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The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.

The jadomycin-derived compound l-digitoxosyl-phenanthroviridin was isolated from fermentations of Streptomyces venezuelae ISP5230 grown in nutrient-deficient media with l-lysine as the sole nitrogen source. Structural elucidation was accomplished using a combination of high-resolution MS, LC-MS/MS, and 1D- and 2D-NMR. The compound was evaluated against the National Cancer Institute (NCI) 60 human tumor cell line screen in both the one-dose and five-dose screens, and cytotoxicity was compared to a small library of jadomycin analogues to probe the structure-activity relationship.

Repressive histone tail modifications have been associated with molecular breast cancer subtypes. We investigated whether histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) were associated with tumor features and subtypes while adjusting for prospectively collected reproductive and lifestyle breast cancer risk factors. We have tissue microarray data with immunohistochemical marker information on 804 incident cases of invasive breast cancer diagnosed from 1976-2000 in the Nurses' Health Study. Tissue microarray sections were stained for global H3K9me3 and H3K27me3, and scored into four categories. Multivariate odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression models for tumor features and subtypes, adjusting for breast cancer risk factors. While there were no significant associations between H3K9me3 and tumor features, H3K27me3 was significantly associated with lower grade tumors compared to high grade tumors in the multivariate model (OR = 1.95, 95 % CI 1.35-2.81, p = 0.0004). H3K27me3 was suggestively associated with estrogen receptor-positive (ER+) tumors (OR = 1.47, 95 % CI 0.97-2.23, p = 0.07). In subtype analyses, H3K27me3 was positively associated with the luminal A subtype compared to all other subtypes (OR = 1.42, 95 % CI 1.14-1.77, p = 0.002), and was inversely associated with HER2-type (OR = 0.58, 95 % CI 0.37-0.91, p = 0.02) and basal-like breast cancer (OR = 0.52, 95 % CI 0.36-0.76, p = 0.0006). In the largest immunohistochemical examination of H3K9me3 and H3K27me3 in breast cancer, we found that H3K27me3 positivity, but not H3K9me3, was associated with lower grade tumors and the luminal A subtype after adjusting for reproductive and lifestyle breast cancer risk factors.

Two studies were conducted to determine the effect of increasing the valine:lysine (V:L) ratio in diets of lactating sows above the minimum proposed by the NRC (1998). The first experiment involved 189 PIC, Camborough product sows (parity 1 to 4) that were allotted to 1 of 3 dietary treatments. Diets were formulated to achieve total dietary V:L ratios of 0.90, 1.05, or 1.25:1, respectively, and were corn and soybean meal-based. The second experiment involved 279 PIC, Camborough sows (parity 1 to 5) that were allotted to 1 of 4 treatments. Diets 1 and 3 were formulated using corn and a fixed inclusion of soybean meal (16.7%), with 0.27% L-lysine HCl. The V:L ratios in diets 1 and 3 were 0.73 and 1.25:1, respectively. Diets 2 and 4 were typical corn-soybean meal diets containing 0.05% L-lysine HCl, with a fixed inclusion of soybean meal (22.7%). The V:L ratios in diets 2 and 4 were 0.86 and 1.25:1, respectively. In both experiments, each litter was standardized to a minimum of 10 pigs, which achieved litter growth rates of 2.22 and 2.56 kg/d in Exp. 1 and 2, respectively. In Exp. 1, increasing the dietary V:L ratio beyond 0.90:1 did not improve (P > 0.10) the number of pigs weaned, survival rate, or piglet growth rate, even though sows were nursing more than 10 pigs per litter for 19 d. In Exp. 2, total lysine intake was similar among treatments and ranged from 52.1 to 55.3 g/d. Valine intake increased as the diet valine concentration increased (diet 1 vs. 3 and diet 2 vs. 4, P < 0.001), ranging from 40.0 to 66.1 g/d. Litter gain tended to improve (P = 0.14) when the 0.27% L-lysine HCl control (0.73 V:L) was supplemented with valine to achieve a 1.25:1 V:L ratio. In contrast, no aspect of sow or litter response was improved when the practical control diet containing 0.05% L-lysine HCl (0.86 V:L) was supplemented with valine to achieve a 1.25:1 V:L ratio. Collectively, this research shows that a V:L ratio in excess of 0.86 does not conserve maternal tissue loss or improve piglet growth rate, but a V:L ratio of 0.73 may compromise litter growth rate.

The need for arthroplasty, especially in the hip, arises primarily because of failure to replace damaged structural proteins as a result of improper balance in essential nutrients. The principal failure is an inadequate production of elastin resulting in cartilage consisting primarily of a collagen that may be flexible but is not elastic. In spite of the fact that an excess of protein, with adequate lysine, is commonly consumed by the affluent societies, this lysine is not utilized because of the inadequate intake of ascorbic acid necessary for virtually every step of the structural protein synthetic reactions. Experiments in animals support these conclusions. It is anticipated that dietary correction in candidates for total hip replacement will be able to restore normal hip cartilage (with corresponding improvements of other structural protein deficits throughout the body) in less than a year. Adoption of this regimen should result in: (1) a greatly decreased need for arthroplasties; and (2) better results in those that are performed, with less failures and less need for revisions. The benefits include much less suffering for patients and far lower medical costs.