Search

Accurate in silico predictions of how strongly small molecules bind to proteins, such as those afforded by relative binding free energy (RBFE) calculations, can greatly increase the efficiency of the hit-to-lead and lead optimization stages of the drug discovery process. The success of such calculations, however, relies heavily on their precision. Here, we show that a recently developed alchemical enhanced sampling (ACES) approach can consistently improve the precision of RBFE calculations on a large and diverse set of proteins and small molecule ligands. The addition of ACES to conventional RBFE calculations lowered the average hysteresis by over 35% (0.3-0.4 kcal/mol) and the average replicate spread by over 25% (0.2-0.3 kcal/mol) across a set of 10 protein targets and 213 small molecules while maintaining similar or improved accuracy. We show in atomic detail how ACES improved convergence of several representative RBFE calculations through enhancing the sampling of important slowly transitioning ligand degrees of freedom.

Background/aims: Lymphoepithelioma-like carcinoma (LELC) is a rare subtype of gastric cancer. We aimed to identify the clinicopathological features and rate of lymph node metastasis (LNM) to investigate the feasibility of endoscopic submucosal dissection for early gastric LELC confined to the mucosa or submucosa., Methods: We compared the clinicopathological characteristics of 116 early gastric LELC patients and 5,753 early gastric well- or moderately differentiated (WD or MD) tubular adenocarcinoma patients treated by gastrectomy., Results: Compared to WD or MD early gastric cancer (EGC) patients, early LELC patients were younger and had a higher prevalence of proximally located tumors. Despite more frequent deep submucosal invasion (86.2% vs 29.8%), lymphatic invasion was less frequent (6.0% vs 16.2%) in early LELC patients than in WD or MD EGC patients. Among tumors with deep submucosal invasion, the tumor size was smaller, lymphatic invasion was less frequent (6.0% vs 40.2%) and the rate of LNM was lower (10.0% vs 19.4%) in patients with LELC than in those with WD or MD EGC. The overall rate of LNM in early LELC patients was 8.6% (10/116). The risk of LNM in patients with mucosal, shallow submucosal invasive, or deep submucosal invasive LELC was 0% (0/6), 0% (0/10), and 10% (10/100), respectively., Conclusions: Early LELC is a distinct subtype of EGC with more frequent deep submucosal invasion but less lymphatic invasion and LNM than WD or MD EGCs. Endoscopic submucosal dissection may be considered curative for patients with early LELC confined to the mucosa or shallow submucosa, given its negligible rate of LNM.

Radiation therapy is a crucial cancer treatment, but it can damage healthy tissues, leading to side effects like skin injuries and molecular alterations. This study aimed to elucidate histological and molecular changes in canine skin post-radiation therapy (post-RT) over nine weeks, focusing on inflammation, stem cell activity, angiogenesis, keratinocyte regeneration, and apoptosis. Four male beagles received a cumulative radiation dose of 48 Gy, followed by clinical observations, histological examinations, and an RT-qPCR analysis of skin biopsies. Histological changes correlated with clinical recovery from inflammation. A post-RT analysis revealed a notable decrease in the mRNA levels of Oct4, Sox2, and Nanog from weeks 1 to 9. VEGF 188 levels initially saw a slight increase at week 1, but they had significantly declined by week 9. Both mRNA and protein levels of COX-2 and Keratin 10 significantly decreased over the 9 weeks following RT, although COX-2 expression surged in the first 2 weeks, and Keratin 10 levels increased at weeks 4 to 5 compared to normal skin. Apoptosis peaked at 2 weeks and diminished, nearing normal by 9 weeks. These findings offer insights into the mechanisms of radiation-induced skin injury and provide guidance for managing side effects in canine radiation therapy.

Vepdegestrant (formerly ARV-471), a novel proteolysis-targeting chimera (PROTAC), targets estrogen receptor alpha (ERα) for degradation, offering a promising option to treat advanced ER-positive breast cancer. We developed and validated a sensitive and rapid liquid chromatography-tandem mass spectrometry method to quantify vepdegestrant in rodent plasma using bavdegalutamide (formerly ARV-110) as an internal standard. Plasma samples were prepared with protein precipitation using acetonitrile and analyzed using reverse-phase C18 columns and a mobile phase of 10 mM ammonium formate in distilled water and acetonitrile. The method demonstrated linearity from 1 to 1000 ng/mL in mouse and rat plasma, meeting all validation criteria, and successfully applied to in vivo and in vitro studies. Pharmacokinetic analysis revealed low-to-moderate clearance (313.3, 1053 mL/h/kg) and oral bioavailability (17.91, 24.12%) of vepdegestrant in mice and rats, respectively. It was unstable in buffer solutions across pH 2-10 and in phosphate-buffered saline (pH 7.4), likely due to adsorption, but remained stable in mouse and rat plasma at varying temperatures. In liver microsomes, vepdegestrant exhibited moderate stability in rats but was stable in mice, dogs, and humans. These findings enhance the understanding of pharmacokinetic properties of vepdegestrant supporting further development of PROTAC drugs.

Competing Interests: Declaration of competing interest Sung Eun Oh, Min-Gew Choi, Jun Ho Lee, Tae Sung Sohn, Jae Moon Bae, and Ji Yeong An have no conflicts of interest or financial ties to disclose.

Purpose: Posture correction bands (PCBs) have been proposed as aids to help chest expansion and to enhance respiratory function. However, the impact of PCBs on community-based older individuals engaged in inspiratory muscle training (IMT) at home remains unclear., Materials and Methods: Community-based individuals aged 65 years and older were divided into the PCB group, wearing PCBs, and the NPCB group, not wearing PCBs. The IMT regimen lasted 8 weeks, with sessions 5 times a week, including 4 sets per day and 15 repetitions per set. Training intensity was set at 50% of the maximum inspiratory pressure of each subject. To assess the effects of IMT, respiratory function, 6-minute walk test, and grip strength were measured before, during, and after the training period. Data were analyzed using repeated-measures analysis of variance, with post-hoc evaluation employing Bonferroni correction., Results: A total of 40 subjects were evenly divided into the PCB group and the NPCB group, with 20 subjects in each group. No significant difference was observed in respiratory muscle strength based on PCB use. However, during the initial 4 weeks, the PCB group exhibited a trend towards an increase in respiratory muscle strength compared to the NPCB group; this trend, however, did not prove to be statistically significant by the end of the 8-week period. Performance on the 6-minute walk test significantly improved in both groups., Conclusion: The PCB group exhibited a tendency for increase in respiratory muscle strength in the first 4 weeks; however, ultimately there was no significant difference compared to the NPCB group., Clinical Trial Registration: This study was registered with the Clinical Research Information Service, part of the World Health Organization's International Clinical Trials Registry Platform (Clinical Research Information Service No. KCT0008075)., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

The current high-capacity lithium-ion batteries (LIBs), reliant on flammable liquid electrolytes (LEs) and nickel-rich cathodes, are plagued by safety hazards, especially the risk of hazardous gas release stemming from internal side reactions. To address these safety concerns, an electron beam (E-beam)-induced gel polymer electrolyte (E-Gel) is introduced, employing dipentaerythritol hexaacrylate (DPH) as a bi-functional cross-linkable additive (CIA). The dual roles of DPH are exploited through a strategically designed E-beam irradiation process. Applying E-beam irradiation on the pre-cycled cells allows DPH to function as an additive during the initial cycle, establishing a protective layer on the surface of the anode and cathode and as a cross-linker during the E-beam irradiation step, forming a polymer framework. The prepared E-Gel with CIA has superior interfacial compatibility, facilitating lithium-ion diffusion at the electrode/E-Gel interface. The electrochemical assessment of 1.2 Ah pouch cells demonstrates that E-Gel substantially reduces gas release by 2.5 times compared to commercial LEs during the initial formation stage and ensures superior reversible capacity retention even after prolonged cycling at 55 °C. The research underscores the synergy of bifunctional CIA with E-beam technology, paving the way for large-scale production of safe, high-capacity, and commercially viable LIBs., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

In this study, we propose a method for predicting welding deformation caused by multi-pass welding using the thermal elastic-plastic finite element method (TEP-FEM) by considering the interpass temperature. This method increases the interpass temperature, which has not been considered in the existing TEP-FEM, from 200 °C to 1000 °C, and simultaneously performs thermal and mechanical analyses. In addition, this method can also evaluate temperature history and the time it takes to weld. By predicting the welding deformation using this method, angular distortion prediction was reduced from 16.75 mm to 10.9 mm compared to the case where the interpass temperature was cooled to room temperature. Additionally, the deformation error was significantly reduced from 6.14% to 2.92% compared to that of the strain as directed boundary method used in a previous study. Additionally, our research demonstrated that interpass temperatures above 800 °C can result in increased deformation errors. In conclusion, it is essential to select an appropriate temperature to minimize deformation error.

Context: Cyclin-dependent kinase 9 (CDK9) plays a significant role in gene regulation and RNA polymerase II transcription under basal and stimulated conditions. The upregulation of transcriptional homeostasis by CDK9 leads to various malignant tumors and therefore acts as a valuable drug target in addressing cancer incidences. Ongoing drug development endeavors targeting CDK9 have yielded numerous clinical candidate molecules currently undergoing investigation as potential CDK9 modulators, though none have yet received Food and Drug Administration (FDA) approval., Methods: In this study, we employ in silico approaches including the molecular docking and molecular dynamics simulations for the virtual screening over the natural compounds library to identify novel promising selective CDK9 inhibitors. The compounds derived from the initial virtual screening were subsequently employed for molecular dynamics simulations and binding free energy calculations to study the compound's stability under virtual physiological conditions. The first-generation CDK inhibitor Flavopiridol was used as a reference to compare with our novel hit compound as a CDK9 antagonist. The 500-ns molecular dynamics simulation and binding free energy calculation showed that two natural compounds showed better binding affinity and interaction mode with CDK9 receptors over the reference Flavopiridol. They also showed reasonable figures in the predicted absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations as well as in computational cytotoxicity predictions. Therefore, we anticipate that the proposed scaffolds could contribute to developing potential and selective CDK9 inhibitors subjected to further validations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: In strawberry farming, phenotypic traits (such as crown diameter, petiole length, plant height, flower, leaf, and fruit size) measurement is essential as it serves as a decision-making tool for plant monitoring and management. To date, strawberry plant phenotyping has relied on traditional approaches. In this study, an image-based Strawberry Phenotyping Tool (SPT) was developed using two deep-learning (DL) architectures, namely "YOLOv4" and "U-net" integrated into a single system. We aimed to create the most suitable DL-based tool with enhanced robustness to facilitate digital strawberry plant phenotyping directly at the natural scene or indirectly using captured and stored images., Methods: Our SPT was developed primarily through two steps (subsequently called versions) using image data with different backgrounds captured with simple smartphone cameras. The two versions (V1 and V2) were developed using the same DL networks but differed by the amount of image data and annotation method used during their development. For V1, 7,116 images were annotated using the single-target non-labeling method, whereas for V2, 7,850 images were annotated using the multitarget labeling method., Results: The results of the held-out dataset revealed that the developed SPT facilitates strawberry phenotype measurements. By increasing the dataset size combined with multitarget labeling annotation, the detection accuracy of our system changed from 60.24% in V1 to 82.28% in V2. During the validation process, the system was evaluated using 70 images per phenotype and their corresponding actual values. The correlation coefficients and detection frequencies were higher for V2 than for V1, confirming the superiority of V2. Furthermore, an image-based regression model was developed to predict the fresh weight of strawberries based on the fruit size (R 2 = 0.92)., Discussion: The results demonstrate the efficiency of our system in recognizing the aforementioned six strawberry phenotypic traits regardless of the complex scenario of the environment of the strawberry plant. This tool could help farmers and researchers make accurate and efficient decisions related to strawberry plant management, possibly causing increased productivity and yield potential., 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 Ndikumana, Lee, Yoo, Yeboah, Park, Lee, Yeoung and Kim.)

Objective: Stereoelectroencephalography (SEEG) is increasingly being recognized as an important invasive modality for presurgical evaluation of epilepsy. This study focuses on the clinical and technical considerations of SEEG investigations when using conventional frame-based stereotaxy, drawing on institutional experience and a comprehensive review of relevant literature., Methods: This retrospective observational study encompassed the surgical implantation of 201 SEEG electrodes in 16 epilepsy patients using a frame-based stereotactic instrument at a single tertiary-level center. We provide detailed descriptions of the operative procedures and technical nuances for bilateral and multiple SEEG insertions, along with several illustrative cases. Additionally, we present a literature review on the technical aspects of the SEEG procedure, discussing its clinical implications and potential risks., Results: Frame-based SEEG electrode placements were successfully performed through sagittal arc application, with the majority (81.2%) of cases being bilateral and involving up to 18 electrodes in a single operation. The median skin-to-skin operation time was 162 minutes (interquartile range [IQR], 145-200), with a median of 13 minutes (IQR, 12-15) per electrode placement for time efficiency. There were two occurrences (1.0%) of electrode misplacement and one instance (0.5%) of a postoperative complication, which manifested as a delayed intraparenchymal hemorrhage. Following SEEG investigation, 11 patients proceeded with surgical intervention, resulting in favorable seizure outcomes for nine (81.8%) and complete remission for eight cases (72.7%)., Conclusion: Conventional frame-based stereotactic techniques remain a reliable and effective option for bilateral and multiple SEEG electrode placements. While SEEG is a suitable approach for selected patients who are strong candidates for epilepsy surgery, it is important to remain vigilant concerning the potential risks of electrode misplacement and hemorrhagic complications.

Head and neck cancer ranks as the sixth-most common malignancy worldwide, characterized by high mortality and recurrence rates. Research studies indicate that molecular diagnostics play a crucial role in the early detection and prognostic evaluation of these diseases. This study aimed to identify potential biomarkers for head and neck cancer and elucidate their interactions with miRNAs and possible therapeutic drugs. Four drivers, namely, FN1 , IL1A , COL1A1 , and MMP9 , were identified using network biology and machine learning approaches. Gene set variation analysis (GSVA) showed that these genes were significantly involved in different biological processes and pathways, including coagulation, UV-response-down, apoptosis, NOTCH signaling, Wnt-beta catenin, and other signal pathways. The diagnostic value of these hub genes was validated using receiver operating characteristic (ROC) curves. The top interactive miRNAs, including miR-128-3p , miR-218-5p , miR-214-3p , miR-124-3p , miR-129-2-3p , and miR-1-3p , targeted the key genes. Furthermore, the interaction between the key genes and drugs was also identified. In summary, the key genes and miRNAs or drugs reported in this study might provide valuable information for potential biomarkers to increase the prognosis and diagnosis of head and neck cancer.

Highly pathogenic avian influenza (HPAI) is an important zoonotic disease. The study aims to identify farmer behaviour types to inform the design of behaviour change programmes for mitigating the transmission of HPAI. Therefore, the study utilised multivariate statistical analysis for gaining a better understanding of the relationships among farmers' 30 biosecurity behaviours, the risk of HPAI infection, and distinct features of commercial broiler farmers, which is different from using simple and few binary biosecurity measures. Convenience sampling was used to collect data from 303 Taiwan's farmers among which 40 farmers (13.2%) self-reported having had a HPAI outbreak in the study year while 16 farmers (5.3%) self-reported having had a HPAI outbreak in the past two years. Using categorical principal components analysis and a two-stage cluster analysis, four farmer clusters were identified with distinct features: 1)'Reserved' (4.6%) tended to choose 'No idea' for answering specific questions about HPAI; 2)'Secure' (76.3%) had a higher biosecurity status than the other farms; 3) 'Jeopardised' (16.8%) had a lower biosecurity status than the other farms; 4) 'No-response' (2.3%) tended to skip specific questions about HPAI. The biosecurity status of the 'Reserved' and 'No-response' clusters was undetermined, placing these farms at risk of HPAI infection. Compared to the 'Secure' cluster, the 'Jeopardised' cluster exhibited higher odds of self-reported HPAI in the study year (OR: 2.61, 95% CI: 1.22-5.58) and in the past two years (OR: 4.28, 95% CI: 1.39-13.19). Additionally, the 'Jeopardised' cluster showed increased odds of HPAI recurrence (OR: 4.01, 95% CI: 1.41-11.43). Our study demonstrates that inadequate biosecurity practices can elevate the occurrence or recurrence of HPAI outbreaks. The findings underscore the importance of distinguishing between these clusters to accurately assess the risk of HPAI infection across farms. Furthermore, understanding farmers' behaviours can inform the development of strategies aimed at behaviour change among farmers., Competing Interests: The authors declare that the research was conducted in absence of any commercial, financial, or other relationships that might be interpreted as representing a potential conflict of interest., (© 2024 The Authors. Published by Elsevier B.V.)

The jawless vertebrates (agnathans/cyclostomes) are ancestral animals comprising lampreys and hagfishes as the only extant representatives. They possess an alternative adaptive immune system (AIS) that uses leucine-rich repeats (LRR)-based variable lymphocyte receptors (VLRs) instead of the immunoglobulin (Ig)-based antigen receptors of jawed vertebrates (gnathostomes). The different VLR types are expressed on agnathan lymphocytes and functionally resemble gnathostome antigen receptors. In particular, VLRB is functionally similar to the B cell receptor and is expressed and secreted by B-like lymphocytes as VLRB antibodies that bind antigens with high affinity and specificity. The potential repertoire scale of VLR-based antigen receptors is believed to be at least comparable to that of Ig-based systems. VLR proteins inherently possess characteristics that render them excellent candidates for biotechnological development, including tractability to recombinant approaches. In recent years, scientists have explored the biotechnological development and utility of VLRB proteins as alternatives to conventional mammalian antibodies. The VLRB antibody platform represents a non-traditional approach to generating a highly diverse repertoire of unique antibodies. In this review, we first describe some aspects of the biology of the AIS of the jawless vertebrates, which recognizes antigens by means of unique receptors. We then summarize reports on the development of VLRB-based antibodies and their applications, particularly those from the inshore hagfish (Eptatretus burgeri) and their potential uses to address microbial diseases in aquaculture. Hagfish VLRB antibodies (we call Ccombodies) are being developed and improved, while obstacles to the advancement of the VLRB platform are being addressed to utilize VLRBs effectively as tools in immunology. VLRB antibodies for novel antigen targets are expected to emerge to provide new opportunities to tackle various scientific questions. We anticipate a greater interest in the agnathan AIS in general and particularly in the hagfish AIS for greater elucidation of the evolution of adaptive immunity and its applications to address microbial pathogens in farmed aquatic animals and beyond., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: When treating undifferentiated-type early gastric cancer (UD-EGC) that is limited to the mucosa (clinically T1a), endoscopic submucosal dissection (ESD) can be considered if the tumor is 2 cm or less and is not ulcerated. However, there is insufficient evidence to determine the relationships between tumor size and oncological safety of ESD in UD-EGC., Methods: The pathology reports of Korean patients who were diagnosed with UD-EGC (n = 5286) were retrospectively reviewed. The cumulative incidence of lymph node metastasis (LNM) according to tumor size was evaluated in subgroups. The tumor-size cut-off was identified as the upper limit of the 95% confidence interval (CI) of cumulative LNM incidence that did not exceed 1.0%., Results: We identified 1516 patients with non-ulcerated T1a tumors ≤2 cm in size. Among patients without lymphatic invasion, 1.5% (95% CI 0.91-2.16%) had LNM. In patients with poorly differentiated tubular adenocarcinoma (PD), LNM increased from 0 to 0.74% based on a tumor size of 1.0 cm. Regardless of tumor size, smaller percentages of undifferentiated-type (UD) and poorly cohesive carcinoma (PCC) patients experienced LNM than did those with PD. In non-ulcerated mucosal cancer without lymphatic invasion and tumor size ≤0.9 cm, no LNM was observed in patients with UD (95% CI 0-0.53%), PCC (95% CI 0-0.59%), or PD (95% CI 0-0.86%) histologic type., Conclusion: In patients diagnosed with non-ulcerated T1a UD-EGC, ESD can be performed if the tumor size is 0.9 cm or less, regardless of histologic type., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Objectives: Hysterectomy is commonly performed for benign uterine pathologies but there is some controversy over whether it is associated with an increased risk of thyroid cancer. This study examines the associations of hysterectomy with ovarian conservation or with bilateral salpingo-oophorectomy and thyroid cancer incidence in Taiwan., Methods: We analyzed data from a nationwide health insurance claims database and identified 29,577 women aged ≥30 years who underwent hysterectomy with ovarian conservation or hysterectomy with bilateral salpingo-oophorectomy between 2000 and 2016. Propensity score-matching analyses were performed at ratios of 1:1 for the hysterectomy and no-hysterectomy groups, to reduce selection bias. We monitored thyroid cancer occurrence in both groups until 2017. Cox regression was used to calculate hazard ratios with 95 % confidence intervals and determine thyroid cancer risk in women who underwent hysterectomy., Results: The study comprised 29,577 patients who underwent any hysterectomy and 29,577 participants who did not. The mean follow-up period was 10.03 ± 4.92 years. Patients who underwent hysterectomy had higher thyroid cancer incidence (4.72 per 10,000 person-years) than those who did not (3.06 per 10,000 person-years) and a greater risk of any thyroid cancer (adjusted hazard ratio = 1.40; 95 % confidence interval = 1.08-1.82). However, there was no association between hysterectomy with bilateral salpingo-oophorectomy and thyroid cancer incidence (p > 0.05)., Conclusions: Our findings suggest that women who undergo hysterectomy are at a higher risk of developing thyroid cancer than those who do not., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mycobacterium abscessus (MAB), a non-tuberculous mycobacterium (NTM), causes chronic pulmonary inflammation in humans. The NLRP3 inflammasome is a multi-protein complex that triggers IL-1β maturation and pyroptosis through the cleavage of caspase-1. In this study, we investigated the roles of NLRP3 and IL-1β in the host's defense against MAB. The IL-1β production by MAB was completely abolished in NLRP3, but not NLRC4, deficient macrophages. The NLRP3 inflammasome components, which are ASC and caspase-1 were also found to be essential for IL-1β production in response to MAB. NLRP3 and IL-1β deficiency did not affect the intracellular growth of MAB in macrophages, and the bacterial burden in lungs of NLRP3- and IL-1β-deficient mice was also comparable to the burden observed in WT mice. In contrast, IL-1β deficiency ameliorated lung pathology in MAB-infected mice. Notably, the lung homogenates of IL-1β-deficient mice had reduced levels of IL-17, but not IFN-γ and IL-4 when compared with WT counterparts. Furthermore, in vitro co-culture analysis showed that IL-1β signaling was essential for IL-17 production in response to MAB. Finally, we observed that the anti-IL-17 antibody administration moderately mitigated MAB-induced lung pathology. These findings indicated that IL-1β production contribute to MAB-induced lung pathology via the elevation of IL-17 production., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Although it is very well known that corticosteroids cause osteonecrosis of the femoral head (ONFH), it is unclear as to which patients develop ONFH. Additionally, there are no studies on the association between corticosteroid use and femoral head collapse in ONFH patients. We aimed to investigate the association between corticosteroid use and the risk of ONFH among the general population and what factors affect ONFH occurrence. Additionally, we aimed to demonstrate which factors affect femoral head collapse and total hip arthroplasty (THA) after ONFH occurrence., Methods: A nationwide, nested case-control study was conducted with data from the National Health Insurance Service Physical Health Examination Cohort (2002 to 2019) in the Republic of Korea. We defined ONFH (N = 3,500) using diagnosis and treatment codes. Patients who had ONFH were matched 1:5 to form a control group based on the variables of birth year, sex, and follow-up duration. Additionally, in patients who have ONFH, we looked for risk factors for progression to THA., Results: Compared with the control group, ONFH patients had a low household income and had more diabetes, hypertension, dyslipidemia, and heavy alcohol use (drinking more than 3 to 7 drinks per week). Systemic corticosteroid use (≥1,800 mg) was significantly associated with an increased risk of ONFH incidence. However, lipid profiles, corticosteroid prescription, and cumulative doses of corticosteroid did not affect the progression to THA., Conclusions: The ONFH risk increased rapidly when cumulative prednisolone use was ≥1,800 mg. However, oral or high-dose intravenous corticosteroid use and cumulative dose did not affect the prognosis of ONFH. Since the occurrence and prognosis of ONFH are complex and multifactorial processes, further study is needed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In general, small stream basins, characterized by narrow channels and steep slopes, face heightened vulnerability to climate change-induced flooding, posing challenges for evacuation procedures. With the increasing intensity of floods and typhoons in recent years, urgent measures are necessary to mitigate damage in such areas. This research endeavors to address these challenges by developing a novel small stream flood early warning system (SSFEWS) tailored to small streams and piloting its application. The proposed system integrates real-time hydrodynamic data collection, flood probability forecasting, and proactive warning issuance through an amalgamation of IoT-based sensor networks, statistical models leveraging measurement data, a robust constrained nonlinear optimization algorithm (RCNOA), and four-parameter logistic method (4PL). Moreover, system accuracy and reliability are enhanced by an automated iterative process that continuously refines forecasting model parameters via a user-defined rainfall-discharge nomograph and rating curve using RCNOA and 4PL. The developed SSFEWS is expected to contribute to the safety of the community as well as prevent possible small stream-related casualties by enabling efficient disaster response. © 2024 Elsevier Ltd. All rights reserved., 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 Author(s). Published by Elsevier Ltd.. All rights reserved.)

An organoid is a self-organized three-dimensional structure derived from stem cells that mimics the structure, cell composition, and functional characteristics of specific organs and tissues and is used for evaluating the safety and effectiveness of drugs and the toxicity of industrial chemicals. Organoid technology is a new methodology that could replace testing on animals testing and accelerate development of precision and regenerative medicine. However, large variations in production can occur between laboratories with low reproducibility of the production process and no internationally agreed standards for quality evaluation factors at endpoints. To overcome these barriers that hinder the regulatory acceptance and commercialization of organoids, Korea established the Organoid Standards Initiative in September 2023 with various stakeholders, including industry, academia, regulatory agencies, and standard development experts, through public and private partnerships. This developed general guidelines for organoid manufacturing and quality evaluation and for quality evaluation guidelines for organoid-specific manufacturing for the liver, intestines, and heart through extensive evidence analysis and consensus among experts. This report is based on the common standard guideline v1.0, which is a general organoid manufacturing and quality evaluation to promote the practical use of organoids. This guideline does not focus on specific organoids or specific contexts of use but provides guidance to organoid makers and users on materials, procedures, and essential quality assessment methods at end points that are essential for organoid production applicable at the current technology level.

This paper presents guidelines for the systematic management of packaging, storage, transportation, and traceability of source cells used for organoid research. Given the important role of source cells in organoid studies, it is important to ensure the preservation of their quality and integrity throughout transportation and distribution processes. The proposed guidelines, therefore, call for a cohesive strategy through these stages to minimize the risks of contamination, deterioration, and loss-threats that significantly compromise the safety, efficacy, and efficiency of source cells. Central to these guidelines is the quality control measures that include roles and responsibilities across the entire supply chain, with recommendations specific to packaging materials, transportation facilities, and storage management. Furthermore, the need for an integrated management system is emphasized, spanning from source cell collection to the final application. This system is crucial for maintaining the traceability and accountability of source cells, facilitating the sharing, distribution, and utilization on a global scale, and supporting to advance organoid research and development.

"Organoids", three-dimensional self-organized organ-like miniature tissues, are proposed as intermediary models that bridge the gap between animal and human studies in drug development. Despite recent advancements in organoid model development, studies on toxicity using these models are limited. Therefore, in this study, we aimed to analyze the functionality and gene expression of pre- and post-differentiated human hepatic organoids derived from induced pluripotent stem cells and utilize them for toxicity assessment. First, we confirmed the functional similarity of this hepatic organoid model to the human liver through various functional assessments, such as glycogen storage, albumin and bile acid secretion, and cytochrome P450 (CYP) activity. Subsequently, utilizing these functionally validated hepatic organoids, we conducted toxicity evaluations with three hepatotoxic substances (ketoconazole, troglitazone, and tolcapone), which are well known for causing drug-induced liver injury, and three non-hepatotoxic substances (sucrose, ascorbic acid, and biotin). The organoids effectively distinguished between the toxicity levels of substances with and without hepatic toxicity. We demonstrated the potential of hepatic organoids with validated functionalities and genetic characteristics as promising models for toxicity evaluation by analyzing toxicological changes occurring in hepatoxic drug-treated organoids., Competing Interests: The authors declare no conflicts of interest.

Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disorder in dogs with a high prevalence, accounting for approximately 75% of all canine heart disease cases. MMVD is a complex disease and shows variable progression from mild valve leakage to severe regurgitation, potentially leading to heart failure. However, the molecular mechanisms and age-related changes that govern disease progression, especially at the early stage (B1) before the development of discernable clinical signs, remain poorly understood. In this prospective study, we aimed to compare gene expression differences between blood samples of aged beagle dogs with stage B1 MMVD and those of healthy controls using RNA sequencing. Clinical evaluation was also conducted, which revealed minimal differences in radiographic and echocardiographic measurements despite distinct biomarker variations between the two groups. Comparative transcriptomics revealed differentially expressed genes associated with extracellular matrix remodeling, prostaglandin metabolism, immune modulation, and interferon-related pathways, which bear functional relevance for MMVD. In particular, the top 10 over- and under-expressed genes represent promising candidates for influencing pathogenic changes in MMVD stage B1. Our research findings, which include identified variations in clinical markers and gene expression, enhance our understanding of MMVD. Furthermore, they underscore the need for further research into early diagnosis and treatment strategies, as, to the best of our knowledge, no prior studies have explored the precise molecular mechanisms of stage B1 in MMVD through total RNA sequencing., Competing Interests: The authors have declared no conflicts of interest in relation to the research, authorship or publication of this article, (Copyright: © 2024 Kim 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.)

An alchemical enhanced sampling (ACES) method has recently been introduced to facilitate importance sampling in free energy simulations. The method achieves enhanced sampling from Hamiltonian replica exchange within a dual topology framework while utilizing new smoothstep softcore potentials. A common sampling problem encountered in lead optimization is the functionalization of aromatic rings that exhibit distinct conformational preferences when interacting with the protein. It is difficult to converge the distribution of ring conformations due to the long time scale of ring flipping events; however, the ACES method addresses this issue by modeling the syn and anti ring conformations within a dual topology. ACES thereby samples the conformer distributions by alchemically tunneling between states, as opposed to traversing a physical pathway with a high rotational barrier. We demonstrate the use of ACES to overcome conformational sampling issues involving ring flipping in ML300-derived noncovalent inhibitors of SARS-CoV-2 Main Protease (M pro ). The demonstrations explore how the use of replica exchange and the choice of softcore selection affects the convergence of the ring conformation distributions. Furthermore, we examine how the accuracy of the calculated free energies is affected by the degree of phase space overlap (PSO) between adjacent states (i.e., between neighboring λ-windows) and the Hamiltonian replica exchange acceptance ratios. Both of these factors are sensitive to the spacing between the intermediate states. We introduce a new method for choosing a schedule of λ values. The method analyzes short "burn-in" simulations to construct a 2D map of the nonlocal PSO. The schedule is obtained by optimizing an alchemical pathway on the 2D map that equalizes the PSO between the λ intervals. The optimized phase space overlap λ-spacing method (Opt-PSO) leads to more numerous end-to-end single passes and round trips due to the correlation between PSO and Hamiltonian replica exchange acceptance ratios. The improved exchange statistics enhance the efficiency of ACES method. The method has been implemented into the FE-ToolKit software package, which is freely available.

Despite its potential for clean hydrogen harvesting, photoelectrochemical (PEC) water-splitting cells face challenges in commercialization, particularly related its harvesting performance and productivity at an industrial scale. Herein, a facile fabrication method of flexible thin-film photoanode for PEC water-splitting to overcome these limitations, based on laser processing technologies, is proposed. Laser-induced graphene, a carbon structure produced through direct laser writing carbonization (DLWC), plays a dual role: a flexible and stable current collector and a substrate for the hydrothermal synthesis of tungsten trioxide (WO 3 ) nanorods (NRs). To facilitate water-splitting, a femtosecond-pulsed laser (fs laser) is focused on the WO 3 NRs, converting their crystalline phase from pristine orthorhombic to monoclinic structure without thermal damage. With NiFe layered double hydroxide (LDH) catalyst, the flexible thin-film photoanode exhibits good PEC performance (1.46 mA cm -2 at 1.23 V RHE ) and retains ≈90% of its performance after 3000 bending cycles. With its excellent mechanical properties, the flexible photoanode can be operated in various shapes with different curvatures, enabling space-efficient PEC water-splitting by loading larger photoanode within a given space. This study is expected to contribute to the advancement of large-scale solar water-splitting cells, introducing a new approach to enhance H 2 /O 2 production and expand its application range., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

Background: The relationship between sarcopenia and chronic obstructive pulmonary disease (COPD) has been increasingly reported, and there is some overlap regarding their clinical features and pulmonary rehabilitation (PR) strategies. No Korean study has reported the actual prevalence of sarcopenia in patients with stable COPD who are recommended for pulmonary rehabilitation. This study evaluated the prevalence and clinical features of sarcopenia in older adult outpatients with stable COPD and the changes after 6 months., Methods: In this cross-sectional and 6-month follow-up study, we recruited 63 males aged ≥ 65 diagnosed with stable COPD. Sarcopenia was diagnosed using the AWGS 2019 criteria, which included hand grip strength testing, bioelectrical impedance analysis, Short Physical Performance Battery administration, and Strength, Assistance with walking, Rising from a chair, Climbing stairs, and Falling screening tool administration. A 6-minute walk test (6 MWT) was conducted, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), maximal inspiratory and expiratory pressures (MIP and MEP, respectively) and peak expiratory flow (PEF) were assessed, and patient-reported questionnaires were administered., Results: At baseline, 14 (22%) patients were diagnosed with possible sarcopenia, and eight (12.6%) were diagnosed with sarcopenia. There were significant differences in the age; body mass index; Body mass index, airflow Obstruction, Dyspnea, and Exercise index; modified Medical Research Council dyspnea scores; and International Physical Activity Questionnaire scores between the normal and sarcopenia groups. Whole-body phase angle, MIP, MEP, PEF, and 6-minute walk distance (6 MWD) also showed significant differences. Over 6 months, the proportion of patients with a reduced FEV 1 increased; however, the proportion of patients with sarcopenia did not increase., Conclusion: A relatively low prevalence of sarcopenia was observed in older adult outpatients with stable COPD. No significant change in the prevalence of sarcopenia was found during the 6-month follow-up period., Trial Registration: The study was registered with the Clinical Research Information Service (KCT0006720). Registration date: 30/07/2021., (© 2024. The Author(s).)

Background: Combining smoking with poor eating habits significantly elevates the risk of chronic illnesses and early death. Understanding of how dietary quality shifts post-smoking cessation remains limited. The objective of this study is to examine dietary quality - using Healthy Eating Index (HEI - 2020) and its 13 components, among current, former, and never smokers, and particularly the impact of quitting and the duration of cessation on dietary habits., Methods: A cross-sectional analysis of 31,569 adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 was conducted. Dietary quality was assessed using HEI-2020 scores, which were determined by NIH developed - simple HEI scoring algorithm per person. Smoking status was categorized into current, former, and never smokers, with further subdivisions for current (heavy/light smokers) and former smokers (duration post-cessation). Descriptive analysis and multiple regression models weighted to represent the US population were performed., Results: The current smoking rate was 19.4%, with a higher prevalence in males (22.5%) than females (17.5%). Current smokers reported statistically significantly lower HEI total score than both former and never smokers. Former smokers exhibited HEI scores similar to those of never smokers. The adjusted HEI total scores for current, former, and never smokers were 49.2, 54.0, and 53.3, respectively, with a statistically significant difference (p < 0.001). Moreover, light smokers had better total HEI score than heavy smokers (46.8 vs. 50.8, p < 0.001, respectively), but former and never smokers scored even higher. Quitting smoking immediately improved dietary quality, with former smokers reaching the dietary levels of never smokers within 5-10 years (53.8 vs. 53.3, p > 0.05, respectively). Compared to current smokers, former smokers tended to consume more beneficial foods (e.g., fruits, vegetables, greens and beans, whole grains, proteins, and fatty acids), while also consuming more sodium and less added sugar., Conclusions: Current smokers, particularly heavy smokers, exhibit poorer dietary habits than former and never smokers. The dietary quality of former smokers aligns with never smokers over time, highlighting the positive impact of smoking cessation on diet. This has implications for reducing chronic disease risks associated with poor diet and smoking., (© 2024. The Author(s).)

Neutrophils perform essential functions in antimicrobial defense and tissue maintenance at mucosal barriers. However, a dysregulated neutrophil response and, in particular, the excessive release of neutrophil extracellular traps (NETs) are implicated in the pathology of various diseases. In this review, we provide an overview of the basic concepts related to neutrophil functions, including NET formation, and discuss the mechanisms associated with NET activation and function in the context of the prevalent oral disease periodontitis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Minority stress has been posited as a cause for sexual and gender minority (SGM) individuals to smoke as a coping mechanism. The purpose of this study was to elucidate the relationship between minority stress processes and nicotine dependence level and stage of change for SGM smokers living in the Deep South region of the United States. Methods: A one-time, cross-sectional online survey was administered to SGM smokers living in the Deep South. Survey measurements included demographics, minority stress processes (prejudice events, perceived stigma, and internalized queerphobia), and smoking cessation outcomes (nicotine dependence level and stage of change). Multivariable linear regression was used to assess the effect of each minority stress process on smoking outcomes, after adjusting for demographics and stratifying by gender and sexual identity. Results: Across all participants ( n  = 1296), lower levels of perceived stigma were significantly associated with further stage of change. Greater levels of internalized queerphobia were significantly associated with greater nicotine dependence level. After stratifying by gender and sexual identity, these significant associations were only maintained in cisgender males and gay individuals. An additional significant association between lower prejudice events and further stage of change for smoking cessation was found only for individuals whose sexual identity was labeled as "other." Conclusion: Addressing minority stress in smoking cessation and prevention programs has the potential to decrease nicotine dependence and further stage of change.

Background: Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients., Methods: We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated., Results: Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex., Conclusions: This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Filippo Pietrantonio reported receiving research grants from BMS, Incyte, Agenus, Amgen, Lilly and AstraZeneca, and personal fees from BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson&Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo outside the submitted work. Alessandra Raimondi reported honoraria for advisory boards outside the submitted work from Elma Academy and Servier., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Frog virus 3 (FV3) in the genus Ranavirus of the family Iridoviridae causes mass mortality in both anurans and urodeles worldwide; however, the phylogenetic origin of FV3-like ranaviruses is not well established. In Asia, three FV3-like ranaviruses have been reported in farmed populations of amphibians and reptiles. Here, we report the first case of endemic FV3-like ranavirus infections in the Korean clawed salamander Onychodactylus koreanus , caught in wild mountain streams in the Republic of Korea (ROK), through whole-genome sequencing and phylogenetic analysis. Two isolated FV3-like ranaviruses ( Onychodactylus koreanus ranavirus, OKRV1 and 2) showed high similarity with the Rana grylio virus (RGV, 91.5%) and Rana nigromaculata ranavirus (RNRV, 92.2%) but relatively low similarity with the soft-shelled turtle iridovirus (STIV, 84.2%) in open reading frame (ORF) comparisons. OKRV1 and 2 formed a monophyletic clade with previously known Asian FV3-like ranaviruses, a sister group of the New World FV3-like ranavirus clade. Our results suggest that OKRV1 and 2 are FV3-like ranaviruses endemic to the ROK, and RGV and RNRV might also be endemic strains in China, unlike previous speculation. Our data have great implications for the study of the phylogeny and spreading routes of FV3-like ranaviruses and suggest the need for additional detection and analysis of FV3-like ranaviruses in wild populations in Asian countries.

Objective: Six months after the onset of stroke, over 60% of patients experience upper limb dysfunction, with spasticity being a major contributor alongside muscle weakness. This study investigated the effect of transcutaneous electrical nerve stimulation (TENS) with taping on wrist spasticity, strength, and upper extremity function in patients with stroke. Methods: In total, 40 patients with stroke were included and randomly divided into two groups: the TENS + taping ( n = 20, age 52.4 ± 9.3 (range: 39 to 70)) and TENS ( n = 20, age 53.5 ± 10.8 (range: 39 to 74)) groups. All subjects performed 30 sessions of task-related training, which included 10 min of postural control training and 20 min of task performance. Additionally, all subjects received TENS on the spastic muscle belly for 30 min before task-related training. In the TENS + taping group, taping was additionally applied to the forearm and wrist but not in the TENS group. The Modified Ashworth Scale was used to measure spasticity, and a handheld dynamometer was used to measure muscle strength. The Fugl-Meyer Assessment of Upper Extremity was used to evaluate the functional ability of the upper extremity. Results: In the TENS + taping group, spasticity and upper extremity function were significantly improved as compared to those in the TENS group ( p < 0.05). However, no significant difference in muscle strength was observed between the two groups ( p > 0.05). Conclusions: This study demonstrated that the combination of TENS and taping for spasticity and function of the upper extremity was more effective in relieving the spasticity than TENS alone. Therefore, we suggest this combination as an additional treatment for spasticity and function of the upper extremity.

At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF)., Methods: The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio., Results: Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle-C2 sagittal vertical alignment (C-C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95)., Conclusions: The authors' results indicate that the occipital condyle-atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology.

Purpose: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals are more likely to smoke than non-LGBTQ individuals. Smoking has been posited as a coping mechanism for LGBTQ individuals facing minority stress. However, the exact relationship between minority stress and smoking behaviors among LGBTQ individuals is unclear. Therefore, the purpose of this systematic review was to examine how minority stress processes are associated with smoking behaviors for LGBTQ individuals. Methods: Searches of the PubMed and PsycINFO databases were conducted for smoking-, LGBTQ-, and minority stress-related terms. No date, geographic, or language limits were used. For inclusion, the study must have (1) been written in English, (2) had an LGBTQ group as the study population or a component of the study population, (3) assessed the cigarette smoking status of patients, and (4) assessed at least one minority stress-related process (internalized stigma, perceived stigma, or prejudice events). Results: The final review included 44 articles. Aside from two outlier studies, all of the reviewed studies exhibited that increased levels of minority stress processes (internalized queerphobia, perceived stigma, and prejudice events) were associated with increased probability of cigarette use in LGBTQ individuals. Increased minority stress was also associated with greater psychological distress/mental health decline. Conclusion: The findings of this review suggest that minority stress processes represent a contributing factor to smoking health disparities in LGBTQ populations. These results highlight the need for smoking cessation and prevention programs to address minority stress and improve smoking disparities in these populations.

Background: The recurrence of thyroid cancer poses challenges compounded by postoperative fibrosis and anatomic changes. By overcoming the limitations of current localizing dye techniques, indocyanine green-macroaggregated albumin-hyaluronic acid (ICG-MAA-HA) mixture dye promises improved localization. This study aimed to evaluate the efficacy and safety of the dye for recurrent thyroid cancer., Methods: The nine patients in this study underwent surgery and postoperative ultrasonography. The dye was injected into recurrent lesions in all the patients preoperatively. During surgery, the lesions were confirmed with an imaging system before and after excision. If the lesion was unidentifiable with the naked eye, surgical excision was performed under the corresponding fluorescent guide. Side effects related to the dye injection and completeness of the surgery were evaluated., Results: No side effects such as bleeding, skin tattooing, or pain during or after the dye injection were reported, and no discoloration occurred that interfered with the surgical field of view during surgery. In three cases (33.3 %), because it was difficult to localize metastatic lesions with the naked eye, the operation was successfully completed using an imaging system. The completeness of the surgical resection was confirmed by ultrasonography after an average of 5 months postoperatively., Conclusion: The study found that ICG-MAA-HA dye effectively located metastatic and recurrent thyroid cancer and had favorable results in terms of minimal procedural side effects and potential for assisting the surgeon. A large-scale multi-institutional study is necessary to prove the clinical significance regarding patient survival and disease control., (© 2024. Society of Surgical Oncology.)

In patients with autoimmune disorders such as rheumatoid arthritis (RA), delayed wound healing is often observed. Timely and effective wound healing is a crucial determinant of a patient's quality of life, and novel materials for skin wound repair, such as bioactive peptides, are continuously being studied and developed. One such bioactive peptide, AESIS-1, has been studied for its well-established anti-rheumatoid arthritis properties. In this study, we attempted to use the anti-RA material AESIS-1 as a therapeutic wound-healing agent based on disease-modifying antirheumatic drugs (DMARDs), which can help restore prompt wound healing. The efficacy of AESIS-1 in wound healing was assessed using a full-thickness excision model in diabetic mice; this is a well-established model for studying chronic wound repair. Initial observations revealed that mice treated with AESIS-1 exhibited significantly advanced wound repair compared with the control group. In vitro studies revealed that AESIS-1 increased the migration activity of human dermal fibroblasts (HDFs) without affecting proliferative activity. Moreover, increased HDF cell migration is mediated by upregulating chemokine receptor expression, such as that of CXC chemokine receptor 2 (CXCR2). The upregulation of CXCR2 through AESIS-1 treatment enhanced the chemotactic reactivity to CXCR2 ligands, including CXC motif ligand 8 (CXCL8). AESIS-1 directly activates the ERK and p38 mitogen-activated protein kinase (MAPK) signaling cascades, which regulate the migration and expression of CXCR2 in fibroblasts. Our results suggest that the AESIS-1 peptide is a strong wound-healing substance that increases the movement of fibroblasts and the expression of CXCR2 by turning on the ERK and p38 MAPK signaling cascades.

Pericapsular nerve group (PENG) block and periarticular injection (PAI) provide motor-sparing analgesia following hip surgery. We hypothesized that PAI offers non-inferior pain relief compared with PENG block in patients undergoing primary total hip arthroplasty (THA). In this randomized trial, 66 patients who underwent primary THA under spinal anesthesia were assigned to the PENG or PAI groups. The primary endpoint was the resting pain score 24 h postoperatively. The secondary endpoints included pain scores at rest and during movement at 6 and 48 h postoperatively, quadriceps strength at 24 h postoperatively, and opioid consumption at 24 and 48 h postoperatively. The mean difference in pain scores at rest between the two groups was 0.30 (95% confidence interval [CI], -0.78 to 1.39) at 24 h postoperatively. The upper 95% CI was lower than the non-inferiority margin, indicating non-inferior performance. No significant between-group differences were observed in the pain scores at 6 and 48 h postoperatively. Additionally, no significant differences in quadriceps strength and opioid consumption were observed between the two groups. The PAI and PENG blocks provided comparable postoperative analgesia during the first 48 h after primary THA. Further investigation is required to determine the optimal PAI technique and local anesthetic mixture.

Background: Plant scientists have largely relied on pathogen growth assays and/or transcript analysis of stress-responsive genes for quantification of disease severity and susceptibility. These methods are destructive to plants, labor-intensive, and time-consuming, thereby limiting their application in real-time, large-scale studies. Image-based plant phenotyping is an alternative approach that enables automated measurement of various symptoms. However, most of the currently available plant image analysis tools require specific hardware platform and vendor specific software packages, and thus, are not suited for researchers who are not primarily focused on plant phenotyping. In this study, we aimed to develop a digital phenotyping tool to enhance the speed, accuracy, and reliability of disease quantification in Arabidopsis., Results: Here, we present the Arabidopsis Disease Quantification (AraDQ) image analysis tool for examination of flood-inoculated Arabidopsis seedlings grown on plates containing plant growth media. It is a cross-platform application program with a user-friendly graphical interface that contains highly accurate deep neural networks for object detection and segmentation. The only prerequisite is that the input image should contain a fixed-sized 24-color balance card placed next to the objects of interest on a white background to ensure reliable and reproducible results, regardless of the image acquisition method. The image processing pipeline automatically calculates 10 different colors and morphological parameters for individual seedlings in the given image, and disease-associated phenotypic changes can be easily assessed by comparing plant images captured before and after infection. We conducted two case studies involving bacterial and plant mutants with reduced virulence and disease resistance capabilities, respectively, and thereby demonstrated that AraDQ can capture subtle changes in plant color and morphology with a high level of sensitivity., Conclusions: AraDQ offers a simple, fast, and accurate approach for image-based quantification of plant disease symptoms using various parameters. Its fully automated pipeline neither requires prior image processing nor costly hardware setups, allowing easy implementation of the software by researchers interested in digital phenotyping of diseased plants., (© 2024. The Author(s).)

HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4 + T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4 + T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The sit-to-stand test is an essential tool used to assess lower limb function and muscle strength in older adults and various patient populations, and also plays a role in sarcopenia screening. Among its forms, the five-time sit-to-stand test (FTSST) is widely used, with previous studies suggesting cutoff values of &gt;10 seconds and &gt;11 seconds for the sitting-to-standing and standing-to-sitting transitions, respectively. The 30-second and 1-minute sit-to-stand tests (30STS and 1MSTS, respectively) also provide comprehensive assessments. While much of the current research on sarcopenia focuses on the FTSST, there is a burgeoning need for an in-depth exploration of the 30STS and 1MSTS. Studies on these tests are vital to refine the criteria for sarcopenia, establish accurate cutoff values, and enhance diagnostic precision and treatment effectiveness. This need highlights the importance of further research into the 30STS and 1MSTS for refining the diagnostic criteria for sarcopenia.

High-capacity silicon (Si) materials hold a position at the forefront of advanced lithium-ion batteries. The inherent potential offers considerable advantages for substantially increasing the energy density in batteries, capable of maximizing the benefit by changing the paradigm from nano- to micron-sized Si particles. Nevertheless, intrinsic structural instability remains a significant barrier to its practical application, especially for larger Si particles. Here, a covalently interconnected system is reported employing Si microparticles (5 µm) and a highly elastic gel polymer electrolyte (GPE) through electron beam irradiation. The integrated system mitigates the substantial volumetric expansion of pure Si, enhancing overall stability, while accelerating charge carrier kinetics due to the high ionic conductivity. Through the cost-effective but practical approach of electron beam technology, the resulting 500 mAh-pouch cell showed exceptional stability and high gravimetric/volumetric energy densities of 413 Wh kg -1 , 1022 Wh L -1 , highlighting the feasibility even in current battery production lines., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Niclosamide is an anthelmintic drug with a long history of use and is generally safe and well tolerated in humans. As the conventional dose of niclosamide results in a low but certain level in systemic circulation, drug interactions with concomitant drugs should be considered. We aimed to investigate the interaction between niclosamide and drug transporters, as such information is currently limited. Niclosamide inhibited the transport activity of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 in vitro. Among them, the inhibitory effects on OAT1, OAT3, and OCT2 were strong, with IC 50 values of less than 1 μM. When 3 mg/kg of niclosamide was co-administered to rats, systemic exposure to furosemide (a substrate of OAT1/3) and metformin (a substrate of OCT2) increased, and the renal clearance (CL r ) of the drugs significantly decreased. These results suggest that niclosamide inhibits renal transporters, OAT1/3 and OCT2, not only in vitro but also in vivo, resulting in increased systemic exposure to the substrates of the transporters by strongly blocking the urinary elimination pathway in rats. The findings of this study will support a meticulous understanding of the transporter-mediated drug interactions of niclosamide and consequently aid in effective and safe use of niclosamide., 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.)

FAF1 (FAS-associated factor 1) is involved in the activation of Fas cell surface death receptors and plays a role in apoptosis and necrosis. In patients with Parkinson's disease, FAF1 is overexpressed in dopaminergic neurons in the substantia nigra. KM-819, an FAF1 inhibitor, has shown potential for preventing dopaminergic neuronal cell death, promoting the degradation of α-synuclein and preventing its accumulation. This study aimed to develop and validate a quantitative analytical method for determining KM-819 levels in rat plasma using liquid chromatography-tandem mass spectrometry. This method was then applied to pharmacokinetic (PK) studies in rats. The metabolic stability of KM-819 was assessed in rat, dog, and human hepatocytes. In vitro metabolite identification and metabolic pathways were investigated in rat, dog, and human hepatocytes. The structural analog of KM-819, namely N -[1-(4-bromobenzyl)-3,5-dimethyl-1 H -pyrazol-4-yl]-2-(phenylsulfanyl) acetamide, served as the internal standard (IS). Proteins were precipitated from plasma samples using acetonitrile. Analysis was carried out using a reverse-phase C18 column with a mobile phase consisting of 0.1% formic acid in distilled water and 0.1% formic acid in acetonitrile. The analytical method developed for KM-819 exhibited linearity within the concentration range of 0.002-10 μg/mL in rat plasma. The precision and accuracy of the intra- and inter-day measurements were <15% for the lower limit of quantification (LLOQ) and all quality control samples. KM-819 demonstrated stability under various sample storage conditions (6 h at room temperature (25 °C), four weeks at -20 °C, three freeze-thaw cycles, and pretreated samples in the autosampler). The matrix effect and dilution integrity met the criteria set by the Food and Drug Administration and the European Medicines Agency. This sensitive, rapid, and reliable analytical method was successfully applied in pharmacokinetic studies in rats. Pharmacokinetic analysis revealed the dose-independent kinetics of KM-819 at 0.5-5 mg/kg, with a moderate oral bioavailability of ~20% in rats. The metabolic stability of KM-819 was also found to be moderate in rat, dog, and human hepatocytes. Metabolite identification in rat, dog, and human hepatocytes resulted in the discovery of six, six, and eight metabolites, respectively. Glucuronidation and mono-oxidation have been proposed as the major metabolic pathways. Overall, these findings contribute to a better understanding of the pharmacokinetic characteristics of KM-819, thereby aiding future clinical studies.

The purpose of this study was to demonstrate the performance of a fully automated, deep learning-based brain segmentation (DLS) method in healthy controls and in patients with neurodevelopmental disorders, SCN1A mutation, under eleven. The whole, cortical, and subcortical volumes of previously enrolled 21 participants, under 11 years of age, with a SCN1A mutation, and 42 healthy controls, were obtained using a DLS method, and compared to volumes measured by Freesurfer with manual correction. Additionally, the volumes which were calculated with the DLS method between the patients and the control group. The volumes of total brain gray and white matter using DLS method were consistent with that volume which were measured by Freesurfer with manual correction in healthy controls. Among 68 cortical parcellated volume analysis, the volumes of only 7 areas measured by DLS methods were significantly different from that measured by Freesurfer with manual correction, and the differences decreased with increasing age in the subgroup analysis. The subcortical volume measured by the DLS method was relatively smaller than that of the Freesurfer volume analysis. Further, the DLS method could perfectly detect the reduced volume identified by the Freesurfer software and manual correction in patients with SCN1A mutations, compared with healthy controls. In a pediatric population, this new, fully automated DLS method is compatible with the classic, volumetric analysis with Freesurfer software and manual correction, and it can also well detect brain morphological changes in children with a neurodevelopmental disorder., (© 2024. The Author(s).)

The cut chrysanthemum holds one of the most substantial segments of the global floriculture market, particularly in Korea. We conducted a detailed assessment of the genetic structures across the cut chrysanthemum breeding lines in Korea. Using standard and spray chrysanthemum breeding lines from leading Korean research institutes, we first compared the variability of 12 horticultural traits, revealing a wide range of variation for most traits. We found that the overall flower diameter (OFD) and ray floret length (RFL) showed a solid positive relationship, regardless of the type. From a multivariate approach, OFD, RFL, and ray floret width (RFW) show consistently high association. Genotypic and phenotypic coefficients of variation analyses further indicated the significant genetic control over most traits. However, certain traits, like the volume of flowers (VF) in standard types, are more influenced by environments. Lastly, our analysis demonstrated substantial variability in broad-sense heritability ( H ); plant height (PH) consistently showed high H in both types. But the number of side branches (NOSB) and VF exhibited inconsistent H scores. These findings highlight the need for type-specific breeding strategies and modulating environmental management to optimize the trait expressions depending on the H scores, which offers significant implications for future breeding strategies.

Two-dimensional (2D) transition metal dichalcogenide (TMD) layers are highly promising as field-effect transistor (FET) channels in the atomic-scale limit. However, accomplishing this superiority in scaled-up FETs remains challenging due to their van der Waals (vdW) bonding nature with respect to conventional metal electrodes. Herein, we report a scalable approach to fabricate centimeter-scale all-2D FET arrays of platinum diselenide (PtSe 2 ) with in-plane platinum ditelluride (PtTe 2 ) edge contacts, mitigating the aforementioned challenges. We realized a reversible transition between semiconducting PtSe 2 and metallic PtTe 2 via a low-temperature anion exchange reaction compatible with the back-end-of-line (BEOL) processes. All-2D PtSe 2 FETs seamlessly edge-contacted with transited metallic PtTe 2 exhibited significant performance improvements compared to those with surface-contacted gold electrodes, e.g., an increase of carrier mobility and on/off ratio by over an order of magnitude, achieving a maximum hole mobility of ∼50.30 cm 2 V -1 s -1 at room temperature. This study opens up new opportunities toward atomically thin 2D-TMD-based circuitries with extraordinary functionalities.