The MK2/3 cascade regulates AMPAR trafficking and cognitive flexibility

The interplay between long-term potentiation and long-term depression (LTD) is thought to be involved in learning and memory formation. One form of LTD expressed in the hippocampus is initiated by the activation of the group 1 metabotropic glutamate receptors (mGluRs). Importantly, mGluRs have been shown to be critical for acquisition of new memories and for reversal learning, processes that are thought to be crucial for cognitive flexibility. Here we provide evidence that MAPK-activated protein kinases 2 and 3 (MK2/3) regulate neuronal spine morphology, synaptic transmission and plasticity. Furthermore, mGluR-LTD is impaired in the hippocampus of MK2/3 double knockout (DKO) mice, an observation that is mirrored by deficits in endocytosis of GluA1 subunits. Consistent with compromised mGluR-LTD, MK2/3 DKO mice have distinctive deficits in hippocampal-dependent spatial reversal learning. These novel findings demonstrate that the MK2/3 cascade plays a strategic role in controlling synaptic plasticity and cognition. © 2014 Macmillan Publishers Limited. All rights reserved.

Structural determinants of oligomerization of the aquaporin-4 channel

The aquaporins (AQP) family of integral membrane protein channels mediate cellular water and solute flow. Although qualitative and quantitative differences in channel permeability, selectivity, subcellular localization and trafficking responses have been observed for different members of the AQP family, the signature homotetrameric quaternary structure is conserved. Using a variety of biophysical techniques, we show that mutations to an intracellular loop (loop D) of human AQP4 reduce oligomerization. Non-tetrameric AQP4 mutants are unable to relocalize to the plasma membrane in response to changes in extracellular tonicity, despite equivalent constitutive surface expression levels and water permeability to wild-type AQP4. A network of AQP4 loop D hydrogen bonding interactions, identified using molecular dynamics simulations and based on a comparative mutagenic analysis of AQPs 1, 3 and 4, suggest that loop D interactions may provide a general structural framework for tetrameric assembly within the AQP family.

Political economy of Caribbean drug trafficking: The case of the Dominican Republic

The purpose of this dissertation was to examine the relationship between narcotics trafficking and the processes of economic liberalization and democratization in the Caribbean. The salient social, political and economic processes were explored at each juncture of the drug trafficking chain to determine why certain groups and locales became integrated in the global narcotics economy. It also considered the national security implications of the global narcotics economy. ^ The Global Commodity Chain framework allowed the study to examine the social, political and economic processes that determine how a commodity is produced, transported, distributed and consumed in the global economy. A case study method was used to specify the commodity (cocaine) and locations (U.S. and Dominican Republic) where these processes were examined. ^ The important contributing factors in the study included: a liberalizing global economy, the social processes of migration, the formation of enclaves in the U.S., the opening of the political process and institutional weakness in the country of origin. All of these factors contributed to the Dominican Republic and Dominican migrants becoming key players in the cocaine commodity chain. It concluded that narcotics trafficking as a national security issue remains a fluid concept, contingent on specific cultural and historic antecedents. ^

Gender, identity, and the security state: The politics of international drug trafficking

This dissertation examined how United States illicit drug control policy, often commonly referred to as the "war on drugs," contributes to the reproduction of gendered and racialized social relations. Specifically, it analyzed the identity producing practices of United States illicit drug control policy as it relates to the construction of U.S. identities. ^ Drawing on the theoretical contributions of feminist postpositivists, three cases of illicit drug policy practice were discussed. In the first case, discourse analysis was employed to examine recent debates (1986-2005) in U.S. Congressional Hearings about the proper understanding of the illicit drug "threat." The analysis showed how competing policy positions are tied to differing understandings of proper masculinity and the role of policymakers as protectors of the national interest. Utilizing critical visual methodologies, the second case examined a public service media campaign circulated by the Office of National Drug Control Policy that tied the "war on drugs" with another security concern in the U.S., the "war on terror." This case demonstrated how the media campaign uses messages about race, masculinity, and femininity to produce privileged notions of state identity and proper citizenship. The third case examined the gendered politics of drug interdiction at the U.S. border. Using qualitative research methodologies including semi-structured interviews and participant observation, it examined how gender is produced through drug interdiction at border sites like Miami International Airport. By paying attention to the discourse that circulates about women drug couriers, it showed how gender is normalized in a national security setting. ^ What this dissertation found is that illicit drug control policy takes the form it does because of the politics of gender and racial identity and that, as a result, illicit drug policy is implicated in the reproduction of gender and racial inequities. It concluded that a more socially conscious and successful illicit drug policy requires an awareness of the gendered and racialized assumptions that inform and shape policy practices.^

Illicit interest groups: The political impact of the Medellin drug trafficking organizations in Colombia

Although drug trafficking organizations (DTOs) exist and have an effect on health, crime, economies, and politics, little research has explored these entities as political organizations. Legal interest groups and movements have been found to influence domestic and international politics because they operate within legal parameters. Illicit groups, such as DTOs, have rarely been accounted for—especially in the literature on interest groups—though they play a measurable role in affecting domestic and international politics in similar ways. Using an interest group model, this dissertation analyzed DTOs as illicit interest groups (IIGs) to explain their political influence. The analysis included a study of group formation, development, and demise that examined IIG motivation, organization, and policy impact. The data for the study drew from primary and secondary sources, which include interviews with former DTO members and government officials, government documents, journalistic accounts, memoirs, and academic research. To illustrate the interest group model, the study examined Medellin-based DTO leaders, popularly known as the "Medellin Cartel." In particular, the study focused on the external factors that gave rise to DTOs in Colombia and how Medellin DTOs reacted to the implementation of counternarcotics efforts. The discussion was framed by the implementation of the 1979 Extradition Treaty negotiated between Colombia and the United States. The treaty was significant because as drug trafficking became the principal bilateral issue in the 1980s; extradition became a major method of combating the illicit drug business. The study's findings suggested that Medellin DTO leaders had a one-issue agenda and used a variety of political strategies to influence public opinion and all three branches of government—the judicial, the legislative, and the executive—in an effort to invalidate the 1979 Extradition Treaty. The changes in the life cycle of the 1979 Extradition Treaty correlated with changes in the political power of Medellin-based DTOs vis-à-vis the Colombian government, and international forces such as the U.S. government's push for tougher counternarcotics efforts.

Intracellular Signaling and Trafficking in Cancer: Role of Rab5-GTPase in Migration and Invasion of Breast Cells

Metastasis is characterized pathologically by uncontrolled cell invasion, proliferation, migration and angiogenesis. Steroid hormones, such as estrogen, and growth factors, which include insulin growth factor I/II (IGF-1/IGF-2) therapy has been associated with most if not all of the features of metastasis. It has been determined that IGF-1 increases cell survival of cancer cells and potentiate the effect of E2 and other ligand growth factors on breast cancer cells. However not much information is available that comprehensively expounds on the roles of insulin growth factor receptor (IGFR) and Rab GTPases may play in breast cancer. The latter, Rab GTPases, are small signaling molecules and critical in the regulation of many cellular processes including cell migration, growth via the endocytic pathway. This research involves the role of Rab GTPases, specifically Rab5 and its guanine exchange factors (GEFs), in the promotion of cancer cell migration and invasion. Two important questions abound: Are IGFR stimulation and downstream effect involved the endocytic pathway in carcinogenesis? What role does Rab5 play in cell migration and invasion of cancer cells? The hypothesis is that growth factor signaling is dependent on Rab5 activity in mediating the aggressiveness of cancer cells. The goal is to demonstrate that IGF-1 signaling is dependent on Rab5 function in breast cancer progression. Here, the results thus far, have shown that while activation of Rab5 may mediate increased cell proliferation, migration and invasion in breast cancer cells, the Rab5 GEF, RIN1 interacts with the IGFR thereby facilitating migration and invasion activities in breast cells. Furthermore, endocytosis of the IGFR in breast cancer cells seems to be caveolin dependent as the data has shown. This taken together, the data shows that IGF-1 signaling in breast cancer cells relies on IGF-1R phosphorylation, caveolae internalization and sequestration to the early endosome RIN1 function and Rab5 activation.

Functional genomic and molecular analyses of transcripts related to glycerol synthesis and trafficking in rainbow smelt (Osmerus mordax) using cold temperature-induced models of glycerol production

The rainbow smelt (Osmerus mordax) is an anadromous teleost that produces type II antifreeze protein (AFP) and accumulates modest urea and high glycerol levels in plasma and tissues as adaptive cryoprotectant mechanisms in sub-zero temperatures. It is known that glyceroneogenesis occurs in liver via a branch in glycolysis and gluconeogenesis and is activated by low temperature; however, the precise mechanisms of glycerol synthesis and trafficking in smelt remain to be elucidated. The objective of this thesis was to provide further insight using functional genomic techniques [e.g. suppression subtractive hybridization (SSH) cDNA library construction, microarray analyses] and molecular analyses [e.g. cloning, quantitative reverse transcription - polymerase chain reaction (QPCR)]. Novel molecular mechanisms related to glyceroneogenesis were deciphered by comparing the transcript expression profiles of glycerol (cold temperature) and non-glycerol (warm temperature) accumulating hepatocytes (Chapter 2) and livers from intact smelt (Chapter 3). Briefly, glycerol synthesis can be initiated from both amino acids and carbohydrate; however carbohydrate appears to be the preferred source when it is readily available. In glycerol accumulating hepatocytes, levels of the hepatic glucose transporter (GLUT2) plummeted and transcript levels of a suite of genes (PEPCK, MDH2, AAT2, GDH and AQP9) associated with the mobilization of amino acids to fuel glycerol synthesis were all transiently higher. In contrast, in glycerol accumulating livers from intact smelt, glycerol synthesis was primarily fuelled by glycogen degradation with higher PGM and PFK (glycolysis) transcript levels. Whether initiated from amino acids or carbohydrate, there were common metabolic underpinnings. Increased PDK2 (an inhibitor of PDH) transcript levels would direct pyruvate derived from amino acids and / or DHAP derived from G6P to glycerol as opposed to oxidation via the citric acid cycle. Robust LIPL (triglyceride catabolism) transcript levels would provide free fatty acids that could be oxidized to fuel ATP synthesis. Increased cGPDH (glyceroneogenesis) transcript levels were not required for increased glycerol production, suggesting that regulation is more likely by post-translational modification. Finally, levels of a transcript potentially encoding glycerol-3-phosphatase, an enzyme not yet characterized in any vertebrate species, were transiently higher. These comparisons also led to the novel discoveries that increased G6Pase (glucose synthesis) and increased GS (glutamine synthesis) transcript levels were part of the low temperature response in smelt. Glucose may provide increased colligative protection against freezing; whereas glutamine could serve to store nitrogen released from amino acid catabolism in a non-toxic form and / or be used to synthesize urea via purine synthesis-uricolysis. Novel key aspects of cryoprotectant osmolyte (glycerol and urea) trafficking were elucidated by cloning and characterizing three aquaglyceroporin (GLP)-encoding genes from smelt at the gene and cDNA levels in Chapter 4. GLPs are integral membrane proteins that facilitate passive movement of water, glycerol and urea across cellular membranes. The highlight was the discovery that AQP10ba transcript levels always increase in posterior kidney only at low temperature. This AQP10b gene paralogue may have evolved to aid in the reabsorption of urea from the proximal tubule. This research has contributed significantly to a general understanding of the cold adaptation response in smelt, and more specifically to the development of a working scenario for the mechanisms involved in glycerol synthesis and trafficking in this species.

International women gather in front of UN to protest the global sex trade and trafficking of women

General note: Title and date provided by Bettye Lane.

International women gather in front of United Nations in hopes of stopping human trafficking in women. Later in the day they spoke to representatives at the United Nations

General note: Title and date provided by Bettye Lane.

Leukotriene B⁴ and platelet-activating factor : assessment of biological significance in neutrophil trafficking

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Leukotriene B⁴ and platelet-activating factor : assessment of biological significance in neutrophil trafficking

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Looking Beyond ‘White Slavery’: Trafficking, the Jewish Association’s representation of ‘the potential victim’, and the dangerous politics of migration control in England, 1890-1910

This article seeks to revise Jo Doezema’s suggestion that ‘the white slave’ was the only dominant representation of ‘the trafficked woman’ used by early anti-trafficking advocates in Europe and the United States, and that discourses based on this figure of injured innocence are the only historical discourses that are able to shine light on contemporary anti-trafficking rhetoric. ‘The trafficked woman’ was a figure painted using many shades of grey in the past, with a number of injurious consequences, not only for trafficked persons but also for female labour migrants and migrant populations at large. In England, dominant organizational portrayals of ‘the trafficked woman’ had first acquired these shades by the 1890s, when trafficking started to proliferate amid mass migration from Continental Europe, and when controversy began to mount over the migration to the country of various groups of working-class foreigner. The article demonstrates these points by exploring the way in which the Jewish Association for the Protection of Girls and Women (JAPGW), one of the pillars of England’s early anti-trafficking movement, represented the female Jewish migrants it deemed at risk from being trafficked into sex work between 1890 and 1910. It argues that the JAPGW stigmatised these women, placing most of the onus for trafficking upon them and positioning them to a greater or a lesser extent as ‘undesirable and undeserving working-class foreigners’ who could never become respectable English women. It also contends that the JAPGW, in outlining what was wrong with certain female migrants, drew a line between ‘the migrant’ and respectable English society at large, and paradoxically endorsed the extension of the very ‘anti-alienist’ and Antisemitic prejudices that it strove to dispel.

Subcellular localization of legionella Dot/Icm effectors

The translocation of effector proteins by the Dot/Icm type IV secretion system is central to the ability of Legionella pneumophila to persist and replicate within eukaryotic cells. The subcellular localization of translocated Dot/Icm proteins in host cells provides insight into their function. Through co-staining with host cell markers, effector proteins may be localized to specific subcellular compartments and membranes, which frequently reflects their host cell target and mechanism of action. In this chapter, we describe protocols to (1) localize effector proteins within cells by ectopic expression using green fluorescent protein fusions and (2) localize effector proteins within infected cells using epitope-tagged effector proteins and immuno-fluorescence microscopy.

Tackling trafficking in human beings in a security integrated Europe: addressing the challenges using trafficking schematics

This paper aims to conceptualise trafficking in human beings (THB) as an organised crime by drawing on the rational choice theory. Utilising crime scripting principles, it proposes trafficking schematics to capture and visualise THB in its entirety. Stemming from its transnational nature and varying conceptualisations, combatting THB faces challenges, such as the lack of harmonisation of policy instruments and differing stakeholder agendas. To mitigate these challenges, this paper proposes trafficking schematics. Their core lies in the modelling of THB constituent elements, including stages and their sequence, key actors and relationships, and financial modus operandi. Trafficking schematics may therefore contribute to addressing THB in a holistic, dynamic and integrated way, by enriching stakeholders’ understanding of the phenomenon and facilitating collaboration to address it. The paper contributes to theory and practice by drawing up a model of the procedural, human, logistical and environmental elements of THB that may be viewed as an instrument of public value creation.

Trafficking in human beings for for forced labour in domestic and international law: a comparative legal study of the kingdom of Saudi Arabia and the United Kingdom

This thesis examines the effect of combating of human trafficking as a crime. Special emphasis has been placed on forced labour and the rights of trafficked victims and their protection. The study explores various legislations undertaken at regional, national and international levels and considers rights of trafficked victims under international human rights and Islamic rights. The aim of the thesis is to provide a critical and comparative analysis of the legal systems of the Kingdom of Saudi Arabia (KSA) and the United Kingdom (UK) in terms of human trafficking. The thesis consists of eight chapter; each covering a different aspect of the study. It begins by providing background information regarding the issue of human trafficking and proceeds to examine developments of legal frameworks across the two jurisdictions to combat this crime and penalize the criminals. It seeks to examine the legal system pertaining to human trafficking for forced labour and analyse the three distinct platforms, that is, prevention, protection, and punishment, by comparing the legal systems of the KSA and the UK. The examination of both countries aims to identify the strength and weaknesses of the KSA system as compared to the UK system. Thus, it concludes that the KSA can improve its ranking from Tier 2 watch list to Tier 1 if reforms are introduced in the legislation and enforcement domains. The study also demonstrates how the UK and the KSA portray ‘human trafficking’ in their regional laws. A problem often faced during the information-gathering and investigation stages is the lack of available evidence against traffickers, a particular issue in the KSA. The thesis concludes that the transnational aspect of this phenomenon makes it necessary to establish a thorough and comprehensive legal framework to cover all matters pertaining to this crime, including the protection of victims and punishment of criminals in the KSA and the UK, including immigration and ‘kafala’ strategies that may be of value in future researches.