A Caribbean perspective on China–Caribbean relations: global IR, dependency and the postcolonial condition

The field of global international relations remains to a great extent aspirational and focussed on the critique of Western-centric perspectives or the appraisal of non-Western theories within their specific geographical and historical contexts. In this essay, we go a step further and transpose a set of Caribbean-based theories that gained prominence in the 1960s and 1970s to apply it to the study of China’s contemporary relations with the Caribbean Community, drawing broader implications for China’s Belt and Road Initiative. The Caribbean’s tradition of critical and radical thought raises important questions about continuing epistemic dependency, structural impediments to development in small and highly open states, and a number of unresolved issues relating to the postcolonial condition in former plantation societies. Drawing upon these insights, we contend that the expectations placed on the emerging ‘South–South’ link with China are easily overstated, given China’s elitist business-centric approach to development, the eschewing of participatory approaches in Sino–Caribbean ventures and the passive incorporation of the Caribbean into China’s global vision.Asian Studie

Hemispheric reconfigurations in Northern Amazonia: The ‘Three Guianas’ amid regional change and Brazilian hegemony

© 2016 Southseries Inc., www.thirdworldquarterly.com. Regional and hemispheric reconfigurations in Latin America and the Caribbean are increasingly mediated by Brazilian power, and the engagement of Guyana, Suriname and French Guiana with this emerging context is intriguing. They are tentatively moving away from a Caribbean region with which they are culturally contiguous, towards a South American continent in which they are geographically located. This is partly a reflection of the gradual opening up of the Northern Amazonian space that they share collectively, and also with Venezuela and Brazil. These processes are occurring as cause and effect of Brazil’s emergence as a regional–and even regionally hegemonic–power. With reference to wider debates on regionalism and hegemony, we analyse the uncertain consequences of these shifts

Identification of Selective Small Molecule Inhibitors of the Nucleotide-Binding Oligomerization Domain 1 (NOD1) Signaling Pathway

<div><p>NOD1 is an intracellular pattern recognition receptor that recognizes diaminopimelic acid (DAP), a peptidoglycan component in gram negative bacteria. Upon ligand binding, NOD1 assembles with receptor-interacting protein (RIP)-2 kinase and initiates a signaling cascade leading to the production of pro-inflammatory cytokines. Increased NOD1 signaling has been associated with a variety of inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. We utilized a cell-based screening approach with extensive selectivity profiling to search for small molecule inhibitors of the NOD1 signaling pathway. Via this process we identified three distinct chemical series, xanthines (SB711), quinazolininones (GSK223) and aminobenzothiazoles (GSK966) that selectively inhibited iE-DAP-stimulated IL-8 release via the NOD1 signaling pathway. All three of the newly identified compound series failed to block IL-8 secretion in cells following stimulation with ligands for TNF receptor, TLR2 or NOD2 and, in addition, none of the compound series directly inhibited RIP2 kinase activity. Our initial exploration of the structure-activity relationship and physicochemical properties of the three series directed our focus to the quinazolininone biarylsulfonamides (GSK223). Further investigation allowed for the identification of significantly more potent analogs with the largest boost in activity achieved by fluoro to chloro replacement on the central aryl ring. These results indicate that the NOD1 signaling pathway, similarly to activation of NOD2, is amenable to modulation by small molecules that do not target RIP2 kinase. These compounds should prove useful tools to investigate the importance of NOD1 activation in various inflammatory processes and have potential clinical utility in diseases driven by hyperactive NOD1 signaling.</p></div

Structure-activity relationship for aminobenzothiazole analogs (GSK966 and compounds 15–21) in the iE-DAP stimulated IL-8 production assay in 293/hNOD1 cells.

<p>Structure-activity relationship for aminobenzothiazole analogs (GSK966 and compounds 15–21) in the iE-DAP stimulated IL-8 production assay in 293/hNOD1 cells.</p

Scheme used to identify selective inhibitors of NOD1 stimulated IL-8 release in cells.

<p>In the primary HTS compounds that prevented iE-DAP induced cytokine in 293/hNOD1 cells were determined, followed by counter-screens to eliminate those compounds that also inhibited IL-8 induced via activation of NOD2, TNFR1 or TLR2, as well as compounds which directly inhibited RIP2 kinase activity. The activity of selective NOD1 inhibitors was then confirmed in HCT116 intestinal epithelial cells which express NOD1/2 endogenously, stimulated with either Tri-DAP or MDP.</p

Structure-activity relationship for xanthine analogs (SB711 and compounds 1–7) in the iE-DAP-stimulated IL-8 production assay in 293/hNOD1 cells.

<p>Structure-activity relationship for xanthine analogs (SB711 and compounds 1–7) in the iE-DAP-stimulated IL-8 production assay in 293/hNOD1 cells.</p

SAR for additional quinazolininone analogs (compounds 22–29) in the 293/hNOD1 assay of iE-DAP stimulated IL-8 production.

<p>SAR for additional quinazolininone analogs (compounds 22–29) in the 293/hNOD1 assay of iE-DAP stimulated IL-8 production.</p

Activity of NOD1 selective compounds and inhibitors of IKK and RIP2 in cell-based assays used for hit identification and triage.

<p>IC₅₀ values are given in micromolar. For each of the cell-based assays, the concentration of IL-8 released into medium was the end-point measured. For the RIPK2 biochemical assay, the level of RIPK2 autophosphorylation was measured. Cell-based assays included are:- Monocyte = human primary peripheral blood monocytes; 293/hNOD1 and 293/hNOD2 = HEK293 cell lines stably expressing full-length human NOD1 or NOD2, respectively; HCT116 = human colon carcinoma cells.</p

Identification of Benzimidazole Diamides as Selective Inhibitors of the Nucleotide-Binding Oligomerization Domain 2 (NOD2) Signaling Pathway

<div><p>NOD2 is an intracellular pattern recognition receptor that assembles with receptor-interacting protein (RIP)-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP) in the host cell cytoplasm, thereby inducing signals leading to the production of pro-inflammatory cytokines. The dysregulation of NOD2 signaling has been associated with various inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. To identify inhibitors of the NOD2 signaling pathway, we utilized a cell-based screening approach and identified a benzimidazole diamide compound designated GSK669 that selectively inhibited an MDP-stimulated, NOD2-mediated IL-8 response without directly inhibiting RIP2 kinase activity. Moreover, GSK669 failed to inhibit cytokine production in response to the activation of Toll-like receptor (TLR)-2, tumor necrosis factor receptor (TNFR)-1 and closely related NOD1, all of which share common downstream components with the NOD2 signaling pathway. While the inhibitors blocked MDP-induced NOD2 responses, they failed to block signaling induced by NOD2 over-expression or single stranded RNA, suggesting specificity for the MDP-induced signaling complex and activator-dependent differences in NOD2 signaling. Investigation of structure-activity relationship allowed the identification of more potent analogs that maintained NOD2 selectivity. The largest boost in activity was achieved by N-methylation of the C2-ethyl amide group. These findings demonstrate that the NOD2 signaling pathway is amenable to modulation by small molecules that do not target RIP2 kinase activity. The compounds we identified should prove useful tools to investigate the importance of NOD2 in various inflammatory processes and may have potential clinical utility.</p></div