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Domestic chickens (Gallus gallus domesticus) fulfill various roles ranging from food and entertainment to religion and ornamentation. To survey its genetic diversity and trace the history of domestication, we investigated a total of 4938 mitochondrial DNA (mtDNA) fragments including 2843 previously published and 2095 de novo units from 2044 domestic chickens and 51 red junglefowl (Gallus gallus). To obtain the highest possible level of molecular resolution, 50 representative samples were further selected for total mtDNA genome sequencing. A fine-gained mtDNA phylogeny was investigated by defining haplogroups A-I and W-Z. Common haplogroups A-G were shared by domestic chickens and red junglefowl. Rare haplogroups H-I and W-Z were specific to domestic chickens and red junglefowl, respectively. We re-evaluated the global mtDNA profiles of chickens. The geographic distribution for each of major haplogroups was examined. Our results revealed new complexities of history in chicken domestication because in the phylogeny lineages from the red junglefowl were mingled with those of the domestic chickens. Several local domestication events in South Asia, Southwest China and Southeast Asia were identified. The assessment of chicken mtDNA data also facilitated our understanding about the Austronesian settlement in the Pacific.

The mammalian target of rapamycin (mTOR) signaling pathway is upregulated in the pathogenesis of many cancers. Arachidonic acid (AA) and its metabolites play critical role in the development of breast cancer, but the mechanisms through which AA promotes mammary tumorigenesis and progression are poorly understood. We found that the levels of AA and cytosolic phospholipase A2 (cPLA2) strongly correlated with the signaling activity of mTORC1 and mTORC2 as well as the expression levels of vascular epithelial growth factor (VEGF) in human breast tumor tissues. In cultured breast cancer cells, AA effectively activated both mTOR complex 1 (mTORC1) and mTORC2. Interestingly, AA-stimulated mTORC1 activation was independent of amino acids, phosphatidylinositol 3-kinase (PI3-K) and tuberous sclerosis complex 2 (TSC2), which suggests a novel mechanism for mTORC1 activation. Further studies revealed that AA stimulated mTORC1 activity through destabilization of mTOR–raptor association in ras homolog enriched in brain (Rheb)-dependent mechanism. Moreover, we showed that AA-stimulated cell proliferation and angiogenesis required mTOR activity and that the effect of AA was mediated by lipoxygenase (LOX) but not cyclooxygenase-2 (COX-2). In animal models, AA-enhanced incidences of rat mammary tumorigenesis, tumor weights and angiogenesis were inhibited by rapamycin. Our findings suggest that AA is an effective intracellular stimulus of mTOR and that AA-activated mTOR plays critical roles in angiogenesis and tumorigenesis of breast cancer.

Leprosy is a chronic infectious and neurological disease that is caused by infection of Mycobacterium leprae ( M. leprae ). A recent genome-wide association study indicated a suggestive association of LRRK2 genetic variant rs1873613 with leprosy in Chinese population. To validate this association and further identify potential causal variants of LRRK2 with leprosy, we genotyped 13 LRRK2 variants in 548 leprosy patients and 1078 healthy individuals from Yunnan Province and (re-)analyzed 3225 Han Chinese across China. Variants rs1427267, rs3761863, rs1873613, rs732374 and rs7298930 were significantly associated with leprosy per se and/or paucibacillary leprosy (PB). Haplotype A-G-A-C-A was significantly associated with leprosy per se ( P =0.018) and PB ( P =0.020). Overexpression of the protective allele (Thr2397) of rs3761863 in HEK293 cells led to a significantly increased nuclear factor of activated T-cells’ activity compared with allele Met2397 after lipopolysaccharides stimulation. Allele Thr2397 could attenuate 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced autophagic activity in U251 cells. These data suggest that the protective effect of LRRK2 variant p.M2397T on leprosy might be mediated by increasing immune response and decreasing neurotoxicity after M. leprae loading. Our findings confirm that LRRK2 is a susceptible gene to leprosy in Han Chinese population.

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The accidental amplification of nuclear mitochondrial pseudogenes (NUMTs) can pose a serious problem for mitochondrial disease studies. This report shows that the mutation spectrum left by spurious amplification of a NUMT can be detected because it usually differs considerably from the authentic natural spectrum. This study examined the problem introduced by an ND5 gene NUMT that was recorded in a proband with hearing loss and reviews other disease studies erroneously reporting NUMT variation as genuine mutations in their patients. NUMTs can emerge in population genetic studies, as exemplified here by cases in this study and from published sources. Appropriate database searches and a phylogenetic approach can prevent hasty claims for novelty of mitochondrial DNA (mtDNA) variants inadvertently derived from NUMTs and help to direct investigators to the real source.

Complement factor H (CFH) is an essential regulator in the homeostasis of the complement system that plays multiple roles in leprosy. We previously reported a preliminary association of CFH with leprosy, but potentially causal variants remain to be identified. In this study, we performed a fine-mapping association analysis in 1110 individuals (527 leprosy patients and 583 controls) followed by bioinformatic analyses. We identified no association of typical missense CFH variants with leprosy and factor H-binding protein was not detected in Mycobacterium leprae . However, robust associations ( P Bonferroni <0.003) of several CFH intronic tag single-nucleotide polymorphisms with leprosy were observed. Expression quantitative trait locus analysis showed that these leprosy-protective alleles were associated with higher CFH level and lower CFHR3 (complement factor H-related 3) level. Our results indicated that CFH variants may contribute to leprosy pathogenesis through altering CFH expression, leading to regulation of complement activity rather than mediating immune evasion by bacteria binding.

Bipolar disorder (BPD), schizophrenia (SCZ) and unipolar major depressive disorder (MDD) are primary psychiatric disorders sharing substantial genetic risk factors. We previously reported that two single-nucleotide polymorphisms (SNPs) rs2709370 and rs6785 in the cAMP responsive element-binding (CREB)-1 gene (CREB1) were associated with the risk of BPD and abnormal hippocampal function in populations of European ancestry. In the present study, we further expanded our analyses of rs2709370 and rs6785 in multiple BPD, SCZ and MDD data sets, including the published Psychiatric Genomics Consortium (PGC) genome-wide association study, the samples used in our previous CREB1 study, and six additional cohorts (three new BPD samples, two new SCZ samples and one new MDD sample). Although the associations of both CREB1 SNPs with each illness were not replicated in the new cohorts (BPD analysis in 871 cases and 1089 controls (rs2709370, P=0.0611; rs6785, P=0.0544); SCZ analysis in 1273 cases and 1072 controls (rs2709370, P=0.230; rs6785, P=0.661); and MDD analysis in 129 cases and 100 controls (rs2709370, P=0.114; rs6785, P=0.188)), an overall meta-analysis of all included samples suggested that both SNPs were significantly associated with increased risk of BPD (11 105 cases and 51 331 controls; rs2709370, P=2.33 × 10−4; rs6785, P=6.33 × 10−5), SCZ (34 913 cases and 44 528 controls; rs2709370, P=3.96 × 10−5; rs6785, P=2.44 × 10−5) and MDD (9369 cases and 9619 controls; rs2709370, P=0.0144; rs6785, P=0.0314), with the same direction of allelic effects across diagnostic categories. We then examined the impact of diagnostic status on CREB1 mRNA expression using data obtained from independent brain tissue samples, and observed that the mRNA expression of CREB1 was significantly downregulated in psychiatric patients compared with healthy controls. The protein–protein interaction analyses showed that the protein encoded by CREB1 directly interacted with several risk genes of psychiatric disorders identified by GWAS. In conclusion, the current study suggests that CREB1 might be a common risk gene for major psychiatric disorders, and further investigations are necessary.

Nanoindentation simulations on a binary metallic glass were performed under various strain rates by using molecular dynamics. The rate-dependent serrated plastic flow was clearly observed, and the spatiotemporal behavior of its underlying irreversible atomic rearrangement was probed. Our findings clearly validate that the serration is a temporally inhomogeneous characteristic of such rearrangements and not directly dependent on the resultant shear-banding spatiality. The unique spatiotemporal distribution of shear banding during nanoindentation is highlighted in terms of the potential energy landscape (PEL) theory.