Within the circulatory system, blood flow regulates vascular remodeling1, stimulates blood stem cell formation2, and plays a role in the pathology of vascular disease3. During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act prior to circulation4. Subsequently, endothelial cells must incorporate the mechanosensory stimulus of blood flow with these early signals to shape the embryonic vascular system4. However, few details are known about how these signals are integrated during development. To investigate this process, we focused on the aortic arch (AA) blood vessels, which are known to remodel in response to blood flow1. By using 2-photon imaging of live zebrafish embryos, we observe that flow is essential for angiogenesis during AA development. We further find that angiogenic sprouting of AA vessels requires a flow-induced genetic pathway in which the mechano-sensitive zinc finger transcription factor klf2a5-7 induces expression of an endothelial-specific microRNA, mir-126, to activate Vegf signaling. Taken together, our work describes a novel genetic mechanism in which a microRNA facilitates integration of a physiological stimulus with growth factor signaling in endothelial cells to guide angiogenesis.

Transition metals (i.e. copper, zinc, iron, cobalt, selenium, manganese) are essential for the health of most organisms, forming integral components of proteins involved in all aspects of biological function. Their ubiquity is governed by their ability to form a wide range of coordination geometries and redox states, which allows these elements to interact with many cellular entities, performing pivotal roles in cellular respiration, oxygen transport, protein stability, free radical scavenging, and the action of many cellular enzymes, as well as for DNA transcription. However, in excess they are toxic, binding to inappropriate biologically sensitive molecules or forming dangerous free radicals. Consequently, there is a fine balance between metal deficiency and surplus and it is vital for organisms to maintain metal homeostasis via balancing absorption and excretion.Fish are unique among the vertebrates, a consequence of having two routes of metal acquisition, from the diet and from the water. This review will focus on the uptake processes present in the gill and intestinal epithelium of teleost fish for the three most abundant nutritive metals: iron, copper and zinc. The majority of the available literature concerns metal uptake processes in freshwater teleosts, but where appropriate examples exist, information on seawater teleosts will be reviewed. Molecular evidence indicates that transporters for these metals identified in yeast, plants or mammals all show high sequence homology in key functional regions ), but to date, none of these transporters have been characterised in fish. However, due to the evolutionary conservation of these proteins between yeast, plants and mammals, it is envisaged that fish metal transporters will also belong to the large iron, copper or zinc metal transporter protein families already identified. This review will combine physiological and molecular data to provide an overview of metal uptake mechanisms in teleost fish. IronIron is an essential nutrient to almost all organisms. Iron positioning in the haem moiety of haemoglobin increases oxygen binding and carrying capacity, enabling oxygen transfer to all tissues in multicellular organisms. One of iron's key cellular functions is to confer redox activity to the cytochromes involved in respiration, due to its ability to exchange electrons in aerobic conditions. A negative consequence of iron's redox flexibility is that it produces oxygen free radicals that are toxic to the cell. Consequently, in excess, iron can be detrimental to health. In addition, excess waterborne iron may be toxic to fish, due to the formation of iron 'flocs' on the gills, resulting in gill clogging and respiratory perturbations (Peuranen et al., 1994;Dalzell and MacFarlane, 1999). Teleost fish iron homeostasisThe iron content of fish is, in general, considerably lower than that of other vertebrates (Van Dijk et al., 1975), but the precise daily iron requirements for fish are at present unknown. 11The Journal of Experimental Biology 206, 11-23 © 2003 The Compa...

The conservation goal of representation of biodiversity (in the broad sense of all species) in protected areas requires best-possible use of available surrogate information. One standard approach is based on 'indicator' groups of taxa. A minimum set of areas having at least one representation of each indicator species is taken to be representative of other organisms. This same minimum-set approach is adapted to other 'attributes' of biodiversity, for example, derived environmental clusters. A weakness of these approaches is that useful information is lost; for example, for environmental clusters, there is no distinction made either among or within clusters. A more powerful surrogate approach can use some expression of environmental and/or biotic pattern so that variation among areas is seen as part of a continuum rather than partitioned into arbitrary clusters/attributes. The challenge in using pattern effectively is to adopt a robust model for the relationship between pattern and the underlying units of biodiversity, i.e. species. An environmental space (a continuum or ordination pattern), combined with the standard ecological continuum model relating species to environmental space, has advantages over other patterns based on hierarchy or distance matrices. Because an environmental space can be estimated either directly (observed environmental data) or indirectly (data on indicator groups), the corresponding surrogate-measure of biodiversity, 'environmental diversity' (ED) makes best-possible use of either kind of data. We conclude that the arbitrariness of the 'attribute' approach can be replaced by a robust surrogate ~pattern' approach that is flexible and avoids unwarranted assumptions.

The physical and hormonal characteristics of 60 male-to-female transsexuals and 30 female-to-male transsexuals were measured before or during treatment with commonly used forms and dosages of hormones. Only two patients (both female-to-male) had either a congenital defect in hormonal production or abnormal genital development. Patients were seen at 3- to 6-month intervals for an average of 18 months. The response to therapy was examined over time; physical parameters, hormonal concentrations, liver function tests, lipids, and glucose were measured. Three patients were changed from ethinyl estradiol to conjugated estrogen because of liver enzyme elevations. Ethinyl estradiol (0.1-0.5 mg/day) was equal to conjugated estrogen (7.5-10 mg/day) in its ability to suppress testosterone and gonadotropins and to promote breast growth. Maximum breast growth required 2 years of therapy. During treatment with testosterone, female-to-male transsexuals had a significant mild elevation of cholesterol and triglyceride. The female-to-male transsexuals receiving testosterone cypionate, 200 mg every 2 weeks, ceased to have menstrual periods and became progressively masculinized. A mean maximal clitoral length of 4.6 cm which achieved by 1 year of therapy. Based on the data generated by this study, we recommend as hormonal therapy 0.1-0.5 mg/day of ethinyl estradiol or 7.5-10 mg/day of conjugated estrogen for male-to-female transsexuals, and intramuscular testosterone cypionate, 200 mg every 2 weeks, for female-to-male transsexuals.

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