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Abstract The process e + e − → K S 0 K S 0 ψ 3686 $$ {e}^{+}{e}^{-}\to {K}_S^0{K}_S^0\psi (3686) $$ is studied by analyzing e + e − collision data samples collected at eight center-of-mass energies ranging from 4.682 to 4.951 GeV with the BESIII detector operating at the BEPCII collider, corresponding to an integrated luminosity of 4.1 fb −1. Observation of the e + e − → K S 0 K S 0 ψ 3686 $$ {e}^{+}{e}^{-}\to {K}_S^0{K}_S^0\psi (3686) $$ process is found for the first time with a statistical significance of 6.3σ, and the cross sections at each center-of-mass energy are measured. The ratio of cross sections of e + e − → K S 0 K S 0 ψ 3686 $$ {e}^{+}{e}^{-}\to {K}_S^0{K}_S^0\psi (3686) $$ relative to e + e − → K + K − ψ(3686) is determined to be σ e + e − → K S 0 K S 0 ψ 3686 σ e + e − → K + K − ψ 3686 = 0.45 ± 0.25 $$ \frac{\sigma \left({e}^{+}{e}^{-}\to {K}_S^0{K}_S^0\psi (3686)\right)}{\sigma \left({e}^{+}{e}^{-}\to {K}^{+}{K}^{-}\psi (3686)\right)}=0.45\pm 0.25 $$ , which is consistent with the prediction based on isospin symmetry. The uncertainty includes both statistical and systematic contributions. Additionally, the K S 0 ψ 3686 $$ {K}_S^0\psi (3686) $$ invariant mass distribution is found to be consistent with three-body phase space. The significance of a contribution beyond three-body phase space is only 0.8σ.

Didi Yan,1 Xinyue Ma,1 Yixin Hu,1 Guogang Zhang,1 Beibei Hu,1 Bo Xiang,2 Xiaokun Cheng,1,3 Yongshuai Jing,1 Xi Chen1,4 1College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, People’s Republic of China; 2Department of Psychiatry, Fundamental and Clinical Research on Mental Disorders Key Laboratory of Luzhou, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3New Drug Research & Development Co., Ltd., North China Pharmaceutical Group Corporation, Shijiazhuang, 050015, People’s Republic of China; 4Hebei Research Center of Pharmaceutical and Chemical Engineering, Shijiazhuang, 050018, People’s Republic of ChinaCorrespondence: Xi Chen, College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, 26 Yuxiang Road, Shijiazhuang, 050018, People’s Republic of China, Tel +86-15203319951, Email chenxi0310@163.comBackground: Paclitaxel-induced blood system disorders and peripheral neuropathy impede the progress of new formulations in clinical trials.Purpose of Study: To mitigate these adverse effects by developing and validating a prodrug strategy that encapsulates a glucose-paclitaxel conjugate within nanomicelles.Material and Methods: Succinic anhydride was used as a bridge to couple C2’-paclitaxel with methyl 2’-glucopyranose and prepare a glucose-paclitaxel conjugate. Nanomicelles were prepared via solid-phase dispersion, and dynamic light scattering was used to determine their average diameter and the polydispersity index. High-performance liquid chromatography (HPLC) was employed to evaluate drug-loading capacity and encapsulation efficiency. Pharmacokinetic studies and in vivo toxicity assays were performed in Sprague-Dawley (SD) rats.Results: The nanomicellar product exhibited a spherical shape with a particle size distribution between 20– 60 nm, a PDI of 0.26 ± 0.01, and an encapsulation efficiency of 95.59 ± 1.73%. The pharmacokinetic profile of glucose-paclitaxel nanomicelles in SD rats was markedly different from that of the paclitaxel solution group. Notably, the plasma drug concentration of glucose-paclitaxel nanomicelles was significantly higher than the paclitaxel solution 15 minutes post-administration, with a Vz at only 40% of that of the paclitaxel solution, while the AUC0-∞ was five times greater than that of the paclitaxel solution. Ultimately, glucose-paclitaxel nanomicelles effectively alleviated blood system disorders and peripheral neuropathy in SD rats.Conclusion: The encapsulation of glucose-paclitaxel conjugates within nanomicelles presents a viable solution to the dose-limiting toxicities associated with paclitaxel, offering new perspectives on safety for the development of paclitaxel-based therapeutics.Keywords: glucose-paclitaxel conjugate, nanomicelles, pharmacokinetics, toxicity of paclitaxel

Wen Hu,1,* Jieqiong Luo,1,* Hui Li,2,* Yushan Luo,1,* Xiaoyuan Zhang,1 Zhen Wu,1 Qian Yang,1 Sirun Zhao,1 Bailong Hu,2 Xiaohua Zou2 1Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bailong Hu; Xiaohua Zou, Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, People’s Republic of China, Tel +86-15185184309 ; +86-13809416036, Fax +86-851-86771013, Email 375896605@qq.com; zouxiaohuazxh@163.comBackground: Esketamine ameliorates propofol-induced brain damage and cognitive impairment in mice. However, the precise role and underlying mechanism of esketamine in perioperative neurocognitive disorders (PND) remain unclear. Therefore, this study aimed to investigate the key genes associated with the role of esketamine in PND through animal modeling and transcriptome sequencing.Methods: The present study established a mice model of PND and administered esketamine intervention to the model, and mice were divided into control, surgical group, and surgical group with esketamine. Behavioral assessments were conducted using the Morris water maze and Y maze paradigms, while transcriptome sequencing was performed on hippocampal samples obtained from 3 groups. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on sequencing data to identify candidate genes related to esketamine treating PND. Thereafter, protein-protein interaction (PPI) network analysis was implemented to select key genes. The genes obtained from each step were subjected to enrichment analysis, and a regulatory network for key genes was constructed.Results: The Morris water maze and Y maze findings demonstrated the successful construction of our PND model, and indicated that esketamine exhibits a certain therapeutic efficacy for PND. Ank1, Cbln4, L1cam, Gap43, and Shh were designated as key genes for subsequent analysis. The 5 key genes were significantly enriched in cholesterol biosynthesis, nonsense mediated decay (NMD), formation of a pool of free 40s subunits, major pathway of rRNA processing in the nucleolus and cytosol, among others. Notably, the miRNAs, mmu-mir-155-5p and mmu-mir-1a-3p, functionally co-regulated the expression of Ank1, Gap43, and L1cam.Conclusion: We uncovered the therapeutic efficacy of esketamine in treating PND and identified 5 key genes (Ank1, Cbln4, L1cam, Gap43, and Shh) that contribute to its therapeutic effects, providing a valuable reference for further mechanistic studies on esketamine’s treatment of PND.Keywords: esketamine, perioperative neurocognitive disorders, key genes, transcriptome sequencing

Abstract Based on 7.33 fb −1 of e + e − collision data collected by the BESIII detector operating at the BEPCII collider at center-of-mass energies from 4.128 to 4.226 GeV, a search for the Majorana neutrino ν m is conducted in the lepton-number-violating decays of D s + $$ {D}_{\textrm{s}}^{+} $$ → h − h 0 e + e +. Here, h − represents a K − or π − , and h 0 represents a π 0, K S 0 $$ {K}_S^0 $$ or ϕ. No significant signal is observed, and the upper limits of their branching fractions at the 90% confidence level are determined to be B $$ \mathcal{B} $$ ( D s + $$ {D}_{\textrm{s}}^{+} $$ → ϕπ − e + e +) < 6.9 × 10 −5, B $$ \mathcal{B} $$ ( D s + $$ {D}_{\textrm{s}}^{+} $$ → ϕK − e + e +) < 9.9 × 10 −5, B $$ \mathcal{B} $$ ( D s + $$ {D}_{\textrm{s}}^{+} $$ → K S 0 $$ {K}_S^0 $$ π − e + e +) < 1.3 × 10 −5, B $$ \mathcal{B} $$ ( D s + $$ {D}_{\textrm{s}}^{+} $$ → K S 0 $$ {K}_S^0 $$ K − e + e +) < 2.9 × 10 −5, B $$ \mathcal{B} $$ ( D s + $$ {D}_{\textrm{s}}^{+} $$ → π − π 0 e + e +) < 2.9 × 10 −5 and B $$ \mathcal{B} $$ ( D s + $$ {D}_{\textrm{s}}^{+} $$ → K − π 0 e + e +) < 3.4 × 10 −5. The Majorana neutrino is searched for with different mass assumptions within the range [0.20, 0.80] GeV/c 2 in the decay of D s + $$ {D}_{\textrm{s}}^{+} $$ → ϕe + ν m with ν m → π − e +, and the upper limits of the branching fractions at the 90% confidence level are at the level of 10 −5–10 −2, depending on the mass of the Majorana neutrino.

Abstract By analyzing e + e − collision data with an integrated luminosity of 7.9 fb −1 collected with the BESIII detector at the center-of-mass energy of 3.773 GeV, the branching fraction of D + → τ + ν τ is determined as B $$ \mathcal{B} $$ = (9.9 ± 1.1stat ± 0.5syst) × 10 −4. Using the most precise result B $$ \mathcal{B} $$ (D + → μ + ν μ ) = (3.981 ± 0.079stat ± 0.040syst) × 10 −4 [1], we determine R τ/μ = Γ(D + → τ + ν τ )/Γ(D + → μ + ν μ ) = 2.49 ± 0.31, achieving a factor of two improvement in precision compared to the previous BESIII result. This measurement is in agreement with the standard model prediction of lepton flavor universality within one standard deviation.

YongCheng Su,1,&ast; Jiangquan Li,1,&ast; Yijia Chen,2,&ast; Jiachen Bao,2 Ziyu Lei,1 Miaomiao Ma,1 Wenqing Zhang,1 Qian Liu,3 Beibei Xu,4 Tianhui Hu,1,3 Yiqun Hu2 1Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China; 2Department of Gastroenterology, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, People’s Republic of China; 3Integrated Chinese and Western Medicine Institute for Children Health & Drug Innovation, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, 330004, People’s Republic of China; 4Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianhui Hu, Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China, Email thu@xmu.edu.cn Yiqun Hu, Department of Gastroenterology, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, People’s Republic of China, Email hyq0826@xmu.edu.cnIntroduction: Crohn’s disease (CD) is a chronic inflammatory condition of the intestines with a rising global incidence. Traditional diagnostic and therapeutic methods have limitations, necessitating the exploration of more effective strategies.Methods: In this study, we employed the Gene Expression Omnibus database to identify genes that are differentially expressed in CD. RT-PCR and immunohistochemical analysis were used to SLC6A14 RNA and protein expression in the colons of CD mice and CD tissues from patients. The mouse model of CD was induced by dextran sodium sulfate (DSS). Infiltrating immune cells in mouse model were screened by flow cytometry.Results: We discovered that SLC6A14 is significantly overexpressed in CD samples, and its expression is positively correlated with the degree of infiltration by CD4+ and CD8+ T cells. The elevated levels of SLC6A14 RNA and protein were confirmed in clinical CD tissues. The SLC6A14 inhibitor α-methyl-tryptophan (α-MT) significantly decreased the expression of SLC6A14 RNA and protein in the colons of CD mice. The α-MT treatment group also exhibited reduced levels of cytokines involved in T cell differentiation (IFN-γ and TNF-α) and the expression of immune cell surface markers CXCR-3 and LAG-3. Flow cytometry analysis revealed a significant increase in the infiltration of CD4+ and CD8+ T cells in the DSS-treated group compared to the control group. Conversely, the α-MT treatment group showed a significant reduction in CD4+ and CD8+ T cell infiltration and the restoration of intestinal parameters in CD mice. These findings underscore the role of SLC6A14 in regulating intestinal immune cell infiltration during CD progression.Discussion: Our findings suggest that SLC6A14 could serve as a potential diagnostic biomarker and therapeutic target for CD. Furthermore, α-MT offers a novel approach for the clinical diagnosis and treatment of CD by targeting SLC6A14 for therapeutic intervention. Keywords: Crohn’s disease, immunosuppressant, α-MT

Ziyang Hu,1,&ast; Changjin Wang,2,&ast; Songyuan Luo,2,&ast; Bangyuan Yang,2 Shengneng Zheng,3 Xiaolu Hu,2,4 Yinghao Sun,2 Jiaohua Chen,2 Ming Fu,2 Ruixin Fan,5 Jianfang Luo,2,4 Jie Li2 1Department of Cardiology, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, People’s Republic of China; 2Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China; 4School of Medicine South China University of Technology, Guangzhou, People’s Republic of China; 5Department of Cardiac Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li; Jianfang Luo, Guangdong Provincial People’s Hospital, &num;96 Dongchuan Road, Yuexiu District, Guangzhou, Guangdong, 510080, People’s Republic of China, Tel +86 020 83827812, Email leomoku1981@163.com; jianfangluo@sina.comBackground: Left ventricular ejection fraction (LVEF) worsening after transcatheter aortic valve replacement (TAVR) was common in clinical practice. However, the effect of acute worsening LVEF is unclear.Methods: All consecutive patients who underwent TAVR between January 2016 and May 2022 were analyzed. Patients were divided into worsened LVEF and non-worsened LVEF according to whether or not they had an LVEF decline of ≥ 5% at discharge. Survival at follow-up was compared between two groups. Logistic regression analysis was used to determine independent predictors of worsening LVEF.Results: A total of 439 patients were included in the analysis, and 112 (25.5%) patients had worsened LVEF. Worsened LVEF was more common in patients with LVEF ≥ 50%. After multivariable logistic analysis, only baseline LVEF was associated with worsening LVEF [OR=1.06 (95% CI: 1.04– 1.08), P < 0.001]. The decline in LVEF recovered to the baseline after one month. There were no significant differences in survival between patients with and without worsened LVEF (Log rank P = 0.48).Conclusion: Acute worsening of LVEF after TAVR was not uncommon but did not affect survival. It could recover to baseline levels after one month. Routine post-TAVR echocardiography should focus on other metrics rather than acute LVEF changes.Keywords: aortic stenosis, transcatheter aortic valve replacement, left ventricular ejection fraction

Abstract Background Huge phages (genome size ≥ 200 kb) have been detected in diverse habitats worldwide, infecting a variety of prokaryotes. However, their evolution and adaptation strategy in soils remain poorly understood due to the scarcity of soil-derived genomes. Results Here, we conduct a size-fractioned ( 41 years) based on the macrodiveristy (interspecies diversity) analysis. A significant increase in the diversity of huge phages communities following glacier retreat were observed according to current database. The phages distributed across sites within late stage demonstrated a remarkable higher microdiversity (intraspecies diversity) compared to other geographic range such as the intra early stage, suggesting that glacial retreat is key drivers of the huge phage speciation. Alongside the shift in huge phage communities, we also noted an evolutionary and functional transition between the early and late stages. The identification of abundant CRISPR-Cas12 and type IV restriction-modification (RM) systems in huge phages indicates their complex mechanisms for adaptive immunity. Conclusions Overall, this study unravels the importance of climate change in shaping the composition, evolution, and function of soil huge phage communities, and such further understanding of soil huge phages is vital for broader inclusion in soil ecosystem models. Video Abstract

Wenquan Gu,1,&ast; Chunhong Yang,1,&ast; Yuhui Wang,2 Wentao Hu,3 Dongmei Wu,4 Sunmei Cai,1 Guoxiong Hong,1 Peng Hu,5 Qi Zhang,1 Yongming Dai5 1Department of Radiology, Shanghai Punan Hospital of Pudong New Area, Shanghai, People’s Republic of China; 2Department of Neurology, Shanghai Punan Hospital of Pudong New Area, Shanghai, People’s Republic of China; 3Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai, People’s Republic of China; 5School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongming Dai, School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, People’s Republic of China, Tel/Fax +86 21 20685265, Email dymdym118@163.com Qi Zhang, Department of Radiology, Shanghai Punan Hospital of Pudong New Area, Shanghai, People’s Republic of China, Tel/Fax +86 21 20302000, Email 18918070996@189.cnPurpose: Conventional brain MRI protocols are time-consuming, which can lead to patient discomfort and inefficiency in clinical settings. This study aims to assess the feasibility of using artificial intelligence-assisted compressed sensing (ACS) to reduce brain MRI scan time while maintaining image quality and diagnostic accuracy compared to a conventional imaging protocol.Patients and Methods: Seventy patients from the department of neurology underwent brain MRI scans using both conventional and ACS protocols, including axial and sagittal T2-weighted fast spin-echo sequences and T2-fluid attenuated inversion recovery (FLAIR) sequence. Two radiologists independently evaluated image quality based on avoidance of artifacts, boundary sharpness, visibility of lesions, and overall image quality using a 5-point Likert scale. Pathological features, including white matter hyperintensities, lacunar infarcts, and enlarged perivascular spaces, were also assessed. The interchangeability of the two protocols was determined by calculating the 95% confidence interval (CI) for the individual equivalence index. Additionally, Cohen’s weighted kappa statistic was used to assess inter-protocol intra-observer agreement.Results: The ACS images demonstrated superior quality across all qualitative features compared to the conventional ones. Both protocols showed no significant difference in detecting pathological conditions. The 95% CI for the individual equivalence index was below 5% for all variables except enlarged perivascular spaces, indicating the interchangeability of the conventional and ACS protocols in most cases. The inter-rater reliability between the two radiologists was strong, with kappa values of 0.78, 0.74, 0.70 and 0.86 for image quality evaluation and 0.74, 0.80 and 0.70 for diagnostic performance, indicating good-to-excellent agreement in their evaluations.Conclusion: The ACS technique reduces brain MRI scan time by 29.2% while achieving higher image quality and equivalent diagnostic accuracy compared to the conventional protocol. This suggests that ACS could be potentially adopted for routine clinical use in brain MRI.Keywords: brain, magnetic resonance imaging, fast imaging, deep learning, compressed sensing

Abstract Acute myeloid leukemia (AML) featuring retinoic acid receptor-gamma (RARG) rearrangements exhibits morphological features resembling those of acute promyelocytic leukemia but is associated with drug resistance and poor clinical outcomes. However, the mechanisms underlying the role of RARG fusions in leukemogenesis remain elusive. Here, we show that RARG fusions disrupt myeloid differentiation and promote proliferation and self-renewal of hematopoietic stem and progenitor cells (HSPCs) by upregulating BCL2 and ATF3. RARG fusions overexpression leads to preleukemic phenotypes but fails to induce oncogenic transformation. However, the co-occurrence of RARG fusions and heterozygous Wt1 loss induce fully penetrant AML by activating MYC and HOXA9/MEIS1 targets. Leveraging Connectivity Map resources and high-throughput screening, we identify venetoclax, homoharringtonine, and daunorubicin as potential therapeutic options for RARG-AML. Overall, our findings provide pivotal insights into the molecular mechanisms governed by RARG fusions and enhanced by WT1 loss in AML development and propose a rational therapeutic strategy for RARG-AML.

Abstract We explore the decay of bound neutrons in the JUNO liquid scintillator detector into invisible particles (e.g., $$n\rightarrow 3 \nu $$ n → 3 ν or $$nn \rightarrow 2 \nu $$ n n → 2 ν ), which do not produce an observable signal. The invisible decay includes two decay modes: $$ n \rightarrow { inv} $$ n → inv and $$ nn \rightarrow { inv} $$ n n → inv . The invisible decays of s-shell neutrons in $$^{12}\textrm{C}$$ 12 C will leave a highly excited residual nucleus. Subsequently, some de-excitation modes of the excited residual nuclei can produce a time- and space-correlated triple coincidence signal in the JUNO detector. Based on a full Monte Carlo simulation informed with the latest available data, we estimate all backgrounds, including inverse beta decay events of the reactor antineutrino $${\bar{\nu }}_e$$ ν ¯ e , natural radioactivity, cosmogenic isotopes and neutral current interactions of atmospheric neutrinos. Pulse shape discrimination and multivariate analysis techniques are employed to further suppress backgrounds. With two years of exposure, JUNO is expected to give an order of magnitude improvement compared to the current best limits. After 10 years of data taking, the JUNO expected sensitivities at a 90% confidence level are $$\tau /B( n \rightarrow { inv} ) > 5.0 \times 10^{31} \, \textrm{years}$$ τ / B ( n → inv ) > 5.0 × 10 31 years and $$\tau /B( nn \rightarrow { inv} ) > 1.4 \times 10^{32} \, \textrm{years}$$ τ / B ( n n → inv ) > 1.4 × 10 32 years .

Jiaojiao Wei, Yibing Hu, Chong Lu, Minli Hu, Qunying Wang Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of ChinaCorrespondence: Qunying Wang, Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of China, Email wqy616717@126.comBackground: Amyloidosis combined with lung cancer is a rare occurrence. To date, there are no reported cases of amyloid light-chain(AL) amyloidosis solely affecting the colon combined with pulmonary adenocarcinoma.Case Summary: Here, we describe a case of a 66-year-old woman who presented with recurrent abdominal pain and was eventually diagnosed with AL amyloidosis with colon involvement and pulmonary adenocarcinoma. We also review the relevant literature and discuss the relationship between amyloidosis and lung malignancies. Significantly, lung cancer may contribute to the deposition of amyloid through paraneoplastic mechanisms. And in published case reports, the pathological type of lung cancer associated with AL amyloidosis was all adenocarcinoma.Conclusion: Such cases are rare but provide new insights into the relationship between amyloidosis and lung malignancies. The mechanism of amyloid protein deposition in relation to lung cancer or malignancies remains unknown, further research in this field is warranted.Keywords: amyloidosis, adenocarcinoma, lung cancer, comorbidity

Abstract Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largely unknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine. By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, including free SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cys redox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteins modified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved in immunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasing with age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cys modifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signaling pathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidative stress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. This work decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulators of oxidative stress and redox signaling.

Measuring pore-water pressure (PWP) in frozen soils poses significant challenges in geotechnical testing experiments, and understanding PWP is crucial for unraveling the mechanism of frost heave generation in cold regions. This paper aims to clarify the development pattern of PWP in frozen soil through laboratory tests, specifically focusing on excess PWP generated under dynamic loading. Seven sets of triaxial tests were conducted to investigate the variations in excess PWP and deformation influenced by temperature, dynamic stress amplitude, and dry density. The results reveal that excess PWP in warm saturated frozen soil undergoes two stages: pore pressure increase and dissipation. The change of external factors mainly affects the peak value of excess PWP and the change rate of excess PWP. Unlike unfrozen soil, excess PWP has a small dissipation rate after the peak and may remain dynamically stable in the later stage of loading. In addition, two empirical models of excess PWP applicable to saturated frozen soils were proposed based on the developmental patterns of excess PWP in frozen soils, and the feasibility was validated using the results obtained from laboratory tests. The model is of great significance for predicting the development of excess PWP in frozen soil under dynamic load.

The low egg production of goose greatly limits the development of the industry. China possesses the most abundant goose breeds resources. In this study, genome resequencing data of swan goose (Anser cygnoides) and domesticated high and low laying goose breeds (Anser cygnoides domestiation) were used to identify key genes related to egg laying ability in geese and verify their functions. Selective sweep analyses revealed 416 genes that were specifically selected during the domestication process from swan geese to high laying geese. Furthermore, SNPs and Indels markers were used in GWAS analyses between high and low laying breed geese. The results showed that RTCB, BPIFC, SYN3, SYNE1, VIP, and ESR1 may be related to the differences in laying ability of geese. Notably, only ESR1 was identified simultaneously by GWAS and selective sweep analysis. The genotype of Indelchr3:54429172, located downstream of ESR1, was confirmed to affect the expression of ESR1 in the ovarian stroma and showed significant correlation with body weight at first egg and laying frequency of geese. CCK-8, EdU, and flow cytometry confirmed that ESR1 can promote the apoptosis of goose pre-hierarchical follicles ganulosa cells (phGCs) and inhibit their proliferation. Combined with transcriptome data, it was found ESR1 involved in the function of goose phGCs may be related to MAPK and TGF-beta signaling pathways. Overall, our study used genomic information from different goose breeds to identify an indel located in the downstream of ESR1 associated with goose laying ability. The main pathways and biological processes of ESR1 involved in the regulation of goose laying ability were identified by cell biology and transcriptomics methods. These results are helpful to further understand the laying ability characteristics of goose and improve the egg production of geese.

Abstract Objectives To quantitatively assess the differences in parameters of dynamic contrast-enhanced MRI (DCE–MRI) in HER2-zero, HER2-low, or HER2-positive tumors, and to build optimal model for early prediction of HER2-low breast cancer (BC). Materials and methods Clinical and DCE–MRI data from 220 BC patients receiving neoadjuvant chemotherapy (NACT) were retrospectively analyzed. Quantitative and semi-quantitative DCE–MRI parameters were compared in the HER2-zero, HER2-low, or HER2-positive groups before and after early NACT. Empirical models were developed to predict HER2-low BC using logistic regression analysis and receiver operating characteristic (ROC) analysis. Results Patients of HER2-low BC have a lower pCR rate compared with HER2-zero and HER2-positive (17.9% vs. 10.4% vs. 29.5%, p

Abstract# It is worth mentioning that the Chinese version of this guideline has been published in the Chinese Journal of Multiple Organ Diseases in the Elderly (Chinese version) in the July 28, 2024 Guidelines and Consensus Column, Vol. 23, No. 7, pages 481-490.: With the rapid advancement of digitalization and intelligence in the medical field, a plethora of cutting-edge technologies are gradually being applied to revolutionize healthcare. In the medical data security privacy protection and artificial intelligence encryption computing, blockchain stands out due to its inherent characteristics of traceability, tamper-proofing, and high credibility. Although blockchain technology has been applied in various industries, its application in the medical field needs more driving force, and its development needs to be standardized. This clinical practice guideline is developed following the World Health Organization's recommended process, adopting Grading of Recommendations Assessment, Development and Evaluation in assessing evidence quality. Considering the integration of blockchain and medical scenarios, we focus on the value and implementability of practical medical applications and provide the guidance on the construction and application of medical blockchain. This practice guideline includesd 10 potential medical application scenarios and usage frameworks. It is worth highlighting that electronic medical record sharing, drug and device anti-counterfeiting, medical digital intellectual property protection, and public health management are considered to be the most easily implemented and effective medical scenarios. The recommendations in this guideline were formulated based on the consideration of stakeholder values and preferences, resource utilization, feasibility, and acceptability, may have a profound impact on the construction of medical blockchain-related scenarios in China and internationally.Registration: Practice Guidance Registration for Transparency (PREPARE) website (http://www.guidelines-registry.cn) Registration No. PREPARE-2023CN637.

Abstract The intricate regulatory roles of small non-coding RNAs (sncRNAs), including PIWI-interacting RNAs (piRNAs) and microRNAs (miRNAs), have been increasingly recognized in the modulation of cellular functions and are associated with the pathogenesis of various diseases, notably cancer. However, the specific dysregulation patterns of sncRNAs in non-muscle-invasive bladder cancer (NMIBC) have yet to be fully delineated, highlighting a significant gap in our current understanding. To elucidate the expressional dynamics of sncRNAs for patients with NMIBC, we characterized the profile of piRNAs and miRNAs by next-generation sequencing. We identified the differentially expressed sncRNAs between tumor and paracancerous tissues and characterized their distribution along the genome. We further revealed a set of immune-related piRNAs and dysregulated miRNAs that might be associated with NMIBC pathogenesis. Differentially expressed piRNAs were predominantly localized at the long arms of chromosomes 13, 1, and 6. Notably, the targets of specific piRNAs, including piR-hsa-2215234, piR-hsa-105306, piR-hsa-102066, and piR-hsa-236465, show significant associated with antigen processing and presentation pathway. Additionally, differentially expressed miRNAs are mainly located on chromosome 14 and their target genes tend to be involved in cancer-related pathways, suggesting their potential regulatory roles in NMIBC. Collectively, this study revealed the global sncRNA dysregulation in NMIBC, and the identified sncRNAs are implicated in the modulation of both immune and cancer pathways, suggesting their contribution to the pathogenesis and potential targets for immunotherapy.

Background: High-intensity Focused Ultrasound (HIFU) is a rapidly developing non-invasive treatment method for tumors in recent years.Objective: The present study aimed to investigate the lesion and temperature effects of HIFU combined with different concentrations and volumes of ethanol on porcine liver.Material and Methods: In this experimental study, different concentrations and volumes of ethanol were injected into the focal area of porcine liver using B-mode ultrasound, and the focal temperature was monitored using a k-type needle thermocouple. The peak negative pressure and sound intensity at the focal point of porcine liver were calculated by Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation. Further, the presence of cavitation effects within porcine liver was further determined by ultrasound hyperechoic. The differences in lesion volume and temperature, caused by different concentrations and volumes of ethanol on porcine liver, were measured.Results: HIFU irradiation combined with ethanol injection caused greater lesion volume and higher focal temperature in porcine liver. At the same HIFU irradiation power, an increase in the volume of ethanol resulted in an increase in lesion volume and focal temperature. At a fixed volume of ethanol injected and HIFU irradiation power, higher ethanol concentrations resulted in higher lesion volumes and focal temperature. Conclusion: The combination of HIFU and ethanol synergistically affects the lesion of porcine liver, manifested as the larger the ethanol concentration and volume, the larger the lesion volume and the higher the focal temperature.

Abstract Background Mother-to-child transmission (MTCT) is one of the main routes of transmission of HBV, and previous studies focused on the efficacy and safety of nucleoside analogues (NAs) in preventing MTCT. There are limited data on virologic changes of chronic hepatitis B (CHB) patients after discontinuing treatment postpartum and the efficacy of retreatment. Methods A retrospective-prospective real-world pilot cohort study on pregnant women with CHB was conducted. Biochemical and virological characteristics (HBsAg, HBeAg and HBV DNA) in patients received NAs treatment pre-pregnancy (n = 24), patients discontinued treatment after delivery (n = 88) and retreatment patients (n = 22) were collected during follow-up. Results The incidences of HBeAg clearance, half decrease of HBsAg, 0.5 lg decrease of HBsAg and HBsAg

Abstract Fetal liver hematopoietic stem cells (HSCs) have the capacity to temporarily engraft, thereby facilitating the reconstitution of hematopoiesis without severe graft-versus-host disease (GVHD). In two cases of acute leukemia, the patients underwent fetal liver transplantation (FLT), receiving cells from multiple donors at doses ranging from 7.02 to 8.3 × 10^8 cells/kg, following an intensive conditioning regimen in 1983 and 1985. Remarkably, both individuals have since achieved sustained complete remission and hematopoietic recovery, and have maintained a normal life for over three decades. Although FLT is no longer a viable clinical option, the positive outcomes of these cases are noteworthy and are shared herein. Our findings underscore the potential of FLT to offer short-term hematopoietic support, contributing to the recovery of patients with acute leukemia and may inspire research into ideal HSCs that emulate the characteristics of fetal liver cells for future transplantation applications.

Abstract Symmetry elegantly governs the fundamental properties and derived functionalities of condensed matter. For instance, realizing the superconducting diode effect (SDE) demands breaking space-inversion and time-reversal symmetries simultaneously. Although the SDE is widely observed in various platforms, its underlying mechanism remains debated, particularly regarding the role of vortices. Here, we systematically investigate the nonreciprocal transport in the chiral type-I superconductor NbGe2. Moreover, we induce type-II superconductivity with elevated superconducting critical temperature on the artificial surface by focused ion beam irradiation, enabling control over vortex dynamics in NbGe2 devices. Strikingly, we observe negligible diode efficiency (Q

Abstract The Salt Lake Mahai in Qaidam Basin, western China contains large and thick lithium-rich clay sediments that exhibit great economic potential for lithium exploration. This study analyzed the occurrence of lithium and related dissolution mechanisms in these clay through mineral identification, chemical analyses, and monitoring of brine composition evolution. Our results show that lithium-rich clay mainly occurred as interbeds between salt layers and fillings between salt crystals. The dominant clay mineral is illite, followed by chlorite, kaolinite, and an illite–smectite mixed layer. The leached lithium content in brine was less than 10% of the total lithium content in the clay samples. Lithium commonly occurred as structurally incorporated or adsorbed pattern within the clay minerals, particularly illite, leading to a relatively slow dissolution rate in brine during leaching. Consequently, optimizing the solvent injection points based on the distribution of silt-bearing and clay-bearing halite, particularly in the eastern and northwestern sections of Salt Lake Mahai where leached lithium concentrations are higher (45 ~ 70 mg/L), and extending the contact time between solvent and ore layers could further enhance lithium recovery.

Abstract Percutaneous transthoracic puncture of small pulmonary nodules is technically challenging. We developed a novel electromagnetic navigation puncture system for the puncture of sub-centimeter lung nodules by combining multiple deep learning models with electromagnetic and spatial localization technologies. We compared the performance of DL-EMNS and conventional CT-guided methods in percutaneous lung punctures using phantom and animal models. In the phantom study, the DL-EMNS group showed a higher technical success rate (95.6% vs. 77.8%, p = 0.027), smaller error (1.47 ± 1.62 mm vs. 3.98 ± 2.58 mm, p

Abstract Background Enolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its impact on mitophagy under bortezomib-induced apoptosis. Methods The bone marrow of clinical MM patients and healthy normal donors was used to compare the expression level of ENO1. Using online databases, we conducted an analysis to examine the correlation between ENO1 expression and both clinicopathological characteristics and patient outcomes. To investigate the biological functions of ENO1 in MM and the underlying molecular mechanisms involved, we conducted the following experiment: construction of a subcutaneous graft tumor model, co-immunoprecipitation, western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and cell functional assays. Results ENO1 was identified as an unfavorable prognostic factor in MM. ENO1 knockdown suppresses tumorigenicity and causes cell cycle arrest. Inhibition of ENO1-regulated mitophagy sensitizes tumor cells to apoptosis. ENO1 enhanced the stability of the YWHAZ protein by increasing the acetylation of lysine in YWHAZ while antagonizing its ubiquitination, which in turn promoted mitophagy. HDAC6 mediates the deacetylation of YWHAZ by deacetylating the K138 site of YWHAZ. Inhibition of HDAC6 increased YWHAZ acetylation and decreased YWHAZ ubiquitination. Furthermore, combination treatment with bortezomib and pharmaceutical agents targeting ENO1 has synergistic anti-MM effects both in vivo and in vitro. Conclusion Our data suggest that ENO1 promotes MM tumorigenesis and progression. ENO1 activates mitophagy by promoting the stability of YWHAZ and inhibits apoptosis and thus, leads to the drug resistance. ENO1-dependent mitophagy promotes MM proliferation and suppresses the level of bortezomib-induced apoptosis. Inhibition of ENO1 may represent a potential strategy to reverse the resistance of MM to bortezomib.

Abstract Ciprofol, a novel γ-aminobutyric acid receptor agonist, outperforms propofol with minimal cardiovascular effects, higher potency, reduced injection pain, and a broader safety margin. Despite these advantages, ciprofol’s clinical research is still emerging. This study compares the median effective dose (ED50) and adverse reactions of ciprofol and propofol, in conjunction with sufentanil, for suppressing cardiovascular responses during tracheal intubation. Fifty-three adult patients scheduled for tracheal intubation under general anesthesia were enrolled and randomly assigned to receive either ciprofol (Group C) or propofol (Group P), according to a random number table. Tracheal intubation was performed using a standardized laryngoscope and endotracheal tube. The Dixon’s up-and-down method was employed to determine the ED50 and 95% effective dose (ED95) of ciprofol and propofol in inhibiting cardiovascular responses during tracheal intubation. Based on the pilot study, the initial dose for ciprofol was set at 0.35 mg/kg (with a 0.01 mg/kg increment) and for propofol at 2.0 mg/kg (with a 0.1 mg/kg increment). Probit analysis was applied to derive dose-response curves, while adverse reactions were continuously monitored. A total of 54 participants were included, with 24 in group C (1 excluded) and 30 in group P. Probit analysis revealed that the ED50 of ciprofol for inhibiting cardiovascular responses to tracheal intubation were 0.326 mg/kg (95% CI 0.304–0.337 mg/kg), and for propofol, 1.541 mg/kg (95% CI 1.481–1.599 mg/kg). The heart rate in group P was significantly higher than the group C at 1 minute (p = 0.026) and 3 minutes (p = 0.016) post-intubation. Systolic and diastolic blood pressures (SBP and DBP) decreased significantly before and after intubation compared to baseline values in both groups (p< 0.05). Group C experienced significantly less injection pain (p = 0.001), although the incidence of other adverse effects was not statistically different between groups (p > 0.05). Clinical Trial Registration: hppts://ClinicalTrials.gov; Identifier: NCT06095570(18/10/2023).

Abstract The study aimed to elucidate the underlying pharmacological mechanism of the traditional Chinese medicine Pue in ameliorating myocardial ischemia-reperfusion injury (MIRI), a critical clinical challenge exacerbated by reperfusion therapy. In vivo MIRI and in vitro anoxia/reoxygenation (A/R) models were constructed. The results demonstrated that Pue pretreatment effectively alleviated MIRI, as manifested by diminishing the levels of serum CK-MB and LDH, mitigating the extent of myocardial infarction and enhancing cardiac functionality. Additionally, Pue significantly alleviated histopathological damage in MIRI-treated myocardium, as evidenced by HE staining and TUNEL assay. In vitro, Pue pretreatment significantly alleviated A/R-induced damage by decreasing LDH levels, increasing cellular activity, inhibiting autophagic lysosomal overactivation, inhibiting oxidative stress (ROS, LIP ROS, MDA), increasing antioxidant defense (SOD, GSH-Px), and increasing P62 protein expression while decreasing LC3II/I ratio. Furthermore, Pue inhibited apoptosis and maintained mitochondrial homeostasis by up-regulating the expression of Hairy and Enhancer of Split-1 (HES1) protein, which was crucial for its cardioprotective effects. Nevertheless, the cardioprotective efficacy of Pue pretreatment was negated via the knockdown of HES1 protein expression via pAD/HES1-shRNA transfection. In conclusion, Pue effectively ameliorated HES1-mediated MIRI-induced autophagy, apoptosis, and mitochondrial dysfunction.

Abstract We present SiCLAT, which introduces a dCas9-dCas13d cassette into the mouse genome. This model enables the stable expression of both dCas9 and dCas13 proteins in diverse cell populations, facilitating concurrent labeling of DNA and RNA across various cell types. Using SiCLAT, we accurately labeled chromatin loop anchor interactions and associated gene transcription during myogenic differentiation. This imaging system offers a novel means of directly observing cis-element interactions and the corresponding gene transcription in living primary cells, thus providing real-time imaging for comprehensive mechanistic investigations of dynamic enhancer-promoter or enhancer-enhancer interactions in regulating transcription activation within living cells.

Abstract Background Survival prediction accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in extra-nodal natural killer/T-cell lymphoma (ENKTL) is controversial. This study aimed to evaluate the prognostic value of 18F-FDG PET/CT parameters including maximum standardized uptake value (SUVmax), total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG), and to develop a new prognostic model for ENKTL. Methods We analyzed 390 ENKTL patients with comprehensive clinical and survival data. All patients received asparaginase-based chemotherapy with or without radiotherapy, or radiotherapy alone. Metabolic tumor volume (MTV) was calculated using a 41% SUVmax threshold, and TLG was computed as MTV multiplied by the average SUV. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier curves and compared with log-rank tests. Optimal cut-off values were determined using the Youden’ index. Cox regression analysis identified significant prognostic factors. A nomogram predicting 1-, 3-, and 5-year survival was developed and validated using the C-index and calibration curves. Statistical significance was set at p 12.8, TMTV > 16.4 cm3, and TLG > 137.0, were significantly associated with poorer OS (p = 0.009) and PFS (p = 0.003). Multivariable Cox regression identified the following as independent predictors of worse OS: age > 60 years (HR = 1.923, 95% CI: 1.001—3.693), presence of B symptoms (HR = 1.861, 1.132—3.059), ECOG score ≥ 2 (HR = 2.076, 1.165—3.699), extranodal involvement ≥ 2 sites (HR = 2.349, 1.384—3.988), bone marrow involvement (HR = 4.884, 2.137—11.163), SUVmax > 12.8 (HR = 2.226, 1.260—3.930), and TMTV > 16.4 cm3 (HR = 1.854, 1.093—3.147). The new prognostic model achieved a C-index of 0.772 for OS and 0.750 for PFS in the training set, and 0.777 for OS and 0.696 for PFS in the validation set. Area under the curve (AUC) values for 1-, 3-, and 5-year OS were 0.841, 0.804, and 0.767 in the training set, and 0.718, 0.786, and 0.893 in the validation set. Risk stratification divided patients into four groups with significant differences in survival (p

Abstract Recent advancements in large language models (LLMs) show significant potential in medical applications but are hindered by limited specialized medical knowledge. We present Me-LLaMA, a family of open-source medical LLMs integrating extensive domain-specific knowledge with robust instruction-following capabilities. Me-LLaMA is developed through continual pretraining and instruction tuning of LLaMA2 models using diverse biomedical and clinical data sources (e.g., biomedical literature and clinical notes). We evaluated Me-LLaMA on six text analysis tasks using 12 benchmarks (e.g., PubMedQA and MIMIC-CXR) and assessed its clinical utility in complex case diagnosis through automatic and human evaluations. Me-LLaMA outperforms existing open medical LLMs in zero-shot and supervised settings and surpasses ChatGPT and GPT-4 after task-specific instruction tuning for most text analysis tasks. Its performance is also comparable to ChatGPT and GPT-4 for diagnosing complex clinical cases. Our findings highlight the importance of combining domain-specific continual pretraining with instruction tuning to enhance performance in medical LLMs.

Chuanchuan Dong, Fei Hu, Zhen Ma, Xinkai Ma, Lulu Zhang, Yupeng Li, Xianglin Du, Liting Feng, Rujie Huo, Yanqing Xing, Peiqi Li, Yanting Dong, Erjing Cheng, Xinrui Tian,&ast; Min Huang&ast; The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinrui Tian, Email tianxr@126.com; Min Huang, Email 147652857@qq.comBackground: The lifting of the regional blockade in early December 2022 in Shanxi Province, China, caused an epidemic of Coronavirus disease 2019 (COVID-19). And the high allergy season from July to September each year.Purpose: To investigate the effect of the COVID-19 epidemic on the respiratory sensitivity status of the population, to provide a scientific and effective basis for the prevention, diagnosis, condition assessment, and treatment of allergic respiratory diseases.Methods: We collected 500 outpatient cases from Shanxi Medical University Second Hospital during the period from July to September 2022 and 500 cases during the period from July to September 2023 and divided them into the pre-COVID-19 epidemic group (the 2022 group) and the post-COVID-19 epidemic group (the 2023 group). We conducted statistical analysis on these patients’ general conditions, pulmonary function test results, laboratory parameters, and fractional exhaled nitric oxide.Results: Compared with 2022, the number of smokers decreased in 2023 (p = 0.007), while the incidence of respiratory allergic diseases such as bronchial asthma and allergic rhinitis increased (p < 0.05). In 2023, the results of pulmonary function tests showed that the positive rate of bronchial provocation/dilatation tests increased (p < 0.001), and the decline in FEV1 during provocation tests became more significant (p < 0.001). At the same time, laboratory results indicated that the count of eosinophils and the level of immunoglobulin E (IgE) in peripheral blood rose (p < 0.001), suggesting that the respiratory sensitivity of the population after COVID-19 infection might have increased.Conclusion: Research results from Shanxi Province, China, indicate that the COVID-19 epidemic leads to increased respiratory sensitization and the incidence of respiratory allergic diseases. This suggests that we should pay attention to the changes in immune status and respiratory sensitivity among the population after COVID-19 infection, to accurately and timely assess and intervene in patients’ conditions.Keywords: COVID-19, airway hyper responsiveness, lung function, IgE

Attaining sustainability and carbon neutrality necessitates a transition towards cleaner biorefinery, while the exploitation of sustainable and eco-friendly pretreatment techniques, as a pivotal stage in lignocellulose biorefinery, represents a challenge. Here, an ultrafast biomass pretreatment strategy enabled by microwave (MW) responsive deep eutectic solvent (DES) is proposed. The solvent properties (Kamlet-Taft parameters) of DES under MW participation are closely correlated with wheat straw fractionation efficiency. The lignin removal exhibits a positive correlation with polarity/polarizability (π*) and hydrogen-bond-donating ability (α), establishing a strong relationship between the tunable DES properties and MW responsiveness. MW reinforces the delignification efficiency of DES with relatively high π* and α, as corroborated by comparative analysis with conventional heating (CH) pretreatment. The reinforcement by MW moderates the pretreatment process and enables ultrafast lignocellulose deconstruction (130 ℃, 150 s, and 96.1% lignin removal), subsequently with 92.4% enzymatic hydrolysis and 8.8 g microbial lipid/100 g wheat straw at a remarkably low severity factor (R0). Life cycle assessment manifests the environmental benefits of MW-assisted DES in mitigating impacts by 63.1%, including global warming potential, resource depletion-fossil fuels, and ecotoxicity, in comparison to CH pretreatment. MW-DES exhibits an economic superiority based on life cycle cost analysis, with pretreatment cost 44.1% lower than CH-DES. The mechanistic insights into MW intensification of DES with specific properties provide a viable protocol for tailoring green solvents with enhanced MW responsiveness for efficient and sustainable biorefineries.

Yunting Hu, Zheng Wang, Zengfa Huang, Yun Hu, Xiang Wang Department of Radiology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430013, People’s Republic of ChinaCorrespondence: Xiang Wang, Department of Radiology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430013, People’s Republic of China, Tel +8613971369643, Email 1368010210@qq.comObjective: Cardiovascular disease is the leading cause of death in postmenopausal women, and certain mammographic features have been linked to cardiovascular risk. This study aimed to investigate the association between mammographic features and the incidence of major adverse cardiac events (MACE) over a 10-year follow-up period in postmenopausal women.Methods: This retrospective cohort study included postmenopausal women with available mammographic data, including mammographic breast density (MBD), breast arterial calcification (BAC), and microcalcifications at the Central Hospital of Wuhan between January and December 2012. The primary outcome was the incidence of MACE over a 10-year period.Results: Among the 857 postmenopausal women, the average age was 59.51 ± 7.31 years. Participants were categorized into four MBD types: Type A (n=249), Type B (n=254), Type C (n=228), and Type D (n=126). Participants with Type B MBD exhibited the highest risk of MACE (13.7%), followed by Type A (10.6%), Type C (4.8%), and Type D (4.0%). Kaplan-Meier analysis revealed that MBD classification and BAC were significantly associated with MACE incidence (P < 0.05). The Cox proportional hazards regression found that type A (HR = 3.12, 95% CI: 1.21– 8.02), Type B (HR = 2.57, 95% CI: 0.98– 6.73) and BAC (HR = 2.37, 95% CI: 1.12– 5.0) were significantly associated with an increased risk of MACE. No significant correlation was found between microcalcifications and MACE risk (P > 0.05).Conclusion: Mammographic features such as MBD and BAC may be associated with an increased risk of MACE in postmenopausal women. These findings suggest that incorporating cardiovascular risk assessment into routine mammography screening could enhance health management and preventative strategies for postmenopausal women.Keywords: mammographic breast density, breast arterial calcification, major adverse cardiac events, cardiovascular risk, postmenopausal women, retrospective cohort study

Abstract. Background:. Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. Methods:. This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. Results:. Eighty-two patients were assigned to variant (n = 42) and wild type groups (n = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUCtau) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. Conclusion:. ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. Registration:. NCT04410965, https://clinicaltrials.gov.

Mengyi Li, Siyong Huang, Jiabao Li, Xiao Hu, Jisheng Chen Key Specialty of Clinical Pharmacy, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, People’s Republic of ChinaCorrespondence: Jisheng Chen, Key Specialty of Clinical Pharmacy, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong, 510080, People’s Republic of China, Tel +86 20-87622305, Fax +86 20-61321967, Email cjslym@163.comPurpose: In order to scientifically evaluate the clinical value of the comprehensive attributes of Calcitonin gene-related peptide (CGRP) inhibitor drugs, a comprehensive literature-based clinical evaluation of CGRP-targeted therapy drugs was conducted using the drug evaluation method modified by expert discussion in the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition).Methods: Based on evidence-based data and the relevant elements and weighting in the “Selection Guidelines” quantification record form for drug evaluation and selection in medical institutions, adjustments were made according to the characteristics of CGRP-targeted therapy drugs. We systematically evaluated erenumab, galcanezumab, fremanezumab, eptinezumab, rimegepant, ubrogepant, atogepant, zavegepant for safety, efficacy, economy, and pharmacological properties.Results: The final assessment result scores from highest to lowest were rimegepant (84.5 points), erenumab (75.78 points), galcanezumab (74.02 points), fremanezumab (73.93 points), atogepant (72.64 points), eptinezumab (71.69 points), ubrogepant (70.37 points), zavegepant (56.44 points).Conclusion: Rimegepant, erenumab, fremanezumab, atogepant, galcanezumab, eptinezumab, ubrogepant can be entered into the medication list of medical institutions as strongly recommended drugs.Keywords: calcitonin gene related peptide, CGRP, migraine, CGRP-targeted therapy drugs, rimegepant

Bo Yang,1– 3 Huiqun Cheng,1– 3 Yu Hu,1– 3 Yizhu Chen,1– 3 Yong Xu,1– 3 Wei Huang,1– 3 Yang Long,1– 3 Chenlin Gao1– 3 1Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Sichuan Clinical Research Center for Nephropathy, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Chenlin Gao, Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Tel +86-830-3165361, Email gaochenlin00@swmu.edu.cnBackground: Erectile dysfunction (ED) is considered one of the complications of diabetes mellitus (DM), affecting about 35– 75% of diabetic patients. Studies suggest that anti-diabetic drugs could potentially alleviate ED in diabetics, yet the effects of different drug classes remain unknown.Objective: Our study aims to investigate the influence of various anti-diabetic drugs on ED.Materials and Methods: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review and meta-analysis were carried out, focusing on clinical research linking anti-diabetic drugs and ED. Relevant studies were sought from PubMed, Embase, and Cochrane Library databases. Review Manager 5.4.1 facilitated meta-analysis and subgroup analysis, while Stata 15.1 was employed for sensitivity analysis to ensure result robustness.Results: An initial search yielded 3,906 articles across databases. After screening the titles and abstracts of 3,906 articles and performing a full-text review of 30 selected articles, we selected three studies for analysis ultimately. Our most significant finding is that glucagon-like peptide-1 receptor agonists (GLP-1RAs) show an advantage over metformin in improving erectile dysfunction in diabetic patients (Z = 2.41, P = 0.02), with a particularly notable effect observed in patients with higher BMI or obesity (Z = 2.26, P = 0.02). This suggests that GLP-1RAs may offer a promising therapeutic option for this patient population. Additionally, thiazolidinediones may enhance sexual function, although their safety and efficacy require further confirmation. Acarbose, insulin, and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) also show potential for positively impacting ED, but more research is needed to establish their efficacy. Finally, the impact of metformin and sulfonylureas on ED remains uncertain, with mixed evidence from existing studies.Conclusion: In conclusion, GLP-1RAs demonstrate an advantage over metformin in improving erectile dysfunction in diabetic patients. Other antidiabetic drugs also show potential for enhancing erectile function in this population, but further extensive clinical trials are needed to address knowledge gaps and safety concerns.Keywords: anti-diabetic drugs, erectile dysfunction, obesity, glucagon-like peptide-1 receptor agonists, vascular endothelial function

Aihua Yan,1,2,&ast; Xiangcheng Pan,1,3,&ast; Siyu Li,1 Yaxin Hu,4 Haiyang Zhang,5 Deyuan Li,5 Liang Huang1,3,4,6 1Department of Pharmacy and Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Pharmaceutical Preparation Section, Children’s Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People’s Republic of China; 4West China School of Pharmacy, Sichuan University, Chengdu, People’s Republic of China; 5Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 6Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liang Huang, Email hliang_1022@163.comBackground: Multidrug-resistant Gram-negative bacteria (MRGN) pose a significant threat and require priority attention. Polymyxin B (PMB) retains substantial activity against MRGN and makes it potentially the last resort therapy for MRGN infections in children. To assess the effectiveness and safety of PMB in treating MRGN infections in Chinese children.Methods: Paediatric patients aged 0– 18 years who were treated with PMB for MRGN infections were enrolled in the study. These cases were then compared with those identified in a literature review. In logistic regression, three independent variables were used for analyzing clinical effectiveness, and two for nephrotoxicity.Results: A cohort of 54 children was included in study and 24 eligible literature of 259 children were included in literature review. Out of the 54 patients, 53.7% showed favorable clinical responses, while 13.0% died during their hospitalization, of which 3.7% died within 30 days after receiving PMB. AKI was observed in 25.9% patients with 11.1% risk stage, 7.4% injury stage and 7.4% failure stage. The PMB co-administration with carbapenems was associated with significantly higher effectiveness (odds rate [OR] = 3.16, 95% confidence interval [CI]: 1.02– 9.86, P = 0.05) and co-administration with potent diuretic (furosemide) may increase the risk of AKI (OR = 4.91, 95% CI: 0.96– 24.98, P = 0.05).Conclusion: PMB has advantages in treating MRGN infections in paediatric patients, showing favorable clinical responses and pathogen clearance. AKI is a notable safety concern. The small sample size might hinder reliable identification of factors affecting clinical effectiveness and adverse effects.Keywords: polymyxin B, multidrug-resistant gram-negative bacteria, children, effectiveness, acute kidney injury

Abstract At present, there is insufficient evidence to evaluate the prognosis of patients with sepsis. This study anazed the clinical data of 822 sepsis patients in the ICU of a tertiary Grade A hospital to construct and validate a nomogram model for predicting the 28-day mortality risk in sepsis patients. The model was constructed using multivariate logistic regression analysis to screen for independent risk factors affecting prognosis, and a mortality risk prediction model was built based on these independent risk factors. The performance of the model was evaluated using the Hosmer–Lemeshow test, receiver operating characteristic curve (ROC), calibration plot, and decision curve analysis (DCA). Multivariate logistic regression identified five independent risk factors for 28-day mortality in sepsis patients: Age, SOFA score, CRP, Mechanical ventilation, and the use of Vasoactive drugs. The odds ratios (OR) and 95% confidence intervals (95% CI) for these factors were 1.037 (1.024–1.050), 1.093 (1.044–1.145), 1.034 (1.026–1.042), 1.967 (1.176–3.328), and 2.515 (1.611–3.941), respectively, with all P-values

Hongsong Peng,1,2,&ast; Qiang Hu,1,2,&ast; Xue Zhang,1,2,&ast; Jiayang Huang,1,2 Shan Luo,1,2 Yiming Zhang,1 Bo Jiang,1 Dawei Sun1 1Department of Ophthalmology, The second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 2Future Medical Laboratory, The second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dawei Sun, Department of Ophthalmology, The second Affiliated Hospital of Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang, 150086, People’s Republic of China, Email sundawei@hrbmu.edu.cnBackground: Diabetic retinopathy (DR), a microvascular disorder linked to diabetes, is on the rise globally. Oxidative stress and immune cell infiltration are linked to illness initiation and progression, according to recent study. This study investigated biomarkers connected to DR and oxidative stress and their connection with immune cell infiltration using bioinformatics analysis and found possible therapeutic medications.Methods: The Gene Expression Omnibus (GEO) database was used to obtain the gene expression data for DR. Differentially expressed genes (DEGs) and oxidative stress (OS)-related genes were intersected. The Enrichment analyses concentrate on OS-related differentially expressed genes (DEOSGs). Analysis of protein-protein interaction (PPI) networks and machine learning algorithms were used to identify hub genes. Single-gene Gene Set Enrichment Analysis (GSEA) identified biological functions, while nomograms and ROC curves assessed diagnostic potential. Immune infiltration analysis and regulatory networks were constructed. Drug prediction was validated through molecular docking, and hub gene expression was confirmed in dataset and animal models.Results: Compared to the control group, 91 DEOSGs were found. Enrichment analyses showed that these DEOSGs were largely connected to oxidative stress response, PI3K/Akt pathway, inflammatory pathways, and immunological activation. Four hub genes were found via PPI networks and machine learning. These hub genes were diagnostically promising according to nomogram and ROC analysis. Analysis of immune cell infiltration highlighted the role of immune cells. Gene regulatory networks for transcription factor (TF) and miRNA were created. Using structural data, molecular docking shows potential drugs and hub genes have high binding affinity. Dataset analysis, Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and Western Blot (WB) confirmed the CCL4 expression difference between DR and controls.Conclusion: CCL4 was identified as potential oxidative stress-related biomarker in DR, providing new insights for DR diagnosis and treatment.Keywords: diabetic retinopathy, oxidative stress, hub genes, immune infiltration, molecular docking

Abstract Background Gastric cancer (GC) is one of the most common malignant tumors in the digestive system. However, the development of its targeted therapies has been slow. Therefore, exploring the mechanisms of malignant behavior of GC is key to developing their treatment methods. Pregnancy-associated plasma protein-A(PAPPA) is thought to play an important role in the occurrence and progression of cancer, yet its significance in the development of GC has not been reported. Methods Bioinformatics analysis elucidated PAPPA's expression in GC and its prognostic significance. The study correlated PAPPA expression with immune infiltration and signaling pathways. Cellular assays, including CCK-8, Western blotting, and flow cytometry, were utilized to examine PAPPA's role in gastric cancer cell apoptosis, migration, and invasion. Results Bioinformatics analysis has demonstrated that the expression of PAPPA is upregulated in GC and correlates with poor prognosis. Correlation and Cox regression analyses have revealed that TNM staging, pathological staging, age, outcome assessment, postoperative tumor residue, and PAPPA expression are prognostic determinants in GC. Further analysis indicates that PAPPA is associated with the infiltration of various immune cells and pathways related to GC. Cellular experiments have shown that PAPPA promotes cell proliferation, and its deficiency can inhibit the proliferation of GC cells, inducing cell cycle arrest at the G1/S phase. Conclusions The findings of this investigation suggest that PAPPA serves as a crucial modulator of GC, underscoring its potential as a GC treatment target.

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (TNANC), time to symptom improvement (TSI), and time of hospital stay (THS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67–0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66–0.88; P

Yuanyuan Sun,&ast; Lei Zhang,&ast; Baisong Huang, Quanwei He, Bo Hu Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Quanwei He; Bo Hu, Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan , 430022, People’s Republic of China, Tel +8613554111043 ; +8613707114863, Email hequanwei2008@126.com; hubo@mail.hust.edu.cnBackground: Pneumonia is among the most dangerous complications of infection after intracerebral hemorrhage. We aimed to create a novel nomogram for pneumonia after intracerebral hemorrhage.Methods and Results: The data from the Chinese Cerebral Hemorrhage: Mechanism and Intervention (CHEERY) study was analyzed. Thirty percent of qualified patients were placed in the validation group (n=763) while seventy percent of them were randomly placed in the training group (n=1784). In the multivariate analysis, ten variables were included in the model: age (β= 0.023, P< 0.001), hospital days (β=0.392, P< 0.001), baseline mRS score (β=0.484, P< 0.001), baseline GCS score (β=− 0.285, P< 0.001), hs-CRP (β=0.328, P< 0.001), hematoma volume (β=0.376, P< 0.001), brainstem hemorrhage (β=0.956, P=0.002), intraventricular hemorrhage (β=0.629, P=0.001), and β-blocker (β=0.899, P< 0.001) In the training subset, the areas under curve were 0.805 (95% CI, 0.773– 0.833). The model was subsequently examined in the validation group, with the area under curve 0.767 (95% CI, 0.716– 0.807). There was strong agreement between the anticipated and actual survival rates in the nomogram calibration curves for both the training and validation groups. The clinical value of the model is assessed by means of Decision Curve Analysis. In addition, we validated other models with this cohort, which showed that our model had better discrimination. Moreover, the area under the curve of the catboost model established using the above nine variables in the training set and the validation set is 0.87(95% CI, 0.80– 0.90) and 0.77(95% CI, 0.72– 0.80).Conclusion: We have established a simple and easy predictive tool. By evaluating the incidence of pneumonia after intracerebral hemorrhage, we can identify high-risk groups early. At the same time, our study also suggests that doctors should be cautious in the use of β-blocker in clinical decision-making.Keywords: pneumonia, inflammation, intracerebral hemorrhage, nomogram, β-blocker

Abstract This study aimed to investigate whether lymphocyte-C-reactive protein ratio (LCR) upon admission can predict disease progression and intensive care unit (ICU) admission in adult patients with diabetic ketoacidosis (DKA). A single-center retrospective study was conducted, including adult DKA patients admitted to the First Affiliated Hospital of Harbin Medical University between March 2018 and March 2023. Multiple demographic and clinical data were collected from the medical records upon admission and during hospitalization. Subsequently, sequential organ failure assessment (SOFA) score and LCR were calculated based on relevant clinical parameters within 24 h of admission. These indicators were compared among different disease severity groups, and factors related to severe DKA, concurrent acute kidney injury (AKI), and ICU admission were further analyzed. Receiver operating characteristic (ROC) curve analysis was performed to determine the sensitivity, specificity, area under the ROC curve (AUC), and cut-off value of LCR. A total of 271 adult DKA patients were enrolled and categorized into three groups: mild group (n = 42), moderate group (n = 64), and severe group (n = 165). Significant differences in demographic and clinical data were observed among these groups. Glasgow coma scale (GCS) score, LCR, pH, and bicarbonate (HCO3 -) were identified as protective factors for severe DKA. Conversely, SOFA score, neutrophil count (NEUT), serum creatinine (SCr), and glucose (GLU) were risk factors for concurrent AKI. Concurrent AKI and SOFA score were risk factors for ICU admission, while pH was a protective factor. The areas under the ROC curve (AUC) of LCR to classify adult DKA patients into mild group, severe group, and ICU admission were 0.679, 0.718, and 0.621, respectively, with cut-off value of 212.80, 96.16, and 63.35, sensitivity of 54.8%, 76.4%, and 78.9%, and specificity of 76.0%, 62.4%, and 46.3%. LCR upon admission provides great potential to predict disease progression and ICU admission in adult patients with DKA.

Abstract Accurately and swiftly characterizing the state of polarization (SoP) of complex structured light is crucial in the realms of classical and quantum optics. Conventional strategies for detecting SoP, which typically involves a sequence of cascaded optical elements, are bulky, complex, and run counter to miniaturization and integration. While metasurface-enabled polarimetry has emerged to overcome these limitations, its functionality predominantly remains confined to identifying SoP within the standard Poincaré sphere framework. The comprehensive detection of SoP on the higher-order Poincaré sphere (HOPS), however, continues to be a huge challenge. Here, we propose a general polarization metrology method capable of fully detecting SoP on any HOPS through a single measurement. The underlying mechanism relies on transforming the optical singularities and Stokes parameters into visualized intensity patterns, facilitating the extraction of all parameters that fully determine a SoP. We actualize this concept through a novel meta-device known as the metasurface photonics polarization clock, which offers an intuitive display of SoP using four distinct pointers. As a proof of concept, we theoretically and experimentally demonstrate fully resolving SoPs on the 0th, 1st, and 2nd HOPSs. Our implementation opens up a new pathway towards real-time polarimetry of arbitrary beams featuring miniaturized size, a simple detection process, and a direct readout mechanism, promising significant advancements in fields reliant on polarization.

Yajun Qi,1– 3 Jian Liu,1,3 Yiming Chen,1,3 Yuedi Hu,1,3 Qiao Zhou,1,3 Dan Huang,1,3 Chengzhi Cong,1,3 Yang Li1,3 1The First College of Clinical Medicine, Anhui University of Chinese Medicine, Hefei, Anhui Province, 230031, People’s Republic of China; 2College of Acupuncture and Massage, Anhui University of Chinese Medicine, Hefei, Anhui Province, 230012, People’s Republic of China; 3Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, 230031, People’s Republic of ChinaCorrespondence: Jian Liu, Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, 230031, People’s Republic of China, Email liujianahzy@126.comObjective: This study evaluates whether Huangqin Qingre Chubi Capsule (HQC), a traditional Chinese medicine (TCM) compound, is associated with the risk of re-admission in patients with ankylosing spondylitis (AS).Methods: In this study, we retrospectively collected the clinical data of 1,296 AS patients. Patients were allocated into HQC and non-HQC groups. Baseline data between the two groups were matched with propensity score matching (PSM). Influencing factors for the risk of re-admission in AS patients were analyzed with the Cox proportional hazards model. The effect of HQC intervention duration on the risk of re-admission was assessed with Kaplan-Meier survival curves. The random walk model and association rule analysis were utilized to determine the correlation between HQC and improvements in immunoinflammatory markers.Results: The re-admission rate was significantly lower in the HQC group than in the non-HQC group (P < 0.01). The risk of re-admission was significantly lower in patients aged > 40 years (P < 0.01) than in patients aged < 40 years and also markedly lower in HQC users than in non-HQC users (P < 0.01), suggesting that age and the use of HQC were key factors influencing the risk of re-admission. Longer HQC intervention duration was associated with better improvements in ESR, CRP, and C4, and HQC was closely correlated with improvements in ESR, CRP, IgA, and C4.Conclusion: HQC treatment can reduce the risk of re-admission in AS patients, which may be associated with improvements in ESR, CRP, IgA, and C4. The risk decreases with prolonged HQC treatment.Keywords: Huangqin Qingre Chubi Capsule, ankylosing spondylitis, re-admission, cohort study, telephone follow-up

Abstract Mitochondrial homeostasis plays a crucial role in the pathogenesis of osteoarthritis (OA), a chronic musculoskeletal disorder characterized by articular cartilage degeneration and chondrocyte apoptosis. However, molecular mechanisms underlying the association between mitophagy and OA remain unclear. Here, we aimed to investigate the role of the autophagy receptor protein optineurin (OPTN) in OA, and explore the effects of dietary intervention on OA symptoms and its relationship with OPTN-mediated mitophagy. Our findings showed the downregulation of OPTN in patients with OA. Using an Optn-knockout mouse model, we demonstrated that OPTN deficiency leads to impaired mitophagy, resulting in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and chondrocyte apoptosis. Furthermore, fasting prevented OA progression by activating OPTN-mediated mitophagy and maintaining mitochondrial homeostasis in mice. The present study revealed a novel mechanism by which OPTN-mediated mitophagy influences chondrocytes and the OA phenotype in Optn-knockout mice, suggesting that OPTN-mediated mitophagy plays a crucial role in OA development and progression. This study provides new insights into the pathogenesis of OA and offers a potential avenue for the development of novel drugs targeting OPTN to mitigate OA progression.

Ting Li,1,2,&ast; Yuechu Zhao,3,&ast; Zhi Cao,2,&ast; Ying Shen,2 Jiaqi Chen,2 Xinran Huang,2 Zhuang Shao,2 Yi Zeng,2 Qi Chen,2 Xiaofei Yan,3 Xin Li,1,2 Yuelin Zhang,1,2 Bei Hu1,2 1School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China; 2Department of Emergency Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuelin Zhang; Bei Hu, Department of Emergency Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510080, People’s Republic of China, Tel +86-20-83827812-20974, Email zhangyuelin1999@163.com; qhubei@hotmail.comBackground: Exosomes sourced from mesenchymal stem cells (MSC-EXOs) have become a promising therapeutic tool for sepsis-induced myocardial dysfunction (SMD). Our previous study demonstrated that Apelin pretreatment enhanced the therapeutic benefit of MSCs in myocardial infarction by improving their paracrine effects. This study aimed to determine whether EXOs sourced from Apelin-pretreated MSCs (Apelin-MSC-EXOs) would have potent cardioprotective effects against SMD and elucidate the underlying mechanisms.Methods: MSC-EXOs and Apelin-MSC-EXOs were isolated and identified. Mice neonatal cardiomyocytes (NCMs) were treated with MSC-EXOs or Apelin-MSC-EXOs under lipopolysaccharide (LPS) condition in vitro. Cardiomyocyte pyroptosis was determined by TUNEL staining. RNA sequencing was used to identify differentially expressed functional miRNAs between MSC-EXOs and Apelin-MSC-EXOs. MSC-EXOs and Apelin-MSC-EXOs were transplanted into a mouse model of SMD induced by cecal ligation puncture (CLP) via the tail vein. Heart function was evaluated by echocardiography.Results: Compared with MSC-EXOs, Apelin-MSC-EXO transplantation greatly enhanced cardiac function in SMD mice. Both MSC-EXOs and Apelin-MSC-EXOs suppressed cardiomyocyte pyroptosis in vivo and in vitro, with the latter exhibiting superior protective effects. miR-34a-5p effectively mediated Apelin-MSC-EXOs to exert their cardioprotective effects in SMD with high mobility group box-1 (HMGB1) as the potential target. Mechanistically, Apelin-MSC-EXOs delivered miR-34a-5p into injured cardiomyocytes, thereby ameliorating cardiomyocyte pyroptosis via regulation of the HMGB1/AMPK axis. These cardioprotective effects were partially abrogated by downregulation of miR-34a-5p in Apelin-MSC-EXOs.Conclusion: Our study revealed miR-34a-5p as a key component of Apelin-MSC-EXOs that protected against SMD via mediation of the HMGB1/AMPK signaling pathway. Keywords: Exosomes, mesenchymal stem cells, apelin, sepsis-induced myocardial dysfunction, pyroptosis

JiangFei Zhou,1,&ast; SongSong Jiao,1,&ast; Jian Huang,2,&ast; TianMing Dai,3,&ast; YangYang Xu,1,&ast; Dong Xia,4,&ast; ZhenCheng Feng,1 JunJie Chen,1 ZhiWu Li,5 LiQiong Hu,4 QingQi Meng1,3 1Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People’s Republic of China; 2Qingdao Medical College, Qingdao University, Qingdao, 266071, People’s Republic of China; 3Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People’s Republic of China; 4Critical Care Medicine Department, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People’s Republic of China; 5Department of Orthopedics, the 2nd People’s Hospital of Bijie, Guizhou, 551700, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: LiQiong Hu; QingQi Meng, Email 13929526981@163.com; mengqingqi@jnu.edu.cnBackground: Synovitis is one of the key pathological feature driving osteoarthritis (OA) development. Diverse programmed cell death (PCD) pathways are closely linked to the pathogenesis of OA, but few studies have explored the relationship between PCD-related genes and synovitis.Methods: The transcriptome expression profiles of OA synovial samples were obtained from the Gene Expression Omnibus (GEO) database. Using machine learning algorithms, Hub PCD-related differentially expressed genes (Hub PCD-DEGs) were identified. The expression of Hub PCD-DEGs was validated in human OA samples by qRT-PCR. A diagnostic model for OA was constructed based on the expression levels of Hub PCD-DEGs. Unsupervised consensus clustering analysis and weighted correlation network analysis (WGCNA) were employed to identify differential clustering patterns of PCD-related genes in OA patients. The molecular characteristics of Hub PCD-DEGs, their role in synovial immune inflammation, and their association with the immune microenvironment were investigated through functional enrichment analysis and ssGSEA immune infiltration analysis. Single-cell RNA sequencing analysis provided insights into the characteristics of distinct cell clusters in OA synovial tissues and their interactions with Hub PCD-DEGs.Results: We identified five Hub PCD-DEGs: TNFAIP3, JUN, PPP1R15A, INHBB, and DDIT4. qRT-PCR analysis confirmed that all five genes were significantly downregulated in OA synovial tissue. The diagnostic model constructed based on these Hub PCD-DEGs demonstrated diagnostic efficiency in distinguishing OA tissues as well as progression of OA. Additionally, a correlation was observed between the expression levels of Hub PCD-DEGs, immune cell infiltration, and inflammatory cytokine levels. We identified two distinct PCD clusters, each exhibiting unique molecular and immunological characteristics. Single-cell RNA sequencing further revealed dynamic and complex cellular changes in OA synovial tissue, with differential expression of Hub PCD-DEGs across various immune cell types.Conclusion: Our study suggests that PCD-related genes may be involved in development of OA synovitis. The five screened Hub PCD-DEGs (TNFAIP3, JUN, PPP1R15A, INHBB and DDIT4) could be explored as candidate biomarkers or therapeutic targets for OA.Keywords: osteoarthritis, programmed cell death, bioinformatics, machine learning, immune infiltration, biomarkers