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Abstract The diagnosis and awareness of transthyretin amyloidosis cardiomyopathy (ATTR-CM) in heart failure with left ventricular ejection fraction (LVEF) > 40% remains under-recognized. This study aimed to investigate the prevalence and characteristics of ATTR-CM in patients with heart failure with LVEF > 40%. Patients with LVEF > 40% and maximal left ventricular wall thickness (MWT) > 10 mm who underwent bone scintigraphy were retrospectively investigated. Patients with a definite cause of heart failure were excluded. ATTR-CM was diagnosed when grade 2 or 3 myocardial uptake was observed on scintigraphy. Among 97 patients (male, 62.5%; median age, 69 years), 13 (13.4%) were diagnosed with ATTR-CM (wild type, 69.2%; hereditary type, 30.8%). Age or biomarker levels did not differ significantly; however, all patients with ATTR-CM were male. The ATTR-CM group had a significantly higher prevalence of polyneuropathy or carpal tunnel syndrome than the non-ATTR-CM group, accompanied by a longer PR interval, thicker MWT, larger left atrial volume index, and higher E/e′. Accordingly, ATTR was present in a substantial number, particularly among men. Clinicians should suspect ATTR when a male patient exhibits neurologic symptoms, diastolic dysfunction, and a long PR interval.

Abstract Branched-chain amino acids (BCAAs), particularly leucine, are indispensable AAs for immune regulation through metabolic rewiring. However, the molecular mechanism underlying this phenomenon remains unclear. Our investigation revealed that T-cell receptor (TCR)-activated human CD4+ T cells increase the expression of BCAT1, a cytosolic enzyme responsible for BCAA catabolism, and SLC7A5, a major BCAA transporter. This upregulation facilitates increased leucine influx and catabolism, which are particularly crucial for Th17 responses. Activated CD4+ T cells induce an alternative pathway of cytosolic leucine catabolism, generating a pivotal metabolite, β-hydroxy β-methylbutyric acid (HMB), by acting on BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL). Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through BCAT1, HPD, or HPDL silencing using shRNA, attenuates IL-17 production, whereas HMB supplementation abrogates this effect. Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α. This finding was corroborated by the observation that treatment with L-β-homoleucine (LβhL), a leucine analog and competitive inhibitor of BCAT1, decreased IL-17 production by TCR-activated CD4+ T cells. In an in vivo experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism, either through a BCAT1 inhibitor or LβhL treatment, mitigated EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells. Our findings elucidate the role of BCAT1-mediated cytoplasmic leucine catabolism in modulating IL-17 production via HMB-mediated regulation of mTORC1-HIF1α, providing insights into its relevance to inflammatory conditions.

Abstract Background High-grade serous ovarian cancer (HGSOC), which is known for its heterogeneity, high recurrence rate, and metastasis, is often diagnosed after being dispersed in several sites, with about 80% of patients experiencing recurrence. Despite a better understanding of its metastatic nature, the survival rates of patients with HGSOC remain poor. Methods Our study utilized spatial transcriptomics (ST) to interpret the tumor microenvironment and computed tomography (CT) to examine spatial characteristics in eight patients with HGSOC divided into recurrent (R) and challenging-to-collect non-recurrent (NR) groups. Results By integrating ST data with public single-cell RNA sequencing data, bulk RNA sequencing data, and CT data, we identified specific cell population enrichments and differentially expressed genes that correlate with CT phenotypes. Importantly, we elucidated that tumor necrosis factor-α signaling via NF-κB, oxidative phosphorylation, G2/M checkpoint, E2F targets, and MYC targets served as an indicator of recurrence (poor prognostic markers), and these pathways were significantly enriched in both the R group and certain CT phenotypes. In addition, we identified numerous prognostic markers indicative of nonrecurrence (good prognostic markers). Downregulated expression of PTGDS was linked to a higher number of seeding sites (≥ 3) in both internal HGSOC samples and public HGSOC TCIA and TCGA samples. Additionally, lower PTGDS expression in the tumor and stromal regions was observed in the R group than in the NR group based on our ST data. Chemotaxis-related markers (CXCL14 and NTN4) and markers associated with immune modulation (DAPL1 and RNASE1) were also found to be good prognostic markers in our ST and radiogenomics analyses. Conclusions This study demonstrates the potential of radiogenomics, combining CT and ST, for identifying diagnostic and therapeutic targets for HGSOC, marking a step towards personalized medicine.

Different dietary patterns affect the gut microbial compositions and diversity. Consistently, microbiome alterations are linked to digestion, immunity, and productivity. Sasa quelpaertensis Nakai (SQ) is a perennial bamboo species rich in proteins and fiber. Previous studies have confirmed the health benefits of SQ; however, the effects of SQ supplementation on gut microbiome and production performance are unclear. Herein, Landrace pigs were supplemented with SQ extract (SQE) and gut microbial compositions as opposed to the control group were assessed using 16S rRNA sequencing. Additionally, the influences of SQE supplementation on average daily gain (ADG) and backfat thickness (BF) were assessed after slaughter. In the SQE group, Firmicutes and Actinobacteria phyla increased significantly, whereas Bacteroidetes and Spirochaetes phyla markedly decreased (p < 0.05). The expression level of Bifidobacterium and Lactobacillus genera increased, whereas that of Treponema, Prevotella, and Turicibacter decreased (p < 0.05). The microbial richness was similar between groups; however, microbial diversity decreased in the SQE supplementation group. Additionally, the SQE supplementation in pigs resulted in a slight increase in ADG. In contrast, BF in the SQE group decreased notably (p < 0.05). These results underscore the significant influence of SQE supplementation on the gut microbiota and demonstrate the potential of SQ as a valuable feed resource for enhancing animal productivity.

Abstract With the increasing prevalence of overweight and obesity in children and adolescents, to actively prevent the occurrence of asthma in this population is important for reducing the burden of the disease. Lifestyle factors, including diet and exercise, are importance for overweight and obese adolescents, as well as an important modifiable factor affecting airway inflammation and asthma, whether healthy lifestyle was correlated with the risk of asthma in adolescents ≥ 12 years has not been reported. We suspected that there might be correlation between healthy lifestyle behaviors and the risk of asthma in overweight and obese adolescents. This cross-sectional study aimed to explore the association between the adherence to a healthy lifestyle behaviors and the risk of asthma in overweight and obese adolescents based on the data of 945 participants aged between 12–18 years from the National Health and Nutrition Examination Surveys (NHANES). Univariable and multivariable weighted Logistic regression models were applied to evaluate the association between healthy lifestyle behaviors with asthma risk in overweight and obese adolescents. Odds ratio (OR) and 95% confidence interval (CI) were applied as estimates. We found that the risk of asthma was reduced in overweight and obese adolescents with intermediate (OR = 0.40, 95%CI: 0.17–0.94) or good lifestyle behaviors (OR = 0.33, 95%CI: 0.13–0.86) in comparison to those with poor lifestyle behaviors. In summary, intermediate or good lifestyle behaviors was correlated with decreased risk of asthma in overweight and obese adolescents, which might provide a reference for making further prevention strategies for asthma in adolescents.

Abstract Background Based on a three-dimensional (3D) orthognathic simulation, this technical report introduces a method for augmentation genioplasty using a proximal bone fragment of the mandible, which is typically discarded in intraoral vertical ramus osteotomy (IVRO). Results A 43-year-old female patient diagnosed with Class III malocclusion, presenting with a protruding mandible and long facial height, underwent surgical treatment. The surgical plan involved mandibular setback position using IVRO and augmentation genioplasty. The 3D orthognathic surgery including augmentation genioplasty simulation was performed. An excessively elongated proximal segment was sectioned following IVRO. The inferior part of the sectioned proximal bone fragment of the mandible was positioned to align with the requirements of advancement genioplasty. After ensuring that the placement of the fragment matched that of the simulated surgery, each bone fragment was fixed. At 1.5 years post-surgery, the grafted bone on the augmentation genioplasty was well maintained, with slight bone resorption. Conclusions Augmentation genioplasty using the proximal bone fragment of the mandible, which is typically discarded in IVRO, reduces the surgical complications associated with chin osteotomy. When a secondary genioplasty is required, genioplasty with osteotomy, movement of the cut bone fragments, partial bone-shaving osteotomy, and additional bone grafting are viable options.

Abstract In our previous study, we developed a triple-negative breast cancer (TNBC) subtype classification that correlated with the TNBC molecular subclassification. In this study, we aimed to evaluate the predictor variables of this subtype classification on the whole slide and to validate the model’s performance by using an external test set. We explored the characteristics of this subtype classification and investigated genomic alterations, including genomic scar signature scores. First, TNBC was classified into the luminal androgen receptor (LAR) and non-luminal androgen receptor (non-LAR) subtypes based on the AR Allred score (≥ 6 and 20% but

In an 8-year period at two medical center, 138 patients underwent uterine artery embolization, and 11 of them were diagnosed with uterine necrosis. Among them, three were successfully conceived. However, one of them developed an arteriovenous malformation after an artificial abortion, and another experienced complications, including placenta previa and placenta accreta spectrum, which resulted in early preterm delivery and recurrent postpartum hemorrhage, necessitating subtotal hysterectomy. Therefore, it is crucial to prepare for potential adverse pregnancy outcomes in subsequent pregnancies for patients with a history of uterine necrosis.

Abstract Although some studies have reported on the expression and clinical significance of Fascin-1 (FSCN1) in liver cancer, the clinical application and differential diagnosis value of FSCN1 in liver cancer are still unclear. The aim of this study was to analyze the expression level of FSCN1 protein in liver cancer tissues and explore its diagnostic and application value in differentiating between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The immunehistochemical analysis was used to detect the expression of FSCN1 in 108 cases of HCC, 26 cases of ICC, 23 cases of liver cirrhosis, and 11 cases of normal liver tissues. The differences in the positive expression rate and strong positive expression rate of FSCN1 among different groups were analyzed. The positive rate of FSCN1 in normal liver tissues, liver cirrhosis, HCC, and ICC tissues was 0.0% (0/11), 0.0% (0/23), 13.9% (15/108), and 92.3% (24/26), respectively, while the strong positive rate was 0.0% (0/11), 0.0% (0/23), 0.9% (1/108), and 69.2% (18/26), respectively. Both the positive rate and strong positive rate of FSCN1 in ICC tissues were significantly higher than those in HCC, liver cirrhosis, and normal liver tissues. Additionally, the positive rate of FSCN1 in moderately to poorly differentiated HCC tissues was 18.8% (15/80), significantly higher than in well-differentiated HCC (0.0%, 0/28) (P = 0.031). In liver cancer, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FSCN1 positive prediction for ICC were 92.3%, 86.1%, 61.5%, and 97.9%, respectively, whereas the sensitivity, specificity, PPV, and NPV of FSCN1 strong positive prediction for ICC were 69.2%, 99.1%, 94.7%, and 93.0%, respectively. These results suggest that FSCN1 may play an important role in the occurrence and progression of liver cancer, and it can be used as a novel diagnostic marker for ICC.

Tissue engineering offers a promising alternative for oral and maxillofacial tissue defect rehabilitation; however, cells within a sizeable engineered tissue construct after transplantation inevitably face prolonged and severe hypoxic conditions, which may compromise the survivability of the transplanted cells and arouse the concern of anaerobic infection. Microalgae, which can convert carbon dioxide and water into oxygen and glucose through photosynthesis, have been studied as a source of oxygen supply for several biomedical applications, but their promise in orofacial tissue regeneration remains unexplored. Here, we demonstrated that through photosynthetic oxygenation, Chlamydomonas reinhardtii (C. reinhardtii) supported dental pulp stem cell (DPSC) energy production and survival under hypoxia. We developed a multifunctional photosynthetic hydrogel by embedding DPSCs and C. reinhardtii encapsulated alginate microspheres (CAMs) within gelatin methacryloyl hydrogel (GelMA) (CAMs@GelMA). This CAMs@GelMA hydrogel can generate a sustainable and sufficient oxygen supply, reverse intracellular hypoxic status, and enhance the metabolic activity and viability of DPSCs. Furthermore, the CAMs@GelMA hydrogel exhibited selective antibacterial activity against oral anaerobes and remarkable antibiofilm effects on multispecies biofilms by disrupting the hypoxic microenvironment and increasing reactive oxygen species generation. Our work presents an innovative photosynthetic strategy for oral tissue engineering and opens new avenues for addressing other hypoxia-related challenges.

High-performance and stable spintronic devices have garnered considerable attention in recent years. Based on first-principle and Monte Carlo calculations, we demonstrate that under reasonable carrier doping, H-VSe2 exhibits 100% spin polarization, a magnetic anisotropy energy of 581 μeV, a tunable easy-axis, and a Curie temperature of 330 K. Moreover, Dzyaloshinskii–Moriya interactions in H-VSe2 and magnetic hysteresis loops are determined theoretically for the first time, which provides more precise and comprehensive descriptions of its magnetic properties under finite temperatures and external magnetic field. This work suggests that H-VSe2 is a powerful candidate for spintronic devices, and it provides solid theoretical support for future experiments. [ABSTRACT FROM AUTHOR]

Abstract Alternative splicing (AS) is a widely observed phenomenon in eukaryotes that plays a critical role in development and stress responses. In plants, the large number of RNA-seq datasets in response to different environmental stressors can provide clues for identification of condition-specific and/or common AS variants for preferred agronomic traits. We report RNA-seq datasets (350.7 Gb) from Capsicum annuum inoculated with one of three bacteria, one virus, or one oomycete and obtained additional existing transcriptome datasets. In this study, we investigated the landscape of AS in response to environmental stressors, signaling molecules, and tissues from 425 total samples comprising 841.49 Gb. In addition, we identified genes that undergo AS under specific and shared stress conditions to obtain potential genes that may be involved in enhancing tolerance to stressors. We uncovered 1,642,007 AS events and identified 4,354 differential alternative splicing genes related to environmental stressors, tissues, and signaling molecules. This information and approach provide useful data for basic-research focused on enhancing tolerance to environmental stressors in hot pepper or establishing breeding programs.

[68Ga]Ga-FAPI-04 is a promising radiopharmaceutical that binds specifically to fibroblast activation protein, which is overexpressed in more than 90% of malignant epithelial tumors but not in normal healthy tissue. This study aimed to develop an efficient method for producing 68Ga-labelled FAPI-04 using a cassette-based automated synthesizer. [68Ga]GaCl3 was eluted from an Eckert & Ziegler Medical germanium-68/gallium-68 generator using 2.5 mL of 0.1 M HCl. The synthesis of the [68Ga]Ga-FAPI-04 was performed using different concentrations of HEPES (1~2.5 M; 4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid) in 3~10 minutes; amounts of FAPI-04 precursor (5~50 µg) and reaction temperature (25°C~100°C) were optimized on the BIKBoxⓇ synthesizer. The labeling efficiency of [68Ga]Ga-FAPI-04 was greater than 96% (decay corrected) using 25 µg FAPI-04 synthesized in 10 minutes at 100°C in 2 M HEPES (pH 3.85), and its stability was greater than 99% at 6 hours. The total synthesis time of [68Ga]Ga-FAPI-04 was 32.4 minutes, and the product met all quality control criteria. In this study, we developed and optimized a labeling method using [68Ga]Ga-FAPI-04 using a cassette-based synthesizer. The devised method is expected to be useful for supplying [68Ga]Ga-FAPI-04 for diagnosis in clinical practice.

Abstract SARS-CoV-2 and its variants are widely prevalent worldwide. With frequent secondary and breakthrough infections, immune dysfunction in RA patients, and long-term use of immune preparations, SARS-CoV-2 infection poses a significant challenge to patients and rheumatologists. Whether SARS-CoV-2 infection causes RA flares and what factors aggravate RA flares are poorly studied. A questionnaire survey was conducted on RA patients infected with SARS-CoV-2 after December 7, 2022, in China through a multicenter and inter-network platform regarding general personal condition, primary disease, comorbidity, SARS-CoV-2 vaccination, viral infection, and impact on the primary disease. A total of 306 RA patients were included in this study, and the patient data were analyzed, in which the general condition of RA patients, medication use before SARS-CoV-2 infection and post-infection typing and manifestations, and medication adjustment did not affect the Flare of RA patients after SARS-CoV-2 infection. The control of disease before SARS-CoV-2 infection (OR = 2.10), RA involving pulmonary lesions (OR = 2.28), and the recovery time of COVID-19 (OR = 2.50) were risk factors for RA flare. RA involving pulmonary lesions, control status of disease before infection, and recovery time of COVID-19 disease are risk factors for RA flare after SARS-CoV-2 infection.

Abstract Background A malignancy might be found at surgery in cases of atypical ductal hyperplasia (ADH) diagnosed via US-guided core needle biopsy (CNB). The objective of this study was to investigate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in predicting ADH diagnosed by US-guided CNB that was upgraded to malignancy after surgery. Methods In this retrospective study, 110 CNB-diagnosed ADH lesions in 109 consecutive women who underwent US, CEUS, and surgery between June 2018 and June 2023 were included. CEUS was incorporated into US BI-RADS and yielded a CEUS-adjusted BI-RADS. The diagnostic performance of US BI-RADS and CEUS-adjusted BI-RADS for ADH were analyzed and compared. Results The mean age of the 109 women was 49.7 years ± 11.6 (SD). The upgrade rate of ADH at CNB was 48.2% (53 of 110). The sensitivity, specificity, positive predictive value, and negative predictive value of CEUS for identification of malignant upgrading were 96.2%, 66.7%,72.9%, and 95.0%, respectively, based on BI-RADS category 4B threshold. The two false-negative cases were low-grade ductal carcinoma in situ. Compared with the US, CEUS-adjusted BI-RADS had better specificity for lesions smaller than 2 cm (76.7% vs. 96.7%, P = 0.031). After CEUS, 16 (10 malignant and 6 nonmalignant) of the 45 original US BI-RADS category 4A lesions were up-classified to BI-RADS 4B, and 3 (1 malignant and 2 nonmalignant) of the 41 original US BI-RADS category 4B lesions were down-classified to BI-RADS 4A. Conclusions CEUS is helpful in predicting malignant upgrading of ADH, especially for lesions smaller than 2 cm and those classified as BI-RADS 4A and 4B on ultrasound.

Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.

Summary: Targeting the stimulator of interferon genes (STING) pathway is a promising strategy to overcome primary resistance to immune checkpoint inhibitors in non-small cell lung cancer with the STK11 mutation. We previously found metformin enhances the STING pathway and thus promotes immune response. However, its low concentration in tumors limits its clinical use. Here, we constructed high-mesoporous Mn-based nanocarrier loading metformin nanoparticles (Mn-MSN@Met-M NPs) that actively target tumors and respond to release higher concentration of Mn2+ ions and metformin. The NPs significantly enhanced the T cells to kill lung cancer cells with the STK11 mutant. The mechanism shows that enhanced STING pathway activation promotes STING, TBKI, and IRF3 phosphorylation through Mn2+ ions and metformin release from NPs, thus boosting type I interferon production. In vivo, NPs in combination with a PD-1 inhibitor effectively decreased tumor growth. Collectively, we developed a Mn-MSN@Met-M nanoactivator to intensify immune activation for potential cancer immunotherapy.

This study screened two probiotic preparations and comprehensively evaluated for anti-obesity efficacy in high-fat diet-induced obese mice. Obese mice were orally administered with low, medium, and high doses of AB-Kefir (ABK) or Lactiplantibacillus plantarum TWK10 (TWK), respectively. After 8 weeks of administration, medium doses and above of ABK and TWK significantly reduced body weight, white adipose tissue weight, serum glucose, and lipid levels and attenuated hepatic steatosis and adipocyte hypertrophy in obese mice without affecting appetite. ABK and TWK also decreased serum adipokine levels and increased the adiponectin/leptin ratio to ameliorate obesity-induced adipose tissue dysfunction and chronic inflammation. Moreover, ABK and TWK reduced adipogenesis/lipogenesis-related transcription factors and enzymes in adipose tissue and improved energy metabolism by activating the AMPK pathway. In particular, TWK showed superior anti-obesity activity compared to ABK. The outcomes of this study will help explore potential anti-obesity probiotic functional foods.

Abstract Background I-131 treatment (RAI) decision relies heavily on serum thyroglobulin (Tg) levels, as higher Tg levels are assumed to be correlated with higher I-131 uptake. Tg elevation, negative iodine scintigraphy (TENIS) definition is becoming more clinically relevant as alternative treatment methods are available. This study examined the correlation between Tg levels with I-131 uptake in remnant thyroid gland to evaluate the reliability of serum Tg levels in predicting I-131 uptake. Methods From March 2012 to July 2019, 281 papillary thyroid cancer patients treated with 150 mCi RAI were retrospectively enrolled. Early (2nd day) and Delayed (7th day) post-RAI whole-body scan (WBS) neck counts were correlated with clinical and pathologic findings. Patients with normal neck ultrasound and undetectable level of serum Tg (

Abstract As warfarin has a narrow therapeutic window and obvious response variability among individuals, it is difficult to rapidly determine personalized warfarin dosage. Adverse drug events(ADE) resulting from warfarin overdose can be critical, so that typically physicians adjust the warfarin dosage through the INR monitoring twice a week when starting warfarin. Our study aimed to develop machine learning (ML) models that predicts the discharge dosage of warfarin as the initial warfarin dosage using clinical data derived from electronic medical records within 2 days of hospitalization. During this retrospective study, adult patients who were prescribed warfarin at Asan Medical Center (AMC) between January 1, 2018, and October 31, 2020, were recruited as a model development cohort (n = 3168). Additionally, we created an external validation dataset (n = 891) from a Medical Information Mart for Intensive Care III (MIMIC-III). Variables for a model prediction were selected based on the clinical rationale that turned out to be associated with warfarin dosage, such as bleeding. The discharge dosage of warfarin was used the study outcome, because we assumed that patients achieved target INR at discharge. In this study, four ML models that predicted the warfarin discharge dosage were developed. We evaluated the model performance using the mean absolute error (MAE) and prediction accuracy. Finally, we compared the accuracy of the predictions of our models and the predictions of physicians for 40 data point to verify a clinical relevance of the models. The MAEs obtained using the internal validation set were as follows: XGBoost, 0.9; artificial neural network, 0.9; random forest, 1.0; linear regression, 1.0; and physicians, 1.3. As a result, our models had better prediction accuracy than the physicians, who have difficulty determining the warfarin discharge dosage using clinical information obtained within 2 days of hospitalization. We not only conducted the internal validation but also external validation. In conclusion, our ML model could help physicians predict the warfarin discharge dosage as the initial warfarin dosage from Korean population. However, conducting a successfully external validation in a further work is required for the application of the models.

[18F]Fluorocholine is a radiopharmaceutical used non-invasively in positron emission tomography to diagnose parathyroid adenoma, prostate cancer, and hepatocellular carcinoma by evaluating the choline metabolism. In this study, a radiolabeling method for [18F]fluorocholine was optimized using a solid phase extraction (SPE) cartridge. [18F]Fluorocholine was labeled in two steps using an automated synthesizer. In the first step, dibromomethane was reacted with [18F]KF/K2.2.2/K2CO3 to obtain the intermediate [18F]fluorobromomethane. In the second step, [18F]fluorobromomethane was passed through a Sep-PakⓇ Silica SPE cartridge to remove the impurities and then reacted with N,N-dimethylaminoethanol (DMAE) in a Sep-PakⓇ C18 SPE cartridge to label [18F]fluorocholine. The reaction conditions of [18F]fluorocholine were optimized. The synthesis yield was confirmed according to the number of silica cartridges and DMAE concentration. No statistically significant difference in the synthesis yield of [18F]fluorocholine was observed when using four or three silica cartridges (P＞0.05). The labeling yield was 11.5±0.5% (N=4) when DMAE was used as its original solution. On the other hand, when diluted to 10% with dimethyl sulfoxide, the radiochemical yield increased significantly to 30.1±5.2% (N=20). In conclusion, [18F]Fluorocholine for clinical use can be synthesized stably in high yield by applying an optimized synthesis method.

The germanium-68/gallium-68 (68Ge/68Ga) generator has high spatial utilization and requires little maintenance, making it economical and easy to produce. Thus, the frequency of use of 68Ga radiopharmaceuticals is rapidly increasing worldwide. Therefore, this study attempted to develop an automated synthesizer for the routine clinical application of 68Ga radiopharmaceuticals. The automated synthesizer was based on a fixed tubing system and the structure was designed after adjusting the position of the parts to reflect the synthesis method. Using various components that can be supplied in Korea, the automated synthesizer was manufactured at a much lower price cost than that of a commercialized automated synthesizer sold by companies. 68Ga-DOTA-[Tyr3]-octreotide (68Ga-DOTATOC) was synthesized to evaluate the performance of the automated synthesizer. 68Ga-DOTATOC could be synthesized with about 65% of non-decay corrected yield, and the synthesized 68Ga-DOTATOC met all quality control standards. We have synthesized 68Ga-DOTATOC more than 100 times, and only faced a few problems caused by mechanical errors. In this study, we successfully developed a simple automated synthesizer for 68Ga radiopharmaceuticals with high reproducibility. As various 68Ga radiopharmaceuticals have recently been developed, it is expected that the automated synthesizer developed in this study will be useful for routine clinical use.

Nuclear marine propulsion has been emerging as a next generation carbon-free power source, for which proper passive residual heat removal systems (PRHRSs) are needed for long-term safety. In particular, the characteristics of unlimited operation time and compact design are crucial in maritime applications due to the difficulties of safety aids and limited space. Accordingly, a compact and long-term-operable PRHRS has been proposed with the key design concept of using both air cooling and seawater cooling in tandem. To confirm its feasibility, this study conducted system design and a transient analysis in an accident scenario. Design results indicate that seawater cooling can considerably reduce the overall system size, and thus the compact and long-term-operable PRHRS can be realized. Regarding the transient analysis, the Multi-dimensional Analysis of Reactor Safety (MARS-KS) code was used to analyze the system behavior under a station blackout condition. Results show that the proposed design can satisfy the design requirements with a sufficient margin: the coolant temperature reached the safe shutdown condition within 36 h, and the maximum cooling rate did not exceed 40 °C/h. Lastly, it was assessed that both air cooling and seawater cooling are necessary for achieving long-term operation and compact design.

This research was in order to supplement the database of Procambarus clarkii materials. Crayfish was harvested in July and August and then classified into different groups (large, medium, and small) based on their weights. The proximate composition, physicochemical properties of crayfish meat, and the approximate components and apparent structure of crayfish shell were investigated. The main component of crayfish meat was moisture(76.53%~79.22%) and protein (17.63%~19.45%), and pH ranged from 6.88 to 7.30. While in the shell of crayfish, the content of chitin (12.07%~17.43%) and calcium (3.31~5.35 g/100 g) were relative high, and CO/HN (41.33%~47.22%) was major in hydrogen bonds, while the β-sheet (35.21%~40.02%) and β-turn (29.68%~33.5%) were major in secondary structure. With the passage of sampling time and the increase of sample weight, the yield of crayfish meat and the gap between muscle fibers gradually decreased, the water holding capacity, the elasticity and hardness of crayfish meat increased. Moreover, the proportion of protein ordered structure of crayfish shell increased, and the hydrogen bond energy and crystallinity increased. This research could provide practical guidance for the transportation and processing of Procambarus clarkii based on the properties of raw materials.

Patients with cirrhosis often exhibit cardiac autonomic dysfunction (CAD), characterized by enhanced cardiac sympathetic activity and diminished cardiac vagal tone, leading to increased morbidity and mortality. This study delineates the cellular and molecular mechanisms associated with altered neuronal activities causing cirrhosis-induced CAD. Biliary and nonbiliary cirrhotic rats were produced by common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Three weeks after CBDL or TAA injection, the assessment of heart rate variability revealed autonomic imbalance in cirrhotic rats. We observed increased excitability in stellate ganglion (SG) neurons and decreased excitability in intracardiac ganglion (ICG) neurons in cirrhotic rats compared to sham-operated controls. Additionally, threshold, rheobase, and action potential duration exhibited opposite alterations in SG and ICG neurons, along with changes in afterhyperpolarization duration. A- and M-type K⁺ channels were significantly downregulated in SG neurons, while M-type K⁺ channels were upregulated, with downregulation of the N- and L-type Ca2⁺ channels in the ICG neurons of cirrhotic rats, both in transcript expression and functional activity. Collectively, these findings suggest that cirrhosis induces an imbalance between cardiac sympathetic and parasympathetic neuronal activities via the differential regulation of K+ and Ca2+ channels. Thus, cirrhosis-induced CAD may be associated with impaired autonomic efferent functions within the homeostatic reflex arc that regulates cardiac functions.

The gut microbiota and barrier function play important roles in bone health. We previously demonstrated that chronic glucocorticoid (GC)-induced bone loss in mice is associated with significant shifts in gut microbiota composition and impaired gut barrier function. Korean Red Ginseng (KRG, Panax Ginseng Meyer, Araliaceae) extract has been shown to prevent glucocorticoid-induced osteoporosis (GIO) in a subcutaneous pellet model in mice, but its effect on gut microbiota and barrier function in this context is not known. The overall goal of this study was to test the effect of KRG extract in a clinically relevant, oral model of GIO and further investigate its role in modulating the gut-bone axis. Growing male mice (CD-1, 8 weeks) were treated with 75 μg/mL corticosterone (∼9 mg/kg/day) or 0.4% ethanol vehicle in the drinking water for 4 weeks. During this 4-week period, mice were treated daily with 500 mg/kg/day KRG extract dissolved in sterile water or an equal amount of sterile water via oral gastric gavage. After 4 weeks of treatment, we assessed bone volume, microbiota composition, gut barrier integrity, and immune cells in the bone marrow (BM) and mesenteric lymph nodes (MLNs). 4 weeks of oral GC treatment caused significant distal femur trabecular bone loss, and this was associated with changes in gut microbiota composition, impaired gut barrier function and altered immune cell composition. Importantly, KRG extract prevented distal femur trabecular bone loss and caused significant alterations in gut microbiota composition but had only modest effects on gut barrier function and immune cell populations. Taken together, these results demonstrate that KRG extract significantly modulates the gut microbiota-bone axis and prevents glucocorticoid-induced bone loss in mice.

Although epoxy-based composites that consist of inorganic fillers and matrixes are widely used in “conventional” electronic packaging applications due to their excellent insulation and robust properties, they limit their uses in “advanced electronic packaging” which requires enhanced thermal conductivity. However, conventional thermal curing methods for fabrication of epoxy-based composites do not fulfill sufficient thermal conductivity. Herein, we apply photo-induced curing strategy for fabricating alumina-incorporated epoxy-siloxane composites that consist of sol-gel derived siloxane matrix and bimodal sized alumina particles as a thermally conductive filler. We investigate how curing mechanism (thermal- or UV-curing) and varying the ratios of the alumina particles of two different sizes affect the various physical properties. It is found that photo-curing process makes greatly enhanced thermal conductivity, low thermal expansion, and high mechanical robustness compared to thermally-cured composites. As the results, we can achieve significantly enhanced thermal conductivity (>11 W/m K) with high thermal stability and mechanical robustness.

Enteroviruses are major etiological agents of aseptic meningitis globally, however information on circulating enterovirus types associated with this disease in Wuxi, China is limited. In this study, cerebrospinal fluid samples were collected from 20 pediatric aseptic meningitis cases in a Wuxi hospital in 2020 and subjected to metagenomic analysis to detect pathogens. Enterovirus B was detected in 9 cases, including 7 echovirus 18 (E18) and 2 echovirus 11 (E11) strains. The E18 strains exhibited 87.5–98.2% nucleotide identity and phylogenetically clustered with other China E18 strains, while the E11 strains showed 97.59% identity and clustered within the D5 subgroup along with other China E11 strains. One E18 strain was identified as a novel recombinants with a distinct recombination breakpoint within 3D gene. These findings expand knowledge on enteroviruses associated with pediatric aseptic meningitis in Wuxi, and highlight the circulation of genetically diverse E18 and E11 strains, including novel E18 recombinants. Characterization of enterovirus diversity by metagenomic analysis is important for molecular diagnosis and epidemiological tracking of aseptic meningitis cases. Continued surveillance of circulating enterovirus strains in Wuxi that may cause future outbreaks is warranted.

Summary: Background: Psoriasis is a chronic inflammatory skin disease with a Th17-skewed immune phenotype. Although it has been generally accepted that regulatory T cells (Tregs) in lesional psoriatic skin have functional impairment due to the local inflammatory microenvironment, the molecular properties of skin-homing psoriatic Tregs have not been well explored. Methods: We designed an extensive 39 marker mass cytometry (CyTOF) panel to deeply profile the immune landscape of skin-homing Tregs from 31 people with psoriasis stratified by psoriasis area severity index score as mild (n = 15) to moderate-severe (n = 16) and 32 healthy controls. We further validated the findings with an in-vitro chemokine-mediated Treg migration assay, immunofluorescent imaging of normal and psoriatic lesional skin and analysed public single-cell RNA-sequencing datasets to expand upon our findings into the local tissue microenvironments. Findings: We discovered an overall decrease in CLAhi Tregs and specifically, CLAhiCCR5+ Tregs in psoriasis. Functional markers CD39 and FoxP3 were elevated in psoriatic Tregs. However, CCR7 expression was significantly increased while CCR4 and CLA expression was reduced in psoriatic Tregs and CLAhi Tregs, which was associated with disease severity. Moreover, psoriatic Tregs revealed increased migratory capacity towards CCR7’s ligands, CCL19/CCL21. Interrogation of public single-cell RNA sequencing data confirmed reduced expression of skin-trafficking markers in lesional-skin Tregs compared to non-lesioned skin, further substantiated by immunofluorescent staining. Interpretation: Psoriatic circulating Tregs showed an impaired skin-trafficking phenotype thus leading to insufficient suppression of ongoing inflammation in the lesional skin, expanding upon our current understanding of the impairment of Treg-mediated immunosuppression in psoriasis. Funding: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and Information and Communications Technology (2020R1C1C1014513, 2021R1A4A5032185, 2020R1F1A1073692); and the new faculty research seed money grant of Yonsei University College of Medicine for 2021 (2021-32-0033).

Background The importance of molecular pathology tests has increased during the last decade, and there is a great need for efficient training of molecular pathology for pathology trainees and as continued medical education. Methods The Molecular Pathology Study Group of the Korean Society of Pathologists appointed a task force composed of experienced molecular pathologists to develop a refined educational curriculum of molecular pathology. A 3-day online educational session was held based on the newly established structure of learning objectives; the audience were asked to score their understanding of 22 selected learning objectives before and after the session to assess the effect of structured education. Results The structured objectives and goals of molecular pathology was established and posted as a web-based interface which can serve as a knowledge bank of molecular pathology. A total of 201 pathologists participated in the educational session. For all 22 learning objectives, the scores of self-reported understanding increased after educational session by 9.9 points on average (range, 6.6 to 17.0). The most effectively improved items were objectives from next-generation sequencing (NGS) section: ‘NGS library preparation and quality control’ (score increased from 51.8 to 68.8), ‘NGS interpretation of variants and reference database’ (score increased from 54.1 to 68.0), and ‘whole genome, whole exome, and targeted gene sequencing’ (score increased from 58.2 to 71.2). Qualitative responses regarding the adequacy of refined educational curriculum were collected, where favorable comments dominated. Conclusions Approach toward the education of molecular pathology was refined, which would greatly benefit the future trainees.

CRISPR–Cas systems are known to be part of the bacterial adaptive immune system that provides resistance against intruders such as viruses, phages and other mobile genetic elements. To combat this bacterial defense mechanism, phages encode inhibitors called Acrs (anti-CRISPR proteins) that can suppress them. AcrIC9 is the most recently identified member of the AcrIC family that inhibits the type IC CRISPR–Cas system. Here, the crystal structure of AcrIC9 from Rhodobacter capsulatus is reported, which comprises a novel fold made of three central antiparallel β-strands surrounded by three α-helixes, a structure that has not been detected before. It is also shown that AcrIC9 can form a dimer via disulfide bonds generated by the Cys69 residue. Finally, it is revealed that AcrIC9 directly binds to the type IC cascade. Analysis and comparison of its structure with structural homologs indicate that AcrIC9 belongs to DNA-mimic Acrs that directly bind to the cascade complex and hinder the target DNA from binding to the cascade.

The distinctive taste of Sichuan sauce-flavored sausage comes from an intricate microbial metabolism. The correlation between microbial composition and distinct flavor components has not been researched. The study used headspace solid-phase microextraction action with gas chromatography mass spectrometry to find flavor components and high-throughput sequencing of 16S rRNA to look at the diversity and succession of microbial communities. The correlation network model forecasted the connection between essential bacteria and the development of flavors. The study revealed that the primary flavor compounds in Sichuan sauce-flavored sausages were alcohols, aldehydes, and esters. The closely related microbes were Leuconostoc, Pseudomonas, Psychrobacter, Flavobacterium, and Algoriella. The microbes aided in the production of various flavor compounds, such as 1-octen-3-ol, benzeneacetaldehyde, hexanal, (R,R)-2,3-butanediol, and ethyl caprylate. This work has enhanced our comprehension of the diverse functions that bacteria serve in flavor development during the fermentation of Sichuan sauce-flavored sausage.

Background: The involvement of neutrophil-related genes (NRGs) in patients with osteosarcoma (OS) has not been adequately explored. In this study, we aimed to examine the association between NRGs and the prognosis as well as the tumor microenvironment of OS. Methods: The OS data were obtained from the TARGET-OS and GEO database. Initially, we extracted NRGs by intersecting 538 NRGs from single-cell RNA sequencing (scRNA-seq) data between aneuploid and diploid groups, as well as 161 up-regulated differentially expressed genes (DEGs) from the TARGET-OS datasets. Subsequently, we conducted Least Absolute Shrinkage and Selection Operator (Lasso) analyses to identify the hub genes for constructing the NRG-score and NRG-signature. To assess the prognostic value of the NRG signatures in OS, we performed Kaplan–Meier analysis and generated time-dependent receiver operating characteristic (ROC) curves. Gene enrichment analysis (GSEA) and gene set variation analysis (GSVA) were utilized to ascertain the presence of tumor immune microenvironments (TIMEs) and immunomodulators (IMs). Additionally, the KEGG neutrophil signaling pathway was evaluated using ssGSEA. Subsequently, PCR and IHC were conducted to validate the expression of hub genes and transcription factors (TFs) in K7M2-induced OS mice. Results: FCER1G and C3AR1 have been identified as prognostic biomarkers for overall survival. The findings indicate a significantly improved prognosis for OS patients. The effectiveness and precision of the NRG signature in prognosticating OS patients were validated through survival ROC curves and an external validation dataset. The results clearly demonstrate that patients with elevated NRG scores exhibit decreased levels of immunomodulators, stromal score, immune score, ESTIMATE score, and infiltrating immune cell populations. Furthermore, our findings substantiate the potential role of SPI1 as a transcription factor in the regulation of the two central genes involved in osteosarcoma development. Moreover, our analysis unveiled a significant correlation and activation of the KEGG neutrophil signaling pathway with FCER1G and C3AR1. Notably, PCR and IHC demonstrated a significantly higher expression of C3AR1, FCER1G, and SPI1 in Balb/c mice induced with K7M2. Conclusions: Our research emphasizes the significant contribution of neutrophils within the TIME of osteosarcoma. The newly developed NRG signature could serve as a good instrument for evaluating the prognosis and therapeutic approach for OS.

In recent years, robot manipulator arms have become increasingly prevalent and are playing pivotal roles across various industries. Their ability to replace human labor in arduous and hazardous tasks has positioned them as indispensable assets. Consequently, there has been a surge in research efforts aimed at enhancing their operational performance. The imperative to improve their efficiency and effectiveness has garnered significant attention within the research community. In this study, a novel fault-tolerant control (FTC) scheme for robot manipulators to handle the effects of the unknown input is proposed to aid robots in achieving good tracking performance. In the first step, an extended state observer (ESO) is constructed to approximate both velocities and the unknown input in the robot system. The observer offers estimation information with good accuracy and quick convergence. The estimated signals are then combined with computed torque control (CTC), which is a useful control technique for trajectory tracking of robot manipulator systems, to construct an active FTC to decrease the influences of the unknown input. The proposed algorithm does not require velocity measurement in the design process. In addition, with a novel design approach, the combination of controller and observer provides a novel control signal that delivers higher tracking performance compared to the traditional design approach. The global and asymptotic stability of the suggested technique is proved through the Lyapunov theory. Finally, simulations are implemented on a 2-degree-of-freedom (DOF) robot manipulator to validate the efficiency of the proposed controller–observer method.

EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the 68Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for 68Ga-labeling. The 68Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the 68Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the 68Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma.