Assignment of the αB-crystallin gene to human chromosome 11

Using a human αB-crystallin genomic probe and human-mouse somatic cell hybrids, the human αB-gene was assigned to chromosome 11 and further corroborated by in situ hybridization to normal metaphase chromosomes. This assignment confirmed and regionally mapped the locus to q22.3–23.1.     

Canalization of Gene Expression and Domain Shifts in the Drosophila Blastoderm by Dynamical Attractors

The variation in the expression patterns of the gap genes in the blastoderm of the fruit fly Drosophila melanogaster reduces over time as a result of cross regulation between these genes, a fact that we have demonstrated in an accompanying article in PLoS Biology (see Manu et al., doi:10.1371/journal.pbio.1000049). This biologically essential process is an example of the phenomenon known as canalization. It has been suggested that the developmental trajectory of a wild-type organism is inherently stable, and that canalization is a manifestation of this property. Although the role of gap genes in the canalization process was established by correctly predicting the response of the system to particular perturbations, the stability of the developmental trajectory remains to be investigated. For many years, it has been speculated that stability against perturbations during development can be described by dynamical systems having attracting sets that drive reductions of volume in phase space. In this paper, we show that both the reduction in variability of gap gene expression as well as shifts in the position of posterior gap gene domains are the result of the actions of attractors in the gap gene dynamical system. Two biologically distinct dynamical regions exist in the early embryo, separated by a bifurcation at 53% egg length. In the anterior region, reduction in variation occurs because of stability induced by point attractors, while in the posterior, the stability of the developmental trajectory arises from a one-dimensional attracting manifold. This manifold also controls a previously characterized anterior shift of posterior region gap domains. Our analysis shows that the complex phenomena of canalization and pattern formation in the Drosophila blastoderm can be understood in terms of the qualitative features of the dynamical system. The result confirms the idea that attractors are important for developmental stability and shows a richer variety of dynamical attractors in developmental systems than has been previously recognized.     

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC(50) = 5.67 microm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC(50) = 6.1 microm) and oral (IC(50) = 4.17 microm) cancers. These compounds could be of use in designing new anti-cancer agents.     

Inhibition of Microsomal Lipid Peroxidation and Cytochrome P-450-Catalyzed Reactions by Nitrofuran Compounds

(5-Nitro-2-furfuryliden)amino compounds bearing triazol-4-yl, benzimidazol-l-yl, pyrazol-l-yl, triazin-4-yl or related groups (a) stimulated superoxide anion radical generated by rat liver microsomes in the presence of NADPH and oxygen; (b) inhibited the NADPH-dependent, iron-catalyzed microsomal lipid peroxidation; (c) prevented the NADPH-dependent destruction of cytochrome P-450; (d) inhibited the NADPH-dependent microsomal aniline 4-hydroxylase activity; (e) failed to inhibit either the cumenyl hydroperoxide-dependent lipid peroxidation or the aniline-4-hydroxylase activity, except for the benzimidazol-l-yl and the substituted triazol-4-yl derivatives, which produced minor inhibitions. Reducing equivalents enhanced the benzimidazol-l-yl derivative inhibition of the cumenyl hydroperoxide-induced lipid peroxidation. The ESR spectrum of the benzimidazol-l-yl derivative, reduced anaerobically by NADPH-supplemented microsomes, showed characteristic spin couplings. Compounds bearing unsaturated nitrogen heterocycles were always more active than those bearing other groups, such as nifurtimox or nitrofurazone. The energy level of the lowest unoccupied molecular orbital was in fair agreement with the capability of nitrofurans for redox-cycling and related actions. It is concluded that nitrofuran inhibition of microsomal lipid peroxidation and cytochrome P-450-catalyzed reactions was mostly due to diversion of reducing equivalents from NADPH to dioxygen. Trapping of free radicals involved in propagating lipid peroxidation might contribute to the overall effect of the benzimidazol-l-yl and substituted triazol-4-yl derivitives.     

Treatment of Visceral Leishmaniasis: Model-Based Analyses on the Spread of Antimony-Resistant L. donovani in Bihar,India

Background

Pentavalent antimonials have been the mainstay of antileishmanial therapy for decades, but increasing failure rates under antimonial treatment have challenged further use of these drugs in the Indian subcontinent. Experimental evidence has suggested that parasites which are resistant against antimonials have superior survival skills than sensitive ones even in the absence of antimonial treatment.

Methods and Findings

We use simulation studies based on a mathematical L. donovani transmission model to identify parameters which can explain why treatment failure rates under antimonial treatment increased up to 65% in Bihar between 1980 and 1997. Model analyses suggest that resistance to treatment alone cannot explain the observed treatment failure rates. We explore two hypotheses referring to an increased fitness of antimony-resistant parasites: the additional fitness is (i) disease-related, by causing more clinical cases (higher pathogenicity) or more severe disease (higher virulence), or (ii) is transmission-related, by increasing the transmissibility from sand flies to humans or vice versa.

Conclusions

Both hypotheses can potentially explain the Bihar observations. However, increased transmissibility as an explanation appears more plausible because it can occur in the background of asymptomatically transmitted infection whereas disease-related factors would most probably be observable. Irrespective of the cause of fitness, parasites with a higher fitness will finally replace sensitive parasites, even if antimonials are replaced by another drug.     

Binding of bovine serum albumin to heparin determined by turbidimetric titration and frontal analysis continuous capillary electrophoresis

The association of proteins with glycosaminoglycans is a subject of growing interest, but few techniques exist for elucidating this interaction quantitatively. Here we demonstrate the application of capillary electrophoresis to the system of serum albumin (SA) and heparin (Hp). These two species form soluble complexes, the interaction increasing with reduction in pH and/or ionic strength (I). The acid-base property of Hp was characterized by potentiometric titration of ion-exchanged Hp. Conditions for complex formation with SA were qualitatively determined by turbidimetry, which revealed points of incipient binding (pH(c)) and phase separation (pH(phi)), both of which depend on I. At pH > pH(phi), i.e., prior to phase separation, frontal analysis continuous capillary electrophoresis was used to measure the concentration of free protein and to determine the protein-HP binding isotherm. The binding isotherms were well fit by the McGhee-von Hippel model to yield quantitative binding information in the form of intrinsic binding constants (K(obs)) and binding site size (n). The strong increase in K(obs) with decrease of pH or I could be explained on the basis of electrostatic interactions, considering the effects of protein charge heterogeneity. The value of n, independent of pH, was rationalized on the basis of size considerations. The implications of these findings for clinical applications of Hp and for its physiological behavior are discussed.     

Pollen-vegetation richness and diversity relationships in the tropics

Tracking changes in biodiversity through time requires an understanding of the relationship between modern diversity and how this diversity is preserved in the fossil record. Fossil pollen is one way in which past vegetation diversity can be reconstructed. However, there is limited understanding of modern pollen-vegetation diversity relationships from biodiverse tropical ecosystems. Here, pollen (palynological) richness and diversity (Hill N₁) are compared with vegetation richness and diversity from forest and savannah ecosystems in the New World and Old World tropics (Neotropics and Palaeotropics). Modern pollen data were obtained from artificial pollen traps deployed in 1-ha vegetation study plots from which vegetation inventories had been completed in Bolivia and Ghana. Pollen counts were obtained from 15 to 22 traps per plot, and aggregated pollen sums for each plot were >?2,500. The palynological richness/diversity values from the Neotropics were moist evergreen forest?=?86/6.8, semi-deciduous dry forest?=?111/21.9, wooded savannah?=?138/31.5, and from the Palaeotropics wet evergreen forest?=?144/28.3, semi-deciduous moist forest?=?104/4.4, forest-savannah transition?=?121/14.1; the corresponding vegetation richness/diversity was 100/36.7, 80/38.7 and 71/39.4 (Neotropics), and 101/54.8, 87/45.5 and 71/34.5 (Palaeotropics). No consistent relationship was found between palynological richness/diversity, and plot vegetation richness/diversity, due to the differential influence of other factors such as landscape diversity, pollination strategy, and pollen source area. Palynological richness exceeded vegetation richness, while pollen diversity was lower than vegetation diversity. The relatively high global diversity of tropical vegetation was found to be reflected in the pollen rain.