The international politics of truth: C. Wright Mills and the sociology of the international

C. Wright Mills's critical work on international relations is well known, but is often dismissed as being unscholarly, reductionist, and overly polemical. However, seeing the work in the context of his earlier career can allow for a new perspective, with Mills's activist views on war and militarism shaped very clearly by his earlier theoretical and political commitments. Mills developed a distinctive political sociological understanding of international politics, theorising the state as a historically-situated structural determinant of international power: a network of elite power that was contextualised by the influence of the socially constructed realities of the international created by elites. Mills's crucial critical contribution was to see the role of the intellectual as criticising these realities through the imaginative reconceptualisation of the world, which he called the ‘politics of truth’. The article argues the international politics of truth was not only Mills's distinctive theory of the international, but that it was clearly supported by his early theorisation of the international. A revised view of the importance of Mills's international relations work can help to situate Mills as part of a broader tradition of IR scholarship, a lost lineage of the critical historical and political sociology of the international.

VgrG-dependent effectors and chaperones modulate the assembly of the type VI secretion system

The type VI secretion system (T6SS) is a spear-like nanomachine found in gram-negative pathogens for delivery of toxic effectors to neighboring bacterial and host cells. Its assembly requires a tip spike complex consisting of a VgrG-trimer, a PAAR protein, and the interacting effectors. However, how the spike controls T6SS assembly remains elusive. Here we investigated the role of three VgrG-effector pairs in Aeromonas dhakensis strain SSU, a clinical isolate with a constitutively active T6SS. By swapping VgrG tail sequences, we demonstrate that the C-terminal ~30 amino-acid tail dictates effector specificity. Double deletion of vgrG1&2 genes (VgrG3+) abolished T6SS secretion, which can be rescued by ectopically expressing chimeric VgrG3 with a VgrG1/2-tail but not the wild type VgrG3. In addition, deletion of effector-specific chaperones also severely impaired T6SS secretion, despite the presence of intact VgrG and effector proteins, in both SSU and Vibrio cholerae V52. We further show that SSU could deliver a V. cholerae effector VasX when expressing a plasmid-borne chimeric VgrG with VasX-specific VgrG tail and chaperone sequences. Pull-down analyses show that two SSU effectors, TseP and TseC, could interact with their cognate VgrGs, the baseplate protein TssK, and the key assembly chaperone TssA. Effectors TseL and VasX could interact with TssF, TssK and TssA in V. cholerae. Collectively, we demonstrate that chimeric VgrG-effector pairs could bypass the requirement of heterologous VgrG complex and propose that effector-stuffing inside the baseplate complex, facilitated by chaperones and the interaction with structural proteins, serves as a crucial structural determinant for T6SS assembly.

Microtubule-modulating agents in the fight against neurodegeneration: Will it ever work?

: The microtubule skeleton plays an essential role in nerve cells as the most important structural determinant of morphology and as a highway for axonal transport processes. Many neurodegenerative diseases are characterized by changes in the structure and organization of microtubules and microtubule-regulating proteins such as the microtubule-associated protein tau, which exhibits characteristic changes in a whole class of diseases collectively referred to as tauopathies. Changes in the dynamics of microtubules appear to occur early under neurodegenerative conditions and are also likely to contribute to age-related dysfunction of neurons. Thus, modulating microtubule dynamics and correcting impaired microtubule stability can be a useful neuroprotective strategy to counteract disruption of the microtubule system in disease and aging. In this article, we review current microtubule-directed approaches for the treatment of neurodegenerative diseases with microtubules as drug target, tau as drug target, and posttranslational modifications as potential modifiers of the microtubule system. We discuss limitations of the approaches that can be traced back to the rather unspecific mechanism of action, which causes undesirable side effects on non-neuronal cell types or which are due to the disruption of non-microtubule-related interactions. We also develop some thoughts on how the specificity of the approaches can be improved and what further targets could be used for modulating substances.

Zipper head mechanism of telomere synthesis by human telomerase

Telomerase, a multi-subunit ribonucleoprotein complex, is a unique reverse transcriptase that catalyzes the processive addition of a repeat sequence to extend the telomere end using a short fragment of its own RNA component as the template. Despite recent structural characterizations of human and Tetrahymena telomerase, it is still a mystery how telomerase repeatedly uses its RNA template to synthesize telomeric DNA. Here, we report the cryo-EM structure of human telomerase holoenzyme bound with telomeric DNA at resolutions of 3.5 Å and 3.9 Å for the catalytic core and biogenesis module, respectively. The structure reveals that a leucine residue Leu980 in telomerase reverse transcriptase (TERT) catalytic subunit functions as a zipper head to limit the length of the short primer–template duplex in the active center. Moreover, our structural and computational analyses suggest that TERT and telomerase RNA (hTR) are organized to harbor a preformed active site that can accommodate short primer–template duplex substrates for catalysis. Furthermore, our findings unveil a double-fingers architecture in TERT that ensures nucleotide addition processivity of human telomerase. We propose that the zipper head Leu980 is a structural determinant for the sequence-based pausing signal of DNA synthesis that coincides with the RNA element-based physical template boundary. Functional analyses unveil that the non-glycine zipper head plays an essential role in both telomerase repeat addition processivity and telomere length homeostasis. In addition, we also demonstrate that this zipper head mechanism is conserved in all eukaryotic telomerases. Together, our study provides an integrated model for telomerase-mediated telomere synthesis.

β2-adrenoceptor ligand efficacy is tuned by a two-stage interaction with the Gαs C terminus

Classical pharmacological models have incorporated an “intrinsic efficacy” parameter to capture system-independent effects of G protein–coupled receptor (GPCR) ligands. However, the nonlinear serial amplification of downstream signaling limits quantitation of ligand intrinsic efficacy. A recent biophysical study has characterized a ligand “molecular efficacy” that quantifies the influence of ligand-dependent receptor conformation on G protein activation. Nonetheless, the structural translation of ligand molecular efficacy into G protein activation remains unclear and forms the focus of this study. We first establish a robust, accessible, and sensitive assay to probe GPCR interaction with G protein and the Gα C terminus (G-peptide), an established structural determinant of G protein selectivity. We circumvent the need for extensive purification protocols by the single-step incorporation of receptor and G protein elements into giant plasma membrane vesicles (GPMVs). We use previously established SPASM FRET sensors to control the stoichiometry and effective concentration of receptor–G protein interactions. We demonstrate that GPMV-incorporated sensors (v-SPASM sensors) provide enhanced dynamic range, expression-insensitive readout, and a reagent level assay that yields single point measurements of ligand molecular efficacy. Leveraging this technology, we establish the receptor–G-peptide interaction as a sufficient structural determinant of this receptor-level parameter. Combining v-SPASM measurements with molecular dynamics (MD) simulations, we elucidate a two-stage receptor activation mechanism, wherein receptor–G-peptide interactions in an intermediate orientation alter the receptor conformational landscape to facilitate engagement of a fully coupled orientation that tunes G protein activation.

Deciphering the structural attributes of protein–heparan sulfate interactions using chemo-enzymatic approaches and NMR spectroscopy

Heparan sulfates (HS) is a polysaccharide found at the cell surface, where it mediates interactions with hundreds of proteins and regulates major pathophysiological processes. HS is highly heterogeneous and structurally complex and examples that define their structure–activity relationships remain limited. Here, in order to characterize a protein–HS interface and define the corresponding saccharide-binding domain, we present a chemo-enzymatic approach that generates 13C-labeled HS-based oligosaccharide structures. Nuclear magnetic resonance (NMR) spectroscopy, which efficiently discriminates between important or redundant chemical groups in the oligosaccharides, is employed to characterize these molecules alone and in interaction with proteins. Using chemokines as model system, docking based on NMR data on both proteins and oligosaccharides enable the identification of the structural determinant involved in the complex. This study shows that both the position of the sulfo groups along the chain and their mode of presentation, rather than their overall number, are key determinant and further points out the usefulness of these 13C-labeled oligosaccharides in obtaining detailed structural information on HS–protein complexes.

Structural Determinants of Poverty in the Savannah Region of Togo

The region of Savanes remains the poorest region of Togo, despite several years of colonial and post-colonial public interventions. The persistence of this multidimensional poverty has led to various questions about the real determinants that seem to limit the results of these various interventions. A review of the available literature and statistical datas, the interviewsl and focus group conducted in 2017 provided key information’s that was triangulated. Subsequent analyzes and results obtained clearly showed that the question of poverty in this region is the result of two structural determinants. The first determinant was the theoretical approach, the theory of growth poles, which has supported public interventions in this region. This approach has made the region of Savanes, a rural or peripheral region without large production processing unit and structurally dependent for its development of large urban centers. The second structural determinant is the mutation of local actors in a cycle of new dependencies on non-state actors for solving their domestic problems and development.