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Silver nanoparticles (AgNPs) were synthesized using the whole plant of Duchesnea indica (DI) which was extracted in different solvents; the antimicrobial effects of the extract were investigated in this study. The extraction of DI was performed using three different solvents: water, pure ethanol (EtOH), and pure dimethyl sulfoxide (DMSO). AgNP formation was monitored by measuring the UV–Vis spectrum of each reaction solution. After synthesis for 48 h, the AgNPs were collected and the negative surface charge and size distribution of the synthesized AgNPs were measured using dynamic light scattering (DLS). The AgNP structure was determined by high-resolution powder X-ray diffraction (XRD) and the AgNP morphology was investigated using transmission electron microscopy (TEM). AgNP antibacterial activities were evaluated against Bacillus cereus, Staphylococcus aureus, Escherichia coli, Salmonella enteritidis, and Pseudomonas aeruginosa using the disc diffusion method. Additionally, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were also determined. Biosynthesized AgNPs showed enhanced antibacterial activity against B. cereus, S. aureus, E. coli, S. enteritidis, and P. aeruginosa compared with that of pristine solvent extract. These results suggest that AgNPs synthesized from extracts of DI are promising antibacterial agents against pathogenic bacteria and can be further applied in the food industry.

Toxic erythema of chemotherapy is an umbrella term for several non-allergic cutaneous reactions to chemotherapeutic agents. Given the heterogenous range of presentations, we will review the differential diagnoses and treatment approaches, particularly for hospitalized patients. Early recognition, holding chemotherapy, or dose reduction and monitoring fluid balance for severely ill patients is the mainstay of treatment. Supportive care with topical steroids, emollients, and wound care have shown benefit. Toxic erythema of chemotherapy can mimic several common eruptions seen in oncologic patients. The recognition of both clinical and pathological features by inpatient dermatologists allows for appropriate management, and dose reduction if necessary, in order for patients to continue oncologic treatment.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a group of chronic inflammatory diseases of the gastrointestinal tract. Although the multifactorial etiology of IBD pathogenesis is relatively well documented, the regulatory factors that confer a risk of IBD pathogenesis remain less explored. In this study, we report that T-cell death-associated gene 51 (TDAG51/PHLDA1) is a novel regulator of the development of dextran sulfate sodium (DSS)-induced colitis in mice. TDAG51 expression was elevated in the colon tissues of DSS-induced experimental colitis mice. TDAG51 deficiency protected mice against acute DSS-induced lethality and body weight changes and disease severity. DSS-induced structural damage and mucus secretion in colon tissues were significantly reduced in TDAG51-deficient mice compared with wild-type mice. We observed similar results in a DSS-induced chronic colitis mouse model. Finally, we showed that the production of inflammatory mediators, including proinflammatory enzymes, molecules and cytokines, was decreased in DSS-treated TDAG51-deficient mice compared with DSS-treated wild-type mice. Thus, we demonstrated that TDAG51 deficiency plays a protective role against DSS-induced colitis by decreasing the production of inflammatory mediators in mice. These findings suggest that TDAG51 is a novel regulator of the development of DSS-induced colitis and is a potential therapeutic target for IBD.

Chitosan (CTS)/gelatin (GEL)/poly(vinyl alcohol) (PVA)-based composite films with different concentrations of

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

We obtain a characterization on self-orthogonality for a given binary linear code in terms of the number of column vectors in its generator matrix, which extends the result of Bouyukliev et al. (2006). As an application, we give an algorithmic method to embed a given binary $k$-dimensional linear code $\mathcal{C}$ ($k = 2,3,4$) into a self-orthogonal code of the shortest length which has the same dimension $k$ and minimum distance $d' \ge d(\mathcal{C})$. For $k > 4$, we suggest a recursive method to embed a $k$-dimensional linear code to a self-orthogonal code. We also give new explicit formulas for the minimum distances of optimal self-orthogonal codes for any length $n$ with dimension 4 and any length $n \not\equiv 6,13,14,21,22,28,29 \pmod{31}$ with dimension 5. We determine the exact optimal minimum distances of $[n,4]$ self-orthogonal codes which were left open by Li-Xu-Zhao (2008) when $n \equiv 0,3,4,5,10,11,12 \pmod{15}$. Then, using MAGMA, we observe that our embedding sends an optimal linear code to an optimal self-orthogonal code., 19 pages; to appear in IEEE Trans. Inform. Theory

Bacillus cereus is a foodborne pathogen and cause a frequent problem due to the biofilms forming in equipment of food production plants. Autoinducer-2 (AI-2) involved in interspecies communication, plays a role in the biofilm formation of B. cereus. In this study, biofilm formation by thirty-nine B. cereus strains isolated from foods produced in Korea was determined. To investigate the effect of AI-2 on biofilm formation by B. cereus SBC27, which had the highest biofilm-forming ability, biofilm densities formed after addition of the AI-2 from Staphylococcus aureus and Escherichia coli were analysed. As a result, it was found that the quorum sensing molecule AI-2 could induce biofilm formation by B. cereus within 24 h, but it may also inhibit biofilm formation when more AI-2 is added after 24 h. Thus, these results improve our understanding of biofilm formation by food-derived B. cereus and provide clues that could help to reduce the impact of biofilms, the biggest problem in food processing environments, which has an impact on public health as well as the economy.

The aim of this study was to investigate the anti-oxidant and anti-inflammatory activities of the Rhododendron weyrichii flower extract fermented using Shindari, a traditional Jeju barley Nuruk-based fermentation. In this study, we examined the antioxidant potential of R. weyrichii flower extracts (RF) and R. weyrichii flower extracts fermented with Nuruk or Shindari (RFFN or RFFS, respectively) using various in vitro antioxidant assays including DPPH and ABTS radical scavenging assays, total phenol content and FRAP assays. We also evaluated the anti-inflammatory activity of the RF and RFFS on murine RAW 264.7 cells. The anti-inflammatory activity was evaluated by treating the RAW 264.7 cells with various concentrations (6.25, 12.5, 25, and 50 μg/ml) of RF or RFFS. As a result, we observed that the ABTS radical scavenging activity and total phenol content of RFFS was higher than that of RF and RFFN. Additionally, lipopolysaccharide- induced nitric oxide (NO) production was significantly lower in RFFS-treated cells when compared to the LPS-treated control. In addition, RFFS-treated cells exhibited decreased expression of inducible NO synthase (iNOS) proteins and high-performance liquid chromatography (HPLC) fingerprinting showed that both the quercetin and quercetin glucoside (quercitrin and isoquercitrin) levels were affected by the fermentation process. In conclusion, our data suggests that traditional fermentation could be an important strategy in improving the biological properties of raw materials including their antioxidant and antiinflammatory activities. Finally, RFFS may be a candidate for developing topical antioxidant and antiinflammatory agents.

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator in adipogenesis. PPARγ forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), to form an active transcriptional complex, and their transcriptional activity is tightly regulated by the association with either coactivators or corepressors. In this study, we identified T-cell death-associated gene 51 (TDAG51) as a novel corepressor of PPARγ-mediated transcriptional regulation. We showed that TDAG51 expression is abundantly maintained in the early stage of adipogenic differentiation. Forced expression of TDAG51 inhibited adipocyte differentiation in 3T3-L1 cells. We found that TDAG51 physically interacts with PPARγ in a ligand-independent manner. In deletion mutant analyses, large portions of the TDAG51 domains, including the pleckstrin homology-like, glutamine repeat and proline-glutamine repeat domains but not the proline-histidine repeat domain, are involved in the interaction with the region between residues 140 and 506, including the DNA binding domain, hinge, ligand binding domain and activation function-2 domain, in PPARγ. The heterodimer formation of PPARγ-RXRα was competitively inhibited in a ligand-independent manner by TDAG51 binding to PPARγ. Thus, our data suggest that TDAG51, which could determine adipogenic cell fate, acts as a novel negative regulator of PPARγ by blocking RXRα recruitment to the PPARγ-RXRα heterodimer complex in adipogenesis.

Electronic nicotine delivery system (ENDS) use is outpacing our understanding of its potential harmful effects. Homeostasis of the lung is maintained through proper balance of cell death, efferocytic clearance, and phagocytosis of pathogens. To investigate whether ENDS use has the potential to alter this balance, we developed physiologically relevant ENDS exposure paradigms for lung epithelial cells and primary macrophages. In our studies, cells were exposed directly to aerosol made from carefully controlled components with and without nicotine. We found that ENDS aerosol exposure led to apoptosis, secondary necrosis, and necrosis in lung epithelial cell models. In contrast, macrophages died mostly by apoptosis and inflammatory caspase-mediated cell death when exposed to ENDS aerosol. The clearance of dead cells and pathogens by efferocytosis and phagocytosis, respectively, is an important process in maintaining a healthy lung. To investigate the impact of ENDS aerosol on macrophage function independent of general toxicity, we used an exposure time that did not induce cell death in primary macrophages. Exposure to ENDS aerosol containing nicotine inhibited nearly all phagocytic and greatly reduced the efferocytic abilities of primary macrophages. When challenged with a bacterial pathogen, there was decreased bacterial clearance. The presence of nicotine in the ENDS aerosol increased its toxicity and functional impact; however, nicotine exposure alone did not have any deleterious effects. These data demonstrate that ENDS aerosol exposure could lead to increased epithelial cell and macrophage death in the lung and impair important macrophage functions that are essential for maintenance of lung function.

Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA. The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6). In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-μg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-μg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01). This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA’s therapeutic effect.

WHAT IS KNOWN AND OBJECTIVE With increased opioid use, drug-drug interactions (DDIs) and associated adverse events are growing among geriatric patients. However, the clinical significance of potential metabolic DDIs associated with opioid use has not been fully evaluated among geriatric patients. Particularly, cytochrome (CYP) P450 enzymes are important in drug metabolism of oxycodone and a black box warning for oxycodone reveals serious risks associated with drug-oxycodone interactions. This study focused on the use of oxycodone in geriatric patients to evaluate its adverse drug reactions (ADRs) and DDIs associated with CYP P450 enzymes. METHODS A retrospective cohort study using patients treated at Korea Veterans Hospital was performed. Data from male patients aged 65 years and older who received oxycodone were analysed. Binomial variables describing patient-related characteristics, drug-related characteristics and CYP-mediating drugs were constructed. Associations between these variables and the frequency of ADRs were determined. The odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariable and multivariable analyses, respectively. RESULTS AND DISCUSSION Among 111 patients, 32.4% experienced at least one ADR. The most common ADR was gastrointestinal-related (n = 21), followed by dizziness and drowsiness (n = 8). Use of either CYP2D6 inhibitors or CYP3A4 inhibitors increased the rate of ADRs by 20.4 and 25.4 times, respectively. In the case of patients taking both inhibitors, the adjusted OR was 48.6, and the attributable risk was 97.9%. WHAT IS NEW AND CONCLUSION This study suggests that inappropriate combinations of oxycodone with CYP2D6 inhibitors and/or CYP3A4 inhibitors may warrant treatment modification to avoid ADRs in geriatric patients. Clinicians should monitor any signs of ADRs that may reflect DDIs while a geriatric patient is taking oxycodone.

In this study, the risk factors associated with sodium overcorrection were investigated with an optimal cutoff for baseline serum sodium for use in daily clinical practice. Electronic medical records of patients who received tolvaptan for non-hypovolemic hyponatremia were reviewed. Demographic and clinical data including age, sex, weight, height, comorbidity, cause of hyponatremia, hypertonic saline use, and comedication were collected. Baseline laboratory parameters measured included serum sodium, serum potassium, serum creatinine, blood urea nitrogen, serum tonicity, ALT, AST, and urine osmolality. The primary outcome was the overcorrection of serum sodium, which was defined as an increase in serum sodium by more than 10 mmol/L in 24 h. From a total of 77 patients included in the analysis, 24 (31.2%) showed sodium overcorrection (> 10 mmol/L/24 h); 2 (2.6%) in heart failure cohort, 17 (22.1%) in SIADH cohort, and 5 (6.5%) in unknown cause cohort. More than half of patients (51.9%) were administered hypertonic saline prior to tolvaptan. Hypertension, cancer, diuretics, baseline serum sodium, and SIADH were associated with the risk of overcorrection in the univariable analysis. Significant factors for the overcorrection from multivariable analysis were lower body mass index, presence of cancer (adjusted odds ratio, 10.87; 95% CI, 1.23–96.44), and lower serum sodium at baseline (adjusted odds ratio, 0.76 for every 1 mEq/L increase; 95% CI, 0.61–0.94). The overcorrection of hyponatremia in non-hypovolemic patients treated with tolvaptan was significantly associated with lower body mass index, presence of cancer, and lower serum sodium at baseline. In subgroup analysis using SIADH patients, baseline sodium and cancer were found to be significant factors of overcorrection.

Biphenyl-degrading bacteria were isolated from contaminated soil and identified as Comamonas species. Among these strains, C. thiooxydans N1 was the most suitable for biphenyl degradation. When 1200 µg/mL of biphenyl was used, it was completely degraded within 24 h. A simple, rapid, and precise, high-performance liquid chromatography (HPLC) method for quantifying biphenyls and their metabolites in the culture medium was optimised and validated. The proposed method was performed using reverse-phase HPLC equipped with a Luna C18 column. The mobile phase was water and acetonitrile (30/70, v/v) under isocratic conditions, and biphenyls and their metabolites were quantified on a SHIMADZU HPLC system with a diode-array detection detector at 254 nm. Peak identity was confirmed by ultraviolet spectroscopy and gas chromatography-mass spectrometry. Validation was performed according to European Union requirements (2002/657/EC) for linearity, accuracy, repeatability, reproducibility, limit of detection, limit of quantification, and detection capability. Linearity was observed in the concentration range of 0.04-20 µg/mL with a high coefficient of determination (R2 ≥ 0.999). The validated method was applied to determine the content of biphenyl and its metabolites in the culture medium.

Chitosan (CTS)/gelatin (GEL)/poly(vinyl alcohol) (PVA)-based composite films with different concentrations of Duchesnea indica extract (DIE) (6.25 and 25 mg/mL), an antimicrobial agent, were manufactured using a casting technique. Results indicated that elongation at break decreased as DIE was added at higher concentrations. Composite films showed no significant differences in thickness, tensile strength, and water vapor permeability. Scanning electron microscopy images revealed that DIE was successfully incorporated into film matrices to interact with polymers. The addition of DIE to the film inhibited the growth of S. aureus by up to 4.9 log CFU/mL. The inhibitory effect on S. aureus using DIE-incorporated coating applied to strawberries was greatest at room temperature storage for 24 h only when it was coated twice or more. The maximum inhibition in strawberries was 2.5 log CFU/g when they were coated twice and 3.2 log CFU/g when they were coated three times. The results of this study suggest that DIE could be used as a natural antimicrobial agent, and DIE-integrated CTS/GEL/PVA films or coatings have potential as a food packaging alternative for preventing foodborne pathogen contamination.

Trade secrets can encompass all forms of intellectual property subject matter, as well as other types of data, information, and knowledge that may not meet the threshold of eligibility for intellectual property rights. Trade secret protection may be used to prolong existing exclusivity or to hedge the balance of interests that the law aims to seek through restrictions to such exclusivity. Against this backdrop, this chapter asks whether, and to what extent, the law of trade secrets can be used privately to create a regime of property rules in an age of digitised trading, using the recently adopted EU Directive on trade secrets as an example. It asks whether the forms of protection and enforcement required under the EU Directive make it a de facto property right, hedging a liability regime into a proprietary regime, which is created unilaterally by ensuring secrecy and by imposing a duty of confidence.

The purpose of this study was to investigate the genetic effects of ADCY9 on ritodrine responses in patients with preterm labor. Five single nucleotide polymorphisms (SNPs) of the ADYC9 gene in 163 patients in preterm labor were genotyped: rs879619, rs2601796, rs2531988, rs2531995, and rs2230739. Additionally, rs598961 of the PDE4B gene and rs1042719 of the ADRB2 gene were included for analysis. Patients with CC genotype of ADCY9 rs879619 had a 2.0-fold (95% confidence interval [CI]: 1.3, 3.2) higher hazard of time to delivery than T allele carriers. Patients with combined genotypes of CC in ADCY9 rs879619, AA in PDE4B rs598961, and GC, CC in ADRB2 rs1042719 showed a greater hazard of time to delivery than patients with other combinations (adjusted hazard ratio [AHR] 3.2, 95% CI: 1.7, 6.3), whereas patients carrying the C allele of ADCY9 rs2531995, G allele of PDE4B rs598961, and GG genotype of ADRB2 rs1042719 had a lower hazard of time to delivery than patients carrying other genotypes (AHR 0.4, 95% CI: 0.2, 0.7). Regarding ritodrine-induced adverse drug events (ADEs), height less than 160 cm and CC genotype of ADCY9 rs2531995 showed a greater risk of ADEs. The results of our study suggest that ADCY9 polymorphisms could affect the efficacy and safety of β2-adrenergic agonists.

Paired box protein 5 (Pax5) is a crucial transcription factor responsible for B-cell lineage specification and commitment. In this study, we identified a negative role of Pax5 in osteoclastogenesis. The expression of Pax5 was time-dependently downregulated by receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) stimulation in osteoclastogenesis. Osteoclast (OC) differentiation and bone resorption were inhibited (68.9% and 48% reductions, respectively) by forced expression of Pax5 in OC lineage cells. Pax5 led to the induction of antiosteoclastogenic factors through downregulation of B lymphocyte-induced maturation protein 1 (Blimp1). To examine the negative role of Pax5 in vivo, we generated Pax5 transgenic (Pax5Tg) mice expressing the human Pax5 transgene under the control of the tartrate-resistant acid phosphatase (TRAP) promoter, which is expressed mainly in OC lineage cells. OC differentiation and bone resorption were inhibited (54.2–76.9% and 24.0–26.2% reductions, respectively) in Pax5Tg mice, thereby contributing to the osteopetrotic-like bone phenotype characterized by increased bone mineral density (13.0–13.6% higher), trabecular bone volume fraction (32.5–38.1% higher), trabecular thickness (8.4–9.0% higher), and trabecular number (25.5–26.7% higher) and decreased trabecular spacing (9.3–10.4% lower) compared to wild-type control mice. Furthermore, the number of OCs was decreased (48.8–65.3% reduction) in Pax5Tg mice. These findings indicate that Pax5 plays a negative role in OC lineage specification and commitment through Blimp1 downregulation. Thus, our data suggest that the Pax5–Blimp1 axis is crucial for the regulation of RANKL-induced osteoclastogenesis.

Bacillus cereus is a foodborne pathogen and cause a frequent problem due to the biofilms forming in equipment of food production plants. Autoinducer-2 (AI-2) involved in interspecies communication, plays a role in the biofilm formation of B. cereus. In this study, biofilm formation by thirty-nine B. cereus strains isolated from foods produced in Korea was determined. To investigate the effect of AI-2 on biofilm formation by B. cereus SBC27, which had the highest biofilm-forming ability, biofilm densities formed after addition of the AI-2 from Staphylococcus aureus and Escherichia coli were analysed. As a result, it was found that the quorum sensing molecule AI-2 could induce biofilm formation by B. cereus within 24 h, but it may also inhibit biofilm formation when more AI-2 is added after 24 h. Thus, these results improve our understanding of biofilm formation by food-derived B. cereus and provide clues that could help to reduce the impact of biofilms, the biggest problem in food processing environments, which has an impact on public health as well as the economy.

Sol-gel-based mesopores allow the entry of target small molecules retained in their cavity and aptamers to bind to target molecules. Herein, sol-gel-based materials are applied to screen-selective aptamers for small molecules, such as pesticides. To enhance the efficiency of aptamer screening using a sol-gel, it is necessary to increase the binding surface. In this study, we applied the sol-gel to an anodized aluminum oxide (AAO) membrane, and the morphological features were observed via electron microscopy after spin coating. The binding and elution processes were conducted and confirmed by fluorescence microscopy and polymerase chain reaction. The sol-gel coating on the AAO membrane formed a hollow nanocolumn structure. A diazinon-binding aptamer was bound to the diazinon-containing sol-gel-coated AAO membrane, and the bound aptamer was effectively retrieved from the sol-gel matrix by thermal elution. As a proof of concept, a sol-gel-coated AAO disc was mounted on the edge of a pipette tip, and the feasibility of the prepared platform for the systematic evolution of ligands by exponential enrichment (SELEX) of the aptamer binding was also confirmed. The proposed approach will be applied to an automated SELEX cycle using an automated dispenser, such as a pipetting robot, in the near future.

Personalised medicine is a new and developing field that carries a great potential for future healthcare applications, for prediction, diagnostic and treatment. Personalised medicine allows targeted treatment of different subgroups of patients, making it possible to tailor the treatment to the best-responding patients, while avoiding non-responders or patients that are likely to suffer adverse effects. Data is crucial in the research for personalised medicine as the interesting potential for the clinical use of personalised medicine may become hampered by absence of reliable large data sets. Conclusive evidence on relevant information of molecular mechanisms is not readily available, as most data often comes from inconclusive and relatively small studies of insufficient quality. Once collected, it is claimed that biomedical data becomes often fragmented, as there are numerous IP claims including both patents and trade secret, as well as the reluctance among the researchers in sharing data. Fragmentation in biomedical data is further exasperated by complex legal, moral and ethical questions surrounding biomedical data. While the need to share personal and private genetic information to advance research and industrial development is acknowledged, there are fundamental moral and ethical questions stemming from the general discomfort against exclusive control of an individual rights’ holder over genetic information. As rights overlap, restriction in one right affects access in other right in personalised medicine. Arguably, the recent move by the US courts to strictly regulate the patentability of diagnostic tools in biomedicine to address the problem of the individual rights holder pushed the shift in protection as trade secrets. Moral and ethical questions become even more controversial where machine learning algorithm (AI artificial intelligence) is used in the personalised medicine. AIs and machine learning algorithms are used to discover genes and variants related to specific decisions, to handle next generation sequencing so that they can be analysed in the full context of other genomics and clinical information to drive personalised medicine research. Not only the data sets, the selection of the correct machine algorithms is crucial in their use in personalised medicines. When AIs routinely processes private medical data, to make sure such algorithm based decision making is morally unbiased and ethically correct, the disclosure of the algorithm may be necessary. However, restricting patenting of algorithms for fear of depriving basic research tools from the public, simultaneously creates incentive to protect these algorithms as trade secret. This chapter explores this conundrum of patent and trade secret trade off in the context of AIs used in personalised medicine. Among others, the chapter discusses how these questions are addressed in the current EU law at the interface of GDPR, trade secret directive and biotechnology Directive. The combination of development in the technological sectors – use of AIs in biomedicines and legal changes – restrictive patent eligibility, genetic privacy and expansive trade secret protection could lead to an under-use of valuable biomedical data, which may result in a new type of tragedy of anti-commons. The paper concludes by revisiting the function of patent right and suggests that it may be necessary to introduce additional regulatory measures to mandate ethical disclosure of algorithm for public policy.

The antimicrobial resistance of food-borne pathogenic bacteria, including Vibrio parahaemolyticus, has been reported globally, warranting the need to identify promising alternative antibiotics such as endolysins that originate from bacteriophages. In our previous study, we characterized a bacteriophage infecting V. parahaemolyticus, vB_VpaP_KF2, at the molecular level. In this study, an open reading frame encoding putative endolysin was cloned from the complete genome data and expressed in the Escherichia coli expression system. The recombinant endolysin, vB_VpaP_KF2_Lys, exhibited a novel lytic property against Gram-negative bacteria regardless of pretreatment with an outer-membrane permeabilizer. It was also stable over a wide range of temperatures, pH, and NaCl concentrations, and its hydrolytic spectrum was broader than that of the parent bacteriophage. From the results, vB_VpaP_KF2_Lys could be used as a biocontrol agent against food-borne pathogens in the field of food safety.

Organophosphorus nerve agents (OPNAs), including both G- and V-type nerve agents such as sarin, soman, tabun and VX, are extremely neurotoxic organophosphorus compounds. Catalytic bioscavengers capable of hydrolyzing OPNAs are under development because of the low protective effects and adverse side effects of chemical antidotes to OPNA poisoning. However, these bioscavengers have certain limitations for practical application, including low catalytic activity and narrow specificity. In this study, we generated a fusion-hybrid form of engineered recombinant human paraoxonase 1 (rePON1) and bacterial organophosphorus hydrolase (OPH), referred to as GV-hybrids, using a flexible linker to develop more promising catalytic bioscavengers against a broad range of OPNAs. These GV-hybrids were able to synergistically hydrolyze both G-type OPNA analogs (paraoxon: 1.7 ~ 193.7-fold, p-nitrophenyl diphenyl phosphate (PNPDPP): 2.3 ~ 33.0-fold and diisopropyl fluorophosphates (DFP): 1.4 ~ 22.8-fold) and V-type OPNA analogs (demeton-Smethyl (DSM): 1.9 ~ 34.6-fold and malathion: 1.1 ~ 4.2-fold above) better than their individual enzyme forms. Among the GV-hybrid clones, the GV7 clone showed remarkable improvements in the catalytic activity toward both G-type OPNA analogs (kcat/Km (106 M-1 min-1): 59.8 ± 0.06 (paraoxon), 5.2 ± 0.02 (PNPDPP) and 47.0 ± 6.0 (DFP)) and V-type OPNA analogs (kcat/Km (M-1 min-1): 504.3 ± 48.5 (DSM) and 1324.0 ± 47.5 (malathion)). In conclusion, we developed GV-hybrid forms of rePON1 and bacterial OPH mutants as effective and suitable catalytic bioscavengers to hydrolyze a broad range of OPNA analogs.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus and cutaneous dry skin. Here, we investigated whether topical application of NI-01 composed of six herbal medicines has a therapeutic effect on AD in vivo. Twelve marker compounds of NI-01 were analyzed by high-performance liquid chromatography with a photodiode array detector for quality control. To induce AD, house dust mite extract was applied to the shaved dorsal skin and ear surfaces of NC/Nga mice twice a week for 6 weeks. NI-01 (1, 2, or 4 mg/mouse) was applied daily to the site for experiment periods. The coefficient of determination of each compound showed good linearity (&ge, 0.9999). The recovery rate of the 12 marker components was 96.77%&ndash, 105.17%, intra and interday precision and repeatability were &le, 1.40%. Topical application of NI-01 reduced house dust mite induced AD symptoms. The increased expressions of interleukin-4 and intercellular adhesion molecule-1 caused by house dust mites were markedly suppressed in NI-01-treated mice. Corticosterone levels significantly decreased, whereas serotonin levels increased with NI-01 application. These results suggest that NI-01 alleviates AD symptoms by inhibiting infiltration of inflammatory cells, thereby decreasing AD-related stress. NI-01 could be beneficial for the treatment of AD-like skin diseases.

N-acetyltransferase 2 (NAT2) acetylator status can be classified into three groups depending on the number of rapid alleles (e.g., NAT2*4): rapid, intermediate, and slow acetylators. Such acetylator status may influence the occurrence of adverse drug reactions (ADRs) during sulfasalazine treatment. This systematic review and meta-analysis aimed to evaluate the association between NAT2 acetylator status and ADRs of sulfasalazine. We searched for qualified studies in PubMed, Web of Science, Embase, and the Cochrane Library. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 acetylator status and ADRs of sulfasalazine. Nine cohort studies involving 1,077 patients were included in the meta-analysis. NAT2 slow acetylators were associated with an increase in overall ADRs (OR 3.37, 95% CI: 1.43 to 7.93; p = 0.005), discontinuation due to overall ADRs (OR 2.89, 95% CI: 1.72 to 4.86; p p NAT2 slow acetylators are at risk of ADRs during sulfasalazine treatment. Based on our findings, NAT2 genotyping may be useful to predict the occurrence of ADRs during sulfasalazine treatment.

Although many earlier studies revealed an effect of glutathione-S-transferase (GST) gene polymorphisms on tyrosine kinase inhibitor (TKI) treatment responses in chronic myeloid leukemia (CML) patients, the significance of this relationship remains controversial. This study aimed to review and meta-analyze treatment responses to TKIs in patients with CML and GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1. We searched four medical databases, PubMed, Web of Science, the Cochrane Library, and Embase, by using keywords related to GST gene polymorphisms and clinical responses in CML patients receiving TKI treatment. The meta-analysis was performed using RevMan version 5.3 and Comprehensive Meta-Analysis software version 3.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association between GSTT1, GSTM1, and GSTP1 polymorphisms and TKI treatment responses in patients with CML. The null polymorphisms of GSTT1 and GSTM1 did not affect TKI treatment responses, while the GSTP1 Ile105Val polymorphism had a significant impact on responses to TKI. Patients who were GSTP1 variant allele carriers (AG + GG) had poor responses to TKI treatment compared to patients who were wild-type homozygote carriers (AA) (OR 1.85, 95% CI 1.31–2.62; p

Aim We performed a systematic review and meta-analysis to compare the efficacy and safety of ticagrelor and prasugrel with those of clopidogrel in CYP2C19 reduced-metabolizers. Methods PubMed, Cochrane and Web of Science were systematically searched for randomized controlled trials or cohort studies up to January 2020. The primary endpoint was major adverse cardiovascular events (MACE), including cardiovascular (CV) death, all-cause death, myocardial infarction (MI), stent thrombosis and stroke. The secondary endpoint was bleeding. Pooled effects were measured by relative risk (RR) with 95% confidence intervals (CIs). Publication bias was evaluated with Egger's regression test and adjusted by trim and fill method. Results Twelve studies comprising 5829 CV patients with CYP2C19 loss-of-function alleles were included. Patients who received ticagrelor or prasugrel showed a lower risk of MACE than those who received clopidogrel (RR 0.524; 95% CI: 0.375, 0.731). The former also had lower risks of CV death (RR 0.409; 95% CI: 0.177, 0.946), all-cause death (RR 0.441; 95% CI: 0.263, 0.739), MI (RR 0.554; 95% CI: 0.414, 0.741) and stent thrombosis (RR 0.587; 95% CI: 0.348, 0.988) than the latter patient group. The risk of stroke was not significantly different between patients receiving the alternatives and those receiving clopidogrel (RR 0.605; 95% CI: 0.257, 1.425). Major and minor bleeding risk was not significantly different between patients treated with alternatives and clopidogrel (RR 1.019; 95% CI: 0.827, 1.260 and RR 1.235; 95% CI: 0.581, 2.628, respectively). Conclusion CYP2C19 reduced-metabolizers can expect better clinical outcome on using prasugrel or ticagrelor rather than clopidogrel.

This systematic review and meta-analysis aimed to evaluate the impact of COVID-19 on pregnant women. We searched for qualified studies in PubMed, Embase, and Web of Science. The clinical characteristics of pregnant women with COVID-19 and their infants were reported as means and proportions with 95% confidence interval (CI). Nine studies involving with 93 pregnant women with COVID-19 and 103 infants were included in the meta-analysis. Pregnant women with COVID-19 have relatively mild symptoms. However, abnormal proportions of laboratory parameters were similar or even increased, compared to general population. Around 30% of pregnant women with COVID-19 experienced preterm delivery, whereas the mean birth weight was 3214.7g. Fetal death, severe neonatal asphyxia, and detection of SARS-CoV-2 were observed in about 2%, whereas no neonatal death was found. In conclusion, the current review will serve as an ideal basis for future considerations in the treatment and management of COVID-19 in pregnant women.

Do inventors have moral rights and does morality matter in patent law? Whilst morality provides a normative justification for property as a right having an erga omnes effect, moral rights of the property owner does not exist a priori. In contrast as property right imposes a duty of abstention, morality may justify such duty. As a specie of property right, intellectual property necessarily includes a dimension of morality implied as restriction. Moreover, as intellectual property includes inalienable, personal mental inputs of the creator and inventors into the abstract objects, moral interests of the creators and inventor also justifies the exclusive right. Despite the foundational significance, the moral interests of an inventor based on patent law is scarcely debated. In contrast to perennial discussion on the morality’s restriction of the patent grants and exercise of patent rights, the perception of patent as a moral right is not widely accepted, nor the expression, ‘moral right’ is found in positive patent law. The absence of academic discussion of moral right for inventors begs the question if morality means and should mean different value in patents than copyright, and if indeed there is no ‘moral interests’ that are protected or should be protected for inventors. The chapter aims to answer this by first conceptualizing morality generally in patent law, and then identify areas where it may be expressed as a right in the European Patent Convention (EPC). Finally, the paper explores one concrete aspect in the positive patent law where the moral interest of an inventor is indeed protected. Using the controversial decision on Broad Institute’s European patent application based on gene-editing invention, CRIPSR, as a case study, this paper illustrates how moral right of an inventor exists and how it may be used as a positive right, which may control the use of the invention, although limited in its scope. As the current right is limited in scope, a cautious normative claim calling for extending a moral right based defence to the inventor is made, as it would imbue fairness into the discussion patent law and ameliorate individual inventor’s position in an increasingly corporate owner-centric patent system.

At the end of 2014, China introduced new specialist intellectual property (IP) courts. Although China had IP tribunals within the People’s Courts, the reform to establish separate IP courts was touted as a significant step in establishing the rule of law in the governance of IPRs in China. This is not surprising considering that an independent judiciary is central to the rule of law. This institution affirms and enforces private rights, as well as providing necessary impartiality in the process of decision-making among peer institutions. China has recently undergone several legislative reforms which amend substantive IP law. It is not surprising that this was followed by both administrative and judicial reforms. Introducing a specialized court with exclusive jurisdiction will likely affect other institutions with similar competences, e.g. general courts or administrative tribunals. Institutional choices significantly affect the outcome of decision-making because the processes of decision-making differ and will involve different stakeholders. Often, institutions move together and a change in one of them is likely to cause a change in another, even without explicit efforts to effect such changes. Therefore, any institutional reform project needs to reflect measures to contain or coordinate unintended consequences or impacts on other institutions resulting from such changes. This paper places Chinese specialized courts in a global context. We will first describe the function of a specialized IP court from a comparative institutional perspective. Next, we place the Chinese specialized IP courts in the context of the national administration-driven IP strategy to highlight the Chinese characteristics. In its analysis, this paper explores whether the perspective of institutional comparison may be applied to Chinese institutional reforms. It also argues that the rationale for introducing specialized IP courts in China may be more than merely improving technological competence and concentration of expertise of the court; it signals a step towards independent judicial decision-making, towards the establishment of the rule of law and market-oriented decision-making.

A linear code with a complementary dual (or LCD code) is defined to be a linear code $C$ whose dual code $C^{\perp}$ satisfies $C \cap C^{\perp}$= $\left\{ \mathbf{0}\right\} $. Let $LCD{[}n,k{]}$ denote the maximum of possible values of $d$ among $[n,k,d]$ binary LCD codes. We give exact values of $LCD{[}n,k{]}$ for $1 \le k \le n \le 12$. We also show that $LCD[n,n-i]=2$ for any $i\geq2$ and $n\geq2^{i}$. Furthermore, we show that $LCD[n,k]\leq LCD[n,k-1]$ for $k$ odd and $LCD[n,k]\leq LCD[n,k-2]$ for $k$ even., Comment: 9 pages, 2 tables

Many pesticides and chemical warfare nerve agents are highly toxic organophosphorus compounds (OPs), which inhibit acetylcholinesterase activity. Human paraoxonase 1 (PON1) has demonstrated significant potential for use as a catalytic bioscavenger capable of hydrolyzing a broad range of OPs. However, there are several limitations to the use of human PON1 as a catalytic bioscavenger, including the relatively difficult purification of PON1 from human plasma and its dependence on the presence of hydrophobic binding partners to maintain stability. Therefore, research efforts to efficiently produce recombinant human PON1 are necessary. In this study, we developed a Drosophila S2 stable cell line expressing recombinant human PON1. The recombinant human PON1 was fused with the human immunoglobulin Fc domain (PON1-hFc) to improve protein stability and purification efficiency. We purified the recombinant human PON1-hFc from the S2 stable cell line and characterized its enzymatic properties for OP hydrolysis. We purified the recombinant human PON1-hFc from the S2 stable cell line and characterized its enzymatic properties for OP hydrolysis compared with those of the recombinant human PON1 derived from E. coli . We observed that the recombinant human PON1-hFc is functionally more stable for OP hydrolyzing activities compared to the recombinant human PON1. The catalytic efficiency of the recombinant PON1-hFc towards diisopropyl fluorophosphate (DFP, 0.26 × 10 6 M −1 min −1 ) and paraoxon hydrolysis (0.015 × 10 6 M −1 min −1 ) was 1.63- and 1.24-fold higher, respectively, than the recombinant human PON1. Thus, we report that the recombinant PON1-hFc exerts hydrolytic activity against paraoxon and DFP.

7,8-dimethoxycoumarin (DMC, C11H10O4), a natural coumarin compound, is present in Citrus plants including Citrus decumana and grapefruit. It is known to have protective effects on the kidneys against Cisplatin and ischemia-reperfusion injury. However, the underlying mechanisms of its inhibitory effects on skin inflammation have not been investigated in vitro. Tumor necrosis factor (TNF)-&alpha, is known to be one of the main causative agents of skin inflammation. It induces pro-inflammatory cytokines and chemokines by activating nuclear factor-&kappa, B (NF-&kappa, B) and mitogen-activated protein kinase (MAPK) signaling. In this study, we investigated the inhibitory effect of DMC on the expression of pro-inflammatory cytokines and chemokines in TNF-&alpha, treated human keratinocyte HaCaT cells. Pretreatment with DMC inhibited TNF-&alpha, treated cytokines (interleukin 6, IL-6) and chemokines (IL-8 and monocyte chemoattractant protein-1). In addition, DMC significantly inhibited TNF-&alpha, treated NF-&kappa, B activation and phosphorylation of MAPKs, such as c-Jun N-terminal kinases (JNK) and extracellular-signal-regulated kinase (ERK). These results suggest that DMC may elicit an anti-inflammatory response by suppressing TNF-&alpha, treated activation of NF-&kappa, B and MAPK pathways in keratinocytes. Hence, it might be a useful therapeutic drug against skin inflammatory diseases.