MethMarkerDB: a comprehensive cancer DNA methylation biomarker database.

DNA methylation plays a crucial role in tumorigenesis and tumor progression, sparking substantial interest in the clinical applications of cancer DNA methylation biomarkers. Cancer-related whole-genome bisulfite sequencing (WGBS) data offers a promising approach to precisely identify these biomarkers with differentially methylated regions (DMRs). However, currently there is no dedicated resource for cancer DNA methylation biomarkers with WGBS data. Here, we developed a comprehensive cancer DNA methylation biomarker database (MethMarkerDB, https://methmarkerdb.hzau.edu.cn/), which integrated 658 WGBS datasets, incorporating 724 curated DNA methylation biomarker genes from 1425 PubMed published articles. Based on WGBS data, we documented 5.4 million DMRs from 13 common types of cancer as candidate DNA methylation biomarkers. We provided search and annotation functions for these DMRs with different resources, such as enhancers and SNPs, and developed diagnostic and prognostic models for further biomarker evaluation. With the database, we not only identified known DNA methylation biomarkers, but also identified 781 hypermethylated and 5245 hypomethylated pan-cancer DMRs, corresponding to 693 and 2172 genes, respectively. These novel potential pan-cancer DNA methylation biomarkers hold significant clinical translational value. We hope that MethMarkerDB will help identify novel cancer DNA methylation biomarkers and propel the clinical application of these biomarkers.

ChromLoops: a comprehensive database for specific protein-mediated chromatin loops in diverse organisms.

Chromatin loops (or chromatin interactions) are important elements of chromatin structures. Disruption of chromatin loops is associated with many diseases, such as cancer and polydactyly. A few methods, including ChIA-PET, HiChIP and PLAC-Seq, have been proposed to detect high-resolution, specific protein-mediated chromatin loops. With rapid progress in 3D genomic research, ChIA-PET, HiChIP and PLAC-Seq datasets continue to accumulate, and effective collection and processing for these datasets are urgently needed. Here, we developed a comprehensive, multispecies and specific protein-mediated chromatin loop database (ChromLoops, https://3dgenomics.hzau.edu.cn/chromloops), which integrated 1030 ChIA-PET, HiChIP and PLAC-Seq datasets from 13 species, and documented 1 491 416 813 high-quality chromatin loops. We annotated genes and regions overlapping with chromatin loop anchors with rich functional annotations, such as regulatory elements (enhancers, super-enhancers and silencers), variations (common SNPs, somatic SNPs and eQTLs), and transcription factor binding sites. Moreover, we identified genes with high-frequency chromatin interactions in the collected species. In particular, we identified genes with high-frequency interactions in cancer samples. We hope that ChromLoops will provide a new platform for studying chromatin interaction regulation in relation to biological processes and disease.

Transcriptome analysis provides insights into copper toxicology in piebald naked carp (Gymnocypris eckloni).

BACKGROUND: Copper was used for many years in aquaculture operations as an effective algaecide or a parasite treatment of fish. It is an essential nutrient with numerous functions in organisms, but is toxic at high concentrations. However, the toxicity of copper to fish remains unclear. In this study, we used the piebald naked carp, Gymnocypris eckloni, as a model. RNA-seq data from different tissues, including gills, kidney, and liver, were used to investigate the underlying mechanism of copper toxicology in G. eckloni. RESULTS: We compared the transcriptomes from different tissues with different time durations of copper ion treatment. After 72 h copper ion treatment, the number of genes with different expression in gills and liver changed dramatically, but not in kidneys. In KEGG functional enrichment, the pattern of differentially expressed genes (DEGs) was also similar in the gills and liver. The most enriched pathway of DEGs was "Ribosome" in both tissues. Furthermore, we analyzed the expression levels of genes involved in oxidative stress response and protein synthesis using qPCR and RNA-seq data. Our results showed that several genes involved in oxidative stress response were up-regulated both in gills and liver. Up-regulation of these genes indicated that copper treatment caused oxidative stress, which is likely to result in ribosome damage. In addition, our results showed that the expression of Eef1b2, a transcription elongation factor, was decreased in the liver under oxidative stress, and the expression of translation initiation factors Eif4ebp1 and eIF2α, and elongation factor eEF2 was up-regulated. These results supported the idea that oxidative stress inhibits protein synthesis in cells. CONCLUSIONS: Our results indicate that copper exposure caused different responses in different tissues, since the gene expression patterns changed substantially either in the gills or liver, while the effect on the kidney was relatively weak. Furthermore, our results indicated that the expression pattern of the genes involved in the ribosome, which is a complex molecular machine orchestrating protein synthesis in the cell, together with translation initiation factor and elongation factors, were affected by copper exposure both in the gills and liver of piebald naked carp. This result leads us to speculate that the downregulation of global protein synthesis is an acute response strategy of fish to metal-induced oxidative stress. Moreover, we speculate that this strategy not only exists in the selective translation of proteins but also exists in the specific translation of functional proteins in tissues and cells.

Calcineurin Immune Signaling in Response to Zinc Challenge in the Naked Carp Gymnocypris eckloni.

Zinc pollution impairs neural processes and protein function and also effects calcium-related transcriptional regulation and enzyme activity. In this study, we investigated pathways that potentially respond to calcium signaling under Zn2+ stress. Specifically we measured relative expressions of GeCNAα, GeCNB, GeMT, GeTNF-α, GeIL-1ß, and GeHsp90 in gills, livers, and kidneys of the indicator species Gymnocypris eckloni and found wide variation in their expression between tissues during the course of Zn2+ exposure. Notably, GeCNAα, GeCNB, GeTNF-α, GeIL-1ß, and GeMT were rapidly and strongly up-regulated in gills; GeIL-1ß and GeHsp90 transcription was quickly induced in kidneys; and GeCNB, GeTNF-α, GeIL-1ß, and GeHsp90 were most rapidly up-regulated in livers. GeCNAα and GeMT showed a contrasting late transcriptional up-regulation. These results suggest independent branches for chelation and immune responses during self-protection against Zn2+ toxicity, and the immune response appears to be faster than metal chelation.

Duplication of toll-like receptor 22 in teleost fishes.

The TLRs of teleost fishes have distinct features and are highly diverse, but the duplication characteristics and expression patterns of the tlr22 gene remain unclear. Here, we identified paralogous tlr22 genes in 13 teleost fishes by screening available fish genomic resources and using molecular cloning. We then conducted comprehensive bioinformatics analyses and investigated spatiotemporal differences in the expression patterns of the tlr22 genes in G. eckloni. The results indicated that more than three paralogous tlr22 genes were possessed by some teleost fishes. Of these, tlr22c is specific to some subfamilies of the Cyprinidae (e.g., Barbinae, Cyprininae, Schizothoracinae, and Leuciscinae). Phylogenetic and syntenic analyses showed that the paralogous tlr22 genes originated from two single-gene duplication events. Molecular clock calculations dated the two gene duplication events at 49.5 and 39.3 MYA, which is before the common carp-specific genome duplication event and well after the fish-specific genome duplication. Gene duplication of tlr22 was followed by gene loss or pseudogene events in certain lineages. Spatiotemporal expression differences between the three duplicated tlr22 genes from G. eckloni suggested that these genes diverged functionally after gene duplication.

In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis.

It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

Dynamic Construction Scheme for Virtualization Security Service in Software-Defined Networks.

For a Software Defined Network (SDN), security is an important factor affecting its large-scale deployment. The existing security solutions for SDN mainly focus on the controller itself, which has to handle all the security protection tasks by using the programmability of the network. This will undoubtedly involve a heavy burden for the controller. More devastatingly, once the controller itself is attacked, the entire network will be paralyzed. Motivated by this, this paper proposes a novel security protection architecture for SDN. We design a security service orchestration center in the control plane of SDN, and this center physically decouples from the SDN controller and constructs SDN security services. We adopt virtualization technology to construct a security meta-function library, and propose a dynamic security service composition construction algorithm based on web service composition technology. The rule-combining method is used to combine security meta-functions to construct security services which meet the requirements of users. Moreover, the RETE algorithm is introduced to improve the efficiency of the rule-combining method. We evaluate our solutions in a realistic scenario based on OpenStack. Substantial experimental results demonstrate the effectiveness of our solutions that contribute to achieve the effective security protection with a small burden of the SDN controller.

A highly selective and sensitive probe for Cu2+ based on rhodamine-pyridazine conjugate and its application.

A naked-eye fluorescent chemodosimeter based on rhodamine-pyridazine conjugate L was synthesized and characterized. L exhibited high selectivity and excellent sensitivity in both absorbance and fluorescence detection of Cu(2+) in aqueous solution with a broad pH span (1-10). The detection limit of the probe was shown to be up to 0.336 ppm. A simple paper test-strip system for the rapid monitoring of Cu(2+) was developed, indicating its convenient use in environmental samples. Furthermore, fluorescence imaging experiments of Cu(2+) in living MGC803 cells demonstrated its value of practical applications in biological systems.

Identification of Fusarium oxysporum Causing Leaf Blight on Dendrobium chrysotoxum in Yunnan Province, China.

Leaf-blight disease caused by the Fusarium oxysporum is an emerging problem in Dendrobium chrysotoxum production in China. Symptoms of leaf blight were observed on seedlings of D. chrysotoxum cultivated in a nursery in Ruili City, Yunnan Province, China. In this study, we isolated the Fusarium sp. associated with leaf-blight disease of D. chrysotoxum from the diseased seedlings. A pathogenicity test was performed to fulfill Koch's postulates to confirm the pathogenicity of isolated strains and identified using morphological and molecular techniques. The results revealed that all four isolated Fusarium sp. isolates (DHRL-01~04) produced typical blight symptoms followed by marginal necrosis of leaves on the D. chrysotoxum plants. On the PDA medium, the fungal colony appeared as a white to purplish color with cottony mycelium growth. Microconidia are oval-shaped, whereas macroconidia are sickle-shaped, tapering at both ends with 2-4 septations. The phylogenetic trees were construed based on internal transcribed spacer (ITS), translation elongation factor (EF-1α), and RNA polymerase subunit genes RPB1 and RPB2 genes, respectively, and blasted against the NCBI database for species confirmation. Based on the NCBI database's blast results, the isolates showed that more than 99% identify with Fusarium oxysporum. To our knowledge, this is the first comprehensive report on the identification of Fusarium oxysporum as the causal agent of Dendrobium chrysotoxum leaf blight in Yunnan Province, China, based on morphological and molecular characteristics.

AraENCODE: A comprehensive epigenomic database of Arabidopsis thaliana.

Arabidopsis is an important model organism in plant biology and genetics, and a large number of a chromatin conformation and epigenomic datasets have been generated to study the biology in Arabidopsis. To make it easier to access the accumulated epigenomic data, a user-friendly and reproducible epigenomic database, AraENCODE was developed. It contains various datasets and resources, including chromatin conformation, epigenomic, and transcriptome data, allowing researchers to investigate the regulation of epigenetic and chromatin interactions in Arabidopsis.

Design, synthesis and vasodilative activity of tanshinone IIA derivatives.

A new series of tanshinone IIA (DIIA) derivatives were synthesized through the reaction of brominated tanshinone IIA (1-Br DIIA) and aromatic acids in the presence of K(2)CO(3). Twenty compounds were synthesized, and all of them were novel. Vasodilative activities for synthesized compounds were valuated in vitro on the contractile response of vascular thoracic aorta smooth muscle from Wistar rats. The results showed that most compounds exhibited a concentration-dependent inhibition on the contractile response of norepinephrine. Four prepared compounds, 4, 5, 8 and 13 revealed relatively remarkable vasodilative activity.

Anti-diabetic effects of linarin from Chrysanthemi Indici Flos via AMPK activation.

Objective: The purpose of this study is to investigate the anti-diabetic effects of linarin, a flavonoid extracted from Chrysanthemi Indici Flos (CIF), and its potential mechanisms. Methods: The effects of linarin on cell viability and glucose consumption in HepG2 cells were measured. Meanwhile, monosodium glutamate (MSG) mouse model was constructed to monitor the changes of insulin tolerance, glucose tolerance, triglyceride and cholesterol. The protein expression levels of p-AMPK, p-ACC, PEPCK and p-GS were detected by Western blot. Results: Linarin could increase the relative glucose consumption of HepG2 cells, improve insulin tolerance and glucose tolerance, and decrease the levels of triglyceride and cholesterol of MSG mice. Simultaneously, the expression levels of p-AMPK and p-ACC in HepG2 cells and the liver tissue of MSG mice were increased, while the expression levels of PEPCK and p-GS were decreased after treatment with linarin. Conclusion: Insulin resistance could be ameliorated by linarin in type 2 diabetes, and its mechanism may be related to AMPK signaling pathway.

Insights Into miRNA-mRNA Regulatory Mechanisms of Cold Adaptation in Gymnocypris eckloni: Ubiquitin-Mediated Proteolysis Is Pivotal for Adaptive Energy Metabolism.

This study aimed to understand cold stress adaptations mechanism in fish. Thus, the transcriptional response to cold conditions in Gymnocypris eckloni was evaluated using RNA-seq and microRNA (miRNA)-seq analyses. Low-temperature (LT) group G. eckloni was cultivated outdoors in waters cooled to 2-4°C for 3 weeks, while individuals in the control temperature (CT) group were exposed to 14-16°C. Significantly different responses were observed in both mRNA and miRNA expression profiles, with more mRNAs (1,833 and 1,869 mRNAs were up- and downregulated, respectively) and fewer miRNAs (15 and 6 were up- and downregulated, respectively) observed in the LT group individuals relative to the CT group individuals. A miRNA-mRNA network involved in the regulation of G. eckloni responses to cold stress was constructed; this network included ubiquitin-mediated proteolysis, protein processing, and oxidative phosphorylation. These results provided new insights into mechanisms of cold tolerance by fish, including decreased metabolic activity in addition to proteolysis.

Synthesis and vasodilative activity of tanshinone IIA derivatives.

A series of 2,2'-(substituted methylene)bis-(1,6,6-trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione) derivatives were synthesized by the reaction of tanshinone IIA (D(1)) and aromatic aldehyde in the presence of p-TsOH. Bromination derivative of D(1) and hydrolysis product of cryptotanshinone (D(2)) were also prepared in this work. Vasodilation activity in vitro of them was valuated on the contractile response of vascular thoracic aorta smooth muscle from Wistar rats for the first time. Most of them exhibited a concentration-dependent inhibition on the contractile response of norepinephrine.

Long-term and longitudinal nutrient stoichiometry changes in oligotrophic cascade reservoirs with trout cage aquaculture.

The potential nutrient stoichiometry changes caused by trout cage aquaculture is concerned especially in oligotrophic waters. Long-term total nitrogen (N), total phosphorus (P) and N:P ratio changes in 6 cascade reservoirs with rainbow trout cage aquaculture in the oligotrophic upstream Yellow River (UYR) were studied from 2013 to 2017 in this paper. The 5-year monitoring results showed that N, P and N:P ratio levels showed no obvious long-term changes in high-altitude oligotrophic waters with rainbow trout cage aquaculture. No obvious longitudinal N, P and N:P ratio level changes were observed in the 6 cascade reservoirs from upstream Longyangxia Reservoir (LYR) to downstream Jishixia Reservoir (JSR). The increased N and P resulting from the cage aquaculture accounted only for 1.74% and 5.2% of the natural N and P levels, respectively, with a fish production of 10,000 tonnes. The upstream Yellow River remained oligotrophic and phosphorus-limited. Results in this study proved that trout cage aquaculture do not necessarily cause nitrogen, phosphorus and N:P ratio changes even in oligotrophic waters. Phosphorus should be considered first when identifying priority nitrogen and phosphorus sources and the corresponding control measures in waters with high N:P ratio.

Effect of GCP-02, a PPARalpha/gamma dual activator, on glucose and lipid metabolism in insulin-resistant mice.

This paper reports on the effect of GCP-02, a dual activator of the peroxisome proliferator-activated receptors alpha/gamma (PPARalpha/gamma), on glucose and lipid metabolism in insulin-resistant obese mice induced by monosodium glutamate. The mice were divided into four groups on the basis of treatment: control group, rosiglitazone (positive control) (7 micromol/kg), and low- and high-dosage GCP-02 (7 micromol/kg and 3.5 micromol/kg, respectively). Drugs were given orally once a day for 19 days, and mice underwent testing for insulin tolerance, oral glucose tolerance and gluconeogenesis, and plasma cholesterol, triglyceride and free fatty acid levels. Mice were sacrificed, and body length and weight were measured; intraperitoneal adipose, heart and liver weighed; and plasma alanine aminotransferase (ALT) level and aspartate aminotransferase (AST) activity measured. Liver, soleus muscle and myocardium were assayed for glycogen, triglyceride and free fatty acid content and myocardia tested for superoxide dismutase (SOD) activity and malonaldehyde content. RT-PCR revealed expression of insulin receptor substrate 1 and 2 (IRS1, IRS2) and related genes in liver. GCP-02 had a more powerful effect than rosiglitazone on improving insulin sensitivity, ameliorating glucose tolerance, suppressing L-alanine-induced gluconeogenesis, and decreasing plasma levels of cholesterol, triglyceride and free fatty acid. It reduced body weight in control mice, significantly lowered hepatic content of glycogen, triglyceride and free fatty acid and myocardial content of triglyceride, and increased myocardial SOD activity. IRS2 mRNA was down-regulated in control mice but up-regulated by GCP-02. Thus, GCP-02 is a potential candidate for the prevention and therapy of diseases associated with insulin resistance such as type 2 diabetes mellitus and cardiovascular disease.

Limonoids isolated from Toona sinensis and their radical scavenging, anti-inflammatory and cytotoxic activities.

A phytochemical investigation of the ethanol extract of Toona sinensis (A. Juss.) Roem resulted in the isolation of ten new limonoids, toonasinenines A-J (1-10), together with two known compounds, toonafolin (11) and toonacilianin D (12). Their structures were determined by spectroscopic analyses. The isolated components were evaluated in vitro for radical scavenging potential using ABTS⋅+ and DPPH test, anti-inflammatory activities for Cox-1 and Cox-2, and cytotoxicies against nine tumour cell lines (A549, BGC-823, CHG-5, HCT15, HeLa, HepG2, MDA-MB-231, SHG-44 and SGC-7901 cells). As a result, 4, 5 and 7-10 showed potent radical scavenging activities, while limonoids 1-4 and 11 exhibited significant anti-inflammatory and cytotoxic potential.

A fluorescence ratiometric chemosensor for Fe³âº based on TBET and its application in living cells.

Based on a through bond energy transfer (TBET) between rhodamine and naphthalimide fluorophores, a fluorescent ratiometric chemosensor L was designed and prepared for highly selective detection of Fe(3+) in aqueous solution and in living EC109 cells. These significant changes in the fluorescence color could be used for naked-eye detection. The reversibility established the potential of the probe as chemosensor for Fe(3+) detection.

The feasibility of using near-infrared spectroscopy and chemometrics for untargeted detection of protein adulteration in yogurt: removing unwanted variations in pure yogurt.

Untargeted detection of protein adulteration in Chinese yogurt was performed using near-infrared (NIR) spectroscopy and chemometrics class modelling techniques. sixty yogurt samples were prepared with pure and fresh milk from local market, and 197 adulterated yogurt samples were prepared by blending the pure yogurt objects with different levels of edible gelatin, industrial gelatin, and soy protein powder, which have been frequently used for yogurt adulteration. A recently proposed one-class partial least squares (OCPLS) model was used to model the NIR spectra of pure yogurt objects and analyze those of future objects. To improve the raw spectra, orthogonal projection (OP) of raw spectra onto the spectrum of pure water and standard normal variate (SNV) transformation were used to remove unwanted spectral variations. The best model was obtained with OP preprocessing with sensitivity of 0.900 and specificity of 0.949. Moreover, adulterations of yogurt with 1% (w/w) edible gelatin, 2% (w/w) industrial gelatin, and 2% (w/w) soy protein powder can be safely detected by the proposed method. This study demonstrates the potential of combining NIR spectroscopy and OCPLS as an untargeted detection tool for protein adulteration in yogurt.

[Spatial distribution of fig wasps in syconia of two monoecious Ficus sp].

In addition to pollinator fig wasps, there are several non-pollinating fig wasps associated with monoecious Ficus sp. In order to understand how pollinator fig wasps and non-pollinating fig wasps are distributed across the same syconium, the spatial distribution of fig wasps associated with Ficus altissima and F. benjamina were compared using the pedicle lengths of galls containing each species. The results indicate that in Ficus altissima, the average pedicel length of galls containing Eupristina sp. is longer than that containing E. altissima. Average pedicel length of galls containing Sycobia sp., Micranisa ralianga and Sycoscapter sp. two did not show significant difference. The range of pedicel lengths of galls containing Sycobia sp., M. ralianga or Sycoscapter sp. two is narrower than that of galls containing E. altissima, indicating these non-pollinating fig wasps and pollinator have partially separated spatial niches. In F. benjamina, E. koningsbergeri was distributed in galls from the outer layer to inner layer, while most Walkerella sp. were found in outer layer galls, indicating E. koningsbergeri and Walkerella sp. have partially separated spatial niches.