Selecting a minimal number of relevant genes from microarray data to design accurate tissue classifiers

It is essential to select a minimal number of relevant genes from microarray data while maximizing classification accuracy for the development of inexpensive diagnostic tests. However, it is intractable to simultaneously optimize gene selection and classification accuracy that is a large parameter optimization problem. We propose an efficient evolutionary approach to gene selection from microarray data which can be combined with the optimal design of various multiclass classifiers. The proposed method (named GeneSelect) consists of three parts which are fully cooperated: an efficient encoding scheme of candidate solutions, a generalized fitness function, and an intelligent genetic algorithm (IGA). An existing hybrid approach based on genetic algorithm and maximum likelihood classification (GA/MLHD) is proposed to select a small number of relevant genes for accurate classification of samples. To evaluate the performance of GeneSelect, the gene selection is combined with the same maximum likelihood classification (named IGA/MLHD) for convenient comparisons. The performance of IGA/MLHD is applied to 11 cancer-related human gene expression datasets. The simulation results show that IGA/MLHD is superior to GA/MLHD in terms of the number of selected genes, classification accuracy, and robustness of selected genes and accuracy.     

Effects of genetic polymorphism of uncoupling protein 2 on body fat and calorie restriction-induced changes

The purpose of this study is to estimate the effects of Ala55Val genetic polymorphism of uncoupling protein 2 on computed tomography-measured body fat area and calorie restriction-induced changes. Among 386 Korean female subjects, the AlaAla type was seen in 30.3%, the AlaVal type was seen in 47.2%, and the ValVal type was seen in 22.5%. This finding was in agreement with Hardy-Weinberg equilibrium. The frequency of the major Ala allele was 0.54, and that of the minor Val allele was 0.46, which were similar to those seen in Caucasian populations. When cross-sectional areas of fat tissues in the subjects were measured by computed tomography, it was shown that the total abdominal fat area and abdominal subcutaneous fat area were significantly smaller in the ValVal type compared with the AlaVal or AlaAla type (p=0.043 and p=0.044, respectively). The Ala55Val polymorphism had no effects on visceral fat area and thigh subcutaneous fat area. Among the 386 subjects, 236 subjects finished the 1-month calorie restriction program. The results showed that the body fat was reduced significantly less in the ValVal type compared with the other types (p=0.016), whereas the changes in lean body mass, protein, mineral, and water contents were not significantly different according to the Ala55Val polymorphism.     

Post-castration retention of reproductive behavior and olfactory preferences in male Siberian hamsters: role of prior experience

Reproductive behavior of virtually all adult male rodents is dependent on concurrent availability of gonadal steroids. The ejaculatory reflex is incompatible with long-term absence of testicular steroids and typically disappears within 3 weeks after castration. Male Siberian hamsters are an exception to this rule; mating culminating in the ejaculatory reflex occurs as many as 6 months after castration (persistent copulation). The emergence of persistent copulation many weeks after gonadectomy is here shown not to require repeated post-castration sexual experience. Preoperative sexual experience, on the other hand, significantly increases the percent of males that copulate after gonadectomy, but is not required for the emergence of this trait in 25% of males. Castration prior to puberty prevents persistent copulation in all individuals in adulthood. Persistent copulators, unlike males that cease mating activity after castration, prefer the odors of estrous over non-estrous females when tested 4 months after castration and 7 weeks after the last mating test. Neural circuits of persistent copulators retain the ability to mediate male sex behavior and preferences for female odors in the complete absence of gonadal steroids; they are influenced by preoperative sexual experience and organizational effects of gonadal hormones at the time of puberty.     

Correlation of carboxylic acid pKa to protein binding and antibacterial activity of a novel class of bacterial translation inhibitors

Previously we reported the discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents which suffered from extensive protein binding. This report describes efforts directed toward understanding the relationship of the acidity of the carboxylic acid with the extent of protein binding. The pK(a) of the acid was modified via the synthesis of a number of anthranilic acid analogs which vary the aromatic ring substituent at the 4-position. The pK(a) and HSA binding constants have been determined for each of the analogs. Our results indicate a correlation between pK(a) and HSA K(d). The physical properties and antibacterial activities will be discussed as well as how these results help address the protein binding issue with this series of compounds.     

Synthesis, biological evaluation and structural determination of beta-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors

Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of beta-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography.     

3-Substituted-(5-arylfuran-2-ylcarbonyl)guanidines as NHE-1 inhibitors

The C-3 substituents effect on NHE-1 inhibitory activity of (5-arylfuran-2-ylcarbonyl)guanidines, previously identified as potent NHE-1 inhibitors, was investigated. The introduction of amine or alkyl groups at the 3-position of the furan ring, next to the acylguanidine moiety, remarkably improves NHE-1 inhibitory potency. Especially the important finding is that 5-(2,5-dichloro)phenyl and 5-(2-methoxy-5-chloro)phenyl derivatives exhibit high NHE-1 inhibitory activities (IC50 < 0.02 microM) that match those of 3-unsubstituted derivatives.     

Aminopyrrolidineamide inhibitors of site-1 protease

The discovery and efficacy of a series of potent aminopyrrolidineamide-based inhibitors of sterol regulatory element binding protein site-1 protease is described.     

Tracking the role of alternative prey in soybean aphid predation by Orius insidiosus: a molecular approach

The soybean aphid, Aphis glycines (Hemiptera: Aphididae), is a pest of soybeans in Asia, and in recent years has caused extensive damage to soybeans in North America. Within these agroecosystems, generalist predators form an important component of the assemblage of natural enemies, and can exert significant pressure on prey populations. These food webs are complex and molecular gut-content analyses offer nondisruptive approaches for examining trophic linkages in the field. We describe the development of a molecular detection system to examine the feeding behaviour of Orius insidiosus (Hemiptera: Anthocoridae) upon soybean aphids, an alternative prey item, Neohydatothrips variabilis (Thysanoptera: Thripidae), and an intraguild prey species, Harmonia axyridis (Coleoptera: Coccinellidae). Specific primer pairs were designed to target prey and were used to examine key trophic connections within this soybean food web. In total, 32% of O. insidiosus were found to have preyed upon A. glycines, but disproportionately high consumption occurred early in the season, when aphid densities were low. The intensity of early season predation indicates that O. insidiosus are important biological control agents of A. glycines, although data suggest that N. variabilis constitute a significant proportion of the diet of these generalist predators. No Orius were found to contain DNA of H. axyridis, suggesting intraguild predation upon these important late-season predators during 2005 was low. In their entirety, these results implicate O. insidiosus as a valuable natural enemy of A. glycines in this soybean agroecosystem.     

Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines

Fifteen polymethoxyflavones (PMFs) and hydroxylated PMFs were isolated from sweet orange (Citrus sinensis) peel extract and synthesized to investigate their biological activity. All obtained compounds were tested in HL-60 cancer cell proliferation and apoptosis induction assays. While some PMFs and hydroxylated PMFs had moderate anti-carcinogenic activities, 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone and 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone showed strong inhibitory activities against the proliferation and induced apoptosis of HL-60 cell lines.