Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

Studies of embryo-fetal development in rats were conducted with two 5-lipoxygenase inhibitors. SB-202235 (1,000 mg/kg/day) or SB-210661 (50, 100, or 500 mg/kg/day) was administered orally by gavage to female rats on days 6-17 postcoitus (pc) or days 7-16 pc. SB-202235 (1,000 mg/kg/day) and SB-210661 (100 mg/kg/day) reduced maternal body weight gain for the treatment period by 16% and 21%, respectively, relative to controls. SB-202235 (1,000 mg/kg/day) or SB-210661 (50 or 100 mg/kg/day), did not affect numbers of resorptions, dead or live fetuses/litter, but 500 mg/kg/day of SB-210661 caused 100% embryo lethality. SB-202235 (1,000 mg/kg/day) and SB-210661 (50 and 100 mg/kg/day) reduced fetal body weight by 15-30% and produced extensive cardiovascular malformations, as well as diaphragmatic hernias. SB-210661 also caused thymic abnormalities and cryptorchidism. Cardiovascular defects included abnormalities in aorticopulmonary septation, the aortic arch, pulmonary trunk, and ventricular septal defects are discussed relative to comparable human syndromes of cardiovascular malformation.     

Independent action of ELF3 and phyB to control hypocotyl elongation and flowering time

Light regulates various aspects of plant growth, and the photoreceptor phytochrome B (phyB) mediates many responses to red light. In a screen for Arabidopsis mutants with phenotypes similar to those of phyB mutants, we isolated two new elf3 mutants. One has weaker morphological phenotypes than previously identified elf3 alleles, but still abolishes circadian rhythms under continuous light. Like phyB mutants, elf3 mutants have elongated hypocotyls and petioles, flower early, and have defects in the red light response. However, we found that elf3 mutations have an additive interaction with a phyB null mutation, with phyA or hy4 null mutations, or with a PHYB overexpression construct, and that an elf3 mutation does not prevent nuclear localization of phyB. These results suggest that either there is substantial redundancy in phyB and elf3 function, or the two genes regulate distinct signaling pathways.     

Simultaneous determination of fixed dose combination of nebivolol and valsartan in human plasma by liquid chromatographic-tandem mass spectrometry and its application to pharmacokinetic study

A rapid, sensitive and accurate liquid chromatographic-tandem mass spectrometry method is described for the simultaneous determination of nebivolol and valsartan in human plasma. Nebivolol and valsartan were extracted from plasma using acetonitrile and separated on a C18 column. The mobile phase consisting of a mixture of acetonitrile and 0.05 mM formic acid (50:50 v/v, pH 3.5) was delivered at a flow rate of 0.25 ml/min. Atmospheric pressure ionization (API) source was operated in both positive and negative ion mode for nebivolol and valsartan, respectively. Selected reaction monitoring mode (SRM) using the transitions of m/z 406.1-->m/z 150.9; m/z 434.2-->m/z 179.0 and m/z 409.4-->m/z 228.1 were used to quantify nebivolol, valsartan and internal standard (IS), respectively. The linearity was obtained over the concentration range of 0.01-50.0 ng/ml and 1.0-2000.0 ng/ml and the lower limits of quantitation were 0.01 ng/ml and 1.0 ng/ml for nebivolol and valsartan, respectively. This method was successfully applied to the pharmacokinetic study of fixed dose combination (FDC) of nebivolol and valsartan formulation product after an oral administration to healthy human subjects.     

Liquid chromatography tandem mass spectrometry method for simultaneous determination of metoprolol tartrate and ramipril in human plasma

A simple, rapid, sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of metoprolol tartrate (MT) and ramipril, in human plasma. Both the drugs were extracted by liquid-liquid extraction with diethyl ether-dichloromethane (70:30, v/v). The chromatographic separation was performed on a reversed-phase C8 column with a mobile phase of 10 mM ammonium formate-methanol (3:97, v/v). The protonated analyte was quantitated in positive ionization by multiple reaction monitoring with a mass spectrometer. The method was validated over the concentration range of 5-500 ng/ml for metoprolol and ramipril in human plasma. The precursor to product ion transitions of m/z 268.0-103.10 and m/z 417.20-117.20 were used to measure metoprolol and ramipril, respectively.     

Carbon sequestration and soil restoration potential of grazing lands under exclosure management in a semi‐arid environment of northern Ethiopia

Exclosures are used to regenerate native vegetation as a way to reduce soil erosion, increase rain water infiltration and provide fodder and woody biomass in degraded grazing lands. Therefore, this study assessed the impact of grazing exclosure on carbon sequestration and soil nutrients under 5 and 10 years of grazing exclosures and freely grazed areas in Tigray, northern Ethiopia. Carbon stocks and soil nutrients increased with increasing grazing exclusion. However, open grazing lands and 5 years of grazing exclosure did not differ in above‐ and belowground carbon stocks. Moreover, 10 years of grazing exclosure had a higher (p < 0.01) grass, herb and litter carbon stocks compared to 5 years exclosure and open grazing lands. The total carbon stock was higher for 10 years exclosure (75.65 t C ha^‐1) than the 5 years exclosure (55.06 t C ha^‐1) and in open grazing areas (51.98 t C ha^‐1). Grazing lands closed for 10 years had a higher SOC, organic matter, total N, available P, and exchangeable K + and Na + compared to 5 year's exclosure and open grazing lands. Therefore, establishment of grazing exclosures had a positive effect in restoring degraded grazing lands, thus improving carbon sequestration potentials and soil nutrients.     

IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration

1. Download high-res image (137KB)
2. Download full-size image

     

Microclimatic buffering in forests of the future: the role of local water balance

Forest canopies buffer climate extremes and promote microclimates that may function as refugia for understory species under changing climate. However, the biophysical conditions that promote and maintain microclimatic buffering and its stability through time are largely unresolved. We posited that forest microclimatic buffering is sensitive to local water balance and canopy cover, and we measured this effect during the growing season across a climate gradient in forests of the northwestern United States (US). We found that forest canopies buffer extremes of maximum temperature and vapor pressure deficit (VPD), with biologically meaningful effect sizes. For example, during the growing season, maximum temperature and VPD under at least 50% forest canopy were 5.3°C and 1.1 kPa lower on average, respectively, compared to areas without canopy cover. Canopy buffering of temperature and vapor pressure deficit was greater at higher levels of canopy cover, and varied with water balance, implying that buffering effects are subject to changes in local hydrology. We project changes in the water balance for the mid‐21st century and predict how such changes may impact the ability of western US forests to buffer climate extremes. Our results suggest that some forests will lose their capacity to buffer climate extremes as sites become increasingly water limited. Changes in water balance combined with accelerating canopy losses due to increases in the frequency and severity of disturbance will create potentially non‐linear changes in the microclimate conditions of western US forests.     

Fungal substances as modulators of NF-κB activation pathway

MCF7 breast cancer cell line, carrying a luciferase reporter gene under the control of nuclear factor kappa B (NF-κB)-responsive promoter, was established and used for the screening of fungal organic extracts for their ability to interfere with the NF-κB activation pathway. Twenty-eight crude fungal extracts, out of 242, were found to inhibit NF-κB reporter activity by more than 40%. Furthermore, positive extracts were used to evaluate their antiproliferative activity as well as their ability to influence the phosphorylation and degradation levels of IκBa. Fungal extracts prepared from Marasmius oreades and Cyathus striatus showed significant inhibitory effects on the NF-κB activation pathway. Taken together, our results support the notion of the presence of novel activities that might be utilized as cancer therapeutics.     

Intrinsic uncertainty explains second responses

In the simplest form of signal-detection theory (SDT), all stimuli give rise to equal-variance Gaussian probability density functions (PDFs) of sensation, with means proportional to stimulus intensity. As this simple SDT cannot accurately describe psychometric functions for two-alternative forced-choice (2AFC) detection experiments, it is commonly modified in one of two ways: with a non-linear transducer or intrinsic uncertainty. Most results can adequately be explained by either modification, but Swets et al.'s (1961) two-response 4AFC (2R4AFC) detection experiment is an exception. Simple SDT cannot predict the relationship between first- and second-response accuracies and non-linear transduction does not help. A previously unacknowledged facet of intrinsic uncertainty is that the same uncertainty required to fit 2AFC psychometric functions also produces an excellent fit to Swets et al.'s 2R4AFC results, without requiring any additional assumptions. This result is derived within the context of a primer on SDT.     

Fluoride and diethylnitrosamine coexposure enhances oxido‐inflammatory responses and caspase‐3 activation in liver and kidney of adult rats

The present study investigated the impact of coexposure to fluoride and diethylnitrosamine (DEN) on hepatorenal function in adult rats. The animals were exposed to fluoride (15 mg/L in drinking water) and DEN (10 mg/kg) singly or coexposed to both compounds for 14 days. Results demonstrated that the fluoride or DEN mediated increase in hepatorenal toxicity was intensified in the coexposure group. Additionally, the decrease in antioxidant enzyme activities as well as the elevation in reactive oxygen and nitrogen species, and lipid peroxidation was markedly aggravated in rats coexposed to DEN and fluoride. Furthermore, the increase in levels of nitric oxide, tumor necrosis factor‐α and interleukin‐1β, myeloperoxidase and caspase‐3 activities as well as histological lesions was more pronounced in the liver and kidney of rats coexposed to DEN and fluoride. Conclusively, coexposure to fluoride and DEN exacerbated hepatorenal damage via enhancement of oxido‐inflammatory responses and caspase‐3 activation in rats.