Identification of KANSARL as the First Cancer Predisposition Fusion Gene Specific to the Population of European Ancestry Origin

Gene fusion is one of the hallmarks of cancer. Recent advances in RNA-seq of cancer transcriptomes have facilitated the discovery of fusion transcripts. In this study, we report identification of a surprisingly large number of fusion transcripts, including six KANSARL (KANSL1-ARL17A) transcripts that resulted from the fusion between the KANSL1 and ARL17A genes using a RNA splicingcode model. Five of these six KANSARL fusion transcripts are novel. By systematic analysis of RNA-seq data of glioblastoma, prostate cancer, lung cancer, breast cancer, and lymphoma from different regions of the World, we have found that KANSARL fusion transcripts were rarely detected in the tumors of individuals from Asia or Africa. In contrast, they exist in 30 - 52% of the tumors from North Americans cancer patients. Analysis of CEPH/Utah Pedigree 1463 has revealed that KANSARL is a familially-inherited fusion gene. Further analysis of RNA-seq datasets of the 1000 Genome Project has indicated that KANSARL fusion gene is specific to 28.9% of the population of European ancestry origin. In summary, we demonstrated that KANSARL is the first cancer predisposition fusion gene associated with genetic backgrounds of European ancestry origin

A CDC2-related kinase from Paramecium tetraurelia

Cell division in higher eukaryotes is mainly controlled by p34cdc2, a serine/ threonine protein kinase, and/or related kinases, and by other components of these kinase complexes. I present evidence that CDC2-like kinases also occur in the ciliate Paramecium tetraurelia. The protein encoded by the isolated Paramecium cdc2 homologue did not bind to pl3sucl , was localized in the macronucleus, its associated kinase activity was high at the initiation of macronuclear DNA synthesis, and it was active as a monomer. To study the relationship between the cellular and molecular events of cell cycle regulation, synchronous cultures are essential. However, in Paramecium, the only reliable technique for obtaining synchronous cell populations has been hand-selection of dividing cells. This technique is only useful for small samples and impractical for biochemical analysis. In this thesis, centrifugal ehxtriation, which fractionates the cell population on the basis of sedimentation properties with minimal perturbation of metabolic function, was applied to the ciliate Paramecium tetraurelia. Only the smallest cell fractions were well synchronized and exhibited synchrony and cell cycle duration equivalent to hand-selected samples. These small cell fractions consisted of a highly synchronous G1 cell population, which was easily obtained by this technique and used for all subsequent molecular and biochemical analysis. With a combination of various polymerase chain reaction (PCR) techniques, a cdc2 homologous sequence was isolated from Paramecium which is referred to as cdc2PtA. The genomic Paramecium cdc2PtA gene contained two short introns near the 5'-end. The corresponding amino acid sequence exhibited about 50 % identity to the cdc2 proteins of other eukaryotes. The Paramecium cdc2PtA gene-encoded protein was 11 amino acids longer than that of Schizosaccharomyces pombe. It had most of the catalytic sites required for CDC2 kinase activity, especially those phosphorylation sites which regulate CDC2 kinase activity in other organisms. There was one amino acid change in the highly conserved PSTAIRE region and other changes in regions which are required for interaction with other regulatory proteins, especially the pl3*"e / binding sites. Southern blot analysis as well as isolation of a second incomplete cDNA sequence from the 3'-end indicated that Paramecium has multiple cdc2 genes. Northern blotting results showed that the Paramecium cdc2PtA gene was much more strongly expressed in actively dividing cells than in starved stationary phase cells in which cdc2PtA mRNA was almost undetectable. There was no significant change in cdc2PtA mRNA level throughout the vegetative cell cycle. Polyclonal antibodies were produced against both a synthetic peptide from the C-tenninal region and a GSTCDC2PTA fusion protein which contained a third of the Paramecium cdc2PtA protein from the N-terminal region. Both antibodies recognized a 36 kDa polypeptide on Western blots. The antibodies did not cross-react with protein extracts from Tetrahymena or S. pombe, nor with the Paramecium 34 kDa polypeptide which was detected by anti- PSTATJRE antibody. The Paramecium CDC2PTA protein level decreased slightly when cells entered stationary phase and was invariant throughout the cell cycle, similar to its transcription pattern. Indirect immunofluorescence results showed that Paramecium CDC2PTA protein was located in the macronucleus, but not observed in the micronuclei or cytoplasm Upon starvation, the strength of the fluorescence signal in the macronucleus dropped slightly, consistent with the result from Western blotting. Native Paramecium CDC2PTA kinase was immunoprecipitated with the Paramecium CDC2PTA specific antibody. The precipitated CDC2PTA kinase phosphorylated both bovine histone HI and casein in vitro, but not retinoblastoma (Rb) protein. Using histone HI as substrate, CDC2PTA kinase activity was assayed in the ehitriation synchronized samples. Histone HI kinase activity was high during the early stages of the cell cycle and reached a peak at around 2.5 hr after ehitriation, which corresponded approximately to the time of the initiation of macronuclear DNA synthesis. This suggests that the isolated Paramecium CDC2PTA kinase may be associated with the regulation of macronuclear DNA synthesis. When Paramecium extracts were probed with anti-PSTAIRE antibody, two polypeptides were detected. The major one migrated at 36 kDa was apparently recognized by anti-CDC2PTA antibody. The minor one migrated at the same position as S. pombe p34cde2 protein. Only the faster migrating one showed affinity for p 13™c7 protein. The phosphotransferase activity of the p13sucl / precipitable protein was very low at early stages and increased at around 1.5 hr before cell division. This kinase activity increase corresponded to the point of commitment to division in Paramecium. Immunoprecipitation results showed that Paramecium CDC2PTA kinase occurred principally as monomers. This was further confirmed by glycerol density gradient centrifugation and gel filtration. These monomers were active as a histone HI kinase in vitro. These observations indicate that isolated Paramecium CDC2-like kinase differs from typical CDC2 kinases in terms of interaction with and regulation by other cell cycle regulatory components.Science, Faculty ofZoology, Department ofGraduat

AGL-Net: An Efficient Neural Network for EEG-Based Driver Fatigue Detection

Background: In recent years, road traffic safety has become a prominent issue due to the worldwide proliferation of vehicles on roads. The challenge of driver fatigue detection involves balancing the efficiency and accuracy of the detection process. While various detection methods are available, electroencephalography (EEG) is considered the gold standard due to its high precision in terms of detecting fatigue. However, deep learning models for EEG-based fatigue detection are limited by their large numbers of parameters and low computational efficiency levels, making it difficult to implement them on mobile devices. Methods: To overcome this challenge, an attention-based Ghost-LSTM neural network (AGL-Net) is proposed for EEG-based fatigue detection in this paper. AGL-Net utilizes an attention mechanism to focus on relevant features and incorporates Ghost bottlenecks to efficiently extract spatial EEG fatigue information. Temporal EEG fatigue features are extracted using a long short-term memory (LSTM) network. We establish two types of models: regression and classification models. In the regression model, we use linear regression to obtain regression values. In the classification model, we classify features based on the predicted values obtained from regression. Results: AGL-Net exhibits improved computational efficiency and a more lightweight design than existing deep learning models, as evidenced by its floating-point operations per second (FLOPs) and Params values of 2.67 M and 103,530, respectively. Furthermore, AGL-Net achieves an average accuracy of approximately 87.3% and an average root mean square error (RMSE) of approximately 0.0864 with the Shanghai Jiao Tong University (SJTU) Emotion EEG Dataset (SEED)-VIG fatigued driving dataset, indicating its advanced performance capabilities. Conclusions: The experiments conducted with the SEED-VIG dataset demonstrate the feasibility and advanced performance of the proposed fatigue detection method. The effectiveness of each AGL-Net module is verified through thorough ablation experiments. Additionally, the implementation of the Ghost bottleneck module greatly enhances the computational efficiency of the model. Overall, the proposed method has higher accuracy and computational efficiency than prior fatigue detection methods, demonstrating its considerable practical application value

Expression of endothelins and their receptors in nonmelanoma skin cancers.

BackgroundEndothelins are paracrine peptides with growth-promoting and vasoactive functions for a variety of cell types. Elevated activation of the endothelin signaling pathway induces cell proliferation and/or survival and is implicated in a variety of malignancies. Increased endothelin 1 was described in solar lentigines in previous reports, raising the possibility that the endothelin pathway may be of significance in keratinocyte proliferation-related disorders. However, detailed investigation on endothelins in skin malignancies is lacking.ObjectivesThis study aims to survey the expression of endothelins and their receptors in keratinocyte-derived benign and malignant tumors of the skin and to test the effects of endothelin inhibitors on the growth and survival of cultured keratinocytes.MethodsQuantitative polymerase chain reaction was used to measure the level of gene transcription of three endothelins (ET-1, -2, and -3) and two endothelin receptors (ETRA and ETRB). The genes with significant messenger ribonucleic acid (mRNA) expression abnormalities were confirmed with immunohistochemical analysis to examine expression differences at the protein levels. To analyze the effect of endothelin inhibitors on the keratinocyte growth and survival, keratinocytes were cultured in the presence of various concentrations of endothelin inhibitors and subjected to tetrazolium bromide assay to quantify the cell numbers over time.ResultsET-1 mRNA was found to be significantly up-regulated in seborrheic keratosis and basal cell carcinoma. However, no significant expression increase was found in actinic keratosis, Bowen's disease, or squamous cell carcinoma. Immunohistochemical analysis of ET-1 peptide confirmed increased expression. In cultured keratinocytes, peptide inhibitors of the endothelin pathway resulted in a marked reduction in cell survival.ConclusionThe endothelin signaling pathway, especially ET-1, is activated in basal keratinocyte neoplasms of the skin, such as basal cell carcinoma and seborrheic keratosis. Blockade of this pathway can reduce cell survival in vitro. Therefore, endothelin inhibitors potentially offer a novel method for the treatment of some keratinocyte-derived skin tumors

An aqueous miscible organic (AMO) process for layered double hydroxides (LDHs) for the enhanced properties of polypropylene/LDH composites

International audienceEnhancing the compatibility between inorganic fillers and polymers to obtain functionalized composites has always been a key issue. In this study, an aqueous miscible organic (AMO) method has been successfully adopted for conventional layered double hydroxide (LDH) fillers. Here, a series of D-LDH hybrid materials, intercalated by an organic antioxidant DBHP (D, 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate), have been organically surface-modified using acetone as the solvent via the AMO method. To understand the effect of acetone exposure on the structure of the AMO D-LDH samples, XRD patterns, FT-IR spectra, TG-DTA curves and radical scavenging activity were thoroughly studied. The results indicate that the AMO method does not affect the layer structure of D-LDH but causes the co-intercalation of D− with CO32− anions, which can change the amount of DBHP in the interlayer and then influence the crystallinity, thermal stability and radical scavenging activity of D-LDH. Subsequently, the series of AMO D-LDH materials were used as anti-aging nanofillers for polypropylene (PP). The thermal stability, thermal-aging properties and migration resistance of the resulting PP/D-LDH (h) composites were investigated systematically. The results indicate that the AMO modification of D-LDH affects the content of DBHP and the interaction between the LDH fillers and PP chains, since an optimized modification time and content of DBHP are found to enhance the anti-aging performance of PP, as well as limits the migration of the DBHP molecules out of the PP films

Expression of endothelins and their receptors in nonmelanoma skin cancers.

BackgroundEndothelins are paracrine peptides with growth-promoting and vasoactive functions for a variety of cell types. Elevated activation of the endothelin signaling pathway induces cell proliferation and/or survival and is implicated in a variety of malignancies. Increased endothelin 1 was described in solar lentigines in previous reports, raising the possibility that the endothelin pathway may be of significance in keratinocyte proliferation-related disorders. However, detailed investigation on endothelins in skin malignancies is lacking.ObjectivesThis study aims to survey the expression of endothelins and their receptors in keratinocyte-derived benign and malignant tumors of the skin and to test the effects of endothelin inhibitors on the growth and survival of cultured keratinocytes.MethodsQuantitative polymerase chain reaction was used to measure the level of gene transcription of three endothelins (ET-1, -2, and -3) and two endothelin receptors (ETRA and ETRB). The genes with significant messenger ribonucleic acid (mRNA) expression abnormalities were confirmed with immunohistochemical analysis to examine expression differences at the protein levels. To analyze the effect of endothelin inhibitors on the keratinocyte growth and survival, keratinocytes were cultured in the presence of various concentrations of endothelin inhibitors and subjected to tetrazolium bromide assay to quantify the cell numbers over time.ResultsET-1 mRNA was found to be significantly up-regulated in seborrheic keratosis and basal cell carcinoma. However, no significant expression increase was found in actinic keratosis, Bowen's disease, or squamous cell carcinoma. Immunohistochemical analysis of ET-1 peptide confirmed increased expression. In cultured keratinocytes, peptide inhibitors of the endothelin pathway resulted in a marked reduction in cell survival.ConclusionThe endothelin signaling pathway, especially ET-1, is activated in basal keratinocyte neoplasms of the skin, such as basal cell carcinoma and seborrheic keratosis. Blockade of this pathway can reduce cell survival in vitro. Therefore, endothelin inhibitors potentially offer a novel method for the treatment of some keratinocyte-derived skin tumors

Expression of Endothelins and Their Receptors in Nonmelanoma Skin Cancers

BackgroundEndothelins are paracrine peptides with growth-promoting and vasoactive functions for a variety of cell types. Elevated activation of the endothelin signaling pathway induces cell proliferation and/or survival and is implicated in a variety of malignancies. Increased endothelin 1 was described in solar lentigines in previous reports, raising the possibility that the endothelin pathway may be of significance in keratinocyte proliferation-related disorders. However, detailed investigation on endothelins in skin malignancies is lacking.ObjectivesThis study aims to survey the expression of endothelins and their receptors in keratinocyte-derived benign and malignant tumors of the skin and to test the effects of endothelin inhibitors on the growth and survival of cultured keratinocytes.MethodsQuantitative polymerase chain reaction was used to measure the level of gene transcription of three endothelins (ET-1, -2, and -3) and two endothelin receptors (ETRA and ETRB). The genes with significant messenger ribonucleic acid (mRNA) expression abnormalities were confirmed with immunohistochemical analysis to examine expression differences at the protein levels. To analyze the effect of endothelin inhibitors on the keratinocyte growth and survival, keratinocytes were cultured in the presence of various concentrations of endothelin inhibitors and subjected to tetrazolium bromide assay to quantify the cell numbers over time.ResultsET-1 mRNA was found to be significantly up-regulated in seborrheic keratosis and basal cell carcinoma. However, no significant expression increase was found in actinic keratosis, Bowen's disease, or squamous cell carcinoma. Immunohistochemical analysis of ET-1 peptide confirmed increased expression. In cultured keratinocytes, peptide inhibitors of the endothelin pathway resulted in a marked reduction in cell survival.ConclusionThe endothelin signaling pathway, especially ET-1, is activated in basal keratinocyte neoplasms of the skin, such as basal cell carcinoma and seborrheic keratosis. Blockade of this pathway can reduce cell survival in vitro. Therefore, endothelin inhibitors potentially offer a novel method for the treatment of some keratinocyte-derived skin tumors