Discovery and structure-activity relationship of 2-phenyl-oxazole-4-carboxamide derivatives as potent apoptosis inducers

As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.     

Kinetic comparison of seven strains of 2,4-dichlorophenoxyacetic acid-degrading bacteria.

Seven strains of 2,4-dichlorophenoxyacetic acid-degrading bacteria, including Pseudomonas, Alcaligenes, and Bordetella spp., were compared on the basis of growth kinetics. Estimates of maximum growth rate (mu max, k1) and half-saturation growth constant (Ks, k3) were obtained by fitting substrate depletion curves to a four-parameter version of the integrated Monod equation. Estimates of Ks ranged from 2.2 micrograms/ml (10 microM) to 33.8 micrograms/ml (154 microM), and estimates of mu max ranged from 0.20 h-1 (Td = 3.5 h) to 0.32 h-1 (Td = 2.2 h). Estimates of mu max, but not Ks, were affected by changes in initial inoculum density. Maximum growth rates (mu max) were also estimated from turbidity measurements. They ranged from 0.10 h-1 (Td = 6.9 h) to 1.0 h-1 (Td = 0.7 h). There was no correlation between estimates of mu max derived from substrate depletion curves and those derived from turbidity measurements (P = 0.20).     

Bt Crops Producing Cry1Ac,Cry2Ab and Cry1F Do Not Harm the Green Lacewing,Chrysoperla rufilabris

The biological control function provided by natural enemies is regarded as a protection goal that should not be harmed by the application of any new pest management tool. Plants producing Cry proteins from the bacterium, Bacillus thuringiensis (Bt), have become a major tactic for controlling pest Lepidoptera on cotton and maize and risk assessment studies are needed to ensure they do not harm important natural enemies. However, using Cry protein susceptible hosts as prey often compromises such studies. To avoid this problem we utilized pest Lepidoptera, cabbage looper (Trichoplusia ni) and fall armyworm (Spodoptera frugiperda), that were resistant to Cry1Ac produced in Bt broccoli (T. ni), Cry1Ac/Cry2Ab produced in Bt cotton (T. ni), and Cry1F produced in Bt maize (S. frugiperda). Larvae of these species were fed Bt plants or non-Bt plants and then exposed to predaceous larvae of the green lacewing Chrysoperla rufilabris. Fitness parameters (larval survival, development time, fecundity and egg hatch) of C. rufilabris were assessed over two generations. There were no differences in any of the fitness parameters regardless if C. rufilabris consumed prey (T. ni or S. frugiperda) that had consumed Bt or non-Bt plants. Additional studies confirmed that the prey contained bioactive Cry proteins when they were consumed by the predator. These studies confirm that Cry1Ac, Cry2Ab and Cry1F do not pose a hazard to the important predator C. rufilabris. This study also demonstrates the power of using resistant hosts when assessing the risk of genetically modified plants on non-target organisms.     

Comparison of Diadegma insulare (Hymenoptera: Ichneumonidae) and Microplitis plutellae (Hymenoptera: Braconidae) as biological control agents of Plutella xylostella (Lepidoptera: Plutellidae): field parasitism, insecticide susceptibility, and host-searching

Parasitism of Plutella xylostella (L.) third and fourth instars was evaluated in a cabbage field in Geneva, NY, in 1999. Over the entire season, average parasitism was 33.6% for third instars and 53.6% for fourth instars, and the main parasitoids were Diadegma insulare (Cresson) and Microplitis plutellae Muesbeck. In the early season, total parasitism was low, and mainly caused by D. insulare. However, later in the season, parasitism reached >80% for the fouth instars and 50% for the third instars. Our survey indicated that M. plutellae heavily parasitized P. xylostella, and provided higher parasitism rates than D. insulare in the late season. Comparison of these two species in laboratory bioassays indicated there were no significant differences in susceptibility to four insecticides commonly used in crucifer fields. For both parasitoids, an experience with P. xylostella on a damaged leaf increased their host-searching efficacy. Compared with M. plutellae, D. insulare was a better host-searcher both for the naive and the experienced adults. Although both parasitoids can cause high mortality rates of P. xylostella, D. insulare may be more suitable to be released in fields to enhance natural control against P. xylostella.     

Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.

Layering of neurons in the cerebral cortex and cerebellum requires Reelin, an extracellular matrix protein, and mammalian Disabled (mDab1), a cytosolic protein that activates tyrosine kinases. Here, we report the requirement for two other proteins, cell surface receptors termed very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Both receptors can bind mDab1 on their cytoplasmic tails and are expressed in cortical and cerebellar layers adjacent to layers that express Reelin. mDab1 expression is upregulated in knockout mice that lack both VLDLR and ApoER2. Inversion of cortical layers and absence of cerebellar foliation in these animals precisely mimic the phenotype of mice lacking Reelin or mDab1. These findings suggest that VLDLR and ApoER2 participate in transmitting the extracellular Reelin signal to intracellular signaling processes initiated by mDab1.     

Variation in thermal tolerances of native freshwater fishes in South Africa's Cape Fold Ecoregion: examining the east–west gradient in species' sensitivity to climate warming

The Cape Fold Ecoregion (CFE) is a biodiversity hotspot with high levels of endemism in its freshwater fish fauna. This study examined inter and intra-specific variation in critical thermal maxima (T_Cmax) for eight native species of freshwater fish from the CFE. Cape galaxias Galaxias zebratus, Breede River redfin Pseudobarbus burchelli, Berg River redfin Pseudobarbus burgi, Clanwilliam redfin Pseudobarbus calidus and fiery redfin Pseudobarbus phlegethon were the most thermally sensitive (T_Cmax = 29.8–32.8°C). Clanwilliam rock-catfish Austroglanis gilli, Eastern Cape redfin Pseudobarbus afer and Cape kurper Sandelia capensis were moderately sensitive (T_Cmax = 33.0–36.8°C). An increase in intra-specific thermal sensitivity of S. capensis was observed from east to west. The results were related to in situ water temperature, which influenced T_Cmax for all species, suggesting that thermal history is a major driver of variation in thermal tolerance amongst populations. These thermal tolerance data for freshwater fishes in the CFE demonstrate that resilience to climate warming follows a geographical cline and that the more sensitive western species and regions are conservation priorities.     

Transferof chlorfenapyr among workers of Reticulitermnes flavipes (Isoptera: Rhinotermitidae) in the laboratory

The potential for transfer of chlorfenapyr among subterranean termites was investigated using a donor-recipient (5:95 ratio) experiment. In one experiment, workers of Reticulitermes flavipes (Kollar) (Isoptera: Rhinotermitidae) were exposed to treated sand at 0, 50, 100, 250, and 500 ppm chlorfenapyr (wt [AI]/wt sand). Exposed workers were allowed to interact with untreated nestmates for 14 d, after which mortality was assessed. The three colonies responded differently to the treatments in this experiment. For two colonies, donor exposure rates of 500 ppm (as well as 250 ppm for colony B) chlorfenapyr resulted in significantly greater recipient mortality than controls. For colony C, donor chlorfenapyr exposure did not significantly influence recipient mortality. In a second experiment examining donor mortality over time, donor termites exposed to all test concentrations of chlorfenapyr (except for 0 ppm) suffered 100% mortality within 5 d. Analysis of donor termite body washes using gas chromatography indicated a linear uptake of chlorfenapyr by termites over the concentration range studied. Thus, for this concentration range, no upper limit (saturation plateau) of termite uptake for chlorfenapyr was reached.     

Development and evaluation of an enzyme-linked immunosorbent assay to detect Pieris rapae remains in guts of arthropod predators

An enzyme-linked immunosorbent assay (ELISA) was developed to detect remains of Pieris rapae L. (Lepidoptera: Pieridae) immature stages in the guts of field collected arthropod predators. The assay can be used to help ascertain the relative importance of arthropod predator species in suppressing P. rapae in cabbage, Brassica oleracea var. capitata L. The ELISA is sensitive to all immature stages of P. rapae, although first and fifth instars can be detected more readily than eggs or pupae and third instars showed intermediate detectability. Assays on whole body homogenates of predators readily detected predation on P. rapae first instars by all seven of the predator species tested, although response generally declined with increasing predator size. Together the results show that the P. rapae ELISA possesses a sufficiently high level of sensitivity and specificity to be a useful tool in helping to elucidate the roles of arthropod predator species in reducing populations of P. rapae in cabbage.     

Tumor Growth Modeling from the Perspective of Multiphase Porous Media Mechanics

Multiphase porous media mechanics is used for modeling tumor growth, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT). This approach incorporates the interaction of more phases than legacy tumor growth models. The tumor is treated as a multiphase system composed of an extracellular matrix, tumor cells which may become necrotic depending on nutrient level and pressure, healthy cells and an interstitial fluid which transports nutrients. The governing equations are numerically solved within a Finite Element framework for predicting the growth rate of the tumor mass, and of its individual components, as a function of the initial tumor-to-healthy cell ratio, nutrient concentration, and mechanical strain. Preliminary results are shown.