Analysis of the impact of globalization and economic growth on food security in developing countries

A pesar de los importantes avances en la reducción del hambre, la seguridad alimentaria continúa siendo un reto de dimensión internacional. La seguridad alimentaria es un concepto amplio y multidimensional, cuyo análisis abarca distintas escalas y horizontes temporales. Dada su complejidad, la identificación de las causas de la inseguridad alimentaria y la priorización de las medias para abordarlas, son dos cuestiones que suscitan un intenso debate en la actualidad. El objetivo de esta tesis es evaluar el impacto de la globalización y el crecimiento económico en la seguridad alimentaria en los países en desarrollo, desde una perspectiva macro y un horizonte temporal a largo plazo. La influencia de la globalización se aborda de una manera secuencial. En primer lugar, se analiza la relación entre la inversión público-privada en infraestructuras y las exportaciones agrarias. A continuación, se estudia el impacto de las exportaciones agrarias en los indicadores de seguridad alimentaria. El estudio del impacto del crecimiento económico aborda los cambios paralelos en la distribución de la renta, y cómo la inequidad influye en el comportamiento de la seguridad alimentaria nacional. Además, se analiza en qué medida el crecimiento económico contribuye a acelerar el proceso de mejora de la seguridad alimentaria. Con el fin de conseguir los objetivos mencionados, se llevan a cabo varios análisis econométricos basados en datos de panel, en el que se combinan datos de corte transversal de 52 países y datos temporales comprendidos en el periodo 1991-2012. Se analizan tanto variables en niveles como variables en tasas de cambio anual. Se aplican los modelos de estimación de efectos variables y efectos fijos, ambos en niveles y en primeras diferencias. La tesis incluye cuatro tipos de modelos econométricos, cada uno de ellos con sus correspondientes pruebas de robustez y especificaciones. Los resultados matizan la importancia de la globalización y el crecimiento económico como mecanismos de mejora de la seguridad alimentaria en los países en desarrollo. Se obtienen dos conclusiones relativas a la globalización. En primer lugar, los resultados sugieren que la promoción de las inversiones privadas en infraestructuras contribuye a aumentar las exportaciones agrarias. En segundo lugar, se observa que las exportaciones agrarias pueden tener un impacto negativo en los indicadores de seguridad alimentaria. La combinación de estas dos conclusiones sugiere que la apertura comercial y financiera no contribuye por sí misma a la mejora de la seguridad alimentaria en los países en desarrollo. La apertura internacional de los países en desarrollo ha de ir acompañada de políticas e inversiones que desarrollen sectores productivos de alto valor añadido, que fortalezcan la economía nacional y reduzcan su dependencia exterior. En relación al crecimiento económico, a pesar del incuestionable hecho de que el crecimiento económico es una condición necesaria para reducir los niveles de subnutrición, no es una condición suficiente. Se han identificado tres estrategias adicionales que han de acompañar al crecimiento económico con el fin de intensificar su impacto positivo sobre la subnutrición. Primero, es necesario que el crecimiento económico sea acompañado de una distribución más equitativa de los ingresos. Segundo, el crecimiento económico ha de reflejarse en un aumento de inversiones en salud, agua y saneamiento y educación. Se observa que, incluso en ausencia de crecimiento económico, mejoras en el acceso a agua potable contribuyen a reducir los niveles de población subnutrida. Tercero, el crecimiento económico sostenible en el largo plazo parece tener un mayor impacto positivo sobre la seguridad alimentaria que el crecimiento económico más volátil o inestable en el corto plazo. La estabilidad macroeconómica se identifica como una condición necesaria para alcanzar una mayor mejora en la seguridad alimentaria, incluso habiéndose mejorado la equidad en la distribución de los ingresos. Por último, la tesis encuentra que los países en desarrollo analizados han experimentado diferentes trayectorias no lineales en su proceso de mejora de sus niveles de subnutrición. Los resultados sugieren que un mayor nivel inicial de subnutrición y el crecimiento económico son responsables de una respuesta más rápida al reto de la mejora de la seguridad alimentaria. ABSTRACT Despite the significant reductions of hunger, food security still remains a global challenge. Food security is a wide concept that embraces multiple dimensions, and has spatial-temporal scales. Because of its complexity, the identification of the drivers underpinning food insecurity and the prioritization of measures to address them are a subject of intensive debate. This thesis attempts to assess the impact of globalization and economic growth on food security in developing countries with a macro level scale (country) and using a long-term approach. The influence of globalization is addressed in a sequential way. First, the impact of public-private investment in infrastructure on agricultural exports in developing countries is analyzed. Secondly, an assessment is conducted to determine the impact of agricultural exports on food security indicators. The impact of economic growth focuses on the parallel changes in income inequality and how the income distribution influences countries' food security performance. Furthermore, the thesis analyzes to what extent economic growth helps accelerating food security improvements. To address the above mentioned goals, various econometric models are formulated. Models use panel data procedures combining cross-sectional data of 52 countries and time series data from 1991 to 2012. Yearly data are expressed both in levels and in changes. The estimation models applied are random effects estimation and fixed effects estimations, both in levels and in first differences. The thesis includes four families of econometric models, each with its own set of robustness checks and specifications. The results qualify the relevance of globalization and economic growth as enabling mechanisms for improving food security in developing countries. Concerning globalization, two main conclusions can be drawn. First, results showed that enhancing foreign private investment in infrastructures contributes to increase agricultural exports. Second, agricultural exports appear to have a negative impact on national food security indicators. These two conclusions suggest that trade and financial openness per se do not contribute directly to improve food security in development countries. Both measures should be accompanied by investments and policies to support the development of national high value productive sectors, to strengthen the domestic economy and reduce its external dependency. Referring to economic growth, despite the unquestionable fact that income growth is a pre-requisite for reducing undernourishment, results suggest that it is a necessary but not a sufficient condition. Three additional strategies should accompany economic growth to intensifying its impact on food security. Firstly, it is necessary that income growth should be accompanied by a better distribution of income. Secondly, income growth needs to be followed by investments and policies in health, sanitation and education to improve food security. Even if economic growth falters, sustained improvements in the access to drinking water may still give rise to reductions in the percentage of undernourished people. And thirdly, long-term economic growth appears to have a greater impact on reducing hunger than growth regimes that combine periods of growth peaks followed by troughs. Macroeconomic stability is a necessary condition for accelerating food security. Finally, the thesis finds that the developing countries analyzed have experienced different non-linear paths toward improving food security. Results also show that a higher initial level of undernourishment and economic growth result in a faster response for improving food security.

Hardware timestamping for image acquisition system based on FlexRIO and IEEE 1588 v2 Standard

Current fusion devices consist of multiple diagnostics and hundreds or even thousands of signals. This situation forces on multiple occasions to use distributed data acquisition systems as the best approach. In this type of distributed systems, one of the most important issues is the synchronization between signals, so that it is possible to have a temporal correlation as accurate as possible between the acquired samples of all channels. In last decades, many fusion devices use different types of video cameras to provide inside views of the vessel during operations and to monitor plasma behavior. The synchronization between each video frame and the rest of the different signals acquired from any other diagnostics is essential in order to know correctly the plasma evolution, since it is possible to analyze jointly all the information having accurate knowledge of their temporal correlation. The developed system described in this paper allows timestamping image frames in a real-time acquisition and processing system using 1588 clock distribution. The system has been implemented using FPGA based devices together with a 1588 synchronized timing card (see Fig.1). The solution is based on a previous system [1] that allows image acquisition and real-time image processing based on PXIe technology. This architecture is fully compatible with the ITER Fast Controllers [2] and offers integration with EPICS to control and monitor the entire system. However, this set-up is not able to timestamp the frames acquired since the frame grabber module does not present any type of timing input (IRIG-B, GPS, PTP). To solve this lack, an IEEE1588 PXI timing device its used to provide an accurate way to synchronize distributed data acquisition systems using the Precision Time Protocol (PTP) IEEE 1588 2008 standard. This local timing device can be connected to a master clock device for global synchronization. The timing device has a buffer timestamp for each PXI trigger line and requires tha- a software application assigns each frame the corresponding timestamp. The previous action is critical and cannot be achieved if the frame rate is high. To solve this problem, it has been designed a solution that distributes the clock from the IEEE 1588 timing card to all FlexRIO devices [3]. This solution uses two PXI trigger lines that provide the capacity to assign timestamps to every frame acquired and register events by hardware in a deterministic way. The system provides a solution for timestamping frames to synchronize them with the rest of the different signals.

Ground and airborne level optical sensors: is it possible to estimate maize crop N status?

Adjusting N fertilizer application to crop requirements is a key issue to improve fertilizer efficiency, reducing unnecessary input costs to farmers and N environmental impact. Among the multiple soil and crop tests developed, optical sensors that detect crop N nutritional status may have a large potential to adjust N fertilizer recommendation (Samborski et al. 2009). Optical readings are rapid to take and non-destructive, they can be efficiently processed and combined to obtain indexes or indicators of crop status. However, other physiological stress conditions may interfere with the readings and detection of the best crop nutritional status indicators is not always and easy task. Comparison of different equipments and technologies might help to identify strengths and weakness of the application of optical sensors for N fertilizer recommendation. The aim of this study was to evaluate the potential of various ground-level optical sensors and narrow-band indices obtained from airborne hyperspectral images as tools for maize N fertilizer recommendations. Specific objectives were i) to determine which indices could detect differences in maize plants treated with different N fertilizer rates, and ii) to evaluate its ability to identify N-responsive from non-responsive sites.

Analysis of Contributions to NO2 Ambient Air Quality Levels in Madrid City (Spain) through Modeling. Implications for the Development of Policies and Air Quality Monitoring

As environmental standards become more stringent (e.g. European Directive 2008/50/EC), more reliable and sophisticated modeling tools are needed to simulate measures and plans that may effectively tackle air quality exceedances, common in large cities across Europe, particularly for NO2. Modeling air quality in urban areas is rather complex since observed concentration values are a consequence of the interaction of multiple sources and processes that involve a wide range of spatial and temporal scales. Besides a consistent and robust multi-scale modeling system, comprehensive and flexible emission inventories are needed. This paper discusses the application of the WRF-SMOKE-CMAQ system to the Madrid city (Spain) to assess the contribution of the main emitting sectors in the region. A detailed emission inventory was compiled for this purpose. This inventory relies on bottom-up methods for the most important sources. It is coupled with the regional traffic model and it makes use of an extensive database of industrial, commercial and residential combustion plants. Less relevant sources are downscaled from national or regional inventories. This paper reports the methodology and main results of the source apportionment study performed to understand the origin of pollution (main sectors and geographical areas) and define clear targets for the abatement strategy. Finally the structure of the air quality monitoring is analyzed and discussed to identify options to improve the monitoring strategy not only in the Madrid city but the whole metropolitan area.

Testing of crop Models for Accurate Predictions of Evapotranspiration and crop Water Use

All crop models, whether site-specific or global-gridded and regardless of crop, simulate daily crop transpiration and soil evaporation during the crop life cycle, resulting in seasonal crop water use. Modelers use several methods for predicting daily potential evapotranspiration (ET), including FAO-56, Penman-Monteith, Priestley-Taylor, Hargreaves, full energy balance, and transpiration water efficiency. They use extinction equations to partition energy to soil evaporation or transpiration, depending on leaf area index. Most models simulate soil water balance and soil-root water supply for transpiration, and limit transpiration if water uptake is insufficient, and thereafter reduce dry matter production. Comparisons among multiple crop and global gridded models in the Agricultural Model Intercomparison and Improvement Project (AgMIP) show surprisingly large differences in simulated ET and crop water use for the same climatic conditions. Model intercomparisons alone are not enough to know which approaches are correct. There is an urgent need to test these models against field-observed data on ET and crop water use. It is important to test various ET modules/equations in a model platform where other aspects such as soil water balance and rooting are held constant, to avoid compensation caused by other parts of models. The CSM-CROPGRO model in DSSAT already has ET equations for Priestley-Taylor, Penman-FAO-24, Penman-Monteith-FAO-56, and an hourly energy balance approach. In this work, we added transpiration-efficiency modules to DSSAT and AgMaize models and tested the various ET equations against available data on ET, soil water balance, and season-long crop water use of soybean, fababean, maize, and other crops where runoff and deep percolation were known or zero. The different ET modules created considerable differences in predicted ET, growth, and yield.

Networked Utopia : the Architecture and Urbanism of the Bata Shoe Company Satellite Cities = Utopia en red : arquitectura y urbanismo en las ciudades satélite de la Bata Shoe Company, 1930 al presente

From its humble beginnings as a small workshop established by Tomáš Baťa in 1874, the Bata Shoe Company became a gigantic concern in the 1920s, built on the principles of scientific management and welfare capitalism. The growth of the company engulfed Zlín (in today’s Czech Republic), its hometown, and transformed it into a modern industrial garden city satisfying the needs of both a growing industrial population, and those of the company itself. As a reaction to the aftermath of the crisis of 1929, the enterprise began a strategy of decentralization and international expansion characterized by the design and construction of a series of modern industrial towns that replicated the model of Zlín around the globe. This study is an exhaustive survey of these cities, their rationale, design, and their postindustrial conditions; it is a comparative work that has used field trips, photography, interviews, and archival material to explain the logics behind Bata’s project, to document the design and implementation of the model to multiple contexts and geographies, and to evaluate of the urban legacy of this undertaking. Finally, the research explores the question of what can the design disciplines, and other parties involved, learn from a full synthesis on the history and urbanism of the Bata satellite cities with regard to the re-imagination and sustainability of contemporary industry-sponsored interventions in developing geographies. RESUMEN Con origen en un humilde y pequeño taller fundado en 1874 por Tomáš Baťa, la Bata Shoe Company creció hasta convertirse en una gigantesca empresa en los anos 20, fundada en principios de control científico de la producción y capitalismo de bienestar. El crecimiento de la compañía se extendió por Zlín (en la actual República Checa), su pueblo de nacimiento, y la transformó en una moderna ciudad jardín industrial capaz de satisfacer las necesidades tanto de una población en alza como de la propia empresa. Como reacción a la crisis de 1929, Bata inició una estrategia de descentralización y expansión internacional caracterizada por el proyecto y construcción de modernas ciudades industriales que replicaron el modelo de Zlín por el mundo. Esta tesis es un estudio exhaustivo de estas ciudades: las razones detrás del proyecto, su diseño, y su condición post-industrial; es un estudio comparativo que se ha servido de trabajo de campo, documentación fotográfica, entrevistas y materiales de archivo para explicar la lógica detrás del proyecto de Bata, documentar el diseño e implementación de tal modelo en múltiples contextos y geografías, y valorar el legado urbano de esta empresa. Finalmente, la investigación evalúa qué podrían aprender las disciplinas del diseño y otras partes implicadas de una síntesis completa de la historia y el urbanismo de las ciudades satélite de Bata, en lo relativo a la reinvención y sostenibilidad de proyectos contemporáneos de la industria en geografías en desarrollo.

Multi-UAV Coordination and Control Interface

The interest in missions with multiple Unmanned Aerial Vehicles (UAVs) has increased significantly in last years. These missions take advantage of the use of fleets instead of single UAVs to ensure the success, reduce the duration or increase the goals of the mission. In addition, they allow performing tasks that require multiple agents and certain coordination (e.g. surveillance of large areas or transport of heavy loads). Nevertheless, these missions suppose a challenge in terms of control and monitoring. In fact, the workload of the operators rises with the utilization of multiple UAVs and payloads, since they have to analyze more information, make more decisions and generate more commands during the mission. This work addresses the operator workload problem in multi-UAV missions by reducing and selecting the information. Two approaches are considered: a first one that selects the information according to the mission state, and a second one that selects it according to the operator preferences. The result is an interface that is able to control the amount of information and show what is relevant for mission and operator at the time.

Glyceraldehyde-3-phosphate dehydrogenase: Nuclear translocation participates in neuronal and nonneuronal cell death

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein levels increase in particulate fractions in association with cell death in HEK293 cells, S49 cells, primary thymocytes, PC12 cells, and primary cerebral cortical neuronal cultures. Subcellular fractionation and immunocytochemistry reveal that this increase primarily reflects nuclear translocation. Nuclear GAPDH is tightly bound, resisting extraction by DNase or salt treatment. Treating primary thymocytes, PC12 cells, and primary cortical neurons with antisense but not sense oligonucleotides to GAPDH prevents cell death. Because cell-death-associated nuclear translocation of GAPDH and antisense protection occur in multiple neuronal and nonneuronal systems, we propose that GAPDH is a general mediator of cell death and uses nuclear translocation as a signaling mechanism.

A 55-kDa protein isolated from human cells shows DNA glycosylase activity toward 3,N4-ethenocytosine and the G/T mismatch

Etheno adducts in DNA arise from multiple endogenous and exogenous sources. Of these adducts we have reported that, 1,N6-ethenoadenine (ɛA) and 3,N4-ethenocytosine (ɛC) are removed from DNA by two separate DNA glycosylases. We later confirmed these results by using a gene knockout mouse lacking alkylpurine-DNA-N-glycosylase, which excises ɛA. The present work is directed toward identifying and purifying the human glycosylase activity releasing ɛC. HeLa cells were subjected to multiple steps of column chromatography, including two ɛC-DNA affinity columns, which resulted in >1,000-fold purification. Isolation and renaturation of the protein from SDS/polyacrylamide gel showed that the ɛC activity resides in a 55-kDa polypeptide. This apparent molecular mass is approximately the same as reported for the human G/T mismatch thymine-DNA glycosylase. This latter activity copurified to the final column step and was present in the isolated protein band having ɛC-DNA glycosylase activity. In addition, oligonucleotides containing ɛC⋅G or G/T(U), could compete for ɛC protein binding, further indicating that the ɛC-DNA glycosylase is specific for both types of substrates in recognition. The same substrate specificity for ɛC also was observed in a recombinant G/T mismatch DNA glycosylase from the thermophilic bacterium, Methanobacterium thermoautotrophicum THF.

Tyrosine-phosphorylated Caveolin-1: Immunolocalization and Molecular Characterization

Caveolin-1 was discovered as a major substrate for v-Src, but the effect of its tyrosine phosphorylation has not been known. We generated a specific antibody (PY14) to caveolin-1 phosphorylated at tyrosine 14 and studied the significance of the modification. By Western blotting of lysates of v-Src–expressing cells, PY14 recognized not only a 22-kDa band (the position of nonphosphorylated caveolin-1) but bands at 23–24 and 25 kDa. Bands of slower mobility were diminished by dephosphorylation and were also observed for mutant caveolin-1 lacking tyrosine 14. By immunofluorescence microscopy, PY14 did not label normal cells but detected large dots in v-Src–expressing cells. Immunoelectron microscopy revealed that the dots corresponded to aggregated caveolae and/or vesicles of various sizes; besides, the label was observed in intramembrane particle-free areas in the plasma membrane, which appeared to have been formed by fusion of flattened caveolae. A positive reaction with PY14 was found in normal cells after vanadate or pervanadate treatment; it occurred mainly at 22 kDa by Western blotting and was not seen as large dots by immunofluorescence microscopy. Detergent solubility, oligomerization, and association with caveolin-2 were observed similarly for caveolin-1 in normal and v-Src–expressing cells. The results indicate that phosphorylation of caveolin-1 in v-Src–expressing cells occurs at multiple residues and induces flattening, aggregation, and fusion of caveolae and/or caveolae-derived vesicles.

Staphylococcal protein A: Unfolding pathways, unfolded states, and differences between the B and E domains

We present multiple native and denaturation simulations of the B and E domains of the three-helix bundle protein A, totaling 60 ns. The C-terminal helix (H3) consistently denatures later than either of the other two helices and contains residual helical structure in the denatured state. These results are consistent with experiments suggesting that the isolated H3 fragment is more stable than H1 and H2 and that H3 forms early in folding. Interestingly, the denatured state of the B domain is much more compact than that of the E domain. This sequence-dependent effect on the dimensions of the denatured state and the lack of correlation with structure suggest that the radius of gyration can be a misleading reaction coordinate for unfolding/folding. Various unfolding and refolding events are observed in the denaturation simulations. In some cases, the transitions are facilitated through interactions with other portions of the protein—contact-assisted helix formation. In the native simulations, the E domain is very stable: after 6 ns, the Cα root-mean-square deviation from the starting structure is less than 1.4 Å. In contrast, the native state of the B domain deviates more and its inter-helical angles fluctuate. In apparent contrast, we note that the B domain is thermodynamically more stable than the E domain. The simulations suggest that the increased stability of the B domain may be due to heightened mobility, and therefore entropy, in the native state and decreased mobility/entropy in the more compact denatured state.

Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode α1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis

The tumor suppressors EXT1 and EXT2 are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate (HS) and its analog, heparin (Hep). Three highly homologous EXT-like genes, EXTL1–EXTL3, have been cloned, and EXTL2 is an α1,4-GlcNAc transferase I, the key enzyme that initiates the HS/Hep synthesis. In the present study, truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, were transiently expressed in COS-1 cells and found to harbor α-GlcNAc transferase activity. EXTL3 used not only N-acetylheparosan oligosaccharides that represent growing HS chains but also GlcAβ1–3Galβ1-O-C2H4NH-benzyloxycarbonyl (Cbz), a synthetic substrate for α-GlcNAc transferase I that determines and initiates HS/Hep synthesis. In contrast, EXTL1 used only the former acceptor. Neither EXTL1 nor EXTL3 showed any glucuronyltransferase activity as examined with N-acetylheparosan oligosaccharides. Heparitinase I digestion of each transferase-reaction product showed that GlcNAc had been transferred exclusively through an α1,4-configuration. Hence, EXTL3 most likely is involved in both chain initiation and elongation, whereas EXTL1 possibly is involved only in the chain elongation of HS and, maybe, Hep as well. Thus, their acceptor specificities of the five family members are overlapping but distinct from each other, except for EXT1 and EXT2 with the same specificity. It now has been clarified that all of the five cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of HS and Hep.

Identification and characterization of a melanin-concentrating hormone receptor

Melanin-concentrating hormone (MCH), a neuropeptide expressed in central and peripheral nervous systems, plays an important role in the control of feeding behaviors and energy metabolism. An orphan G protein-coupled receptor (SLC-1/GPR24) has recently been identified as a receptor for MCH (MCHR1). We report here the identification and characterization of a G protein-coupled receptor as the MCH receptor subtype 2 (MCHR2). MCHR2 has higher protein sequence homology to MCHR1 than any other G protein-coupled receptor. The expression of MCHR2 has been detected in many regions of the brain. In contrast to MCHR1, which is intronless in the coding region and is located at the chromosomal locus 22q13.3, the MCHR2 gene has multiple exons and is mapped to locus 6q21. MCHR2 is specifically activated by nanomolar concentrations of MCH, binds to MCH with high affinity, and signals through Gq protein. This discovery is important for a full understanding of MCH biology and the development of potential therapeutics for diseases involving MCH, including obesity.

Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B.

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have antimitogenic, anticarcinogenic, antiinflammatory, and immunomodulatory properties. The molecular basis for these diverse properties is not known. Since the role of the nuclear factor NF-kappa B in these responses has been documented, we examined the effect of CAPE on this transcription factor. Our results show that the activation of NF-kappa B by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose- and time-dependent manner. Besides TNF, CAPE also inhibited NF-kappa B activation induced by other inflammatory agents including phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Since the reducing agents reversed the inhibitory effect of CAPE, it suggests the role of critical sulfhydryl groups in NF-kappa B activation. CAPE prevented the translocation of the p65 subunit of NF-kappa B to the nucleus and had no significant effect on TNF-induced I kappa B alpha degradation, but did delay I kappa B alpha resynthesis. The effect of CAPE on inhibition of NF-kappa B binding to the DNA was specific, in as much as binding of other transcription factors including AP-1, Oct-1, and TFIID to their DNA were not affected. When various synthetic structural analogues of CAPE were examined, it was found that a bicyclic, rotationally constrained, 5,6-dihydroxy form was superactive, whereas 6,7-dihydroxy variant was least active. Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and antiinflammatory activities.

Gene targeting approaches to complex genetic diseases: atherosclerosis and essential hypertension.

Gene targeting allows precise, predetermined changes to be made in a chosen gene in the mouse genome. To date, targeting has been used most often for generation of animals completely lacking the product of a gene of interest. The resulting "knockout" mice have confirmed some hypotheses, have upset others, but have rarely been uninformative. Models of several human genetic diseases have been produced by targeting--including Gaucher disease, cystic fibrosis, and the fragile X syndrome. These diseases are primarily determined by defects in single genes, and their modes of inheritance are well understood. When the disease under study has a complex etiology with multiple genetic and environmental components, the generation of animal models becomes more difficult but no less valuable. The problems associated with dissecting out the individual genetic factors also increases substantially and the distinction between causation and correlation is often difficult. To prove causation in a complex system requires rigorous adherence to the principle that the experiments must allow detection of the effects of changing only a single variable at one time. Gene targeting experiments, when properly designed, can test the effects of a precise genetic change completely free from the effects of differences in any other genes (linked or unlinked to the test gene). They therefore allow proofs of causation.