Pure Americanism : building a modern St. Louis and the reign of Know Nothingism

This thesis will explore the relationship between the rise of the Know Nothing Party and the modernization of St. Louis, the first Western metropolis. By the mid-1850s, two distinct visions of St. Louis existed. On one side of the ideological aisle, Democrats and conservative Whigs cautiously pursued an economic policy that advocated a slow but steady growth in St. Louis’ city infrastructure. But by 1850, a new faction of wealthy Yankee merchants, stirred by dreams of empire and western supremacy, challenged the traditional approach and strategically joined the national Know Nothing movement. Influenced by the intellectual currents of the American Revolution, Nativists engendered a new form of republicanism termed “pure Americanism,” which incorporated notions of honor and civic virtue that served as a foundation for a myriad of intellectual and social systems they privately funded across the city. These institutions defined their vision of a modern city, where order and class distinctions were respected and private domains served as models for masculine conceptions of behavior and public propriety. Recasting the character of St. Louis ultimately moved beyond the borders of Missouri as Nativists explored how St. Louis and the pure Americanism paradigm could serve as a remedy for the rancorous spirit that had threatened national unity by 1857. The modern city, the group poignantly argued, would save the country. Ultimately, this thesis will tell an altogether different story of St. Louis, through the successes and dilemmas of the Know Nothing Party as it engineered contemporary social reform. Utilizing the interplay of class and republican ideology, I will demonstrate the relationship between conceptions of modernity and westward expansion in antebellum America

Mutation of Vav1 adaptor region reveals a new oncogenic activation

International audienceVav family members function as remarkable scaffold proteins that exhibit both GDP/GTP exchange activity for Rho/Rac GTPases and numerous protein-protein interactions via three adaptor Src-homology domains. The exchange activity is under the unique regulation by phosphorylation of tyrosine residues hidden by intra-molecular interactions. Deletion of the autoinhibitory N-terminal region results in an oncogenic protein, onco-Vav, leading to a potent activation of Rac GTPases whereas the proto-oncogene barely leads to transformation. Substitution of conserved residues of the SH2-SH3 adaptor region in onco-Vav reverses oncogenicity. While a unique substitution D797N did not affect transformation induced by onco-Vav, we demonstrate that this single substitution leads to transformation in the Vav1 proto-oncogene highlighting the pivotal role of the adaptor region. Moreover, we identified the cell junction protein β-catenin as a new Vav1 interacting partner. We show that the oncogenicity of activated Vav1 proto-oncogene is associated with a non-degradative phosphorylation of β-catenin at residues important for its functions and its redistribution along the cell membrane in fibroblasts. In addition, a similar interaction is evidenced in epithelial lung cancer cells expressing ectopically Vav1. In these cells, Vav1 is also involved in the modulation of β-catenin phosphorylation. Altogether, our data highlight that only a single mutation in the proto-oncogene Vav1 enhances tumorigenicity. INTRODUCTION The Vav1 proto-oncogene has a restricted hematopoietic expression and exhibits both GTP/GDP exchange activities (GEF) for Rho family GTPases and adaptor functions within signalling complexes [1, 2]. Two other genes, Vav2 and Vav3 belong to the same family of signalling effectors and share high structural similarities and properties with Vav1. Unlike Vav1, Vav2 and Vav3 have an ubiquitous expression [3, 4]. Vav proteins display a number of characteristic structural domains with homology for: Calponin (CH), Dbl (DH), Pleckstrin (PH) and Src (SH2 and SH3) altogether with acidic residues-rich (AcR) and cysteine-rich (CR) motives. These domains mediate interactions with membrane receptors

Regulatory interplay between Vav1, Syk and β-catenin occurs in lung cancer cells

International audienceVav1 exhibits two signal transducing properties as an adaptor protein and a regulator of cytoskeleton organization through its Guanine nucleotide Exchange Factor module. Although the expression of Vav1 is restricted to the hematopoietic lineage, its ectopic expression has been unraveled in a number of solid tumors. In this study, we show that in lung cancer cells, as such in hematopoietic cells, Vav1 interacts with the Spleen Tyrosine Kinase, Syk. Likewise, Syk interacts with β-catenin and, together with Vav1, regulates the phosphorylation status of β-catenin. Depletion of Vav1, Syk or β-catenin inhibits Rac1 activity and decreases cell migration suggesting the interplay of the three effectors to a common signaling pathway. This model is further supported by the finding that in turn, β-catenin regulates the transcription of Syk gene expression. This study highlights the elaborated connection between Vav1, Syk and β-catenin and the contribution of the trio to cell migration

Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia

International audienceIn Chronic Lymphocytic Leukemia (CLL), infiltration of lymph nodes by leukemic cells is observed in patients with progressive disease and adverse outcome. We have previously demonstrated that B-cell receptor (BCR) engagement resulted in CXCR4 down-regulation in CLL cells, correlating with a shorter progression-free survival in patients. In this study, we show a simultaneous down-regulation of CXCR4, CXCR5 and CD62L upon BCR triggering. While concomitant CXCR4 and CXCR5 down-regulation involves PKDs, CD62L release relies on PKC activation. BCR engagement induces PI3K-δ-dependent phosphorylation of PKD2 and 3, which in turn phosphorylate CXCR4 Ser324/325. Moreover, upon BCR triggering, PKD phosphorylation levels correlate with the extent of membrane CXCR4 decrease. Inhibition of PKD activity restores membrane expression of CXCR4 and migration towards CXCL12 in BCR-responsive cells in vitro. In terms of pathophysiology, BCR-dependent CXCR4 down-regulation is observed in leukemic cells from patients with enlarged lymph nodes, irrespective of their IGHV mutational status. Taken together, our results demonstrate that PKD-mediated CXCR4 internalization induced by BCR engagement in B-CLL is associated with lymph node enlargement and suggest PKD as a potential druggable target for CLL therapeutics

A polyphenol-rich cranberry extract reverses insulin resistance and hepatic steatosis independently of body weight loss

Objective: Previous studies have reported that polyphenol-rich extracts from various sources can prevent obesity and associated gastro-hepatic and metabolic disorders in diet-induced obese (DIO) mice. However, whether such extracts can reverse obesity-linked metabolic alterations remains unknown. In the present study, we aimed to investigate the potential of a polyphenol-rich extract from cranberry (CE) to reverse obesity and associated metabolic disorders in DIO-mice. Methods: Mice were pre-fed either a Chow or a High Fat-High Sucrose (HFHS) diet for 13 weeks to induce obesity and then treated either with CE (200 mg/kg, Chow + CE, HFHS + CE) or vehicle (Chow, HFHS) for 8 additional weeks. Results: CE did not reverse weight gain or fat mass accretion in Chow- or HFHS-fed mice. However, HFHS + CE fully reversed hepatic steatosis and this was linked to upregulation of genes involved in lipid catabolism (e.g., PPARα) and downregulation of several pro-inflammatory genes (eg, COX2, TNFα) in the liver. These findings were associated with improved glucose tolerance and normalization of insulin sensitivity in HFHS + CE mice. The gut microbiota of HFHS + CE mice was characterized by lower Firmicutes to Bacteroidetes ratio and a drastic expansion of Akkermansia muciniphila and, to a lesser extent, of Barnesiella spp, as compared to HFHS controls. Conclusions: Taken together, our findings demonstrate that CE, without impacting body weight or adiposity, can fully reverse HFHS diet-induced insulin resistance and hepatic steatosis while triggering A. muciniphila blooming in the gut microbiota, thus underscoring the gut-liver axis as a primary target of cranberry polyphenols. Author Video: Author Video Watch what authors say about their articles Keywords: Akkermansia, Barnesiella, Obesity, Vaccinium macrocarpon, Flavonoid