1,206 research outputs found
Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8
Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. Here, we report the bioengineering of a set of next-generation AAV vectors, named AAV-SYDs (where “SYD” stands for Sydney, Australia), with increased human hepato-tropism in a liver xenograft mouse model repopulated with primary human hepatocytes. We followed a two-step process that staggered directed evolution and domain-swapping approaches. Using DNA-family shuffling, we first mapped key AAV capsid regions responsible for efficient human hepatocyte transduction in vivo. Focusing on these regions, we next applied domain-swapping strategies to identify and study key capsid residues that enhance primary human hepatocyte uptake and transgene expression. Our findings underscore the potential of AAV-SYDs as liver gene therapy vectors and provide insights into the mechanism responsible for their enhanced transduction profile
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ERK1/2 signaling dominates over RhoA signaling in regulating early changes in RNA expression induced by endothelin-1 in neonatal rat cardiomyocytes
Cardiomyocyte hypertrophy is associated with changes in gene expression. Extracellular signal-regulated kinases 1/2 (ERK1/2) and RhoA [activated by hypertrophic agonists (e.g. endothelin-1)] regulate gene expression and are implicated in the response, but their relative significance in regulating the cardiomyocyte transcriptome is unknown. Our aim was to establish the significance of ERK1/2 and/or RhoA in the early cardiomyocyte transcriptomic response to endothelin-1.Cardiomyocytes were exposed to endothelin-1 (1 h) with/without PD184352 (to inhibit ERK1/2) or C3 transferase (C3T, to inhibit RhoA). RNA expression was analyzed using microarrays and qPCR. ERK1/2 signaling positively regulated approximately 65% of the early gene expression response to ET-1 with a small (approximately 2%) negative effect, whereas RhoA signaling positively regulated approximately 10% of the early gene expression response to ET-1 with a greater (approximately 14%) negative contribution. Of RNAs non-responsive to endothelin-1, 66 or 448 were regulated by PD184352 or C3T, respectively, indicating that RhoA had a more significant effect on baseline RNA expression. mRNAs upregulated by endothelin-1 encoded a number of receptor ligands (e.g. Ereg, Areg, Hbegf) and transcription factors (e.g. Abra/Srf) that potentially propagate the response.ERK1/2 dominates over RhoA in the early transcriptomic response to endothelin-1. RhoA plays a major role in maintaining baseline RNA expression but, with upregulation of Abra/Srf by endothelin-1, RhoA may regulate changes in RNA expression over longer times. Our data identify ERK1/2 as a more significant node than RhoA in regulating the early stages of cardiomyocyte hypertrophy
Water Policies and Conflict Resolution of Public Participation Decision-Making Processes Using Prioritized Ordered Weighted Averaging (OWA) Operators
[EN] There is a growing interest in environmental policies about how to implement public participation engagement in the context of water resources management. This paper presents a robust methodology, based on ordered weighted averaging (OWA) operators, to conflict resolution decision-making problems under uncertain environments due to both information and stakeholders' preferences. The methodology allows integrating heterogeneous interests of the general public and stakeholders on account of their different degree of acceptance or preference and level of influence or power regarding the measures and policies to be adopted, and also of their level of involvement (i.e., information supply, consultation and active involvement). These considerations lead to different environmental and socio-economic outcomes, and levels of stakeholders' satisfaction. The methodology establishes a prioritization relationship over the stakeholders. The individual stakeholders' preferences are aggregated through their associated weights, which depend on the satisfaction of the higher priority decision maker. The methodology ranks the optimal management strategies to maximize the stakeholders' satisfaction. It has been successfully applied to a real case study, providing greater fairness, transparency, social equity and consensus among actors. Furthermore, it provides support to environmental policies, such as the EU Water Framework Directive (WFD), improving integrated water management while covering a wide range of objectives, management alternatives and stakeholders.Llopis Albert, C.; Merigó-Lindahl, JM.; Liao, H.; Xu, Y.; Grima-Olmedo, J.; Grima-Olmedo, C. (2018). Water Policies and Conflict Resolution of Public Participation Decision-Making Processes Using Prioritized Ordered Weighted Averaging (OWA) Operators. 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J Hydrol Eng 12(2):206–217. https://doi.org/10.1061/(ASCE)1084-0699(2007)12:2(206).Kirchherr J, Charles KJ, Walton MJ (2016) Multi-causal pathways of public opposition to dam project in Asia: A fuzzy set qualitative comparative analysis (fsQCA). Glob Environ Chang 41:33–45. https://doi.org/10.1016/j.gloenvcha.2016.08.001Llopis-Albert C, Pulido-Velazquez D (2015) Using MODFLOW code to approach transient hydraulic head with a sharp-interface solution. Hydrol Process 29(8):2052–2064. https://doi.org/10.1002/hyp.10354Llopis-Albert C, Palacios-Marqués D, Soto-Acosta P (2015) Decision-making and stakeholders constructive participation in environmental projects. J Bus Res 68:1641–1644. https://doi.org/10.1016/j.jbusres.2015.02.010Llopis-Albert C, Merigó JM, Xu Y, Huchang L (2017) Improving regional climate projections by prioritized aggregation via ordered weighted averaging operators. Environ Eng Sci. https://doi.org/10.1089/ees.2016.0546Maia R (2017) The WFD Implementation in the European Member States. Water Resour Manag 31(10):3043–3060. https://doi.org/10.1007/s11269-017-1723-5Malczewski J, Chapman T, Flegel C, Walters D, Shrubsole D, Healy MA (2003) GIS - multicriteria evaluation with ordered weighted averaging (OWA): case study of developing watershed management strategies. Environ Plan A 35:1769–1784. https://doi.org/10.1068/a35156Merigó JM, Casanovas M (2011) The uncertain generalized owa operator and its application to financial decision making. Int J Inf Technol Decis Mak 10(2):211–230Merigó JM, Yager RR (2013) Generalized moving averages, distance measures and OWA operators. Int J Uncertain, Fuzziness Knowl-Based Syst 21(4):533–559Merigó JM, Palacios-Marqués D, Ribeiro-Navarrete B (2015) Aggregation systems for sales forecasting. J Bus Res 68:2299–2304Mesiar R, Stupnanová A, Yager RR (2015) Generalizations of OWA Operators. IEEE Trans Fuzzy Syst 23(6):2154–2162O’Hagan M (1988) Aggregating Template Rule Antecedents in Real-time Expert Systems with Fuzzy Set Logic. In: Proceedings of 22nd annual IEEE Asilomar Conference on Signals. IEEE and Maple Press, Pacific Grove, Systems and Computers, pp 681–689Rahmani MA, Zarghami M (2013) A new approach to combine climate change projections by ordered weighting averaging operator; applications to northwestern provinces of Iran. Glob Planet Chang 102:41–50Ran LG, Wei GW (2015) Uncertain prioritized operators and their application to multiple attribute group decision making. Technol Econ Dev Econ 21:118–139Ruiz-Villaverde, A., García-Rubio, M.A. (2017). Public Participation in European Water Management: from Theory to Practice. Water Resour Manag 31(8), 2479–2495. https://doi.org/10.1007/s11269-016-1355-1Sadiq R, Tesfamariam S (2007) Probability density functions based weights for ordered weighted averaging (OWA) operators: An example of water quality indices. Eur J Oper Res 182:1350–1368Sadiq R, Rodríguez MJ, Tesfamariam S (2010) Integrating indicators for performance assessment of small water utilities using ordered weighted averaging (OWA) operators. Expert Syst Appl 37:4881–4891Verma R, Sharma B (2016) Prioritized information fusion method for triangular fuzzy information and its application to multiple attribute decision making. Int J Uncertain, Fuzziness Knowl-Based Syst 24:265–290Wang HM, Xu YJ, Merigó JM (2014) Prioritized aggregation for non-homogeneous group decision making in water resource management. Econ Comput Econ Cybern Stud Res 48(1):247–258Wei GW (2012) Hesitant fuzzy prioritized operators. Knowl-Based Syst 31:176–182Wei CP, Tang XJ (2012) Generalized prioritized aggregation operators. Int J Intell Syst 27:578–589Xu ZS (2005) An Overview of Methods for Determining OWA Weights. 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Eur J Oper Res 198:259–265Zarghami M, Ardakanian R, Memariani A, Szidarovszky F (2008) Extended OWA Operator for Group Decision Making on Water Resources Projects. J Water Resour Plan Manag 134(3):266–275. https://doi.org/10.1061/(ASCE)0733-9496(2008)134:3(266)Zarghami M, Szidarovszky F, Ardakanian R (2009) Multi-attribute decision making on inter-basin water transfer projects. Transaction E. Ind Eng 16(1):73–80Zhao XF, Li QX, Wei GW (2014) Some prioritized aggregating operators with linguistic information and their application to multiple attribute group decision making. J Intell Fuzzy Syst 26:1619–1630Zhao N, Xu ZS, Ren ZL (2016) On typical hesitant fuzzy prioritized “or” operator in multi-attribute decision making. Int J Intell Syst 31:73–100Zhou LY, Lin R, Zhao XF, Wei GW (2013) Uncertain linguistic prioritized aggregation operators and their application to multiple attribute group decision making. 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Towards Design Patterns for Augmented Reality Serious Games
For professional workers today, keeping up with knowledge and the continuous technology progress is challenging. Increased innovation speed and dynamic work situations shorten preparation times for new tasks significantly. Traditional professional training approaches preparing employees for new tasks are becoming inappropriate. Thus new educational means are needed. These would help employees get acquainted with new situations faster and more efficiently.
According to learning theories such as action learning and situated learning, which embed the learning process in the application context and challenge the learner to be actively involved help to improve the learning process. These theories are the basis for mobile learning and serious games. From research in Serious Games we know that games have the potential to actively involve learners and to immerse them in a learning situation and increase their engagement.
With Augmented Reality (AR) and wearable devices a new generation of tools and applications becomes available, which inherently are mobile, contextualized and personalized. First successful application scenarios show the potential of these new technologies for education and training.
While the application of game-design patterns to learning processes help to systematically design learning games supporting specific learning outcomes, an empirically tested, systematic approach towards the design of AR-based learning solutions is still missing.
Based on the state of the art in AR research and in applying design patterns for serious games, we consequently propose a research methodology to apply game design patterns to augmented reality-based learning games for the training of professionals in dynamic situations
Prognostic value of hedgehog signal component expressions in hepatoblastoma patients
<p>Abstract</p> <p>Objective</p> <p>Activation of hedgehog (Hh) pathway has been implicated in the development of human malignancies. Hh as well as related downstream target genes has been extensively studied in many kinds of malignant tumours for clinical diagnostic or prognostic utilities. This study aimed at investigating whether Hh molecules provides a molecular marker of hepatoblastoma malignancy.</p> <p>Methods</p> <p>We obtained tissue sections from 32 patients with hepatoblastoma as well as cholestasis and normal control. Immunohistochemical analysis were performed to determine Hh signal components in human hepatoblastoma. The prognostic significance of single expression of Hh signal components were evaluated using Cox proportional hazards regression models and Kaplan-Meier survival analysis for statistical analysis.</p> <p>Results</p> <p>Expression of Hh signal components showed an increase in hepatoblastoma compared with chole stasis and normal tissues. There was a positive correlation between Smo or Gli1 expression and tumor clinicopathological features, such as histological type, tumor grade, tumor size and clinical stage. Both Smo or Gli1 protein high expression was significantly associated with poor prognosis by univariate analyses and multivariate analyses.</p> <p>Conclusions</p> <p>Abnormal Hh signaling activation plays important roles in the malignant potential of hepatoblastoma. Gli1 expression is an independent prognostic marker.</p
Small-Molecule Synthetic Compound Norcantharidin Reverses Multi-Drug Resistance by Regulating Sonic Hedgehog Signaling in Human Breast Cancer Cells
Multi-drug resistance (MDR), an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC) transporters and activated Sonic hedgehog (Shh) signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX), we examined the effect and mechanism of norcantharidin (NCTD), a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S) and DOX-resistant (MCF-7R) cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells
Automated functional classification of experimental and predicted protein structures
BACKGROUND: Proteins that are similar in sequence or structure may perform different functions in nature. In such cases, function cannot be inferred from sequence or structural similarity. RESULTS: We analyzed experimental structures belonging to the Structural Classification of Proteins (SCOP) database and showed that about half of them belong to multi-functional fold families for which protein similarity alone is not adequate to assign function. We also analyzed predicted structures from the LiveBench and the PDB-CAFASP experiments and showed that accurate homology-based functional assignments cannot be achieved approximately one third of the time, when the protein is a member of a multi-functional fold family. We then conducted extended performance evaluation and comparisons on both experimental and predicted structures using our Functional Signatures from Structural Alignments (FSSA) algorithm that we previously developed to handle the problem of classifying proteins belonging to multi-functional fold families. CONCLUSION: The results indicate that the FSSA algorithm has better accuracy when compared to homology-based approaches for functional classification of both experimental and predicted protein structures, in part due to its use of local, as opposed to global, information for classifying function. The FSSA algorithm has also been implemented as a webserver and is available at
Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay
The decay channel
is studied using a sample of events collected
by the BESIII experiment at BEPCII. A strong enhancement at threshold is
observed in the invariant mass spectrum. The enhancement can be fit
with an -wave Breit-Wigner resonance function with a resulting peak mass of
and a
narrow width that is at the 90% confidence level.
These results are consistent with published BESII results. These mass and width
values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics
Tripeptide tyroserleutide plus doxorubicin: therapeutic synergy and side effect attenuation
<p>Abstract</p> <p>Background</p> <p>Tripeptide tyroserleutide (YSL) is a novel small molecule anti-tumor polypeptide that has been shown to inhibit the growth of human liver cancer cells. In this study, we investigated the effects of YSL plus doxorubicin on the growth of human hepatocellular carcinoma BEL-7402 cells that had been transplanted into nude mice.</p> <p>Methods</p> <p>Nude mice bearing human hepatocellular carcinoma BEL-7402 tumors were treated with successive intraperitoneal injections of saline; low-, mid-, or high-dose doxorubicin; or low-, mid-, or high-dose doxorubicin plus YSL. Effects on the weight and volume of the tumors were evaluated.</p> <p>Results</p> <p>Co-administration of YSL and high-dose doxorubicin (6 mg/kg every other day) prolonged the survival time of tumor-bearing mice as compared to high-dose doxorubicin alone. As well, the anti-tumor effects of mid- and low-dose doxorubicin (2 and 0.7 mg/kg every other day, respectively) were enhanced when supplemented with YSL; the tumor growth inhibition rates for YSL plus doxorubicin were greater than the inhibition rates for the same dosages of doxorubicin alone. The combination of YSL and doxorubicin decreased chemotherapy-associated weight loss, leukocyte depression, and heart, liver, and kidney damage as compared to doxorubicin alone.</p> <p>Conclusion</p> <p>The combination of YSL plus doxorubicin enhances the anti-tumor effect and reduces the side effects associated with doxorubicin chemotherapy.</p
Arginase activities and global arginine bioavailability in wild-type and ApoE-deficient mice: Responses to high fat and high cholesterol diets
Increased catabolism of arginine by arginase is increasingly viewed as an important pathophysiological factor in cardiovascular disease, including atherosclerosis induced by high cholesterol diets. Whereas previous studies have focused primarily on effects of high cholesterol diets on arginase expression and arginine metabolism in specific blood vessels, there is no information regarding the impact of lipid diets on arginase activity or arginine bioavailability at a systemic level. We, therefore, evaluated the effects of high fat (HF) and high fat-high cholesterol (HC) diets on arginase activity in plasma and tissues and on global arginine bioavailability (defined as the ratio of plasma arginine to ornithine + citrulline) in apoE-/- and wild-type C57BL/6J mice. HC and HF diets led to reduced global arginine bioavailability in both strains. The HC diet resulted in significantly elevated plasma arginase in both strains, but the HF diet increased plasma arginase only in apoE-/- mice. Elevated plasma arginase activity correlated closely with increased alanine aminotransferase levels, indicating that liver damage was primarily responsible for elevated plasma arginase. The HC diet, which promotes atherogenesis, also resulted in increased arginase activity and expression of the type II isozyme of arginase in multiple tissues of apoE-/- mice only. These results raise the possibility that systemic changes in arginase activity and global arginine bioavailability may be contributing factors in the initiation and/or progression of cardiovascular disease
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