The spread of culture and language in human populations is explained by two alternative models: the demic diffusion model, which involves mass movement of people; and the cultural diffusion model, which refers to cultural impact between populations and involves limited genetic exchange between them. The mechanism of the peopling of Europe has long been debated, a key issue being whether the diffusion of agriculture and language from the Near East was concomitant with a large movement of farmers. Here we show, by systematically analysing Y-chromosome and mitochondrial DNA variation in Han populations, that the pattern of the southward expansion of Han culture is consistent with the demic diffusion model, and that males played a larger role than females in this expansion. The Han people, who all share the same culture and language, exceed 1.16 billion (2000 census), and are by far the largest ethnic group in the world. The expansion process of Han culture is thus of great interest to researchers in many fields.

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelialto-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting druginduced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.

Cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and selectively affects the expression of genes involved in the DNA damage response (DDR) and mRNA processing. Yet, the mechanisms underlying such selectivity remain unclear. Here we show that CDK12 inhibition in cancer cells lacking CDK12 mutations results in gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlates with an increased number of intronic polyadenylation sites, a feature especially prominent among DDR genes. Phosphoproteomic analysis indicated that CDK12 directly phosphorylates pre-mRNA processing factors, including those regulating PCPA. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition primarily due to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.

Immunotherapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting incompletely understood mechanisms of the immune checkpoint pathways. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interaction with components of endocytosis and nucleocytoplasmic transport pathways, which is regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune response-related genes and consequently enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune response gene expression, thereby advocating for targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.

LncRNA DANCR suppresses differentiation of epithelial cells, however, its function in prostate cancer development is still unknown. In the present study, we found the expression of DANCR increases in prostate cancer tissues and cells compared to normal prostate tissues and cells, moreover, DANCR promotes invasion and migration of prostate cancer cells in vitro and metastasis of tumor xenografts in nude mice. Mechanistically, we found that TIMP2/3, which are critical metastasis inhibitor of prostate cancer, were down-regulated by DANCR synergistically with EZH2 through epigenetically silencing their promoter by chromatin immunoprecipitation assay. In addition, we further investigated whether DANCR is regulated by the differentiation-promoting androgen-androgen receptor (AR) pathway and found that DANCR expression is repressed by androgen-AR; furthermore, DANCR impedes the upregulation of TIMP2/3 and the suppression of invasion and migration by androgen-AR. On the other hand, interestingly, we found that in prostate cancer cells DANCR knockdown decreased the promotion of invasion and migration by the treatment of enzalutamide, which is an AR inhibitor. In summary, our results indicate that DANCR promotes prostate cancer invasion and metastasis through repressing the expression of TIMP2/3, and suggest that DANCR could be a potential target for preventing prostate cancer metastasis, and knockdown DANCR may lessen the potential side effect of AR inhibitor.

Rationale: Pyroptosis is a morphologically and mechanistically distinct form of cell death and is characterized by gasdermin D (GSDMD) or gasdermin E (GSDME)-mediated necrosis with excessive inflammatory factor release. Cardiomyocyte necrosis and inflammation play key roles in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. However, whether cardiomyocytes undergo pyroptosis and the underlying mechanism in myocardial I/R injury remain unclear. Objective: We aimed to investigate the role of pyroptosis in myocardial I/R injury. Methods and Results: In vivo and in vitro experiments were used to investigate pyroptosis of cardiomyocyte and the associated mechanisms during I/R injury. Wild-type (WT), Myh6-Cre and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) male mice were subjected to I/R. Human peripheral blood samples were collected from STEMI (acute ST-segment-elevation myocardial infarction) patients or control patients at 0, 1 and 24 h after PCI (percutaneous coronary intervention) in our department. The serum levels of GSDMD were measured by ELISA. H/R (hypoxia/reoxygenation) induced cardiomyocyte pyroptosis and the release of mature IL-18 but not IL-1β, which mechanistically resulted from GSDMD cleavage by caspase-11 in cardiomyocytes. Furthermore, GSDMD gene deletion blocked H/R-induced cardiomyocyte pyroptosis and IL-18 release. GSDMD and its pyroptosis-inducing N-terminal fragment (GSDMD-N) were upregulated in myocardial tissues after I/R injury. Immunofluorescence analysis showed that GSDMD was mainly localized in cardiomyocytes. GSDMD deficiency in cardiomyocytes significantly reduced the I/R-induced myocardial infarct size. Moreover, increased GSDMD serum levels were detected in patients exhibiting I/R injury 1 h after PCI for STEMI. Conclusions: Our results show that GSDMD-mediated cardiomyocyte pyroptosis is a key event during myocardial I/R injury and that the caspase-11/GSDMD pathway may be essential to this process. Additionally, GSDMD inhibition significantly reduces cardiomyocyte pyroptosis and I/R-induced myocardial injury.

We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).

Hmong-Mien (H-M) is a major language family in East Asia, and its speakers distribute primarily in southern China and Southeast Asia. To date, genetic studies on H-M speaking populations are virtually absent in the literature. In this report, we present the results of an analysis of genetic variations in the mitochondrial DNA (mtDNA) hypervariable segment 1 (HVS1) region and diagnostic variants in the coding regions in 537 individuals sampled from 17 H-M populations across East Asia. The analysis showed that the haplogroups that are predominant in southern East Asia, including B, R9, N9a, and M7, account for 63% (ranging from 45% to 90%) of mtDNAs in H-M populations. Furthermore, analysis of molecular variance (AMOVA), phylogenetic tree analysis, and principal component (PC) analysis demonstrate closer relatedness between H-M and other southern East Asians, suggesting a general southern origin of maternal lineages in the H-M populations. The estimated ages of the mtDNA lineages that are specific to H-M coincide with those based on archeological cultures that have been associated with H-M. Analysis of genetic distance and phylogenetic tree indicated some extent of difference between the Hmong and the Mien populations. Together with the higher frequency of north-dominating lineages observed in the Hmong people, our results indicate that the Hmong populations had experienced more contact with the northern East Asians, a finding consistent with historical evidence. Moreover, our data defined some new (sub-)haplogroups (A6, B4e, B4f, C5, F1a1, F1a1a, and R9c), which will direct further efforts to improve the phylogeny of East Asian mtDNAs.