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Find video protocols related to scientific articles indexed in Pubmed.
Mitogen-Activated Protein Kinase Signal Transduction in Solid Tumors.
Asian Pac. J. Cancer Prev.
PUBLISHED: 11-07-2014
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Mitogen-activated protein kinase (MAPK) is an important signaling pathway in living beings in response to extracellular stimuli. There are 5 main subgroups manipulating by a set of sequential actions: ERK(ERK1/ ERK2), c-Jun N(JNK/SAPK), p38 MAPK(p38?, p38?, p38? and p38?), and ERK3/ ERK4/ ERK5. When stimulated, factors of upstream or downstream change, and by interacting with each other, these groups have long been recognized to be related to multiple biologic processes such as cell proliferation, differentiation, death, migration, invasion and inflammation. However, once abnormally activated, cancer may occur. Several components of the MAPK network have already been proposed as targets in cancer therapy, such as p38, JNK, ERK, MEK, RAF, RAS, and DUSP1. Among them, alteration of the RAS-RAF-MEK-ERK-MAPK(RAS-MAPK) pathway has frequently been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations in genes. The reported roles of MAPK signaling in apoptotic cell death are controversial, so that further in-depth investigations are needed to address these controversies. Based on an extensive analysis of published data, the goal of this review is to provide an overview on recent studies about the mechanism of MAP kinases, and how it generates certain tumors, as well as related treatments.
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Genetic Analysis of a Novel Tubulin Mutation That Redirects Synaptic Vesicle Targeting and Causes Neurite Degeneration in C. elegans.
PLoS Genet.
PUBLISHED: 11-01-2014
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Neuronal cargos are differentially targeted to either axons or dendrites, and this polarized cargo targeting critically depends on the interaction between microtubules and molecular motors. From a forward mutagenesis screen, we identified a gain-of-function mutation in the C. elegans ?-tubulin gene mec-12 that triggered synaptic vesicle mistargeting, neurite swelling and neurodegeneration in the touch receptor neurons. This missense mutation replaced an absolutely conserved glycine in the H12 helix with glutamic acid, resulting in increased negative charges at the C-terminus of ?-tubulin. Synaptic vesicle mistargeting in the mutant neurons was suppressed by reducing dynein function, suggesting that aberrantly high dynein activity mistargeted synaptic vesicles. We demonstrated that dynein showed preference towards binding mutant microtubules over wild-type in microtubule sedimentation assay. By contrast, neurite swelling and neurodegeneration were independent of dynein and could be ameliorated by genetic paralysis of the animal. This suggests that mutant microtubules render the neurons susceptible to recurrent mechanical stress induced by muscle activity, which is consistent with the observation that microtubule network was disorganized under electron microscopy. Our work provides insights into how microtubule-dynein interaction instructs synaptic vesicle targeting and the importance of microtubule in the maintenance of neuronal structures against constant mechanical stress.
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RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 10-30-2014
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Neurons remodel their connectivity in response to various insults, including microtubule disruption. How neurons sense microtubule disassembly and mount remodeling responses by altering genetic programs in the soma are not well defined. Here we show that in response to microtubule disassembly, the Caenorhabditis elegans PLM neuron remodels by retracting its synaptic branch and overextending the primary neurite. This remodeling required RHGF-1, a PDZ-Rho guanine nucleotide exchange factor (PDZ-RhoGEF) that was associated with and inhibited by microtubules. Independent of the myosin light chain activation, RHGF-1 acted through Rho-dependent kinase LET-502/ROCK and activated a conserved, retrograde DLK-1 MAPK (DLK-1/dual leucine zipper kinase) pathway, which triggered synaptic branch retraction and overgrowth of the PLM neurite in a dose-dependent manner. Our data represent a neuronal remodeling paradigm during development that reshapes the neural circuit by the coordinated removal of the dysfunctional synaptic branch compartment and compensatory extension of the primary neurite.
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Oxidized high-density lipoprotein impairs endothelial progenitor cells function by activation of CD36-MAPK-TSP-1 pathways.
Antioxid. Redox Signal.
PUBLISHED: 10-15-2014
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Aims: High density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which is susceptible to oxidative modifications and then leads to potential pro-atherosclerotic effects. We proposed that oxidized high density lipoprotein (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms. Results: ox-HDL was shown to increase apoptosis and intracellular ROS levels, but reduce migration, angiogenesis and cholesterol efflux of EPCs in a dose dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-?B were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with shRNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inversely correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases or CAD and type 2 diabetes also supported it. Meanwhile HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, furthermore supporting our proposal. Innovation: This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic, but also pro-apoptotic effects of HDL separated from patients' serum. Conclusion: Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease.
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iNOS Inhibitory Activity of Sesquiterpenoids and a Monoterpenoid from the Rhizomes of Curcuma wenyujin.
J. Nat. Prod.
PUBLISHED: 10-02-2014
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Eleven new sesquiterpenoids, wenyujinins A-K (1-11), and a new monoterpenoid, wenyujinin L (12), were isolated from the rhizomes of Curcuma wenyujin. Their structures and relative configurations were elucidated using 1D and 2D NMR, X-ray crystallographic analysis, and HRESIMS data. The absolute configurations of 1, 2, 3, 4, 6, 8, 9, and 10 were determined by comparison of the experimental and calculated ECD spectra. The absolute configuration of 5 was determined from the ECD data of the [Rh2(OCOCF3)4] complex, whereas those of 7 and 12 were determined from the ECD spectra of the compounds alone. Compounds 7 and 7a strongly inhibited the induction of NO production by LPS, with IC50 values of 7.6 and 8.5 ?M, respectively. Compounds 6 and 10 moderately inhibited NO production with IC50 values of 47.7 and 48.6 ?M, respectively.
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Modified Salicylanilide and 3-Phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione Derivatives as Novel Inhibitors of Osteoclast Differentiation and Bone Resorption.
J. Med. Chem.
PUBLISHED: 09-25-2014
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Inhibition of osteoclast formation is a potential strategy to prevent inflammatory bone resorption and to treat bone diseases. In the present work, the purpose was to discover modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives as potential antiosteoclastogenic agents. Their inhibitory effects on RANKL-induced osteoclastogenesis from RAW264.7 cells were evaluated by TRAP stain assay. The most potent compounds, 1d and 5d, suppressed RANKL-induced osteoclast formation and TRAP activity dose-dependently. The cytotoxicity assay on RAW264.7 cells suggested that the inhibition of osteoclastic bone resorption by these compounds did not result from their cytotoxicity. Moreover, both compounds downregulated RANKL-induced NF-?B and NFATc1 in the nucleus, suppressed the expression of osteoclastogenesis-related marker genes during osteoclastogenesis, and prevented osteoclastic bone resorption but did not impair osteoblast differentiation in MC3T3-E1. Therefore, these modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones could be potential lead compounds for the development of a new class of antiresorptive agents.
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The application of flow cytometry for evaluating biological aggressiveness of intracranial meningiomas.
Cytometry B Clin Cytom
PUBLISHED: 09-23-2014
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Meningiomas have classically been considered to include benign and atypical/anaplastic tumors. Despite the availability of clinical and pathologic parameters for prognostic prediction prognosis, the behavior of each meningioma may be difficult to predict. Here, we used DNA flow-cytometric studies to predict biological tumor behaviors of intracranial meningiomas.
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Mining Tissue-specific Contigs from Peanut (Arachis hypogaea L.) for Promoter Cloning by Deep Transcriptome Sequencing.
Plant Cell Physiol.
PUBLISHED: 09-16-2014
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Peanut (Arachis hypogaea L.), one of the most important oil legumes in the world, is heavily damaged by white grubs. Tissue-specific promoters are needed to incorporate insect resistance genes into peanut by genetic transformation to control the subterranean pests. Transcriptome sequencing is the most effective way to analyze differential gene expression in this non-model species and contribute to promoter cloning. The transcriptomes of the roots, seeds and leaves of peanut were sequenced using Illumina technology. A simple digital expression profile was established based on number of transcripts per million clean tags (TPM) from different tissues. Subsequently, 584 root-specific candidate transcript assembly contigs (TACs) and 316 seed-specific candidate TACs were identified. Among these candidate TACs, 55.3% were root-specific and 64.6% were seed-specific by semi-quantitative RT-PCR analysis. Moreover, the consistency of semi-quantitative RT-PCR with the simple digital expression profile was correlated with the length and TPM value of TACs. The results of gene ontology showed that some root-specific TACs are involved in stress resistance and respond to auxin stimulus, whereas, seed-specific candidate TACs are involved in embryo development, lipid storage and long-chain fatty acid biosynthesis. One root-specific promoter was cloned and characterized. We developed a high-yield screening system in peanut by establishing a simple digital expression profile based on Illumina sequencing. The feasible and rapid method presented by this study can be used for other non-model crops to explore tissue-specific or spatially specific promoters.
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Immunization with advanced glycation end products modified low density lipoprotein inhibits atherosclerosis progression in diabetic apoE and LDLR null mice.
Cardiovasc Diabetol
PUBLISHED: 09-15-2014
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BackgroundDiabetes propitiates atherosclerosis through undefined molecular mechanisms. Hyperglycemia induces formation of advanced glycation end product (AGE)-modified low-density lipoprotein (LDL). Anti-AGE-LDL autoantibodies favor atherosclerosis (AS) progression in humans, while anti oxidized LDL immunization inhibits AS in hypercholesterolemic, non-diabetic mice. We here investigated if AGE-LDL immunization protects against AS in diabetic mice.MethodsAfter diabetes induction with streptozotocin and high fat diet, both low density lipoprotein receptor (LDLR)¿/¿ and apoE female mice were randomized to: AGE-LDL immunization with aluminum hydroxide (Alum) adjuvant; Alum alone; or PBS.ResultsAGE-LDL immunization: significantly reduced AS; induced specific plasma IgM and IgG antibodies; upregulated splenic Th2, Treg and IL-10 levels, without altering Th1 or Th17 cells; and increased serum high density lipoprotein(HDL) while numerically lowering HbA1c levels.ConclusionsSubcutaneous immunization with AGE-LDL significantly inhibits atherosclerosis progression in hyperlipidemic diabetic mice possibly through activation of specific humoral and cell mediated immune responses and metabolic control improvement.
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Phosphatidylethanolamine deficiency disrupts ?-synuclein homeostasis in yeast and worm models of Parkinson disease.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 09-08-2014
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Phosphatidylserine decarboxylase, which is embedded in the inner mitochondrial membrane, synthesizes phosphatidylethanolamine (PE) and, in some cells, synthesizes the majority of this important phospholipid. Normal levels of PE can decline with age in the brain. Here we used yeast and worms to test the hypothesis that low levels of PE alter the homeostasis of the Parkinson disease-associated protein ?-synuclein (?-syn). In yeast, low levels of PE in the phosphatidylserine decarboxylase deletion mutant (psd1?) cause decreased respiration, endoplasmic reticulum (ER) stress, a defect in the trafficking of the uracil permease, ?-syn accumulation and foci, and a slow growth phenotype. Supplemental ethanolamine (ETA), which can be converted to PE via the Kennedy pathway enzymes in the ER, had no effect on respiration, whereas, in contrast, this metabolite partially eliminated ER stress, decreased ?-syn foci formation, and restored growth close to that of wild-type cells. In Caenorhabditis elegans, RNAi depletion of phosphatidylserine decarboxylase in dopaminergic neurons expressing ?-syn accelerates neurodegeneration, which supplemental ETA rescues. ETA fails to rescue this degeneration in worms that undergo double RNAi depletion of phosphatidylserine decarboxylase (psd-1) and choline/ETA phosphotransferase (cept-1), which encodes the last enzyme in the CDP-ETA Kennedy pathway. This finding suggests that ETA exerts its protective effect by boosting PE through the Kennedy pathway. Overall, a low level of PE causes ER stress, disrupts vesicle trafficking, and causes ?-syn to accumulate; such cells likely die from a combination of ER stress and excessive accumulation of ?-syn.
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Impact of vehicular networks on emergency medical services in urban areas.
Int J Environ Res Public Health
PUBLISHED: 08-25-2014
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The speed with which emergency personnel can provide emergency treatment is crucial to reducing death and disability among acute and critically ill patients. Unfortunately, the rapid development of cities and increased numbers of vehicles are preventing emergency vehicles from easily reaching locations where they are needed. A significant number of researchers are experimenting with vehicular networks to address this issue, but in most studies the focus has been on communication technologies and protocols, with few efforts to assess how network applications actually support emergency medical care. Our motivation was to search the literature for suggested methods for assisting emergency vehicles, and to use simulations to evaluate them. Our results and evidence-based studies were cross-referenced to assess each method in terms of cumulative survival ratio (CSR) gains for acute and critically ill patients. Simulation results indicate that traffic light preemption resulted in significant CSR increases of between 32.4% and 90.2%. Route guidance was found to increase CSRs from 14.1% to 57.8%, while path clearing increased CSRs by 15.5% or less. It is our hope that this data will support the efforts of emergency medical technicians, traffic managers, and policy makers.
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[Effect of advanced glycation end products on the function and angiogenesis of adipose tissue-derived stem cells and the protective effect of danhong injection: an experimental study].
Zhongguo Zhong Xi Yi Jie He Za Zhi
PUBLISHED: 08-21-2014
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OBJECTIVE To investigate the effect of Nepsilon-(carboxymethyl) lysine albumin (CMLs), a primary advanced glycation end products (AGEPs) isoform in diabetic body, on the function and angiogenesis of adipose tissue-derived stem cells (ADSCs) and the protective effect of Danhong Injection (DH). METHODS Human ADSCs were cultured and separated from human subcutaneous fatty tissue using enzymatic digestion and centrifugation. The morphology was observed using optical microscope and differentiation capacities assessed. Cells were exposed to 5 different interventions respectively for 24 h, i.e., PBS, 60 1 microg/mL BSA, 60 microg/mL CML-BSA, 100 microL/mL DH, and 60 micro./mL CML-BSA +100 microL/mL DH. Their effect on the proliferation, migration, apoptosis, and secretion were observed using WST-1 assay, Transwell assay, Annexin V-FITC/PI flow meter test reagent kit, human VEGF reagent kit, ELISA reagent kit, respectively. The effect on ADSCs angiogenesis was observed by in vitro angiogenesis test.
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Comparative analyses between retained introns and constitutively spliced introns in Arabidopsis thaliana using random forest and support vector machine.
PLoS ONE
PUBLISHED: 08-11-2014
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One of the important modes of pre-mRNA post-transcriptional modification is alternative splicing. Alternative splicing allows creation of many distinct mature mRNA transcripts from a single gene by utilizing different splice sites. In plants like Arabidopsis thaliana, the most common type of alternative splicing is intron retention. Many studies in the past focus on positional distribution of retained introns (RIs) among different genic regions and their expression regulations, while little systematic classification of RIs from constitutively spliced introns (CSIs) has been conducted using machine learning approaches. We used random forest and support vector machine (SVM) with radial basis kernel function (RBF) to differentiate these two types of introns in Arabidopsis. By comparing coordinates of introns of all annotated mRNAs from TAIR10, we obtained our high-quality experimental data. To distinguish RIs from CSIs, We investigated the unique characteristics of RIs in comparison with CSIs and finally extracted 37 quantitative features: local and global nucleotide sequence features of introns, frequent motifs, the signal strength of splice sites, and the similarity between sequences of introns and their flanking regions. We demonstrated that our proposed feature extraction approach was more accurate in effectively classifying RIs from CSIs in comparison with other four approaches. The optimal penalty parameter C and the RBF kernel parameter [Formula: see text] in SVM were set based on particle swarm optimization algorithm (PSOSVM). Our classification performance showed F-Measure of 80.8% (random forest) and 77.4% (PSOSVM). Not only the basic sequence features and positional distribution characteristics of RIs were obtained, but also putative regulatory motifs in intron splicing were predicted based on our feature extraction approach. Clearly, our study will facilitate a better understanding of underlying mechanisms involved in intron retention.
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MicroRNA-26a/b Regulate DNA Replication Licensing, Tumorigenesis, and Prognosis by Targeting CDC6 in Lung Cancer.
Mol. Cancer Res.
PUBLISHED: 08-06-2014
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Cancer is characterized by mutations, genome rearrangements, epigenetic changes, and altered gene expression that enhance cell proliferation, invasion, and metastasis. To accommodate deregulated cellular proliferation, many DNA replication-initiation proteins are overexpressed in human cancers. However, the mechanism that represses the expression of these proteins in normal cells and the cellular changes that result in their overexpression are largely unknown. One possible mechanism is through miRNA expression differences. Here, it is demonstrated that miR26a and miR26b inhibit replication licensing and the proliferation, migration, and invasion of lung cancer cells by targeting CDC6. Importantly, miR26a/b expression is significantly decreased in human lung cancer tissue specimens compared with the paired adjacent normal tissues, and miR26a/b downregulation and the consequential upregulation of CDC6 are associated with poorer prognosis of patients with lung cancer. These results indicate that miR26a/b repress replication licensing and tumorigenesis by targeting CDC6.
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Persistent organic pollutants (POPs) and metals in primiparous women: a comparison from Canada and Mexico.
Sci. Total Environ.
PUBLISHED: 07-30-2014
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Under the North American Commission for Environmental Cooperation (CEC) and its Sound Management of Chemicals (SMOC) program, a tri-national human contaminant monitoring initiative was completed to provide baseline exposure information for several environmental contaminants in Canada, Mexico and the United States (U.S). Blood samples were collected from primiparous women in Canada and Mexico, and were analysed for a suite of environmental contaminants including polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene(p,p'-DDE),beta-hexachlorocyclohexane (?-HCH), mercury and lead. A multiple stepwise linear regression analysis was conducted using data from Canadian and Mexican primiparous mothers, adjusting for ethnicity group, age, pre-pregnancy BMI, years at current city and ever-smoking status. Concentrations of p,p'-DDE, ?-HCH, and lead were found to be higher among Mexican participants; however, concentrations of most PCBs among Mexican participants were similar to Canadian primiparous women after adjusting for covariates. Concentrations of total mercury were generally higher among Mexican primiparous women although this difference was smaller as age increased. This initial dataset can be used to determine priorities for future activities and to track progress in the management of the selected chemicals, both domestically and on a broader cooperative basis within North America.
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Antitumor effects of dammarane-type saponins from steamed Notoginseng.
Pharmacogn Mag
PUBLISHED: 07-24-2014
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Six dammarane-type saponins were extracted from steamed Panax notoginseng. Their chemical structures were identified spectroscopically as ginsenosides Rh1 (1), Rg1 (2), 20 (S)-Rg3 (3), 20 (R)-Rg3 (4), Rb3 (5), and Rb1 (6). Compounds (0.1-10 ?M) were tested for inhibition of tumor necrosis factor-? (TNF)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) luciferase reporter activity using a human kidney 293T cell-based assay. Ginsenoside Rb3 (5) showed the most significant activity with an IC50 of 8.2 ?M. This compound also inhibited the induction of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) messenger Ribonucleic acid (mRNA) in a dose-dependent manner after HepG2 cells had been treated with TNF-? (10 ng/mL).
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Sro7 and Sro77, the yeast homologues of the Drosophila lethal giant larvae (Lgl), regulate cell proliferation via the Rho1-Tor1 pathway.
Microbiology (Reading, Engl.)
PUBLISHED: 07-24-2014
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Saccharomyces cerevisiae Sro7 and Sro77 are homologues of the Drosophila tumour suppressor lethal giant larvae (Lgl), which regulates cell polarity in Drosophila epithelial cells. Here, we showed that double mutation of SRO7/SRO77 was defective in colony growth. The colony of the SRO7/SRO77 double deletion was much smaller than the WT and appeared to be round with a smooth surface, compared with the WT. Analysis using transmission electron microscopy revealed multiple defects of the colony cells, including multiple budding, multiple nuclei, cell lysis and dead cells, suggesting that the double deletion caused defects in cell polarity and cell wall integrity (CWI). Overexpression of RHO1, one of the central regulators of cell polarity and CWI, fully recovered the sro7?/sro77? phenotype. We further demonstrated that sro7?/sro77? caused a decrease of the GTP-bound, active Rho1, which in turn caused an upregulation of TOR1. Deletion of TOR1 in sro7?/sro77? (sro7?/sro77?/tor1?) recovered the cell growth and colony morphology, similar to WT. Our results suggested that the tumour suppressor homologue SRO7/SRO77 regulated cell proliferation and yeast colony development via the Rho1-Tor1 pathway.
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Multidisciplinary care improves clinical outcome and reduces medical costs for pre-end-stage renal disease in Taiwan.
Nephrology (Carlton)
PUBLISHED: 07-09-2014
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Multidisciplinary care (MDC) for patients with chronic kidney disease (CKD) may help to optimize disease care and improve clinical outcomes. Our study aimed to evaluate the effectiveness of pre-end-stage renal disease (ESRD) patients under MDC and usual care in Taiwan.
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Identification and characterization of two novel spliced genes located in the orf47-orf46-orf45 gene locus of Kaposi's sarcoma-associated herpesvirus.
J. Virol.
PUBLISHED: 06-25-2014
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The orf47-orf46-orf45 gene cluster of Kaposi's sarcoma-associated herpesvirus (KSHV) is known to serially encode glycoprotein L (gL), uracil DNA glycosylase, and a viral tegument protein. Here, we identify two novel mRNA variants, orf47/45-A and orf47/45-B, alternatively spliced from a tricistronic orf47-orf46-orf45 mRNA that is expressed in the orf47-orf46-orf45 gene locus during the early stages of viral reactivation. The spliced gene products, ORF47/45-A and ORF47/45-B, consist of only a partial region of gL (ORF47), a unique 7-amino-acid motif, and the complete tegument protein ORF45. Like the ORF45 protein, ORF47/45-A and ORF47/45-B expressed in cells sufficiently activate the phosphorylation of p90 ribosomal S6 kinase (RSK) and extracellular signal-regulated protein kinase (ERK). However, unlike ORF45, both ORF47/45-A and ORF47/45-B contain a signal peptide sequence and are localized at the endoplasmic reticulum (ER). Additionally, we found that ORF47/45-A and ORF47/45-B have an extra function that mediates the upregulation of GRP78, a master regulator of ER homeostasis. The important event regarding GRP78 upregulation can be observed in all tested KSHV-positive cell lines after viral reactivation, and knockdown of GRP78 in cells significantly impairs viral lytic cycle progression, especially at late lytic stages. Compared with some other viral glycoproteins synthesized through the ER, our results strongly implicate that the ORF47/45 proteins may serve as key effectors for controlling GRP78 expression and ER homeostasis in cells. Taken together, our findings provide evidence showing the reciprocal association between the modulation of ER homeostasis and the progression of the KSHV lytic cycle.
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Ultra-early versus delayed coil treatment for ruptured poor-grade aneurysm.
Neuroradiology
PUBLISHED: 06-19-2014
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The timing of definitive aneurysm treatment (coiling or clipping) in poor-grade (Hunt-Hess IV or V) subarachnoid haemorrhage (SAH) patients has been a controversial topic. The purpose of this retrospective study was to analyse whether ultra-early coiling of ruptured intracranial aneurysms improves the clinical outcomes of poor-grade SAH patients.
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Design, synthesis and biological activity of flavonoid derivatives as selective agonists for neuromedin U 2 receptor.
Bioorg. Med. Chem.
PUBLISHED: 06-16-2014
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Central neuromedin U 2 receptor (NMU2R) plays important roles in the regulation of food intake and body weight. Identification of NMU2R agonists may lead to the development of pharmaceutical agents to treat obesity. Based on the structure of rutin, a typical flavonoid and one of the NMU2R agonists we previously identified from an in-house made natural product library, 30 flavonoid derivatives have been synthesized and screened on a cell-based reporter gene assay. A number of compounds were found to be selective and highly potent to NMU2R. For example, the EC50 value of compound NRA 4 is very close to that of NMU, the endogenous peptide ligand of NMU2R. Structure-activity relationship analysis revealed that a 3-hydroxyl group in ring C and a 2'-fluoride group in ring B were essential for this class of compounds to be active against NMU2R.
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Nanomechanical biomarkers of single circulating tumor cells for detection of castration resistant prostate cancer.
Prostate
PUBLISHED: 05-21-2014
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Emerging evidence shows that nanomechanical phenotypes of circulating tumor cells (CTC) could become potential biomarkers for metastatic castration resistant prostate cancer (mCRPC).
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Synthesizing genetic sequential logic circuit with clock pulse generator.
BMC Syst Biol
PUBLISHED: 04-28-2014
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Rhythmic clock widely occurs in biological systems which controls several aspects of cell physiology. For the different cell types, it is supplied with various rhythmic frequencies. How to synthesize a specific clock signal is a preliminary but a necessary step to further development of a biological computer in the future.
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Addressing the unmet need for visualizing conditional random fields in biological data.
BMC Bioinformatics
PUBLISHED: 04-24-2014
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The biological world is replete with phenomena that appear to be ideally modeled and analyzed by one archetypal statistical framework - the Graphical Probabilistic Model (GPM). The structure of GPMs is a uniquely good match for biological problems that range from aligning sequences to modeling the genome-to-phenome relationship. The fundamental questions that GPMs address involve making decisions based on a complex web of interacting factors. Unfortunately, while GPMs ideally fit many questions in biology, they are not an easy solution to apply. Building a GPM is not a simple task for an end user. Moreover, applying GPMs is also impeded by the insidious fact that the "complex web of interacting factors" inherent to a problem might be easy to define and also intractable to compute upon.
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Guibitang, a traditional herbal medicine, induces apoptotic death in A431 cells by regulating the activities of mitogen-activated protein kinases.
BMC Complement Altern Med
PUBLISHED: 04-22-2014
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Guibi-tang (GBT), a traditional herbal formula, mainly has been shown to possess immune regulation, antioxidant and protective effect of the gastric mucosa. Constituent herbs of GBT are frequently used to treat various diseases; however, their pharmacological effects, especially on cancer cells, differ from those of GBT. Furthermore, the molecular mechanisms behind effects of GBT remain unclear. In the present study, we explored the mechanism of chemopreventive/chemotherapeutic efficacy of GBT against human squamous cell carcinoma without cytotoxicity in normal cells and proved the efficacy of GBT through performing in vivo xenograft assay.
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Removal of endobronchial malignant mass by cryotherapy improved performance status to receive chemotherapy.
ScientificWorldJournal
PUBLISHED: 04-06-2014
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Although malignant endobronchial mass (MEM) has poor prognosis, cryotherapy is reportedly a palliative treatment. Clinical data on postcryotherapy MEM patients in a university-affiliated hospital between 2007 and 2011 were evaluated. Survival curve with or without postcryotherapy chemotherapy and performance status (PS) improvement of these subjects were analyzed using the Kaplan-Meier method. There were 59 patients (42 males), with median age of 64 years (range, 51-76, and median performance status of 2 (interquartile range [IQR], 2-3). Postcryotherapy complications included minor bleeding (n = 12) and need for multiple procedures (n = 10), while outcomes were relief of symptoms (n = 51), improved PS (n = 45), and ability to receive chemotherapy (n = 40). The survival of patients with chemotherapy postcryotherapy was longer than that of patients without such chemotherapy (median, 534 versus 106 days; log-rank test, P = 0.007; hazard ratio, 0.25; 95% confidence interval, 0.10-0.69). The survival of patients with PS improvement postcryotherapy was longer than that of patients without PS improvement (median, 406 versus 106 days; log-rank test, P = 0.02; hazard ratio, 0.28; 95% confidence interval, 0.10-0.81). Cryotherapy is a feasible treatment for MEM. With better PS after cryotherapy, further chemotherapy becomes possible for patients to improve survival when MEM caused dyspnea and poor PS.
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Deafness induced by Connexin 26 (GJB2) deficiency is not determined by endocochlear potential (EP) reduction but is associated with cochlear developmental disorders.
Biochem. Biophys. Res. Commun.
PUBLISHED: 03-31-2014
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Connexin 26 (Cx26, GJB2) mutations are the major cause of hereditary deafness and are responsible for >50% of nonsyndromic hearing loss. Mouse models show that Cx26 deficiency can cause congenital deafness with cochlear developmental disorders, hair cell degeneration, and the reduction of endocochlear potential (EP) and active cochlear amplification. However, the underlying deafness mechanism still remains undetermined. Our previous studies revealed that hair cell degeneration is not a primary cause of hearing loss. In this study we investigated the role of EP reduction in Cx26 deficiency-induced deafness. We found that the EP reduction is not associated with congenital deafness in Cx26 knockout (KO) mice. The threshold of auditory brainstem response (ABR) in Cx26 KO mice was even greater than 110 dB SPL, demonstrating complete hearing loss. However, the EP in Cx26 KO mice varied and not completely abolished. In some cases, the EP could still remain at higher levels (>70 mV). We further found that the deafness in Cx26 KO mice is associated with cochlear developmental disorders. Deletion of Cx26 in the cochlea before postnatal day 5 (P5) could cause congenital deafness. The cochlea had developmental disorders and the cochlear tunnel was not open. However, no congenital deafness was found when Cx26 was deleted after P5. The cochlea also displayed normal development and the cochlear tunnel was open normally. These data suggest that congenital deafness induced by Cx26 deficiency is not determined by EP reduction and may result from cochlear developmental disorders.
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Effect of serum interleukin 21 on the development of coronary artery disease.
APMIS
PUBLISHED: 03-28-2014
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There has been more and more evidence to confirm the essential role of inflammatory processes in the development of coronary artery disease (CAD). Interleukin-21 (IL-21), the most recently discovered CD132-dependent cytokine, plays a key role in regulating inflammation. The aim of the study was to understand the effect of peripheral IL-21 on the pathogenesis and progression of CAD. Serum level of IL-21 in 92 CAD patients and 73 controls was measured by the enzyme-linked immunosorbent assay. Data showed that IL-21 expression was significantly increased in CAD than in controls (p < 0.001). Interestingly, when comparing IL-21 level with different genders, male subjects revealed higher IL-21 than female subjects (p = 0.024). Also, we observed that patients with hypertension had upregulated level of serum IL-21 (p = 0.002). Moreover, serum level of IL-21 was positively correlated with total cholesterol level (p = 0.015) or low-density lipoprotein cholesterol (p = 0.0009) of CAD cases. In addition, we analyzed IL-21 level with the severity of CAD, and identified that cases with 3-vessel affected had significantly elevated level of IL-21 than those with 1-vessel or 2-vessel affected. These data suggested that serum level of IL-21 may be closely associated with the development and progression of CAD.
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Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis.
Genes Chromosomes Cancer
PUBLISHED: 03-27-2014
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Sclerosing and spindle cell rhabdomyosarcoma (RMS) are rare types of RMS recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS (ERMS). Although sclerosing and spindle cell RMS share clinical and morphologic features, a pathogenetic link based on shared molecular alterations has not been established. Spindle cell RMS in children have been associated with a less aggressive clinical course compared to adults. Recently, recurrent MYOD1 mutations were described in 44% of adult spindle cell RMS, but no pediatric tumors or sclerosing RMS were studied for comparison. Thus, we investigated 16 RMS (5 sclerosing and 11 spindle cell) in children and adults for the presence of MYOD1 mutations by targeted Polymerase Chain Reaction (PCR). Remarkably, all 5 sclerosing RMS and 4 of 11 spindle cell RMS showed the MYOD1 p.L122R hot-spot mutation. Of the five pediatric tumors, 2/2 sclerosing RMS and 2/3 spindle cell RMS showed MYOD1 mutations. Three of nine MYOD1-mutant RMS showed coexistent PIK3CA mutations, while no MDM2 amplifications were identified. All four pediatric MYOD1-mutated RMS patients died of the disease at 12-35 months following diagnosis. In conclusion, spindle cell and sclerosing RMS show recurrent MYOD1 mutations, in keeping with a single pathologic entity, regardless of age at presentation. This group however, is distinct from the infantile RMS associated with NCOA2 fusions. Although our study suggests that pediatric MYOD1-mutant RMS follow an aggressive behavior with high mortality, further studies are required to confirm this finding.
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Effectiveness of a national transitional care program in reducing acute care use.
J Am Geriatr Soc
PUBLISHED: 03-17-2014
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This study evaluated the effectiveness of a national transitional care program for elderly adults with complex care needs and limited social support. The Aged Care Transition (ACTION) Program was designed to improve coordination and continuity of care and reduce rehospitalizations and visits to emergency departments (EDs). Dedicated care coordinators provided coaching to help individuals and families understand the individuals' conditions, effectively articulate their preferences, and enable self-management and care planning. Participants were individuals aged 65 and older hospitalized and enrolled from five public general hospitals in Singapore between February 2009 and July 2010 (N = 4,132). The coordinators worked with participants during hospitalization and followed up with telephone calls and home visits for 1 to 2 months after discharge and coordinated placements with appropriate community service providers. Unplanned rehospitalization and ED visit (up to 6 months after discharge) rates were compared with those of a comparator group of individuals who did not receive care coordination using propensity score-based weighting. Participant and caregiver surveys on quality of life and self-rated health were also administered. Recipients of the ACTION program had fewer unplanned rehospitalizations and ED visits after discharge. Propensity score-adjusted odds ratios of participants versus control for number of unplanned rehospitalization and ED visits were 0.5 (95% confidence interval (CI) = 0.5-0.6) and 0.81 (95% CI = 0.72-0.90) 30 days after discharge and 0.6 (95% CI = 0.6-0.7) and 0.90 (95% CI = 0.82-0.99) 180 days after discharge. Quality of life and self-rated health were better 4 to 6 weeks after discharge than 1 week after discharge. These findings confirm the effectiveness of the ACTION program in improving the transition of vulnerable older adults from hospital to community. Such transitional care should be considered as an integral part of care integration.
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Bioinformatics analysis of alternative polyadenylation in green alga Chlamydomonas reinhardtii using transcriptome sequences from three different sequencing platforms.
G3 (Bethesda)
PUBLISHED: 03-15-2014
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Messenger RNA 3'-end formation is an essential posttranscriptional processing step for most eukaryotic genes. Different from plants and animals where AAUAAA and its variants routinely are found as the main poly(A) signal, Chlamydomonas reinhardtii uses UGUAA as the major poly(A) signal. The advance of sequencing technology provides an enormous amount of sequencing data for us to explore the variations of poly(A) signals, alternative polyadenylation (APA), and its relationship with splicing in this algal species. Through genome-wide analysis of poly(A) sites in C. reinhardtii, we identified a large number of poly(A) sites: 21,041 from Sanger expressed sequence tags, 88,184 from 454, and 195,266 from Illumina sequence reads. In comparison with previous collections, more new poly(A) sites are found in coding sequences and intron and intergenic regions by deep-sequencing. Interestingly, G-rich signals are particularly abundant in intron and intergenic regions. The prevalence of different poly(A) signals between coding sequences and a 3'-untranslated region implies potentially different polyadenylation mechanisms. Our data suggest that the APA occurs in about 68% of C. reinhardtii genes. Using Gene Ontolgy analysis, we found most of the APA genes are involved in RNA regulation and metabolic process, protein synthesis, hydrolase, and ligase activities. Moreover, intronic poly(A) sites are more abundant in constitutively spliced introns than retained introns, suggesting an interplay between polyadenylation and splicing. Our results support that APA, as in higher eukaryotes, may play significant roles in increasing transcriptome diversity and gene expression regulation in this algal species. Our datasets also provide useful information for accurate annotation of transcript ends in C. reinhardtii.
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Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin.
Genes Chromosomes Cancer
PUBLISHED: 03-13-2014
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Polymorphous low-grade adenocarcinoma (PLGA) and cribriform adenocarcinoma of minor salivary gland (CAMSG) are low-grade carcinomas arising most often in oral cavity and oropharynx, respectively. Controversy exists as to whether these tumors represent separate entities or variants of one spectrum, as they appear to have significant overlap, but also clinicopathologic differences. As many salivary carcinomas harbor recurrent translocations, paired-end RNA sequencing and FusionSeq data analysis was applied for novel fusion discovery on two CAMSGs and two PLGAs. Validated rearrangements were then screened by fluorescence in situ hybridization (FISH) in 60 cases. Histologic classification was performed without knowledge of fusion status and included: 21 CAMSG, 18 classic PLGA, and 21 with "mixed/indeterminate" features. The RNAseq of 2 CAMSGs showed ARID1A-PRKD1 and DDX3X-PRKD1 fusions, respectively, while no fusion candidates were identified in two PLGAs. FISH for PRKD1 rearrangements identified 11 additional cases (22%), two more showing ARID1A-PRKD1 fusions. As PRKD2 and PRKD3 share similar functions with PRKD1 in the diacylglycerol and protein kinase C signal transduction pathway, we expanded the investigation for these genes by FISH. Six additional cases each showed PRKD2 and PRKD3 rearrangements. Of the 26 (43%) fusion-positive tumors, there were 16 (80%) CAMSGs and 9 (45%) indeterminate cases. A PRKD2 rearrangement was detected in one PLGA (6%). We describe novel and recurrent gene rearrangements in PRKD1-3 primarily in CAMSG, suggesting a possible pathogenetic dichotomy from "classic" PLGA. However, the presence of similar genetic findings in half of the indeterminate cases and a single PLGA suggests a possible shared pathogenesis for these tumor types.
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Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1.
Stem Cells
PUBLISHED: 03-01-2014
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Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44(+) /CD24(-/low) cancer stem cells (CSCs), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an antimalarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44(+) /CD24(-/low) CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus, the objectives of this study were to examine the potential enhanced efficacy arising from addition of CQ to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44(+) /CD24(-/low) CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2)-signal transducer and activator of transcription 3 signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1.
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pH-responsive polymer-liposomes for intracellular drug delivery and tumor extracellular matrix switched-on targeted cancer therapy.
Biomaterials
PUBLISHED: 02-27-2014
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This study presents a tumor-extracellular matrix pH-induced targeting liposome (ECM-targeting liposomes), crosslinked from methoxy-poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide-co-histidine)-cholesterol copolymers and biotin2-polyethylene glycol crosslinkers by hydrogen bonds to overcome the defects of liposomes. In this study, ECM-targeting liposomes were completely investigated their pH-responsibility, drug releasing behaviors, anticancer efficiencies and the time-dependent organ distribution and toxic effects. Experimental results indicate that ECM-targeting liposomes showed rapid drug releasing profiles in acidic conditions. Because the ECM-targeting liposomes accumulated preferentially in tumor, the ECM-targeting liposomes exhibited exceptional anticancer activity in vivo and lower hepatic and renal toxicity. The ECM-targeting liposomes which are switched on the targeting ability in tumor ECM possess potential for future application in anticancer therapy.
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MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction.
J. Am. Soc. Nephrol.
PUBLISHED: 02-27-2014
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Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemia-induced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose-induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose-stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR-29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.
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Analgesic use, parents' clan, and coffee intake are three independent risk factors of chronic kidney disease in middle and elderly-aged population: a community-based study.
Ren Fail
PUBLISHED: 02-10-2014
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Chronic kidney disease (CKD) is a world-wide public health problem. The purpose of this study was to identify the role of some controversial potential risk factors in development of CKD. "Community Complex Health Screening" is a large-scale, free, health program for individuals ?40 years of age that has been available since January 2002 in Chiayi County, Taiwan. A questionnaire was administered to study participants, collecting information on ethnicity, use of analgesics, and life habits. Age, sex, and blood biochemical analyses were considered as potential confounders. A high prevalence and low awareness of CKD were noted in this population. Females with CKD had a lower awareness of their illness than males. Analgesic users had a significantly lower estimated glomerular filtration rate (eGFR). Age (OR?=?1.095), females (OR?=?0.348), fasting plasma glucose (OR?=?1.005), level of uric acid (UA) (OR?=?1.517), and analgesic usage (OR?=?1.512) remained independent predictors of CKD. Multivariate linear regression found that use of analgesics, father' clan from Fujian, mother' clan from Fujian, and coffee intake were independent determinants of renal outcome with coefficient of regression (?) of -0.102, -0.192, 0.210 and 0.88, respectively. The prevalence of CKD decreased with advanced education. Further, there was no significant difference between education background and analgesics use. In conclusion, analgesic use, parents' clan, and coffee intake were independent risk factors for CKD in middle-aged and elderly Taiwanese. Thus, an effective educational program that increases the awareness of such individuals residing in rural counties is warranted.
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Ring fusion strategy for the synthesis of anthra[2,3-d]oxazole-2-thione-5,10-dione homologues as DNA topoisomerase inhibitors and as antitumor agents.
Eur J Med Chem
PUBLISHED: 02-07-2014
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The efficient synthesis of mono-substituted anthraquinones and ring fusion into anthra[2,3-d]oxazole-2-thione-5,10-dione derivatives were developed, and all the compounds were tested for their cytotoxicity against PC-3 cancer cell lines. Compounds 8, 14, 17 and 23 were selected by the NCI and 12, 17 and 19 were evaluated for topoisomerase I-mediated DNA relaxation. Among them, 17 appeared to be the most active compound of this series and not only showed higher inhibition when indicated from the low IC50 values against PC-3 cancer cell line but also attenuated the in vitro topoisomerase I-mediated DNA relaxation at low micromolar concentrations. All test compounds exhibited different cytostatic and cytotoxic activities for further developing potential anticancer drugs.
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Heparin-binding epidermal growth factor-like growth factor restores Wnt/?-catenin signaling in intestinal stem cells exposed to ischemia/reperfusion injury.
Surgery
PUBLISHED: 01-31-2014
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We have previously demonstrated that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) protects the intestines from injury in several different experimental animal models. In the current study, we investigated whether the ability of HB-EGF to protect the intestines from ischemia/reperfusion (I/R) injury was related to its effects on Wnt/?-catenin signaling in intestinal stem cells (ISC).
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Synthesising periodic triggering signals with genetic oscillators.
IET Syst Biol
PUBLISHED: 01-24-2014
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The potential of the clock lies in its role of triggering logic reaction for sequential biological circuits. This research introduces an idea of designing a genetic clock generator by Fourier series based on the genetic oscillators. The authors generalise the design idea using a combination of fundamental sinusoidal signals. Since biochemical reaction of the biological system is extremely slow, however, transition between minimal and maximal levels is instantaneous for an ideal clock signal; it is thus not directly realisable in biological systems. That means it would be hard to directly synthesize a square wave generator for use as a genetic clock. They apply Fourier series to represent a square wave as a finite summation of sinusoidal waves generated by some genetic oscillators with different harmonic oscillating frequencies, in which the amplitude alternates at a constant frequency between the fixed minimal and maximal levels with the same duration of time.
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Comparison of the efficacy of ciclesonide with that of budesonide in mild to moderate asthma patients after step-down therapy: a randomised parallel-group study.
NPJ Prim Care Respir Med
PUBLISHED: 01-17-2014
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Inhaled corticosteroids (ICSs) are widely used in asthma control. Ciclesonide (CIC) is an ICS with on-site lung activation for potent anti-inflammatory activity.
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SCOPE++: sequence classification of homoPolymer emissions.
Genomics
PUBLISHED: 01-09-2014
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mRNA polyadenylation, the addition of a poly(A) tail to the 3'-end of pre-mRNA, is a process critical to gene expression and regulation in eukaryotes. To understand the molecular mechanisms governing polyadenylation and other relevant biological processes, it is important to identify these poly(A) tails accurately in transcriptome sequencing data and differentiate them from artificial adapter sequences added in the sequencing process. But the annotation of these tails is complicated by the presence of sequencing errors and post-transcriptional modifications. While determining that a tail is present in a given transcript fragment is straight-forward, these obfuscations make the problem of boundary identification a challenge; conventional seed-and-extend algorithms struggle to accurately identify these poly(A) tail end-points. Further, all existing tools that we are aware of focus exclusively on the trimming of poly(A) tails, failing to provide the detailed information needed for studying the polyadenylation process.
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The effects of gout on left atrial volume remodelling: a prospective echocardiographic study.
Rheumatology (Oxford)
PUBLISHED: 01-09-2014
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The aim of the present study was to investigate the effect of gout on left ventricular (LV) diastolic function and left atrial volume (LAV).
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Cannabinoid receptor 1 disturbance of PPAR?2 augments hyperglycemia induction of mesangial inflammation and fibrosis in renal glomeruli.
J. Mol. Med.
PUBLISHED: 01-07-2014
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Intensive fibrosis in the glomerular microenvironment is a prominent feature of diabetic nephropathy. Cannabinoid receptor 1 (CB1R) reportedly mediates diabetes-induced renal injury. However, studies on the molecular events underlying CB1R promotion of renal dysfunction are limited. This study is undertaken to investigate whether CB1R signaling via Ras or PPAR? pathway regulates mesangial fibrosis in diabetic kidneys. In streptozotocin-induced diabetic rats, hyperglycemia induced glomerular hypertrophy and fibrosis in association with increased IL-1?, fibronectin, and CB1R expressions and reduced PPAR?2 signaling. CB1R transgenic mice gained kidney weight, and renal glomeruli strongly displayed IL-1? and fibrotic matrices. Disruption of CB1R by antisense oligonucleotides or inverse agonist AM251 restored PPAR?2 signaling and reduced the promotional effects of hyperglycemia on the expression of fibrogenic transcription factor c-Jun, inflammation regulator SOCS3, proinflammatory cytokines, and accumulation of fibrotic matrix. PPAR? agonist rosiglitazone reduced the hyperglycemia-mediated enhancement of CB1R signaling, inflammation, and glomerular fibrosis in diabetic animals. In vitro, CB1R antagonism restored PPAR?2 action and reduced the promotional effects of high glucose on Ras, ERK, c-Jun, SOCS3 signaling, IL-1?, and fibronectin expression in renal mesangial cells. Activation of PPAR?2 reduced the high glucose-induced CB1R expression in mesangial cells. Taken together, CB1R signaling contributes to the hyperglycemia disturbance of PPAR?2 signaling and increases inflammatory cytokine secretion and fibrotic matrix deposition in renal glomeruli. CB1R mediates the hyperglycemia-induced inflammation and fibrosis in mesangial cells by regulating Ras, ERK, and PPAR?2 signaling. CB1R blockade has a therapeutic potential to reduce the deleterious actions of hyperglycemia on renal glomerular integrity.
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Comparing plasma concentrations of persistent organic pollutants and metals in primiparous women from northern and southern Canada.
Sci. Total Environ.
PUBLISHED: 01-06-2014
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The exposure of Aboriginal peoples in the Canadian Arctic to persistent organic pollutants (POPs) and metals through the consumption of traditional food items is well recognized; however, less information is available for Canadian immigrants. The direct comparison of blood chemical concentrations for expectant primiparous women sampled in the Inuvik and Baffin regions of the Canadian Arctic, as well as Canadian- and foreign-born women from five southern Canadian centers (Halifax, Vancouver, Hamilton, Ottawa, and Calgary), provides relative exposure information for samples of northern and southern mothers in Canada. Based on our analyses, Canadian mothers are exposed to a similar suite of contaminants; however, Inuit first birth mothers residing in the Canadian Arctic had higher age-adjusted geometric mean concentrations for several legacy POPs regulated under the Stockholm Convention, along with lead and total mercury. Significant differences in exposure were observed for Inuit mothers from Baffin who tended to demonstrate higher blood concentrations of POPs and total mercury compared with Inuit mothers from Inuvik. Conversely, northern mothers showed a significantly lower age-adjusted geometric mean concentration for a polybrominated diphenyl ether (PBDE-153) compared to southern mothers. Furthermore, southern Canadian mothers born outside of Canada showed the highest individual concentrations measured in the study: 1700 ?g/kg lipids for p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and 990 ?g/kg lipids for ?-hexachlorocyclohexane (?-HCH). Data from Cycle 1 (2007-2009) of the nationally-representative Canadian Health Measures Survey (CHMS) places these results in a national biomonitoring context and affirms that foreign-born women of child-bearing age experience higher exposures to many POPs and metals than their Canadian-born counterparts in the general population.
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detectIR: A Novel Program for Detecting Perfect and Imperfect Inverted Repeats Using Complex Numbers and Vector Calculation.
PLoS ONE
PUBLISHED: 01-01-2014
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Inverted repeats are present in abundance in both prokaryotic and eukaryotic genomes and can form DNA secondary structures - hairpins and cruciforms that are involved in many important biological processes. Bioinformatics tools for efficient and accurate detection of inverted repeats are desirable, because existing tools are often less accurate and time consuming, sometimes incapable of dealing with genome-scale input data. Here, we present a MATLAB-based program called detectIR for the perfect and imperfect inverted repeat detection that utilizes complex numbers and vector calculation and allows genome-scale data inputs. A novel algorithm is adopted in detectIR to convert the conventional sequence string comparison in inverted repeat detection into vector calculation of complex numbers, allowing non-complementary pairs (mismatches) in the pairing stem and a non-palindromic spacer (loop or gaps) in the middle of inverted repeats. Compared with existing popular tools, our program performs with significantly higher accuracy and efficiency. Using genome sequence data from HIV-1, Arabidopsis thaliana, Homo sapiens and Zea mays for comparison, detectIR can find lots of inverted repeats missed by existing tools whose outputs often contain many invalid cases. detectIR is open source and its source code is freely available at: https://sourceforge.net/projects/detectir.
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Impact of gout on left atrial function: a prospective speckle-tracking echocardiographic study.
PLoS ONE
PUBLISHED: 01-01-2014
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The purpose of our study was to evaluate the left ventricular (LV) and left atrial (LA) function in patients with gout. A total of 173 patients underwent a comprehensive Doppler-echocardiography examination. Participants were divided into four groups-Stage 0: control (n = 35), Stage I: asymptomatic hyperuricemia (n = 30), Stage II: gouty arthritis without tophi (n = 58), and Stage III: tophaceous gout (n = 50). Serum uric acid levels were not significantly different between stage I, II and III. Stage III patients demonstrated a higher ratio of the transmitral and myocardial peak early diastolic velocities (E/Em) (10.50 ± 3.18 vs. 8.58 ± 2.07; P = 0.008), and larger maximal LA volume index (LAVi) (29.60 ± 9.89 vs. 20.07 ± 4.76 ml/m(2); P<0.001) compared with controls. Stage III patients had decreased LV global longitudinal systolic strain (LV?) compared with controls (-20.2 ± 3.06 vs. -21.79 ± 2.27; P = 0.002). Stage III patients also had decreased peak atrial longitudinal strain rate during ventricular systole (ALSR(syst)), peak atrial longitudinal strain rate during ventricular early diastole (ALSR(early)), and peak atrial longitudinal strain rate during ventricular late diastole (ALSR(late)) compared with controls (1.73 ± 0.48 vs. 2.05 ± 0.55 1/s, -1.44 ± 0.53 vs. -2.07 ± 0.84 1/s, -2.07 ± 0.7 vs. -2.66 ± 0.91 1/s, respectively; all P<0.005). Multiple regression analysis revealed severity of gout had an independent negative impact on LA pump function (ALSR(late)). In conclusion, gout caused LV diastolic dysfunction, LV subclinical systolic dysfunction and LA reservoir, conduit, and booster pump dysfunction.
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YouGenMap: a web platform for dynamic multi-comparative mapping and visualization of genetic maps.
Front Genet
PUBLISHED: 01-01-2014
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Comparative genetic maps are used in examination of genome organization, detection of conserved gene order, and exploration of marker order variations. YouGenMap is an open-source web tool that offers dynamic comparative mapping capability of users' own genetic mapping between 2 or more map sets. Users' genetic map data and optional gene annotations are uploaded, either publically or privately, as long as they follow our template which is available in several standard file formats. Data is parsed and loaded into MySQL relational database to be displayed and compared against users' genetic maps or other public data available on YouGenMap. With the highly interactive GUIs, all public data on YouGenMap are maps available for visualization, comparison, search, filtration and download. YouGenMap web tool is available on the website (http://conifergdb.miamioh.edu/yougenmap) with the source-code repository at (http://sourceforge.net/projects/yougenmap/?source=directory).
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Influences of agents with a self-reputation awareness component in an evolutionary spatial IPD game.
PLoS ONE
PUBLISHED: 01-01-2014
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Iterated prisoner's dilemma (IPD) researchers have shown that strong positive reputations plus an efficient reputation evaluation system encourages both sides to pursue long-term collaboration and to avoid falling into mutual defection cycles. In agent-based environments with reliable reputation rating systems, agents interested in maximizing their private interests must show concern for other agents as well as their own self-reputations--an important capability that standard IPD game agents lack. Here we present a novel learning agent model possessing self-reputation awareness. Agents in our proposed model are capable of evaluating self-behaviors based on a mix of public and private interest considerations, and of testing various solutions aimed at meeting social standards. Simulation results indicate multiple outcomes from the addition of a small percentage of self-reputation awareness agents: faster cooperation, faster movement toward stability in an agent society, a higher level of public interest in the agent society, the resolution of common conflicts between public and private interests, and a lower potential for rational individual behavior to transform into irrational group behavior.
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A MATLAB-based tool for accurate detection of perfect overlapping and nested inverted repeats in DNA sequences.
Bioinformatics
PUBLISHED: 11-08-2013
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Palindromic sequences, or inverted repeats (IRs), in DNA sequences involve important biological processes such as DNA-protein binding, DNA replication and DNA transposition. Development of bioinformatics tools that are capable of accurately detecting perfect IRs can enable genome-wide studies of IR patterns in both prokaryotes and eukaryotes. Different from conventional string-comparison approaches, we propose a novel algorithm that uses a cumulative score system based on a prime number representation of nucleotide bases. We then implemented this algorithm as a MATLAB-based program for perfect IR detection. In comparison with other existing tools, our program demonstrates a high accuracy in detecting nested and overlapping IRs.Availability and implementation: The source code is freely available on (http://bioinfolab.miamioh.edu/bioinfolab/palindrome.php) CONTACT: liangc@miamioh.edu or karroje@miamioh.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Neuronal aging: learning from C. elegans.
J Mol Signal
PUBLISHED: 10-23-2013
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The heterogeneity and multigenetic nature of nervous system aging make modeling of it a formidable task in mammalian species. The powerful genetics, simple anatomy and short life span of the nematode Caenorhabditis elegans offer unique advantages in unraveling the molecular genetic network that regulates the integrity of neuronal structures and functions during aging. In this review, we first summarize recent breakthroughs in the morphological and functional characterization of C. elegans neuronal aging. Age-associated morphological changes include age-dependent neurite branching, axon beading or swelling, axon defasciculation, progressive distortion of the neuronal soma, and early decline in presynaptic release function. We then discuss genetic pathways that modulate the speed of neuronal aging concordant with alteration in life span, such as insulin signaling, as well as cell-autonomous factors that promote neuronal integrity during senescence, including membrane activity and JNK/MAPK signaling. As a robust genetic model for aging, insights from C. elegans neuronal aging studies will contribute to our mechanistic understanding of human brain aging.
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Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors-molecular characterization shows genetic overlap with endometrial stromal sarcoma.
Genes Chromosomes Cancer
PUBLISHED: 10-15-2013
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PHF1 gene rearrangements have been recently described in around 50% of ossifying fibromyxoid tumors (OFMT) including benign and malignant cases, with a small subset showing EP400-PHF1 fusions. In the remaining cases no alternative gene fusions have been identified. PHF1-negative OFMT, especially if lacking S100 protein staining or peripheral ossification, are difficult to diagnose and distinguish from other soft tissue mimics. In seeking more comprehensive molecular characterization, we investigated a large cohort of 39 OFMT of various anatomic sites, immunoprofiles and grades of malignancy. Tumors were screened for PHF1 and EP400 rearrangements by FISH. RNA sequencing was performed in two index cases (OFMT1, OFMT3), negative for EP400-PHF1 fusions, followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. Two novel fusions were identified ZC3H7B-BCOR in OFMT1 and MEAF6-PHF1 in OFMT3. After being validated by FISH and RT-PCR, these abnormalities were screened on the remaining cases. With these additional gene fusions, 33/39 (85%) of OFMTs demonstrated recurrent gene rearrangements, which can be used as molecular markers in challenging cases. The most common abnormality is PHF1 gene rearrangement (80%), being present in benign, atypical and malignant lesions, with fusion to EP400 in 44% of cases. ZC3H7B-BCOR and MEAF6-PHF1 fusions occurred predominantly in S100 protein-negative and malignant OFMT. As similar gene fusions were reported in endometrial stromal sarcomas, we screened for potential gene abnormalities in JAZF1 and EPC1 by FISH and found two additional cases with EPC1-PHF1 fusions. © 2013 Wiley Periodicals, Inc.
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Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer.
Clin. Cancer Res.
PUBLISHED: 09-27-2013
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Epigenetic regulation by promoter methylation plays a key role in tumorigenesis. Our goal was to investigate whether altered DNA methylation signatures associated with oncogenic signaling delineate biomarkers predictive of endometrial cancer recurrence.
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Estimator design for re-entry targets.
ISA Trans
PUBLISHED: 09-24-2013
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This study proposes a trajectory estimation scheme for tactical ballistic missiles (TBMs). Target information acquired from the ground-based radar system is investigated by incorporating input estimation (IE) and extended Kalman filtering techniques. In addition to estimate the missiles position and velocity, our special focus is put on the estimation of the TBMs evasive acceleration and ballistic coefficient. In the demonstrative example, radar measurement errors are served as specifications while characterizing the acquirable zone of the ground-based radar system. Effect of the proposed design is fully verified by examining the estimation performance.
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Design, synthesis and antiproliferative evaluation of fluorenone analogs with DNA topoisomerase I inhibitory properties.
Bioorg. Med. Chem.
PUBLISHED: 08-09-2013
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A series of 2,7-diamidofluorenones were designed, synthesized, and screened by SRB assay. Some synthesized compounds exhibited antitumor activities in submicromolar range. Ten compounds (3a, 3b, 3c, 3g, 3j, 3l, 4a, 4h, 4i, and 4j) were also selected by NCI screening system and 3c (GI50=1.66 ?M) appeared to be the most active agent of this series. Furthermore, 3c attenuated topoisomerase I-mediated DNA relaxation at low micromolar concentrations. These results indicated that fluorenones have potential to be further developed into anticancer drugs.
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Design of synthetic biological logic circuits based on evolutionary algorithm.
IET Syst Biol
PUBLISHED: 08-08-2013
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The construction of an artificial biological logic circuit using systematic strategy is recognised as one of the most important topics for the development of synthetic biology. In this study, a real-structured genetic algorithm (RSGA), which combines general advantages of the traditional real genetic algorithm with those of the structured genetic algorithm, is proposed to deal with the biological logic circuit design problem. A general model with the cis-regulatory input function and appropriate promoter activity functions is proposed to synthesise a wide variety of fundamental logic gates such as NOT, Buffer, AND, OR, NAND, NOR and XOR. The results obtained can be extended to synthesise advanced combinational and sequential logic circuits by topologically distinct connections. The resulting optimal design of these logic gates and circuits are established via the RSGA. The in silico computer-based modelling technology has been verified showing its great advantages in the purpose.
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The effect of renal function on surgical outcomes of intracapsular hip fractures with osteosynthesis.
Arch Orthop Trauma Surg
PUBLISHED: 07-08-2013
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Chronic kidney disease (CKD) affects many physiologic systems, including bone quality, nutrition, and cardiovascular condition. Femoral neck fractures in patients on dialysis are associated with frequent complications and a high risk of mortality. However, the effect of CKD on clinical outcomes of patients with hip fractures treated with osteosynthesis remains unclear.
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Comparative analysis of error-prone replication mononucleotide repeats across baculovirus genomes.
Virus Res.
PUBLISHED: 07-06-2013
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Genome replication by the baculovirus DNA polymerase often generates errors in mononucleotide repeat (MNR) sequences due to replication slippage. This results in the inactivation of genes that affects different stages of the cell infection cycle. Here we mapped these MNRs in the 59 baculovirus genomes. We found that the MNR frequencies of baculovirus genomes are different and not correlated with the genome sizes. Although the average A/T content of baculoviruses is 58.67%, the A/T MNR frequency is significantly higher than that of the G/C MNRs. Furthermore, the A7/T7 MNRs are the most frequent of those we studied. Finally, MNR frequencies in different classes of baculovirus genes, such as immediate early genes, show differences between baculovirus genomes, suggesting that the distribution and frequency of different MNRs are unique to each baculovirus species or strain. Therefore, the results of this study can help select appropriate baculoviruses for the development of biological insecticides.
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The "Aging Males Symptoms" (AMS) Scale assesses depression and anxiety.
Aging Male
PUBLISHED: 07-04-2013
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Emotional distress may be associated with severe aging symptoms. This study aimed to investigate aging symptoms in male psychiatric outpatients and their relationship with anxiety and depression.
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A peroxisome biogenesis deficiency prevents the binding of alpha-synuclein to lipid droplets in lipid-loaded yeast.
Biochem. Biophys. Res. Commun.
PUBLISHED: 06-27-2013
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Using a yeast model of Parkinsons disease, we found that alpha-synuclein (?S) binds to lipid droplets in lipid-loaded, wild-type yeast cells but not to lipid droplets in lipid-loaded, peroxisome-deficient cells (pex3?). Our analysis revealed that pex3? cells have both fewer lipid droplets and smaller lipid droplets than wild-type cells, and that the acyl chains of the phospholipids on the surface of the lipid droplets from pex3? cells are on average shorter (C16) than those (C18) on the surface of lipid droplets from wild-type cells. We propose that the shift to shorter (C18?C16) acyl chains contributes to the reduced binding of ?S to lipid droplets in pex3? cells.
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Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.
Genes Chromosomes Cancer
PUBLISHED: 06-19-2013
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Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT-PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino-nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1-related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1-3 rearrangements in benign and malignant, visceral, and soft tissue GTs.
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Oleanane-triterpenoids from Panax stipuleanatus inhibit NF-?B.
J Ginseng Res
PUBLISHED: 05-30-2013
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In continuation of our research to find biological components from Panax stipuleanatus, four oleanane-type triterpenes (12 to 15) were isolated successively. Fifteen oleanane-type saponins (1 to 15) were evaluated for nuclear factor (NF)-?B activity using a luciferase reporter gene assay in HepG2 cells. Compounds 6 to 11 inhibited NF-?B, with IC50 values between 3.1 to 18.9 ?M. The effects on inducible nitric oxide synthase and cyclooxygenase-2 by compounds 8, 10, and 11 were also examined using reverse transcription-polymerase chain reaction. Three compounds (8, 10, and 11) inhibited NF-?B activity by reducing the concentration of inflammatory factors in HepG2 cells.
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Effect of interleukin-2 level and genetic variants on coronary artery disease.
Inflammation
PUBLISHED: 05-30-2013
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Inflammation plays important roles in the development of atherosclerosis and coronary artery disease (CAD). Interleukin-2 (IL-2) is a proinflammatory cytokine and induces proliferation of T cells. The aim of the study was to understand the effect of IL-2 on the development of CAD from genetic polymorphism perspective and serum level perspective. IL-2 -330T/G and +114T/G polymorphisms were tested in 692 CAD cases and 723 healthy controls. IL-2 expression of these two polymorphisms was compared. Serum level of IL-2 in CAD patients and controls was analyzed. Data showed that prevalence of IL-2 -330GG genotype was significantly increased in CAD than in controls (p = 5.1 × 10(-6)). Function analysis revealed that subjects carrying IL-2 -330GG genotype had higher serum level of IL-2 than those with TG or TT genotypes (p < 0.01). Serum level of IL-2 in the study subjects was further analyzed, and results showed that CAD patients had significantly increased IL-2 level than healthy controls (p < 0.01). Also, cases with three vessels affected were observed to have higher IL-2 level than cases with one vessel affected (p < 0.05). These data suggested IL-2 polymorphism could affect the susceptibility to CAD by elevating protein expression, and serum level of IL-2 may be closed correlated with the development and progression of this disease.
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[Algorithm of locally adaptive region growing based on multi-template matching applied to automated detection of hemorrhages].
Guang Pu Xue Yu Guang Pu Fen Xi
PUBLISHED: 05-24-2013
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In order to automatically detect hemorrhages in fundus images, and develop an automated diabetic retinopathy screening system, a novel algorithm named locally adaptive region growing based on multi-template matching was established and studied. Firstly, spectral signature of major anatomical structures in fundus was studied, so that the right channel among RGB channels could be selected for different segmentation objects. Secondly, the fundus image was preprocessed by means of HSV brightness correction and contrast limited adaptive histogram equalization (CLAHE). Then, seeds of region growing were founded out by removing optic disc and vessel from the resulting image of normalized cross-correlation (NCC) template matching on the previous preprocessed image with several templates. Finally, locally adaptive region growing segmentation was used to find out the exact contours of hemorrhages, and the automated detection of the lesions was accomplished. The approach was tested on 90 different resolution fundus images with variable color, brightness and quality. Results suggest that the approach could fast and effectively detect hemorrhages in fundus images, and it is stable and robust. As a result, the approach can meet the clinical demands.
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The effect of PEG-5K grafting level and particle size on tumor accumulation and cellular uptake.
Int J Pharm
PUBLISHED: 05-16-2013
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PEG-modified gold nanoparticles (PEG-modified GNs) with diameters of 40 nm and 70 nm were prepared to elucidate the effect of extent of PEG (M.W. 5000) grafting and particle size on tumor accumulation and cellular uptake. Flow cytometry reveals that cellular uptake is strongly related to the size of PEG-modified GNs, rather than the extent of PEG-5K grafting level. Cytotoxicity analysis based on the intracellular release of drugs showed that the 70 nm PEG-modified GNs have the higher cytotoxicity, beccause of their greater cellular uptake. Also, particle size, rather than PEG-5K grafting level affects tumor accumulation. However, PEG-5K grafting level significantly affects the accumulation of particles in the liver and spleen. This finding is important in determining the proper PEG-5K grafting level and particle size for designing nano-medicines.
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Three new guaiane sesquiterpene lactones from rhizomes of Curcuma wenyujin.
J Asian Nat Prod Res
PUBLISHED: 05-16-2013
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Three new guaiane sesquiterpene lactones (4S)-4-hydroxy-gweicurculactone (1), zedoalactone G (2), and (1R, 4R, 5S, 10S)-zedoalactone B (3), and three known guaiane sesquiterpene lactones, including zedoarolide B (4), zedoalactone B (5), and a new natural product (+)-zedoalactone A (6), were isolated from the rhizomes of Curcuma wenyujin Y.H. Chen et C. Ling. The structures were elucidated by spectroscopic methods including 1D and 2D NMR and HR-ESI-MS. The absolute configuration of 2 was determined via the calculated electronic circular dichroism (ECD), whereas the absolute configurations of 1 and 3 were determined via the ECD data of the [Rh2(OCOCF3)4] complex and [Mo2(OAc)4] complex, respectively. The inhibitory effects of compounds 1-6 on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated. All of them exhibited weak anti-inflammatory activity.
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Comprehensive methylome analysis of ovarian tumors reveals hedgehog signaling pathway regulators as prognostic DNA methylation biomarkers.
Epigenetics
PUBLISHED: 05-10-2013
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Women with advanced stage ovarian cancer (OC) have a five-year survival rate of less than 25%. OC progression is associated with accumulation of epigenetic alterations and aberrant DNA methylation in gene promoters acts as an inactivating "hit" during OC initiation and progression. Abnormal DNA methylation in OC has been used to predict disease outcome and therapy response. To globally examine DNA methylation in OC, we used next-generation sequencing technology, MethylCap-sequencing, to screen 75 malignant and 26 normal or benign ovarian tissues. Differential DNA methylation regions (DMRs) were identified, and the Kaplan-Meier method and Cox proportional hazard model were used to correlate methylation with clinical endpoints. Functional role of specific genes identified by MethylCap-sequencing was examined in in vitro assays. We identified 577 DMRs that distinguished (p < 0.001) malignant from non-malignant ovarian tissues; of these, 63 DMRs correlated (p < 0.001) with poor progression free survival (PFS). Concordant hypermethylation and corresponding gene silencing of sonic hedgehog pathway members ZIC1 and ZIC4 in OC tumors was confirmed in a panel of OC cell lines, and ZIC1 and ZIC4 repression correlated with increased proliferation, migration and invasion. ZIC1 promoter hypermethylation correlated (p < 0.01) with poor PFS. In summary, we identified functional DNA methylation biomarkers significantly associated with clinical outcome in OC and suggest our comprehensive methylome analysis has significant translational potential for guiding the design of future clinical investigations targeting the OC epigenome. Methylation of ZIC1, a putative tumor suppressor, may be a novel determinant of OC outcome.
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Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma.
Genes Chromosomes Cancer
PUBLISHED: 04-15-2013
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Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion-negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong transcription factor E3 (TFE3) immunoreactivity, fluorescence in situ hybridization (FISH) analysis for TFE3 gene rearrangement was applied to the index case as well as to nine additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, nine pseudomyogenic HE, and three epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in six cases, lung in three and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and reverse transcription polymerase chain reaction (RT-PCR). YAP1 gene rearrangements were then confirmed in seven of the remaining nine TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3-rearranged EHEs showed similar morphologic features with at least focally, well-formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary, we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions.
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Heparin-binding epidermal growth factor-like growth factor attenuates acute lung injury and multiorgan dysfunction after scald burn.
J. Surg. Res.
PUBLISHED: 04-09-2013
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Impaired gut barrier function and acute lung injury (ALI) are significant components of the multiorgan dysfunction syndrome that accompanies severe burns. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to reduce inflammation, preserve gut barrier function, and protect the lungs from acute injury in several models of intestinal injury; however, comparable effects of HB-EGF after burn injury have never been investigated. The present studies were based on the hypothesis that HB-EGF would reduce the severity of ALI and multiorgan dysfunction after scald burns in mice.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.