factors: one is Pstruc, which is more related to the structure of the intermediate, and the other is Papp, which is more related to the stability of the intermediate. Kinetic hydrogen–deuterium exchange data from disulfide-intact ribonuclease A and from cytochrome c are discussed to explain the use and implications of these two definitions.

Sustained in vivo cardiac protection by a rationally designed peptide that causes ɛ protein kinase C translocation

Brief periods of cardiac ischemia trigger protection from subsequent prolonged ischemia (preconditioning). ɛ Protein kinase C (ɛPKC) has been suggested to mediate preconditioning. Here, we describe an ɛPKC-selective agonist octapeptide, ψɛ receptor for activated C-kinase (ψɛRACK), derived from an ɛPKC sequence homologous to its anchoring protein, ɛRACK. Introduction of ψɛRACK into isolated cardiomyocytes, or its postnatal expression as a transgene in mouse hearts, increased ɛPKC translocation and caused cardio-protection from ischemia without any deleterious effects. Our data demonstrate that ɛPKC activation is required for protection from ischemic insult and suggest that small molecules that mimic this ɛPKC agonist octapeptide provide a powerful therapeutic approach to protect hearts at risk for ischemia.

Radiation-induced Release of Transforming Growth Factor α Activates the Epidermal Growth Factor Receptor and Mitogen-activated Protein Kinase Pathway in Carcinoma Cells, Leading to Increased Proliferation and Protection from Radiation-induced Cell Death

Exposure of A431 squamous and MDA-MB-231 mammary carcinoma cells to ionizing radiation has been associated with short transient increases in epidermal growth factor receptor (EGFR) tyrosine phosphorylation and activation of the mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) pathways. Irradiation (2 Gy) of A431 and MDA-MB-231 cells caused immediate primary activations (0–10 min) of the EGFR and the MAPK and JNK pathways, which were surprisingly followed by later prolonged secondary activations (90–240 min). Primary and secondary activation of the EGFR was abolished by molecular inhibition of EGFR function. The primary and secondary activation of the MAPK pathway was abolished by molecular inhibition of either EGFR or Ras function. In contrast, molecular inhibition of EGFR function abolished the secondary but not the primary activation of the JNK pathway. Inhibition of tumor necrosis factor α receptor function by use of neutralizing monoclonal antibodies blunted primary activation of the JNK pathway. Addition of a neutralizing monoclonal antibody versus transforming growth factor α (TGFα) had no effect on the primary activation of either the EGFR or the MAPK and JNK pathways after irradiation but abolished the secondary activation of EGFR, MAPK, and JNK. Irradiation of cells increased pro-TGFα cleavage 120–180 min after exposure. In agreement with radiation-induced release of a soluble factor, activation of the EGFR and the MAPK and JNK pathways could be induced in nonirradiated cells by the transfer of media from irradiated cells 120 min after irradiation. The ability of the transferred media to cause MAPK and JNK activation was blocked when media were incubated with a neutralizing antibody to TGFα. Thus radiation causes primary and secondary activation of the EGFR and the MAPK and JNK pathways in autocrine-regulated carcinoma cells. Secondary activation of the EGFR and the MAPK and JNK pathways is dependent on radiation-induced cleavage and autocrine action of TGFα. Neutralization of TGFα function by an anti-TGFα antibody or inhibition of MAPK function by MEK1/2 inhibitors (PD98059 and U0126) radiosensitized A431 and MDA-MB-231 cells after irradiation in apoptosis, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), and clonogenic assays. These data demonstrate that disruption of the TGFα–EGFR–MAPK signaling module represents a strategy to decrease carcinoma cell growth and survival after irradiation.

The role of antigen and IL-12 in sustaining Th1 memory cells in vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge

IL-12 plays a central role in both the induction and magnitude of a primary Th1 response. A critical question in designing vaccines for diseases requiring Th1 immunity such as Mycobacterium tuberculosis and Leishmania major is the requirements to sustain memory/effector Th1 cells in vivo. This report examines the role of IL-12 and antigen in sustaining Th1 responses sufficient for protective immunity to L. major after vaccination with LACK protein (LP) plus rIL-12 and LACK DNA. It shows that, after initial vaccination with LP plus rIL-12, supplemental boosting with either LP or rIL-12 is necessary but not sufficient to fully sustain long-term Th1 immunity. Moreover, endogenous IL-12 is also shown to be required for the induction, maintenance, and effector phase of the Th1 response after LACK DNA vaccination. Finally, IL-12 is required to sustain Th1 cells and control parasite growth in susceptible and resistant strains of mice during primary and secondary infection. Taken together, these data show that IL-12 is essential to sustain a sufficient number of memory/effector Th1 cells generated in vivo to mediate long-term protection to an intracellular pathogen.

Protection from superoxide damage associated with an increased level of the YggX protein in Salmonella enterica

The deleterious effect of superoxide radicals on cell growth and survival is predominately caused by rapid oxidation of labile [Fe-S] clusters in proteins. Oxidation of these clusters releases Fe(II) ions, which participate in Fenton chemistry that damages DNA. Here it is shown that elevated levels of the YggX protein increase the resistance of Salmonella enterica to superoxide stress, reverse enzymatic defects attributed to oxidized [Fe-S] clusters, and decrease the spontaneous mutation frequency. The data are consistent with a model in which YggX protects protein [Fe-S] clusters from oxidation.

Life Is Getting Worse in ESS Data: Is This Due to Micro or Macro Factors? Bruges European Economic Research (BEER) Papers 28/November 2013

In order to evaluate the success of a society, measuring well-being might be a fruitful avenue. For a long time, governments have trusted economic measures, Gross Domestic Product (GDP) in particular, to assess their success. However GDP is only a limited measure of economic success, which is not enough to show whether policies implemented by governments have a positive perceived impact on the people they represent. This paper belongs to the studies of the relationship between measures of well-being and economic factors. More precisely, it tries to evaluate the decrease in happiness and life satisfaction that can be observed in European countries in the 2000-2010 decade. It asks whether this deterioration is mainly due to microeconomic factors, such as income and individual characteristics, or rather to environmental (macroeconomics) factors such as unemployment, inflation or income inequality. Such aggregate factors could impact individual happiness per se because they are related to the perception of an aggregate risk of unemployment or income fall. In order to strengthen this interpretation, this paper checks whether the type of social protection regime existing in different countries mediates the impact of macroeconomic volatility on individual well-being. To go further, adopting the classification of welfare regimes proposed by Esping-Andersen (1990), it verifies whether the decreasing pattern of subjective well-being varies across these regimes. This is partly due to the aggregate social protection expenditure. Hence, this paper brings some additional evidence to the idea that macroeconomic uncertainty has a cost in terms of well-being. More protective social regimes are able to reduce this cost. It also proposes an evaluation of the welfare cost of unemployment and inflation (in terms of happiness and life satisfaction), in each of the different social protection regimes. Finally different measures of well-being, i.e. cognitive, hedonic and eudaimonic, are used to confirm the above mentioned result.

Protection from experimental autoimmune encephalomyelitis by polyclonal IgG requires adjuvant-induced inflammation

BACKGROUND Intravenous immunoglobulin (IVIG) proved to be an efficient anti-inflammatory treatment for a growing number of neuroinflammatory diseases and protects against the development of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). METHODS The clinical efficacy of IVIG and IVIG-derived F(ab')2 fragments, generated using the streptococcal cysteine proteinase Ide-S, was evaluated in EAE induced by active immunization and by adoptive transfer of myelin-specific T cells. Frequency, phenotype, and functional characteristics of T cell subsets and myeloid cells were determined by flow cytometry. Antibody binding to microbial antigen and cytokine production by innate immune cells was assessed by ELISA. RESULTS We report that the protective effect of IVIG is lost in the adoptive transfer model of EAE and requires prophylactic administration during disease induction. IVIG-derived Fc fragments are not required for protection against EAE, since administration of F(ab')2 fragments fully recapitulated the clinical efficacy of IVIG. F(ab')2-treated mice showed a substantial decrease in splenic effector T cell expansion and cytokine production (GM-CSF, IFN-γ, IL-17A) 9 days after immunization. Inhibition of effector T cell responses was not associated with an increase in total numbers of Tregs but with decreased activation of innate myeloid cells such as neutrophils, monocytes, and dendritic cells. Therapeutically effective IVIG-derived F(ab')2 fragments inhibited adjuvant-induced innate immune cell activation as determined by IL-12/23 p40 production and recognized mycobacterial antigens contained in Freund's complete adjuvant which is required for induction of active EAE. CONCLUSIONS Our data indicate that F(ab')2-mediated neutralization of adjuvant contributes to the therapeutic efficacy of anti-inflammatory IgG. These findings might partly explain the discrepancy of IVIG efficacy in EAE and MS.

Data storage and retrieval system for pilot watewater treatment research /

Mode of access: Internet.

Testing the validity of the lognormal probability model : computer analysis of carbon monoxide data from U.S. cities /

Mode of access: Internet.