LrrA, a novel leucine-rich repeat protein involved in cytoskeleton remodeling, is required for multicellular morphogenesis in Dictyostelium discoideum

AbstractCell sorting by differential cell adhesion and movement is a fundamental process in multicellular morphogenesis. We have identified a Dictyostelium discoideum gene encoding a novel protein, LrrA, which composes almost entirely leucine-rich repeats (LRRs) including a putative leucine zipper motif. Transcription of lrrA appeared to be developmentally regulated with robust expression during vegetative growth and early development. lrrA null cells generated by homologous recombination aggregated to form loose mounds, but subsequent morphogenesis was blocked without formation of the apical tip. The cells adhered poorly to a substratum and did not form tight cell–cell agglomerates in suspension; in addition, they were unable to polarize and exhibit chemotactic movement in the submerged aggregation and Dunn chamber chemotaxis assays. Fluorescence-conjugated phalloidin staining revealed that both vegetative and aggregation competent lrrA− cells contained numerous F-actin-enriched microspikes around the periphery of cells. Quantitative analysis of the fluorescence-stained F-actin showed that lrrA− cells exhibited a dramatically increase in F-actin as compared to the wild-type cells. When developed together with wild-type cells, lrrA− cells were unable to move to the apical tip and sorted preferentially to the rear and lower cup regions. These results indicate that LrrA involves in cytoskeleton remodeling, which is needed for normal chemotactic aggregation and efficient cell sorting during multicellular morphogenesis, particularly in the formation of apical tip

An emerging research: the role of hepatocellular carcinoma-derived exosomal circRNAs in the immune microenvironment

Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is one of the leading causes of cancer-related death and is associated with a poor prognosis. The tumor microenvironment (TME) of HCC comprises immune, immunosuppressive, and interstitial cells with hypoxic, angiogenic, metabolic reprogramming, inflammatory, and immunosuppressive features. Exosomes are nanoscale extracellular vesicles that secrete biologically active signaling molecules such as deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microribonucleic acid (miRNA), proteins, and lipids. These signaling molecules act as messengers in the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Exosomal circRNAs reshape the tumor microenvironment by prompting hypoxic stress response, stimulating angiogenesis, contributing to metabolic reprogramming, facilitating inflammatory changes in the HCC cells and inducing tumor immunosuppression. The exosomes secreted by HCC cells carry circRNA into immune cells, which intervene in the activation of immune cells and promote the overexpression of immune checkpoints to regulate immune response, leading tumor cells to acquire immunosuppressive properties. Furthermore, immunosuppression is the final result of a combination of TME-related factors, including hypoxia, angiogenesis, metabolic reprogramming, and inflammation changes. In conclusion, exosomal circRNA accelerates the tumor progression by adjusting the phenotype of the tumor microenvironment and ultimately forming an immunosuppressive microenvironment. HCC-derived exosomal circRNA can affect HCC cell proliferation, invasion, metastasis, and induction of chemoresistance. Therefore, this review aimed to summarize the composition and function of these exosomes, the role that HCC-derived exosomal circRNAs play in microenvironment formation, and the interactions between exosomes and immune cells. This review outlines the role of exosomal circRNAs in the malignant phenotype of HCC and provides a preliminary exploration of the clinical utility of exosomal circRNAs

Multi-task Neural Network for Non-discrete Attribute Prediction in Knowledge Graphs

Many popular knowledge graphs such as Freebase, YAGO or DBPedia maintain a list of non-discrete attributes for each entity. Intuitively, these attributes such as height, price or population count are able to richly characterize entities in knowledge graphs. This additional source of information may help to alleviate the inherent sparsity and incompleteness problem that are prevalent in knowledge graphs. Unfortunately, many state-of-the-art relational learning models ignore this information due to the challenging nature of dealing with non-discrete data types in the inherently binary-natured knowledge graphs. In this paper, we propose a novel multi-task neural network approach for both encoding and prediction of non-discrete attribute information in a relational setting. Specifically, we train a neural network for triplet prediction along with a separate network for attribute value regression. Via multi-task learning, we are able to learn representations of entities, relations and attributes that encode information about both tasks. Moreover, such attributes are not only central to many predictive tasks as an information source but also as a prediction target. Therefore, models that are able to encode, incorporate and predict such information in a relational learning context are highly attractive as well. We show that our approach outperforms many state-of-the-art methods for the tasks of relational triplet classification and attribute value prediction.Comment: Accepted at CIKM 201

Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease

Hirschsprung disease (HSCR) is a common developmental disorder of the enteric nervous system (ENS). However, the disease mechanisms have not been fully elucidated. To better understand the etiology of HSCR, the role and mechanism of HSCR associated PTPRR (protein tyrosine phosphatase receptor-type R) in the multipotency of ENS progenitors and ENS development were explored. In the present study, the downregulated PTPRR expression in HSCR was reflected by microarray and validated by real-time PCR analyses. Moreover, PTPRR protein was mainly expressed in the cytoplasmic area of primary cultured ENS progenitors (Enteric neural crest cells, ENCCs) and significantly decreased after differentiation induction, which implies the anti-differentiation role in ENCCs. Further study employed an adenovirus transfection system. After genetic modulation, the ENCCs maintained undifferentiated patterns even in GDNF (Glial cell-line derived neurotrophic factor)-mediated directional differentiation, as well as significantly increased EdU positive immunofluorescence in the PTPRR overexpressing group while the development of the ENS was stunted in the PTPRR knockdown fetal gut. Moreover, the expression of ERK1/2 activated by GDNF was significantly decreased as reflected by western-blot or immunofluorescence analyses after genetic modulation in the PTPRR overexpressing group, which suggests the potential mechanism in regulating the MAPK/ERK1/2 pathway. Taken together, These data support the idea that PTPRR may ensure a certain number of neural precursor cells by inhibiting ENCC overt differentiation and maintaining ENCC proliferation, which is considered to be the multipotency of ENCCs, and eventually participate in the development of the ENS, and establish PTPRR protein as negative regulator of MAPK/ERK1/2 signaling cascades in neuronal differentiation and demonstrate their involvement in the pathophysiology of HSCR

Inhibition of yes-associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model.

Yes-associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030-BrM3(K-rasG12C mutation) and PC9-BrM3 (EGFRΔexon19 mutation) had a significantly decreased p-YAP(S127)/YAP ratio compared to parental H2030 (K-rasG12C mutation) and PC9 (EGFRΔexon19 mutation) cells (P < .05). H2030-BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P < .05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030-BrM3 cells (P < .05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030-BrM3 cells (P < .05). We are first to show that mice inoculated with YAP shRNA-transfected H2030-BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P < .05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030-BrM3 cell brain metastasis in a murine model

Proteomic identification of OsCYP2, a rice cyclophilin that confers salt tolerance in rice (Oryza sativa L.) seedlings when overexpressed

<p>Abstract</p> <p>Background</p> <p>High Salinity is a major environmental stress influencing growth and development of rice. Comparative proteomic analysis of hybrid rice shoot proteins from Shanyou 10 seedlings, a salt-tolerant hybrid variety, and Liangyoupeijiu seedlings, a salt-sensitive hybrid variety, was performed to identify new components involved in salt-stress signaling.</p> <p>Results</p> <p>Phenotypic analysis of one protein that was upregulated during salt-induced stress, cyclophilin 2 (OsCYP2), indicated that <it>OsCYP2 </it>transgenic rice seedlings had better tolerance to salt stress than did wild-type seedlings. Interestingly, wild-type seedlings exhibited a marked reduction in maximal photochemical efficiency under salt stress, whereas no such change was observed for <it>OsCYP2</it>-transgenic seedlings. <it>OsCYP2</it>-transgenic seedlings had lower levels of lipid peroxidation products and higher activities of antioxidant enzymes than wild-type seedlings. Spatiotemporal expression analysis of <it>OsCYP2 </it>showed that it could be induced by salt stress in both Shanyou 10 and Liangyoupeijiu seedlings, but Shanyou 10 seedlings showed higher <it>OsCYP2 </it>expression levels. Moreover, circadian rhythm expression of <it>OsCYP2 </it>in Shanyou 10 seedlings occurred earlier than in Liangyoupeijiu seedlings. Treatment with PEG, heat, or ABA induced <it>OsCYP2 </it>expression in Shanyou 10 seedlings but inhibited its expression in Liangyoupeijiu seedlings. Cold stress inhibited <it>OsCYP2 </it>expression in Shanyou 10 and Liangyoupeijiu seedlings. In addition, OsCYP2 was strongly expressed in shoots but rarely in roots in two rice hybrid varieties.</p> <p>Conclusions</p> <p>Together, these data suggest that OsCYP2 may act as a key regulator that controls ROS level by modulating activities of antioxidant enzymes at translation level. OsCYP2 expression is not only induced by salt stress, but also regulated by circadian rhythm. Moreover, OsCYP2 is also likely to act as a key component that is involved in signal pathways of other types of stresses-PEG, heat, cold, or ABA.</p

REG1A and RUNX3 Are Potential Biomarkers for Predicting the Risk of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Clinical features are traditionally used to predict DKD, yet with low diagnostic efficacy. Most of the recent biomarkers used to predict DKD are based on transcriptomics and metabolomics; however, they also should be used in combination with many other predictive indicators. The purpose of this study was thus to identify a simplified class of blood biomarkers capable of predicting the risk of developing DKD. The Gene Expression Omnibus database was screened for DKD biomarkers, and differentially expressed genes (DEGs) in human blood and kidney were identified via gene expression analysis and the Least Absolute Shrinkage and Selection Operator regression. A comparison of the area under the curve (AUC) profiles on multiple receiver operating characteristic curves of the DEGs in DKD and other renal diseases revealed that REG1A and RUNX3 had the highest specificity for DKD diagnosis. The AUCs of the combined expression of REG1A and RUNX3 in kidney (AUC = 0.929) and blood samples (AUC = 0.917) of DKD patients were similar to each other. The AUC of blood samples from DKD patients and healthy individuals obtained for external validation further demonstrated that REG1A combined with RUNX3 had significant diagnostic efficacy (AUC=0.948). REG1A and RUNX3 expression levels were found to be positively and negatively correlated with urinary albumin creatinine ratio and estimated glomerular filtration rate, respectively. Kaplan-Meier curves also revealed the potential of REG1A and RUNX3 for predicting the risk of DKD. In conclusion, REG1A and RUNX3 may serve as biomarkers for predicting the risk of developing DKD

Can Overconfidence be Debiased by Low-Probability/High-Consequence Events?

During the first half of 2008, China suffered three natural disasters: a heavy snow storm, an outbreak of hand-foot-mouth disease, and a severe earthquake. The aim of the present study is to explore how low-probability/high-consequence events influence overconfidence. In Study 1, opportunity samples were obtained by recruiting residents in three different types of disaster-hit areas to answer a peer-comparison probability judgment questionnaire about 1 month after the corresponding disaster occurred. The performance of 539 participants in disaster-hit areas was compared with that of 142 residents in a nondisaster area. The findings indicate that residents in disaster-hit areas were less overconfident than those in the nondisaster area on both positive and negative events. In Study 2, we surveyed a total of 336 quake-victims 4 and 11 months after the earthquake to examine whether the impact of disasters on overconfidence would decay with time. The resulting data indicate that the disaster victims became more overconfident as time elapsed. The overall findings suggest that low-probability/high-consequence events could make people less overconfident and more rational and seem to serve as a function of debiasing.</p

Changes in Volatile Profiles and Activity of Hydroperoxide Lyase and Alcohol Dehydrogenase During the Development of Cabernet Sauvignon Grapes (Vitis vinifera L.)

In this study we focused on the development of Cabernet Sauvignon grapes and investigated changes in theactivity of alcohol dehydrogenase (ADH) and hydroperoxide lyase (HPL) in different tissues. We sampledgrape skin at four, six, seven, eight, nine, 10, 12, 14 and 16 weeks after anthesis; developing flowers whenblooming at 0%, 5%, 50%, and 90%; and leaves at two and four weeks before anthesis and at two, four,six, eight, nine, and 10 weeks after anthesis. We also examined the type and fluctuation of volatile contents.ADH activity increased with the development of flowers and grape skins, which led to the increasing oftypes and concentration of alcohols. Low levels of 9-HPL led to low concentrations of C9 compounds.According to this paper, C6 compounds became abundant with the development of grape berries, while theactivity of 13-HPL kept at a low level in the flowers and grape skins. There might have been a high level of13-HPL activity from the end of flowering until fruit setting that we did not detect. Furthermore, similarC6 and C5 compounds were detected across all tissues, including hexanal, (E)-2-hexenal, (Z)-3-hexenal,(Z)-2-penten-1-ol, (Z)-3-hexen-1-ol, 1-hexanol and 3-hexen-1-ol. Generally speaking, the concentrations ofC6 and C5 compounds could be used as the criterion of maturation of the three grape tissues