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ABSTRACT Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents that potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into phase 2a clinical trials. Previous cell culture-based viral breakthrough assays identified the HIV-1(Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. Although both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect the direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor-mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCDY99H/A128T + PIR complex. Consequently, full-length INY99H/A128T was substantially less susceptible to the PIR-induced hyper-multimerization than the WT protein, and HIV-1(Y99H/A128T IN) conferred >150-fold resistance to the inhibitor compared with the WT virus. By rationally modifying PIR, we have developed its analog EKC110, which readily induced hyper-multimerization of INY99H/A128T in vitro and was ~14-fold more potent against HIV-1(Y99H/A128T IN) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use.IMPORTANCEAntiretroviral therapies save the lives of millions of people living with HIV (PLWH). However, the evolution of multi-drug-resistant viral phenotypes is a major clinical problem, and there are limited or no treatment options for heavily treatment-experienced PLWH. Allosteric HIV-1 integrase inhibitors (ALLINIs) are a novel class of antiretroviral compounds that work by a unique mechanism of binding to the non-catalytic site on the viral protein and inducing aberrant integrase multimerization. Accordingly, ALLINIs potently inhibit both wild-type HIV-1 and all drug-resistant viral phenotypes that have so far emerged against currently used therapies. Pirmitegravir, a highly potent and safe investigational ALLINI, is currently advancing through clinical trials. Here, we have elucidated the structural and mechanistic bases behind the emergence of HIV-1 integrase mutations in infected cells that confer resistance to pirmitegravir. In turn, our findings allowed us to rationally develop an improved ALLINI with substantially enhanced potency against the pirmitegravir-resistant virus.

ABSTRACT In humans, sterile alpha motif (SAM) domain- and histidine–aspartic acid (HD) domain-containing protein 1 (SAMHD1) is a dNTPase enzyme that prevents HIV-1 infection in non-cycling cells, such as differentiated THP-1 cells and human primary macrophages. Although phosphorylation of threonine 592 (T592) in SAMHD1 is recognized as the primary regulator of the ability to prevent HIV-1 infection, the contributions of SAMHD1 acetylation to this ability remain unknown. Mass spectrometry analysis of SAMHD1 proteins derived from cycling and non-cycling THP-1 cells, primary cycling B cells, and primary macrophages revealed that SAMHD1 is preferentially acetylated at lysine residues 354, 494, and 580 (K354, K494, and K580). In non-cycling cells, SAMHD1 is preferentially acetylated at K580, suggesting that this post-translational modification may contribute to the ability of SAMHD1 to block HIV-1 infection. Consistent with this finding, we found that mutations in K580 disrupted the ability of SAMHD1 to block HIV-1 infection without affecting the ability of SAMHD1 to deplete cellular dNTP levels. Gene editing of SAMHD1 in macrophage-like cells revealed that an intact K580 is required for HIV-1 restriction. This finding suggests that K580 acetylation in SAMHD1 is essential for blocking HIV-1 infection. More importantly, we found that a larger proportion of SAMHD1 featuring K580 acetylation could be detected in human primary macrophages when compared to human primary monocytes. In agreement, we found that SAMHD1 is acetylated during the monocyte-to-macrophage differentiation process. This finding agrees with the idea that the blockade of HIV-1 infection in macrophages requires SAMHD1 acetylation.IMPORTANCEThe natural inhibitor of HIV-1, sterile alpha motif (SAM) domain- and histidine–aspartic acid (HD) domain-containing protein 1 (SAMHD1), plays a pivotal role in preventing HIV-1 infection of macrophages and dendritic cells, which are vital components of the immune system. This study unveils that SAMHD1 undergoes post-translational modifications, specifically acetylation at lysines 354, 494, and 580. Our research underscores the significance of these modifications, demonstrating that acetylation at residue K580 is indispensable for SAMHD1's efficacy in blocking HIV-1 infection. Notably, K580 is found in a critical regulatory domain of SAMHD1, highlighting acetylation as a novel layer of SAMHD1 regulation for HIV-1 restriction in humans. A comprehensive understanding of the regulation mechanisms governing this anti-HIV-1 protein is crucial for leveraging nature's defense mechanisms against HIV-1 and could pave the way for innovative therapeutic strategies.

Abstract Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

IntroductionEvaluating the anticancer property of Padina boergesenii mediated bimetallic nanoparticles.MethodsThe present study focuses on synthesizing Se-ZnO bimetallic nanoparticles from an aqueous algal extract of brown algae Padina boergesenii.Synthesized Se-ZnO NPs were characterized by UV, FTIR, SEM-EDS and HRTEM for confirmation along with the anticancer activity by MTT assay.ResultsThe UV gave an absorbance peak at 342 and 370 nm, and the FTIR showed functional groups involved in synthesizing Se-ZnO NPs. The TEM micrographs indicated the crystalline nature and confirmed the size of the Se-ZnO NPs to be at an average size of 26.14 nm. Anticancer efficacy against the MCF-7 breast and HepG2 (hepatoblastoma) cell lines were also demonstrated, attaining an IC50 value of 67.9 µg and 74.9 µg/ml respectively, which caused 50% cell death.DiscussionThis work aims to highlight an effective method for delivering bioactive compounds extracted from brown algae and emphasize its future therapeutic prospects. The potential of Selenium-Zinc oxide nanoparticles is of great interest due to the biocompatibility and low toxicity aspects of selenium combined with the cost-effectiveness and sustainability of zinc metal. The presence of bioactive compounds contributed to the stability of the nanoparticles and acted as capping properties.

Fibrous dysplasia (FD) is a rare bone disorder characterized by the replacement of normal bone with benign fibro-osseous tissue. Developments in our understanding of the pathophysiology and treatment options are impeded by the lack of suitable research models. In this study, we developed an in vitro organotypic model capable of recapitulating key intrinsic and phenotypic properties of FD. Initially, transcriptomic profiling of individual cells isolated from patient lesional tissues unveiled intralesional molecular and cellular heterogeneity. Leveraging these insights, we established patient-derived organoids (PDOs) using primary cells obtained from patient FD lesions. Evaluation of PDOs demonstrated preservation of fibrosis-associated constituent cell types and transcriptional signatures observed in FD lesions. Additionally, PDOs retained distinct constellations of genomic and metabolic alterations characteristic of FD. Histological evaluation further corroborated the fidelity of PDOs in recapitulating important phenotypic features of FD that underscore their pathophysiological relevance. Our findings represent meaningful progress in the field, as they open up the possibility for in vitro modeling of rare bone lesions in a three-dimensional context and may signify the first step towards creating a personalized platform for research and therapeutic studies.

Niclosamide is a commonly used anthelmintic; however, its poor aqueous solubility limits its oral bioavailability. Enhancing its solubility and oral bioavailability is crucial for its repositioning as an anticancer agent. Here, we aimed to develop new sodium alginate-poloxamer microparticles with different crystallinities to increase drug solubility and oral bioavailability. Sodium alginate and poloxamer were used as the polymer and surfactant, respectively, to prepare niclosamide-loaded microparticles via spray drying. The optimized amorphous and crystalline microparticles were prepared with niclosamide/sodium alginate/poloxamer weight ratios of 1:2.5:3 and 1:1.125:0.375, respectively. Their solubilities, dissolution rates, physicochemical properties, and oral bioavailabilities were compared with those of drug powder in rats. Physicochemical characterization of the developed particles revealed changed structure from crystalline to amorphous, with no irregular crystalline characteristics but decreased particle size. Compared to the pure drug powder, crystalline microparticles retained their crystalline nature with no significant changes in particle size. Both microparticles showed significantly higher aqueous solubilities, dissolution rates, and oral bioavailabilities than niclosamide powder in rats. Amorphous microparticles showed higher solubility (approximately 1775-fold) and oral bioavailability (approximately 5.6-fold) than niclosamide powder due to the crystalline-to-amorphous change and decreased particle size. The developed amorphous microparticles can be used to improve niclosamide solubility and oral bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

The current state of quality assessment methods for agricultural produce, particularly fruits, heavily relies on manual inspection techniques, which could be subjective, time-consuming, and prone to human errors. Consequently, there have been emerging trends and needs for non-destructive methods to evaluate fruit quality accurately and practically. This research aimed to develop a novel approach for predicting the physicochemical properties of papayas using a convolutional neural network (CNN) model that combines image analysis and weight assessment. This study involved capturing images of papayas at different ripening stages, measuring papaya weights, and determining various physicochemical properties such as texture, pH, total soluble solids, and seed weight. A total of 532 images were obtained from 132 papayas, and an additional 1064 images were generated through image augmentation. The dataset was divided into three sets with an 8:1:1 ratio for training, validation, and testing. The CNN model was trained using papaya images and weights as input values to predict and estimate the physicochemical property values. Model performance was evaluated using mean squared error (MSE) and the coefficient of determination (R 2 ) as metrics. The CNN model, integrated with image processing, could predict the diverse physicochemical properties of papayas with high accuracy. The MSE values estimated for the training and validation sets were 0.0284 and 0.1729, respectively. The R 2 values for the test dataset ranged from 0.71 to 0.94. These findings demonstrate that CNN-based models could provide detailed and quantitative insights, facilitating improved understanding and management of papaya quality while enhancing predictive modeling accuracy in agriculture. PRACTICAL APPLICATION: This research introduces a new method for accurately predicting the quality of papayas using a computer model. Instead of relying on manual inspection, which can be slow and prone to errors, this model uses images of papayas and their weights to predict properties, including texture, pH, total soluble solids, and seed weight. This can help manage papaya quality better while also improving agricultural production and transportation processes., (© 2024 Institute of Food Technologists.)

Research Question: Can GV-oocytes serve as an effective model to test the efficacy of ultra-fast vitrification (UFV)/ rapid elution (RE) treatments to support reliable, high survival rates and sustained functionality?, Design: Prospective pilot cohort studies were performed to investigate the feasibility of non-equilibration, UFV to sustain cellular integrity and development in contrast to control vitrification (CV: 10-15min ES/ 1min VS). In Phase 1, we applied a 2 × 2 factorial design (n=25-30 eggs/group) to evaluate post-warming dilution treatments: conventional multi-step (CD) versus rapid elution (RE; one-step), including an apriori fresh egg control group. Phase 1/2 focused on survival and maturation assessments, including meiotic spindle formation (Phase 2)., Results: The survival of EG/DMSO treated UFV oocytes in Phase 1 and 2 was not different to spontaneous degeneration seen in the fresh IVM control groups (3.2%) but was higher than CV treated oocytes immediately post-warming (p<0.03). Of the intact GVs, no difference in IVM-MII development was detected (52.6 -58.3%) at +48h IVM across all groups. Meiotic spindle integrity of MII oocytes was normal in all treatment groups., Conclusions: As originally reported by Gallardo (2019), non-equilibrated dehydrated human oocytes can effectively vitrify after UFV/CD treatment. We further verified the resiliency of oocytes to withstand RE treatment and continue to develop normally, like fresh GV-matured oocytes. Furthermore, we confirmed that the meiotic spindle formation and density of UFV/RE-treated GV oocytes was similar to fresh controls. Overall, the GV-model proved to be a useful resource to substantiate the promising potential of UFV technology to reliably achieve high survival and normal developmental competence in a more time efficient manner., (Copyright © 2024. Published by Elsevier Ltd.)

Pyrolysis has been proposed to stabilize heavy metals present in livestock manure. However, many studies have not considered the applicability of manure-derived biochar containing endogenous heavy metals as an agricultural fertilizer. This study investigated the mechanisms through which pyrolysis stabilizes endogenous heavy metals in swine manure and the long-term stability of endogenous heavy metals in the biochar. As pyrolysis temperature increased from 300 °C to 700 °C, the potential ecological risk index decreased from 46.3 to 4.8 because the unstable fraction converted to organic-sulfide bonds and residues. Biochar prepared at 600 °C was the most stable and met the World Health Organization's phyto-availability standards (Cu 10 mg/kg, Zn 0.6 mg/kg). Fourier transform infrared spectroscopy and X-ray diffraction analyses indicated that endogenous heavy metals were stabilized by complexation with organic matter and precipitated as metal-phosphate forms. After 40 cycles of wet-dry aging, the leachability of heavy metals (Cu 6.0 mg/kg, Zn 460.6 mg/kg) from biochar was still lower than that of swine manure (Cu 102.5 mg/kg and Zn 704.9 mg/kg), indicating the long-term stability of the heavy metals in the biochar. Pyrolysis dramatically lowered the environmental threat posed by endogenous heavy metals, demonstrating the applicability of swine manure-derived biochar compared to manure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous contaminants which are also found in drinking water. Concentration levels in drinking water vary widely and range from a very low contribution to total daily exposure for humans to being the major source of uptake of PFAS. PFAS concentrations in Norwegian drinking water has been rarely reported. We investigated concentrations of 31 PFAS in 164 water samples, representing both source water (i.e., before drinking water treatment) and finished drinking water. Samples were taken from 18 different water bodies across Norway. The 17 waterworks involved supply drinking water to 41 % of the Norwegian population. Only four of the waterworks utilised treatment involving activated carbon which was able to significantly reduce PFAS from the source water. Samples of source water from waterworks not employing activated carbon in treatment were therefore considered to represent drinking water with regards to PFAS (142 samples). All samples from one of the water bodies exceeded the environmental quality standard (EQS) for perfluorooctane sulfonic acid (PFOS) according to the water framework directive (0.65 ng/L). No concentrations exceeded the sum of (20) PFAS (100 ng/L) specified in the EU directive 2020/2184 for drinking water. Several EU countries have issued lower guidelines for the sum of the four PFAS that the European Food Safety Authority (EFSA) has established as the tolerable weekly intake (TWI) for PFOS, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS). Denmark and Sweden have guidelines specifying 2 and 4 ng/L for the sum of these PFAS. Only one of the 142 drinking water samples exceeded the Danish TWI and contained a sum of 6.6 ng/L PFAS. A population exposure model, for individuals drinking water from the investigated sources, showed that only 0.5 % of the population was receiving PFAS concentrations above the Danish limit of 2 ng/L., Competing Interests: Declaration of competing interest Merete Grung reports financial support was provided by Norwegian Water Association. The participating waterworks paid Norwegian Institute for Water Research (NIVA) for analysing the PFAS in their water samples. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Sleep deprivation in adolescents is a common but serious public health issue. Adolescents often have a progressive circadian delay and suffer from insufficient sleep during weekdays due to the school schedule. Temporal patterns in internet search activity data can provide relevant information for understanding the characteristic sleep problems of the adolescent population., Objective: We aimed to reveal whether adolescents exhibit distinct temporal seasonal and weekly patterns in internet search activity on insomnia compared to adults., Methods: We hypothesized that adolescents exhibit larger variations in the internet search volume for insomnia, particularly in association with the school schedule (e.g., academic vacations and weekends). We extracted the daily search volume for insomnia in South Korean adolescents (13-18 years old), adults (19-59 years old), and young adults (19-24 years old) during the years 2016-2019 using NAVER DataLab, the most popular search engine in South Korea. The daily search volume data for each group were normalized with the annual median of each group. The time series of the search volume was decomposed into slow fluctuation (over a year) and fast fluctuation (within a week) using fast Fourier transform. Next, we compared the normalized search volume across months in a year (slow fluctuation) and days in a week (fast fluctuation)., Results: In the annual trend, 2-way ANOVA revealed a significant (group) × (month) interaction (P<.001). Adolescents exhibited much greater seasonal variations across a year than the adult population (coefficient of variation=0.483 for adolescents vs 0.131 for adults). The search volume for insomnia in adolescents was notably higher in January, February, and August, which are academic vacation periods in South Korea (P<.001). In the weekly pattern, 2-way ANOVA revealed a significant (group) × (day) interaction (P<.001). Adolescents showed a considerably increased search volume on Sunday and Monday (P<.001) compared to adults. In contrast, young adults demonstrated seasonal and weekly patterns similar to adults., Conclusions: Adolescents demonstrate distinctive seasonal and weekly patterns in internet searches on insomnia (ie, increased search in vacation months and weekend-weekday transitions), which are closely associated with the school schedule. Adolescents' sleep concerns might be potentially affected by the disrupted daily routine and the delayed sleep phase during vacations and weekends. As we demonstrated, comparing various age groups in infodemiology and infoveillance data might be helpful in identifying distinctive features in vulnerable age groups., (©Kwangyeol Baek, Jake Jeong, Hyun-Woo Kim, Dong-Hyeon Shin, Jiyoung Kim, Gha-Hyun Lee, Jae Wook Cho. Originally published in JMIR Formative Research (https://formative.jmir.org), 11.10.2024.)

Targeted protein degradation and induced proximity refer to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of glues remains challenging, unbiased discovery methods are needed to unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for the unbiased identification of molecular glue targets. By mapping the targets of 20 CRBN-binding molecular glues, we identify 298 protein targets and demonstrate the utility of enrichment methods for identifying novel targets overlooked using established methods. We use a computational workflow to estimate target confidence and perform a biochemical screen to identify a lead compound for the new non-ZF target PPIL4. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying new drug-induced protein interactions in cell lysates., Competing Interests: E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Stelexis Biosciences, and Neomorph, Inc. (also board of directors). He is an equity holder and SAB member for Avilar Therapeutics, Photys Therapeutics, and Ajax Therapeutics and an equity holder in Lighthorse Therapeutics and Anvia Therapeutics. E.S.F. is a consultant to Novartis, EcoR1 capital, Odyssey and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer and Astellas. K.A.D receives or has received consulting fees from Kronos Bio and Neomorph Inc. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Lighthorse, Inception, Matchpoint, Shenandoah (board member), Larkspur (board member) and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline and Sanofi.

Objectives: This study investigated the impact of the COVID-19 pandemic and associated control strategies on the incidence of appendicitis in Seoul, using data from 2018 to 2020 from South Korea's National Health Insurance., Methods: We analyzed records of total, complicated, and uncomplicated appendicitis cases, as well as the ratio of complicated to uncomplicated appendicitis, using natural spline and piecewise regression models to identify trends and breakpoints. Bayesian structural time-series (BSTS) models were used to evaluate the causal impact of social distancing on appendicitis incidences., Results: The spline regression analysis indicated decreasing trends in both total and uncomplicated appendicitis cases. Conversely, the incidence of complicated appendicitis and the ratio of complicated to uncomplicated cases increased. Breakpoints for a decline in uncomplicated appendicitis and a rise in the ratio occurred at 31 weeks in 2020 (95% confidence interval [CI], 23.2 to 38.8) and at 33.9 weeks (95% CI, 28.3 to 39.6), respectively. The BSTS model demonstrated a 7.8% reduction in total appendicitis cases (95% credible interval [CrI], -12.0% to -3.3%). It also showed a 17% decrease in uncomplicated cases (95% CrI, -22% to -12%) and increases of 13% (95% CrI, 4.9% to 22.0%) in complicated cases and 39% (95% CrI, 27.0% to 53.0%) in the ratio of complicated to uncomplicated appendicitis., Conclusion: The COVID-19 pandemic resulted in a decrease in both total and uncomplicated appendicitis cases, while the number of complicated cases increased. Reduced medical visits likely accounted for these changes. Strategies are needed to manage changes in disease pathophysiology resulting from altered healthcare utilization during health crises.

Electrochemical oxidation has emerged as an effective and straightforward technology for groundwater remediation. While recent studies have investigated parameters such as current, electrolyte composition, and electrode materials, most have been conducted using small-scale batch or flow reactors, limiting their applicability to real-world conditions. In this study, a pilot-scale sandbox reactor was employed to simulate realistic groundwater conditions and assess the removal of sulfanilamide, a model organic contaminant. Various electrode configurations were systematically evaluated to identify the key operational parameters influencing pollutant removal efficiency, providing insights for practical applications in groundwater treatment. This study proposes three configurations, including a single well with the anode and cathode, a double well with the separated anode and cathode, and an e-barrier with electrodes separately mounted inside a permeable barrier. Single well had the lowest removal efficiency (60%) because cathodic reaction inhibited the anodic oxidation. A double well with a separate anode and cathode can achieve 80% removal efficiency. However, effluent pH can reach up to 13.2, which can adversely impact groundwater. Meanwhile, the e-barrier not only achieved complete removal, but also maintained a neutral pH of 7.0 over 30 days. The e-barriers proved to be the most effective configuration based on their removal efficiency (100%) while yielding an effluent with neutral pH. The energy consumption of the e-barrier was most effective at 1.54 kWh/m 3 , while the other configurations were 5.40 and 22.18 kWh/m 3 . E-barriers are deemed a very reasonable configuration, both in terms of removal efficiency and practical application in groundwater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hydrogel is widely used for the sustained delivery of bioactive molecules that can treat various injuries, diseases, and tissue defects. However, inserting hydrogel implants without disrupting their functionality and microstructure often requires a large incision, leading to potential complications, such as infection, scarring, and pain. The gel implant is often manually rolled and inserted through a catheter for a minimally invasive delivery. However, success heavily depends on the user's skills, which can inadvertently damage the implant. To address this issue, we developed a reconfigurable hydrogel patch that can self-fold into a small tube and unfold spontaneously after implantation through a catheter. The hydrogel path was assembled by layering a drug-releasing poly(ethylene glycol) diacrylate (PEGDA) hydrogel sheet onto a PEGDA and polyethylenimine (PEI) hydrogel sheet, which rapidly swells and degrades homogeneously at controlled rates. The dynamics of the self-folding and unfolding process could be controlled by differences in the expansion ratio and elastic modulus between the two gel layers according to a mathematical model that closely matched experimental results. The unfolding process triggered a sustained release of the protein cargo. Specifically, the reconfigurable gel loaded with angiopoietin 1 significantly enhanced neovascularization, nearly doubling the vascular density compared to the control group following implantation through a tube with 15% smaller diameter than the original shape of the gel patch. This gel biopatch will be broadly useful for the minimally invasive delivery of a wide array of therapeutic molecules, potentially enhancing therapeutic outcomes.

Purpose: This study aimed to investigate the relationship between meteorological factors, specifically temperature and precipitation, and the incidence of appendicitis in Seoul, South Korea., Methods: Using data from the National Health Insurance Service spanning 2010-2020, the study analyzed 165,077 appendicitis cases in Seoul. Time series regression modeling with distributed-lag non-linear models was employed., Results: Regarding acute appendicitis and daily average temperature, the incidence rate ratio (IRR) showed an increasing trend from approximately - 10 °C to 10 °C. At temperatures above 10 °C, the increase was more gradual. The IRR approached a value close to 1 at temperatures below - 10 °C and above 30 °C. Both total and complicated appendicitis exhibited similar trends. Increased precipitation was negatively associated with the incidence of total acute appendicitis around the 50 mm/day range, but not with complicated appendicitis., Conclusions: The findings suggest that environmental factors, especially temperature, may play a role in the occurrence of appendicitis. This research underscores the potential health implications of global climate change and the need for further studies to understand the broader impacts of environmental changes on various diseases., (© 2024. The Author(s) under exclusive licence to International Society of Biometeorology.)

There is limited research on the factors that impact mental distress among Korean American (KA) church leaders even though their unique social situation can create many barriers to seeking mental health assistance. This study compared factors impacting mental distress and help-seeking behaviors between KA church leaders (CLs) and church members (CMs) in the greater Los Angeles area. The respondents ( N = 243) were mostly female, married, educated, first-generation immigrants with a mean age of 47.9 years ( SD = 19.7). The Hopkins Symptoms Checklist 10 was used to measure anxiety and depression. Hierarchal linear regressions showed that health status exerted the strongest effect on both anxiety and depression among CLs and CMs. Beyond health status, education (only for depression), informal resource use, and resiliency impacted mental distress scores for CLs. Only resiliency and religious coping predicted depression scores among CMs. To effectively reach this population, community-based organizations and behavioral health specialists should consider collaborating with churches to promote and provide essential mental health support. Our findings also highlight that the needs of church leaders (CLs) and church members (CMs) differ, which should guide the development of culturally tailored interventions that build on the resilience of both groups.

A Gram-stain-negative, obligately aerobic, non-motile, rod-shaped bacterial strain designated SJW1-29 T was isolated from brackish water samples collected from the Seomjin River, Republic of Korea. The purpose of this study was to characterize strain SJW1-29 T and determine its taxonomic position as a potential new genus within the family Spirosomaceae . The strain grew within the range of 10-30 °C (optimum, 25 °C), pH 5.0-10.0 (optimum, 7.0), and 1-4% NaCl (optimum, 3%). Phylogenetic analysis based on the 16S rRNA gene revealed that strain SJW1-29 T belongs to the family Spirosomaceae and is closely related to Persicitalea jodogahamensis Shu-9-SY12-35C T (91.3% similarity), Rhabdobacter roseus R491 T (90.6%), and Arundinibacter roseus DMA-K-7a T (90.0%), while the similarities to strains within the order Cytophagales were lower than 90.0%. The genome is 7.1 Mbp with a G+C content of 50.7 mol%. The use of genome-relatedness indices confirmed that this strain belongs to a new genus. The major polar lipid profile consisted of phosphatidylethanolamine, and MK-7 was the predominant menaquinone. The predominant fatty acids were summed feature 3 (C 16:1 ω 7 c and/or C 16:1 ω 6 c ), iso-C 15:0 , iso-C 17:0 3-OH, and C 16:0 , representing more than 80% of the total fatty acids. The phenotypic, chemotaxonomic, genetic, and phylogenetic properties suggest that strain SJW1-29 T represents a novel species within a new genus in the family Spirosomaceae , for which the name Salmonirosea aquatica gen. nov., sp. nov., is proposed. The type strain of Salmonirosea aquatica is SJW1-29 T (=KCTC 72493 T = NBRC 114061 T = FBCC-B16924 T ).

Background and Aims: Drug-induced liver injury (DILI) is a major failure mode in pharmaceutical development. This study aims to address the limitations of existing preclinical models by assessing a high-throughput, microfluidic liver-on-a-chip system, termed "Curio Barrier Liver Chips," and its capacity to recapitulate the effects of chronic hepatotoxic drug treatment through metabolic and phenotypic characterization., Methods: Curio Barrier liver chips (Curiochips), fabricated in an 8 × 2 well configuration, were utilized to establish three dimensional liver organoid cultures. Human-induced pluripotent stem cells were differentiated into human liver organoids, and their viability, liver-specific functions, and pharmacological responses were assessed over 28 days., Results: The Curiochips successfully maintained liver physiology and function, showing strong albumin secretion and cytochrome (CYP) P450 activities for 28 days. Unlike traditional models requiring millimolar drug concentrations to detect hepatotoxicity, this platform showed increased sensitivity for acetaminophen and fialuridine at micromolar concentrations. In situ differentiation of foregut spheroids to liver organoids was also achieved, further simplifying the establishment of liver chips. Furthermore, the chips demonstrated viability, function, and DILI responsiveness for 28 days, making this an improved model for studying idiosyncratic DILI with prolonged drug exposure and high-throughput capabilities compared to other available systems or primary human hepatocytes., Conclusion: The Curiochips offer an advanced, miniaturized in vitro model for early-stage drug development and a sensitive, responsive, and cost-effective means to detect direct hepatotoxicity. Induced pluripotent stem cell liver organoids, in conjunction with the Curiochip, deliver a high-throughput platform with robust functionality and pharmacological responsiveness that make it a promising tool for improving the prediction and understanding of DILI risk prediction, especially with prolonged drug exposure. The model also opens new avenues for research in other chronic liver diseases., (© 2024 The Authors.)

Mesenchymal stromal cells (MSCs) continue to be proposed for clinical investigation to treat myriad diseases given their purported potential to stimulate endogenous regenerative processes, such as angiogenesis. However, MSC functional heterogeneity has hindered clinical success and still poses a substantial manufacturing challenge from a product quality control perspective. Here, a quantitative bioassay based on an enhanced-throughput is described, microphysiological system (MPS) to measure the specific bioactivity of MSCs to stimulate angiogenesis as a potential measure of MSC potency. Using this novel bioassay, MSCs derived from multiple donors at different passages are co-cultured with human umbilical vein endothelial cells and exhibit significant heterogeneity in angiogenic potency between donors and cell passage. Depending on donor source and cellular passage number, MSCs varied in their ability to stimulate tip cell dominant or stalk cell dominant phenotypes in angiogenic sprout morphology which correlated with expression levels of hepatocyte growth factor (HGF). These findings suggest that MSC angiogenic bioactivity may be considered as a possible potency attribute in MSC quality control strategies. Development of a reliable and functionally relevant potency assay for measuring clinically relevant potency attributes of MSCs will help to improve consistency in quality and thereby, accelerate clinical development of these cell-based products., (© 2023 Wiley‐VCH GmbH.)

Electrochemical advanced oxidation processes (EAOPs) are effective in removing persistent contaminants from groundwater. However, their practical applicability depends significantly on various site-specific characteristics. Therefore, the primary objective of this investigation was to study the feasibility of EAOPs and pyrite, which is a sulfide mineral, to effectively remove the mixture of arsenic (As (III)), chromium (Cr (VI)), and sulfanilamide in groundwater. We conducted a comparison of three systems: (1) EAOP alone, (2) pyrite alone, and (3) a combined EAOP and pyrite system. In EAOP alone, sulfanilamide was effectively oxidized (80%), while the electrochemical transformation of As(III)/Cr(VI) into As(V)/Cr(III) was limited. In just the pyrite system, As(III), Cr(VI), and sulfanilamide were adsorbed onto the surface of pyrite (60%, 20%, and 18%). Neither the EAOP nor the pyrite system alone could effectively treat the contaminants mixture. Nonetheless, the combined system completely removed As(III), Cr(VI), and sulfanilamide by the synergistic reaction. This could be attributed to the formation of green rust, a natural adsorbent mineral produced as a reaction of dissolved iron, generated via electrochemical pyrite oxidation, with the groundwater electrolyte (e.g., CO 3 or SO 4 ). This system harmonized the combined approach of EAOP and pyrite to effectively eliminate both organic and inorganic contaminants. ENVIRONMENTAL IMPLICATION: A paper proposed electrochemical oxidation (EO) with pyrite to remove both organic and inorganic contaminants from groundwater. The removal performance of the combined system was evaluated, and the synergistic mechanism was revealed. The combination of EO and pyrite with synergistic removal effectively removed the mixture of both contaminants. This could be attributed by the formation of green-rust by electrochemical activation for pyrite. Compared to the single system of EO and pyrite alone, the combined system with EO and pyrite improved removal performance. Results suggested that the combined system could be used for green groundwater remediation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Symptomatic hypoglycemia is a common problem in the emergency department (ED). However, without appropriate recognition and management, hypoglycemia remains a potentially fatal condition. The cause of sudden death associated with hypoglycemia might be attributed to cardiac arrhythmias and hypoxia with seizures. Despite advances in diabetes mellitus management and social background, the frequency and characteristics of patients with hypoglycemia-related seizures have remained unknown. Hence, our study aimed to investigate the frequency and characteristics of patients with hypoglycemia presenting with seizures in the ED., Methods: This retrospective observational study was conducted in a single tertiary care center. Patient information was retrieved from the final diagnostic records in the ED. We reviewed all medical records and included patients with symptomatic hypoglycemia aged 16 years or older. The primary outcome was the frequency of seizures in patients with hypoglycemia. We also compared the initial blood sugar levels of the patients with and without seizures., Results: We included a total of 380 patients (median age, 72 years, IQR 64-80 years; median initial blood sugar, 34 mg/dL, IQR 24-46; 62.9% male). Nineteen of 380 patients (5.0%) had seizures. Although 16 of the 19 patients had diabetes mellitus, none of the 19 patients had a history of epilepsy. The initial blood sugar levels of the patients with and without seizures were not significantly different ( p  = 0.97)., Conclusion: Approximately 5% of the patients with hypoglycemia presented with seizures. Blood glucose levels of hypoglycemic patients with and without seizures did not differ., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: This study investigated the prevalence and associated factors of musculoskeletal pain among professional dancers who experienced a lapse in group practice due to coronavirus disease 2019., Methods: General characteristics, practice time, region of musculoskeletal pain due to injury using the visual numeric scale (VNS), and causative motion were surveyed among professional dancers. Pain of VNS 0 to 3 was categorized as "no or minor," 4 to 6 was categorized as "moderate," and 7 to 10 was categorized as "severe." The causal motions of musculoskeletal pain were analyzed according to body region. Factors other than motion associated with pain were also analyzed., Results: In total, 368 participants were included. In the univariate analysis, age and practice time were positively associated with "moderate" pain. Practice time, dance experience, and postural accuracy were positively associated with "severe" pain, as was performing Korean traditional dance. In the multivariable analysis, practice time, group practice, and age were positively associated with pain of VNS 4 to 10, and practice time, group practice, and Korean traditional dance were positively associated with pain of VNS 7 to 10., Conclusion: Among the factors related to dancer training, practice time, group practice, and dance type affect the occurrence of pain.

Paxlovid is the first approved oral treatment for coronavirus disease 2019 and includes nirmatrelvir, a protease inhibitor targeting the main protease (M pro ) of SARS-CoV-2, as one of the key components. While some specific mutations emerged in M pro were revealed to significantly reduce viral susceptibility to nirmatrelvir in vitro , there is no report regarding resistance to nirmatrelvir in patients and animal models for SARS-CoV-2 infection yet. We recently developed xenograft tumors derived from Calu-3 cells in immunodeficient mice and demonstrated extended replication of SARS-CoV-2 in the tumors. In this study, we investigated the effect of nirmatrelvir administration on SARS-CoV-2 replication. Treatment with nirmatrelvir after virus infection significantly reduced the replication of the parental SARS-CoV-2 and SARS-CoV-2 Omicron at 5 days post-infection (dpi). However, the virus titers were completely recovered at the time points of 15 and 30 dpi. The virus genomes in the tumors at 30 dpi were analyzed to investigate whether nirmatrelvir-resistant mutant viruses had emerged during the extended replication of SARS-CoV-2. Various mutations in several genes including ORF1ab, ORF3a, ORF7a, ORF7b, ORF8, and N occurred in the SARS-CoV-2 genome; however, no mutations were induced in the M pro sequence by a single round of nirmatrelvir treatment, and none were observed even after two rounds of treatment. The parental SARS-CoV-2 and its sublineage isolates showed similar IC 50 values of nirmatrelvir in Vero E6 cells. Therefore, it is probable that inducing viral resistance to nirmatrelvir in vivo is challenging differently from in vitro passage.

SARS-CoV-2 Omicron has the largest number of mutations among all the known SARS-CoV-2 variants. The presence of these mutations might explain why Omicron is more infectious and vaccines have lower efficacy to Omicron than other variants, despite lower virulence of Omicron. We recently established a long-term in vivo replication model by infecting Calu-3 xenograft tumors in immunodeficient mice with parental SARS-CoV-2 and found that various mutations occurred majorly in the spike protein during extended replication. To investigate whether there are differences in the spectrum and frequency of mutations between parental SARS-CoV-2 and Omicron, we here applied this model to Omicron. At 30 days after infection, we found that the virus was present at high titers in the tumor tissues and had developed several rare sporadic mutations, mainly in ORF1ab with additional minor spike protein mutations. Many of the mutant isolates had higher replicative activity in Calu-3 cells compared with the original SARS-CoV-2 Omicron virus, suggesting that the novel mutations contributed to increased viral replication. Serial propagation of SARS-CoV-2 Omicron in cultured Calu-3 cells resulted in several rare sporadic mutations in various viral proteins with no mutations in the spike protein. Therefore, the genome of SARS-CoV-2 Omicron seems largely stable compared with that of the parental SARS-CoV-2 during extended replication in Calu-3 cells and xenograft model. The sporadic mutations and modified growth properties observed in Omicron might explain the emergence of Omicron sublineages. However, we cannot exclude the possibility of some differences in natural infection., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The Montreal Cognitive Assessment (MoCA) is recommended for general cognitive evaluation in Parkinson's disease (PD) patients. However, age- and education-adjusted cutoffs specifically for PD have not been developed or systematically validated across PD cohorts with diverse education levels., Methods: In this retrospective analysis, we utilized data from 1,293 Korean patients with PD whose cognitive diagnoses were determined through comprehensive neuropsychological assessments. Age- and education-adjusted cutoffs were formulated based on 1,202 patients with PD. To identify the optimal machine learning model, clinical parameters and MoCA domain scores from 416 patients with PD were used. Comparative analyses between machine learning., Methods: and different cutoff criteria were conducted on an additional 91 consecutive patients with PD., Results: The cutoffs for cognitive impairment decrease with increasing age within the same education level. Similarly, lower education levels within the same age group correspond to lower cutoffs. For individuals aged 60-80 years, cutoffs were set as follows: 25 or 24 years for those with more than 12 years of education, 23 or 22 years for 10-12 years, and 21 or 20 years for 7-9 years. Comparisons between age- and education-adjusted cutoffs and the machine learning method showed comparable accuracies. The cutoff method resulted in a higher sensitivity (0.8627), whereas machine learning yielded higher specificity (0.8250)., Conclusion: Both the age- and education-adjusted cutoff., Methods: and machine learning., Methods: demonstrated high effectiveness in detecting cognitive impairment in PD patients. This study highlights the necessity of tailored cutoffs and suggests the potential of machine learning to improve cognitive assessment in PD patients.

Background: Research on job training and job satisfaction has been conducted from various perspectives. Job training is thought to be associated with job satisfaction, which is known as an important factor for depression among workers. We hypothesized that job training duration could influence depression through potential mediators (job satisfaction, motivation to work, and work engagement)., Methods: This study encompassed participants from the sixth Korean Working Conditions Survey (KWCS), conducted between 2020 and 2021. To show the relationships between demographic or occupational characteristics and risk of depression, a χ 2 test was conducted. The association between job training duration, potential mediators, and risk of depression was analyzed by constructing multiple logistic regression models. The mediating effects of potential mediators on job training duration and risk of depression was evaluated with flexible mediation analysis with weighting-based methods., Results: The final study population consisted of 25,294 participants. Longer job training duration significantly decreased risk of depression after adjusting for confounders. In the group that received the longest job training duration (≥ 10 days), compared with the group without job training, the odds ratio (OR) for high risk of depression was 0.46 (95% confidence interval [CI], 0.39-0.54). Each three potential mediators showed statistically significant indirect effects and direct effect. Although indirect effects were not strong compared to direct effect, motivation to work had the strongest mediating effect in this study, with an OR of 0.94 (95% CI, 0.92-0.95)., Conclusions: Job training duration was found to have a statistically significant negative association on the risk of depression, and three mediators partially mediating this effect. Although the mechanism was unknown, our findings suggest that job training has a positive influence on workers' mental health. Furthermore, by suggesting the possibility of other pathways existing between job training and depression, we provide directions for future research., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Korean Society of Occupational & Environmental Medicine.)

This study compares rivaroxaban-loaded polymeric microsphere systems with three types of surface microstructure. Three types of polymeric microspheres loaded with rivaroxaban were fabricated using a spray-drying technique: solvent-evaporated, surface-attached, and solvent-wet microspheres, depending on whether the drug and additives used are soluble in the solvent. The solvent-evaporated and surface-attached microspheres had a rivaroxaban/polyvinylpyrrolidone/sodium lauryl sulfate (SLS) weight ratio of 1/0.25/2.2, and the solvent-wetted microspheres contained rivaroxaban/polyvinyl alcohol/SLS in equal weight ratio (1/0.25/2). The physicochemical properties of the microspheres were evaluated using scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and particle size distribution analysis. The aqueous solubility and dissolution rate of rivaroxaban in the three types of microspheres were compared to those of the drug powder. The solvent-evaporated, surface-attached, and solvent-wetted microspheres were approximately 208, 140, and 172 times as soluble as the drug powder, and the final dissolution rate (120 min) was approximately 5, 2, and 4 times that of the drug powder, respectively. In addition, the oral bioavailability increased by approximately 2, 1.3, and 1.6 times compared to that of the drug powder (area under drug concentration-time curve: 2101.3 ± 314.8, 1325.2 ± 333.3, and 1664.0 ± 102.6 h·ng/mL, respectively). Finally, the solvent-evaporated microspheres showed the greatest improvement (solvent evaporating microspheres > solvent wetted microspheres > surface-attached microspheres ≥ drug powder). Therefore, the solvent-evaporated microspheres may represent a novel oral dosage form that improves the oral bioavailability of rivaroxaban, a poorly soluble drug., (© 2023. Controlled Release Society.)

This study discloses a dataset of electric vehicles' (EVs') charging transactions at a scale for multi-faceted analysis from both EV charger and user perspectives. The data comprises whole sessions that occurred during a charging operation company's annual commercial operation period, specifically including identifiers and charger location categories. For data acquisition, machine-to-machine wireless communication system with proper retransmission for interruption is utilised. The entire dataset is newly collected and is available with 72,856 sessions from 2,337 EV users and 2,119 chargers. The dataset can be used in a variety of ways for the functioning of power systems and markets, including EV charging service businesses, charger installation siting, demand transaction market design, and long-term investment planning of EV-related infrastructure., (© 2024. The Author(s).)

Metal-based anodes have been used for a long time in the electrochemical oxidation processes to remediate groundwater. However, the high cost of this technique as well as the release of potentially toxic metals (ex, lead), are major barriers being fully implemented. As an alternative of metal-based anodes, in recent years, carbon-based anodes have been paid attention due to their eco-friendliness and cost-effectiveness. This study evaluated the oxidation performance of carbon fiber (CF) anode in a flow-through system. The CF anode degraded 45-87% of the target pollutant (sulfanilamide), depending on the current intensity applied. However, no further degradation of sulfanilamide was observed after the cathode, indicating that sulfanilamide degradation occurred mainly at the anode. This study also determined the effect of electrolytes on electrochemical oxidation using chloride (Cl - ), sulfate (SO 4 2- ), bicarbonate (CO 3 - ), and synthetic groundwater. Cl - and SO 4 2- electrolytes were converted electrochemically into active species, thereby enhancing sulfanilamide degradation, while the bicarbonate and groundwater electrolytes inhibited oxidation performance by scavenging hydroxyl radicals. A series of scavenger tests and characterization showed that the direct oxidation and hydroxyl radicals involved the sulfanilamide degradation. Especially, the production of hydroxyl radicals is more favorable in high currents than in low currents. That is, CF anode contributed to the degradation by direct oxidation of carbon-based electrodes and generation of hydroxyl radicals. In summary, this study highlights how a CF anode is capable of effectively degrading organic pollutants via anodic oxidation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Activin A, a member of the TGF-β superfamily, is a homodimer of the inhibin β Α subunit that plays a diversity of roles in biological processes. Because of its multiple functions, significant efforts have been made to produce activin A, however, unsatisfactory results were obtained due to its low level of expression. In this study, a stable CHO cell line exhibiting high expression of rhActivin A was isolated and production of rhActivin A was achieved using the cell line from 11-day fed-batch cultures in a 7.5 L bioreactor. The production rate was 0.22 g/L, substantially higher than those reported in previous studies. The culture supernatant of the bioreactor was used to purify rhActivin A (purity: >99%, recovery rate: 47%). The purified rhActivin A exhibited biological activity, with an EC50 of 3.893 ng/mL and a specific activity of 1.38 × 10 3  IU/mg. The control of process-related impurities in the purified rhActivin A was successful and met the USP recommendations for use in cell therapy. Thus, our production and purification methods were appropriate for large-scale GMP-grade rhActivin A production, which can be used for various purposes including cell therapy.

We recently established a long-term SARS-CoV-2 infection model using lung-cancer xenograft mice and identified mutations that arose in the SARS-CoV-2 genome during long-term propagation. Here, we applied our model to the SARS-CoV-2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS-CoV-2. We observed limited mutations in SARS-CoV-2 Delta during long-term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein. We analyzed two representative isolates, Delta-10 and Delta-12, with both predominant mutations and some additional mutations. Delta-10 and Delta-12 showed lower replication capacity compared with SARS-CoV-2 Delta in cultured cells; however, Delta-12 was more lethal in K18-hACE2 mice compared with SARS-CoV-2 Delta and Delta-10. Mice infected with Delta-12 had higher viral titers, more severe histopathology in the lungs, higher chemokine expression, increased astrocyte and microglia activation, and extensive neutrophil infiltration in the brain. Brain tissue hemorrhage and mild vacuolation were also observed, suggesting that the high lethality of Delta-12 was associated with lung and brain pathology. Our long-term infection model can provide mutant viruses derived from SARS-CoV-2 Delta and knowledge about the possible contributions of emergent mutations to the properties of new variants., (© 2024 Wiley Periodicals LLC.)

Background: Neurodegenerative diseases, including Parkinson's disease, Amyotropic Lateral Sclerosis (ALS) and Alzheimer's disease, present significant challenges for therapeutic development due to drug delivery restrictions and toxicity concerns. Prevailing strategies often employ adeno-associated viral (AAV) vectors to deliver neuroprotective survival genes directly into the central nervous system (CNS). However, these methods have been limited by triggering immunogenic responses and risk of tumorigenicity, resulting from overexpression of survival genes in peripheral blood mononuclear cells (PBMC), thereby increasing the risk of tumorigenicity in specific immune cells. Thus, by coding selectively suppressive microRNA (miRNA) target sequences in AAV genome, we designed CNS-targeted neuroprotective gene expression vector system without leakage to blood cells., Methods: To minimize the potential for transgene contamination in the blood, we designed a CNS-specific AAV system. Our system utilized a self-complementary AAV (scAAV), encoding a quadruple repeated target sequence of the hematopoietic cell-specific miR142-3p at the 3' untranslated region (UTR). As a representative therapeutic survival gene for Parkinson's disease treatment, we integrated DX2, an antagonistic splice variant of the apoptotic gene AIMP2, known to be implicated in Parkinson's disease, into the vector., Results: This configuration ensured that transgene expression was stringently localized to the CNS, even if the vector found its way into the blood cells. A single injection of scAAV-DX2 demonstrated marked improvement in behavior and motor activity in animal models of Parkinson's disease induced by either Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, comprehensive preclinical data adhering to Good Laboratory Practice (GLP) standards revealed no adverse effects in the treated animals., Conclusions: Our CNS-specific vector system, which encodes a survival transgene DX2, signifies a promising avenue for safe gene therapy, avoiding unintended expression of survival gene in blood cells, applicable to various neurodegenerative diseases., (© 2024. The Author(s).)

Objectives: Using cases in the Korean workplace, this study preliminarily investigated whether ISO 45001-certified and non-certified workplaces differ in 4 aspects of occupational safety and health (OSH) management., Methods: Data were obtained from the 2021 Survey on the Status of Safety and Health in the Workplace in Korea. This study used a matched-pair analysis of certified and non-certified workplaces., Results: The results suggest that although ISO 45001-certified workplaces have a more safety-friendly internal institutional context than non-certified workplaces, there is no significant difference in the number of injuries and fatalities., Conclusions: The results indicate that ISO 45001-certified workplaces do not achieve better OSH performance than non-certified workplaces because ISO 45001 remains in the early stages of expansion, and certification does not require the achievement of OSH performance. A longitudinal analysis is needed to confirm the accurate outcomes of ISO 45001 certification., (© The Author(s) [2023]. Published by Oxford University Press on behalf of Journal of Occupational Health.)

Background: Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2 ought to be a therapeutic target for the disease, regrettably, it is deemed undruggable due to its non-enzymatic nature and predominant localization within the tRNA synthetase multi-complex. Instead, AIMP2 possesses an antagonistic splice variant, designated DX2, which counteracts AIMP2-induced apoptosis in the p53 or inflammatory pathway. Consequently, we examined whether DX2 competes with AIMP2 for PARP-1 activation and is therapeutically effective in Parkinson's disease., Methods: The binding affinity of AIMP2 and DX2 to PARP-1 was contrasted through immunoprecipitation. The efficacy of DX2 in neuronal cell death was assessed under 6-OHDA and H2O2 in vitro conditions. Additionally, endosomal and exosomal activity of synaptic vesicles was gauged in AIMP2 or DX2 overexpressed hippocampal primary neurons utilizing optical live imaging with VAMP-vGlut1 probes. To ascertain the role of DX2 in vivo, rotenone-induced behavioral alterations were compared between wild-type and DX2 transgenic animals. A DX2-encoding self-complementary adeno-associated virus (scAAV) was intracranially injected into 6-OHDA induced in vivo animal models, and their mobility was examined. Subsequently, the isolated brain tissues were analyzed., Results: DX2 translocates into the nucleus upon ROS stress more rapidly than AIMP2. The binding affinity of DX2 to PARP-1 appeared to be more robust compared to that of AIMP2, resulting in the inhibition of PARP-1 induced neuronal cell death. DX2 transgenic animals exhibited neuroprotective behavior in rotenone-induced neuronal damage conditions. Following a single intracranial injection of AAV-DX2, both behavior and mobility were consistently ameliorated in neurodegenerative animal models induced by 6-OHDA., Conclusion: AIMP2 and DX2 are proposed to engage in bidirectional regulation of parthanatos. They physically interact with PARP-1. Notably, DX2's cell survival properties manifest exclusively in the context of abnormal AIMP2 accumulation, devoid of any tumorigenic effects. This suggests that DX2 could represent a distinctive therapeutic target for addressing Parkinson's disease in patients., (© 2024. The Author(s).)

Tactile function is essential for human life as it enables us to recognize texture and respond to external stimuli, including potential threats with sharp objects that may result in punctures or lacerations. Severe skin damage caused by severe burns, skin cancer, chemical accidents, and industrial accidents damage the structure of the skin tissue as well as the nerve system, resulting in permanent tactile sensory dysfunction, which significantly impacts an individual's daily life. Here, we introduce a fully-implantable wireless powered tactile sensory system embedded artificial skin (WTSA), with stable operation, to restore permanently damaged tactile function and promote wound healing for regenerating severely damaged skin. The fabricated WTSA facilitates (i) replacement of severely damaged tactile sensory with broad biocompatibility, (ii) promoting of skin wound healing and regeneration through collagen and fibrin-based artificial skin (CFAS), and (iii) minimization of foreign body reaction via hydrogel coating on neural interface electrodes. Furthermore, the WTSA shows a stable operation as a sensory system as evidenced by the quantitative analysis of leg movement angle and electromyogram (EMG) signals in response to varying intensities of applied pressures., (© 2024. The Author(s).)

Antibiotics contaminate diverse ecosystems and threaten human health. In ecosystems including water, sediment, and soil, the amount of antibiotics present is tiny compared to the amount of natural organic matter. However, most studies have ignored the co-presence of natural organic matter in the adsorption of target antibiotics. In this study, we quantitatively evaluated the effect of co-presenting natural organic matter on the adsorption of sulfamethazine (SMZ) through batch and column experiments using low-grade charcoal, an industrial by-product. SMZ was used as a model antibiotic compound and humic acid (HA) was used to represent natural organic matter. The co-presence of 2000 mg/L HA (400 times the concentration of SMZ) lowered the adsorption rate of SMZ from 0.023 g/mg·min to 0.007 g/mg·min, and the maximum adsorption capacity from 39.8 mg/g to 15.6 mg/g. HA blocked the charcoal's pores and covered its surface adsorption sites, which dramatically lowered its capacity to adsorb SMZ. Similar results were obtained in the flow-through column experiments, where the co-presence of natural organic matter shortened the lifetime of the charcoal. As a result, the co-presence of a relatively high concentration of natural organic matter can inhibit the adsorption of SMZ and likely other antibiotic compounds, and thus the presence of natural organic matter should be accounted for in the design of adsorption processes to treat antibiotics in water., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a significant concern, particularly among patients taking bisphosphonates (BPs), denosumab, and selective estrogen receptor modulators (SERMs) for osteoporosis. Despite the known risks, large-scale cohort studies examining the incidence and severity of MRONJ are lacking. We aimed to ascertain the incidence and risk of MRONJ among these patients, whom we stratified by age groups, medication types, and duration of use., Methods: We utilized data from the National Health Insurance Service's sample cohort database, focusing on patients aged 40 years and above diagnosed with osteoporosis. The patients were divided into three groups: those prescribed BPs only, those prescribed SERMs only, and those prescribed both., Results: The overall incidence rate of MRONJ was 0.17%. A significantly higher incidence rate was observed among those taking osteoporosis medications, particularly among females with a relative risk of 4.99 (95% confidence interval, 3.21-7.74). The SERM group also had an incidence rate comparable to that of the BP group. Severity was assessed based on the invasiveness of the treatment methods, with 71.3% undergoing invasive treatment in the medication group., Conclusion: This study provides valuable insights into the incidence and severity of MRONJ among a large cohort of patients with osteoporosis. It underscores the need for comprehensive guidance on MRONJ risks across different medication groups and sets the stage for future research focusing on specific populations and treatment outcomes.