Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis

In human cells, the RIPK1-RIPK3-MLKL-PGAM5-Drp1 axis drives tumor necrosis factor (TNF)-induced necroptosis through mitochondrial fission, but whether this pathway is conserved among mammals is not known. To answer this question, we analyzed the presence and functionality of the reported necroptotic axis in mice. As in humans, knockdown of receptorinteracting kinase-3 (RIPK3) or mixed lineage kinase domain like (MLKL) blocks TNF-induced necroptosis in L929 fibrosarcoma cells. However, repression of either of these proteins did not protect the cells from death, but instead induced a switch from TNF-induced necroptosis to receptor-interacting kinase-1 (RIPK1) kinase-dependent apoptosis. In addition, although mitochondrial fission also occurs during TNF-induced necroptosis in L929 cells, we found that knockdown of phosphoglycerate mutase 5 (PGAM5) and dynamin 1 like protein (Drp1) did not markedly protect the cells from TNF-induced necroptosis. Depletion of Pink1, a reported interactor of both PGAM5 and Drp1, did not affect TNF-induced necroptosis. These results indicate that in these murine cells mitochondrial fission and Pink1 dependent processes, including Pink-Parkin dependent mitophagy, apparently do not promote necroptosis. Our data demonstrate that the core components of the necrosome (RIPK1, RIPK3 and MLKL) are crucial to induce TNF-dependent necroptosis both in human and in mouse cells, but the associated mechanisms may differ between the two species or cell types

Een 18de-eeuwse wraksite op de Buiten Ratel-zandbank (Belgische territoriale wateren): 1. Multidisciplinair onderzoek van het vondstenmateriaal

In 1996 werd op de Buiten Ratel-zandbank, op 9 mijl van de kust, ter hoogte van Koksijde, een houten scheepswrak gelokaliseerd. Het werd onderzocht door een groep sportduikers, met de naam NATA. Jarenlange verkenning van de wraksite leverde talrijke vondsten op. In 2003 zochten de duikers steun bij het toenmalige IAP (Instituut voor het Archeologisch Patrimonium), nu Vlaams Instituut voor het Onroerend Erfgoed (VIOE), om het onderzoek en de conservatie op wetenschappelijke basis verder te zetten. Het VIOE ontfermde zich over het onderzoek van de tot nu toe geborgen materiële resten van de wraksite. Het eerste hoofdstuk van het artikel geeft een overzicht van de observaties van de wraksite via duikonderzoek en via gespecialiseerde technieken vanop een onderzoeksschip. In hoofdstuk 2 worden de objecten beschreven, hun betekenis aan boord van het schip besproken, evenals hun datering en herkomst. Hoofdstuk 3 brengt alle informatie samen en geeft aan wat er in de toekomst nog aan onderzoek kan gebeuren

Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease

Recent studies show that in Alzheimer's disease (AD), alterations in neurogenesis contribute to the neurodegenerative process. Neurodegeneration in AD has been associated with aberrant signaling through the cyclin-dependent kinase-5 (CDK5) pathway via its activators p35/p25; however, the role of CDK5 in the mechanisms of defective adult neurogenesis in AD is unknown. First, to study AD-like abnormal activation of CDK5 signaling in an in vitro model of neurogenesis, neuronal progenitor cells (NPCs) were infected with a viral vector expressing p35, and exposed to amyloid-β protein (Aβ1−42). These conditions resulted in impaired maturation and neurite outgrowth in vitro, and these effects were reversed by pharmacological or genetic inhibition of CDK5. Similarly, neurogenesis was impaired in a transgenic mouse model of AD that expresses high levels of amyloid precursor protein (APP), and this effect was reversed in transgenic mice crossed with a CDK5 heterozygous-deficient mouse line. A similar rescue effect was observed in APP transgenic mice treated with Roscovitine, a pharmacological inhibitor of CDK5. Taken together, these data suggest that the CDK5 signaling pathway has a critical role in maintaining the integrity of NPCs and neuronal maturation in the adult hippocampus. Moreover, potential therapeutic approaches could focus on modulating the aberrant activity of CDK5 to target the neurogenic and neurodegenerative alterations in AD

Developing core elements and checklist items for global hospital antimicrobial stewardship programmes:a consensus approach

International audienc

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005

Post Paleozoic cooling and uplift of the Brabant Massif as revealed by apatite fission track analysis

A fission track study has been carried out on apatite from the igneous rock belt running along the southern border of the Brabant Massif. The study includes age determinations and a length analysis of both surface tracks and confined tracks. Apatite fission track ages vary between 146 Ma and 209 Ma. Confined track length distributions and the projected length age spectra indicate that the rocks cooled relatively rapidly from above 100-degrees-C to ambient temperatures. The fission track ages therefore date a cooling phase of the Brabant Massif which is interpreted as reflecting an important uplift during the major part of the Jurassic, related to the Cimmerian tectonism which affected the North Sea basin and adjacent areas. Two apatite samples from the southerly Dinant Basin yield fission track ages around 200 Ma, similar to the oldest ages observed in the Brabant Massif, and with comparable track length characteristics. This indicates that the uplift was not limited to the Brabant region but also affected the Hercynian basement to the south