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Vitamin A deficiency is still a public health concern affecting millions of pregnant women and children. Retinoic acid, the active form of vitamin A, is critical for proper mammalian embryonic development. Embryos can generate retinoic acid from maternal circulating β-carotene upon oxidation of retinaldehyde produced via the symmetric cleavage enzyme β-carotene 15,15′-oxygenase (BCO1). Another cleavage enzyme, β-carotene 9′,10′-oxygenase (BCO2), asymmetrically cleaves β-carotene in adult tissues to prevent its mitochondrial toxicity, generating β-apo-10′-carotenal, which can be converted to retinoids (vitamin A and its metabolites) by BCO1. However, the role of BCO2 during mammalian embryogenesis is unknown. We found that mice lacking BCO2 on a vitamin A deficiency-susceptible genetic background ( Rbp4 −/− ) generated severely malformed vitamin A-deficient embryos. Maternal β-carotene supplementation impaired fertility and did not restore normal embryonic development in the Bco2 −/− Rbp4 −/− mice, despite the expression of BCO1. These data demonstrate that BCO2 prevents β-carotene toxicity during embryogenesis under severe vitamin A deficiency. In contrast, β-apo-10′-carotenal dose-dependently restored normal embryonic development in Bco2 −/− Rbp4 −/− but not Bco1 −/− Bco2 −/− Rbp4 −/− mice, suggesting that β-apo-10′-carotenal facilitates embryogenesis as a substrate for BCO1-catalyzed retinoid formation. These findings provide a proof of principle for the important role of BCO2 in embryonic development and invite consideration of β-apo-10′-carotenal as a nutritional supplement to sustain normal embryonic development in vitamin A-deprived pregnant women.

Color vision in birds is mediated by four types of cone photoreceptors whose maximal sensitivities (λmax) are evenly spaced across the light spectrum. In the course of avian evolution, the λmax of the most shortwave-sensitive cone, SWS1, has switched between violet (λmax > 400 nm) and ultraviolet (λmax < 380 nm) multiple times. This shift of the SWS1 opsin is accompanied by a corresponding short-wavelength shift in the spectrally adjacent SWS2 cone. Here, we show that SWS2 cone spectral tuning is mediated by modulating the ratio of two apocarotenoids, galloxanthin and 11’,12’-dihydrogalloxanthin, which act as intracellular spectral filters in this cell type. We propose an enzymatic pathway that mediates the differential production of these apocarotenoids in the avian retina, and we use color vision modeling to demonstrate how correlated evolution of spectral tuning is necessary to achieve even sampling of the light spectrum and thereby maintain near-optimal color discrimination. The pioneering eye doctor André Rochon-Duvigneaud once wrote that “a bird is a wing guided by an eye”. With this statement, he underscored the sophistication of the bird’s eye, which surpasses our own in several respects. Compared to humans who have three types of cone photoreceptor, birds have four, meaning they can see an extra dimension of color. Birds precisely tune their violet-, blue-, green- and red-sensitive cones by coupling light-sensitive proteins with light-filtering pigments called carotenoids. This combination of sensors and filters increases the number of colors a bird can see. Another exceptional aspect of bird vision is that some species – for example finches and sparrows – can see ultraviolet (UV) light. This ability results from a change in the light-sensitive protein within the violet cone photoreceptor that shifts its sensitivity towards UV light. This expansion of vision into the UV is complemented by a shift in the sensitivity of the blue cone photoreceptor. However, it is not well understood exactly how the sensitivity of the blue cone is shifted and how this shift impacts color vision. To find answers to these questions, Toomey et al. characterized the light-filtering carotenoid pigments from bird species with violet or UV sensitivity, and used computational models of bird vision to predict how these pigments affect the number of colors a bird can see. This approach revealed that blue cone sensitivity is fine-tuned through a change in the chemical structure of the light-filtering carotenoid pigments within the photoreceptor. Computational models also indicated the sensitivity of the violet and blue cones must shift in a coordinated manner to maximize the number of colors a bird can see. These results suggest that both blue and violet cone cells have been fine-tuned during evolution to enhance color vision in birds. An important next step is to investigate the underlying molecular mechanisms that coordinate the modification of the carotenoid pigments and the tuning of light-sensitive proteins in a wide range of bird species.

N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic retinoid, less toxic than the parent all-trans retinoic acid (RA). Unlike RA, 4-HPR induces apoptosis in tumor cells. Because 4-HPR can hydrolyze to liberate RA, a potent human teratogen, the unhydrolyzable ketone analog of 4-HPR, 4-hydroxybenzylretinone (4-HBR) has been prepared and has been found to cause apoptosis in tumor cells and shrink carcinogen-induced rat mammary tumors as 4-HPR does. Herein, we examined the mechanism whereby 4-HPR and 4-HBR induce apoptosis and death in breast cancer cells. Gene expression profiling was conducted in MCF-7 cells over a 1.5- to 6-h time course and changes were validated by quantitative polymerase chain reaction (qPCR). Growth arrest and DNA damage-inducible protein 153 (GADD153 or C/EBP homologous protein, CHOP) was knocked down and the effect on 4-HPR-induced cell death and gene expression was assessed. 4-HPR synergy with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) was also examined. Drug treatment induced increased expression of endoplasmic reticulum (ER) stress-related and pro-apoptotic genes. Gene expression changes were verified by qPCR in three invasive ductal breast carcinoma cell lines (MCF-7, T-47D, MDA-MB-231). GADD153 showed the largest increase in the microarray experiment; however, knockdown of GADD153 did not abrogate apoptosis and death. Genes related to the extrinsic pathway of apoptosis including a receptor for TRAIL, death receptor 5 (DR5), were up-regulated by drug treatment. A dose of 4-HPR that alone is ineffective in killing TRAIL-resistant MCF-7 cells, synergized with recombinant TRAIL to induce breast cancer cell death. 4-HPR and analogs might be useful in sensitizing tumor cells to death receptor agonists.

Este artículo analiza las múltiples y complejas relaciones entre los representantes locales de la Iglesia, el Estado y la población, para contribuir a una interpretación más crítica del mosaico de posibilidades que caracterizaron la Reforma liberal durante el último tercio del siglo XIX. Se ha optado por observar una serie de casos encontrados en cuatro poblaciones de Jalisco: Ahualulco, Chapala, Tapalpa y Teocaltiche. A partir de una escala local es posible mirar por debajo y por detrás las pretensiones de Estado y observar un proceso histórico más desordenado y menos teleológico. El argumento central es que los vecinos actuaron a favor de intereses diversos y movilizaron a la Iglesia y el Estado en su defensa de acuerdo a contingencias históricas. En cuanto a las fuentes que se han utilizado, corresponden a dos acervos distintos. En el Archivo Histórico de Jalisco se encontraron fuentes generadas en el marco de la oficialía, que vincula el gobierno del estado con poderes civiles locales, como los ayuntamientos, la jefatura política y sus oficinas locales. Estos documentos tratan asuntos en los que las autoridades civiles deben interpretar las leyes de secularización para casos locales. En el Archivo Histórico de la Arquidiócesis de Guadalajara se trabajó con fuentes que representan las relaciones entre fieles, la parroquia y el arzobispado. This article analyzes the multiple, complex relationships between the local representations of the church, the state and the population, thus contributing to a more critical interpretation of the mosaic of possibilities that characterized the Liberal Reform during the last third of the 19th Century. For this purpose, we have opted to observe a series of contrasting cases in four Jalisco towns: Ahualulco, Chapala, Tapalpa and Teocaltiche. At the local scale, it is possible to gain a perspective from below, one that goes beyond the aims of the state to account for a more disordered, less teleological historical process. The central argument is that people acted in defense of varied interests and mobilized the church and state in their defense in accordance with historical contingencies. The sources used come from two different archives. The Jalisco History Archive contains sources generated by the civil registry, which connects the state government with local authorities, such as municipal governments, police forces and its local representatives. These documents deal with matters in which the authorities interpreted the laws on secularization in terms of local cases. The other, the History Archive of the Archdiocese of Guadalajara, provided sources on the relationships between believers, the parish and the Archbishop.