Cross-species transmission of viruses from wildlife animal reservoirs poses a marked threat to human and animal health . Bats have been recognized as one of the most important reservoirs for emerging viruses and the transmission of a coronavirus that originated in bats to humans via intermediate hosts was responsible for the high-impact emerging zoonosis, severe acute respiratory syndrome (SARS) . Here we provide virological, epidemiological, evolutionary and experimental evidence that a novel HKU2-related bat coronavirus, swine acute diarrhoea syndrome coronavirus (SADS-CoV), is the aetiological agent that was responsible for a large-scale outbreak of fatal disease in pigs in China that has caused the death of 24,693 piglets across four farms. Notably, the outbreak began in Guangdong province in the vicinity of the origin of the SARS pandemic. Furthermore, we identified SADS-related CoVs with 96-98% sequence identity in 9.8% (58 out of 591) of anal swabs collected from bats in Guangdong province during 2013-2016, predominantly in horseshoe bats (Rhinolophus spp.) that are known reservoirs of SARS-related CoVs. We found that there were striking similarities between the SADS and SARS outbreaks in geographical, temporal, ecological and aetiological settings. This study highlights the importance of identifying coronavirus diversity and distribution in bats to mitigate future outbreaks that could threaten livestock, public health and economic growth.

The identification of stem-cell-like cancer cells through conventional methods that depend on stem-cell markers is often unreliable. We developed a mechanical method of selecting tumourigenic cells by culturing single cancer cells in fibrin matrices of ~100 Pa in stiffness. When cultured within these gels, primary human cancer cells or single cancer cells from mouse or human cancer cell lines grew within a few days into individual round colonies that resembled embryonic stem-cell colonies. Subcutaneous or intravenous injection of 10 or 100 fibrin-cultured cells in syngeneic or severe-combined-immunodeficiency mice led to the formation of solid tumours at the site of injection or at the distant lung organ much more efficiently than control cancer cells selected using conventional surface marker methods or cultured on conventional rigid dishes or on soft gels. Remarkably, as few as 10 such cells were able to survive and form tumours in the lungs of wild-type non-syngeneic mice.

Tumour-repopulating cells (TRCs) are a self-renewing, tumorigenic subpopulation of cancer cells critical in cancer progression. However, the underlying mechanisms of how TRCs maintain their self-renewing capability remain elusive. Here we show that relatively undifferentiated melanoma TRCs exhibit plasticity in Cdc42-mediated mechanical stiffening, histone 3 lysine residue 9 (H3K9) methylation, Sox2 expression and self-renewal capability. In contrast to differentiated melanoma cells, TRCs have a low level of H3K9 methylation that is unresponsive to matrix stiffness or applied forces. Silencing H3K9 methyltransferase G9a or SUV39h1 elevates the self-renewal capability of differentiated melanoma cells in a Sox2-dependent manner. Mechanistically, H3K9 methylation at the Sox2 promoter region inhibits Sox2 expression that is essential in maintaining self-renewal and tumorigenicity of TRCs both in vitro and in vivo. Taken together, our data suggest that 3D soft-fibrin-matrix-mediated cell softening, H3K9 demethylation and Sox2 gene expression are essential in regulating TRC self-renewal.

cells of Cajal (ICC) have important functions in regulation of motor activity in the gastrointestinal tract. In murine small intestine, ICC are gathered in the regions of the myenteric plexus (ICC-MY) and the deep muscular plexus (ICC-DMP). These two classes of ICC have different physiological functions. ICC-MY are pacemaker cells and generate the slow-wave electrical rhythmicity of gastrointestinal organs. ICC-DMP form synaptic connections with the varicose nerve terminals of enteric motor neurons and are involved in reception and transduction of motor neurotransmission. Gene expression underlying specific functions of ICC classes is incompletely understood. In the present study, we used recently developed highly selective techniques to isolate the two functional ICC classes from enzymatically dispersed intestinal muscles by fluorescence-activated cell sorting. The transcriptomes of ICC-MY and ICC-DMP were investigated using oligonucleotide microarray analysis. Differential expression of functional groups of genes defined by standard gene ontology terms was also studied. There were substantial numbers of genes expressed more abundantly in ICC than in the tunica muscularis, and we also detected marked phenotypic differences between ICC-MY and ICC-DMP. Notably, genes related to cell junction, process guidance, and vesicle trafficking were upregulated in ICC. Consistent with their specific functions, metabolic and Ca 2ϩ transport genes were relatively upregulated in ICC-MY, whereas genes for signaling proteins involved in transduction of neurotransmitter functions were relatively upregulated in ICC-DMP. Our results may lead to the identification of novel biomarkers for ICC and provide directions for further studies designed to understand ICC function in health and disease.Affymetrix Mouse Genome 430.2 GeneChips; Bioconductor; enteric nervous system; ion channel; signal transduction MOTOR PATTERNS of the gastrointestinal (GI) tract require the coordinated contractions of the smooth muscle cell component of the organs. One level of coordination comes from the fact that the smooth muscle cells are electrically coupled, and their electrical activity is driven by pacemaker cells known as interstitial cells of Cajal (ICC) that lie in the plane of the myenteric plexus between the circular and longitudinal muscle layers (ICC-MY) (16, 58). ICC-MY are electrically coupled to each other via gap junctions and form a network of cells that extends around the circumference and along the length of the small intestine (1, 39, 58). The ICC-MY network is electrically coupled to smooth muscle cells of both layers, providing a low-resistance pathway for the conduction of pacemaker activity to the musculature (9). ICC-MY possess the ionic conductances necessary to initiate electrical slow waves and to propagate these events actively (cf. Ref. 43).A second level of control of GI motor function comes from the intrinsic motor neurons arising from enteric ganglia. Both inhibitory and excitatory motor neurons innervate the muscle layers, an...

TACE-sorafenib side effects were acceptable, and this treatment may improve overall survival in patients with HCC with first-order or lower-branch PVTT when compared with patients who underwent TACE alone.