Modified Kirchhoffs theory of plates including transverse shear deformations

A primary flexure problem defined by Kirchhoff theory of plates in bending is considered. Significance of auxiliary function introduced earlier in the in-plane displacements in resolving Poisson-Kirchhoffs boundary conditions paradox is reexamined with reference to reported sixth order shear deformation theories, in particular, Reissner's theory and Hencky's theory. Sixth order modified Kirchhoff's theory is extended here to include shear deformations in the analysis. (C) 2011 Elsevier Ltd. All rights reserved.

GyrI: a counter-defensive strategy against proteinaceous inhibitors of DNA gyrase

DNA gyrase is the target of two plasmid-encoded toxins CcdB and microcin B17, which ensure plasmid maintenance. These proteins stabilize gyrase-DNA covalent complexes leading to double-strand breaks in the genome. In contrast, the physiological role of chromosomally encoded inhibitor of DNA gyrase (Gyrl) in Escherichia coli is unclear and its mechanism of inhibition has not been established. We demonstrate that the mode of inhibition of GyrI is distinct from all other gyrase inhibitors. It inhibits DNA gyrase prior to, or at the step of, binding of DNA by the enzyme. Gyrl reduces intrinsic as well as toxin-stabilized gyrase-DNA covalent complexes. Furthermore, Gyri reduces microcin B17-mediated double-strand breaks in vivo, imparting protection to the cells against the toxin, substantiating the in vitro results. Thus, Gyrl is an antidote to DNA gyrase-specific proteinaceous poisons encoded by plasmid addiction systems.

Voltage and Temperature Scalable Gate Delay and Slew Models Including Intra-Gate Variations

We investigate the feasibility of developing a comprehensive gate delay and slew models which incorporates output load, input edge slew, supply voltage, temperature, global process variations and local process variations all in the same model. We find that the standard polynomial models cannot handle such a large heterogeneous set of input variables. We instead use neural networks, which are well known for their ability to approximate any arbitrary continuous function. Our initial experiments with a small subset of standard cell gates of an industrial 65 nm library show promising results with error in mean less than 1%, error in standard deviation less than 3% and maximum error less than 11% as compared to SPICE for models covering 0.9- 1.1 V of supply, -40degC to 125degC of temperature, load, slew and global and local process parameters. Enhancing the conventional libraries to be voltage and temperature scalable with similar accuracy requires on an average 4x more SPICE characterization runs.

Voltage and Temperature Scalable Gate Delay and Slew Models Including Intra-Gate Variations

We investigate the feasibility of developing a comprehensive gate delay and slew models which incorporates output load, input edge slew, supply voltage, temperature, global process variations and local process variations all in the same model. We find that the standard polynomial models cannot handle such a large heterogeneous set of input variables. We instead use neural networks, which are well known for their ability to approximate any arbitrary continuous function. Our initial experiments with a small subset of standard cell gates of an industrial 65 nm library show promising results with error in mean less than 1%, error in standard deviation less than 3% and maximum error less than 11% as compared to SPICE for models covering 0.9- 1.1 V of supply, -40degC to 125degC of temperature, load, slew and global and local process parameters. Enhancing the conventional libraries to be voltage and temperature scalable with similar accuracy requires on an average 4x more SPICE characterization runs.

Interplay between NS3 protease and human La protein regulates translation-replication switch of Hepatitis C virus

HCV NS3 protein plays a central role in viral polyprotein processing and RNA replication. We demonstrate that the NS3 protease (NS3(pro)) domain alone can specifically bind to HCV-IRES RNA, predominantly in the SLIV region. The cleavage activity of the NS3 protease domain is reduced upon HCV-RNA binding. More importantly, NS3(pro) binding to the SLIV hinders the interaction of La protein, a cellular IRES-trans acting factor required for HCV IRES-mediated translation, resulting in inhibition of HCV-IRES activity. Although overexpression of both NS3(pro) as well as the full length NS3 protein decreased the level of HCV IRES mediated translation, replication of HCV replicon RNA was enhanced significantly. These observations suggest that the NS3(pro) binding to HCV IRES reduces translation in favor of RNA replication. The competition between the host factor (La) and the viral protein (NS3) for binding to HCV IRES might regulate the molecular switch from translation to replication of HCV.

Angiotensin converting enzyme inhibitors in the treatment of hypertension

Angiotensin converting enzyme (ACE) catalyses the conversion of angiotensin I (Ang I) to angiotensin II (Ang II). The ACE activity directly related to hypertension as Ang II is the blood pressure regulating hormone. Therefore, ACE inhibitors are a major class of antihypertensive drugs. Captopril, chemical name, was the first orally active ACE inhibitory antihypertensive drug, discovered in 1977. Since then, a number of such drugs have been synthesized. Enzyme-inhibitor bound crystal structural studies reveal a great deal of understanding about the interactions of the inhibitors at the active site of ACE. This can be helpful in the rational design of ACE inhibitors. With the advancement of the combination therapy, it is known that ACE inhibitors having antioxidant activity can be beneficial for the treatment of hypertension. This study describes the development of ACE inhibitors in the treatment of hypertension. Importance of ACE inhibitors having antioxidant activity is also described.

Benzothiophene Carboxamide Derivatives as Inhibitors of Plasmodium falciparum Enoyl-ACP Reductase

Benzothiophene derivatives like benzothiophene sulphonamides, biphenyls, or carboxyls have been synthesized and have found wide pharmacological usage. Here we report, bromo-benzothiophene carboxamide derivatives as potent, slow tight binding inhibitors of Plasmodium enoyl-acyl carrier protein (ACP) reductase (PfENR). 3-Bromo-N-(4-fluorobenzyl)-benzo[b]thiophene-2-carboxamide (compound 6) is the most potent inhibitor with an IC(50) of 115 nM for purified PfENR. The inhibition constant (K(i)) of compound 6 was 18 nM with respect to the cofactor and 91 nM with respect to crotonoyl-CoA. These inhibitors showed competitive kinetics with cofactor and uncompetitive kinetics with the substrate. Thus, these compounds hold promise for the development of potent antimalarials. (C) 2011 IUBMB IUBMB Life, 63(12): 1101-1110, 2011

Characterization of Major Zinc Containing Myonecrotic and Procoagulant Metalloprotease `Malabarin' from Non Lethal Trimeresurus malabaricus Snake Venom with Thrombin Like Activity: Its Neutralization by Chelating Agents

A major myonecrotic zinc containing metalloprotease `malabarin' with thrombin like activity was purified by the combination of gel permeation and anion exchange chromatography from T. malabaricus snake venom. MALDI-TOF analysis of malabarin indicated a molecular mass of 45.76 kDa and its N-terminal sequence was found to be Ile-Ile-Leu-Pro(Leu)-Ile-Gly-Val-Ile-Leu(Glu)-Thr-Thr. Atomic absorption spectral analysis of malabarin raveled the association of zinc metal ion. Malabarin is not lethal when injected i.p. or i.m. but causes extensive hemorrhage and degradation of muscle tissue within 24 hours. Sections of muscle tissue under light microscope revealed hemorrhage and congestion of blood vessel during initial stage followed by extensive muscle fiber necrosis with elevated levels of serum creatine kinase and lactate dehydrogenase activity. Malabarin also exhibited strong procoagulant action and its procoagulant action is due to thrombin like activity; it hydrolyzes fibrinogen to form fibrin clot. The enzyme preferentially hydrolyzes A alpha followed by B beta subunits of fibrinogen from the N-terminal region and the released products were identified as fibrinopeptide A and fibrinopeptide B by MALDI. The myonecrotic, fibrinogenolytic and subsequent procoagulant activities of malabarin was neutralized by specific metalloprotease inhibitors such as EDTA, EGTA and 1, 10-phenanthroline but not by PMSF a specific serine protease inhibitor. Since there is no antivenom available to neutralize local toxicity caused by T. malabaricus snakebite, EDTA chelation therapy may have more clinical relevance over conventional treatment.

Functional regulation of PVBV Nuclear Inclusion protein-a protease activity upon interaction with Viral Protein genome-linked and phosphorylation

Regulation of NIa-Pro is crucial for polyprotein processing and hence, for successful infection of potyviruses. We have examined two novel mechanisms that could regulate NIa-Pro activity. Firstly, the influence of VPg domain on the proteolytic activity of NIa-Pro was investigated. It was shown that the turnover number of the protease increases when these two domains interact (as: two-fold; trans: seven-fold) with each other. Secondly, the protease activity of NIa-Pro could also be modulated by phosphorylation at Ser129. A mutation of this residue either to aspartate (phosphorylation-mimic) or alanine (phosphorylation-deficient) drastically reduces the protease activity. Based on these observations and molecular modeling studies, we propose that interaction with VPg as well as phosphorylation of Ser129 could relay a signal through Trp143 present at the protein surface to the active site pocket by subtle conformational changes, thus modulating protease activity of NIa-Pro. (C) 2011 Elsevier Inc. All rights reserved.

Inhibition of Mycobacterium tuberculosis RNA Polymerase by Binding of a Gre Factor Homo log to the Secondary Channel

Because of its essential nature, each step of transcription, viz., initiation, elongation, and termination, is subjected to elaborate regulation. A number of transcription factors modulate the rates of transcription at these different steps, and several inhibitors shut down the process. Many modulators, including small molecules and proteinaceous inhibitors, bind the RNA polymerase (RNAP) secondary channel to control transcription. We describe here the first small protein inhibitor of transcription in Mycobacterium tuberculosis. Rv3788 is a homolog of the Gre factors that binds near the secondary channel of RNAP to inhibit transcription. The factor also affected the action of guanosine pentaphosphate (pppGpp) on transcription and abrogated Gre action, indicating its function in the modulation of the catalytic center of RNAP. Although it has a Gre factor-like domain organization with the conserved acidic residues in the N terminus and retains interaction with RNAP, the factor did not show any transcript cleavage stimulatory activity. Unlike Rv3788, another Gre homolog from Mycobacterium smegmatis, MSMEG_6292 did not exhibit transcription-inhibitory activities, hinting at the importance of the former in influencing the lifestyle of M. tuberculosis.

Antioxidant activity of peptide-based angiotensin converting enzyme inhibitors

Angiotensin converting enzyme (ACE) inhibitors are important for the treatment of hypertension as they can decrease the formation of vasopressor hormone angiotensin II (Ang II) and elevate the levels of vasodilating hormone bradykinin. It is observed that bradykinin contains a Ser-Pro-Phe motif near the site of hydrolysis. The selenium analogues of captopril represent a novel class of ACE inhibitors as they also exhibit significant antioxidant activity. In this study, several di- and tripeptides containing selenocysteine and cysteine residues at the N-terminal were synthesized. Hydrolysis of angiotensin I (Ang I) to Ang II by ACE was studied in the presence of these peptides. It is observed that the introduction of L-Phe to Sec-Pro and Cys-Pro peptides significantly increases the ACE inhibitory activity. On the other hand, the introduction of L-Val or L-Ala decreases the inhibitory potency of the parent compounds. The presence of an L-Pro moiety in captopril analogues appears to be important for ACE inhibition as the replacement of L-Pro by L-piperidine 2-carboxylic acid decreases the ACE inhibition. The synthetic peptides were also tested for their ability to scavenge peroxynitrite (PN) and to exhibit glutathione peroxidase (GPx)-like activity. All the selenium-containing peptides exhibited good PN-scavenging and GPx activities.

Reactive power optimization with different objectives in large power systems including HVDC systems and FACTS devices

Present day power systems are growing in size and complexity of operation with inter connections to neighboring systems, introduction of large generating units, EHV 400/765 kV AC transmission systems, HVDC systems and more sophisticated control devices such as FACTS. For planning and operational studies, it requires suitable modeling of all components in the power system, as the number of HVDC systems and FACTS devices of different type are incorporated in the system. This paper presents reactive power optimization with three objectives to minimize the sum of the squares of the voltage deviations (ve) of the load buses, minimization of sum of squares of voltage stability L-indices of load buses (¿L2), and also the system real power loss (Ploss) minimization. The proposed methods have been tested on typical sample system. Results for Indian 96-bus equivalent system including HVDC terminal and UPFC under normal and contingency conditions are presented.