Inhibition of the Interaction Between NS3 Protease and HCV IRES With a Small Peptide: A Novel Therapeutic Strategy

Recently, we have demonstrated that the protease domain of NS3 alone can bind specifically to hepatitis C virus (HCV) internal ribosome entry site (IRES) near the initiator AUG, dislodges human La protein and inhibits translation in favor of viral RNA replication. Here, by using a computational approach, the contact points of the protease on the HCV IRES were putatively mapped. A 30-mer NS3 peptide was designed from the predicted RNA-binding region that retained RNA-binding ability and also inhibited IRES-mediated translation. This peptide was truncated to 15 mer and this also demonstrated ability to inhibit HCV RNA-directed translation as well as replication. More importantly, its activity was tested in an in vivo mouse model by encapsulating the peptide in Sendai virus virosomes followed by intravenous delivery. The study demonstrates for the first time that the HCV NS3-IRES RNA interaction can be selectively inhibited using a small peptide and reports a strategy to deliver the peptide into the liver.

Semi-supervised SVMs for classification with unknown class proportions and a small labeled dataset

In the design of practical web page classification systems one often encounters a situation in which the labeled training set is created by choosing some examples from each class; but, the class proportions in this set are not the same as those in the test distribution to which the classifier will be actually applied. The problem is made worse when the amount of training data is also small. In this paper we explore and adapt binary SVM methods that make use of unlabeled data from the test distribution, viz., Transductive SVMs (TSVMs) and expectation regularization/constraint (ER/EC) methods to deal with this situation. We empirically show that when the labeled training data is small, TSVM designed using the class ratio tuned by minimizing the loss on the labeled set yields the best performance; its performance is good even when the deviation between the class ratios of the labeled training set and the test set is quite large. When the labeled training data is sufficiently large, an unsupervised Gaussian mixture model can be used to get a very good estimate of the class ratio in the test set; also, when this estimate is used, both TSVM and EC/ER give their best possible performance, with TSVM coming out superior. The ideas in the paper can be easily extended to multi-class SVMs and MaxEnt models.

Network-error correcting codes using small fields

Recently, Ebrahimi and Fragouli proposed an algorithm to construct scalar network codes using small fields (and vector network codes of small lengths) satisfying multicast constraints in a given single-source, acyclic network. The contribution of this paper is two fold. Primarily, we extend the scalar network coding algorithm of Ebrahimi and Fragouli (henceforth referred to as the EF algorithm) to block network-error correction. Existing construction algorithms of block network-error correcting codes require a rather large field size, which grows with the size of the network and the number of sinks, and thereby can be prohibitive in large networks. We give an algorithm which, starting from a given network-error correcting code, can obtain another network code using a small field, with the same error correcting capability as the original code. Our secondary contribution is to improve the EF Algorithm itself. The major step in the EF algorithm is to find a least degree irreducible polynomial which is coprime to another large degree polynomial. We suggest an alternate method to compute this coprime polynomial, which is faster than the brute force method in the work of Ebrahimi and Fragouli.

Wheeler-Feynman absorber revisited: a useful technique to calculate decay rates and lifetimes in small scale optical systems

The Wheeler-Feynman (WF) absorber theory of radiation though no more of interest in explaining self interaction of an electron, can be very useful in today's research in small scale optical systems. The significance of the WF absorber is the use of time-symmetrical solution of Maxwell's equations as opposed to only the retarded solution. The radiative coupling of emitters to nano wires in the near field and change in their lifetimes due to small mode volume enclosures have been elucidated with the retarded solutions before. These solutions have also been shown to agree with quantum electrodynamics, thus allowing for classical electromagnetic approaches in such problems. It is here assumed that the radiative coupling of the emitter with a body is in proportion to its contribution to the classical force of radiative reaction as derived in the WF absorber theory. Representing such nano structures as a partial WF absorber acting on the emitter makes the computations considerably easier than conventional electromagnetic solutions for full boundary conditions.

Probing p300/CBP associated Factor (PCAF)-dependent pathways with a small molecule inhibitor

PCAF (KAT2B) belongs to the GNAT family of lysine acetyltransferases (KAT) and specifically acetylates the histone H3K9 residue and several nonhistone proteins. PCAF is also a transcriptional coactivator. Due to the lack of a PCAF KAT-specific small molecule inhibitor, the exclusive role of the acetyltransferase activity of PCAF is not well understood. Here, we report that a natural compound of the hydroxybenzoquinone class, embelin, specifically inhibits H3Lys9 acetylation in mice and inhibits recombinant PCAF-mediated acetylation with near complete specificity in vitro. Furthermore, using embelin, we have identified the gene networks that are regulated by PCAF during muscle differentiation, further highlighting the broader regulatory functions of PCAF in muscle differentiation in addition to the regulation via MyoD acetylation.

MPK-09, a small molecule inspired from bioactive styryllactone restores the wild-type function of mutant p53

In the search for more efficacious and less toxic cancer drugs, the tumor suppressor p53 protein has long been a desirable therapeutic target. In the recent past, few independent studies have demonstrated that the antitumor activity of wild-type p53 can be restored in cancer cells harboring mutant form of p53 using small molecule activators. In this study, we describe a novel small molecule MPK-09, which is selective and highly potent against allele specific p53 mutations mainly, R175H, R249S, R273H, R273C, and E285K. Except E285K, all other mutations tested are among the six ``hot spot'' p53 mutations reported in majority of human cancer. Furthermore, our study conclusively demonstrates that the apoptotic activity of the small molecule MPK-09 against cancer cells harboring R273C and E285K mutations is due to restoration of the wild-type conformation to the corresponding mutant form of p53.

Depth: a web server to compute depth, cavity sizes, detect potential small-molecule ligand-binding cavities and predict the pK(a) of ionizable residues in proteins

Residue depth accurately measures burial and parameterizes local protein environment. Depth is the distance of any atom/residue to the closest bulk water. We consider the non-bulk waters to occupy cavities, whose volumes are determined using a Voronoi procedure. Our estimation of cavity sizes is statistically superior to estimates made by CASTp and VOIDOO, and on par with McVol over a data set of 40 cavities. Our calculated cavity volumes correlated best with the experimentally determined destabilization of 34 mutants from five proteins. Some of the cavities identified are capable of binding small molecule ligands. In this study, we have enhanced our depth-based predictions of binding sites by including evolutionary information. We have demonstrated that on a database (LigASite) of similar to 200 proteins, we perform on par with ConCavity and better than MetaPocket 2.0. Our predictions, while less sensitive, are more specific and precise. Finally, we use depth (and other features) to predict pK(a)s of GLU, ASP, LYS and HIS residues. Our results produce an average error of just <1 pH unit over 60 predictions. Our simple empirical method is statistically on par with two and superior to three other methods while inferior to only one. The DEPTH server (http://mspc.bii.a-star.edu.sg/depth/) is an ideal tool for rapid yet accurate structural analyses of protein structures.

Waiting for Gajah: an elephant mutualist's contingency plan for an endangered megafaunal disperser

Large animals are disproportionately likely to go extinct, and the effects of this on ecosystem processes are unclear. Megaherbivores (weighing over 1000kg) are thought to be particularly effective seed dispersers, yet only a few plant species solely or predominantly adapted for dispersal by megaherbivores have been identified. The reasons for this paradox may be elucidated by examining the ecology of so-called megafaunal fruiting species in Asia, where large-fruited species have been only sparsely researched. We conducted focal tree watches, camera trapping, fruit ageing trials, dung seed counts and germination trials to understand the ecology of Dillenia indica, a large-fruited species thought to be elephant-dispersed, in a tropical moist forest (Buxa Tiger Reserve, India). We find that the initial hardness of the fruit of D.indica ensures that its small (6mm) seeds will primarily be consumed and dispersed by elephants and perhaps other megaherbivores. Elephants removed 63.3% of camera trap-monitored fruits taken by frugivores. If the fruit of D.indica is not removed by a large animal, the seeds of D.indica become available to successively smaller frugivores as its fruits soften. Seeds from both hard and soft fruits are able to germinate, meaning these smaller frugivores may provide a mechanism for dispersal without megaherbivores.Synthesis. Dillenia indica's strategy for dispersal allows it to realize the benefits of dispersal by megaherbivores without becoming fully reliant on these less abundant species. This risk-spreading dispersal behaviour suggests D.indica will be able to persist even if its megafaunal disperser becomes extinct.

Quorum sensing and pathogenesis: role of small signalling molecules in bacterial persistence

The pathogenesis of Mycobacterium tuberculosis is associated with its ability to survive inside the human host and the bacteria use a variety of mechanism to evade the host's defence. A clearer understanding of the host pathogen interaction is needed to follow the pathogenicity and virulence. Recent advances in the study of inter and intra-cellular communication in bacteria had prompted us to study the role of quorum sensing in bacterial survival and pathogenicity. The cell cell communication in bacteria (quorum sensing) is mediated through the exchange of small molecules called as autoinducers that allow bacteria to modulate their gene expression in response to change in cell-population density. It is a coordinated response that confers multicellularity to a bacterial population in response to stress from external environment. Quorum sensing molecules are the global regulators and regulate a wide range of physiological processes including biofilm formation, motility, cell differentiation, long-term survival and many others. Many bacterial pathogens require quorum sensing to produce the virulence factors in response to host pathogen interaction. Here, we summarize our current understanding on small molecule signalling and their role in the bacterial persistence. New discoveries in these areas have enriched our knowledge on intracellular signalling and their role in the long-term survival of mycobacteria under nutrient starvation.

Diketopyrrolopyrrole-Based Conjugated Polymers and Small Molecules for Organic Ambipolar Transistors and Solar Cells

The present highlight discusses major work in the synthesis of low bandgap diketopyrrolopyrrole (DPP)-based polymers with donor-acceptor-donor (D-A-D) approach and their application in organic electronics. It examines the past and recent significant advances which have led to development of low bandgap DPP-based materials with phenyl and thiophene as donors. (c) 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4241-4260

Small-scale mechanical testing of materials

Small-scale mechanical testing of materials has gained prominence in the last decade or so due to the continuous miniaturization of components and devices in everyday application. This review describes the various micro-fabrication processes associated with the preparation of miniaturized specimens, geometries of test specimens and the small scale testing techniques used to determine the mechanical behaviour of materials at the length scales of a few hundred micro-meters and below. This is followed by illustrative examples in a selected class of materials. The choice of the case studies is based on the relevance of the materials used in today's world: evaluation of mechanical properties of thermal barrier coatings (TBCs), applied for enhanced high temperature protection of advanced gas turbine engine components, is essential since its failure by fracture leads to the collapse of the engine system. Si-based substrates, though brittle, are indispensible for MEMS/NEMS applications. Biological specimens, whose response to mechanical loads is important to ascertain their role in diseases and to mimic their structure for attaining high fracture toughness and impact resistance. An insight into the mechanisms behind the observed size effects in metallic systems can be exploited to achieve excellent strength at the nano-scale. A future outlook of where all this is heading is also presented.

Formation flying of small satellites using suboptimal MPSP guidance

Using the recently developed model predictive static programming (MPSP), a suboptimal guidance logic is presented in this paper for formation flying of small satellites. Due to the inherent nature of the problem formulation, MPSP does not require the system dynamics to be linearized. The proposed guidance scheme is valid both for high eccentricity chief satellite orbits as well as large separation distance between chief and deputy satellites. Moreover, since MPSP poses the desired conditions as a set of `hard constraints', the final accuracy level achieved is very high. The proposed guidance scheme has been tested successfully for a variety of initial conditions and for a variety of formation commands as well. Comparison with standard Linear Quadratic Regulator (LQR) solution (which serves as a guess solution for MPSP) and another nonlinear controller, State Dependent Riccati Equation (SDRE) reveals that MPSP guidance achieves the objective with higher accuracy and with lesser amount of control usage as well.

Experimental study of a small partial admission axial turbine with low aspect ratio blade

Experimental study of a small partial admission axial turbine with low aspect ratio blade has been done. Tests were also performed with full admission stator replacing the partial one for the same rotor to assess the losses occurring due to partial admission. Further tests were conducted with stator admission area split into two and three sectors to study the effects of multiple admission sectors. The method of Ainley and Mathieson with suitable correction for aspect ratio in secondary losses, as proposed by Kacker and Okapuu, gives a good estimate of the efficiency. Estimates of partial admission losses are made and compared with experimentally observed values. The Suter and Traupel correlations for partial admission losses yielded reasonably accurate estimates of efficiency even for small turbines though limited to the region of design u/c(is). Stenning's original concept of expansion losses in a single sector is extended to include multiple sectors of opening. The computed efficiency debit due to each additional sector opened is compared with test values. The agreement is observed to be good. This verified Stenning's original concept of expansion losses. When the expression developed on this extended concept is modified by a correction factor, the prediction of partial admission efficiencies is nearly as good as that of Suter and Traupel. Further, performance benefits accrue if the turbine is configured with increased aspect ratio at the expense of reduced partial admission.

Velocity Fluctuations in Helical Propulsion: How Small Can a Propeller Be

Helical propulsion is at the heart of locomotion strategies utilized by various natural and artificial swimmers. We used experimental observations and a numerical model to study the various fluctuation mechanisms that determine the performance of an externally driven helical propeller as the size of the helix is reduced. From causality analysis, an overwhelming effect of orientational noise at low length scales is observed, which strongly affects the average velocity and direction of motion of a propeller. For length scales smaller than a few micrometers in aqueous media, the operational frequency for the propulsion system would have to increase as the inverse cube of the size, which can be the limiting factor for a helical propeller to achieve locomotion in the desired direction.