A rationally designed anticancer drug targeting a unique binding cavity of tubulin

A novel mono-THF containing synthetic anticancer drug (WHI-261) was designed for targeting a previously unrecognized unique narrow binding cavity on the surface of tubulin. The anti-cancer activity of WHI-261 was confirmed using MTT assays. The structure-based design, synthesis, and biological activity of WHI-261 are reported.     

An experimental test of the relationship between yolk testosterone and the social environment in a colonial passerine

Maternal hormones can be transferred to offspring during prenatal development in response to the maternal social environment, and may adaptively alter offspring phenotype. For example, numerous avian studies show that aggressive competition with conspecifics tends to result in females allocating more testosterone to their egg yolks, and this may cause offspring to have more competitive phenotypes. However, deviations from this pattern of maternal testosterone allocation are found, largely in studies of colonial species, and have yet to be explained. Colonial species may have different life‐history constraints causing different yolk testosterone allocation strategies in response to conspecific competition, but few studies have experimentally tested whether colonial species do indeed differ from that of solitary species. To test this, we collected eggs from zebra finches Taeniopygia guttata, a colonial species, in the presence and absence of conspecific intrusions. Females did not alter the concentration of testosterone deposited in eggs laid during intrusions despite becoming more aggressive. These results suggest that maternal effects are not characterized by a uniform response to the social environment, but rather need to be contextualized with life‐history traits.     

Mitochondrial sheath movement and detachment in mammalian,but not nonmammalian,sperm induced by disulfide bond reduction

The successful completion of the fertilization process requires the properly choreographed unsheathing of the tightly packaged sperm once it has been fully incorporated into the egg's cytoplasm. The nuclear and accessory structures of mammalian sperm become stabilized by disulfide bonds (S-S) during epididymal maturation. This stabilization is reversed during fertilization by the reduction of S-S cross-linking, but little is known about the effect of S-S reduction on individual disulfide-hardened structures such as the sperm's connecting piece, fibrous sheath, and mitochondria. Here, we demonstrate the action of the S-S-reducing environment on the mitochondrial sheath of mammalian sperm, visualized by the vital fluorescent probe Mito Tracker and by electron microscopy. In both human and bull sperm, mitochondria form a compact helix (mitochondrial sheath) wrapped around the midpiece and connecting piece that can be fluorescently labelled by a short incubation with 100 mM Mito-Tracker. Exposure of bull sperm to 0.1–10 mM dithiothreitol (DTT; a disulfide bond-reducing agent) induced a time and dose-dependent sliding of the mitochondrial sheath down the axoneme, accompanied by the excision of the sperm tail and decondensation of the sperm nucleus. Increasing the concentration of DTT to 100 mM accelerated mitochondrial movement, causing a completed stripping of sperm mitochondria and partial disassembly of the connecting piece. Likewise, human sperm responded to DTT treatment by the sliding or removal of the mitochondrial sheath and decondensation of the sperm chromatin. These events were not observed in the sperm of lower vertebrates and invertebrates (Xenopus laevis and Lytechinus pictus, respectively) exposed to an excess of DTT. Thus the sensitivity of sperm mitochondria to the S-S reducing environment seems to be an exclusive feature of mammalian sperm. The movement of sperm mitochondria induced by S-S reduction may be an initial critical step in the disassembly of the mammalian sperm tail during fertilization. Mol. Reprod. Dev. 47:79–86, 1997. © 1997 Wiley-Liss, Inc.     

Yolk androgens as pleiotropic mediators of physiological processes: a mechanistic review

Avian egg yolks are made up of complex mixtures of physiologically relevant substances. Androgens, in particular, accumulate in yolks in variable amounts based on social and environmental conditions experienced by laying females, and using experimental elevations of yolk androgen content, researchers have unveiled potent physiological and behavioral effects on offspring. These patterns and effects are exciting in an adaptive context, as the transfer of endogenously-produced substances such as androgens to egg yolks may allow fine manipulation of offspring phenotype to maximize reproductive success. However, to gain an in-depth understanding of how yolk androgens function in an adaptive context, we must first understand the complex entanglement of physiological and endocrine interrelationships that change after exposure to yolk androgens. Here, we take a comparative approach towards a discussion of how yolk androgens can simultaneously affect multiple body systems within developing birds, ultimately resulting in the large-scale phenotypic endpoints that may represent adaptive consequences of exposure to elevated levels of yolk androgens.     

Prenatal environmental influences on the production of sex-specific traits in mammals

The determination of offspring sex represents a delicate balancing act during which offspring must pass through several developmental levels in the presence of influential environmental factors. Successful expression of sex-specific traits requires genetic and hormone-based effects on several organizational and activational levels. Environmental factors can exert controls and disruptions at each of these levels. This review addresses the developmental stages at which environmental factors may influence the processes of sex determination, with an in depth focus on the prenatal stages, including the production of the primary and secondary sex ratios and the differentiation of functional secondary sexual characters.     

Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain

Human embryonic stem cell (hESC) pluripotency has been reported by several groups to be best maintained by culture under physiological oxygen conditions. Building on that finding, we inhibited complex III of the mitochondrial respiratory chain using antimycin A or myxothiazol to examine if specifically targeting the mitochondria would have a similar beneficial result for the maintenance of pluripotency. hESCs grown in the presence of 20 nM antimycin A maintained a compact morphology with high nuclear/cytoplasmic ratios. Furthermore, real-time PCR analysis demonstrated that the levels of Nanog mRNA were elevated 2-fold in antimycin A-treated cells. Strikingly, antimycin A was also able to replace bFGF in the media without compromising pluripotency, as long as autocrine bFGF signaling was maintained. Further analysis using low-density quantitative PCR arrays showed that antimycin A treatment reduced the expression of genes associated with differentiation, possibly acting through a ROS-mediated pathway. These results demonstrate that modulation of mitochondrial function results in increased pluripotency of the cell population, and sheds new light on the mechanisms and signaling pathways modulating hESC pluripotency.     

Pluripotency genes overexpressed in primate embryonic stem cells are localized on homologues of human chromosomes 16, 17, 19, and X

While human embryonic stem cells (hESCs) are predisposed toward chromosomal aneploidities on 12, 17, 20, and X, rendering them susceptible to transformation, the specific genes expressed are not yet known. Here, by identifying the genes overexpressed in pluripotent rhesus ESCs (nhpESCs) and comparing them both to their genetically identical differentiated progeny (teratoma fibroblasts) and to genetically related differentiated parental cells (parental skin fibroblasts from whom gametes were used for ESC derivation), we find that some of those overexpressed genes in nhpESCs cluster preferentially on rhesus chromosomes 16, 19, 20, and X, homologues of human chromosomes 17, 19, 16, and X, respectively. Differentiated parental skin fibroblasts display gene expression profiles closer to nhpESC profiles than to teratoma cells, which are genetically identical to the pluripotent nhpESCs. Twenty over- and underexpressed pluripotency modulators, some implicated in neurogenesis, have been identified. The overexpression of some of these genes discovered using pedigreed nhpESCs derived from prime embryos generated by fertile primates, which is impossible to perform with the anonymously donated clinically discarded embryos from which hESCs are derived, independently confirms the importance of chromosome 17 and X regions in pluripotency and suggests specific candidates for targeting differentiation and transformation decisions.     

Low Gestational Weight Gain Skews Human Sex Ratios towards Females

Background

Human males are more vulnerable to adverse conditions than females starting early in gestation and continuing throughout life, and previous studies show that severe food restriction can influence the sex ratios of human births. It remains unclear, however, whether subtle differences in caloric intake during gestation alter survival of fetuses in a sex-specific way. I hypothesized that the ratio of male to female babies born should vary with the amount of weight gained during gestation. I predicted that women who gain low amounts of weight during gestation should produce significantly more females, and that, if gestational weight gain directly influences sex ratios, fetal losses would be more likely to be male when women gain inadequate amounts of weight during pregnancy.

Methods

I analyzed data collected from over 68 million births over 23 years to test for a relationship between gestational weight gain and natal sex ratios, as well as between gestational weight gain and sex ratios of fetal deaths at five gestational ages.

Results

Gestational weight gain and the proportion of male births were positively correlated; a lower proportion of males was produced by women who gained less weight and this strong pattern was exhibited in four human races. Further, sex ratios of fetal losses at 6 months of gestation were significantly male-biased when mothers had gained low amounts of weight during pregnancy, suggesting that low caloric intake during early fetal development can stimulate the loss of male fetuses.

Conclusion

My data indicate that human sex ratios change in response to resource availability via sex-specific fetal loss, and that a pivotal time for influences on male survival is early in fetal development, at 6 months of gestation.     

Protoporphyrin‐based eggshell pigmentation predicts hatching success and offspring sex ratio in the barn swallow

Inter‐ and intraspecific variation in eggshell colouration has long fascinated evolutionary biologists. Among species, such variation may accomplish different functions, the most obvious of which is camouflage and background matching. Within species, it has been proposed that inter‐female variation in eggshell pigmentation patterns can reflect egg, maternal or paternal traits and hence may provide cues to conspecifics about egg, maternal or paternal phenotypic quality. However, the relationship between protoporphyrin‐based eggshell pigmentation and egg or maternal/paternal traits appears to be highly variable among species. We investigated patterns of intraspecific variation in Eurasian barn swallow Hirundo r. rustica protoporphyrin‐based eggshell pigmentation, and analysed its association with egg and clutch characteristics, maternal/paternal phenotypic traits and parental feeding effort. Eggshell pigmentation pattern significantly varied between breeding colonies, was significantly repeatable in first clutches laid by the same females in different years (intraclass correlation coefficient ranging between 0.56 and 0.63), but it was not significantly associated with egg traits, such as position in the laying sequence, egg mass, yolk testosterone concentration and antioxidant capacity. It was weakly or non‐significantly associated with female and male traits (sexual ornaments), but females laying darker (higher pigment intensity) first clutches had higher hatching success, suggesting that eggshell pigment intensity may predict fitness. Male nestling feeding effort was not predicted by eggshell pigmentation. In addition, females with darker breast plumage colouration (a melanin‐based trait related to fitness) laid highly protoporphyrin‐covered eggs, suggesting the presence of a previously unappreciated link between protoporphyrin biosynthesis and plumage melanisation. Moreover, the proportion of male offspring increased in clutches originating from highly protoporphyrin‐covered eggs, suggesting that parents could acquire visual cues about their future brood sex composition before egg hatching. Our results support the idea that intraspecific signalling via eggshell pigmentation is a species‐specific rather than a general feature of avian taxa.