Editorial: Discovery and Development of Drugs for Neglected Diseases: Chagas Disease, Human African Trypanosomiasis, and Leishmaniasis

Twenty tropical diseases have been listed by the World Health Organization (WHO) as Neglected Tropical Diseases (NTDs). These tropical diseases are called “neglected” for three primary reasons: 1) These diseases are widespread worldwide among the economically weaker (neglected?) section of the society; 2) Although the total number of mortality, morbidity, disability, and health disparity caused annually by the NTDs is more than that attributed by the so-called elite diseases like cancer, diabetes, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), cardio- or neurological diseases but NTD patients do not receive comparable attention or treatment opportunities either from the governments or healthcare professionals or non-governmental organizations (NGOs); 3) The scope of drug development research in this field is minimal due to insufficient (negligible) funding, and pharma giants are not interested in developing effective drugs for NTDs on time, due to insignificant profit. It is highly challenging to develop new and novel drugs to combat these tropical diseases to upthrust the lifespan and lifestyle of the socioeconomically deprived people affected by NTDs (Figure 1). The major goal of this research topic is to shed light on the global scenario (current status of the ailments, treatment options, and recent drug development efforts) of three major NTDs, viz. Chagas disease (American trypanosomiasis), Human African trypanosomiasis (HAT), and Leishmaniasis. This research topic contains three reviews and seven research articles

On the size and shape of excluded volume polymers confined between parallel plates

A number of recent experiments have provided detailed observations of the configurations of long DNA strands under nano-to-micrometer sized confinement. We therefore revisit the problem of an excluded volume polymer chain confined between two parallel plates with varying plate separation. We show that the non-monotonic behavior of the overall size of the chain as a function of plate-separation, seen in computer simulations and reproduced by earlier theories, can already be predicted on the basis of scaling arguments. However, the behavior of the size in a plane parallel to the plates, a quantity observed in recent experiments, is predicted to be monotonic, in contrast to the experimental findings. We analyze this problem in depth with a mean-field approach that maps the confined polymer onto an anisotropic Gaussian chain, which allows the size of the polymer to be determined separately in the confined and unconfined directions. The theory allows the analytical construction of a smooth cross-over between the small plate-separation de Gennes regime and the large plate-separation Flory regime. The results show good agreement with Langevin dynamics simulations, and confirm the scaling predictions.Comment: 15 pages, 3 figure

Recombinant Promoter (MUASCsV8CP) Driven Totiviral Killer Protein 4 (KP4) Imparts Resistance Against Fungal Pathogens in Transgenic Tobacco

Development of disease-resistant plant varieties achieved by engineering anti-microbial transgenes under the control of strong promoters can suffice the inhibition of pathogen growth and simultaneously ensure enhanced crop production. For evaluating the prospect of such strong promoters, we comprehensively characterized the full-length transcript promoter of Cassava Vein Mosaic Virus (CsVMV; -565 to +166) and identified CsVMV8 (-215 to +166) as the highest expressing fragment in both transient and transgenic assays. Further, we designed a new chimeric promoter ‘MUASCsV8CP’ through inter-molecular hybridization among the upstream activation sequence (UAS) of Mirabilis Mosaic Virus (MMV; -297 to -38) and CsVMV8, as the core promoter (CP). The MUASCsV8CP was found to be ∼2.2 and ∼2.4 times stronger than the CsVMV8 and CaMV35S promoters, respectively, while its activity was found to be equivalent to that of the CaMV35S2 promoter. Furthermore, we generated transgenic tobacco plants expressing the totiviral ‘Killer protein KP4’ (KP4) under the control of the MUASCsV8CP promoter. Recombinant KP4 was found to accumulate both in the cytoplasm and apoplast of plant cells. The agar-based killing zone assays revealed enhanced resistance of plant-derived KP4 against two deuteromycetous foliar pathogenic fungi viz. Alternaria alternata and Phoma exigua var. exigua. Also, transgenic plants expressing KP4 inhibited the growth progression of these fungi and conferred significant fungal resistance in detached-leaf and whole plant assays. Taken together, we establish the potential of engineering “in-built” fungal stress-tolerance in plants by expressing KP4 under a novel chimeric caulimoviral promoter in a transgenic approach

Semiflexible polymers: Dependence on ensemble and boundary orientations

We show that the mechanical properties of a worm-like-chain (WLC) polymer, of contour length $L$ and persistence length \l such that t=L/\l\sim{\cal O}(1), depend both on the ensemble and the constraint on end-orientations. In the Helmholtz ensemble, multiple minima in free energy near $t=4$ persists for all kinds of orientational boundary conditions. The qualitative features of projected probability distribution of end to end vector depend crucially on the embedding dimensions. A mapping of the WLC model, to a quantum particle moving on the surface of an unit sphere, is used to obtain the statistical and mechanical properties of the polymer under various boundary conditions and ensembles. The results show excellent agreement with Monte-Carlo simulations.Comment: 15 pages, 15 figures; version accepted for publication in Phys. Rev. E; one new figure and discussions adde

A GEANT-based study of atmospheric neutrino oscillation parameters at INO

We have studied the dependence of the allowed space of the atmospheric neutrino oscillation parameters on the time of exposure for a magnetized Iron CALorimeter (ICAL) detector at the India-based Neutrino Observatory (INO). We have performed a Monte Carlo simulation for a 50 kTon ICAL detector generating events by the neutrino generator NUANCE and simulating the detector response by GEANT. A chi-square analysis for the ratio of the up-going and down-going neutrinos as a function of $L/E$ is performed and the allowed regions at 90% and 99% CL are displayed. These results are found to be better than the current experimental results of MINOS and Super-K. The possibilities of further improvement have also been discussed.Comment: 8 pages, 13 figures, a new figure added, version accepted in IJMP

Triple minima in free energy of semiflexible polymers

We study the free energy of the worm-like-chain model, in the constant-extension ensemble, as a function of the stiffness for finite chains of length L. We find that the polymer properties obtained in this ensemble are "qualitatively" different from those obtained using constant-force ensembles. In particular we find that as we change the stiffness parameter, the polymer makes a transition from the flexible to the rigid phase and there is an intermediate regime of parameter values where the free energy has three minima and both phases are stable. This leads to interesting features in the force-extension curves.Comment: Published version, 4 pages, 5 figures, revte

Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis, In Vitro, and In Silico Evaluations

World Health Organization (WHO) identified twenty tropical disease categories as neglected tropical diseases (NTDs)1. Chagas’ disease (also known as American trypanosomiasis) and leishmaniasis are two major classes of NTDs. The total number of mortality, morbidity, and disability attributed each year due to these two categories of diseases in magnitudes is much higher than the so-called elite diseases like cancer, diabetes, AIDS, cardiovascular and neurodegenerative diseases. Impoverished communities around the world are the major victim of NTDs. The development of new and novel drugs in the battle against Chagas’ disease and leishmaniasis is highly anticipated. An easy and straightforward on-water green access to synthesize benzopyrazines is reported. This ultrasound-assisted procedure does not require any catalyst/support/additive/hazardous solvents and maintains a high atom economy. A series of eleven benzopyrazines has been synthesized, and most of the synthesized compounds possess the drug-likeness following Lipinski’s “Rule of 5”. Benzopyrazines 3 and 4 demonstrated moderate leishmanicidal activity against L. mexicana (M378) strain. The selective lead compound 1 showed good leishmanicidal, and trypanocidal activities (in vitro) against both L. mexicana (M378) and T. cruzi (NINOA) strains compared to the standard controls. The in vitro trypanocidal and leishmanicidal activities of the lead compound 1 have been validated by molecular docking studies against four biomolecular drug targets viz. T. cruzi histidyl-tRNA synthetase, T. cruzi trans-sialidase, leishmanial rRNA A-site, and leishmania major N-myristoyl transferase

Direct test of defect mediated laser induced melting theory for two dimensional solids

We investigate by direct numerical solution of appropriate renormalization flow equations, the validity of a recent dislocation unbinding theory for laser induced freezing/melting in two dimensions. The bare elastic moduli and dislocation fugacities which are inputs to the flow equations are obtained for three different 2-d systems (hard disk, inverse $12^{th}$ power and the Derjaguin-Landau-Verwey-Overbeek potentials) from a restricted Monte Carlo simulation sampling only configurations {\em without} dislocations. We conclude that (a) the flow equations need to be correct at least up to third order in defect fugacity to reproduce meaningful results, (b) there is excellent quantitative agreement between our results and earlier conventional Monte Carlo simulations for the hard disk system and (c) while the qualitative form of the phase diagram is reproduced for systems with soft potentials there is some quantitative discrepancy which we explain.Comment: 11 pages, 14 figures, submitted to Phys. Rev.

Synthesis and Piezoelectric Response of Cubic and Spherical LiNbO3 Nanocrystals

Methods have been developed for the shape-selective synthesis of ferroelectric LiNbO3 nanoparticles. Decomposition of the single-source precursor, LiNb(O-Et)6, in the absence of surfactants, can reproducibly lead to either cube- or sphere-like nanoparticles. X-Ray diffraction shows that the LiNbO3 nanoparticles are rhombohedral (R3c). Sample properties were examined by piezoresponse force microscopy (PFM) and Raman where both sets of nanoparticles exhibit ferroelectricity. The longitudinal piezoelectric coefficients, d33, varied with shape where the largest value was exhibited in the nanocubes (17 pm V21 for the cubes versus 12 pm V21 for spheres)