304Nuclear targeting apelin induces phenotypic transition of vascular smooth muscle cells

Background: Apelin, and its receptor APJ, are a peptidic system playing a crucial role in vascular diseases. However, the role of apelin in atherogenesis and smooth muscle cell (SMC) proliferation remains unclear. We isolated 2 distinct SMC phenotypes from porcine coronary artery: spindle-shaped (S) and rhomboid (R). Biological features of R-SMCs (i.e. enhanced proliferative and migratory activities as well as poor level of differentiation) explain their capacity to accumulate into the intima. S100A4 is a marker of R-SMCs in vitro and of intimal SMCs, both in pig and human. S100A4 is a Ca2+-binding protein that can also be secreted; it has extracellular functions probably via the receptor for advanced glycation end products (RAGE). Purpose: Investigate the effects of apelin on SMC phenotypic transition and S100A4 expression and release. Methods and Results: We observed that apelin was highly expressed in R-SMCs particularly in their nucleus. P-SORT software analysis of preproapelin sequence suggested that N-terminal truncated apelin may target the nucleus, and we confirmed this in SMCs by overexpression of mutated preproapelin-His-tag. Transfection of mutated preproapelin-His-tag encoding plasmid in differentiated S-SMCs induced a transition towards a R-phenotype associated with increased proliferative activity, downregulation of SMC differentiation markers (i.e. alpha-smooth muscle actin), and increased nuclear expression and release of S100A4. In contrast, transfection of S-SMCs with wild type preproapelin-His-tag encoding plasmid did not induce nuclear targeting of Apelin or S100A4, and did not change the S-phenotype. Stimulation of S-SMCs with PDGF-BB, known to induce a transition to the R-phenotype, yielded nuclear targeting of both apelin and S100A4. In vivo, Apelin was expressed in SMC nuclei of stent-induced intimal thickening while its expression in the media was mainly cytoplasmic. Conclusions: Our results suggest that nuclear targeting of apelin in SMCs acts on S100A4 expression and release, cell proliferation and differentiation. The pathophysiological consequences of this retargeting could be instrumental in the understanding of artherosclerosi

Protamine is an antagonist of Apelin receptor, and its activity is reversed by heparin

In the accompanying Comment, Suzuki et al. confirmed our previous findings that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) does not functionally inhibit the NMDAR at concentrations relevant to its antidepressant actions recently reported in mice (that is, approximately 10 μM)

Parameter Estimation for Personalization of Liver Tumor Radiofrequency Ablation

International audienceMathematical modeling has the potential to assist radiofrequency ablation (RFA) of tumors as it enables prediction of the extent of ablation. However, the accuracy of the simulation is challenged by the material properties since they are patient-specific, temperature and space dependent. In this paper, we present a framework for patient specific radiofrequency ablation modeling of multiple lesions in the case of metastatic diseases. The proposed forward model is based upon a computational model of heat diffusion, cellular necrosis and blood flow through vessels and liver which relies on patient images. We estimate the most sensitive material parameters, those need to be personalized from the available clinical imaging and data. The selected parameters are then estimated using inverse modeling such that the point to-mesh distance between the computed necrotic area and observed lesions is minimized. Based on the personalized parameters, the ablation of the remaining lesions are predicted. The framework is applied to a dataset of seven lesions from three patients including pre- and post-operative CT images. In each case, the parameters were estimated on one tumor and RFA is simulated on the other tumor(s) using these personalized parameters, assuming the parameters to be spatially invariant within the same patient. Results showed significantly good correlation between predicted and actual ablation extent (average point-to-mesh errors of 4.03 mm)

Non Mycobacterial Virulence Genes in the Genome of the Emerging Pathogen Mycobacterium abscessus

Mycobacterium abscessus is an emerging rapidly growing mycobacterium (RGM) causing a pseudotuberculous lung disease to which patients with cystic fibrosis (CF) are particularly susceptible. We report here its complete genome sequence. The genome of M. abscessus (CIP 104536T) consists of a 5,067,172-bp circular chromosome including 4920 predicted coding sequences (CDS), an 81-kb full-length prophage and 5 IS elements, and a 23-kb mercury resistance plasmid almost identical to pMM23 from Mycobacterium marinum. The chromosome encodes many virulence proteins and virulence protein families absent or present in only small numbers in the model RGM species Mycobacterium smegmatis. Many of these proteins are encoded by genes belonging to a “mycobacterial” gene pool (e.g. PE and PPE proteins, MCE and YrbE proteins, lipoprotein LpqH precursors). However, many others (e.g. phospholipase C, MgtC, MsrA, ABC Fe(3+) transporter) appear to have been horizontally acquired from distantly related environmental bacteria with a high G+C content, mostly actinobacteria (e.g. Rhodococcus sp., Streptomyces sp.) and pseudomonads. We also identified several metabolic regions acquired from actinobacteria and pseudomonads (relating to phenazine biosynthesis, homogentisate catabolism, phenylacetic acid degradation, DNA degradation) not present in the M. smegmatis genome. Many of the “non mycobacterial” factors detected in M. abscessus are also present in two of the pathogens most frequently isolated from CF patients, Pseudomonas aeruginosa and Burkholderia cepacia. This study elucidates the genetic basis of the unique pathogenicity of M. abscessus among RGM, and raises the question of similar mechanisms of pathogenicity shared by unrelated organisms in CF patients

Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

11 páginas, 2 figuras, 1 tablaInappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)Peer reviewe

APLNR (apelin receptor)

Review on APLNR (apelin receptor), with data on DNA, on the protein encoded, and where the gene is implicated

Apelin signalling: a promising pathway from cloning to pharmacology.

International audienceThe discovery of new signalling pathways is always followed by the development of pharmacological agents as drugs that can be used in the treatment of diseases resulting from a dysfunction of the signalling pathway in question. Apelin signalling plays a role in the central and peripheral regulation of the cardiovascular system, in water and food intake, and possibly in immune function. Up-regulation of ligand and receptor is also associated with pathophysiological states such as cardiac dysfunction and neovascularisation. Finally, the apelin receptor is a coreceptor for the entry of several HIV-1 and SIV strains. In view of these features, the apelin receptor constitutes a very interesting target for the design of new drugs for treating the prime causes of human mortality