Intelligent Control For Locating Fault in Transmission Lines

This paper presents a new approach for locating fault in transmission line using intelligent control relaying. Fault must be detected at its inception by issuing an output signal indicating this condition. Neural network approach for locating fault can be posed as a pattern-recognition to recognize pure sinusoidal signals as indicators of a normal system condition; abrupt changes of amplitude, phase, or the presence of transient components as indicators of fault. This method uses the fundamental frequency components of voltage and current basically current at pre-fault and post fault condition, measured at each phase from any one end of the selected power system. In this approach the data sets were trained using the available data from the system which comprises of different fault types data, and fault inception angles. This approach of locating fault using intelligent control can be used for supporting a new generation of very high speed protective relaying system

Antidotal Efficacy of Antioxidants against Cyanide Poisoning in vitro.

Cyanide is a potent homicidal, genocidal and chemical warfare agent. Besides, its known inhibitory effects on various enzyme Systems, its other pronounced toxic effects include lipid peroxidation (LPx), particularly in the central nervous system or neuronal cells in vitro. The present study assessed the cytotoxicity of potassium cyanide (KCN) in two non-neuronal mammalian cell cultures, viz., human embryonic lung epithelium (L-132) and baby hamster kidney (BHK-21 ) cells. In addition, the cytoprotective potential of two antioxidant agents, namely, curcumin (CMN) and N-acetylcysteine (NAC) against KCN (2 and 4 mM) in vitro was evaluated. In both the cell lines, KCN reduced cell viability as indicated by trypan blue dye exclusion, leakage of cytosolic lactate dehydrogenase and neutral red uptake. Protein content was unaffected in L-132 cells while cellular respiration determined by MTT assay) was impaired in both the cells. A dose-dependent glutathione mediated LPx was observed in BHK-21 cells alone. The above cytotoxic changes produced by KCN were more effectively minimised by NAC as compared to CMN. Efficacy of CMN and NAC have therapeutic implications as adjuncts to existing cyanide antidotes

Small molecules that affect the p53 pathway and their potential use in the treatment of cancer

The tumor suppressor p53 was identified 35 years ago and has since then been studied extensively, but despite all efforts, no drug or therapy directly involving it has been clinically approved - yet! A lot of potential new drugs are on their way that can reactivate p53 function by various mechanisms. Even a whole new approach called cyclotherapy has been established, during which p53 is activated in normal cells to protect patients from the adverse effects of chemotherapy while tumor cells are still being killed efficiently. In this thesis, 16 drug combinations are being described in this context (paper I). Four individual p53-activating compounds, i.e. tenovin-6, leptomycin B (LMB), nutlin-3 and actinomycin D at low doses (LDactD), were used prior to the addition of each one clinically approved chemotherapeutic agent, i.e vinblastine, vinorelbine, cytosine arabinoside or gemcitabine. LDactD, which is clinically approved, showed the most promising results. Unexpectedly, we identified two compounds that can inhibit p53’s ability to induce p21, i.e. the novel SirT2 inhibitor tenovin-D3 (paper II) and the widely used histone deacetylase inhibitor (HDACi) trichostatin A (TSA) (paper III). Inhibition of p21 in tumor cells might be desirable during cancer treatment to prevent tumor cells from undergoing cell cycle arrest, which would make them more vulnerable to classic chemotherapy. On the other hand, an inhibition of cell cycle arrest in normal cells might occur, which may worsen the side effects caused by chemotherapy. However, SirT2 plays a role in neurodegenerative diseases, and hence compounds like tenovin-D3 may be of use in the treatment thereof. Furthermore, the decrease in p21 levels may be a contributing factor in the previously observed increase in efficacy during the generation of induced pluripotent stem cells upon treatment with TSA; also tenovin-D3 could be useful in this context. With the aid of a cell-based screen we identified two small molecules that can activate p53: 1) MJ05 was one of the most active hit compounds and was very selective (paper IV); it was highly cytotoxic in ARN8, especially when combined with nutlin-3, whereas it was cytostatic or had a very mild effect in other tumor cell lines and normal cells. It inhibited tumor growth in vivo, an effect that was enhanced upon co-treatment with nutlin-3. Furthermore, MJ05 selectively killed chronic myelogenous leukemia stem cells ex vivo while having milder effects in leukocyte stem cells derived from cord blood. Preliminary data strongly suggest that MJ05 acts by inhibition of pyrimidine (deoxy-) nucleotide synthesis. 2) Despite being a hit compound in our screen, MJ25 was not very potent at activating p53 (paper V). Nevertheless, its ability to inhibit thiredoxin reductase 1 (TrxR1) and its selectivity towards melanoma cell lines compared with normal cells were interesting features. We compared it with the TrxR1 inihibitor auranofin, which was very potent and selective at killing melanoma cells in cell viability assays. The insolubility of MJ25 at concentrations required for in vivo studies prevented us from testing it on xenografts in mice. Furthermore, MJ25 might not be specific for TrxR1, so the identification of additional targets could be investigated in the future. Auranofin, the other hand, has a more defined mechanism of action and is clinically approved for the treatment of rheumatoid arthritis. These traits combined with its potentially selective cytotoxic effect at low micromolar concentrations in melanoma cells may turn this compound into a potential drug candidate to be tested in patients suffering from malignant melanoma. In the final study presented in this thesis (paper VI) we tested the small molecule tenovin-6 in zebrafish embryos The compound had been described previously by our group. The original aim of this study was to investigate if the activation of p53 in an organism could affect the ability of tumor cells to disseminate. Even though tenovin-6 did not activate wild-type p53 under the conditions tested, in vivo activity of the compound was still detectable, since embryos expressing mutant p53 (M214K) displayed an increase in p53 protein levels; furthermore, the compound was lethal in a dose- and time-dependent manner, and the embryos lost most of their brown/black pigmentation. The exact mechanism behind the latter observation could not be elucidated in the course of the project. However, tyrosinase, a key enzyme in melanogenesis, was not inhibited by tenovin-6, and the combination of data obtained by others on mutated or pharmacologically inhibited vacuolar H+-ATPase (V- ATPase) and yeast mutant strains suggested that the compound may target V-ATPase

Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy

p53-based cyclotherapy is proving to be a promising approach to palliate undesired effects of chemotherapy in patients with tumours carrying p53 mutations. For example, pre-treatment of cell cultures with Nutlin-3, a highly-selective inhibitor of the p53-mdm2 interaction, has been successfully used as a cytostatic agent to protect normal cells, but not p53-defective cells, from subsequent treatment with mitotic poisons or S-phase specific drugs. Here we sought to evaluate whether low doses of Actinomycin D (LDActD), a clinically-approved drug and potent p53 activator, could substitute Nutlin-3 in p53-based cyclotherapy. We found that pre-treatment with LDActD before adding the aurora kinase inhibitor VX-680 protects normal fibroblasts from polyploidy and nuclear morphology abnormalities induced by VX-680. However, and although to a lower extent than normal fibroblasts, tumour cell lines bearing p53 mutations were also protected by LDActD (but not Nutlin-3) from VX-680-induced polyploidy. We also report that a difference between the response of p53 wild-type cells and p53-defective cells to the LDActD/VX-680 sequential combination is that only the former fail to enter S-phase and therefore accumulate in G1/G0. We propose that drugs that incorporate into DNA during S-phase may perform better as second drugs than mitotic poisons in cyclotherapy approaches using LDActD as a cytostatic agent

A Honeycomb Proportional Counter for Photon Multiplicity Measurement in the ALICE Experiment

A honeycomb detector consisting of a matrix of 96 closely packed hexagonal cells, each working as a proportional counter with a wire readout, was fabricated and tested at the CERN PS. The cell depth and the radial dimensions of the cell were small, in the range of 5-10 mm. The appropriate cell design was arrived at using GARFIELD simulations. Two geometries are described illustrating the effect of field shaping. The charged particle detection efficiency and the preshower characteristics have been studied using pion and electron beams. Average charged particle detection efficiency was found to be 98%, which is almost uniform within the cell volume and also within the array. The preshower data show that the transverse size of the shower is in close agreement with the results of simulations for a range of energies and converter thicknesses.Comment: To be published in NIM