Kusum Lata

Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: A perspective

BACKGROUND Estrogens are steroid hormones responsible for the primary and secondary sexual characteristics in females. While pre-menopausal women use estrogens as the main constituents of contraceptive pills, post-menopausal women use the same for Hormone Replacement Therapy. Estrogens produce reactive oxygen species by increasing mitochondrial activity and redox cycling of estrogen metabolites. The phenolic hydroxyl group present at the C3 position of the A ring of estrogens can get oxidized either by accepting an electron or by losing a proton. Thus, estrogens might act as pro-oxidant in some settings, resulting in complicated non-communicable diseases, namely, cancer and cardiovascular disorders. However, in some other settings the phenolic hydroxyl group of estrogens may be responsible for the anti-oxidative beneficial functions and thus protect against cardiovascular and neurodegenerative diseases. SCOPE OF REVIEW To date, no single review article has mentioned the implication of estrogen receptors in both the pro-oxidative and anti-oxidative actions of estrogens. MAJOR CONCLUSION The controversial role of estrogens as pro-oxidant or anti-oxidant is largely dependent on cell types, ratio of different types of estrogen receptors present in a particular cell and context specificity of the estrogen hormone responses. Both pro-oxidant and anti-oxidant effects of estrogens might involve different estrogen receptors that can have either genomic or non-genomic action to manifest further hormonal response. GENERAL SIGNIFICANCE This review highlights the role of estrogen receptors in the pro-oxidative and anti-oxidative actions of estrogens with special emphasis on neuronal cells.

Knockdown of receptor for advanced glycation end products attenuate 17α-ethinyl-estradiol dependent proliferation and survival of MCF-7 breast cancer cells

BACKGROUND 17α-ethinyl-estradiol (17α-EE), a synthetic estrogen is the worlds most widely and commonly used orally bioactive estrogen. Currently, 17α-EE is in use in all formulations of contraceptive pills and is implicated in the complication of breast cancer. Receptor for advanced glycation end products (RAGE) is a cell surface immunoglobulin class of molecule. RAGE is involved in the complication of various cancers. METHODS AND RESULTS This study indicates that treatment of MCF-7 breast cancer cells with 17α-EE enhances the expression of estrogen receptor related receptor gamma (ERRγ), followed by enhanced level of oxidative stress and subsequent activation of the transcription factor, nuclear factor kappa-B (NF-кB), leading to increase in RAGE expression. RAGE thus expressed by 17α-EE treatment causes further enhancement of the oxidative stress which, in turn, activates expression of cell cycle protein cyclin D1 and subsequent induction of MCF-7 breast cancer cell proliferation. RAGE also enhanced phosphorylation of prosurvival protein AKT and increased expression of Bcl2, an antiapoptotic protein. CONCLUSION In MCF-7 breast cancer cells, 17α-EE-ERRγ interaction induces the expression of RAGE, which in turn, enhances the number of MCF-7 breast cancer cells through a multiprong action on the divergent molecules like cyclin D1, AKT and Bcl2. GENERAL SIGNIFICANCE This is the first report which explains the intermediate role of ERRγ in the 17α-EE dependent RAGE expression in MCF-7 breast cancer cells. This report for the first time explains that RAGE is important not only for MCF-7 breast cancer cell proliferation but also for its survival and anti-apoptotic activities.

Towards formal verification of analog mixed signal designs using SPICE circuit simulation traces

An extension to a formal verification approach of hybrid systems is proposed to verify analog and mixed signal (AMS) designs. AMS designs can be formally modeled as hybrid systems and therefore lend themselves to the formal analysis and verification techniques applied to hybrid systems. The proposed approach employs simulation traces obtained from an actual design implementation of AMS circuit blocks (for example, in the form of SPICE netlists) to carry out formal analysis and verification. This enables the same platform used for formally validating an abstract model of an AMS design, to be also used for validating its different refinements and design implementation; thereby, providing a simple route to formal verification at different levels of implementation. The feasibility of the proposed approach is demonstrated with a case study based on a tunnel diode oscillator. Since the device characteristic of a tunnel diode is highly non-linear with a negative resistance region, dynamic behavior of circuits in which it is employed as an element is difficult to model, analyze and verify within a general hybrid system formal verification tool. In the case study presented the formal model and the proposed computational techniques have been incorporated into CheckMate, a formal verification tool based on MATLAB and Simulink-Stateflow Framework from MathWorks.

ADPLL design and implementation on FPGA

This paper presents the ADPLL design using Verilog and its implementation on FPGA. ADPLL is designed using Verilog HDL. Xilinx ISE 10.1 Simulator is used for simulating Verilog Code. This paper gives details of the basic blocks of an ADPLL. In this paper, implementation of ADPLL is described in detail. Its simulation results using Xilinx are also discussed. It also presents the FPGA implementation of ADPLL design on Xilinx vertex5 xc5vlx110t chip and its results. The ADPLL is designed of 200 kHz central frequency. The operational frequency range of ADPLL is 189 Hz to 215 kHz, which is lock range of the design.

ALL Digital Phase-Locked Loop (ADPLL): A Survey

basic details of an ADPLL. It provides brief summary of the basic ADPLL principle applicable to control systems and digital communication. It also reports components of ADPLL and comparison among them.

Verification of a MEMS based adaptive cruise control system using simulation and semi-formal approaches

In this paper we present a verification approach for a MEMS based hybrid system. The hybrid system is an adaptive cruise controller (ACC) involving a MEMS based gyroscope for speed measurement, for the motion control of a platoon of cars. A transformation based approach to obtain a continuous time solution of the states of the hybrid system is presented. This is then integrated into the Simulink/Stateflow (SS) tool framework from MathWorks Inc., where the validation of the ACC is carried out using simulation on the differential equation based and analytical function based continuous time domain dynamic behavior. We also show how this approach and the framework is amenable to verification using formal and semi-formal approaches.

Low-leakage and process-variation-tolerant write-read disturb-free 9T SRA cell using CMOS and FinFETs

For 22nm SoC products, we propose a 9T SRAM cell with low voltage operation and low leakage power using Bulk CMOS and FinFETs. This is achieved by adopting single-ended write & read operation and serial transistor assembly for stacking effect. Proposed cell is designed and simulated in CMOS 22nm technology and results shows that proposed 9T cell achieves 42.2% improvement in write noise margin, 30.1% and 24.7% reduction in read & write power respectively,10^7 times reduced read and write failure probabilities, 31.8% reduced leakage current when compared to Conventional 6T SRAM cell design. Also, designing SRAM cells using fin-shaped field effect transistors shows more process variation tolerance and improvement of ~23% in power consumption, 2.04 times read SNM at VDD=500mV over CMOS design counterpart. Leakage reduction and enhanced read-write stability of proposed cell are verified under process variations. Also, proposed cell is observed to have 32% larger layout area when compared to Conv. 6T design.

Helicobacter pylori TlyA Agglutinates Liposomes and Induces Fusion and Permeabilization of the Liposome Membranes

Helicobacter pylori TlyA is a pore-forming hemolysin with potent cytotoxic activity. To explore the potential membrane-damaging activity of H. pylori TlyA, we have studied its interaction with the synthetic liposome vesicles. In our study, H. pylori TlyA shows a prominent ability to associate with the liposome vesicles without displaying an obligatory requirement for any protein receptor on the liposome membranes. Interaction of TlyA triggers agglutination of the liposome vesicles. Such agglutinating activity of TlyA could also be observed with erythrocytes before the induction of its pore-forming hemolytic activity. In addition to its agglutinating activity against liposomes, TlyA also induces fusion and disruption of the liposome membranes. Altogether, our study highlights novel membrane-damaging properties of H. pylori TlyA that have not been documented previously with any other TlyA family protein.

Formal Verification of Analog and Mixed Signal Designs Using SPICE Circuit Simulation Traces

Analog and Mixed Signal (AMS) designs can be formally modeled as hybrid systems [45] and therefore formal verification techniques applicable to hybrid systems can be deployed to verify them. An extension to a formal verification approach applicable to hybrid systems is proposed to verify AMS designs [31]. In this approach formal verification (FV) is carried out on an AMS block using simulation traces from SPICE, a simulator widely used in the design and verification of analog and AMS blocks. A broader implication of this approach is the ability to carry out hierarchical verification using relevant simulation traces obtained at different abstraction levels of a design when modeled in appropriate platforms. This enables a seamless transition of design and verification artifacts from the highest level of abstraction to the lowest level of implementation at the transistor level of any AMS design and a resulting increase in confidence on the correctness of the final implementation. The proposed approach has been justified with its applications to different AMS design blocks. For each design, its formal model and the proposed computational techniques have been incorporated into CheckMate [11] - a FV tool for hybrid systems based on MATLAB and the Simulink/Stateflow framework from MathWorks. A further justification of the proposed approach is the resulting improvements observed in terms of reduced verification time for different specifications in each design.

Helicobacter pylori TlyA Forms Amyloid-like Aggregates with Potent Cytotoxic Activity.

Helicobacter pylori is a potent human gastric pathogen. It is known to be associated with several gastroenteric disorders, including gastritis, peptic ulcer, and gastric cancer. The H. pylori genome encodes a gene product TlyA that has been shown to display potent membrane damaging properties and cytotoxic activity. On the basis of such properties, TlyA is considered as a potential virulence factor of H. pylori. In this study, we show that the H. pylori TlyA protein has a strong propensity to convert into the amyloid-like aggregated assemblies, upon exposure to elevated temperatures. Even at the physiological temperature of 37 °C, TlyA shows a strong amyloidogenic property. TlyA aggregates that are generated upon exposure at temperatures of ≥37 °C show prominent binding to dyes like thioflavin T and Nile Red. Transmission electron microscopy also demonstrates the presence of typical amyloid-like fibrils in the TlyA aggregates generated at 37 °C. Conversion of TlyA into the amyloid-like aggregates is found to be associated with major alterations in the secondary and tertiary structural organization of the protein. Finally, our study shows that the preformed amyloid-like aggregates of TlyA are capable of exhibiting potent cytotoxic activities against human gastric adenocarcinoma cells. Altogether, such a propensity of H. pylori TlyA to convert into the amyloid-like aggregated assemblies with cytotoxic activity suggests potential implications for the virulence functionality of the protein.