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Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A genome-wide association study identified a female-specific AIS susceptibility locus near the PAX1 gene. Here, we use mouse enhancer assays, three mouse enhancer knockouts, and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterize a sequence, PEC7, which overlaps the AIS-associated variant, and find it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, or deletion of both sequences lead to a kinky tail phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicates several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism.

QC 20230922

The human spinal column is a dynamic, segmented, bony, and cartilaginous structure that protects the neurologic system and simultaneously provides balance and flexibility. Children with developmental disorders that affect the patterning or shape of the spine can be at risk of neurologic and other physiologic dysfunctions. The most common developmental disorder of the spine is scoliosis, a lateral deformity in the shape of the spinal column. Scoliosis may be part of the clinical spectrum that is observed in many developmental disorders, but typically presents as an isolated symptom in otherwise healthy adolescent children. Adolescent idiopathic scoliosis (AIS) has defied understanding in part due to its genetic complexity. Breakthroughs have come from recent genome-wide association studies (GWAS) and next generation sequencing (NGS) of human AIS cohorts, as well as investigations of animal models. These studies have identified genetic associations with determinants of cartilage biogenesis and development of the intervertebral disc (IVD). Current evidence suggests that a fraction of AIS cases may arise from variation in factors involved in the structural integrity and homeostasis of the cartilaginous extracellular matrix (ECM). Here, we review the development of the spine and spinal cartilages, the composition of the cartilage ECM, the so-called "matrisome" and its functions, and the players involved in the genetic architecture of AIS. We also propose a molecular model by which the cartilage matrisome of the IVD contributes to AIS susceptibility.

The human spinal column is a dynamic, segmented, bony, and cartilaginous structure that protects the neurologic system and simultaneously provides balance and flexibility. Children with developmental disorders that affect the patterning or shape of the spine can be at risk of neurologic and other physiologic dysfunctions. The most common developmental disorder of the spine is scoliosis, a lateral deformity in the shape of the spinal column. Scoliosis may be part of the clinical spectrum that is observed in many developmental disorders, but typically presents as an isolated symptom in otherwise healthy adolescent children. Adolescent idiopathic scoliosis (AIS) has defied understanding in part due to its genetic complexity. Breakthroughs have come from recent genome-wide association studies (GWAS) and next generation sequencing (NGS) of human AIS cohorts, as well as investigations of animal models. These studies have identified genetic associations with determinants of cartilage biogenesis and development of the intervertebral disc (IVD). Current evidence suggests that a fraction of AIS cases may arise from variation in factors involved in the structural integrity and homeostasis of the cartilaginous extracellular matrix (ECM). Here, we review the development of the spine and spinal cartilages, the composition of the cartilage ECM, the so-called "matrisome" and its functions, and the players involved in the genetic architecture of AIS. We also propose a molecular model by which the cartilage matrisome of the IVD contributes to AIS susceptibility.

Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in non-coding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral disks (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and chromatin immunoprecipitation-sequencing against H3 lysine 27 acetylation in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in non-coding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral disks (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and chromatin immunoprecipitation-sequencing against H3 lysine 27 acetylation in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to >4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10(-9)) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10(-10), OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10(-9)) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10(-10), OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder. Published 2013 Wiley Periodicals, Inc.

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder. Published 2013 Wiley Periodicals, Inc.

Restricted until 12 Aug. 2012., This dissertation attempts to explain why Iran is the most significant country in the Middle East. The historical reasons for the influence of Iran in the region are discussed. These include social, cultural, and religious norms espoused by Iranians that have significantly impacted the development of the region and beyond. The political development of Iran in the last one hundred years is essential to understanding the current conflict between secular and radical religious forces in the region.; The institutional structure of the Islamic Republic of Iran (IRI) and how it functions are examined. Due to the diffusion of power within the state and the infusion of power within the office of the Supreme Religious Leader, there is no internal mechanism for reforming the system and its inefficient institutions. The redundant framework of dual institutions creates rent-seeking, corruption, misallocation of scarce resources, an ineffective massive governmental bureaucracy, central planning, capital flight and a general state of insecurity.; Institutional impediments in the National Security Council, the State Department and intelligence agencies in the US prevent a clear understanding of the IRI and hinder the formation of effective policies towards the IRI. As a result of continued radicalization of the regime and its supporters due to the framework of the institutions of the IRI, the pursuit of nuclear weapons by the IRI may lead to a nuclear confrontation with the state of Israel. The likelihood of a nuclear confrontation in the Middle East and the effectiveness of the deterrent nuclear policy of the state of Israel are analyzed.; Finally, the prospects of peace in the Middle East as well as the defeat of radical ideology and terrorism in the region will not be possible without a secular democratic Iran.

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

The Peruvian government's lack of commitment in promoting the development of energy projects between 1935 and 1990 resulted in budget deficits and a scarcity of priva te investment in that sector. In the 1990s, this situation started to change. The threshold level was based on new legal agreements. This paper studies the interactions between the Peruvian government, firms and the international institutions in developing the energy market by means of oil and gas exploitation of oil and gas and improved quality services in the electricity sector. The paper also focuses on the quality of management capacities at different levels of government (central and local). lt illustrates the steps taken by the Fujimori government to strike a balance between energy sector management and privatization. To this end, regulatory policies were introduced to establish a climate of confidence between firms and consumers. Furthermore, policies were introduced to protect indigenous communities to forestal! actions that might be harmful to these people when prívate firms began to exploit natural resources in these areas., Desde 1935 hasta 1990 el desarrollo energético del Perú se basó en un aparente escenario de explotación del petróleo y en la falta de compromiso del Estado para explotar el gas natural. Tanto es así, que se caracterizó por el uso excesivamente politizado de herramientas de política que contribuyeron a su atraso en más de 20 años. No obstante, la aprobación de una nueva legislación modernizadora en la década de 1990 estableció un nuevo impulso de crecimiento en dicho sector. El presente documento analiza cada una de las etapas por las que ha atravesado el país para fomentar una posición competitiva en el sector energético. Desde costosas exploraciones y extracciones de petróleo ejecutadas por capital netamente extranjero en la década de 1930, hasta la expropiación por parte del Estado de la empresa canadiense lnternational Petroleum Company en 1968 y el camino a convertirse en un país netamente importador de petróleo. También se analiza el seudo-desarrollo hidroeléctrico que afrontó el Estado con falta de capacidad de gestión y principalmente la falta de recursos económicos que no pudieron ser apalancados ni con el sector privado. A todo esto siguió el escenario alentador de la década de 1990, cuando el gobierno de Fujimori, después de corregir todos los problemas económico-financieros generados en el gobierno de García, puso en marcha un conjunto de medidas que apuntaban hacia la privatización del sector. Entre ellas destacan la creación de procesos regulatorios, la protección del derecho de los pueblos nativos que se ubican alrededor de las áreas de explotación de recursos naturales, la transferencia de los recursos a los gobiernos locales y la participación activa de ONG ambientalistas, lo que trajo consigo la presencia de una sociedad vigilante ante la gestión del Estado.

The Peruvian government's lack of commitment in promoting the development of energy projects between 1935 and 1990 resulted in budget deficits and a scarcity of priva te investment in that sector. In the 1990s, this situation started to change. The threshold level was based on new legal agreements. This paper studies the interactions between the Peruvian government, firms and the international institutions in developing the energy market by means of oil and gas exploitation of oil and gas and improved quality services in the electricity sector. The paper also focuses on the quality of management capacities at different levels of government (central and local). lt illustrates the steps taken by the Fujimori government to strike a balance between energy sector management and privatization. To this end, regulatory policies were introduced to establish a climate of confidence between firms and consumers. Furthermore, policies were introduced to protect indigenous communities to forestal! actions that might be harmful to these people when prívate firms began to exploit natural resources in these areas., Desde 1935 hasta 1990 el desarrollo energético del Perú se basó en un aparente escenario de explotación del petróleo y en la falta de compromiso del Estado para explotar el gas natural. Tanto es así, que se caracterizó por el uso excesivamente politizado de herramientas de política que contribuyeron a su atraso en más de 20 años. No obstante, la aprobación de una nueva legislación modernizadora en la década de 1990 estableció un nuevo impulso de crecimiento en dicho sector. El presente documento analiza cada una de las etapas por las que ha atravesado el país para fomentar una posición competitiva en el sector energético. Desde costosas exploraciones y extracciones de petróleo ejecutadas por capital netamente extranjero en la década de 1930, hasta la expropiación por parte del Estado de la empresa canadiense lnternational Petroleum Company en 1968 y el camino a convertirse en un país netamente importador de petróleo. También se analiza el seudo-desarrollo hidroeléctrico que afrontó el Estado con falta de capacidad de gestión y principalmente la falta de recursos económicos que no pudieron ser apalancados ni con el sector privado. A todo esto siguió el escenario alentador de la década de 1990, cuando el gobierno de Fujimori, después de corregir todos los problemas económico-financieros generados en el gobierno de García, puso en marcha un conjunto de medidas que apuntaban hacia la privatización del sector. Entre ellas destacan la creación de procesos regulatorios, la protección del derecho de los pueblos nativos que se ubican alrededor de las áreas de explotación de recursos naturales, la transferencia de los recursos a los gobiernos locales y la participación activa de ONG ambientalistas, lo que trajo consigo la presencia de una sociedad vigilante ante la gestión del Estado.

Unrestricted, This dissertation discusses the political and economic forces, both external and domestic, that have shaped Brazilian trade policy in the 1990s and 2000s. Marked by concurrent multilateral and regional trade negotiations, the country has simultaneously embraced orthodoxy and liberalization of the past, while also falling back on protectionist practices. For instance, after implementing steep unilateral tariff cuts in the late 1980s and early 1990s, trade policy has subsequently undergone only piecemeal change; in fact, "industrial subsidies" were maintained and even reinforced in the period 1988-2005. I analyze how the domestic institutional framework shaped Brazil's global strategy, swaying policymakers to opt for a regional integration initiative (Mercosur) and a rigid negotiating position in the multilateral sphere (WorldTrade Organization). At the same time, Brazil shirked its commitments with developed countries in the context of the Free Trade Area of the Americas and the European Union-Mercosur negotiations.; The methodological approach taken here is an interdisciplinary one which draws on economics, international relations, and political science. I begin with a historical-comparative narrative concerning the choice of development models (eg. import-substitution industrialization), the nature of domestic economic institutions and bureaucracies, and the interaction of both with powerful interest groups as determinants of trade policy. Secondly, I explore the interaction between global forces, and Brazil's policy responses. I then conduct an econometric analysis using panel data which cover ten industrial sectors over seventeen years, my goal being to explain two trade policy variables - tariffs and subsidized loans. By applying the assumptions of neoclassical trade theory (Heckscher-Ohlin and Ricardo-Viner), as well as those of the new growth theories to the Brazilian case, my results show that collective action and factor endowment variables explain patterns

Unrestricted, This dissertation analyzes legal and institutional responses to economic liberalization in Colombia. The main hypothesis is that the increasing use of alternative dispute resolution mechanisms (ADRMs) by economic agents is the consequence of global economic pressures, as well as an attempt to address the crisis of the national judicial system. ADRM's reduce transaction costs, and offer more efficient, predictable, and independent venues for resolving litigation. Consequently, they create a more stable environment for investors. This, in turn, suggests that the relationship between law and economics is rapidly changing at the structural level in Colombia; this latter point constitutes a secondary hypothesis, wherein market-friendly governance structures guided by private interests are displacing those dominated by the state.; This study criticizes and transcends macro-regional analyses of the economic model and indices of institutional reform as the main indicators of economic "success." The analysis favors a micro case studies approach to better comprehend the interconnection between legal institutions and the development of the private sector. It analyzes 112 actual arbitration cases heard before the Center for Arbitration and Conciliation of the Bogotá Chamber of Commerce, between 1985 and 2007. The cases are organized by parties to the arbitration, commercial transaction in dispute, legal pretensions and defense mechanisms of the litigants, length of the arbitration process, means of proof or evidence requested, costs, and demand trends for arbitration.; In sum, this dissertation offers a more informed understanding of the relationship between law and economics at the practical level from a specific Latin American domestic standpoint. At the same time, it creates a framework for analysis applicable to other Latin American countries, and developing and transition economies in general.