Selection of Catechin Biosynthesis-Related Genes and Functional Analysis from Chromosome-Level Genome Assembly in C. sinensis L. Variety 'Sangmok'.

Camellia is an important plant genus that includes well-known species such as C. sinensis, C. oleifera, and C. japonica. The C. sinensis cultivar 'Sangmok', one of Korea's standard types of tea landraces, is a small evergreen tree or shrub. Genome annotation has shown that Korean tea plants have special and unique benefits and superior components, such as catechin. The genome of Camellia sinensis cultivar 'Sangmok' was assembled on the chromosome level, with a length of 2678.62 Mbp and GC content of 38.16%. Further, 15 chromosome-scale scaffolds comprising 82.43% of the assembly (BUSCO completeness, 94.3%) were identified. Analysis of 68,151 protein-coding genes showed an average of 5.003 exons per gene. Among 82,481 coding sequences, the majority (99.06%) were annotated by Uniprot/Swiss-Prot. Further analysis revealed that 'Sangmok' is closely related to C. sinensis, with a divergence time of 60 million years ago. A total of 3336 exclusive gene families in 'Sangmok' were revealed by gene ontology analysis to play roles in auxin transport and cellular response mechanisms. By comparing these exclusive genes with 551 similar catechin genes, 17 'Sangmok'-specific catechin genes were identified by qRT-PCR, including those involved in phytoalexin biosynthesis and related to cytochrome P450. The 'Sangmok' genome exhibited distinctive genes compared to those of related species. This comprehensive genomic investigation enhances our understanding of the genetic architecture of 'Sangmok' and its specialized functions. The findings contribute valuable insights into the evolutionary and functional aspects of this plant species.

Combined translational pharmacometrics approach to support the design and conduct of the first-in-human study of DWP16001.

AIMS: The objective of this study was to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, and predict efficacious doses for the first-in-human study using various translational approaches. METHODS: A mechanistic PK/PD model was developed for DWP16001 using nonlinear mixed-effect modelling to describe animal PK/PD properties. Using allometry and in silico physiologically based equations, human PK parameters were predicted. Human PD parameters were scaled by applying interspecies difference and in vitro drug-specific factors. Human parameters were refined using early clinical data. Model-predicted PK and PD outcomes were compared to observations before and after parameter refinement. RESULTS: The PK/PD model of DWP16001 was developed using a 2-compartment model with first-order absorption and indirect response. Efficacious doses of 0.3 and 2 mg of DWP16001 were predicted using human half-maximal inhibitory concentration values translated from Zucker Diabetic Fatty rats and normal rats, respectively. After parameter refinement, doses of 0.2 and 1 mg were predicted to be efficacious for each disease model, which improved the prediction results to within a 1.2-fold difference between the model prediction and observation. CONCLUSIONS: This study predicted efficacious human doses of DWP16001 using population PK/PD modelling and a combined translational pharmacometrics approach. Early clinical data allowed the methods used to translate in vitro and in vivo findings to clinical PK/PD values for DWP16001 to be optimized. This study has shown that a refinement step can be readily applied to improve model prediction and further support the study design and conduct of a first-in-human study.

Association Between Depressed Mood Changes and Physical Activity Among Adolescents Post COVID-19 Pandemic.

Objectives: Following the coronavirus disease 2019 (COVID-19) pandemic, adolescents have experienced decreased physical activity and a decline in mental health. This study analyzed the association between changes in depressed mood after the COVID-19 pandemic and physical activity among adolescents. Methods: The analysis was based on the results of the 17th Youth Health Behavior Online Survey conducted in 2021, which included 54848 middle and high school students in South Korea. Information on physical activity included low-intensity physical activity lasting >60 min/day, high-intensity physical activity, and strength training exercises. A logistic regression analysis was performed to evaluate the association between physical activity and changes in depression after the COVID-19 pandemic. Results: After adjusting for sociodemographic characteristics and previous depression, adolescents who performed strength training exercises more than once per week had a 0.95-fold lower risk (odds ratio [OR]=0.948, 95% confidence interval [CI]=0.905-0.994, p= 0.027) of increasing depression after the COVID-19 pandemic, while the risk of decreasing depression increased by 1.22-fold (OR=1.215, 95% CI=1.131-1.305, p<0.001). The results were not significant for low-intensity physical activity for >60 min/day and high-intensity physical activity. Conclusion: Strength-training exercises are significantly associated with the prevention of depression among adolescents following the COVID-19 pandemic.

Dietary Carotene Intake and Suicidal Ideation in Korean Females: Analysis of Data From the Korea National Health and Nutrition Examination Survey (2012, 2013, and 2015).

OBJECTIVE: The suicide rate in Korea was the highest among countries in the Organisation for Economic Co-operation and Development in 2019. In a previous study, higher intake of vegetables and fruits was associated with a lower risk of suicidal ideation, and carotene-rich fruits and vegetables lowered the risk of depression. This study aimed to examine the direct relationship between carotene intake and suicidal ideation, adjusting for the effect on depression. METHODS: This study used data from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted in 2012, 2013, and 2015. Carotene intake was assessed through a food intake frequency survey with a 24-hour recall. Suicidal ideation and depression were assessed using the mental health section of the KNHANES. We applied logistic regression to assess the relationship between carotene intake and suicidal ideation, adjusting for potential confounders. RESULTS: A total of 5,480 females aged 19-64 years were included in this study. Carotene intake was significantly lower in the suicidal ideation group (3,034.5±1,756.4 µg/day) than in the nonsuicidal ideation group (3,225.4±1,795.1 µg/day) (p=0.015). We found a significant inverse association between carotene intake and the risk of suicidal ideation after adjusting for potential confounders (odds ratio=0.934, 95% confidence interval=0.873-0.999). CONCLUSION: These results suggest that carotene intake may be inversely associated with the risk of suicidal ideation. Our findings may inform the development of new nutritional interventions to prevent increases in the risk of suicide worldwide.

Spatiotemporal Patterns of Suicide in Korea From 2009 to 2019 Using Geographic Information Systems.

Objective: When analyzing factors related to suicide, it is necessary to consider the regional characteristics of the areas where individuals live in addition to individual factors. This study aimed to investigate the spatiotemporal association between suicide rates and geographic features and the patterns of this association for all administrative areas in South Korea from 2009 to 2019. Methods: The data used in this study were obtained from the National Statistical Office of the Korean Statistical Information Service. For suicide rates, age-standardized mortality index data per 100 000 people were used. All administrative districts from 2009 to 2019 were divided into 229 regions. Emerging hotspot analysis was used for a 3-dimensional analysis to simultaneously evaluate temporal and spatial clusters. Results: In the 229 regions, there were 27 (11.8%) hotspots and 60 (26.2%) cold spots. Hotspot pattern analysis found 2 (0.9%) new spots, 1 (0.4%) persistent spot, 23 (10.0%) sporadic spots, and 1 (0.4%) oscillating spot. Conclusion: This study found geographic differences in the spatiotemporal patterns of suicide rates in South Korea. The utilization of national resources for suicide prevention should be selectively and intensively prioritized in 3 areas that exhibit unique spatiotemporal patterns.

Identification of the novel HLA-DQA1*01:03:07 allele using next-generation sequencing.

The HLA-DQA1*01:03:07 allele differs from HLA-DQA1*01:03:01:01 allele by a single nucleotide in codon -8.

DallphinAtoM: Physiologically based pharmacokinetics software predicting human PK parameters based on physicochemical properties, in vitro and animal in vivo data.

BACKGROUND AND OBJECTIVES: In silico experiments and simulations using physiologically based pharmacokinetic (PBPK) and allometric approaches have played an important role in pharmaceutical research and drug development. These methods integrate diverse data from preclinical and clinical development, and have been widely applied to in vitro-in vivo extrapolation (IVIVE) of absorption, distribution, metabolism, and excretion (ADME). METHODS: To develop a user-friendly open tool predicting human PK, we assessed various references on PBPK and allometric methods published so far. They were integrated into a software system named "DallphinAtoM" (Drugs with ALLometry and PHysiology Inside-Animal to huMan), which has a user-friendly platform that can handle complex PBPK models and allometric models with a relatively small amount of essential information of the drug. The models of DallphinAtoM support the integration of data gained during the nonclinical development phase, enable translation from animal to human, and allow the prediction of concentration-time profiles with predicted PK parameters. RESULTS: We presented two illustrative applications using DallphinAtoM: (1) human PK simulation of an orally administered drug using PBPK method; and (2) simulation of intravenous infusion following a two-compartment model using the allometric scaling method. CONCLUSIONS: We conclude that this is a straightforward and transparent tool allowing fast and reliable human PK simulation based on the latest knowledge on biochemical processes and physiology and provides valuable information for decision making during the early-phase drug development.

Association Between Suicide and Drinking Habits in Adolescents.

OBJECTIVES: Adolescent suicide is a serious social problem. Adolescent alcohol use is one of the most important risk factors for adolescent suicide. This study aimed to identify the relationship between drinking habits and suicide among Korean adolescents. METHODS: Data from the 14th and 15th Korean Youth Risk Behavior Web-based Survey, conducted in 2018 and 2019, were used for analysis. Multiple logistic regression analysis was used to identify the relationship between drinking habits-including the age of drinking initiation, frequency of drinking, average drinking amount, frequency of drunkenness-and suicidal ideation, plans, and attempts. RESULTS: Even after adjusting for age, sex, school grade, academic achievement, socioeconomic status, depression, stress, and drinking habits, the frequencies of drinking and drunkenness increased the risk of suicide attempts. Suicide attempts were associated with the frequency of drinking in girls and middle school students, and with the frequency of drunkenness in boys and high school students. CONCLUSION: This study identified associations between drinking habits (the age of drinking initiation, frequency of drinking, average amount of drinking, frequency of drunkenness) and suicidal behavior in adolescents. Our findings suggest that to prevent adolescent suicide, it might be necessary to investigate drinking habits, including the frequencies of drinking and drunkenness. Moreover, considering the differences in sex and school grade, it is important to include the individual group characteristics when evaluating drinking habits.

Association between Early Spermarche and Suicide Attempts in Boys: the Korea Youth Risk Behavior Web-based Survey.

BACKGROUND: Puberty is a biologically and psychologically unstable period, and pubertal changes differ by sex. However, most previous studies on pubertal timing and suicide have focused on girls. This study investigated the association between early spermarche and suicide attempts in boys. METHODS: We analyzed a nationally representative sample of Korean adolescents (The Korea Youth Risk Behavior Web-Based Survey, KYRBS) that included approximately 35,000 boys annually from 2011 to 2015. Pubertal timing in boys was defined by spermarche. Complex sampling logistic regression analyses were performed to evaluate the odds ratios (ORs) for suicide attempts between the early and average spermarche groups. RESULTS: The ORs for suicide attempts in boys with early spermarche were significantly higher than those in boys with average spermarche after adjustment for age, perceived stress, depressive symptoms, and suicidal ideation. The ORs from 2011 to 2015 were as follows: 1.782 (P < 0.001), 1.490 (P = 0.002), 1.693 (P < 0.001), 1.541 (P = 0.001), and 1.393 (1.024-1.895; P = 0.035), respectively. CONCLUSION: These findings suggest that early pubertal timing is a risk factor for suicide attempts in Korean boys after adjustment for depressive symptoms, perceived stress, and suicidal ideation, which have been previously reported as risk factors for suicide attempts. Therefore, careful attention should be paid to the prevention of suicide in boys who experience early spermarche in Korea.

Production of protein hydrolysate from Protaetia brevitarsis seulensis (Kolbe) larvae by enzyme treatment under high pressure.

To improve the industrial use of health-functional materials based on edible insects, the objective of this study was to establish optimal conditions for improving the quality of Protaetia brevitarsis seulensis larval (PBSL) hydrolysates. PBSL was extracted using four methodologies: atmospheric pressure 50 °C-water extraction, atmospheric pressure 95 °C-water extraction, atmospheric pressure 50 °C-water enzymatic hydrolysis, and enzyme treatment under high pressure (HPE). The quality characteristics of soluble solid content, extraction yield, total protein content, protein yield, protein content with low molecular weight (LMW) (< 1kD), and the amino acid composition of hydrolysates were compared based on the different methods. All of the quality characteristics were found to be higher for HPE extracts than for the other extracts. Under optimized HPE conditions, extraction yield, protein yield, protein content with LMW, amino acid content and the content of essential amino acids increased by 3.4, 4.4 1.4 1.5, and 1.3 times respectively, compared to the other methods.

Psychological Development during Medical School Clerkship: Relationship to Resilience.

OBJECTIVE: The authors investigated changes in medical students' defenses during clerkship and examined the effects of these changes on students' resilience. METHODS: Between 2012 and 2014, all year-2 preclinical students (N = 249) at Gyeongsang National University Medical School were asked to participate. Those who agreed to participate (N = 237) completed the Korean version of the Defense Style Questionnaire (K-DSQ) and the Connor-Davidson resilience scale-10 (CD-RISC-10). After clerkship, students who proceeded to year 4 in 2 years (n = 187 (93 females), aged 24-38 years (mean, 28.9 ± 2.8 years)) completed the K-DSQ, CD-RISC-10, and the Korean version of the Hospital Anxiety and Depression Scale (K-HADS) in September 2014, 2015, and 2016. RESULTS: The use of adaptive (W = 11,603.5, p < 0.001, r = 0.39) and self-inhibiting (W = 10,901.5, p < 0.001, r = 0.32) styles increased significantly after clerkship. A multiple linear regression analysis showed that changes in adaptive defense styles (B = 1.336, SE = 0.386, ß = 0.218, p = 0.001) during clerkship were significantly related to resilience after adjusting for age, sex, depression, and anxiety. CONCLUSIONS: Both positive personality development and maladaptive changes in defenses were evident. An increase in the adaptive defense style score was related to resilience.

The complete chloroplast genome sequence of economical standard tea plant, Camellia sinensis L. cultivar Sangmok, in Korea.

The complete chloroplast genome sequence of Camellia sinensis L. cultivar Sangmok was determined using high-throughput sequencing technology. We sequenced Sangmok chloroplast genome and performed comparative with 21 published other Camellia and species from different genus for phylogenetic analysis. Chloroplast genome was 153,044 bp in length, containing a pair of 24,627 bp inverted repeat (IR) regions, which were separated by small and large single-copy regions (SSC and LSC) of 19,155 and 64,665 bp, respectively. The chloroplast genome contained 97 genes (63 protein-coding genes, 29 tRNA genes, and 5 rRNA genes). The overall GC content of the chloroplast genome was 37.2%. The phylogenetic analysis among species in number of the genus Camellia provided that C. sinensis L. cultivar Sangmok is closely related to KJ806277 Camellia pubicosta.

Early menarche as a risk factor for suicidal ideation in girls: The Korea youth risk behavior web-based survey.

Puberty, at which point girls experience menarche, is a biologically and psychologically unstable period. This study investigated the association between early menarche and suicidal ideation in girls. This study analyzed data from approximately 35,000 girls from the Korea Youth Risk Behavior Web-Based Survey every year from 2011 to 2015. The odds ratios of suicidal ideation were compared between the early and average menarche groups. Generally, the odds ratios of suicidal ideation in girls with early menarche were significantly higher than those with average menarche.

Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment.

The phosphoinositide 3-kinase (PI3K) and RAS signaling pathways are frequently co-activated and altered during oncogenesis. Owing to their regulatory cross-talk, the early attempts of targeting only one pathway have mostly ended up promoting the development of drug resistance. Here, we propose using small interfering RNA (siRNA) therapeutics to directly target the undruggable KRAS (siKRAS) in combination with the pan-PI3K inhibitor GDC-0941 (GDC) to simultaneously block both PI3K and RAS signaling, thereby exerting synergistic anti-tumor effects on ovarian cancers with PTEN deficiency and KRASG12D mutation. For successful delivery of siKRAS, tGC/psi-nanoparticle formulation of polymerized siRNA and thiol-modified glycol chitosan nanoparticle-was used for KRAS specific inhibition in vitro and in vivo. GDC or siKRAS monotherapy each impede downstream signaling, leading to some delay in cell proliferation and migration. When combined, however, they engender much higher inhibition of PI3K signaling and stimulation of apoptosis in an ovarian allograft model compared to monotherapies. Our results show the feasibility of developing new combination strategies for the management of multiple oncogenic mutations activating PI3K and RAS signaling.

The Mediating Effect of Impulsivity on Resilience and Depressive Symptoms In Korean Conscripts.

OBJECTIVE: Resilience and impulsivity have opposite effects on depression in stressful situations. This study aimed to investigate the association among resilience, impulsivity, and depression in young males. METHODS: The participants consisted of 429 conscripts who underwent military training over 5 weeks. The surveys included the Connors- Davidson Resilience Scale-Korean version, the Barratt Impulsiveness Scale-11-Revised, and the Center for Epidemiological Studies- Depression Scale. The surveys were administered both before and after training. RESULTS: When simultaneously considering impulsivity and resilience, resilience was not associated with depression. Impulsivity had a complete negative mediating effect on resilience and depressive symptoms. Impulsivity is a significant negative mediating factor for the protective effect of resilience on depression. CONCLUSION: This study recommends considering impulsivity when evaluating the protective role of resilience against depression.

Effects of Emotional Stability on Insomnia through Anxiety in Patients with Cataracts.

This study investigated the effect of emotional stability (ES) on insomnia through anxiety in preoperative patients with cataracts. Fifty-four subjects completed a self-questionnaire that included the Insomnia Severity Index (ISI), the International Personality Item Pool (IPIP) for ES, and the Hospital Anxiety and Depression scale (HADS). Pathway analysis was performed to analyze the mediating effects of ES, the anxiety subscale scores of the HADS, and the ISI scores. The low-ES group exhibited an insomnia severity that was significantly higher than that of the high-ES group (p=0.048). According to the pathway analysis, the significant indirect effect of ES on the ISI scores was mediated by the scores on the anxiety subscale of the HADS. Cataract patients with low ES waiting to undergo surgery have a high risk of experiencing insomnia due to anxiety. Before surgery, it is essential to identify patients' personality characteristics and provide appropriate intervention.

A review of three years' experience of the first pharmacometrics company in Korea.

As the pharmaceutical industry in Korea is reaching the golden era of drug discovery due to increased investments in research and development and government funds, the need for a more efficient tool for the quantitative analysis has emerged. Therefore, the demand for pharmacometrics (PMx) consultancy services increased. Higher quality service suitable for regulatory submission and out-licensing deals were desired. In this analysis, we compiled and summarized 3 years of experiences of Q-fitter, the first PMx consultancy service company providing PMx analysis to the pharmaceutical industry in Korea. The projects were organized by companies, company types, indications, therapeutic areas, drug development stages, purposes, and scope of services. Within each category, we subcategorized the sections and assessed proportions and a year-over-year trend. As a result, we observed an increase in the number of projects in an average of ~170% per year, with the most frequent types of companies collaborated being the domestic pharmaceutical companies. Among the projects, ~72% involved modeling and simulation using population pharmacokinetic (PK) models, and the other included non-compartmental analysis (NCA), drug-drug interaction (DDI) prediction, and interpretation of the modeling results. The most sought-after purpose in PMx analysis was first-in-human (FIH) dose prediction followed by PK analysis, next clinical trial prediction, and scenario-based simulation. Oncology has been the top therapeutic area of interest every year consisting of ~38% of total projects, followed by Neurology (~13%). From this review, we were able to characterize the PMx service needs and spot the trend of current PMx practices in Korea.

Metabolic syndrome status over 2 years predicts incident chronic kidney disease in mid-life adults: a 10-year prospective cohort study.

We investigated whether changes in MetS status over two years modify the 10-year risk of CKD and proteinuria. A prospective cohort study was conducted in 7,251 subjects without CKD at baseline. We categorized subjects according to MetS status over two years: non-MetS (no MetS at either visit), intermittent MetS (positive for MetS at one assessment), and persistent MetS (positive for MetS at two assessments). The hazard ratio (HR) of new-onset CKD over 10-year was calculated using Cox models. During the 10-year follow-up period, 923 (12.7%) developed CKD. Compared to the non-MetS group, the fully adjusted HR for new-onset CKD was the highest in the persistent MetS group (HR, 1.53; 95% CI, 1.23-1.90), followed by the intermittent MetS group (HR, 1.29; 95% CI, 1.04-1.59) (P for trend <0.001). The HR for developing proteinuria was 1.79 (95% CI, 1.15-2.79) in the persistent MetS group and 0.70 (95% CI, 0.42-1.19) in the intermittent MetS group when the non-MetS group was considered as the reference group. Temporal changes in MetS status over two years influenced the 10-year risk of incident CKD and proteinuria. Our findings suggest that monitoring and strictly controlling MetS are important in preventing renal function decline.

Craving Behavior from Opioid Addiction Controlled with Olanzapine in an Advanced Cancer Patient: A Case Report.

Opioid addiction, although uncommon in cancer patients, can be a significant challenge for optimal pain management in certain patients. We present a case of a 59-year-old man with advanced colon cancer whose compulsive craving for the buccal tablet of fentanyl citrate (BTFC) was improved with the use of olanzapine. He was hospitalized for abdominal pain caused by disease progression. He had visited several times at outpatient follow-up to obtain a prescription for BTFC because he took all medications before the appointed times. After admission, intravenous infusion of oxycodone and opioid rotation were applied to the patient to control his pain. However, he complained that the pain was not relieved at all and persistently asked for only BTFC 7 to 15 times per day. With the diagnosis of opioid addiction, the transdermal buprenorphine patch was applied, but was ineffective for controlling the addictive behaviors. Finally, olanzapine (10 mg/day per os), a dopamine receptor antagonist, was given to control the craving behavior because psychological dependence is mediated by the dopaminergic system. Three days later, opioid craving was reduced from five to one on a 5-point Likert scale. The pain was well controlled to numeric rating scale 1 or 2 without cravings for BTFC. Craving behavior as a result of opioid addiction may be controlled with olanzapine. Further prospective studies on this issue are warranted.

Pharmacokinetics and bioequivalence of 0.5 mg lobeglitazone tablets in healthy male subjects
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OBJECTIVE: This study was conducted to evaluate the pharmacokinetics and bioequivalence of two formulations of -DuvieTM (0.5-mg lobeglitazone sulfate). MATERIALS AND METHODS: This study was designed as an open-label, randomized, single-dose, crossover bioequivalence study in healthy male subjects. A total of 28 subjects were randomized into two groups: one group received the test drug, 0.5-mg DuvieTM tablets, which have formulations available on the global market; and the other group received the reference drug, the initially-approved 0.5-mg DuvieTM tablets. Plasma samples were collected for up to 48 hours after drug treatment and were analyzed for lobeglitazone using validated liquid chromatography-tandem mass spectrometry. Individual pharmacokinetic properties were determined by noncompartmental methods. Safety assessments were performed. RESULTS: 28 subjects completed the study and were included in the pharmacokinetic analysis. The mean (standard deviation) values of -AUClast for the test and reference formulations were 367.49 (157.92) and 362.40 (140.05) ng×h/mL, respectively. The mean (standard deviation) values of Cmax for the test and reference formulations were 50.35 (6.94) and 49.29 (6.71) ng/mL, respectively. The 90% confidence intervals for AUClast and Cmax were 0.9150 - 1.1088 and 0.9879 - 1.0561, respectively. All adverse events were mild, and there were no serious adverse events. CONCLUSION: This study suggests that the two lobeglitazone tablet formulations have similar exposure and absorption rates. Therefore, the newly-developed formulation of the 0.5-mg DuvieTM tablet is expected to contribute to the treatment of patients with type 2 diabetes.
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