Anatomical distribution of scavenger endothelial cells in bony fishes (Osteichthyes)

The scavenger endothelial cells (SECs) of vertebrates are an important class of endocytic cells responsible for clearance of foreign and physiological waste macromolecules, partitioning in the immune system, functioning as a cellular powerplant by producing high energy metabolites like lactate and acetate. All animal phyla possess SECs, but the tissue localization of SECs has only been investigated in a limited number of species. By using a specific ligand for scavenger receptors (formalin treated bovine serum albumin), the study revealed that in all tetrapod species (amphibia, reptiles, birds and mammals) the SECs were found lining the sinusoids of the liver. No SECs were found in the liver of any of the bony fishes (Osteichthyes) investigated. Interestingly, we found the SECs not only to be located in the heart of marine species but also in some freshwater species such as Lota lota, Percichthys trucha and Perca fluviatilis. In some fish species, the SECs were found both in the heart and/or kidney in a number of marine and freshwater fishes, whereas in some marine, diadromous and freshwater fishes the SECs were confined only to the kidney tissue. However, from these results it can be suggested that there is neither a clear phylogenetic trend when it came to anatomical localization of SECs nor any pattern in terms of habitat (salinity preferences)

Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2

The atypical MAP kinases ERK3 and ERK4 are activated by phosphorylation of a serine residue lying within the activation loop signature sequence S-E-G. However, the regulation of ERK3 and ERK4 phosphorylation and activity is poorly understood. Here we report that the inducible nuclear dual-specificity MAP kinase phosphatase (MKP) DUSP2, a known regulator of the ERK and p38 MAPKs, is unique amongst the MKP family in being able to bind to both ERK3 and ERK4. This interaction is mediated by a conserved common docking (CD) domain within the carboxyl-terminal domains of ERK3 and ERK4 and the conserved kinase interaction motif (KIM) located within the non-catalytic amino terminus of DUSP2. This interaction is direct and results in the dephosphorylation of ERK3 and ERK4 and the stabilization of DUSP2. In the case of ERK4 its ability to stabilize DUSP2 requires its kinase activity. Finally, we demonstrate that expression of DUSP2 inhibits ERK3 and ERK4-mediated activation of its downstream substrate MK5. We conclude that the activity of DUSP2 is not restricted to the classical MAPK pathways and that DUSP2 can also regulate the atypical ERK3/4-MK5 signalling pathway in mammalian cells

Serine residue 115 of MAPK-activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function

The mitogen-activated protein kinase-activated protein kinase-5 (MK5) resides predominantly in the nucleus of resting cells, but p38MAPK, extracellular signal-regulated kinases-3 and -4 (ERK3 and ERK4), and protein kinase A (PKA) induce nucleocytoplasmic redistribution of MK5. The mechanism by which PKA causes nuclear export remains unsolved. In the study reported here we demonstrated that Ser-115 is an in vitro PKA phosphoacceptor site, and that PKA, but not p38MAPK, ERK3 or ERK4, is unable to redistribute MK5 S115A to the cytoplasm. However, the phosphomimicking MK5 S115D mutant resides in the cytoplasm in untreated cells. While p38MAPK, ERK3 and ERK4 fail to trigger nuclear export of the kinase dead T182A and K51E MK5 mutants, S115D/T182A and K51E/S115D mutants were able to enter the cytoplasm of resting cells. Finally, we demonstrated that mutations in Ser-115 affect the biological properties of MK5. Taken together, our results suggest that Ser-115 plays an essential role in PKA-regulated nuclear export of MK5, and that it also may regulate the biological functions of MK5

Role of Antiplatelet Therapy in Patients Managed for Complex Aortic Aneurysms using Fenestrated or Branched Endovascular Repair

Abstract Objective Despite the increasing number of fenestrated and branched endovascular aortic repair (F/B-EVAR) procedures, evidence on post-operative antiplatelet therapy is very limited. This study aimed to investigate the role of single antiplatelet therapy (SAPT) vs. double antiplatelet therapy (DAPT) after F/B-EVAR in 30 day and follow up outcomes. Methods A multicentre retrospective analysis was conducted, including F/B-EVAR patients managed from 1 January 2018 to 31 December 2022. Comparative outcomes were assessed according to post-operative antiplatelet therapy. The cohort was divided into the SAPT group (acetylsalicylic acid [ASA] or clopidogrel) and DAPT group (ASA and clopidogrel). The duration of SAPT or DAPT was one to six months. Primary outcomes were 30 day death, and cardiovascular ischaemic and major haemorrhagic events. Secondary outcomes were survival and target vessel (TV) patency during follow up. Results A total of 1 430 patients were included: 955 under SAPT and 475 under DAPT. The 30 day mortality rate was similar (SAPT 2.1% vs. DAPT 1.5%; p = .42). Cardiovascular ischaemic events were lower in the DAPT group (SAPT 11.9% vs. DAPT 8.2%; p = .040), with DAPT being an independent protector for acute mesenteric (p = .009) and lower limb ischaemia (p = .020). No difference was found in 30 day major haemorrhagic events (SAPT 7.5% vs. DAPT 6.3%; p = .40). The mean follow up was 21.8 ± 2.9 months. Cox regression showed no survival confounders, with similar rates between groups (log rank p = .71). DAPT patients enjoyed higher TV patency (SAPT 93.4%, standard error [SE] 0.7% vs. DAPT 97.0%, SE 0.6%; log rank p = .007) at thirty six months. Cox regression revealed B-EVAR as a predictor of worse TV patency (hazard ratio 2.03, 95% confidence interval 1.36 – 3.03; p < .001). DAPT was related to higher patency within B-EVAR patients (SAPT 87.2%, SE 2.1% vs. DAPT 94.9%, SE 1.9%; p < .001). Conclusion DAPT after F/B-EVAR was associated with lower risk of cardiovascular ischaemic events and higher TV patency, especially in B-EVAR cases. No difference in major haemorrhagic events was observed at 30 day

The novel RAGE interactor PRAK is associated with autophagy signaling in Alzheimer’s disease pathogenesis

BACKGROUND: The receptor for advanced glycation end products (RAGE) has been found to interact with amyloid β (Aβ). Although RAGE does not have any kinase motifs in its cytosolic domain, the interaction between RAGE and Aβ triggers multiple cellular signaling involved in Alzheimer’s disease (AD). However, the mechanism of signal transduction by RAGE remains still unknown. Therefore, identifying binding proteins of RAGE may provide novel therapeutic targets for AD. RESULTS: In this study, we identified p38-regulated/activated protein kinase (PRAK) as a novel RAGE interacting molecule. To investigate the effect of Aβ on PRAK mediated RAGE signaling pathway, we treated SH-SY5Y cells with monomeric form of Aβ. We demonstrated that Aβ significantly increased the phosphorylation of PRAK as well as the interaction between PRAK and RAGE. We showed that knockdown of PRAK rescued mTORC1 inactivation induced by Aβ treatment and decreased the formation of Aβ-induced autophagosome. CONCLUSIONS: We provide evidence that PRAK plays a critical role in AD pathology as a key interactor of RAGE. Thus, our data suggest that PRAK might be a potential therapeutic target of AD involved in RAGE-mediated cell signaling induced by Aβ. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0068-5) contains supplementary material, which is available to authorized users

Detection of BK virus DNA in nasopharyngeal aspirates from children with respiratory infections but not in saliva from immunodeficient and immunocompetent adult patients.

Our understanding of important stages in the pathogenesis of the human polyomavirus BK virus (BKV) and JC virus (JCV) infections is limited. In this context, nasopharyngeal aspirates from 201 children with respiratory diseases and saliva from 60 human immunodeficiency virus type 1-infected adults and 10 healthy adult controls were collected and analyzed for the presence of BKV and JCV DNA by PCR. Neither BKV nor JCV DNA was detected in the saliva specimens. We demonstrated BKV DNA, but no infectious BKV, in 2 of 201 nasopharyngeal aspirates. Each sample contained one unique rearranged noncoding control region variant of BKV. The results indicate that (i) BKV and JCV are not regularly associated with respiratory infections in children requiring hospitalization, (ii) nasopharyngeal cells are not an important site for primary replication of human polyomavirus BKV and JCV, and (iii) the salivary glands and oropharyngeal cells seem not to be involved in BKV and JCV persistence. We propose that for the polyomaviruses BKV and JCV the alimentary tract should be considered as a portal of entrance to the human organism

Detection of BK virus DNA in nasopharyngeal aspirates from children with respiratory infections but not in saliva from immunodeficient and immunocompetent adult patients

Our understanding of important stages in the pathogenesis of the human polyomavirus BK virus (BKV) and JC virus (JCV) infections is limited. In this context, nasopharyngeal aspirates from 201 children with respiratory diseases and saliva from 60 human immunodeficiency virus type 1-infected adults and 10 healthy adult controls were collected and analyzed for the presence of BKV and JCV DNA by PCR. Neither BKV nor JCV DNA was detected in the saliva specimens. We demonstrated BKV DNA, but no infectious BKV, in 2 of 201 nasopharyngeal aspirates. Each sample contained one unique rearranged noncoding control region variant of BKV. The results indicate that (i) BKV and JCV are not regularly associated with respiratory infections in children requiring hospitalization, (ii) nasopharyngeal cells are not an important site for primary replication of human polyomavirus BKV and JCV, and (iii) the salivary glands and oropharyngeal cells seem not to be involved in BKV and JCV persistence. We propose that for the polyomaviruses BKV and JCV the alimentary tract should be considered as a portal of entrance to the human organism.</jats:p