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The present study investigated the effects of wing shapes and flapping motions on the aerodynamic forces and vortex structures of insect flight. Aerodynamic force measurements and flow visualizations were performed in a water tank by cross-applying the wing shapes of bumblebee, hawkmoth, and hummingbird to their hovering flapping motions. When the three different wings were measured making the same motions, the average difference of lift-to-drag ratio was 2.7%. In the aspect ratio and wing area distribution range, where three wing shapes were distributed, aerodynamic performances were similar according to wing shape. However, the average difference of lift-to-drag ratio was 34.3% when flapping motion was differed within the same wing shape. The aerodynamic performances of three flapping motions varied significantly with changes in sweeping speed and wing rotation. The difference of average in aerodynamic efficiency was 4.9% among the three wings when making the same motion, and 43.7% when the motions were differed in the same wing. The results showed that flapping motions had significant effects on aerodynamic performance. Visualization results also showed that the vortex structure changes significantly when motions are different in the same wing shapes. These findings provide valuable data for designing flapping micro air vehicles and morphing aircraft., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objectives: We hypothesized that the duration of pulsed radiofrequency (PRF) application may affect the effectiveness of PRF in patients with chronic lumbosacral radicular pain (LRP)., Materials and Methods: In this prospective, double-blind, randomized study, 68 patients were randomly allocated to two groups: a 6-minute group, in which PRF was applied at 42 °C for 2 minutes followed by a 2-minute pause, repeated three times; and a 12-minute group, with a continuous application at 42 °C for 12 minutes. The total application time in each group was equal. After PRF, 2 to 3 mL of 1% lidocaine with 5 mg of dexamethasone was injected. The primary outcome was the intensity of leg pain measured using a numerical rating scale (NRS) three months after the procedure. The secondary outcomes were intensities of leg and back pain, the Oswestry Disability Index (ODI), the Medication Quantification Scale III (MQS), the Global Perceived Effect of Satisfaction (GPES), and the incidence of adverse events during follow-up. Primary and secondary outcomes were analyzed using a linear mixed-effect model in the modified intention-to-treat population., Results: Each group comprised 34 patients. Three patients in each group did not receive the allocated intervention owing to alleviation of pain. The estimated NRS mean of leg pain at three months was 4.0 (95% CI, 3.2-4.9) and 4.5 (95% CI, 3.6-5.4) in the 6- and 12-minute groups, respectively, with no significant difference between groups (estimated mean difference, -0.5; 95% CI, -1.8 to 0.8; p = 0.436). Regarding the intensities of leg and back pain, ODI, MQS, and GPES, there was no significant difference between the two groups except for GPES at six months. No adverse events were observed in the groups., Conclusions: Among patients with chronic LRP, a prolonged PRF application of 12 minutes, compared with 6 minutes, caused no significant difference in leg pain intensity., Clinical Trial Registration: The Clinicaltrials.gov registration number under the Clinical Trial Registry of Korea for the study is KCT0003850; https://cris.nih.go.kr., Competing Interests: Conflict of Interest The authors report no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

This study proposes a novel approach for generating dual-targeted adversarial examples in Graph Neural Networks (GNNs), significantly advancing the field of graph-based adversarial attacks. Unlike traditional methods that focus on inducing specific misclassifications in a single model, our approach creates adversarial samples that can simultaneously target multiple models, each inducing distinct misclassifications. This innovation addresses a critical gap in existing techniques by enabling adversarial attacks that are capable of affecting various models with different objectives. We provide a detailed explanation of the method's principles and structure, rigorously evaluate its effectiveness across several GNN models, and visualize the impact using datasets such as Reddit and OGBN-Products. Our contributions highlight the potential for dual-targeted attacks to disrupt GNN performance and emphasize the need for enhanced defensive strategies in graph-based learning systems., Competing Interests: Declarations. Conflicts of Interest: The authors declare that there are no conflicts of interest regarding the publication of this article. Ethical and informed consent for data used: All authors give ethical and informed consent. There are no human or animal experiments in this paper. Also, there is no copyrighted data related to the figures., (© 2025. The Author(s).)

The aim of this study was to determine whether closed-loop vibration stimulation, delivered at +3% of the heart rate frequency at an imperceptible intensity before waking, could reduce sleep inertia. Participants napped on a bed equipped with a woofer that delivered vibration stimulation every 5 min, starting 30 min before their scheduled wake time. The effects of the stimulation were assessed using a Psychomotor Vigilance Task performed immediately upon waking, along with the analysis of salivary cortisol and melatonin levels, as well as subjective arousal ratings based on the Karolinska Sleepiness Scale and the Stanford Sleepiness Scale. The results indicated that vibration stimulation at +3% of the heart rate frequency improved Psychomotor Vigilance Task reaction times and increased self-reported arousal scores, thus reducing sleep inertia compared with the control condition without stimulation. Additionally, salivary melatonin levels were lower immediately after waking. These findings suggest that closed-loop vibration stimulation at +3% of the heart rate frequency before waking could be an effective method to reduce sleep inertia. This non-invasive approach may facilitate cognitive recovery following sleep. Further research is required to investigate the underlying mechanisms, and confirm these findings across different populations and settings., (© 2025 European Sleep Research Society.)

Objective: To investigate the impact of dexamethasone on the antibiotic susceptibility of common ocular pathogens in dogs and identify safe antibiotic-steroid combinations for veterinary ophthalmology., Methods: This study utilized 30 bacterial isolates of Staphylococcus pseudintermedius, Streptococcus canis, and Pseudomonas aeruginosa, collected from canine patients with suspected bacterial keratitis. The isolates were tested against 17 antibiotics in the presence of dexamethasone concentrations ranging from 0 to 2 mg/mL. Minimum inhibitory concentrations (MICs) were determined using standardized broth microdilution techniques, and changes in susceptibility were analyzed statistically., Results: Dexamethasone administration resulted in a significant increase in resistance for ciprofloxacin, ticarcillin, tobramycin, and ceftiofur in S. pseudintermedius; ticarcillin in S. canis; and ciprofloxacin and moxifloxacin in P. aeruginosa. Despite these increases, amikacin and cefazolin showed minimal impact on resistance when combined with dexamethasone, indicating their potential for safe use in combination therapies., Conclusion: The findings highlight the potential for dexamethasone to alter antibiotic susceptibility in canine ocular pathogens. While dexamethasone can increase resistance in certain antibiotics, amikacin and cefazolin appear to be safer options for combination therapy., (© 2025 American College of Veterinary Ophthalmologists.)

Chronic kidney disease (CKD) progresses through mechanisms involving inflammation, fibrosis, and oxidative stress, leading to the gradual structural and functional deterioration of the kidneys. Tormentic acid (TA), a triterpenoid compound with known anti-inflammatory and antioxidant properties, shows significant potential in counteracting these pathological processes. This study explored the protective role of TA in a unilateral ureteral obstruction (UUO)-induced CKD model. Mice received TA through intraperitoneal injections at a dosage of 5 mg/kg per day for 8 consecutive days, commencing a day before the UUO procedure. The TA treatment significantly improved both structural and functional kidney injury. It suppressed cytokine expression and reduced immune cell infiltration, inhibited the activation of the mitogen-activated protein kinase cascade, and alleviated endoplasmic reticulum stress. Moreover, TA displayed potent anti-fibrotic effects by reversing epithelial-to-mesenchymal transition and inhibiting Smad2/3 activation, reducing extracellular matrix deposition. TA also mitigated oxidative stress by attenuating lipid peroxidation and boosting antioxidant defenses. Additionally, it inhibited apoptosis and ferroptosis by reducing oxidative stress and modulating key cell death markers. Collectively, these findings indicate that TA provides comprehensive renoprotection in the UUO model by effectively targeting inflammation, fibrosis, oxidative stress, and tubular cell death in CKD progression.

The main focus of this study is to explore the complex interactions between aquatic ecosystem health (AEH) and time-varying hydro-environmental factors. We measure AEH in the Namhan River of South Korea using stream health index (SHI) scores for the trophic diatom index (TDI), benthic macroinvertebrate index (BMI), and fish assessment index (FAI) for 2008 to 2022. Key hydro-environmental variables associated with AEH, including their time-lagged responses, are identified. Water quality parameters such as chemical oxygen demand (COD) are significantly and negatively correlated with TDI (r=-0.68), BMI (r=-0.87), and FAI (r=-0.70), highlighting the critical role of water quality in the sensitivities of diatoms, macroinvertebrates, and fish health. The apparent response lag of aquatic ecosystems to hydrological parameters, such as a one-year-lagged correlation of BMI with mean flow (r=0.74) and annual flow anomalies (r=0.73), suggests their potential use as predictors in AEH models. A longitudinal analysis of SHIs over a decade showed consistent changes in AEH from upstream to downstream, with notable trends in the deterioration and improvement of SHIs in different areas. The upstream TDI and BMI deteriorated, while the upstream FAI improved. A multiple-linear-regression-based predictive model demonstrated efficacy in predicting AEH under various hydro-environmental conditions, achieving R 2 values up to 0.85 for BMI and also has the potential to simulate the impacts of anticipated climatic and hydrological changes., 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.)

Background: The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study was aimed to characterize the composition of TILs and investigate their clinicopathological and prognostic significance with a special focus on the spatial distribution of TILs in TNBCs., Methods: We analyzed TNBC samples through PanCancer Immune Profiling using NanoString nCounter assays to identify immune-related genes that are expressed differentially in relation to TIL levels and evaluated protein expression of selected markers through immunohistochemical staining on tissue microarrays. For a comprehensive assessment of the expression of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell markers, a CTL-NK score was devised based on CD8 + , CD56 + , CD57 + , GNLY + , and GZMB + TIL levels., Results: Gene expression analysis revealed significant upregulation of CTL and NK cell-associated genes including GNLY, KLRC2, and GZMB in TIL-high TNBCs. Immunohistochemical validation confirmed that TNBCs with higher TILs had a greater amount of CD56 + , CD57 + , GNLY + , and GZMB + TILs not only in absolute number but also in proportion relative to CD4 + or CD8 + TILs. High TIL and its subset (CD4 + , CD8 + , CD56 + , CD57 + , GNLY + , and GZMB + TIL) infiltration correlated with favorable clinicopathological features of tumor. In survival analysis, high CTL-NK score was found to be an independent prognostic factor for better disease-free survival (DFS) of the patients. Furthermore, uniformly high TIL infiltration was linked to better DFS, whereas cases with heterogeneous TIL infiltration showed no difference in survival compared to those with uniformly low TIL infiltration., Conclusion: Our study showed that CTL and NK cell-associated gene expression and protein levels differ significantly according to TIL levels and that CTL-NK score and distribution of TILs within tumors have a prognostic value. These findings emphasize the importance of CTLs and NK cells as well as the spatial uniformity of TIL infiltration in clinical outcome of TNBC patients, providing valuable insights for refining prognostic assessments and guiding immunotherapeutic strategies., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the institutional review board (IRB No B-2210-786-303), and the requirement of informed consent was waived. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: This study aimed to explore anatomical differences in the aqueous humor (AH) outflow pathway between male and female dogs using ultrasound biomicroscopy (UBM)., Animals Studied: Clinical data were collected from 30 eyes of 30 dogs (15 males: 10 right eyes, 5 left eyes; and 15 females: 7 right eyes, 8 left eyes) treated at the Veterinary Medical Teaching Hospital of Chungbuk National University, South Korea, between August 2018 and February 2024., Procedure: The study conducted an in-depth UBM examination, specifically observing peripheral anterior chamber depth (ACD), geometric iridocorneal angle (ICA), and angle-opening distance (AOD) alongside measurements of ciliary cleft width (CCW), length (CCL), and area (CCA), and assessed the longitudinal fibers of ciliary muscle thickness (Lf-CMT) and the longitudinal and radial fibers of ciliary muscle thickness (LRf-CMT) for gender-based differences., Results: The study identified a significant sex difference in peripheral ACD, with females displaying shallower depths compared to males, potentially clarifying the higher incidence of glaucoma in female dogs. No significant gender differences were found in ICA, AOD, CC parameters, or ciliary muscle parameters measurements., Conclusion: This research uncovered that peripheral ACD is significantly shallower in females than in males, potentially indicating a risk factor that could contribute to the development of primary angle-closure glaucoma., (© 2024 American College of Veterinary Ophthalmologists.)

Introduction: This study aimed to examine the relationship between the relative opening of the ICA (RO-ICA) and the structure of the ciliary cleft (CC) using Ultrasound Biomicroscopy (UBM)., Materials and Methods: Clinical data from 31 eyes of 17 dogs at the Veterinary Teaching Hospital of Chungbuk National University, Korea, were analyzed. RO-ICA was categorized as "Slightly Narrow", "Narrow", "Open", and "Wide Open", with eyes further grouped into "Narrow" (including Slightly Narrow and Narrow) and "Open" (including Open and Wide Open) for analysis. Statistical methods, including linear regression and average comparisons between groups, were employed to explore correlations between RO-ICA and parameters such as ICA, CC width (CCW), CC length (CCL), and CC area (CCA)., Results: The distribution showed "Narrow" (3 eyes, 9.7%), "Slightly Narrow" (13 eyes, 41.9%), and "Open" (14 eyes, 45.2%) as the predominant categories. In the Open group, CCL and CCA were significantly larger compared to the Narrow group. A positive correlation was observed between RO-ICA and CCL, and CCA across all groups. Notably, in the Narrow group, RO-ICA demonstrated a particularly significant positive correlation with all assessed parameters, including ICA, CCW, CCL, and CCA. However, no significant correlation was observed between RO-ICA and the assessed parameters in the Open group. In conclusion, while a smaller RO-ICA generally correlates with a smaller CC, a larger RO-ICA does not guarantee a larger CC., Conclusion: Additional UBM examinations are recommended for comprehensive evaluations, particularly in cases where gonioscopy indicates an open iridocorneal angle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Kwon, Hwang, Jung and Park.)

Diffuse midline gliomas with H3 K27-alteration (DMGH3) are lethal and inoperable brain tumors. Although DMGH3s mainly occur in pediatric patients, they have also occurred in adult patients. This study aimed to analyze the clinicopathological significance of targetable genetic alterations in non-pediatric DMGH3. Next-generation sequencing (NGS) was conducted on 18 non-pediatric DMGH3 patients to analyze additional genetic alterations. The median age at diagnosis was 35 years, and the mean follow-up duration was 762 days. Fourteen cases involved the thalamus-hypothalamus (77.8%). Histologic high-grade features (WHO histologic grade ≥ 3) were observed in 11 (61.1%) patients. H3F3A (H3 K27 M) alterations were identified in all 18 patients using immunohistochemistry and NGS. TP53 mutations were found in 11 patients (61.1%), FGFR1 or PIK3CA in 3 (16.7%), ATRX in 6 (33.3%), NF1 in 4 (22.2%), and KRAS or ATM in 1 (5.6%). TP53 mutations were significantly correlated with high-grade histological features and worse overall survival (OS) (P < 0.05). Despite non-pediatric DMGH3 cases exhibiting superior OS compared to pediatric DMGH3 cases, TP53 mutations were associated with poorer OS outcomes. Notably, FGFR1 and PIK3CA mutations, which have been identified as potential targetable genes, were detected. In conclusion, non-pediatric DMGH3s showed predominant tumor localization within the thalamus and improved prognosis compared to those in pediatric cases, with TP53 alterations correlating with high-grade histology and shorter survival. Genetic profiling, particularly identifying targetable mutations like FGFR1 and PIK3CA, could inform personalized treatment strategies and improve patient outcomes., Competing Interests: Declaration of interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Clear cell renal cell carcinoma (ccRCC) often harbors Polybromo 1 (PBRM1) alterations. These alterations are associated with immune checkpoint blockade response in ccRCC, particularly antiprogrammed cell death 1 (PD1)/programmed cell death ligand 1 (PD-L1)-targeted therapy. However, the association between PBRM1 alterations and PD-L1 expression in ccRCC remains unclear., Materials and Methods: We analyzed alterations in PBRM1 and PD-L1 expression using immunohistochemistry (IHC) targeting PBRM1 and PD-L1 (22C3) in tissues collected from patients with localized ccRCC (Cohort 1) and advanced ccRCC (Cohort 2). Additionally, next-generation sequencing (NGS) was conducted on Cohort 2 patients to analyze PBRM1 alterations., Results: Cohort 1 comprised 526 patients, of whom 139 (26.4%) exhibited PD-L1 positivity and 205 (38.9%) exhibited loss of PBRM1 expression in IHC. PD-L1 expression was positively associated with the loss of PBRM1 expression (P < 0.001) in localized ccRCC. Kaplan-Meier analysis indicated that PBRM1 expression loss and PD-L1 expression positively correlated with tumor recurrence (P < 0.001 and P = 0.003, respectively). Cohort 2 comprised 59 patients with advanced ccRCC, of whom 33 (56.9%) exhibited PBRM1 genetic alterations. PBRM1 IHC exhibited a sensitivity of 84.48% and specificity of 87.5% compared to NGS results. We did not find a significant association between PBRM1 mutation and PD-L1 expression, in contrast to the findings in Cohort 1. However, we frequently observed that PBRM1 mutation and PD-L1 expression occur concurrently, with 60% of PBRM1-altered ccRCC cases being PD-L1 positive., Conclusion: Although our study did not establish a correlation between PBRM1 mutations and PD-L1 expression, it demonstrated that the occurrence of PBRM1-altered ccRCC with PD-L1 expression is not uncommon. Therefore, the presence of PBRM1 alterations may challenge the use of PD-L1 IHC as a predictive marker for PD-L1 blockade in ccRCC., 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.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment., Competing Interests: Declaration of competing interest The authors declare that the research was conducted without any commercial or financial relationship., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chaperonin containing TCP1 (CCT) is an essential protein that controls proteostasis following spinal cord damage. In particular, CCT2 plays an important role in neuronal death in various neurological disorders; however, few studies have investigated the effects of CCT2 on ischemic damage in the spinal cord. In the present study, we synthesized a cell-permeable Tat-CCT2 fusion protein and observed its effects on H 2 O 2 -induced oxidative damage in NSC34 motoneuron-like cells and in the spinal cord after ischemic injury. Tat-CCT2, but not its control protein CCTs, was delivered into NSC34 cells in a concentration- and incubation time-dependent manner, and a clear cytosolic location of the delivered protein was observed. In addition, the delivered protein gradually degraded, and nearly control levels were observed 24 h after Tat-CCT2 treatment. Tat-CCT2 treatment significantly ameliorated 200 µM H 2 O 2 -induced neuronal damage in NSC34 cells at 8.0 µM protein treatment. Additionally, Tat-CCT2 significantly ameliorated H 2 O 2 -induced reactive oxygen species formation and DNA fragmentation. In the rabbit spinal cord, Tat-CCT2 was efficiently delivered into the spinal cord 4 h after 0.125 mg/kg protein treatment. In addition, treatment with Tat-CCT2 significantly improved the neurological scores based on the Tarlov criteria 24 and 72 h after ischemia/reperfusion. Moreover, the number of surviving neurons in the ventral horn of the spinal cord was significantly increased in the Tat-CCT2-treated group 3 and 7 days after ischemia compared to vehicle-treated group. Treatment with Tat-CCT2 alleviated the ischemia-induced oxidative stress and ferroptosis-related factor (malondialdehyde, 8-iso-prostaglandin F2α, and high mobility group box 1) and pro-inflammatory cytokine (interleukin-1β, interleukin-6, and tumor necrosis factor-α) releases in the ventral horn of the spinal cord 8 and 24 h after ischemia/reperfusion. In addition, Tat-CCT2 treatment significantly ameliorated ischemia-induced microglial activation in the ventral horn of spinal cord 24 h after reperfusion. These results suggest that Tat-CCT2 mitigates ischemia-induced neuronal damage in the spinal cord., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To analyze bacterial isolates associated with canine bacterial keratitis and their antibiotic susceptibility patterns in Korea, focusing on multidrug resistance (MDR) and identifying effective antibiotic combinations for clinical treatment., Animal Studied: A total of 146 dogs diagnosed with suspected bacterial keratitis between October 2022 and October 2023 in Korea, with 157 eye samples collected for analysis., Procedure: Eye samples were cultured to isolate bacteria, and antibiotic susceptibility testing was performed using the minimum inhibitory concentration (MIC) method. Bacterial identification was conducted using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF). The study assessed the efficacy of individual antibiotics and combination therapies., Results: Bacteria were isolated in 55.4% of the samples. The most common genera were Staphylococcus species (48.5%, 48/99), Streptococcus species (13.1%, 13/99), Pseudomonas species (9.1%, 9/99), and Escherichia coli (9.1%, 9/99). Amikacin (84.8%) showed the highest antibiotic susceptibility, while doxycycline exhibited the lowest (17.2%). The most effective antibiotic combinations were amikacin-moxifloxacin (93%). MDR isolates accounted for 52.5% (52/99) of the total bacterial samples., Conclusions: Staphylococcus species were the most common isolates, with 52.5% showing MDR, underscoring the need to curb antibiotic misuse. While antibiotics like amikacin demonstrated high susceptibility rates, their use should be reserved for resistant infections to prevent further resistance development. Rather than focusing solely on finding effective combinations of antibiotics, it is crucial to consider alternative treatment strategies that offer more sustainable solutions. Rather than relying on antibiotic combinations, attention should shift to sustainable alternatives to treat bacterial keratitis and reduce antibiotic dependence in clinical practice., (© 2024 American College of Veterinary Ophthalmologists.)

This study investigates the changes in hippocampal proteomic profiles during demyelination and remyelination using the cuprizone model. Employing two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry for protein profiling, we observed significant alterations in the expression of ketimine reductase mu-crystallin (CRYM) and protein disulfide isomerase A3 precursor (PDIA3) following exposure to and subsequent withdrawal from cuprizone. Immunohistochemical staining validated these protein expression patterns in the hippocampus, revealing that both PDIA3 and CRYM were downregulated in the hippocampal CA1 region during demyelination and upregulated during remyelination. Additionally, we explored the potential protective effects of CRYM and PDIA3 against cuprizone-induced demyelination by synthesizing cell-permeable Tat peptide-fusion proteins (Tat-CRYM and Tat-PDIA3) to facilitate their crossing through the blood-brain barrier. Our results indicated that administering Tat-CRYM and Tat-PDIA3 mitigated the reduction in proliferating cell and differentiated neuroblast counts compared to the group receiving cuprizone alone. Notably, Tat-PDIA3 demonstrated significant effects in enhancing myelin basic protein expression alongside phosphorylation of CREB in the hippocampus, suggesting its potential therapeutic role in the prevention or treatment of demyelination, and by extension, in conditions such as multiple sclerosis., (© 2024. The Author(s).)

The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) plays an essential role in glycolysis and in the antioxidant pathway associated with glutathione. Therefore, we investigated the effects of PFKFB3 on oxidative and ischemic damage. We synthesized a fusion protein of transactivator of transcription (Tat)-PFKFB3 to facilitate its passage into the intracellular space and examine its effects against oxidative stress induced by hydrogen peroxide (H 2 O 2 ) treatment and ischemic damage caused by occlusion of the common carotid arteries for 5 min in gerbils. The Tat-PFKFB3 protein was efficiently delivered into HT22 cells in a concentration- and time-dependent manner, with higher levels observed 18 h after treatment. Furthermore, treatment with 6 µM Tat-PFKFB3 demonstrated intracellular delivery into HT22 cells, as analyzed through immunocytochemical staining. Moreover, it significantly ameliorated the reduction of cell viability induced by 200 µM H 2 O 2 treatment. Tat-PFKFB3 treatment also alleviated H 2 O 2 -induced DNA fragmentation and reactive oxygen species formation in HT22 cells. In gerbils, the intraperitoneal administration of 2 mg/kg Tat-PFKFB3 efficiently delivered the substance to all hippocampal areas, including the hippocampal CA1 region. This administration significantly mitigated ischemia-induced hyperlocomotion, long-term memory deficits, and ischemic neuronal death in the hippocampal CA1 region after ischemia. Additionally, treatment with 2 mg/kg Tat-PFKFB3 significantly ameliorated the translocation of Cdk5 from the cytosol to the nucleus in the hippocampal CA1 region 24 h after ischemia, but not in other regions. The treatment also significantly reduced reactive oxygen species formation in the CA1 region. These findings suggest that Tat-PFKFB3 reduces neuronal damage in the hippocampal CA1 region after ischemia through the reduction of Cdk5 signaling and reactive oxygen species formation. Therefore, Tat-PFKFB3 may have potential applications in reducing ischemic damage., (© 2024. The Author(s).)

Background : The peptidyl-prolyl isomerase (PIN1) plays a vital role in cellular processes, including intracellular signaling and apoptosis. While oxidative stress is considered one of the primary mechanisms of pathogenesis in brain ischemic injury, the precise function of PIN1 in this disease remains to be elucidated. Objective : We constructed a cell-permeable PEP-1-PIN1 fusion protein and investigated PIN1's function in HT-22 hippocampal cells as well as in a brain ischemic injury gerbil model. Methods : Transduction of PEP-1-PIN1 into HT-22 cells and signaling pathways were determined by Western blot analysis. Intracellular reactive oxygen species (ROS) production and DNA damage was confirmed by DCF-DA and TUNEL staining. Cell viability was determined by MTT assay. Protective effects of PEP-1-PIN1 against ischemic injury were examined using immunohistochemistry. Results : PEP-1-PIN1, when transduced into HT-22 hippocampal cells, inhibited cell death in H 2 O 2 -treated cells and markedly reduced DNA fragmentation and ROS production. This fusion protein also reduced phosphorylation of mitogen-activated protein kinase (MAPK) and modulated expression levels of apoptosis-signaling proteins in HT-22 cells. Furthermore, PEP-1-PIN1 was distributed in gerbil hippocampus neuronal cells after passing through the blood-brain barrier (BBB) and significantly protected against neuronal cell death and also decreased activation of microglia and astrocytes in an ischemic injury gerbil model. Conclusions : These results indicate that PEP-1-PIN1 can inhibit ischemic brain injury by reducing cellular ROS levels and regulating MAPK and apoptosis-signaling pathways, suggesting that PIN1 plays a protective role in H 2 O 2 -treated HT-22 cells and ischemic injury gerbil model.

Introduction: Recent studies have investigated the autonomic modulation method using closed-loop vibration stimulation (CLVS) as a novel strategy for enhancing sleep quality. This study aimed to explore the effects of CLVS on sleep quality, autonomic regulation, and brain activity in individuals with poor sleep quality., Methods: Twenty-seven participants with poor sleep quality (Pittsburgh sleep quality index >5) underwent two experimental sessions using polysomnography and a questionnaire, one with CLVS (STIM) and the other without (SHAM)., Results: Sleep macrostructure analysis first showed that CLVS significantly reduced the total time, proportion, and average duration of waking after sleep onset. These beneficial effects were paralleled by significantly increased self-reported sleep quality. Moreover, there was a significant increase in the normalized high-frequency (nHF) and electroencephalography relative powers of delta activity during N3 sleep under STIM. Additionally, coherence analysis between nHF and delta activity revealed strengthened coupling between cortical and cardiac oscillations., Discussion: This study demonstrated that CLVS significantly improves sleep quality in individuals with poor sleep quality by enhancing both subjective and objective measures. These findings suggest that CLVS has the potential to be a practical, noninvasive tool for enhancing sleep quality in individuals with sleep disturbances, offering an effective alternative to pharmacological treatments., Competing Interests: HK, KP, and HY are inventors of patents (10-1989402, Korea and US11013920B2, USA). KP is consulting BRLAB, Inc. HK, JJ, BC, and HY were employed by the Research Institute of BRLAB, Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kwon, Jeong, Choi, Park, Joo and Yoon.)

Actionable mutations of RET kinase have been identified as oncogenic drivers of solid tumors, including thyroid cancer, metastatic colorectal cancer, and nonsmall cell lung cancer. Although multikinase inhibitors and RET selective inhibitors are used to treat patients with RET alterations, there is insufficient research addressing certain issues: which actionable mutations arise from these therapies, how to improve the clinical response rate to RET inhibitors, and how to design new inhibitors to overcome drug resistance. Therefore, the development of sophisticated tool compounds is required to investigate the molecular mechanisms of actionable mutations and to develop breakthrough therapeutics for different RET alterations. Herein, we present our investigation into the side chains of imidazopyridazine hinge binders that are capable of inducing protein-ligand interaction patterns from the gatekeeper to the waterfront regions. Extending the substituents at the second and sixth positions enhanced the IC 50 up to < 0.5 nM for diverse RET alterations., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Drought is a complex natural hazard that occurs when a region experiences a prolonged period of dry conditions, leading to water scarcity and negative impacts on the environment. This study analyzed the recurrence of drought and wet spells in Baluchistan province, Pakistan. Reconnaissance Drought Index (RDI), Standardized Precipitation Evapotranspiration Index (SPEI), and Vegetation Condition Index (VCI) were used to analyze droughts in Baluchistan during 1986-2021. Statistical analysis i.e. run theory, linear regression, and correlation coefficient were used to quantify the trend and relationship between meteorological (RDI, SPEI) and agricultural (VCI) droughts. The meteorological drought indices (1, 3, 6, and 12-month RDI and SPEI) identified severe to extreme drought spells during 1986, 1988, 1998, 2000-2002, 2004, 2006, 2010, 2018-2019, and 2021 in most meteorological stations (met-stations). The Lasbella met-station experienced the most frequent extreme to severe droughts according to both the 12-month RDI (8.82%) and SPEI (15.38%) indices. The Dalbandin met-station (8.34%) follows closely behind for RDI, while Khuzdar (5.88%) comes in second for the 12-month SPEI. VCI data showed that Baluchistan experienced severe to extreme drought in 2000, 2001, 2006, and 2010. The most severe drought occurred in 2000 and 2001, affecting 69% of the study region. A positive correlation was indicated between meteorological (RDI, SPEI) and agricultural drought index (VCI). The multivariate indices can provide valuable knowledge about drought episodes and preparedness to mitigate drought impacts., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Rafiq et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Soft sensors based on deep learning regression models are promising approaches to predict real-time fermentation process quality measurements. However, experimental datasets are generally sparse and may contain outliers or corrupted data. This leads to insufficient model prediction performance. Therefore, datasets with a fully distributed solution space are required that enable effective exploration during model training. In this study, the robustness and predictive capability of the underlying model of a soft sensor was improved by generating synthetic datasets for training. The monitoring of intensified ethanol fermentation is used as a case study. Variational autoencoders were employed to create synthetic datasets, which were then combined with original datasets (experimental) to train neural network regression models. These models were tested on original versus augmented datasets to assess prediction improvements. Using the augmented datasets, the soft sensor predictive capability improved by 34%, and variability was reduced by 82%, based on R 2 scores. The proposed method offers significant time and cost savings for dataset generation for the deep learning modeling of ethanol fermentation and can be easily adapted to other fermentation processes. This work contributes to the advancement of soft sensor technology, providing practical solutions for enhancing reliability and robustness in large-scale production.

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10 -8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells., (© 2024. The Author(s).)

The development of cost-effective and high-performance oxygen evolution reaction (OER) catalysts is a significant challenge. This study presents the synthesis of binder-free NiFe@NiFe layered double hydroxide (NNF) via one-pot electrodeposition on carbon paper and Ni foam at high current densities. The presence of Ni sulfate residues on the prepared NNF is also investigated. The findings indicate that Ni sulfate significantly improves OER performance and durability. The sulfate content can be controlled by varying the method and duration of washing. NNF prepared through dipping (NNF-D) exhibits outstanding OER activity with a low overpotential of 241 mV, which is 25 mV lower than that of NNF washed for 60 s (NNF-W-60 s) at 10 mA cm -2 in 1 m KOH. Furthermore, density functional theory analyses indicate that the Ni sulfate residue helps modify the electronic structure, thereby optimizing the binding strength of *OOH. This synthetic strategy is expected to inspire the development of next-generation catalysts utilizing various adsorbates., (© 2024 Wiley‐VCH GmbH.)

Recent studies have shown that novel antibody-drug conjugates (ADCs) can improve clinical outcomes in patients with HER2-low breast cancers. This study aimed to investigate alteration of HER2 status during breast cancer progression with an emphasis on HER2-low status. Using 386 paired samples of primary and recurrent breast cancers, HER2 discordance rate between primary and matched recurrent samples, the relationships between HER2 discordance and clinicopathological characteristics and clinical outcomes of the patients were analyzed. HER2 discordance rate between primary breast cancer and first recurrence was 25.9% (κ = 0.586) with mostly zero-to-low (10.6%) or low-to-zero (9.3%) conversion. There was no significant difference in the discordant rates according to type or location of the recurrence. Of 70 cases with a second recurrence, HER2 discordance rate between the primary tumor and the second recurrence was 27.1% (κ = 0.554). HER2 discordance was associated with lower HER2 level, lymphovascular invasion, and progesterone receptor positivity of the primary tumor. In further analyses, HER2-zero-to-low conversion was associated with lymph node metastasis and hormone receptor (HR) positivity, whereas HER2-low-to-zero conversion was associated with HR negativity and triple-negative subtype. In survival analyses, HER2 discordance was associated with decreased overall survival of patients in the HR-positive group but not in the HR-negative group. Furthermore, patients with HER2-low-to-zero converted tumors showed worse overall survival compared with those with HER2-low concordant tumors. In conclusion, HER2 status changes during breast cancer progression in significant proportions, mostly between zero and low status. As HER2 instability increases during progression and affects clinical outcome, HER2 status needs to be reevaluated in recurrent settings., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Microplastics are persistent pollutants discovered and extensively researched in marine, freshwater, and terrestrial ecosystems but have yet to receive attention in an atmospheric context. Although recent reports stated the presence of microplastics in the air, their global existence and distribution are not critically discussed to date. This review aimed to investigate the current status of research on atmospheric microplastics through bibliometric analysis and by comparing and summarising published research on global distribution. The review also provides a summary of methods that have been used to collect samples, identify microplastics, quantify their occurrence, and determine their transport mechanisms. The bibliometric analysis revealed that atmospheric microplastic studies predominantly originated in China. Clothing, vehicle, and tire materials were the major primary sources while house furniture, construction materials, landfills, urban dust, plastic recycling processes, and agricultural sludge were precursor secondary sources. Polyethylene, polypropylene, and polyethylene terephthalate microfibres have most frequently found in indoor and outdoor atmospheres. Level of urbanization and temporal or spatial distributions governs the fate of airborne microplastics, however, the knowledge gap in the retention and circulation of microplastics through the atmosphere is still large. Many challenges and limitations were identified in the methods used, presentation of data, aerodynamic processes facilitating atmospheric transport, and scarcity of research in spatially and temporally diverse contexts. The review concluded that there was a greater need for globalization of research, methods and data standardization, and emphasizes the potential for future research with atmospheric transportation modelling and thermochemical analysis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hyun-Han Kwon reports financial support was provided by Korea Ministry of Environment. Meththika Vithanage reports article publishing charges and travel were provided by The University of Western Australia. 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 Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Human epidermal growth factor receptor 2 (HER2)-low status has recently gained attention because of the potential therapeutic benefits of antibody-drug conjugates (ADCs) in breast cancer patients. We aimed to investigate the concordance of HER2 status between core needle biopsy (CNB) and subsequent surgical resection specimens focusing on the HER2-low status., Methods: This retrospective study was conducted in 1,387 patients with invasive breast cancer whose HER2 status was evaluated in both CNB and surgical resection specimens. The discordance rates between CNB and surgical resection specimens and the clinicopathological features associated with HER2 status discordance were analyzed., Results: The overall concordance rates of HER2 status between CNB and surgical resection specimens were 99.0% (κ = 0.925) for two-group classification (negative vs. positive) and 78.5% (κ = 0.587) for three-group classification (zero vs. low vs. positive). The largest discordance occurred in CNB-HER2-zero cases with 42.8% of them reclassified as HER2-low in surgical resection. HER2 discordance was associated with lower histologic grade, tumor multiplicity, and luminal A subtype. In multivariate analysis, tumor multiplicity and estrogen receptor (ER) positivity were independent predictive factors for HER2-zero to low conversion., Conclusions: Incorporation of HER2-low category in HER2 status interpretation reduces the concordance rate between CNB and surgical resection specimens. Tumor multiplicity and ER positivity are predictive factors for conversion from HER2-zero to HER2-low status. Therefore, HER2 status should be re-evaluated in resection specimens when considering ADCs in tumors exhibiting multiplicity and ER positivity., (© 2024. The Author(s).)

Background: Cervical epidural block (CEB) is an effective intervention for managing cervical radicular pain. This study aimed to investigate the current status of performing CEB in South Korea., Methods: Pain physicians affiliated with the Korean Pain Society were asked to complete anonymous questionnaires regarding CEB between September and October 2022. The questionnaire consisted of 24 questions assessing the current status and methods of CEB in detail., Results: Of the 198 surveys collected, 171 physicians (86.4%) reported performing CEB. Among those, the majority (94.7%) used fluoroscopy during the procedure. The paramedian interlaminar (IL) approach was the most preferred method (50.3%). Respondents performing fluoroscopic-guided IL CEB were categorized into two groups based on clinical experience: those with ≤10 years of experience (≤10-year group, n = 91) and those with >10 years of experience (>10-year group, n = 71). The proportion of physicians obtaining informed consent in the ≤10-year group and >10-year group was 50.5% and 56.3%, respectively. When entering the epidural space during IL CEB, the contralateral oblique view was the second most frequently used in both groups (≤10-year group, 42.9%; >10-year group, 29.6%). In targeting the upper cervical lesions (C3-4), the proportion of respondents who used an IL space higher than C6-7 was 17.6% in the ≤10-year group and 29.5% in the >10-year experience group., Conclusions: This study demonstrated variability in the CEB technique used by pain physicians in South Korea. The findings highlight the need for education on informed consent and techniques to enhance safety.

Background : Increasing evidence supporting the clinical effectiveness of cooled radiofrequency ablation (RFA) therapy for genicular nerves in patients with chronic knee osteoarthritis (OA) exists. However, no study has been conducted to eliminate the potential influence of a placebo effect associated with this procedure. Therefore, we evaluated the efficacy of cooled RFA compared with a sham procedure in patients with painful knees due to OA. Methods : In this double-blind, randomized, controlled study, participants were randomly assigned to receive cooled RFA of the knee (cooled RFA group, n = 20) or a sham procedure (sham group, n = 20). The primary outcome was the proportion of successful responders at the three-month follow-up. The secondary outcomes were successful responders at one and six months; pain intensity of the knee; functional status; medication; and satisfaction at one, three, and six months after the procedures. Results : For the primary outcome, the successful responder rate was significantly higher in the cooled RFA group (76.5%) than in the sham group (33.3%) ( p = 0.018). For the secondary outcome, more successful responders were observed in the cooled RFA group than in the sham group at one and six months after the procedure ( p = 0.041 and 0.007, respectively). The decreased knee pain intensity was maintained throughout the six-month follow-up period in the cooled RFA group. No differences were observed in functional status, medication change, or satisfaction in both groups. Conclusions : The cooled RFA of genicular nerves offers significant pain relief and surpasses the effects attributable to a placebo.

The histone acetyltransferase p300 plays a pivotal role in regulating gene expression and cellular phenotype through epigenetic mechanisms. It significantly influences lipid metabolism, which is a key factor in the pathogenesis of non-alcoholic steatohepatitis (NASH), by modulating the transcription of genes involved in lipid synthesis and accumulation. This study aimed to investigate the protective potential of inhibiting p300 in NASH. Male C57BL/6J mice were subjected to a methionine- and choline-deficient (MCD) diet for 4 weeks to induce NASH, and during this period, the p300 inhibitor C646 (10 mg/kg) was administered three times a week. C646 treatment reduced the elevation of p300 expression and histone H3 acetylation, leading to a decrease in liver injury markers in the serum and an improvement in the histological abnormalities observed in MCD diet-fed mice. C646 also reduced lipid accumulation by modulating de novo lipogenesis and suppressed inflammation, including cytokine overproduction and macrophage infiltration. Furthermore, C646 mitigated liver fibrosis and myofibroblast accumulation. This protective effect was achieved through the inhibition of apoptosis by reducing p53 and Bax expression and the suppression of ferroptosis by decreasing lipid peroxidation while enhancing antioxidant defenses. Additionally, C646 alleviated endoplasmic reticulum stress, as evidenced by the downregulation of unfolded protein response signaling molecules. These results highlight the potential of p300 as a therapeutic target for NASH., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jaechan Leem reports financial support was provided by the 10.13039/501100003725National Research Foundation of Korea (NRF). Yun-A Kim reports financial support was provided by the 10.13039/501100003725National Research Foundation of Korea (NRF). Jung-Yeon Kim reports financial support was provided by the 10.13039/501100003725National Research Foundation of Korea (NRF). 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., (© 2024 The Authors.)

Atopic dermatitis (AD), marked by intense itching and eczema-like lesions, is a globally increasing chronic skin inflammation. Kahweol, a diterpene that naturally occurs in coffee beans, boasts anti-inflammatory, antioxidative, and anti-cancer properties. This research explores the anti-inflammatory action of kahweol on HaCaT human keratinocytes stimulated by tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), focusing on key signal transduction pathways. Our results demonstrate that kahweol markedly reduces the production of IL-1β, IL-6, C-X-C motif chemokine ligand 8, and macrophage-derived chemokine in TNF-α/IFN-γ-activated HaCaT cells. Furthermore, it curtails the phosphorylation of key proteins in the mitogen-activated protein kinase (MAPK) pathways, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38. Additionally, kahweol impedes the phosphorylation and nuclear translocation of the NF-κB p65 subunit and constrains its DNA-binding capability. It also hampers the phosphorylation, nuclear translocation, and DNA-binding activities of signal transducer and activator of transcription 1 (STAT1) and STAT3. Collectively, these findings suggest that kahweol hinders the generation of cytokines and chemokines in inflamed keratinocytes by inhibiting the MAPK, NF-κB, and STAT cascades. These insights position kahweol as a promising agent for dermatological interventions, especially in managing inflammatory skin conditions such as AD.

Purpose: Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non-small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples., Materials and Methods: A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed., Results: TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs., Conclusion: Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.

Osteosarcoma, which has poor prognosis after metastasis, is the most common type of bone cancer in children and adolescents. Therefore, plant-derived bioactive compounds are being actively developed for cancer therapy. Artemisia apiacea Hance ex Walp. is a traditional medicinal plant native to Eastern Asia, including China, Japan, and Korea. Vitexicarpin (Vitex), derived from A. apiacea, has demonstrated analgesic, anti-inflammatory, antitumour, and immunoregulatory properties; however, there are no published studies on Vitex isolated from the aerial parts of A. apiacea. Thus, this study aimed to evaluate the antitumour activity of Vitex against human osteosarcoma cells. In the present study, Vitex (>99% purity) isolated from A. apiacea induced significant cell death in human osteosarcoma MG63 cells in a dose- and time-dependent manner; cell death was mediated by apoptosis, as evidenced by the appearance of cleaved-PARP, cleaved-caspase 3, anti-apoptotic proteins (Survivin and Bcl-2), pro-apoptotic proteins (Bax), and cell cycle-related proteins (Cyclin D1, Cdk4, and Cdk6). Additionally, a human phosphokinase array proteome profiler revealed that Vitex suppressed AKT-dependent downstream kinases. Further, Vitex reduced the phosphorylation of PRAS40, which is associated with autophagy and metastasis, induced autophagosome formation, and suppressed programmed cell death and necroptosis. Furthermore, Vitex induced antimetastatic activity by suppressing the migration and invasion of MMP13, which is the primary protease that degrades type I collagen for tumour-induced osteolysis in bone tissues and preferential metastasis sites. Taken together, our results suggest that Vitex is an attractive target for treating human osteosarcoma.

Introduction: Fluoroscopy can improve the success rate of thoracic epidural catheter placement (TECP). Real-time ultrasound (US)-guided TECP was recently introduced and showed a high first-pass success rate. We tested whether real-time US-guided TECP results in a non-inferior first-pass success rate compared with that of fluoroscopy-guided TECP., Methods: In this single-center, non-inferiority, randomized trial, the primary outcome was the comparison of the first-pass success rate of TECP between real-time US guidance (US group) and fluoroscopic guidance (fluoroscopy group). Secondary outcomes included time to identifying epidural space, procedure time, total number of needle passes, number of skin punctures, final success, and cross-over success., Results: We randomly assigned 132 patients to the allocated groups. The difference in the first-pass success rate between the groups did not exceed the non-inferiority margin of 15% (US group: 66.7% vs fluoroscopy group: 68.2%; difference -1.5%, 95% exact CI: -14.9% to 11.9%). The difference in the final success rate also did not differ between the groups (98.5% vs 100.0%; difference -1.5%, 95% exact CI: -4.0% to 1.0%). The time to identifying epidural space (45.6 (34-62) vs 59.0 (42-77) s, p=0.004) and procedure time (39.5 (28-78) vs 112.5 (93-166) s, p<0.001) were significantly shorter in the US group., Conclusions: Real-time US guidance provided a non-inferior success rate and shorter time spent on preparation and procedure compared with fluoroscopic guidance in TECP., Trial Registration Number: KCT0006521., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

In this study, 1-bromohexyl-1methylpiperidinium bromide (Br-6-MPRD) ionic liquid grafted quaternized chitosan (QCS) and polyvinyl alcohol (PVA) blends were composited with glycidyl trimethyl ammonium chloride (GTMAC) quaternized silica (QSiO 2 ) at different dosages. Glutaraldehyde (GA) crosslinked the membranes and then processed into hydroxide form with an aqueous potassium hydroxide solution. The resultant IL-QCS/PVA/QSiO 2 membranes exhibit significantly improved ionic conductivity, moderate water absorption and swelling ratio compared with the pristine IL-QCS/PVA anion exchange membrane (AEM). Among them, the hydroxide ion conductivity and power density of IL-QCS/PVA/QSiO 2 -7 membrane can reach up to 78 mS cm -1 at 80 °C and 115 mW cm -2 at 60 °C respectively. In addition, IL-QCS/PVA/QSiO 2 membranes have excellent thermal, mechanical, and chemical stabilities, which can meet the application requirements of AEM for fuel cells., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes., Competing Interests: Declaration of interests Y.S.J. is a genomic co-founder and chairman of Genome Insight., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Non-alcoholic steatohepatitis (NASH) is becoming an increasingly serious global health threat, distinguished by hepatic lipid accumulation, inflammation, and fibrosis. There is a lack of approved pharmaceutical interventions for this disease, highlighting the urgent need for effective treatment. This study explores the hepatoprotective potential of 6-shogaol, a natural compound derived from ginger, in a methionine- and choline-deficient (MCD) dietary mouse model of NASH. Male C57BL/6J mice were subjected to the MCD diet for 4 weeks to induce NASH, with concurrent intraperitoneal administration of 6-shogaol (20 mg/kg) three times a week. While 6-shogaol did not impact body weight, liver weight, or hepatic lipid accumulation, it effectively mitigated liver injury, inflammation, and fibrosis in MCD diet-fed mice. Mechanistically, 6-shogaol inhibited lipid and DNA oxidation, restored hepatic glutathione levels, and regulated the expression of pro-oxidant and antioxidant enzymes. Furthermore, 6-shogaol inhibited apoptosis and necroptosis, as indicated by a decrease in TUNEL-stained cells and downregulation of apoptosis- and necroptosis-associated proteins. Additionally, 6-shogaol alleviated endoplasmic reticulum (ER) stress, as demonstrated by decreased expression of molecules associated with unfolded protein response pathways. These findings underscore the potential of 6-shogaol as a therapeutic intervention for NASH by targeting pathways related to oxidative stress, cell death, and ER stress.

Acute ischemic stroke is a cerebrovascular disease associated with high mortality and severe aftereffects which is caused by the blockage of cerebral blood vessels by a thrombus or embolus. Treatments for this condition are extremely limited. Herein, we aimed to explore the potential of 2,3,4-trihydroxybenzophenone (THB), a drug that suppresses oxidative stress and neuroinflammation, to promote functional recovery through neurite outgrowth, and to identify its protective effects in a mouse model of ischemic stroke. To determine the effects of THB on neurite outgrowth, neurite-bearing cells and neurite lengths were measured in Neuro2a cells. 1,1-Diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) scavenging assays were further performed to determine the antioxidant activity of THB, while lipopolysaccharide-activated BV2 cells were used to determine the anti-inflammatory effects of THB. Transient middle cerebral artery occlusion (tMCAO) was further performed in a mouse model to determine the effects of THB on ischemic stroke. THB increased neurite outgrowth in mouse neuroblastoma cell lines and exhibits antioxidant and anti-neuroinflammatory properties. In addition, THB reduced infarct volume in a concentration-dependent manner in the tMCAO model, leading to an increase in survival rate. Moreover, THB significantly suppressed microglial activation in the cortex and striatum. These results suggest that THB has potential for treating transient cerebral ischemic stroke.

Knee osteoarthritis (OA) is a prevalent and debilitating musculoskeletal condition that significantly affects the quality of life of millions of individuals worldwide. In recent years, cooled radiofrequency ablation (CRFA) has become a viable treatment option for knee OA. This review thoroughly evaluated the existing literature on CRFA therapy for knee OA. It delved into the mechanisms behind CRFA, evaluated its clinical efficacy, and investigated potential avenues for future research and application. The insights gained from this review are crucial for healthcare professionals, researchers, and policymakers, offering an updated perspective on CRFA's role as a viable therapeutic option for knee OA.

Aim: In this study, we investigated the effects of Dendropanax morbifera extract (DME) on neuroprotection against ischemic damage in gerbils., Methods: DME (100 or 300 mg/kg) was orally administered to gerbils for three weeks, and 2 h after the last DME treatment, transient forebrain ischemia in the common carotid arteries was induced for 5 min. The forebrain ischemia-related cognitive impairments were assessed by spontaneous motor activity and passive avoidance test one and four days after ischemia, respectively. In addition, surviving and degenerating neurons were morphologically confirmed by neuronal nuclei immunohistochemical staining and Fluoro-Jade C staining, respectively, four days after ischemia. Changes of glial morphology were visualized by immunohistochemical staining for each marker such as glial fibrillary acidic protein and ionized calcium-binding protein. Oxidative stress was determined by measurements of dihydroethidium, O 2 · (formation of formazan) and malondialdehyde two days after ischemia. In addition, glutathione redox system such as reduced glutathione, oxidized glutathione levels, glutathione peroxidase, and glutathione reductase activities were measured two days after ischemia., Results: Spontaneous motor activity monitoring and passive avoidance tests showed that treatment with 300 mg/kg DME, but not 100 mg/kg, significantly alleviated ischemia-induced memory impairments. In addition, approximately 67 % of mature neurons survived and 29.3 % neurons were degenerated in hippocampal CA1 region four days after ischemia, and ischemia-induced morphological changes in astrocytes and microglia were decreased in the CA1 region after 300 mg/kg DME treatment. Furthermore, treatment with 300 mg/kg DME significantly ameliorated ischemia-induced oxidative stress, such as superoxide formation and lipid peroxidation, two days after ischemia. In addition, ischemia-induced reduction of the glutathione redox system in the hippocampus, assessed two days after the ischemia, was ameliorated by treatment with 300 mg/kg DME. These suggest that DME can potentially reduce ischemia-induced neuronal damage through its antioxidant properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Bain ischemia is a disease that occurs for various reasons, induces reactive oxygen species (ROS), and causes fatal damage to the nervous system. Protective effect of HPCA on ischemic injury has not been extensively studied despite its significance in regulating calcium homeostasis and promoting neuronal survival in CA1 region of the brain., Objective: We investigate the role of HPCA in ischemic injury using a cell-permeable Tat peptide fused HPCA protein (Tat-HPCA)., Methods: Western blot analysis determined the penetration of Tat-HPCA into HT-22 cells and apoptotic signaling pathways. 5-CFDA, AM, DCF-DA, and TUNEL staining confirmed intracellular ROS production and DNA damage. The intracellular Ca 2+ was measured in primary cultured neurons treated with H 2 O 2 . Protective effects were examined using immunohistochemistry and cognitive function tests by passive avoidance test and 8-arm radial maze test., Results: Tat-HPCA effectively penetrated into HT-22 cells and inhibited H 2 O 2 -induced apoptosis, oxidative stress, and DNA fragmentation. It also effectively inhibited phosphorylation of JNK and regulated the activation of Caspase, Bax, Bcl-2, and PARP, leading to inhibition of apoptosis. Moreover, Ca 2+ concentration decreased in cells treated with Tat-HPCA in primary cultured neurons. In an animal model of ischemia, Tat-HPCA effectively penetrated the hippocampus, inhibited cell death, and regulated activities of astrocytes and microglia. Additionally, Cognitive function tests show that Tat-HPCA improves neurobehavioral outcomes after cerebral ischemic injury., Conclusion: These results suggest that Tat-HPCA might have potential as a therapeutic agent for treating oxidative stress-related diseases induced by ischemic injury, including ischemia., Competing Interests: 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., (© 2023 The Authors.)

Introduction: Although the contralateral oblique (CLO) view at 50°±5° is clinically useful for cervical epidural access, no previous studies have confirmed its safety. This prospective observational study was conducted to assess the safety profile, including the risk of dural puncture, in fluoroscopically guided cervical epidural access using the CLO view., Methods: In cervical epidural access using the CLO view, the incidence of dural puncture was investigated as the primary outcome. Other intraprocedural complications, including intravascular entry, subdural entry, spinal cord injury and vasovagal injury, and postprocedural complications were investigated as secondary outcomes. Procedural variables including first-pass success, final success, needling time, total number of needle passes and false loss of resistance (LOR) were evaluated., Results: Of the 393 patients who underwent cervical interlaminar epidural access were included for analysis, no instances of dural puncture or spinal cord injury were observed. The incidence of intravascular entry, vasovagal reaction and subdural entry were 3.1%, 0.5% and 0.3%, respectively. All procedures were successfully performed, with 85.0% of first-pass success rate. The mean needling time was 133.8 (74.9) s. The false-positive and false-negative LOR rates were 8.2% and 2.0%, respectively. All needle tips were visualized clearly during the procedure., Conclusions: The fluoroscopy-guided CLO view at 50°±5° avoided dural puncture or spinal cord injury and decreased the incidence of false LOR during cervical epidural access with a paramedian approach., Trial Registration Number: NCT04774458., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

CCT2 is a eukaryotic chaperonin TCP-1 ring complex subunit that mediates protein folding, autophagosome incorporation, and protein aggregation. In this study, we investigated the effects of CCT on oxidative and ischemic damage using in vitro and in vivo experimental models. The Tat-CCT2 fusion protein was efficiently delivered into HT22 cells in a concentration- and time-dependent manner, and the delivered protein was gradually degraded in HT22 cells. Incubation with Tat-CCT2 significantly ameliorated the 200 µM hydrogen peroxide (H 2 O 2 )-induced reduction in cell viability in a concentration-dependent manner, and 8 µM Tat-CCT2 treatment significantly alleviated H 2 O 2 -induced DNA fragmentation and reactive oxygen species formation in HT22 cells. In gerbils, CCT2 protein was efficiently delivered into pyramidal cells in CA1 region by intraperitoneally injecting 0.5 mg/kg Tat-CCT2, as opposed to control CCT2. In addition, treatment with 0.2 or 0.5 mg/kg Tat-CCT2 mitigated ischemia-induced hyperlocomotive activity 1 d after ischemia and confirmed the neuroprotective effects by NeuN immunohistochemistry in the hippocampal CA1 region 4 d after ischemia. Tat-CCT2 treatment significantly reduced the ischemia-induced activation of astrocytes and microglia in the hippocampal CA1 region 4 d after ischemia. Furthermore, treatment with 0.2 or 0.5 mg/kg Tat-CCT2 facilitated ischemia-induced autophagic activity and ameliorated ischemia-induced autophagic initiation in the hippocampus 1 d after ischemia based on western blotting for LC3B and Beclin-1, respectively. Levels of p62, an autophagic substrate, significantly increased in the hippocampus following treatment with Tat-CCT2. These results suggested that Tat-CCT2 exerts neuroprotective effects against oxidative stress and ischemic damage by promoting the autophagic removal of damaged proteins or organelles., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A rapid, simple, and robust LC-MS/MS method was developed and validated for the quantitation of colistin and colistin methanesulfonate (CMS) in human plasma. The method also prevented overestimation of colistin concentration by establishing the stability of CMS under sample preparation conditions, including blood and plasma storage conditions. Polymyxin B1 was used as an internal standard, and positive-ion electrospray ionization in multiple reaction monitoring mode was used for quantification. Chromatographic separation was achieved using a Zorbax eclipse C18 column (3.5 µm, 2.1 mm i.d. × 100 mm), with a flow rate of 0.5 mL/min, 5 μL injection volume, and gradient elution with a mixture of acetonitrile-water (containing 0.1 % trifluoroacetic acid). The method had a quantifiable range of 0.043-8.61 and 0.057-11.39 μg/mL for colistin A and B in human plasma, respectively, under a total runtime of 6.0 min. Further, it demonstrated appropriate extraction efficiency, no significant interference from co-eluting endogenous compounds, and satisfactory intraday and interday precision and accuracy. The proposed procedure for sample preparation successfully addressed the issue of CMS instability, consequently diminishing the probability of overestimating the concentration of colistin. Therefore, this simple and robust LC-MS/MS method for CMS and colistin quantification in human plasma is a valuable tool for clinicians to accurately monitor colistin treatment in patients with infections caused by multidrug-resistant (MDR) Gram-negative bacteria., 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 B.V. All rights reserved.)

We investigated the effects of heat shock protein 10 (HSP10) protein on memory function, hippocampal neurogenesis, and other related genes/proteins in adult and aged mice. To translocate the HSP10 protein into the hippocampus, the Tat-HSP10 fusion protein was synthesized, and Tat-HSP10, not HSP10, was successfully delivered into the hippocampus based on immunohistochemistry and western blotting. Tat-HSP10 (0.5 or 2.0 mg/kg) or HSP10 (control protein, 2.0 mg/kg) was administered daily to 3- and 21-month-old mice for 3 months, and observed the senescence maker P16 was significantly increased in aged mice and the treatment with Tat-HSP10 significantly decreased P16 expression in the hippocampus of aged mice. In novel object recognition and Morris water maze tests, aged mice demonstrated decreases in exploratory preferences, exploration time, distance moved, number of object contacts, and escape latency compared to adult mice. Treatment with Tat-HSP10 significantly improved exploratory preferences, the number of object contacts, and the time spent swimming in the target quadrant in aged mice but not adults. Administration of Tat-HSP10 increased the number of proliferating cells and differentiated neuroblasts in the dentate gyrus of adult and aged mice compared to controls, as determined by immunohistochemical staining for Ki67 and doublecortin, respectively. Additionally, Tat-HSP10 treatment significantly mitigated the reduction in sirtuin 1 mRNA level, N -methyl-D-aspartate receptor 1, and postsynaptic density 95 protein levels in the hippocampus of aged mice. In contrast, Tat-HSP10 treatment significantly increased sirtuin 3 protein levels in both adult and aged mouse hippocampus. These suggest that Tat-HSP10 can potentially reduce hippocampus-related aging phenotypes.

Competing Interests: The authors have nothing to disclose.

In the human brain, neurophysiological activity is modulated by the movement of neurotransmitters and neurosteroids. To date, the similarity between cerebral organoids and actual human brains has been evaluated using comprehensive multiomics approaches. However, a systematic analysis of both neurotransmitters and neurosteroids from cerebral organoids has not yet been reported. Here, we performed quantitative and qualitative assessments of neurotransmitters and neurosteroids over the course of cerebral organoid differentiation. Our multiomics approaches revealed that the expression levels of neurotransmitter-related proteins and RNA, including neurosteroids, increase as cerebral organoids mature. We also found that the electrophysiological activity of human cerebral organoids increases in tandem with the expression levels of both neurotransmitters and neurosteroids. Our study demonstrates that the expression levels of neurotransmitters and neurosteroids can serve as key factors in evaluating the maturity and functionality of human cerebral organoids.

Background: : Hypertonic saline is used for treating chronic pain; however, clinical studies that aid in optimizing therapeutic protocols are lacking. We aimed to determine the concentration of intrathecally injected hypertonic saline at which the effect reaches its peak as well as the underlying γ-aminobutyric acid (GABA) receptor-related antinociceptive mechanism., Methods: : Spinal nerve ligation (SNL; left L5 and L6) was performed to induce neuropathic pain in rats weighing 250-300 g. Experiment 1: one week after implanting the intrathecal catheter, 60 rats were assigned randomly to intrathecal injection with 0.45%, 0.9%, 2.5%, 5%, 10%, and 20% NaCl, followed by behavioral testing at baseline and after 30 minutes, 2 hours, 1 day, and 1 week to determine the minimal concentration which produced maximal analgesia. Experiment 2: after determining the optimal intrathecal hypertonic saline concentration, 60 rats were randomly divided into four groups: Sham, hypertonic saline without pretreatment, and hypertonic saline after pretreatment with one of two GABA receptor antagonists (GABA A [bicuculline], or GABA B [phaclofen]). Behavioral tests were performed at weeks 1 and 3 following each treatment., Results: : Hypertonic saline at concentrations greater than 5% alleviated SNL-induced mechanical allodynia and had a significant therapeutic effect, while showing a partial time- and dose-dependent antinociceptive effect on thermal and cold hyperalgesia. However, pretreatment with GABA receptor antagonists inhibited the antinociceptive effect of 5% NaCl., Conclusions: : This study indicates that the optimal concentration of hypertonic saline for controlling mechanical allodynia in neuropathic pain is 5%, and that its analgesic effect is related to GABA A and GABA B receptors.

Stress is an inevitable part of life and, simultaneously, a stimulus that can trigger various neuropsychiatric disorders. Therefore, proper stress management is essential for maintaining a healthy life. In this study, we investigated the suppression of stress-induced cognitive deficit by controlling changes in synaptic plasticity caused by stress and confirmed that ethyl pyruvate (EP) has such an effect. Corticosterone, a stress hormone, suppresses long-term potentiation (LTP) in mouse acute hippocampal slices. EP blocked the LTP inhibitory effect of corticosterone by regulating GSK-3β function. Restraint stress for 2 weeks increased the anxiety levels and caused the cognitive decline in the experimental animals. Administration of EP for 14 days did not affect the increase in anxiety caused by stress but improved cognitive decline caused by stress. In addition, the decrease in neurogenesis and synaptic function deficits in the hippocampus, which cause of cognitive decline due to stress, were improved by EP administration. These effects appear via regulation of Akt/GSK-3β signaling, as in in vitro studies. These results suggest that EP prevents stress-induced cognitive decline through the modulation of Akt/GSK-3β-mediated synaptic regulation., 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 Inc. All rights reserved.)