Passage survival of European and American eels at Francis and propeller turbines.

We present the magnitude of losses of European eel Anguilla anguilla and American eel A. rostrata in passage through propeller and Francis turbines at hydroelectric projects. Survival and injury rates and types were turbine type related. Overall, eel survival was higher (mean ± 90% CI = 95.1 ± 5.3%,) and injury rate lower (12.5 ± 10.5) at Francis than propeller turbines (survival = 80.7 ± 6.4%; injury rate = 25.7 ± 7.9%). The common injury type at Francis turbines was bruises and at propeller turbines was severance. Blade shape and thickness of the leading edge of the blades (rounded, thick buckets of Francis turbines v. flatter, sharper edged blades in propeller turbines); eel entry routes into the turbines; their flexible, cylindrical body shape and orientation probably contributed to these differences. Relationship between survival and injury and turbine characteristics was turbine specific. For Francis turbines, one negative correlation (r = -0.986, P < 0.01) between survival and runner speed was found and two positive correlations between injury rates and fish length (r = 0.740, P < 0.10) and number of blades (r = 0.835, P < 0.05) were noted for propeller turbines. Several severely injured eels remained active 48 h after turbine passage suggesting caution is warranted when using telemetric movement for estimating eel survival. We conclude there is a need to (a) better understand travel paths and approach orientation of eels through turbines; (b) determine where only eel passage is of concern at hydropower plants that have both turbine types and therefore preferential operation of Francis turbines may be considered; (c) inform hydropower plant operators where turbine replacement is being considered and downstream eel passage is of concern that replacement by Francis or bulb turbines may prove beneficial for eel passage.

Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans.

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route.

This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.