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  • 1
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    Global shape mimicry of tRNA within a viral internal ribosome entry site mediates translational reading frame selection (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-11-09
    Description: The dicistrovirus intergenic region internal ribosome entry site (IRES) adopts a triple-pseudoknotted RNA structure and occupies the core ribosomal E, P, and A sites to directly recruit the ribosome and initiate translation at a non-AUG codon. A subset of dicistrovirus IRESs directs translation in the 0 and +1 frames to produce the viral structural proteins and a +1 overlapping open reading frame called ORFx, respectively. Here we show that specific mutations of two unpaired adenosines located at the core of the three-helical junction of the honey bee dicistrovirusIsraeli acute paralysis virus(IAPV) IRES PKI domain can uncouple 0 and +1 frame translation, suggesting that the structure adopts distinct conformations that contribute to 0 or +1 frame translation. Using a reconstituted translation system, we show that ribosomes assembled on mutant IRESs that direct exclusive 0 or +1 frame translation lack reading frame fidelity. Finally, a nuclear magnetic resonance/small-angle X-ray scattering hybrid approach reveals that the PKI domain of the IAPV IRES adopts an RNA structure that resembles a complete tRNA. The tRNA shape-mimicry enables the viral IRES to gain access to the ribosome tRNA-binding sites and form intermolecular contacts with the ribosome that are necessary for initiating IRES translation in a specific reading frame.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation (2019)
    National Academy of Sciences
    Details
    Publication Date: 2019-03-19
    Description: Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (orEPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression ofEPHX2mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress (2016)
    National Academy of Sciences
    Details
    Publication Date: 2016-03-14
    Description: Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease (2018)
    National Academy of Sciences
    Details
    Publication Date: 2018-05-07
    Description: Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder, and the deposition of specific protein aggregates of α-synuclein, termed Lewy bodies, is evident in multiple brain regions of PD patients. Although there are several available medications to treat PD symptoms, these medications do not prevent the progression of the disease. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with the pathogenesis of PD. Here we found that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity in the mouse striatum was attenuated by subsequent repeated administration of TPPU, a potent sEH inhibitor. Furthermore, deletion of the sEH gene protected against MPTP-induced neurotoxicity, while overexpression of sEH in the striatum significantly enhanced MPTP-induced neurotoxicity. Moreover, the expression of the sEH protein in the striatum from MPTP-treated mice or postmortem brain samples from patients with dementia of Lewy bodies (DLB) was significantly higher compared with control groups. Interestingly, there was a positive correlation between sEH expression and phosphorylation of α-synuclein in the striatum. Oxylipin analysis showed decreased levels of 8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid in the striatum of MPTP-treated mice, suggesting increased activity of sEH in this region. Interestingly, the expression of sEH mRNA in human PARK2 iPSC-derived neurons was higher than that of healthy control. Treatment with TPPU protected against apoptosis in human PARK2 iPSC-derived dopaminergic neurons. These findings suggest that increased activity of sEH in the striatum plays a key role in the pathogenesis of neurodegenerative disorders such as PD and DLB. Therefore, sEH may represent a promising therapeutic target for α-synuclein–related neurodegenerative disorders.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Analysis of the Metals in Soil-Water Interface in a Manganese Mine (2015)
    Hindawi
    Details
    Publication Date: 2015-06-18
    Description: In order to reveal the influence of the metals of soil-water interface in a manganese mine (Xiangtan, China), on local water environment, there are six kinds of metals (Mn, Ni, Cu, Zn, Cd, and Pb) characterized by measuring their concentration, correlation, source, and special distribution using principal component analysis, single factor, and Nemero comprehensive pollution index. The results showed that the corresponding average concentration was 0.3358, 0.045, 0.0105, 0.0148, 0.0067, and 0.0389 mg/L. The logarithmic concentration of Mn, Zn, and Pb was normal distribution. The correlation coefficients (between Mn and Pb, Mn and Zn, Mn and Ni, Cu and Zn, Cu and Pb, and Zn and Cd) were found to range from 0.5 to 0.6, and those between Cu and Ni and Cu and Cd were below 0.3. It was found that Zn and Mn pollution were caused primarily by ore mining, mineral waste transportation, tailing slag, and smelting plants, while Cu and Ni mainly originate from the mining industry activities and the traffic transportation in the mining area. In addition, the Cd was considered to be produced primarily from the agricultural or anthropogenic activities. The pollution indexes indicated that metal pollution degree was different in soil-water interface streams as listed in increasing order of pollution level as Zn 〉 Ni 〉 Cu 〉 Pb 〉 Mn 〉 Cd. For all of the pollution of the soil-water interface streams, there was moderate metal pollution but along the eastern mine area the pollution seemed to get more serious. There was only a small amount of soil-water interface streams not contaminated by the metals.
    Print ISSN: 2090-8865
    Electronic ISSN: 2090-8873
    Topics: Chemistry and Pharmacology
    Published by Hindawi
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  • 6
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    Inventory Model with Partial Backordering When Backordered Customers Delay Purchase after Stockout-Restoration (2016)
    Hindawi
    Details
    Publication Date: 2016-02-11
    Description: Many inventory models with partial backordering assume that the backordered demand must be filled instantly after stockout restoration. In practice, however, the backordered customers may successively revisit the store because of the purchase delay behavior, producing a limited backorder demand rate and resulting in an extra inventory holding cost. Hence, in this paper we formulate the inventory model with partial backordering considering the purchase delay of the backordered customers and assuming that the backorder demand rate is proportional to the remaining backordered demand. Particularly, we model the problem by introducing a new inventory cost component of holding the backordered items, which has not been considered in the existing models. We propose an algorithm with a two-layer structure based on Lipschitz Optimization (LO) to minimize the total inventory cost. Numerical experiments show that the proposed algorithm outperforms two benchmarks in both optimality and efficiency. We also observe that the earlier the backordered customer revisits the store, the smaller the inventory cost and the fill rate are, but the longer the order cycle is. In addition, if the backordered customers revisit the store without too much delay, the basic EOQ with partial backordering approximates our model very well.
    Print ISSN: 1024-123X
    Electronic ISSN: 1563-5147
    Topics: Mathematics , Technology
    Published by Hindawi
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  • 7
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    A Numerical Method of the Euler-Bernoulli Beam with Optimal Local Kelvin-Voigt Damping (2014)
    Hindawi
    Details
    Publication Date: 2014-06-24
    Description: This paper deals with the numerical approximation problem of the optimal control problem governed by the Euler-Bernoulli beam equation with local Kelvin-Voigt damping, which is a nonlinear coefficient control problem with control constraints. The goal of this problem is to design a control input numerically, which is the damping and distributes locally on a subinterval of the region occupied by the beam, such that the total energy of the beam and the control on a given time period is minimal. We firstly use the finite element method (FEM) to obtain a finite-dimensional model based on the original PDE system. Then, using the control parameterization method, we approximate the finite-dimensional problem by a standard optimal parameter selection problem, which is a suboptimal problem and can be solved numerically by nonlinear mathematical programming algorithm. At last, some simulation studies will be presented by the proposed numerical approximation method in this paper, where the damping controls act on different locations of the Euler-Bernoulli beam.
    Print ISSN: 1110-757X
    Electronic ISSN: 1687-0042
    Topics: Mathematics
    Published by Hindawi
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  • 8
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    Inventory Model with Partial Backordering When Backordered Customers Delay Purchase after Stockout-Restoration (2016)
    Hindawi
    Details
    Publication Date: 2016-01-01
    Description: Many inventory models with partial backordering assume that the backordered demand must be filled instantly after stockout restoration. In practice, however, the backordered customers may successively revisit the store because of the purchase delay behavior, producing a limited backorder demand rate and resulting in an extra inventory holding cost. Hence, in this paper we formulate the inventory model with partial backordering considering the purchase delay of the backordered customers and assuming that the backorder demand rate is proportional to the remaining backordered demand. Particularly, we model the problem by introducing a new inventory cost component of holding the backordered items, which has not been considered in the existing models. We propose an algorithm with a two-layer structure based on Lipschitz Optimization (LO) to minimize the total inventory cost. Numerical experiments show that the proposed algorithm outperforms two benchmarks in both optimality and efficiency. We also observe that the earlier the backordered customer revisits the store, the smaller the inventory cost and the fill rate are, but the longer the order cycle is. In addition, if the backordered customers revisit the store without too much delay, the basic EOQ with partial backordering approximates our model very well.
    Print ISSN: 1024-123X
    Electronic ISSN: 1563-5147
    Topics: Mathematics , Technology
    Published by Hindawi
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  • 9
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    Vehicle Routing Problems with Fuel Consumption and Stochastic Travel Speeds (2017)
    Hindawi
    Details
    Publication Date: 2017-01-01
    Description: Conventional vehicle routing problems (VRP) always assume that the vehicle travel speed is fixed or time-dependent on arcs. However, due to the uncertainty of weather, traffic conditions, and other random factors, it is not appropriate to set travel speeds to fixed constants in advance. Consequently, we propose a mathematic model for calculating expected fuel consumption and fixed vehicle cost where average speed is assumed to obey normal distribution on each arc which is more realistic than the existing model. For small-scaled problems, we make a linear transformation and solve them by existing solver CPLEX, while, for large-scaled problems, an improved simulated annealing (ISA) algorithm is constructed. Finally, instances from real road networks of England are performed with the ISA algorithm. Computational results show that our ISA algorithm performs well in a reasonable amount of time. We also find that when taking stochastic speeds into consideration, the fuel consumption is always larger than that with fixed speed model.
    Print ISSN: 1024-123X
    Electronic ISSN: 1563-5147
    Topics: Mathematics , Technology
    Published by Hindawi
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  • 10
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    Estimation of Jointly Normally Distributed Demand for Cross-Selling Items in Inventory Systems with Lost Sales (2019)
    Hindawi
    Details
    Publication Date: 2019-07-16
    Description: Demand estimation is often confronted with incomplete information of censored demand because of lost sales. Many estimators have been proposed to deal with lost sales when estimating the parameters of demand distribution. This study introduces the cross-selling effect into estimations, where two items are cross-sold because of the positive externality in a newsvendor-type inventory system. We propose an approach to estimate the parameters of a jointly normally distributed demand for two cross-selling items based on an iterative framework considering lost sales. Computational results based on more than two million numerical examples show that our estimator achieves high precision. Compared with the point estimations without lost sales, all the relative errors of the estimations of demand expectation, standard deviation, and correlation coefficient are no larger than 2% on average if the sample size is no smaller than 800. In particular, for demand expectation, the error is smaller than 1% if the comprehensive censoring level is no larger than four standard deviations (implying a 2σ-level of safety stock for each item), even if the sample size decreases to 50. This implies that the demand estimator should be competent in modern inventory systems that are rich in data.
    Print ISSN: 1024-123X
    Electronic ISSN: 1563-5147
    Topics: Mathematics , Technology
    Published by Hindawi
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