Dahuang Zhechong pill attenuates CCl4-induced rat liver fibrosis via the PI3K-Akt signaling pathway

It is well characterized that activated hepatic stellate cells (HSCs) exert critical functions in accelerating the progression of liver fibrosis. Previous studies have indicated that Dahuang Zhechong pill (DHZCP), a traditional Chinese herbal medicine, is capable of inactivating HSCs and thus attenuate the formation of liver fibrosis in rats. However, pharmacological mechanisms of DHZCP in alleviating liver fibrosis remain unclear. This study aims to investigate the antifibrotic role of DHZCP through inhibiting the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway. DHZCP was found to significantly suppresses extracellular matrix formation and immune cell infiltration, thus alleviating liver fibrosis symptoms in the in vivo model. Moreover, DHZCP reduced serum levels of transforming growth factor β1 and tumor necrosis factor-α in rats with liver fibrosis. DHZCP treatment remarkably downregulated protein levels of PI3K and phosphorylated Akt, as well as fibrosis markers. In vitro experiments further demonstrated that DHZCP markedly suppressed HSCs proliferation by downregulating PI3K/Akt, which exerted a synergistic effect with the PI3K inhibitor LY294002. To sum up, our results confirmed that DHZCP exerted an antifibrotic effect in the animal model through inactivating the PI3K/Akt pathway, thus protecting rats from liver injury.     

Long noncoding RNA LINC01234 promoted cell proliferation and invasion via miR-1284/TRAF6 axis in colorectal cancer

Colorectal cancer is one of the most common and leading malignancies globally. Long noncoding RNAs (lncRNAs) function as potentially critical regulator in colorectal cancer. LINC01234, a novel lncRNA in tumor biology, regulates the progression of various tumors. However, the tumorigenic mechanism of LINC01234 in colorectal cancer is still unclear. This study was performed with the aim to prospectively investigate clinical significance, effect, and mechanism of lncRNA LINC01234 in colorectal cancer. First, we found that LINC01234, localized in the cytoplasm, was increased in both colorectal cancer cell lines and tissues. Subsequent functional assays suggested LINC01234 knockdown suppressed cell proliferation, migration, and invasion of colorectal cancer cells, while blocked cell cycle and induced cell apoptosis. Moreover, we identified that miR-1284 was target of LINC01234, we further demonstrated a negative correlation with LINC01234 in colorectal cancer tissues and cells. Furthermore, miR-1284 targeted and suppressed tumor necrosis factor receptor–associated factor 6 (TRAF6). Loss-of-function assay revealed that LINC01234 silencing suppressed colorectal cancer progression through inhibition of miR-1284. In vivo subcutaneous xenotransplanted tumor model indicated LINC01234 knockdown inhibited in vivo tumorigenic ability of colorectal cancer via downregulation of TRAF6. Collectively, this study clarified the biological significance of LINC01234/miR-1284/TRAF6 axis in colorectal cancer progression, providing insights into LINC01234 as novel potential therapeutic target for colorectal cancer therapeutic from bench to clinic.     

Genome Wide Identification of C2H2-Type Zinc Finger Proteins of Tomato and Expression Analysis Under Different Abiotic Stresses

In plants, C2H2-type zinc finger proteins play important roles in multiple processes, including plant growth and development, as well as biotic and abiotic responses. In the present study, based on the presence of the C2H2 domain (CX2~4CX3FX5LX2HX3~5H), 112 C2H2-type zinc finger proteins were predicted in tomato. Through gene and protein structures analyses and phylogenetic analysis, the 112 C2H2-type zinc finger proteins were divided into five subfamilies. Members of the same subfamily shared similarities in gene and protein structures, while members of different subfamilies contained different numbers of the C2H2 domain. The tissue expression pattern analysis showed that 24 C2H2-type zinc finger proteins are constitutively expressed in all tissues, indicating that they may play important roles in the growth and development of all tissues. In addition, under chilling (4 °C), heat (42 °C), high salinity (200 Mm NaCl), and osmotic (20% PEG) stresses, members of C2H2-type zinc finger family were induced to varying degrees, which suggested that these genes were involved in multiple abiotic stress responses. This study will provide theoretical basis for further research of C2H2-type zinc finger proteins in tomato.

     

ProDCoNN: Protein design using a convolutional neural network

Designing protein sequences that fold to a given three-dimensional (3D) structure has long been a challenging problem in computational structural biology with significant theoretical and practical implications. In this study, we first formulated this problem as predicting the residue type given the 3D structural environment around the C _α atom of a residue, which is repeated for each residue of a protein. We designed a nine-layer 3D deep convolutional neural network (CNN) that takes as input a gridded box with the atomic coordinates and types around a residue. Several CNN layers were designed to capture structure information at different scales, such as bond lengths, bond angles, torsion angles, and secondary structures. Trained on a very large number of protein structures, the method, called ProDCoNN (protein design with CNN), achieved state-of-the-art performance when tested on large numbers of test proteins and benchmark datasets.     

Joint analysis of single-cell and bulk tissue sequencing data to infer intratumor heterogeneity

Many computational methods have been developed to discern intratumor heterogeneity (ITH) using DNA sequence data from bulk tumor samples. These methods share an assumption that two mutations arise from the same subclone if they have similar mutant allele-frequencies (MAFs), and thus it is difficult or impossible to distinguish two subclones with similar MAFs. Single-cell DNA sequencing (scDNA-seq) data can be very informative for ITH inference. However, due to the difficulty of DNA amplification, scDNA-seq data are often very noisy. A promising new study design is to collect both bulk and single-cell DNA-seq data and jointly analyze them to mitigate the limitations of each data type. To address the analytic challenges of this new study design, we propose a computational method named BaSiC (B ulk tumor a nd Si ngle C ell), to discern ITH by jointly analyzing DNA-seq data from bulk tumor and single cells. We demonstrate that BaSiC has comparable or better performance than the methods using either data type. We further evaluate BaSiC using bulk tumor and single-cell DNA-seq data from a breast cancer patient and several leukemia patients.     

Randomization inference with general interference and censoring

Interference occurs between individuals when the treatment (or exposure) of one individual affects the outcome of another individual. Previous work on causal inference methods in the presence of interference has focused on the setting where it is a priori assumed that there is “partial interference,” in the sense that individuals can be partitioned into groups wherein there is no interference between individuals in different groups. Bowers et al. (2012, Political Anal, 21, 97–124) and Bowers et al. (2016, Political Anal, 24, 395–403) consider randomization-based inferential methods that allow for more general interference structures in the context of randomized experiments. In this paper, extensions of Bowers et al. that allow for failure time outcomes subject to right censoring are proposed. Permitting right-censored outcomes is challenging because standard randomization-based tests of the null hypothesis of no treatment effect assume that whether an individual is censored does not depend on treatment. The proposed extension of Bowers et al. to allow for censoring entails adapting the method of Wang et al. (2010, Biostatistics, 11, 676–692) for two-sample survival comparisons in the presence of unequal censoring. The methods are examined via simulation studies and utilized to assess the effects of cholera vaccination in an individually randomized trial of 73 000 children and women in Matlab, Bangladesh.     

Deregulation of UCA1 expression may be involved in the development of chemoresistance to cisplatin in the treatment of non-small-cell lung cancer via regulating the signaling pathway of microRNA-495/NRF2

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. As a platinum-based chemotherapeutic drug, cisplatin has been used for over 30 years in NSCLC treatment while its effects are diminished by drug resistance. Therefore, we aimed to study the potential role of UCA1 in the development of chemoresistance against cisplatin. Real-time polymerase chain reaction, western-blot analysis, and immunofluorescence were used to study the involvement of UCA1, miR-495, and NRF2 in chemoresistance against cisplatin. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine the effect of cisplatin on cell proliferation. Computational analysis and luciferase assay were carried out to explore the interaction among UCA1, miR-495, and NRF2. The cisplatin-R group exhibited lower levels of UCA1 and NRF2 expression but a higher level of miR-495 expression than the cisplatin-S group. The growth rate and half-maximal inhibitory concentration of cellular dipeptidyl peptidase (cisplatinum) of the cisplatin-R group were much higher than those in the cisplatin-S group. MiR-495 contained a complementary binding site of UCA1, and the luciferase activity of wild-type UCA1 was significantly reduced after the transfection of miR-495 mimics. MiR-495 directly targeted the 3′-untranslated region (3′-UTR) of NRF2, and the luciferase activity of wild-type NRF2 3′-UTR was evidently inhibited by miR-495 mimics. Finally, UCA1 and NRF2 expressions in the effective group were much lower than that in the ineffective group, along with a much higher level of miR-495 expression. We suggested for the first time that high expression of UCA1 contributed to the development of chemoresistance to cisplatin through the UCA1/miR-495/NRF2 signaling pathway.     

Study of FABP's interactome and detecting new molecular targets in clear cell renal cell carcinoma

Fatty acids (FAs) play a crucial role in the development of clear cell renal cell carcinoma (ccRCC), FAs function requires the participation of fatty-acid-binding protein (FABP). Current studies have shown that different members of the FABP's family play different roles in the tumorigenesis of ccRCC. Therefore, the systematic analysis of FABPs will be of great significance. However, the diverse expression patterns and prognostic values of nine FABPs have yet to be elucidated. In this study, through multiple analysis and verification of multiple databases, such as ONCOMINE, The Human Protein Atlas, UALCAN, Gene Expression Profiling Interactive Analysis, and cBioPortal, we found that the expression of FABP1 was significantly downregulated and the expression of FABP5/6/7 was significantly upregulated in ccRCC compared with renal tissues, and the patients with high messenger RNA (mRNA) levels of the FABP5/6/7 or low mRNA levels of FABP1 were predicted to have a lower overall survival or disease-free survival. Further analysis by the protein–protein interaction (PPI), Gene Ontology pathway, and Kyoto Encyclopedia of Genes and Genomes pathway showed that FABPs were mainly involved in the peroxisome proliferator-activated receptor (PPAR) pathway. In coexpression analysis, we found that FABP1/5/6/7 was coexpressed with transforming growth factor-β1 (TGF-β1), PPARA, and LPL. This study implied that FABP1/5/6/7 could act as an important tumor biomarker of ccRCC; the role of FABPs may be related to PPAR or TGF-β pathway.     

Identification of novel LncRNA targeting Smad2/PKCα signal pathway to negatively regulate malignant progression of glioblastoma

Glioblastoma multiforme (GBM) is a highly proliferative cancer with generally poor prognosis and accumulating evidence has highlighted the potential of long noncoding RNAs (lncRNAs) in the biological behaviors of glioma cells. This study focused on the identification of lncRNAs to identify targets for possible GBM prognosis. Microarray expression profiling found that 1,759 lncRNAs and 3,026 messenger RNAs (mRNAs) were upregulated, and 1932s lncRNA and 2,979 mRNAs were downregulated in GBM. Bioinformatics analysis and experimental verification identified TCONS_00020456 (TCON) for further analysis. In situ hybridization, along with immunohistochemical and receiver operating characteristic analysis determined TCON (truncation value = 3.5) as highly sensitive and specific in GBM. Grade IV patients with glioma life span with different lncRNA staining scores were analyzed. TCON staining scores below 3.5 indicated poor prognosis (life span ranging from 0.25 to 7 months), even if the glioma was surgically removed. TCON decreased significantly in GBM, and showed a coexpressional relationship with Smad2 and protein kinase C α (PKCα). Overexpression of TCON reduced the proliferation on one hand and migration, invasion on the other. TCON also inhibited epithelial–mesenchymal transformation and glioma progression in vivo, based on a nude mouse tumorigenicity assay. In addition, we predicted a potential binding site and intersection that microRNAs targeting Smad2, PKCα, and TCON through RACE pretest and bioinformatics analysis. Taken together, TCON, regarded as oncosuppressor, targeting the Smad2/PKCα axis plays a novel role in inhibiting the malignant progression of glioma. Moreover, it also demonstrates that the level of TCON can be used as a prognostic and diagnostic biomarker for GBM.