P19-25. A vaccine model to prevent the depletion of uninfected bystander CD4 cells during HIV infection

International audiencen.

Higher-order Kerr terms allow ionization-free filamentation in gases

We show that higher-order nonlinear indices ($n_4$, $n_6$, $n_8$, $n_{10}$) provide the main defocusing contribution to self-channeling of ultrashort laser pulses in air and Argon at 800 nm, in contrast with the previously accepted mechanism of filamentation where plasma was considered as the dominant defocusing process. Their consideration allows to reproduce experimentally observed intensities and plasma densities in self-guided filaments.Comment: 11 pages, 6 figures (11 panels

Viremic HIV Infected Individuals with High CD4 T Cells and Functional Envelope Proteins Show Anti-gp41 Antibodies with Unique Specificity and Function

BACKGROUND: CD4 T-cell decay is variable among HIV-infected individuals. In exceptional cases, CD4 T-cell counts remain stable despite high plasma viremia. HIV envelope glycoprotein (Env) properties, namely tropism, fusion or the ability to induce the NK ligand NKp44L, or host factors that modulate Env cytopathic mechanisms may be modified in such situation. METHODS: We identified untreated HIV-infected individuals showing non-cytopathic replication (VL>10,000 copies/mL and CD4 T-cell decay<50 cells/µL/year, Viremic Non Progressors, VNP) or rapid progression (CD4 T-cells<350 cells/µL within three years post-infection, RP). We isolated full-length Env clones and analyzed their functions (tropism, fusion activity and capacity to induce NKp44L expression on CD4 cells). Anti-Env humoral responses were also analyzed. RESULTS: Env clones isolated from VNP or RP individuals showed no major phenotypic differences. The percentage of functional clones was similar in both groups. All clones tested were CCR5-tropic and showed comparable expression and fusogenic activity. Moreover, no differences were observed in their capacity to induce NKp44L expression on CD4 T cells from healthy donors through the 3S epitope of gp41. In contrast, anti- Env antibodies showed clear functional differences: plasma from VNPs had significantly higher capacity than RPs to block NKp44L induction by autologous viruses. Consistently, CD4 T-cells isolated from VNPs showed undetectable NKp44L expression and specific antibodies against a variable region flanking the highly conserved 3S epitope were identified in plasma samples from these patients. Conversely, despite continuous antigen stimulation, VNPs were unable to mount a broad neutralizing response against HIV. CONCLUSIONS: Env functions (fusion and induction of NKp44L) were similar in viremic patients with slow or rapid progression to AIDS. However, differences in humoral responses against gp41 epitopes nearby 3S sequence may contribute to the lack of CD4 T cell decay in VNPs by blocking the induction of NKp44L by gp41

Modelling the criticality of silicon nitride surface imperfections under rolling and sliding contact

Ceramic rolling elements of hybrid bearings may initially include surface imperfections. In order to provide reliable operation of a bearing, the criticality of such imperfections under rolling contact fatigue is examined by defining them as Star features: intersecting semi-elliptical surface cracks. Parametric study is conducted using Finite Element Method and discussed with help of previously published experimental observations. The effects of the Star feature morphology and configuration, contact pressure and crack face friction are investigated in terms of stress intensity factors. Possible crack propagation scenarios are explained in the present study

Finite elements based approaches for the modelling of radial crack formation upon Vickers indentation in silicon nitride ceramics

© 2019 By having superior properties silicon nitride ceramics can be considered as the state-of-the-art material in the bearing industry. Vickers indentation of this material is typically accompanied by formation of cracks visible on surface. Two Finite Elements models are developed in the current work: the first model is based on fracture mechanics and the second on cleavage stress criterion. Plastic behavior of silicon nitride is included in the modeling, and since little is known on the plasticity of this material, the Drucker-Prager model (used for non-metallic materials)along with the classical J2-plasticity are explored. The results of the fracture mechanics based model correlate well with experimental results in terms of surface crack length. The numerical results in terms of the morphology of the indented zone (including cracks and plastic zone)are provided by the stress criterion based model, and these results correlate well too, with the experimental data

HIV gp41 Engages gC1qR on CD4+ T Cells to Induce the Expression of an NK Ligand through the PIP3/H2O2 Pathway

CD4+ T cell loss is central to HIV pathogenesis. In the initial weeks post-infection, the great majority of dying cells are uninfected CD4+ T cells. We previously showed that the 3S motif of HIV-1 gp41 induces surface expression of NKp44L, a cellular ligand for an activating NK receptor, on uninfected bystander CD4+ T cells, rendering them susceptible to autologous NK killing. However, the mechanism of the 3S mediated NKp44L surface expression on CD4+ T cells remains unknown. Here, using immunoprecipitation, ELISA and blocking antibodies, we demonstrate that the 3S motif of HIV-1 gp41 binds to gC1qR on CD4+ T cells. We also show that the 3S peptide and two endogenous gC1qR ligands, C1q and HK, each trigger the translocation of pre-existing NKp44L molecules through a signaling cascade that involves sequential activation of PI3K, NADPH oxidase and p190 RhoGAP, and TC10 inactivation. The involvement of PI3K and NADPH oxidase derives from 2D PAGE experiments and the use of PIP3 and H2O2 as well as small molecule inhibitors to respectively induce and inhibit NKp44L surface expression. Using plasmid encoding wild type or mutated form of p190 RhoGAP, we show that 3S mediated NKp44L surface expression on CD4+ T cells is dependent on p190 RhoGAP. Finally, the role of TC10 in NKp44L surface induction was demonstrated by measuring Rho protein activity following 3S stimulation and using RNA interference. Thus, our results identify gC1qR as a new receptor of HIV-gp41 and demonstrate the signaling cascade it triggers. These findings identify potential mechanisms that new therapeutic strategies could use to prevent the CD4+ T cell depletion during HIV infection and provide further evidence of a detrimental role played by NK cells in CD4+ T cell depletion during HIV-1 infection

Sildenafil attenuates pulmonary arterial pressure but does not improve oxygenation during ARDS

OBJECTIVE: Pulmonary hypertension is a characteristic feature of acute respiratory distress syndrome (ARDS) and contributes to mortality. Administration of sildenafil in ambulatory patients with pulmonary hypertension improves oxygenation and ameliorates pulmonary hypertension. Our aim was to determine whether sildenafil is beneficial for patients with ARDS. DESIGN: Prospective, open-label, multicenter, interventional cohort study. SETTING: Medical-surgical ICU of two university hospitals. PATIENTS: Ten consecutive patients meeting the NAECC criteria for ARDS. INTERVENTIONS: A single dose of 50 mg sildenafil citrate administered via a nasogastric tube. MAIN RESULTS: Administration of sildenafil in patients with ARDS decreased mean pulmonary arterial pressure from 25 to 22 mmHg (P = 0.022) and pulmonary artery occlusion pressure from 16 to 13 mmHg (P = 0.049). Systemic mean arterial pressures were markedly decreased from 81 to 75 mmHg (P = 0.005). Sildenafil did not improve pulmonary arterial oxygen tension, but resulted in a further increase in the shunt fraction. CONCLUSION: Although sildenafil reduced pulmonary arterial pressures during ARDS, the increased shunt fraction and decreased arterial oxygenation render it unsuitable for the treatment of patients with ARD

Echocardiography practice, training and accreditation in the intensive care: document for the World Interactive Network Focused on Critical Ultrasound (WINFOCUS)

Echocardiography is increasingly used in the management of the critically ill patient as a non-invasive diagnostic and monitoring tool. Whilst in few countries specialized national training schemes for intensive care unit (ICU) echocardiography have been developed, specific guidelines for ICU physicians wishing to incorporate echocardiography into their clinical practice are lacking. Further, existing echocardiography accreditation does not reflect the requirements of the ICU practitioner. The WINFOCUS (World Interactive Network Focused On Critical UltraSound) ECHO-ICU Group drew up a document aimed at providing guidance to individual physicians, trainers and the relevant societies of the requirements for the development of skills in echocardiography in the ICU setting. The document is based on recommendations published by the Royal College of Radiologists, British Society of Echocardiography, European Association of Echocardiography and American Society of Echocardiography, together with international input from established practitioners of ICU echocardiography. The recommendations contained in this document are concerned with theoretical basis of ultrasonography, the practical aspects of building an ICU-based echocardiography service as well as the key components of standard adult TTE and TEE studies to be performed on the ICU. Specific issues regarding echocardiography in different ICU clinical scenarios are then described

Unconventional Repertoire Profile Is Imprinted during Acute Chikungunya Infection for Natural Killer Cells Polarization toward Cytotoxicity

Chikungunya virus (CHIKV) is a worldwide emerging pathogen. In humans it causes a syndrome characterized by high fever, polyarthritis, and in some cases lethal encephalitis. Growing evidence indicates that the innate immune response plays a role in controlling CHIKV infection. We show here that CHIKV induces major but transient modifications in NK-cell phenotype and function soon after the onset of acute infection. We report a transient clonal expansion of NK cells that coexpress CD94/NKG2C and inhibitory receptors for HLA-C1 alleles and are correlated with the viral load. Functional tests reveal cytolytic capacity driven by NK cells in the absence of exogenous signals and severely impaired IFN-γ production. Collectively these data provide insight into the role of this unique subset of NK cells in controlling CHIKV infection by subset-specific expansion in response to acute infection, followed by a contraction phase after viral clearance

Expression Analysis of the Ligands for the Natural Killer Cell Receptors NKp30 and NKp44

BACKGROUND: The natural cytotoxicity receptors (NCR) are important to stimulate the activity of Natural Killer (NK) cells against transformed cells. Identification of NCR ligands and their level of expression on normal and neoplastic cells has important implications for the rational design of immunotherapy strategies for cancer. METHODOLOGY/PRINCIPAL FINDINGS: Here we analyze the expression of NKp30 ligand and NKp44 ligand on 30 transformed or non-transformed cell lines of different origin. We find intracellular and surface expression of these two ligands on almost all cell lines tested. Expression of NKp30 and NKp44 ligands was variable and did not correlate with the origin of the cell line. Expression of NKp30 and NKp44 ligand correlated with NKp30 and NKp44-mediated NK cell lysis of tumor cells, respectively. The surface expression of NKp30 ligand and NKp44 ligand was sensitive to trypsin treatment and was reduced in cells arrested in G(2)/M phase. CONCLUSION/SIGNIFICANCE: These data demonstrate the ubiquitous expression of the ligands for NKp30 and NKp44 and give an important insight into the regulation of these ligands