DNA Double-Strand Break Repair Inhibitors as Cancer Therapeutics

Among DNA damages, double-strand breaks (DSBs) are one of the most harmful lesions to a cell. Failure in DSB repair could lead to genomic instability and cancer. Homologous recombination (HR) and nonhomologous end joining (NHEJ) are major DSB repair pathways in higher eukaryotes. It is known that expression of DSB repair genes is altered in various cancers. Activation of DSB repair genes is one of the reasons for chemo-and radioresistance. Therefore, targeting DSB repair is an attractive strategy to eliminate cancer. Besides, therapeutic agents introduce breaks in the genome as an intermediate. Therefore, blocking the residual repair using inhibitors can potentiate the efficacy of cancer treatment. In this review, we discuss the importance of targeting DSB repair pathways for the treatment of cancer. Recent advances in the development of DSB repair inhibitors and their clinical relevance are also addressed.

Magnetic frustration and dielectric relaxation in insulating Nd2NiMnO6 double perovskites

We have investigated structural, dielectric, and magnetic properties of polycrystalline double perovskite Nd2NiMnO6 compound. The compound crystallizes in monoclinic P2(1)/n symmetry and is partially B-site disordered depending on the synthesis conditions. It undergoes second-order ferromagnetic transition at 192K and shows glassy behaviour at low temperature. The glassy phase is due to anti-site disorder within the homogeneous sample. Temperature and frequency dependent dielectric measurements reveal colossal values of dielectric constant and is best interpreted using Maxwell-Wagner interfacial polarization model. Impedance spectroscopy has been used to analyse the intrinsic dielectric response. This enabled us to differentiate the conduction process at the grain and grain boundaries. Arrhenius behaviour is favoured at the grain boundary, while variable range hopping mechanism is considered most suitable within the grain region. dc conductivity measurements corroborate variable range hopping conduction. (C) 2015 AIP Publishing LLC.

Optimal Pulse Width Modulation of Voltage-Source Inverter fed Motor Drives with Relaxation of Quarter Wave Symmetry Condition

Optimal switching angles for minimization of total harmonic distortion of line current (I-THD) in a voltage source inverter are determined traditionally by imposing half-wave symmetry (HWS) and quarter-wave symmetry (QWS) conditions on the pulse width modulated waveform. This paper investigates optimal switching angles with QWS relaxed. Relaxing QWS expands the solution space and presents the possibility of improved solutions. The optimal solutions without QWS are shown here to outperform the optimal solutions with QWS over a range of modulation index (M) between 0.82 and 0.94 for a switching frequency to fundamental frequency ratio of 5. Theoretical and experimental results are presented on a 2.3kW induction motor drive.

Poly(alkylene itaconate)s - an interesting class of polyesters with periodically located exo-chain double bonds susceptible to Michael addition

Itaconic acid is a bio-sourced dicarboxylic acid that carries a double bond; although several reports have dealt with the radical-initiated chain polymerization of dialkyl itaconates, only a few studies have utilized it as a di-acid monomer to prepare polyesters. In this study, we demonstrate that dibutyl itaconate can be melt-condensed with aliphatic diols to generate unsaturated polyesters; importantly, we show that the double bonds remain unaffected during the melt polymerization. A particularly useful attribute of these polyesters is that the exo-chain double bonds are conjugated to the ester carbonyl and, therefore, can serve as excellent Michael acceptors. A variety of organic thiols, such as alkane thiols, MPEG thiol, thioglycerol, derivatized cysteine etc., were shown to quantitatively Michael-add to the exo-chain double bonds and generate interesting functionalized polyesters. Similarly, organic amines, such as N-methyl-benzylamine, diallyl amine and proline, also add across the double bond; thus, these poly(alkylene itaconate)s could serve as potentially bio-benign polyesters that could be quantitatively transformed into a variety of interesting and potentially useful functionalized polymers.

Small signal Nonquasi-Static Model for Common Double-Gate MOSFETs Adapted to Gate Oxide Thickness Asymmetry

We present a physics-based closed form small signal Nonquasi-static (NQS) model for a long channel Common Double Gate MOSFET (CDG) by taking into account the asymmetry that may prevail between the gate oxide thickness. We use the unique quasi-linear relationship between the surface potentials along the channel to solve the governing continuity equation (CE) in order to develop the analytical expressions for the Y parameters. The Bessel function based solution of the CE is simplified in form of polynomials so that it could be easily implemented in any circuit simulator. The model shows good agreement with the TCAD simulation at-least till 4 times of the cut-off frequency for different device geometries and bias conditions.

Low-frequency dc bus ripple cancellation in single phase pulse-width modulation inverters

This study presents a topology for a single-phase pulse-width modulation (PWM) converter which achieves low-frequency ripple reduction in the dc bus even when there are grid frequency variations. A hybrid filter is introduced to absorb the low-frequency current ripple in the dc bus. The control strategy for the proposed filter does not require the measurement of the dc bus ripple current. The design criteria for selecting the filter components are also presented in this study. The effectiveness of the proposed circuit has been tested and validated experimentally. A smaller dc-link capacitor is sufficient to keep the low-frequency bus ripple to an acceptable range in the proposed topology.

Changes in the expression of DNA double strand break repair genes in primordial follicles from immature and aged rats

Oocytes present at birth undergo a progressive process of apoptosis in humans and other mammals as they age. Accepted opinion is that no fresh oocytes are produced other than those present at the time of birth. Studies have shown that DNA repair genes in oocytes of mice and women decline with age, and lack of these genes show higher DNA breaks and increased oocyte death rates. In contrast to the ethical problems associated with monitoring the changes in DNA double-strand breaks in oocytes from young and old humans, it is relatively easy to carry out such a study using a rodent model. In this study, the mRNA levels of DNA repair genes are compared with protein products of some of the genes in the primordial follicles isolated from immature (18-20 days) and aged (400-450 days) female rats. Results revealed a significant decline in mRNA levels of BRAC1 (P < 0.01), RAD51 (P < 0.05), ERCC2 (P < 0.05), and H2AX (P < 0.01) of DNA repair genes and phospho-protein levels of BRAC1 (P < 0.01) and H2AX (P < 0.05) in primordial follicles of aged rats. Impaired DNA repair is confirmed as a mechanism of oocyte ageing. (C) 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Medieval pulse of great earthquakes in the central Himalaya: Viewing past activities on the frontal thrust

The Himalaya has experienced three great earthquakes during the last century1934 Nepal-Bihar, 1950 Upper Assam, and arguably the 1905 Kangra. Focus here is on the central Himalayan segment between the 1905 and the 1934 ruptures, where previous studies have identified a great earthquake between thirteenth and sixteenth centuries. Historical data suggest damaging earthquakes in A.D. 1255, 1344, 1505, 1803, and 1833, although their sources and magnitudes remain debated. We present new evidence for a great earthquake from a trench across the base of a 13m high scarp near Ramnagar at the Himalayan Frontal Thrust. The section exposed four south verging fault strands and a backthrust offsetting a broad spectrum of lithounits, including colluvial deposits. Age data suggest that the last great earthquake in the central Himalaya most likely occurred between A.D. 1259 and 1433. While evidence for this rupture is unmistakable, the stratigraphic clues imply an earlier event, which can most tentatively be placed between A.D. 1050 and 1250. The postulated existence of this earlier event, however, requires further validation. If the two-earthquake scenario is realistic, then the successive ruptures may have occurred in close intervals and were sourced on adjacent segments that overlapped at the trench site. Rupture(s) identified in the trench closely correlate with two damaging earthquakes of 1255 and 1344 reported from Nepal. The present study suggests that the frontal thrust in central Himalaya may have remained seismically inactive during the last similar to 700years. Considering this long elapsed time, a great earthquake may be due in the region.

Adaptive Pulse Width Control and Sampling for Low Power Pulse Oximetry

Remote sensing of physiological parameters could be a cost effective approach to improving health care, and low-power sensors are essential for remote sensing because these sensors are often energy constrained. This paper presents a power optimized photoplethysmographic sensor interface to sense arterial oxygen saturation, a technique to dynamically trade off SNR for power during sensor operation, and a simple algorithm to choose when to acquire samples in photoplethysmography. A prototype of the proposed pulse oximeter built using commercial-off-the-shelf (COTS) components is tested on 10 adults. The dynamic adaptation techniques described reduce power consumption considerably compared to our reference implementation, and our approach is competitive to state-of-the-art implementations. The techniques presented in this paper may be applied to low-power sensor interface designs where acquiring samples is expensive in terms of power as epitomized by pulse oximetry.

Investigations on Optimal Pulse-Width Modulation to Minimize Total Harmonic Distortion in the Line Current

PWM waveforms with positive voltage transition at the positive zero crossing of the fundamental voltage (type-A) are generally considered for PWM waveform with even number of switching angles per quarter whereas, waveforms with negative voltage transition at the positive zero crossing (type-B) are considered for odd number of switching angles per quarter. Optimal PWM, for minimization of total harmonic distortion of line to line (VWTHD), is generally solved with the aforementioned criteria. This paper establishes that a combination of both types of waveforms gives better performance than any individual type in terms of minimum VWTHD for complete range of modulation index (M). Optimal PWM for minimum VWTHD is solved for PWM waveforms with pulse numbers (P) of 5 and 7. Both type-A and type-B waveforms are found to be better in different ranges of M. The theoretical findings are confirmed through simulation and experimental results on a 3.7 kW squirrel cage induction motor in an open-loop V/f drive. Further, the optimal PWM is analysed from a space vector point of view.

Ignition delay of 3-carene: single pulse shock tube study

Ignition delay experiments of 3-carene, a biofuel, have been carried out in a single-pulse shock tube for three equivalence ratios, 0.5, 1 and 2. The temperature was varied from 1140 to 1606 K. In the above-mentioned conditions, ignition delay was found to vary from 1.180 ms to 144 mu s. The ignition delay values of 3-carene were found to be lower than those of JP-10, a kerosene-based fuel being considered for hypersonic applications.

Pulse transit time differential measurement by fiber Bragg grating pulse recorder

The present study reports a noninvasive technique for the measurement of the pulse transit time differential (PTTD) from the pulse pressure waveforms obtained at the carotid artery and radial artery using fiber Bragg grating pulse recorders (FBGPR). PTTD is defined as the time difference between the arrivals of a pulse pressure waveform at the carotid and radial arterial sites. The PTTD is investigated as an indicator of variation in the systolic blood pressure. The results are validated against blood pressure variation obtained from a Mindray Patient Monitor. Furthermore, the pulse wave velocity computed from the obtained PTTD is compared with the pulse wave velocity obtained from the color Doppler ultrasound system and is found to be in good agreement. The major advantage of the PTTD measurement via FBGPRs is that the data acquisition system employed can simultaneously acquire pulse pressure waveforms from both FBGPRs placed at carotid and radial arterial sites with a single time scale, which eliminates time synchronization complexity. (C) 2015 Society of Photo-Optical Instrumentation Engineers (SPIE)

N-Terminal Disordered Domain of Saccharomyces cerevisiae Hop1 Protein Is Dispensable for DNA Binding, Bridging, and Synapsis of Double-Stranded DNA Molecules But Is Necessary for Spore Formation

The cytological architecture of the synaptonemal complex (SC), a meiosis-specific proteinaceous structure, is evolutionarily conserved among eukaryotes. However, little is known about the biochemical properties of SC components or the mechanisms underlying their roles in meiotic chromosome synapsis and recombination. Functional analysis of Saccharomyces cerevisiae Hop1, a key structural component of SC, has begun to reveal important insights into its function in interhomolog recombination. Previously, we showed that Hop1 is a structure-specific DNA-binding protein, exhibits higher binding affinity for the Holliday junction, and induces structural distortion at the core of the junction. Furthermore, Hop1 promotes DNA condensation and intra- and intermolecular synapsis between duplex DNA molecules. Here, we show that Hop1 possesses a modular domain organization, consisting of an intrinsically disordered N-terminal domain and a protease-resistant C-terminal domain (Hop1CTD). Furthermore, we found that Hop1CTD exhibits strong homotypic as well as heterotypic protein protein interactions, and its biochemical activities were similar to those of the full-length Hop1 protein. However, Hop1CTD failed to complement the meiotic recombination defects of the Delta hop1 strain, indicating that both N- and C-terminal domains of Hop1 are essential for meiosis and spore formation. Altogether, our findings reveal novel insights into the structure-function relationships of Hop1 and help to further our understanding of its role in meiotic chromosome synapsis and recombination.

Analysis of Wrist Pulse Signals Using Spatial Features in Time Domain

Wrist pulse signal contains more important information about the health status of a person and pulse signal diagnosis has been employed in oriental medicine since very long time. In this paper we have used signal processing techniques to extract information from wrist pulse signals. For this purpose we have acquired radial artery pulse signals at wrist position noninvasively for different cases of interest. The wrist pulse waveforms have been analyzed using spatial features. Results have been obtained for the case of wrist pulse signals recorded for several subjects before exercise and after exercise. It is shown that the spatial features show statistically significant changes for the two cases and hence they are effective in distinguishing the changes taking place due to exercise. Support vector machine classifier is used to classify between the groups, and a high classification accuracy of 99.71% is achieved. Thus this paper demonstrates the utility of the spatial features in studying wrist pulse signals obtained under various recording conditions. The ability of the model to distinguish changes occurring under two different recording conditions can be potentially used for health care applications.