Charlotte A. G. H. van Gelder
Dec 1, 2020; 19:1952-1967
Research

Nadine Prust
Dec 17, 2020; 0:RA120.002232v1-mcp.RA120.002232
Research

Qin Zhang
Nov 17, 2020; 0:RA120.002325v1-mcp.RA120.002325
Research

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
Research

The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein–coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule–binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR.

In Alzheimer's disease (AD), tau, a microtubule-associated protein (MAP), becomes hyperphosphorylated, aggregates, and accumulates in the somato-dendritic compartment of neurons. In parallel to its intracellular accumulation in AD, tau is also released in the extracellular space, as revealed by its increased presence in cerebrospinal fluid (CSF). Consistent with this, recent studies, including ours, have reported that neurons secrete tau, and several therapeutic strategies aim to prevent the intracellular tau accumulation. Previously, we reported that late endosomes were implicated in tau secretion. Here, we explore the possibility of preventing intracellular tau accumulation by increasing tau secretion. Using neuronal models, we investigated whether overexpression of the vesicle-associated membrane protein 8 (VAMP8), an R-SNARE found on late endosomes, could increase tau secretion. The overexpression of VAMP8 significantly increased tau secretion, decreasing its intracellular levels in the neuroblastoma (N2a) cell line. Increased tau secretion by VAMP8 was also observed in murine hippocampal slices. The intracellular reduction of tau by VAMP8 overexpression correlated to a decrease of acetylated tubulin induced by tau overexpression in N2a cells. VAMP8 staining was preferentially found on late endosomes in N2a cells. Using total internal reflection fluorescence (TIRF) microscopy, the fusion of VAMP8-positive vesicles with the plasma membrane was correlated to the depletion of tau in the cytoplasm. Finally, overexpression of VAMP8 reduced the intracellular accumulation of tau mutants linked to frontotemporal dementia with parkinsonism and α-synuclein by increasing their secretion. Collectively, the present data indicate that VAMP8 could be used to increase tau and α-synuclein clearance to prevent their intracellular accumulation.

Neutrophils are primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils prevent the spread of pathogens is NETosis, the extrusion of cellular DNA resulting in neutrophil extracellular traps (NETs). The protease neutrophil elastase (NE) has been implicated in the formation of NETs through proteolysis of nuclear proteins leading to chromatin decondensation. In addition to NE, neutrophils contain three other serine proteases that could compensate if the activity of NE was neutralized. However, whether they do play such a role is unknown. Thus, we deployed recently described specific inhibitors against all four of the neutrophil serine proteases (NSPs). Using specific antibodies to the NSPs along with our labeled inhibitors, we show that catalytic activity of these enzymes is not required for the formation of NETs. Moreover, the NSPs that decorate NETs are in an inactive conformation and thus cannot participate in further catalytic events. These results indicate that NSPs play no role in either NETosis or arming NETs with proteolytic activity.

Genetic mutations related to ALS, a progressive neurological disease, have been discovered in the gene encoding σ-1 receptor (σ1R). We previously reported that σ1RE102Q elicits toxicity in cells. The σ1R forms oligomeric states that are regulated by ligands. Nevertheless, little is known about the effect of ALS-related mutations on oligomer formation. Here, we transfected NSC-34 cells, a motor neuronal cell line, and HEK293T cells with σ1R-mCherry (mCh), σ1RE102Q-mCh, or nontagged forms to investigate detergent solubility and subcellular distribution using immunocytochemistry and fluorescence recovery after photobleaching. The oligomeric state was determined using crosslinking procedure. σ1Rs were soluble to detergents, whereas the mutants accumulated in the insoluble fraction. Within the soluble fraction, peak distribution of mutants appeared in higher sucrose density fractions. Mutants formed intracellular aggregates that were co-stained with p62, ubiquitin, and phosphorylated pancreatic eukaryotic translation initiation factor-2-α kinase in NSC-34 cells but not in HEK293T cells. The aggregates had significantly lower recovery in fluorescence recovery after photobleaching. Acute treatment with σ1R agonist SA4503 failed to improve recovery, whereas prolonged treatment for 48 h significantly decreased σ1RE102Q-mCh insolubility and inhibited apoptosis. Whereas σ1R-mCh formed monomers and dimers, σ1RE102Q-mCh also formed trimers and tetramers. SA4503 reduced accumulation of the four types in the insoluble fraction and increased monomers in the soluble fraction. The σ1RE102Q insolubility was diminished by σ1R-mCh co-expression. These results suggest that the agonist and WT σ1R modify the detergent insolubility, toxicity, and oligomeric state of σ1RE102Q, which may lead to promising new treatments for σ1R-related ALS.

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Nicholas D. LeBlond
Dec 1, 2020; 61:1697-1706
Research Articles

The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves  are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as  prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using -3 supplementation show unclear and sometimes negative results. Using animal models of corneal nerve damage, we show that treating corneas with pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) increases nerve regeneration, wound healing, and tear secretion. The mechanism involves the activation of a calcium-independent phospholipase A2 (iPLA2) that releases the incorporated DHA from phospholipids and enhances the synthesis of docosanoids neuroprotectin D1 (NPD1) and a new resolvin stereoisomer  RvD6i. NPD1 stimulates the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and of semaphorin 7A (Sema7A).  RvD6i treatment of injured corneas modulates gene expression in the TG resulting in enhanced neurogenesis; decreased neuropathic pain and increased sensitivity. Taken together, these results represent a promising therapeutic option to re-establish the homeostasis of the cornea.

Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

N-acylethanolamines (NAEs) are endogenous lipid-signaling molecules derived from fatty acids that regulate numerous biological functions, including in the brain. Interestingly, NAEs are elevated in the absence of fatty acid amide hydrolase (FAAH) and following CO₂-induced ischemia/hypercapnia, suggesting a neuroprotective response. Tetracosahexaenoic acid (THA) is a product and precursor to DHA; however, the NAE product, tetracosahexaenoylethanolamide (THEA), has never been reported. Presently, THEA was chemically synthesized as an authentic standard to confirm THEA presence in biological tissues. Whole brains were collected and analyzed for unesterified THA, total THA, and THEA in wild-type and FAAH-KO mice that were euthanized by either head-focused microwave fixation, CO₂ + microwave, or CO₂ only. PPAR activity by transient transfection assay and ex vivo neuronal output in medium spiny neurons (MSNs) of the nucleus accumbens by patch clamp electrophysiology were determined following THEA exposure. THEA in the wild-type mice was nearly doubled (P < 0.05) following ischemia/hypercapnia (CO₂ euthanization) and up to 12 times higher (P < 0.001) in the FAAH-KO compared with wild-type. THEA did not increase (P > 0.05) transcriptional activity of PPARs relative to control, but 100 nM of THEA increased (P < 0.001) neuronal output in MSNs of the nucleus accumbens. Here were identify a novel NAE, THEA, in the brain that is elevated upon ischemia/hypercapnia and by KO of the FAAH enzyme. While THEA did not activate PPAR, it augmented the excitability of MSNs in the nucleus accumbens. Overall, our results suggest that THEA is a novel NAE that is produced in the brain upon ischemia/hypercapnia and regulates neuronal excitation.

The dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis. Using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), we aimed to clarify the role of myeloid-specific AMPK signaling in male and female mice made acutely atherosclerotic by injection of AAV vector encoding a gain-of-function mutant PCSK9 (PCSK9-AAV) and WD feeding. After 6 weeks of WD feeding, mice received a daily injection of either the AMPK activator A-769662 or a vehicle control for an additional 6 weeks. Following this (12 weeks total), we assessed myeloid cell populations and differences between genotype or sex were not observed. Similarly, aortic sinus plaque size, lipid staining, and necrotic area did not differ in male and female MacKO mice compared with their littermate floxed controls. Moreover, therapeutic intervention with A-769662 showed no treatment effect. There were also no observable differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area and markers of autophagy showed no effect of either lacking AMPK signaling or AMPK activation. Our data suggest that while defined roles for each catalytic AMPK subunit have been identified, complete deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Additionally, these findings suggest that intervention with the first-generation AMPK activator A-769662 is not able to stem the progression of atherosclerosis.

Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.

The assembly of the postsynaptic transmitter sensing machinery at inhibitory nerve cell synapses requires the intimate interplay between cell adhesion proteins, scaffold and adaptor proteins, and γ-aminobutyric acid (GABA) or glycine receptors. We developed an in vitro membrane system to reconstitute this process, to identify the essential protein components, and to define their mechanism of action, with a specific focus on the mechanism by which the cytosolic C terminus of the synaptic cell adhesion protein Neuroligin-2 alters the conformation of the adaptor protein Collybistin-2 and thereby controls Collybistin-2-interactions with phosphoinositides (PtdInsPs) in the plasma membrane. Supported hybrid membranes doped with different PtdInsPs and 1,2-dioleoyl-sn-glycero-3-{[N-(5-amino-1-carboxypentyl)iminodiacetic acid]succinyl} nickel salt (DGS-NTA(Ni)) to allow for the specific adsorption of the His6-tagged intracellular domain of Neuroligin-2 (His-cytNL2) were prepared on hydrophobically functionalized silicon dioxide substrates via vesicle spreading. Two different collybistin variants, the WT protein (CB2SH3) and a mutant that adopts an intrinsically 'open' and activated conformation (CB2SH3/W24A-E262A), were bound to supported membranes in the absence or presence of His-cytNL2. The corresponding binding data, obtained by reflectometric interference spectroscopy, show that the interaction of the C terminus of Neuroligin-2 with Collybistin-2 induces a conformational change in Collybistin-2 that promotes its interaction with distinct membrane PtdInsPs.

Ventilator-associated pneumonia (VAP) is a common hospital-acquired infection, leading to high morbidity and mortality. Currently, bronchoalveolar lavage (BAL) is used in hospitals for VAP diagnosis and guiding treatment options. Although BAL collection procedures are invasive, alternatives such as endotracheal aspirates (ETA) may be of diagnostic value, however, their use has not been thoroughly explored. Longitudinal ETA and BAL were collected from 16 intubated patients up to 15 days, of which 11 developed VAP. We conducted a comprehensive LC–MS/MS based proteome and metabolome characterization of longitudinal ETA and BAL to detect host and pathogen responses to VAP infection. We discovered a diverse ETA proteome of the upper airways reflective of a rich and dynamic host-microbe interface. Prior to VAP diagnosis by microbial cultures from BAL, patient ETA presented characteristic signatures of reactive oxygen species and neutrophil degranulation, indicative of neutrophil mediated pathogen processing as a key host response to the VAP infection. Along with an increase in amino acids, this is suggestive of extracellular membrane degradation resulting from proteolytic activity of neutrophil proteases. The metaproteome approach successfully allowed simultaneous detection of pathogen peptides in patients' ETA, which may have potential use in diagnosis. Our findings suggest that ETA may facilitate early mechanistic insights into host-pathogen interactions associated with VAP infection and therefore provide its diagnosis and treatment.

The neuronal basis of complex social behavior is still poorly understood. In honeybees, reproductive investment decisions are made at the colony-level. Queens develop from female-destined larvae that receive alloparental care from nurse bees in the form of ad-libitum royal jelly (RJ) secretions. Typically, the number of raised new queens is limited but genetic breeding of "royal jelly bees" (RJBs) for enhanced RJ production over decades has led to a dramatic increase of reproductive investment in queens. Here, we compare RJBs to unselected Italian bees (ITBs) to investigate how their cognitive processing of larval signals in the mushroom bodies (MBs) and antennal lobes (ALs) may contribute to their behavioral differences. A cross-fostering experiment confirms that the RJB syndrome is mainly due to a shift in nurse bee alloparental care behavior. Using olfactory conditioning of the proboscis extension reflex, we show that the RJB nurses spontaneously respond more often to larval odors compared with ITB nurses but their subsequent learning occurs at similar rates. These phenotypic findings are corroborated by our demonstration that the proteome of the brain, particularly of the ALs differs between RJBs and ITBs. Notably, in the ALs of RJB newly emerged bees and nurses compared with ITBs, processes of energy and nutrient metabolism, signal transduction are up-regulated, priming the ALs for receiving and processing the brood signals from the antennae. Moreover, highly abundant major royal jelly proteins and hexamerins in RJBs compared with ITBs during early life when the nervous system still develops suggest crucial new neurobiological roles for these well-characterized proteins. Altogether, our findings reveal that RJBs have evolved a strong olfactory response to larvae, enabled by numerous neurophysiological adaptations that increase the nurse bees' alloparental care behavior.

Small admixtures in water, e.g. of metal ions, often act as cell growth regulators. Here we report that enrichment of deuterium content in water, normally found at 8 mm concentration, two-three folds increases cell proliferation and lowers the oxidative stress level as well. Acting as an anti-oxidant, deuterium-enriched water prevents the toxic effect of such oxidative agents as hydrogen peroxide and auranofin. This action is opposite to that of deuterium depletion that is known to suppress cell growth and induce oxidative stress in mitochondria. We thus hypothesize that deuterium may be a natural cell growth regulator that controls mitochondrial oxidation-reduction balance. Because growth acceleration is reduced approximately by half by addition to water a minute amount (0.15%) of ¹⁸O isotope, at least part of the deuterium effect on cell growth can be explained by the isotopic resonance phenomenon. A slight (2-fold) enrichment of deuterium in water accelerates human cell growth. Quantitative MS based proteomics determined changes in protein abundances and redox states and found that deuterium-enriched water acts mainly through decreasing ROS production in mitochondria. This action is opposite to that of deuterium depletion that suppresses cell growth by inducing oxidative stress. Thus deuterium may be a natural cell growth regulator that controls mitochondrial oxidation-reduction balance. The role of isotopic resonance in this effect was validated by further experiments on bacteria.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

At neuronal synapses, activation of group I metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-induced signaling pathways, we integrated quantitative phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy in cultured hippocampal neurons stimulated with DHPG, a specific agonist for group I mGluRs. We identified several kinases with important roles in DHPG-induced mGluR activation, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation were identified, whereby Intersectin-1 was validated as a novel player in this pathway. This study revealed several new insights into the molecular pathways downstream of group I mGluR activation in hippocampal neurons, and provides a rich resource for further analyses.

En fonction de leurs causes, les douleurs du côté droit peuvent se manifester de différentes manières. Les symptômes de ces douleurs peuvent également varier d’une personne à une autre. Certaines personnes décrivent les douleurs du côté comme des sensations de crampes, de brûlures ou de piqûres. D’autres en revanche parlent de douleurs sourdes ou lancinantes qui irradient […]

L’article Douleurs côté droit sous les côtes : comment les soulager naturellement est apparu en premier sur Ortho Doc France.

Pour beaucoup de personnes, la perte de poids rime obligatoirement avec une période de privation. Mais contrairement à ces idées reçues, il est bien possible d’observer un régime pour perdre du poids tout en vous faisant plaisir. Découvrez notre recette minceur de biscuits croquants sans beurre aux flocons d’avoine qui raviront vos papilles sans pour autant vous apporter […]

L’article Quelle est la meilleure recette minceur à base de biscuits aux flocons d’avoine ? est apparu en premier sur Ortho Doc France.

Pour de nombreuses personnes, perte de poids rime obligatoirement avec privations. Et si vous appreniez aujourd’hui que vous pouvez perdre efficacement vos kilos en trop sans pour autant vous priver excessivement ? De nombreux programmes minceur et de rééquilibrage, notamment Croq’kilos offrent ce genre d’alternative. Mais de quoi s’agit-il réellement ? C’est quoi Croq’Kilos ? Croq’Kilos […]

L’article Croq’Kilos : programme minceur, rééquilibrage alimentaire est apparu en premier sur Ortho Doc France.

Hirschsprung disease (HSCR) is a heterogeneous group of neurocristopathy characterized by the absence of the enteric ganglia along a variable length of the intestine. Genetic defects play a major role in the pathogenesis of HSCR while family studies of pathogenic variants in all the known genes (loci) only demonstrate incomplete penetrance and variable expressivity for unknown reasons. Here, we applied large-scale, quantitative proteomics of human colon tissues from 21 patients using iTRAQ method followed by bioinformatics analysis. Selected findings were confirmed by parallel reaction monitoring (PRM) verification. At last the interesting differentially expressed proteins were confirmed by western blot. A total of 5341 proteins in human colon tissues were identified. Among them, 664 proteins with >1.2-fold difference were identified in 6 groups: groups A1 and A2 pooled protein from the ganglionic and aganglionic colon of male, long-segment HSCR patients (L-HSCR, n=7); groups B1 and B2 pooled protein from the ganglionic and aganglionic colon of male, short-segment HSCR patients (S-HSCR, n=7); and groups C1 and C2 pooled protein from the ganglionic and aganglionic colon of female, S-HSCR patients (n=7). Based on these analyses, 49 proteins from 5 pathways were selected for PRM verification, including ribosome, endocytosis, spliceosome, oxidative phosphorylation and cell adhesion. The downregulation of three neuron projection development genes ARF4, KIF5B and RAB8A in the aganglionic part of the colon were verified in 15 paired colon samples using WB. The findings of this study will shed new light on the pathogenesis of HSCR and facilitate the development of therapeutic targets.

Extracellular vesicle (EV) proteins from acute myeloid leukemia (AML) cell lines were analyzed using mass spectrometry. The analyses identified 2450 proteins, including 461 differentially expressed proteins (290 upregulated and 171 downregulated). CD53 and CD47 were upregulated and were selected as candidate biomarkers. The association between survival of patients with AML and the expression levels of CD53 and CD47 at diagnosis was analyzed using mRNA expression data from The Cancer Genome Atlas database. Patients with higher expression levels showed significantly inferior survival than those with lower expression levels. Enzyme-linked immunosorbent assay results of the expression levels of CD53 and CD47 from EVs in the bone marrow of patients with AML at diagnosis and at the time of complete remission with induction chemotherapy revealed that patients with downregulated CD53 and CD47 expression appeared to relapse less frequently. Network model analysis of EV proteins revealed several upregulated kinases, including LYN, CSNK2A1, SYK, CSK, and PTK2B. The potential cytotoxicity of several clinically applicable drugs that inhibit these kinases was tested in AML cell lines. The drugs lowered the viability of AML cells. The collective data suggest that AML-derived EVs could reflect essential leukemia biology.

Staphylococcus aureus is a major cause of infections worldwide and infection results in a variety of diseases. As of no surprise, protein phosphorylation is an important game player in signaling cascades and has been shown to be involved in S. aureus virulence. Albeit long neglected, eukaryotic-type serine/threonine kinases in S. aureus have been implicated in this complex signaling cascades. Due to the sub-stoichiometric nature of protein phosphorylation and a lack of suitable analysis tools, the knowledge of these cascades is however, to date, still limited.

Here, were apply an optimized protocol for efficient phosphopeptide enrichment via Fe3+-IMAC followed by LC-MS/MS to get a better understanding of the impact of protein phosphorylation on the complex signaling networks involved in pathogenicity. By profiling a serine/threonine kinase and phosphatase mutant from a methicillin-resistant S. aureus mutant library, we generated the most comprehensive phosphoproteome dataset of S. aureus to date, aiding a better understanding of signaling in bacteria. With the identification of 3800 class I p-sites we were able to increase the number of identifications by more than 21 times compared to recent literature. In addition, we were able to identify 74 downstream targets of the only reported eukaryotic-type Ser/Thr kinase of the S. aureus strain USA300, Stk1. This work allowed an extensive analysis of the bacterial phosphoproteome and indicates that Ser/Thr kinase signaling is far more abundant than previously anticipated in S. aureus.

Drones and the European Union: Prospects for a Common Future Research paper sysadmin 30 January 2018

The debate over the use of drones is an opportunity for states to identify elements of military practice that their publics find uncomfortable or troubling, and to explain these areas of military operations in context.

Summary

• The debate over the use of drones is an opportunity for states to identify elements of military practice that their publics find uncomfortable or troubling, and to explain these areas of military operations in context.
• Countries would benefit from working together to identify accountability gaps arising from fundamental elements of military cooperation, including the role of intelligence transfers in joint operations, and the distribution of responsibility for lethal actions in the context of coalition operations.
• Transparency in investigation procedures, as well as devoting sufficient resources towards ensuring that mistakes are identified, will improve the perception of drone use among domestic audiences.
• Identifying and communicating common standards and practices of mitigating complicity should be a priority for countries to ensure that they do not unwittingly become complicit in unlawful lethal operations.
• Although operational safety may hinder the ability of states to be completely transparent, understanding among the general public could be improved through the communication of policies and procedures regarding non-lethal assistance to partner states conducting lethal operations, both inside and outside the context of an armed conflict.

Exploring Transatlantic Responses to Far-right Populism in Europe: Simulation Exercise Research paper sysadmin 1 May 2018

A new paper summarizes the findings of a recent simulation exercise exploring how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state.

Summary

• To better understand how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state, Chatham House organized a simulation event involving a group of experts drawn from the public sector, academia and NGOs.
• Simulation exercises enable the testing and modelling of the responses of different actors when presented with specific situations; participants’ interactions in a given set of circumstances are explored, and patterns of negotiation are captured and analysed.
• In this simulation, European, US and multilateral representatives were given the task of managing relations with Baltia, a fictional Eastern European state on the verge of electing a far-right nationalist, Eurosceptic government. They were then challenged to manage their relationship with Baltia after it had elected such a government, which was pushing for a ‘leave’ vote in a planned referendum on the country’s continued EU membership.
• The simulation highlighted a number of issues:
  • Limited instruments are available to liberal democratic governments where there is cause for concern regarding the outcome of an election in an allied country. There are relatively few tools at the disposal of governments to support political allies, or to prevent outcomes that are perceived as threatening democratic norms. The simulation reinforced the view that interventionist moves, either from the European Commission or from individual national governments, would be more likely to come in response to an unfavourable development rather than pre-emptively.
  • The EU, and caucuses of European states, are the main international interlocutors in this type of political crisis involving an EU member state. The US opted to play a limited role in the negotiations; the same was largely true for NATO, aside from its action in sharing intelligence about a potential coup in Baltia. France and Germany formed a natural working partnership, taking meetings together and coordinating policies first before discussing them with a wider European circle, although their positions did not always align.
  • The UK’s capacity to shape the outcome of collective EU discussions appeared more restricted, while Brexit also seemed to shape the response of other EU states to the developing situation in Baltia. Although member states were undoubtedly reluctant to see another country go down this route, they were also resolute in demonstrating a unity of approach and limited flexibility in the face of the new populist government’s attempt to divide them.

Cesar Hernandez scored 91 runs last season, the Phillies' highest mark since Rollins scored 102 in 2012. Now the luster is no longer there for players who score 100 runs or post 100 RBIs, but Hernandez should score at least 100 runs this season, if he stays healthy and if the Phillies' offense improves as expected.

Business Development in Madagascar: How to Enable Entrepreneurialism 15 November 2017 — 12:00PM TO 1:00PM Anonymous (not verified) 9 November 2017 Chatham House, London

Russia and Eurasia

Research on the former Soviet region explores geopolitics of various states, the domestic, foreign and security policy of Russia, and the conflict in Ukraine.

Key projects currently include examining Russia’s military mobilization, Ukraine’s reforms, the foreign policy of smaller states such as Armenia, oligarchy, and broader inter-state relations.

The Russia and Eurasia programme at Chatham House is a globally recognised focal point for analysis on how developments in this region impact on other states and institutions. 

War on Ukraine: The energy crisis and Europe’s impending long winter 2 November 2022 — 5:00PM TO 6:00PM Anonymous (not verified) 4 October 2022 Online

Can Europe remain unified over the long winter?

Since Russia’s invasion of Ukraine, the global community has been responding to significant price shocks, especially energy. As Europe heads into a particularly difficult winter, policymakers are grappling with the costs, both political and economic, required to make sure Russian energy blackmail does not succeed.

Retaining a unified front against Russia and providing continued support to the Ukrainian government will be great challenges. As the cold begins to bite, war fatigue may accelerate among the populations of Europe. Providing their people with adequate heat will not come cheaply for governments across the continent at a time of economic uncertainty.

At this critical moment of Russia’s invasion, experts discuss:

• Have European preparations been sufficient to stave off an energy crisis this winter?
• What will be Russia’s reaction during and after the winter period, particularly if Europe avoids energy market failures?
• How will this ‘energy crisis’ ensure future dependencies on single state actors of goods and services do not occur in the future?

Read the transcript. 

The World in Brief: European Court of Justice The World Today Anonymous (not verified) 29 July 2021

EU brings members into line over fundamental rights

The European Union has had a challenging start to the summer trying to uphold the rule of law and avoid democratic regression in its member states.

On July 14, the Polish constitutional court ruled that the country did not have to comply with the measures imposed by the European Court of Justice against its controversial judicial reforms, citing that these measures were not in line with the Polish constitution.

The ruling Law and Justice Party, known as PiS, has introduced extensive changes to the judiciary since coming to power six years ago. In 2018, the government appointed new judges and set up a disciplinary chamber for the Supreme Court, which was given a temporary suspension by the European Court of Justice in an interim decision last year.

PiS reasoned that the changes were necessary to eliminate corruption stemming from the communist era, but critics say it merely allows the government to punish judges it regards as disloyal. Under the disciplinary system, Polish judges can have sanctions imposed on them for their judgments in the lower courts or if they refer cases to EU courts for preliminary rulings.

In the day following the Polish top court’s decision, the stand-off worsened when the European Court of Justice ruled that the disciplinary chamber undermines judicial independence and violates EU law. It ordered its immediate suspension and reiterated that the EU has primacy over national law – a vital condition countries agree to when joining the EU.

Didier Reynders, the European justice commissioner, sent a letter to Warsaw with an August 16 deadline for an answer on whether Poland would comply with the ruling. If the EU does not receive a satisfactory answer, it will impose financial sanctions on the state.

The former communist country, which joined the EU in 2004, is one of the bloc’s success stories. Its economy has boomed, and most people hold favourable views about the union – less than a handful of other member states have greater support for EU membership.

A recent survey by the Bertelsmann Stiftung showed that ‘although only 35 per cent of Poles are satisfied with the democracy in their own country, a full 70 per cent express positive views on the state of democracy in the EU’. These figures feed into a larger picture of many Europeans welcoming the EU as a supervisory agent that is capable of intervening when individual states falter.

Recently, however, the EU has had to step up its efforts as members express anger over the gradual dismantling of fundamental rights under populist governments, not only in Poland.

The persistent backsliding in Viktor Orbán’s Hungary has led to concerns in the EU parliament, which is putting pressure on the European Commission to do more to protect the EU’s values and legal order.

In a simultaneous battle in July, the commission launched legal action against Poland and Hungary, challenging anti-LGBTQ laws in those countries. It was triggered by a decision of more than 100 Polish regions to pass resolutions declaring themselves free of ‘LGBTQ ideology’, and a recently adopted law in Hungary banning any depiction of LGBTQ people on television or in books for under-18s.

An annual report on the rule of law in the union, released by the commission in July, singled out the two countries for their non-compliance. The report, the second of its kind, is a new tool to address concerns that the union was not scrutinizing democratic backsliding within its own bloc. Critics were quick to point out, however, that there is no mention of enforcement actions.

At the start of the year the EU vowed to be tougher in upholding democracy with a new regulation that lets it withhold money from member states that breach the rule of law. The EU has already delayed approving spending plans for Hungary and Poland as part of the €800 billion pandemic recovery fund.

As the European Parliament calls for the commission to reduce budget allocations to those that undermine democratic rights, Poland and Hungary could see the new mechanism put to the test this autumn.

The future of Europe post-Brexit 28 September 2021 — 5:00PM TO 6:00PM Anonymous (not verified) 17 August 2021 Online

In conversation with Michel Barnier, Chief Brexit Negotiator, European Union (2016-2019).

Drawing on the diary he kept during the 1600 days of complex and acrimonious Brexit negotiations, Michel Barnier explores the political and practical implications for Europe post-Brexit.

Britain’s departure from the European Union has been a long and difficult journey. Many questions remain about what future lies ahead for the UK and EU and the relations between them.

• To what extent were UK negotiating positions shaped by politics within the ruling Conservative government? How did domestic politics in EU member states shape EU positions? What were key turning points in the negotiations?
• What are the hopes and expectations for bilateral relations between the UK and EU states?
• What is the scope for UK – EU cooperation on transatlantic issues and relations with China

This event forms part of Chatham House’s ongoing work on Effective Multilateralism.

Read a transcript.

As with all Chatham House member events, questions from members drive the conversation. Attending this event and watching the full event video is for Chatham House members only. Not a member? Find out more.

Europe's strategic choices 2021 4 November 2021 TO 5 November 2021 — 8:00AM TO 5:30PM Anonymous (not verified) 21 September 2021 Ritz Carlton Berlin

The 2021 conference will consider how Europe can navigate its political, economic and security challenges, in the context of the lasting effects of the coronavirus pandemic and an increasingly competitive geopolitical environment.

Registration is a two step process and you will receive a link to register on the conference virtually in advance. Please email if you wish to attend in-person.

The Eighth Annual Europe’s Strategic Choices conference, jointly developed and hosted by Chatham House, the Institute for Security Policy at the University of Kiel and the Konrad-Adenauer-Stiftung, aims to understand the complex set of challenges facing Europe in the areas of security, economic competitiveness, trade, technology, and global influence.

Set against the backdrop of a Europe emerging gradually from the COVID-19 pandemic, this annual forum brings together policymakers, and representatives from business, civil society and academia, to explore how European countries can best respond, individually and collectively to their common challenges in an increasingly competitive geopolitical environment.

The conference will be hosted in hybrid format to enable speakers and participants to join in person and allow others to engage virtually via the Conference Plus digital platform. This format ensures we can connect with a geographically diverse audience whilst incorporating important elements of in person engagement in accordance with German Federal government guidelines.

Memory politics: the challenge of commemoration in post-Soviet Eastern Europe and the Caucasus 5 October 2021 — 1:00PM TO 2:30PM Anonymous (not verified) 21 September 2021 Online

This event explores how to address memory and commemoration in the former Soviet states, considering their role in political processes and violent conflict. 

How the past is remembered and commemorated plays a large role – perhaps too large – in contemporary political debates and in how conflicts are negotiated.

Perceptions of history influence people’s actions and are used to judge or dismiss the actions of others. Nowhere is this more so than in the political, territorial and social debates and disputes across the former Soviet Union.
 
This event examines how to address the problems caused by entrenched memory debates – and proposes a framework for ‘ethical political commemoration’ for use across historical enquiry, political processes, and conflict transformation initiatives.

The speakers explore the topic through the context of Turkey and the Armenian genocide, as well as more broadly through their own experiences in conflict transformation and peace processes.

Director’s breakfast briefing: Shifts in European foreign policy since 9/11 14 October 2021 — 8:00AM TO 9:15AM Anonymous (not verified) 4 October 2021 Chatham House

Former MI6 chief, Sir Alex Younger, discusses shifts in European foreign policy since 9/11.

Former MI6 chief Sir Alex Younger, discusses shifts in European foreign policy since 9/11.

The dramatic events surrounding the withdrawal from Afghanistan demonstrates a profound shift in European security priorities since the beginning of the ‘war on terror’. Against the backdrop of the 20th anniversary of 9/11, former MI6 chief, Sir Alex Younger, discusses recent shifts in European foreign policy.

How has the focus on counterterrorism changed over the last two decades particularly in light of new and evolving strategic challenges? Why were many long-term objectives in Afghanistan left unachieved? Has the threat of terrorism changed across Europe? How has cooperation between security and intelligence services across the world changed particularly across the Atlantic? And, 20 years on, is the ‘war on terror’ really over?

This event is only open to Chatham House Partners and Major Corporate Members as well as selected giving circles of Chatham House. If you would like to attend, please RSVP to Linda Bedford at RSVP@chathamhouse.org.

Undercurrents: Europe's far-right educational institutions Audio bhorton.drupal 8 October 2021

In Hungary, France and Spain, new political movements from the far-right are attempting to reshape their education systems.

Under the supportive eye of Prime Minister Viktor Orbán, the recently established National University of Public Service seeks to embed nationalist illiberal values in a new generation of Hungarian students. Meanwhile in France and Spain, far-right public figure Marion Maréchal has turned away from the electoral politics of the Front Nationale to set up a new conservative research institute, ISSEP.

Both of these developments represent a challenge to the liberal values which underpin the existing international order. To find out more, Ben spoke with Professor Dorit Geva and Dr Felipe Santos, whose recent article in International Affairs considers the implications of this illiberal educational turn. 

Why Europe must end limbo for Afghans seeking asylum Expert comment Anonymous (not verified) 14 October 2021

With a focus on evacuations from Afghanistan, the situation in Europe is often forgotten as thousands of asylum seekers continue to wait for their cases to be settled.

Following the Taliban’s takeover of Afghanistan, European leaders shared messages to welcome those evacuated, but the reality of European responses to displacement in Afghanistan paints a more contentious picture. 

As of July 2021, 33,325 cases of Afghan asylum applicants were pending in Germany, in France 18,410 people were waiting on a decision, while in Greece the numbers were 13,660. 

Arguably, such numbers are manageable given European states’ size and their functioning asylum systems but, while 56 per cent of Afghans in Europe receive protection status, a large proportion is still in limbo in differing European countries’ asylum systems. 

Europe hosts fewer than ten per cent of the three million UN-registered displaced Afghans globally, as neighbouring countries carry the burden of Afghanistan’s forced displacement: Iran hosts almost one million Afghan refugees and Pakistan 1.5 million, and these numbers double when adding undocumented or Afghan passport holders.
 
But despite these manageable numbers, national authorities in Europe often leave people waiting for months or even years to receive an asylum decision. Deportations to Afghanistan were halted only after the Taliban’s takeover of Kabul and even then there was resistance to this from certain European countries, while Austria suggested setting up ‘deportation centres’ in countries neighbouring Afghanistan. 

Europe remains a fortress

The European Commission’s Draft Action Plan responding to the events in Afghanistan confirmed the willingness of the European Union (EU) to continue returns to non-European ‘third countries’. So Europe remains a fortress, despite pledging support for ‘the safe and orderly departure of foreign nationals and Afghans who wish to leave the country’. 

The wall by Greece at its border with Turkey and Poland’s treatment of Afghan asylum seekers trapped at its border with Belarus illustrate this hardline stance. The president of the European Council Charles Michel and EU Home Affairs Chief Ylva Johansson both confirm the priority is to secure European borders. 

This is further backed up by the European Council’s latest set of Conclusions on Afghanistan which focuses on security and ‘preventing illegal migration’ while avoiding reference to any domestic asylum efforts or the establishment of protection pathways for Afghans. 

This disconnect is not new. At the national level, reports of illegal pushbacks on European land and sea borders alarmingly intensified in 2020 as authorities intercepted and sent migrants back to neighbouring countries without assessing asylum claims. 

At the EU level, development aid to countries such as Afghanistan has long been conditional on their governments’ adherence to the bloc’s migration objectives of preventing asylum seekers from reaching European borders and facilitating the repatriation of those refused asylum in Europe. 

But this latest displacement crisis from Afghanistan exposes clear inconsistencies in European approaches to asylum and humanitarianism. Migration remains a divisive issue in European politics, but European governments must act promptly to support Afghans already residing in their territories alongside establishing robust international commitments.

Time for concrete action

European countries should firstly improve the treatment of those Afghans currently in limbo within their respective asylum systems by expediting pending Afghan asylum applications and family reunification cases, re-examining rejected asylum applications, and facilitating integration.

Secondly, national authorities should not return asylum seekers to Afghanistan or any third countries deemed ‘safe’. For Europe to coordinate evacuations from Afghanistan while simultaneously deporting asylum seekers undermines the international refugee regime and threaten Europe’s global credibility. 

The law as a tool for EU integration could be ending Expert comment NCapeling 15 October 2021

Poland is not the only EU member state challenging the supremacy of European law, as historic change is happening in how European integration functions.

The Polish Constitutional Tribunal’s ruling that several articles of the European treaties are incompatible with the Polish constitution is prompting much debate, especially in terms of both the similarities and differences between it and rulings by the German constitutional court which have also challenged the European Court of Justice (ECJ).

Pro-Europeans are keen to draw a sharp distinction between the reasoning deployed by the two courts. They see the Polish court’s challenge as an exceptional case which the European Union (EU) cannot ‘tolerate’ because it would lead to the ‘demolition of the EU’s legal order from within’ and argue the EU must take a tough approach to Poland by re-asserting the supremacy of EU law.

But this view misses a bigger long-term shift in the EU. Both the German and Polish cases illustrate some of the basic conflicts within the EU’s legal system for decades. What is being challenged increasingly openly – even since the UK left the EU – is the idea of the EU as a de facto federation in which non-majoritarian institutions such as the ECJ have final say about the quality of democracy in member states.

ECJ’s quiet revolution

Historically ‘integration through law’ was central to the European project and the ECJ was a key institution driving forward integration – usually benefiting from what Erik Stein called ‘benign neglect by the powers that be and the mass media’. Even when European integration in the form of treaties stalled in the 1960s and 1970s, ‘judicial integration’ through the ECJ continued, including its notable 1964 decision that EU law was supreme.

This self-empowerment of the ECJ – what another scholar of European constitutionalism Joseph Weiler calls ‘a quiet revolution’ – was possible because there was a ‘permissive consensus’ in member states which allowed judicial integration to continue largely unchallenged. But this has now changed as both politicians and national courts are more willing to challenge what they see as judicial overreach.

There are important differences between the approach of the German and the Polish constitutional courts. The Law and Justice Party has politicized the Polish court, packing it with judges sympathetic to that party, whereas the German court is more independent.

In addition, whereas the German court made qualified and subdued objections to measures taken in response to the euro crisis during the past decade and, in particular, the steps towards the mutualization of eurozone debt – but often backed down with ‘all bark and no bite’ as Christoph Schmid put it – the Polish court is driven by political considerations and has challenged the supremacy of EU law in a more direct and general way.

However, the German court has made it clear it is the guardian of the German constitution and seeks to impose limits on the ECJ’s self-empowerment by arguing Europe is not a federation. According to the German court’s theory of ‘constitutional pluralism’, there is in effect a constant dialogue and accommodation between the national and EU level rather than a simple primacy of EU law over national law.

The court sees itself as the ultimate arbiter of whether steps in European integration are consistent with the German constitution, and is likely to challenge any further steps in fiscal integration even if the ECJ deems them in accordance with the treaties – as it did with the European Central Bank’s quantitative easing programme.

Supremacy of EU law is under pressure

Right across Europe, courts and politicians are increasingly challenging the ECJ and questioning the supremacy of EU law. Michel Barnier called for France to regain ‘legal sovereignty’ and should no longer be subject to the judgments of the ECJ – an extraordinary demand from the EU Brexit negotiator who regularly lectured the UK about the sanctity of the EU’s legal order.

Other possible French presidential candidates such as Valérie Pécresse and Eric Zemmour are also openly challenging the primacy of EU law. The UK, of course, is fighting its own battle with the EU about the ECJ’s role in the Northern Ireland Protocol.

It was not the current Polish government but the people of France and the Netherlands who blocked the attempt at explicit constitutionalisation of the EU in a referendum just one year after the 2004 enlargement. Whereas the Constitutional Treaty ‘would have codified the doctrine of EU legal supremacy’, that provision was dropped from its successor the Lisbon Treaty, again indicating consensus on EU legal supremacy is not as strong as is often claimed.

How do Eurasian kleptocracies earn and use their money? 9 November 2021 — 1:00PM TO 2:30PM Anonymous (not verified) 22 October 2021 Chatham House and Online

This event explores the presence of corrupt funds from Eurasia in Western democracies, what they are used for, and how they can be constrained.

The Pandora Papers once again shone the spotlight on the UK being home to corrupt funds from kleptocracies, where the ruling elite abuse their political power for private gain.

In recent years much focus has been placed on this term, and the possible effects such money could have on Western democracies.

• How do such states create this wealth in the first place?
• How do these funds make their way to the UK?
• Is the term kleptocracy appropriate for the majority of countries in Eurasia?
• What evidence is there that such funds are ‘weaponized’ to achieve foreign policy goals?

This event discusses the term, how it can be applied, and the differences between how ’grey’ funds are used by various countries. It also highlights how the UK and the wider international community can counteract these flows, both from a legal point of view, and via other methods.

Belarus-EU border crisis reveals wider security threat Expert comment NCapeling 8 December 2021

By engineering a crisis at the Belarus border, Lukashenka is attempting to exacerbate vulnerabilities within the EU. Securitizing migration is not the answer.

When thousands of migrants began freezing to death in the forests on the Belarus border with Poland, Belarusian leader Aliaksandr Lukashenka was forcing the European Union (EU) into a tough choice – either give in to blackmail and welcome migrants whose attempts to trespass the EU border were a result of his policy of luring them to Belarus to put pressure on the EU, or keep the borders closed and declare solidarity with Poland despite its known mistreatment and illegal pushbacks of potential asylum-seekers.

Lukashenka’s action was aptly exploiting three key pressure points of the EU – as a normative power where the human dignity of migrants is overlooked while the European border and coastguard agency Frontex stands by, as a geopolitical actor seeking to externalize its migration problem by signing readmission agreements with transit countries, and as a community of values with the EU-Poland dispute over rule of law.

His approach is typical ‘dictaplomacy’ and democracies which have confronted such a ‘continuation of war by other means’ in their past dealings with dictatorships know that blackmail mostly serves to divert attention away from a rogue leader’s misdemeanours towards his own population. But if this had been game of chess the EU would have been in check.

Thankfully checkmate was avoided – so far – as a compromise was found following weeks of heightened diplomatic efforts. Lukashenka was forced to back-pedal and take care of the migrants, and no humanitarian corridor was needed as the EU sent funds and took measures to support organizations providing shelter for the migrants in Belarus, while airlines and governments in the source countries were pressured to restrict flights to Minsk and started repatriating part of the migrants.

Causing a nuisance

‘Operation Gateway’ – the outline of which was allegedly drawn several years ago and tested by Russia in 2016 at its own borders with Norway and Finland – certainly caused a nuisance, but it ultimately backfired as Lukashenka now has to manage the remaining 2,000-5,000 migrants who refused to be flown back, as well as facing increased international sanctions. However, the fact that Angela Merkel had to personally call him made it look as if Lukashenka did not back down for nothing.

The EU and NATO, including the UK, only reacted collectively to this crisis once it was already out of hand, leaving questions over whether this experience of Lukashenka’s dictaplomacy is a wake-up call to boost resilience against rogue warfare, and to upgrade strategic assessments of the ‘Lukashenka problem’ too.

Back in June, the Belarus ministry of foreign affairs (MFA) announced its withdrawal from the Eastern Partnership and the visa facilitation and readmission agreement with the EU, while Lithuania sent early warnings about a ‘hybrid attack’ at its own border with Belarus. In August, Der Spiegel reported details of an alleged smuggling scheme whereby Tsentr Kurort – a company closely linked to the Administration of the President of Belarus with offices in the Middle East – was handling the shipping, accommodation, and relocation of migrants.

The smuggling of migrants was entirely predictable as Lukashenka has hinted many times Belarus could stop ‘protecting the EU from armed migrants’ seeking to enter it illegally. He has upped his rhetoric beyond notions of hybrid warfare by saying he needs Russian nuclear-capable bombers to ‘help him navigate the migrant crisis’, even hinting Belarus could station both Russian nuclear weapons and S-400 anti-aircraft missile systems. This shows Lukashenka is feeling increasingly cornered – which could lead to more unpredictable security crises.

Russia and Belarus are deepening relations

Although there is no smoking gun pointing to direct Russian involvement in orchestrating the hybrid attack at the EU’s borders, a new step in the military rapprochement between the two countries came when Putin and Lukashenka approved a new Military Doctrine of the Union-State of Russia and Belarus – a non-public document including a joint concept of migration policy. Lukashenka has also come off the fence over Crimea by openly accepting the legality of the peninsula’s integration with Russia.

Given Russia is also sabre-rattling over Ukraine, the risk of an accidental escalation into armed conflict is increasing in what feels like a return to classic Cold War logic, with the difference that the East is now offensively using the South for confronting the West. In recognition of the threat, the UK has joined the US, Canada, and the EU in the fresh sanctions on Belarus.

Crisis on Europe’s doorstep 2 February 2022 — 4:00PM TO 5:00PM Anonymous (not verified) 4 January 2022 Online

Domestic instability and foreign interference is destabilizing Bosnia, with the declining strength of the 1995 Dayton Agreement symbolic of the troubles growing within the country. 

Milorad Dodik’s continuing efforts to remove the international judicial and security presence in Bosnia, along with calls for the secession of Republic Sprska and increasing Russian efforts to destabilize the country are concerning many, particularly nearby European Union (EU) member states.

On 3 November 2021, the United Nations (UN) Security Council voted unanimously to extend the EU-led multinational stabilization force for another year, as well as NATO Headquarters Sarajevo.

However, the role played by the Office of High Representative was absent from the outcome and leaves the implementation of civilian aspects emanating from the Dayton Accords in a position of uncertainty.

Against a background of ongoing troubles in the country and the growing proxy conflict between the West and Russia, the situation in Bosnia is worrying.

The expert panel discusses:

• Why has the situation in Bosnia been allowed to deteriorate to such a condition?
• What is Europe’s best solution to resolve issues in Bosnia and how is it acting to remedy them?
• How have international efforts been hampered to support development in Bosnia?
• What are Russia’s aims in the country? 
• Does US foreign policy recognize Bosnia as a strategic partner?

Read the transcript

This event forms part of Chatham House’s work on Reinvigorating Multilateralism.