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Lipid droplets (LDs), the highly dynamic intracellular organelles, are critical for lipid metabolism. Dynamic alterations in the configurations and functions of LDs during innate immune responses to bacterial infections and the underlying mechanisms, however, remain largely unknown. In this study, we trace the time-course morphology of LDs in fat bodies of Drosophila after transient bacterial infection. Detailed analysis shows that perilipin1 (plin1), a core gene involved in the regulation of LDs, is suppressed by the immune deficiency signaling, one major innate immune pathway in Drosophila. During immune activation, downregulated plin1 promotes the enlargement of LDs, which in turn alleviates immune reaction–associated reactive oxygen species stress. Thus, the growth of LDs is likely an active adaptation to maintain redox homeostasis in response to immune deficiency activation. Therefore, our study provides evidence that plin1 serves as a modulator on LDs’ reconfiguration in regulating infection-induced pathogenesis, and plin1 might be a potential therapeutic target for coordinating inflammation resolution and lipid metabolism.

Preeclampsia (PE) is one type of hypertension during pregnancy that seriously threatens maternal and infant health. Trophoblast dysfunction, such as decreased proliferation and migration, is closely related to the occurrence and development of PE. MicroRNAs (miRNAs) have been proven to play an important role in many diseases, including PE. miR-384 was reported to play a regulatory role in promoting cell apoptosis and inhibiting proliferation, migration and invasion in a variety of tumors. Previously, we found that miR-384 is upregulated in the placenta and plasma in the context of PE. In this study, we elucidated the function of miR-384 in the trophoblast cell line HTR-8/SVneo and the trophoblastic tumor cell line JEG-3. Cell proliferation and migration were inhibited by miR-384 overexpression but promoted by miR-384 downregulation. Subsequently, polypyrimidine tract-binding protein 3(PTBP3) was found to be a direct target gene of miR-384. PTBP3 was downregulated in placental tissues from PE patients, and a negative correlation was found between PTBP3 and miR-384. Our results suggest that the miR-384/PTBP3 axis plays an important role in regulating trophoblast function during the progression of PE, and these data provide novel insight into the molecular pathogenesis of this disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that causes a range of social communication and behavioral impairments. ASD typically manifests in young children, often with developmental delay or intellectual disabilities (DD/ID) as comorbidities. Accruing evidence indicates that ASD is highly heritable and genomewide studies on ASD cohorts have defined numerous genetic contributors. Notably, most of these studies have been performed with individuals of European and Hispanic ancestry and thus there is a paucity of genetic analyses of ASD in the East Asian population. Here, we performed whole-exome sequencing on 772 ASD trios from China, combining with a previous study of 369 Chinese ASD trios, to identify de novo variants in a total of 1141 ASD trios. We found that ASD probands without DD/ID carried less disruptive de novo variants, including protein-truncating and missense variants, than ASD with DD/ID. Surprisingly, we showed that expression of genes with de novo variants found in ASD probands without DD/ID were enriched in a specific group of neural progenitor cells, suggesting a potential mechanism underlying high-functioning autism. Importantly, some ASD risk genes from this study are not present in the current ASD gene database, suggesting that there are novel genetic contributors to ASD in East Asian populations. We validated one such novel ASD risk gene – SLC35G1 by showing that mice harboring heterozygous deletion of Slc35g1 exhibited defects in social interaction behaviors. Together, this work nominates novel ASD risk genes and indicates that ASD genetic studies in different geographic populations are essential to reveal the comprehensive genetic architecture of ASD.

In higher plants, the light-harvesting chlorophyll a/b-binding (Lhc) proteins function in multiple processes that are critical to plant growth, development, and abiotic stress response. However, the Lhc gene family has not been well characterized in the important fruit crop, apple (Malus × domestica Borkh.). In this study, we identified 27 Lhc genes in the apple genome. Phylogenetic analysis showed that the Lhc gene family could be classified into three major subfamilies, each of whose members shared similar conserved motifs. Evolutionary analysis indicated that duplicated MdLhc genes were primarily under purifying selection. MdLhcs were expressed at varying levels in all tissues examined and showed different expression patterns under drought stress. The overexpression of MdLhcb4.3 in transgenic Arabidopsis and apple callus enhanced their tolerance to drought and osmotic stress. Taken together, these results demonstrate the important role of Lhc proteins in the regulation of plant resistance to drought and osmotic stress and provide valuable information for further study of Lhc functions in apple.

Due to the high mutation and recombination rates of the influenza virus, current clinically licensed influenza vaccines and anti-influenza drugs provide limited protection against the emerging influenza virus epidemic. Therefore, universal influenza vaccines with high efficacy are urgently needed to ensure human safety and health. Passive immunization of influenza broadly neutralizing antibodies may become an ideal option for controlling influenza infection. CR9114 isolated from the peripheral blood mononuclear cells of healthy donors is a broadly neutralizing monoclonal antibody that targets different types of influenza viruses. As the adenovirus vector is one of the most promising delivery vehicles, we employed the chimpanzee adenoviral vector, AdC68, to express CR9114 as a universal anti-influenza vaccine, termed AdC68-CR9114, and evaluated its antibody expression and its broad spectrum of prophylactic and therapeutic effects in animal models. Based on our findings, AdC68-CR9114-infected cell expressed the broadly neutralizing antibody at a high level in vitro and in vivo, exhibited biological functions, and protected mice from different types of influenza virus infection at different time points. The findings from this study shed light on a new strategy for controlling and preventing influenza infection.

Chimeric Antigen Receptor (CAR)-T cells have great efficacy against CD19+ leukemia but little success for solid tumors. This study explored the effectiveness of third generation anti-HER2 CAR-T cells alone or in combination with anti-PD1 antibody on breast tumor cells expressing HER2 in vitro and in immune competent mouse model. The PDL1-positive mouse mammary tumor cell line 4T1 engineered to express luciferase and human HER2 was used as the target cell line (4T1-Luc-HER2). Anti-HER2 CAR-T cells were generated by transducing mouse spleen T cells with recombinant lentiviruses. ELISA analysis showed that IL-2 and IFN-γ secretion was increased in CAR-T cells co-cultured with the target cells, and the secretion of these two cytokines was increased further with the addition of anti-PD1 antibody. Lactate dehydrogenase assay revealed that CAR-T cells displayed a potent cytotoxicity against the target cells, and the addition of anti-PD1 antibody further enhanced the cytotoxicity. At the effector: target ratio of 16:1, cytotoxicity was 39.8% with CAR-T cells alone, and increased to 49.5% with the addition of anti-PD1 antibody. In immune competent syngeneic mouse model, CAR-T cells were found to be present in tumor stroma, inhibited tumor growth and increased tumor apoptosis significantly. Addition of anti-PD1 antibody further enhanced these anti-tumor activities. Twenty-one days after treatment, tumor weight was reduced by 50.0% and 73.3% in CAR-T group and CAR-T plus anti-PD1 group compared with blank T group. Our results indicate that anti-PD1 antibody can greatly increase the efficacy of anti-HER2 CAR-T against HER2-positive solid tumors.

Rabies continues to poses serious threats to the public health in many countries. The development of novel inexpensive, safe and effective vaccines has become a high priority for rabies control worldwide. We previously generated a novel recombinant rabies vaccine by cloning rabies virus glycoprotein into a chimpanzee adenoviral vector, termed ChAd68-Gp. The present study evaluated the immune responses and protection afforded by this vaccine in beagle dogs. The results demonstrated that intramuscular immunization with both low-dose and high-dose of ChAd68-Gp induced strong immune responses and provided complete protection in beagles even at low-dose. However, when administered orally, high-dose vaccination was protective while low-dose vaccination was ineffective. Further investigation indicated that the low-pH value of gastric juice in the stomach of beagles might decompose the adenovirus. Therefore, suitable formulation for adenovirus-based oral vaccine should be considered and developed. The chimpanzee adenovirus-vectored rabies vaccine ChAd68-Gp warrants extensive test for clinical application.

Gastric cancer is a malignant disease of the digestive system with high rates of incidence and mortality. S‑phase kinase‑associated protein 2 (Skp2) is a novel oncogene, which has been identified to be important in tumor progression and metastasis. In order to clarify the role of Skp2 in human gastric cancer, the present study detected the expression of Skp2 in human gastric cancer tissues, and investigated the molecular mechanism of Skp2 in the progression of gastric carcinoma. The results of the initial bioinformatics analysis showed that Skp2 was significantly upregulated in 31 specimens of primary gastric cancer from a UK patient cohort, and in 10 gastric cancer lines of a side population, compared with normal gastric tissues (P

Effects of the Epstein-Barr virus (EBV) on cellular protein expression are essential for viral pathogenesis. To characterize the cellular response to EBV infection, differential proteomes of gastric epithelial AGS cells were analyzed with two-dimensional gel electrophoresis (2-DE) followed by matrix-assisted laser desorption/ionization- time of flight (MALDI-TOF) and liquid chromatography electrospray/ionization ion trap (LC-ESI-IT) mass spectrometry identification. Mass spectrometry identified 9 altered cellular proteins, including 5 up-regulated and 4 down-regulated proteins after EBV infection. Notably 2-DE analysis revealed that EBV infection induced increased expression of heat shock cognate 71 kDa protein, actin cytoplasmic 1, pyridoxine-5'-phosphate oxidase, caspase 9, and t-complex protein 1 subunit alpha. In addition, EBV infection considerably suppressed those cellular proteins of zinc finger protein 2, cyclin-dependent kinase 2, macrophage-capping protein, and growth/ differentiation factor 11. Furthermore, the differential expressional levels of partial proteins (cyclin-dependent kinase 2 and caspase 9) were confirmed by Western blot analysis.Thus, this work effectively provided useful protein-related information to facilitate further investigation of the mechanisms underlying EBV infection and pathogenesis.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRs) are single-stranded, noncoding RNAs that are important in many biological processes. Although the oncogenic and tumor-suppressive functions of several miRs have been characterized, their precise biological roles remain largely unexplored. In the present study, the role of miR-133b was identified in the regulation of CRC cell proliferation and apoptosis. miR-133b expression was shown to be greatly downregulated in human CRC cells compared to normal colon cells. Downregulation of miR-133b expression was also significant in six of eight human CRC tissues compared with adjacent normal tissues. In the CRC cell lines SW-620 and HT-29, ectopic expression of miR-133b potently affected tumor cell proliferation and apoptosis in vitro and in vivo by direct targeting of the receptor tyrosine kinase MET. Transfection of SW-620 and HT-29 cells with miR-133b significantly suppressed a luciferase-reporter containing the MET-3'-untranslated region. Taken together, these results provide evidence that miR-133b regulated tumor cell proliferation and apoptosis through modulation of the MET signaling pathway.

Background Mitochondrial defects have been associated with various human conditions including cancers. Methods We analyzed the mutations at the mitochondrial DNA (mtDNA) in patients with different thyroid lesions. In particular, in order to investigate if the accumulation of mtDNA mutations play a role in tumor progression, we studied the highly variable main control region of mtDNA, the displacement-loop (D-loop) in patients with non-tumor nodular goiters, with benign thyroid adenomas, and with malignant thyroid carcinomas. Total thyroid tumor or goiter samples were obtained from 101 patients, matched with nearby normal tissue and blood from the same subject. Results Noticeably, mitochondrial microsatellite instability (mtMSI) was detected in 2 of 19 nodular goiters (10.53%), and 8 of 77 (10.39%) malignant thyroid carcinomas. In addition, 6 patients, including 5 (6.49%) with malignant thyroid carcinomas and 1 (5.26%) with nodular goiter, were found to harbor point mutations. The majority of the mutations detected were heteroplasmic. General significance Our results indicate that mtDNA alterations in the D-loop region could happen before tumorigenesis in thyroid, and they might also accumulate during tumorigenesis.