Inhibition of type IA topoisomerase by a monoclonal antibody through perturbation of DNA cleavage-religation equilibrium

Type IA DNA topoisomerases, typically found in bacteria, are essential enzymes that catalyse the DNA relaxation of negative supercoils. DNA gyrase is the only type II topoisomerase that can carry out the opposite reaction (i.e. the introduction of the DNA supercoils). A number of diverse molecules target DNA gyrase. However, inhibitors that arrest the activity of bacterial topoisomerase I at low concentrations remain to be identified. Towards this end, as a proof of principle, monoclonal antibodies that inhibit Mycobacterium smegmatis topoisomerase I have been characterized and the specific inhibition of Mycobacterium smegmatis topoisomerase I by a monoclonal antibody, 2F3G4, at a nanomolar concentration is described. The enzyme-bound monoclonal antibody stimulated the first transesterification reaction leading to enhanced DNA cleavage, without significantly altering the religation activity of the enzyme. The stimulated DNA cleavage resulted in perturbation of the cleavagereligation equilibrium, increasing single-strand nicks and proteinDNA covalent adducts. Monoclonal antibodies with such a mechanism of inhibition can serve as invaluable tools for probing the structure and mechanism of the enzyme, as well as in the design of novel inhibitors that arrest enzyme activity.

New Mass Limit for White Dwarfs: Super-Chandrasekhar Type Ia Supernova as a New Standard Candle

Type Ia supernovae, sparked off by exploding white dwarfs of mass close to the Chandrasekhar limit, play the key role in understanding the expansion rate of the Universe. However, recent observations of several peculiar type Ia supernovae argue for its progenitor mass to be significantly super-Chandrasekhar. We show that strongly magnetized white dwarfs not only can violate the Chandrasekhar mass limit significantly, but exhibit a different mass limit. We establish from a foundational level that the generic mass limit of white dwarfs is 2.58 solar mass. This explains the origin of overluminous peculiar type Ia supernovae. Our finding further argues for a possible second standard candle, which has many far reaching implications, including a possible reconsideration of the expansion history of the Universe. DOI: 10.1103/PhysRevLett.110.071102

A POSSIBLE EVOLUTIONARY SCENARIO OF HIGHLY MAGNETIZED SUPER-CHANDRASEKHAR WHITE DWARFS: PROGENITORS OF PECULIAR TYPE Ia SUPERNOVAE

Several recently discovered peculiar Type Ia supernovae seem to demand an altogether new formation theory that might help explain the puzzling dissimilarities between them and the standard Type Ia supernovae. The most striking aspect of the observational analysis is the necessity of invoking super-Chandrasekhar white dwarfs having masses similar to 2.1-2.8 M-circle dot, M-circle dot being the mass of Sun, as their most probable progenitors. Strongly magnetized white dwarfs having super-Chandrasekhar masses have already been established as potential candidates for the progenitors of peculiar Type Ia supernovae. Owing to the Landau quantization of the underlying electron degenerate gas, theoretical results yielded the observationally inferred mass range. Here, we sketch a possible evolutionary scenario by which super-Chandrasekhar white dwarfs could be formed by accretion on to a commonly observed magnetized white dwarf, invoking the phenomenon of flux freezing. This opens multiple possible evolution scenarios ending in supernova explosions of super-Chandrasekhar white dwarfs having masses within the range stated above. We point out that our proposal has observational support, such as the recent discovery of a large number of magnetized white dwarfs by the Sloan Digital Sky Survey.

Type IA topoisomerase inhibition by clamp closure

Bacterial DNA topoisomerase I (topoI) catalyzes relaxation of negatively supercoiled DNA. The enzyme alters DNA topology through protein-operated DNA gate, switching between open and closed conformations during its reaction. We describe the mechanism of inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis topoI by monoclonal antibodies (mAbs) that bind with high affinity and inhibit at 10-50 nM concentration. Unlike other inhibitors of topoisomerases, the mAbs inhibited several steps of relaxation reaction, namely DNA binding, cleavage, strand passage, and enzyme-DNA dissociation. The enhanced religation of the cleaved DNA in presence of the mAb indicated closing of the enzyme DNA gate. The formation of enzyme-DNA heterocatenane in the presence of the mAbs as a result of closing the gate could be inferred by the salt resistance of the complex, visualized by atomic force microscopy and confirmed by fluorescence measurements. Locking the enzyme-DNA complex as a closed clamp restricted the movements of the DNA gate, affecting all of the major steps of the relaxation reaction. Enzyme trapped on DNA in closed clamp conformation formed roadblock for the elongating DNA polymerase. The unusual multistep inhibition of mycobacterial topoisomerases may facilitate lead molecule development, and the mAbs would also serve as valuable tools to probe the enzyme mechanism.

Modified Einstein's gravity as a possible missing link between sub- and super-Chandrasekhar type Ia supernovae

We explore the effect of modification to Einstein's gravity in white dwarfs for the first time in the literature, to the best of our knowledge. This leads to significantly sub- and super-Chandrasekhar limiting masses of white dwarfs, determined by a single model parameter. On the other hand, type Ia supernovae (SNeIa), a key to unravel the evolutionary history of the universe, are believed to be triggered in white dwarfs having mass close to the Chandrasekhar limit. However, observations of several peculiar, under- and over-luminous SNeIa argue for exploding masses widely different from this limit. We argue that explosions of the modified gravity induced sub- and super-Chandrasekhar limiting mass white dwarfs result in under- and over-luminous SNeIa respectively, thus unifying these two apparently disjoint sub-classes and, hence, serving as a missing link. Our discovery raises two fundamental questions. Is the Chandrasekhar limit unique? Is Einstein's gravity the ultimate theory for understanding astronomical phenomena? Both the answers appear to be no!

Imprint of modified Einstein's gravity on white dwarfs: Unifying Type Ia supernovae

We establish the importance of modified Einstein's gravity (MG) in white dwarfs (WDs) for the first time in the literature. We show that MG leads to significantly sub- and super-Chandrasekhar limiting mass WDs, depending on a single model parameter. However, conventional WDs on approaching Chandrasekhar's limit are expected to trigger Type Ia supernovae (SNeIa), a key to unravel the evolutionary history of the universe. Nevertheless, observations of several peculiar, under-and over-luminous SNeIa argue for the limiting mass widely different from Chandrasekhar's limit. Explosions of MG induced sub-and super-Chandrasekhar limiting mass WDs explain under-and over-luminous SNeIa respectively, thus unifying these two apparently disjoint sub-classes. Our discovery questions both the global validity of Einstein's gravity and the uniqueness of Chandrasekhar's limit.

Working group report: Dictionary of Large Hadron Collider signatures

We report on a plan to establish a `Dictionary of LHC Signatures', an initiative that started at the WHEPP-X workshop in Chennai, January 2008. This study aims at the strategy of distinguishing 3 classes of dark matter motivated scenarios such as R-parity conserved supersymmetry, little Higgs models with T-parity conservation and universal extra dimensions with KK-parity for generic cases of their realization in a wide range of the model space. Discriminating signatures are tabulated and will need a further detailed analysis.

On the dielectric dispersion and absorption in nanosized manganese zinc mixed ferrites

The temperature and frequency dependence of dielectric permittivity and dielectric loss of nanosized Mn1-xZnxFe2O4 (for x = 0, 0.2, 0.4, 0.6, 0.8, 1) were investigated. The impact of zinc substitution on the dielectric properties of the mixed ferrite is elucidated. Strong dielectric dispersion and broad relaxation were exhibited by Mn1-xZnxFe2O4. The variation of dielectric relaxation time with temperature suggests the involvement of multiple relaxation processes. Cole-Cole plots were employed as an effective tool for studying the observed phenomenon. The activation energies were calculated from relaxation peaks and Cole-Cole plots and found to be consistent with each other and indicative of a polaron conduction.

Estimation of cosmological parameters from neutral hydrogen observations of the post-reionization epoch

The emission from neutral hydrogen (HI) clouds in the post-reionization era (z <= 6), too faint to be individually detected, is present as a diffuse background in all low frequency radio observations below 1420MHz. The angular and frequency fluctuations of this radiation (similar to 1 mK) are an important future probe of the large-scale structures in the Universe. We show that such observations are a very effective probe of the background cosmological model and the perturbed Universe. In our study we focus on the possibility of determining the redshift-space distortion parameter beta, coordinate distance r(nu), and its derivative with redshift r(nu)('). Using reasonable estimates for the observational uncertainties and configurations representative of the ongoing and upcoming radio interferometers, we predict parameter estimation at a precision comparable with supernova Ia observations and galaxy redshift surveys, across a wide range in redshift that is only partially accessed by other probes. Future HI observations of the post-reionization era present a new technique, complementing several existing ones, to probe the expansion history and to elucidate the nature of the dark energy.

Solid-State Acyl Migration In Salicylamides - An X-Ray Study Of The Ortho-Propionyl And Normal-Propionyl Derivatives

In recent years there has been an upsurge of interest in the study of organic reactions in the solid state. It is now realised that the crystalline matrix provides an extra-ordinary spatial control on the initiation and progress of these reactions. Electronic and dipolar effects which are important in solution are replaced by structural and geometric effects in solids. These 'spatial' or 'topochemical' aspects are important in understanding the mechanistic details of the reaction. In our laboratory, the thermally induced acyl migration in salicylamides from 0- to N- position in the solid state has been under study (Scheme 1). The structures of the acetyl and benzoyl derivatives (Ia,IIa, Ib and IIb) have been reported.

Thermally Induced Acyl Migration in Salicylamides. 1. Structures of the Reactants, O-Acetylsalicylamide and O-Benzoylsalicylamide

O-Acetylsalicylamide (Ia), C9H9NO3, M r =179.18, monoclinic, P2Jc, a=8.155(5), b=8.571 (2), c= 13.092 (3)A, fl=99.54 (5) ° , V= 902.4(6)A 3, Z=4, Dm=l.31, Dx=l.319gcm -3, 2(Mo Ka) = 0.71069 A,/~ = 1.08 cm -1, F(000) = 376, T = 295 K, R = 0.076 for 1604 reflections. O-Benzoylsalicylamide (Ib), C14HtlNO 3, M,=241.2, monoclinic, P2t/e, a=9.423(1), b=5.116(1), e= 26.424 (2) A, fl= 103.97 (1)% V= 1236.2 (3)/~3, Z= 4, D~ = 1.28, D x = 1.296 gcm -3, ,;L(Cu Ks) = 1.5418 A, p = 7.71 cm-', F(000) = 504, T= 295 K, R =0.050 for 2115 reflections. The dihedral angles between the amide group and the benzene ring are 39.9 ° (Ia) and 37.9 ° (Ib), whereas between the acyl group and the benzene ring they are 78.1 ° (Ia) and 93.4 ° (Ib). The differences in the packing of the two structures are brought out in terms of the observed hydrogen-bonding patterns. Based on the crystallographic results, an intramolecular mechanism for the migration of the acyl group from the O to the N position is suggested in both compounds.

Effect of Ethanol Extract of Whole Plant of Trichosanthes cucumerina var. cucumerina L. on Gonadotropins, Ovarian Follicular Kinetics and Estrous Cycle for Screening of Antifertility Activity in Albino Rats

Ethanol extract of whole plant of Trichosanthes cucumerina L. var. cucumerina was evaluated for antiovulatory activity in adult rats. The ethanol extract at the doses 200 and 400mg/kg body weight (orally) affected the normal estrous cycle showing a significant increase in estrus and metestrus phases and decrease in diestrus and proestrus phases. The extract also significantly reduced the number of healthy follicles (Class I-Class VI) and corpora lutea and increased the number of regressing follicles (Stage IA, Stage IB, Stage IIA, and Stage IIB). The protein and glycogen content in the ovaries were significantly reduced in treated rats. The cholesterol level was significantly increased, whereas, the enzyme activities like 3b-HSD and 17b-HSD were significantly inhibited in the ovary of treated rats. Serum FSH and LH levels were significantly reduced in the treated groups were measured by RIA. In acute toxicity test, neither mortality nor change in the behavior or any other physiological activities in mice were observed in the treated groups. In chronic toxicity studies, no mortality was recorded and there were no significant differences in the body and organ weights were observed between controls and treated rats. Hematological analysis showed no significant differences in any of the parameters examined (RBC, WBC count and Hemoglobin estimation). These observations showed the antiovulatory activity of ethanol extract of whole plant of Trichosanthes cucumerina L. var. cucumerina in female albino rats.

High-Frequency Current Source Inverter

The frequency range of the current source inverter (CSI) is limited by the slow commutation process in the inverter circuit. A method to reduce the commutation time and to limit the commutation capacitor voltage is proposed. A brief description of the conventional CSI and a detailed analysis of the commutation intervals of the proposed circuit are given. The experimental waveforms observed in the laboratory verify the validity of the analysis.