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Thrombospondin-4 (TSP-4) belongs to the extracellular matrix glycoprotein family of thrombospondins (TSPs). The multidomain, pentameric structure of TSP-4 allows its interactions with numerous extracellular matrix components, proteins and signaling molecules that enable its modulation to various physiological and pathological processes. Characterization of TSP-4 expression under development and pathogenesis of disorders has yielded important insights into mechanisms underlying the unique role of TSP-4 in mediating various processes including cell-cell, cell-extracellular matrix interactions, cell migration, proliferation, tissue remodeling, angiogenesis, and synaptogenesis. Maladaptation of these processes in response to pathological insults and stress can accelerate the development of disorders including skeletal dysplasia, osteoporosis, degenerative joint disease, cardiovascular diseases, tumor progression/metastasis and neurological disorders. Overall, the diverse functions of TSP-4 suggest that it may be a potential marker or therapeutic target for prognosis, diagnosis, and treatment of various pathological conditions upon further investigations. This review article highlights recent findings on the role of TSP-4 in both physiological and pathological conditions with a focus on what sets it apart from other TSPs.

Weiqing Zhang,1,&ast; Zengze Yuan,1,&ast; Yihan Wang,1 Zhaokai Jin,2 Ziyue Luo,1 Xinchang Wang1 1The Second Affiliated Hospital of Zhejiang Chinese Medical University (Xinhua Hospital of Zhejiang Province), Hangzhou, Zhejiang, People’s Republic of China; 2The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinchang Wang, Email ossani@126.comPurpose: Life’s Essentials 8 (LE8) is a new indicator developed by the American Heart Association to assess cardiovascular health, including diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose and blood pressure. And more and more studies have shown that this index can evaluate other diseases, such as chronic kidney disease, abdominal aortic calcification and so on. However, there is no relevant study to evaluate the association between LE8 and psoriasis. The purpose of this study was to investigate the relationship between LE8 and the prevalence of psoriasis in American adults.Patients and Methods: The data are from the National Health and Nutrition Examination Survey (NHANES) of the United States from 2003 to 2006, 2009 to 2014. Psoriasis was the dependent variable. LE8 is an independent variable and is divided into three levels: high, medium and low. Multivariate logistic regression model was used to explore the relationship between LE8 and psoriasis.Results: A total of 13430 people were included in this study, including 391 patients with psoriasis and 13039 patients without psoriasis. The prevalence of psoriasis was 2.91%. In the fully adjusted logistic regression model, LE8 score was negatively correlated with psoriasis (OR=0.99; 95% CI, 0.98– 0.99, P=0.0003). And this result still exists when LE8 is divided into high, medium and low groups. Compared with the low LE8 group, the high LE8 group had a 61% lower risk of psoriasis (OR=0.39; 95% CI, 0.26– 0.57, p < 0.0001).Conclusion: This cross-sectional study suggested that LE8 score was negatively correlated with psoriasis risk.Keywords: Life’s Essentials 8, NHANES, Cross-sectional study, Psoriasis

Jian Gao,1 Jiannan Li,2 Zengyou Luo,1 Hongyong Wang,3 Zhiming Ma1 1Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 3Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Zhiming Ma, Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China, Email mazhiming@jlu.edu.cnAbstract: Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory condition characterized by recurring inflammation of the intestinal mucosa. However, the existing IBD treatments are ineffective and have serious side effects. The etiology of IBD is multifactorial and encompasses immune, genetic, environmental, dietary, and microbial factors. The nanoparticles (NPs) developed based on specific targeting methodologies exhibit great potential as nanotechnology advances. Nanoparticles are defined as particles between 1 and 100 nm in size. Depending on their size and surface functionality, NPs exhibit different properties. A variety of nanoparticle types have been employed as drug carriers for the treatment of inflammatory bowel disease (IBD), with encouraging outcomes observed in experimental models. They increase the bioavailability of drugs and enable targeted drug delivery, promoting localized treatment and thus enhancing efficacy. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines.Keywords: nanoparticles, inflammatory bowel diseases, targeted delivery, passive targeting, active targeting, drug delivery system

Jie Cheng,1,&ast; Ya Liu,2,&ast; Guangli Zhang,3 Liping Tan,1 Zhengxiu Luo3 1Department of Emergency, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Big Data Engineering Center, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, People’s Republic of China; 2Department of Pediatrics, Chongqing Youyoubaobei Women and Children’s Hospital, Chongqing, 401147, People’s Republic of China; 3Department of Respiratory Medicine, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Big Data Engineering Center, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengxiu Luo, Email luozhengxiu816@hospital.cqmu.edu.cnObjective: Mycoplasma pneumoniae (MP) is highly resistant to macrolides in China. However, macrolides still exhibit clinical effectiveness in some macrolide-resistant patients. We tend to explore azithromycin effectiveness in Mycoplasma pneumoniae pneumonia (MPP) children with A2063/2064G mutation.Methods: This retrospective observational cohort study was conducted at the Children’s Hospital of the Chongqing Medical University. Children with macrolide-resistant mutations (A2063/2064G) diagnosed as MPP were retrospectively enrolled. Receiver operating characteristic (ROC) curves and logistic regression analysis were used to evaluate and identify independent risk factors for treatment failure (progress to refractory Mycoplasma pneumoniae pneumonia [RMPP]) in macrolide-unresponsive Mycoplasma pneumoniae pneumonia (MUMPP) children with the A2063/2064G mutation.Results: One hundred fifty-five children were retrospectively enrolled. More than 20% (36/155, 23.23%) of patients experienced defervescence within 3 days of azithromycin treatment. RMPP was diagnosed in 54 patients (54/155, 34.84%) and the incidence of RMPP during hospitalization was 22.72 per 1000 person-days. Logistic regression analysis showed that lactate dehydrogenase (LDH) ≥ 399 (U/L) was an independent risk factor for RMPP (odds ratio [OR] 4.66, 95% confidence interval [CI] 1.31– 17.10, P=0.017). During the year followed, RMPP patients had a significantly higher incidence of bronchiolitis obliterans and bronchiectasis than non-RMPP patients (16.67% vs 1.98%, P=0.001; 9.26% vs 0.00%, P=0.005, respectively).Conclusion: Azithromycin was effective in children with MPP with the A2063/2064G mutation. For MUMPP children with A2063/2064G mutation, children with LDH ≥ 399 (U/L) had significant higher risk for progression to RMPP, and should consider to be treated with alternative antibiotics (eg tetracyclines, and fluoroquinolones).Keywords: azithromycin effectiveness, A2063/2064G mutation, mycoplasma pneumoniae pneumonia, children

Xiaoqing Peng,1– 4,&ast; Yuanyuan Yang,3,4,&ast; Ruirui Hou,1 Longbiao Zhang,1 Can Shen,3 Xiaoyan Yang,3 Zhigang Luo,5 Zongzhi Yin,3,4 Yunxia Cao3,4 1School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of China; 2Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, Anhui, People’s Republic of China; 3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 4The Key National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, People’s Republic of China; 5Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunxia Cao; Zongzhi Yin, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Sushan District, Hefei, Anhui, People’s Republic of China, Email caoyunxia5972@ahmu.edu.cn; yinzongzhi@ahmu.edu.cnAbstract: Mitochondrial carrier homolog 2 (MTCH2) is a member of the solute carrier 25 family, located on the outer mitochondrial membrane. MTCH2 was first identified in 2000. The development in MTCH2 research is rapidly increasing. The most well-known role of MTCH2 is linking to the pro-apoptosis BID to facilitate mitochondrial apoptosis. Genetic variants in MTCH2 have been investigated for their association with metabolic and neurodegenerative diseases, however, no intervention or therapeutic suggestions were provided. Recent studies revealed the physiological and pathological function of MTCH2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction via regulating mitochondrial apoptosis, metabolic shift between glycolysis and oxidative phosphorylation, mitochondrial fusion/fission, epithelial-mesenchymal transition, etc. This review endeavors to assess a total of 131 published articles to summarise the structure and physiological/pathological role of MTCH2, which has not previously been conducted. This review concludes that MTCH2 plays a crucial role in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction, and the predominant molecular mechanism is regulation of mitochondrial function. This review gives a comprehensive state of current knowledgement on MTCH2, which will promote the therapeutic research of MTCH2. Keywords: Mimp, MTCH2, mitochondrial carrier homolog 2, BID, apoptosis

Yang Li,1 Xue Yan,2 Zhen Luo,1 Xianxian Fu,1 Zhongju Li,1 Qiuzhu Xu,3 Juanjuan Chen,1 Jingmin Yang,2,4,5 Daru Lu4,5 1Department of Nephropathy, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Hainan, People’s Republic of China; 2Department of Medicine, Shanghai WeHealth Biomedical Technology Co., Ltd., Shanghai, People’s Republic of China; 3Department of Central Supply Service Department, Haikou Orthopedic and Diabetes Hospital, Hainan, People’s Republic of China; 4NHC Key Laboratory of Birth Defects and Reproductive Health (Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning, Science and Technology Research Institute), Chongqing, People’s Republic of China; 5State Key Laboratory of Genetic Engineering and MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Jingmin Yang; Daru Lu, Email jingmin.yang@we-health.vip; Email drlu@fudan.edu.cnIntroduction: X-linked Alport syndrome (XLAS) is caused by pathogenic variants in COL4A5 which lead to abnormalities of the glomerular basement membrane (GBM) structural and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities. The aim of this study was to identify gene mutations in a Chinese family with XLAS by whole-exome sequencing (WES) and verified the pathogenicity of the mutation in vitro experiments.Case Presentation: A five-generation pedigree with a total of 49 family members originating from Hainan province of China was investigated in this study. The proband was a 23-year-old male who developed microscopic hematuria, proteinuria and end-stage kidney disease (ESKD) at age 17. WES identified a novel splicing mutation c.321+5G>A of COL4A5, which cause exon skip. Further co-segregation analysis confirmed that this mutation exists in relatives who had renal abnormalities using Sanger sequencing. According to American College of Medical Genetics and Genomics guidelines (ACMG), the mutation was determined to be of uncertain significance (VUS). In vitro splicing experiments have shown that the COL4A5 variant induces aberrant mRNA splicing and transcript deletion.Conclusion: We identified a novel intronic COL4A5 pathogenic mutation (c.321+5G>A) in a Chinese XLAS family and described the phenotypes of affected relatives. This study expands the mutation spectrum of COL4A5 gene in XLAS and demonstrates the importance of gene screening for AS.Keywords: Alport syndrome, COL4A5, whole exome sequencing, mRNA splicing, case series

Yanxia He,1,&ast; Zhumei Luo,1,&ast; Haoqing Chen,2,3,&ast; Liqing Ping,2,3 Cheng Huang,2,3 Yan Gao,2,3 Huiqiang Huang2,3 1Department of Oncology, The Third People’s Hospital of Chengdu, Sichuan, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiqiang Huang; Yan Gao, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China, Email huanghqsysucc@163.com; gaoyan@sysucc.org.cnBackground: Systemic inflammation, immunity, and nutritional status are closely related to patients’ outcomes in several kinds of cancers. This study aimed to establish a new nomogram based on inflammation-immunity-nutrition score (IINS) to predict the prognosis of extranodal natural killer/T-cell lymphoma (ENKTL) patients.Methods: The clinical data of 435 patients with ENTKL were retrospectively reviewed and randomly assigned to training cohort (n=305) and validation cohort (n=131) at a ratio of 7:3. Cox regression analysis was employed to identify independent prognostic factors and develop a nomogram in the training cohort. Harrell’s concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) curve were employed to assess the performance of the nomogram and compare it with traditional prognostic systems (PINK, IPI, KPI). Internal validation was performed using 1000 bootstrap resamples in the validation cohort. Kaplan-Meier survival analyses were conducted to compare the overall survival (OS) of patients in different risk groups.Results: In the training cohort, in addition to several classic parameters, IINS was identified as an independent prognostic factor significantly associated with the OS of patients. The nomogram established based on the independent prognostic indicators showed superior survival prediction efficacy, with C-index of 0.733 in the training cohort and 0.759 in the validation cohort compared to the PINK (0.636 and 0.737), IPI (0.81 and 0.707), and KPI (0.693 and 0.639) systems. Furthermore, compared with PINK, IPI, and IPI systems, the nomogram showed relatively superior calibration curves and more powerful prognostic discrimination ability in predicting the OS of patients. DCA curves revealed some advantages in terms of clinical applicability of the nomogram compared to the PINK, IPI, and IPI systems.Conclusion: Compared with traditional prognostic systems, the nomogram showed promising prospects for risk stratification in ENKTL patient prognosis, providing new insights into the personalized treatment.Keywords: inflammation-immunity-nutrition score, extranodal natural killer/T-cell lymphoma, nomogram, prognosis, overall survival

Xiaodong Chen,1,&ast; Xiangyuan Wang,1,&ast; Shangqing Huang,1 Wenxuan Luo,1 Zebin Luo,1,&ast; Zipan Chen2,&ast; 1Radiology Imaging Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang City, People’s Republic of China; 2Health Management Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zipan Chen; Zebin Luo, Email 41881014@qq.com; gdmcfsjd@qq.comObjective: To explore the value of a new model based on CT radiomics in predicting the staging of patients with bronchial asthma (BA).Methods: Patients with BA from 2018 to 2021 were retrospectively analyzed and underwent plain chest CT before treatment. According to the guidelines for the prevention and treatment of BA (2016 edition), they were divided into two groups: acute attack and non-acute attack. The images were processed as follows: using Lung Kit software for image standardization and segmentation, using AK software for image feature extraction, and using R language for data analysis and model construction (training set: test set = 7: 3). The efficacy and clinical effects of the constructed model were evaluated with ROC curve, sensitivity, specificity, calibration curve and decision curve.Results: A total of 112 patients with BA were enrolled, including 80 patients with acute attack (range: 2– 86 years old, mean: 53.89± 17.306 years old, males of 33) and 32 patients with non-acute attack (range: 4– 79 years old, mean: 57.38± 19.223 years old, males of 18). A total of 10 imaging features are finally retained and used to construct model using multi-factor logical regression method. In the training group, the AUC, sensitivity and specificity of the model was 0.881 (95% CI:0.808– 0.955), 0.804 and 0.818, separately; while in the test group, it was 0.792 (95% CI:0.608– 0.976), 0.792 and 0.80, respectively.Conclusion: The model constructed based on radiomics has a good effect on predicting the staging of patients with BA, which provides a new method for clinical diagnosis of staging in BA patients.Keywords: bronchial asthma, BA, Radiomics, computed tomography, CT

Ting He,1,&ast; Kangzhi Chen,1,&ast; Yi Li,1 Zhaohui Luo,1 Mengchuan Luo,2 Huan Yang1 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huan Yang, Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, People’s Republic of China, Email 403850@csu.edu.cnPurpose: To decipher the discrepancies between muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) and double-seropositive myasthenia gravis (DSP-MG), and to determine prognostic factors for minimal manifestation status (MMS) achievement in MG patients with MuSK autoantibodies (MuSK-Ab).Patients and Methods: A total of 34 MG patients seropositive for MuSK-Ab were enrolled in this study. The demographic and clinical features were compared between MuSK-MG (n = 28) and DSP-MG (n = 6) patients, and factors affecting MMS induction in all patients with MuSK-Ab were identified using Cox regression analysis.Results: Compared to MuSK-MG patients, those with DSP-MG had similar clinical characteristics, except that they had a lower frequency of bulbar muscle involvement at nadir (50% vs 92.9%; P = 0.029) and higher proportions of comorbidities with diabetes mellitus (33.3% vs 0%; P = 0.027) and thymic abnormalities (33.3% vs 0%; P = 0.027). Higher MG Activities of Daily Living (MG-ADL) scores (HR = 0.16, 95% CI: 0.037– 0.7, P = 0.015) and axial muscle involvement at nadir (HR = 0.39, 95% CI: 0.16– 0.94, P = 0.035) were negative prognostic factors for MMS achievement in patients with MuSK-Ab regardless of acetylcholine receptor antibody (AChR-Ab) positivity. Multivariable Cox regression analysis further established higher MG-ADL scores at the nadir (HR = 0.19, 95% CI: 0.04– 0.94; P = 0.042) as an independent risk factor for MMS achievement.Conclusion: DSP-MG was comparable to MuSK-MG and could be considered a single entity in our cohort. In all MG patients with MuSK-Ab, a higher MG-ADL score at nadir may herald a lower chance of MMS achievement, with no observed potential effect of AChR-Ab presence.Keywords: double-seropositive myasthenia gravis, muscle-specific kinase antibody, acetylcholine receptor antibody, minimal manifestation status, myasthenia gravis activities of daily living

Naigeng Wang,1 Fei Li,2 Jing Du,3 Jianhong Hao,1 Xin Wang,2 Yueru Hou,3 Zhenguo Luo1 1Department of Anesthesiology, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 3Second Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of ChinaCorrespondence: Zhenguo Luo, Email luozhenguo@stu.xjtu.edu.cnBackground: This study aims to investigate the protective effect of quercetin against global cerebral ischemia‒reperfusion (GCI/R) injury in rats and elucidate the underlying mechanism.Methods: A GCI/R injury rat model was established using a four-vessel occlusion (4-VO) method. An oxygen–glucose deprivation/reoxygenation (OGD/R) injury model was induced in BV2 cells. The extent of injury was assessed by evaluating neurological deficit scores (NDS) and brain water content and conducting behavioral tests. Pathomorphological changes in the prefrontal cortex were examined. Additionally, the study measured the levels of inflammatory cytokines, the degree of microglial activation and polarization, and the protein expression of Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor inducing interferon-β (TRIF).Results: Quercetin pretreatment significantly ameliorated neurological impairment, improved learning and memory abilities, and reduced anxiety in rats subjected to GCI/R injury. Furthermore, quercetin administration effectively mitigated neuronal injury and brain edema. Notably, it suppressed microglial activation and hindered polarization toward the M1 phenotype. Simultaneously, quercetin downregulated the expression of TLR4 and TRIF proteins and attenuated the release of IL-1β and TNF-α.Conclusion: This study highlights the novel therapeutic potential of quercetin in alleviating GCI/R injury. Quercetin demonstrates its neuroprotective effects by inhibiting neuroinflammation and microglial activation while impeding their transformation into the M1 phenotype through modulation of the TLR4/TRIF pathway.Keywords: quercetin, cerebral ischemia, neuroprotection, neuroinflammation

Beijie Qi,1,&ast; Yuqi Li,2,&ast; Zhen Peng,2 Zhiwen Luo,3 Xingyu Zhang,2 Jiwu Chen,2 Guoqi Li,2 Yaying Sun2 1Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China; 2Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaying Sun; Guoqi Li, Tel +86 17621642602 ; +86 13816307547, Email yaying.sun@shgh.cn; etherlords@163.comBackground: Acute skeletal muscle injury is common in sports. The injured muscle cannot fully recover due to fibrosis resulting from myofibroblasts. Understanding the origin of fibroblasts is, therefore, important for the development of anti-fibrotic therapies. Accumulating evidence shows that a mechanism called macrophage-myofibroblast transition (MMT) can lead to tissue or organ fibrosis, yet it is still unclear whether MMT exists in skeletal muscle and the exact mechanisms.Methods: Single-cell transcriptome of mice skeletal muscle after acute injury was analyzed with a specific attention on the process of MMT. Cell–cell interaction network, pseudotime trajectory analysis, Gene Ontology (GO), and Kyoto Genome Encyclopedia (KEGG) were conducted. A series of experiments in vivo and in vitro were launched for verification.Results: Single cell transcriptomic analysis indicated that, following acute injury, there were much interactions between macrophages and myofibroblasts. A detailed analysis on macrophages indicated that, CD68+α-SMA+ cells, which represented the status of MMT, mainly appeared at five days post-injury. KEGG/GO analysis underlined the involvement of complement system, within which C3ar1, C1qa, C1qb, and C1qc were up-regulated. Trajectory analysis also confirmed a potential shift from macrophages to myofibroblasts. These findings were verified by histological study in mice skeletal muscle, that there were much MMT cells at five days, declined gradually, and vanished 14 days after trauma, when there was remarkable fibrosis formation within the injured muscle. Moreover, C3a stimulation could directly induce MMT in BMDMs.Conclusion: Fibrosis following acute injury is disastrous to skeletal muscle, but the origin of myofibroblasts remains unclear. We proved that, following acute injury, macrophage-myofibroblast transition happened in skeletal muscle, which may contribute to fibrosis formation. This phenomenon mainly occurred at five days post-injury. The complement system can activate MMT. More evidence is needed to directly support the pro-fibrotic role of MMT in skeletal muscle fibrosis after acute injury.Keywords: skeletal muscle, fibrosis, macrophage-myofibroblast transition, single-cell transcriptomic analysis, complement system

The root system harbours complex bacterial communities, which are critical for plant growth and health. Significant differences exist between bacterial communities in the root compartments; however, limited reports have explored their phylogenetic composition and niche conservatism in the root system of sorghum. We used the sorghum Hongyingzi cultivar as test plant, and applied 16S rRNA high‐throughput sequencing and various statistical approaches. Phylogenetic composition of bacterial communities in root compartments were primarily driven by closely related species with similar environmental adaptations. We also found evidence of phylogenetic niche conservatism in bacterial communities for edaphic factors in the various root compartments, with pH and available N playing essential roles in shaping community composition. Environmental threshold analysis revealed threshold ranges of dominant taxa for pH and available N, indicating wider adaptive thresholds for more abundant taxa. Reconstruction of ancestral states suggested evolutionary changes in adaptability of certain bacterial taxa to edaphic factors, suggesting a shift towards slightly acidic, high N environments and reflecting the prolonged mutual interaction between bacteria and plants in cultivated soils. These findings enhance our understanding of environmental responses and evolutionary dynamics of root‐associated microbiota in young sorghum plants and provide novel insights into ecological adaptations, shedding light on their responses to environmental factors. Our study contributes to a better understanding of the ecological dynamics of root‐associated microbiota and offers analytical pathways for exploring the nutritional regulation of root microbiota. [ABSTRACT FROM AUTHOR]

Clinopodium gracile is one of the commonly used medicinal herbs of the She ethnic minority in China. The whole plant of C. gracile is rich in flavonoids. This study pioneers the investigation to improve flavonoid yield by the use of response surface methodology (RSM) and microwave irradiation pretreatment method. The antimicrobial activities of its extracts was also tested. The significant parameters of extraction conditions of the whole plant of C. gracile flavonoids (WPCF) were as follows: wetted time of 25.514 min, microwave radiation pretreatment time of 38.024 s, microwave power of 411.557 w, and mass of vaporization solvent of 1.841 mL. For the convenience of the experiment, the optimum process parameters were modified as follows: wetted time of 25 min, microwave radiation pretreatment time of 38 s, microwave power of 420 w, and mass of vaporization solvent of 1.8 mL. Under these conditions, the yield of WPCF was 145.677 mg/g, which was increased by 25.450% compared to the traditional water bath extraction, a significant difference was observed. Antimicrobial experimentations showed that the extracts of ethyl acetate exhibited good activities against Pseudomonas aeruginosa (ATCC9027), Staphylococcus aureus (ATCC29213), Staphylococcus aureus (SA1) with minimal inhibitory concentration (MIC) value of 16 mg/mL, 8 mg/mL, 8 mg/mL, respectively. Therefore, the processing technology in this study was successful and microwave irradiation pretreatment provided some practical significance for the extraction of WPCF. The results also suggest that the extracts from C. gracile could be used as a potential antimicrobial source. [ABSTRACT FROM AUTHOR]

In order to study the unsteady flow and vortex characteristics of tongue cavitation, numerical calculation is carried out for the whole flow channel given different conditions. Then, the calculation results are verified experimentally. The results show that after the occurrence of tongue cavitation in the centrifugal pump, it deteriorates with the decrease of NPSHa. However, when NPSHa is reduced to 3.78 m, it does not change significantly anymore with the decrease of NPSHa. The extrusion of fluid by the vapor at the tongue promotes the formation of the separation vortex, and the re-jet flow caused by the separation vortex leads to vapor shedding. The frequency of cavitation shedding is consistent with the frequency of vortex shedding. In the vorticity transport equation, the relative vortex stretching term and the relative vortex dilatation term dominate the vapor shedding by controlling the change in vorticity. The baroclinic torque term mainly affects the change of vorticity at the vapor-liquid interface, but to a much lesser extent than the first two terms. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) is the most common form of adult muscular dystrophy. Characterized by life-threatening muscle weakness, compromised respiration, and often cardiac conduction abnormalities, DM1 has high unmet medical need. DM1 is caused by a CTG repeat expansion in the 3ʹ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene which causes aggregation of DMPK mRNA hairpin structures as insoluble ribonuclear foci and sequestration of several RNA-binding proteins. Sequestration of key splicing regulators such as muscleblind like splicing regulator 1 (MBNL-1) drives aberrant splicing of hundreds of downstream transcripts. These splicing defects are thought to be a key driver of DM1 disease pathogenesis. We have developed a novel myotropic delivery platform comprising a myotropic AAV capsid and a promoter with strong activity in all muscle cells. We tested the ability of this novel platform to deliver a DMPK-targeting miRNA (AAV-amiR DMPK) and correct DM1-associated splicing defects. First, we treated immortalized human DM1 myotubes with AAV-amiR DMPK and analyzed the splicing profile of 36 genes previously shown to be affected in DM1 by NanoString analysis. Here, we observed significant splicing improvement for a subset of the 36 genes (MBNL1, GOLGA4, SOS1, CLASP1, zTTN and PKM). Subsequently, we performed splicing analysis of cardiac and skeletal muscles of a mouse model of DM1 (DMSXL mice), treated with a single intravenous dose of AAV-amiR DMPK, and we showed that treatment resulted in improved splicing in both tissues. Together, our data demonstrate that our novel myotropic delivery platform can improve a key marker of the disease in the cellular and animal models of DM1. [ABSTRACT FROM AUTHOR]

Heart regeneration was mainly achieved by intrinsic capacity. Exosomes are crucial in cardiovascular disease, yet their involvement in myocardial regeneration remains underexplored. To understand the role of cardiomyocyte-derived exosomes (CM-Exos) in heart regeneration. We established mouse models of myocardial infarction and apical resection in neonates to investigate the potential benefits of exosomes in response to injury. Rab27a knockout (KO) mice were constructed as an exosome decrease model. Distinct fibrosis appears in the infarcted and resection area in the KO mice 21 days after heart injury. The proliferation marker pH 3, Ki67, and Aurora B were detected 3 days after surgery, which decreased in KO mice compared to WT mice. Intravenous injection of CM-Exos increased cardiomyocyte proliferation and partially restored heart function in KO mice. Rab27a knockdown in vitro reduced the expression of pH 3, Ki67, and Aurora B positive cardiomyocytes. However, the supplementation of CM-Exos increased the proliferation of cardiomyocytes. Exosomal miRNA sequencing was subsequently applied, and miR-21-5p was a promising candidate that promoted cardiomyocyte proliferation through its target genes Spry-1 and PDCD4. Intravenous injection of miR-21-5p exhibited similar proliferative effects as CM-Exos. Our results indicate that CM-Exos promotes cardiomyocyte cycle reentry by delivering miR-21-5p, highlighting the endogenous factors of myocardial regeneration., (© 2024 Federation of American Societies for Experimental Biology.)

Elevated CO 2 was a potential strategy for strawberry preservation. However, the regulatory mechanism remained unclear. In current study, transcriptome analysis showed that elevated CO 2 played important roles in regulating strawberry fruit quality at the transcriptional level, and plant hormones metabolism at least partially involved in the regulatory process. Further, ABA was demonstrated to play important roles in the response to elevated CO 2 . Elevated CO 2 inhibited the accumulation of ABA, which was 61% lower than that in control. Elevated CO 2 repressed ABA synthesis by inhibiting NCED activity and the expression of FaNCED1/2, leading to the reduction of ABA accumulation as a result. Meanwhile, elevated CO 2 also decreased ABA sensitivity by down-regulating FaSnRK2.4/2.6 and FaABI5 expression. The dual down-regulation of ABA signaling accounted for the regulation of fruit quality under elevated CO 2 treatment. These results provide new insights into the mechanism of strawberry fruit response to elevated CO 2 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Two new acylphloroglucinol-nerolidol meroterpenoids (APNMs) [(±)-1 and (±)-2], with a skeleton of mixed sesquiterpene and dimeric acylphloroglucinol biosynthetic origin, were isolated from the medicinal pteridophyte Dryopteris crassirhizoma . Inspired by the proposed biosynthetic pathway, we initially completed the biomimetic syntheses of eight optically active Dryopteris APNMs (1-8) in a one-pot domino reaction. The structures of APNMs 1-8 including their absolute configurations were unambiguously established by a combination of NMR analysis, ECD calculations, and synthetic methods. Furthermore, an underlying method based on NMR data to assign the stereochemistry of the long-chain alcohol moieties in APNMs was revealed. Anti-triple negative breast cancer (anti-TNBC), antifungal and antibacterial activities of the synthetic meroterpenoids were evaluated. All tested compounds exhibited cytotoxicity against TNBC cells MDA-MB-231 with IC 50 values in the range of 1.22-27.43 μM, with (-)-8 being the most potent antitumor agent (IC 50 : 0.48 μM; selectivity index: 32.04). This study resulted in the biomimetic synthesis of APNMs for the first time and positioned APNMs from D . crassirhizoma as a new class of promising candidates for the development of new anti-TNBC drugs.

Cushing's syndrome is caused by an elevation of endogenous or pharmacologically administered glucocorticoids. Acyl coenzyme A binding protein (ACBP, encoded by the gene diazepam binding inhibitor, Dbi) stimulates food intake and lipo-anabolic reactions. Here we found that plasma ACBP/DBI concentrations were elevated in patients and mice with Cushing's syndrome. We used several methods for ACBP/DBI inhibition in mice, namely, (1) induction of ACBP/DBI autoantibodies, (2) injection of a neutralizing monoclonal antibody, (3) body-wide or hepatocyte-specific knockout of the Dbi gene, (4) mutation of the ACBP/DBI receptor Gabrg2 and (5) injections of triiodothyronine or (6) the thyroid hormone receptor-β agonist resmetirom to block Dbi transcription. These six approaches abolished manifestations of Cushing's syndrome such as increased food intake, weight gain, excessive adiposity, liver damage, hypertriglyceridaemia and type 2 diabetes. In conclusion, it appears that ACBP/DBI constitutes an actionable target that is causally involved in the development of Cushing's syndrome., Competing Interests: Competing interests: O.K. is a scientific co-founder of Samsara Therapeutics. I.M. consults for Osasuna Therapeutics. G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio; is in the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences; and is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. Among these patents, one, ‘Methods for weight reduction’ (US11905330B1), is relevant to this study. G.K.’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. G.K.’s wife, Laurence Zitvogel, has held research contracts with GSK, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a co-founder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study, in the writing of the manuscript or in the decision to publish the results. The other authors declare no competing interests., (© 2024. The Author(s).)

A series of new small-molecule acceptors-NA9, NA10, and NA11-based on benzo[ b ]phenazine are synthesized. The chlorinated NA10 and brominated NA11 exhibit improved molecular packing and enhanced charge transport, resulting in higher power conversion efficiencies (PCEs) of 15.65% and 16.64%, respectively, compared to 11.66% for the non-halogenated NA9. These results underscore the great potential of peripheral halogenation particularly bromination, in achieving high-performance OSCs.

Bromodomain-containing protein 4 (BRD4) is the most promising target for the treatment of triple-negative breast cancer (TNBC). However, its inherent resistant and acquired drug resistance limits its potential clinical application. Recently it has been shown that cyclin-dependent kinases 4/6 (CDK4/6) inhibitors can reincrease the sensitivity of TNBC cells to BRD4 inhibitors by combination therapy, so we designed a series of dual target CDK6/BRD4 inhibitors. Among the newly synthesized compounds, BC13 exhibited potent inhibitory activity against CDK6 and BRD4. It also displayed potent antiproliferative activity against TNBC cells. In vivo experiments showed that BC13 has potent antitumor activity in the MDA-MB-231 xenograft mouse model, without observable side effects. BC13 demonstrates profound synergistic antitumor effects with ferroptosis inducer in TNBC cells. Therefore, BC13 is a novel dual inhibitor of CDK6/BRD4 for the treatment of TNBC either as a single agent or in combination with RSL3.

Label-free surface-enhanced Raman spectroscopy (SERS) is capable of capturing rich compositional information from complex biosamples by providing vibrational spectra that are crucial for biosample identification. However, increasing complexity and subtle variations in biological media can diminish the discrimination accuracy of traditional SERS excited by a single laser wavelength. Herein, we introduce a multiwavelength SERS approach combined with machine learning (ML)-based classification to improve the discrimination accuracy of human urine specimens for bladder cancer (BCa) diagnosis. This strategy leverages the excitation-wavelength-dependent SERS spectral profiles of complex matrices, which are mainly attributed to wavelength-related vibrational changes in individual analytes and differences in the variation ratios of SERS intensity across different wavelengths among various analytes. By capturing SERS fingerprints under multiple excitation wavelengths, we can acquire more comprehensive and unique chemical information on complex samples. Further experimental examinations with clinical urine specimens, supported by ML algorithms, demonstrate the effectiveness of this multiwavelength strategy and improve the diagnostic accuracy of BCa and staging of its invasion with SERS spectra from increasing numbers of wavelengths. The multiwavelength SERS holds promise as a convenient, cost-effective, and broadly applicable technique for the precise identification of complex matrices and diagnosis of diseases based on body fluids.

Objective: The present study aimed to investigate the functional connectivity (FC) of the anterior and posterior hypothalamus with the whole brain in insomnia disorder (ID) patients. Additionally, we explored the relationship between FC values and serum levels of arousal-promoting neurotransmitters (orexin-A and histamine) in ID patients., Methods: This study enrolled 30 ID patients and 30 age- and gender-matched healthy controls. Resting-state functional magnetic resonance imaging (RS-fMRI) was employed to assess the FC of the anterior and posterior hypothalamus with the whole brain. Serum concentrations of orexin-A and histamine were measured using enzyme-linked immunosorbent assay (ELISA). Moreover, Spearman correlation analysis was conducted to investigate the relationship between FC values and serum levels of arousal-promoting neurotransmitters in ID patients., Results: Our findings showed decreased FC between the posterior hypothalamus and several brain regions including the bilateral orbital superior frontal gyrus, the bilateral angular gyrus, the right anterior cingulate cortex, the left precuneus, and the right medial superior frontal gyrus in ID patients. Additionally, decreased FC was observed between the anterior hypothalamus and the right anterior cingulate cortex among ID patients. Compared to the healthy controls, ID patients showed significantly elevated serum concentrations of orexin-A and histamine. Furthermore, we identified a positive correlation between the FC of the right medial superior frontal gyrus with posterior hypothalamus and histamine levels in ID patients., Conclusion: ID patients exhibited aberrant FC in brain regions related to sleep-wake regulation, particularly involving the default mode network and anterior cingulate cortex, which may correlate with the peripheral levels of histamine. These findings contribute to our understanding of the potential neuroimaging and neurohumoral mechanism underlying ID patients., Competing Interests: The authors declare that they have no competing interests., (© 2024 Lin et al.)

Congenital heart defects (CHDs) represent one of the most prevalent categories of neonatal defects, and maternal dietary patterns have been linked to the risk of these conditions. Branched-chain amino acids (BCAAs), particularly leucine, are essential for various metabolic and physiological processes involved in heart development. In this study, we examined the molecular mechanisms through which elevated levels of leucine induce defects in cardiac microvascular endothelial cells. We collected plasma samples from healthy controls and neonatal patients with CHDs, employed a high-leucine diet for pregnant female mice, and applied high-leucine treatment in human cardiac microvascular endothelial cells (HCMECs). The impacts of high-leucine levels on WD Repeat Containing Planar Cell Polarity Effector (WDPCP)/MAPK signaling axis were investigated in the cell and animal models. We reported heightened plasma leucine levels in neonatal patients with CHDs and observed that a high-leucine diet in pregnant mice was associated with reduced expression of WDPCP and attenuated MAPK/ERK signaling. High-leucine treatment in HCMECs impaired epithelial-mesenchymal transition (EMT) and cell migration; however, overexpression of WDPCP or activation of MAPK exhibited a rescue effect. The upregulation of endomucin (EMCN) under high-leucine conditions contributed to the impaired EMT and migratory capacity of HCMECs, and the WDPCP/MAPK signaling axis regulated EMCN overexpression in response to high-leucine treatment. High levels of leucine in neonatal patients with CHDs may inhibit the WDPCP/MAPK axis, leading to an increase in EMCN expression that undermines the function of cardiac microvascular endothelial cells. These findings suggest the potential of targeting the WDPCP/MAPK axis as an intervention strategy for neonatal CHDs., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)