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Carfilzomib (CFZ) is the second-in-class proteasome inhibitor with much improved efficacy and safety profiles over bortezomib in multiple myeloma patients. In expanding the utility of CFZ to solid cancer therapy, the poor aqueous solubility and in vivo instability of CFZ are considered major drawbacks. We investigated whether a nanocrystal (NC) formulation can address these issues and enhance anticancer efficacy of CFZ against breast cancer. The surface of NC was coated with albumin in order to enhance the formulation stability and drug delivery to tumors via interactions with albumin-binding proteins located in and near cancer cells. The novel albumin-coated NC formulation of CFZ (CFZ-alb NC) displayed improved metabolic stability and enhanced cellular interactions, uptake and cytotoxic effects in breast cancer cells in vitro. Consistently, CFZ-alb NC showed greater anticancer efficacy in a murine 4T1 orthotopic breast cancer model than the currently used cyclodextrin-based formulation. Overall, our results demonstrate the potential of CFZ-alb NC as a viable formulation for breast cancer therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of this study was to determine factors influencing the hand hygiene compliance of a physician. We found a strong correlation between a leader's (staff member's or fellow's) and a follower's (resident's) hand hygiene compliance. Followers' appropriate hand hygiene compliance was significantly associated with the compliance of the leader ( P = .01).

Scabies is a re-emerging parasitic disease, particularly in hospitalized patients. This is a retrospective study analyzing adult patients with scabies admitted to a referral university hospital between 2008 and 2018. All patients were treated an average of 3times using scabicides; the median isolation period and time to cure were 14 and 15days, respectively., (Copyright © 2018 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate the prevalence of diaper dermatitis (DD), knowledge of DD prevention and treatment, and diaper hygiene practices among mothers with diaper-wearing children., Methods: The participants were 176 mothers who presented to an outpatient clinic at a children's hospital with diaper-wearing children. Data were collected using a structured self-administered questionnaire., Results: The percent of correct answer for knowledge about DD was 59.7%. Almost half of the participants' children had experienced at least 1 episode of DD during the last 6 months. Inappropriate diaper hygiene practices, such as using talcum powder on DD and rubbing with a dry towel after cleansing, were reported. Moreover, only 37% of mothers used the recommended skin barrier to prevent DD. Although many children suffer from DD, levels of educational experience and perceived need for education on this topic were low. Almost 70% of mothers obtained DD-related information through internet sites., Conclusion: Educating parents about the etiology of DD and evidence-based diaper hygiene practices is an important aspect of effective DD prevention and treatment. Internet sites or smartphone apps may be effective methods for education on DD prevention and treatment considering parents' preferences for ways to obtain health information., Competing Interests: No existing or potential conflict of interest relevant to this article was reported., (Copyright © 2019 Korean Academy of Child Health Nursing. All rights reserved.)

High metabolic activity, reflected in increased glucose uptake, is one of the hallmarks of many cancers including breast cancer. However, not all cancers avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus, we aim to generate a genomic signature of glucose hypermetabolism in breast cancer and examine its clinical relevance. To identify genes significantly associated with glucose uptake, gene expression data were analyzed together with the standardized uptake values (SUVmax) of 18 F-fluorodeoxy-glucose on positron emission tomography (PET) for 11 breast cancers. The resulting PET signature was evaluated for prognostic significance in four large independent patient cohorts (n = 5417). Potential upstream regulators accountable for the high glucose uptake were identified by gene network analysis. A PET signature of 242 genes was significantly correlated with SUVmax in breast cancer. In all four cohorts, high PET signature was significantly associated with poorer prognosis. The prognostic value of this PET signature was further supported by Cox regression analyses (hazard ratio 1.7, confidential interval 1.48-2.02; P < 0.001). The PET signature was also strongly correlated with previously established prognostic genomic signatures such as PAM50, Oncotype DX, and NKI. Gene network analyses suggested that MYC and TBX2 were the most significant upstream transcription factors in the breast cancers with high glucose uptake. A PET signature reflecting high glucose uptake is a novel independent prognostic factor in breast cancer. MYC and TBX2 are potential regulators of glucose uptake., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this study, a time-dependent corrosion depth estimation method using atmospheric corrosion monitor (ACM) sensor data to evaluate time-dependent corrosion behaviors is proposed. For the time-dependent corrosion depth estimation of uncoated carbon steel and weathering steel, acceleration corrosion tests were conducted in salt-spray corrosion environments and evaluated with a corrosion damage estimation method using ACM sensing data and corrosion loss data of the tested steel specimens. To estimate the time-dependent corrosion depth using corrosion current by an ACM sensor, the relationship between the mean corrosion depth calculated from the weight loss method and the corrosion current was evaluated. The mean corrosion depth was estimated by calculating the corrosion current and evaluating the relationship between the mean corrosion depth and corrosion current during the expected period. From the test and estimation results, the corrosion current demonstrated a good linear correlation with the mean corrosion depth of carbon steel and weathering. The calculated mean corrosion depth is nearly the same as that of the tested specimen, which can be well used to estimate corrosion rate for the uncoated carbon steel and weathering steel.

Previous observations demonstrated that cimetidine decreased the clearance of procainamide (PA) and/or N -acetylprocainamide (NAPA; the primary metabolite of PA) resulting in the increased systemic exposure and the decrease of urinary excretion. Despite an abundance of in vitro and in vivo data regarding pharmacokinetic interactions between PA/NAPA and cimetidine, however, a mechanistic approach to elucidate these interactions has not been reported yet. The primary objective of this study was to construct a physiological model that describes pharmacokinetic interactions between PA/NAPA and cimetidine, an inhibitor of rat organic cation transporter 2 (rOCT2) and rat multidrug and toxin extrusion proteins (rMATE1), by performing extensive in vivo and in vitro pharmacokinetic studies for PA and NAPA performed in the absence or presence of cimetidine in rats. When a single intravenous injection of PA HCl (10 mg/kg) was administered to rats, co-administration of cimetidine (100 mg/kg) significantly increased systemic exposure and decreased the systemic (CL) and renal (CL R ) clearance of PA, and reduced its tissue distribution. Similarly, cimetidine significantly decreased the CL R of NAPA formed by the metabolism of PA and increased the AUC of NAPA. Considering that these drugs could share similar renal secretory pathways (e.g., via rOCT2 and rMATE1), a physiologically-based pharmacokinetic (PBPK) model incorporating semi-mechanistic kidney compartments was devised to predict drug-drug interactions (DDIs). Using our proposed PBPK model, DDIs between PA/NAPA and cimetidine were successfully predicted for the plasma concentrations and urinary excretion profiles of PA and NAPA observed in rats. Moreover, sensitivity analyses of the pharmacokinetics of PA and NAPA showed the inhibitory effects of cimetidine via rMATE1 were probably important for the renal elimination of PA and NAPA in rats. The proposed PBPK model may be useful for understanding the mechanisms of interactions between PA/NAPA and cimetidine in vivo., Competing Interests: +(QKI-QU)∙CRBL+QRE∙Cart-QCO∙Cven-Dose rate(A3)

Carotenoid pigments are valuable components of the human diet. A notable example is β-carotene, or provitamin A, which is converted into the derivatives astaxanthin and capsanthin, via the common intermediate zeaxanthin. To generate rice varieties producing diverse carotenoids beyond β-carotene, we specifically used a Capsicum β-carotene hydroxylase gene, B (CaBch) and a codon optimized version of the same gene, stB (stBch) to increase zeaxanthin synthesis. We also used a recombinant BAK gene (CaBch-2A-HpBkt), consisting of the CaBch sequence and a Haematococcus β-carotene ketolase gene (HpBkt) linked by a bicistronic 2 A sequence, as well as a codon optimized recombinant stBAK gene (stBch-2A-stBkt) to create astaxanthin synthesis. The four cassettes to seed-specifically express the B, stB, BAK and stBAK genes were individually combined with a PAC gene (CaPsy-2A-PaCrtI) cassette to previously impart β-carotene-enriched trait in rice endosperm. The single T-DNA vectors of B-PAC, stB-PAC, BAK-PAC and stBAK-PAC resulted in the accumulation of zeaxanthin and astaxanthin in the endosperm of the transgenic rice seeds. In addition, an extended version on the carotenoid pathway was introduced into rice to allow the production of capsanthin, by intercrossing a B-PAC rice line with a Ccs rice line, which harbors a Capsicum capsanthin-capsorubin synthase gene. Ultimately, we developed three functional rice varieties: B-PAC (0.8 μg/g zeaxanthin, deep yellow), stBAK-PAC (1.4 μg/g ketocarotenoids, including astaxanthin, pinkish red) and B-PAC x Ccs (0.4 μg/g of ketoxanthophylls, including capsanthin, orange-red) with the similar levels of total carotenoids to PAC rice, suggesting the capacity was dependent on β-carotene levels. Collectively, a combination of genetic engineering and conventional breeding is effective for multi-step metabolic engineering and biochemical pathway extension., (Copyright © 2018 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

Background: In-hospital detection of newly diagnosed active pulmonary tuberculosis (TB) is important for prevention of potential outbreaks. Here, we report our experience of the aggressive contact investigation strategy in a university hospital in the Republic of Korea after healthcare workers (HCWs), patients, and visitors experience an in-hospital exposure to active pulmonary TB., Methods: A contact investigation after the unexpected detection of newly diagnosed active pulmonary TB (index patients) was performed in a university hospital from August 2016 to April 2017. Initial and 3-month-post-exposure chest radiographs were advised for all patients, visitors, and HCWs in close contact with the index patients. An additional tuberculous skin test or interferon gamma releasing assay was performed at the time of exposure and 3 months post-exposure in HCWs in close contact with the index patients., Results: Twenty-four index patients were unexpectedly diagnosed with active pulmonary TB after admission to the hospital with unassociated diseases. The median time from admission to TB diagnosis was 5 days (range, 1-22 days). In total, 1,057 people were investigated because of contact with the index patients, 528 of which had close contact (206 events in 157 HCWs, 322 patients or visitors). Three months post exposure, 9 (9.2%) among 98 TB-naïve close contact HCWs developed latent tuberculosis infections (LTBIs). Among the 65 close contact patients or visitors, there was no radiological or clinical evidence of active pulmonary TB., Conclusion: An aggressive contact investigation after an unexpected in-hospital diagnosis of active pulmonary TB revealed a high incidence of LTBI among TB-naïve HCWs who had contact with the index patients., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose.

Endogenous canine ATP binding cassette B1 (cABCB1) is expressed abundantly in Madin-Darby canine kidney type II (MDCKII) cells, and its presence often complicates phenotyping of the transport process. Errors in estimating the corrected efflux ratio (cER), as a result of the variable expression of cABCB1, were examined for the dual substrates of ABCB1 and ABCG2 in MDCKII cells expressing human ABCG2 (hABCG2). cABCB1 mRNA and protein expression was 60% and 55% lower, respectively, in MDCKII cells expressing hABCG2 compared with the wild type, suggesting that the expression of endogenous cABCB1 became variable after the expression of hABCG2. To minimize the contribution of endogenous efflux, cABCB1 was suppressed kinetically (using verapamil as a selective inhibitor) or biochemically (transfecting short-hairpin RNA against cABCB1). Under these suppression conditions, cER values for irinotecan and topotecan (dual substrates of ABCB1 and ABCG2) were elevated by more than 4-fold and 2-fold, respectively, compared with cER values without the suppression. The cER of olaparib was similarly increased to 3- and 5-fold in MDCKII cells under the kinetic and biochemical suppression of cABCB1, respectively, suggesting that hABCG2-mediated efflux cannot be ruled out for olaparib. Since the substrate selectivity for ABCB1 and ABCG2 overlapped considerably, the possibility of an inaccurate estimation of cER must be considered for dual substrates in the case of the variable expression of cABCB1 in MDCKII cells., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: We analyzed the angle between the glenoid anterior surface and glenoid axis, the range of the glenoid apex and the location of the glenoid apex for assistance during shoulder surgery., Methods: Sixty-two patients underwent a computed tomography of the shoulder with a proximal humerus fracture. In the range of the glenoid apex, the ratios of the distribution of triangles with a Constant anterior and posterior area of the glenoid were measured. The location of glenoid apex was confirmed as the percentage of the position with respect to the upper part of the glenoid with the center of the part, analyzed the angle between the glenoid anterior surface and glenoid axis was measured., Results: The angle between the glenoid anterior surface and glenoid axis was 19.80° ± 3.88°. The location of the glenoid apex is 60.36% ± 9.31%, with the upper end of the glenoid as the reference. The range of the glenoid apex was 21.16% ± 4.98%. When the height of the glenoid becomes smaller, the range of the glenoid apex tends to become larger ( p =0.001) and the range of the glenoid apex becomes wider ( p =0.001) as the glenoid width narrows., Conclusions: We believe the anatomical measurements of the glenoid will be helpful for a more accurate insertion in glenoid component. It is thought that more accurate insertion is possible if we can set other anatomical measurements using computed tomography imaging of the glenoid which can develop into the study of other anatomical measurements., Competing Interests: Conflict of interest None., (Copyright © 2018 Korean Shoulder and Elbow Society.)

Background: The purpose of this study was to assess the relevance of preoperative magnetic resonance imaging (MRI) evaluation by occupation ratio (OR) at maximum diameter of supraspinatus muscle., Methods: Patients from the Inje University Sanggye Paik Hospital who received rotator cuff repair and underwent pre- and postoperative MRI were selected as subjects of this study. On T1-weighted MRIs, OR of fat and muscle at Y-shaped view, OR at a location on supraspinatus muscle where its diameter was maximum on coronal view, and pre- and postoperative Goutallier Classification and changes in the tangent sign were measured. Statistical significance of postoperative OR was assessed regarding time from symptom onset to surgery, size of rotator cuff tear, preoperative OR, and the difference between ORs measured at maximum diameter of supraspinatus muscle and Y-shaped view., Results: Preoperative OR at Y-shaped view was 52.28 ± 8.57 (32.5-65.3). Preoperative OR difference between maximum diameter and Y-shaped view was 13.76 ± 10.51 (2.38-42.04), and Pearson correlation coefficient was 0.604 ( p =0.001). Postoperative OR at Y-shaped view was 63.77 ± 9.35 (37.3-76.1). Pearson correlation coefficient of pre- and postoperative Goutallier Classification was -0.579 ( p =0.002) and Pearson correlation coefficient of the postoperative difference between ORs measured at maximum diameter of supraspinatus muscle and Y-shaped view was -0.386 ( p =0.047)., Conclusions: Fatty degeneration of supraspinatus muscle in rotator cuff tear patients should be evaluated not only in the conventional Y-shaped view, but also at location of maximum diameter of supraspinatus muscle to establish patients' therapeutic plan., Competing Interests: Conflict of interest None., (Copyright © 2018 Korean Shoulder and Elbow Society.)

Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.

Hepatocellular carcinoma (HCC) is a heterogeneous disease. Mouse models are commonly used as preclinical models to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Here, integration of genomic signatures from molecularly and clinically defined human HCC ( n = 11) and mouse models of HCC ( n = 9) identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 knockout (KO), Sav1 KO, and SV40 T antigen mouse models effectively recapitulated subtypes of human HCC with a poor prognosis, whereas the Myc transgenic model best resembled human HCCs with a more favorable prognosis. The Myc model was also associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa , and diethylnitrosamine (DEN)-induced models were heterogeneous and were unequally split into poor and favorable prognoses. Mst1/2 KO and Sav1 KO models best resemble human HCC with hepatic stem cell characteristics. Applying a genomic predictor for immunotherapy, the six-gene IFNγ score, the Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis showed that elevated expression of immune-inhibitory genes ( Cd276 and Nectin2/ Pvrl2 ) in Mst1/2 KO, Sav1 KO, and SV40 models and decreased expression of immune stimulatory gene ( Cd86 ) in the DEN model might be accountable for the lack of predictive response to immunotherapy. Implication: The current genomic approach identified the most relevant mouse models to human liver cancer and suggests immunotherapeutic potential for the treatment of specific subtypes. Mol Cancer Res; 16(11); 1713-23. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC 50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.

This study was performed to determine the primary factor(s) governing the oral absorption of edaravone, a novel anti-oxidant for the treatment of amyotrophic lateral sclerosis, in rats. While the aqueous solubility of edaravone widely varied depending on the vehicle used, the oral bioavailability of the drug was not low when it was adequately solubilized, as evidenced by the fact that the oral exposure was high (in terms of the absolute bioavailability of 50-90%) at all dose ranges (i.e., 0.5-27 mg/kg) under solubilized conditions in rats. The sum of the in vitro clearance values for edaravone, 12.7 mL/(min × kg), obtained from metabolic stability studies with tissue-homogenates from the rat liver, kidney, intestine, and with the rat plasma, was found to be virtually identical to the systemic clearance of the drug in rats. It was noted that the liver represented over 83.9% of the total elimination with a hepatic extraction ratio of approximately 0.137, indicative of the minor role of hepatic first pass metabolism in the systemic absorption of edaravone after its oral administration. In studies with Ussing chamber with rat intestinal segments and Madin-Darby canine kidney (MDCKII) cells, edaravone was found to be highly permeable (i.e., P app over 10 × 10 -6  cm/s), and appeared to be a substrate for rat P-glycoprotein (P-gp; estimated K m of 421 μM). In contrast, however, the drug did not appear to be a substrate for human P-gp in transport studies with MDCKII-hMDR1 cells. Collectively, these observations suggest that the primary determining factor for the intestinal absorption of edaravone is its solubilization in vehicle/intestinal fluids, rather than permeability, pre-systemic first-pass metabolism, or efflux transport. Considering the fact that the newly approved indication of the drug would require prolonged administration, probably via oral administration, the findings reported herein provide relevant information regarding its use., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In oriental medicine, centipede Scolopendra subspinipes mutilans has long been used as a remedy for rheumatoid arthritis (RA), a well-known chronic autoimmune disorder. However, the molecular identities of its bioactive components have not yet been extensively investigated. We sought to identify bioactive molecules that control RA with a centipede. A novel antimicrobial peptide (AMP) (scolopendrasin IX) was identified from Scolopendra subspinipes mutilans. Scolopendrasin IX markedly activated mouse neutrophils, by enhancing cytosolic calcium increase, chemotactic cellular migration, and generation of superoxide anion in neutrophils. As a target receptor for scolopendrasin IX, formyl peptide receptor (FPR)2 mediates neutrophil activation induced by the AMP. Furthermore, scolopendrasin IX administration strongly blocked the clinical phenotype of RA in an autoantibody-injected model. Mechanistically, the novel AMP inhibited inflammatory cytokine synthesis from the joints and neutrophil recruitment into the joint area. Collectively, we suggest that scolopendrasin IX is a novel potential therapeutic agent for the control of RA via FPR2.

A number of severe norovirus outbreaks due to the consumption of contaminated shellfish have been reported recently. In this study, we evaluated the distribution of coliphage densities to determine their efficacy as fecal indicators of enteric viruses, including noroviruses, in water samples collected from a shellfish growing area in Republic of Korea over a period of approximately 1 year. Male-specific and somatic coliphages in water samples were analyzed using the single agar layer method, and norovirus genogroups I and II, which infect mainly humans, were analyzed using duplex reverse transcription quantitative PCR. Male-specific and somatic coliphages were detected widely throughout the study area. Several environmental parameters, including salinity, precipitation, temperature, and wind speed were significantly correlated with coliphage concentrations (P < 0.05). Moreover, the concentrations of male-specific coliphages were positively correlated with the presence of human noroviruses (r = 0.443; P < 0.01). The geospatial analysis with coliphage concentrations using a geographic information system revealed that densely populated residential areas were the major source of fecal contamination. Our results indicate that coliphage monitoring in water could be a useful approach to prevent norovirus contamination in shellfish.

Summary: Next-generation sequencing (NGS) technologies have led to the accumulation of high-throughput sequence data from various organisms in biology. To apply gene annotation of organellar genomes for various organisms, more optimized tools for functional gene annotation are required. Almost all gene annotation tools are mainly focused on the chloroplast genome of land plants or the mitochondrial genome of animals. We have developed a web application AGORA for the fast, user-friendly and improved annotations of organellar genomes. Annotator for Genes of Organelle from the Reference sequence Analysis (AGORA) annotates genes based on a basic local alignment search tool (BLAST)-based homology search and clustering with selected reference sequences from the NCBI database or user-defined uploaded data. AGORA can annotate the functional genes in almost all mitochondrion and plastid genomes of eukaryotes. The gene annotation of a genome with an exon-intron structure within a gene or inverted repeat region is also available. It provides information of start and end positions of each gene, BLAST results compared with the reference sequence and visualization of gene map by OGDRAW., Availability and Implementation: Users can freely use the software, and the accessible URL is https://bigdata.dongguk.edu/gene&#95;project/AGORA/. The main module of the tool is implemented by the python and php, and the web page is built by the HTML and CSS to support all browsers., Supplementary Information: Supplementary data are available at Bioinformatics online.

Lymphedema is a common complication associated with cancer itself or with cancer treatment. Lymphedema infrequently occurs after drug therapy. Bee venom is one of the materials used in acupuncture, and it has been used in the treatment of a variety of inflammatory diseases including arthritis. We report a 74-year-old male patient with late-onset post-radiation lymphedema provoked by bee venom therapy. He was free of lymphedema for 5 years after the complete remission of prostate cancer which had been treated with transurethral resection and radiation therapy. The patient developed left leg swelling after undergoing bee venom therapy for left hip pain. Computed tomography and lymphoscintigraphy showed lymphedema without tumor recurrence or infection. The lymphatic system was suspected to be injured by bee venom therapy and lymphedema was provoked. Bee venom therapy should be used cautiously in patients prone to lymphedema.

Local corrosion damage of steel structures can occur due to damage to the paint-coated surface of structures. Such damage can affect the structural behavior and performance of steel structures. Compressive loading tests were, thus, carried out in this study to examine the effect of local corrosion damage on the structural behavior and strength of tubular members. Artificial cross-sectional damage on the surface of the tubular members was introduced to reflect the actual corroded damage under exposure to a corrosion environment. The compressive failure modes and compressive strengths of the tubular members were compared according to the localized cross-sectional damage. The compressive loading test results showed that the compressive strengths were affected by the damaged width within a certain range. In addition, finite element analysis (FEA) was conducted with various parameters to determine the effects of the damage on the failure mode and compressive strength of the stub column. From the FEA results, the compressive strength was decreased proportionally with the equivalent cross-sectional area ratio and damaged volume ratio.

Various waterborne pathogens originate from human or animal feces and may cause severe gastroenteric outbreaks. Bacteroides spp. that exhibit strong host- or group-specificities are promising markers for identifying fecal sources and their origins. In the present study, 240 water samples were collected from two major aquaculture areas in Republic of Korea over a period of approximately 1 year, and the concentrations and occurrences of four host-specific Bacteroides markers (human, poultry, pig, and ruminant) were evaluated in the study areas. Host-specific Bacteroides markers were detected widely in the study areas, among which the poultry-specific Bacteroides marker was detected at the highest concentration (1.0-1.2 log 10 copies L -1 ). During the sampling period, high concentrations of host-specific Bacteroides markers were detected between September and December 2015. The host-specific Bacteroides marker-combined geospatial map revealed the up-to-downstream gradient of fecal contamination, as well as the effects of land-use patterns on host-specific Bacteroides marker concentrations. In contrast to traditional bacterial indicators, the human-specific Bacteroides marker correlated with human specific pathogens, such as noroviruses (r=0.337; P<0.001). The present results indicate that host-specific Bacteroides genetic markers with an advanced geospatial analysis are useful for tracking fecal sources and associated pathogens in aquaculture areas.

Purpose: To compare the bone responses of chemically modified implants using the plasma immersion ion implantation and deposition method with those of blasted implants., Materials and Methods: The titanium implants were blasted with resorbable blasting media (RBM) and designated as controls. The ion-implanted implants were divided into two test groups, namely, calcium (Ca) and magnesium (Mg) implants. Six implants (two implants per group) were placed into the proximal tibias of 11 New Zealand white rabbits. Fluorochrome labeling was administered at 2 and 4 weeks after surgery. Resonance frequency analysis (RFA) was conducted immediately after surgery and at 6 weeks of healing. The removal torque was measured in half of the tibiae. The implants in another tibia were subjected to fluorescence analysis and histologic and histomorphometric evaluations., Results: The fluorescence analysis suggested that osteoconductivity was improved in the early osseointegration stages in the Ca and Mg implants. In the cortical region, the bone-to-implant contact in the Mg implants and the bone area % in the Ca and Mg implants were higher than those in the RBM implants (P < .05). All groups demonstrated similar biomechanical strengths with respect to the RFA and the removal torque measurements., Conclusion: The osseointegration speed and the bone contact were positively affected by the Ca and Mg ion implantation, especially in the Mg implants, because of the synergistic effect. However, no remarkable differences were found in biomechanical strength in the later osseointegration stages.

Betulinic acid (BA), a plant-derived pentacyclic triterpenoid, may interact with the members of the organic anion transporting polypeptide 1B subfamily. Here, we investigated the interactions of BA and its analogs with OATP1B1/3 and rat Oatp1b2 in vitro and in vivo. BA inhibited the activity of OATP1B1/3 and rat Oatp1b2 in vitro. Systemic exposure of atorvastatin was substantially altered with the intravenous co-administration of BA (20 mg/kg). Preincubation (incubation with inhibitors, followed by washout) with BA led to a sustained inhibition of OATP1B3, which recovered rapidly in the media containing 10% fetal bovine serum. The addition of albumin to the media decreased intracellular concentrations of BA and expedited the recovery of OATP1B3 activity following preincubation. For asunaprevir and cyclosporin A (previously known to inhibit OATP1B3 upon preincubation), the addition of albumin to the media shortened recovery time with asunaprevir, but not with cyclosporin A. Overall, our results showed that BA inhibits OATP1B transporters in vitro and may incur hepatic transporter-mediated drug interactions in vivo. Our results identify BA as another OATP1B3 inhibitor with preincubation effect and suggest that the preincubation effect and its duration is impacted by altered equilibrium of inhibitors between intracellular and extracellular space (e.g., albumin in the media)., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

In this study, an improved analytical method for the detection of the colorant Brown FK in foods using high-performance liquid chromatography was developed. The method, which employed an RC-C18 column and diode array detection at 254 nm with sodium acetate solution and methanol as mobile phases, exhibited good linearity (R2 = 1.0), and its limits of detection and quantification were determined to be 0.06 and 0.19 μg/mL, respectively. The precision was found to be 0-1.2% and the accuracy was between 86.5% and 94.8%. Liquid chromatography-tandem mass spectrometry was also performed to identify Brown FK in peaks. The pretreatment method was optimized for three different food sample groups, i.e., seafood, noodles and other, affording recoveries of 86.5-92.8%, 90.8-94.8% and 90.0-92.3%, respectively. In addition, inter-laboratory testing was also conducted to check the precision., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We previously reported that MDR-1339, an inhibitor of β-amyloid protein aggregation, was likely to be eliminated by biotransformation in rats. The objective of this study was to determine the chemical identity of metabolites derived from this aggregate inhibitor and to characterize the kinetics of formation of these metabolites in rats. Using high performance liquid chromatography coupled with mass spectrometry with a hybrid triple quadrupole-linear ion trap, 7 metabolites and 1 potential metabolic intermediate were identified in RLM incubations containing MDR-1339. In addition to these, 3 glucuronide metabolites were detected in urine samples from rats receiving a 10 mg/kg oral dose of MDR-1339. When the kinetics of the formation of two major metabolites, M1 and M2, were analyzed assuming simple Michaelis-Menten kinetics, the V max and K m values were found to be 0.459 ± 0.0196 nmol/min/mg protein and 28.3 ± 3.07 μM for M1, and 0.101 ± 0.00537 nmol/min/mg protein and 14.7 ± 2.37 μM for M2, respectively. When chemically synthesized M1 and M2 were individually administered to rats intravenously at the dose of 5 mg/kg respectively, the volume of distribution and elimination clearance were determined to be 4590 ± 709 mL/kg and 68.4 ± 5.60 mL/min/kg for M1 and 15300 ± 8110 mL/kg and 98.0 ± 19.5 mL/min/kg for M2, respectively. When MDR-1339 was intravenously administered to rats at a dose of 5 mg/kg, the parent drug and M1 were readily detected for periods of up to 6 h after the administration, but M2 was observed only from 2 to 4 h. A standard moment analysis indicates that the formation clearance of M1 is 6.01 mL/min/kg, suggesting that 19.7% of the MDR-1339 dose was eliminated in rats. These observations indicate that the hepatic biotransformation of MDR-1339 results in the formation of at least 10 metabolites and that M1 is the major metabolite derived from this aggregation inhibitor in rats., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of the present study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose-dependent way. HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) levels and apoptotic cells with caspase-3 and -9 activation. HL156A inhibited the expression and activation of insulin-like growth factor (IGF)-1 and its downstream proteins, AKT, mammalian target of rapamycin (mTOR), and ERK1/2. In addition, HL156A activated AMP-activated protein kinase/nuclear factor kappa B (AMPK-NF-κB) signaling of FaDu and YD-10B cells. A xenograft mouse model further showed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by down-regulated p-IGF-1, p-mTOR, proliferating cell nuclear antigen (PCNA) and promoted p-AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: To analyze CT features that predict major gastrointestinal tract (GIT) complication after hepatic radiofrequency ablation (RFA)., Materials and Methods: Of 3933 patients who underwent RFA for hepatic malignancy from January 2005 to September 2016, 52 patients (1.32%) who had GIT complications were retrospectively enrolled. Electronic medical records and CT results were reviewed for location (left vs. right lobe, subcapsular vs. non-subcapsular) and tumor size, distance from the hepatic capsule, number and length of needles, ablation time, presence of artificial ascites, previous history of percutaneous treatment or operation, injured organs, length and thickness of injured GIT, presence of adjacent infiltration, ascites, mucosal discontinuity, and free air, and eccentricity. Patients were divided into those that recovered with conservative treatment (minor group) and those that required operation (major group). Chi-square test, Fisher's exact test, and Mann-Whitney U test analyzed differences between the two groups; however, the most significant variable was found using binary logistic regression analysis., Results: Of 52 patients who had GIT complications after hepatic RFA, 2 patients (0.05%) had major GIT complications, while the remaining 50 patients (1.27%) had minor complications. Most (47/52, 90.4%) of the tumors were located at subcapsular portion. 66% of tumors were located at the left hepatic lobe. Stomach was the most frequent injured organ (28/52, 53.8%), followed by colon (17/52, 32.7%) and small bowel (7/52, 13.5%). Patients with major GIT complications had significantly thicker (1.8 vs. 1.1 cm) and concentric (2/2, 100% vs. 1/50, 2.0%) bowel wall thickening with mucosal discontinuity (2/2, 100% vs. 0/50, 0%) than those with minor complications (P < 0.05)., Conclusion: GIT complication after hepatic RFA is rare and often requires conservative treatment. However, patients who show >1.65-cm-thick, concentric bowel wall thickening with mucosal disruption on CT after hepatic RFA may have major GIT injury that requires bowel surgery.

Background: Cold hypersensitivity in the hands and feet (CHHF) is a symptom patients usually feel cold in their hands and feet, but not dealt with a disease in western medicine. However, it is often appealed by patients at a clinic of Korean medicine (KM), considered to be a sort of key diagnostic indicator, and actively treated by physicians. Nevertheless, there is no standardized diagnostic definition for CHHF. Therefore, we surveyed KM experts' opinions to address the clinical definition, diagnostic criteria, and other relevant things on CHHF., Methods: We developed a survey to assess the definition, diagnosis, causes, and accompanying symptoms on CHHF. 31 experts who work at specialized university hospitals affiliated with KM hospitals consented to participation. Experts responded to survey questions by selecting multiple-choice answers or stating their opinions., Results: Vast majority of experts (83.8%) agreed with our definition on CHHF ("a feeling of cold as a symptom; that one's hands or feet become colder than those of average people in temperatures that are not normally perceived as cold"). 77.4% of experts considered subjective symptoms on CHHF were more important than medical instrument results. Constitution or genetic factors (87.1%) and stress (64.5%) were the most common causes reported for CHHF., Conclusions: This study offers an expert consensus regarding the themes, opinions, and experiences of practitioners with CHHF. Our results underscore the need for standardized definitions and diagnostic criteria for CHHF.

We found that formyl peptide receptor (FPR) 1 and FPR3 were expressed intracellularly and/or the nucleus of naïve CD4 T cell. Activation of naïve CD4 T cells with synthetic intracellular agonists dTAT-WKYMVm and CTP-WKYMVm for FPR members stimulated CD4 T cell migration via pertussis toxin-sensitive manner. Knockdown of FPR1, but not knockdown of FPR3, blocked dTAT-WKYMVm-induced naïve CD4 T cell migration. Stimulation of naïve CD4 T cells with dTAT-WKYMVm elicited the activation of ERK, p38 MAPK, and Akt. Activation of CD4 T cells with anti-CD3 and anti-CD28 antibodies caused surface expression of FPR1 and FPR3, but not FPR2. CD4 T cells isolated from sepsis patients expressed the three members of FPR family on their cell surface. Taken together, our results suggest that intracellular FPR in naïve CD4 T cells and surface FPRs in activated CD4 T cells might regulate immune responses by regulating CD4 T cell activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Toxic chemicals inside building materials have long-term harmful effects on human bodies. To prevent secondary damage caused by the evaporation of latent chemicals, it is necessary to detect the chemicals inside building materials at an early stage. Deep Raman spectroscopy is a potential candidate for on-site detection because it can provide molecular information about subsurface components. However, it is very difficult to spectrally distinguish the Raman signal of the internal chemicals from the background signal of the surrounding materials and to acquire the geometric information of chemicals. In this study, we developed hyperspectral wide-depth spatially offset Raman spectroscopy coupled with a data processing algorithm to identify toxic chemicals, such as chemical warfare agent (CWA) simulants in building materials. Furthermore, the spatial distribution of the chemicals and the thickness of the building material were also measured from one-dimensional (1D) spectral variation.

Study Design: A retrospective comparative study., Objective: The aim of this study was to analyze the exact distal fusion level in the treatment of major thoracolumbar and lumbar (TL/L) adolescent idiopathic scoliosis (AIS) using rod derotation (RD) and direct vertebral rotation (DVR) following pedicle screw instrumentation (PSI)., Summary of Background Data: Proper determination of distal fusion level is a very important factor in deformity correction and preservation of motion segments in the treatment of major TL/L AIS., Methods: AIS patients with major TL/L curves (n = 64) treated by PSI with RD and DVR methods with a minimum 2-year follow-up were divided into AL3 (flexible) and BL3 (rigid) according to the flexibility and rotation by preoperative bending radiographs., Results: There was no significant difference in TL/L (major) curve between the AL3 and BL3 groups postoperatively (P = 0.933) and at the last follow-up (P = 0.144). In addition, there was no significant difference in thoracic (minor) and compensatory (caudal) curve postoperatively (thoracic curve: P = 0.828, compensatory curve: P = 0.976); however, there was a significant difference in compensatory (caudal) curve at the last follow-up (P = 0.041). The overall prevalence of unsatisfactory results was 28.1% (18/64 patients), and the prevalence was 15.2% (7/46) in the AL3 group and 61.1% (11/18) in the BL3 group, which was significantly different (P < 0.05)., Conclusion: Lowest instrumented vertebra (LIV) would be selected at L3 (EV) when the curve is flexible; L3 crosses CSVL with a rotation of less than grade II in preoperative bending radiographs. However, if the curve is rigid, LIV should be extended to L4 (EV + 1) in order to prevent the adding-on phenomenon in the treatment of major TL/L AIS using RD and DVR following PSI., Level of Evidence: 4.

Noroviruses are major causative pathogen of nonbacterial acute gastroenteritis worldwide. Of the seven genogroups of noroviruses suggested recently, genogroup II genotype 4 (GII.4) had been the most common genotype identified in hospitalized patients in the last few decades. However, since the latter half of 2014, new variants of GII.17 have been reported as the main causes of outbreaks over GII.4 in East Asia and have also occurred in America and Europe. In this study, we monitored norovirus GII in coastal streams at South Gyeongsang province and South Jeolla province of South Korea from March 2015 to May 2016. Norovirus GII.17 capsid sequences were predominantly detected until September 2015 in water samples. However, we found that the number of positive cases of the norovirus GII.4 Sydney 2012 capsid sequence has been increasing since December 2015, overtaking that of GII.17 in 2016. The RdRp genotype of this predominant GII.4 variant in 2016 was identified as GII.P16. The emergence and predominance of the GII.4 pandemic capsid sequence harboring a different RdRp genotype suggested the potential for a future pandemic.

The objective of the current study was to determine the minimum permeability coefficient, P, needed for perfusion-limited distribution in PBPK. Two expanded kinetic models, containing both permeability and perfusion terms for the rate of tissue distribution, were considered: The resulting equations could be simplified to perfusion-limited distribution depending on tissue permeability. Integration plot analyses were carried out with theophylline in 11 typical tissues to determine their apparent distributional clearances and the model-dependent permeabilities of the tissues. Effective surface areas were calculated for 11 tissues from the tissue permeabilities of theophylline and its PAMPA P. Tissue permeabilities of other drugs were then estimated from their PAMPA P and the effective surface area of the tissues. The differences between the observed and predicted concentrations, as expressed by the sum of squared log differences with the present models were at least comparable to or less than the values obtained using the traditional perfusion-limited distribution model for 24 compounds with diverse PAMPA P values. These observations suggest that the use of a combination of the proposed models, PAMPA P and the effective surface area can be used to reasonably predict the pharmacokinetics of 22 out of 24 model compounds, and is potentially applicable to calculating the kinetics for other drugs. Assuming that the fractional distribution parameter of 80% of the perfusion rate is a reasonable threshold for perfusion-limited distribution in PBPK, our theoretical prediction indicates that the pharmacokinetics of drugs having an apparent PAMPA P of 1×10 -6 cm/s or more will follow the traditional perfusion-limited distribution in PBPK for major tissues in the body., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: This study aimed to demonstrate the safety and reliability of combined preoperative angioplasty and free flap transfer in patients with peripheral arterial occlusive disease (PAOD) by analyzing the surgical outcomes., Methods: Between October 2011 and October 2015, patients who had undergone lower extremity angiography and subsequent free flap transfer were retrospectively reviewed. Data collected included demographics, perioperative data, and postoperative outcomes. The cases were divided into two groups: one group with microanastomosis performed on revascularized artery by balloon angioplasty and the other group performed on native artery. Multiple logistic regression model using propensity score and linear regression was computed to determine the association between preoperative angioplasty and the surgical outcomes., Results: A total of 62 lower limb reconstruction cases (19 angioplastied cases and 43 nonangioplastied cases) were included in the study. Complications occurred in 6 cases in the angioplastied group and in 11 cases in the control group. The overall limb salvage rate was 100% during the average follow-up of 29.5 months in the angioplastied group and 97.7% in the nonangioplastied control group during the average follow-up of 31.1 months. Preoperative angioplasty was not a significant predictor of increased complications and longer postoperative downtime in logistic and linear regression model, both in the weighted and unweighted model., Conclusions: The combined approach of preoperative endovascular revascularization and free flap transfer for limb reconstruction in PAOD patients can be performed safely and effectively with acceptable morbidity., (Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

EC-18 (i.e., 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol), an active ingredient in Rockpid ® , has been reported to be useful in controlling various types of inflammations, particularly those caused by neutropenia. Although this product was originally approved as a functional food in Korea, it is currently in phase II clinical trials for use in managing the severe chemotherapy-induced neutropenia in patients with advanced breast cancer who are receiving intermediate febrile neutropenia risk chemotherapy. The objective of this study was to develop a rapid, sensitive method for the determination of EC-18 in rat and mouse plasma and to evaluate the applicability of the assay in pharmacokinetic studies. EC-18 was extracted with MeOH from rat and mouse plasma samples, and the extract directly introduced onto an LC-MS/MS system. The analyte and EC-18-d3, an internal standard, were analyzed by multiple reaction monitoring (MRM) at m/z transitions of 635.4→355.4 for EC-18 and 638.4→338.4 for the internal standard, respectively. The lower limit of quantification (LLOQ) was determined at 50ng/mL, with an acceptable linearity in the range from 50 to 10,000ng/mL (r>0.999) for both matrices. Validation parameters such as accuracy, precision, dilution, recovery, matrix effects and stability were found to be within the acceptance criteria of the assay validation guidelines, indicating that the assay is applicable for estimating EC-18 in concentrations in the range examined. EC-18 was readily determined in plasma samples for periods of up to 8h following an intravenous bolus injection of 1mg/kg in rats and at 5mg/kg in mice, respectively, and up to 24h following the oral administration of 2000mg/kg in mice. The findings indicate that the current analytical method is applicable for pharmacokinetic studies of EC-18 in small animals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cytochrome P450 enzymes and human organic anion transporting polypeptide (OATP) 1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new peroxisome proliferator-activated receptor γ agonist. Atorvastatin (ATV), a substrate for CYP3A and human OATP1B1, is likely to be coadministered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was administered intravenously with ATV, the systemic clearance and volume of distribution at steady state for LB remained unchanged (2.67 ± 0.63 ml/min per kg and 289 ± 20 ml/kg, respectively), compared with that of LB without ATV (2.34 ± 0.37 ml/min per kg and 271 ± 20 ml/kg, respectively). Although the tissue-to-plasma partition coefficient (K p ) of LB was not affected by ATV in most major tissues, the liver K p for LB was decreased by ATV coadministration. Steady-state liver K p values for three levels of LB were significantly decreased as a result of ATV coadministration. LB uptake was inhibited by ATV in rat OATP1B2-overexpressing Madin-Darby canine kidney cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a physiologically based pharmacokinetics model, the characteristics of LB distribution to the liver were consistent with the findings of the in vivo study. It thus appears that the distribution of LB to the liver is mediated by the hepatic uptake of transporters such as rat OATP1B2, and carrier-mediated transport is involved in the liver-specific drug-drug interaction between LB and ATV in vivo., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Glyceollins synthesized in soybeans that are exposed to biotic or abiotic stress have been reported to have health benefits. Considering that glyceollins are de novo synthesized from daidzein via several enzymatic steps and that isoflavone concentration widely varies among soybean varieties, the abilities of 60 soybean cultivars to synthesize glyceollins were compared under different elicitation conditions. Soybeans accumulated glyceollins differentially depending upon the cultivar when elicited with Aspergillus sojae . Contrary to our hypothesis that high isoflavone varieties may accumulate glyceollins more efficiently upon elicitation, glyceollin accumulation in response to fungal elicitation was not related with the concentration of either total isoflavones or daidzein in soybeans. Rather the glyceollin levels were significantly affected by soybean cultivar and most effectively increased by fungal infection. The data suggest that the selection of a strong fungal elicitor and a soybean cultivar with genotype that highly expresses the genes involved in glyceollin biosynthesis is essential for efficient glyceollin production.

Human norovirus (HNoV), a positive-sense RNA virus, is the main causative agent of acute viral gastroenteritis. Multiple pandemic variants of the genogroup II genotype 4 (GII.4) of NoV have attracted great attention from researchers worldwide. However, novel variants of GII.17 have been overtaking those pandemic variants in some areas of East Asia. To investigate the environmental occurrence of GII in South Korea, we collected water samples from coastal streams and a neighboring waste water treatment plant in North Jeolla province (in March, July, and December of 2015). Based on capsid gene region C analysis, four different genotypes (GII.4, GII.13, GII.17, and GII.21) were detected, with much higher prevalence of GII.17 than of GII.4. Additional sequence analyses of the ORF1-ORF2 junction and ORF2 from the water samples revealed that the GII.17 sequences in this study were closely related to the novel strains of GII.P17-GII.17, the main causative variants of the 2014-2015 HNoV outbreak in China and Japan. In addition, the GII.P21-GII.21 variants were identified in this study and they had new amino acid sequence variations in the blockade epitopes of the P2 domain. From these results, we present two important findings: 1) the novel GII.P17-GII.17 variants appeared to be predominant in the study area, and 2) new GII.21 variants have emerged in South Korea.

Brassinosteroids (BRs) are plant polyhydroxy-steroids that play important roles in plant growth and development via extensive signal integration through direct interactions between regulatory components of different signaling pathways. Recent studies have shown that diverse helix-loop-helix/basic helix-loop-helix (HLH/bHLH) family proteins are actively involved in control of BR signaling pathways and interact with other signaling pathways. In this study, we show that ATBS1-INTERACTING FACTOR 2 (AIF2), a nuclear-localized atypical bHLH transcription factor, specifically interacts with BRASSINOSTEROID-INSENSITIVE 2 (BIN2) among other BR signaling molecules. Overexpression of AIF2 down-regulated transcript expression of growth-promoting genes, thus resulting in retardation of growth. AIF2 renders plants hyposensitive to BR-induced root growth inhibition, but shows little effects on BR-promoted hypocotyl elongation. Notably, AIF2 was dephosphorylated by BR, and the dephosphorylated AIF2 was subject to proteasome-mediated degradation. AIF2 degradation was greatly induced by BR and ABA, but relatively slightly by other hormones such as auxin, gibberellin, cytokinin and ethylene. Moreover, AIF2 transcription was significantly suppressed by a BRI1/BZR1-mediated BR signaling pathway through a direct binding of BRASSINAZOLE RESISTANT 1 (BZR1) to the BR response element (BRRE) region of the AIF2 promoter. In conclusion, our study suggests that BIN2-driven AIF2 phosphorylation could augment the BIN2/AIF2-mediated negative circuit of BR signaling pathways, and the BR-induced transcriptional repression and protein degradation negatively regulate AIF2 transcription factor, reinforcing the BZR1/BES1-mediated positive BR signaling pathway., (© The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The task of improving a fungal strain is highly time-consuming due to the requirement of a large number of flasks in order to obtain a library with enough diversity. In addition, fermentations (particularly those for fungal cells) are typically performed in high-volume (100-250 ml) shake-flasks. In this study, for large and rapid screening of itaconic acid (IA) high-yielding mutants of Aspergillus terreus , a miniaturized culture method was developed using 12-well and 24-well microtiter plates (MTPs, working volume = 1-2 ml). These miniaturized MTP fermentations were successful, only when highly filamentous forms were induced in the growth cultures. Under these conditions, loose-pelleted morphologies of optimum sizes (less than 0.5 mm in diameter) were casually induced in the MTP production cultures, which turned out to be the prerequisite for the active IA biosynthesis by the mutated strains in the miniaturized fermentations. Another crucial factor for successful MTP fermentation was to supply an optimal amount of dissolved oxygen into the fermentation broth through increasing the agitation speed (240 rpm) and reducing the working volume (1 ml) of each 24-well microtiter plate. Notably, almost identical fermentation physiologies resulted in the 250 ml shake-flasks, as well as in the 12-well and 24-well MTP cultures conducted under the respective optimum conditions, as expressed in terms of the distribution of IA productivity of each mutant. These results reveal that MTP cultures could be considered as viable alternatives for the labor-intensive shake-flask fermentations even for filamentous fungal cells, leading to the rapid development of IA high-yield mutant strains.

Purpose: To retrospectively evaluate the risk factors for the development of late enophthalmos in pure blowout fractures., Methods: We reviewed 49 cases of pure blowout fractures diagnosed in Ajou University Hospital, South Korea, from January 2005 to June 2015. We assumed that several factors influence the development of late enophthalmos, including bony defect size, volume of displaced soft tissue, number of fracture sites, involvement of floor, soft tissue incarceration through the bony defect, and patient age., Results: Twenty-one patients were diagnosed with late enophthalmos (group 1) while 28 patients were not (group 2). Soft tissue incarceration, presumably causing the soft tissue injury, was the only factor that increased the risk for late enophthalmos in this study (p = 0.04, odds ratio 4.5). In contrast with previous studies, there were no meaningful correlation between bony defect size or volume of displaced soft tissue and development of late enophthalmos. Number of fracture sites, involvement of floor, and patient age did not increase the risk for late enophthalmos., Conclusions: We suggest that the delayed orbital tissue atrophy due to soft tissue injury plays a more important role than other hypotheses in the development of late enophthalmos. It is necessary to overcorrect to some extent if there is soft tissue incarceration through the bony defect in the initial computed tomography, and clinicians should warn patients about the development of late enophthalmos despite orbital reconstructive surgery.

The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis. Importantly, TRAF6 and γH2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of HIF1α-driven tumorigenesis, glycolysis and metastasis. Our findings suggest that TRAF6-mediated mono-ubiquitylation and subsequent phosphorylation of H2AX may serve as potential means for cancer diagnosis and therapy.

This study aimed to evaluate the antioxidant activity of various plant extracts. A total of 94 kinds of edible plant extracts obtained from the Korea Plant Extract Bank were screened for cytotoxicity, following which the total phenolic content of 24 shortlisted extracts was determined. Of these, extracts from three plants, namely, Castanea crenata (CC) leaf, Camellia japonica (CJ) fruit, and Viburnum dilatatum (VD) leaf, were examined for antioxidant capabilities by measuring radical scavenging activity, ferric reducing/antioxidant power, and lipid peroxidation inhibitory activity. In addition, cellular antioxidant activities of the three extracts were assessed by a cell-based dichlorofluorescein assay and antioxidant response element (ARE) reporter activity assay. The results demonstrated that all three extracts concentration-dependently scavenged free radicals, inhibited lipid peroxidation, reduced the cellular level of reactive oxygen species, and increased ARE-luciferase activity, indicating antioxidant enzyme-inducing potential. In particular, CJ extract showed significantly greater antioxidative activity and antimigratory effect in a breast cancer cell line compared to CC and VD extracts. Hence, CJ extract deserves further study for its in vivo functionality or biologically active constituents.

Plastoglobules (PGs) are thylakoid membrane microdomains within plastids that are known as specialized locations of carotenogenesis. Three rice phytoene synthase proteins (OsPSYs) involved in carotenoid biosynthesis have been identified. Here, the N-terminal 80-amino-acid portion of OsPSY2 (PTp) was demonstrated to be a chloroplast-targeting peptide by displaying cytosolic localization of OsPSY2(ΔPTp):mCherry in rice protoplast, in contrast to chloroplast localization of OsPSY2:mCherry in a punctate pattern. The peptide sequence of a PTp was predicted to harbor two transmembrane domains eligible for a putative PG-targeting signal. To assess and enhance the PG-targeting ability of PTp, the original PTp DNA sequence ( PTp ) was modified to a synthetic DNA sequence ( stPTp ), which had 84.4% similarity to the original sequence. The motivation of this modification was to reduce the GC ratio from 75% to 65% and to disentangle the hairpin loop structures of PTp . These two DNA sequences were fused to the sequence of the synthetic green fluorescent protein (sGFP) and drove GFP expression with different efficiencies. In particular, the RNA and protein levels of stPTp-sGFP were slightly improved to 1.4-fold and 1.3-fold more than those of sGFP, respectively. The green fluorescent signals of their mature proteins were all observed as speckle-like patterns with slightly blurred stromal signals in chloroplasts. These discrete green speckles of PTp - sGFP and stPTp - sGFP corresponded exactly to the red fluorescent signal displayed by OsPSY2:mCherry in both etiolated and greening protoplasts and it is presumed to correspond to distinct PGs. In conclusion, we identified PTp as a transit peptide sequence facilitating preferential translocation of foreign proteins to PGs, and developed an improved PTp sequence, a s tPTp , which is expected to be very useful for applications in plant biotechnologies requiring precise micro-compartmental localization in plastids., Competing Interests: The authors declare no conflict of interest.

This paper describes the physics case for a new fixed target facility at CERN SPS. The SHiP (search for hidden particles) experiment is intended to hunt for new physics in the largely unexplored domain of very weakly interacting particles with masses below the Fermi scale, inaccessible to the LHC experiments, and to study tau neutrino physics. The same proton beam setup can be used later to look for decays of tau-leptons with lepton flavour number non-conservation, [Formula: see text] and to search for weakly-interacting sub-GeV dark matter candidates. We discuss the evidence for physics beyond the standard model and describe interactions between new particles and four different portals-scalars, vectors, fermions or axion-like particles. We discuss motivations for different models, manifesting themselves via these interactions, and how they can be probed with the SHiP experiment and present several case studies. The prospects to search for relatively light SUSY and composite particles at SHiP are also discussed. We demonstrate that the SHiP experiment has a unique potential to discover new physics and can directly probe a number of solutions of beyond the standard model puzzles, such as neutrino masses, baryon asymmetry of the Universe, dark matter, and inflation.

Background: Cardiac valvular calcification is associated with the overall coronary plaque burden and considered an independent cardiovascular risk and prognostic factor. The purpose of this study was to evaluate the relationship between the presence of valvular calcification and plaque morphology and/or vulnerability., Methods: Transthoracic echocardiography was used to assess valvular calcification in 280 patients with coronary artery disease who underwent radiofrequency intravascular ultrasound (Virtual Histology IVUS, VH-IVUS). A propensity score-matched cohort of 192 patients (n = 96 in each group) was analyzed. Thin-capped fibroatheroma (TCFA) was defined as a necrotic core (NC) >10% of the plaque area with a plaque burden >40% and NC in contact with the lumen for ≥3 image slices. A remodeling index (lesion/reference vessel area) >1.05 was considered to be positive., Results: Patients were divided into two groups: any calcification in at least one valve (152 patients) vs. no detectable valvular calcification (128 patients). Groups were similar in terms of age, risk factors, clinical diagnosis, and angiographic analysis after propensity score-matched analysis. Gray-scale IVUS analysis showed that the vessel size, plaque burden, minimal lumen area, and remodeling index were similar. By VH-IVUS, % NC and % dense calcium (DC) were greater in patients with valvular calcification (p = 0.024, and p = 0.016, respectively). However, only % DC was higher at the maximal NC site by propensity score-matched analysis (p = 0.029). The frequency of VH-TCFA occurrence was higher depending on the complexity (p = 0.0064) and severity (p = 0.013) of valvular calcification., Conclusions: There is a significant relationship between valvular calcifications and VH-IVUS assessment of TCFAs. Valvular calcification indicates a greater atherosclerosis disease complexity (increased calcification of the coronary plaque) and vulnerable coronary plaques (higher incidence of VH-TCFA)., Competing Interests: The authors have declared that no competing interests exist.

The presence of human norovirus in the aquatic environment can cause outbreaks related to recreational activities and the consumption of norovirus-contaminated clams. In this study, we investigated the prevalence of norovirus genogroups I (GI) and II (GII) in the coastal aquatic environment in South Korea (March 2014 to February 2015). A total of 504 water samples were collected periodically from four coastal areas (total sites = 63), of which 44 sites were in estuaries (clam fisheries) and 19 were in inflow streams. RT-PCR analysis targeting ORF2 region C revealed that 20.6% of the water samples were contaminated by GI (13.3%) or GII (16.6%). The prevalence of human norovirus was higher in winter/spring than in summer/fall, and higher in inflow streams (50.0%) than in estuaries (7.9%). A total of 229 human norovirus sequences were identified from the water samples, and phylogenetic analysis showed that the sequences clustered into eight GI genotypes (GI.1, 2, 3, 4, 5, 6, 7, and 9) and nine GII genotypes (GII.2, 3, 4, 5, 6, 11, 13, 17, and 21). This study highlighted three issues: 1) a strong correlation between norovirus contamination via inflow streams and coastal areas used in clam fisheries; 2) increased prevalence of certain non-GII.4 genotypes, exceeding that of the GII.4 pandemic variants; 3) seasonal shifts in the dominant genotypes of both GI and GII., Competing Interests: The authors have declared that no competing interests exist.

Background: Enterovirus (EV) 71 is the main pathogen associated with hand, foot and mouth disease (HFMD) or herpangina. Outbreaks of HFMD caused by EV71 infection are associated severe neurological disease and high mortality rates in children. Several sporadic cases of EV71 infection occurred in the Republic of Korea (ROK) in 2000, and EV71 infections were not reported thereafter until 2006. In this prospective study, we report the epidemic and virologic characteristics of the EV71 endemic from 2007 to 2012 in the Republic of Korea., Methods: We analyzed characteristics of the EV71 infection-associated epidemic from collected specimens and clinical information from 9987 patients with suspected EV infection from the National EV Surveillance System in ROK. To identify the EV71 subgenotype, the homology of viral protein 1 sequences obtained using reverse transcription polymerase chain reaction was compared with the sequences on other countries available from GenBank database., Results: EV71 was detected in 585 (16.7 %) specimens (cerebrospinal fluid, stool or rectal swabs, throat swabs and blood) during study period and was most frequently observed during epidemic seasons in 2009-2012. Major manifestations due to EV71 infection were HFMD (62.2 %) and HFMD with severe neurological complications (28.4 %). Five deaths (0.9 %) due to EV71 infection occurred, with an increased mortality rate during the period after 2009. Most patients (476; 81.4 %) were less than 5 years of age. Analysis of the monthly distribution showed that there was an obvious seasonal pattern to the epidemics, with infections appearing from June to August. The major subgenotype of EV71 isolates circulating in ROK was the C4a strain, which has also appeared in China, Japan and Vietnam., Conclusions: This surveillance provided valuable data on the epidemic characteristics of EV71 infections in ROK during a 6-year period. Our findings provide data to assist during future outbreaks of EV71 and associated acute neurologic disease.