Search

Background: Upper extremity (UE) motor function impairment is a major poststroke complication whose recovery remains one of the most challenging tasks in neurological rehabilitation. This study examined the efficacy and safety of the personalized neuroimaging-guided high-dose theta-burst stimulation (TBS) for poststroke UE motor function recovery., Methods: Patients after stroke with UE motor impairment from a China rehabilitation center were randomly assigned to receive high-dose intermittent TBS (iTBS) to ipsilesional UE sensorimotor network, continuous TBS (cTBS) to contralesional UE sensorimotor network, or sham stimulation, along with conventional therapy for 3 weeks. The primary outcome was the score changes on the Fugl-Meyer assessment-UE from baseline to 1 and 3 weeks. The secondary outcomes included the response rate on Fugl-Meyer assessment-UE scores posttreatment (≥9-point improvement) and score changes in multidimensional scales measuring UE, lower extremity, and activities and participation., Results: From June 2021 to June 2022, 45 participants were randomized and 43 were analyzed. The iTBS and continuous TBS groups showed significantly greater improvement in Fugl-Meyer assessment-UE (mean improvement, iTBS: 10.73 points; continuous TBS: 10.79 points) than the sham group (2.43 points) and exhibited significantly greater response rates on Fugl-Meyer assessment-UE (iTBS, 60.0%; continuous TBS, 64.3%) than the sham group (0.0%). The active groups consistently exhibited superior improvement on the other 2 UE assessments at week 3. However, only the iTBS group showed greater efficacy on 1 lower extremity assessment than the sham group at week 3. Both active groups showed significant improvements in activities and participation assessments., Conclusions: The study provides evidence for the efficacy and safety of high-dose TBS in facilitating poststroke UE rehabilitation., Registration: URL: www.chictr.org.cn; Unique identifier: ChiCTR2100047340., Competing Interests: Dr Liu receives compensation from Neural Galaxy, Inc, for consultant services. R. Pan, M. Ding, and J. Sun are employees of the company, which is not a sponsor of this study. The other authors report no conflicts.

Background: Chemotherapeutic agents including cisplatin, gemcitabine, and pemetrexed, significantly enhance the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) by increasing PD-L1 expression and potentiating T cell cytotoxicity. However, the low response rate and adverse effects limit the application of chemotherapy/ICI combinations in patients., Methods: We screened for medicinal herbs that could perturb PD-L1 expression and enhance T cell cytotoxicity in the presence of anti-PD-L1 antibody, and investigated the underlying mechanisms., Results: We found that the aqueous extracts of Centipeda minima (CM) significantly enhanced the cancer cell-killing activity and granzyme B expression level of CD8 + T cells, in the presence of anti-PD-L1 antibody. Both CM and its active component 6-O-angeloylplenolin (6-OAP) upregulated PD-L1 expression by suppressing GSK-3β-β-TRCP-mediated ubiquitination and degradation. CM and 6-OAP significantly enhanced ICI-induced reduction of tumor burden and prolongation of overall survival of mice bearing NSCLC cells, accompanied by upregulation of PD-L1 and increase of CD8 + T cell infiltration. CM also exhibited anti-NSCLC activity in cells and in a patient-derived xenograft mouse model., Conclusions: These data demonstrated that the induced expression of PD-L1 and enhancement of CD8 + T cell cytotoxicity underlay the beneficial effects of 6-OAP-rich CM in NSCLCs, providing a clinically available and safe medicinal herb for combined use with ICIs to treat this deadly disease., 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 GmbH. All rights reserved.)

Post-translational modifications (PTMs) influence protein functionality by modulating protein stability, localization, and interactions with other molecules, thereby controlling various cellular processes. Common PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, SUMOylation, methylation, sulfation, and nitrosylation. Among these modifications, O-GlcNAcylation has been shown to play a critical role in cancer development and progression, especially in hepatocellular carcinoma (HCC). This review outlines the role of O-GlcNAcylation in the development and progression of HCC. Moreover, we delve into the underlying mechanisms of O-GlcNAcylation in HCC and highlight compounds that target O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) to improve treatment outcomes. Understanding the role of O-GlcNAcylation in HCC will offer insights into potential therapeutic strategies targeting OGT and OGA, which could improve treatment for patients with HCC.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 μg/g body weight) in 100 μL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 μg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Long noncoding RNAs play an important role in several pathogenic processes in diabetic nephropathy, but the relationship with epithelial-mesenchymal transition in DN is unclear. Herein, we found that KIFAP3-5:1 expression was significantly down-regulated in DN plasma samples, db/db mouse kidney tissues and high glucose treated renal tubular epithelial cells compared to normal healthy samples and untreated cells. Overexpression of KIFAP3-5:1 improved renal fibrosis in db/db mice and rescued epithelial-mesenchymal transition of high glucose cultured renal tubular epithelial cells. The silence of KIFAP3-5:1 will exacerbate the progression of EMT. Mechanistically, KIFAP3-5:1 was confirmed to directly target to the -488 to -609 element of the PRRX1 promoter and negatively modulate PRRX1 mRNA and protein expressions. Furthermore, rescue assays demonstrated that the knockdown of PRRX1 counteracted the KIFAP3-5:1 low expression-mediated effects on EMT in hRPTECs cultured under high glucose. The plasma KIFAP3-5:1 of DN patients is highly correlated with the severity of renal dysfunction and plays an important role in the prediction model of DN diseases. These findings suggested that KIFAP3-5:1 plays a critical role in regulation of renal EMT and fibrosis through suppress PRRX1, and highlight the clinical potential of KIFAP3-5:1 to assist in the diagnosis of diabetic nephropathy., (© 2024. The Author(s).)

Cancer cachexia-associated muscle wasting as a multifactorial wasting syndrome, is an important factor affecting the long-term survival rate of tumor patients. Photobiomodulation therapy (PBMT) has emerged as a promising tool to cure and prevent many diseases. However, the effect of PBMT on skeletal muscle atrophy during cancer progression has not been fully demonstrated yet. Here, we found PBMT alleviated the atrophy of myotube diameter induced by cancer cells in vitro, and prevented cancer-associated muscle atrophy in mice bearing tumor. Mechanistically, the alleviation of muscle wasting by PBMT was found to be involved in inhibiting E3 ubiquitin ligases MAFbx and MuRF-1. In addition, transcriptomic analysis using RNA-seq and GSEA revealed that PI3K/AKT pathway might be involved in PBMT-prevented muscle cachexia. Next, we showed the protective effect of PBMT against muscle cachexia was totally blocked by AKT inhibitor in vitro and in vivo. Moreover, PBMT-activated AKT promoted FoxO3a phosphorylation and thus inhibiting the nucleus entry of FoxO3a. Lastly, in cisplatin-treated muscle cachexia model, PBMT had also been shown to ameliorate muscle atrophy through enhancing PI3K/AKT pathway to suppress MAFbx and MuRF-1 expression. These novel findings revealed that PBMT could be a promising therapeutic approach in treating muscle cachexia induced by cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chondrocyte ferroptosis plays a critical role in the pathogenesis of osteoarthritis (OA), regulated by the SLC7A11/GPX4 signaling pathway. Icariin (ICA), a flavonoid glycoside, exhibits strong anti-inflammatory and antioxidant activities. This study investigated whether ICA could modulate the SLC7A11/GPX4 signaling to inhibit chondrocyte ferroptosis and alleviate OA., Purpose: The objective was to explore the impact of ICA on chondrocyte ferroptosis in OA and its modulation of the SLC7A11/GPX4 signaling pathway., Methods: The anti-ferroptosis effects of ICA were evaluated in an interleukin-1β (IL-1β)-treated SW1353 cell model, using Ferrostatin-1 (Fer-1) and Erastin (Era) as ferroptosis inhibitor and inducer, respectively, along with GPX4 knockdown via lentivirus-based shRNA. Additionally, the therapeutic efficacy of ICA on OA-related articular cartilage damage was assessed in rats through histopathology and immunohistochemistry (IHC)., Results: IL-1β treatment upregulated the expression of OA-associated matrix metalloproteinases (MMP3 and MMP1), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-5), and increased intracellular ROS, lipid ROS, and MDA levels while downregulating collagen II and SOX9 expression in SW1353 cells. ICA treatment countered the IL-1β-induced upregulation of MMPs and ADAMTS-5, restored collagen II and SOX9 expression, and reduced intracellular ROS, lipid ROS, and MDA levels. Furthermore, IL-1β upregulated P53 but downregulated SLC7A11 and GPX4 expression in SW1353 cells, effects that were mitigated by ICA or Fer-1 treatment. Significantly, ICA also alleviated Era-induced ferroptosis, whereas it had no effect on GPX4-silenced SW1353 cells. In vivo, ICA treatment reduced articular cartilage damage in OA rats by partially restoring collagen II and GPX4 expression, inhibiting cartilage extracellular matrix (ECM) degradation and chondrocyte ferroptosis., Conclusion: ICA treatment mitigated chondrocyte ferroptosis and articular cartilage damage by enhancing the SLC7A11/GPX4 signaling, suggesting its potential as a therapeutic agent for OA interventions., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Breaking the poor permeability of immune checkpoint inhibitors (ICIs) caused by the stromal barrier and reversing the immunosuppressive microenvironment are significant challenges in pancreatic cancer immunotherapy. In this study, we synthesized core-shell Fe 3 O 4 @TiO 2 nanoparticles to act as carriers for loading VISTA monoclonal antibodies to form Fe 3 O 4 @TiO 2 @VISTAmAb (FTV). The nanoparticles are designed to target the overexpressed ICIs VISTA in pancreatic cancer, aiming to improve magnetic resonance imaging-guided sonodynamic therapy (SDT)-facilitated immunotherapy. Laser confocal microscopy and flow cytometry results demonstrate that FTV nanoparticles are specifically recognized and phagocytosed by Panc-2 cells. In vivo experiments reveal that ultrasound-triggered TiO 2 SDT can induce tumor immunogenic cell death (ICD) and recruit T-cell infiltration within the tumor microenvironment by releasing damage-associated molecular patterns (DAMPs). Furthermore, ultrasound loosens the dense fibrous stroma surrounding the pancreatic tumor and increases vascular density, facilitating immune therapeutic efficiency. In summary, our study demonstrates that FTV nanoparticles hold great promise for synergistic SDT and immunotherapy in pancreatic cancer., Competing Interests: The authors declare that there is no competing financial interest., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: This research investigates the biomechanical impact of the split-step technique on forehand and backhand lunges in badminton, aiming to enhance players' on-court movement efficiency. Despite the importance of agile positioning in badminton, the specific contributions of the split-step to the biomechanical impact of lunging footwork still need to be determined., Methods: This study examined the lower limb kinematics and ground reaction forces of 18 male badminton players performing forehand and backhand lunges. Data were collected using the VICON motion capture system and Kistler force platforms. Variability in biomechanical characteristics was assessed using paired-sample t -tests and Statistical Parametric Mapping 1D (SPM1D)., Results: The study demonstrates that the split-step technique in badminton lunges significantly affects lower limb biomechanics. During forehand lunges, the split-step increases hip abduction and rotation while decreasing knee flexion at foot contact. In backhand lunges, it increases knee rotation and decreases ankle rotation. Additionally, the split-step enhances the loading rate of the initial ground reaction force peak and narrows the time gap between the first two peaks., Conclusions: These findings underscore the split-step's potential in optimizing lunging techniques, improving performance and reducing injury risks in badminton athletes.

Tumor-associated macrophages (TAM) subtypes have been shown to impact cancer prognosis and resistance to immunotherapy. However, there is still a lack of systematic investigation into their molecular characteristics and clinical relevance in different cancer types. Single-cell RNA sequencing data from three different tumor types were used to cluster and type macrophages. Functional analysis and communication of TAM subpopulations were performed by Gene Ontology-Biological Process and CellChat respectively. Differential expression of characteristic genes in subpopulations was calculated using zscore as well as edgeR and Wilcoxon rank sum tests, and subsequently gene enrichment analysis of characteristic genes and anti-PD-1 resistance was performed by the REACTOME database. We revealed the heterogeneity of TAM, and identified eleven subtypes and their impact on prognosis. These subtypes expressed different molecular functions respectively, such as being involved in T cell activation, apoptosis and differentiation, or regulating viral bioprocesses or responses to viruses. The SPP1 pathway was identified as a critical mediator of communication between TAM subpopulations, as well as between TAM and epithelial cells. Macrophages with high expression of SPP1 resulted in poorer survival. By in vitro study, we showed SPP1 mediated the interactions between TAM clusters and between TAM and tumor cells. SPP1 promoted the tumor-promoting ability of TAM, and increased PDL1 expression and stemness of tumor cells. Inhibition of SPP1 attenuated N-cadherin and β-catenin expression and the activation of AKT and STAT3 pathway in tumor cells. Additionally, we found that several subpopulations could decrease the sensitivity of anti-PD-1 therapy in melanoma. SPP1 signal was a critical pathway of communication between macrophage subtypes. Some specific macrophage subtypes were associated with immunotherapy resistance and prognosis in some cancer types., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Purpose: To investigate the differences in the prevalence of ligamentum teres (LT) tears and other radiographic measurements in borderline dysplasia of the hip (BDDH) with/without microinstability and to evaluate the associations between these imaging findings and the prevalence of microinstability in patients with BDDH., Methods: This was a retrospective study of symptomatic patients with BDDH (18° ≤ lateral center-edge angle <25°) treated with arthroscopy in our hospital between January 2016 and December 2021. These patients were divided into the BDDH with microinstability (mBDDH) group and the stable BDDH (nBDDH) group. The radiographic parameters associated with hip joint stability, such as the state of LT, acetabular versions, femoral neck version, Tönnis angle, combined anteversions, and anterior/posterior acetabular coverage, were reviewed and analyzed., Results: There were 54 patients (49 female/5 male, 26.7 ± 6.9 years) in the mBDDH group and 81 patients (74 female/7 male, 27.2 ± 7.7 years) in the nBDDH group. The mBDDH group had greater LT tear (43/54 vs 5/81) and general laxity rates, increased femoral neck version, acetabular version and combined anteversion (52.4 ± 5.9 vs 41.5 ± 7.1 at 3-o'clock level) than the nBDDH group. Binary logistic regression showed that LT tears (odds ratio 6.32, 95% confidence interval 1.38-28.8; P = .02; R 2  = .458) and combined anteversion at the 3-o'clock level (odds ratio 1.42, 95% confidence interval 1.09-1.84; P < .01; R 2  = .458) were independent predictors of microinstability in patients with BDDH. The cutoff value of combined anteversion at 3-o'clock level was 49.5°. In addition, LT tear was correlated with increased combined anteversion at 3-o'clock level in patients with BDDH (P < .01, η 2  = 0.29)., Conclusions: LT tears and increased combined anteversion at the 3-o'clock level on the acetabular clockface were associated with hip microinstability in patients with BDDH, suggesting that patients with BDDH and LT tears might have a greater prevalence of anterior microinstability., Level of Evidence: Level III, case‒control study., (Copyright © 2023 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Processing of Chinese medicinal materials is an important part in the Chinese medicine heritage, and the temperature control in the processing has a direct impact on the quality and efficacy of traditional Chinese medicines. However, the processing of Chinese medicinal materials has the problems of subjective temperature judgement, determination of the end point based on experience, unclear processing mechanism, unstable quality of products, and inconsistent processing standards. The temperature control in the processing is reflected in the appearance and internal quality of Chinese medicinal materials. The theory of quality evaluation through morphological identification is developed based on the comprehensive evaluation of the shape, color, taste, and components, which is associated with the temperature control in the processing. To solve the problems above, this paper puts forward the following solutions. The first is literature mining. By review of the ancient medical works and pharmaceutical experience, the temperature control in processing and the evolution of processing methods can be revealed. Second, according to the ancient method, the processing principle can be explored, on the basis of which the processing technology can be innovated. Third, the standard operating procedure(SOP) should be established to quantify the fire temperature, providing a theoretical basis for the formulation of Chinese medicinal material processing standards. Moreover, it provides a basis for improving the quality of processed products and increasing the safety and effectiveness of traditional Chinese medicines.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an insidious, rapidly progressing malignancy of the gastrointestinal tract. Due to its dense fibrous stroma and complex tumor microenvironment, neither of which is sensitive to radiotherapy, pancreatic adenocarcinoma is one of the malignancies with the poorest prognosis. Therefore, detailed elucidation of the inhibitory microenvironment of PDAC is essential for the development of novel therapeutic strategies. Methods: We analyzed the association between cancer-associated fibroblasts (CAFs) and resistance to ferroptosis in PDAC using conditioned CAF medium and co-culture of pancreatic cancer cells. Abnormal cysteine metabolism was observed in CAFs using non-targeted metabolomics analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The regulatory effects of cysteine were investigated in PDAC cells through measurement of cell cloning, cell death, cell function, and EdU assays. The effects of exogenous cysteine intake were examined in a mouse xenograft model and the effects of the cysteine pathway on ferroptosis in PDAC were investigated by western blotting, measurement of glutathione and reactive oxygen species levels, among others. Results: It was found that CAFs played a critical role in PDAC metabolism by secreting cysteine, which could increase tumor resistance to ferroptosis. A previously unrecognized function of the sulfur transfer pathway in CAFs was identified, which increased the extracellular supply of cysteine to support glutathione synthesis and thus inducing ferroptosis resistance. Cysteine secretion by CAFs was found to be mediated by the TGF-β/SMAD3/ATF4 signaling axis. Conclusion: Taken together, the findings demonstrate a novel metabolic relationship between CAFs and cancer cells, in which cysteine generated by CAFs acts as a substrate in the prevention of oxidative damage in PDAC and thus suggests new therapeutic targets for PDAC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: This research explored the relationship between a patient's nutritional state and inflammatory markers and the prognosis of their non-small cell lung cancer (NSCLC) treatment while receiving a combination of chemotherapy and immunotherapy., Method: This retrospective and single-center analysis included NSCLC patients who received a combination of chemotherapy and immunotherapy at the Department of Oncology at Shanghai Lung Hospital. Patients were categorized based on malnutrition, sarcopenia, sarcopenic obesity, and advanced-lung-cancer-inflammation-index (ALI) scores after collecting nutritional and inflammatory indices. Kaplan-Meier and the Cox models were utilized to analyze survival., Results: There was a significant correlation between malnutrition, sarcopenia, sarcopenic obesity, and low ALI scores with lower overall survival (OS) and progression-free survival (PFS) (p < 0.05). Low ALI score and malnutrition were independent factors influencing patient survival in terms of both OS and PFS (p < 0.01)., Conclusion: The nutritional and inflammatory indices of immunotherapy-treated NSCLC patients substantially affect their prognosis. Assessing these variables could aid in optimizing treatment strategies and improving patient outcomes. Additional research is required to comprehend the intricate relationship between nutrition, inflammation, and cancer progression and to develop individualized therapies., 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 © 2023. Published by Elsevier Inc.)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1046/coif). R.Z. reports that this study was financially supported by the Natural Science Foundation of Fujian Province of China (No. 2021J011282). The other authors have no conflicts of interest to declare.

Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Although Qixue Shuangbu Prescription (QSP) is a classic Chinese medicine prescription for treating chronic heart failure. Low bioavailability due to the insolubility and poor biofilm permeability of the main bioactive ingredients of QSP is still a key factor limiting its efficacy. In this study, a novel self-microemulsifying drug delivery system was proposed to effectively improve the bioavailability of QSP. The qualified ultra-high-performance liquid chromatography-tandem mass spectrometry methodology was established to investigate the pharmacokinetics characteristics of the QSP self-microemulsifying drug delivery system. Our results showed that 11 components in the self-microemulsifying drug delivery system group had prolonged T 1/2 and MRT 0-t values compared with QSP extract. The Cmax of calycosin-7-glucoside (CG), vanillic acid and paeoniflorin increased 2.5 times, 2.4 times and 2.3 times, respectively. The relative bioavailability values of CG, paeoniflorin and ononin were most significantly affected, increasing by 383.2%, 336.5% and 307.1%, respectively. This study promoted the development of new dosage forms of QSP and provided a useful reference for improving dosage forms to solve the problem of low bioavailability of traditional Chinese medicine., (© 2023 Wiley-VCH GmbH.)

As conserved regulatory agents, noncoding RNAs (ncRNAs) have an important impact on many aspects of plant life, including growth, development, and environmental response. Noncoding RNAs can travel through not only plasmodesma and phloem but also intercellular barriers to regulate distinct processes. Increasing evidence shows that the intercellular trans-kingdom transmission of ncRNAs is able to modulate many important interactions between plants and other organisms, such as plant response to pathogen attack, the symbiosis between legume plants and rhizobia and the interactions with parasitic plants. In these interactions, plant ncRNAs are believed to be sorted into extracellular vesicles (EVs) or other nonvesicular vehicles to pass through cell barriers and trigger trans-kingdom RNA interference (RNAi) in recipient cells from different species. There is evidence that the features of extracellular RNAs and associated RNA-binding proteins (RBPs) play a role in defining the RNAs to retain in cell or secrete outside cells. Despite the few reports about RNA secretion pathway in plants, the export of extracellular ncRNAs is orchestrated by a series of pathways in plants. The identification and functional analysis of mobile small RNAs (sRNAs) are attracting increasing attention in recent years. In this review, we discuss recent advances in our understanding of the function, sorting, transport, and regulation of plant extracellular ncRNAs., (© 2022 The Authors. The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Ethylsulfonylpyridines are a novel chemical class of insecticides with excellent broad-spectrum activity and an unprecedented mode of action. With the objective of discovering novel ethylsulfonylpyridines with a broader spectrum, wider range of uses, and/or improved properties, we have started a research program aimed at introducing silicon motifs and studying their biological effects. We designed a series of Oxazosulfyl analogues where the hydrogen atom at the 5-position of the pyridyl moiety is replaced by a trialkylsilyl group and prepared these compounds applying denovo synthetic methodology. Our novel ethylsulfonylpyridines exhibit excellent insecticidal activities. The best compound, A18 , resulting from our research exhibited an LC 50 value of 0.30 mg/L against Plutella xylostella and reached the activity level of the commercial standard Oxazosulfyl. Our findings confirmed our working hypothesis that at the 5-position of the pyridyl moiety larger groups with different hydrophobic, electronic, and steric properties are tolerated.

Silicon-containing compounds are sporadically used in crop protection and drug discovery and have demonstrated to increase the biological efficacy as well as to reduce toxicity, improve physicochemical properties, and favorably impact the environmental profile. As part of our research, we have investigated the application of bioisosteric silicon replacements in meta -diamide insecticides and studied the biological activity and molecular properties of the corresponding novel compounds. At all meaningful structural elements of the meta -diamides, silicon-containing substituents were introduced and synthetic methodology was developed for their syntheses. As the most promising compound, silicon-containing meta -diamide II-18 emerged, which exhibits a very low LC 50 value of 2.00 mg/L against Mythimna separata and compares well to the reference compounds 28 (LC 50 = 0.17 mg/L) and II-20 (LC 50 = 0.27 mg/L). Our research on silicon-containing crop protection compounds once again confirmed that the biological activity can be beneficially affected by the insertion of silicone substituents and that the introduction of well-chosen silicone motifs is an excellent strategy for agrochemical research.

Objectives: To compare the effects of moxibustion and acupuncture of combined "Biao-Ben" acupoints (Biao indicates pathogenic factors of disease, Ben refers to body constitution) on a rat model of irritable bowel syndrome with diarrhea (IBS-D)., Methods: Forty female SD rats were randomly divided into 4 groups：normal group, model group, moxibustion group, and acupuncture group, with 10 rats in each group. The IBS-D rat model was established by administering acute-chronic stress combined with folium sennae gavage for 28 days. Rats in the moxibustion group received moxibustion at bilateral "Zusanli"(ST36), "Guanyuan"(CV4), and "Neiguan"(PC6), while those in the acupuncture group received acupuncture at the same acupoints, both for 15 min every time, once a day. The treatments were administered for 21 days. The loose stool rate was observed. Colonic pain threshold and colonic distension threshold were measured by a self-made balloon catheter. Total distance traveled and grid crossing numbers were observed by open field test. Heart rate variability(HRV) time domain indexes SDANN and PNN50 were acguired by using electrophysiological recorder. Histopathological changes in the colon tissue were observed after HE staining. Contents of interleukin-6(IL-6), IL-8, and tumor necrosis factor-alpha(TNF-α) in serum were detected by ELISA., Results: Compared with the normal group, rats in the model group showed increased loose stool rate( P <0.05), decreased pain threshold and distension threshold( P <0.05), reduced total distance traveled and grid crossing numbers in the open field test( P <0.05), decreased HRV time domain indexes SDANN and PNN50( P <0.01, P <0.05), and elevated levels of serum IL-6, IL-8, and TNF-α contents( P <0.05). Compared with the model group, the moxibustion group and acupuncture group showed decreased loose stool rate( P <0.05), increased total distance traveled and grid crossing numbers in the open field test( P <0.05), increased pain threshold and distension threshold( P <0.05), increased SDANN and PNN50 ( P <0.05), and decreased levels of serum IL-6, IL-8, and TNF-α contents( P <0.05). Compared with the acupuncture group, the moxibustion group showed further decreased loose stool rate( P <0.05), increased total distance traveled and grid crossing numbers in the open field test( P <0.05), increased pain threshold and distension threshold( P <0.05), increased SDANN and PNN50( P <0.05), and decreased levels of serum IL-6, IL-8, and TNF-α contents( P <0.05). No significant pathological changes were observed in the colon tissue of rats in each group., Conclusions: Moxibustion of combined "Biao-Ben" acupoints is more effective in regulating HRV and serum IL-6, IL-8, and TNF-α contents in the IBS-D rat model. Based on the combined "Biao-Ben" acupoints method, moxibustion has better therapeutic effects on IBS-D than acupuncture.

The targeted identification of α-glucosidase inhibitors from the crude ethyl acetate of Lycopodiella cernua (L.) Pic. Serm ( L.cernua ) was guided by high-resolution inhibition profiling. The α-glucosidase inhibition profiling and HPLC-QTOF-MS showed tannins and serratenes were the corresponding antidiabetic constituents. Two new serratenes named 3β, 21β-dihydroxyserra-14-en-24-oic acid-3β-(4'-methoxy-5'-hydroxybenzoate) ( 4 ), 3β, 21α-dihydroxyserra-14-en-24-oic acid-3β-(4'-methoxy-5'-hydroxybenzoate) ( 7 ), together with two known compounds ( 5 and 6 ) were isolated. Their structures were elucidated by HR-ESI-MS and NMR. Compounds 5 - 7 inhibited the α-glucosidase activity in a non-competitive manner with Ki values ranging from 1.29 to 12.9 µM. The molecular docking result unveiled that 4 - 7 bound to the residues at the channel site, which enabled to block the substrate access. In addition, the molecular dynamics (MD) simulation of the most active compound 7 and α-glucosidase indicated the 4'-methoxy-5'-hydroxybenzoate group formed the stable hydrogen bonds and pi-pi T-shaped interactions with Arg312, Gln350 and Phe300 residues, while the rings D and E were stabilized by hydrophobic interaction.

Spray drying technology is one of the most commonly used unit operations in the production of traditional Chinese medicine(TCM) preparations, offering advantages such as short drying time and uniform product quality. However, due to the properties of TCM extracts, such as high viscosity, strong hygroscopicity, and poor flowability, there is limited scope to solve the problems of wall adhesion and clumping in spray drying from the macroscopic perspective of pharmaceutical production. Therefore, it has become a trend to study and optimize the spray drying process from the microscopic point of view by investigating single droplet evaporation behavior. Based on the reaction engineering approach(REA), the single droplet drying system, as a novel method for studying droplets, collects parameter data on individual TCM droplets during the drying process and uses the REA to process the data and establish predictive models. This approach is crucial for understanding the mechanism of TCM spray drying. This paper summarized and analyzed the cha-racteristics of various single droplet systems, the application of REA in single droplet drying systems, and its significance in optimizing the process, predicting drying states, and shortening the development cycle in the field of TCM spray drying, and looked ahead to the prospects of this method, including the introduction of new parameters and imaging techniques, aiming to provide a reference for further research in the field of TCM spray drying.

Approximately 59 % of patients with breast cancer with one or two sentinel lymph nodes (1-2 SLN) macrometastases do not benefit from axillary lymph node dissection (ALND), which may also incur morbidities. It is necessary to evaluate the association between various clinicopathological characteristics and non-sentinel lymph node metastases (non-SLNM) in patients with breast cancer with 1-2 SLN macrometastases, and determine whether they 1-2 should avoid ALND. Eight electronic literature databases (PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal, Wanfang, and Chinese Biomedical Literature) were searched from their inception to June 30, 2023, and two reviewers independently extracted the data and assessed the risk of bias. Association strength was summarized using odds ratios (OR) and 95 % confidence intervals (CI). Heterogeneity was accounted for using a subgroup analysis. Publication bias was evaluated using funnel plots and Egger's test. There were 25 studies with 8021 participants, and 27 potential risk factors were evaluated. The risk factors for non-SLNM in patients with 1-2 SLN macrometastatic breast cancer include the following: factors of primary tumor: multifocality (OR (95 % CI (2.63 (1.96, 3.54))), tumor size ≥ T2 (2.64 (2.22, 3.14)), tumor localization (upper outer quad) (2.06 (1.23, 3.43)), histopathological grade (G3) (2.45 (1.70, 3.52)), vascular invasion (VI) (2.60 (1.35, 4.98)), lymphovascular invasion (LVI) (2.87 (1.80, 4.56)), perineural invasion (PNI) (3.16 (1.18,8.43)). Factors of lymph nodes: method of SLNs detected (blue dye) (3.85 (1.54, 9.60)), SLN metastasis ratio ≥0.5 (2.79 (2.24, 3.48)), two positive SLNs (3.55, (2.08, 6.07)), zero negative SLN (3.72 (CI 2.50, 4.29)), extranodal extension (ENE) (4.69 (2.16, 10.18)). Molecular typing: Her-2 positive (2.08 (1.26, 3.43)), Her-2 over-expressing subtype (1.83 (1.22, 2.73)). Factors of examination/inspection: axillary lymph nodes (ALNs) positive on imaging (3.18 (1.68, 6.00)), cancer antigen 15-3 (CA15-3) (4.01 (2.33,6.89)), carcinoembryonic antigen (CEA) (2.13 (1.32-3.43)). This review identified the risk factors for non-SLNM in patients with 1-2 SLN macrometastatic breast cancer. However, additional studies are needed to confirm the above findings owing to the limited number and types of studies included., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

A high beam quality diode-pumped Nd:YAG master oscillator power-amplifier (MOPA) laser with three end-pumped slab amplifiers is developed. The Q -swtiched side-pumped rod oscillator presented a pulse energy 3.1 mJ with beam quality factors of M x 2=1.17 and M y 2=1.15 at a repetition of 1 kHz. The MOPA system delivered a pulse energy of 1.36 J with a pulse width of 48.2 ns and an extraction efficiency of 44.8%. The beam quality factors of M x 2=1.72 and M y 2=3.85 are measured without any phase-conjugators or adaptive optics.

Semantic segmentation and instance segmentation based on deep learning play a significant role in intelligent dairy goat farming. However, these algorithms require a large amount of pixel-level dairy goat image annotations for model training. At present, users mainly use Labelme for pixel-level annotation of images, which makes it quite inefficient and time-consuming to obtain a high-quality annotation result. To reduce the annotation workload of dairy goat images, we propose a novel interactive segmentation model called UA-MHFF-DeepLabv3+, which employs layer-by-layer multi-head feature fusion (MHFF) and upsampling attention (UA) to improve the segmentation accuracy of the DeepLabv3+ on object boundaries and small objects. Experimental results show that our proposed model achieved state-of-the-art segmentation accuracy on the validation set of DGImgs compared with four previous state-of-the-art interactive segmentation models, and obtained 1.87 and 4.11 on mNoC@85 and mNoC@90, which are significantly lower than the best performance of the previous models of 3 and 5. Furthermore, to promote the implementation of our proposed algorithm, we design and develop a dairy goat image-annotation system named DGAnnotation for pixel-level annotation of dairy goat images. After the test, we found that it just takes 7.12 s to annotate a dairy goat instance with our developed DGAnnotation, which is five times faster than Labelme.

Background: Myocardial ischemia-reperfusion (MI/R) can exacerbate the initial cardiac damage in the myocardial functional changes, including dysfunction of left ventricular contractility. Oestrogen has been proven to protect the cardiovascular system. However, whether the oestrogen or its metabolites play the main role in attenuating dysfunction of left ventricular contractility is unknown., Methods and Results: This study used the LC-MS/MS to detect oestrogen and its metabolites in clinical serum samples (n = 62) with heart diseases. After correlation analysis with markers of myocardial injury including cTnI (P < 0.01), CK-MB (P < 0.05), and D-Dimer (P < 0.001), 16α-OHE1 was identified. The result from LC-MS/MS in female and ovariectomised (OVX) rat serum samples (n = 5) matched the findings in patients. In MI/R model of animal, the recovery of left ventricular developed pressure (LVDP), rate pressure product (RPP), dp/dt max and dp/dt min after MI/R in OVX or male group were worsened than those in female group. Also, the infarction area of OVX or male group was larger than that in females (n = 5, p < 0.01). Furthermore, LC3 II in the left ventricle of OVX and male group was lower than that in females (n = 5, p < 0.01) by immunofluorescence. In H9C2 cells, after the application of 16α-OHE1, the number of autophagosomes was further increased and other organelles improved in MI/R. Simultaneously, LC3 II, Beclin1, ATG5, and p-AMPK/AMPK were increased, and p-mTOR/mTOR was decreased (n = 3, p < 0.01) by Simple Western., Conclusion: 16α-OHE1 could attenuate left ventricle contractility dysfunction via autophagy regulation after MI/R, which also offered fresh perspectives on therapeutical treatment for attenuating MI/R injury., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest ., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Aphasia affects approximately one-third of stroke patients and yet its rehabilitation outcomes are often unsatisfactory. More effective strategies are needed to promote recovery., Objective: We aimed to examine the efficacy and safety of the theta-burst stimulation (TBS) on the language area in the superior frontal gyrus (SFG) localized by personalized functional imaging, in facilitating post-stroke aphasia recovery., Methods: This randomized sham-controlled trial uses a parallel design (intermittent TBS [iTBS] in ipsilesional hemisphere vs. continuous TBS [cTBS] in contralesional hemisphere vs. sham group). Participants had aphasia symptoms resulting from their first stroke in the left hemisphere at least one month prior. Participants received three-week speech-language therapy coupled with either active or sham stimulation applied to the left or right SFG. The primary outcome was the change in Western Aphasia Battery-Revised (WAB-R) aphasia quotient after the three-week treatment. The secondary outcome was WAB-R aphasia quotient improvement after one week of treatment., Results: Ninety-seven patients were screened between January 2021 and January 2022, 45 of whom were randomized and 44 received intervention (15 in each active group, 14 in sham). Both iTBS (estimated difference = 14.75, p < 0.001) and cTBS (estimated difference = 13.43, p < 0.001) groups showed significantly greater improvement than sham stimulation after the 3-week intervention and immediately after one week of treatment (p's < 0.001). The adverse events observed were similar across groups. A seizure was recorded three days after the termination of the treatment in the iTBS group., Conclusion: The stimulation showed high efficacy and SFG is a promising stimulation target for post-stroke language recovery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H.L. is the chief scientist of Neural Galaxy. R.P., J.S., M.D., and W.W. are employees of Neural Galaxy and have participated in data collection and processing. Neural Galaxy is not a sponsor of this study and did not provide any other support. The remaining authors declare no conflict of interest regarding the publication of this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aconitum carmichaelii is widely used to treat chronic and intractable diseases due to its remarkable curative effect, but it is also a highly toxic herb with severe cardiac and neurotoxicity. It has been combined with honey for thousands of years to reduce toxicity and enhance efficacy, but there has been no study on the chemical constituent changes in the honey-processing so far. In this study, the chemical constituents of A. carmichaelii before and after honey-processing were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry. The results showed that a total of 118 compounds were identified, of which six compounds disappeared and five compounds were newly produced after honey-processing, and the cleavage pathway of main components was elucidated. At the same time, 25 compounds were found to have significant effects on different products, among which four compounds with the biggest difference were selected for quantitative analysis by ultra-high-performance liquid chromatography-tandem mass spectrometry. This study not only explained the chemical differences between the different products, but also helped to control the quality of the honey-processed products more effectively, and laid a foundation for further elucidating the mechanism of chemical constituent change during the honey-processing of A. carmichaelii., (© 2023 Wiley-VCH GmbH.)

Background: The effect of circular RNA in many human cancers is widely studied. Nevertheless, their specific biological functions and mechanisms in glioma remain unclear., Methods: CircEXOC6, miR-433-3p, and frizzled class receptor 6 (FZD6) mRNA expression levels were measured by quantitative reverse transcription polymerase chain reaction assay. Cell proliferation, migration, invasion, apoptosis, and angiogenesis were tested by colony formation, cell-light 5-ethynyl-2'-deoxyuridine, transwell, and tube formation assays, respectively. Moreover, glucose consumption and lactate production were calculated to evaluate the glycolytic metabolism using the respective kits. Western blot assay was carried out to measure the protein levels of apoptotic markers (Bcl-2 and Bax), glycolytic markers (HK2 and GLUT1), and FZD6. The targeted relationship of miR-433-3p and circEXOC6 or FZD6 was verified by dual-luciferase reporter or RNA immunoprecipitation assays. In vivo , xenograft and immunohistochemistry assay was conducted to discriminate the effect of circEXOC6., Results: CircEXOC6 and FZD6 were highly expressed, while miR-433-3p was significantly lowly expressed in glioma tissues or cells. Deficiency of circEXOC6 inhibited cell proliferation, migration, invasion, angiogenesis, and glycolysis, and triggered cell apoptosis ratio in glioma; simultaneously, it could block the growth of tumor in vivo . In addition, miR-433-3p was a target of circEXOC6, and downregulated miR-433-3p could partly weaken the inhibitory effect of circEXOC6 deficiency. Besides, miR-433-3p enrichment inhibited cell progression and glycolysis in glioma, and the effect was reversed by overexpression of FZD6., Conclusion: Deletion of circEXOC6 restrained cell progression and glycolysis by sponging miR-433-3p and interacting with FZD6, which might provide an underlying target for glioma treatment., Competing Interests: Conflict of interest: The authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter.)

Objective: To observe the effect of acupuncture and moxibustion of the combined "Biao-Ben" acupoints on autonomic nervous function and related factors in rats with irritable bowel syndrome diarrhea (IBS-D)., Methods: Female SD rats were randomly divided into normal control, IBS-D model, "Biao-Ben" acupoint combination, and conventional acupoint combination groups, with 10 rats in each group. The IBS-D model was established by repeated chronic stress stimulation (water or food deprivation, painful tail pinching, exposure to a 43 ℃ environment, forced swimming in 4 ℃ water, day-night inversion and horizontal vibration) for 28 d, and followed by acute restraint stress (wrapping of shoulders, forelimbs and trunk) for 1 h and gavage of senna fluid, once daily for 28 d. For rats of the "Biao-Ben" acupoint combination group, acupuncture and moxibustion were applied to "Guanyuan" (CV4), bilateral "Zusanli" (ST36), and "Neiguan" (PC6), and for rats of the conventional acupoint combination group, acupuncture and moxibustion were applied to bilateral ST36, "Tianshu"(ST25), and "Shangjuxu"(ST37). Both acupuncture and suspension moxibustion treatment were conduced for 15 min, once daily for 21 days. The fecal water content was calculated, and the spontaneous activity behaviors (total distance of crossing and the number of squares crossed in 5 min) were evaluated by open-field tests. The abdominal withdrawal reflex (AWR) was detected. H.E. staining was used to observe the histopathological changes of colon tissue. The domains of heart rate variability (HRV) including low frequency (LF), high frequency (HF), and LF/HF were analyzed using an electrophysiological recorder. The contents of calcitonin gene-related peptide (CGRP) in serum and noradrenaline (NE) in plasma were detected using ELISA. The expression level and immunoactivity of 5-hydroxytryptamine (5-HT) in colon tissues were detected by Western blot and immunofluorescence histochemistry, separately., Results: Compared with the normal group, the model group had a striking increase in fecal water content, AWR scores at 20, 40, 60, and 80 mm Hg, NE and CGRP contents, LF, LF/HF, and 5-HT protein expression and immunoactivity ( P <0.01), and an obvious decrease in the total distance of crossing, the number of squares crossed, and HF of HRV ( P <0.01). In comparison with the model group, the fecal water content, AWR scores at 20, 40, 60, and 80 mm Hg, NE and CGRP contents, LF, LF/HF, and 5-HT protein expression and immunoactivity were significantly decreased ( P <0.01, P <0.05), while the total distance of cros-sing, number of squares crossed, HF of HRV were considerably increased ( P <0.01, P <0.05) in both "Biao-Ben" acupoint combination and conventional acupoint combination groups. The effects of the "Biao-Ben" acupoint combination were apparently superior to those of conventional acupoint combination in down-regulating the fecal water content, AWR score at 20, 40, 60 and 80 mm Hg, NE and CGRP contents, LF, LF/HF, and 5-HT expression and immunoactivity, and in increasing the number of squares crossed, and HF of HRV ( P <0.01, P <0.05). HE staining showed no pathological changes in colonic mucosa in all groups., Conclusion: Acupuncture and moxibustion stimulation of combined "Biao-Ben" acupoints can effectively improve the symptoms (spontaneous activities, visceral hypersensitivity) of IBS-D model rats, which may be related to its functions in regulating autonomic nervous activities, and down-regulating blood NE and CGRP contents and colonic 5-HT protein expression and immunoactivity, and the effects of "Biao-Ben" acupoint combination are superior to those of conventional acupoint combination.

Background: The number of non-intubated general anesthesia outside the operating room is growing as the increasing demand for comfort treatment. Non-intubated general anesthesia outside the operating room requires rapid onset of anesthesia, smoothness, quick recovery, and few postoperative complications. Traditional anesthetic regimens (propofol alone or propofol and opioids/dezocine/midazolam, etc.) have severe respiratory and circulatory depression and many systemic adverse effects. In this paper, we compare the effectiveness and safety of propofol and subclinical doses of esketamine with other traditional regimens applied to non-intubated general anesthesia through a systematic review and meta-analysis., Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and Sinomed databases for the period from January 2000 to October 2022. We rigorously screened the literature according to predefined inclusion and exclusion criteria, while risk assessment of the studies was performed using The Cochrane Collaboration's tool, and statistical analysis of the data was performed using RevMan 5.4 software. The main outcome indicators we evaluated were the various hemodynamic parameters and incidence of various adverse effects between the experimental and control groups after induction of anesthesia., Results: After a rigorous screening process, a total of 14 papers were included in the final meta-analysis. After risk bias assessment, three of the papers were judged as low risk and the others were judged as having moderate to high risk. Forest plots were drawn for a total of 16 indicators. Meta-analysis showed statistically significant differences in HR' WMD 3.27 (0.66, 5.87), MAP' WMD 9.68 (6.13, 13.24), SBP' WMD 5.42 (2.11, 8.73), DBP' WMD 4.02 (1.15, 6.88), propofol dose' SMD -1.39 (-2.45, -0.33), hypotension' RR 0.30 (0.20, 0.45), bradycardia' RR 0.33 (0.14, 0.77), hypoxemia or apnea' RR 0.45 (0.23, 0.89), injection pain' RR 0.28 (0.13, 0.60), intraoperative choking' RR 0.62 (0.50, 0.77), intraoperative body movements' RR 0.48 (0.29, 0.81) and overall incidence of adverse reactions' RR 0.52 (0.39, 0.70).The indicators that were not statistically different were time to wake up' WMD - 0.55 (-1.29, 0.19), nausea and vomiting 0.84' RR (0.43, 1.67), headache and dizziness' RR 1.57 (0.98, 2.50) and neuropsychiatric reaction' RR 1.05 (0.28, 3.93). The funnel plot showed that the vast majority of studies fell within the funnel interval, but the symmetry was relatively poor., Conclusion: In non-intubated general anesthesia, the combination of subclinical doses of esketamine and propofol did reduce circulatory and respiratory depression, injection pain, and other adverse effects, while the incidence of esketamine's own side effects such as neuropsychiatric reactions did not increase, and the combination of the two did not cause the occurrence of new and more serious adverse reactions, and the combination of the two was safe and effective., Trial Registration: PROSPREO registration number: CRD 42022368966., (© 2023. The Author(s).)

Introduction: Acute patellar dislocation is a common but serious injury that can significantly impact a patient's functional prognosis. The objective of this retrospective study is to evaluate the clinical outcomes of arthroscopic medial patellofemoral ligament (MPFL) reconstruction and plication of the medial patellar retinaculum using suture anchors in adolescent patients with first-time acute patellar dislocation (APD) and MPFL insertion injury., Hypothesis: Tightening repair of the medial retinaculum complex can result in favorable clinical and functional outcomes in this patient population., Materials and Methods: A total of 84 adolescent patients with first-time APD and with an average age of 15.5 years (10-22) were included in the study. Of these patients, 61 (7 male and 54 female) underwent arthroscopic suture anchor plication for medial patellar retinaculum, while the other 23 were successfully treated non-operatively. Radiographic outcomes, including the congruence angle (CA), lateral patellofemoral angle (LPA), and patellar tilt angle (PTA), were evaluated preoperatively and at the last follow-up visit in the surgical group. Functional outcomes were assessed using the Lille Patello-Femoral Score, Lysholm Score, and Kujala Score at the same time points. In addition, the surgical and non-operative treatment success groups were compared in terms of both radiographic and functional outcomes., Results: Mean follow-up was 40.9 months (24-60). Fifty-nine knees showed excellent or good results postoperatively, 2 patients had a recurrent patellar subluxation. The Lille Patello-Femoral Score was 96.9±4.7 at the last follow-up. The subjective Lysholm Score and Kujala Score improved significantly, from 58.6 to 91.9 and from 60.4 to 88.9, respectively. The radiographic CA, LPA and PTA improved significantly, from 19.8±2.1° to -6.7±1.7°, from -7.4±2.2° to 5.7±1.8° and from 23.8±2.9° to 12.3±2.3°, respectively. There was no statistically significant difference in functional and radiographic assessments between the success with non-operative treatment group and the surgery group., Conclusion: The results of this study suggest that arthroscopic MPFL insertion reconstruction and plication using suture anchors, which is less invasive and improves patella stability, can lead to favorable clinical and functional outcomes in adolescent patients with first-time acute patellar dislocation and insertion injury. This treatment approach should be considered as a viable option for this patient population., Level of Evidence: IV; monocentric retrospective descriptive study., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: This study aimed to assess the efficacy and safety of postoperative adjuvant transarterial chemoembolization (PA-TACE) plus immune checkpoint inhibitor (ICI) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT)., Patients and Methods: This study was conducted on three centers from June 2018 to December 2020. Patients were divided into the PA-TACE (n = 48) and PA-TACE plus ICI groups (n = 42). The recurrence-free survival (RFS) and overall survival (OS) curves were depicted by Kaplan-Meier method, and the differences between the two groups were compared using log-rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for RFS and OS. Adverse events (AEs) were assessed according to the Common Terminology Criteria for AEs (CTCAE) version 5.0., Results: The median RFS of the PA-TACE plus ICI group was significantly longer than the PA-TACE group (12.76 months vs. 8.11 months; P = 0.038). The median OS of the PA-TACE plus ICI group was also significanfly better than the PA-TACE group (24.5 months vs. 19.1 months; P = 0.032). PA-TACE plus ICI treatment was an independent prognostic factor for RFS (HR: 0.54, 95% CI: 0.32-0.9, P = 0.019) and OS (HR: 0.47, 95% CI: 0.26-0.86, P = 0.014). Only one patient experienced grade ≥3 immune-related AEs in the PA-TACE plus ICI group., Conclusions: PA-TACE plus ICI treatment had better efficacy in preventing recurrence and prolonging survival than PA-TACE alone for HCC patients with PVTT after R0 resection. This novel treatment modality may be an appropriate option for HCC with PVTT., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Renal interstitial fibrosis (RIF) is one of the main features of diabetic nephropathy (DN), but the molecular mechanisms mediating RIF in DN has yet been fully understood. S100A8 and S100A9 are the proteins associated with immune and inflammation response. Here we reported the expression of S100A8 and S100A9 were significantly increased on tubular epithelial cells in diabetic kidneys through a proteomic analysis., Methods: We detected the expression of S100A8/A9 in diabetic kidneys by using immunoblotting, real-time PCR and immunostaining. RNA silencing and overexpression were performed by using S100A8/A9 expression/knockdown lentivirus to investigate the connection between S100A8/A9 and epithelial to mesenchymal transition (EMT) process. We also identify the expression of TLR4/NFκB pathway-related molecules in the case mentioned above. Afterwards a CO-IP assay was used to verify that compound AB38b ameliorates the EMT by interfering S100A8/A9 expression., Results: The expression of S100A8 and S100A9 were significantly increased on tubular epithelial cells in diabetic kidneys. S100A8/A9 knocking-down alleviate and over-expression promote the renal interstitial fibrosis of diabetic mice. Mechanically, high levels of S100A8/A9 expression in tubular epithelial cells during diabetic condition activated the TLR4/NF-κB signal pathway which promoted the EMT process and finally led to RIF progression. S100A8/A9 knockdown ameliorated RIF of diabetic mice. Further experiments revealed that compound AB38b inhibited the EMT progression of tubular epithelial cells induced by S100A8/A9 through interfering the expressions of S100A8/A9., Conclusions: Our study suggest that abnormal expression of S100A8/A9 in the disease condition promotes EMT process and RIF through TLR4/NF-κB signal pathway. Using small molecular inhibitor AB38b to inhibit the abnormal expressions of S100A8/A9 might be a novel therapeutic strategy in treating DN., Competing Interests: Declaration of competing interest The authors declared that no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Despite numerous studies on broadband photodetectors, the problematic query that remains unaddressed is the limited photoresponsivity while broadening the spectral regime. Here, for the first time, a rational design of a hybrid 1D CdSe nanobelt/2D PbI 2 flake heterojunction device is constructed, which substantially boosts the photocurrent while significantly attenuating the dark current, resulting in improved photodetector figures-of-merit. Thanks to the excellent quality of the nanobelt/flake and built-in electric field at the CdSe/PbI 2 interface heterojunction, photogenerated carriers are promptly segregated and more photoexcitons are accumulated by the respective electrodes, enabling a high responsivity of ∼10 6 A/W, making this one of the highest values among similar reported hybrid heterojunction photodetectors, together with a large linear dynamic range, superior sensitivity, excellent detectivity and external quantum efficiency, an ultrafast response, and a broadband spectral response range. The similar 1D/2D hybrid heterojunction device architecture assembled on the flexible polyimide tape substrate exhibits excellent folding endurance and mechanical, flexural, and long-term environmental stability. The present device architecture and robust operational stability in an ambient environment reveals that the combination of the present 1D/2D hybrid heterojunction has incredible potential for future flexible photoelectronic devices.

X-linked adrenoleukodystrophy (ALD) is a genetic disorder of the ABCD1 gene. We aimed to treat ALD via direct intracerebral injection of lentiviral ABCD1 (LV.ABCD1). Lentiviral vectors (LVs) were injected into the brain of wild type mice to access toxicities and biodistribution. Confocal microscopy illustrated supraphysiological ABCD1 expression surrounding the injection sites, and LVs were also detected in the opposite site of the unilaterally injected brain. In multi-site bilateral injections (4, 6, 8, and 9 sites), LV.ABCD1 transduced most brain regions including the cerebellum. Investigation of neuronal loss, astrogliosis and microglia activation did not detect abnormality. For efficacy evaluation, a novel ALD knockout (KO) mouse model was established by deleting exons 3 to 9 of the ABCD1 gene based on CRISPR/Cas9 gene editing. The KO mice showed behavioral deficit in open-field test (OFT) and reduced locomotor activities in rotarod test at 6 and 7 months of age, respectively. We treated 3-month-old KO mice with bilateral LV.ABCD1 injections into the external capsule and thalamus. ABCD1 expression was detected 15 days later, and the impaired motor ability was gradually alleviated. Our studies established an early onset ALD model and illustrated neurological improvement after LV.ABCD1 intracerebral injection without immunopathological toxicity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT., Methods: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays., Results: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation., Interpretation: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256., (© 2022 American Neurological Association.)

Transumbilical laparoendoscopic single-site surgery (TU-LESS) is a new and evolving surgical method suitable for gynecological diseases, because of its minimal invasion and good cosmetic results. However, since the incision required for this procedure is longer than that for traditional laparoscopy, it may be associated with a higher incidence of postoperative incision complications, such as umbilical hernia, infection, hematoma, and poor wound healing. Moreover, the patient may be left with a misshapen umbilicus because intensive surgery is performed through a single umbilical incision. To minimize the incisional complications and meet patients' cosmetic expectations, we designed a novel suturing technique, named "Zheng's anchor suture technique". This video demonstrates the specific steps and shows photographs of patients' umbilici that were sutured by this technique, taken after recovery from various operations., (© 2022. The Author(s).)

As a minimally invasive method of physical stimulation, manual acupuncture (MA) is used globally as a sort of therapy for neuromusculoskeletal disorders. In addition to selecting appropriate acupoints, acupuncturists should also determine the stimulation parameters of needling, such as the manipulation (lifting-thrusting or twirling), needling amplitude, velocity, and stimulation time. At present, most studies focus on acupoint combination and mechanism of MA, the relationship between stimulation parameters and their therapeutic effects, as well as the influence on mechanism of action are relatively scattered, and lack of systematic summary and analysis. This paper reviewed the three types of stimulation parameters of MA, their common options and values, corresponding effects and potential mechanisms of action. The purpose of such efforts is to provide a useful reference for the dose-effect relationship of MA and the quantification and standardization of its clinical treatment of neuromusculoskeletal disorders to further promote the application of acupuncture in the world., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Xu, Yang, Xie, Xu and Tang.)

Background: Antihuman T lymphocyte porcine immunoglobulin (p-ATG) has been the most common ATG preparation in immunosuppressive therapy (IST) in Chinese patients with severe aplastic anemia (SAA) since 2009., Objectives: This study aimed to evaluate the early hematologic response and long-term outcomes of a large cohort of patients with SAA who received p-ATG plus cyclosporine (CsA) as first-line therapy from 2010 to 2019., Design: This is a single-center retrospective study of medical records., Methods: We analyzed the data of 1023 consecutive patients with acquired aplastic anemia (AA) who underwent p-ATG combined with CsA as a first-line IST treatment from 2010 to 2019 at our department., Results: The median age of the patients was 24 (4-75) years, and the median follow-up time was 57.2 months (3 days-137.5 months). There was an early mortality rate of 2.8% with a median death time of 0.9 months (3 days-2.9 months). The overall response rates were 40.6% and 56.1% at 3 and 6 months, respectively. The 5-year cumulative incidences of relapse and clonal evolution were 9.0% [95% confidence interval (CI) = 4.2-16.0%] and 4.5% (95% CI = 1.4-10.6%), respectively. The 5-year overall survival (OS) and event-free survival rates were 83.7% (95% CI = 81.1-86.0%) and 50.4% (95% CI = 47.1-53.5%), respectively., Conclusion: p-ATG combined with CsA for the treatment of AA is effective and safe, and p-ATG can be used as an alternative ATG preparation for the standard IST regimen in areas in which h-ATG is not available., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

The analysis of hierarchical interactions has long been a challenging problem due to the large number of candidate main effects and interaction effects, and the need for accommodating the "main effects, interactions" hierarchy. The two-stage analysis methods enjoy simplicity and low computational cost, but contradict the fact that the outcome of interest is attributable to the joint effects of multiple main factors and their interactions. The existing joint analysis methods can accurately describe the underlying data generating process, but suffer from prohibitively high computational cost. And it is not straightforward to extend their optimization algorithms to general loss functions. To address this need, we develop a new computational method that is much faster than the existing joint analysis methods and rivals the runtimes of two-stage analysis. The proposed method, HierFabs, adopts the framework of the forward and backward stagewise algorithm and enjoys computational efficiency and broad applicability. To accommodate hierarchy without imposing additional constraints, it has newly developed forward and backward steps. It naturally accommodates the strong and weak hierarchy, and makes optimization much simpler and faster than in the existing studies. Optimality of HierFabs sequences is investigated theoretically. Simulations show that it outperforms the existing methods. The analysis of TCGA data on melanoma demonstrates its competitive practical performance., Competing Interests: Conflict of interest statement: The authors report there are no competing interests to declare.

In the absence of adequate treatment, effective bone regeneration remains a great challenge. Exploring hydrogels with properties of excellent bioactivity, stability, non-immunogenicity, and commercialization is an important step to develop hydrogel-based bone regeneration materials. In this study, we engineered a self-assembled chelating peptide hydrogel loaded with an osteogenic metal ion cluster extracted from the processed pyritum decoction, including Fe 2+ , Cu 2+ , Zn 2+ , Mn 2+ , Mg 2+ , and Ca 2+ ions, named processed pyritum hydrogel (PPH). We demonstrated that as a reservoir of beneficial metal ion clusters in bone regeneration, PPH has been shown to regulate a variety of genes in the process of bone regeneration. These genes are mainly involved in extracellular matrix synthesis, cell adhesion and migration, cytokine expression, antimicrobial and inflammation. Therefore, PPH accelerated the progress of various bone healing stages, and shortened the bone healing cycle by 4 weeks. Our investigation outcomes showed that the engineered metal ion cluster hydrogel is a novel, simple, and commercializable bone-regenerating hydrogel with potential clinical use., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: To investigate the persistent symptoms in preschool children after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection, and to provide a basis for developing follow-up plans after infection and reducing and preventing related symptoms after infection., Methods: The children, aged 0-5 years, who had Omicron BA.2 infection and were discharged from the pediatric ward of Shanghai Renji Hospital South Branch from April 13 to May 8, 2022, were enrolled as subjects, and related demographic and clinical data were collected. The children were followed up from the time to SARS-CoV-2 clearance for two consecutive tests with an interval of >24 hours till 4-5 weeks after clearance, and telephone follow-up was performed on the primary caregivers to investigate related persistent symptoms., Results: Among the 103 children who met the inclusion criteria, there were 61 boys and 42 girls, with a median age of 18 months. The primary caregivers who had received two or more doses of COVID-19 vaccine accounted for 64.1% (66/103). Fever (98.1%, 101/103) was the most common symptom in these children, followed by cough/expectoration (63.1%, 65/103), gastrointestinal problems (37.9%, 39/103), loss of appetite (30.1%, 31/103), weakness (27.2%, 28/103), and nasal obstruction/runny nose (16.5%, 17/103). The follow-up at 1 month after discharge reported that 44 children (42.7%) had at least one persistent symptom, including respiratory symptoms in 14 children (13.6%) and gastrointestinal problems in 19 children (18.4%). The children whose primary caregivers received two or more doses of COVID-19 vaccine had a significantly shorter time to SARS-CoV-2 clearance than those whose primary caregivers did not receive or only received one dose of COVID-19 vaccine ( P <0.05), while there was no significant difference between the two groups in the proportion of children with at least one persistent symptom ( P >0.05)., Conclusions: Nearly half of the preschool children may have related persistent symptoms after SARS-CoV-2 Omicron variant infection, mainly gastrointestinal and respiratory symptoms. Most of the symptoms may be mild, and continuous follow-up is needed to observe their outcomes. Vaccination of COVID-19 vaccine for primary caregivers has a certain protective effect on children.

Purpose: This study aimed to explore the prevalence and distribution of mental disorders in the elderly population 5 years after the Lushan earthquake in Ya'an, China., Methods: A multi-stage, group-matching random sampling method was adopted with 2579 elderly participants (≥ 60 years old) who were interviewed from January to May 2019. Preliminary screening was conducted using the scale by trained psychiatric nurses, followed by a diagnostic interview during the second stage using Chinese Version of the 5th edition of the Diagnostic and Statistical Manual of Mental Disorder by trained psychiatrists., Results: A total of 2561 participants were included in this study with complete data. The weighted lifetime prevalence of all mental disorders in the elderly was 16.2% (95% CI 15.3-17.1), and the weighted 12-month prevalence was 15.2% (95% CI 13.4-17.0). Depressive disorders, anxiety disorders, substance-related and addictive disorders were the most common mental disorders. The 12-month prevalence of all mental disorders were significantly higher in the elderly living alone, with chronic somatic disease, and being poor (P < 0.05). The 12-month prevalence of posttraumatic stress disorder (PTSD) was significantly higher in the elderly in extremely severely earthquake-affected areas (P < 0.001)., Conclusion: The results of this study show that mental health status of the elderly in Ya'an area differ by socio-economic development, geographical location, and natural disasters. The social and economic development characteristics, the impact of major natural disasters (e.g., earthquakes), and population characteristics should be combined to formulate strategies and interventions to promote the mental health of the elderly., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: This study aimed to clarify the formation and fixation of the annulus of Zinn (AZ) and its relationship with the extraocular muscles by using ultrathin plastination and three-dimensional models., Methods: Eighteen cadaveric heads (36 sides of the orbital apex) were plastinated to coronal (16 sides), sagittal (13 sides), and horizontal (5 sides) ultrathin plastination sections to be investigated at both macroscopic and microscopic levels. One cadaveric head was used for endoscopic dissection to identify anatomic landmarks., Results: There were two fibrous triangles adhered to both ends of the anterior surface of the optic strut. The superior rectus muscle originated from the superior fibrous triangle, and the lateral, inferior, and medial rectus muscles emerged from the inferior fibrous triangle. It was not until 5.46 ± 0.41 mm anterior to the optic strut that the complete tendinous ring composed of rectus muscles, optic nerve sheath, and periosteum was formed. The superior oblique and levator palpebrae superioris muscles originated from the medial fibrous band of the AZ. At the posterior of the AZ, there was a potential passage between the medial rectus muscle and the optic nerve., Conclusions: The fixation of the AZ was composed of the connection of the annular tendon to the optic strut posteriorly and the attachment of the complete tendinous ring to the lesser and greater wings of the sphenoid bone anteriorly. The triangular route area between the optic nerve and medial rectus muscle was located on the anterior side of the base of the optic strut.

Background: This study aimed to explore the impacts of COVID-19 outbreak on mental health status in general population in different affected areas in China., Methods: This was a comparative study including two groups of participants: (1) general population in an online survey in Ya'an and Jingzhou cities during the COVID-19 outbreak from 10-20 February 2020; and (2) matching general population selected from the mental health survey in Ya'an in 2019 (from January to May 2019). General Health Questionnaire (GHQ-12), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS) were used., Results: There were 1775 participants (Ya'an in 2019 and 2020: 537 respectively; Jingzhou in 2020: 701). Participants in Ya'an had a significantly higher rate of general health problems (GHQ scores ⩾3) in 2020 (14.7%) than in 2019 (5.2%) ( p < 0.001). Compared with Ya'an (8.0%), participants in Jingzhou in 2020 had a significantly higher rate of anxiety (SAS scores ⩾50, 24.1%) ( p < 0.001). Participants in Ya'an in 2020 had a significantly higher rate of depression (SDS scores ⩾53, 55.3%) than in Jingzhou (16.3%) ( p < 0.001). The risk factors of anxiety symptoms included female, number of family members (⩾6 persons), and frequent outdoor activities. The risk factors of depression symptoms included participants in Ya'an and uptake self-protective measures., Conclusions: The prevalence of psychological symptoms has increased sharply in general population during the COVID-19 outbreak. People in COVID-19 severely affected areas may have higher scores of GHQ and anxiety symptoms. Culture-specific and individual-based psychosocial interventions should be developed for those in need during the COVID-19 outbreak.