Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention.

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

Effect of Fluid and Caffeine Management on Quality of Life in Older Women with Overactive Bladder in Rural Korea: A Pilot Study.

Purpose: This study aimed to investigate the effectiveness of the simplified intervention, consisting of fluid and caffeine management alone in older women with overactive bladder symptoms. Patients and Methods: A quasi-experimental pretest-posttest design was used. Rural, community-dwelling older women were recruited at four senior centers in South Korea. Of the 63 participants initially enrolled, 34 met the inclusion criteria. One group (n = 15) used fluid and caffeine management alone (FM), and the other group (n = 12) used a combination of fluid and caffeine management and pelvic floor muscle training (FM+PFMT). Urinary symptom-specific health-related quality of life was measured using the Korean version of KHQ. Sleep quality was measured using the Pittsburgh Sleep Quality Index. After the intervention, participants were assessed 4 and 8 weeks. A linear mixed model was used for the analysis. Results: The mean age of the participants was 74.44 ± 5.67 years. Among the nine domains of KHQ, impact on life and physical limitations decreased significantly in both groups, without significant between-group differences. Sleep/energy increased in both groups, and the scores in the FM+PFMT group were significantly improved. The number of micturition episodes per day and the quality of sleep did not differ significantly between the two groups. Conclusion: A simplified intervention, consisting of fluid and caffeine management alone can be considered as the first-line intervention to improve health-related quality of life in rural, community-dwelling, older women with overactive bladder symptoms. Healthcare providers should consider providing a relatively simple, but equally effective intervention to maximize the adherence and effectiveness.

Effectiveness of a Nurse-Led Mobile-Based Health Coaching Program for Patients With Prostate Cancer at High Risk of Metabolic Syndrome: Randomized Waitlist Controlled Trial.

BACKGROUND: Androgen deprivation therapy (ADT), a standard treatment for prostate cancer (PC), causes many physical side effects. In particular, it causes metabolic changes such as fasting glucose abnormalities or accumulation of body fat, and its continuation can lead to metabolic syndrome (MetS), which is closely related to diabetes and cardiovascular disease. Therefore, it is important to maintain and practice a healthy lifestyle in patients with PC. OBJECTIVE: This study aims to evaluate the effectiveness of a nurse-led mobile-based program that aims to promote a healthy lifestyle in patients with PC undergoing ADT with MetS risk factors. METHODS: This was a single-blind, randomized, waitlist control interventional study. A total of 48 patients were randomly assigned to the experimental and waitlist control groups at the urology cancer clinic of a tertiary general hospital in South Korea. The inclusion criteria were patients who had undergone ADT for >6 months, had at least 1 of the 5 MetS components in the abnormal range, and could access a mobile-based education program. The experimental group attended a 4-week mobile-based program on exercise and diet that included counseling and encouragement to maintain a healthy lifestyle, whereas the control group was placed on a waitlist and received usual care during the follow-up period, followed by the intervention. The primary outcome was a change in the lifestyle score. The secondary outcomes were changes in 5 MetS components, body composition, and health-related quality of life. The outcomes were measured at 6 weeks and 12 weeks after the initiation of the intervention. Each participant was assigned to each group in a sequential order of enrollment in a 4×4 permuted block design randomization table generated in the SAS (SAS Institute) statistical program. A linear mixed model was used for statistical analysis. RESULTS: A total of 24 participants were randomly assigned to each group; however, 2 participants in the experimental group dropped out for personal reasons before starting the intervention. Finally, 46 participants were included in the intention-to-treat analysis. The experimental group showed more positive changes in the healthy lifestyle score (ß=29.23; P≤.001), level of each MetS component (fasting blood sugar: ß=-12.0; P=.05 and abdominal circumference: ß=-2.49; P=.049), body composition (body weight: ß=-1.52; P<.001 and BMI: ß=-0.55; P<.001), and the urinary irritative and obstructive domain of health-related quality of life (ß=14.63; P<.001) over time than the waitlist control group. CONCLUSIONS: Lifestyle changes through nurse-led education can improve level of each MetS components, body composition, and ADT side effects. Nurses can induce positive changes in patients' lifestyles and improve the self-management of patients starting ADT through this program. TRIAL REGISTRATION: Clinical Research Information Service KCT0006560; http://tinyurl.com/yhvj4vwh.

New machine learning-based automatic high-throughput video tracking system for assessing water toxicity using Daphnia Magna locomotory responses.

Daphnia magna is an important organism in ecotoxicity studies because it is sensitive to toxic substances and easy to culture in laboratory conditions. Its locomotory responses as a biomarker are highlighted in many studies. Over the last several years, multiple high-throughput video tracking systems have been developed to measure the locomotory responses of Daphnia magna. These high-throughput systems, used for high-speed analysis of multiple organisms, are essential for efficiently testing ecotoxicity. However, existing systems are lacking in speed and accuracy. Specifically, speed is affected in the biomarker detection stage. This study aimed to develop a faster and better high-throughput video tracking system using machine learning methods. The video tracking system consisted of a constant temperature module, natural pseudo-light, multi-flow cell, and an imaging camera for recording videos. To measure Daphnia magna movements, we developed a tracking algorithm for automatic background subtraction using k-means clustering, Daphnia classification using machine learning methods (random forest and support vector machine), and tracking each Daphnia magna location using the simple online real-time tracking algorithm. The proposed tracking system with random forest performed the best in terms of identification (ID) precision, ID recall, ID F1 measure, and ID switches, with scores of 79.64%, 80.63%, 78.73%, and 16, respectively. Moreover, it was faster than existing tracking systems such as Lolitrack and Ctrax. We conducted an experiment to observe the impact of toxicants on behavioral responses. Toxicity was measured manually in the laboratory and automatically using the high-throughput video tracking system. The median effective concentration of Potassium dichromate measured in the laboratory and using the device was 1.519 and 1.414, respectively. Both measurements conformed to the guideline provided by the Environmental Protection Agency of the United States; therefore, our method can be used for water quality monitoring. Finally, we observed Daphnia magna behavioral responses in different concentrations after 0, 12, 18, and 24 h and found that there was a difference in movement according to the concentration at all hours.

Quality of life patterns and its association with predictors among non-muscle invasive bladder cancer survivors: A latent profile analysis.

Objective: This study identified group patterns in the quality of life (QOL), as well as examining factors associated with group membership, among non-muscle invasive bladder cancer (NMIBC) survivors. Methods: This was a cross-sectional study involving 278 participating NMIBC survivors. Mplus version 7.2 was used to perform the latent profile analysis of QOL using the EORTC QLQ-NMIBC-24. The participants' social support, self-efficacy, knowledge level, depression, perceived severity of and susceptibility of cancer recurrence, and their demographic and clinical characteristics were compared between the subgroups, with a logistic regression analysis being adopted to examine the factors associated with the QOL subgroups. Results: The NMIBC survivors based on the QOL were classified into two subgroups: "QOL-high" (81.3%) and "QOL-low" (18.7%). Having ≥ 3 disease recurrences, perceived susceptibility toward and severity of cancer recurrence, and having depressive symptoms were significantly associated with the "QOL-low" group. Conclusions: Participants with frequent recurrences of NMIBC, higher perceived susceptibility and severity levels, and depressive symptoms had lower QOL. Therefore, it is necessary to develop intervention programs targeting participants with these characteristics to improve their QOL.

Effectiveness of behavioral sleep interventions on children's and mothers' sleep quality and maternal depression: a systematic review and meta-analysis.

This systematic review and meta-analysis was conducted to investigate the effectiveness of behavioral sleep interventions (BSIs) on the number of child night awakenings, and maternal sleep quality and depression. The search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) using PubMed, CINAHL, Cochrane, and EMBASE databases and retrieved studies published until April 2021. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for child sleep problems, and the mean differences (MD) and 95% CI for the number of child night awakenings, and maternal sleep quality and depression. Ten studies of 1628 initial searched were included in the final analysis. Two of the 10 studies were divided into two subgroups by participants and intervention type; thus, 12 subgroups were included in the meta-analysis. BSIs significantly reduced child sleep problems (OR 0.51; 95% CI 0.37-0.69) and improved maternal sleep quality (MD - 1.30; 95% CI - 1.82 to - 0.77) in the intervention group. There were no significant differences in the number of child night awakenings and maternal depression between the two groups. More RCTs to examine the effect of BSIs considering children's age, duration of intervention, and outcome measuring time points are needed.

Thermal Gelation for Synthesis of Surface-Modified Silica Aerogel Powders.

A spherical silica aerogel powder with hydrophobic surfaces displaying a water contact angle of 147° was synthesized from a water glass-in-hexane emulsion through ambient pressure drying. Water glass droplets containing acetic acid and ethyl alcohol were stabilized in n-hexane with a surfactant. Gelation was performed by heating the droplets, followed by solvent exchange and surface modification using a hexamethyldisilazane (HMDS)/n-hexane solution. The pH of the silicic acid solution was crucial in obtaining a highly porous silica aerogel powder with a spherical morphology. The thermal conductivity, tapped density, pore volume, and BET surface area of the silica aerogel powder were 22.4 mW·m-1K-1, 0.07 g·cm-3, 4.64 cm3·g-1, and 989 m2·g-1, respectively. Fourier transform infrared (FT-IR) spectroscopy analysis showed that the silica granule surface was modified by Si-CH3 groups, producing a hydrophobic aerogel.

Factors Associated with Subsequent Childbirth between Marriage Years in Korea.

This study aimed to identify differences in factors associated with subsequent childbirth between the marriage years of 1996-2005 (Group 1) and 2006-2015 (Group 2) using the 2015 National Survey. A total of 5097 eligible participants (2492 and 2605 women in each group, respectively) were included. The main variables consisted of demographic characteristics, socio-economic status, value for child and son, and social support for raising child. For statistical analysis, discrete-time hazard models were used. The common factors associated with subsequent childbirth in both groups were son preference (Group 1: HR = 1.16; 95% CI = 1.06-1.27, Group 2: HR = 1.14; 95% CI = 1.04-1.24) and the favorable value on children (HR = 1.12; 95% CI = 1.01-1.25, HR = 1.11; 95% CI = 1.01-1.22). Only in Group 2, age at the first childbirth (HR = 1.35; 95% CI = 1.31-1.39) and more monthly income (≥4600, <6000: HR = 1.18; 95% CI = 1.04-1.33, ≥6000: HR = 1.15; 95% CI = 1.00-1.32) were significantly associated with subsequent children. Whereas, working women (HR = 0.86; 95% CI = 0.78-0.94) were less likely to have subsequent children. To increase fertility in Korea, the government must provide childcare and deal with factors associated with low fertility considering the reduction in role incomparability for women due to changes in demographic characteristics.

A Basic Domain-Derived Tripeptide Inhibits MITF Activity by Reducing its Binding to the Promoter of Target Genes.

The keratinocytes in UV-irradiated skin produce and secrete α-melanocyte-stimulating hormone. α-Melanocyte-stimulating hormone upregulates the expression of MITF in melanocytes through the cAMP‒protein kinase A‒CREB signaling pathway. Thereafter, MITF induces the expression of melanogenic genes, including the tyrosinase gene TYR and TYRP-1 and TYRP-2 genes, which leads to the synthesis and accumulation of melanin. In this study, we examined whether MITF basic region-derived tripeptides can bind to the DNA-binding domain of MITF and inhibit MITF-induced melanogenesis through the inhibition of MITF‒DNA binding. MITF-KGR, a representative MITF-derived tripeptide, suppressed the transcriptional activity of MITF by disrupting its binding to the promoter region of the target genes, which resulted in the inhibition of skin epidermis thickness and melanin synthesis in vivo and in vitro. Our results indicate that MITF-KGR exerts an inhibitory effect on melanogenesis by targeting MITF.

Fabrication of Durable Ni-YSZ Hydrogen Electrode for High-Temperature Solid Electrolyzer Cells.

Solid oxide electrolyzer cells with an Ni-Fe-yttria-stabilized zirconia (Ni-Fe-YSZ) hydrogen electrode as the cathode, lanthanum strontium ferrite (LSCF)-gadolinia-doped ceria (GDC) air electrode as the anode, and YSZ as the electrolyte were fabricated, and the oxidation protection effect of sacrificial Fe particles was investigated. X-ray diffraction analysis indicated that Ni was protected from oxidation under a water vapor atmosphere by sacrificial Fe. Scanning electron microscopy observations suggested that the Ni particles accumulated in the Ni-YSZ hydrogen electrode, which might have been associated with the partial oxidation of Ni during cell operation at 700 °C in 50% H2O/15% H2/35% Ar atmosphere. No appreciable microstructural changes were observed for the Ni-Fe-YSZ hydrogen electrode. Furthermore, the presence of the sacrificial Fe particles could be responsible for the superior durability of the cell, compared with that of the cell featuring the conventional Ni-YSZ hydrogen electrode.

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

A Quantile Regression Analysis of Factors Associated with First-Time Maternal Fatigue in Korea.

The aim of this cross-sectional study was to identify the factors associated with different percentiles of first-time maternal fatigue. A total of 123 first-time healthy mothers aged 18 years or older participated through an online survey. The fatigue was measured by the Korean version of the fatigue severity scale. Main variables were constructed based on the integrated fatigue model, which included mothers' sleep quality, parenting stress, the amount of free time mothers have, the number of the child's night wakings, general characteristics including socioeconomic status, and working status. Quantile regression was used to analyze the associated factors according to the fatigue level of first-time mothers with a young child. The mean age of the mothers and children were 32.11 years and 20.81 months, respectively. Mean fatigue score was 6.16 among the 75% quantile with high fatigue score. Lack of adequate free time in mothers, advanced maternal age, being a housewife, having a moderate income, and frequent night wakings of their child significantly increased fatigue among mothers in the third quantile of fatigue. To reduce fatigue, healthcare providers should focus on exploring ways to reduce maternal sleep disturbance and improve maternal sleep quality.

CD99-PTPN12 Axis Suppresses Actin Cytoskeleton-Mediated Dimerization of Epidermal Growth Factor Receptor.

The epidermal growth factor receptor (EGFR), a member of ErbB receptor tyrosine kinase (RTK) family, is activated through growth factor-induced reorganization of the actin cytoskeleton and subsequent dimerization. We herein explored the molecular mechanism underlying the suppression of ligand-induced EGFR dimerization by CD99 agonists and its relevance to tumor growth in vivo. Epidermal growth factor (EGF) activated the formation of c-Src/focal adhesion kinase (FAK)-mediated intracellular complex and subsequently induced RhoA-and Rac1-mediated actin remodeling, resulting in EGFR dimerization and endocytosis. In contrast, CD99 agonist facilitated FAK dephosphorylation through the HRAS/ERK/PTPN12 signaling pathway, leading to inhibition of actin cytoskeletal reorganization via inactivation of the RhoA and Rac1 signaling pathways. Moreover, CD99 agonist significantly suppressed tumor growth in a BALB/c mouse model injected with MDA-MB-231 human breast cancer cells. Taken together, these results indicate that CD99-derived agonist ligand inhibits epidermal growth factor (EGF)-induced EGFR dimerization through impairment of cytoskeletal reorganization by PTPN12-dependent c-Src/FAK inactivation, thereby suppressing breast cancer growth.

Fabrication of Ce-Promoted Ni/Al2O3 Methane Steam Reforming Catalysts by Impregnation.

CeO2-promoted Ni/Al2O3 catalysts were fabricated by impregnation. The effects of the CeO2 promotion and impregnation order on the microstructural evolution and catalytic durability were investigated for methane steam reforming. The CeO2-promoter nanoparticles resulted in good dispersion and reduced particle size of Ni catalysts. The enhanced durability of CeO2-promoted Ni/Al2O3 catalysts might be associated with the depression of carbon deposition by the presence of CeO2-promoter nanoparticles.

Synthesis of Ceramic/Polymer Nanocomposite Electrolytes for All-Solid-State Batteries.

Lithium-ion conducting nanocomposite solid electrolytes were synthesized from polyethylene oxide (PEO), poly(methyl methacrylate) (PMMA), LiClO4, and Li1.3Al0.3Ti1.7(PO4)3 (LATP) ceramic particles. The synthesized nanocomposite electrolyte consisted of LATP particles and an amorphous polymer. LATP particles were homogeneously distributed in the polymer matrix. The nanocomposite electrolytes were flexible and self-standing. The lithium-ion conductivity of the nanocomposite electrolyte was almost an order of magnitude higher than that of the PEO/PMMA solid polymer electrolyte.

Association between urinary urgency and falls among rural dwelling older women.

AIM: To examine the association between urinary urgency and falls in older women living in rural areas in South Korea. DESIGN: A secondary analysis was conducted using cross-sectional data. METHODS: This study used dataset obtained from 246 women aged 65 years or older living in 15 rural mountain communities in South Korea between February 2016-March 2016. Falls were measured by self-reports including the number, location, reasons of falls during the past year. Frequency of urinary urgency and nocturia were assessed by self-reports. Covariates included age, body mass index, self-reported health problems. Mixed-effects negative binomial regression was used to analyse the association between urinary urgency and the number of falls. RESULTS: The mean age of the 246 women was 77.3 years. Among the sample, 30.1% experienced at least one fall in the past year and 16% had required hospital treatments. The analysis showed that urinary urgency and osteoporosis were significantly associated with a greater number of falls after adjusting for other covariates. Among those who had experienced falls, nearly 60% reported that the reasons for falls were environmental factors, such as slippery floors or uneven sidewalks/thresholds. CONCLUSION: Improving urinary urgency may be a strategy to decrease the fall risk in older women. Accordingly, community nurses can provide intervention programs on lifestyle and behavioural changes such as bladder training, dietary modification and pelvic floor muscle training. Interventions for fall prevention need to be developed while considering the unique features of indoor and outdoor environments. IMPACT: The findings have implications for healthcare providers and policy makers with regard to the development of safer indoor and outdoor environments for older women living in rural areas by remodelling their residential spaces and neighbourhoods. In addition, more prospective studies using larger samples are needed to investigate the causal mechanism between urinary urgency and falls.

Alleviation of Ultraviolet-B Radiation-Induced Photoaging by a TNFR Antagonistic Peptide, TNFR2-SKE.

Ultraviolet (UV) radiation of the sunlight, especially UVA and UVB, is the primary environmental cause of skin damage, including topical inflammation, premature skin aging, and skin cancer. Previous reports show that activation of nuclear factor-κB (NF-κB) in human skin fibroblasts and keratinocytes after UV exposure induces the expression and release of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), and subsequently leads to the production of matrix metalloproteases (MMPs) and growth factor basic fibroblast growth factor (bFGF). Here, we demonstrated that TNFR2-SKEE and TNFR2-SKE, oligopeptides from TNF receptor-associated factor 2 (TRAF2)-binding site of TNF receptor 2 (TNFR2), strongly inhibited the interaction of TNFR1 as well as TNFR2 with TRAF2. In particular, TNFR2-SKE suppressed UVB- or TNF-α-induced nuclear translocalization of activated NF-κB in mouse fibroblasts. It decreased the expression of bFGF, MMPs, and COX2, which were upregulated by TNF-α, and increased procollagen production, which was reduced by TNF-α. Furthermore, TNFR2-SKE inhibited the UVB-induced proliferation of keratinocytes and melanocytes in the mouse skin and the infiltration of immune cells into inflamed tissues. These results suggest that TNFR2-SKE may possess the clinical potency to alleviate UV-induced photoaging in human skin.

Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927.

The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.

Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft.

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.