Structural effects of a dimer interface mutation on catalytic activity of triosephosphate isomerase.The role of conserved residues and complementary mutations

The active site of triosephosphate isomerase (TIM, EC: 5.3.1.1), a dimeric enzyme, lies very close to the subunit interface. Attempts to engineer monomeric enzymes have yielded well-folded proteins with dramatically reduced activity. The role of dimer interface residues in the stability and activity of the Plasmodium falciparum enzyme, PfTIM, has been probed by analysis of mutational effects at residue 74. The PfTIM triple mutant W11F/W168F/Y74W (Y74W*) has been shown to dissociate at low protein concentrations, and exhibits considerably reduced stability in the presence of denaturants, urea and guanidinium chloride. The Y74W* mutant exhibits concentration-dependent activity, with an approximately 22-fold enhancement of kcat over a concentration range of 2.5–40 μm, suggesting that dimerization is obligatory for enzyme activity. The Y74W* mutant shows an approximately 20-fold reduction in activity compared to the control enzyme (PfTIM WT*, W11F/W168F). Careful inspection of the available crystal structures of the enzyme, together with 412 unique protein sequences, revealed the importance of conserved residues in the vicinity of the active site that serve to position the functional K12 residue. The network of key interactions spans the interacting subunits. The Y74W* mutation can perturb orientations of the active site residues, due to steric clashes with proximal aromatic residues in PfTIM. The available crystal structures of the enzyme from Giardia lamblia, which contains a Trp residue at the structurally equivalent position, establishes the need for complementary mutations and maintenance of weak interactions in order to accommodate the bulky side chain and preserve active site integrity.

Use of a volatile buffer at ambient temperature *1: Versatile approach to the purification of self-complementary synthetic deoxyoligonucleotides by reversed-phase high-performance liquid chromatography

Abstract is not available.

Impact of energy quantisation in single electron transistor island on hybrid complementary metal oxide semiconductor-single electron transistor integrated circuits

For the first time, the impact of energy quantisation in single electron transistor (SET) island on the performance of hybrid complementary metal oxide semiconductor (CMOS)-SET transistor circuits has been studied. It has been shown through simple analytical models that energy quantisation primarily increases the Coulomb Blockade area and Coulomb Blockade oscillation periodicity of the SET device and thus influences the performance of hybrid CMOS-SET circuits. A novel computer aided design (CAD) framework has been developed for hybrid CMOS-SET co-simulation, which uses Monte Carlo (MC) simulator for SET devices along with conventional SPICE for metal oxide semiconductor devices. Using this co-simulation framework, the effects of energy quantisation have been studied for some hybrid circuits, namely, SETMOS, multiband voltage filter and multiple valued logic circuits. Although energy quantisation immensely deteriorates the performance of the hybrid circuits, it has been shown that the performance degradation because of energy quantisation can be compensated by properly tuning the bias current of the current-biased SET devices within the hybrid CMOS-SET circuits. Although this study is primarily done by exhaustive MC simulation, effort has also been put to develop first-order compact model for SET that includes energy quantisation effects. Finally, it has been demonstrated that one can predict the SET behaviour under energy quantisation with reasonable accuracy by slightly modifying the existing SET compact models that are valid for metallic devices having continuous energy states.

High On-Off Ratio Bilayer Graphene Complementary Field Effect Transistors

In this paper, we propose a novel S/D engineering for dual-gated Bilayer Graphene (BLG) Field Effect Transistor (FET) using doped semiconductors (with a bandgap) as source and drain to obtain unipolar complementary transistors. To simulate the device, a self-consistent Non-Equilibrium Green's Function (NEGF) solver has been developed and validated against published experimental data. Using the simulator, we predict an on-off ratio in excess of 10(4) and a subthreshold slope of similar to 110mV/decade with excellent scalability and current saturation, for a 20nm gate length unipolar BLG FET. However, the performance of the proposed device is found to be strongly dependent on the S/D series resistance effect. The obtained results show significant improvements over existing reports, marking an important step towards bilayer graphene logic devices.

Fusion of Complementary Online and Offline Strategies for Recognition of Handwritten Kannada Characters

This work describes an online handwritten character recognition system working in combination with an offline recognition system. The online input data is also converted into an offline image, and parallely recognized by both online and offline strategies. Features are proposed for offline recognition and a disambiguation step is employed in the offline system for the samples for which the confidence level of the classifier is low. The outputs are then combined probabilistically resulting in a classifier out-performing both individual systems. Experiments are performed for Kannada, a South Indian Language, over a database of 295 classes. The accuracy of the online recognizer improves by 11% when the combination with offline system is used.

Progress in tuberculosis vaccine development and host-directed therapies-a state of the art review

Tuberculosis continues to kill 1.4 million people annually. During the past 5 years, an alarming increase in the number of patients with multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has been noted, particularly in eastern Europe, Asia, and southern Africa. Treatment outcomes with available treatment regimens for drug-resistant tuberculosis are poor. Although substantial progress in drug development for tuberculosis has been made, scientific progress towards development of interventions for prevention and improvement of drug treatment outcomes have lagged behind. Innovative interventions are therefore needed to combat the growing pandemic of multidrug-resistant and extensively drug-resistant tuberculosis. Novel adjunct treatments are needed to accomplish improved cure rates for multidrug-resistant and extensively drug-resistant tuberculosis. A novel, safe, widely applicable, and more effective vaccine against tuberculosis is also desperately sought to achieve disease control. The quest to develop a universally protective vaccine for tuberculosis continues. So far, research and development of tuberculosis vaccines has resulted in almost 20 candidates at different stages of the clinical trial pipeline. Host-directed therapies are now being developed to refocus the anti-Mycobacterium tuberculosis-directed immune responses towards the host; a strategy that could be especially beneficial for patients with multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis. As we are running short of canonical tuberculosis drugs, more attention should be given to host-directed preventive and therapeutic intervention measures.

Insulin-Like Growth Factor System in Cancer: Novel Targeted Therapies

Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies.

A Zero-Crossing Rate Property of Power Complementary Analysis Filterbank Outputs

We establish zero-crossing rate (ZCR) relations between the input and the subbands of a maximally decimated M-channel power complementary analysis filterbank when the input is a stationary Gaussian process. The ZCR at lag is defined as the number of sign changes between the samples of a sequence and its 1-sample shifted version, normalized by the sequence length. We derive the relationship between the ZCR of the Gaussian process at lags that are integer multiples of Al and the subband ZCRs. Based on this result, we propose a robust iterative autocorrelation estimator for a signal consisting of a sum of sinusoids of fixed amplitudes and uniformly distributed random phases. Simulation results show that the performance of the proposed estimator is better than the sample autocorrelation over the SNR range of -6 to 15 dB. Validation on a segment of a trumpet signal showed similar performance gains.