Different effects of subchronic doses of 17-beta estradiol in two ethologically based models of anxiety utilizing female rats

Estrogen may have differing effects on 'anxiety' responses under different conditions. The current study tested the effects of estrogen on anxiety-like behavior when administered for 6-7 days in ovariectomized (OVX) female rats. Two animal paradigms were utilized; the elevated plus maze (EPM), measuring changes in innate fear of exploration of open spaces; and the social interaction test (SIT), measuring the exploration of a novel, same gender partner. In the EPM, estradiol-treated OVX females both entered and spent more time in the open arms than control OVX females, indicating an anxiolytic-like action of estradiol. In contrast, estradiol treated OVX females interacted less with the partner animal in the SIT compared with controls suggesting anxiogenic-like effects. The possible anxiogenic effect of estradiol in the SIT is supported by two findings: (1) the effect is reversed by the anxiolytic drug alprazolam and (2) estrogen did not affect locomotion and therefore, the reduced social interaction is not due to reduced activity. Acute administration of progesterone (5 mg/kg), which has anxiolytic properties, did not reverse estradiol-induced social interaction deficits, suggesting that lack of progesterone did not account for estradiol's anxiogenic effects. These results, while seemingly contradictory when interpreted within a unified concept of anxiety, may well reflect the ethological roles of reproductive hormones and their effects on different types of exploratory anxiety.     

Defective in cuticular ridges (DCR) of Arabidopsis thaliana, a gene associated with surface cutin formation, encodes a soluble diacylglycerol acyltransferase

A key step in the triacylglycerol (TAG) biosynthetic pathway is the final acylation of diacylglycerol (DAG) by DAG acyltransferase. In silico analysis has revealed that the DCR (defective in cuticular ridges) (At5g23940) gene has a typical HX(4)D acyltransferase motif at the N-terminal end and a lipid binding motif VX(2)GF at the middle of the sequence. To understand the biochemical function, the gene was overexpressed in Escherichia coli, and the purified recombinant protein was found to acylate DAG specifically in an acyl-CoA-dependent manner. Overexpression of At5g23940 in a Saccharomyces cerevisiae quadruple mutant deficient in DAG acyltransferases resulted in TAG accumulation. At5g23940 rescued the growth of this quadruple mutant in the oleate-containing medium, whereas empty vector control did not. Lipid particles were localized in the cytosol of At5g23940-transformed quadruple mutant cells, as observed by oil red O staining. There was an incorporation of 16-hydroxyhexadecanoic acid into TAG in At5g23940-transformed cells of quadruple mutant. Here we report a soluble acyl-CoA-dependent DAG acyltransferase from Arabidopsis thaliana. Taken together, these data suggest that a broad specific DAG acyltransferase may be involved in the cutin as well as in the TAG biosynthesis by supplying hydroxy fatty acid.     

Uncoupling of eNOS causes superoxide anion production and impairs NO signaling in the cerebral microvessels of hph-1 mice

J. Neurochem. (2012) 122, 1211-1218. ABSTRACT: In this study, we used the GTP cyclohydrolase I-deficient mice, i.e., hyperphenylalaninemic (hph-1) mice, to test the hypothesis that the loss of tetrahydrobiopterin (BH(4) ) in cerebral microvessels causes endothelial nitric oxide synthase (eNOS) uncoupling, resulting in increased superoxide anion production and inhibition of endothelial nitric oxide signaling. Both homozygous mutant (hph-1(-/-) ) and heterozygous mutant (hph-1(+/-) mice) demonstrated reduction in GTP cyclohydrolase I activity and reduced bioavailability of BH(4) . In the cerebral microvessels of hph-1(+/-) and hph-1(-/-) mice, increased superoxide anion production was inhibited by supplementation of BH(4) or NOS inhibitor- L- N(G) -nitro arginine-methyl ester, indicative of eNOS uncoupling. Expression of 3-nitrotyrosine was significantly increased, whereas NO production and cGMP levels were significantly reduced. Expressions of antioxidant enzymes namely copper and zinc superoxide dismutase, manganese superoxide dismutase, and catalase were not affected by uncoupling of eNOS. Reduced levels of BH(4) , increased superoxide anion production, as well as inhibition of NO signaling were not different between the microvessels of male and female mice. The results of our study are the first to demonstrate that, regardless of gender, reduced BH(4) bioavailability causes eNOS uncoupling, increases superoxide anion production, inhibits eNOS/cGMP signaling, and imposes significant oxidative stress in the cerebral microvasculature.     

Potential Changes in Tree Species Richness and Forest Community Types following Climate Change

Potential changes in tree species richness and forest community types were evaluated for the eastern United States according to five scenarios of future climate change resulting from a doubling of atmospheric carbon dioxide (CO₂). DISTRIB, an empirical model that uses a regression tree analysis approach, was used to generate suitable habitat, or potential future distributions, of 80 common tree species for each scenario. The model assumes that the vegetation and climate are in equilibrium with no barriers to species migration. Combinations of the individual species model outcomes allowed estimates of species richness (from among the 80 species) and forest type (from simple rules) for each of 2100 counties in the eastern United States. Average species richness across all counties may increase slightly with climatic change. This increase tends to be larger as the average temperature of the climate change scenario increases. Dramatic changes in the distribution of potential forest types were modeled. All five scenarios project the extirpation of the spruce–fir forest types from New England. Outputs from only the two least severe scenarios retain aspen–birch, and they are largely reduced. Maple–beech–birch also shows a large reduction in area under all scenarios. By contrast, oak–hickory and oak–pine types were modeled to increase by 34% and 290%, respectively, averaged over the five scenarios. Although many assumptions are made, these modeled outcomes substantially agree with a limited number of predictions from researchers using paleoecological data or other models. Received 12 May 2000; accepted 20 October 2000.     

Dual PPAR-alpha and -gamma activators derived from novel benzoxazinone containing thiazolidinediones having antidiabetic and hypolipidemic potential

2,4-Thiazolidinedione derivatives of 1,3-benzoxazinone were synthesized and evaluated for their PPAR-alpha and -gamma dual activation. DRF-2519, a compound obtained through SAR of TZD derivatives of benzoxazinone, has shown potent dual PPAR activation. In ob/ob mice, it showed better efficacy than the comparator molecules. In fat fed rat model, it showed significant improvement in lipid parameters, which was better than fibrates.     

Antibody recognition and neutralization determinants on domains I and II of West Nile Virus envelope protein

Previous studies have demonstrated that monoclonal antibodies (MAbs) against an epitope on the lateral surface of domain III (DIII) of the West Nile virus (WNV) envelope (E) strongly protect against infection in animals. Herein, we observed significantly less efficient neutralization by 89 MAbs that recognized domain I (DI) or II (DII) of WNV E protein. Moreover, in cells expressing Fc gamma receptors, many of the DI- and DII-specific MAbs enhanced infection over a broad range of concentrations. Using yeast surface display of E protein variants, we identified 25 E protein residues to be critical for recognition by DI- or DII-specific neutralizing MAbs. These residues cluster into six novel and one previously characterized epitope located on the lateral ridge of DI, the linker region between DI and DIII, the hinge interface between DI and DII, and the lateral ridge, central interface, dimer interface, and fusion loop of DII. Approximately 45% of DI-DII-specific MAbs showed reduced binding with mutations in the highly conserved fusion loop in DII: 85% of these (34 of 40) cross-reacted with the distantly related dengue virus (DENV). In contrast, MAbs that bound the other neutralizing epitopes in DI and DII showed no apparent cross-reactivity with DENV E protein. Surprisingly, several of the neutralizing epitopes were located in solvent-inaccessible positions in the context of the available pseudoatomic model of WNV. Nonetheless, DI and DII MAbs protect against WNV infection in mice, albeit with lower efficiency than DIII-specific neutralizing MAbs.     

Model and Scenario Variations in Predicted Number of Generations of Spodoptera litura Fab. on Peanut during Future Climate Change Scenario

The present study features the estimation of number of generations of tobacco caterpillar, Spodoptera litura. Fab. on peanut crop at six locations in India using MarkSim, which provides General Circulation Model (GCM) of future data on daily maximum (T.max), minimum (T.min) air temperatures from six models viz., BCCR-BCM2.0, CNRM-CM3, CSIRO-Mk3.5, ECHams5, INCM-CM3.0 and MIROC3.2 along with an ensemble of the six from three emission scenarios (A2, A1B and B1). This data was used to predict the future pest scenarios following the growing degree days approach in four different climate periods viz., Baseline-1975, Near future (NF) -2020, Distant future (DF)-2050 and Very Distant future (VDF)—2080. It is predicted that more generations would occur during the three future climate periods with significant variation among scenarios and models. Among the seven models, 1–2 additional generations were predicted during DF and VDF due to higher future temperatures in CNRM-CM3, ECHams5 & CSIRO-Mk3.5 models. The temperature projections of these models indicated that the generation time would decrease by 18–22% over baseline. Analysis of variance (ANOVA) was used to partition the variation in the predicted number of generations and generation time of S. litura on peanut during crop season. Geographical location explained 34% of the total variation in number of generations, followed by time period (26%), model (1.74%) and scenario (0.74%). The remaining 14% of the variation was explained by interactions. Increased number of generations and reduction of generation time across the six peanut growing locations of India suggest that the incidence of S. litura may increase due to projected increase in temperatures in future climate change periods.     

1,2,3‐Triazole Tagged 3H‐Pyrano[2,3‐d]pyrimidine‐6‐carboxylate Derivatives: Synthesis,in Vitro Cytotoxicity,Molecular Docking and DNA Interaction Studies

A series of novel ethyl 2,7‐dimethyl‐4‐oxo‐3‐[(1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]‐4,5‐dihydro‐3H‐pyrano[2,3‐d]pyrimidine‐6‐carboxylate derivatives 7a – 7m were efficiently synthesized employing click chemistry approach and evaluated for in vitro cytotoxic activity against four tumor cell lines: A549 (human lung adenocarcinoma cell line), HepG2 (human hematoma), MCF‐7 (human breast adenocarcinoma), and SKOV3 (human ovarian carcinoma cell line). Among the compounds tested, the compounds 7a , 7b , 7f , 7l , and 7m have shown potential and selective activity against human lung adenocarcinoma cell line (A549) with IC₅₀ ranging from 0.69 to 6.74 μm . Molecular docking studies revealed that the compounds 7a , 7b , 7f , 7l , and 7m are potent inhibitors of human DNA topoisomerase‐II and also showed compliance with stranded parameters of drug likeness. The calculated binding constants, k_b, from UV/VIS absorptional binding studies of 7a and 7l with CT‐DNA were 10.77 × 10⁴, 6.48 × 10⁴, respectively. Viscosity measurements revealed that the binding could be surface binding mainly due to groove binding. DNA cleavage study showed that 7a and 7l have the potential to cleave pBR322 plasmid DNA without any external agents.