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We report herein the potential of colony-stimulating factor-1 receptor (CSF1R) inhibitors as therapeutic agents in neuroinflammatory diseases, with a focus on Alzheimer’s disease (AD). Employing a carefully modified scaffold, N-(4-heterocycloalkyl-2-cycloalkylphenyl)-5-methylisoxazole-3-carboxamide, we identify highly selective and potent CSF1R inhibitors─7driand 7dsi. Molecular docking studies shed light on the binding modes of these key compounds within the CSF1R binding site. Remarkably, kinome-wide selectivity assessment underscores the impressive specificity of 7drifor CSF-1R. Notably, 7driemerges as a potent CSF-1R inhibitor with favorable cellular activity and minimal cytotoxicity among the synthesized compounds. Demonstrating efficacy in inhibiting CSF1R phosphorylation in microglial cells and successfully mitigating neuroinflammation in an in vivoLPS-induced model, 7driestablishes itself as a promising antineuroinflammatory agent.

A versatile analytical method was developed for simple detection of minocycline residues in porcine muscle and milk using liquid chromatography-triple quadrupole tandem mass spectrometry (LC/MS/MS) with electrospray ionization. Samples were extracted with a mixture of acetonitrile and ethyl acetate (2:1, v/v), and then defatted using n-hexane. No cleanup procedure was deemed necessary. Minocycline was separated on a reversed-phase analytical column using a combination of 0.1 % formic acid in water (A) and 0.1 % formic acid in acetonitrile (B) as the mobile phase. Matrix-matched calibration showed good linearity over a concentration range of 10–60 μg/kg with a determination coefficient (R2) of 0.9727. Fortified porcine and milk samples having concentrations equivalent to and double the limit of quantification (LOQ = 10 ng/g), respectively, yielded recovery ranges between 83.02 and 8.03 % and relative standard deviations <18 %. Samples collected from a large market located in Seoul, Korea, tested negative for minocycline residue. These results show that a combination of acetonitrile and ethyl acetate can effectively extract minocycline from porcine muscle and milk without solid-phase extraction, a step usually required for cleanup before analysis. The developed method is simple, sensitive, and can be extrapolated to other food animal products that are rich in protein and fats.

The current study was carried out to detect metrafenone residues and estimate the half-lives in lettuce grown under greenhouse conditions using gas chromatography with a micro-electron capture detector. Metrafenone was applied in two and three doses (with a 7-day interval) to two different sites in Naju (distance between sites 1 and 2 = 6.5 km) in different seasons (spring and autumn). Samples were extracted with acetone and matrix components were purified using a silica solid-phase extraction (SPE) cartridge. The calibration curve over the concentration range of 0.02–5.0 mg/L was linear with a determination coefficient (R2) = 0.9993. The limits of detection and quantification were 0.003 and 0.01 mg/L, respectively. Recoveries at two fortification levels (0.1 and 0.5 mg/kg) ranged from 78.5 to 113.3 % with a relative standard deviation <8 %. The calculated half-lives were 2.3 and 2.2 days and 4.9 and 5.0 days for the double and triple doses at sites 1 and 2, respectively. These results suggest that the method is effective and sensitive for the determination of metrafenone residues in field-incurred lettuce samples, and the difference in the reported half-lives is due to seasonal variation.

Leaves from a natural population of Artemisia princepsvar. orientalis(Pamp.) H. Hara were collected monthly from April through October and characterized for composition of secondary metabolite compounds and their phytotoxic effects on seed germination and seedling growth of Achyranthes japonicaand Lactuca sativa. The compounds were identified using gas chromatography/mass spectrometry (GC/MS) coupled with a solvent-free solid injector (SFSI). GC/MS analyses of all samples revealed qualitative variability in the composition of secondary metabolites. The greatest number of compounds was identified in July (56) followed by September (30) and April (24), and the lowest number was found in June (2) and August (2). Among 92 compounds, the major compounds were various terpenes (23) (mono-, sesqui, di-, and tri-terpenes) followed by heterocyclic compounds (18) and hydrocarbons (14). The higher the concentration of the secondary metabolites, the lower the seed germination and seedling growth of A. japonicaand L. sativa.Plant samples collected in July and August were most detrimental. Taken together, variability in the secondary metabolites compounds of A. princepsvar. orientaliswas verified during different seasons, and the compounds were successfully identified by a combination of SFSI and GC/MS. Notably, the antimicrobial and antioxidative effects were inconsistent throughout the various seasons.

In the present study, brown rice was steeped in 20 % wettable powder fludioxonil for 24 h, subsequently germinated, and transplanted in paddy fields. The harvested rice was tested at 156 days to detect residue levels using gas chromatography-nitrogen phosphorus detector. Validation was carried out to assess the following parameters: linearity, limit of detection and limit of quantitation (LOQ), recovery, and storage stability. Using matrix-matched calibrations, the determination coefficients were >0.999 in both matrices. Mean recoveries were 73.5–101.0 % with relative standard deviations <10 % in both matrices. The LOQ (0.006 mg/kg) was lower than the maximum residue limit (MRL = 0.02 mg/kg) set by the Ministry of Food and Drug Safety, Republic of Korea. The developed method was applied successfully, and no residues were detected in field-incurred rice and/or rice straw samples.

Here we describe the development of a rapid and facile method for the colorimetric detection of penicillin antibiotics, including penicillin G, penicillin V, nafcillin, oxacillin, cloxacillin and dicloxacillin, using hybrid magnetic nanoparticle clusters (HMNCs) and penicillin class-selective, antibody-functionalized platinum nanoparticles (Ab-Pt). Amine-functionalized HMNCs were used to chemically capture antibiotics from sample solution through the formation of amide bonds between amine groups of HMNCs and carboxyl groups of the antibiotics. Ab-Pt was then allowed to bind to antibiotic–HMNC complexes, after which the resulting Pt–antibiotic–HMNCs were added to a 3,3′,5,5′-tetramethylbenzidine (TMB) solution. The color change caused by platinum nanoparticle-mediated oxidation of TMB enabled antibiotics to be identified with the naked eye and quantified by measuring light absorption. The use of the penicillin class-selective antibody allowed the simultaneous detection of penicillin class antibiotics, thereby reducing the cost, time, and effort associated with prescreening antibiotic residues in sample specimens.

This paper proposes a real-time HD stereo images rectification hardware design architecture in order to remove vertical parallax of images caused by distortion within the cameras and alignment between them. After calculating calibration parameters of images using Matlab Toolbox designed by J.Y Bouguet as a prior step for the above purpose, the researcher designed rectification hardware based on the algorithms of Heikkilä and Silven. When stereo cameras are installed, it becomes difficult to find corresponding points owing to geometric errors between the cameras. However, in case corresponding points are located in the same line in two images, corresponding points can be found only in the line and therefore calculation becomes simple and errors are reduced. The line where the corresponding points are situated is called an epipolar line. In order to make the lines become an epipolar line, geometric image transformation technique called rectification should be used. Here, in order to heighten precision of result images, the researcher employed a floating point calculator generated using a core generator of Xilinx. Through this, it was verified that rectification hardware which has higher precision than other rectification hardware designed using a look-up table and which operates on a real-time basis may be designed.

This paper suggests a design of high quality real-time rotation face detection architecture for gesture recognition of smart TV. For high performance rotated face detection, the multiple-MCT(Modified Census Transform) architecture, which is robust against lighting change, was used. The Adaboost learning algorithm was used for creating optimized learning data. The proposed hardware structure was composed of Color Space Converter, Image Resizer, Noise Filter, Memory Controller Interface, Image Rotator, Image Scaler, MCT Generator, Candidate Detector, Confidence Switch, Confidence Mapper, Position Resizer, Data Grouper, Overlay Processor and Color Overlay Processer. As a result, suggested face detection device can conduct real-time processing at speed of at least 30 frames per second.

Poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel dose in clinical trials. We show that PEG-b-PLA micelles act as a 3-in-1 nanocontainer for paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin for multiple drug solubilization. 3-in-1 PEG-b-PLA micelles were ca. 40 nm in diameter; dissolved paclitaxel, 17-AAG, and rapamycin in water at 9.0 mg/mL; and were stable for 24 h at 25 °C. The half-life for in vitrodrug release (t1/2) for 3-in-1 PEG-b-PLA micelles was 1–15 h under sink conditions and increased in the order of 17-AAG, paclitaxel, and rapamycin. The t1/2values correlated with log Po/wvalues, implicating a diffusion-controlled mechanism for drug release. The IC50value of 3-in-1 PEG-b-PLA micelles for MCF-7 and 4T1 breast cancer cell lines was 114 ± 10 and 25 ± 1 nM, respectively; combination index (CI) analysis showed that 3-in-1 PEG-b-PLA micelles exert strong synergy in MCF-7 and 4T1 breast cancer cell lines. Notably, concurrent intravenous (iv) injection of paclitaxel, 17-AAG, and rapamycin using 3-in-1 PEG-b-PLA micelles was well-tolerated by FVB albino mice. Collectively, these results suggest that PEG-b-PLA micelles carrying paclitaxel, 17-AAG, and rapamycin will provide a simple yet safe and efficacious 3-in-1 nanomedicine for cancer therapy.

In this study, a simplified method for the extraction and determination of seven fluoroquinolone residues (danofloxacin, difloxacin, enrofloxacin, marbofloxacin, orbifloxacin, ofloxacin, and sarafloxacin) and three quinolones (oxolinic acid, flumequine, and nalidixic acid), in porcine muscle, table eggs, and commercial whole milk, which required no cleanup step, was devised. This procedure involves the extraction of analytes from the samples vialiquid‐phase extraction, and the subsequent quantitative determination was accomplished viaLC‐fluorescence detection. Analyte separation was successfully conducted on an XBridge‐C18column, with a linear gradient mobile phase composed of acetonitrile and 0.01 M oxalic acid buffer at pH=3.5. The one‐step liquid‐liquid extraction method evidenced good selectivity, precision (RSDs=0.26–15.07%), and recovery of the extractable analytes, ranging from 61.12 to 115.93% in matrices. The LOQs ranged from 0.3 to 25 μg/kg. A survey of ten samples purchased from local markets was conducted, and none of the samples harbored fluoroquinolone residues. This method is an improvement over existing methodologies, since no additional cleanup was necessary.

Several methods used for the multiresidue analysis of pesticides from the environment and drinking water have been reported. However, most of these reports dealt with a small number of targeted pesticides or some special groups. A method that is simple, faster, and more cost‐effective than the environmental protection agency (EPA) method has been developed for the analysis of 82 frequently used pesticides in water samples obtained from Yeongsan and Sumjin rivers, as well as rice fields located in various locations around the two rivers. The samples were extracted by dichloromethane, and the pesticides were analyzed using a GC‐electron capture detector (ECD), followed by confirmation with GC‐MS. Recoveries were found to be between 82 and 120.1% for most of the tested pesticides, which were in agreement with the standard values dictated by the EPA. The method was potentially applied to 66 water samples for human consumption and 90 water samples from the rice fields and irrigation ditches that were collected from June to September 2007. Oxadiazon, butachlor, and alachlor were detected in some of the river water samples collected in June, iprobenfos (IBP) was detected in samples collected in August, and no pesticide was detected in September. On the other hand, chlorpyrifos‐methyl, IBP, hexaconazole, diazinon, oxadiazon, butachlor, and isoprothiolane were detected at relatively high concentrations in 48 rice paddy field water samples collected between June and September 2007. Alachlor in one sample and procymidone in some of the rice paddy field water samples were also detected in trace amounts. The results were consistent with the temporal pattern of pesticide application in Korean rice fields.

The principal goal of this work was to develop an efficient method for the simultaneous determination of four pyrethroid (PYR) insecticides, cyfluthrin, cyhalothrin, cypermethrin, and deltamethrin, in porcine muscle and pasteurized milk using liquid–liquid extraction (LLE). Sample extraction was carried out with and without additional column cleanup procedures, and the final determination was made using GC with electron‐capture detector (ECD). The pesticide identity was confirmed using GC‐MS in the SIM mode. Since there were minor differences between the extraction procedures, extraction without the additional cleanup procedure was used throughout the work. The method was validated by fortifying blank samples with half, two, and four times the maximum residue limit (MRL) of each PYR. The average recoveries (n= 6) ranged from 83.5 to 99.2% and 82.9 to 109% in porcine muscle and pasteurized milk, respectively. The repeatability of measurements expressed as RSDs, was in the range of 1.7–11.9 and 1.5–10.3% in porcine muscle and pasteurized milk, respectively. The LODs ranged from 3.3 to 9 and 3 to 8.1 ppm, whereas the LOQs ranged from 10 to 27.4 and 9 to 24.6 ppm, in porcine muscle and pasteurized milk, respectively. The applicability of the method was demonstrated by analyzing real samples collected from major cities in the Republic of Korea. No residues of the selected pesticides were detected in any of the samples.

The current study was undertaken to validate the performance for the determination of both TBA and β‐trenbolone (β‐TB) residues in porcine muscle at concentrations required to monitor compliance with the maximum residue limit (MRL). The method involves a one phase liquid–liquid extraction, cleanup with low‐temperature fat precipitation, separation of the respective compounds by HPLC on a Capcell pak C18column, use of a methanol–water isocratic system as an eluent, and measurement by UV absorbance detection at 340 nm. Both compounds were confirmed using LC‐MS/MS with electrospray interface (ESI) and a triple quadrupole (QqQ) analyzer. The method was found to be precise and accurate, with a linearity range of 1–10 μg/kg (r2>0.973). The intra‐ and interday precision showed good reproducibility with RSDs ⪇13.25%. The LODs were 0.12 and 0.22 μg/kg, and the LOQs were 0.37 and 0.66 μg/kg, for TBA and β‐TB, respectively. The applicability of the method was demonstrated by analyzing real samples collected from major cities in the Republic of Korea. No residues of the selected compounds were detected in any of the samples. The advantages of our method are that it is: selective, sensitive, requires a short time for analysis (13 min), and performs simple sample extraction and clean‐up procedure with low‐temperature fat precipitation as compared to the previously published methods.

This study was carried out to measure the concentration of heavy metals (Pb, Mn, Cr, Cd, Ni, Zn, and Cu) in water and Bolti fish (Tilapia nilotica) samples collected from Rasheed branch of River Nile, north of El-Giza Governorate, Egypt by atomic absorption spectrophotometry. The investigated districts through which the branch passes include El-Manashi, Gezzaya, El Katta, Abo Ghaleb and Wardan. Based on WHO and FAO safety reference standards, the results of the current study showed that water and fish tissues were found to contain heavy metals at significantly variable concentration levels among the investigated districts. They were polluted with respect to all the metals tested at Gezzaya district. However, the levels of analyzed metals in water and fish tissues were found lower than legal limits in other districts. The heavy metals showed differential bioaccumulation in fish tissues of the different districts as the accumulation pattern (as total heavy metal residues) was district dependant as follow: Gezzaya > Wardan > El Katta > Abo Ghaleb > El Manashi.

Toxicology screening following treatment with astemizole, a histamine receptor antagonist, at oral doses of 0, 10, 30 and 60 mg/kg was carried out in male cynomolgus monkeys (Macaca fascicularis). No dose-related changes in mortality, clinical signs, body weight changes, food consumption, or urine analysis occurred in any animal compared to the vehicle control. However, the high-dose group showed a decrease in BUN and ALP compared to vehicle control group. In addition, the levels of TG, AST, ALP and CK increased. Although astemizole did not produce significant toxicological changes at any dose tested, we predict that it can cause toxicological changes of the liver and heart based on the changes in the serum parameters related to the heart and liver. The Action Potential Duration (APD) was prolonged in the heart of 60 mg/kg treatment group compared to the control group. The APD increase in 60 mg/kg treatment group along the other related changes in toxicological parameters imply that astemizole has major cardiotoxic effects in the cynomolgus monkey. This study is a valuable assessment for predicting the general toxicity and cardiotoxic effects of antihistamine drugs using nonhuman primates.

A simultaneous multiresidue method to determine 14 different pesticides, namely: flufenoxuron, fenitrothion, chlorfluazuron, chlorpyrifos, hexythiazox, methidathion, chlorfenapyr, tebuconazole, EPN, bifenthrin, cyhalothrin, spirodiclofen, difenoconazole, and azoxystrobin in green tea using pressurized liquid extraction (PLE) is described and compared with that of liquid–liquid extraction (LLE). For PLE, the extraction conditions were not optimized. Rather they were selected based upon previous successful investigations published by our laboratory. Analysis was performed by GC with electron capture detector (GC‐ECD), and the pesticide identity of the positive samples was confirmed by GC‐MS in a selected ion‐monitoring (SIM) mode. Calibration curves showed an excellent linearity for concentrations ranging from 0.006 to 36.049 ppm, with r2>0.995. Green tea spiked at each of the two fortification levels, yielded average recoveries in the range of 87–112% and 71–109% for PLE and LLE, respectively. Precision values, expressed as RSDs, were below 6% at various spiking levels. With respect to the existing procedures, both methods gave LOQs that were lower than the maximum residue limits (MRLs) established by the Korea Food and Drug Administration (KFDA). Both methods have been successfully applied to the analysis of real samples, and bifenthrin was the only pesticide residue quantified in incurred green tea samples, with concentrations ranging from 0.093 ppm (LLE) to 0.1 ppm (PLE). These concentration levels were relatively low compared to KFDA‐MRL (0.3 ppm). According to the validation data and performance characteristics, both methods are appropriate for multiresidue analysis of pesticide residues in green tea. PLE methodology showed superiority in recoveries of some pesticides, acceptable accuracy and precision while minimizing environmental concerns, time, and labor, and can be applied in routine analytical laboratories.

To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat.The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situintestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis.No correlation (r2= 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r2= 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r2> 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns.The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.

Physical solubility and diffusivity of N2O and CO2 in pure water and of N2O in aqueous sodium glycinate solutions of mass fraction (0.1 to 0.5) were measured at T = (303.15 to 323.15) K. Since it was not possible to measure these properties for CO2 due to the chemical reaction between CO2 and the amine group of sodium glycinate, these were estimated using the well-known N2O analogy. While the physical solubility increases with a decrease in temperature and with a decrease in mass fraction, diffusivity decreases with a decrease in temperature as well as an increase in mass fraction except for concentrated solution (mass fraction 0.4 and 0.5) where it increases with a decrease in temperature.

Purpose. To synthesize amino acid ester prodrugs of floxuridine (FUdR) and to investigate the effects of structure, stereochemistry, and site of esterification of promoiety on the rates of hydrolysis of these prodrugs in Caco-2 cell homogenates. Methods. Amino acid ester prodrugs of FUdR were synthesized using established procedures. The kinetics of hydrolysis of prodrugs was evaluated in human adenocarcinoma cell line (Caco-2) homogenates and pH 7.4 phosphate buffer. Results. 3′-Monoester, 5′-monoester, and 3′,5′-diester prodrugs of FUdR utilizing proline, L-valine, D-valine, L-phenylalanine, and D-phenylalanine as promoieties were synthesized and characterized. In Caco-2 cell homogenates, the L-amino acid ester prodrugs hydrolyzed 10 to 75 times faster than the corresponding D-amino acid ester prodrugs. Pro and Phe ester prodrugs hydrolyzed much faster (3- to 30-fold) than the corresponding Val ester prodrugs. Further, the 5′-monoester prodrugs hydrolyzed significantly faster (3-fold) than the 3′,5′-diester prodrugs. Conclusions. Novel amino acid ester prodrugs of FUdR were successfully synthesized. The results presented here clearly demonstrate that the rate of FUdR prodrug activation in Caco-2 cell homogenates is affected by the structure, stereochemistry, and site of esterification of the promoiety. Finally, the 5′-Val and 5′-Phe monoesters exhibited desirable characteristics such as good solution stability and relatively fast enzymatic conversion rates.

To investigate a possible role by cytochrome P450 (P450) in ethyl carbamate-induced immunosuppression, an attempt to assess the ability of ethyl carbamate, its metabolites produced by P450 (i.e., ethyl N-hydroxycarbamate and vinyl carbamate), and methyl carbamate to suppress the polyclonal antibody response induced by bacterial lipopolysaccharide was made in splenocyte cultures isolated from female Balb/C mice. The results showed that vinyl carbamate and ethyl N-hydroxycarbamate were more immunosuppressive compared to ethyl carbamate. A structurally related analogue, methyl carbamate, did not suppress the antibody response. These results indicate that metabolism of ethyl carbamate by P450 may produce more immunosuppressive metabolites as in ethyl carbamate-induced carcinogenicity. A pre-incubation study with phenobarbital-induced liver microsomes in the presence of NADPH-generating system showed that the antibody response was suppressed by ethyl carbamate when splenocytes were pre-incubated with ethyl carbamate and microsomes simultaneously. Moreover, the suppression was completely recovered by the addition of a P450 inhibitor, aminoacetonitrile, in the pre-incubation. Taken together, the present results indicate that metabolism of ethyl carbamate by P450 enzyme(s) may be an important pathway to cause immunosuppression.

The effects of ZrO2-coating on the surface of LiCoO2have been studied using synchrotron-based in situ x-ray diffraction (XRD) technique. Although both ZrO2-coated LiCoO2and uncoated LiCoO2showed capacity fading during high voltage (4.8V)cycling, the ZrO2coated one showed better cycle performance. After observing capacity fade for both samples through 10 charge-discharge cycles, in situ XRD patterns were collected during the 11th charge with reduced current density. With reduced current density, both samples restored part of their lost capacity. However, in situ XRD data shows that the ZrO2-coated LiCoO2sample has much better structural change behaviors than the uncoated LiCoO2. The partial restoration of the lost capacity and the recovered structural variations observed at reduced current density clearly indicates that the lost capacity is very closely related to the increased polarization, which is most likely due to the precipitation of the electrolyte decomposition products on the surface of LiCoO2cathode material. ZrO2coating layer may provide some protection for the LiCoO2cathode surface and help to reduce the electrolyte decomposition at higher voltages.

A new local feature extraction method is introduced. The directionality of local facial regions is regarded as essential information for discriminating faces in our approach, which is motivated by the directional selectivity of the Gabor wavelet transformation, which has been preferred to others for face recognition. The discriminative directional information is forced to be compacted in a few coefficients by applying principle-component analysis with the support of directional classification in the discrete cosine transform domain. The local features extracted by our method are better at discriminating face patterns than previous ones, as was verified by comparison of class-separability results. Also, in face recognition simulations using rigid and flexible face matching strategies based on locally extracted features, our proposed method showed outstanding performance.