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Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages
No full textSpinal muscular atrophy (SMA) is an autosomal recessive disease linked to survival motor neuron (SMN) protein deficiency. While SMN protein is expressed ubiquitously, its deficiency triggers tissue-specific hallmarks, including motor neuron death and muscle atrophy, leading to impaired motor functions and premature death. Here, using stable miR-mediated knockdown technology in zebrafish, we developed the first vertebrate system allowing transgenic spatio-temporal control of the smn1 gene. Using this new model it is now possible to investigate normal and pathogenic SMN function(s) in specific cell types, independently or in synergy with other cell populations. We took advantage of this new system to first test the effect of motor neuron or muscle-specific smn1 silencing. Anti-smn1 miRNA expression in motor neurons, but not in muscles, reproduced SMA hallmarks, including abnormal motor neuron development, poor motor function and premature death. Interestingly, smn1 knockdown in motor neurons also induced severe late-onset phenotypes including scoliosis-like body deformities, weight loss, muscle atrophy and, seen for the first time in zebrafish, reduction in the number of motor neurons, indicating motor neuron degeneration. Taken together, we have developed a new transgenic system allowing spatio-temporal control of smn1 expression in zebrafish, and using this model, we have demonstrated that smn1 silencing in motor neurons alone is sufficient to reproduce SMA hallmarks in zebrafish. It is noteworthy that this research is going beyond SMA as this versatile gene-silencing transgenic system can be used to knockdown any genes of interest, filling the gap in the zebrafish genetic toolbox and opening new avenues to study gene functions in this organism.11 page(s
Configurable heralded two-photon states on a chip
No full textWe show the potential of a hybrid technology for realizing highly complex circuits for quantum photonic applications. We demonstrate the most advanced chip enabling four photon generation and manipulation for heralding tunable two-photon states.2 page(s
Implementation of independent improved neutral current controller using four leg PV-VSI
No full textAn independent improved neutral current controller is implemented in a three-phase (3p) four-wire (4w) low voltage (LV) distribution network with a four-leg voltage source inverter (VSI) and photovoltaic (PV) installations in this paper. The PV VSI is designed to control active power at unity power factor (p.f) with additional improvement in the neutral current controller using the load generated neutral current as a direct reference. As, inherently, most of the three-phase four-wire LV distribution networks exhibit voltage unbalance characteristics due to divergent load connection types such as single-and three-phase loads, the independent control over neutral current at the point of common coupling (PCC) becomes imperative especially for decentralized controllers. The improved performance of the neutral current controller both at customer's installation and at the distribution transformer (DT) terminal is investigated by implementing the designed PV-VSI with actual Australian (Energex) LV network model in PSCAD/EMTDC software environment. The performance of the designed four-leg VSI is compared with the traditional active neutral compensator with actual single phase customer loads. The results show that, with the proposed independent neutral current controller, improved neutral compensation can be achieved for unbalanced LV networks for whole day operations.6 page(s
Implementing Security Council Resolution 1325 in Asia : the role of national action plans on women, peace and security
No full text17 page(s
Empowering RMG workers : towards a conceptual framework
No full textIn the Bangladeshi Ready-made Garment (RMG) industry, workers face constant hardships in communicating with government, accessing regulations and policies, banking to reduce poverty and disasters, educating themselves for a better life and accessing government services. Recently, scholars from developing countries have suggested that mobile phones have the potential to empower the deprived and disadvantaged. However, in the Bangladeshi context the topic is still under researched. This research fills a gap by presenting an initial mobile phone based empowerment framework for RMG workers. The framework examines possible mobile phone based empowerment tools that could provide workers with access to information, market and government. The framework suggests that outcomes include an increased sense of control, self-efficacy, knowledge and competency. In future, the empowerment framework presented in this research will be applied to the development of a mobile based information system for RMG workers. This research is significant as it adopts an empowerment focus rather than an individual consumer focused development outcomes. The outcomes and results of this research will be of potential value to the government, development agencies and mobile telecommunications in accelerating the development of mobile based services in Bangladesh and in other developing countries.7 page(s
One-step conjugation of glycyrrhetinic acid to cationic polymers for high-performance gene delivery to cultured liver cell
No full textGene therapies represent a promising therapeutic route for liver cancers, but major challenges remain in the design of safe and efficient gene-targeting delivery systems. For example, cationic polymers show good transfection efficiency as gene carriers, but are hindered by cytotoxicity and non-specific targeting. Here we report a versatile method of one-step conjugation of glycyrrhetinic acid (GA) to reduce cytotoxicity and improve the cultured liver cell -targeting capability of cationic polymers. We have explored a series of cationic polymer derivatives by coupling different ratios of GA to polypropylenimine (PPI) dendrimer. These new gene carriers (GA-PPI dendrimer) were systematically characterized by UV-vis,¹H NMR titration, electron microscopy, zeta potential, dynamic light-scattering, gel electrophoresis, confocal microscopy and flow cytometry. We demonstrate that GA-PPI dendrimers can efficiently load and protect pDNA, via formation of nanostructured GA-PPI/pDNA polyplexes. With optimal GA substitution degree (6.31%), GA-PPI dendrimers deliver higher liver cell transfection efficiency (43.5% vs 22.3%) and lower cytotoxicity (94.3% vs 62.5%, cell viability) than the commercial bench-mark DNA carrier bPEI (25kDa) with cultured liver model cells (HepG₂). There results suggest that our new GA-PPI dendrimer are a promising candidate gene carrier for targeted liver cancer therapy.11 page(s
Bochner-Riesz profile of anharmonic oscillator L = -d²/dx² + |x|
No full textWe investigate spectral multipliers, Bochner–Riesz means and the convergence of eigenfunction expansion corresponding to the Schrödinger operator with anharmonic potential L = -d²/dx² + |x|. We show that the Bochner–Riesz profile of the operator completely coincides with such profile of the harmonic oscillator H = -d²/dx² + x². It is especially surprising because the Bochner–Riesz profile of the one-dimensional standard Laplace operator is known to be essentially different and the case of operators H and L resembles more the profile of multidimensional Laplace operators. Another surprising element of the main obtained result is the fact that the proof is not based on restriction type estimates and instead an entirely new perspective has to be developed to obtain the critical exponent for Bochner–Riesz means convergence.56 page(s
The pharmacology of valinate and tert-leucinate synthetic cannabinoids
No full textTheoretical thesis.Bibliography: pages 88-97.1. Introduction -- 2. Methods -- 3. Pharmacology of valinate and tert-leucinate synthetic cannabinoids -- 4. Desensitization of CB1 and CB2 receptor signaling by valinate and tert-leucinate synthetic cannabinoids -- 5. Summary and prospects -- Appendices -- References.Synthetic cannabinoids (SCs) with indole or indazole cores and featuring L-valinate or L-tert leucinate groups are epidemic recreational drugs in many parts of the world, and are reported to be associated with severe toxicity. We evaluated the cannabimimetic activity of these compounds on human cannabinoid type 1 (CB1) and type 2 (CB2) receptors. We also examined desensitization of CB1 receptor signaling on continued exposure to SCs.We used a fluorescence-based membrane potential assay to measure the potassium channel-mediated cellular hyperpolarization of AtT20 cells expressing CB1 or CB2. Compound 101, Trametinib and SCH772984 were used to study the involvement of G Protein-Coupled Receptor Kinase2/3 (GRK), Mitogen activated protein kinase enzyme (MEK) and extracellular signal regulated kinase (ERK) in CB1 receptor desensitization.All 16 indole and indazole SCs tested activated CB1 and CB2, with a modest preference for CB1. The most potent was 5F-MDMB-PICA, with an EC₅₀ of 0.45 nM at CB1 receptor. The desensitization of the CB1 mediated hyperpolarization produced by EC₅₀ and EC₉₀ concentrations of 5F-MDMB-PICA was 65±5% and 78±2% after 30 min (n=6). Like CB1 receptor, CB2 receptor also shows a decline in signaling on continuous exposure to EC₅₀ and EC₉₀ of 5F-MDMB-PICA. A significant change in fluorescence was observed for somatostatin after 30 mins of EC₉₀ 5F-MDMB-PICA to that of SST alone at CB2 receptor (P<0.05). Although, the hyperpolarization to a subsequent application of SST (100 nM) after SCs to SST alone was unchanged at CB1 receptor. In cells treated with Cmpd101 (10 μM), we did not observe any difference in the desensitization of CB1 receptor evoked by the EC₉₀ concentration of 5F-MDMB-PICA, but at a concentration of 10 μM 5F-MDMB-PICA, Cmpd 101 reduced desensitization from 97±3.9% to 77±3.5%. Inhibition of MEK or ERK had no effect on CB1 receptor desensitization.All SCs tested in this study have greater potency and maximum effect than Δ⁹-THC. CB1 receptor desensitization was largely homologous, with little effect on the native SST receptor responses, whereas desensitization at CB2 receptors was found to be both homologous and heterologous. Our data demonstrate a role of GRK2/3 in CB1 receptor desensitization to high concentrations of agonist in AtT20 cells, but suggest that other mechanisms may be recruited by lower concentrations of drug.Mode of access: World wide web1 online resource (xiv, 97 pages) colour illustration