Redirecting an Anticancer to an Antibacterial Hit Against Methicillin-Resistant Staphylococcus aureus

YM155 is a clinically evaluated anticancer with a fused naphthoquinone-imidazolium scaffold. In this study, we demonstrated that based on weak or cryptic antibacterial activity of YM155 against methicillin-resistant Staphylococcus aureus (MRSA) (MIC of 50 μg/ml), some congeneric compounds with short alkyl chains (e.g., c5 with a hexyl chain) at the N3 position of the scaffold, displayed more potent antibacterial activity against MRSA (MIC of 3.13 μg/ml), which is in a clinically achievable range. Their antibacterial activity was evident against Gram-negative bacteria, only in the presence of the outer membrane-permeabilizing agent, polymyxin B. The antibacterial efficacy of c5 was confirmed using the Drosophila systemic infection model. We also characterized five spontaneous c5-resistant MRSA mutants that carry mutations in the ubiE gene, for quinone metabolism and respiratory electron transfer, and subsequently exhibited reduced respiration activity. The antibacterial activity of c5 was compromised either by an antioxidant, N-acetylcysteine, or in an anaerobic condition. These suggest that the antibacterial mechanism of c5 involves the generation of reactive oxygen species (ROS), presumably during respiratory electron transport. This study provides an insight into “drug redirecting,” through a chemical modification, based on an ROS-generating pharmacophore

Autophagy pathway upregulation in a human iPSC-derived neuronal model of Cohen syndrome with VPS13B missense mutations

Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with autophagy in CS. Transcriptomic analysis focusing on the autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian ATG4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that autophagy is upregulated in CS neurons. The autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.This work was supported by National Research Foundation (NRF2017R1D1A3B03030972), the National Honor Scientist Program, the Korea Health Technology R&D Project (HI18C0158), and the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (2017M3A9G7073521) to J.-A L

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

The Different Contributors to Antioxidant Activity in Thermally Dried Flesh and Peel of Astringent Persimmon Fruit

In the thermal-drying processing of astringent persimmon fruit, the tissue-specific changes in the key antioxidants have hardly been investigated, while they have been well investigated in the flesh. We report here the different patterns of the antioxidant activities in the thermally processed flesh and peel of astringent persimmon, with analyses of the carotenoids, the condensed and hydrolysable tannins, and the total phenolics and flavonoids. The persimmon powders presented different colors on the basis of the drying temperatures: brown in 30 °C; light yellow in 60 °C; and dark brown in 90 °C, respectively. Non-maillard reaction and reduction of carotenoids caused the light-yellow color of 60 °C dried persimmon. Thermal drying reduced the antioxidant activities of the flesh in a temperature-dependent manner, with decreases in the carotenoids, the condensed and hydrolysable tannins, and the total phenolics and flavonoids, whereas it enhanced the antioxidant activities of the peel. The increase in the antioxidant activities in the peel were mainly the result of the increase in the total phenolics by the thermal effect, and especially in the content of the hydrolysable tannins, although the thermal processing decreased the other components. The heat-induced increase of antioxidant activity in the peel showed a strong significant correlation only with the contents of total phenolics (r2 = 0.9493) and total hydrolysable tannins (r2 = 0.9288), suggesting that the main antioxidant contributors differ from the flesh

2014 경제발전경험모듈화사업 : 마약청정국을 위한 우리나라의 정책수립 경험

Summary Chapter 1 Introduction 1. Introduction: Korean Government Efforts to Keep the Country Drug-Free 2. Change in the Environment and Threat Factor Chapter 2 Criminal Proceeds Confiscation System for Restriction of Narcotics Offenders 1. Background of the Legislation 2. Introduction of Criminal Proceeds Confiscation System 3. Meaning of Criminal Proceeds Confiscation System Chapter 3 Introduction and Operation Trends of Criminal Proceeds Confiscation System of Various Countries 1. Criminal Proceeds Confiscation System of Various Countries 2. Comparison of Criminal Proceeds Confiscation and Collection System of Various Countries Chapter 4 Enactment and Operation Status of 「Act on Special Cases Concerning the Confiscations of Criminal」 Proceeds 1. Enactment of the 「Act on Special Cases Concerning the Prevention of Illegal Trafficking in Narcotics, etc.」 2. Granting of Duty of Cooperation on Financial Institutions 3. Construction of Pan-National Narcotic Crime Response System 4. Creation of the Organization in Charge of Confiscation of Crime Profit Chapter 5 Factors for Successful Confiscation and Collection – Main Examples 1. Factors for Successful Confiscation and Collection 2. Confiscation and Collection of Proceeds from Smuggling and Trafficking of Methamphetamine [Case 1] 3. Large-Scale Arrest of Drug Substitute Traffickers [Case 2] 4. Confiscation of Illegal Profit and Property of Drug Crime [Case 3] 5. Confiscation and Collection of Methamphetamine Sales Profit [Case 4] 6. Problem and Improvement Plan for Deprivation of Narcotics Fund 7. Analysis of Performance of Criminal Proceeds Confiscation System in Korea Chapter 6 Suggestion for Establishment of Policy for Developing Countries 1. Active Securing of Means of Investigation 2. Alert of Investigation Expediency 3. Securing Professional Investigation Personnel and Fund Tracing Education 4. Relaxation of Saving Confidentiality Principle 5. Expansion of Obligation of Financial Institutions 6. Expansion of Role of Korea Financial Intelligence Unit (FIU) 7. Close Cooperative Investigation and Cooperation Relation References Appendice

Changes in Quercetin Derivatives and Antioxidant Activity in Marigold Petals (Tagetes patula L.) Induced by Ultraviolet-B Irradiation and Methyl Jasmonate

Marigold petals contain numerous antioxidative flavonoids and carotenoids that can be affected by environmental stressors. There is yet no detailed study on the relationship between phytochemical accumulation and stressors in marigold petals. This study evaluated quercetin derivatives and antioxidant activity in marigold petals in response to ultraviolet-B (UV-B) irradiation and methyl jasmonate (MeJA) treatment. The limiting UV-B radiation intensity and MeJA dose that caused no wilting damage under 1-h daily treatment for 10 days were <2 W∙m−2∙s−1 and <10 mM, respectively. Marigold petals contained three major flavonoids, quercetin-7-O-glucoside (Q7G, 6.6 mg∙g−1dw), quercetin-3-O-glucoside (Q3G, 62.7 mg), and quercetin (26.6 mg), possessing different antioxidant potential and exhibiting the highest power in quercetin and next value in Q7G. Single UV-B irradiation exerted a limited effect on the changes in the content of the three quercetin derivatives, whereas combined treatment with 1 W UV-B radiation and 5 mM MeJA resulted in the highest total quercetin content, showing >20% increase compared to that without treatment. This increase primarily resulted in an increase in quercetin content. MeJA treatment positively affected the increase in Q3G and Q7G contents in a dose-dependent manner during the 10-d experimental period but exerted no considerable effect on quercetin accumulation. The antioxidant activity was increased when flowers were exposed to mild MeJA treatment of 5–10 mM. UV-B irradiation decreased the antioxidant activity of marigold petals, but this decrease could be compensated by MeJA treatment

Impact of Dry Processing on Secondary Metabolites in the Petals of Marigold (<i>Tagetes</i> spp.) Cultivar

The edible flowers of marigold (Tagetes spp.) are cultivated for their aesthetic appeal and high utility as functional health food ingredients. Carotenoid and flavonoid contents in marigold petals highlight the importance of selecting the appropriate cultivar and its processing methods for their industrial applications. The comparative understanding of the effects of dry processing on functional components across different marigold cultivars is still lacking. Therefore, this study investigated functional compound changes in the dry processing effect on four marigold cultivars with distinct flower shapes (Durango, Inca) and colors (yellow, orange). The petals in hot air drying (HAD) with 30, 60, and 90 °C applications were analyzed for the measurement of their individual secondary metabolite contents, total phenolic and flavonoid contents, and antioxidant activities. In freeze drying (FD), the lutein content varied significantly based on flower color, exhibiting higher levels in cultivars with orange petals. Otherwise, the levels of quercetin derivatives displayed distinct differences based on varieties other than color, with Inca cultivars demonstrating higher levels of quercetin 7-O-glucoside (Q7G) than Durango cultivars. In HAD, the lutein levels show a tendency to increase above 60 °C regardless of the cultivar. The content of quercetin glycosides decreased, while the aglycone increased in HAD treatments, regardless of the temperatures. Correlation and PCA results highlighted the impact of phenol compounds on antioxidant activity. Overall, these findings underscore the significance of variety and color in determining the chemical composition and antioxidant properties of marigold flowers