The deep population history of East Asia remains poorly understood due to a lack of ancient DNA data and sparse sampling of present-day people 1 , 2 . We report genome-wide data from 166 East Asians dating to 6000 BCE – 1000 CE and 46 present-day groups. Hunter-gatherers from Japan, the Amur River Basin, and people of Neolithic and Iron Age Taiwan and the Tibetan plateau are linked by a deeply-splitting lineage likely reflecting a Late Pleistocene coastal migration. We follow Holocene expansions from four regions. First, hunter-gatherers of Mongolia and the Amur River Basin have ancestry shared by Mongolic and Tungusic language speakers but do not carry West Liao River farmer ancestry contradicting theories that their expansion spread these proto-languages. Second, Yellow River Basin farmers at ~3000 BCE likely spread Sino-Tibetan languages as their ancestry dispersed both to Tibet where it forms up ~84% to some groups and to the Central Plain where it contributed ~59–84% to Han Chinese. Third, people from Taiwan ~1300 BCE to 800 CE derived ~75% ancestry from a lineage also common in modern Austronesian, Tai-Kadai and Austroasiatic speakers likely deriving from Yangtze River Valley farmers; ancient Taiwan people also derived ~25% ancestry from a northern lineage related to but different from Yellow River farmers implying an additional north-to-south expansion. Fourth, Yamnaya Steppe pastoralist ancestry arrived in western Mongolia after ~3000 BCE but was displaced by previously established lineages even while it persisted in western China as expected if it spread the ancestor of Tocharian Indo-European languages. Two later gene flows affected western Mongolia: after ~2000 BCE migrants with Yamnaya and European farmer ancestry, and episodic impacts of later groups with ancestry from Turan.

The deep population history of East Asia remains poorly understood due to a lack of ancient DNA data and sparse sampling of present-day people. We report genome-wide data from 191 individuals from Mongolia, northern China, Taiwan, the Amur River Basin and Japan dating to 6000 BCE – 1000 CE, many from contexts never previously analyzed with ancient DNA. We also report 383 present-day individuals from 46 groups mostly from the Tibetan Plateau and southern China. We document how 6000-3600 BCE people of Mongolia and the Amur River Basin were from populations that expanded over Northeast Asia, likely dispersing the ancestors of Mongolic and Tungusic languages. In a time transect of 89 Mongolians, we reveal how Yamnaya steppe pastoralist spread from the west by 3300-2900 BCE in association with the Afanasievo culture, although we also document a boy buried in an Afanasievo barrow with ancestry entirely from local Mongolian hunter-gatherers, representing a unique case of someone of entirely non-Yamnaya ancestry interred in this way. The second spread of Yamnaya-derived ancestry came via groups that harbored about a third of their ancestry from European farmers, which nearly completely displaced unmixed Yamnaya-related lineages in Mongolia in the second millennium BCE, but did not replace Afanasievo lineages in western China where Afanasievo ancestry persisted, plausibly acting as the source of the early-splitting Tocharian branch of Indo-European languages. Analyzing 20 Yellow River Basin farmers dating to ∼3000 BCE, we document a population that was a plausible vector for the spread of Sino-Tibetan languages both to the Tibetan Plateau and to the central plain where they mixed with southern agriculturalists to form the ancestors of Han Chinese. We show that the individuals in a time transect of 52 ancient Taiwan individuals spanning at least 1400 BCE to 600 CE were consistent with being nearly direct descendants of Yangtze Valley first farmers who likely spread Austronesian, Tai-Kadai and Austroasiatic languages across Southeast and South Asia and mixing with the people they encountered, contributing to a four-fold reduction of genetic differentiation during the emergence of complex societies. We finally report data from Jomon hunter-gatherers from Japan who harbored one of the earliest splitting branches of East Eurasian variation, and show an affinity among Jomon, Amur River Basin, ancient Taiwan, and Austronesian-speakers, as expected for ancestry if they all had contributions from a Late Pleistocene coastal route migration to East Asia.

Graphene oxide (GO), owing to its large surface area and abundance of oxygen-containing functional groups, is emerging as a potential adsorbent for polychlorinated biphenyls (PCBs), which accumulate over time and are harmful to both natural ecosystems and human health. However, the effect of GO against PCB-induced toxicity remains largely unexplored. The present study aimed to investigate the protective effect of GO against PCB 52 induced cytotoxic and genotoxic response in mammalian cells at various exposure conditions and clarify the protective role of autophagy. Pretreatment with GO dramatically decreased PCB 52 induced cytotoxicity and CD59 gene mutation in human-hamster hybrid (AL) cells. The toxic response in cells either pretreated with PCB 52 and then treated with GO or concurrently treated with GO and PCB 52 did not differ significantly from the toxic response in the cells treated with PCB 52 alone. Using autophagy inhibitors (3-methyladenine and wortmannin) and inducers (trehalose and rapamycin), we found that genuine autophagy induced by GO was involved in decreasing PCB 52 induced toxicity. These findings suggested that GO has an antagonistic effect against the toxicity of PCB 52 mainly by triggering a genuine autophagic process, which might provide new insights into the potential application of GO in PCB disposal and environmental and health risk assessment.

Vasohibin-1 is an intrinsic angiogenesis inhibitor, and is expressed in endothelial cells via induction by pro-angiogenesis factors. It is known to inhibit several processes of angiogenesis, with different mechanisms from extrinsic angiogenesis inhibitors. Vasohibin-2 is mainly expressed by mononuclear cells which have been mobilized from bone marrow. It not only promotes angiogenesis, but also modulates the releases of FGF-2 and VEGF, which are the two major inducers for vasohibin1. Hypoxic environment induces the expression of hypoxia-inducible Factor 1α with a result of VEGF release nearly in all tumor cell lines and tissues. However, it has been observed that hypoxia reduces the inducible effects of VEGF on vasohibin, which indicates that a complicated mechanism exists in the angiogenesis. Vasohibin and its family members play important roles in both the physiological and pathological procedures, in contrary but complementary patterns. Furthermore, human aortic smooth muscle cells and fibroblast have also been detected to express vasohibin on a moderate to weak scale range. Recently, the results of an increasing number of studies in vivo have shown that vasohibin can also be detected in several cancers, and is associated with micro-vessel densities, histology grades, invasions, poor clinical features, metastasis, and dissemination in abdominal cavities, as well as EMT. In more recent reports, it has been confirmed that, along with being angiogenesis regulators, a variety of other roles have been associated with this family. The focus of this study was the upstream regulatory mechanisms of vasohibin expressions, and their role in regard to the downstream target proteins of vasohibin, especially in carcinoma. Vasohibin is considered to be an original angiogenesis inhibitor, and has a much broader significance in pathological processes. It can be taken as an independent prognostic factor, as well as a potential strategy for cancer therapy programs.

Spexin/NPQ is a novel highly conserved neuropeptide. It has a widespread expression in the periphery and central nervous system. However, the effects of central spexin on acute inflammatory pain are still unknown. This study explored the mechanisms and effects of supraspinal spexin on inflammatory pain. The results from the mouse formalin test show that i.c.v. administration of spexin decreased licking/ biting time during the late and early phases. The nonamidated spexin had no effect on pain response. The antinociception of spexin was blocked by galanin receptor 3 antagonist SNAP 37889. The Galr3 and Adcy4 mRNA levels in the brain were increased after injection with spexin. The antinociceptive effects of spexin were completely reversed by opioid receptor antagonist naloxone and k-opioid receptor antagonist nor-binaltorphimine dihydrochloride. Spexin up-regulated the dynorphin and k-opioid receptor gene and protein expression. PCR array assay and real-time PCR analysis show that spexin up-regulated the mRNA level of the FBJ osteosarcoma oncogene (Fos). T-5224, the inhibitor of c FBJ osteosarcoma oncogene (c-Fos)/activator protein 1 (AP-1), blocked the increased mRNA level of Pdyn and Oprk1 induced by spexin. I.C.V. spexin (2.43 mg/kg) increased the number of c-Fosepositive neurons in most subsections of periaqueductal gray. In addition, in the acetic acideinduced writhing test, i.c.v. spexin produced an antinociceptive effect. Our results indicate that spexin might be a novel neuropeptide with an antinociceptive effect against acute inflammatory pain. (Am J Pathol 2019, 189: 886e899; https://doi.org/10. 1016/j.ajpath.2018.12.009) Recently, some physiological functions of spexin have been found, such as appetite, bowel movement, energy metabolism, cardiovascular function, and hyperoxia. Spexin

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Lung cancer is the leading cause of cancer-related death worldwide. The underlying molecular mechanisms that trigger this disease remain largely unknown. The I-BAR family is involved in regulating cell membrane formation and some members, such as BAIAP2L1, IRSp53 and MIM have been shown to participate in tumorigenic progression. However, the role of BAI1-associated protein 2-like 2 (BAIAP2L2) in cancer development is unclear. In the present study, we determined that BAIAP2L2 was upregulated in lung adenocarcinoma tissues and various lung cancer cell lines. In vitro, BAIAP2L2 silencing resulted in decreased viability and colony formation capacity of both A549 and H1299 cells. By contrast, BAIAP2L2 overexpression promoted the proliferation and growth of 95D cells. These results indicated that BAIAP2L2 was essential for lung cancer cell proliferation and growth. We also found that BAIAP2L2 knockdown increased the apoptosis of A549 and H1299 cells. At the molecular level, BAIAP2L2 knockdown led to dysregulation of numerous genes, among which the Estrogen-mediated S-phase Entry pathway was significantly suppressed. Collectively, our findings revealed BAIAP2L2 as a novel biomarker and potential therapeutic target for lung cancer.

Endosulfan as a new member of persistent organic pollutants has been shown to induce reproductive dysfunction in various animal models. However, the action mechanism of endosulfan-produced reproductive toxicity remains largely unknown. This study was focused on investigating the reproductive toxicity induced by α-endosulfan and clarifying the role of mitochondria and genotoxic response genes in germ cell apoptosis of Caenorhabditis elegans. Our data showed that endosulfan induced a dose-dependent decrease of life span, fecundity, and hatchability, whereas the germ cell apoptosis was dose-dependently increased. The mitochondria membrane potential was disrupted by endosulfan, leading to a significant increase of germ cell apoptosis in mev-1(kn-1) mutant. However, the apoptotic effects of endosulfan were blocked in mutants of cep-1(w40), egl-1(n487), and hus-1(op241), indicating conserved genotoxic response genes played an essential role in endosulfan-induced germ cell apoptosis. Furthermore, exposure to endosulfan induced the accumulation of HUS-1::GFP foci and the germ cell cycle arrest. These findings provided clear evidence that endosulfan caused significant adverse effects on the reproduction system of C. elegans and increased germ cell apoptosis, which was regulated by mitochondrial dysfunction and DNA damage response genes. This study may help to understand the signal transduction pathways involved in endosulfan-induced reproductive toxicity.