New and Evolving Trends in International Security

This report focuses on selected international security areas. At the theoretical level, it discusses new approaches to security dominated by multiplicity and complexity, with a special emphasis on three emerging concepts that have been increasingly used in security studies: globalization, human security and securitization. At the empirical level, it first looks at the a number of new security challenges, namely terrorism, health pandemics, international migration, environmental security, and energy security; assesses the impact of these challenges on the broader international security system; and examines the response these challenges have been given. Second, the report considers the changes to the international security system brought about by the rise of the BRICS. Third, it explores the changing nature of war, with an emphasis on the rise in civil wars, their relation to limited statehood and the role of external actors. Overall, the report presents an overarching analysis of developments in international security that will shape the way the subject is understood and approached in coming years

Protein kinase CK2 contributes to the organization of sodium channels in axonal membranes by regulating their interactions with ankyrin G

In neurons, generation and propagation of action potentials requires the precise accumulation of sodium channels at the axonal initial segment (AIS) and in the nodes of Ranvier through ankyrin G scaffolding. We found that the ankyrin-binding motif of Nav1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Nav channel interaction with ankyrins. Furthermore, we observed that CK2 is highly enriched at the AIS and the nodes of Ranvier in vivo. An ion channel chimera containing the Nav1.2 ankyrin-binding motif perturbed endogenous sodium channel accumulation at the AIS, whereas phosphorylation-deficient chimeras did not. Finally, inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G

Simultaneous Multi-Harmonic Imaging of Nanoparticles in Tissues for Increased Selectivity

We investigate the use of Bismuth Ferrite (BFO) nanoparticles for tumor tissue labelling in combination with infrared multi-photon excitation at 1250 nm. We report the efficient and simultaneous generation of second and third harmonic by the nanoparticles. On this basis, we set up a novel imaging protocol based on the co-localization of the two harmonic signals and demonstrate its benefits in terms of increased selectivity against endogenous background sources in tissue samples. Finally, we discuss the use of BFO nanoparticles as mapping reference structures for correlative light-electron microscopy.Comment: 19 pages, 6 figure

Ankyrin G restricts ion channel diffusion at the axonal initial segment before the establishment of the diffusion barrier

Ion channel immobilization by ankyrin G is regulated by casein kinase 2 in immature hippocampal neurons

αTAT1 catalyses microtubule acetylation at clathrin-coated pits.

In most eukaryotic cells microtubules undergo post-translational modifications such as acetylation of α-tubulin on lysine 40, a widespread modification restricted to a subset of microtubules that turns over slowly. This subset of stable microtubules accumulates in cell protrusions and regulates cell polarization, migration and invasion. However, mechanisms restricting acetylation to these microtubules are unknown. Here we report that clathrin-coated pits (CCPs) control microtubule acetylation through a direct interaction of the α-tubulin acetyltransferase αTAT1 (refs 8, 9) with the clathrin adaptor AP2. We observe that about one-third of growing microtubule ends contact and pause at CCPs and that loss of CCPs decreases lysine 40 acetylation levels. We show that αTAT1 localizes to CCPs through a direct interaction with AP2 that is required for microtubule acetylation. In migrating cells, the polarized orientation of acetylated microtubules correlates with CCP accumulation at the leading edge, and interaction of αTAT1 with AP2 is required for directional migration. We conclude that microtubules contacting CCPs become acetylated by αTAT1. In migrating cells, this mechanism ensures the acetylation of microtubules oriented towards the leading edge, thus promoting directional cell locomotion and chemotaxis

Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance

International audienceAbstract Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression

p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer

The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.Fil: Lodillinsky, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre National de la Recherche Scientifique; FranciaFil: Infante, E.. Centre National de la Recherche Scientifique; FranciaFil: Guichard, A.. Centre National de la Recherche Scientifique; FranciaFil: Chaligné, R.. Génétique Et Biologie Du Développement; FranciaFil: Fuhrmann, L.. Centre National de la Recherche Scientifique; FranciaFil: Cyrta, J.. Centre National de la Recherche Scientifique; FranciaFil: Irondelle, Marie. Centre National de la Recherche Scientifique; FranciaFil: Lagoutte, Emilie. Centre National de la Recherche Scientifique; FranciaFil: Vacher, Sophie. Institut Curie; FranciaFil: Bonsang-Kitzis, H.. Institut Curie; FranciaFil: Glukhova, M.. Centre National de la Recherche Scientifique; FranciaFil: Reyal, F.. Institut Curie; FranciaFil: Bièche, I.. Institut Curie; FranciaFil: Vincent Salomon, Anne. Institut Curie; Francia. Génétique Et Biologie Du Développement; FranciaFil: Chavrier, Philippe. Centre National de la Recherche Scientifique; Franci