Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.     

Measurement of storage time, estimation of ion number and study of absorption line profile in a Paul trap

Europium (Eu⁺) ions were confined in a Paul trap and detected by non-destructive method. Storage time of Eu⁺ ions achieved in vacuum was improved by orders of magnitude employing buffer gas cooling. The experimentally detected signal was fitted to the ion response signal and the total number of ions trapped was estimated. It is found that the peak signal amplitude as well as the product of FWHM and the peak signal amplitude is proportional to the total number of trapped ions. The trapped ion secular frequency was swept at different rates and its effect on the absorption line profile was studied both experimentally and theoretically.     

Thermal desorption of interacting molecules from mixed adlayers

A Monte Carlo simulation method is used to study thermal desorption of gas molecules from mixed adlayers containing two species. The effects of lateral interactions among adatoms and initial surface coverage on the desorption spectra are examined. It is shown that attractive lateral interactions lead to sharper peaks and that desorption occurs at high temperatures, whereas repulsive interactions lead to multiple peak spectra. It is found that interactions between unlike molecules affect the spectra for species with lower desorption energy only, and that the two species desorb together only in certain cases. Lateral interactions also affect the desorption kinetics significantly and very different behavior for the two species may be obtained.     

High-rate vector quantization for detection

We investigate high-rate quantization for various detection and reconstruction loss criteria. A new distortion measure is introduced which accounts for global loss in best attainable binary hypothesis testing performance. The distortion criterion is related to the area under the receiver-operating-characteristic (ROC) curve. Specifically, motivated by Sanov's theorem, we define a performance curve as the trajectory of the pair of optimal asymptotic Type I and Type II error rates of the most powerful Neyman-Pearson test of the hypotheses. The distortion measure is then defined as the difference between the area-under-the-curve (AUC) of the optimal pre-encoded hypothesis test and the AUC of the optimal post-encoded hypothesis test. As compared to many previously introduced distortion measures for decision making, this distortion measure has the advantage of being independent of any detection thresholds or priors on the hypotheses, which are generally difficult to specify in the code design process. A high-resolution Zador-Gersho type of analysis is applied to characterize the point density and the inertial profile associated with the optimal high-rate vector quantizer. The analysis applies to a restricted class of high-rate quantizers that have bounded cells with vanishing volumes. The optimal point density is used to specify a Lloyd-type algorithm which allocates its finest resolution to regions where the gradient of the pre-encoded likelihood ratio has greatest magnitude.     

Direct and inverse estimates for a new family of linear positive operators

In the present paper we introduce a new family of linear positive operators and study some direct and inverse results in simultaneous approximation.     

Modified Householder iterative method free from second derivatives for nonlinear equations

In this paper, we suggest and analyze a new two-step predictor–corrector type iterative method free from second derivatives for solving nonlinear equations of the type f(x)=0. This new method includes the two-step Newton method as a special case. We prove that the new iterative method is of fourth-order. Several examples are given to illustrate the efficiency of this new method and its comparison with other iterative methods. This method can be considered as a significant improvement of the Newton method and its variant forms.     

Power gain in feedback amplifiers, a classic revisited

A tutorial review of a classic paper by Samuel J. Mason (1954) is described. That paper contained the first definition of a unilateral power gain for a linear two-port and the first proof that this grain is invariant with respect to linear lossless reciprocal four-port embeddings, thereby making it useful as a figure of merit intrinsic to the device. In this work, that original paper is brought up to date, a tutorial exposition of its contents is presented in a modern form, and its significance and applications in microwave engineering are discussed. The subsequent advances in the subject area are summarized, so that the original paper can be placed within a broader context and understood with a more general perspective     

On the dispersion of a solute in oscillating flow of a non-Newtonian fluid in a channel

The paper presents an exact analysis of the dispersion of an immiscible solute in a non-Newtonian fluid (known as an incompressible second-order fluid which shows viscoelastic behaviour) flowing slowly in a parallel plate channel in the presence of a periodic pressure gradient. Using a generalized dispersion model which is valid for all times after the solute injection, the diffusion coefficients K _i (τ)(i=1,2,3,…) are obtained as functions of time τ in the case when the initial solute distribution is in the form of a slug of finite extent. The analysis leads to the novel result that K ₂(τ) (which is a measure of the longitudinal dispersion coefficient of the solute) has a steady part S in addition to a fluctuating part D ₂(τ) due to the pulsatility of the flow. It is found that S decreases with increase in the viscoelastic parameter M for given values of the amplitude λ and frequency ω of the pressure pulsation. On the other hand, it is found that at a fixed instant τ, the amplitude of D ₂(τ) increases with increase in M for given values of λ and ω. Further it is shown that at a given instant τ, the amplitude of D ₂(τ) decreases with increase in ω for given λ and M and the profile for D ₂(τ) becomes progressively flatter with increase in ω. Finally the axial distribution of the average concentration θ _m of the solute over the channel cross-section is determined at different instants after the solute injection for several values of M, λ and ω. The present study is likely to have important bearing on the problem of dispersion of tracers in blood flow through arteries.     

Test Generation for Crosstalk-Induced Faults: Framework and Computational Results

Due to technology scaling and increasing clock frequency, problems due to noise effects lead to an increase in design/debugging efforts and a decrease in circuit performance. This paper addresses the problem of efficiently and accurately generating two-vector tests for crosstalk induced effects, such as pulses, signal speedup and slowdown, in digital combinational circuits. These noise effects can propagate through a circuit and create a logic error in a latch or at a primary output. We have developed a mixed-signal test generator, called XGEN, that incorporates classical static values as well as dynamic signals such as transitions and pulses, and timing information such as signal arrival times, rise/fall times, and gate delay. In this paper we first discuss the general framework of the test generation algorithm followed by computational results. Comparison of results with SPICE simulations confirms the accuracy of this approach.     

Cems characterization of SnO2 films obtained by sputtering and sol-gel route

Conversion electron Mössbauer spectroscopy (CEMS) has been used to study tin oxide films prepared by sol-gel dipping and sputtering. The spectra of films prepared by sol-gel route result close to that of crystalline SnO₂ after heat treatment at a temperature as low as 150°C. The Mössbauer parameters of as sputter deposited films indicate that the structure of the deposited stannic oxide has an amorphous character more pronounced for thinner samples. The structure becomes predominantly that of crystalline SnO₂ by heating at 550°C for 30 min provided the film thickness is higher than 10 nm.