Large deep neural networks are powerful, but exhibit undesirable behaviors such as memorization and sensitivity to adversarial examples. In this work, we propose mixup, a simple learning principle to alleviate these issues. In essence, mixup trains a neural network on convex combinations of pairs of examples and their labels. By doing so, mixup regularizes the neural network to favor simple linear behavior in-between training examples. Our experiments on the ImageNet-2012, CIFAR-10, CIFAR-100, Google commands and UCI datasets show that mixup improves the generalization of state-of-the-art neural network architectures. We also find that mixup reduces the memorization of corrupt labels, increases the robustness to adversarial examples, and stabilizes the training of generative adversarial networks. * Alphabetical order.

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Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through αB-crystallin (CRYAB), which is known to suppress neuroinflammation. We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wild-type mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease.

p53, circRNAs and miRNAs are important components of the regulatory network that activates the EMT program in cancer metastasis. In prostate cancer (PCa), however, it has not been investigated whether and how p53 regulates EMT by circRNAs and miRNAs. Here we show that a Amotl1-derived circRNA, termed circAMOTL1L, is downregulated in human PCa, and that decreased circAMOTL1L facilitates PCa cell migration and invasion through downregulating E-cadherin and upregulating vimentin, thus leading to EMT and PCa progression. Mechanistically, we demonstrate that circAMOTL1L serves as a sponge for binding miR-193a-5p in PCa cells, relieving miR-193a-5p repression of Pcdha gene cluster (a subset of the cadherin superfamily members). Accordingly, dysregulation of the circAMOTL1L-miR-193a-5p-Pcdha8 regulatory pathway mediated by circAMOTL1L downregulation contributes to PCa growth in vivo. Further, we show that RBM25 binds directly to circAMOTL1L and induces its biogenesis, whereas p53 regulates EMT via direct activation of RBM25 gene. These findings have linked p53/RBM25-mediated circAMOTL1L-miR-193a-5p-Pcdha regulatory axis to EMT in metastatic progression of PCa. Targeting this newly identified regulatory axis provides a potential therapeutic strategy for aggressive PCa.

The vascular response to pro-atherosclerotic factors is a multifactorial process involving endothelial cells (ECs), macrophages (MACs), and smooth muscle cells (SMCs), although the mechanism by which these cell types communicate with each other in response to environmental cues is yet to be understood. Here, we show that miR-155, which is significantly expressed and secreted in Krüppel-like factor 5 (KLF5)-overexpressing vascular smooth muscle cells (VSMCs), is a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. VSMCs-derived exosomes mediate the transfer of KLF5-induced miR-155 from SMCs to ECs, which, in turn, destroys tight junctions and the integrity of endothelial barriers, leading to an increased endothelial permeability and enhanced atherosclerotic progression. Moreover, overexpression of miR-155 in ECs inhibits endothelial cell proliferation/migration and re-endothelialization in vitro and in vivo and thus increases vascular endothelial permeability. Blockage of the exosome-mediated transfer of miR-155 between these two cells may serve as a therapeutic target for atherosclerosis.

IntroductionAcute myeloid leukemia (AML) is a heterogeneous group of blood cancers characterized by increased, uncontrolled proliferation of hematopoietic progenitors, and a blockage in myeloid differentiation is the major characteristic of AML. 1 According to the French-American-British classification system, AMLs involving the monocytic and granulocytic lineage account for 85% (M1 to M5 subtypes) of adult patients. 2 Under normal conditions, monocytes and granulocytes develop from long-term hematopoietic stem cells (LT-HSCs) in BM under the influence of a complex network of cytokins such as G-CSF, GM-CSF, and M-CSF, and transcription factors such as PU.1, C/EBP, IFN consensus sequence binding protein/IFN regulatory factor 8, Krüppel-like factor 4, c-Maf, and C/EBP⑀. [3][4][5][6] MicroRNAs (miRNAs) that negatively regulate gene expression at posttranscriptional level 7 have also been identified as crucial regulators in normal and malignant myeloid differentiation. Expression and function analyses have unraveled their important regulatory roles during hematopoiesis. 8 In a previous study, we demonstrated a significantly decreased expression of miR-29a and 142-3p in the peripheral blood mononuclear cells (PBMNCs) from AML patients (French-AmericanBritish M1 to M5 subtypes). 9 These 2 miRNAs were also reported to be down-regulated in a variety of tumors and to act as tumor suppressors. [10][11][12] The miR-29a cluster is one of the most studied miRNA clusters. Down-regulation of miR-29a was observed in AML samples with deletions of 7q (del7q). 10 Several genes have been reported to be silenced by miR-29, most of which are potential oncogenes, such as SKI, Tcl1, the p53 upstream inhibitors p85a and CDC42, and the Bcl2 family members Bcl2 and Mcl1. 11 Meanwhile, miR-142-3p, first identified as being uniquely expressed in hematopoietic system, is aberrantly expressed in T-cell and B-cell leukemia. 12 In addition, increased miR-142-3p expression has been observed at different stages of normal granulocytopoiesis. 13 Validated targets of miR-142-3p include ADCY9, 14 CD133, 16 and the RAC1. 17 In this study, we sought to investigate role of these 2 miRNAs in monocytic and granulocytic differentiation (also called myeloid differentiation), and to test whether their down-regulation is related to the differentiation block in AML blasts. Using the leukemia cell lines, NB4, HL-60, and THP-1 18-23 we observed up-regulation of miR-29a and miR-142-3p expression during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation and phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation, and examined effects of overexpression or knockdown of each miRNA on myeloid differentiations. Moreover, we identified targets of both miRNAs and examined direct effect of the target genes on myeloid differentiation. Similar results were also obtained in myeloid induction cultures of CD34 ϩ hematopoietic stem/ progenitor cells (HSPCs) derived from normal human umbilical cord blood (UCB) and BM from healthy donors and AML p...

In order to further promote the standardization of diagnosis and treatment of gastrointestinal stromal tumor (GIST) in China, the members of Chinese Society of Clinical Oncology (CSCO) Expert Committee on GIST thoroughly discussed the key contents of the consensus guidelines, and voted on the controversial issue. In final, the Chinese consensus guidelines for the diagnosis and management of GIST (2017 edition) was formed on the basis of 2013 edition consensus guidelines, which is hereby announced. The consensus included the pathological diagnosis, recurrence risk classification evaluation, targeted agent therapy, surgery and principles of surveillance of GIST.