Deorphanization of Malonyl CoA:ACP Transacylase Drug Target in Plasmodium falciparum (PfFabD) Using Bacterial Antagonists: A Piggyback' Approach for Antimalarial Drug Discovery

Quest for new drug targets in Plasmodium sp. has underscored malonyl CoA:ACP transacylase (PfFabD) of fatty acid biosynthetic pathway in apicoplast. In this study, a piggyback approach was employed for the receptor deorphanization using inhibitors of bacterial FabD enzymes. Due to the lack of crystal structure, theoretical model was constructed using the structural details of homologous enzymes. Sequence and structure analysis has localized the presence of two conserved pentapeptide motifs: GQGXG and GXSXG and five key invariant residues viz., Gln109, Ser193, Arg218, His305 and Gln354 characteristic of FabD enzyme. Active site mapping of PfFabD using substrate molecules has disclosed the spatial arrangement of key residues in the cavity. As structurally similar molecules exhibit similar biological activities, signature pharmacophore fingerprints of FabD antagonists were generated using 0D-3D descriptors for molecular similarity-based cluster analysis and to correlate with their binding profiles. It was observed that antagonists showing good geometrical fitness score were grouped in cluster-1, whereas those exhibiting high binding affinities in cluster-2. This study proves important to shed light on the active site environment to reveal the hotspot for binding with higher affinity and to narrow down the virtual screening process by searching for close neighbors of the active compounds.

Antibody-mediated catalysis: Induction and therapeutic relevance

Abzymes are immunoglobulins endowed with enzymatic activities. The catalytic activity of an abzyme resides in the variable domain of the antibody, which is constituted by the close spatial arrangement of amino acid residues involved in catalysis. The origin of abzymes is conferred by the innate diversity of the immunoglobulin gene repertoire. Under deregulated immune conditions, as in autoimmune diseases, the generation of abzymes to self-antigens could be deleterious. Technical advancement in the ability to generate monoclonal antibodies has been exploited in the generation of abzymes with defined specificities and activities. Therapeutic applications of abzymes are being investigated with the generation of monoclonal abzymes against several pathogenesis-associated antigens. Here, we review the different contexts in which abzymes are generated, and we discuss the relevance of monoclonal abzymes for the treatment of human diseases.

Spatial B-jump at sudden channel enlargements with abrupt drop

An analytical and experimental study of the hydraulic jump in stilling basins with abrupt drop and sudden enlargement, called the spatial B-jump here, is carried out for finding the sequent depth ratio and resulting energy dissipation. The spatial B-jump studied has its toe downstream of the expansion section, and the stream lines at the toe are characterized by downward curvature. An expression is obtained for the sequent depth ratio based on the momentum equation with suitable assumptions for the extra pressure force term because of the abrupt drop in the bed and sudden enlargement in the basin width. Predictions compare favorably with experiments. It is shown that the spatial B-jump needs less tailwater depth, thereby enhancing the stability of the jump when compared either with spatial jump, which forms in sudden expanding channels, or with B-jump, which forms in a channel with an abrupt drop in bed. It is also shown that there is a significant increase in relative energy loss for the spatial B-jump compared to either the spatial jump or B-jump alone.

Spatial distribution of aerosol black carbon over India during pre-monsoon season

Aerosol black carbon (BC) mass concentrations ([BC]), measured continuously during a multi-platform field experiment, Integrated Campaign for Aerosols gases and Radiation Budget (ICARB, March-May 2006), from a network of eight observatories spread over geographically distinct environments of India, (which included five mainland stations, one highland station, and two island stations (one each ill Arabian Sea and Bay of Bengal)) are examined for their spatio-temporal characteristics. During the period of study, [BC] showed large variations across the country, with values ranging from 27 mu g m(3) over industrial/urban locations to as low as 0.065 mu g m(-3) over the Arabian Sea. For all mainland stations, [BC] remained high compared to highland as well as island stations. Among the island stations, Port Blair (PBR) had higher concentration of BC, compared to Minicoy (MCY), implying more absorbing nature of Bay of Bengal aerosols than Arabian Sea. The highland station Nainital (NTL), in the central Himalayas, showed low values of [BC], comparable or even lower than that of the island station PBR, indicating the prevalence of cleaner environment over there. An examination of the changes in the mean temporal features, as the season advances from winter (December-February) to pre-monsoon (March-May), revealed that: (a) Diurnal variations were pronounced over all the mainland stations, with all afternoon low and a nighttime high: (b) At the islands, the diurnal variations, though resembled those over the mainlands, were less pronounced; and (c) In contrast to this, highland station showed an opposite pattern with an afternoon high and a late night or early morning low. The diurnal variations at all stations are mainly caused by the dynamics of local Atmospheric Boundary Layer (ABL), At the entire mainland as well as island stations (except HYD and DEL), [BC] showed a decreasing trend from January to May, This is attributed to the increased convective mixing and to the resulting enhanced vertical dispersal of species in the ABL. In addition, large short-period modulations were observed at DEL and HYD, which appeared to be episodic, An examination of this in the light of the MODIS-derived fire count data over India along with the back-trajectory analysis revealed that advection of BC from extensive forest fires and biomass-burning regions upwind were largely responsible for this episodic enhancement in BC at HYD and DEL.

Non-linear regression model for spatial variation in precipitation chemistry for South India

Chemical composition of rainwater changes from sea to inland under the influence of several major factors - topographic location of area, its distance from sea, annual rainfall. A model is developed here to quantify the variation in precipitation chemistry under the influence of inland distance and rainfall amount. Various sites in India categorized as 'urban', 'suburban' and 'rural' have been considered for model development. pH, HCO3, NO3 and Mg do not change much from coast to inland while, SO4 and Ca change is subjected to local emissions. Cl and Na originate solely from sea salinity and are the chemistry parameters in the model. Non-linear multiple regressions performed for the various categories revealed that both rainfall amount and precipitation chemistry obeyed a power law reduction with distance from sea. Cl and Na decrease rapidly for the first 100 km distance from sea, then decrease marginally for the next 100 km, and later stabilize. Regression parameters estimated for different cases were found to be consistent (R-2 similar to 0.8). Variation in one of the parameters accounted for urbanization. Model was validated using data points from the southern peninsular region of the country. Estimates are found to be within 99.9% confidence interval. Finally, this relationship between the three parameters - rainfall amount, coastline distance, and concentration (in terms of Cl and Na) was validated with experiments conducted in a small experimental watershed in the south-west India. Chemistry estimated using the model was in good correlation with observed values with a relative error of similar to 5%. Monthly variation in the chemistry is predicted from a downscaling model and then compared with the observed data. Hence, the model developed for rain chemistry is useful in estimating the concentrations at different spatio-temporal scales and is especially applicable for south-west region of India. (C) 2008 Elsevier Ltd. All rights reserved.

Effect of spatial dispersion of the dielectric on the binding energy of D- ion in Si and Ge

Using a multivalley effective mass theory, we obtain the binding energy of a D- ion in Si and Ge taking into account the spatial variation of the host dielectric function. We find that on comparison with experimental results the effect of spatial dispersion is important in the estimation of binding energy for the D- formed by As in Si and Ge. The effect is less significant for the case of D- formed by P and Sb donors.

Spatial Variability of the Depth of Weathered and Engineering Bedrock using Multichannel Analysis of Surface Wave Method

In this paper an attempt has been made to evaluate the spatial variability of the depth of weathered and engineering bedrock in Bangalore, south India using Multichannel Analysis of Surface Wave (MASW) survey. One-dimensional MASW survey has been carried out at 58 locations and shear-wave velocities are measured. Using velocity profiles, the depth of weathered rock and engineering rock surface levels has been determined. Based on the literature, shear-wave velocity of 330 ± 30 m/s for weathered rock or soft rock and 760 ± 60 m/s for engineering rock or hard rock has been considered. Depths corresponding to these velocity ranges are evaluated with respect to ground contour levels and top surface levels have been mapped with an interpolation technique using natural neighborhood. The depth of weathered rock varies from 1 m to about 21 m. In 58 testing locations, only 42 locations reached the depths which have a shear-wave velocity of more than 760 ± 60 m/s. The depth of engineering rock is evaluated from these data and it varies from 1 m to about 50 m. Further, these rock depths have been compared with a subsurface profile obtained from a two-dimensional (2-D) MASW survey at 20 locations and a few selected available bore logs from the deep geotechnical boreholes.

X-ray studies on crystalline complexes involving amino acids and peptides. Part XIV: Closed conformation and head-to-tail arrangement in a new crystal form of L-histidine L-aspartate monohydrate

A new form of L-histidine L-aspartate monohydrate crystallizes in space group P22 witha = 5.131(1),b = 6.881(1),c= 18.277(2) Å,β= 97.26(1)° and Z = 2. The structure has been solved by the direct methods and refined to anR value of 0.044 for 1377 observed reflections. Both the amino acid molecules in the complex assume the energetically least favourable allowed conformation with the side chains staggered between the α-amino and α-scarboxylate groups. This results in characteristic distortions in some bond angles. The unlike molecules aggregate into alternating double layers with water molecules sandwiched between the two layers in the aspartate double layer. The molecules in each layer are arranged in a head-to-tail fashion. The aggregation pattern in the complex is fundamentally similar to that in other binary complexes involving commonly occurring L amino acids, although the molecules aggregate into single layers in them. The distribution of crystallographic (and local) symmetry elements in the old form of the complex is very different from that in the new form. So is the conformation of half the histidine molecules. Yet, the basic features of molecular aggregation, particularly the nature and the orientation of head-to-tail sequences, remain the same in both the forms. This supports the thesis that the characteristic aggregation patterns observed in crystal structures represent an intrinsic property of amino acid aggregation.

Spatial correlations around a Kondo impurity

We present a method for calculating zero-frequency, spatially varying response and correlation functions around a magnetic impurity in metals. We illustrate the procedure which involves a combination of perturbative scaling and nonperturbative renormalization-group methods for the spin-(1/2) Kondo impurity. We explain the factorization of the temperature and spatial dependence of the Knight shift observed in NMR experiments.

On the Arrangement of Cliques in Chordal Graphs with respect to the Cuts

A cut (A, B) (where B = V - A) in a graph G = (V, E) is called internal if and only if there exists a vertex x in A that is not adjacent to any vertex in B and there exists a vertex y is an element of B such that it is not adjacent to any vertex in A. In this paper, we present a theorem regarding the arrangement of cliques in a chordal graph with respect to its internal cuts. Our main result is that given any internal cut (A, B) in a chordal graph G, there exists a clique with kappa(G) + vertices (where kappa(G) is the vertex connectivity of G) such that it is (approximately) bisected by the cut (A, B). In fact we give a stronger result: For any internal cut (A, B) of a chordal graph, and for each i, 0 <= i <= kappa(G) + 1 such that vertical bar K-i vertical bar = kappa(G) + 1, vertical bar A boolean AND K-i vertical bar = i and vertical bar B boolean AND K-i vertical bar = kappa(G) + 1 - i. An immediate corollary of the above result is that the number of edges in any internal cut (of a chordal graph) should be Omega(k(2)), where kappa(G) = k. Prompted by this observation, we investigate the size of internal cuts in terms of the vertex connectivity of the chordal graphs. As a corollary, we show that in chordal graphs, if the edge connectivity is strictly less than the minimum degree, then the size of the mincut is at least kappa(G)(kappa(G)+1)/2 where kappa(G) denotes the vertex connectivity. In contrast, in a general graph the size of the mincut can be equal to kappa(G). This result is tight.

The scale-invariance of spatial patterning in a developing system

Regulating systems, that is, those which exhibit scale-invariant patterns in the adult, are supposed, to do so on account of interactions between cells during development. The nature of these interactions has to be such that the system of positional information (ldquomaprdquo) in the embryo also regulates. To our knowledge, this supposition regarding a regulating map has not been subjected to a direct test in any embryonic system. Here we do so by means of a simple and novel criterion and use it to examine tip regeneration in the mulicellular stage (slug) ofDictyostelium discoideum. When anterior, tip-containing fragments of slugs are amputated, a new tip spontaneously regenerates at the cut surface of the (remaining) posterior fragment. The time needed for regeneration to occur depends on the relative size of the amputated fragment but is independent of the total size of the slug. We conclude from this finding that there is at least one system underlying positional information in the slug which regulates.

Reverse Channel Training For Reciprocal Mimo Systems With Spatial Multiplexing

This paper investigates the problem of designing reverse channel training sequences for a TDD-MIMO spatial-multiplexing system. Assuming perfect channel state information at the receiver and spatial multiplexing at the transmitter with equal power allocation to them dominant modes of the estimated channel, the pilot is designed to ensure an stimate of the channel which improves the forward link capacity. Using perturbation techniques, a lower bound on the forward link capacity is derived with respect to which the training sequence is optimized. Thus, the reverse channel training sequence makes use of the channel knowledge at the receiver. The performance of orthogonal training sequence with MMSE estimation at the transmitter and the proposed training sequence are compared. Simulation results show a significant improvement in performance.

Spatial patterning of the distribution of Ca-2+ in Dictyostelium discoideum

We have shown previously that the Ca2+-specific fluorescent dyes chlortetracycline (CTC) and indo-1/AM can be used to distinguish between prestalk and prespore cells in Dictyostelium discoideum at a very early stage. In the present study, pre- and post-aggregative amoebae of Dictyostelium discoideum were labelled with CTC or indo-1 and their fluorescence monitored after being drawn into a fine glass capillary. The cells rapidly form two zones of Ca2+-CTC or Ca2+-indo-1 fluorescence. Anterior (air side) cells display a high level of fluorescence; the level drops in the middle portion of the capillary and rises again to a lesser extent in the posteriormost cells (oil side). When bounded by air on both sides, the cells display high fluorescence at both ends. When oil is present at both ends of the capillary, there is little fluorescence except for small regions at the ends. These outcomes are evident within a couple of minutes of the start of the experiment and the fluorescence pattern intensifies over the course of time. By using the indicator neutral red, as well as with CTC and indo-1, we show that a band displaying strong fluorescence moves away from the anterior end before stabilizing at the anterior-posterior boundary. We discuss our findings in relation to the role of Ca2+ in cell-type differentiation in Dictyostelium discoideum.

Urban Growth Analysis Using Spatial and Temporal Data

Urban growth identification, quantification, knowledge of rate and the trends of growth would help in regional planning for better infrastructure provision in environmentally sound way. This requires analysis of spatial and temporal data, which help in quantifying the trends of growth on spatial scale. Emerging technologies such as Remote Sensing, Geographic Information System (GIS) along with Global Positioning System (GPS) help in this regard. Remote sensing aids in the collection of temporal data and GIS helps in spatial analysis. This paper focuses on the analysis of urban growth pattern in the form of either radial or linear sprawl along the Bangalore - Mysore highway. Various GIS base layers such as builtup areas along the highway, road network, village boundary etc. were generated using collateral data such as the Survey of India toposheet, etc. Further, this analysis was complemented with the computation of Shannon's entropy, which helped in identifying prevalent sprawl zone, rate of growth and in delineating potential sprawl locations. The computation Shannon's entropy helped in delineating regions with dispersed and compact growth. This study reveals that the Bangalore North and South taluks contributed mainly to the sprawl with 559% increase in built-up area over a period of 28 years and high degree of dispersion. The Mysore and Srirangapatna region showed 128% change in built-up area and a high potential for sprawl with slightly high dispersion. The degree of sprawl was found to be directly proportional to the distances from the cities.

Spatial variation of sequestered calcium in the multicellular stage of Dictyostelium discoideum as assayed by chlortetracycline fluorescence

Abstract. We have used chlortetracycline (CTC) as a fluorescent probe to detect the distribution of sequestered calcium in multicellular stages of Dictyostelium discoideum. Tips of late aggregates, slugs and early culminating masses fluoresce very strongly. Most of the fluorescence is intracellular in origin and emanates from a small number of intense punctate sources. The sources correspond in part to autophagic vacuoles viz. neutral-red staining, acidic digestive vesicles, and may also include intracellular organelles; cytoplasmic fluorescence is much weaker in comparison. The level of fluorescence drops in the middle portion of slugs and rises again in the posteriormost region, though not to as high a level as in the tip. This holds good irrespective of whether CTC is applied only in the neighbourhood of the aggregate centre, only in the aggregate periphery, or to the whole aggregate. We infer that there must be a good deal of mixing in the stages leading from aggregation to slug formation; thus the serial order in which cells enter an aggregate does not bear any relation to their ultimate fates. The other implication of our study is that calcium sequestration is much more extensive in prestalk and anterior-like cells than in prespore cells. These findings are discussed with regard to possible implications for pattern formation.