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Topologically associating domains (TADs) are chromatin domains in the eukaryotic genome. TADs often comprise several sub-TADs. The boundaries of TADs and sub-TADs are enriched in CTCF, an architectural protein. Deletion of CTCF-binding motifs at one boundary disrupts the domains, often resulting in a transcriptional decrease in genes inside the domains. However, it is not clear how TAD and sub-TAD affect each other in the domain formation. Unaffected gene transcription was observed in the β-globin locus when one boundary of TAD or sub-TAD was destroyed. Here, we disrupted β-globin TAD and sub-TAD by deleting CTCF motifs at both boundaries in MEL/ch11 cells. Disruption of TAD impaired sub-TAD, but sub-TAD disruption did not affect TAD. Both TAD and sub-TAD disruption compromised the β-globin transcription, accompanied by the loss of enhancer-promoter interactions. However, histone H3 occupancy and H3K27ac were largely maintained across the β-globin locus. Genome-wide analysis showed that putative enhancer-promoter interactions and gene transcription were decreased by the disruption of CTCF-mediated topological domains in neural progenitor cells. Collectively, our results indicate that there is unequal relationship between TAD and sub-TAD formation. TAD is likely not sufficient for gene transcription, and, therefore, sub-TAD appears to be required. TAD-dependently formed sub-TADs are considered to provide chromatin environments for enhancer-promoter interactions enabling gene transcription., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective: Ultradian rhythms are biological rhythms with periods of a few seconds to a few hours. Along with circadian rhythms, ultradian rhythms influence human physiology. However, such rhythms have not been studied as intensively as circadian rhythms. This study aimed to identify ultradian rest-activity rhythms induced by the dopamine D2/D3 agonist quinpirole in mice., Methods: We used 10 mice from the Institute of Cancer Research. Quinpirole was administered at a dose of 0.5 mg/kg. We assessed free rest-activity using infrared detectors and conducted wavelet analysis to measure the period and its variation. We also used the paired t test to compare ultradian rhythm patterns., Results: Quinpirole did not significantly change total 24-hour locomotor activity ( p = 0.065). However, it significantly increased locomotor activity during the dark phase ( p = 0.001) and decreased it during the light phase ( p = 0.016). In the continuous wavelet transform analysis, the mean period was 5.618 hours before quinpirole injection and 4.523 hours after injection. The period showed a significant decrease ( p = 0.040), while the variation remained relatively consistent before and after quinpirole injection., Conclusion: This study demonstrated ultradian rest-activity rhythms induced by quinpirole using wavelet analysis. Quinpirole-induced ultradian rhythms exhibited rapid oscillations with shortened periods and increased activity during the dark phase. To better understand these changes in ultradian rhythms caused by quinpirole, it is essential to compare them with the effects of other psychopharmacological agents. Furthermore, investigating the pharmacological impact on ultradian rest-activity rhythms may have valuable applications in clinical studies.

Gelsolin is known as one of the actin-binding proteins capable of severing and capping filamentous actin, and of undergoing structural changes in the presence of calcium ions to interact with actin filaments. In this study, single-particle 3D reconstruction using electron microscopy (EM) revealed that, in the presence of calcium, the structure of gelsolin undergoes structural changes before interacting with actin. These differences are subtle with similarities, as confirmed by the EM map. According to the results of the molecular dynamics simulations, these nuanced structural differences primarily manifest at the domain level when calcium is present. These results provide structural evidence that, in the presence of calcium, gelsolin enters a phase of conformational preparation to transition into the active state. This process enables gelsolin to bind to actin, whereupon gelsolin undergoes more drastic structural changes upon interaction with actin filaments, which allows it to participate in binding and severing to regulate the cytoskeleton. This is the first visualization of full-length gelsolin, and helps to clarify crucial aspects of the as of yet incompletely understood interaction between gelsolin and actin., 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 Inc. All rights reserved.)

Diazeniumdiolates spontaneously release nitric oxide (NO) in aqueous solutions. Therefore, protected diazeniumdiolates have been developed for the controlled administration of NO to specific targets. Diazeniumdiolates with photoprotecting groups are useful for spatiotemporal NO delivery. To develop photoactivated NO donors, understanding the photodissociation dynamics of photoprotected diazeniumdiolates is essential. The dynamics of photoexcited V-PYRRO/NO (a well-studied liver-selective NO prodrug) was investigated to understand the photodissociation mechanism of protected diazeniumdiolates at the molecular level. Upon excitation at 305 nm, the N═N bond of V-PYRRO/NO was cleaved within 0.3 ps, producing N-nitrosopyrrolidine and CH 2 ═CHON. CH 2 ═CHON, the first oxynitrene directly observed in the solution in real-time, was formed in the singlet state and rearranged into CH 2 ═CHNO with a time constant of 16 ± 5 ns. The calculated potential energy surfaces of the excited states confirmed the unusual breakage of the N═N bond. The findings can be utilized to develop more effective photoactivated diazeniumdiolates.

Objective: This study aimed to investigate the effect of three-dimensional (3D) printed clear aligners (CA) with different designs on the extrusion of mandibular premolars using a force/moment measurement system and digital image correlation (DIC)., Methods: The forces and moments applied to the mandibular canines, first and second premolars were measured using a multi-axis force/moment transducer when an extrusion of 0.5 mm was planned, assuming the mandibular first premolars were intruded by 1 mm. In addition, displacement and strain changes in the CA were analyzed using the DIC method. CA designs were categorized based on the presence of first premolar attachment and subdivided into equigingival margins, 1-mm extended margins, equi-margins with 1-mm thickness and height, and equi-margins with 1-mm reduced buccolingual width. The CA was printed directly at a thickness of 0.5 mm, and the experiments were conducted at 37°C., Results: The results showed that attachment played an important role in the extrusion of first premolars in both the force/moment measurement system and the DIC method. Intrusion was observed without attachment, even though extrusion was planned. CA designs apply greater force to the cervical region by extending the margin or reducing the buccolingual width, thereby improving extrusion efficiency., Conclusions: Force and moment changes in direct 3D printed CA are complex and difficult to predict; however, modifying aligner designs, such as extending the margin or reducing buccolingual width, and using appropriate attachments could minimize unwanted tooth movement, optimize planned treatment, and increase treatment predictability.

Salinity poses a significant challenge to plant growth and crop productivity by adversely affecting crucial processes, including photosynthesis. Efforts to enhance abiotic stress tolerance in crops have been hindered by the trade-off effect, where increased stress resistance is accompanied by growth reduction. In this study, we identified and characterized a plastocyanin gene (PaPC) from the Antarctic moss Polytrichastrum alpinum, which enhanced photosynthesis and salt stress tolerance in Arabidopsis thaliana without compromising growth. While there were no differences in growth and salt tolerance between the wild type and Arabidopsis plastocyanin genes (AtPC1 and AtPC2)-overexpressing plants, PaPC-overexpressing plants demonstrated superior photosynthetic efficiency, increased biomass, and enhanced salt tolerance. Similarly, PaPC-overexpressing rice plants exhibited improved yield potential and photosynthetic efficiency under both normal and salt stress conditions. Key amino acid residues in PaPC responsible for this enhanced functionality were identified, and their substitution into AtPC2 conferred improved photosynthetic performance and stress tolerance in Arabidopsis, tobacco, and tomato. These findings not only highlight the potential of extremophiles as valuable genetic resources but also suggest a photosynthesis-based strategy for developing stress-resilient crops without a growth penalty., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Intensive blood pressure (BP) management within 24 hours after successful reperfusion following endovascular thrombectomy (EVT) is associated with worse functional outcomes than conventional BP management in Asian randomized controlled trials. Given the high prevalence of intracranial atherosclerotic stenosis (ICAS) in Asia, ICAS may influence these outcomes., Aims: We aimed to assess whether ICAS affects the outcomes of intensive BP management after successful EVT., Methods: We conducted a secondary analysis of the Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control trial, which enrolled participants from June 2020 to November 2022. Patients with anterior circulation large vessel occlusion (LVO) were stratified into ICAS-related and embolic LVO groups. Clinical outcomes for intensive (target systolic BP<140 mmHg) and conventional BP management (target systolic BP 140-180 mmHg) were analyzed in each group. The primary outcome was a favorable outcome, defined as a modified Rankin Scale score of 0 to 2 at 3 months. Safety outcomes included symptomatic intracerebral hemorrhage within 36 hours and stroke-related death within 3 months., Results: Among 192 patients, 59 were in the ICAS-related LVO group, and 133 were in the embolic LVO group. In the ICAS-related LVO group, the rate of achieving a favorable outcome at 3 months was 37.5% with intensive BP management and 55.6% with conventional management (adjusted OR, 0.49 [95% CI, 0.14-1.75]; P=0.27). In the embolic LVO group, these rates were 29.9% and 42.4%, respectively (adjusted OR, 0.64 [95% CI, 0.28-1.45]; P=0.29). No significant interaction was found (P for interaction=0.68). Additionally, the ICAS-related LVO group receiving intensive BP management had lower rates of successful reperfusion at 24 hours compared to conventional management (67.7% vs 91.7%; P=0.03), while no significant difference was found in the embolic LVO group. A significant interaction effect on successful reperfusion at 24 hours was observed between ICAS-related and embolic LVO groups (P for interaction=0.04). No significant differences in safety outcomes were observed between intensive BP management and conventional management within both ICAS-related LVO and embolic LVO groups., Conclusions: ICAS did not significantly affect outcomes of intensive BP management within 24 hours after successful EVT. After successful reperfusion by EVT, intensive BP management should be avoided regardless of ICAS presence.

Monosodium glutamate (MSG) is a widely used flavor enhancer in processed foods and valued for its ability to enhance the savory taste known as umami. MSG is classified as non-toxic and recognized as a safe food additive with no specific usage restrictions in many countries. However, neurotoxic studies on MSG have primarily focused on neurons, and the effects of MSG on neural stem cells (NSCs) have not been reported. This study aimed to evaluate the neurotoxic effect of MSG on NSCs and hippocampal neurogenesis in a rodent model. In vitro studies showed that MSG induces cytotoxicity in primary neuron cultures but has no toxic effect on NSCs. Furthermore, in vivo studies on 4-week-old male C57BL/6 mice orally administered MSG and sodium chloride (NaCl) for two weeks revealed that neither MSG nor NaCl induced changes in the expressions of neuronal markers or glutamate receptors in the hippocampus. In addition, no differences in NSC proliferation or survival were detected, and MSG did not adversely affect the neuronal differentiation of NSCs. Moreover, neurobehavioral tests showed that MSG treatment did not impair spatial learning and memory. These findings provide a first assessment of the neurotoxic effects of MSG on NSCs and hippocampal neurogenesis., 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 Ltd.)

Background: There is ongoing debate regarding the association between telogen effluvium (TE) and COVID-19, as well as COVID-19 vaccines., Objectives: To investigate the impact of the COVID-19 pandemic and vaccination on the development of TE among patients visiting dermatology clinics in South Korea., Methods: Between 2017 and 2022, data regarding patients with TE and other types of hair loss were collected from 22 hospitals in South Korea. An interrupted time series analysis was conducted, dividing the time into periods before and after the COVID-19 pandemic, as well as before and after the COVID-19 vaccination., Results: There was a significant slope change in the percentage of cases of TE during the postpandemic period (slope change 0.011, 95% confidence interval 0.005-0.017, P < 0.001), but no significant changes were observed after vaccination. The percentage of patients with other types of hair loss was not associated with COVID-19 or vaccination. The retrospective nature of the study may have limited the ability to establish causation., Conclusions: This multicentre study provides insights into the epidemiology of TE, showing a significant increase in cases of TE following the COVID-19 pandemic. However, there was no association between the occurrence of TE and COVID-19 vaccines., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Amid the COVID-19 pandemic, outpatients' concerns about infection risk have increased. It is crucial to understand the factors that contribute to this fear of infection to promote patient safety and encourage outpatients to seek proper follow-up treatment without fear. This study aims to understand the relationship between outpatients' experiences of patient safety and their fear of infection., Design: This was a secondary analysis of national data from the Healthcare Service Experience Survey in 2020., Setting and Participants: A total of 4416 patients with experience using outpatient services in the past year were included in South Korea., Primary and Secondary Outcome Measures: Demographic characteristics, fear of infection and safety experiences were assessed in the original survey. Fear of infection served as the dependent variable, with safety experiences-specifically, patient identification, preinjection explanations, hand hygiene, proper use of injection supplies, skin disinfection and adverse drug reactions-as the independent variables., Results: Approximately 14% of outpatients had a fear of infection when receiving medical care. The unadjusted model showed that all patient safety categories were determinants of fear of infection, and the multivariate logistic model identified hand hygiene and medication safety experiences as significant factors associated with fear of infection., Conclusions: This study revealed that patient safety experiences are associated with fear of infection in outpatient settings. Improving healthcare professionals' hand hygiene and managing adverse drug reactions are crucial for enhancing patient safety., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Novel palladium and nickel-sulfur clusters were synthesized using a diamidocarbene-derived carbon disulfide ligand. Structural characterization revealed a tetranuclear metal-sulfur cluster geometry with each metal center exhibiting square-planar coordination. The ligand was redox-active, accommodating oxidation states ranging from 0 to -2.

Objective: To evaluate the effectiveness of a community-based structured exercise program, compared to usual care, in enhancing physical, functional, and psychological outcomes for ambulatory individuals with spinal cord injury (SCI)., Design: Randomized controlled trial comparing exercise group with usual care group., Setting: One university-affiliated rehabilitation hospital., Participants: Fifty-seven participants with chronic SCI who could walk more than 10 meters., Interventions: A supervised 20-session program focusing on flexibility, aerobic, and strengthening exercises was provided over 8 weeks for the exercise group, while the usual care group maintained their regular daily exercise routines., Main Outcome Measures: Primary outcome included 6-minute walk test, while secondary outcomes assessed EuroQol-5 Dimensions 5-Level, Spinal Cord Independence Measure III, Berg Balance Scale (BBS), timed up and go, grip strength, 30-second sit to stand (30-STS) test, sit and reach test (SRT), Beck Anxiety Inventory, Beck Depression Inventory, and bioelectrical impedance analysis., Results: The 51 participants were allocated to intervention (n=36) and usual care (n=15) groups, consisting of 34 males and 17 females (average age 59.78±13.19 years). The participants included 24 with cervical, 17 with thoracic, 8 with lumbar, and 2 with sacral lesions, with all participants having motor incomplete injuries. The exercise group showed significant improvement compared to the usual care group in the 6-Minute Walk Test by 49.80 meters (95% CI: 13.04, 86.55), BBS scores by 3.50 (95% CI: 0.96, 6.03), 30-STS by 2.38 (95% CI: 0.29, 4.47), and SRT by 3.89 centimeters (95% CI: 0.96, 6.82). The adherence rate was remarkably high at 89.6%, suggesting the feasibility of community exercise programs for this population. However, no significant changes were observed in psychological and quality of life measures., Conclusion: Community-based structured exercise programs have been shown to be both feasible and effective in improving walking capacity, balance, lower extremity strength, and flexibility in ambulatory individuals with SCI., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Inc.)

Aqueous zinc-ion batteries (AZIBs) are highly attractive as energy-storage systems owing to their inherent safety, low cost, and simple assembly processes. However, the growth of Zn dendrites and side reactions at the Zn metal anode significantly degrade their electrochemical performance. To address these challenges, this study introduces a surface modification that increases the lifespan and cycling stability of AZIBs by constructing an artificial zinc sulfide (ZnS) protective layer on the Zn anode. For the first time, the fundamental mechanism of uniform Zn plating underneath the ZnS protective layer is demonstrated through experiments and density functional theory simulations. In addition, the artificial ZnS protective layer of optimized thickness is formed using a simple, thickness-controllable coating method. Notably, the ZnS protective layer favors Zn atom adsorption while suppressing clustering, enabling uniform Zn deposition. In addition, defects within the thin ZnS coating modulate Zn 2+ adsorption and diffusion, which facilitates Zn plating underneath the protective layer. This mechanism promotes uniform Zn nucleation and enhances the kinetics of Zn 2+ , preventing dendrite formation and side reactions and thereby improving the stability and electrochemical performance of the battery. The resulting Zn@ZnS||Zn@ZnS symmetric cell exhibits a cycle life of over 1600 h and excellent rate performance. Moreover, it maintains a high coulombic efficiency of 99.5 % and capacity retention of 80.1 % after 1500 cycles at a current density of 0.5 A g -1 , demonstrating exceptional long-term cycling stability. These insights into developing effective artificial protective layers that enable uniform nucleation will promote durable, dendrite-free Zn anodes for advanced AZIBs., 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 Inc. All rights reserved.)

We explored the influence of D 2 O on the fibrillation kinetics and structural dynamics of amyloid intrinsically disordered proteins (IDPs), including α-synuclein, amyloid-β 1-42, and K18. Our findings revealed that fibrillation of IDPs was accelerated in D 2 O compared to that in H 2 O, exhibiting faster kinetics in contrast to the structured protein, insulin. Structural investigations using electrospray ionization ion mobility mass spectrometry and small-angle X-ray scattering combined with molecular dynamics simulations demonstrated that IDPs did not show significant structural changes that could influence accelerated fibrillation in D 2 O. Umbrella sampling of protein protofibrils verified that an increased level of hydrogen bonding of D 2 O and enhanced hydrophobic interactions stabilized β-sheet structured fibrils in D 2 O. These findings indicate that stabilizing β-sheet fibrils and a more hydrophobic microenvironment in D 2 O result in enhanced and faster fibrillation of IDPs. The study highlights the importance of considering D 2 O's differential impact on protein interactions when conducting structural and kinetic analyses, particularly for native peptides and proteins.

The recently proposed partial denitrification (PD), terminating nitrate reduction to nitrite, has been regarded as a promising alternative to nitrite supplying for anammox bacteria. The most important aspect of the PD process for engineering application is the stable and continuous supply of nitrite. However, the activity of nitrate reductase is often higher than that of nitrite reductase (NIR), making it difficult to accumulate nitrite during the denitrification process. Herein, a strategy for achieving efficient and stable partial denitrification using the biosafe additive dimethyl sulfoxide (DMSO) was constructed, and the mechanism of DMSO inhibiting NIR was analyzed. DMSO addition reduced the expression of NIR gene, and 1% DMSO addition can significantly inhibit NIR enzyme activity to achieve a stable PD process. When the DMSO concentration increased to 3.5%, the NIR enzyme activity was almost inhibited with the enzyme activity of only 0.95 mg nitrite/min. However, the addition of DMSO has almost no inhibitory effect on the nitrate reductase (NAR) enzyme. The affinity constant of DMSO with the NAR enzyme is -2.4 kcal/mol, while the affinity constant of DMSO with the NIR enzyme is as high as -3.1 kcal/mol. DMSO shows a higher affinity for NIR. Moreover, DMSO and nitrite occupy the same catalytic cavity in the NIR enzyme, which is the fundamental reason why DMSO selectively inhibits the NIR enzyme. This study provides a new idea for realizing efficient and stable partial denitrification function.

Photomedicine, which utilizes light for therapeutic purposes, has several hurdles such as limited tissue penetration for short-wavelength light and inadequate deep tissue efficacy for long-wavelength light. Photon energy upconversion (UC) reveals promise in photomedicine because it enables the conversion of lower-energy photons into higher-energy photon. Lanthanide (Ln)-based inorganic UC system has been extensively studied but faces challenges, including high excitation laser power density, intrinsically subpar UC quantum efficiency, and potential biotoxicity. Recently, an organic-based triplet-triplet annihilation UC (TTA-UC) system has emerged as a novel UC system due to its prolonged emission lifetime upon low power laser excitation and exceptional UC quantum yield. In this study, we developed water-dispersible hyaluronic acid (HA)-conjugated polycaprolactone (PCL) nanoparticles loaded with TTA-UC chromophores (HA-PCL/UC NPs), which allow deeper tissue penetration by converting red light (635 nm) into blue light (470 nm) for noninvasive transdermal delivery. HA-PCL/UC NPs demonstrated a 1.6% high quantum yield in distilled water, improved cellular imaging in HeLa cells, and effectively penetrated the deep tissue of porcine skin, showing upconverted blue light. Our strategy holds significant potential as a next-generation noninvasive photomedicine platform for bioimaging, photo-triggered drug delivery, and photodynamic therapy, ultimately advancing targeted and effective therapeutic interventions., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Hye Eun Choi et al.)

This study addresses the critical public health issue of fecal coliform contamination in the four major rivers in South Korea (Han, Nakdong, Geum, and Yeongsan rivers) by applying advanced machine learning (ML) algorithms combined with Explainable Artificial Intelligence to enhance both prediction accuracy and interpretability. Both traditional and machine learning models often face challenges in accurately estimating fecal coliform levels due to the complexity of environmental variables and data limitations. To address this limitation, we employed two tree-based models (i.e., random forest [RF] and extreme gradient boost [XGBoost]), and two neural network models (i.e., deep neural network and convolutional neural network [CNN]). we employed the use of Shapley Additive Explanations (SHAP) to facilitate a more comprehensive understanding of the influence exerted by each variable on the model's predictions. Based on a comprehensive dataset collected from the National Institute of Environmental Research covering 16 water quality parameters and meteorological data from 2014 to 2022, our study improved the accuracy of fecal coliform estimation using XGBoost and CNN models. The optimal result was obtained using XGBoost, which had a validation Nash-Sutcliffe efficiency of 0.597 in the Han River. In addition, this study provides insights into the significant factors influencing fecal coliform concentrations across different river environments using the SHAP model. The results indicated that the XGBoost model provided superior estimation accuracy and explanations for the contributions of variables. The SHAP results provided the precise contribution of each water quality variable that affected the fecal estimation results using the XGBoost model. The study facilitates an improved understanding of the relationship between water quality variables and fecal coliform contamination mechanisms in the four major rivers in South Korea., 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.)

Objective: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but debilitating disease characterized by a progressive necrosis of jaw bones in patients who have received anti-resorptive or anti-angiogenic therapies. Unfortunately, we still have no validated preventive or pharmaceutical interventions to help these patients, primarily due to our limited understanding of MRONJ pathogenesis. Here, we offer an extensive review of recent studies relevant to MRONJ pathogenesis. We present a hypothesis regarding the coupling of bone resorption and angiogenesis that relies on osteoblast-derived, matrix-bound vascular endothelial growth factors to explain why ONJ is associated with both anti-resorptive and anti-angiogenic agents., Methods: A narrative review was conducted by searching databases, including PubMed, Scopus, Google Scholar, and Web of Science, to retrieve relevant reports., Results: Reduced bone resorption leads to reduced angiogenesis, and vice versa, creating a vicious cycle that ultimately results in ischemic necrosis of the jaw. Additionally, we suggest that reduced angiogenesis, induced by anti-resorptive or anti-angiogenic agents, aggravates bacterial infection-induced bone necrosis, explaining why the jaw bone is particularly susceptible to necrosis., Conclusion: Our novel hypothesis will facilitate the advancement of future research and the development of more targeted approaches to managing MRONJ., (© 2024 The Author(s). Oral Diseases published by John Wiley & Sons Ltd.)

Existing evidence regarding the impact of continuity of care (COC) in asthma patients is limited, and its quality is low to moderate. This study aimed to investigate associations between relational COC within primary care and asthma-related hospitalizations in children using a robust methodology. This study is a population-based cohort study that utilized a national claims database in South Korea. The study comprised 136,296 individuals under 20 years old who were newly diagnosed with asthma between 2015 and 2016. These were classified into high, medium, and low continuity groups based on the continuity of care index (COCI). The primary outcome measure was the incidence of asthma-related hospitalizations. During a two-year follow-up period, 10,922 patients (8.01%) were hospitalized: 2520 (5.59%) in the high-continuity group, 3188 (6.98%) in the medium-continuity group, and 3867 (8.48%) in the low-continuity group. After adjusting for confounding covariates, patients in the low- and medium-continuity groups exhibited significantly higher risks of hospital admission (adjusted hazard ratio (aHR) = 1.30 [95% confidence interval = 1.24-1.37] and aHR = 1.14 [1.08-1.20], than those in the high-continuity group. Sensitivity and subgroup analyses findings were consistent. In a young population with asthma increased continuity of primary care was associated with less hospitalization., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Proteolysis-targeting chimeras (PROTACs) have emerged as a promising technology for inducing targeted protein degradation by leveraging the intrinsic ubiquitin-proteasome system (UPS). While the potential druggability of PROTACs toward undruggable proteins has accelerated their rapid development and the wide-range of applications across diverse disease contexts, off-tissue effects and side-effects of PROTACs have recently received attentions to improve their efficacy. To address these issues, spatial or temporal target protein degradation by PROTACs has been spotlighted. In this review, we explore chemical strategies for modulating protein degradation in a cell type-specific (spatio-) and time-specific (temporal-) manner, thereby offering insights for expanding PROTAC applications to overcome the current limitations of target protein degradation strategy., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)

Alzheimer's disease (AD) is a progressive neurological disorder and the leading cause of dementia. Despite significant efforts, treatment strategies targeting amyloid-β have been less successful than anticipated. Recently, the role of neuroinflammation and adaptive immune response in AD pathogenesis has gained attention. Here, we performed immune cell-enriched single-cell RNA sequencing of brain parenchymal cells from 12-month-old 5xFAD, an AD mouse model. We analyzed 11,587 single cells and found distinct differences in T cell and choroid plexus cell populations between 5xFAD mouse and littermate control. Subsequent sub-clustering of T cells in the 5xFAD mouse revealed distinct subtypes, with CD8 + resident memory T cells (T RM ) being the most prevalent T cell type. In addition, we observed an increase in T cell exhaustion markers, including Pdcd1, Ctla4, and Havcr2, with a particularly significant elevation of PD-1 and TIM-3 in CD8 + T RM in 5xFAD mouse. Furthermore, choroid plexus (ChP) epithelial cells showed altered gene expression patterns, with higher expression of MHC class I and Type I IFN-stimulated genes in 5xFAD mouse compared to the control mouse, suggesting an association with clonal expansion of AD-specific T cells in the brain. Through single-cell RNA sequencing (scRNA-seq) analysis, our study highlights the potential role of resident memory CD8 + T cell and their possible interactions with ChP epithelial cells. This study provides an exploration of the brain microenvironment landscape in AD, revealing critical insights into its underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

COVID-19 pandemic was accompanied by many healthcare-related issues. Concrete national data regarding the care performance of critical ill cases of COVID-19 does not exist in Korea. The current study aimed to describe the treatment outcome and healthcare resource utilization of critically ill COVID-19 patients. Our multicenter retrospective cohort study enrolled critically ill COVID-19 patients from 22 tertiary care hospitals in Korea. Inclusion criteria: (1) patients aged 19 years or older, (2) patients with laboratory-confirmed SARS-CoV-2 infection who received at least one of following initial treatments such as high-flow oxygen therapy (HFOT) or noninvasive ventilation (NIV) or invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation. During the study wave, a total of 1358 eligible participants were enrolled, with 21 institutions participating in the study. Among them, data from 1113 patients were available and analyzed. Of 921 (82.7%), 621 (55.8%) were supported by IMV. Of the 921 patients supported by HFOT or NIV, 438 (47.6%) recovered without IMV, 429 (46.6%) required IMV, and 54 died who DNR after NIV was applied. Prone position ventilation was administered to 163 (33.1%) patients with IMV and 25 (6.2%) patients with HFOT. Extracorporeal membrane oxygenation was administered to 128 (20.6%) patients treated with IMV. The overall mortality rate was 26.4%. In South Korea, mortality rates for patients with severe COVID-19 pneumonia have been shown substantial fatality, with the highest mortality rates observed in wave 3. The increased mortality rate in wave 3 could be associated with the rapid escalation of critically ill COVID-19 patients and the consequent saturation of intensive care unit capacities. Patients received NIV therapy and prone position ventilation more frequently in wave 3 as the number of cases increased., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Nanoplastics (NPs) are emerging environmental contaminants present in atmospheric, freshwater, and aquatic environments. NPs can rapidly permeate cell membranes and build up in human tissues and organs, causing a potential threat to human health. As the skeletal muscle undergoes aging, myogenesis gradually deteriorates, leading to loss of muscle mass. While previous studies have demonstrated the adverse and toxic effects of polystyrene (PS)-NPs, gaps remain in understanding aging effects and specific mechanisms by PS-NPs in pre-differentiated myoblasts. In this study, we investigated the cellular internalization, aggregation, and senescent effects of PS-NPs using an in vitro model of pre-differentiated C2C12 myoblasts. Pre-differentiated C2C12 myoblasts were exposed to increasing concentrations of PS-NPs and internalization was observed in myoblasts using flow cytometry and transmission electron microscopy (TEM). We further investigated whether internalization of these PS-NPs at sublethal cytotoxic concentrations led to an increase in senescence hallmarks, such as increased β-galactosidase activity, increased expression of p16, p21 and senescence-related secretory phenotypes, and cell cycle arrest. In addition, PS-NP treatment caused notable mitochondrial superoxide production and damage, including mitochondrial membrane depolarization, content loss, fragmentation, and decreased ATP production. Rotenone, a mitochondrial function inhibitor, and exacerbated PS-NP-induced cell proliferation inhibition, whereas Mito-TEMPO, a mitochondrial superoxide scavenger, restored the cell proliferation rate and rescued cellular senescence. Therefore, our findings indicate the senescent effects of PS-NPs through mitochondrial superoxide production and dysfunction in pre-differentiated myoblasts., 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.)

In this article, we explicitly construct the coordinates associated with the Penrose diagram in spacetimes connected via a spacelike thin shell in the following two examples: the generalized black-to-white hole bounce with mass difference and the Schwarzschild-to-de Sitter transition. We point out the issue of the first junction condition in the Penrose diagram constructed by cutting and pasting analytically known metrics with spherical symmetry by a static spacelike thin shell. With the goal of a global conformal coordinate chart associated with the corresponding Penrose diagram without discontinuity at the thin shell, we give a procedure consisting of three conformal transformations that serve different purposes. The first two of them are used to generate a continuous coordinate patch covering the entire thin shell, and therefore, the Penrose diagram can be constructed properly by patches with overlapping. The third transformation removes any coordinate singularity reintroduced by the first two transformations at the event horizons., (© 2024. The Author(s).)

Ionizing radiation (IR) has garnered growing attention because of its biological effects on aquatic organisms and humans. Here, we identify the most impacted organs and uncover the molecular mechanisms causing the changes in the context of vertebrate development using single-cell RNA sequencing. Alterations in cellular composition and biological functions were explored using transcriptomic profiling of zebrafish embryos exposed to 5 Gy. Single-cell RNA sequencing analyses unveiled notable shifts in the proportions of brain/central nervous system and hatching gland clusters. Although IR exposure led to increased expression of hatching enzymes, a significant but mild delay in hatching was observed following 5 Gy IR exposure. Gene Ontology analysis showed an increased expression of tissue inhibitors of metalloproteinases (TIMPs), known as matrix metalloproteinase inhibitors, which was confirmed via whole-mount in situ hybridization. Correlation analysis linked TIMPs to transcription factors cebpb and cebpd, which were significantly correlated post-IR exposure. Although no morphological changes were observed in some organs, including the brain, the study reveals substantial alterations in developing vertebrates. Notably, despite increased hatching enzymes, elevated TIMPs in the hatching gland suggest a regulatory mechanism impacting hatching activity. This research contributes to comprehending the ecological repercussions of IR exposure, emphasizing the importance of safety measures for aquatic ecosystems and overall environmental health., (© 2024 Federation of European Biochemical Societies.)

Background: The Controlling Nutritional Status (CONUT) score is an immunonutritional test tool based on serum albumin, total cholesterol, and lymphocyte counts. It has been studied as a simple prognostic predictor for various carcinomas. This study aimed to investigate the association between preoperative CONUT scores and the clinicopathological characteristics in papillary thyroid carcinoma (PTC) patients., Methods: This study included 2,403 PTC patients who underwent total thyroidectomy between 2012 and 2016 at a single tertiary medical center. The CONUT scores were calculated based on preoperative blood tests. The clinicopathological characteristics were retrospectively reviewed. The patients were categorized by the CONUT score (relatively low, 0-2; relatively high, 3-5)., Results: Among the 2,997 PTC patients who underwent total thyroidectomy at Pusan National University Hospital between 2012 and 2016, those without preoperative blood test were excluded (n=149). Finally 2,403 patients were analyzed after excluding 439 patients taking lipid-lowering drugs and six patients without available T stage data after surgery. Based on the CONUT score, the relatively high score group had a lower body mass index (23.7±3.3 kg/m2 vs. 21.9±2.9 kg/m2, P<0.001), more advanced T stage (T stage 3/4, 5.9% vs. 11.4%, P=0.045), and higher extrathyroidal extension (2.1% vs. 7.6%, P=0.005)., Conclusion: Patients included in this large, single-center study all had a preoperative CONUT score of 0-5, but this study demonstrated that higher preoperative CONUT scores were significantly associated with advanced T stage and extrathyroidal extension. The CONUT score, which can be easily used in clinical practice, is thought to be helpful in predicting the aggressiveness of PTC.

22 illicit drugs were monitored in Seoul, the capital of South Korea for 21 days using wastewater-based epidemiology to assess the drug usage patterns for the first time by region and social status. Among the targeted compounds, 10 were detected, with consistent detection of methamphetamine in samples over the entire sampling period. In addition, ketamine had the highest estimated consumption rate at 47.5 mg/day/1000 people, followed by methamphetamine at 12.5 mg/day/1000 people. Methamphetamine and MDMA(3,4-methylenedioxymethamphetamine) exhibited relatively stable daily patterns, with coefficients of variation of 7.03 %, and 13.4 % respectively. Furthermore, no statistically significant differences were observed between weekends and weekdays for all compounds (Mann-Whitney Rank Sum test, p > 0.05). Statistically significant regional differences in drug consumption were observed for methamphetamine, MDMA, and ketamine (Mann-Whitney Rank Sum test, p < 0.05). These differences were found to be related to average annual income and educational levels., 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.)

Early and accurate detection of colorectal cancer (CRC) is critical for improving patient outcomes. Existing diagnostic techniques are often invasive and carry risks of complications. Herein, we introduce a plasmonic gold nanopolyhedron (AuNH)-coated needle-based surface-enhanced Raman scattering (SERS) sensor, integrated with endoscopy, for direct mucus sampling and label-free detection of CRC. The thin and flexible stainless-steel needle is coated with polymerized dopamine, which serves as an adhesive layer and simultaneously initiates the nucleation of gold nanoparticle (AuNP) seeds on the needle surface. The AuNP seeds are further grown through a surface-directed reduction using Au ions-hydroxylamine hydrochloride solution, resulting in the formation of dense AuNHs. The formation mechanism of AuNHs and the layered structure of the plasmonic needle-based SERS (PNS) sensor are thoroughly analyzed. Furthermore, a strong field enhancement of the PNS sensor is observed, amplified around the edges of the polyhedral shapes and at nanogap sites between AuNHs. The feasibility of the PNS sensor combined with endoscopy system is further investigated using mouse models for direct colonic mucus sampling and verifying noninvasive label-free classification of CRC from normal controls. A logistic regression-based machine learning method is employed and successfully differentiates CRC and normal mice, achieving 100% sensitivity, 93.33% specificity, and 96.67% accuracy. Moreover, Raman profiling of metabolites and their correlations with Raman signals of mucus samples are analyzed using the Pearson correlation coefficient, offering insights for identifying potential cancer biomarkers. The developed PNS-assisted endoscopy technology is expected to advance the early screening and diagnosis approach of CRC in the future., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The increasing urgency of global environmental degradation, particularly across diverse economic development stages, underscores a critical need for nuanced understanding and targeted strategies to achieve Sustainable Development Goals. Our study examines environmental efficiency trends over 27 years in 163 countries, utilizing greenhouse gases and particulate matter 2.5 as indicators. We address the challenge by developing and applying a two-stage method that combines a hyperbolic distance function with a stochastic meta frontier approach to assess environmental meta-efficiency. The average meta efficiency of these countries is 0.464, which remains at a relatively low level. Our model indicates that the high-income country group needs to reduce greenhouse gas and pollutant emissions by 25% and increase non-fossil energy usage by 33% to improve environmental efficiency. This suggests these countries must transition towards more sustainable energy sources and practices. Moreover, recognizing that existing income grouping inadequately characterizes each country, we use k-means cluster analysis for regrouping, more accurately reflecting individual differences. The regrouping results show that some high-income countries are classified into inactive groups, implying serious environmental problems. Our findings advocate for collaborative and tailored strategies to address these disparities. We conclude that income levels cannot solely drive environmental efficiency but must also consider geographical and climatic factors, which are pivotal in shaping a country's environmental policies and efforts. This approach offers a clearer understanding of current inefficiencies and sets the stage for more informed policy-making that can better address the specific needs and capabilities of different countries., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sangmok Kang reports financial support was provided by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF-2021S1A5A2A01069262)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study analyzed the metabolite profiles and antioxidant capacities of two waxy and non-waxy Korean red rice accessions newly bred. Fifteen phenolic compounds were detected in the rice samples. Accession1 had high fatty acids, phytosterols, and vitamin E; accession3 had high vitamin E and phytosterol; and accession4 had a high total flavonoid. The correlation analysis findings from this study validated the positive association between all the metabolites and antioxidant activity. in silico results revealed that protocatechuic acid had a docking score of -9.541, followed by luteolin, quercetin, and caffeic acid, all of which had significant docking scores and a significant number of contacts. Similarly, molecular dynamics simulations showed that phytochemicals had root mean square deviation values of <2.8 Å with Keap 1, indicating better stability. This study provides valuable insights into potential directions for future investigations and improvements in the functional qualities of other colored rice varieties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Previous studies reported that short-term exposure to ground-level ozone is associated with mortality risk. However, due to the limited monitored areas, existing studies were limited in assessing the nationwide risk and suggesting specific vulnerable populations to the ozone-mortality risk., Methods: We performed a nationwide time-stratified case-crossover study to evaluate the association between short-term ozone and cause-specific mortality in South Korea (2015-2019). A machine learning-ensemble prediction model (a test R 2  > 0.96) was used to assess the short-term ozone exposure. Stratification analysis was conducted to examine the high-risk populations, and the excess mortality due to non-compliance with the WHO guideline was also assessed., Results: For all-cause mortality (1,343,077 cases), the risk associated with ozone (lag0- 1) was weakly identified (odd ratio: 1.005 with 95% CI: 0.997-1.014), and the risk was prominent in mortality with circulatory system diseases. In addition, based on the point estimates, the ozone-mortality risk was higher in people aged less than 65y, and this pattern was also observed in circulatory system disease deaths and urban areas., Conclusions: This study provides national estimates of mortality risks associated with short-term ozone. Results showed that the benefits of stricter air quality standards could be greater in vulnerable populations., 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 Inc. All rights reserved.)

Perceived temperature (PT), which encompasses meteorological factors such as wind speed, cloud cover, and humidity, reflects the actual effect of temperature on the human body. However, limited data exist on the health implications of prolonged exposure to low temperatures during winter in individuals with chronic kidney disease (CKD). We investigated the association between winter PT and long-term outcomes among CKD patients. A total of 32,870 CKD patients from three tertiary hospitals in Seoul were enrolled in this retrospective study (2001-2018). PT was calculated using Staiger's equation, integrating temperature data from 29 automated weather stations across Seoul, along with dew point temperature, wind velocity, and cloud cover data. Kriging interpolation was utilized to estimate PT values at the patients' locations. Overall mortality and major adverse cardiovascular events (MACEs) were assessed using a time-varying Cox proportional hazards model. Additionally, the Cox regression model evaluated PT corresponding to temperature thresholds for cold surge watches or warnings. Over a median follow-up of 6.14 ± 3.96 years, 6147 deaths (18.7%) were recorded. We found that as the average or minimum PT and Ta decreased by 1 °C, the risk of overall mortality significantly increased. In multivariable analyses, the hazard ratio (HR) for the average PT was 1.049 (95% confidence interval [CI] 1.028-1.071), and that for the minimum PT was 1.038 (CI 1.027-1.052). Furthermore, a cold surge warning at a PT of -25.63 °C indicated an HR of 1.837 (CI 1.764-1.914) and a C-index of 0.792. The increased risk of mortality was more pronounced in patients with low or middle socioeconomic statuses. For MACEs, lower average and minimum PT and Ta were associated with an increased risk, following a similar trend to overall mortality, although not all results reached statistical significance. These findings emphasize the importance of targeted public health policies to mitigate risks among vulnerable CKD patients., 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 Inc.)

This study aimed to investigate the characteristics of out-of-office blood pressure (BP) measurements in patients with apparent treatment-resistant hypertension (aRH) enrolled from 15 tertiary care centers in South Korea. aRH was defined as having uncontrolled office BP ≥ 130/80 mmHg despite receiving three classes of antihypertensive medication or any level of BP despite receiving ≥4 classes of antihypertensive medication. Patients with complete data for office BP, 24-h ambulatory BP monitoring (ABPM), and home BP measurements at baseline were included. BP control status between ABPM and home BP measurements was compared. Out of 1457 patients, 823 meeting the enrollment criteria were included (mean age: 59.9 ± 13.6 years; 57.5% male patients). Among them, 7.2% had controlled BP, 8.7% had whitecoat uncontrolled hypertension, 15.1% had masked uncontrolled hypertension, and 69% had sustained hypertension, as measured through baseline ABPM. Additionally, 43% of patients with controlled BP based on home BP measurement had nocturnal hypertension. Relying solely on home BP measurement may result in misclassifying 70% of patients as having either controlled BP or whitecoat uncontrolled BP. This study reaffirms the circadian pattern of resistant hypertension, characterized by a higher prevalence of non-dipping and rising patterns, even in patients with BP controlled based on ABPM. Considering the persistent difference between home BP measurement and ABPM, even at a lower home BP threshold, integrating both measurements into the management of aRH is advisable., Competing Interests: Compliance with ethical standards Conflict of interest JS have nothing to declare. CJL received lecture honoraria from Novartis, Hanmi Pharmaceutical, Yuhan, Boryung Pharmaceutical, and Daiichi Sankyo. DHK received honoraria from Viatris, Organon, Boryoung, Hanmi, Daewoong, Celltrion, Daiichi Sankyo, and Chong Kun Dang and a research grant from Daewoong Pharmaceutical. SYK received honoraria from Norvatis, Amgen Korea, BMS Korea, Bayer Korea, Viatris, Boryoung, Hanmi, Menarini, JW Pharmaceutical, Inno N, Dongkook, Yuhan, Chong Kun Dang, GC Biopharma, and Daewon. JHP received honoraria from Viatris, Jeil, Boryoung, Daewoong, Hanmi, Yuhan, Chong Kun Dang, BMS. ICK received honoraria from Abbott, Novartis, Yuhan, Viatris, Organon, Boryoung, Hanmi, Daewoong, Celltrion, Servier, Daiichi Sankyo, Chong Kun Dang, and Daewon. JHL received honoraria from Daewoong Pharmaceutical, Handok Pharmaceuticals, Novartis, Chong Kun Dang Pharmaceutical Corp, Menarini Korea, Samjin Pharmaceuticals Co. Ltd, Daiichi Sankyo Korea, Hanmi Pharmaceutical, Yuhan Corporation, Boryung Pharmaceutical, Bayer. HYL received honoraria from Viatris, Organon, Boryoung, Hanmi, Daewoong, Donga, Celltrion, Servier, Daiichi Sankyo, Chong Kun Dang, and Daewon, and a research grant from Daiichi Sankyo. HYL also received consultation fee from Skylab. JWC received honoraria from Bayer, Astrazeneca, Organon, Hanmi, Yuhan, Daewoong, Chong Kun Dang, JW, Boryoung, GC Corp, Donga, Handok, Ildong, Jeil, Daewon, Ahn-gook, Samjin, Daiichi Sankyo, Otsuka, Mitsubishi Tanabe, Hyundai, Kuhnil, Bukwang and Aju. JWC also received research grants from Handok, Daewon, Boryung, GC Corp, Addpharma, and Kyung Dong. SHI received honoraria from Boryoung, Daewoong, Donga, Celltrion, Servier, Daiichi Sankyo, and Menarini, and a research grant from Daiichi Sankyo. SHI has received consultation fee from Skylab. JS received honoraria from Boryoung, Daiichi Sankyo, Chong Kun Dang, and Inno-N and consultaion fee from Skylab and Inbody. SP received honoraria from Viatris, Organon, Boryoung, Hanmi, Daewoong, Donga, Celltrion, Servier, Daiichi Sankyo, Chong Kun Dang, and Daewon, and a research grant from Daiichi Sankyo. SP has received consultation fee from Skylab. Also, SP has received stock option from Mediwhale. Others have nothing to declare., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Echinochrome A (Ech A) isolated from marine organisms is a therapeutic effector for various cardiovascular diseases, but its precise mechanisms are unclear. This study identified the role and mechanisms mediating the effects of Ech A on the migration of vascular smooth muscle cells (VSMCs) induced by high-mobility group box 1 (HMGB1). Compared to the control cells, the migration of VSMCs stimulated with HMGB1 (100 ng/ml) was markedly increased, which was significantly attenuated in cells pretreated with MPIIIB10 (100 ng/ml), a neutralizing monoclonal antibody for osteopontin (OPN). In VSMCs stimulated with HMGB1, the increased expression of OPN mRNA and protein was accompanied by an increased OPN promoter activity. In reporter gene assays using OPN promoter-luciferase constructs, the promoter region 538-234 bp of the transcription start site containing the binding sites for activator protein 1 (AP-1) was shown to be responsible for the increased transcriptional activity by HMGB1. In addition, the binding activity of AP-1 was increased in HMGB1-stimulated cells, highlighting the pivotal role of AP-1 on OPN expression in HMGB1-stimulated VSMCs. An examination of the vascular effects of Ech A showed that the increased AP-1 binding/promoter activities and OPN expression induced by HMGB1 were attenuated in cells pretreated with Ech A (3 or 10 μM). Similarly, Ech A inhibited HMGB1-induced VSMC migration in a concentration-dependent manner. These findings suggest that Ech A inhibits VSMC migration by suppressing OPN expression. Hence, Ech A is suggested as a potential therapeutic strategy for vascular remodeling in the injured vasculatures.

Heart diseases are a significant contributor to global morbidity and mortality, and despite their diverse and complex mechanisms, treatment options remain limited. Maltol, a natural compound with antioxidant and anti-inflammatory activities, exhibits potential for addressing this need. This study evaluates the cardioprotective effects of maltol in isoproterenol (ISO)-induced cardiac stress models and Duchenne muscular dystrophy (DMD). Maltol's cardiac cytotoxicity was assessed in rodent (H9c2) and human (AC16) cells and compared with that of dapagliflozin to illustrate its cardiac safety. In ISO-induced stress models, maltol significantly reduced hypertrophic markers and inflammation while enhancing autophagy and antioxidant pathways. In the mdx mice, a DMD model, maltol treatment improved cardiac contractility and reduced pathogenic remodeling. Enhanced phosphorylation of phospholamban and trends toward higher SERCA2a expression indicated enhanced Ca 2+ handling, which is crucial in DMD cardiomyopathy. This study demonstrated that maltol has the potential to provide therapeutic benefits for DMD and other cardiac conditions characterized by hypertrophy and inflammation, as evidenced by its well-known antioxidant properties, low cytotoxicity, and capacity to enhance cardiac function and Ca 2+ handling.

Complex structural variations (cxSVs) are often overlooked in genome analyses due to detection challenges. We developed ARC-SV, a probabilistic and machine-learning-based method that enables accurate detection and reconstruction of cxSVs from standard datasets. By applying ARC-SV across 4,262 genomes representing all continental populations, we identified cxSVs as a significant source of natural human genetic variation. Rare cxSVs have a propensity to occur in neural genes and loci that underwent rapid human-specific evolution, including those regulating corticogenesis. By performing single-nucleus multiomics in postmortem brains, we discovered cxSVs associated with differential gene expression and chromatin accessibility across various brain regions and cell types. Additionally, cxSVs detected in brains of psychiatric cases are enriched for linkage with psychiatric GWAS risk alleles detected in the same brains. Furthermore, our analysis revealed significantly decreased brain-region- and cell-type-specific expression of cxSV genes, specifically for psychiatric cases, implicating cxSVs in the molecular etiology of major neuropsychiatric disorders., Competing Interests: Declaration of interests M.P.S. is a co-founder and on the advisory boards of Personalis, Qbio, January AI, SensOmics, Filtricine, Protos, Mirvie, Onza, Marble Therapeutics, Iollo, and NextThought AI. He is also on the advisory boards of Jupiter, Applied Cognition, Neuvivo, Mitrix, and Enovone. W.J.G. is a consultant for 10× Genomics, Guardant Health, Quantapore, and Ultima Genomics, a co-founder of Protillion Biosciences, and is named on ATAC-seq patents. A.K. is a consulting fellow with Illumina; a member of the SABs of OpenTargets (GSK), PatchBio, and SerImmune; and a co-founder of RavelBio. S.B.M. is an advisor for BioMarin, MyOme, and Tenaya Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to identify novel prognostic factors for Morbihan disease (MD) treatment outcomes and evaluate the efficacy of combination therapy in an Asian population, addressing the gaps in current understanding of this rare condition., Methods: We conducted a retrospective analysis of MD patients diagnosed and treated at a tertiary hospital between 2017 and 2023. Patients received combinations of oral medications (tetracycline, isotretinoin, corticosteroids), topical treatments (tacrolimus, ivermectin), and intralesional steroid injections. Treatment response (TR) was defined as complete symptom remission, while partial remission or recurrence was considered a poor response (PR). Clinical, histological, and biochemical parameters were analyzed to identify prognostic factors., Results: The study included 24 patients (18 men; mean age 61.3 years). Ten patients (41.7%) achieved TR, while 14 (58.3%) showed PR. Significant prognostic factors for TR included shorter symptom duration (≤ 3 months, p = 0.016), lower LDL cholesterol levels (≤ 89 mg/dL, p = 0.046), combination treatment with oral and topical medications (p = 0.033 at 6 months), and partial response at 1 month (p = 0.017). GLMM analysis identified the number of visits (p < 0.001), symptom duration (p = 0.020), and dyslipidemia (p = 0.006) as significant prognostic factors. Histologically, perivascular and perifollicular lymphocytic infiltration were the most common findings (83.3%). Notably, 50% of patients were ANA-positive, challenging previous diagnostic criteria., Conclusion: This study identifies novel prognostic factors for favorable outcomes in MD, including early intervention and lipid management. Combination therapy, particularly with tacrolimus ointment, shows promise in improving treatment responses. These findings suggest a potential link between lipid metabolism and MD pathophysiology, opening new avenues for targeted therapies., Competing Interests: Declarations Ethics approval and consent to participate All procedures involving human participants in this study were conducted in accordance with the ethical standards of the institutional and/or national research committees, as well as with the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Pusan National University Hospital (IRB no. 2105-040-103). Informed consent was obtained from all participants included in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Proximity to parks has been suggested as a factor influencing physical activity in older adults. However, it remains unclear the optimal distance between residences and parks for promoting physical activity and reducing sedentary time and whether these associations vary by the time of day. We examined whether the proximity to neighbourhood parks at varying distances is associated with all-day and time-specific physical activity and sedentary behaviour in older adults., Methods: Data were collected from 214 older adults receiving hospital services in Taipei, Taiwan. The number of parks within 400m, 800m, and 1,600m of participants' residences. Physical activity and sedentary behaviour, stratified by time of day (morning, afternoon, and evening), were measured using accelerometers. Adjusted linear regression models were used to estimate associations of park proximity with activity and sedentary outcomes., Results: Parks located within 400m and 800m of participants' residences were more markedly associated with longer time in physical activity and less sedentary time compared to parks located 1,600m away. A greater number of parks within 400m and 800m was positively associated with walking steps and light-intensity physical activity while both distances were negatively associated with sedentary time. The associations between park proximity and behavioural outcomes were mainly attributable to that during the afternoon and evening., Conclusions: Our findings suggest that favourable access to parks within 800m of older adults' residences is associated with more physical activity and less sedentary time, particularly during the afternoon and evening. Future longitudinal studies are required to corroborate these associations., Competing Interests: Declarations Human ethics and consent to participate Each participant signed an informed consent form prior to each start of the survey. This study was approved by the Research Ethics Committee of the National Taiwan University Hospital (202008046RINC). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)