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Background Although urbanization is often an important topic in climate change studies, the complex effect of urbanization on heat vulnerability in urban and rural areas has rarely been studied. We investigated the disparate effects of urbanization on heat vulnerability in urban and rural areas, using nationwide data. Methods We collected daily weather data for all 229 administrative districts in South Korea (2011–17). Population density was applied as an urbanization indicator. We calculated the heat-mortality risk using a distributed lag nonlinear model and analysed the relationship with population density. We also examined district characteristics that can be related to the spatial heterogeneity in heat-mortality risk. Results We found a U-shaped association between population density and heat-mortality risk, with the highest risk for rural populations; in urban areas, risk increases with increasing population density. Higher heat-mortality risk was associated with a lower number of hospital beds per person and higher percentage of people requiring recuperation. The association between hospital beds and heat-mortality risk was prominent in high-density urban areas, whereas the association between the percentage of people requiring recuperation and heat-mortality risk was pronounced in rural areas. Conclusions Our findings indicate that the association between population density and heat-mortality risk is different in urban and rural areas, and that district characteristics related to heat-mortality risk also differ by urbanicity. These results can contribute to understanding the complex role of urbanization on heat vulnerability and can provide evidence to policy makers for prioritizing resources.

MHC genes are highly polymorphic as antigen presenting molecules for adaptive immune response in vertebrates. In this study, we evaluated the diversity of dog leukocyte antigen (DLA) class II genes among two Korean breeds, the Sapsaree and the Jindo, and three Chinese native breeds, Tibetan Mastiff, Pug, and Pekingese, and determined their genetic relationships. Sequence-based typing of DLA-DRB1 and DLA-DQB1 was performed in 138 dogs. We identified 27 alleles for DRB1 and 24 for DQB1, including five new alleles. DRB1*015:01 was shared among all five breeds and was a major allele for the Pug, Tibetan Mastiff, and Sapsaree. The observed heterozygosity for the five breeds ranged from 0.67 to 1.00 for DRB1 and from 0.80 to 1.00 for DQB1. A total of 40 DRB1-DQB1 haplotypes, including nine new haplotypes, were identified. Interestingly, most haplotypes (33/40, 82%) were specific to a single breed, and only seven were present in multiple breeds. Haplotype sharing analysis together with previously available data from 109 breeds revealed that compared to within region distances, Asian breeds were more distant than breeds from other regions. As a first report on the analysis of DLA genes of dog breeds in Korean peninsula, our results show that these breeds carry unique DLA class II haplotype lineages. Our results indicate that the diversity and breed specificity of DLA class II genes are much higher among East Asian breeds than among breeds from other regions.

Remediation of toxic chlorinated ethenes via microbial reductive dechlorination can lead to ethene formation; however, the process stalls in acidic groundwater, leading to the accumulation of carcinogenic vinyl chloride (VC). This study explored the feasibility of cometabolic VC degradation by moderately acidophilic methanotrophs. Two novel isolates, Methylomonas sp. strain JS1 and Methylocystis sp. strain MJC1, were obtained from distinct alpine peat bogs located in South Korea. Both isolates cometabolized VC with CH4 as the primary substrate under oxic conditions at pH at or below 5.5. VC cometabolism in axenic cultures occurred in the presence (10 μM) or absence (

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1–3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors. The development, characterization and phase I clinical testing of the RAF inhibitor belvarafenib in cancer and a new resistance mechanism mediated by ARAF mutations are described.

Currently, several methods are available for the isolation of bacterial DNA and RNA. However, the diversity and complexity of cell envelope structures limit their efficiency depending on the target bacterial species. In this study, we compared the differences in yield and integrity of RNA prepared from four gram-negative and six gram-positive bacterial species using bead-beating, bacteriolytic protein, and PMAP36-vortexing methods. Similarly, we also compared the efficiency of DNA extraction from Staphylococcus aureus. Physical disruption of bacterial cells showed versatility in breaking cells against all tested species; however, a decrease in the integrity of isolated DNA and RNA was observed. Among membranolytic proteins, PMAP36 showed the most promising results, in terms of both the yield and integrity of the prepared nucleic acids. Our results show that each method has inherent advantages and disadvantages depending on its application. Therefore, the characteristics of each method and target species should be considered before the extraction of bacterial DNA and RNA.

Studies on the pattern of heatwave mortality using nationwide data that include rural areas are limited. This study aimed to assess the risk of heatwave-related mortality and evaluate the health risk-based definition of heatwave. We collected data on daily temperature and mortality from 229 districts in South Korea in 2011&ndash, 2017. District-specific heatwave-related mortality risks were calculated using a distributed lag model. The estimates were pooled in the total areas and for each urban and rural area using meta-regression. In the total areas, the threshold point of heatwave mortality risk was estimated at the 93rd percentile of temperature, and it was lower in urban areas than in rural areas (92nd percentile vs. 95th percentile). The maximum risk of heatwave-related mortality in the total area was 1.11 (95% CI: 1.01&ndash, 1.22), and it was slightly greater in rural areas than in the urban areas (RR: 1.23, 95% CI: 0.99&ndash, 1.53 vs. RR: 1.10, 95% CI: 1.01&ndash, 1.20). The results differ by age- and cause-specific deaths. In conclusion, the patterns of heatwave-related mortality risk vary by area and sub-population in Korea. Thus, more target-specific heatwave definitions and action plans should be established according to different areas and populations.

1. The purpose of this study was to investigate the involvement of rat Mrp2 and human MRP2 in benzylpenicillin transport using canalicular liver plasma membrane (cLPM) vesicles isolated from Sprague-Dawley or Easai hyperbilirubinemic (EHBR) rats, and MDCKII cells overexpressing MRP2. 2. The adenosine triphosphate (ATP)-dependent uptake of benzylpenicillin and oestradiol-17beta-D-glucuronide (E(2)17betaG), a representative substrate for Mrp2, into EHBR-cLPM vesicles was decreased relative to that seen with control-cLPM vesicles, which may reflect the absence of Mrp2 in the EHBR. The ATP-dependent uptake of taurocholate, which is not a substrate for Mrp2, was similar in both control and EHBR-cLPM vesicles. The concentration dependence of ATP-dependent benzylpenicillin uptake was reflected in a K(m) of 44.0 microM and a V(max) of 508.4 pmol mg(-1) min(-1). Additional inhibition studies using E(2)17betaG and methotrexate as representative substrates for Mrp2/MRP2 demonstrated the involvement of rat Mrp2, but not human MRP2, in benzylpenicillin efflux. Benzylpenicillin appears not to be a substrate for or inhibitor of other human efflux transporters such as MDR1, MRP1, MRP3, or BCRP. 3. In conclusion, rat Mrp2, but not human MRP2, plays an important role in ATP-dependent benzylpenicillin uptake in the bile canalicular membrane, which may explain why biliary excretion of benzylpenicillin is high in the rat but negligible in humans.