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Spatial remote sensing images are usually degraded during image capturing procedures mainly due to the mixed factors of atmospheric turbulence, spacecraft motion, and out of focus lenses. The real point spread function (PSF) of the whole imaging system is the convolution of all factors contributing to degradation. The exact degradation PSF model estimation is important for the image restoration result. In this paper, we considered the properties of the mixed degradation factors and proposed a new blind deconvolution model to simultaneously estimate and remove blurs from remote sensing images. Inconsistent with existing models, which mainly focus on only one degradation type and estimate blur kernel parameters using the fixed regularizer, we concentrated on the diversity of different PSF types and used the variable exponent regularizer to improve kernel flexibility. The proposed model could estimate not only single PSF types, such as motion, uniform, and Gaussian, but also composite PSFs of different types. Following the split Bregman method, we employed an efficient computational method, which did not require PSF initial values, to minimize the proposed cost function iteratively. Experimental results demonstrated the effectiveness and robustness of the proposed method for simulated and real remote sensing images with different PSFs' types.

Cable fire caused by arc faults is one of the essential factors threatening the safe operation of a power system. The ignition and flame propagation of cable fire dependent on the characteristics of the arc discharge is lackingin in-depth understanding at present. In this work, with the constant electric power deposited into the arc discharge, the effects of arc size on the ignition and flame propagation of 110 kV XLPE cable fire are investigated for the first time. The arc size is changed by varying the gap distance of electrodes from 1.5 cm to 2.5 cm. It is interesting to find that the larger the arc size is, the faster the cable fire is ignited and propagates, and the larger the damaged area of the sheath of the cable is. Therein, when the gap distance increases from 1.3 cm to 3.1 cm, the equivalent impedance and the length of the arc discharge increase nearly seven times and three times, respectively. However, the gas temperature of the arc decreases slightly from 2280 K to 2100 K. In addition, a 3D model of the cable fire ignited by arc discharge is computed by Pyrosim software with fire dynamic simulation (FDS) module. Simulated results show that as the arc size increases, the cable fire is ignited faster, the flame propagates both vertically and horizontally increasing significantly, which is agreed well with the experimental results. This study deepens the understanding of the cable fire ignited by arc discharge and therefore it is useful for the evaluation and prevention of cable fire.

According to the Chinese Pharmacopoeia 2015, only processed Aconitum tubers can be clinically applied, and the effect of processing is unclear. This research aimed to explore the effect of processing on cardiac efficacy of alkaloids in Aconitum tubers. First, the chemical ingredients in unprocessed and processed Aconitum tubers were identified and compared by using high performance liquid chromatography time-of-flight mass spectrometry (HPLC-TOF/MS) and multivariate pattern recognition methods. Then the representative alkaloids in Aconitum tubers, aconitine, benzoylaconine, and aconine, which belong to diester-diterpenoid alkaloids, monoester-diterpenoid alkaloids, and amine-diterpenoid alkaloids, respectively, were selected for further validation of attenuated mechanism. Subsequent pharmacological experiments with aconitine, benzoylaconine, and aconine in SD rats were used for validate the effect of processing on cardiac functions. After processing the Aconitum tubers, it was found that the contents of diester-diterpenoid alkaloids were reduced, and those of monoester-diterpenoid alkaloids and amine-diterpenoid alkaloids were increased, suggesting that diester-diterpenoid alkaloids were transformed into monoester-diterpenoid alkaloids and amine-diterpenoid alkaloids. Through further decocting the aconitine in boiling water, it was confirmed that the three alkaloids could be progressively transformed. Pharmacological experiments with aconitine, benzoylaconine, and aconine in SD rats showed that aconitine at a dose of 0.01 mg/kg and aconine at a dose of 10 mg/kg enhanced the cardiac function, while benzoylaconine at a dose of 2 mg/kg weakened the cardiac function. The effect of processing is attributed to the transformation of the most toxic diester-diterpenoid alkaloids into less toxic monoester-diterpenoid alkaloids and amine-diterpenoid alkaloids.

Background: Acute ischemic stroke is one of the most important factors leading to disability and death with the characterization of accumulated neuron death and injured supportive neurovascular structures. Raf-1 kinase inhibitory protein (RKIP) is a key molecule in cell response to survival or death stimuli. However, the role of RKIP in stroke is worthy to be further studied. Methods: We used lentivirus mediated RKIP knockdown and overexpression to investigate the effect of RKIP on animal models of focal cerebral ischemia. Cell Counting Kit-8 assay, lactate dehydrogenase release analysis, and Annexin V-APC apoptosis assay were used to detect the effect RKIP on microglial cell apoptosis and survival. Transwell migration assay was carried out to evaluate the migration of microglia cells. The releases of inflammatory cytokines were determined by ELISA. The activation of NF-kappaB signaling pathway was determined by western blot. Results: Overexpression of RKIP reduced focal cerebral ischemia injury. RKIP knockdown and overexpression regulated survival, activation, and motility via the NF-κB pathway. NF-κB inhibitor BAY 11-7082 blocked the changes caused by RKIP down-regulation after oxygen-glucose deprivation (OGD). RKIP overexpression inhibited the upregulation of phosphorylation of NF-κB induced by OGD and cerebral ischemia. Conclusions: The present study showed that RKIP protects against ischemic stroke through inhibition of microglial excessive activation, inhibits its motility, and promotes neuronal survival partly though IKKβ-IκBα-NF-κB signaling axis and indicate that RKIP is a new target for the treatment of ischemic stroke.

Nicotinamide (NAM) has a long history in clinical applications and can be safely used for treating various diseases. In recent years, NAM was found to exhibit antimicrobial activities, inhibiting the growth of Plasmodium falciparum, Mycobacterium tuberculosis, and human immunodeficiency virus (HIV). Here we investigated the activity of NAM against Candida albicans, one of the most prevalent human fungal pathogens. Our results showed that NAM exhibited significant antifungal activity against C. albicans, including fluconazole-resistant isolates. NAM could also effectively suppress biofilm formation. In addition, NAM exhibited antifungal activity against non-Candida albicans species and Cryptococcus neoformans. Combination of NAM and fluconazole showed an even strong antifungal activity. The antifungal activity of NAM was further confirmed in a mouse model of disseminated candidiasis. Confocal laser scanning microscopy revealed that NAM increased cell wall β-glucans exposure and chitin content while decreased mannan level. Furthermore, by screening the C. albicans homozygous deletion mutant library, the C. albicans mutant lacking GIN4, which encodes a septin regulatory protein kinase and is essential for the maintenance of cell wall integrity, was identified to be high sensitive to NAM. These findings suggested that NAM might exhibit antifungal activities through affecting cell wall organization.

This paper is based on the Takagi-Sugeno (T-S) fuzzy models to construct a coronary artery system (CAS) T-S fuzzy controller and considers the uncertainties of system state parameters in CAS. We propose the fuzzy model of CAS with uncertainties. By using T-S fuzzy model of CAS and the use of parallel distributed compensation (PDC) concept, the same fuzzy set is assigned to T-S fuzzy controller. Based on this, a PDC controller whose fuzzy rules correspond to the fuzzy model is designed. By constructing a suitable Lyapunov-Krasovskii function (LKF), the stability conditions of the linear matrix inequality (LMI) are exported. Simulation results show that the method proposed in this paper is correct and effective and has certain practical significance.

The aim of the present study was to investigate the role of nitric oxide (NO) in the antifungal activity of Shikonin (SK) against Candida albicans (C. albicans) and to clarify the underlying mechanism. The results showed that the NO donors S-nitrosoglutathione (GSNO) and L-arginine could enhance the antifungal activity of SK, whereas the NO production inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) attenuated antifungal action. Using the fluorescent dye 3-amino,4-aminomethyl-2′, 7-difluorescein, diacetate (DAF-FM DA), we found that the accumulation of NO in C. albicans was increased markedly by SK in a time- and dose-dependent manner. In addition, the results of real-time reverse transcription-PCR (RT-PCR) demonstrated that the transcription level of YHB1 in C. albicans was greatly increased upon incubation of SK. Consistently, the YHB1-null mutant (yhb1Δ/Δ) exhibited a higher susceptibility to SK than wild-type cells. In addition, although the transcription level of CTA4 in C. albicans was not significantly changed when exposed to SK, the CTA4-null mutant (cta4Δ/Δ) was more susceptible to SK. Collectively, SK is the agent found to execute its antifungal activity directly via endogenous NO accumulation, and NO-mediated damage is related to the suppression of YHB1 and the function of CTA4.

Purpose: This study aimed to identify the active components of Fuzheng Huayu (FZHY) formula and the mechanism by which they inhibit the viability of hepatic stellate cells (HSCs) by a combination of network pharmacology and transcriptomics.Methods: The active components of FZHY formula were screened out by text mining. Similarity match and molecular docking were used to predict the target proteins of these compounds. We then searched the STRING database to analyze the key enriched processes, pathways and related diseases of these target proteins. The relevant networks were constructed by Cytoscape. A network analysis method was established by integrating data from above network pharmacology with known transcriptomics analysis of quiescent HSCs-activated HSCs to identify the most possible targets of the active components in FZHY formula. A cell-based assay (LX-2 and T6 cells) and surface plasmon resonance (SPR) analysis were used to validate the most possible active component-target protein interactions (CTPIs).Results: 40 active ingredients in FZHY formula and their 79 potential target proteins were identified by network pharmacology approach. Further network analysis reduced the 79 potential target proteins to 31, which were considered more likely to be the target proteins of the active components in FZHY formula. In addition, further enrichment analysis of 31 target proteins indicated that the HIF-1, PI3K-Akt, FoxO, and chemokine signaling pathways may be the primary pathways regulated by FZHY formula in inhibiting the HSCs viability for the treatment of liver fibrosis. Of the 31 target proteins, peroxisome proliferator activator receptor gamma (PPARG) was selected for validation by experiments at the cellular and molecular level. The results demonstrated that schisandrin B, salvianolic acid A and kaempferol could directly bind to PPARG, decreasing the viability of HSCs (T6 cells and LX-2 cells) and exerting anti-fibrosis effects.Conclusion: The active ingredients of FZHY formula were successfully identified and the mechanisms by which they inhibit HSC viability determined, using network pharmacology and transcriptomics. This work is expected to benefit the clinical application of this formula.

Based on the Hodgkin-Huxley model, the present study established a fully connected structural neural network to simulate the neural activity and energy consumption of the network by neural energy coding theory. The numerical simulation result showed that the periodicity of the network energy distribution was positively correlated to the number of neurons and coupling strength, but negatively correlated to signal transmitting delay. Moreover, a relationship was established between the energy distribution feature and the synchronous oscillation of the neural network, which showed that when the proportion of negative energy in power consumption curve was high, the synchronous oscillation of the neural network was apparent. In addition, comparison with the simulation result of structural neural network based on the Wang-Zhang biophysical model of neurons showed that both models were essentially consistent.

Candida albicans, one of the most common fungal pathogens, is responsible for several yeast infections in human hosts, being resistant to classically used antifungal drugs, such as azole drugs. Multifactorial and multistep alterations are involved in the azole resistance in Candida albicans. In this study, a FCZ-resistant C. albicans strain was obtained by serial cultures of a FCZ-susceptible C. albicans strain in incrementally increasing concentrations of FCZ. We performed an integrated profile of different classes of molecules related to azole resistance in C. albicans by combining several mass-spectrometry based methodologies. The comparative metabolomic study was performed with the sensitive and resistant strains of C.albicans to identify metabolites altered during the development of resistance to fluconazole, while the intervention strains and non-intervention strains of C.albicans to identify metabolites altered involved in cross-resistant to azole drugs. Our analysis of the different metabolites identified molecules mainly involved in metabolic processes such as amino acid metabolism, tricarboxylic acid cycle and phospholipid metabolism. We also compared the phospholipid composition of each group, revealing that the relative content of phospholipids significantly changed during the development of resistance to azole drugs. According with these results, we hypothesized that the metabolism shift might contribute to azole drugs resistance in C.albicans from multifactorial alterations. Our result paves the way to understand processes underlying the resistance to azole drugs in C. albicans, providing the basis for developing new antifungal drugs.

The paper focuses on the design and nonlinear control of the humanoid wrist/shoulder joint based on the cable-driven parallel mechanism which can realize roll and pitch movement. In view of the existence of the flexible parts in the mechanism, it is necessary to solve the vibration control of the flexible wrist/shoulder joint. In this paper, a cable-driven parallel robot platform is developed for the experiment study of the humanoid wrist/shoulder joint. And the dynamic model of the mechanism is formulated by using the coupling theory of the flexible body’s large global motion and small flexible deformation. Based on derived dynamics, antivibration control of the joint robot is studied with a nonlinear control method. Finally, simulations and experiments were performed to validate the feasibility of the developed parallel robot prototype and the proposed control scheme.

Feasible real-time swing angle measurement is significant to improve the efficiency and safety of industrial crane systems. This paper presents a wireless microelectromechanical system (MEMS)-based swing angle measurement system. The system consists of two attitude heading reference system (AHRS) sensing units with a wireless communication function, which are mounted on the hook (or payload) and the jib (or base) of the crane, respectively. With a combination of a three-axis accelerometer, a three-axis gyroscope and a three-axis magnetometer, the standard extended Kalman filter (EKF) is used to estimate the desired orientation of the payload and the base. Wireless ZigBee communication is employed to transmit the orientation of the payload to the sensing unit mounted on the base, which measures the orientation of the base. Because several physical parameters from the payload to the base can be acquired from the original crane control system, the swing angles of the payload can be calculated based on the two measured orientation parameters together with the known physical parameters. Experiments were performed to show the feasibility and effectiveness of the proposed swing angle measurement system.

Transformation Induced Plasticity (TRIP) steels with silicon−manganese (Si−Mn) as the main element have attracted a lot of attention and great interest from steel companies due to their low price, high strength, and high plasticity. Retained austenite is of primary importance as the source of high strength and high plasticity in Si−Mn TRIP steels. In this work, the cold rolled sheets of Si−Mn low carbon steel were treated with TRIP and Dual Phase (DP) treatment respectively. Then, the microstructure and composition of the Si−Mn low carbon steel were observed and tested. The static tensile test of TRIP steel and DP steel was carried out by a CMT5305 electronic universal testing machine. The self-built true stress−strain curve model of TRIP steel was verified. The simulation results were in good agreement with the experimental results. In addition, the phase transformation energy of retained austenite and the work borne by austenite in the sample during static stretching were calculated. The work done by austenite was 14.5 J, which was negligible compared with the total work of 217.8 J. The phase transformation energy absorption of retained austenite in the sample was 9.12 J. The role of retained austenite in TRIP steel is the absorption of excess energy at the key place where the fracture will occur, thereby increasing the elongation, so that the ferrite and bainite in the TRIP steel can absorb energy for a longer time and withstand more energy.

We describe the use of a unique DNA-modification-dependent restriction endonuclease AbaSI coupled with sequencing (Aba-seq) to map high-resolution hydroxymethylome of mouse E14 embryonic stem cells. The specificity of AbaSI enables sensitive detection of 5-hydroxymethylcytosine (5hmC) at low-occupancy regions. Bioinformatic analysis suggests 5hmCs in genic regions closely follow the 5mC distribution. 5hmC is generally depleted in CpG islands and only enriched in a small set of repetitive elements. A regularly spaced and oscillating 5hmC pattern was observed at the binding sites of CTCF. 5hmC is enriched at the poised enhancers with the monomethylated histone H3 lysine 4 (H3K4me1) marks, but not at the active enhancers with the acetylated histone H3 lysine 27 (H3K27Ac) marks. Non-CG hydroxymethylation appears to be prevalent in the mitochondrial genome. We propose that some amounts of transiently stable 5hmCs may indicate a poised epigenetic state or demethylation intermediate, whereas others may suggest a locally accessible chromosomal environment for the TET enzymatic apparatus.

Chiral separations of five β-adrenergic antagonists (propranolol, esmolol, atenolol, metoprolol, and bisoprolol) were studied by capillary electrophoresis using six cyclodextrins (CDs) as the chiral selectors. Carboxymethylated-β-cyclodextrin (CM-β-CD) exhibited a higher enantioselectivity power compared to the other tested CDs. The influences of the concentration of CM-β-CD, buffer pH, buffer concentration, temperature, and applied voltage were investigated. The good chiral separation of five β-adrenergic antagonists was achieved using 50 mM Tris buffer at pH 4.0 containing 8 mM CM-β-CD with an applied voltage of 24 kV at 20 °C. In order to understand possible chiral recognition mechanisms of these racemates with CM-β-CD, host-guest binding procedures of CM-β-CD and these racemates were studied using the molecular docking software Autodock. The binding free energy was calculated using the Autodock semi-empirical binding free energy function. The results showed that the phenyl or naphthyl ring inserted in the hydrophobic cavity of CM-β-CD and the side chain was found to point out of the cyclodextrin rim. Hydrogen bonding between CM-β-CD and these racemates played an important role in the process of enantionseparation and a model of the hydrogen bonding interaction positions was constructed. The difference in hydrogen bonding formed with the –OH next to the chiral center of the analytes may help to increase chiral discrimination and gave rise to a bigger separation factor. In addition, the longer side chain in the hydrophobic phenyl ring of the enantiomer was not beneficial for enantioseparation and the chiral selectivity factor was found to correspond to the difference in binding free energy.

Nanofibrillated cellulose (NFC) and graphene oxide (GO) with reinforcing and film-forming properties were employed with graphene to develop a novel and thin electric heating membrane with heat dissipation controllability. A negative charge was found on the surface of GO and NFC in aqueous dispersions, which contributed to the homogeneous distribution of the graphene sheets. The membrane had a good laminated structure with three-dimensional interaction between GO and NFC, with embedded graphene sheets. Conductivity was characterized as a function of the amount of graphene, thus giving control over to the heating power by adjusting the ratio of graphene. Subsequent electric heating tests can remove irregularities on the GO and graphene sheet, improving the laminated structure further. The temperature on the surface of the membrane presented an exponential increasing regularity with time. Under the same power density and time, the stabilized temperature rise of membranes was higher when grammage was higher, which was characterized by the linear function of the power density. Low-grammage membranes (1 and 4 g·m−2) also exhibited regular and even stabilized temperature rises. The indicated structure and heating performance of the membrane, as well as the variation induced by Joule heating, would drive its applications.

The forecasting of the load profile of the domestic sector is an area of increased concern for the power grid as it appears in many applications, such as grid operations, demand side management, energy trading, and so forth. Accordingly, a bottom-up forecasting framework is presented in this paper based upon bottom level data about the electricity consumption of household appliances. In the proposed framework, a load profile for group households is obtained with a similar day extraction module, household behavior analysis module, and household behavior prediction module. Concretely, similar day extraction module is the core of the prediction and is employed to extract similar historical days by considering the external environmental and household internal influence factors on energy consumption. The household behavior analysis module is used to analyse and formulate the consumption behavior probability of appliances according to the statistical characteristics of appliances’ switch state in historical similar days. Based on the former two modules, household behavior prediction module is responsible for the load profile of group households. Finally, a case study based on the measured data in a practical residential community is performed to illustrate the feasibility and effectiveness of the proposed bottom-up household load forecasting approach.

To study the influence of indentation on the fatigue strength of untreated and carbonitrided specimens of S38C steel, the fatigue limit of specimens with and without indentations was tested. Fracture surfaces were observed using scanning electron microscopy (SEM). The results show that the fatigue strength of the untreated specimen decreases with increasing dimension of indentation, without significant difference compared to the predicted results. Compared to the fatigue limit of the untreated specimen, those of the carbonitrided specimen and the carbonitrided specimen whose compound layer was polished were improved by 12% and 40%, respectively. The fatigue strength of the carbonitrided specimen decreased sharply with increasing indentation size because of the presence of microcracks in the compound layer. When the compound layer was removed, the fatigue limit was observed to be less sensitive to indentation than that of the carbonitrided specimen.

A method for measuring the nonlinearity of laser interferometer using optical frequency tuning technique is presented in this paper. The basic principle of this method is to make the fractional part of an interference fringe change by tuning the laser frequency and determining the nonlinearity of interferometer by comparing the fractional fringe change measured by the interferometer to that calculated from the laser frequency change. An experimental interferometric system with a wavelength tunable laser source is set up and the nonlinearity of the interferometer is measured. Since it does not require the precise displacement mechanism to produce the optical path difference change, this method is more convenient to use and may achieve a higher accuracy than the conventional measurement methods. The nonlinearity of the arbitrary interferometric phase can be measured by changing the laser frequency with this method. Experiments results have shown that the repeatability of nonlinearity measurement is less than 0.2 nm. This method can be applied to interferometry-based high precision dimensional measurements, such as coordinate measurement and displacement sensor calibration.

BACKGROUND: Hypothyroidism is a chronic condition of endocrine disorder and its precise molecular mechanism remains obscure. In spite of certain efficacy of thyroid hormone replacement therapy in treating hypothyroidism, it often results in other side effects because of its over-replacement, so it is still urgent to discover new modes of treatment for hypothyroidism. Sini decoction (SND) is a well-known formula of traditional Chinese medicine (TCM) and is considered as efficient agents against hypothyroidism. However, its holistic effect assessment and mechanistic understanding are still lacking due to its complex components. METHODOLOGY/PRINCIPAL FINDINGS: A urinary metabonomic method based on ultra performance liquid chromatography coupled to mass spectrometry was employed to explore global metabolic characters of hypothyroidism. Three typical hypothyroidism models (methimazole-, propylthiouracil- and thyroidectomy-induced hypothyroidism) were applied to elucidate the molecular mechanism of hypothyroidism. 17, 21, 19 potential biomarkers were identified with these three hypothyroidism models respectively, primarily involved in energy metabolism, amino acid metabolism, sphingolipid metabolism and purine metabolism. In order to avert the interference of drug interaction between the antithyroid drugs and SND, the thyroidectomy-induced hypothyroidism model was further used to systematically assess the therapeutic efficacy of SND on hypothyroidism. A time-dependent recovery tendency was observed in SND-treated group from the beginning of model to the end of treatment, suggesting that SND exerted a recovery effect on hypothyroidism in a time-dependent manner through partially regulating the perturbed metabolic pathways. CONCLUSIONS/SIGNIFICANCE: Our results showed that the metabonomic approach is instrumental to understand the pathophysiology of hypothyroidism and offers a valuable tool for systematically studying the therapeutic effects of SND on hypothyroidism.

DNA methylation is the most frequent form of epigenetic modification in the cell, which involves gene regulation in eukaryotes and protection against restriction enzymes in prokaryotes. Even though many methyltransferases exclusively modify their cognate sites, there have been reports of those that exhibit promiscuity. Previous experimental approaches used to characterize these methyltransferases do not provide the exact concentration at which off-target methylation occurs. Here, we present the first reported fidelity index (FI) for a number of DNA methyltransferases. We define the FI as the ratio of the highest amount of methyltransferase that exhibits no star activity (off-target effects) to the lowest amount that exhibits complete modification of the cognate site. Of the methyltransferases assayed, M.MspI and M.AluI exhibited the highest fidelity of ≥250 and ≥500, respectively, and do not show star activity even at very high concentrations. In contrast, M.HaeIII, M.EcoKDam and M.BamHI have the lowest fidelity of 4, 4 and 2, respectively, and exhibit star activity at concentrations close to complete methylation of the cognate site. The fidelity indexes provide vital information on the usage of methyltransferases and are especially important in applications where site specific methylation is required.

There are three types of power lines in the 10 kV distribution network in China, i.e., copper power cables, overhead power conductors and aluminum alloy power cables. It is necessary to give a comprehensive evaluation to choose the type of power line in some delicate practical engineering. This paper presents a life cycle cost (LCC)-based analysis method for the three types of power lines. An LCC model of the power line in the 10 kV distribution network is established, which considers four parts: investment cost, operation and maintenance cost, failure cost and discard cost. A detailed calculation model for the four parts is presented, and to calculate the failure cost, the Monte Carlo algorithm is employed to simulate the values of expected energy not supplied (EENS). Two practical 10 kV power line projects in Fujian Province in China were analyzed based on the proposed LLC model and corresponding developed software, which has helped the power company select the appropriate power line successfully.

The goal of realistic image rendition is to recover the acquired image under imperfect illuminant conditions, where non–uniform illumination may degrade image quality with high contrast and low SNR. In this paper, the assumption regarding illumination is modified and a variable exponent functional model for Retinex is proposed to remove non–uniform illumination and reduce halo artifacts. The theoretical derivation is provided and experimental results are presented to illustrate the effectiveness of the proposed model.

BACKGROUND: In spite of great advances in target-oriented Western medicine for treating myocardial infarction (MI), it is still a leading cause of death in a worldwide epidemic. In contrast to Western medicine, Traditional Chinese medicine (TCM) uses a holistic and synergistic approach to restore the balance of Yin-Yang of body energy so the body's normal function can be restored. Sini decoction (SND) is a well-known formula of TCM which has been used to treat MI for many years. However, its holistic activity evaluation and mechanistic understanding are still lacking due to its complex components. METHODOLOGY/PRINCIPAL FINDINGS: A urinary metabonomic method based on nuclear magnetic resonance and ultra high-performance liquid chromatography coupled to mass spectrometry was developed to characterize MI-related metabolic profiles and delineate the effect of SND on MI. With Elastic Net for classification and selection of biomarkers, nineteen potential biomarkers in rat urine were screened out, primarily related to myocardial energy metabolism, including the glycolysis, citrate cycle, amino acid metabolism, purine metabolism and pyrimidine metabolism. With the altered metabolism pathways as possible drug targets, we systematically analyze the therapeutic effect of SND, which demonstrated that SND administration could provide satisfactory effect on MI through partially regulating the perturbed myocardial energy metabolism. CONCLUSIONS/SIGNIFICANCE: Our results showed that metabonomic approach offers a useful tool to identify MI-related biomarkers and provides a new methodological cue for systematically dissecting the underlying efficacies and mechanisms of TCM in treating MI.

BACKGROUND: Doxorubicin (DOX) is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Though numerous studies have ascribed DOX cardiomyopathy to specific cellular pathways, the precise mechanism remains obscure. Sini decoction (SND) is a well-known formula of Traditional Chinese Medicine (TCM) and is considered as efficient agents against DOX-induced cardiomyopathy. However, its action mechanisms are not well known due to its complex components. METHODOLOGY/PRINCIPAL FINDINGS: A tissue-targeted metabonomic method using gas chromatography-mass spectrometry was developed to characterize the metabolic profile of DOX-induced cardiomyopathy in mice. With Elastic Net for classification and selection of biomarkers, twenty-four metabolites corresponding to DOX-induced cardiomyopathy were screened out, primarily involving glycolysis, lipid metabolism, citrate cycle, and some amino acids metabolism. With these altered metabolic pathways as possible drug targets, we systematically analyzed the protective effect of TCM SND, which showed that SND administration could provide satisfactory effect on DOX-induced cardiomyopathy through partially regulating the perturbed metabolic pathways. CONCLUSIONS/SIGNIFICANCE: The results of the present study not only gave rise to a systematic view of the development of DOX-induced cardiomyopathy but also provided the theoretical basis to prevent or modify expected damage.

Trehalose is a non-reducing disaccharide and can be accumulated in response to heat or oxidative stresses in Candida albicans. Here we showed that a C. albicans tps1Δ mutant, which is deficient in trehalose synthesis, exhibited increased apoptosis rate upon H(2)O(2) treatment together with an increase of intracellular Ca(2+) level and caspase activity. When the intracellular Ca(2+) level was stimulated by adding CaCl(2) or A23187, both the apoptosis rate and caspase activity were increased. In contrast, the presence of two calcium chelators, EGTA and BAPTA, could attenuate these effects. Moreover, we investigated the role of Ca(2+) pathway in C. albicans apoptosis and found that both calcineurin and the calcineurin-dependent transcription factor, Crz1p, mutants showed decreased apoptosis and caspase activity upon H(2)O(2) treatment compared to the wild-type cells. Expression of CaMCA1, the only gene found encoding a C. albicans metacaspase, in calcineurin-deleted or Crz1p-deleted cells restored the cell sensitivity to H(2)O(2). Our results suggest that Ca(2+) and its downstream calcineurin/Crz1p/CaMCA1 pathway are involved in H(2)O(2)-induced C. albicans apoptosis. Inhibition of this pathway might be the mechanism for the protective role of trehalose in C. albicans.

The Type IIS restriction endonuclease BtsI recognizes and digests at GCAGTG(2/0). It comprises two subunits: BtsIA and BtsIB. The BtsIB subunit contains the recognition domain, one catalytic domain for bottom strand nicking and part of the catalytic domain for the top strand nicking. BtsIA has the rest of the catalytic domain that is responsible for the DNA top strand nicking. BtsIA alone has no activity unless it mixes with BtsIB to reconstitute the BtsI activity. During characterization of the enzyme, we identified a BtsIB mutant R119A found to have a different digestion pattern from the wild type BtsI. After characterization, we found that BtsIB(R119A) is a novel restriction enzyme with a previously unreported recognition sequence CAGTG(2/0), which is named as BtsI-1. Compared with wild type BtsI, BtsI-1 showed different relative activities in NEB restriction enzyme reaction buffers NEB1, NEB2, NEB3 and NEB4 and less star activity. Similar to the wild type BtsIB subunit, the BtsI-1 B subunit alone can act as a bottom nicking enzyme recognizing CAGTG(-/0). This is the first successful case of a specificity change among this restriction endonuclease type.