Publications by authors named "Yu Sun"

2,485 Publications

  • Page 1 of 1

Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes.

Cell Discov 2022 Jun 28;8(1):60. Epub 2022 Jun 28.

Department of Biochemistry and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301-600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases.
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http://dx.doi.org/10.1038/s41421-022-00426-xDOI Listing
June 2022

Metabolome analysis of genus Forsythia related constituents in Forsythia suspensa leaves and fruits using UPLC-ESI-QQQ-MS/MS technique.

PLoS One 2022 28;17(6):e0269915. Epub 2022 Jun 28.

Shijiazhuang Institute of Pomology, Hebei Academy of Agricultural and Forestry Sciences, Shijiazhuang, Hebei, China.

Forsythia suspensa is a traditional Chinese herb. Its numerous metabolites have important roles, as they possessed a wide range of biological activities. This study explored the accumulations of F. suspensa metabolites by performing widely targeted metabolomic analysis. The metabolites were studied at four stages of fruit development. Metabolites in the fruits and leaves of F. suspensa during fruit development included phenolic acids, flavonoids, lipids, lignans and coumarins, amino acids and their derivatives, terpenes, organic acids, nucleotides and their derivatives, alkaloids, quinones, steroids, and tannins. Fourteen Forsythia related metabolites were detected. Their contents varied among the developmental stages. Statistically significant correlations were found between the levels of forsythoside B and 11-methyl-forsythide, and forsythialan B and phillygenin, in both leaves and fruits. According to the correlation analysis between metabolites, Forsythia related metabolites were divided into two classes and five subclasses. In total, 33 compounds presented significant correlations in both fruits and leaves, which indicated the potential relationship in the synthesis of Forsythia related metabolites. Forsythialan B and phillygenin were both negatively correlated with L-valine, while Z-6,7-epoxyligustilid was positively correlated with both compounds. The quality control compounds forsythiaside A and phillyrin were positively and negatively correlated with uracil, respectively. These metabolomics results may facilitate the biosynthesis of Forsythia related metabolites.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0269915PLOS
June 2022

Comprehensive genetic testing improves the clinical diagnosis and medical management of pediatric patients with isolated hearing loss.

BMC Med Genomics 2022 Jun 27;15(1):142. Epub 2022 Jun 27.

Department of Otorhinolaryngology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Purpose: Genetic testing is widely used in diagnosing genetic hearing loss in patients. Other than providing genetic etiology, the benefits of genetic testing in pediatric patients with hearing loss are less investigated.

Methods: From 2018-2020, pediatric patients who initially presented isolated hearing loss were enrolled. Comprehensive genetic testing, including GJB2/SLC26A4 multiplex amplicon sequencing, STRC/OTOA copy number variation analysis, and exome sequencing, were hierarchically offered. Clinical follow-up and examinations were performed.

Results: A total of 80 pediatric patients who initially presented isolated hearing loss were considered as nonsyndromic hearing loss and enrolled in this study. The definitive diagnosis yield was 66% (53/80) and the likely diagnosis yield was 8% (6/80) through comprehensive genetic testing. With the aid of genetic testing and further clinical follow-up and examinations, the clinical diagnoses and medical management were altered in eleven patients (19%, 11/59); five were syndromic hearing loss; six were nonsyndromic hearing loss mimics.

Conclusion: Syndromic hearing loss and nonsyndromic hearing loss mimics are common in pediatric patients who initially present with isolated hearing loss. The comprehensive genetic testing provides not only a high diagnostic yield but also valuable information for clinicians to uncover subclinical or pre-symptomatic phenotypes, which allows early diagnosis of SHL, and leads to precise genetic counseling and changes the medical management.
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http://dx.doi.org/10.1186/s12920-022-01293-xDOI Listing
June 2022

The Significance of the Ocular Adverse Effect Induced by Systemic Taxane Application.

Front Biosci (Landmark Ed) 2022 May;27(6):171

Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, Shaanxi, China.

In recent years, in-depth research on anti-tumor therapy has brought the emergence of new active chemotherapeutic agents and combination regimens. However, as one of them, taxane drugs are widely used in clinical practice, but it should be noted that many side reactions caused by their application bring some difficulties to routine management. Among the side reactions related to taxane anti-tumor therapy, ocular adverse reactions are occasionally reported and are not life-threatening but may seriously affect patients' life quality. Thus, the continuation, reduction and cessation of taxane chemotherapy still need to be further evaluated by ophthalmologists and oncologists once the side effects show up. To prevent ocular side reactions, close attention should be paid to complications during medication. To facilitate the oncology department and ophthalmologists to comprehensively understand the ophthalmic adverse reactions of taxane drugs and their possible mechanisms and improve drug use efficiency, we collected relevant literature and reviewed and provided some suggestions for the monitoring and managing of ophthalmic toxicity.
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http://dx.doi.org/10.31083/j.fbl2706171DOI Listing
May 2022

Prevalence and Risk Factors of Surgical Treatment for Klippel-Feil Syndrome.

Front Surg 2022 7;9:885989. Epub 2022 Jun 7.

Key Laboratory of Spinal Disease Research, Department of Orthopedic Surgery, Peking University Third Hospital, Peking University, Beijing, China.

Background: Recently, there have been some reports on surgical treatment for Klippel-Feil syndrome, but the prevalence and risk factors of surgery have not been well evaluated. This study sought to find the prevalence and potential risk factors of surgical treatment.

Methods: A retrospective radiographic review of 718 Klippel-Feil syndrome patients seen at Peking University Third Hospital from January 2010 to October 2017 was performed. Parameters included age, gender, deformity, cervical instability, Samartzis classification, and surgical treatment. Based on the surgical treatment they received, patients were divided into a surgery group and a non-surgery group. Prevalence and possible risk factors of surgical treatment were assessed.

Results: A total of 718 Klippel-Feil syndrome patients, including 327 men and 391 women, with an average age of 46.8 years were enrolled. According to the Samartzis classification scheme, 621 cases (86.5%) were classified as type I, 48 cases (6.7%) were classified as type II, and 49 cases (6.8%) were classified as type III, respectively. The most commonly fused segments were C2-3 (54.9%) and C5-6 (9.3%). Of all 718 patients, 133 (18.5%) patients underwent surgical treatment, mainly via the posterior approach (69.9%). The clinical factors included age, gender, deformity, instability, and Samartzis classification. Men were more likely to require surgical treatment ( < 0.001). Patients with instability ( < 0.001) or patients with deformity ( = 0.004) were also more likely to undergo surgery. All three of these variables were included in the binary regression analysis. Finally, gender ( < 0.001) and unstable joints ( < 0.001) were identified to be independently associated with surgical treatment. Gender was the most important risk factor with men being 2.39 times more likely to have surgical treatment, while patients with instability were 2.31 times more likely to receive surgery.

Conclusion: The prevalence of patients with Klippel-Feil syndrome requiring surgery was 18.5%, with the majority undergoing posterior cervical surgery. Gender and instability were indemnified as independent risk factors leading to surgical treatment.
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http://dx.doi.org/10.3389/fsurg.2022.885989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209654PMC
June 2022

A Review on Basalt Fiber Composites and Their Applications in Clean Energy Sector and Power Grids.

Polymers (Basel) 2022 Jun 12;14(12). Epub 2022 Jun 12.

Hebei Key Laboratory of Distributed Energy Storage and Micro-Grid, North China Electric Power University, Yonghua North Street No. 619, Baoding 071003, China.

Basalt fiber (BF) has a high mechanical strength, excellent temperature resistance, good chemical stability, low energy consumption, and an environmentally friendly production process. In addition, BF-reinforced polymers (BFRPs) have good corrosion resistance and designability; thus, they meet the application requirements of electrical equipment, such as new conductors, insulating pull rods, and composite cross-arms. However, there are still a series of technical issues in the mass production of BF, and the stability of the products needs to be further improved. Therefore, the research on the production, modification, and application of BF is necessary. This paper discusses the chemical composition and production technology of BF, describes the morphology and properties of BF, summarizes the interface problems and modification methods of composites, and finally, introduces the application prospects of BF in the field of electrical materials, which is expected to provide a reference for the application and promotion of BFRP in the future.
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http://dx.doi.org/10.3390/polym14122376DOI Listing
June 2022

Recycling Non-Metallic Powder of Waste Printed Circuit Boards to Improve the Performance of Asphalt Material.

Materials (Basel) 2022 Jun 12;15(12). Epub 2022 Jun 12.

School of Materials Science and Engineering, Central South University, Changsha 410017, China.

Non-metallic fractions (NMFs) from waste printed circuit boards (PCBs) are mostly composed of cured resin and fiber. In this study, NMF material from a PCB was ground into powder and added into matrix asphalt to produce PCB-NMF-modified asphalt. To improve the compatibility of PCB-NMF and asphalt, a compatibilizer consisting of tung oil and glycerol was also developed. The optimum compatibilizer content was determined to be 8% by weight of the PCB-NMF through a series of laboratory tests, including the softening point, penetration, ductility, and softening point difference (SPD). The micro-mechanism of NMF powder-modified asphalt was analyzed through Fourier transform infrared spectroscopy (FTIR) and a scanning electron microscope test (SEM). The performances of PCB-NMF-modified asphalt were evaluated by the dynamic shear rheology (DSR) test and the low-temperature bending beam rheometer (BBR) test. The optimum compatibilizer content was 8% by weight of the NMF powder and the optimum content of NMF powder was determined to be 30% by weight of the asphalt based on a comprehensive evaluation. The results show that PCB-NMF can significantly improve stiffness, rutting resistance, high-temperature stability, and temperature sensitivity of asphalt material at an appropriate content. The BBR tests revealed that PCB-NMF slightly weakened the cracking resistance of asphalt at low temperatures. The SEM test showed that the addition of a compatibilizer can increase the compatibility by making the NMF powder evenly dispersed. The FTIR test results implied that a chemical reaction may not have happened between PCB-NMF, compatibilizer, and the matrix asphalt. Overall, it is a promising and sustainable way to utilize PCB-NMF as a modifier for asphalt material and reduce electronic waste treatment at a low cost.
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http://dx.doi.org/10.3390/ma15124172DOI Listing
June 2022

Predicting MGMT Promoter Methylation in Diffuse Gliomas Using Deep Learning with Radiomics.

J Clin Med 2022 Jun 15;11(12). Epub 2022 Jun 15.

Department of Radiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.

This study aimed to investigate the feasibility of predicting oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in diffuse gliomas by developing a deep learning approach using MRI radiomics. A total of 111 patients with diffuse gliomas participated in the retrospective study (56 patients with MGMT promoter methylation and 55 patients with MGMT promoter unmethylation). The radiomics features of the two regions of interest (ROI) (the whole tumor area and the tumor core area) for four sequences, including T1 weighted image (T1WI), T2 weighted image (T2WI), apparent diffusion coefficient (ADC) maps, and T1 contrast-enhanced (T1CE) MR images were extracted and jointly fed into the residual network. Then the deep learning method was developed and evaluated with a five-fold cross-validation, where in each fold, the dataset was randomly divided into training (80%) and validation (20%) cohorts. We compared the performance of all models using area under the curve (AUC) and average accuracy of validation cohorts and calculated the 10 most important features of the best model via a class activation map. Based on the ROI of the whole tumor, the predictive capacity of the T1CE and ADC model achieved the highest AUC value of 0.85. Based on the ROI of the tumor core, the T1CE and ADC model achieved the highest AUC value of 0.90. After comparison, the T1CE combined with the ADC model based on the ROI of the tumor core exhibited the best performance, with the highest average accuracy (0.91) and AUC (0.90) among all models. The deep learning method using MRI radiomics has excellent diagnostic performance with a high accuracy in predicting MGMT promoter methylation in diffuse gliomas.
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http://dx.doi.org/10.3390/jcm11123445DOI Listing
June 2022

The Reduction in Microtubule Arrays Caused by the Dysplasia of the Non-Centrosomal Microtubule-Organizing Center Leads to a Malformed Organ of Corti in the Cx26-Null Mouse.

Biomedicines 2022 Jun 9;10(6). Epub 2022 Jun 9.

Institute of Otorhinolaryngology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Mutations in the gene account for approximately 20-50% of all non-syndromic hereditary deafness cases. The malformed organ of Corti (OC) was observed in different Cx26-null mouse models, which was mainly caused by the developmental arrest of pillar cells (PCs). However, the mechanism of developmental abnormalities in PCs caused by Cx26 deletion is still unclear. In this study, the ultrastructure of PCs at different postnatal days was observed in Cx26-null mice. Knockout of cochlear Cx26 led to the malformed assembly of non-centrosomal microtubule-organizing centers (MTOCs) far from the centrosome rather than near the centrosome. Additionally, the microtubule (MT) arrays emitted by abnormal non-centrosomal MTOCs were significantly reduced. In addition, we found that the protein expression of calmodulin-regulated, spectrin-associated protein2 (camsap2), a microtubule minus-end targeting protein associated with the organization of non-centrosomal MTs, was decreased in juvenile PCs in the Cx26-null group. Our results indicated that the malformation of non-centrosomal MTOCs in cochlear PCs might lead to the corresponding MTs' failure to be captured and anchored in Cx26-null mice, which results in the deformity of OC. Additionally, this abnormal developmental process might be correlated with the reduced expression of camsap2 caused by Cx26 deletion in the early developmental stage.
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http://dx.doi.org/10.3390/biomedicines10061364DOI Listing
June 2022

Di-n-butyl phthalate negatively affects humic acid conversion and microbial enzymatic dynamics during composting.

J Hazard Mater 2022 08 6;436:129306. Epub 2022 Jun 6.

Technical Centre for Soil, Agriculture and Rural Ecology and Environment, Ministry of Ecology and Environment, Beijing 100012, China. Electronic address:

To understand the effects of phthalic acid esters (PAEs) on humic acid (HA) conversion, enzymatic and specific metabolic dynamics during composting under di-n-butyl phthalate (DBP) stress were evaluated for the first time. The results indicated that HA conversion was mainly related to bacteria rather than fungi, with positive associations with Actinobacteria, Chloroflexi, and Gemmatimonadota (all P < 0.05), and negative associations with Proteobacteria and Bacteroidota (all P < 0.05), while DBP stress retarded HA formation by altering the core microbes related to HA formation and their metabolic functions. Moreover, typical hydrolase and oxidoreductase activities were altered under DBP stress, proteases and cellulases were hindered, and peroxidases as well as polyphenol oxidases were promoted during composting. Overall, our data shows that DBP stress can retard HA formation and compost maturation by interfering with microbial activity. This study provides potentially useful information for the degradation and reuse of PAE-contaminated waste.
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http://dx.doi.org/10.1016/j.jhazmat.2022.129306DOI Listing
August 2022

Effects of a ketogenic diet in women with PCOS with different uric acid concentrations: a prospective cohort study.

Reprod Biomed Online 2022 Apr 2. Epub 2022 Apr 2.

Department of Obstetrics and Gynecology, Air Force Medical Center, PLA Beijing, China.

Research Question: Do overweight/obese women with PCOS with different uric acid concentrations show different effects after a ketogenic diet intervention?

Design: The study involved women with PCOS with a body mass index (BMI) of ≥24 kg/m. Groups showing different uric acid concentrations were given ketogenic diet guidance for 12 weeks. Weight, BMI, body fat percentage, fasting blood glucose, triacylglyerols, total cholesterol, uric acid and other metabolism-related indexes were measured.

Results: After 12 weeks of the ketogenic diet intervention, body weight (hyperuricaemia group: P=0.001; non-hyperuricaemia group: P<0.001), BMI (hyperuricaemia group: P = 0.025; non-hyperuricaemia group: P<0.001) and body fat percentage (hyperuricaemia group: P<0.001; non-hyperuricaemia group: P<0.001) were decreased in both groups. There was greater weight loss in the non-hyperuricaemia group (hyperuricaemia group 11.2±4.6 kg versus non-hyperuricaemia group 14.7±4.8 kg; P < 0.05). In the non-hyperuricaemia group, uric acid concentrations increased significantly after 6 weeks of the ketogenic diet intervention (week 0: 5.69±0.84 mg/dl versus week 6: 8.41 ± 2.33 mg/dl; P < 0.001) and reached the concentrations of the hyperuricaemia group (week 6: 9.37 ± 2.43 mg/dl; P > 0.05).

Conclusions: A ketogenic diet intervention is beneficial for overweight/obese women with PCOS with different serum uric acid concentrations. Participants with normal basal uric acid concentrations showed a greater fluctuation of serum uric acid concentrations during the ketogenic diet intervention and had a greater weight loss.
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http://dx.doi.org/10.1016/j.rbmo.2022.03.023DOI Listing
April 2022

Blocking TIGIT/CD155 signalling reverses CD8 T cell exhaustion and enhances the antitumor activity in cervical cancer.

J Transl Med 2022 Jun 21;20(1):280. Epub 2022 Jun 21.

Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Address: No.107, west culture road, Jinan, 250012, Shandong, China.

Objective: TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer.

Methods: The expression of CD155 and TIGIT in cervical cancer tissues was detected using flow cytometry, immunohistochemistry (IHC) and gene expression profiling. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8 T cells to produce cytokines. Changes in the NF-κB and ERK pathways were detected using western blotting (WB) after blocking TIGIT/CD155 signalling.

Results: TIGIT expression was elevated in patients with cervical cancer. High TIGIT expression in CD8 T lymphocytes from patients with cervical cancer promotes the exhaustion of CD8 T lymphocytes. In addition, CD155 is expressed at high levels in cervical cancer tissues and is negatively correlated with the level of infiltrating CD8 T cells. We found that TIGIT, upon binding to CD155 and being phosphorylated, inhibited NF-κB and ERK activation by recruiting SHIP-1, resulting in the downregulation of cytokine production. Blocking TIGIT in activated CD8 T cells attenuates the inhibitory effect of SHIP-1 on CD8 T cells and enhances the activation of NF-κB and ERK. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8 T cells to produce cytokines. Injecting the blocking antibody TIGIT in vivo inhibits tumour growth and enhances CD8 T lymphocyte function. Treatment with a combination of TIGIT and PD-1 inhibitors further increases the efficacy of the TIGIT blocking antibody.

Conclusions: Our research shows that TIGIT/CD155 is a potential therapeutic target for cervical cancer.
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http://dx.doi.org/10.1186/s12967-022-03480-xDOI Listing
June 2022

International student perceptions of online medical education during the COVID-19 epidemic.

Biochem Mol Biol Educ 2022 Jun 21. Epub 2022 Jun 21.

Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.

This study aimed to investigate how international students enrolled on medical and surgical bachelor's degree programs (MBBS) in China perceived online medical education course, compared to native Chinese students during the Covid-19 pandemic. The perceptions of 38 MBBS and 31 Chinese sophomores were surveyed using the Chaoxing platform. The international student group's mean satisfaction with online teaching was 2.737 on a 5-point scale, much lower than the Chinese students' mean score of 4.355 (p < 0.05). Similarly, the international students expressed less satisfaction than the Chinese learners with other aspects of the course, including the teacher's level, at 3.964 ± 0.818 versus 4.445 ± 0.548 (p < 0.05); curriculum organization, at 3.651 ± 0.848 versus 4.333 ± 0.568 (p < 0.05); and self-learning level, at 3.634 ± 0.996 versus 3.686 ± 0.949 (p > 0.05), respectively. There were also noteworthy differences between the progress made by the international students in Chinese language learning, which was positively correlated with satisfaction with teaching on the online medical education (p < 0.05). The results suggest that, while online teaching was a necessary response to the Covid-19 pandemic, satisfaction with this mode of education is lower among international students than their Chinese counterparts.
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http://dx.doi.org/10.1002/bmb.21641DOI Listing
June 2022

Epigoitrin alleviates lipid and glucose metabolic disorders induced by a high-fat diet.

Food Funct 2022 Jun 20. Epub 2022 Jun 20.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning 530004, P.R. China.

As living standards improve, obesity has become an increasingly serious health problem. Natural extracts from a wide range of sources are non-toxic and have significant potential as drugs for the prevention and treatment of obesity. We assessed 243 natural small molecules in a HepG2 fat accumulation model and found that epigoitrin (EP) from reduced intracellular fat deposition, increased short-chain acyl CoA dehydrogenase (SCAD) activity, promoted glucose uptake and glycogen storage, increased ATP production and reduced glutathione (GSH) content, reduced reactive oxygen species (ROS), and enhanced superoxide dismutase (SOD) activity. In a murine high-fat diet model, the addition of EP to the high-fat diet significantly reduced fat deposition, increased glucose tolerance, improved insulin sensitivity, and increased energy expenditure. In conclusion, EP alleviated obesity caused by a high-fat diet and improved disorders of lipid and glucose metabolism.
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http://dx.doi.org/10.1039/d2fo00242fDOI Listing
June 2022

Fluoride-coated high-purity magnesium cage promotes bone fusion in goat models.

Ann Transl Med 2022 May;10(10):537

Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Background: Cervical fusion devices made by polyether ether ketone (PEEK) cause concomitant effects which decompress the spinal cord and nerve roots. Magnesium has good biocompatibility and bioactivity as a biodegradable orthopedic implant material; however, its fusion rate is low. In this paper, we aimed to improve interbody fusion rate of high-purity magnesium (HP-Mg) by coating it with fluoride.

Methods: Fluoride-coated HP-Mg (F-HP-Mg) cages were prepared, and HP-Mg cages served as controls. We tested hydrogen release in phosphate-buffered saline (PBS) and weight loss in chromic acid. Anterior cervical discectomy and bone graft fusion (ACDF) was performed at the C2-C3 segment on goats with F-HP-Mg and HP-Mg cages to evaluate fusion score.

Results: Hydrogen release of F-HP-Mg cages was significantly lower than that of HP-Mg cages. Weight was significantly decreased in both types of cages after rinsing with chromic acid, while F-HP-Mg cages were more resistant to corrosion compared to HP-Mg cages. There were no significant differences in disc space height (DSH) and remaining cage volume between the two groups in computed tomography (CT) images of goat cervical spine, while cavities were found at postoperative 12 weeks and confirmed by histological staining. No complications were found, while serum aspartate aminotransaminase (AST) level was significantly higher in the HP-Mg group compared to the F-HP-Mg group. Fusion rate at 24 weeks after ACDF was significantly higher with F-HP-Mg cages.

Conclusions: The use of F-HP-Mg improved histological fusion in the cervical intervertebral space of goats compared to HP-Mg and showed good biosafety.
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http://dx.doi.org/10.21037/atm-22-2098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201168PMC
May 2022

Cryopreservation of porcine skin-derived stem cells using melatonin or trehalose maintains their ability to self-renew and differentiate.

Cryobiology 2022 Jun 16. Epub 2022 Jun 16.

College of Life Sciences, Institute of Reproductive Sciences, Qingdao Agricultural University, Qingdao, 266109, China. Electronic address:

Porcine skin-derived stem cells (pSDSCs) are a type of adult stem cells (ASCs) that retain the ability to self-renew and differentiate. Currently, pSDSCs research has entered an intense period of development; however there has been no research regarding methods of cryopreservation. In this paper, we explored an efficient cryopreservation method for pSDSCs. Our results demonstrated that cryopreserving 50 μm diameter pSDSCs aggregates resulted in a lower apoptosis rate and a greater ability to proliferate to form larger spherical cell aggregates than during single-cell cryopreservation. To further optimize the cryopreservation method, we added different concentrations of melatonin (N-acetyl-5-methoxytryptamine, MLT) and trehalose (d-trehalose anhydrous, TRE) to act as cryoprotectants (CPAs) for the pSDSCs. After comparative experiments, we found that the cryopreservation efficiency of 50 mM TRE was superior. Further experiments demonstrated that the reason why 50 mM TRE improved cryopreservation efficiency was that it reduced the intracellular oxidative stress and mitochondrial damage caused by cryopreservation. Taken together, our results suggest that cryopreserving 50 μm diameter pSDSCs aggregates in F12 medium with 10% dimethyl sulfoxide (DMSO) and 50 mM TRE promotes the long-term storage of pSDSCs.
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http://dx.doi.org/10.1016/j.cryobiol.2022.06.002DOI Listing
June 2022

A Carbon-Based Biosensing Platform for Simultaneously Measuring the Contraction and Electrophysiology of iPSC-Cardiomyocyte Monolayers.

ACS Nano 2022 Jun 17. Epub 2022 Jun 17.

Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario M5S 3G8, Canada.

Heart beating is triggered by the generation and propagation of action potentials through the myocardium, resulting in the synchronous contraction of cardiomyocytes. This process highlights the importance of electrical and mechanical coordination in organ function. Investigating the pathogenesis of heart diseases and potential therapeutic actions requires biosensing technologies which allow for long-term and simultaneous measurement of the contractility and electrophysiology of cardiomyocytes. However, the adoption of current biosensing approaches for functional measurement of cardiac models is hampered by low sensitivity, difficulties in achieving multifunctional detection, and costly manufacturing processes. Leveraging carbon-based nanomaterials, we developed a biosensing platform that is capable of performing on-chip and simultaneous measurement of contractility and electrophysiology of human induced pluripotent stem-cell-derived cardiomyocyte (iPSC-CM) monolayers. This platform integrates with a flexible thin-film cantilever embedded with a carbon black (CB)-PDMS strain sensor for high-sensitivity contraction measurement and four pure carbon nanotube (CNT) electrodes for the detection of extracellular field potentials with low electrode impedance. Cardiac functional properties including contractile stress, beating rate, beating rhythm, and extracellular field potential were evaluated to quantify iPSC-CM responses to common cardiotropic agents. In addition, an model of drug-induced cardiac arrhythmia was established to further validate the platform for disease modeling and drug testing.
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http://dx.doi.org/10.1021/acsnano.2c04676DOI Listing
June 2022

SLC25A47 is a novel determinant of hepatic mitochondrial function implicated in liver fibrosis.

J Hepatol 2022 Jun 14. Epub 2022 Jun 14.

Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. Electronic address:

Background & Aims: Transporters of the SLC25 mitochondrial carrier superfamily bridge cytoplasmic and mitochondrial metabolism by channeling metabolites across mitochondrial membranes and are pivotal for metabolic homeostasis. Despite their physiological relevance as gatekeepers of cellular metabolism, most of the SLC25 family members remain uncharacterized. We undertook a comprehensive tissue distribution analysis of all Slc25 family members across metabolic organs and identified SLC25A47 as a liver-specific mitochondrial carrier.

Method: We used a murine loss-of-function model to unravel the role of this transporter in mitochondrial and hepatic homeostasis. We performed extensive metabolic phenotyping and molecular characterization of newly generated Slc25a47 and Slc25a47-Fgf21 mice.

Results: Slc25a47 mice displayed a wide variety of metabolic abnormalities, as a result of sustained energy deficiency in the liver originating from impaired mitochondrial respiration in this organ. This mitochondrial phenotype was associated with an activation of the mitochondrial stress response (MSR) in the liver, and the development of fibrosis, which was exacerbated upon feeding a high-fat high-sucrose diet. The MSR induced the secretion of several mitokines, amongst which FGF21 played a preponderant role on systemic physiology. To dissect the FGF21-dependent and -independent physiological changes induced in Slc25a47 mice, we generated a double Slc25a47-Fgf21 mouse model and demonstrated that several aspects of the hypermetabolic state were driven by hepatic secretion of FGF21. On the other hand, the metabolic fuel inflexibility observed in Slc25a47 mice could not be rescued with the genetic removal of Fgf21.

Conclusion: Collectively, our data place SLC25A47 at the center of mitochondrial homeostasis, which upon dysfunction triggers robust liver-specific and systemic adaptive stress responses. The prominent role of SLC25A47 in hepatic fibrosis identifies this carrier, or its transported metabolite, as a potential target for therapeutic intervention.

Lay Summary: SLC25A47 is a liver-specific mitochondrial carrier. Slc25a47 mice are unable to maintain mitochondrial homeostasis in hepatocytes and show impaired mitochondrial respiration resulting in chronic energy deficiency, mitochondrial stress, and fibrosis in hepatocytes. Hepatic mitochondrial stress is characterized by the secretion of the mitokine FGF21 which drives a strong and systemic hypermetabolic state impacting whole-body physiology.
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http://dx.doi.org/10.1016/j.jhep.2022.05.040DOI Listing
June 2022

Bionic Microbubble Neutrophil Composite for Inflammation-Responsive Atherosclerotic Vulnerable Plaque Pluripotent Intervention.

Research (Wash D C) 2022 3;2022:9830627. Epub 2022 Jun 3.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.

Rupture or erosion of inflammatory atherosclerotic vulnerable plaque is essential to acute coronary events, while the target intervene of vulnerable plaque is very challenging, due to the relatively small volume, high hemodynamic shear stress, and multifactorial nature of the lesion foci. Herein, we utilize the biological functionality of neutrophil and the versatility of microbubble in the acoustic field, to form Neu-balloon through CD11b antibody binding. The Neu-balloon inherits the advantage of neutrophils on firming the endothelium adhesion even at shear stress up to 16 dyne/cm and also maintains the acoustic enhancement property from the microbubble, to accumulate at atherosclerotic lesions under acoustic in an atherosclerotic Apo E mice model. Interestingly, Neo-balloon also has high and broad drug loading capacity, which enables the delivery of indocyanine green and miR-126a-5p into vulnerable plagues . Overall, the bionic Neu-balloon holds great potential to boost on-demand drug transportation into plaques .
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http://dx.doi.org/10.34133/2022/9830627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188677PMC
June 2022

Intestinal stem cell aging signature reveals a reprogramming strategy to enhance regenerative potential.

NPJ Regen Med 2022 Jun 16;7(1):31. Epub 2022 Jun 16.

Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.

The impact of aging on intestinal stem cells (ISCs) has not been fully elucidated. In this study, we identified widespread epigenetic and transcriptional alterations in old ISCs. Using a reprogramming algorithm, we identified a set of key transcription factors (Egr1, Irf1, FosB) that drives molecular and functional differences between old and young states. Overall, by dissecting the molecular signature of aged ISCs, our study identified transcription factors that enhance the regenerative capacity of ISCs.
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http://dx.doi.org/10.1038/s41536-022-00226-7DOI Listing
June 2022

JAML promotes acute kidney injury mainly through a macrophage-dependent mechanism.

JCI Insight 2022 Jun 16. Epub 2022 Jun 16.

Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.

Although macrophages are undoubtedly attractive therapeutic targets for acute kidney injury (AKI) because of their critical roles in renal inflammation and repair, the underlying mechanisms of macrophage phenotype switching and efferocytosis in the regulation of inflammatory responses during AKI are still largely unclear. The present study was to elucidate the role of JAML (junctional adhesion molecule-like protein) in the pathogenesis of AKI. We found that JAML was significantly up-regulated in the kidney from two different murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI. By generation of bone marrow chimeric mice, macrophage-specific and tubular-specific Jaml conditional knockout mice, we demonstrated JAML promotes AKI mainly via a macrophage-dependent mechanism and found that JAML-mediated macrophage phenotype polarization and efferocytosis is one of critical signal transduction pathways linking inflammatory responses to AKI. Mechanistically, the effects of JAML on the regulation of macrophages was at least in part, associated with a Mincle-dependent mechanism. Collectively, our studies for the first time explore new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacologic targeting of JAML mediated signaling pathways at multiple levels may provide a novel therapeutic strategy for patients with AKI.
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http://dx.doi.org/10.1172/jci.insight.158571DOI Listing
June 2022

Differential OAT methylation correlates with cell infiltration in tumor microenvironment and overall survival post-radiotherapy in oral squamous cell carcinoma patient.

J Oral Pathol Med 2022 Jun 16. Epub 2022 Jun 16.

State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Background: Given that DNA methylation and tumor microenvironment (TME) are susceptible to radiotherapy, we aimed to figure out specific differential DNA methylation to reflect oral squamous cell carcinoma (OSCC) prognosis and associated effect on TME changes post-radiotherapy, performing as an efficient biomarker.

Materials And Methods: Differentially methylation analysis was performed using data from TCGA. Curves of Kaplan Meier (K-M) survival, cumulative hazard and events, Cox proportional hazards and Linear regression model were conducted to screen and validate differential methylation genes, while multiple regression equation to analyze if ornithine aminotransferase (OAT) methylation correlates with radiotherapy. For correlation between OAT methylation and immune infiltrates, CIBERSORT and ESTIMATE algorithms were performed, following GSEA and ssGSEA analysis to evaluate biological process.

Results: Compared to normal tissues, only OAT in OSCC was differential significantly by K-M analysis (p = 0.0364). OAT hypermethylation was associated with increased overall survival (HR: 0.65, p = 0.0358). Radiotherapy correlated with OAT methylation (β = -0.01, p = 0.0061); most patients with OAT hypermethylation were radiation-sensitive. Hypomethylated OAT correlated with higher cell infiltrations in TME. Neuroactive ligand-receptor interaction was most significantly related to OAT methylation (p = 9.2e-10). Sulfur metabolism was the most significantly in OAT hypermethylation group (p = 0.0041) and RIG-I-like receptor in OAT hypomethylation group (p = 0.0094).

Conclusion: OAT methylation can serve as a predictor of OSCC prognosis post-radiotherapy with potential mechanism by changing cell infiltrations in TME, but further experimental study deserves to carry out confirming the role and mechanism of OAT methylation in OSCC. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jop.13328DOI Listing
June 2022

The protective effects of systemic dexamethasone on sensory epithelial damage and hearing loss in targeted Cx26-null mice.

Cell Death Dis 2022 Jun 10;13(6):545. Epub 2022 Jun 10.

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Mutations in the GJB2 gene (encoding Connexin26(Cx26)) are the most common cause of hereditary deafness, accounting for about a quarter of all cases. Sensory epithelial damage is considered to be one of the main causes of deafness caused by GJB2 gene mutation. Dexamethasone (DEX) is widely used in the treatment of a variety of inner ear diseases including sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), and deafness caused by ototoxic drugs. Whether DEX has a direct therapeutic effect on hereditary deafness, especially GJB2-related deafness, remains unclear. In this study, we revealed that DEX can effectively prevent hair cell death caused by oxidative stress in cochlear explants. Additionally, two distinct Cx26-null mouse models were established to investigate whether systemic administration of DEX alleviate the cochlear sensory epithelial injury or deafness in these models. In a specific longitudinally Cx26-null model that does not cause deafness, systemic administration of DEX prevents the degeneration of outer hair cells (OHCs) induced by Cx26 knockout. Similarly, in a targeted-Deiter's cells (DCs) Cx26-null mouse model that causes deafness, treatment with DEX can almost completely prevent OHCs loss and alleviates auditory threshold shifts at some frequencies. Additionally, we observed that DEX inhibited the recruitment of CD45-positive cells in the targeted-DCs Cx26-null mice. Taken together, our results suggest that the protective effect of dexamethasone on cochlear sensory epithelial damage and partially rescue auditory function may be related to the regulation of inner ear immune response in Cx26 deficiency mouse models.
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http://dx.doi.org/10.1038/s41419-022-04987-3DOI Listing
June 2022

Intrinsic phase-amplitude coupling on multiple spatial scales during the loss and recovery of consciousness.

Comput Biol Med 2022 Jun 3;147:105687. Epub 2022 Jun 3.

College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310027, China. Electronic address:

Background: Recent studies have demonstrated that changes in brain information processing during anesthetic-induced loss of consciousness (LOC) might be influenced by phase-amplitude coupling (PAC) in electroencephalogram (EEG). However, most anesthesia research on PAC typically focuses on delta and alpha oscillations. Studies of spatial-frequency characteristics by PAC for EEG may yield additional insights into understanding the impaired information processing under anesthesia unconsciousness and provide potential improvements in anesthesia monitoring.

Objective: Considering different frequency bands of EEG represent neural activities on different spatial scales, we hypothesized that functional coupling simultaneously appears in multiple frequency bands and specific brain regions during anesthesia unconsciousness. In this paper, PAC analysis on whole-brain EEG besides delta and alpha oscillations was investigated to understand the influence of multiple cross-frequency coordination coupling on information processing during the loss and recovery of consciousness.

Method: EEG data from fifteen patients without cognitive diseases (7 males/8 females, aged 43.8 ± 13.4 years, weighing 63.3 ± 14.9 kilograms) undergoing lower limb surgery and sevoflurane anesthesia was recorded. To investigate the spatial-frequency characteristics of EEG source signals during loss and recovery of consciousness, the time-resolved PAC (tPAC) was calculated to reflect cross-frequency coordination in different frequency bands (delta, theta, alpha, beta, gamma) and different functional regions (Visual, Limbic, Dorsal attention, Ventral attention, Default, Somatomotor, Control, Salience networks). Furthermore, different patterns (peak-max and trough-max) of PAC were examined by constructing phase-amplitude histograms using phase bins to investigate the different information processing during LOC. The multivariate analysis of variance (MANOVA) and trend analysis were used for statistical analysis.

Results: Theta-alpha and alpha-beta PAC were observed during sevoflurane-induced LOC, which significantly changed during loss and recovery of consciousness (F = 16.553, p < 0.001 for theta-alpha PAC and F = 12.446, p < 0.001 for alpha-beta PAC, MANOVA test). Simultaneously, PAC was distributed in specific functional regions, i.e., Visual, Limbic, Default, Somatomotor, etc. Furthermore, peak-max patterns of theta-alpha PAC were observed while alpha-beta PAC showed trough-max patterns and vice versa.

Conclusion: Theta-alpha and alpha-beta PAC observed in specific brain regions represent information processing on multiple spatial scales, and the opposite patterns of PAC indicate opposite information processing on multiple spatial scales during LOC. Our study demonstrates the regulation of local-global information processing during sevoflurane-induced LOC. It suggests the utility of evaluating the balance of functional integration and segregation in monitoring anesthetized states.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105687DOI Listing
June 2022

Recent Progress in Smart Polymeric Gel-based Information Storage for Anti-counterfeiting.

Adv Mater 2022 Jun 9:e2201262. Epub 2022 Jun 9.

Key Laboratory of Marine Materials and Related Technologies, Zhejiang Key Laboratory of Marine Materials and Protective Technologies, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, 315201, China.

Information security protection has a tremendous impact on human life, social stability, and national security, leading to the rapid development of anti-counterfeiting materials and related techniques. However, the traditional stored information on hard or dry media is often static and lacks functions, which makes it challenging to deal with increasing and powerful counterfeiting technologies. Modified intelligent polymeric gels exhibit color changes and shape morphing under external stimuli, which give them great potential for applications in information storage. This paper provides an overview of the latest progress in polymeric gel-based information storage materials in relation to counterfeiting. Following a brief introduction of anti-counterfeiting materials, the preparation methods for intelligent gels with adjustable colors (e.g., chemical colors and physical colors) and various encryption/decryption modes involving dimensions and diverse colors are outlined. Finally, the challenges and prospects for information storage and anti-counterfeiting based on smart gels are discussed. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/adma.202201262DOI Listing
June 2022

Lightweight-Convolutional Neural Network for Apple Leaf Disease Identification.

Front Plant Sci 2022 24;13:831219. Epub 2022 May 24.

College of Information Technology, Jilin Agricultural University, Changchun, China.

As a widely consumed fruit worldwide, it is extremely important to prevent and control disease in apple trees. In this research, we designed convolutional neural networks (CNNs) for five diseases that affect apple tree leaves based on the AlexNet model. First, the coarse-grained features of the disease are extracted in the model using dilated convolution, which helps to maintain a large receptive field while reducing the number of parameters. The parallel convolution module is added to extract leaf disease features at multiple scales. Subsequently, the series 3 × 3 convolutions shortcut connection allows the model to deal with additional nonlinearities. Further, the attention mechanism is added to all aggregated output modules to better fit channel features and reduce the impact of a complex background on the model performance. Finally, the two fully connected layers are replaced by global pooling to reduce the number of model parameters, to ensure that the features are not lost. The final recognition accuracy of the model is 97.36%, and the size of the model is 5.87 MB. In comparison with five other models, our model design is reasonable and has good robustness; further, the results show that the proposed model is lightweight and can identify apple leaf diseases with high accuracy.
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http://dx.doi.org/10.3389/fpls.2022.831219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171387PMC
May 2022

Comparison of the Characteristics and Outcomes of COVID-19 Patients Treated by a Hospital-at-Home Service in Japan during the Alpha and Delta Waves.

J Clin Med 2022 Jun 2;11(11). Epub 2022 Jun 2.

Department of Health Services Research, Faculty of Medicine, University of Tsukuba, 1-1-1 Tenno-dai, Tsukuba 305-8577, Ibaraki, Japan.

Coronavirus infections occurred in repeated waves caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with the number of patients increasing during each wave. A private after-hours house-call (AHHC) service provides hospital-at-home (HaH) services to patients in Japan requiring oxygen when hospital beds are in short supply. This retrospective study aimed to compare the characteristics of COVID-19 patients treated by the AHHC service during the COVID-19 waves caused by the Alpha (March-June 2021) and Delta (July-December 2021) SARS-CoV-2 variants. All patients with COVID-19 treated by the AHHC service from March to December 2021 while awaiting hospitalization were included. The data were collected from medical records and follow-up telephone interviews. The AHHC service treated 55 and 273 COVID-19 patients during the Alpha and Delta waves, respectively. The patients treated during the Delta wave were significantly younger than those treated during the Alpha wave (median: 63 years and 47 years, respectively; < 0.001). Disease severity did not differ significantly between the two waves, but the crude case-fatality rate was significantly higher during the Alpha wave (10/55, 18.2%) than during the Delta wave (4/273, 1.4%; < 0.001). The patient characteristics and outcomes differed between the Alpha and Delta waves.
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http://dx.doi.org/10.3390/jcm11113185DOI Listing
June 2022

: A Comprehensive Review of its Botany, Phytochemistry, Pharmacology and Clinical Application.

Am J Chin Med 2022 Jun 8:1-35. Epub 2022 Jun 8.

School of Pharmacy, Shaanxi University of Chinese Medicine, Xian Yang, Shaanxi 712046, P. R. China.

is the dry stem of (Thunb.) Rehd et Wils. () and (Thunb.) Rehd. et Wils. var. Rehd. et Wils and is mainly distributed in China and Japan. As a traditional Chinese medicine (TCM) for dispelling wind and dampness in China, it is widely distributed and has a long history of drug use. In recent years, with the increase of the incidence of rheumatoid disease, has become the focus of research. This paper reviews the literature on the chemical constituents, pharmacological effects, clinical applications and pharmacokinetics and safety of from the past 60 years. At present, more than 210 natural compounds have been isolated from , including alkaloids, lignans, triterpenoid saponins, steroids, and other structures. Pharmacological activities of were mainly reported on anti-inflammatory, analgesic, anti-allergic, immunosuppressive, anti-tumor, liver-protective, anti-oxidative, and other effects, and clinical applications were mainly recorded on rheumatoid arthritis, ankylosing spondylitis, and other diseases. The clinical use of SIN has fewer side effects and more safety; only a small number of gastrointestinal reactions occurred, and the symptoms disappeared after the drug stopped. The purpose of this paper is to lay a foundation and provide reference for the follow-up research and wide application of .
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http://dx.doi.org/10.1142/S0192415X22500501DOI Listing
June 2022

Real-time biomechanical modelling of the liver using LightGBM model.

Int J Med Robot 2022 Jun 9:e2433. Epub 2022 Jun 9.

State Key Laboratory of Robotics and System, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.

Background: Accurate and real-time biomechanical modelling of the liver is a major challenge in computer-assisted surgery. Finite element method is often used to predict the deformation of organs for its high modelling accuracy. However, its high computation cost hinders its application in real time, such as virtual surgery simulations.

Method: A liver model with biomechanical properties similar to real one is created using finite element method and a data set of the liver deformation with different forces (whose magnitude ranges from 0.1 to 0.5 N in omni-direction) acting on different surface points is generated. The mechanical behaviour of liver is simulated in real time by a tree-based LightGBM regression model trained with the generated data set.

Results: In comparison with the Random Forest and XGBoost, the LightGBM model achieves the best accuracy with 0.0774 mm, 0.0786 mm, 0.0801 mm in the mean absolute error (MAE) and 0.0591 mm, 0.0609 and 0.0622 mm in the root mean square error (RMSE) along x, y and z axis, respectively. In addition, it only takes 33 ms for the LightGBM model to estimate the deformation of the liver, which is much faster than finite element model (29.91 s).

Conclusion: These results lay a foundation for the future development of real-time virtual surgery systems of simulating liver deformation during minimally invasive surgeries using our method.
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http://dx.doi.org/10.1002/rcs.2433DOI Listing
June 2022

The Impact of T cell Immunity on Chemotherapy Response in Childhood Acute Lymphoblastic Leukemia.

Blood 2022 Jun 8. Epub 2022 Jun 8.

St. Jude Children's Research Hospital, Memphis, Tennessee, United States.

Although acute lymphoblastic leukemia (ALL) is highly responsive to chemotherapy, it is unknown how and which host immune factors influence the long-term remission of this cancer. To this end, we systematically evaluated the effects of T cell immunity on Ph+ ALL therapy outcomes. Using a murine Arf-/-BCR-ABL1 B-ALL model, we showed that loss of T cells in the host drastically increased leukemia relapse following dasatinib or cytotoxic chemotherapy. Although ABL1 mutations emerged early during dasatinib treatment in both immunocompetent and immunocompromised hosts, T cell immunity was essential for suppressing the outgrowth of drug-resistant leukemia. Bulk and single-cell transcriptome profiling of T cells during therapy pointed to the activation Type I immunity-related cytokine signaling linked to long-term leukemia remission in mice. Consistent with these observations, IFNG and IL12 directly modulated dasatinib anti-leukemia efficacy in vivo. Finally, we evaluated peripheral blood immune cell composition in 102 children with ALL during chemotherapy and observed a significant association of T cell abundance with treatment outcomes. Together, these results suggest that T cell immunity plays pivotal roles in maintaining long-term remission of ALL, highlighting that the interplay between host immunity and drug resistance can be harnessed to improve ALL chemotherapy outcomes.
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http://dx.doi.org/10.1182/blood.2021014495DOI Listing
June 2022
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