The role of promyelocytic leukemia (PML) protein in regulation of adult subventricular zone neurogenesis

The control of cell fate in neural progenitor/stem cells (NPCs/NSCs) is essential for central nervous system (CNS) development. NSCs are also found within the adult brain. In particular, NSCs in the subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) and terminally differentiate in the olfactory bulb (OB). However, our understanding of mechanisms regulating cell migration during SVZ neurogenesis remains limited. Previous work from our lab showed that the promyelocytic leukaemia protein (PML), a growth suppressor inactivated in leukaemia, controls cell fate during corticogenesis, with implications for regulation of brain size. The main aim of the present work was to investigate the role of PML in the context of adult SVZ neurogenesis. Our findings show that PML loss leads to reduction of the more primitive NSC pool accompanied by expansion of transit-amplifying NPCs and neuroblasts. However, PML-deficient neuroblasts display impaired migratory capacity through the RMS, thus resulting in reduced number of terminally differentiated neurons and a smaller OB. These changes can be recapitulated in vitro, demonstrating an intrinsic defect of PML KO NSCs. Mechanistically, our findings suggest that PML controls NSC expansion and migration via Polycomb Repressive Complex-2 (PRC-2) - dependent suppression of a transcriptional programme involving the axon guidance genes Slit2/Robo1 and the key epithelial-to-mesenchymal transition (EMT) gene Twist1. Notably, Twist1 is part of an amplification loop for transcriptional induction of Slit2. I was also involved in work aimed at determining whether the PML/Slit axis is functional in neoplastic settings. In this respect, alterations of adult neurogenesis are believed to lead to glioblastoma multiforme (GBM), and tumour spreading through the brain parenchyma is one of key factors underlying GBM aggressiveness. Our work revealed that a PML/Slit axis controls cell migration also in GBM cells, suggesting that mechanisms underlying cell migration are common to normal and neoplastic cells in the CNS. 6 Overall, these findings have important implications for our understanding of adult neurogenesis and may provide novel insights into the process of oncogenesis in the CNS

Cryptocapsinepoxide-type Carotenoids from Red Mamey, Pouteria sapota

Three new carotenoids, cryptocapsin-5,6-epoxide, 3ʹ-deoxycapsanthin-5,6-epoxide, and cryptocapsin-5,8-epoxides, have been isolated from the ripe fruits of red mamey (Pouteria sapota). Cryptocapsin-5,6-epoxide was prepared by partial synthesis via epoxidation of cryptocapsin and the (5R,6S)- and (5S,6R)-stereoisomers were identified by HPLC-ECD analysis. Spectroscopic data of the natural (anti) and semisynthetic (syn) derivatives obtained by acid-catalyzed rearrangement of cryptocapsin-5,8-epoxide stereoisomers were compared for structural elucidation. Chiral HPLC separation of natural and semisynthetic samples of cryptocapsin-5,8-epoxides was performed and HPLC-ECD analysis allowed configurational assignment of the separated stereoisomers

Reducing the clinical burden of ranibizumab treatment for neovascular age-related macular degeneration using an individually planned regimen.

AIMS: The purpose of this study was to clinically validate an individually planned treatment regimen for neovascular age-related macular degeneration (nAMD), termed, observe and plan. This regimen was based on the predictability of an individual's need for retreatment and aimed to reduce the clinical burden, while obtaining good functional results. METHODS: This was a prospective case series that included 104 patients (115 eyes) with treatment-naive nAMD. Following three loading doses of ranibizumab, monthly observation visits allowed the disease recurrence interval to be determined. The recurrence interval was reduced by 2 weeks to give the retreatment interval for the next three injections. Periodical control visits (at least every 6 months) allowed the effectiveness of the treatment to be assessed and individual intervals adjusted. RESULTS: Mean visual acuity (VA) improved by 8.7 and 9.8 letters in months 3 and 12, respectively. The mean number of injections during the 12-month study was 7.8, while the mean number of ophthalmic examinations between months 3 and 12 was 3.97. The mean treatment interval after the loading doses was 1.97 months. CONCLUSIONS: The observe-and-plan regimen significantly improved VA. This was obtained with fewer clinic visits compared with other regimens, which could ease the burden of nAMD treatment. TRIAL REGISTRATION NUMBER: Commission cantonale (VD) d'éthique de la recherché Clinique, Université de Lausanne, Protocole 351/11

Pengendalian Modul Rotary Handling Station Bebasis Sequential Function Chart (Sfc)

The system used in this day and age has made progress in its operations. In industry itself many use automated systems that only require a small operator to run a tool because it saves time, and safety is guaranteed. In this time the tool discussed Handling Station Rotary pneumatic system uses motion to move this tool. So that the tool can be moved according to plan also required the "brains" to run this tool. Where the brain is a Program Logic Controller (PLC) to save a program that has been created in order to move the tool. Program created in this thesis using Sequential Function Chart (SFC) using Zelio Soft application. For components that are needed in this form of censorship tool as a reader, selonoid as air regulator to move from such a device

3-D Tracking and Visualization of Hundreds of Pt-Co Fuel Cell Nanocatalysts During Electrochemical Aging

We present an electron tomography method that allows for the identification of hundreds of electrocatalyst nanoparticles with one-to-one correspondence before and after electrochemical aging. This method allows us to track, in three-dimensions (3-D), the trajectories and morphologies of each Pt-Co nanocatalyst on a fuel cell carbon support. The use of atomic-scale electron energy loss spectroscopic imaging enables the correlation of performance degradation of the catalyst with changes in particle/inter-particle morphologies, particle-support interactions and the near-surface chemical composition. We found that, aging of the catalysts under normal fuel cell operating conditions (potential scans from +0.6 V to +1.0 V for 30,000 cycles) gives rise to coarsening of the nanoparticles, mainly through coalescence, which in turn leads to the loss of performance. The observed coalescence events were found to be the result of nanoparticle migration on the carbon support during potential cycling. This method provides detailed insights into how nanocatalyst degradation occurs in proton exchange membrane fuel cells (PEMFCs), and suggests that minimization of particle movement can potentially slow down the coarsening of the particles, and the corresponding performance degradation.Comment: Nano Letters, accepte

A Kernelisation Approach for Multiple d-Hitting Set and Its Application in Optimal Multi-Drug Therapeutic Combinations

Therapies consisting of a combination of agents are an attractive proposition, especially in the context of diseases such as cancer, which can manifest with a variety of tumor types in a single case. However uncovering usable drug combinations is expensive both financially and temporally. By employing computational methods to identify candidate combinations with a greater likelihood of success we can avoid these problems, even when the amount of data is prohibitively large. Hitting Set is a combinatorial problem that has useful application across many fields, however as it is NP-complete it is traditionally considered hard to solve exactly. We introduce a more general version of the problem (α,β,d)-Hitting Set, which allows more precise control over how and what the hitting set targets. Employing the framework of Parameterized Complexity we show that despite being NP-complete, the (α,β,d)-Hitting Set problem is fixed-parameter tractable with a kernel of size O(αdkd) when we parameterize by the size k of the hitting set and the maximum number α of the minimum number of hits, and taking the maximum degree d of the target sets as a constant. We demonstrate the application of this problem to multiple drug selection for cancer therapy, showing the flexibility of the problem in tailoring such drug sets. The fixed-parameter tractability result indicates that for low values of the parameters the problem can be solved quickly using exact methods. We also demonstrate that the problem is indeed practical, with computation times on the order of 5 seconds, as compared to previous Hitting Set applications using the same dataset which exhibited times on the order of 1 day, even with relatively relaxed notions for what constitutes a low value for the parameters. Furthermore the existence of a kernelization for (α,β,d)-Hitting Set indicates that the problem is readily scalable to large datasets

Blood-brain carrier co-culture models to study nanoparticle penetration : focus on co-culture systems

The blood-brain barrier, as a physical, active transport and metabolic barrier represents the main obstacle in the treatment of central nervous system diseases. The field of nanoparticle delivery systems is rapidly developing and nanocarriers seem to be promising for drug delivery or targeting to the brain. For testing the toxicity, uptake and transcellular transport of nanoparticles culture models of the blood-brain barrier are widely used, including immortalized brain endothelial cell lines, primary brain endothelial cells in static or dynamic culture conditions, and in co-culture systems with glial cells and/or pericytes. This mini-review gives a brief summary of blood-brain barrier co-culture models that were used for testing nanocarriers, the types of different nanoparticle systems that were examined on blood-brain barrier models, and the advantages, limitations and suitability of the blood-brain barrier models for nanoparticle penetration studies

Chronic eccentric exercise and antioxidant supplementation: effects on lipid profile and insulin sensitivity

Eccentric exercise has been shown to exert beneficial effects in both lipid profile and insulin sensitivity. Antioxidant supplementation during chronic exercise is controversial as it may prevent the physiological training-induced adaptations. The aim of this study was to investigate: 1) the minimum duration of the eccentric exercise training required before changes on metabolic parameters are observed and 2) whether antioxidant supplementation during training would interfere with these adaptations. Sixteen young healthy men were randomized into the Vit group (1 g of vitamin C and 400 IU vitamin E daily) and the placebo (PL) group. Subjects received the supplementation for 9 weeks. During weeks 5-9 all participants went through an eccentric exercise training protocol consisting of two exercise sessions (5 sets of 15 eccentric maximal voluntary contractions) per week. Plasma triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), apolipoproteins (Apo A1, Apo B and Lpa) and insulin sensitivity (HOMA) were assessed before the supplementation (week 0), at weeks 5, 6, 7, 8 and 9. TG, TC and LDL were significantly lower compared to pre supplementation at both weeks 8 and 9 (P<0.05) in both groups. HDL was significantly elevated after 4 weeks of training (p < 0.005) in both groups. There was no effect of the antioxidant supplementation in any of the variables. There was no effect of either the training or the supplementation protocol in apolipoproteins levels and insulin sensitivity. A minimum duration of 3 weeks of eccentric exercise training is required before beneficial effects in lipid profile can be observed in healthy young men. Concomitant antioxidant supplementation does not interfere with the training-induced adaptations