Foxtail millet (Setaria italica) is an important grain crop that is grown in arid regions. Here we sequenced 916 diverse foxtail millet varieties, identified 2.58 million SNPs and used 0.8 million common SNPs to construct a haplotype map of the foxtail millet genome. We classified the foxtail millet varieties into two divergent groups that are strongly correlated with early and late flowering times. We phenotyped the 916 varieties under five different environments and identified 512 loci associated with 47 agronomic traits by genome-wide association studies. We performed a de novo assembly of deeply sequenced genomes of a Setaria viridis accession (the wild progenitor of S. italica) and an S. italica variety and identified complex interspecies and intraspecies variants. We also identified 36 selective sweeps that seem to have occurred during modern breeding. This study provides fundamental resources for genetics research and genetic improvement in foxtail millet.

Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, HO, or hypoxia promotes the transition of ROS M-BCSCs to a ROS E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.

As an ancient cereal of great importance for dryland agriculture even today, foxtail millet (Setaria italica) is fast becoming a new plant genomic model crop. A genotypic analysis of 250 foxtail millet landraces, which represent 1% of foxtail millet germplasm kept in the Chinese National Gene Bank (CNGB), was conducted with 77 SSRs covering the foxtail millet genome. A high degree of molecular diversity among the landraces was found, with an average of 20.9 alleles per locus detected. STRUCTURE, neighbor-jointing, and principal components analyses classify the accessions into three clusters (topmost hierarchy) and, ultimately, four conservative subgroups (substructuring within the topmost clusters) in total, which are in good accordance with eco-geographical distribution in China. The highest subpopulation diversity was identified in the accessions of Pop3 from the middle regions of the Yellow River, followed by accessions in Pop1 from the downstream regions of the Yellow River, suggesting that foxtail millet was domesticated in the Yellow River drainage area first and then spread to other parts of the country. Linkage disequilibrium (LD) decay of less than 20 cM of genetic distance in the foxtail millet landrace genome was observed, which suggests that it could be possible to achieve resolution down to the 20 cM level for association mapping.

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BackgroundFoxtail millet (Setaria italica (L.) P. Beauv.), one of the most ancient domesticated crops, is becoming a model system for studying biofuel crops and comparative genomics in the grasses. However, knowledge on the level of genetic diversity and linkage disequilibrium (LD) is very limited in this crop and its wild ancestor, green foxtail (Setaria viridis (L.) P. Beauv.). Such information would help us to understand the domestication process of cultivated species and will allow further research in these species, including association mapping and identification of agricultural significant genes involved in domestication.ResultsIn this study, we surveyed DNA sequence for nine loci across 50 accessions of cultivated foxtail millet and 34 of its wild progenitor. We found a low level of genetic diversity in wild green foxtail (θ = 0.0059), θ means Watterson's estimator of θ. Despite of a 55% loss of its wild diversity, foxtail millet still harbored a considerable level of diversity (θ = 0.0027) when compared to rice and sorghum (θ = 0.0024 and 0.0034, respectively). The level of LD in the domesticated foxtail millet extends to 1 kb, while it decayed rapidly to a negligible level within 150 bp in wild green foxtail. Using coalescent simulation, we estimated the bottleneck severity at k = 0.6095 when ρ/θ = 1. These results indicated that the domestication bottleneck of foxtail millet was more severe than that of maize but slightly less pronounced than that of rice.ConclusionsThe results in this study establish a general framework for the domestication history of foxtail millet. The low level of genetic diversity and the increased level of LD in foxtail millet are mainly caused by a population bottleneck, although gene flow from foxtail millet to green foxtail is another factor that may have shaped the pattern of genetic diversity of these two related gene pools. The knowledge provided in this study will benefit future population based studies in foxtail millet.

Highly tumorigenic stem-like cells, considered tumor-initiating cells (TICs), are the main cause of lung cancer initiation, relapse, and drug resistance. In this study, we identified that Ca2+/calmodulin-dependent protein kinase IIγ (CaMKIIγ) was aberrantly expressed in highly tumorigenic stem-like lung cancer cells, and was also correlated with poor prognosis in human lung cancer. Functionally, CaMKIIγ enhanced stem-like traits and the tumorigenicity of lung cancer cells in an Akt- and β-catenin-dependent manner. In addition, we found that CaMKIIγ upregulated Oct4 expression via Akt-mediated histone acetylation. Taken together, our findings reveal a critical role of CaMKIIγ in regulating the stemness and tumorigenicity of lung cancer cells and offer a promising therapeutic target for TICs.

Background:Epidemiological studies have indicated that noise exposure is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the nature of the connection between noise exposure and T2DM remains to be explored.Objectives:We explored whether and how noise exposure affects glucose homeostasis in mice as the initial step toward T2DM development.Methods:Male ICR mice were randomly assigned to one of four groups: the control group and three noise groups (N20D, N10D, and N1D), in which the animals were exposed to white noise at 95 decibel sound pressure level (dB SPL) for 4 hr per day for 20 successive days, 10 successive days, or 1 day, respectively. Glucose tolerance and insulin sensitivity were evaluated 1 day, 1 week, and 1 month after the final noise exposure (1DPN, 1WPN, and 1MPN). Standard immunoblots, immunohistochemical methods, and enzyme-linked immunosorbent assays (ELISA) were performed to assess insulin signaling in skeletal muscle, the morphology of β cells, and plasma corticosterone levels.Results:Noise exposure for 1 day caused transient glucose intolerance and insulin resistance, whereas noise exposure for 10 and 20 days had no effect on glucose tolerance but did cause prolonged insulin resistance and an increased insulin response to glucose challenge. Akt phosphorylation and GLUT4 translocation in response to exogenous insulin were decreased in the skeletal muscle of noise-exposed animals.Conclusions:Noise exposure at 95 dB SPL caused insulin resistance in male ICR mice, which was prolonged with longer noise exposure and was likely related to the observed blunted insulin signaling in skeletal muscle.Citation:Liu L, Wang F, Lu H, Cao S, Du Z, Wang Y, Feng X, Gao Y, Zha M, Guo M, Sun Z, Wang J. 2016. Effects of noise exposure on systemic and tissue-level markers of glucose homeostasis and insulin resistance in male mice. Environ Health Perspect 124:1390–1398; http://dx.doi.org/10.1289/EHP162

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