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Ethnopharmacological Relevance: Meibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD., Aim of the Study: To observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism., Materials and Methods: After establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting., Results: EDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport., Conclusion: EDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices., 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.)

Dictionary representations and deep learning Autoencoder (AE) models have proven effective in hyperspectral anomaly detection. Dictionary representations offer self-explanation but struggle with complex scenarios. Conversely, autoencoders can capture details in complex scenes but lack self-explanation. Complex scenarios often involve extensive spatial information, making its utilization crucial in hyperspectral anomaly detection. To effectively combine the advantages of both methods and address the insufficient use of spatial information, we propose an attention constrained low-rank and sparse autoencoder for hyperspectral anomaly detection. This model includes two encoders: an attention constrained low-rank autoencoder (AClrAE) trained with a background dictionary and incorporating a Global Self-Attention Module (GAM) to focus on global spatial information, resulting in improved background reconstruction; and an attention constrained sparse autoencoder (ACsAE) trained with an anomaly dictionary and incorporating a Local Self-Attention Module (LAM) to focus on local spatial information, resulting in enhanced anomaly reconstruction. Finally, to merge the detection results from both encoders, a nonlinear fusion scheme is employed. Experiments on multiple real and synthetic datasets demonstrate the effectiveness and feasibility of the proposed method., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In this study, deep eutectic solvent (DES) prepared from choline chloride, lactic acid, and one of the four polyols (ethylene glycol, glycerol, xylitol, and sorbitol) were compared and assessed for their effectiveness in extracting chitin from lobster shells. Our results revealed that as the number of hydroxyl groups in polyols increased, the hydrogen bond network within the DESs became denser. However, this led to a corresponding increase in viscosity, which impacted the efficiency of chitin extraction. Among all prepared DESs, choline chloride-lactic acid/glycerol (CCLaGly) exhibited superior extractive ability, resulting in the extraction of pure chitin from lobster shells. The purity, crystallinity, and molecular weight of the extracted chitin using CCLaGly DES were comparable to those of chemically-isolated chitin, with purity reaching 94.76 ± 0.33 %, crystallinity at 78.78 %, and a molecular weight of 655 kDa. Additionally, the physicochemical properties of the DES-extracted chitins were characterized using Fourier-transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and scanning electron microscopy. This study conducted a comparative analysis of polyol effects on chitin extraction from lobster shells, thereby opening a promising avenue for the utilization of various crustacean shells in sustainable biomaterial production., 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.)

Importance: There is a burgeoning interest in therapeutic development for cutaneous neurofibromas (cNFs), a major cause of morbidity in persons with neurofibromatosis type 1 (NF1). To determine meaningful clinical trial outcomes, deeper understanding is needed regarding how cNFs are associated with quality of life (QoL). However, this understanding has been hampered by challenges in recruiting participants with this rare genetic disease., Objective: To develop a large, crowdsourced validated registry of persons with NF1 and determine the association of specific cNF features with QoL, pain, and itch., Design, Setting, and Participants: From May 2021 to December 2023, a decentralized platform was developed and recruited persons 40 years or older with NF1 and at least 1 cNF from 49 states and 12 countries, who provided clinical survey data, detailed photographs, and genetic sequencing data. Photographs from 583 participants were scored on 12 features of cNFs, including general severity, number, size, facial severity, color, and subtypes., Exposure: cNF features derived from participant-supplied photographs., Main Outcomes and Measures: Total Skindex scores and subdomain scores (symptoms, emotion, function, pain, and itch)., Results: Of 583 participants, 384 (65.9%) were female, and the mean (range) age was 51.7 (40.0-83.0) years. Female sex, general severity, number, size, and facial severity of cNFs were negatively associated with QoL, as demonstrated by increased total Skindex scores. QoL had the largest association with the number of cNFs and presence of facial cNFs. Increasing number of cNFs was associated with worse QoL, and even individuals with a low cNF burden (<10 total cNFs) experienced a decrease in QoL., Conclusions and Relevance: The results of this study suggest that reducing cNF number, particularly on the face, may be associated with improved QoL in individuals with NF1. In addition, early intervention before the development of numerous tumors may lead to the highest benefit in QoL. These data potentially provide insight into which individuals and cNF tumors may benefit most from therapy and highlights the utility of a completely decentralized, photograph-validated and age-controlled study for rare genetic disease. This cohort will allow analysis of disease and tumor heterogeneity after full phenotypic expression is achieved in NF1 and potentially serves as an example in its design for other rare diseases that struggle from poor recruitment.

Background: The structure of proanthocyanidins (PC) contains a large number of active phenolic hydroxyl groups, which makes it have strong antioxidant capacity. This study investigated the structural and functional properties of ovalbumin (OVA) modified by its interaction with PC., Results: It was found that on increasing the concentration ratio of PC to OVA from 10:1 to 40:1, the free amino and total sulfhydryl contents of OVA decreased from 470.59 ± 38.77 and 29.81 ± 0.31 nmol mg -1 to 96.61 ± 4.55 and 21.22 ± 0.78 nmol mg -1 , respectively, and the free sulfhydryl content increased from 7.65 ± 0.41 to 9.48 ± 0.58 nmol mg -1 . These results indicated that CN and CS bonds were formed and PC was covalently linked with OVA. The PC content in the OVA-PC conjugates increased from 281.93 ± 12.92 to 828.81 ± 46.09 nmol mg -1 on increasing the concentration ratio of PC to OVA from 10:1 to 40:1. The contents of α-helix and β-turn of OVA decreased, and the contents of β-sheet and random coil increased, confirmed by circular dichroism. The tertiary structure of OVA was also altered according to the results of fluorescence and ultraviolet absorption spectra. The surface hydrophobicity of OVA-PC conjugates decreased with increasing bound polyphenol content. The conjugation of OVA to PC significantly improved its emulsification and antioxidant activity and denaturation temperature., Conclusion: This study may provide valuable information for improving OVA's functional properties and its PC conjugates for applications in the food industry. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Objectives: The Baveno VII consensus recommends endoscopic screening for varicose veins in cases of liver stiffness measurement (LSM) ≥ 20 kPa or platelet count ≤ 150 × 10 9 /L. Whether this approach was appropriate for patients with primary biliary cholangitis (PBC) remains uncertain. This study expanded the observed risk factors by adding analysis of ultrasound images as a non-invasive tool to predict the risk of esophageal or fundic varices., Methods: We enrolled 111 patients with PBC whose complete ultrasound images, measurement data, and LSM data were available. The value of the periportal hypoechoic band (PHB), splenic area, and LSM in determining the risk of varicose veins and variceal rupture was analyzed. A prospective cohort of 67 patients provided external validation., Results: The area under the receiver operating characteristic curve (AUC) for predicting varicose veins using LSM > 12.1 kPa or splenic areas > 41.2 cm 2 was 0.806 (95% confidence interval (CI): 0.720-0.875) and 0.852 (95% CI: 0.772-0.912), respectively. This finding could assist in avoiding endoscopic screening by 76.6% and 83.8%, respectively, with diagnostic accuracy surpassing that suggested by Baveno VII guidelines. The AUCs for predicting variceal rupture using splenic areas > 56.8 cm 2 was 0.717 (95% CI: 0.623-0.798). The diagnostic accuracy of PHB for variceal rupture was higher than LSM and splenic areas (75.7% vs. 50.5% vs. 68.5%)., Conclusion: We recommend LSM > 12.1 kPa as a cutoff value to predict the risk of varicosity presence in patients with PBC. Additionally, the splenic area demonstrated high accuracy and relevance for predicting varicose veins and variceal rupture, respectively. The method is simple and reproducible, allowing endoscopy to be safely avoided., Clinical Relevance Statement: The measurement of the splenic area and identification of the periportal hypoechoic band (PHB) on ultrasound demonstrated high accuracy and relevance for predicting the risk of esophageal or fundic varices presence and variceal rupture, respectively., Key Points: Predicting varices in patients with primary biliary cholangitis (PBC) can reduce the morbidity and mortality of gastrointestinal hemorrhage. Transient elastography (TE) and ultrasound play an important role in predicting patients with PBC with varices. TE and ultrasound can predict varicose veins and variceal rupture. Liver stiffness measurement and splenic area measurements can allow endoscopy to be safely avoided., (© 2024. The Author(s).)

Reactive oxygen species (ROS) and oxidative stress accelerate cellular aging, but their impact on different tissues varies. The cornea, known for its robust antioxidant defense systems, is relatively resistant to age-related diseases like cancer. However, the precise mechanisms by which the cornea maintains ROS homeostasis during aging remain unclear. Through comparative single-cell transcriptomic analysis of the cornea and other tissues in young and old nonhuman primates, we identified that a ZNF281 coding transcriptomic program is specifically activated in cornea during aging. Further investigation revealed that ZNF281 forms a positive feedback loop with FOXO3 to sense elevated levels of ROS and mitigate their effects potentially by regulating the mitochondrial respiratory chain and superoxide dismutase (SOD) expression. Importantly, we observed that overexpression of ZNF281 in MSCs prevented cellular senescence. In summary, these findings open up possibilities for understanding tissue-specific aging and developing new therapies targeting ROS damage., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Ultrasound Localization Microscopy (ULM) surpasses the constraints imposed by acoustic diffraction, achieving sub-wavelength resolution visualization of microvasculature through the precise localization of minute microbubbles (MBs). Nonetheless, the analysis of densely populated regions with overlapping MB point spread responses introduces significant localization errors, limiting the use of technique to low-concentration conditions. This raises a trade-off issue between localization efficiency and MB density. In this work, we present a new deep learning framework that combines Transformer and U-Net architectures, termed ULM-TransUNet. As a non-linear model, it is able to learn the complex data patterns of overlapping MBs in dense conditions for accurate localization. To evaluate the performance of ULM-TransUNet, a series of numerical simulations and in vivo experiments are carried out. Numerical simulation results indicate that ULM-TransUNet achieves high-quality ULM imaging, with improvements of 21.93 % in detection rate, 17.36 % in detection precision, and 20.53 % in detection sensitivity, compared to previous state-of-the-art deep learning (DL) method (e.g., ULM-UNet). For the in vivo experiments, ULM-TransUNet achieves the highest spatial resolution (9.4 μm) and rapid inference speed (26.04 ms/frame). Furthermore, it consistently detects more small vessels and resolves closely spaced vessels more effectively. The outcomes of this work imply that ULM-TransUNet can potentially enhance the microvascular imaging performance on high-density MB conditions., 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.)

Protein-based subunit vaccines like RBD-Fc are promising tools to fight COVID-19. RBD-Fc fuses the receptor-binding domain (RBD) of the SARS-CoV-2 virus spike protein with the Fc region of human IgG1, making it more immunogenic than RBD alone. Earlier work showed that combining RBD-Fc with iNKT cell agonists as adjuvants improved neutralizing antibodies but did not sufficiently enhance T cell responses, a limitation RBD-Fc vaccines share with common adjuvants. Here we demonstrate that aluminum hydroxide combined with α-C-GC, a C-glycoside iNKT cell agonist, significantly improved the RBD-Fc vaccine's induction of RBD-specific T-cell responses. Additionally, aluminum hydroxide with α-GC-CPOEt, a phosphonate diester derivative, synergistically elicited more robust neutralizing antibodies. Remarkably, modifying αGC with phosphate (OPO 3 H 2 ) or phosphonate (CPO 3 H 2 ) to potentially enhance aluminum hydroxide interaction did not improve efficacy over unmodified αGC with aluminum hydroxide. These findings underscore the straightforward yet potent potential of this approach in advancing COVID-19 vaccine development and provide insights for iNKT cell-based immunotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rui Luo, Zheng Liu, Ya-Qian Li, and Cheng Yan are listed as inventors on a pending patent application about αGC-CPOEt. All other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Chronic diseases, such as heart disease, cancer, and diabetes, are the leading causes of death and disability. Loneliness is linked to a greater risk of chronic disease. However, the lack of loneliness may change this relationship., Methods: The 4th Survey of the Aged Population in Urban and Rural China (SSAPUR) was performed. 222,179 people over 60 years old were recruited. Chronic disease was defined by self-reported tumble incidents using the fourth SSAPUR questionnaire. We found that the residuals were well normally distributed. Subsequently, we analyzed the association between each studied factor and chronic disease by univariate logistic regression analysis. Finally, we stratified the population by age, gender, and urban and rural., Results: 77,448 individuals experienced loneliness, while 137,593 did not. Loneliness correlated significantly with urban-rural classification, age, and gender (P < 0.001). There was a significant association between chronic diseases and loneliness (P < 0.05). Compared to lonely individuals, those with low level of loneliness had a lower incidence of gastric diseases (OR = 0.752, 95% CI, 0.736-0.769, P < 0.001), osteoarthritis (OR = 0.685, 95% CI, 0.673-0.697, P < 0.001), chronic obstructive pulmonary disease (COPD) (OR = 0.678, 95% CI, 0.659-0.698, P < 0.001), asthma (OR = 0.608, 95% CI, 0.583-0.633, P < 0.001), malignant tumors (OR = 0.892, 95% CI, 0.822-0.968, P = 0.006), and reproductive system diseases (OR = 0.871, 95% CI, 0.826-0.918, P < 0.001)., Conclusion: In summary, loneliness is an important risk factor in the occurrence and development of chronic diseases in the elderly in China, and it has adverse effects on hypertension, stomach disease, cataract or glaucoma, osteoarthrosis, chronic lung disease, asthma, malignant tumor, and reproductive system diseases., (© 2024. The Author(s).)

We developed a protocol for the synthesis of highly functionalized 5,6-dihydro-imidazo[1,2- c ][1,2,3]triazole derivatives 4 - 5 (DHITs) from 1-diazonaphthalen-2(1 H )-one derivatives with heterocyclic ketene aminals (HKAs). This strategy involved cycloaddition and skeletal rearrangement entailing the heating of a mixture of substrates 1 with HKAs 2 - 3 and THF without any catalyst. As a result, a series of DHITs 4 - 5 were produced by cleaving one bond (1 C═N bond) and forming three bonds (1 N-N and 2 C-N bonds) in a single step. This protocol achieved the dual functionalization of diazo building blocks involving both the aromatic nitrogen alkylation reaction to form an ArC-N bond without any metal catalyst and the intermolecular cycloaddition of the N═N bond. These strategies can be used to synthesize functionalized DHITs for combinatorial and parallel syntheses via one-pot reactions without any catalyst.

Introduction: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t (15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood., Case Report: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As 2 O 3 ) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative., Conclusion: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

Background: The aim of the study was to evaluate the efficacy and safety of induction and consolidation with all-trans retinoic acid (ATRA) +arsenic trioxide (ATO) +anthracyclines and maintenance with ATRA +Realgar- Indigo naturalis formula (RIF) for high-risk APL., Methods: Twenty-one patients with high-risk APL treated with ATRA+ATO+ anthracyclines for induction and consolidation and ATRA+RIF for maintenance from 2012 to 2021 were analyzed. Endpoints include morphological complete remission (CR) and complete molecular remission (CMR), early death (ED) and relapse, survival and adverse events (AEs)., Results: After induction treatment, all 21 patients (100%) achieved morphological CR and 14 people (66.7%) achieved CMR. Five of the 21 patients did not undergo immunological minimal residual disease (MRD) examination after induction; however, 14 of the remaining 16 patients were MRD negative (87.5%). The median time to achieve CR and CMR was 26 days (range: 16-44) and 40 days (range: 22-75), respectively. The cumulative probability of achieving CR and CMR in 45 days was 100% and 76.2% (95% CI: 56.9-91.3%), respectively. All patients achieved CMR and MRD negativity after the three courses of consolidation treatment. The median follow-up was 66 months (25-142), with no central nervous system relapse and bone marrow morphological or molecular relapse until now, and all patients survived with 100% overall survival and 100% event-free survival. Grade 4 adverse events (AEs) were observed in 3 patients (14.3%) during the induction period including arrhythmia (n = 1), pulmonary infection (n = 1) and respiratory failure (n = 1); and the most frequent grade 3 AEs were pulmonary infection, accounting for 62.0% and 28.6%, respectively, during induction and consolidation treatment, followed by neutropenia, accounting for 42.9% and 38.1%, respectively., Conclusion: For newly diagnosed high-risk APL patients, induction and consolidation with ATRA+ATO+anthracyclines and maintenance with ATRA+RIF is a highly curative treatment approach., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Liu et al.)

Detecting roads in automatic driving environments poses a challenge due to issues such as boundary fuzziness, occlusion, and glare from light. We believe that two factors are instrumental in addressing these challenges and enhancing detection performance: global context dependency and effective feature representation that prioritizes important feature channels. To tackle these issues, we introduce DTRoadseg, a novel duplex Transformer-based heterogeneous feature fusion network designed for road segmentation. DTRoadseg leverages a duplex encoder architecture to extract heterogeneous features from both RGB images and point-cloud depth images. Subsequently, we introduce a multi-source Heterogeneous Feature Reinforcement Block (HFRB) for fusion of the encoded features, comprising a Heterogeneous Feature Fusion Module (HFFM) and a Reinforcement Fusion Module (RFM). The HFFM leverages the self-attention mechanisms of Transformers to achieve effective fusion through token interactions, while the RFM focuses on emphasizing informative features while downplaying less important ones, thereby reinforcing feature fusion. Finally, a Transformer decoder is utilized to produce the final semantic prediction. Furthermore, we employ a boundary loss function to optimize the segmentation structure area, reduce false detection areas, and improve model accuracy. Extensive experiments are carried out on the KITTI road dataset. The results demonstrate that, compared with state-of-the-art methods, DTRoadseg exhibits superior performance, achieving an average accuracy of 97.01%, a Recall of 96.35%, and runs at a speed of 0.09 s per picture., (© 2024. The Author(s).)

Electrolytes with anion-dominated solvation are promising candidates to achieve dendrite-free and high-voltage potassium metal batteries. However, it's challenging to form anion-reinforced solvates at low salt concentrations. Herein, we construct an anion-reinforced solvation structure at a moderate concentration of 1.5 M with weakly coordinated cosolvent ethylene glycol dibutyl ether. The unique solvation structure accelerates the desolvation of K + , strengthens the oxidative stability to 4.94 V and facilitates the formation of inorganic-rich and stable electrode-electrolyte interface. These enable stable plating/stripping of K metal anode over 2200 h, high capacity retention of 83.0 % after 150 cycles with a high cut-off voltage of 4.5 V in K 0.67 MnO 2 //K cells, and even 91.5 % after 30 cycles under 4.7 V. This work provides insight into weakly coordinated cosolvent and opens new avenues for designing ether-based high-voltage electrolytes., (© 2024 Wiley-VCH GmbH.)

Lentiviral vectors have markedly enhanced gene therapy efficiency in treating congenital diseases, but their long-term safety remains controversial. Most gene therapies for congenital eye diseases need to be carried out at early ages, yet the assessment of related risks to ocular development posed by lentiviral vectors is challenging. Utilizing single-cell transcriptomic profiling on human retinal organoids, this study explored the impact of lentiviral vectors on the retinal development and found that lentiviral vectors can cause retinal precursor cells to shift toward photoreceptor fate through the up-regulation of key fate-determining genes such as PRDM1. Further investigation demonstrated that the intron and intergenic region of PRDM1 was bound by PHLDA1, which was also up-regulated by lentiviral vectors exposure. Importantly, knockdown of PHLDA1 successfully suppressed the lentivirus-induced differentiation bias of photoreceptor cells. The findings also suggest that while lentiviral vectors may disrupt the fate determination of retinal precursor cells, posing risks in early-stage retinal gene therapy, these risks could potentially be reduced by inhibiting the PHLDA1-PRDM1 axis., (© 2024. The Author(s).)

Using Origin2022Pro, PAST4.09, GraphPad, and ArcGIS, this study analyzed the big data of the fourth national survey of traditional Chinese medicine resources in Jilin province from five dimensions: differences in resource quantity, taxonomic group, family, and genus, regional distribution, and spatiotemporal distribution, aiming to fully elucidate the biodiversity of medicinal plants in Jilin province. The results indicated that 2 241 species of medicinal plants existed in Jilin province, belonging to 881 genera of 243 families, with 20 dominant families and 3 dominant genera. There were 1 901 species of medicinal plants(belonging to 778 genera of 227 families) in the eastern mountainous region, 1 503 species(belonging to 690 genera of 225 families) in the mid-mountainous areas of the central mountainous region, and 811 species(belonging to 436 genera of 136 families) in the western plain region. The biodiversity of medicinal plants in Jilin province was high and presented a trend of high in the east and low in the west. The medicinal plant resources were mainly concentrated in the eastern mountainous region, and the number of medicinal plant groups had significant diffe-rences between regions, following the trend of western region &gt; central region &gt; eastern region. The species richness was in the order of eastern region &gt; western region &gt; central region. The species diversity structure in the central region was similar to that in the eastern and western regions, while it was significantly different between the western and eastern regions. Compared with the third national survey of traditional Chinese medicine resources, the fourth survey showed an increase of 1 417 species, a decrease of 580 species, and 824 common species, indicating significant changes in the biodiversity of medicinal plants in Jilin province. The reasons for these changes need to be further explored. This article elucidates the background and biodiversity changes of medicinal plant resources in Jilin province, laying a foundation for the protection, utilization, and industrial development of traditional Chinese medicine resources in Jilin province.

Objective: Percutaneous repair is an alternative to open surgical repair of the Achilles tendon with comparable, functional results and low re-rupture and infection rates; however, sural nerve injury is a known complication. The purpose of this study is to design a new surgical procedure, the minimally invasive peritendinous submembrane access technique (MIS-PSAT). It offers optimal results, with excellent functional outcomes, and with minimal soft tissue complications and sural nerve injury., Methods: This retrospective study included 249 patients with acute closed Achilles tendon ruptures treated at our institution between 2009 and 2019. All patients underwent MIS-PSAT at our institution and were followed up for 8-48 months. Functional evaluation was based on the Achilles tendon total rupture score (ATRS) and the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS), associated with local complications and isokinetic tests., Results: None of the patients had infection, necrosis, or sural nerve injury. Re-rupture occurred in two cases. The average times to return to work and sports was 10.4 and 31.6 weeks, respectively. The average ATRS and AOFAS-AHS scores were 90.2 and 95.7, respectively, with an excellent rate of 99.5%. Isokinetic tests showed that ankle function on the affected side was comparable with that on the healthy side (p > 0.05)., Conclusion: The MIS-PSAT for acute Achilles tendon rupture is easy to perform with few complications. Importantly, the surgical technique reduces the risk of sural nerve injuries. Patients have high postoperative satisfaction, low re-rupture rates, and muscle strength, and endurance can be restored to levels similar to those on the healthy side., (© 2024 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Aim: To examine the prevalence and potential risk factors of multimorbidity among older adult in China. In addition, we investigated the pattern of multimorbidity., Methods: This study is based on data from the fourth Sample Survey of the Aged Population in Urban and Rural China (SSAPUR) in 2015, a comprehensive survey of individuals aged 60 years or older in China. We calculated baseline data and prevalence rates for comorbidities, stratified by household registration, age, sex, education, exercise, and health insurance. Univariate and multivariate logistic regression analyses were conducted to identify potential risk factors for comorbidities. Furthermore, we determined the prevalence rates for the three most frequent disease combinations., Results: A total of 215,040 participants were included in our analysis. The prevalence of multimorbidity was 50.5% among the older adult in China. The prevalence rate was slightly higher in rural areas than in urban areas, with rates of 51.5 and 49.6%, respectively ( p  < 0.001). Moreover, the prevalence rate was higher in females than in males, with rates of 55.2 and 45.3%, respectively ( p  < 0.001). Multivariate logistic regression analysis revealed that individuals aged 70-79 years (OR:1.40, 95% CI: 1.38-1.43, p  < 0.001) and over 80 years (OR:1.41, 95% CI: 1.38-1.45, p  < 0.001) had a higher prevalence of multimorbidity than those aged 60-69 years. The most prevalent pair of comorbidities was hypertension and osteoarthropathy, with 19.6% of the participants having these two conditions, accounting for 5.4% of the total participants., Conclusion: Our findings indicate a high prevalence of multimorbidity among the older adult in China. Increased expenditure on preventive health care, popularization of general medicine and popular medical education may be adopted by the Government to cope with the high prevalence of multimorbidity., 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 Hu, Li, Wei, Wu, Meng, Li, Xu, Zhang, Ma, Li, Zeng, Zhang, Li and Liu.)

Significance: Type 2 diabetes mellitus (T2DM) is a global health concern with significant implications for vascular health. The current evaluation methods cannot achieve effective, portable, and quantitative evaluation of foot microcirculation., Aim: We aim to use a wearable device laser Doppler flowmetry (LDF) to evaluate the foot microcirculation of T2DM patients at rest., Approach: Eleven T2DM patients and twelve healthy subjects participated in this study. The wearable LDF was used to measure the blood flows (BFs) for regions of the first metatarsal head (M1), fifth metatarsal head (M5), heel, and dorsal foot. Typical wavelet analysis was used to decompose the five individual control mechanisms: endothelial, neurogenic, myogenic, respiratory, and heart components. The mean BF and sample entropy (SE) were calculated, and the differences between diabetic patients and healthy adults and among the four regions were compared., Results: Diabetic patients showed significantly reduced mean BF in the neurogenic ( p = 0.044 ) and heart ( p = 0.001 ) components at the M1 and M5 regions ( p = 0.025 ) compared with healthy adults. Diabetic patients had significantly lower SE in the neurogenic ( p = 0.049 ) and myogenic ( p = 0.032 ) components at the M1 region, as well as in the endothelial ( p < 0.001 ) component at the M5 region and in the myogenic component at the dorsal foot ( p = 0.007 ), compared with healthy adults. The SE in the myogenic component at the dorsal foot was lower than at the M5 region ( p = 0.050 ) and heel area ( p = 0.041 ). Similarly, the SE in the heart component at the dorsal foot was lower than at the M5 region ( p = 0.017 ) and heel area ( p = 0.028 ) in diabetic patients., Conclusions: This study indicated the potential of using the novel wearable LDF device for tracking vascular complications and implementing targeted interventions in T2DM patients., (© 2024 The Authors.)

The house fly is a significant pest in agriculture and human health that is increasingly difficult to manage due to multiple limitations including resistance development. To explore alternative pesticides, the topical toxicity and repellency profiles of 17 essential oil components (EOCs) were evaluated against a resistant and a susceptible strain of house fly, Musca domestica L., using topical application and Y-tube olfactometers, respectively. Six of the most toxic EOCs based on the LD 50 were further investigated against a susceptible strain of house fly. Thymol, (+)-pulegone, eugenol, and carvacrol were always the top four most toxic chemicals tested against the resistant house fly strain. Little to no resistance was observed to the top six EOCs based on the comparison of the results between resistant and susceptible house fly strains. P-Cymene, citronellic acid, R-(+)-limonene, linalool, γ-terpinene, estragole, and eugenol were repellent to adult house flies at certain concentrations while (-)-carvone and thymol were attractive to adult house flies. This screening of a wide variety of individual EOCs provides a stronger foundation of information for further research. This should encourage further investigation into the topical toxicity and repellency in field studies, which will provide more insight into the performance of biopesticides for house fly management and potential commercialization.

Background: There is growing evidence linking the age-adjusted Charlson comorbidity index (aCCI), an assessment tool for multimorbidity, to fragility fracture and fracture-related postoperative complications. However, the role of multimorbidity in osteoporosis has not yet been thoroughly evaluated. We aimed to investigate the association between aCCI and the risk of osteoporosis in older adults at moderate to high risk of falling., Methods: A total of 947 men were included from January 2015 to August 2022 in a hospital in Beijing, China. The aCCI was calculated by counting age and each comorbidity according to their weighted scores, and the participants were stratified into two groups by aCCI: low (aCCI < 5), and high (aCCI ≥5). The Kaplan Meier method was used to assess the cumulative incidence of osteoporosis by different levels of aCCI. The Cox proportional hazards regression model was used to estimate the association of aCCI with the risk of osteoporosis. Receiver operating characteristic (ROC) curve was adapted to assess the performance for aCCI in osteoporosis screening., Results: At baseline, the mean age of all patients was 75.7 years, the mean BMI was 24.8 kg/m 2 , and 531 (56.1%) patients had high aCCI while 416 (43.9%) were having low aCCI. During a median follow-up of 6.6 years, 296 participants developed osteoporosis. Kaplan-Meier survival curves showed that participants with high aCCI had significantly higher cumulative incidence of osteoporosis compared with those had low aCCI (log-rank test: P < 0.001). When aCCI was examined as a continuous variable, the multivariable-adjusted model showed that the osteoporosis risk increased by 12.1% (HR = 1.121, 95% CI 1.041-1.206, P = 0.002) as aCCI increased by one unit. When aCCI was changed to a categorical variable, the multivariable-adjusted hazard ratios associated with different levels of aCCI [low (reference group) and high] were 1.00 and 1.557 (95% CI 1.223-1.983) for osteoporosis (P <  0.001), respectively. The aCCI (cutoff ≥5) revealed an area under ROC curve (AUC) of 0.566 (95%CI 0.527-0.605, P = 0.001) in identifying osteoporosis in older fall-prone men, with sensitivity of 64.9% and specificity of 47.9%., Conclusions: The current study indicated an association of higher aCCI with an increased risk of osteoporosis among older fall-prone men, supporting the possibility of aCCI as a marker of long-term skeletal-related adverse clinical outcomes., (© 2024. The Author(s).)

Dexmedetomidine (Dex) has been used in surgery to improve patients' postoperative cognitive function. However, the role of Dex in stress-induced anxiety-like behaviors and cognitive impairment is still unclear. In this study, we tested the role of Dex in anxiety-like behavior and cognitive impairment induced by acute restrictive stress and analyzed the alterations of the intestinal flora to explore the possible mechanism. Behavioral and cognitive tests, including open field test, elevated plus-maze test, novel object recognition test, and Barnes maze test, were performed. Intestinal gut Microbe 16S rRNA sequencing was analyzed. We found that intraperitoneal injection of Dex significantly improved acute restrictive stress-induced anxiety-like behavior, recognition, and memory impairment. After habituation in the environment, mice (male, 8 weeks, 18-23 g) were randomly divided into a control group (control, N = 10), dexmedetomidine group (Dex, N = 10), AS with normal saline group (AS + NS, N = 10) and AS with dexmedetomidine group (AS + Dex, N = 10). By the analysis of intestinal flora, we found that acute stress caused intestinal flora disorder in mice. Dex intervention changed the composition of the intestinal flora of acute stress mice, stabilized the ecology of the intestinal flora, and significantly increased the levels of Blautia (A genus of anaerobic bacteria) and Coprobacillus. These findings suggest that Dex attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora., (© 2024. The Author(s).)

V-type granular starches (VGSs) were prepared via an ethanol-alkaline (EA) method using maize starch with different amylose contents, specifically, high amylose (HAM), normal maize starch (MS), and waxy maize starch (WS). The X-ray diffraction pattern of the native starch was completely transformed into a V-type pattern after the EA treatment, indicating a structural change in the starch granules. The VGSs prepared by HAM had highest relative crystallinity (31.8°), while the VGSs prepared by WS showed amorphous diffraction pattern. Excessive NaOH, however, would disrupt the formation of V-type structures and cause granular shape rupture. The quantity of double-helical structures, particularly those formed by amylopectin at the starch granules' periphery, significantly decreased. Conversely, single-helical structures formed by amylose increased. A notable rise in the relative crystallinity of V crystals. Four VGS samples, characterized by granular integrity, were chosen for the next investigation of physicochemical and digestive properties. VGS prepared from HAM exhibited higher granular integrity, lower cold-water swelling extent (59.0 and 161.0 cP), improved thermal stability (the value of breakdown as lower as 57.67 and 186.67 cP), and higher resistance to digestion (RS content was up to 10.38 % and 9.00 % higher than 5.86 % and 5.66 % of VGS prepared from WS and MS). The results confirmed that amylose content has a substantial impact on the microstructural and physicochemical properties of VGSs., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This study aimed to investigate the mechanism of long noncoding ribonucleic acid (lncRNA) SNHG16 on kidney clear cell carcinoma (KIRC) cells by targeting miR-506-3p/ETS proto-oncogene 1, transcription factor (ETS1)/RAS/Extracellular regulated protein kinases (ERK) molecular axis, thus to provide reference for clinical diagnosis and treatment of KIRC in the future., Methods: Thirty-six patients with KIRC were enrolled in this study, and their carcinoma tissues and adjacent tissues were obtained for the detection of SNHG16/miR-506-3p/ETS1/RAS/ERK expression. Then, over-expressed SNHG16 plasmid and silenced plasmid were transfected into KIRC cells to observe the changes of their biological behavior., Results: SNHG16 and ETS1 were highly expressed while miR-506- 3p was low expressed in KIRC tissues; the RAS/ERK signaling pathway was significantly activated in KIRC tissues (P < 0.05). After SNHG16 silence, KIRC cells showed decreased proliferation, invasion and migration capabilities and increased apoptosis rate; correspondingly, increase in SNHG16 expression achieved opposite results (P < 0.05). Finally, in the rescue experiment, the effects of elevated SNHG16 on KIRC cells were reversed by simultaneous increase in miR-506-3p, and the effects of miR-506-3p were reversed by ETS1. Activation of the RAS/ERK pathway had the same effect as increase in ETS1, which further worsened the malignancy of KIRC. After miR-506-3p increase and ETS1 silence, the RAS/ERK signaling pathway was inhibited (P < 0.05). At last, the rescue experiment (co-transfection) confirmed that the effect of SNHG16 on KIRC cells is achieved via the miR-506-3p/ETS1/RAS/ERK molecular axis., Conclusion: SNHG16 regulates the biological behavior of KIRC cells by targeting the miR-506-3p/ETS1/RAS/ERK molecular axis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Mingli Gu reports financial support was provided by Natural Science Key Project of Anhui Provincial Education Department. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The etiology of chronic prostatitis remains unclear; consequently, this disease is associated with recurrence and ineffective clinical therapy. Therefore, there is an urgent need to investigate the underlying pathogenesis of chronic prostatitis in order to develop more efficacious treatments., Objective: The previous study found that knocking out of PEBP4 leads to chronic prostatitis in the male mice. This research aimed to identify the role of PEBP4 in prostatitis, determine the molecular pathogenic mechanisms associated with chronic prostatitis, and provide guidelines for the development of new treatment strategies for chronic prostatitis., Materials and Methods: A PEBP4 exon knockout strain (PEBP4 -/- ) was established in C57BL/6 mice via the Cre-loxP system. Hematoxylin-eosin (H&E) staining was used to investigate histological changes. RNA-sequencing was used to investigate the gene expression signature of the prostate and the levels of inflammatory cytokines were determined by real-time polymerase chain reaction (RT-PCR). The expression of PEBP4 protein in prostate tissue was determined by immunohistochemistry in specimens from patients with BPH and BPH combined with chronic prostatitis. Finally, we used a CRISPR-Cas9 plasmid to knockout PEBP4 in RWPE-1 cells; western blotting was subsequently used to measure the level of activation in the NF-κB signaling pathway after activating with TNF-α., Results: Hemorrhage and inflammatory cell infiltration were incidentally observed in the seminal vesicles and prostate glands of PEBP4 -/- mice after being fed with a normal diet for 1 year. In addition, we found significantly lower (p < 0.001) expression levels of PEBP4 protein in prostate tissues from patients with benign prostate hyperplasia (BPH) and chronic and non-bacterial prostatitis (CNP) when compared to those with BPH only. The reduced expression of PEBP4 led to a higher risk of prostatitis recurrence in patients after 2 years of follow-up. Increased levels of NF-κB and IκB phosphorylation were observed in PEBP4-knockout RWPE-1 cells and prostate glands from PEBP4 -/- mice., Conclusion: The knockout of PEBP4 in experimental mice led to chronic prostatitis and the reduced expression of PEBP4 in patients with higher risk of chronic and non-bacterial prostatitis suggested that PEBP4 might act as a protective factor against chronic prostatitis. The knockout of PEBP4 in RWPE-1 cells led to the increased activation of NF-κB and IκB, thus indicating that inhibition of PEBP4 faciliated the NF-κB signaling cascade. Our findings provide a new etiology and therapeutic target for chronic prostatitis., (© 2024 American Society of Andrology and European Academy of Andrology.)

The nanoscale Cu-rich precipitates (CRPs) are one of the most critical microstructural features responsible for degrading the mechanical properties of reactor pressure vessel (RPV) steels. The prospect of the rapid regeneration of the service performance of degraded materials through electropulsing is attractive, and electropulsing has been proven to have the application potential to eliminate the CRPs and recover the mechanical properties of RPV materials. However, few studies have investigated the secondary service issue of electropulsing. This paper provides experimental findings from microstructural investigations and property evaluations of a FeCu RPV model alloy subjected to re-aging following recovery electropulsing and annealing treatments. The evolution behavior of CRPs and the changes in the hardness of the alloy during the re-aging process after electropulsing treatment were consistent with the initial aging process, while the re-aging process of the annealing treatment group was quite different from the initial aging. The difference between the electropulsing and annealing treatment groups was that the annealing treatment failed to eliminate the precipitates completely, leaving behind some large precipitates. This work demonstrates the potential application of EPT in this field.

Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8‒118.2) and 88.4 (77.7‒102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status., (© 2024. The Author(s).)

Background: Hyperuricaemia (HUA) is a disorder of purine metabolism in the body. We previously synthesized a hesperitin (Hsp)-Cu(II) complex and found that the complex possessed strong uric acid (UA)-reducing activity in vitro. In this study we further explored the complex's UA-lowering and nephroprotective effects in vivo., Methods: A mouse with HUA was used to investigate the complex's hypouricemic and nephroprotective effects via biochemical analysis, RT-PCR, and Western blot., Results: Hsp-Cu(II) complex markedly decreased the serum UA level and restored kidney tissue damage to normal in HUA mice. Meanwhile, the complex inhibited liver adenosine deaminase (ADA) and xanthine oxidase (XO) activities to reduce UA synthesis and modulated the protein expression of urate transporters to promote UA excretion. Hsp-Cu(II) treatment significantly suppressed oxidative stress and inflammatory in the kidney, reduced the contents of cytokines and inhibited the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway., Conclusions: Hsp-Cu(II) complex reduced serum UA and protected kidneys from renal inflammatory damage and oxidative stress by modulating the NLRP3 pathway. Hsp-Cu(II) complex may be a promising dietary supplement or nutraceutical for the therapy of hyperuricemia.

Background: Adverse psychosocial factors play an important role in cardio-cerebral vascular disease (CCVD). The aim of this study was to evaluate the impact of the cumulative burden of loneliness on the risk of CCVD in the Chinese older adult., Methods: A total of 6,181 Chinese older adult over the age of 62 in the monitoring survey of the fourth Sample Survey of the Aged Population in Urban and Rural China (SSAPUR) were included in this study. The loneliness cumulative burden (scored by cumulative degree) was weighted by the loneliness score for two consecutive years (2017-2018) and divided into low- and high-burden groups. The outcome was defined as the incidence of CCVD 1 year later (2018-2019). A multivariate logistic regression model was used to examine the relationship between the cumulative burden of loneliness and the new onset of CCVD., Results: Among participants, 18.9% had a higher cumulative burden of loneliness, and 11.5% had a CCVD incidence within 1 year. After multivariate adjustment, the risk of developing CCVD in the high-burden group was approximately 37% higher than that in the low-burden group (OR 1.373, 95%CI 1.096-1.721; p  = 0.006). Similar results were obtained when calculating the burden based on cumulative time. Longitudinal change in loneliness was not significantly associated with an increased risk of CCVD. A higher cumulative burden of loneliness may predict a higher risk of developing CCVD in older adult individuals aged 62-72 years or in those with diabetes., Conclusion: The cumulative burden of loneliness can be used to assess the risk of new-onset CCVD in the older adult in the short term., 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 Wu, Hu, Meng, Li, Xu, Zhang, Ma, Li, Zeng, Li, Zhang and Liu.)

Emergency myelopoiesis (EM) is essential in immune defense against pathogens for rapid replenishing of mature myeloid cells. During the EM process, a rapid cell-cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs) is critical. How the rapid proliferation of MPs during EM is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor, is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB)-mobilized hematopoietic stem/progenitor cells (HSPCs) with ATG7 knockdown or HSPCs derived from ATG7 -/- human embryonic stem cells (hESCs) exhibit severe defect in proliferation during fate transition from HSPCs to MPs. Mechanistically, we show that ATG7 deficiency reduces p53 localization in lysosome for a potential autophagy-mediated degradation. Together, we reveal a previously unrecognized role of autophagy to regulate p53 for a rapid proliferation of MPs in human myelopoiesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Osteoarthritis (OA) is a degenerative joint disease which is categorized via destruction of joint cartilage and it also affects the various joints, especially knees and hips. Sinomenine active phytoconstituents isolated from the stem of Sinomenium acutum and already proof anti-inflammatory effect against the arthritis model of rodent. In this experimental protocol, we scrutinized the anti-osteoarthritis effect of sinomenine against monosodium iodoacetate (MIA) induced OA in rats., Methods: MIA (3 mg/50 μL) was used for inducing the OA in the rats, and rats received the oral administration of sinomenine (2.5, 5 and 7.5 mg/kg body weight) up to the end of the experimental study (four weeks). The body and organs weight were estimated. Aggrecan, C-terminal cross-linked telopeptide of type II collagen (CTX-II), glycosaminoglycans (GCGs), monocyte chemoattractant protein-1 (MCP-1), Interferon gamma (IFN-γ), antioxidant, inflammatory cytokines, inflammatory mediators and matrix metalloproteinases (MMP) were analyzed., Results: Sinomenine significantly (P < 0.001) boosted the body weight and reduced the heart weight, but the weight of spleen and kidney remain unchanged. Sinomenine significantly (P < 0.001) reduced the level of nitric oxide, MCP-1 and improved the level of aggrecan, IFN-γ and GCGs. Sinomenine remarkably upregulated the level of glutathione, superoxide dismutase and suppressed the level of malonaldehyde. It effectually modulated the level of inflammatory cytokines and inflammatory mediators and significantly (P < 0.001) reduced the level of MMPs, like MMP-1, 2, 3, 9 and 13., Conclusions: Sinomenine is a beneficial active agent for the treatment of OA disease.

Genetically engineered macrophages (GEMs) have emerged as an appealing strategy to treat cancers, but they are largely impeded by the cell availability and technical challenges in gene transfer. Here, we develop an efficient approach to generate large-scale macrophages from human induced pluripotent stem cells (hiPSCs). Starting with 1 T150 dish of 10 6 hiPSCs, more than 10 9 mature macrophages (iMacs) could be generated within 1 month. The generated iMacs exhibit typical macrophage properties such as phagocytosis and polarization. We then generate hiPSCs integrated with an IL-12 expression cassette in the AAVS1 locus to produce iMacs secreting IL-12, a strong proimmunity cytokine. hiPSC-derived iMacs&#95;IL-12 prevent cytotoxic T cell exhaustion and activate T cells to kill different cancer cells. Furthermore, iMacs&#95;IL-12 display strong antitumor effects in a T cell-dependent manner in subcutaneously or systemically xenografted mice of human lung cancer. Therefore, we provide an off-the-shelf strategy to produce large-scale GEMs for cancer therapy., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Due to the increasing demand for health-conscious and environmentally friendly products, D-mannose has gained significant attention as a natural, low-calorie sweetener. The use of D-mannose isomerases (D-MIases) for D-mannose production has emerged as a prominent area of research, offering superior advantages compared with conventional methods such as plant extraction and chemical synthesis. In this study, a gene encoding D-MIase was cloned from Bifidobacterium and expressed in E. coli BL21 (DE3). The heterologously expressed enzyme, Bifi-mannose, formed a trimer with a molecular weight of 146.3 kDa and a melting temperature (T m ) of 63.39 ± 1.3 °C. Bifi-mannose exhibited optimal catalytic activity at pH 7.5 and 55 °C, and retained more than 80% of its activity after a 3-hour incubation at 55 °C, demonstrating excellent thermal stability. The K m , V max , and k cat /K m values of Bifi-mannose for D-fructose isomerization were determined as 538.7 ± 62.5 mM, 11.7 ± 0.9 μmol·mg 1 ·s 1 , and 1.02 ± 0.3 mM 1 ·s 1 , respectively. Notably, under optimized conditions, catalytic yields of 29.4, 87.1, and 148.5 mg·mL 1 were achieved when using 100, 300, and 500 mg·mL 1 of D-fructose as substrates, resulting in a high conversion rate (29%). Furthermore, kinetic parameters and molecular docking studies revealed that His387 residue primarily participates in the opening of the pyranose ring, while His253 acts as a basic catalyst in the isomerization process., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To analyze the diagnostic efficacy of the periportal hypoechoic band (PHB) in the histological stage of patients with primary biliary cholangitis (PBC)., Methods: We prospectively included 77 cases of PBC pathologically or clinically confirmed, and high-frequency ultrasound (HFUS) measurements of the PHB were performed in all included patients. Ludwig staging system of histopathology was used as the gold standard., Results: The width of the PHB was positively correlated with histological staging (r = 0.844, p < 0.001). By area under the receiving operating characteristic curve (AUROC), the best cutoff value for PHB for advanced stage (≥ stage 3) was 2.4 mm (AUROC: 0.934; 95%CI: 0.841-0.981) and 0.93 for sensitivity, and 0.91 for specificity, the concordance rates of PHB vs. liver biopsy was 90.3%. The correct rate for early-stage PBC was 87.9% and for the progressive stage was 93.1%. After multi-factor regression analysis, the PHB (OR = 1.331, CI = 1.105-1.603, p = 0.003) and total bilirubin (OR = 1.156, CI = 1.041-1.285, p = 0.007) were independent influencing factors for progressive PBC., Conclusions: Measurement of the PHB to assess advanced PBC is a simple and effective method. This method may complement current methods for the histological staging assessment of patients with PBC., Registration: Clinical trial registration: ChiCTR 2000032053, 2020/04/19., Clinical Relevance Statement: The measurement of periportal hypoechoic band (PHB) provides a simple and easy assessment of the degree of disease progression in patients with PBC and provides an important clinical reference in predicting the histological staging of PBC from an ultrasound perspective., Key Points: • The PHB is correlated with histological staging in the patient with PBC. • The area under the ROC curves of PHB for detecting advanced stage (≥ stage 3) were 0.934 and 0.93 for sensitivity, and 0.91 for specificity, the concordance rates of PHB vs. liver biopsy was 90.3%. The application of PHB can better assess the advanced PBC. • Measurement of the PHB to assess advanced PBC is a simple and effective method that can significantly reduce the need for liver biopsy., (© 2023. The Author(s).)

Skin cutaneous melanoma (SKCM) poses a significant challenge in skin cancers. Recent immunotherapy breakthroughs have revolutionized melanoma treamtment, yet tumor heterogeneity persists as an obstacle. Epigenetic modifications orchestrated by DNA methylation contributed to tumorigenesis, thus potentially unveiling melanoma prognosis. Here, we identified an interferon-gamma (IFN-g) sensitive subtype, which possesses favorable outcomes, robust infiltration CD8+T cells, and IFN-g score in bulk RNA-seq profile. Subsequently, we established an IFN-g sensitivity signature based on machine learning. We validated that PSMB9 is strongly correlated with immunotherapy response in both methylation and expression cohorts in this 10-probe signature. We assumed that PSMB9 acts as a putative melanoma suppressor, for its activation of CD8+T cell; capacity to modulate IFN-γ secretion; and dynamics altering IFN-g receptors in bulk tissue. We performed single-cell RNA-seq on immunotherapy patients' tissue to uncover the nuanced role of PSMB9 in activating CD8T + cells, enhancing IFN-g, and influencing malignant cells receptors and transcriptional factors. Overexpress PSMB9 in two SKCM cell lines to mimic the hypomethylated state to approve our conjecture. Strong cell proliferation and migration inhibition were detected on both cells, indicating that PSMB9 is present in tumor cells and that high expression is detrimental to tumor growth and migration. Overall, comprehensive integrated analysis shows that PSMB9 emerges as a vital prognostic marker, acting predictive potential regarding immunotherapy in melanoma. This evidence not only reveals the multifaceted impact of PSMB9 on both malignant and immune cells but also serves as a prospective target for undergoing immunotherapeutic strategies in the future., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

MicroRNAs (miRs) play multiple roles during cutaneous squamous cell carcinoma (CSCC) progression. Previous studies suggest miR-124 could inhibit cancer development in CSCC., Methods: Obtained 63 pairs of CSCC and adjacent tissues for analysis. Cultured HaCaT and two CSCC cell lines (A431 and SCL-1) in DMEM (10 % FBS). Transfected cells using Lipofectamine 2000 with various miR-124 mimics, inhibitors, or Snail family transcriptional repressor 2 (SNAI2) expression plasmid. Performed a series of assays, including real-time quantitative PCR, Western blot, CCK8, wound healing, transwell, and luciferase reporter gene assay, to examine the effects of miR-124 on CSCC cells., Results: An evident downregulation of miR-124 in CSCC tissues, which was related to advanced disease stage and nodal metastasis. Overexpressing miR-124 could reduce the proliferation, migration, and invasion abilities of CSCC cells. It was verified that miR-124 targets the SNAI2 in CSCC cells. Moreover, ectopic expression of SNAI2 rescued the suppressive effects on CSCC cells induced by miR-124 overexpression. Furthermore, miR-124 increased cell sensitivity to cisplatin. Besides, SNAI2 is a critical factor in the immune-related aspects of CSCC and its modulation may influence the response to immunotherapy., Conclusion: We demonstrate that miR-124 inhibits CSCC progression through downregulating SNAI2, and thus it may be a molecular candidate for treating CSCC in the clinic., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a prominent therapeutic strategy for tumor suppression. However, the wide application of GPX4 inhibitors in tumor therapy is hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-assembly, we develop a peptide-ferriporphyrin conjugate with tumor microenvironment specific activation to improve tumor penetration, endocytosis and GPX4 inhibition, ultimately enhancing its anticancer activity via ferroptosis. Briefly, a GPX4 inhibitory peptide is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferriporphyrin to produce the peptide-ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenvironment of the tumor, the Gi-F-CAA self-assembles into large nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of CAA, improving tumor endocytosis efficiency. Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (AEB) effect, augmenting the oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our findings suggest that this peptide-ferriporphyrin conjugate design with AEB effect can improve the therapeutic effect via induction of ferroptosis, providing an alternative strategy for overcoming chemoresistance., (© 2024. The Author(s).)

Ivermectin (IVM), a semi-synthetic macrolide parasiticide, has demonstrated considerable effectiveness in combating internal and external parasites, particularly nematodes and arthropods. Its remarkable ability to control parasites has earned it significant recognition, culminating in Satoshi Omura and William C. Campbell's receipt of the 2015 Nobel Prize in Physiology or Medicine for their contributions to the development of IVM. In recent years, investigations have revealed that IVM possesses antitumor properties. It can suppress the growth of various cancer cells, including glioma, through a multitude of mechanisms such as selective targeting of tumor-specific proteins, inducing programmed cell death, and modulation of tumor-related signaling pathways. Hence, IVM holds tremendous potential as a novel anticancer drug. This review seeks to provide an overview of the underlying mechanisms that enable IVM's capacity to suppress glioma. Furthermore, it aims to elucidate the challenges and prospects associated with utilizing IVM as a new anticancer agent., (© 2023 Wiley Periodicals LLC.)

Background: Melanoma, a frequently encountered cutaneous malignancy characterized by a poor prognosis, persists in presenting formidable challenges despite the advancement in molecularly targeted drugs designed to improve survival rates significantly. Unfortunately, as more therapeutic choices have developed over time, the gradual emergence of drug resistance has become a notable impediment to the effectiveness of these therapeutic interventions. The hepatocyte growth factor (HGF)/c-met signaling pathway has attracted considerable attention, associated with drug resistance stemming from multiple potential mutations within the c-met gene. The activation of the HGF/c-met pathway operates in an autocrine manner in melanoma. Notably, a key player in the regulatory orchestration of HGF/c-met activation is the long non-coding RNA MEG3., Methods: Melanoma tissues were collected to measure MEG3 expression. In vitro validation was performed on MEG3 to prove its oncogenic roles. Bioinformatic analyses were conducted on the TCGA database to build the MEG3-related score. The immune characteristics and mutation features of the MEG3-related score were explored., Results: We revealed a negative correlation between HGF and MEG3. In melanoma cells, HGF inhibited MEG3 expression by augmenting the methylation of the MEG3 promoter. Significantly, MEG3 exhibits a suppressive impact on the proliferation and migration of melanoma cells, concurrently inhibiting c-met expression. Moreover, a predictive model centered around MEG3 demonstrates notable efficacy in forecasting critical prognostic indicators, immunological profiles, and mutation statuses among melanoma patients., Conclusions: The present study highlights the potential of MEG3 as a pivotal regulator of c-met, establishing it as a promising candidate for targeted drug development in the ongoing pursuit of effective therapeutic interventions., (© 2023 John Wiley & Sons, Ltd.)

Background: Our study aimed to analyze the characteristics of ultrasound images corresponding to each histological stage of primary biliary cholangitis (PBC)., Methods: We prospectively analyzed 75 confirmed cases of PBC and used liver biopsy as the gold standard to determine the disease stage., Results: The typical ultrasound images of patients with PBC were characterized by a thickening of the portal vein wall (PVW) and periportal hypoechoic band (PHB) width with increasing histological stages, and significant increases in the left hepatic lobe diameter (LHLD) in stage II (by 64.0%) and stage III (by 69.2%). PHB width (r = 0.857, p < 0.001), PVW thickness (r = 0.488, p < 0.001), and spleen area (r = 0.8774, p < 0.001) were positively correlated with the histological stage. Significant changes were noted in the liver surface, echo texture, and edge between different stages. The areas under the receiver operating characteristic curve of composite indicators were 0.965 for predicting progressive PBC(≥ stage 2), and 0.926 for predicting advanced PBC(≥ stage 3)., Conclusions: The ultrasound imaging characteristics of patients with PBC varied according to the histological staging. LHLD, PVW thickness, and PHB width were significantly correlated with the histological stage. A combination of high- and low-frequency ultrasound imaging can provide relevant cues regarding the degree of PBC progression and important clinical reference values. The application of all the ultrasound image findings as the composite indicators can better predict progressive and advanced PBC, providing important clinical reference values., (© 2023. The Author(s).)

The instability of palladium-based binary alloys hinders their wide application in the oxygen reduction processes. Here, we prepared Mo-doped PdCu nanoparticles with controllable dopant content and valence. Further research has revealed that Mo, particularly Mo 5+ , may effectively suppress the oxidation of Pd and Cu, optimize the oxygen binding of Pd, and increase catalytic activity and stability. In particular, Mo-PdCu-1/C with the highest Mo 5+ content shows the best oxygen reduction reaction (ORR) mass activity (1.20 A mg -1 Pd ), which is 4.8 times higher than that of PdCu/C. It also exhibits outstanding stability, retaining 80.8% of the original mass activity after 20 000 cycles. This study clearly explains the mechanism by which Mo doping affects the performance and provides a reference for further optimization of catalyst performance for fuel cell industrialization.

The activation of toll-like receptor 4 (TLR4) signaling is crucial for initiating and coordinating the immune response against infections, and is proved as a vital target for inflammatory diseases. Herein, TLR4 with sufficient amount and functional activity was generated by heterologous expression and used to investigate the mechanism of apigenin (Api)/chrysin (Chr) inhibition of TLR4 activation. The results demonstrated that Api/Chr exhibited a strong fluorescence quenching effect through a static quenching and a high binding affinity (K a > 10 5  L·mol -1 ) with TLR4, indicating the potential of Api/Chr as a TLR4 inhibitor. Additionally, the binding of Api/Chr induced a loose and unstable conformation of TLR4 with evidence like the decreased hydrophobicity of the tryptophan microenvironment, decreased α-helix content and increased free sulfhydryl content, resulting in reduced stability of the TLR4. The computer simulations revealed that Api/Chr occupied the myeloid differentiation factor 2 (MD-2) binding region, preventing MD-2 from binding to TLR4. Furthermore, the accuracy of the binding site between Api/Chr and TLR4 was confirmed through genetic mutations. Overall, the mechanism by which Api/Chr inhibited TLR4 activation was elucidated at the macroscopic and molecular levels, providing the worthful information concerning the future therapeutic application of Api/Chr as a natural TLR4 inhibitor., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2023. Published by Elsevier B.V.)

Aberrant DNA methylation is a critical regulator of gene expression in the development and progression of glioblastoma (GBM). However, the impact of methylation-driven gene PCDHB4 changes on GBM occurrence and progression remains unclear. Therefore, this study aimed to identify the PCDHB4 gene for early diagnosis and prognostic evaluation and clarify its functional role in GBM. Methylation-driven gene PCDHB4 was selected for GBM using the multi-omics integration method based on publicly available data sets. The diagnostic capabilities of PCDHB4 methylation and 5-hydroxymethylcytosines were validated in tissue and blood cell-free DNA (cfDNA) samples, respectively. Combined survival analysis of PCDHB4 methylation and immune infiltration cells evaluated the prognostic predictive performance of GBM patients. We identified that the PCDHB4 gene achieved high discriminative capabilities for GBM and normal tissues with an area under the curve value of 0.941. PCDHB4 hypermethylation was observed in cfDNA blood samples from GBM patients. Compared with GBM patients with PCDHB4 hypermethylation level, patients with PCDHB4 hypomethylation level had significantly poorer overall survival (p = 0.035). In addition, GBM patients with PCDHB4 hypermethylation and high infiltration of CD4 + T cell activation level had a favorable survival (p = 0.026). Moreover, we demonstrated that mRNA expression of PCDHB4 was downregulated in GBM tissues and upregulated in GBM cell lines with PCDHB4 demethylation, and PCDHB4 overexpression inhibited GBM cell proliferation and migration. In summary, we discovered a novel methylation-driven gene PCDHB4 for the diagnosis and prognosis of GBM and demonstrated that PCDHB4 is a tumor suppressor in vitro experiments., (© 2023 Wiley Periodicals LLC.)

iNKT cells are a type of T lymphocyte that recognizes glycolipid antigens presented by CD1d protein. αGC is an agonistic glycolipid that activates iNKT cells and triggers immune modulatory cytokine responses, making it a promising vaccine adjuvant. To find more potent immunostimulating glycolipids, we prepared 4,6- O -galactosyl conformationally restricted analogues of αGC. Mice vaccinated with the SARS-CoV-2 RBD-Fc vaccine adjuvanted with these newly developed glycolipids produced robust anti-RBD antibody responses, comparable to those achieved with αGC. Importantly, we also found that omitting αGC, α-C-GalCer (Th1-type agonist), or C20:2 (Th2-type agonist) from the booster vaccine had negligible impact on antibody and cellular responses, potentially reducing the frequency of adjuvant use required to maintain potent immune responses., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Atrial fibrillation (AF) is a very common type of cardiac arrhythmia. The main characteristic of AF is an abnormally rapid and disordered atrial rhythm causing an atrial dysfunction, which can be visualized on an electrocardiograph (ECG) and distinguished by irregular fluctuations. Despite continuous and considerable efforts to analyze the pathophysiology of AF, it is challenging to determine the underlying pathogenesis of the disease in individual patients. This study aims to build a bridge between ECG and electroencephalogram (EEG) signals to probe the strong influence between human brain activity and AF by AI methods. We first found that the one-second data fragment shows the most excellent performance in our time window configuration. Secondly, in our proposed measurement, most cortical potentials were partly associated with AF. Thirdly, we found that only a few channels of data were sufficient for analysis. Finally, our experiment shows δ wave has the best performance compared to other wave bands. By AI methods, the paper contributes to concluding that δ wave band of EEG is the most associated brain wave type with AF. By EEG signals from typical regions, the central region, parietal and Occipital might be the most associated encephalic regions with AF. The clinical trial registration number for our study is ChiCTR2300068625., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Different treatment methods have been developed for acute Achilles tendon rupture (ATR), including conservative treatment, minimally invasive or transdermal surgery, and open surgery, and there is no consensus about which method is superior. It is important to clarify the presence of Achilles tendon (AT) degeneration, the rupture site, and the rupture shape before surgery to determine whether minimally invasive or open surgery should be selected, thereby reducing the re-rupture rate following acute ATR. The aim of this study was to investigate the diagnostic value of MRI in identifying the presence of AT degeneration, the rupture site, and the rupture shape for acute closed ATR., Methods: From January 2016 to December 2019, patients with acute closed ATR who had undergone repair surgery were retrospectively enrolled. All patients received MRI examination, and the distance between the insertion site and broken end and the rupture shape (types I, II, and III) were independently determined by two observers. Then, the stump of the AT was exposed during the operation. The rupture site and rupture shape were recorded and compared and analyzed with the MRI results. Consistency analyses (using Cohen's kappa coefficient or intraclass correlation coefficient-ICC) and calculation of diagnostic performance indexes were, respectively, conducted to evaluate the diagnostic value of the MRI., Results: This study included 47 consecutive patients with acute ATR, with an average age of 38.4 years. Among them, 40 were male, and seven were female. The intraoperative exploration demonstrated a total of 34 (72.3%), 10 (21.3%), and three (6.4%) patients with type I, II, and III ruptures, respectively. The average distance between the insertion site and the proximal broken end measured intraoperatively was 4.07 ± 1.57 cm. High or excellent consistencies were found for ATR classifications (kappa: 0.739-0.770, p < 0.001) and rupture sites (ICC: 0.962-0.979, p < 0.001) between two observers and between observers 1 and 2 and intraoperative findings. Tendinopathy was identified in 22 patients by MRI and confirmed during surgery., Conclusions: MRI scanning of acute closed ATR can help determine whether there is degeneration of the AT, as well as the location and shape of the rupture, which can guide the selection of the optimal operation method for orthopedic surgeons. Therefore, it is necessary to take preoperative MRI scans for patients with acute Achilles tendon ruptures., (© 2023 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Objective: The outbreak of coronavirus disease (COVID-19) coincided with the season of influenza A pneumonia, a common respiratory infectious disease. Therefore, this study compared ultrasonography and computed tomography (CT) for the diagnosis of the two diseases., Methods: Patients with COVID-19 or influenza A infection hospitalized at our hospital were included. The patients were examined by ultrasonography every day. The CT examination results within 1 day before and after the day of the highest ultrasonography score were selected as the controls. The similarities and differences between the ultrasonography and CT results in the two groups were compared., Results: There was no difference between the ultrasonography and CT scores (P = .307) for COVID-19, while there was a difference between ultrasonography and CT scores for influenza A pneumonia (P = .024). The ultrasonography score for COVID-19 was higher than that for influenza A pneumonia (P = .000), but there was no difference between the CT scores (P = .830). For both diseases, there was no difference in ultrasonography and CT scores between the left and right lungs; there were differences between the CT scores of the upper and middle lobes, as well as between the upper and lower lobes of the lungs; however, there was no difference between the lower and middle lobes of the lungs., Conclusion: Ultrasonography is equivalent to the gold standard CT for diagnosing and monitoring the progression of COVID-19. Because of its convenience, ultrasonography has important application value. Furthermore, the diagnostic value of ultrasonography for COVID-19 is higher than that for influenza A pneumonia., (© 2023 American Institute of Ultrasound in Medicine.)