Publications by authors named "Eunyoung Park"

78 Publications

Advanced Organic Transistor-Based Sensors Utilizing a Solvatochromic Medium with Twisted Intramolecular Charge-Transfer Behavior and Its Application to Ammonia Gas Detection.

ACS Appl Mater Interfaces 2021 Dec 19;13(47):56385-56393. Epub 2021 Nov 19.

Department of Materials Science and Chemical Engineering, Hanyang University, Ansan, Gyeonggi 15588, Republic of Korea.

Here, we designed and developed an organic field-effect transistor (OFET)-based gas sensor by applying solvatochromic dye (Nile red, NR) with twisted intramolecular charge-transfer (TICT) behavior depending on the polarity of the surrounding molecules, as an auxiliary NR sensing medium (aNR-SM). As a polar molecule approaches, intra-charge transfers from the donor diethylamine group to the ketone group occur in the NR molecule, resulting in the twisting of the donor functional group and thereby increasing its dipole moment. Using this characteristic, NR was applied as an auxiliary sensing medium to the OFET for detecting ammonia (NH), a representative toxic gas. The Top-NR case, where the aNR-SM covers only the top of the organic semiconductor layer, showed the best gas sensing performance, and its response and recovery rates were improved by 46 and 94%, respectively, compared to the pristine case. More importantly, a sensitivity of 0.87 ± 0.045 ppm % was measured, having almost perfect linearity (0.999) over the range of measured NH concentrations, which is the result of solving the saturation problem in the sensing characteristics of the OFET-based gas sensor. Our result not only improved the sensing performance of the OFET-based sensor but also made an important advance in that the reliability of the sensing performance was easily secured by applying solvatochromic and TICT behaviors of an auxiliary sensing medium.
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http://dx.doi.org/10.1021/acsami.1c15116DOI Listing
December 2021

The structural basis of PTEN regulation by multi-site phosphorylation.

Nat Struct Mol Biol 2021 10 8;28(10):858-868. Epub 2021 Oct 8.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol-3,4,5-triphosphate (PIP) phospholipid phosphatase that is commonly mutated or silenced in cancer. PTEN's catalytic activity, cellular membrane localization and stability are orchestrated by a cluster of C-terminal phosphorylation (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385, but the molecular details of this multi-faceted regulation have remained uncertain. Here we use a combination of protein semisynthesis, biochemical analysis, NMR, X-ray crystallography and computational simulations on human PTEN and its sea squirt homolog, VSP, to obtain a detailed picture of how the phospho-C-tail forms a belt around the C2 and phosphatase domains of PTEN. We also visualize a previously proposed dynamic N-terminal α-helix and show that it is key for PTEN catalysis but disordered upon phospho-C-tail interaction. This structural model provides a comprehensive framework for how C-tail phosphorylation can impact PTEN's cellular functions.
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http://dx.doi.org/10.1038/s41594-021-00668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549118PMC
October 2021

Overcoming the obstacles of current photodynamic therapy in tumors using nanoparticles.

Bioact Mater 2022 Feb 26;8:20-34. Epub 2021 Jun 26.

Department of Medical Life Sciences, Department of Biomedicine & Health Sciences, and Catholic Photomedicine Research Institute, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.

Photodynamic therapy (PDT) has been applied in clinical treatment of tumors for a long time. However, insufficient supply of pivotal factors including photosensitizer (PS), light, and oxygen in tumor tissue dramatically reduces the therapeutic efficacy of PDT. Nanoparticles have received an influx of attention as drug carriers, and recent studies have demonstrated their promising potential to overcome the obstacles of PDT in tumor tissue. Physicochemical optimization for passive targeting, ligand modification for active targeting, and stimuli-responsive release achieved efficient delivery of PS to tumor tissue. Various trials using upconversion NPs, two-photon lasers, X-rays, and bioluminescence have provided clues for efficient methods of light delivery to deep tissue. Attempts have been made to overcome unfavorable tumor microenvironments via artificial oxygen generation, Fenton reaction, and combination with other chemical drugs. In this review, we introduce these creative approaches to addressing the hurdles facing PDT in tumors. In particular, the studies that have been validated in animal experiments are preferred in this review over proof-of-concept studies that were only performed in cells.
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http://dx.doi.org/10.1016/j.bioactmat.2021.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424083PMC
February 2022

Structure and substrate specificity determinants of NfnB, a dinitroaniline herbicide-catabolizing nitroreductase from Sphingopyxis sp. strain HMH.

J Biol Chem 2021 10 30;297(4):101143. Epub 2021 Aug 30.

Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address:

Nitroreductases are emerging as attractive bioremediation enzymes, with substrate promiscuity toward both natural and synthetic compounds. Recently, the nitroreductase NfnB from Sphingopyxis sp. strain HMH exhibited metabolic activity for dinitroaniline herbicides including butralin and pendimethalin, triggering the initial steps of their degradation and detoxification. However, the determinants of the specificity of NfnB for these herbicides are unknown. In this study, we performed structural and biochemical analyses of NfnB to decipher its substrate specificity. The homodimer NfnB is a member of the PnbA subgroup of the nitroreductase family. Each monomer displays a central α + β fold for the core domain, with a protruding middle region and an extended C-terminal region. The protruding middle region of Val75-Tyr129 represents a structural extension that is a common feature to members of the PnbA subgroup and functions as an opening wall connecting the coenzyme FMN-binding site to the surface, therefore serving as a substrate binding site. We performed mutational, kinetic, and structural analyses of mutant enzymes and found that Tyr88 in the middle region plays a pivotal role in substrate specificity by determining the dimensions of the wall opening. The mutation of Tyr88 to phenylalanine or alanine caused significant changes in substrate selectivity toward bulkier dinitroaniline herbicides such as oryzalin and isopropalin without compromising its activity. These results provide a framework to modify the substrate specificity of nitroreductase in the PnbA subgroup, which has been a challenging issue for its biotechnological and bioremediation applications.
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http://dx.doi.org/10.1016/j.jbc.2021.101143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484813PMC
October 2021

Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation.

Proc Natl Acad Sci U S A 2021 09;118(36)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215;

The RAF/MEK/ERK pathway is central to the control of cell physiology, and its dysregulation is associated with many cancers. Accordingly, the proteins constituting this pathway, including MEK1/2 (MEK), have been subject to intense drug discovery and development efforts. Allosteric MEK inhibitors (MEKi) exert complex effects on RAF/MEK/ERK pathway signaling and are employed clinically in combination with BRAF inhibitors in malignant melanoma. Although mechanisms and structures of MEKi bound to MEK have been described for many of these compounds, recent studies suggest that RAF/MEK complexes, rather than free MEK, should be evaluated as the target of MEKi. Here, we describe structural and biochemical studies of eight structurally diverse, clinical-stage MEKi to better understand their mechanism of action on BRAF/MEK complexes. We find that all of these agents bind in the MEK allosteric site in BRAF/MEK complexes, in which they stabilize the MEK activation loop in a conformation that is resistant to BRAF-mediated dual phosphorylation required for full activation of MEK. We also show that allosteric MEK inhibitors act most potently on BRAF/MEK complexes rather than on free active MEK, further supporting the notion that a BRAF/MEK complex is the physiologically relevant pharmacologic target for this class of compounds. Our findings provide a conceptual and structural framework for rational development of RAF-selective MEK inhibitors as an avenue to more effective and better-tolerated agents targeting this pathway.
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http://dx.doi.org/10.1073/pnas.2107207118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433572PMC
September 2021

Isolation of Bacillus cereus from Soft Soybean Curd and the Kinetic Behavior of B. cereus Isolates at Changing Temperatures.

J Food Prot 2021 09;84(9):1555-1559

Department of Food and Nutrition, Sookmyung Women's University, Seoul 04310, Korea.

Abstract: In this study, Bacillus cereus was isolated from soft soybean curds, and a dynamic model was developed to describe the kinetic behavior of these isolates during transfer and storage. B. cereus isolates recovered from soft soybean curds were inoculated into soft soybean curd, and the levels were determined during storage at 10 to 30°C. The B. cereus counts were fitted to the Baranyi model to calculate maximum growth rate (μmax) and lag-phase duration (LPD). These kinetic parameters were then analyzed with a polynomial equation to evaluate the effects of temperature on the kinetic parameters. The developed model was validated with observed values, and the differences between predicted and observed values were determined by calculating the root mean square error (RMSE). A dynamic model was then developed with a combination of primary and secondary models to describe B. cereus growth under changing temperature conditions. B. cereus was detected in two soft soybean curd samples (5.1%) at 0.7 log CFU/g. The μmax was -0.04 to 0.47 log CFU/g/h, and the ln(LPD) was 3.94 to 0.04 h, depending on the storage temperature. The model performance was appropriate with a 0.216 RMSE and accurately described the kinetic behavior of B. cereus in soft soybean curd samples. These results suggest that B. cereus can contaminate soft soybean curds and that the models developed with the B. cereus isolates are useful for describing the kinetic behavior of B. cereus in soft soybean curd.

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http://dx.doi.org/10.4315/JFP-21-026DOI Listing
September 2021

Engineering 3D Cortical Spheroids for an Ischemic Stroke Model.

ACS Biomater Sci Eng 2021 08 19;7(8):3845-3860. Epub 2021 Jul 19.

Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, 291, Daehak-ro, Daejeon 34141, Republic of Korea.

Three-dimensional (3D) spheroids composed of brain cells have shown great potential to mimic the pathophysiology of the brain. However, a 3D spheroidal brain-disease model for cerebral ischemia has not been reported. This study investigated an ultralow attachment (ULA) surface-mediated formation of 3D cortical spheroids using primary rat cortical cells to recapitulate the cerebral ischemic responses in stroke by oxygen-glucose deprivation-reoxygenation (OGD-R) treatment. Comparison between two-dimensional (2D) and 3D cell culture models confirmed the better performance of the 3D cortical spheroids as normal brain models. The cortical cells cultured in 3D maintained their healthy physiological morphology of a less activated state and suppressed mRNA expressions of pathological stroke markers, S100B, IL-1β, and MBP, selected based on stroke model. Interestingly, the spheroids formed on the ULA surface exhibited striking aggregation dynamics involving active cell-substrate interactions, whereas those formed on the agarose surface aggregated passively by the convective flow of the media. Accordingly, ULA spheroids manifested a layered arrangement of neurons and astrocytes with higher expressions of integrin β1, integrin α5, N-cadherin, and fibronectin than the agarose spheroids. OGD-R-induced stroke model of the ULA spheroids successfully mimicked the ischemic response as evidenced by the upregulated mRNA expressions of the key markers for stroke, S100B, IL-1β, and MBP. Our study suggested that structurally and functionally distinct cortical spheroids could be generated by simply tuning the cell-substrate binding activities during dynamic spheroidal formation, which should be an essential factor to consider in establishing a brain-disease model.
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http://dx.doi.org/10.1021/acsbiomaterials.1c00406DOI Listing
August 2021

Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade.

J Immunother Cancer 2021 07;9(7)

ABL Bio Inc, Seongnam, Korea

Background: Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.

Methods: To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.

Results: Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8 T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.

Conclusion: The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
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http://dx.doi.org/10.1136/jitc-2021-002428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261887PMC
July 2021

Physical analysis reveals distinct responses of human bronchial epithelial cells to guanidine and isothiazolinone biocides.

Toxicol Appl Pharmacol 2021 08 23;424:115589. Epub 2021 May 23.

School of Environmental Engineering, University of Seoul, 163 Seoulsiripdae-ro, Dongdaemun-gu, Seoul 02504, Republic of Korea. Electronic address:

Changes in the physical state of the cells can serve as important indicators of stress responses because they are closely linked with the changes in the pathophysiological functions of the cells. Physical traits can be conveniently assessed by analyzing the morphological features and the stresses at the cell-matrix and cell-cell adhesions in both single-cell and monolayer model systems in 2D. In this study, we investigated the mechano-stress responses of human bronchial epithelial cells, BEAS-2B, to two functionally distinct groups of biocides identified during the humidifier disinfectant accident, namely, guanidine (PHMG) and isothiazolinone (CMIT/MIT). We analyzed the physical traits, including cell area, nuclear area, and nuclear shape. While the results showed inconsistent average responses to the biocides, the degree of dispersion in the data set, measured by standard deviation, was remarkably higher in CMIT/MIT treated cells for all traits. As mechano-stress endpoints, traction and intercellular stresses were also measured, and the cytoskeletal actin structures were analyzed using immunofluorescence. This study demonstrates the versatility of the real-time imaging-based biomechanical analysis, which will contribute to identifying the temporally sensitive cellular behaviors as well as the emergence of heterogeneity in response to exogenously imposed stress factors. This study will also shed light on a comparative understanding of less studied substance, CMIT/MIT, in relation to a more studied substance, PHMG, which will further contribute to more strategic planning for proper risk management of the ingredients involved in toxicological accidents.
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http://dx.doi.org/10.1016/j.taap.2021.115589DOI Listing
August 2021

High Prevalence of in Smoked Duck: Antibiotic and Heat Resistance, Virulence, and Genetics of the Isolates.

Food Sci Anim Resour 2021 Mar 1;41(2):324-334. Epub 2021 Mar 1.

Department of Food and Nutrition, Sookmyung Women's University, Seoul 04310, Korea.

This study aimed at determining the genetic and virulence characteristics of the from smoked ducks. was isolated by plating, and the isolated colonies were identified by PCR. All the obtained seven isolates possessed the virulence genes (A, B, B, and A) and a 385 bp A amplicon. The isolates (SMFM2018 SD 1-1, SMFM 2018 SD 4-1, SMFM 2018 SD 4-2, SMFM 2018 SD 5-2, SMFM 2018 SD 5-3, SMFM 2018 SD 6-2, and SMFM 2018 SD 7-1) were inoculated in tryptic soy broth (TSB) containing 0.6% yeast extract at 60°C, followed by cell counting on tryptic soy agar (TSA) containing 0.6% yeast extract at 0, 2, 5, 8, and 10 min. We identified five heat resistant isolates compared to the standard strain ( ATCC13932), among which three exhibited the serotype 1/2b and D-values of 5.41, 6.48, and 6.71, respectively at 60°C. The optical densities of the cultures were regulated to a 0.5 McFarland standard to assess resistance against nine antibiotics after an incubation at 30°C for 24 h. All isolates were penicillin G resistant, possessing the virulence genes (A, B, B, and A) and the 385-bp A amplicon, moreover, three isolates showed clindamycin resistance. In conclusion, this study allowed us to characterize isolates from smoked ducks, exhibiting clindamycin and penicillin G resistance, along with the 385-bp A amplicon, representing higher invasion efficiency than the 268-bp A, and the higher heat resistance serotype 1/2b.
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http://dx.doi.org/10.5851/kosfa.2021.e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115007PMC
March 2021

SMFM2017-NK4 Isolated from Kimchi Can Prevent Obesity by Inhibiting Fat Accumulation.

Foods 2021 Apr 4;10(4). Epub 2021 Apr 4.

Department of Food and Nutrition, Sookmyung Women's University, Seoul 04310, Korea.

This study evaluated the anti-obesity effects of lactic acid bacteria. Thirty-one lactic acid bacteria were examined in vitro for their ability to inhibit α-glucosidase activity, lipase activity, and 3T3-L1 cell differentiation. Four selected lactic acid bacteria were administered to obese C57BL/6J mice models for 8 weeks. The degree of improvement in obesity was determined by weight gain and serum biochemical analysis. The expression levels of genes ( and ) related to obesity in the liver were analyzed by quantitative reverse transcription (qRT)-PCR. In addition, antioxidant protein levels (SOD-2, CAT, and GPx-1) in the liver were evaluated. The lactic acid bacteria-treated groups (PPGK1, LFNK3, LPNK2, and LFNK4) showed lower weight increase rate than the control group. The total cholesterol (T-chol), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in the blood serum of the LFNK4 group were the lowest among other groups, compared to the control group. The expression levels of lipid metabolism-related genes ( and ) in the liver of the LFNK4 group were lower in and higher in than in the control group. The antioxidant protein expression levels (SOD-2, CAT, and GPx-1) in the liver tissue were also higher in the LFNK4 group. These results indicate that SMFM2017-NK4 has anti-obesity effects.
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http://dx.doi.org/10.3390/foods10040772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066894PMC
April 2021

Development of a Selective Agar for Improving Campylobacter jejuni Detection in Food.

J AOAC Int 2021 Sep;104(5):1344-1349

Sookmyung Women's University, Risk Analysis Research Center, Seoul, 04310, Korea.

Background: Campylobacter jejuni is a major gastroenteritis-causing foodborne pathogen. However, it is difficult to isolate when competing bacteria or cold-damaged cells are present.

Objective: Herein, a medium (Campylobacter selective agar, CSA) was developed and supplemented with catalase, L-serine, L-cysteine, and quercetin for the selective detection of C. jejuni in food.

Method: The C. jejuni-detection efficiency in media broth and chicken tenders was evaluated. The pathogen was enumerated on modified charcoal-cefoperazone-deoxycholate agar (mCCDA), CSA supplemented with 4 µM catalase (CSA-C4), 8 µM catalase (CSA-C8), 20 mM L-serine (CSA-S20) or 50 mM L-serine (CSA-S50), and mCCDA supplemented with 0.5 mM L-cysteine (mCCDA-LC0.5), 1 mM L-cysteine (mCCDA-LC1), 40 µM quercetin (mCCDA-Q40) or 320 µM quercetin (mCCDA-Q320). The detection efficiency was then evaluated by counting colonies on the selective agar media. Quantitative assessment was also performed using chicken and duck carcasses.

Results: The C. jejuni detection efficiencies were higher (P < 0.05) in the groups CSA-C4 or CSA-C8, and CSA-S20 or CSA-S50, than mCCDA, and the detection efficiencies were maintained even in the presence of Acinetobacter baumannii, a competing bacterium. In the quantitative test, CSA-C8 and CSA-S50 demonstrated higher C. jejuni-detection efficiencies than mCCDA (control).

Conclusions: Therefore, CSA-C8 and CSA-S50 improved the detection efficiency of C. jejuni in poultry products by promoting the recovery of cold-damaged cells.

Highlights: When using CSA-C8 or CSA-S50 developed in this study for detection of C. jejuni in food, detection efficiency was higher than mCCDA.
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http://dx.doi.org/10.1093/jaoacint/qsab055DOI Listing
September 2021

Prenatal Exposure to Parabens Affects Birth Outcomes through Maternal Glutathione S-Transferase (GST) Polymorphisms: From the Mothers and Kids Environmental Health (MAKE) Study.

Int J Environ Res Public Health 2021 03 15;18(6). Epub 2021 Mar 15.

Division of Cancer Prevention and Early Detection, National Cancer Control Institute, Cancer Center, Goyang 10408, Korea.

Introduction: Human exposure to parabens is very common in daily life, and prenatal exposure to these chemicals is associated with poor birth outcomes. Therefore, the aim of this study was to investigate the effect of glutathione S-transferase (GST) polymorphisms on the association between prenatal exposure to parabens and birth outcomes.

Methods: We conducted a multivariate analysis involving 177 subjects to determine the association between paraben concentrations and birth outcomes in mothers with GST mu 1 (GSTM1) and GST theta 1 (GSTT1) polymorphisms from 2017 to 2019. Furthermore, we determined the interactive effect between paraben levels and GSTM1/GSTT1 polymorphisms using regression analysis, in addition to a generalized linear model after stratifying GSTM1/GSTT1 genotype into three categories.

Results: Methyl and propyl paraben concentrations were significantly and positively associated with birth weight (methyl, β = 116.525, 95% confidence interval (CI) = 22.460-210.590; propyl, β = 82.352, 95% CI = 9.147-155.557) in individuals with the GSTM1-null genotype. Moreover, the propyl paraben concentration was significantly associated with an increase in gestational age (β = 0.312, 95% CI = 0.085-0.539) in individuals with the GSTM1-null genotype.

Conclusions: This study reported the association between prenatal paraben exposure and birth outcomes in individuals with GST polymorphisms. We found positive relationships of maternal exposure to methyl parabens with birth weight in both mothers with GSTM1 and GSTT1-null genotypes.
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http://dx.doi.org/10.3390/ijerph18063012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998485PMC
March 2021

Method for the simultaneous analysis of 300 pesticide residues in hair by LC-MS/MS and GC-MS/MS, and its application to biomonitoring of agricultural workers.

Chemosphere 2021 Aug 15;277:130215. Epub 2021 Mar 15.

Pesticide Chemistry and Toxicology Laboratory, Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, South Korea. Electronic address:

Multiresidual pesticide analysis in hair can provide useful perspectives on the relationship between pesticides and human health. To establish a rapid and simultaneous analytical method using LC-MS/MS and GC-MS/MS, optimization of hair pulverization, extraction solvent and purification with dispersive SPE was performed for 300 pesticides. Hair pulverization was standardized with a ball mill, at 30 Hz for 20 min (10 min twice), using 3-mm diameter beads. For extraction, 0.1% formic acid in acetonitrile was selected, and PSA d-SPE was chosen for clean-up among three different types of solid phase extraction. The limits of quantitation (LOQs) in this method were between 2.5 and 7.5 pg mg. In recovery test, fifty milligrams of hair powder were extracted with 0.1% formic acid in acetonitrile, and incubated for three h at 40 ℃. The crude extract was treated using PSA-dSPE, dried under nitrogen gas, and reconstructed with acetonitrile. An aliquot was analyzed with LC- and GC-MS/MS. Recovery ranges were 22.7-131.1%, in LC-MS/MS analysis, and 81.1-151.8% in GC-MS/MS analysis. The validated analysis systems were applied to biomonitoring of ten agricultural workers, and residues of 28 target pesticides were detected in their hair.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130215DOI Listing
August 2021

Enriching neural stem cell and anti-inflammatory glial phenotypes with electrical stimulation after traumatic brain injury in male rats.

J Neurosci Res 2021 07 26;99(7):1864-1884. Epub 2021 Mar 26.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA.

Traumatic brain injury (TBI) by an external physical impact results in compromised brain function via undesired neuronal death. Following the injury, resident and peripheral immune cells, astrocytes, and neural stem cells (NSCs) cooperatively contribute to the recovery of the neuronal function after TBI. However, excessive pro-inflammatory responses of immune cells, and the disappearance of endogenous NSCs at the injury site during the acute phase of TBI, can exacerbate TBI progression leading to incomplete healing. Therefore, positive outcomes may depend on early interventions to control the injury-associated cellular milieu in the early phase of injury. Here, we explore electrical stimulation (ES) of the injury site in a rodent model (male Sprague-Dawley rats) to investigate its overall effect on the constituent brain cell phenotype and composition during the acute phase of TBI. Our data showed that a brief ES for 1 hr on day 2 of TBI promoted anti-inflammatory phenotypes of microglia as assessed by CD206 expression and increased the population of NSCs and Nestin astrocytes at 7 days post-TBI. Also, ES effectively increased the number of viable neurons when compared to the unstimulated control group. Given the salience of microglia and neural stem cells for healing after TBI, our results strongly support the potential benefit of the therapeutic use of ES during the acute phase of TBI to regulate neuroinflammation and to enhance neuroregeneration.
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http://dx.doi.org/10.1002/jnr.24834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360147PMC
July 2021

Identification of Pathogenic Variations in Seafood Vibrio parahaemolyticus Isolates by Comparing Genome Sequences.

J Food Prot 2021 Jul;84(7):1141-1149

Risk Analysis Research Center, Sookmyung Women's University, Seoul 04310, Korea.

Abstract: An investigation of the pathogenic characteristics of isolates of Vibrio parahaemolyticus was conducted by identifying the pathogenic tdh gene and then performing adherence and cytotoxicity assays. Genome sequences of the seafood isolates were analyzed using the Illumina HiSeq 2500 platform. The isolated strains were then mapped by comparing the genomes to the reference genome, and variations in the nucleotide sequences and amino acids were identified with the CLC Genomics Workbench program. The tdh gene was identified in four isolates of V. parahaemolyticus, of which three-SMFM201809-CPC7-3, SMFM201809-CF8-2, and SMFM201809-CF8-3-showed high cytotoxicity and differences in cell adhesion. These isolates were selected to identify virulence factors and genomic variations. All three isolates had the same virulence factors, such as adherence, secretion system, and toxin. In addition, amino acid variants were identified in the regions of type IV pilus, T3SS1 and T3SS1 secreted effectors, and thermolabile hemolysin. These results indicate that variations in amino acids found in regions related to adherence and cytotoxicity result in differences in adhesion efficiency and cytotoxicity; therefore, the isolates with these variations may cause more serious foodborne illness compared with other strains.

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http://dx.doi.org/10.4315/JFP-20-437DOI Listing
July 2021

Optimized Combination of Photodynamic Therapy and Chemotherapy Using Gelatin Nanoparticles Containing Tirapazamine and Pheophorbide a.

ACS Appl Mater Interfaces 2021 Mar 24;13(9):10812-10821. Epub 2021 Feb 24.

Department of Medical Life Sciences, Department of Biomedicine & Health Sciences, and Catholic Photomedicine Research Institute, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.

In combination therapy, synergetic effects of drugs and their efficient delivery are essential. Herein, we screened 12 anticancer drugs for combination with photodynamic therapy (PDT) using pheophorbide a (Pba). On the basis of combination index (CI) values in cell viability tests, we selected tirapazamine (TPZ) and developed self-assembled gelatin nanoparticles (NPs) containing both Pba and TPZ. The resulting TPZ-Pba-NPs showed a synergetic effect to kill tumor cells because TPZ was activated under the hypoxic conditions that originated from the PDT with Pba and laser irradiation. After they were injected into tumor-bearing mice via the tail vein, TPZ-Pba-NPs showed 3.17-fold higher blood concentration and 4.12-fold higher accumulation in tumor tissue 3 and 24 h postinjection, respectively. Upon laser irradiation to tumor tissue, TPZ-Pba-NPs successfully suppressed tumor growth by efficient drug delivery and synergetic effects . These overall results suggest that screening of drugs based on CI values, mechanism studies in hypoxia, and real-time imaging are promising strategies in developing NPs for optimized combination therapy.
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http://dx.doi.org/10.1021/acsami.1c02316DOI Listing
March 2021

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8 tumor-infiltrating lymphocytes.

Sci Adv 2021 Jan 15;7(3). Epub 2021 Jan 15.

Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1Tim-3 "terminally differentiated" subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB-expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3-positive cancers as monotherapy and combination therapy with PD-1 blockade.
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http://dx.doi.org/10.1126/sciadv.aax3160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810375PMC
January 2021

The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.

Dev Neurosci 2020 20;42(5-6):170-186. Epub 2021 Jan 20.

Department of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates a critical threonine (T410) in the activation loop. Thus, Eya1 inactivates aPKC, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.
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http://dx.doi.org/10.1159/000512976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118085PMC
November 2021

Synthesis of nitrogen-doped carbon nanodots to destroy bacteria competing with Campylobacter jejuni in enrichment medium, and development of a monoclonal antibody to detect C. jejuni after enrichment.

Int J Food Microbiol 2021 Feb 8;339:109014. Epub 2020 Dec 8.

Risk Analysis Research Center, Sookmyung Women's University, Seoul 04310, Republic of Korea; Department of Food and Nutrition, Sookmyung Women's University, Seoul 04310, Republic of Korea. Electronic address:

The objective of this study was to develop a method with improved sensitivity for Campylobacter jejuni detection in foods. Nitrogen-doped carbon nanodots (N-CNDs) were synthesized and added to an enrichment medium (Bolton broth) at a concentration of 10 mg/mL. A light-emitting diode (LED) at a wavelength of 425 nm was used to irradiate the N-CNDs-supplemented enrichment medium to induce an exothermic reaction for 1 h. Additionally, a monoclonal antibody specific to C. jejuni NCTC11168 was developed using hybridoma cells to aid detection. The C. jejuni detection capabilities of N-CNDs-supplemented enrichment medium and the conventional Bolton broth enrichment, were compared using duck samples. C. jejuni in the enrichment was detected with the monoclonal antibody based-indirect enzyme-linked immunosorbent assay (ID-ELISA). The N-CNDs-supplemented enrichment medium showed a better C. jejuni detection capability than the conventional Bolton broth enrichment. Additionally, data from ID-ELISA showed excellent detection efficiency and a shortened detection time in the N-CNDs-supplemented enrichment medium after LED irradiation at 425 nm. These results indicate that 1-h LED irradiation at 425 nm to Bolton broth supplemented with the N-CNDs increased the detection efficiency and shortened the detection time with the monoclonal antibody for C. jejuni in food.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2020.109014DOI Listing
February 2021

Nursing students' perception of class immersion facilitators in psychiatric nursing: Team-based learning combined with flipped learning.

Nurse Educ Today 2021 Mar 7;98:104653. Epub 2020 Nov 7.

Chungnam National University, College of Nursing, Daejeon, South Korea. Electronic address:

Background: Psychiatric nursing is a complex subject for nursing students due to abstract concepts and required pre-licensure competencies including collaboration and communication. A student-centred educational approach is needed to encourage engagement and immersion in class.

Objectives: This study aimed to use students' perspectives to explore factors facilitating class immersion in a psychiatric nursing subject using team-based learning combined with flipped learning.

Design: This study used a qualitative approach.

Settings: Team-based learning combined with flipped learning was applied in a 3-credit psychiatric nursing subject over a 15-week semester at a university in Daejeon, South Korea.

Participants: Participants included 12 senior nursing students who had completed a psychiatric nursing subject.

Methods: Data were collected using individual interviews, and analysed by reflexive thematic analysis. Data analysis was based on constructivist learning theory.

Results: The following four main themes emerged, teacher as a facilitator, inquiry-based learning, collaboration, and reflection. The teacher's role as a facilitator was to guide student's self-directed learning and immersion in enjoyable classes with a non-hierarchical environment. Realistic complex problems allowed students to prepare for future clinical practice and helped students with immersion. Students actively integrated different opinions through collaboration with team members and became immersed in class. Students were able to immerse more in class through critical thinking process and immediate feedback.

Conclusions: The findings suggest that team-based learning combined with flipped learning based on constructivist learning theory may be an effective instructional approach for increasing class immersion in a psychiatric nursing subject, thereby improving instructor's design for the subject.
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http://dx.doi.org/10.1016/j.nedt.2020.104653DOI Listing
March 2021

Influence of milk microbiota on survival during cheese ripening.

Food Sci Nutr 2020 Sep 31;8(9):5071-5076. Epub 2020 Jul 31.

Department of Food and Nutrition Sookmyung Women's University Seoul Korea.

This study aimed to compare the three strains of survival in raw milk cheese and pasteurized milk cheese and to suggest the effect of milk microbiota on survival. cell counts decreased in all cheese as ripening time increased, and the survival rate was different for the strains of . Furthermore, survived longer in raw milk cheese than in pasteurized milk cheese. The difference of bacterial survival in each cheese was independent of A or the spp. populations in cheeses; there was no difference in A or spp. populations in all cheeses. The richness of microbiota in raw milk was little higher than in pasteurized milk, and five phyla (Chloroflexi, Cyanobacteria, Deinococcus-Thermus, Lentisphaerae, and Verrucomicrobia) were present only in raw milk. Also, organic acid-producing bacteria were presented more in pasteurized milk compared with raw milk; thus, the growth of was slower in pasteurized milk. In conclusion, differences in the microbial community of milk can affect the growth of . Making cheese using raw milk is a risk of infection; thus, efforts to prevent growth of such as the use of appropriate food additives are required.
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http://dx.doi.org/10.1002/fsn3.1806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500772PMC
September 2020

Perceived Barriers to Rural Elderly Women's Health-Promoting Behaviors: An Ecological Perspective.

Int J Environ Res Public Health 2020 08 21;17(17). Epub 2020 Aug 21.

College of Nursing, Chungnam National University, Daejeon 35015, Korea.

This study multidimensionally examines rural elderly women's subjective barriers to practicing health-promoting behaviors. Twenty-six rural elderly women participated in three focus group interviews. Content analysis and a qualitative research method were used. The results, based on an ecological model, show that the implementation of health-promoting behaviors in rural elderly women was comprehensively related to intrapersonal (functional decline, passive attitude, and lack of implementation), interpersonal (lack of social support), community (restrictive conditions, accessibility issues, and lack of infrastructure), and public policy (lack of policy support) factors. Interventions addressing each factor can help reduce or eliminate the perceived barriers to health-promoting behaviors through interactions. Our findings can contribute to the development of health-promoting programs focused specifically on the socialization of rural elderly women and community-centered health policies in the future.
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http://dx.doi.org/10.3390/ijerph17176107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503892PMC
August 2020

Barriers to and Facilitators of Physical Activity among Korean Female Adults with Knee Osteoarthritis and Comorbidity: A Qualitative Study.

Healthcare (Basel) 2020 Jul 23;8(3). Epub 2020 Jul 23.

Department of Orthopedic Surgery, College of Medicine, Chungbuk National University, Chungdae-ro 1, Seowon-Gu, Cheongju, Chungbuk 28644, Korea.

When knee osteoarthritis is combined with comorbidity, it is associated with limited physical activity. This study aimed to identify barriers to and facilitators of physical activity among Korean female adults with knee osteoarthritis and comorbidity, such as hypertension, diabetes, and dyslipidemia. A qualitative content analysis study was conducted. Ten female knee osteoarthritis participants with comorbidity were recruited at an orthopedic outpatient center in South Korea. Data were collected using in-depth interviews and were analyzed using a conventional content analysis method. Ten participants with a mean age of 70.7 years participated in this study. Four categories of barriers and three of facilitators were identified. Barriers to physical activity were physical hardships, lack of motivation, environmental restrictions, and lack of knowledge. Categories of facilitators were pain management, self-control in physical activity, and understanding the importance of physical activity. Participants did not express any social or environmental facilitators of physical exercise. Healthcare professionals should include social support and environmental facilities to achieve medical and institutional compliance. Understanding female adults with knee osteoarthritis and comorbidity would support provision of appropriately tailored interventions that account for the characteristics of the comorbidity.
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http://dx.doi.org/10.3390/healthcare8030226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551821PMC
July 2020

Korean Nursing Students' First Experiences of Clinical Practice in Psychiatric Nursing: A Phenomenological Study.

Healthcare (Basel) 2020 Jul 17;8(3). Epub 2020 Jul 17.

College of Nursing, Chungnam National University, Daejeon 35015, Korea.

Nursing students have a more negative attitude toward psychiatric practice than other practices. In particular, Korean nursing students experience increased pressure during clinical practice in psychiatric nursing due to sociocultural and institutional influences, such as prejudices, fear, and anxiety towards mental illnesses. This study aimed to conduct an investigation on students' first experiences of clinical practice in psychiatric nursing. Participants were 12 fourth year nursing students in South Korea. The data were collected through semi-structured interviews, and data analysis was done using Colaizzi's phenomenological method. The students' experiences of clinical practice in psychiatric nursing could be categorized into emotional fluctuation, burnout, transformation, and growth. The results of this study show that nursing students experienced emotional fluctuation and burnout at the beginning of their clinical practice in psychiatric nursing. At the end of the clinical practice, they experienced transformation and growth. The study suggests that nursing instructors and on-site staff need to interact with nursing students to understand the nature of these first experiences and support them through teaching and field guidance.
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http://dx.doi.org/10.3390/healthcare8030215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551649PMC
July 2020

Pharmacokinetic Parameters of Watermelon (Rind, Flesh, and Seeds) Bioactive Components in Human Plasma: A Pilot Study to Investigate the Relationship to Endothelial Function.

J Agric Food Chem 2020 Jul 30;68(28):7393-7403. Epub 2020 Jun 30.

Food Science and Nutrition Department, Center for Nutrition Research, Institute for Food Safety and Health, Illinois Institute of Technology, Bedford Park, Illinois 60501, United States.

This study aimed to investigate the metabolic fate of bioactive components in watermelon and explore their effect on endothelial function. Six healthy overweight/obese (BMI: 28.7 ± 1.6 kg/m) adults received 100 kcal of watermelon flesh (WF), rind (WR), seeds (WS), or control meal. l-Citrulline, arginine, and (poly)phenolic metabolites were characterized in plasma over 24 h using UHPLC-MS. Endothelial function was assessed using a flow mediated dilation (FMD) technique over 7 h. Maximum concentration () and area under the curve (AUC) of l-citrulline were significantly higher after WF- and WR-containing test meals compared to control ( < 0.05). Likewise, several individual phenolic metabolites in plasma had significantly higher after WR, WF, or WS intake compared to control. FMD responses were not different among test meals. Our results provide insights on circulating metabolites from watermelon flesh, seed, and rind and lay the foundation for future clinical trials on vascular benefits of watermelon.
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http://dx.doi.org/10.1021/acs.jafc.0c02756DOI Listing
July 2020

Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations.

Angew Chem Int Ed Engl 2020 08 9;59(34):14481-14489. Epub 2020 Jul 9.

Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA, 02215, USA.

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.
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http://dx.doi.org/10.1002/anie.202003500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686272PMC
August 2020

Structural and functional evidence of bacterial antiphage protection by Thoeris defense system via NAD degradation.

Nat Commun 2020 06 4;11(1):2816. Epub 2020 Jun 4.

Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Korea.

The intense arms race between bacteria and phages has led to the development of diverse antiphage defense systems in bacteria. Unlike well-known restriction-modification and CRISPR-Cas systems, recently discovered systems are poorly characterized. One such system is the Thoeris defense system, which consists of two genes, thsA and thsB. Here, we report structural and functional analyses of ThsA and ThsB. ThsA exhibits robust NAD cleavage activity and a two-domain architecture containing sirtuin-like and SLOG-like domains. Mutation analysis suggests that NAD cleavage is linked to the antiphage function of Thoeris. ThsB exhibits a structural resemblance to TIR domain proteins such as nucleotide hydrolases and Toll-like receptors, but no enzymatic activity is detected in our in vitro assays. These results further our understanding of the molecular mechanism underlying the Thoeris defense system, highlighting a unique strategy for bacterial antiphage resistance via NAD degradation.
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http://dx.doi.org/10.1038/s41467-020-16703-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272460PMC
June 2020

Combined Enrichment and Quantitative Polymerase Chain Reaction to Improve Sensitivity and Reduce Time of Detection of in Mushrooms.

Foodborne Pathog Dis 2020 04 18;17(4):276-283. Epub 2019 Dec 18.

Department of Food and Nutrition, Sookmyung Women's University, Seoul, Korea.

This study evaluated a combined method for the detection of in mushrooms, involving enrichment and quantitative real-time polymerase chain reaction (qPCR), to improve sensitivity and reduce detection time. The growth was evaluated in enrichment broth (LEB) with modified carbon and nitrogen sources, increasing sodium concentrations, and added micronutrients. Primers targeting the (1 2), (1-6), and (1-4) genes were developed and their sensitivity and specificity were evaluated. The greatest increase in cell count was observed after 6-h incubation at 30°C in LEB+2 × FAC (LEB plus 20 mL/L ferric ammonium citrate), where cell count increased by 1.4 log CFU (colony-forming unit)/mL, compared with 0.9 log CFU/mL in LEB ( < 0.05). 2 primers targeting the gene showed high specificity and were the most sensitive among those tested, with a detection limit of 2 log CFU/mL in LEB medium, 3.1 log CFU/g in golden needle mushroom, and 3.5 log CFU/g in large oyster mushroom. When applied to detection in golden needle mushrooms, a combination of 3-h incubation in LEB+2 × FAC medium and qPCR analysis with 2 primers permitted detection of , even at an inoculum of 1 log CFU/g. Similarly, in large oyster mushrooms, 10-h enrichment in LEB+2 × FAC medium resulted in a cell count of 3.7 log CFU/g. These results indicate that a combined detection method, using LEB+2 × FAC medium for enrichment followed by qPCR with 2 primer pair, can reduce enrichment time and improve the sensitivity and specificity of detection in mushrooms.
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http://dx.doi.org/10.1089/fpd.2019.2688DOI Listing
April 2020
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