Mechanism of ethidium bromide inhibition of RNA polymerase.

2-Oxo-3-phenyl-1,3-oxazetidine was found to thermally undergo a 2,2-cyclo-reversion reaction with an enthalpy of activation of 30.8 Kcal. This suggests that an oxazetidine fused to a flavin could be the labile light producing intermediate in the bacterial luciferase reaction since the reaction would be favored by ring fusion and the lower excited state of flavin.     

Elephant Genomes Reveal Accelerated Evolution in Mechanisms Underlying Disease Defenses

Disease susceptibility and resistance are important factors for the conservation of endangered species, including elephants. We analyzed pathology data from 26 zoos and report that Asian elephants have increased neoplasia and malignancy prevalence compared with African bush elephants. This is consistent with observed higher susceptibility to tuberculosis and elephant endotheliotropic herpesvirus (EEHV) in Asian elephants. To investigate genetic mechanisms underlying disease resistance, including differential responses between species, among other elephant traits, we sequenced multiple elephant genomes. We report a draft assembly for an Asian elephant, and defined 862 and 1,017 conserved potential regulatory elements in Asian and African bush elephants, respectively. In the genomes of both elephant species, conserved elements were significantly enriched with genes differentially expressed between the species. In Asian elephants, these putative regulatory regions were involved in immunity pathways including tumor-necrosis factor, which plays an important role in EEHV response. Genomic sequences of African bush, forest, and Asian elephant genomes revealed extensive sequence conservation at TP53 retrogene loci across three species, which may be related to TP53 functionality in elephant cancer resistance. Positive selection scans revealed outlier genes related to additional elephant traits. Our study suggests that gene regulation plays an important role in the differential inflammatory response of Asian and African elephants, leading to increased infectious disease and cancer susceptibility in Asian elephants. These genomic discoveries can inform future functional and translational studies aimed at identifying effective treatment approaches for ill elephants, which may improve conservation.     

Upregulation of DNA repair genes and cell extrusion underpin the remarkable radiation resistance of Trichoplax adhaerens

Trichoplax adhaerens is the simplest multicellular animal with tissue differentiation and somatic cell turnover. Like all other multicellular organisms, it should be vulnerable to cancer, yet there have been no reports of cancer in T. adhaerens or any other placozoan. We investigated the cancer resistance of T. adhaerens, discovering that they are able to tolerate high levels of radiation damage (218.6 Gy). To investigate how T. adhaerens survive levels of radiation that are lethal to other animals, we examined gene expression after the X-ray exposure, finding overexpression of genes involved in DNA repair and apoptosis including the MDM2 gene. We also discovered that T. adhaerens extrudes clusters of inviable cells after X-ray exposure. T. adhaerens is a valuable model organism for studying the molecular, genetic, and tissue-level mechanisms underlying cancer suppression.

The placozoan Trichoplax adhaerens is able to tolerate high levels of radiation and is resilient to DNA damage; this study reveals that exposure to X-rays triggers the extrusion of cell clusters which subsequently die, and that radiation exposure induces the overexpression of genes involved in DNA repair.     

Fetal microchimerism and maternal health: A review and evolutionary analysis of cooperation and conflict beyond the womb

The presence of fetal cells has been associated with both positive and negative effects on maternal health. These paradoxical effects may be due to the fact that maternal and offspring fitness interests are aligned in certain domains and conflicting in others, which may have led to the evolution of fetal microchimeric phenotypes that can manipulate maternal tissues. We use cooperation and conflict theory to generate testable predictions about domains in which fetal microchimerism may enhance maternal health and those in which it may be detrimental. This framework suggests that fetal cells may function both to contribute to maternal somatic maintenance (e.g. wound healing) and to manipulate maternal physiology to enhance resource transmission to offspring (e.g. enhancing milk production). In this review, we use an evolutionary framework to make testable predictions about the role of fetal microchimerism in lactation, thyroid function, autoimmune disease, cancer and maternal emotional, and psychological health. Also watch the Video Abstract .     

Differences in circular dichroism and fluorescence between the DNA complexes formed with 3-amino- and 3,8- diaminophenanthridinium derivatives

The conformation of DNA complexes formed with various 3-amino- and 3,8-diamino-phenanthridinium derivatives were examined by CD and fluorescence methods. The CD of these complexes is characterized by major bands in the 300–350-nm and the 400–550-nm regions. The CD properties of the complexes formed with diaminophenanthridinium derivatives suggest that the structure of such complexes is well represented by the intercalation complex formed between DNA and ethidium bromide. The substantial and regular increases in ellipticities near 308 nm that occur with increasing DNA-bound diaminophenanthridinium to DNA phosphate ratios (r) may result from direct interactions between molecules intercalated in neighbouring binding sites. In contrast, the changes in the shape of the CD of DNA complexes of monoaminophenanthridinium derivatives with r and the much lower maximum ellipticities attained suggest that near-neighbor interactions among intercalated monoaminophenanthridinium derivatives occur much less efficiently than in the corresponding diamino complexes, if at all. Although alternative explanations for the differences in the optical properties between the mono- and diaminophenanthridinium complexes of DNA may be offered, such results seem to indicate that complexes formed with monoaminophenanthridinium derivatives are characterized by a conformation which is quite distinct and different from that of the DNA–diaminophenanthridinium complexes. This conclusion is further supported by the considerable increase in fluorescence that accompanies the binding of the diaminophenanthridinium derivatives to DNA as compared to the minor increases, which occur upon the binding of the monoaminophenanthridinium compounds. The importance of conformation as a factor influencing template, function, especially with respect to the RNA polymerase-catalyzed synthesis of RNA, is now well appreciated. Therefore, methods which could provide information readily about changes in the conformation of a template, i.e., as a result of dye intercalation, are expected to facilitate our understanding of the effects of conformational change on the function and activity of templates.     

Cancer susceptibility and reproductive trade-offs: a model of the evolution of cancer defences

The factors influencing cancer susceptibility and why it varies across species are major open questions in the field of cancer biology. One underexplored source of variation in cancer susceptibility may arise from trade-offs between reproductive competitiveness (e.g. sexually selected traits, earlier reproduction and higher fertility) and cancer defence. We build a model that contrasts the probabilistic onset of cancer with other, extrinsic causes of mortality and use it to predict that intense reproductive competition will lower cancer defences and increase cancer incidence. We explore the trade-off between cancer defences and intraspecific competition across different extrinsic mortality conditions and different levels of trade-off intensity, and find the largest effect of competition on cancer in species where low extrinsic mortality combines with strong trade-offs. In such species, selection to delay cancer and selection to outcompete conspecifics are both strong, and the latter conflicts with the former. We discuss evidence for the assumed trade-off between reproductive competitiveness and cancer susceptibility. Sexually selected traits such as ornaments or large body size require high levels of cell proliferation and appear to be associated with greater cancer susceptibility. Similar associations exist for female traits such as continuous egg-laying in domestic hens and earlier reproductive maturity. Trade-offs between reproduction and cancer defences may be instantiated by a variety of mechanisms, including higher levels of growth factors and hormones, less efficient cell-cycle control and less DNA repair, or simply a larger number of cell divisions (relevant when reproductive success requires large body size or rapid reproductive cycles). These mechanisms can affect intra- and interspecific variation in cancer susceptibility arising from rapid cell proliferation during reproductive maturation, intrasexual competition and reproduction.     

Ultraviolet light-induced changes in ribonuclease conformation

Ultraviolet light-induced inactivation of RNase A is accompanied by a decrease in the circular dichroism (CD) at the extrema observed at 239 nm and 275 nm. As inactivation progresses a new CD band centered near 325 nm also develops. For RNase maintaining up to one half of its original activity an isoelliptic point may be noted near 257 nm. These findings are consistent with initial normalization of a “buried” tyrosyl residue followed by chemical modification of the protein. Further chemical change and extensive conformational reorganization of the protein appear to accompany advanced inactivation.