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The aim of this study was to analyze the role of blood biomarkers regarding preoperative inflammation and coagulation in predicting the postoperative in-hospital mortality of patients with type A acute aortic dissection (AAD). A total of 206 patients with type A AAD who had received surgical treatment were enrolled in this study. Patients were divided into two groups: the death group (28 patients who died during hospitalization) and the survival group (178 patients). Peripheral blood samples were collected before anesthesia induction. Preoperative levels of D-dimer, fibrinogen (FIB), platelet (PLT), white blood cells (WBC) and neutrophil (NEU) were compared between the two groups. Univariable and multivariable logistic regression analysis were utilized to identify the independent risk factors for postoperative in-hospital deaths of patients with type A AAD. Receiver operating characteristic (ROC) curve were used to analyze the predictive value of these indices in the postoperative in-hospital mortality of the patients. Univariable logistic regression analysis showed that the P values of the five parameters including D-dimer, FIB, PLT, WBC and NEU were all less than 0.1, which may be risk factors for postoperative in-hospital deaths of patients with type A AAD. Further multivariable logistic regression analysis indicated that higher preoperative D-dimer and WBC levels were independent risk factors for postoperative in-hospital mortality of patients with type A AAD. ROC curve analysis indicated that application of combining FIB and PLT could improve accuracy in prediction of postoperative in-hospital mortality in patients with type A AAD. Both preoperative D-dimer and WBC in patients with type A AAD may be used as independent risk factors for the postoperative in-hospital mortality of such patients. The combination of FIB and PLT may improve the accuracy of clinical prognostic assessment.

Plateau zokor inhabits in sealed burrows from 2,000 to 4,200 meters at Qinghai-Tibet Plateau. This extreme living environment makes it a great model to study animal adaptation to hypoxia, low temperature, and high carbon dioxide concentration. We provide an integrated resource, ZokorDB, for tissue specific regulatory network annotation for zokor. ZokorDB is based on a high-quality draft genome of a plateau zokor at 3,300 m and its transcriptional profiles in brain, heart, liver, kidney, and lung. The conserved non-coding elements of zokor are annotated by their nearest genes and upstream transcriptional factor motif binding sites. ZokorDB provides a general draft gene regulatory network (GRN), i.e., potential transcription factor (TF) binds to non-coding regulatory elements and regulates the expression of target genes (TG). Furthermore, we refined the GRN by incorporating matched RNA-seq and DNase-seq data from mouse ENCODE project and reconstructed five tissue-specific regulatory networks. A web-based, open-access database is developed for easily searching, visualizing, and downloading the annotation and data. The pipeline of non-coding region annotation for zokor will be useful for other non-model species. ZokorDB is free available at the website (bigd.big.ac.cn/zokordb/).

The prenatal-to-postnatal transition is a pivotal process in the life cycle whereby an organism shifts from responding to intrauterine cues to undergoing extrauterine stresses with many physiological adaptations. However, the molecular basis underlying the evolutionarily conserved physiological adaptations remains elusive. Here, we analyze the transcriptomes of seven organs across developmental time points from five mammalian species by constructing computational coexpression networks and report a developmental shift of gene expression at the perinatal stage. The low-to-high and high-to-low expressed genes tightly coalesce in the functional categories and gene regulatory pathways that implicate the physiological adaptions during the prenatal-to-postnatal transition, including lipid metabolism, circadian rhythm, immune response, cell cycle, and cell division. The low-to-high and high-to-low expressed genes around the perinatal stage tend to form the mutually inhibitory toggle switch gene pairs linking the gene regulatory networks in response to the environmental changes. We thus propose the toggle switch model for the developmental shift of gene expression as a mechanic framework to investigate how the physiological adaptations occur during the prenatal-to-postnatal transition.

Cancer stem cells (CSCs) are characterized by their ability to self-renew, to differentiate into multiple cell types and also drive tumor formation, altogether making them important cellular targets for therapeutic intervention. However, existing CSC-targeting drugs do not significantly improve clinical outcomes. More recently, preclinical studies of natural product-derived compounds have demonstrated their potential usefulness as a therapeutic cancer treatment through their cytotoxic actions on CSCs.Here, we identify CSC-specific compounds derived from natural products and characterize their putative mechanisms of action in CSCs.Glioblastoma stem cells (GSCs) were labeled with EGFP via homologous recombination and utilized for a high-throughput screen of 8,344 fractions from 386 herbal medicines. The fractions that extinguished EGFP fluorescence signal were then further characterized by LC-MS/MS. Next, several putative cytotoxic compounds were evaluated for their cytotoxic effects on GSCs, cancer cell lines and immortalized cells using a variety of methods to study cell proliferation (EdU incorporation assay), cell death (cleaved-Caspase-3 immunostaining), DNA damage (comet assay), mitochondrial membrane changes (JC-1 immunostaining), and tumor formation in vitro (soft agar colony forming assay). We also performed surface plasmon resonance analysis, western blotting, and immunohistochemistry to characterize the putative mechanisms underlying the cytotoxic effects of putative compounds on GSCs. Finally, we carried out xenograft tumor growth assays to study the cytotoxic potential of several candidates in vivo.Our high throughput screen led to the identification of the furostanol saponin taccaoside A and its two homologs from the rhizomatous geophyte Tacca. subflabellata that were cytotoxic to GSCs. Interestingly, the cytotoxic effect of taccaoside A on cell lines was significantly less compared to its homologs, owing to stereochemical differences of a carbon-carbon double bond between C-20 and C-22. Molecular studies revealed that taccaoside A binds to RAS to inhibit downstream effector signaling. Correspondingly, blockade of the interaction between taccaoside A and RAS abolished the inhibitory effect of this compound on CSCs. Furthermore, taccaoside A treatment was effective in limiting tumor cell growth in vivo.Our study yielded an effective approach to screen for CSC-specific agents. Through this approach, we identified taccaoside A from the rhizomatous geophyte Tacca. subflabellata are cytotoxic to CSCs through a molecular mechanism that involves RAS binding and suppression of its downstream signaling. Our findings indicate taccaoside A is a potential lead compound for anti-CSC drug discovery.

Myocardial ischaemia-reperfusion injury (MIRI) is a main pathophysiologic change following CPB surgery. L-carnitine, a natural amino acid, is able to transport fatty acids for generating energy and has a protective effect on MIRI. We aim to investigate the protective effect of L-carnitine on MIRI in patients with rheumatic valvular heart disease (RVHD) performed CPB surgical operation and the underlying mechanism. In this study, patients were randomized to three groups. L-carnitine was added to the crystalloid cardioplegic solution for experimental group 1 (6 g/L) and experimental group 2 (12 g/L), whereas no L-carnitine was used in the control group. Our results showed that L-carnitine significantly attenuated myocardial injury after surgery in these patients. L-carnitine decreased serum markers of myocardial injury including CK-MB, cTnI, hs-cTnT and IMA. L-carnitine increased left ventricular ejection fraction (LVEF) but reduced wall motion score index (WMSI) after operation. L-carnitine also inhibited myeloperoxidase (MPO) activity and inflammatory cytokines in the myocardium of patients after unclamping the aorta. Additionally, L-carnitine increased levels of superoxide dismutase (SOD) and catalase (CAT) while decreased levels of malondialdehyde (MDA) and protein carbonyl content in the myocardium of patients after unclamping the aorta. Moreover, L-carnitine suppressed the activation of nuclear factor kappa B (NF-κB) and activated nuclear factor erythroid 2-related factor 2 (Nrf2). There was also no significant difference in these indices between two experimental groups after unclamping the aorta. Taken together, L-carnitine had a protective effect against CPB-induced MIRI in patients with RVHD, which might be related to its modulation of NF-κB and Nrf2 activities.

Acute aortic dissection is one of the most severe vascular diseases. The molecular mechanisms of aortic expansion and dissection are unclear. Clinical studies have found that statins play a protective role in aortic dissection development and therapy, however, the mechanism of statins’ effects on the aorta is unknown. The Gene Expression Omnibus (GEO) dataset GSE52093, GSE2450and GSE8686 were analyzed, and genes expressed differentially between aortic dissection samples and normal samples were determined using the Networkanalyst and iDEP tools. Weight gene correlation network analysis (WGCNA), functional annotation, pathway enrichment analysis, and the analysis of the regional variations of genomic features were then performed. We found that the minichromosome maintenance proteins (MCMs), a family of proteins targeted by statins, were upregulated in dissected aortic wall tissues and play a central role in cell-cycle and mitosis regulation in aortic dissection patients. Our results indicate a potential molecular target and mechanism for statins’ effects in patients with acute type A aortic dissection.

Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we demonstrate that inactivation of Cdkn2b (p15ink4b) is necessary for induction of pancreatic cancer by oncogenic KRASG12D expression and inactivation of Tp53 and Cdkn2a in adult mouse pancreatic ductal cells (P60 or older). KRASG12D overexpression in these cells activated transforming growth factor-β signaling and expression of CDKN2B, which, along with CDKN2A, led to cellular senescence and protected cells from KRAS-mediated transformation via inhibition of retinoblastoma phosphorylation. These results show a critical role of CDKN2B inactivation in pancreatic carcinogenesis, and provide a useful adult animal model by genetic engineering via lentiviral delivery.

Maintenance of lipid homeostasis is crucial for cells in response to lipid requirements or surplus. The SREBP transcription factors play essential roles in regulating lipid metabolism and are associated with many metabolic diseases. However, SREBP regulation of lipid metabolism is still not completely understood. Here, we showed that reduction of SBP-1, the only homolog of SREBPs in Caenorhabditis elegans, surprisingly led to a high level of zinc. On the contrary, zinc reduction by mutation of sur-7, encoding a member of the cation diffusion facilitator (CDF) family, restored the fat accumulation and fatty acid profile of the sbp-1(ep79) mutant. Zinc reduction resulted in iron overload, which thereby directly activated the conversion activity of stearoyl-CoA desaturase (SCD), a main target of SREBP, to promote lipid biosynthesis and accumulation. However, zinc reduction reversely repressed SBP-1 nuclear translocation and further downregulated the transcription expression of SCD for compensation. Collectively, we revealed zinc-mediated regulation of the SREBP-SCD axis in lipid metabolism, distinct from the negative regulation of SREBP-1 or SREBP-2 by phosphatidylcholine or cholesterol, respectively, thereby providing novel insights into the regulation of lipid homeostasis.

// Yaohui Tong 1, 2, * , Junjun Hao 3, * , Qiu Tu 2, 4, * , Hualin Yu 5 , Lanzhen Yan 2, 6 , Yuan Li 2, 4, 7 , Longbao Lv 6 , Fei Wang 5 , Antonio Iavarone 8 , Xudong Zhao 2, 6 1 School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China 2 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China 3 State Key Lab of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China 4 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China 5 Department of Neurological Surgery, The First Affiliated Hospital, Kunming Medical University, Kunming, Yunnan, 650032, China 6 Kunming Primate Research Center, Chinese Academy of Sciences, Kunming, Yunnan 650223, China 7 Kunming University of Science and Technology, Kunming, Yunnan, 650500, China 8 Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA * These authors contributed equally to this work Correspondence to: Xudong Zhao, email: zhaoxudong@mail.kiz.ac.cn Keywords: glioblastoma, animal model, tree shrew, P53 Received: June 03, 2016 Accepted: January 16, 2017 Published: February 09, 2017 ABSTRACT Tupaia belangeri (tree shrew), an animal species whose genome has significantly higher similarity to primates than rodents, has been used in biomedical research. To generate animal models that reproduce the human tumors more faithfully than rodents, we present the first report of a cancer model mimicking human tumor genetics in tree shrew. By engineering a lentiviral system for the transduction of mutant H-Ras and a shRNA against tree shrew p53, we successfully generated malignant glioma in tree shrew. The tree shrew glioma exhibited aggressive behavior and a relatively short latency, and markedly reduced animal survival. Remarkably, the biological features of human high-grade glioma (necrosis, microvascular proliferation, pseudopalisading) were all present in tree shrew glioma. Furthermore, genetic analysis of tree shrew glioma revealed that the tumors were clustered within the mesenchymal subgroup of human glioblastoma multiforme. Compared with the corresponding mouse glioma, tree shrew gliomas were markedly more similar to human glioblastoma at gene expression profile. The tree shrew glioma model provides colleagues working in the field of gliomas and cancer in general with a more accurate animal model.

BackgroundThe Chinese white wax scale insect, Ericerus pela, is best known for producing wax, which has been widely used in candle production, casting, Chinese medicine, and wax printing products for thousands of years. The secretion of wax, and other unusual features of scale insects, is thought to be an adaptation to their change from an ancestral ground-dwelling lifestyle to a sedentary lifestyle on the higher parts of plants. As well as helping to improve its economic value, studies of E. pela might also help to explain the adaptation of scale insects. However, no genomic data are currently available for E. pela.FindingsTo assemble the E. pela genome, 303.92 Gb of data were generated using Illumina and Pacific Biosciences sequencing, producing 277.22 Gb of clean data for assembly. The assembled genome size was 0.66 Gb, with 1,979 scaffolds and a scaffold N50 of 735 kb. The guanine + cytosine content was 33.80%. A total of 12,022 protein-coding genes were predicted, with a mean coding sequence length of 1,370 bp. Twenty-six fatty acyl-CoA reductase genes and 35 acyltransferase genes were identified. Evolutionary analysis revealed that E. pela and aphids formed a sister group and split ∼241.1 million years ago. There were 214 expanded gene families and 2,219 contracted gene families in E. pela.ConclusionWe present the first genome sequence from the Coccidae family. These results will help to increase our understanding of the evolution of unique features in scale insects, and provide important genetic information for further research.

Myocardial ischaemia-reperfusion injury (MIRI) is a main pathophysiologic change following CPB surgery. L-carnitine, a natural amino acid, is able to transport fatty acids for generating energy and has a protective effect on MIRI. We aim to investigate the protective effect of L-carnitine on MIRI in patients with rheumatic valvular heart disease (RVHD) performed CPB surgical operation and the underlying mechanism. In this study, patients were randomized to three groups. L-carnitine was added to the crystalloid cardioplegic solution for experimental group 1 (6 g/L) and experimental group 2 (12 g/L), whereas no L-carnitine was used in the control group. Our results showed that L-carnitine significantly attenuated myocardial injury after surgery in these patients. L-carnitine decreased serum markers of myocardial injury including CK-MB, cTnI, hs-cTnT and IMA. L-carnitine increased left ventricular ejection fraction (LVEF) but reduced wall motion score index (WMSI) after operation. L-carnitine also inhibited myeloperoxidase (MPO) activity and inflammatory cytokines in the myocardium of patients after unclamping the aorta. Additionally, L-carnitine increased levels of superoxide dismutase (SOD) and catalase (CAT) while decreased levels of malondialdehyde (MDA) and protein carbonyl content in the myocardium of patients after unclamping the aorta. Moreover, L-carnitine suppressed the activation of nuclear factor kappa B (NF-κB) and activated nuclear factor erythroid 2-related factor 2 (Nrf2). There was also no significant difference in these indices between two experimental groups after unclamping the aorta. Taken together, L-carnitine had a protective effect against CPB-induced MIRI in patients with RVHD, which might be related to its modulation of NF-κB and Nrf2 activities.

Significance Triple-negative breast cancer (TNBC) is responsible for significant mortality among breast cancer subtypes, with its treatment largely unsuccessful due to ineffective targeted therapies. Our bioinformatics analysis demonstrates a unique alternative splicing pattern in TNBC compared with those of other breast cancers. In analyzing the underlying mechanism of the distinct alternative splicing profile, TDP43, a critical gene previously implicated in neurodegenerative disease, is found to promote TNBC progression. Mechanistically, TDP43 regulates extensive alternative splicing events, including downstream gene PAR3, by forming a complex with SRSF3 to regulate alternative splicing events coordinately. Splicing factors TDP43 and SRSF3, which are likely responsible for the unique alternative splicing, could serve as potential targets for TNBC therapy., Aberrant alternative splicing has been highlighted as a potential hallmark of cancer. Here, we identify TDP43 (TAR DNA-binding protein 43) as an important splicing regulator responsible for the unique splicing profile in triple-negative breast cancer (TNBC). Clinical data demonstrate that TDP43 is highly expressed in TNBC with poor prognosis. Knockdown of TDP43 inhibits tumor progression, including proliferation and metastasis, and overexpression of TDP43 promotes proliferation and malignancy of mammary epithelial cells. Deep sequencing analysis and functional experiments indicate that TDP43 alters most splicing events with splicing factor SRSF3 (serine/arginine-rich splicing factor 3), in the regulation of TNBC progression. The TDP43/SRSF3 complex controls specific splicing events, including downstream genes PAR3 and NUMB. The effect of reduced metastasis and proliferation upon the knockdown of TDP43 or SRSF3 is mediated by the splicing regulation of PAR3 and NUMB exon 12, respectively. The TDP43/SRSF3 complex and downstream PAR3 isoform are potential therapeutic targets for TNBC.

The problem of synchronization for a class of complex delayed dynamical networks via pinning periodically intermittent control is considered in this Letter. Some novel and useful exponential synchronization criteria are obtained by utilizing the methods which are different from the techniques employed in the existing works, and the derived results are less conservative. Especially, the traditional assumptions on control width and time delays are released in our results. Moreover, a pinning scheme deciding what nodes should be chosen as pinned candidates and how many nodes are needed to be pinned for a fixed coupling strength is provided. A Barabasi–Albert network example is finally given to illustrate the effectiveness of the theoretical results.

Node positioning is a fundamental problem in applications of wireless sensor networks (WSNs). In this paper, a new range-free algorithm, called spring swarm localization algorithm (SSLA), is proposed for positioning WSNs. To determine the locations of sensor nodes, the proposed algorithm uses network topology information and a small fraction of sensor nodes which know their locations. Numerical simulations show that high positioning accuracy can be obtained by using the algorithm. Some examples are given to illustrate the effectiveness of the algorithm.

In this Letter, exponential synchronization of a complex network with nonidentical time-delayed dynamical nodes is considered. Two effective control schemes are proposed to drive the network to synchronize globally exponentially onto any smooth goal dynamics. By applying open-loop control to all nodes and adding some intermittent controllers to partial nodes, some simple criteria for exponential synchronization of such network are established. Meanwhile, a pinning scheme deciding which nodes need to be pinned and a simply approximate formula for estimating the least number of pinned nodes are also provided. By introducing impulsive effects to the open-loop controlled network, another synchronization scheme is developed for the network with nonidentical time-delayed dynamical nodes, and an estimate of the upper bound of impulsive intervals ensuring global exponential stability of the synchronization process is also given. Numerical simulations are presented finally to demonstrate the effectiveness of the theoretical results.

Cytotoxic indole alkaloids from Melodinus suaveolens, which belongs to the toxic plant family Apocynaceae, demonstrated impressive antitumor activities in many tumor types, but less application in glioblastoma, which is the lethal brain tumor. In the present study, we reported the anti-glioblastoma activity of an indole alkaloid, 3α-acetonyltabersonine, which was isolated from Melodinus suaveolens. 3α-acetonyltabersonine was cytotoxic to glioblastoma cell lines (U87 and T98G) and stem cells at low concentrations. We verified 3α-acetonyltabersonine could suppress tumor cell proliferation and cause apoptosis in glioblastoma stem cells (GSCs). Moreover, detailed investigation of transcriptome study and Western blotting analysis indicated the mitogen activated protein kinase (MAPK) pathway was activated by phosphorylation upon 3α-acetonyltabersonine treatment. Additionally, we found 3α-acetonyltabersonine inhibited DNA damage repair procedures, the accumulated DNA damage stimulated activation of MAPK pathway and, finally, induced apoptosis. Further evidence was consistently obtained from vivo experiments on glioblastoma mouse model: treatment of 3α-acetonyltabersonine could exert pro-apoptotic function and prolong the life span of tumor-bearing mice. These results in vitro and in vivo suggested that 3α-acetonyltabersonine could be a potential candidate antitumor agent.

Wide-field optical coherence tomography has a promising application for its high scanning rate and resolution. The principle of a wide-field optical coherence tomography system is described, and 2D images of glass slides are reconstructed using eight-stepped phase-shifting method in the system. Using VC6.0 and OpenGL programming, 3D images are reconstructed based on the Marching Cube algorithm with 2D image sequences. The experimental results show that the depth detection and three-dimensional tomography for translucent materials could be implemented efficiently in the WFOCT system.

MiRNAs, which are a family of small non-coding RNAs, regulate a broad array of physiological and developmental processes. However, their regulatory roles have remained largely mysterious. E2F is a positive regulator of cell cycle progression and also a potent inducer of apoptosis. Positive feedback loops in the regulation of Rb-E2F pathway are predicted and shown experimentally. Recently, it has been discovered that E2F induce a cluster of miRNAs called miR449. In turn, E2F is inhibited by miR449 through regulating different transcripts, thus forming negative feedback loops in the interaction network. Here, based on the integration of experimental evidence and quantitative data, we studied Rb-E2F pathway coupling the positive feedback loops and negative feedback loops mediated by miR449. Therefore, a mathematical model is constructed based in part on the model proposed in Yao-Lee et al. (2008) and nonlinear dynamical behaviors including the stability and bifurcations of the model are discussed. A comparison is given to reveal the implication of the fundamental differences of Rb-E2F pathway between regulation and deregulation of miR449. Coherent with the experiments it predicts that miR449 plays a critical role in regulating the cell cycle progression and provides a twofold safety mechanism to avoid excessive E2F-induced proliferation by cell cycle arrest and apoptosis. Moreover, numerical simulation and bifurcation analysis shows that the mechanisms of the negative regulation of miR449 to three different transcripts are quite distinctive which needs to be verified experimentally. This study may help us to analyze the whole cell cycle process mediated by other miRNAs more easily. A better knowledge of the dynamical behaviors of miRNAs mediated networks is also of interest for bio-engineering and artificial control.

This paper studies the synchronization of coupled chaotic systems with time-varying delays in the presence of parameter mismatches by means of periodically intermittent control. Some novel and useful quasisynchronization criteria are obtained by using the methods which are different from the techniques employed in the existing works, and the derived results are less conservative. Especially, a strong constraint on the control width that the control width should be larger than the time delay imposed by the current references is released in this paper. Moreover, our results show that the synchronization criteria depend on the ratio of control width to control period, but not the control width or the control period. Finally, some numerical simulations are given to show the effectiveness of the theoretical results.

Multiplex community networks, consisting of several different types of simplex networks and interconnected among them, are ubiquitous in the real world. In this paper, we carry out a quantitative discussion on the interaction among these diverse simplex networks. First, we define two measures, mutual-path-strength and proximity-node-density, based on twoplex community networks and then propose an impact-strength-index (ISI) to describe the influence of a simplex network on the other one. Finally, we apply the measure ISI to make an explanation for the challenge system of social relations from the viewpoint of network theory. Numerical simulations show that the measure ISI can describe the interaction between multiplex community networks perfectly.

We propose a new modularity criterion in complex networks, called the unifying modularity q which is independent of the number of partitions. It is shown that, for a given network, the relationship between the upper limit of Q and the number of the partitions, k, is sup(Qk) = (k − 1)/k. Since the range of Q for each partition number is inconsistent, we try to extend the concept Q to unifying modularity q, which is independent of the number of partitions. Subsequently, we indicate that it is more accurately to determine the number of partitions by using unifying modularity q than Q.