Gain and loss events in the evolution of the apolipoprotein family in vertebrata.

BACKGROUND: Various apolipoproteins widely distributed among vertebrata play key roles in lipid metabolism and have a direct correlation with human diseases as diagnostic markers. However, the evolutionary progress of apolipoproteins in species remains unclear. Nine human apolipoproteins and well-annotated genome data of 30 species were used to identify 210 apolipoprotein family members distributed among species from fish to humans. Our study focused on the evolution of nine exchangeable apolipoproteins (ApoA-I/II/IV/V, ApoC-I~IV and ApoE) from Chondrichthyes, Holostei, Teleostei, Amphibia, Sauria (including Aves), Prototheria, Marsupialia and Eutheria. RESULTS: In this study, we reported the overall distribution and the frequent gain and loss evolutionary events of apolipoprotein family members in vertebrata. Phylogenetic trees of orthologous apolipoproteins indicated evident divergence between species evolution and apolipoprotein phylogeny. Successive gain and loss events were found by evaluating the presence and absence of apolipoproteins in the context of species evolution. For example, only ApoA-I and ApoA-IV occurred in cartilaginous fish as ancient apolipoproteins. ApoA-II, ApoE, and ApoC-I/ApoC-II were found in Holostei, Coelacanthiformes, and Teleostei, respectively, but the latter three apolipoproteins were absent from Aves. ApoC-I was also absent from Cetartiodactyla. The apolipoprotein ApoC-III emerged in terrestrial animals, and ApoC-IV first arose in Eutheria. The results indicate that the order of the emergence of apolipoproteins is most likely ApoA-I/ApoA-IV, ApoE, ApoA-II, ApoC-I/ApoC-II, ApoA-V, ApoC-III, and ApoC-IV. CONCLUSIONS: This study reveals not only the phylogeny of apolipoprotein family members in species from Chondrichthyes to Eutheria but also the occurrence and origin of new apolipoproteins. The broad perspective of gain and loss events and the evolutionary scenario of apolipoproteins across vertebrata provide a significant reference for the research of apolipoprotein function and related diseases.

Anatomy and RNA-Seq reveal important gene pathways regulating sex differentiation in a functionally Androdioecious tree, Tapiscia sinensis.

BACKGROUND: Gametogenesis is a key step in the production of ovules or pollen in higher plants. The sex-determination aspects of gametogenesis have been well characterized in the model plant Arabidopsis. However, little is known about this process in androdioecious plants. Tapiscia sinensis Oliv. is a functionally androdioecious tree, with both male and hermaphroditic individuals. Hermaphroditic flowers (HFs) are female-fertile flowers that can produce functional pollen and set fruits. However, compared with male flowers (MFs), the pollen viability and number of pollen grains per flower are markedly reduced in HFs. MFs are female-sterile flowers that fail to set fruit and that eventually drop. RESULTS: Compared with HF, a notable cause of MF female sterility in T. sinensis is when the early gynoecium meristem is disrupted. During the early stage of HF development (stage 6), the ring meristem begins to form as a ridge around the center of the flower. At this stage, the internal fourth-whorl organ is stem-like rather than carpelloid in MF. A total of 52,945 unigenes were identified as transcribed in MF and HF. A number of differentially expressed genes (DEGs) and metabolic pathways were detected as involved in the development of the gynoecium, especially the ovule, carpel and style. At the early gynoecium development stage, DEGs were shown to function in the metabolic pathways regulating ethylene biosynthesis and signal transduction (upstream regulator), auxin, cytokinin transport and signalling, and sex determination (or flower meristem identity). CONCLUSIONS: Pathways for the female sterility model were initially proposed to shed light on the molecular mechanisms of gynoecium development at early stages in T. sinensis.

Human Ccr4 and Caf1 Deadenylases Regulate Proliferation and Tumorigenicity of Human Gastric Cancer Cells via Modulating Cell Cycle Progression.

Cancer cells generally have reprogrammed gene expression profiles to meet the requirements of survival, continuous division, and metastasis. An interesting question is whether the cancer cells will be affected by interfering their global RNA metabolism. In this research, we found that human Ccr4a/b (hCcr4a/b) and Caf1a/b (hCaf1a/b) deadenylases, the catalytic components of the Ccr4-Not complex, were dysregulated in several types of cancers including stomach adenocarcinoma. The impacts of the four deadenylases on cancer cell growth were studied by the establishment of four stable MKN28 cell lines with the knockdown of hCcr4a/b or hCaf1a/b or transient knockdown in several cell lines. Depletion of hCcr4a/b or hCaf1a/b significantly inhibited cell proliferation and tumorigenicity. Mechanistic studies indicated that the cells were arrested at the G2/M phase by knocking down hCaf1a, while arrested at the G0/G1 phase by depleting hCaf1b or hCcr4a/b. The four enzymes did not affect the levels of CDKs and cyclins but modulated the levels of CDK-cyclin inhibitors. We identified that hCcr4a/b, but not hCaf1a/b, targeted the p21 mRNA in the MKN28 cells. Furthermore, depletion of any one of the four deadenylases dramatically impaired processing-body formation in the MKN28 and HEK-293T cells. Our results highlight that perturbating global RNA metabolism may severely affect cancer cell proliferation, which provides a potential novel strategy for cancer treatment.

Complete chloroplast genome of an endangered tree species, Toona ciliata (Sapindales: Meliaceae).

The whole cp genome of T. ciliata was 159,502 bp in length, containing a pair of inverted repeat (26,961 bp for each), a large single copy (87,199 bp) and a small single copy (18,381 bp) regions. The cp genome encoded 138 genes, including 89 protein-coding genes, 40 tRNA genes, 8 rRNA genes and 1 pseudogene. The nucleotide composition was asymmetric (30.7% A, 19.3% C, 18.6% G and 31.4% T) with an overall GC content of 37.9%. The maximum likelihood phylogenetic analysis based on 21 complete cp genome sequences showed that T. ciliata closely related to Azadirachta indica.

[Object-oriented segmentation and classification of forest gap based on QuickBird remote sensing image.] / 基于面向对象的QuickBird遥感影像林隙分割与分类.

Traditional field investigation and artificial interpretation could not satisfy the need of forest gaps extraction at regional scale. High spatial resolution remote sensing image provides the possibility for regional forest gaps extraction. In this study, we used object-oriented classification method to segment and classify forest gaps based on QuickBird high resolution optical remote sensing image in Jiangle National Forestry Farm of Fujian Province. In the process of object-oriented classification, 10 scales (10-100, with a step length of 10) were adopted to segment QuickBird remote sensing image; and the intersection area of reference object (RAor) and intersection area of segmented object (RAos) were adopted to evaluate the segmentation result at each scale. For segmentation result at each scale, 16 spectral characteristics and support vector machine classifier (SVM) were further used to classify forest gaps, non-forest gaps and others. The results showed that the optimal segmentation scale was 40 when RAor was equal to RAos. The accuracy difference between the maximum and minimum at different segmentation scales was 22%. At optimal scale, the overall classification accuracy was 88% (Kappa=0.82) based on SVM classifier. Combining high resolution remote sensing image data with object-oriented classification method could replace the traditional field investigation and artificial interpretation method to identify and classify forest gaps at regional scale.

Identification of metabolism-associated genes and pathways involved in different stages of clear cell renal cell carcinoma.

The lack of early diagnostic markers and novel therapeutic targets for clear cell renal cell carcinoma (ccRCC) negatively affects patient prognosis. Cancer metabolism is an attractive area for the understanding of the molecular mechanism of carcinogenesis. The present study attempted to identify metabolic changes from the view of the expression of metabolism-associated genes between control samples and those of ccRCC at different disease stages. Data concerning ccRCC gene expression obtained by RNA-sequencing was obtained from The Cancer Genome Atlas and data on metabolism-associated genes were extracted using the Recon2 model. Following analysis of differential gene expression, multiple differentially expressed metabolic genes at each tumor-node-metastasis disease stage were identified, compared with control non-disease samples: Metabolic genes (305) were differentially expressed in stage I disease, 323 in stage II disease, 355 in stage III disease and 363 in stage IV disease. Following enrichment analysis for differential metabolic genes, 22 metabolic pathways were identified to be dysregulated in multiple stages of ccRCC. Abnormalities in hormone, vitamin, glucose and lipid metabolism were present in the early stages of the disease, with dysregulation to reactive oxygen species detoxification and amino acid metabolism pathways occurring with advanced disease stages, particularly to valine, leucine, and isoleucine metabolism, which was substantially dysregulated in stage IV disease. The xenobiotic metabolism pathway, associated with multiple cytochrome P450 family genes, was dysregulated in each stage of the disease. This pathway is worthy of substantial attention since it may aid understanding of drug resistance in ccRCC. The results of the present study offer information to aid further research into early diagnostic biomarkers and therapeutic targets of ccRCC.

Low expression of aging-related NRXN3 is associated with Alzheimer disease: A systematic review and meta-analysis.

BACKGROUND: Alzheimer disease (AD) is a common neurodegenerative disorder with distinct pathological features, with aging considered the greatest risk factor. We explored how aging contributes to increased AD risk, and determined concurrent and coordinate changes (including genetic and phenotypic modifications) commonly exhibited in both normal aging and AD. METHODS: Using the Gene Expression Omnibus (GEO) database, we collected 1 healthy aging-related and 3 AD-related datasets of the hippocampal region. The normal aging dataset was divided into 3 age groups: young (20-40 years old), middle-aged (40-60 years old), and elderly (>60 years old). These datasets were used to analyze the differentially expressed genes (DEGs). The Gene Ontology (GO) terms, pathways, and function network analysis of these DEGs were analyzed. RESULTS: One thousand two hundred ninety-one DEGs were found to be shared in the natural aging groups and AD patients. Among the shared DEGs, ATP6V1E1, GNG3, NDUFV2, GOT1, USP14, and NAV2 have been previously found in both normal aging individuals and AD patients. Furthermore, using Java Enrichment of Pathways Extended to Topology (JEPETTO) analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we determined that changes in aging-related KEGG annotations may contribute to the aging-dependence of AD risk. Interestingly, NRXN3, the second most commonly deregulated gene identified in the present study, is known to carry a mutation in AD patients. According to functional network analysis, NRXN3 plays a critical role in synaptic functions involved in the cognitive decline associated with normal aging and AD. CONCLUSION: Our results indicate that the low expression of aging-related NRXN3 may increase AD risk, though the potential mechanism requires further clarification.

Comparison of the toxic effects of different mycotoxins on porcine and mouse oocyte meiosis.

BACKGROUND: Aflatoxin B1 (AFB1), deoxynivalenol (DON), HT-2, ochratoxin A (OTA), zearalenone (ZEA) are the most common mycotoxins that are found in corn-based animal feed which have multiple toxic effects on animals and humans. Previous studies reported that these mycotoxins impaired mammalian oocyte quality. However, the effective concentrations of mycotoxins to animal oocytes were different. METHODS: In this study we aimed to compare the sensitivity of mouse and porcine oocytes to AFB1, DON, HT-2, OTA, and ZEA for mycotoxin research. We adopted the polar body extrusion rate of mouse and porcine oocyte as the standard for the effects of mycotoxins on oocyte maturation. RESULTS AND DISCUSSION: Our results showed that 10 µM AFB1 and 1 µM DON significantly affected porcine oocyte maturation compared with 50 µM AFB1 and 2 µM DON on mouse oocytes. However, 10 nM HT-2 significantly affected mouse oocyte maturation compared with 50 nM HT-2 on porcine oocytes. Moreover, 5 µM OTA and 10 µM ZEA significantly affected porcine oocyte maturation compared with 300 µM OTA and 50 µM ZEA on mouse oocytes. In summary, our results showed that porcine oocytes were more sensitive to AFB1, DON, OTA, and ZEA than mouse oocytes except HT-2 toxin.

A strategy to find novel candidate anti-Alzheimer's disease drugs by constructing interaction networks between drug targets and natural compounds in medical plants.

BACKGROUND: Alzheimer' disease (AD) is an ultimately fatal degenerative brain disorder that has an increasingly large burden on health and social care systems. There are only five drugs for AD on the market, and no new effective medicines have been discovered for many years. Chinese medicinal plants have been used to treat diseases for thousands of years, and screening herbal remedies is a way to develop new drugs. METHODS: We used molecular docking to screen 30,438 compounds from Traditional Chinese Medicine (TCM) against a comprehensive list of AD target proteins. TCM compounds in the top 0.5% of binding affinity scores for each target protein were selected as our research objects. Structural similarities between existing drugs from DrugBank database and selected TCM compounds as well as the druggability of our candidate compounds were studied. Finally, we searched the CNKI database to obtain studies on anti-AD Chinese plants from 2007 to 2017, and only clinical studies were included. RESULTS: A total of 1,476 compounds (top 0.5%) were selected as drug candidates. Most of these compounds are abundantly found in plants used for treating AD in China, especially the plants from two genera Panax and Morus. We classified the compounds by single target and multiple targets and analyzed the interactions between target proteins and compounds. Analysis of structural similarity revealed that 17 candidate anti-AD compounds were structurally identical to 14 existing approved drugs. Most of them have been reported to have a positive effect in AD. After filtering for compound druggability, we identified 11 anti-AD compounds with favorable properties, seven of which are found in anti-AD Chinese plants. Of 11 anti-AD compounds, four compounds 5,862, 5,863, 5,868, 5,869 have anti-inflammatory activity. The compound 28,814 mainly has immunoregulatory activity. The other six compounds have not yet been reported for any biology activity at present. DISCUSSION: Natural compounds from TCM provide a broad prospect for the screening of anti-AD drugs. In this work, we established networks to systematically study the connections among natural compounds, approved drugs, TCM plants and AD target proteins with the goal of identifying promising drug candidates. We hope that our study will facilitate in-depth research for the treatment of AD in Chinese medicine.

The identification and molecular mechanism of anti-stroke traditional Chinese medicinal compounds.

Stroke is a worldwide epidemic disease with high morbidity and mortality. The continuously exploration of anti-stroke medicines and molecular mechanism has a long way to go. In this study, in order to screen candidate anti-stroke compounds, more than 60000 compounds from traditional Chinese medicine (TCM) database were computationally analyzed then docked to the 15 known anti-stroke targets. 192 anti-stroke plants for clinical therapy and 51 current anti-stroke drugs were used to validate docking results. Totally 2355 candidate anti-stroke compounds were obtained. Among these compounds, 19 compounds are structurally identical with 16 existing drugs in which part of them have been used for anti-stroke treatment. Furthermore, these candidate compounds were significantly enriched in anti-stroke plants. Based on the above results, the compound-target-plant network was constructed. The network reveals the potential molecular mechanism of anti-stroke for these compounds. Most of candidate compounds and anti-stroke plants are tended to interact with target NOS3, PSD-95 and PDE5A. Finally, using ADMET filter, we identified 35 anti-stroke compounds with favorable properties. The 35 candidate anti-stroke compounds offer an opportunity to develop new anti-stroke drugs and will improve the research on molecular mechanism of anti-stroke.

Different impairment of immune and inflammation functions in short and long-term after ischemic stroke.

Ischemic stroke therapy and prognosis outcomes largely depend on the time periods after symptom onset. This study aims to explore the difference of global gene expression profiles and impairment of biological functions between short-term and long-term after stroke onset. We compared three short-term (3 h, 5 h and 24 h) and a long-term (6-month) gene expression levels by a multi-platform microarray data integration method. RankProd was used to calculate the differentially expressed genes between stroke patients and controls. DAVID Bioinformatics Resources was utilized to determine affected biological functions. Consensus cluster and hierarchical cluster methods were employed to compare the gene expression patterns of the commonly biological functions among these four time course groups. The results showed that severe impairment of inflammation and immune related functions in 5 h and 24 h after symptom onset. However, these functions were less affected in the 3 h and the 6-month groups. In addition, several key genes (CCL20, THBS1, EREG, and IL6 et al.) were dramatically down-regulated in 5 h and 24 h groups, whereas these genes showed no change or even a slight contrary expression in 3 h or 6-month groups. This study has identified the large differences of altered immune and inflammation functions based on gene levels between short and long-term after stroke onset. The findings provide valuable insight into the clinical practice and prognosis evaluation of ischemic stroke.

Integrated Analysis of Alzheimer's Disease and Schizophrenia Dataset Revealed Different Expression Pattern in Learning and Memory.

Alzheimer's disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.

Integrated analysis of ischemic stroke datasets revealed sex and age difference in anti-stroke targets.

Ischemic stroke is a common neurological disorder and the burden in the world is growing. This study aims to explore the effect of sex and age difference on ischemic stroke using integrated microarray datasets. The results showed a dramatic difference in whole gene expression profiles and influenced pathways between males and females, and also in the old and young individuals. Furthermore, compared with old males, old female patients showed more serious biological function damage. However, females showed less affected pathways than males in young subjects. Functional interaction networks showed these differential expression genes were mostly related to immune and inflammation-related functions. In addition, we found ARG1 and MMP9 were up-regulated in total and all subgroups. Importantly, IL1A, ILAB, IL6 and TNF and other anti-stroke target genes were up-regulated in males. However, these anti-stroke target genes showed low expression in females. This study found huge sex and age differences in ischemic stroke especially the opposite expression of anti-stroke target genes. Future studies are needed to uncover these pathological mechanisms, and to take appropriate pre-prevention, treatment and rehabilitation measures.

In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database.

There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency.

Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28-75 were enrolled in this study from September 2005-December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk.