An iPSC Patient Specific Model of CFH (Y402H) Polymorphism Displays Characteristic Features of AMD and Indicates a Beneficial Role for UV Light Exposure

Age related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease, however these do not exist for the dry form. Complement factor H (CFH) polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, retinal pigment epithelium (RPE) damage and visual decline. We have derived and characterised induced pluripotent stem cell (iPSCs) lines from two patients without AMD and low risk genotype and two patients with advanced AMD and high risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H (FH), factor I (FI) and factor H like 1 (FHL-1). The iPSC RPE cells derived from high risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy and deposition of “drüsen” like deposits. The low and high risk RPE cells respond differently to intermittent exposure to UV light which leads to an improvement in cellular and functional phenotype only in the high risk AMD-RPE cells. Taken together our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing

Staphylococcus aureus ultrastructure and the action of bactericidal antibiotics

The bacterial envelope of Staphylococcus aureus consists of the plasma membrane and a multi- layered peptidoglycan cell wall with the exoplasm between them. This structure is essential for growth, division, protection and turgor maintenance. The cell wall is also of clinical importance as its synthesis is the target of various antibiotics. The aim of this study was to investigate the maintenance of S. aureus viability, focusing on the roles of the exoplasm, cell wall dynamics and the action of bactericidal antibiotics. I optimised the electron microscopy techniques for a thorough analysis of the bacterial envelope with focus on the exoplasmic space, and present results that establish the basis for further research into the maintenance of this compartment and its importance for cell viability. My analysis of the morphological changes observed during the action of bactericidal antibiotics was performed as part of a collaborative interdisciplinary investigation into cell wall peptidoglycan homeostasis. I tested a simple predictive model for bacterial life and death based on cell wall homeostasis, and present evidence which stresses the essentiality of peptidoglycan synthesis and hydrolysis for growth; as interruption of either leads to cell death while loss of both leads to stasis. The bactericidal mechanisms that lead to cell death, due to β-lactams and vancomycin, involve a complex process of multiple highly-regulated hydrolases with redundancy in function. The major peptidoglycan hydrolase SagB is a growth-associated hydrolase and is implicated in an increase in size and number of cell wall perforating holes that lead to antibiotic- induced lysis. β-lactam antibiotics also have an additional mode of cell killing that culminates in plasmolysis. This β-lactam-induced death derives from the continued action of various hydrolases involved in cell separation, such as Atl, provoking large cell wall perforating holes and the early septal scission of incomplete septa that lead to plasmolysis and lysis. My project has set the bactericidal activity of antibiotics within a simple, overarching model for cell viability, growth and division. This sets a framework for the development of new control regimes for important pathogens

Poseidonia-Paestum III - Forum Nord

Greco Emanuele, Theodorescu Dinu. Poseidonia-Paestum III - Forum Nord. Rome : École Française de Rome, 1987. 294 p. (Publications de l'École française de Rome, 42-3

Poseidonia-Paestum III - Forum Nord

Greco Emanuele, Theodorescu Dinu. Poseidonia-Paestum III - Forum Nord. Rome : École Française de Rome, 1987. 294 p. (Publications de l'École française de Rome, 42-3

Centrality dependence of the charged-particle multiplicity density at mid-rapidity in Pb-Pb collisions at sNN\sqrt{s_{NN}} = 2.76 TeV

The centrality dependence of the charged-particle multiplicity density at mid-rapidity in Pb-Pb collisions at $\sqrt{s_{NN}}$ = 2.76 TeV is presented. The charged-particle density normalized per participating nucleon pair increases by about a factor 2 from peripheral (70-80%) to central (0-5%) collisions. The centrality dependence is found to be similar to that observed at lower collision energies. The data are compared with models based on different mechanisms for particle production in nuclear collisions.The centrality dependence of the charged-particle multiplicity density at mid-rapidity in Pb-Pb collisions at $\sqrt{s_{\rm NN}}$ = 2.76 TeV is presented. The charged-particle density normalized per participating nucleon pair increases by about a factor 2 from peripheral (70-80%) to central (0-5%) collisions. The centrality dependence is found to be similar to that observed at lower collision energies. The data are compared with models based on different mechanisms for particle production in nuclear collisions