The Languages Spoken in the Water Body (or the Biological Role of Cyanobacterial Toxins)

Although intensification of toxic cyanobacterial blooms over the last decade is a matter of growing concern due to bloom impact on water quality, the biological role of most of the toxins produced is not known. In this critical review we focus primarily on the biological role of two toxins, microcystins and cylindrospermopsin, in inter- and intra-species communication and in nutrient acquisition. We examine the experimental evidence supporting some of the dogmas in the field and raise several open questions to be dealt with in future research. We do not discuss the health and environmental implications of toxin presence in the water body

Derivation of Xeno-Free and GMP-Grade Human Embryonic Stem Cells – Platforms for Future Clinical Applications

Clinically compliant human embryonic stem cells (hESCs) should be developed in adherence to ethical standards, without risk of contamination by adventitious agents. Here we developed for the first time animal-component free and good manufacturing practice (GMP)-compliant hESCs. After vendor and raw material qualification, we derived xeno-free, GMP-grade feeders from umbilical cord tissue, and utilized them within a novel, xeno-free hESC culture system. We derived and characterized three hESC lines in adherence to regulations for embryo procurement, and good tissue, manufacturing and laboratory practices. To minimize freezing and thawing, we continuously expanded the lines from initial outgrowths and samples were cryopreserved as early stocks and banks. Batch release criteria included DNA-fingerprinting and HLA-typing for identity, characterization of pluripotency-associated marker expression, proliferation, karyotyping and differentiation in-vitro and in-vivo. These hESCs may be valuable for regenerative therapy. The ethical, scientific and regulatory methodology presented here may serve for development of additional clinical-grade hESCs

The p38/MK2/Hsp25 Pathway Is Required for BMP-2-Induced Cell Migration

Background: Bone morphogenetic proteins (BMPs) have been shown to participate in the patterning and specification of several tissues and organs during development and to regulate cell growth, differentiation and migration in different cell types. BMP-mediated cell migration requires activation of the small GTPase Cdc42 and LIMK1 activities. In our earlier report we showed that activation of LIMK1 also requires the activation of PAKs through Cdc42 and PI3K. However, the requirement of additional signaling is not clearly known. Methodology/Principal Findings: Activation of p38 MAPK has been shown to be relevant for a number of BMP-2¿s physiological effects. We report here that BMP-2 regulation of cell migration and actin cytoskeleton remodelling are dependent on p38 activity. BMP-2 treatment of mesenchymal cells results in activation of the p38/MK2/Hsp25 signaling pathway downstream from the BMP receptors. Moreover, chemical inhibition of p38 signaling or genetic ablation of either p38¿ or MK2 blocks the ability to activate the downstream effectors of the pathway and abolishes BMP-2-induction of cell migration. These signaling effects on p38/MK2/Hsp25 do not require the activity of either Cdc42 or PAK, whereas p38/MK2 activities do not significantly modify the BMP-2-dependent activation of LIMK1, measured by either kinase activity or with an antibody raised against phospho-threonine 508 at its activation loop. Finally, phosphorylated Hsp25 colocalizes with the BMP receptor complexes in lamellipodia and overexpression of a phosphorylation mutant form of Hsp25 is able to abolish the migration of cells in response to BMP-2. Conclusions: These results indicate that Cdc42/PAK/LIMK1 and p38/MK2/Hsp25 pathways, acting in parallel and modulating specific actin regulatory proteins, play a critical role in integrating responses during BMP-induced actin reorganization and cell migration

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: An international case-cohort study

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (\u3baw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the Cindex. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (\u3baw=0.65, IQR 0.53-0.72, p20 years of experience (C-index=0.72, IQR 0.0-0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70-0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72-0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts

Kératoplastie transfixiante combinée à une greffe de membrane amniotique au cours du syndrome d’insuffisance en cellules souches limbiques

International audiencePurpose: To describe the outcomes of simultaneous penetrating keratoplasty (PK) and amniotic membrane transplantation (AMT) performed both as a ring-shaped graft and as a temporary patch in eyes with a history of limbal stem cell deficiency (LSCD).Methods: Prospective observational case series including 48 simultaneous PK/AMT procedures (48 patients) in eyes with a history of partial or total LSCD. Patients with total LSCD were first treated with limbal stem cell transplantation. The preoperative indication was graft failure in 58.3% of cases. Most recipients (89.6%) were at high-risk for rejection.Results: The mean graft reepithelialization time was 29.2 ± 30.8 days. Graft reepithelialization was achieved in 30 days in 70.8% of cases. No AMT-related adverse events were observed. The mean time from keratoplasty-to-last visit was 84.5 ± 54.5 months. The 3-year graft survival rate was 62.5%. Recurrence of corneal epithelial defects after graft reepithelialization (47.9%) was associated with lower graft survival (P = 0.004). In eyes with successful grafts at the last visit, the mean LogMAR visual acuity was 1.90 (20/1575) ± 5 lines before keratoplasty and 0.89 (20/155) ± 10 lines at 5 years. A ring of amniotic membrane was visible between the graft stroma and the corneal epithelium on slit-lamp examination and optical coherence tomography in all successful cases.Conclusions: In this series of eyes with a history of LSCD and at high-risk of rejection, simultaneous PK and AMT were associated with satisfactory graft survival and no additional adverse events.Introduction: Notre but est de rapporter les résultats de la kératoplastie transfixiante (KT) combinée à une greffe de membrane amniotique (GMA) en anneau et en patch temporaire au cours du déficit en cellules souches limbiques (DCSL).Matériel et méthodes: Il s’agit d’une série prospective observationnelle incluant 48 chirurgies combinées KT/GMA (48 patients) réalisées dans des yeux ayant des antécédents de DCSL partiel ou total. Les patients ayant un DCSL total ont été traités préalablement par une greffe de cellules souches limbiques. L’indication de la greffe était un échec de greffe dans 58,3 % des cas. La plupart des receveurs (89,6 %) étaient à haut risque de rejet.Résultats: Le temps moyen de réépithélialisation du greffon était de 29,2 ± 30,8 jours. Le greffon était réépithélialisé au cours du premier mois dans 70,8 % des cas. Aucun effet indésirable lié à la GMA n’a été observé. Le délai moyen entre la greffe et la dernière visite était de 84,5 ± 54,5 mois. Le taux de survie du greffon à 3 ans était de 62,5 %. La récurrence de défects épithéliaux après réépithélialisation du greffon (47,9 %) était associée à une survie du greffon diminuée (p = 0,004). En cas de présence d’un greffon clair lors de la dernière visite, l’acuité visuelle LogMAR moyenne était de 1,90 (0,013) ± 5 lignes avant greffe et 0,89 (0,13) ± 10 lignes à 5 ans. Un anneau de membrane amniotique était visible à la lampe à fente et en tomographie à cohérence optique entre le stroma du greffon et l’épithélium cornéen dans tous les cas de succès de la greffe.Conclusions: Dans cette série de yeux à haut risque de rejet ayant un DCSL, la chirurgie combine KT/GMA a permis une survie du greffon satisfaisante sans créer d’effet indésirable supplémentaire