Conserved microRNA editing in mammalian evolution, development and disease.

BACKGROUND: Mammalian microRNAs (miRNAs) are sometimes subject to adenosine-to-inosine RNA editing, which can lead to dramatic changes in miRNA target specificity or expression levels. However, although a few miRNAs are known to be edited at identical positions in human and mouse, the evolution of miRNA editing has not been investigated in detail. In this study, we identify conserved miRNA editing events in a range of mammalian and non-mammalian species. RESULTS: We demonstrate deep conservation of several site-specific miRNA editing events, including two that date back to the common ancestor of mammals and bony fishes some 450 million years ago. We also find evidence of a recent expansion of an edited miRNA family in placental mammals and show that editing of these miRNAs is associated with changes in target mRNA expression during primate development and aging. While global patterns of miRNA editing tend to be conserved across species, we observe substantial variation in editing frequencies depending on tissue, age and disease state: editing is more frequent in neural tissues compared to heart, kidney and testis; in older compared to younger individuals; and in samples from healthy tissues compared to tumors, which together suggests that miRNA editing might be associated with a reduced rate of cell proliferation. CONCLUSIONS: Our results show that site-specific miRNA editing is an evolutionarily conserved mechanism, which increases the functional diversity of mammalian miRNA transcriptomes. Furthermore, we find that although miRNA editing is rare compared to editing of long RNAs, miRNAs are greatly overrepresented among conserved editing targets

Taking ethical photos of children for medical and research purposes in low-resource settings: an exploratory qualitative study.

Photographs are commonly taken of children in medical and research contexts. With the increased availability of photographs through the internet, it is increasingly important to consider their potential for negative consequences and the nature of any consent obtained. In this research we explore the issues around photography in low-resource settings, in particular concentrating on the challenges in gaining informed consent

Explosivity : an unusual challenge in drug development

There remains an urgent global need for new drugs to combat diseases such as malaria, tuberculosis and cancer, as well as overcoming increasing antibiotic resistance. Chemists are moving into ‘new chemical space’ for drug design (1,2) and with this comes the possibility of traditional (and stable) ‘carbon-carbon’ bond structures being replaced by more ‘exotic’ bonding arrangements. While the implication of this on pharmaceutical stability can often be mitigated by suitable formulation and storage strategies, we came across an unusual case of chemical stability: the possibility that the drug was an explosive! By pushing drug designing into uncharted chemical space it could be argued that the possibility of finding explosive molecules of pharmaceutical interest will increase

The Birmingham Boron Neutron Capture Therapy (BNCT) project : developments towards selective internal particle therapy

This paper will review progress on two aspects of the Birmingham BNCT project. Firstly on evaluation of the effects of high and low LET radiations when delivered simultaneously, and secondly on attempts to optimise delivery of the boron carrier compound BPA through pharmacokinetic studies. Simultaneous or non-simultaneous irradiations of V79 cells with alpha-particle and X-ray irradiations were performed. Alpha doses of 2 and 2.5 Gy were chosen and the impact on survival when delivered separately or simultaneously with variable doses of X-rays was evaluated. The pharmacokinetics of the delivery of a new formulation of BPA (BPA-mannitol) are being investigated in brain tumour patients through a study with 2 × 2 design featuring intravenous and intracarotid artery infusion of BPA, with or without a mannitol bolus. On the combined effect of low and high LET radiations, a synergistic effect was observed when alpha and X-ray doses are delivered simultaneously. The effect is only present at the 2.5 Gy alpha dose and is a very substantial effect on both the shape of the survival curve and the level of cell killing. This indicates that the alpha component may have the effect of inhibiting the repair of damage from the low LET radiation dose delivered simultaneously. On the pharmacokinetics of BPA, data on the first three cohorts indicate that bioavailability of BPA in brain ECF is increased substantially through the addition of a mannitol bolus, as well as by the use of intracarotid artery route of infusion. In both cases, for some patients the levels after infusion approach those seen in blood, whereas the ECF levels for intravenous infusion without mannitol are typically less than 10% of the blood values

Collective Flow from the Intranuclear Cascade Model

The phenomenon of collective flow in relativistic heavy ion collisions is studied using the hadronic cascade model ARC. Direct comparison is made to data gathered at the Bevalac, for Au+Au at $p=1-2$ GeV/c. In contrast to the standard lore about the cascade model, collective flow is well described quantitatively without the need for explicit mean field terms to simulate the nuclear equation of state. Pion collective flow is in the opposite direction to nucleon flow as is that of anti-nucleons and other produced particles. Pion and nucleon flow are predicted at AGS energies also, where, in light of the higher baryon densities achieved, we speculate that equation of state effects may be observable.Comment: 9 pages, 2 figures include

Delays Associated with Elementary Processes in Nuclear Reaction Simulations

Scatterings, particularly those involving resonances, and other elementary processes do not happen instantaneously. In the context of semiclassical nuclear reaction simulations, we consider delays associated with an interaction for incident quantum wave-packets. As a consequence, we express delays associated with elementary processes in terms of elements of the scattering matrix and phase shifts for elastic scattering. We show that, to within the second order in density, the simulation must account for delays in scattering consistently with the mean field in order to properly model thermodynamic properties such as pressure and free-energy density. The delays associated with nucleon-nucleon and pion-nucleon scattering in free space are analysed with their nontrivial energy dependence. Finally, an example of s-channel scattering of massless partons is studied, and scattering schemes in nuclear reaction simulations are investigated in the context of scattering delays.Comment: 45 pages, 5 uuencoded Postscript figure

Convergent origination of a Drosophila-like dosage compensation mechanism in a reptile lineage

Sex chromosomes differentiated from different ancestral autosomes in various vertebrate lineages. Here, we trace the functional evolution of the XY Chromosomes of the green anole lizard (Anolis carolinensis), on the basis of extensive high-throughput genome, transcriptome and histone modification sequencing data and revisit dosage compensation evolution in representative mammals and birds with substantial new expression data. Our analyses show that Anolis sex chromosomes represent an ancient XY system that originated at least ≈160 million years ago in the ancestor of Iguania lizards, shortly after the separation from the snake lineage. The age of this system approximately coincides with the ages of the avian and two mammalian sex chromosomes systems. To compensate for the almost complete Y Chromosome degeneration, X-linked genes have become twofold up-regulated, restoring ancestral expression levels. The highly efficient dosage compensation mechanism of Anolis represents the only vertebrate case identified so far to fully support Ohno’s original dosage compensation hypothesis. Further analyses reveal that X up-regulation occurs only in males and is mediated by a male-specific chromatin machinery that leads to global hyperacetylation of histone H4 at lysine 16 specifically on the X Chromosome. The green anole dosage compensation mechanism is highly reminiscent of that of the fruit fly, Drosophila melanogaster. Altogether, our work unveils the convergent emergence of a Drosophila-like dosage compensation mechanism in an ancient reptilian sex chromosome system and highlights that the evolutionary pressures imposed by sex chromosome dosage reductions in different amniotes were resolved in fundamentally different ways

Elastic scattering and breakup of 17^F at 10 MeV/nucleon

Angular distributions of fluorine and oxygen produced from 170 MeV 17^F incident on 208^Pb were measured. The elastic scattering data are in good agreement with optical model calculations using a double-folding potential and parameters similar to those obtained from 16^O+208^Pb. A large yield of oxygen was observed near \theta_lab=36 deg. It is reproduced fairly well by a calculation of the (17^F,16^O) breakup, which is dominated by one-proton stripping reactions. The discrepancy between our previous coincidence measurement and theoretical predictions was resolved by including core absorption in the present calculation.Comment: 9 pages, 5 figure

Quantum Tunneling in Nuclear Fusion

Recent theoretical advances in the study of heavy ion fusion reactions below the Coulomb barrier are reviewed. Particular emphasis is given to new ways of analyzing data, such as studying barrier distributions; new approaches to channel coupling, such as the path integral and Green function formalisms; and alternative methods to describe nuclear structure effects, such as those using the Interacting Boson Model. The roles of nucleon transfer, asymmetry effects, higher-order couplings, and shape-phase transitions are elucidated. The current status of the fusion of unstable nuclei and very massive systems are briefly discussed.Comment: To appear in the January 1998 issue of Reviews of Modern Physics. 13 Figures (postscript file for Figure 6 is not available; a hard copy can be requested from the authors). Full text and figures are also available at http://nucth.physics.wisc.edu/preprints

Sex-related differences in COPD in five Latin American cities: the PLATINO study

There is evidence to suggest sex differences exists in chronic obstructive pulmonary disease (COPD) clinical expression. We investigated sex differences in health status perception, dyspnoea and physical activity, and factors that explain these differences using an epidemiological sample of subjects with and without COPD.PLATINO is a cross-sectional, population-based study. We defined COPD as post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio = 2 versus 35% of males. A similar trend was observed in females with COPD (63% versus 44%). in the entire study population, female sex was a factor explaining dyspnoea (OR 1.60, 95% CI 1.40-1.84) and SF-12 physical score (OR -1.13, 95% CI -1.56- -0.71). 40% of females versus 28% of males without COPD reported their general health status as fair-to-poor. Females with COPD showed a similar trend (41% versus 34%). Distribution of COPD severity was similar between sexes, but currently smoking females had more severe COPD than currently smoking males.There are important sex differences in the impact that COPD has on the perception of dyspnoea, health status and physical activity limitation.Boehringer Ingelheim GmbH (Ingelheim, Germany)Asociacion Latinoamericana de Torax (ALAT)Univ Republica, Fac Med, Montevideo, UruguayCent Univ Venezuela, Fac Med, Caracas, VenezuelaUniv Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USAInst Resp Dis, Mexico City, DF, MexicoUniversidade Federal de São Paulo, São Paulo, BrazilUniv Fed Pelotas, Postgrad Program Epidemiol, Pelotas, BrazilPontificia Univ Catolica Chile, Santiago, ChileUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc