Elucidating cardiac evolution has been frustrated by lack of fossils. One celebrated enigma in cardiac evolution involves the transition from a cardiac outflow tract dominated by a multi-valved conus arteriosus in basal actinopterygians, to an outflow tract commanded by the non-valved, elastic, bulbus arteriosus in higher actinopterygians. We demonstrate that cardiac preservation is possible in the extinct fish Rhacolepis buccalis from the Brazilian Cretaceous. Using X-ray synchrotron microtomography, we show that Rhacolepis fossils display hearts with a conus arteriosus containing at least five valve rows. This represents a transitional morphology between the primitive, multivalvar, conal condition and the derived, monovalvar, bulbar state of the outflow tract in modern actinopterygians. Our data rescue a long-lost cardiac phenotype (119-113 Ma) and suggest that outflow tract simplification in actinopterygians is compatible with a gradual, rather than a drastic saltation event. Overall, our results demonstrate the feasibility of studying cardiac evolution in fossils.

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))^1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K_IV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. ^3–7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K_IV7–8. We identify compounds that bind to apo(a) K_IV7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).

The angular distribution of photons scattered by breast tissue samples (20 normal and 13 malignant) was measured in the interval of momentum transfer 0.02 Å ⁻¹ ≤ x ≤ 0.62 Å ⁻¹ , using a powder diffractometer apparatus operating in reflection mode and equipped with a monochromator in the scattering beam. The x‐ray tube had a Cu anode and added Ni filtration. Experimental data was corrected for all background sources, polarization, self‐attenuation and geometric effect in order to provide the linear differential scattering coefficient µ _s (scattering profile) of each sample. Discriminant analysis was applied to these profiles in order to quantify the differences existing between normal and malignant tissues. In this analysis, each momentum transfer measured was considered as an independent variable, and the scores of each sample on a discriminant function were obtained. The classification method of decision tree induction was applied to these scores, which allowed tissue characterization. The classification results were validated and compared with histological sample classifications obtained by microscopic analyses. The results have shown that discriminant analysis was able to successfully identify differences between the scattering profiles from normal and malignant tissues. Also, classification results allowed the correct identification of 97% of the analyzed samples. These results suggest that the scattering profile may be an effective marker to be used in the diagnosis of breast cancer. Copyright © 2006 John Wiley & Sons, Ltd.