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Abstract Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3− and CD25−Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1β2 (LTα1β2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1β2-lymphotoxin β receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.

Abstract Peripheral CD8+ T cell number is tightly controlled but the precise molecular mechanism regulating this process is still not fully understood. In this study, we found that epilepsy patients with loss of function mutation of DEPDC5 had reduced peripheral CD8+ T cells, and DEPDC5 expression positively correlated with tumor-infiltrating CD8+ T cells as well as overall cancer patient survival, indicating that DEPDC5 may control peripheral CD8+ T cell homeostasis. Significantly, mice with T cell-specific Depdc5 deletion also had reduced peripheral CD8+ T cells and impaired anti-tumor immunity. Mechanistically, Depdc5-deficient CD8+ T cells produced high levels of xanthine oxidase and lipid ROS due to hyper-mTORC1-induced expression of ATF4, leading to spontaneous ferroptosis. Together, our study links DEPDC5-mediated mTORC1 signaling with CD8+ T cell protection from ferroptosis, thereby revealing a novel strategy for enhancing anti-tumor immunity via suppression of ferroptosis.

Abstract Endo-lysosomes transport along microtubules and clustering in the perinuclear area are two necessary steps for microbes to activate specialized phagocyte functions. We report that RUN and FYVE domain-containing protein 3 (RUFY3) exists as two alternative isoforms distinguishable by the presence of a C-terminal FYVE domain and by their affinity for phosphatidylinositol 3-phosphate on endosomal membranes. The FYVE domain-bearing isoform (iRUFY3) is preferentially expressed in primary immune cells and up-regulated upon activation by microbes and Interferons. iRUFY3 is necessary for ARL8b + /LAMP1+ endo-lysosomes positioning in the pericentriolar organelles cloud of LPS-activated macrophages. We show that iRUFY3 controls macrophages migration, MHC II presentation and responses to Interferon-γ, while being important for intracellular Salmonella replication. Specific inactivation of rufy3 in phagocytes leads to aggravated pathologies in mouse upon LPS injection or bacterial pneumonia. This study highlights the role of iRUFY3 in controlling endo-lysosomal dynamics, which contributes to phagocyte activation and immune response regulation.

Abstract Background The protein phosphatase 2 (PP2A) is one of the major serine/threonine phosphatases in humans. The most frequently reported pathogenic PP2A variants have been identified in PPP2R5D, encoding the regulatory subunit B’ delta, and are known to cause intellectual developmental disorder autosomal dominant 35 (MRD35). Case presentation Herein, we describe a unique case of a patient with a heterozygous pathogenic variant, c.592G>A/p.(Glu198Lys) in the PPP2R5D gene which was associated with hyperpigmented skin lesions arising from increased melanin production, known as Café-au-lait macules (CALMs). To our knowledge, this is the first reported case of a PPP2R5D-related neurodevelopmental disorder associated with CALMs. Conclusions Our findings suggest that the documentation and reporting of CALMs when associated with one or more physical and/or neurodevelopmental findings are of utmost importance as they could be indicative of an underreported phenotype and may extend the phenotypic spectrum of MRD35.

Assessing metabolic activity within single cells rather than at a population level has a number of advantages. Here, the authors use a flow and mass cytometry based approach that assess the metabolic differences between populations of human immune stimulatory and tolerogenic dendritic cells.

Abstract Background Founder populations that have recently undergone important genetic bottlenecks such as French-Canadians and Ashkenazi Jews can harbor some pathogenic variants at a higher carrier rate than the general population, putting them at a higher risk for certain genetic diseases. In these populations, there can be considerable benefit to performing ethnic-based or expanded preconception carrier screening, which can help in the prevention or early diagnosis and management of some genetic diseases. Acadians are descendants of French immigrants who settled in the Atlantic Coast of Canada in the seventeenth century. Yet, the Acadian population has never been investigated for the prevalence/frequency of disease-causing genetic variants. Methods An exome sequencing panel for 312 autosomal recessive and 30 X-linked diseases was designed and specimens from 60 healthy participants were sequenced to assess carrier frequency for the targeted diseases. Results In this study, we show that a sample population of Acadians in South-East New Brunswick harbor variants for 28 autosomal recessive and 1 X-linked diseases, some of which are significantly more frequent in comparison to reference populations. Conclusion Results from this pilot study suggests a need for further investigation of genomic variation in this population and possibly implementation of targeted carrier and neonatal screening programs.

Abstract PAX5 and EBF1 work synergistically to regulate genes that are involved in B lymphocyte differentiation. We used the KIS-1 diffuse large B cell lymphoma cell line, which is reported to have elevated levels of PAX5 expression, to investigate the mechanism of EBF1- and PAX5-regulated gene expression. We demonstrate the lack of expression of hallmark B cell genes, including CD19, CD79b, and EBF1, in the KIS-1 cell line. Upon restoration of EBF1 expression we observed activation of CD19, CD79b and other genes with critical roles in B cell differentiation. Mass spectrometry analyses of proteins co-immunoprecipitated with PAX5 in KIS-1 identified components of the MLL H3K4 methylation complex, which drives histone modifications associated with transcription activation. Immunoblotting showed a stronger association of this complex with PAX5 in the presence of EBF1. Silencing of KMT2A, the catalytic component of MLL, repressed the ability of exogenous EBF1 to activate transcription of both CD19 and CD79b in KIS-1 cells. We also find association of PAX5 with the MLL complex and decreased CD19 expression following silencing of KMT2A in other human B cell lines. These data support an important role for the MLL complex in PAX5-mediated transcription regulation.

We report here that RUFY4, a newly characterized member of the ‘RUN and FYVE domain-containing’ family of proteins previously associated with autophagy enhancement, is highly expressed in alveolar macrophages (AM). We show that RUFY4 interacts with mitochondria upon stimulation by microbial-associated molecular patterns of AM and dendritic cells. RUFY4 interaction with mitochondria and other organelles is dependent on a previously uncharacterized OmpH domain located immediately upstream of its C-terminal FYVE domain. Further, we demonstrate that rufy4 messenger RNA can be translated from an alternative translation initiation codon, giving rise to a N-terminally truncated form of the molecule lacking most of its RUN domain and with enhanced potential for its interaction with mitochondria. Our observations point towards a role of RUFY4 in selective mitochondria clearance in activated phagocytes.

Although great advances have been made in understanding the pathobiology of mixed lineage leukemia-rearranged (MLL-r) leukemias, therapies for this leukemia have remained limited, and clinical outcomes remain bleak. In order to identify novel targets for immunotherapy treatments, we compiled a lineage-independent MLL-r leukemia gene signature using publicly available data sets. Data from large leukemia repositories were filtered through the in silico human surfaceome, providing a list of highly predicted cell surface proteins overexpressed in MLL-r leukemias. LAMP5, a lysosomal associated membrane protein, is expressed highly and specifically in MLL-r leukemia. We found that LAMP5 is a direct target of the oncogenic MLL-fusion protein. LAMP5 depletion significantly inhibited leukemia cell growth in vitro and in vivo. Functional studies showed that LAMP-5 is a novel modulator of innate-immune pathways in MLL-r leukemias. Downregulation of LAMP5 led to inhibition of NF-kB signaling and increased activation of type-1 interferon signaling downstream of Toll-like receptor/interleukin 1 receptor activation. These effects were attributable to the critical role of LAMP-5 in transferring the signal flux from interferon signaling endosomes to pro-inflammatory signaling endosomes. Depletion of IRF7 was able to partially rescue the cell growth inhibition upon LAMP5 downregulation. Lastly, LAMP-5 was readily detected on the surface of MLL-r leukemia cells. Targeting surface LAMP-5 using an antibody-drug conjugate leads to significant cell viability decrease specifically in MLL-r leukemias. Overall, based on the limited expression throughout human tissues, we postulate that LAMP-5 could potentially serve as an immunotherapeutic target with a wide therapeutic window to treat MLL-r leukemias.

Zdhhc family genes are composed of 24 members that regulate palmitoylation, a post-translational modification process for proteins. Mutations in genes that alter palmitoylation or de-palmitoylation could result in neurodegenerative diseases and inflammatory disorders. In this study, we found that Zdhhc2 was robustly induced in psoriatic skin and loss of Zdhhc2 in mice by CRISPR/Cas9 dramatically inhibited pathology of the ear skin following imiquimod treatment. As psoriasis is an inflammatory disorder, we analyzed tissue infiltrating immune cells and cytokine production. Strikingly we found that a master psoriatic cytokine interferon-α (IFN-α) in the lesioned skin of wildtype (WT) mice was 23-fold higher than that in Zdhhc2 deficient counterparts. In addition, we found that CD45+ white blood cells (WBC) infiltrating in the skin of Zdhhc2 deficient mice were also significantly reduced. Amelioration in psoriasis and dramatically reduced inflammation of Zdhhc2 deficient mice led us to analyze the cellular components that were affected by loss of Zdhhc2. We found that imiquimod induced plasmacytoid dendritic cell (pDC) accumulation in psoriatic skin, spleen, and draining lymph nodes (DLN) were drastically decreased in Zdhhc2 deficient mice, and the expression of pDC activation marker CD80 also exhibited significantly inhibited in psoriatic skin. In further experiments, we confirmed the cell intrinsic effect of Zdhhc2 on pDCs as we found that loss of zDHHC2 in human CAL-1 pDC dampened both interferon regulatory factor 7 (IRF7) phosphorylation and IFN-α production. Therefore, we identified novel function of Zdhhc2 in controlling inflammatory response in psoriasis in mice and we also confirmed that crucial role of Zdhhc2 in pDCs by regulating IRF7 activity and production of the critical cytokine. Our results finding the dependence of IFN-α production on Zdhhc2 in inflamed murine skin and in human pDCs provide rationale for targeting this new molecule in treatment of inflammation.

Intracellular trafficking is essential for cell structure and function. In order to perform key tasks such as phagocytosis, secretion or migration, cells must coordinate their intracellular trafficking, and cytoskeleton dynamics. This relies on certain classes of proteins endowed with specialized and conserved domains that bridge membranes with effector proteins. Of particular interest are proteins capable of interacting with membrane subdomains enriched in specific phosphatidylinositol lipids, tightly regulated by various kinases and phosphatases. Here, we focus on the poorly studied RUFY family of adaptor proteins, characterized by a RUN domain, which interacts with small GTP-binding proteins, and a FYVE domain, involved in the recognition of phosphatidylinositol 3-phosphate. We report recent findings on this protein family that regulates endosomal trafficking, cell migration and upon dysfunction, can lead to severe pathology at the organismal level.

Abstract Background As several studies indicated an increase in Lyme disease (LD), notably in neighbouring countries, concerns have arisen regarding the evolution of Lyme disease in Belgium. In order to confirm or infirm the increase of LD in Belgium, we focused on hospital admissions of patients diagnosed with LD between 2000 and 2013 based on hospital admission databases from two hospitals in Belgium. Methods Hospital databases are a stable recording system. We did a retrospective analysis of the medical files of patients hospitalized with Lyme disease in two Belgian hospitals between 2000 and 2013. Results The annual number of cases of LD for the two studied Belgian hospitals remained stable between 2000 and 2013, ranging from 1 for the Cliniques universitaires Saint-Luc to 15 for the the Clinique Saint-Pierre. No increasing trend were noted in the estimated annual incidence rate but the average estimated annual incidence rate was higher for the hospital Saint-Pierre (8.1 ± 3.7 per 100,000 inhabitants) than Saint-Luc (2.2 ± 1.5 per 100,000 inhabitants). The number of hospital cases of LD peaked between June and November. Conclusions Based on hospital admissions with LD, no increasing trend was observed for the period 2000–2013 in the two studied Belgian hospitals. This is in line with other studies carried out in Belgium.

TLR9 is highly expressed by plasmacytoid dendritic cells and detects nucleic acids, but to discriminate between host and microbial nucleic acids TLR9 is sorted into different endosomal compartments. Here the authors show that BAD-LAMP limits type 1 interferon responses by sorting TLR9 to late endosomal compartments.

The critical state of a granular material made of rounded tetrahedral particles is studied through DEM simulations of triaxial compressions. A minimum number of 7,500 particles is first obtained as the representative volume element (RVE) for the present triaxial simulations. Then, the macroscopic critical state line (CSL) is shown to be increasing in the (stress, density) space for low confining pressures. Such an unexpected behaviour is explained by the existence of a significant proportion of rattlers. Considering rattlers as voids indeed reinstates a classically decreasing CSL.

We experimentally investigated cohesion of artificially bonded granular materials made of spherical glass beads cemented by solid paraffin bonds. By means of laboratory tests designed and carried out for investigation at different scales, we measured the tensile yield strength for solid bonds both at the inter-particle micro-scale and cemented samples at the meso-scale. A parametric study has been performed by varying some of the granular material properties (bead diameter, paraffin content as well as the dimension of the sample for the meso-scale tensile tests. We finally propose a discusion on: (i) the relationship between the microscopic and macroscopic cohesion forces relying on classical homogenisation laws ; (ii) the potential impact of size effects based on a simple phenomenological model.

This contribution tackles the issue of incipient conditions for initiation of erosion by a fluid flow at the surface of cohesive materials. To this end, a typical assessment procedure consists of subjecting a soil sample to progressive hydrodynamic stresses induced by a submerged impinging jet flow whose injection velocity is gradually increased. This paper presents the results of an extensive use of this protocol both in experiments and numerical simulations, the latter being based on a coupled DEM and LBM approach. Here we consider the specific case of weakly cemented soils, either made experimentally of glass beads bonded by solid bridges or modelled numerically by a solid bond rheology with a parabolic yield condition involving the micromechanical traction, shearing and bending of the bonds. The results show that, as expected, the hydrodynamic stress for erosion onset substantially increases with solid cohesion as compared to cohesionless cases but can, however, be satisfactorily predicted by a simple extension of the usual Shields criterion that only applies for cohesion-less granular sediments. This extension includes a cohesion number, the granular Bond number, with a simple definition based on tensile yield values.

Alkyne and azide analogs of natural compounds that can be coupled to sensitive tags by click chemistry are powerful tools to study biological processes. Arachidonic acid (AA) is a FA precursor to biologically active compounds. 19-Alkyne-AA (AA-alk) is a sensitive clickable AA analog; however, its use as a surrogate to study AA metabolism requires further evaluation. In this study, AA-alk metabolism was compared with that of AA in human cells. Jurkat cell uptake of AA was 2-fold greater than that of AA-alk, but significantly more AA-Alk was elongated to 22:4. AA and AA-alk incorporation into and remodeling between phospholipid (PL) classes was identical indicating equivalent CoA-independent AA-PL remodeling. Platelets stimulated in the pre­sence of AA-alk synthesized significantly less 12-lipoxygenase (12-LOX) and cyclooxygenase products than in the presence of AA. Ionophore-stimulated neutrophils produced significantly more 5-LOX products in the presence of AA-alk than AA. Neutrophils stimulated with only exogenous AA-alk produced significantly less 5-LOX products compared with AA, and leukotriene B4 (LTB4)-alk was 12-fold less potent at stimulating neutrophil migration than LTB4, collectively indicative of weaker leukotriene B4 receptor 1 agonist activity of LTB4-alk. Overall, these results suggest that the use of AA-alk as a surrogate for the study of AA metabolism should be carried out with caution.

Mrf4 is a transcription factor important for muscle development, but despite high expression its function in adults is unknown. Here the authors show that interfering with Mrf4 in adult mice leads to muscle hypertrophy by activating MEF2-dependent transcription and promoting protein synthesis.

Multi-organ failure in response to uncontrolled microbial infection is characterized by low blood pressure accompanied by a systemic over-inflammation state, caused by massive pro-inflammatory cytokines release and liver damage. Recently, the integrated stress response (ISR), characterized by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, was involved with controlling apoptosis in stressed hepatocytes and associated with poor survival to endotoxin challenge. Lipopolysaccharide (LPS) alone is able to induce the ISR in hepatocytes and can trigger massive liver damage along with tumor necrosis factor-alpha (TNF-α) expression. Consequently, drugs interfering with eIF2α phosphorylation may represent potential candidates for the treatment of such pathologies. We, therefore, used Guanabenz (GBZ), a small compound with enhancing eIF2α phosphorylation activity to evaluate its effect on bacterial LPS sensing and endotoxemia. GBZ is confirmed here to have an anti-inflammatory activity by increasing in vitro interleukin-10 (IL-10) production by LPS-stimulated dendritic cells. We further show that in the d-galactosamine (d-galN)/LPS-dependent lethality model, intraperitoneal injection of GBZ promoted mice survival, prevented liver damage, increased IL-10 levels, and inhibited TNF-α production. GBZ and its derivatives could therefore represent an interesting pharmacological solution to control systemic inflammation and associated acute liver failure.

Suffusion is one mechanism of internal erosion, which occurs in gap-graded or broadly graded soils when the fine particles are detached and transported by the seepage flow through the void space formed by the granular soil skeleton. Suffusion is therefore a particle scale mechanism. During this microscale, the initial soil fabric may change due to both fines migration and coarse grains rearrangement, leading to an increase/decrease of global/local porosity and hydraulic conductivity, besides of a probable appearance of heterogeneity, which can, in turn, impact the mechanical behaviour of the eroded soil. In the literature, suffusion test results give only a macroscopic point of view and fail to quantify the effect of suffusion at the scale of the soil's induced heterogeneities. In this paper, x-ray tomography is used to get microscopic observations of soil sample microstructure evolution during a suffusion test. The results reveal that suffusion is not a homogeneous process; the removal of fine particles takes place mainly around the soil sample circumference leading to a higher void ratio at the periphery. Besides, the inter-granular void ratio decreases significantly but almost uniformly throughout the sample owing to the progressive collapse and reorganization of the coarse grains induced by the loss in fines.

Changes in fatty acid (FA) and glycerophospholipid (GPL) metabolism associated with cell cycle entry are not fully understood. In this study FA-GPL remodeling was investigated in resting and proliferating primary human T cells. Significant changes were measured in the composition and distribution of FAs in GPLs following receptor activation of human T cells. The FA distribution of proliferating T cells was very similar to that of the human Jurkat T cell line and when the stimulus was removed from proliferating T cells, they stopped proliferating and the FA distribution largely reverted back to that of resting T cells. The cellular content of saturated and monounsaturated FAs was significantly increased in proliferating cells, which was associated with an induction of FA synthase and stearoyl-CoA desaturase-1 gene expression. Additionally, cellular arachidonate was redistributed in GPLs in a distinct pattern that was unlike any other FAs. This redistribution was associated with an induction of CoA-dependent and CoA-independent remodeling. Accordingly, significant changes in the expression of several acyl-CoA synthetases, lysophospholipid acyltransferases, and phospholipase A2 were measured. Overall, these results suggest that metabolic pathways are activated in proliferating T cells that may represent fundamental changes associated with human cell proliferation.

LAMP5 is member of the LAMP family of membrane proteins. In contrast to the canonical members of this protein family, LAMP1 and LAMP2, which show widespread expression in many tissues, LAMP 5 is brain specific in mice. In C. elegans, the LAMP5 ortholog UNC-46 has been suggested to act a trafficking chaperone, essential for the correct targeting of the nematode vesicular GABA-transporter UNC-47. We show here that in the mouse brain LAMP5 is expressed in subpopulations of GABAergic forebrain neurons in the striato-nigral system and the olfactory bulb. The protein was present at synaptic terminals, overlapping with the mammalian vesicular GABA-transporter VGAT. In LAMP5-deficient mice localization of the transporter was unaffected arguing against a conserved role in VGAT trafficking. Electrophysiological analyses in mutants showed alterations in short term synaptic plasticity suggesting that LAMP5 is involved in controlling the dynamics of evoked GABAergic transmission. At the behavioral level, LAMP5 mutant mice showed decreased anxiety and deficits in olfactory discrimination. Altogether, this work implicates LAMP5 function in GABAergic neurotransmission in defined neuronal subpopulations.

Translational control depends on phosphorylation of eIF2α by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse forebrain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2α phosphorylation and ATF4 expression were diminished and were associated with enhanced behavioral perseveration, decreased prepulse inhibition, reduced fear extinction, and impaired behavioral flexibility. Treatment with the glycine transporter inhibitor SSR504734 normalized eIF2α phosphorylation, ATF4 expression, and behavioral flexibility in PERK-deficient mice. Moreover, the expression levels of PERK and ATF4 were reduced in the frontal cortex of human patients with schizophrenia. Together, our findings reveal that PERK plays a critical role in information processing and cognitive function and that modulation of eIF2α phosphorylation and ATF4 expression may represent an effective strategy for treating behavioral inflexibility associated with several neurological disorders such as schizophrenia.

Here we investigate the physical mechanisms behind the surface erosion of a cohesive granular soil induced by an impinging jet by means of numerical simulations coupling fluid and grains at the microscale. The 2D numerical model combines the Discrete Element and Lattice Boltzmann methods (DEM-LBM) and accounts for the granular cohesion with a contact model featuring a paraboloidal yield surface. Here we review first the hydrodynamical conditions imposed by the fluid jet on a solid granular packing, turning then the attention to the impact of cohesion on the erosion kinetics. Finally, the use of an additional subcritical debonding damage model based on the work of Silvani and co-workers provides a novel insight into the internal solicitation of the cohesive granular sample by the impinging jet.

Localized fluidization within a granular packing along an almost cylindrical chimney is observed when an upward fluid-flow, injected through a small port diameter, exceeds a critical flow-rate. Once this threshold reached, a fluidized area is first initiated in the close vicinity of the injection hole before gradually growing upward to the top surface of the granular layer. In this work, we present an experimental investigation specifically dedicated to the kinetics of chimney fluidization in an immersed granular bed. Two different transient regimes are identified depending on wether the expansion of the fluidized area is rather fast and regular, reaching the final chimney state typically in less than 10 seconds, or, on the contrary, slow and very progressively accelerated, giving rise to transient duration up to 1 hour or even more. Some systematic investigations allow to propose several empirical scaling relations for the kinetics of chimney fluidization in the fast regular regime.

Using a recently developed 2D numerical modelling that combines Discrete Element (DEM) and Lattice Boltzmann methods (LBM), we simulate the destabilisation by an hydraulic gradient of a cohesive granular soil clogging the top of an underground conduit. We aim to perform a multi-scale study that relates the grain scale behavior to the macroscopic erosion process. In particular, we study the influence of the flow conditions and the inter-particle contact forces intensity on the erosion kinetic.

Internal erosion is a complex phenomenon which represents one of the main sources of risk to the safety of earth hydraulic structures such as embankment dams, dikes and levees. Its occurrence may cause instability and failure of these structures with consequences that can be dramatic. Erosion by suffusion corresponds to the process of detachment and transport, under the action of hydraulic flow, of the finest soil particles within the porous media formed mainly of large grains. Its occurrence usually causes change of the initial microstructure and hence a change in the physical, hydraulic and mechanical characteristics of the soil. In this study, we present first an experimental characterization of the erosion mechanism during its occurrence within a granular soil. Particular emphasis was put on the role of hydraulic conditions in triggering of fines migration. Thereafter, we present a preliminary microstructural characterization of the erosion process through direct visualization by optical techniques of particles migration using crushed glass samples as model materials.

Erosion of soils affects both natural landscapes and engineering constructions as embankment dams or levees. Improving the safety of such earthen structures requires in particular finding out more about the elementary mechanisms involved in soil erosion. Towards this end, an experimental work was undertaken in three steps. First, several model materials were developed, made of grains (mostly glass beads) with solid bridges at particle contacts whose mechanical yield strength can be continuously varied. Furthermore, for most of them, we succeeded in obtaining a translucent system for the purpose of direct visualization. Second, these materials were tested against surface erosion by an impinging jet to determine a critical shear stress and a kinetic coefficient [2, 3]. Note that an adapted device based on optical techniques (combination of Refractive Index Matching and Planar Laser Induced Fluorescence [3]) was used specifically for the transparent media. Third, some specifically developed mechanical tests, and particularly traction tests, were implemented to estimate the mechanical strength of the solid bridges both at micro-scale (single contact) and at macro-scale (sample) and to investigate a supposed relationship with soil resistance to erosion.

We focus here on the major and always topical issue of soil erosion by fluid flows, and more specifically on the determination of both a critical threshold for erosion occurrence and a kinetics that specifies the rate of eroded matter entrainment. A synthetic state-of-the-art is first proposed with a critical view on the most commonly used methods and erosion models. It is then discussed an alternative strategy, promoting the use of model materials that allow systematic parametric investigations with the purpose of first identifying more precisely the local mechanisms responsible for soil particle erosion and second ultimately quantifying both critical onsets and kinetics, possibly through existing or novel empirical erosion laws. Finally, we present and discuss several examples following this methodology, implemented either by means of experiments or numerical simulations, and coupling erosion tests in several particular hydrodynamical configurations with wisely selected mechanical tests.

In bacteria, protein synthesis can be coupled to transcription, but in eukaryotes it is believed to occur solely in the cytoplasm. Using pulses as short as 5 s, we find that three analogues--L-azidohomoalanine, puromycin (detected after attaching fluors using 'click' chemistry or immuno-labeling), and amino acids tagged with 'heavy' 15N and 13C (detected using secondary ion mass spectrometry)--are incorporated into the nucleus and cytoplasm in a process sensitive to translational inhibitors. The nuclear incorporation represents a significant fraction of the total, and labels in both compartments have half-lives of less than a minute; results are consistent with most newly-made peptides being destroyed soon after they are made. As nascent RNA bearing a premature termination codon (detected by fluorescence in situ hybridization) is also eliminated by a mechanism sensitive to a translational inhibitor, the nuclear turnover of peptides is probably a by-product of proof-reading the RNA for stop codons (a process known as nonsense-mediated decay). We speculate that the apparently-wasteful turnover of this previously-hidden ('dark-matter') world of peptide is involved in regulating protein production.

We previously reported that leukocyte specific β2 integrins contribute to hypertrophy after muscle overload in mice. Because intercellular adhesion molecule-1 (ICAM-1) is an important ligand for β2 integrins, we examined ICAM-1 expression by murine skeletal muscle cells after muscle overload and its contribution to the ensuing hypertrophic response. Myofibers in control muscles of wild type mice and cultures of skeletal muscle cells (primary and C2C12) did not express ICAM-1. Overload of wild type plantaris muscles caused myofibers and satellite cells/myoblasts to express ICAM-1. Increased expression of ICAM-1 after muscle overload occurred via a β2 integrin independent mechanism as indicated by similar gene and protein expression of ICAM-1 between wild type and β2 integrin deficient (CD18-/-) mice. ICAM-1 contributed to muscle hypertrophy as demonstrated by greater (p

Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.

Brucella is an intracellular pathogen able to persist for long periods of time within the host and establish a chronic disease. We show that soon after Brucella inoculation in intestinal loops, dendritic cells from ileal Peyer's patches become infected and constitute a cell target for this pathogen. In vitro, we found that Brucella replicates within dendritic cells and hinders their functional activation. In addition, we identified a new Brucella protein Btp1, which down-modulates maturation of infected dendritic cells by interfering with the TLR2 signaling pathway. These results show that intracellular Brucella is able to control dendritic cell function, which may have important consequences in the development of chronic brucellosis.

« En même temps, la persistance voire l’aggravation des inégalités, ce fossé qui se creuse entre les quartiers difficiles et le reste du pays, font mentir le principe d’égalité des chances et menacent de déchirer notre pacte républicain […]. L’égalité des chances a de tout temps été le combat de la République. La ligne de front de ce combat passe désormais dans les quartiers. Comment demander à leurs habitants de se reconnaître dans la nation et dans ses valeurs ...

Comment s’élabore la construction de l’identité d’un cadre en entreprise qui vit l’expérience de plusieurs mobilités internationales et comment s’opèrent alors les apprentissages d’ordre interculturel qu’il développe ? Qu’en retirent aussi sa famille et ses proches ? Tel est l’objet d’étude de cet article construit sous forme de témoignage et qui s’intéresse aux nouvelles réalités du management interculturel. Une position de gestionnaire des ressources ...

Pour les sciences sociales, la mondialisation interroge aussi bien les fondements de l’intégration des minorités dans l’État-Nation, que la capacité d’institutions (firmes multinationales, ong, associations religieuses, partis politiques…) à mobiliser des sujets porteurs d’enracinements culturels pouvant être très éloignés. Au moment où les discours célèbrent la mobilité accrue des hommes, des produits et des capitaux, tend parallèlement à s’épanouir un mouvement opposé de réinscription identitaire du sujet autour de revendications régionales (défense des langues, des patrimoines locaux), d’identités religieuses (fondamentalisme juif, intégrisme chrétien, musulman…), d’identités sexuelles (féminisme radical, mouvements homosexuels) ou encore ethniques. L’idée d’une humanité ne formant à terme qu’un « seul tout », celle d’un progrès compris comme un ensemble de changements nécessaires et réalisables autour de la rationalisation et l’industrialisation des moyens de production, de la démocratisation politique et de l’avènement d’une société de consommation apparaissent aujourd’hui partout remises en cause. Le mimétisme culturel n’implique pas un nécessaire partage des valeurs. Cette dissociation croissante entre mouvements de revendication d’une identité et forces d’intégration qui concourent à renouveler le capitalisme, questionne le sens même d’un espace possible de la moralité publique et de la démocratie.

La réforme en France des services publics, qu’ils appartiennent directement à l’Administration d’État ou bien qu’ils possèdent le statut d’entreprises publiques, pose la question de leurs modes de gestion des ressources humaines, de leur organisation du travail et de leur aptitude à se « rénover ». Précisément, les nombreuses injonctions à se transformer, adressées de partout aux services publics, et qualifiées de modernisations, sont présentées, tantôt comme ...

Abstract The goal of this paper is to analyze the stochastic dynamics of childhood infectious disease time series. We present an univariate time series analysis of pertussis, mumps, measles and rubella based on Box-Jenkins or AutoRegressive Integrated Moving Average (ARIMA) modeling. The method, which enables the dependency structure embedded in time series data to be modeled, has potential research applications in studies of infectious disease dynamics. Canadian chronological series of pertussis, mumps, measles and rubella, before and after mass vaccination, are analyzed to characterize the statistical structure of these diseases. Despite the fact that these infectious diseases are biologically different, it is found that they are all represented by simple models with the same basic statistical structure. Aside from seasonal effects, the number of new cases is given by the incidence in the previous period and by periodically recurrent random factors. It is also shown that mass vaccination does not change this stochastic dependency. We conclude that the Box-Jenkins methodology does identify the collective pattern of the dynamics, but not the specifics of the diseases at the biological individual level.

Knowledge co-production is a solution-oriented approach to analysing real-life problems such as making the right decision in a given scenario. The most popular examples come from evidence-based policymaking contexts. Political decisions made in this way rely on specialist expertise co-produced in organisations that can be characterised as Hybrid Fora. However, despite the rise in popularity of Hybrid Fora and evidence-based policymaking processes, there are only a few studies that analyse the influencing factors of knowledge co-production in these contexts. The case study presented here addresses this new area of research through a documentary analysis and 11 expert interviews, both analysed via qualitative content analysis. First, the study reconstructs how knowledge is produced within an Expert Group of the European Commission. Second, it reflects how the produced knowledge is "de facto" included as "evidence" into the decision-making processes of the relevant policy area. The results of this study show that in this expert group, pragmatic and extra-scientific criteria such as specific stakes and interests as well as the group hierarchy controlled the process of knowledge co-production. Moreover, it also seems that knowledge produced by the interaction of experts within the examined Expert Group has a more symbolic, policy-orientated function, rather than being specifically used as decision-making evidence.