Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3×10−62, SLC24A5 P = 9.6×10−9) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4×10−27, TYR P = 1.1×10−9, APBA2[OCA2] P = 1.5×10−8, SLC45A2 P = 6×10−9) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (∼44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ∼70% of the estimated heritability.

A significant part of the compounds present in wines having six carbon atoms, the C 6 -compounds, derive from grape polyunsaturated fatty acids (primarily originated from membrane lipids), namely linoleic and ␣-linolenic acids, through a cascade of enzymatic reactions. This biochemical pathway yield C 6 -aldehydes, which are subsequently reduced to C 6 -alcohols, which can, in turn, be esterified to produce esters. As the C 6compounds derive from varietal precursors, they could hypothetically contribute to judge wine origin and affiliation. In this way, two C 6 -alcohols, (E)-3-hexenol and (Z)-3-hexenol, have been referred as the most important because its ratio can act as an indicator of the variety of origin.This study presents the results, concerning the concentration of the three main C 6 -alcohols, 1-hexanol, (E)-3-hexenol and (Z)-3-hexenol, as well as ratios between them, for 43 monovarietal wines from Vinhos Verdes demarcated region, belonging to six white -Alvarinho (8), Arinto (1), Avesso (9), Azal (1), Loureiro (17) and Trajadura (4) -and three red -Amaral (1), Borraçal (1) and Vinhão (1) -grape varieties. Wines were produced at experimental scale using slightly different winemaking practices and representing various terroirs and vintages, being analyzed after different conservation periods.The results showed that (E)-3-hexenol/(Z)-3-hexenol ratio clearly discriminates Loureiro wines from those of Alvarinho, Avesso and Trajadura. Moreover, 1-hexanol/(E)-3-hexenol and 1-hexanol/(Z)-3-hexenol ratios may also be able to discriminate Vinhos Verdes monovarietal wines, and can act on a second level differentiation. The remaining monovarietal wines produced results which may be observed as indicative, since only one sample of each was analysed.

BackgroundImmune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.MethodsCutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.ResultsPD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.ConclusionsIn this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0344-8) contains supplementary material, which is available to authorized users.

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A return word of a factor of a Sturmian word starts at an occurrence of that factor and ends exactly before its next occurrence. Derivated words encode the unique decomposition of a word in terms of return words. Vuillon has proved that each factor of a Sturmian word has exactly two return words. We determine these two return words, as well as their first occurrence, for the prefixes of characteristic Sturmian words. We then characterize words derivated from a characteristic Sturmian word and give their precise form. Finally, we apply our results to obtain a new proof of the characterization of characteristic Sturmian words which are fixed points of morphisms.