Development of Two Korean IACUC Guidance Documents to Foster Implementation of the Three Rs.

In Korea, Institutional Animal Care and Use Committees (IACUCs) have been legally required to apply the Three Rs principles (i.e. replacement, reduction and refinement) and undertake the ethical review of animal study protocols, since 2008. According to Korean law, each IACUC is required to appoint at least one lay member recommended by a non-governmental animal protection organisation, who participates in the ethical review process as part of this role. Despite the importance of the Three Rs and the ethical review process, limited information and practical resources are available for IACUC members in the Korean language, particularly for lay members who are inexperienced in animal experimentation. In January 2020, the Animal and Plant Quarantine Agency announced the funding for a six-month research project to develop guidance to assist IACUC members in carrying out effective and efficient protocol reviews in line with Korean legislative requirements. This funding was awarded for the production of two IACUC guidance documents - 'Guide for Animal Study Protocols' and 'Guide for the IACUC Lay Member' - which were published in December 2020. These guidance documents aim to foster the implementation of the Three Rs and provide practical resources for IACUC members, researchers and other relevant personnel. This paper describes the framework for animal use in Korea and the overall production of these two IACUC Guidance Documents.

Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease.

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

Effect of flanged diffuser divergence angle on wind turbine: A numerical investigation.

Power augmentation in a small-scale horizontal axis wind turbine, with its rotor encased in a flanged diffuser is explored. The power output of the wind turbine varies with changes in the diffuser design and the resulting back pressure. Reduction in this back pressure also results in early flow separation at the diffuser surface, which hinders turbine performance. The main aim of this study is to numerically investigate the local configuration of the wind turbine location inside the diffuser by varying diffuser angles and wind speeds. Therefore, shroud and flange were modeled and analyzed using the computational fluid dynamic (CFD) analyses and experiments were performed at two wind speeds 6 m/s and 8 m/s with and without the diffuser for model validation. The divergence angle of 4° was found to have no flow separation, thus maximizing flow rate. The proposed design shows wind speed improvement of up to 1.68 times compared to the baseline configuration. The corresponding optimum flange height was found to be 250 mm. However, increasing the divergence angle had a similar output. The dimensionless location of wind turbine was found to be between 0.45 and 0.5 for 2° and 4° divergence angle respectively. Furthermore, the maximum augmentation location varies with wind speed and diffuser's divergence angle as described by dimensionless location of wind turbine, thus presenting a noteworthy contribution to the horizontal axis wind turbine area with the flanged diffuser.

Analysis of Particle Size and Concentration in Die Sinking Electric Discharge Machining.

Electric discharge machining with a powder mix dielectric is a promising technique to harden a work piece's surface using electricity with a high energy density. The quality of the electrical discharge-machined surface is related to its surface integrity in which the surface's roughness, residual stresses, micro hardness and surface micro cracks are some of the major factors. In this research, graphite powder was mixed in a dielectric with a particle size of 20 µm, 30 µm, and 40 µm, with the concentration of the graphite powder ranging from 2 g/L to 4 g/L. Moreover, the peak current and pulse time on were also coupled with an additive of graphite powder to investigate the effect on the surface quality, i.e., the recast layer thickness, micro hardness and crater depth as well as the material removal rate (MRR) and tool wear rate (TWR). A Box-Behnken design was employed to design the experiments and the experimental results revealed that the graphite powder size and concentration coupled with the electrical parameters (peak current and pulse time on) significantly influenced the recast layer thickness, micro hardness, crater size, MRR and TWR. The crater depth and micro hardness were maximized at a higher concentration and particle size, while the recast layer thickness was reduced with a higher gain size.

Improving Cyclability of All-Solid-State Batteries via Stabilized Electrolyte-Electrode Interface with Additive in Poly(propylene carbonate) Based Solid Electrolyte.

In this study, tetraethylene glycol dimethyl ether (TEGDME) is demonstrated as an effective additive in poly(propylene carbonate) (PPC) polymers for the enhancement of ionic conductivity and interfacial stability and a tissue membrane is used as a backbone to maintain the mechanical strength of the solid polymer electrolytes (SPEs). TEGDME in the PPC allows the uniform distribution of conductive LiF species throughout the cathode electrolyte interface (CEI) layer which plays a critically important role in the formation of a stable and efficient CEI. In addition, the high modulus of SPEs suppresses the formation of a protrusion-type CEI on the cathode. The SPE with the optimized TEGDME content exhibits a high ionic conductivity of 0.89 mS cm-1 , an adequate potential stability of up to 4.89 V, and a high Li-ion transference number of 0.81 at 60 °C. Moreover, the Li/SPE/Li cell demonstrates excellent cycling stability for 1650 h, and the Li/SPE/LFP full cell exhibits an initial reversible capacity of 103 mAh g-1 and improved stability over 500 cycles at a rate of 1 C. The TEGDME additive improves the electrochemical properties of the SPEs and promotes the creation of a stable interface, which is crucial for ASSLIBs.

Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer.

Microtubules are one of the major targets for anticancer drugs because of their role in cell proliferation and migration. However, as anticancer drugs targeting microtubules have side effects, including the death of normal cells, it is necessary to develop anticancer agents that can target microtubules by specifically acting on cancer cells only. In this study, we identified chemicals that can act as anticancer agents by specifically binding to acetylated microtubules, which are predominant in triple-negative breast cancer (TNBC). The chemical compounds disrupted acetylated microtubule lattices by interfering with microtubule access to alpha-tubulin acetyltransferase 1 (αTAT1), a major acetyltransferase of microtubules, resulting in the increased apoptotic cell death of MDA-MB-231 cells (a TNBC cell line) compared with other cells, such as MCF-10A and MCF-7, which lack microtubule acetylation. Moreover, mouse xenograft experiments showed that treatment with the chemical compounds markedly reduced tumor growth progression. Taken together, the newly identified chemical compounds can be selective for acetylated microtubules and act as potential therapeutic agents against microtubule acetylation enrichment in TNBC.

Promoting and improving three Rs practice: the Korean guidelines.

Scientists planning research that involves the use of animals are required to examine the possibilities for replacement, reduction, or refinement (the Three Rs), and their protocol must be reviewed by the Institutional Animal Care and Use Committee. Good scientific practice involving appropriate search techniques on the available Three Rs resources is essential for both ethical and scientific reasons. Appropriate experimental design and statistical analysis techniques are particularly necessary for research involving the use of animals, because this can improve animal welfare and scientific outcomes, as well as saving animal lives. There are a number of resources to help researchers improve their search techniques, experimental design strategies, and their reporting of research involving the use of animals. However, there is little specific information or resources on the Three Rs alternatives that is readily available in the Korean language. This paper outlines the common errors made by submitting researchers that have been repeatedly observed during the ethical review of experimental protocols over the last ten years, and provides information on the Korean resources available to promote good scientific practice. This could help to bridge the gap between Korean scientists and animal welfare advocates assisting scientists to improve ethical considerations and conduct responsible research. [BMB Reports 2017; 50(12): 610-614].

Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes.

We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM against human and mouse DGAT1, also good druggability as well as microsomal stability and safety profiles such as hERG, CYP and cytotoxicity. Compound 43c significantly reduced plasma triglyceride levels in vivo (in rodents and zebrafish) and also showed bodyweight gain reduction and glucose area under curve (AUC) lowering efficacy in diet-induced obesity (DIO) mice.

A comparison of temperature profile depending on skin types for laser hair removal therapy.

Although numerous lasers with different wavelengths are available for laser hair removal, their use in individuals with dark-pigmented skin remains a challenge. The present study aims to develop a numerical heat diffusion model considering skin types over various wavelengths. This numerical mode uses Pennes approximation to represent heat from metabolism, blood perfusion and an external heating source. The heat diffusion model is experimentally validated by using agar-based skin tissue phantoms. Diode lasers with four different wavelengths were used with two antithetical skin models. The pulse width and beam spot size were set to 200 ms and 1 cm(2), respectively. Temperature distribution along the hair structure and skin tissue was examined to determine both thermal confinement and heat transfer to the hair follicle. Experimental results are well matched with the numerical results. The results show that for the light skin model, thermal confinement is well achieved over various wavelengths, and treatment efficacy is expected to be better at a shorter wavelength. Otherwise, for the dark skin model, thermal confinement is poorly achieved as the wavelength decreases (<808 nm) and the temperature gap between the hair tip and the hair root is significantly large compared with the light skin model, which may lead to adverse effects. We believe that the developed numerical model will help to establish optimal laser parameters for different individuals during laser hair removal.

Individual and collective responsibility to enhance regulatory compliance of the Three Rs.

Investigators planning to use animals in their research and the Institutional Animal Care and Use Committee (IACUC) members who review the research protocols must take personal responsibility for ensuring that they have the skills and knowledge to perform their duties, applying the Three Rs principles of Russell and Burch. The two Korean laws introduced in 2008 and 2009 regulating animal use for scientific purposes in line with the Three Rs principles have been revised a total of 11 times over the last 6 years. Both regulatory agencies, e.g., the Animal and Plant Quarantine Agency and the Ministry of Food and Drug Safety, provide regular training based on the legal requirements. Based on the amended Animal Welfare Act, the IACUC appointment framework has been upgraded: appointments are now for two-year terms and require a qualified training certificate issued by the Animal and Plant Quarantine Agency since 2012. The authors reviewed the current curricular programs and types of training conducted by the two governing agencies through Internet searches. Our Internet survey results suggest that: a) diversity should be provided in training curricula, based on the roles, backgrounds and needs of the individual trainees; b) proper and continued educational programs should be provided, based on trainees' experiences; and c) active encouragement by government authorities can improve the quality of training curricula.

Searching and review on the Three Rs information in Korea: time for quality assessment and continued education.

Scientists planning research that involves the use of animals are required by international and/or national law to examine the possibilities for the implementation of Replacement, Reduction and/or Refinement (the Three Rs principles of Russell and Burch) in experiments for research, testing, and education. There are two Korean laws legislating humane use of animals and ethical review prior to animal experiments. This report reviews current practice of the literature search by the researchers and protocol review by the Institutional Animal Care and Use Committees on the Replacement, Reduction and Refinement alternatives in Korea. The promotion and protection of the laboratory animals are one of the core competencies of investigators exploring the ethical conduct of research and good science.

Progress in promoting the Three Rs in Korea: efficiency and consistency.

The Korea National Information Center for the 3Rs was established in August 2011, to enhance humane science and animal welfare in Korea. It is a national Three Rs platform, with the goal of exchanging knowledge and sharing examples of best practice, in order to help replace laboratory animal use in education and training. This paper briefly summarises the progress made and the challenges that have become apparent during the initial operation of the collaborative project. There is a need to recognise and manage the challenges resulting from policy changes, especially misinterpretation of the objectives by the decision makers at the participating academic institutions and the government. The collective power of this type of collaborative project can be used to leverage an ongoing commitment to essentials such as consistent funding for operational and support staff, as well as allocation of the required space.

The current status of animal use and alternatives in Korean veterinary medical schools.

Two new Korean laws regulating animal welfare and the humane use of animals in science came into effect in 2008 and 2009. Both these laws impose ethical committee review prior to the performance of animal experiments in research, testing and education. This study briefly summarises the new Korean laws, and investigates the current status regarding the numbers of animals used, the alternatives to animals which are used, the curricula relating to the humane use of animals, and ethical review practices in Korean veterinary education. Approximately 4,845 animals, representing 20 different species, were used in veterinary medical education in Korea in 2007. Korea has begun to introduce formal courses on animal welfare for the humane treatment of animals used in experiments, and an ethical protocol review system prior to animal use in education. Korea is moving toward better animal welfare, by incorporating practices consistent with international standards. The information presented represents the first such data gathered in Korea, which should prove useful for monitoring the implementation of replacement, reduction, and refinement measures in animal use for education purposes.

An International Comparison of Female and Male Students' Attitudes to the Use of Animals.

Previous research has demonstrated that in households where the male partner is more dominant, there is convergence in male and female attitudes towards animals, whereas if the female partner is empowered they exhibit greater empathy towards animals than the male partner. We tested this theory of 'female empowered empathy' internationally in a survey of female and male students' attitudes towards use of animals, conducted in 11 Eurasian countries: China, Czech Republic, Great Britain, Iran, Ireland, South Korea, Macedonia, Norway, Serbia, Spain and Sweden. Gender empowerment was estimated for each country using the Gender Empowerment Measure designed by the United Nations. The survey was administered via the internet in universities within countries, and 1,902 female and 1,530 male student responses from 102 universities were received. Respondents rated the acceptability of 43 major concerns about human use of animals, and the importance of 13 world social issues, including animal protection, environmental protection and sustainable development. Females had greater concern for animal welfare and rights than males. There was a positive correlation between the Gender Empowerment Measure and the ratio of female to male concern for animal welfare and rights, but not for other world issues. Thus in countries where females were more empowered, principally Sweden, Norway and Great Britain, females had much greater concern than males for animal issues, whereas in other countries the responses of males and females were more similar. Across countries female students were more likely to avoid meat and less likely to avoid eggs, milk and seafood than male students, and were more likely to have kept pets than males. Females rated cats as more sentient than males did. The results demonstrate that females have greater concern for animal welfare and rights than males, and that this is more likely to be expressed in countries where females are relatively empowered, suggesting that 'emancipated female empathy' operates across countries as well as at a local level.

Antiplatelet activity of BRX-018, (6aS,cis)-malonic acid 3-acetoxy-6a9-bis-(2-methoxycarbonyl-acetoxy)-6,6a,7,11b-tetrahydro-indeno[2,1-c]chromen-10-yl ester methylester.

Brazilin (7,11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10 (6H)-tetrol), the major component of Caesalpinia sappan L., was reported to show antiplatelet activity through the inhibition of phospholipase A2 (PLA2) activity and the increase in intracellular free Ca2+ concentration ([Ca2+]i). To search more potential antiplatelet agent, brazilin derivatives were synthesized and examined for their effects on the platelet aggregation. Among those compounds, BRX-018, (6aS,cis)-Malonic acid 3-acetoxy-6a9-bis-(2-methoxycarbonyl-acetoxy)-6,6a,7,11b-tetrahydro-indeno[2,1-c]chromen-10-yl ester methylester, was confirmed as one of the potential antiplatelet agents. In the present study, we investigated the antiplatelet mechanism of BRX-018. BRX-018 inhibited the thrombin-, collagen-, and ADP-induced rat platelet aggregation in a concentration-dependent manner, with IC50 values of 35, 15, and 25 microM, respectively. BRX-018 also inhibited thrombin-induced dense granule secretion, thromboxane A2 (TXA2) synthesis, and [Ca2+]i elevation in platelets. BRX-018 was also found to inhibit A23187-induced [Ca2+]i and aggregation in the presence of apyrase (ADP scavenger) but not in the presence of both apyrase and indomethacin (a specific inhibitor of cyclooxygenase, COX). Although BRX-018 significantly inhibited arachidonic acid (AA)-induced aggregation and TXA2 synthesis, it had no significant inhibitory effect on cyclooxygenase activity in vitro. In contrast, BRX-018 inhibited the activity of purified PLA2. Dixon plot showed that this inhibition was mixed type with an inhibition constant of Ki=23 microM. Taken together, the present study suggests that BRX-018 may be a promising antiplatelet agent and that its antiplatelet activity may be based on the inhibitory mechanisms on TXA2 synthesis in stimulated platelets.

A Phase II Study with Gemcitabine and Carboplatin in Patients with Advanced Non-small Cell Lung Cancer.

PURPOSE: To evaluate the efficacy and safety of gemcitabine and carboplatin (GC) in the treatment of advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Between November 1999 and April 2001, 34 patients were enrolled in this study. The median age was 66 (range: 52-74) years old and all were male. Sixteen patients demonstrated stage IIIB, 15 stage IV, and 3 recurrence of disease after surgery. Twenty-two patients showed a ECOG performance status of 0 or 1 and 12 had 2. Twenty patients presented with squamous cell carcinoma, 11 adenocarcinoma and 3 unclassified NSCLC. The treatment regimen consisted of intravenous carboplatin AUC of 6 on day 1 and gemcitabine 1,250 mg/m2 on day 1 and 8. The treatment was repeated every 28 days. Toxicities were evaluated according to WHO toxicity criteria. RESULTS: All thirty-four patients were evaluable. Partia responses were observed in 15 patients. The overall response rate was 44% (95% confidence interval: 27-61%) and the median response duration was 26 (range 8-60 ) weeks. The median survival of all patients was 50 (range 8-70 ) weeks. During a total of 144 cycles, granulocytopenia greater than WHO grade 2 occurred in 2%, thrombocytopenia in 2%, and anemia in 3%, respectively. Non- hematologic toxicities were minor and easily controlled. CONCLUSION: A combination chemotherapy of intravenous gemcitabine and carboplatin has a relatively high activity with acceptable toxicities in patients with advanced NSCLC.