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The co-loading of radionuclides and small-molecule chemotherapeutic drugs as nanotheranostic platforms using nanozymes holds tremendous potential for imaging-guided synergistic therapy. This study presents such nanotheranostic platform ( 177 Lu-MFeCu@Tan) via co-assembling 177 Lu radionuclide and tanshinone (Tan) into Fe/Cu dual-metal nanozyme (MFeCu). This platform simultaneously enables single-photon emission computed tomography (SPECT) imaging and a quadruple-synergistic tumor therapy approach, including internal radioisotope therapy (RIT), catalysis therapy, chemotherapy, and MFeCu-mediated ferroptosis and cuproptosis therapy. In this platform, the MFeCu can catalyze excessive intracellular hydrogen peroxide (H 2 O 2 ) to generate radical oxygen species (ROS) and deplete glutathione (GSH). The excess of H 2 O 2 and GSH are main factors for radioresistance and chemoresistance, reducing them can enhance chemotherapy and RIT. The generated ROS and depleted GSH further induce mitochondrial dysfunction and promote the aggregation of lipoylated dihydrolipoamide S-acetyltransferase and lipid peroxidation, causing the enhance of ferroptosis and cuproptosis. The in vitro and in vivo results demonstrate that this quadruple-synergistic approach shows significant therapeutic efficacy to complete tumor eradication and reduced recurrence in vivo. In conclusion, this work presents a promising strategy for designing SPECT imaging-guided quadruple-synergistic therapy and highlights the feasibility of developing a self-assembled radionuclide and small molecule chemotherapy drugs nanotherapeutic platform for combined treatment of cancer., (© 2024 Wiley‐VCH GmbH.)

Monitoring peroxynitrite (ONOO - ) fluctuations is particularly important for assessing pathological progression and oxidative damage due to their crucial role in maintaining the redox balance of organisms. However, due to the lack of efficient tools for differentially monitoring ONOO - fluctuations at different concentration ranges in vivo, the precise detection of endogenous ONOO - fluctuations under pathological conditions in living systems remains challenging. Herein, we rationally designed a double-enhanced emission cascade activatable near-infrared (NIR) fluorescent probe ( B-TCF ) for the measurement of ONOO - , which consists of a borate ester response group and a malononitrile hemicyanine fluorophore. Especially, after sequential oxidative hydrolysis of the borate ester group and xanthene skeleton, B-TCF exhibited a sequentially double-enhanced NIR emission response at 776 and 625 nm for different ONOO - concentration ranges. Moreover, B-TCF revealed excellent and promising performance for ONOO - in terms of high selectivity, sensitivity, and reaction rate ( k = 28.2 M -1 s -1 ). Motivated by the two-step emission signal enhancement and large wavelength shift in the NIR region, B-TCF enabled discriminative imaging of ONOO - with the low and high concentrations in living cells. Importantly, B-TCF was successfully applied for assessing the pathological progression of isoniazid and acetaminophen-induced liver damage in vivo by detecting the endogenous different ONOO - levels. Overall, this study not only demonstrates the first double-enhanced emission cascade activatable NIR fluorescent probe for measuring the dynamic variation of ONOO - in related diseases but also shows great potential as an effective molecular tool for evaluating the various stages of drug-induced liver damage.

The investigation of important prevalent tick-borne pathogens is central to the control of tick-borne diseases. To understand the prevalence of Borrelia burgdorferi s.l., Borrelia miyamotoi, and the Alongshan virus in ticks and patients in Shaanxi Province, China, a total of 670 adult ticks and 524 patient blood samples were collected in the region between 2022 and 2023. In this study, PCR was used to estimate the prevalence of the three pathogens. The results revealed that the overall positive rates of B. burgdorferi s.l, B. miyamotoi, and ALSV infection in the collected ticks were 13.58 %, 2.46 %, and 4.17 %, respectively. Three genospecies of B. burgdorferi s.l. were detected in this study, namely, B. garinii, B. afzelii, and B. bavariensis, with positive rates of 4.63 %, 3.58 %, and 5.37 %, respectively. The prevalence rates of B. miyamotoi, ALSV  and B. burgdorferi s.l. in the patients were 0.38 %, 0.95 %, and 15 %, respectively. Moreover, B. burgdorferi s.l. and ALSV coinfection was also detected in three patients. Evolutionary analysis revealed that the isolate of B. miyamotoi belongs to the Asian type (Siberian type) and that of ALSV is closely related to that of Finland. To our knowledge, this is the first report on B. miyamotoi and ALSV detection in both ticks and humans in Shaanxi Province; the prevalence indicates that the regions in this province might be endemic areas. The results also suggest that humans in these regions are at risk of infection with these three tick-borne diseases., Competing Interests: Declaration of competing interest All authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

To determine the low-carbon development path of Ordos, three scenarios （baseline scenario, low carbon scenario, and enhanced low carbon scenario） were constructed based on the LEAP model to forecast the energy demand and carbon emission in Ordos from 2020 to 2050 and to analyze the contribution of various policy initiatives to reduce carbon emission. The results showed that under the enhanced low carbon scenario, the energy demand in Ordos peaked at 52 million tons of standard coal equivalent in 2025 and decreased to 40 million tons of standard coal equivalent in 2050, and carbon emissions peaked at 163 million tons in 2025 and decreased to 16 million tons in 2050, which was 88% lower than that in 2020. Regarding emission reduction contribution, comparing the baseline scenario and the enhanced low-carbon scenario, the increase in renewable energy power generation installation, the reduction in energy consumption of terminal energy use, and the increase in terminal electrification rate contributed to the emission reductions of 43%, 25%, and 24%, respectively. The Ordos should vigorously develop renewable energy and make full use of the rich endowment of wind and light resources； at the same time, it should promote economic transformation and gradually increase the proportion of high-value-added and low-energy-consuming industries in the industrial structure. For the power sector, the power generation structure should be adjusted. Traditional thermal power generation should be replaced by zero-carbon and low-carbon power generation technologies. For the industrial and transportation sectors, the terminal electrification rate should be increased, and the energy intensity should be reduced.

Background : This study examines the relationship between physical and mental function and frailty, independently and in conjunction with polypharmacy, among older adults. Methods : This cross-sectional study consisted of 368 participants aged ≥60 years. The participants were categorized into either robust or frail groups using Fried's frailty phenotype. Physical functions were assessed using grip strength, gait speed, Timed Up and Go (TUG), the Five Chair Sit to Stand Test (FCSST) and the Six-Minute Walk Test (SMWT). Mental functions were assessed using cognitive function and depression. Cognitive function was measured using Mini-Mental State Examination (MMSE). Depression was assessed with the Korean version of the Short Geriatric Depression Scale (SGDS). Results : The mean age of study population was 75.4 years. In this population, we identified 78.8% ( n = 290) robust participants and 21.2% ( n = 78) frail participants. The study examined frailty status (frail vs. non-frail) and frailty with and without polypharmacy using multivariate logistic regressions, adjusting for age and sex. In the logistic regression model estimating the risk of frailty, after adjustments for age, sex, BMI, and number of medications, individuals with low SMWT showed a significantly increased risk of frailty, with an odds ratio (OR) of 8.66 and a 95% confidence interval (CI) of 4.55-16.48. Additionally, global cognitive function was associated with a 1.97-fold increase in frailty risk (95% CI: 1.02-3.67). Moreover, in models adjusted for age, sex, and BMI to assess frailty risk linked to polypharmacy, the TUG, SMWT, and SGDS all showed increased risks, with ORs of 3.65 (95% CI: 1.07-12.47), 5.06 (95% CI: 1.40-18.32), and 5.71 (95% CI: 1.79-18.18), respectively. Conclusions : Physical function (SMWT, FCSST, TUG) and mental function (depression, cognition) were associated with frailty. By comprehensively examining these factors, we will gain valuable insights into frailty and enable more precise strategies for intervention and prevention.

Objectives: To evaluate the predictive value of fasting plasma glucose (FPG) for in-hospital mortality in patients with acute myocardial infarction (AMI) with different glucose metabolism status., Methods: We selected 5,308 participants with AMI from the prospective, nationwide, multicenter CAMI registry, of which 2,081 were diabetic and 3,227 were nondiabetic. Patients were divided into high FPG and low FPG groups according to the optimal cutoff values of FPG to predict in-hospital mortality for diabetic and nondiabetic cohorts, respectively. The primary endpoint was in-hospital mortality., Results: Overall, 94 diabetic patients (4.5%) and 131 nondiabetic patients (4.1%) died during hospitalization, and the optimal FPG thresholds for predicting in-hospital death of the two cohorts were 13.2 mmol/L and 6.4 mmol/L, respectively. Compared with individuals who had low FPG, those with high FPG were significantly associated with higher in-hospital mortality in diabetic cohort (10.1% vs . 2.8%; odds ratio [OR] = 3.862, 95% confidence interval [CI]: 2.542-5.869) and nondiabetic cohort (7.4% vs . 1.7%; HR = 4.542, 95%CI: 3.041-6.782). After adjusting the potential confounders, this significant association was not changed. Furthermore, FPG as a continuous variable was positively associated with in-hospital mortality in single-variable and multivariable models regardless of diabetic status. Adding FPG to the original model showed a significant improvement in C-statistic and net reclassification in diabetic and nondiabetic cohorts., Conclusions: This large-scale registry indicated that there is a strong positive association between FPG and in-hospital mortality in AMI patients with and without diabetes. FPG might be useful to stratify patients with AMI., (© 2024 JGC All rights reserved; www.jgc301.com.)

Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80 + I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity., (© 2024. The Author(s).)

Objective: Small extracellular vesicle (sEV)-mediated intercellular communication is increasingly the key for the understanding of venous malformations (VMs). This study aims to clarify the detailed changes of sEVs in VMs., Subjects and Methods: Fifteen VM patients without treatment history and twelve healthy donors were enrolled in the study. sEVs were isolated from both fresh lesions and cell supernatant, and were examined by western blotting, nanoparticle tracking analysis and transmission electron microscopy. Western blot analysis, immunohistochemistry and immunofluorescence were adopted to screening candidate regulator of sEV size. Specific inhibitors and siRNA were employed to validate the role of dysregulated p-AKT/vacuolar protein sorting-associated protein 4B (VPS4B) signaling on the size of sEVs in endothelial cells., Results: The size of sEVs derived from both VM lesion tissues and cell model was significantly increased. VPS4B, whose expression level was mostly significantly downregulated in VM endothelial cells, was responsible for the size change of sEVs. Targeting abnormal AKT activation corrected the size change of sEVs by recovering the expression level of VPS4B., Conclusion: Downregulated VPS4B in endothelial cells, resulted from abnormally activated AKT signaling, contributed to the increased size of sEVs in VMs., (© 2023 Wiley Periodicals LLC.)

Background: Lack of social support is a known predictor of the prognosis after acute myocardial infarction (AMI). Although as a common factor associated with social support, there are limited data on long-term prognostic impact of living status in young and middle-aged patients with AMI., Methods: We analyzed data from the China Acute Myocardial Infarction (CAMI) Registry, consecutive AMI young and middle-aged patients admitted at 108 hospitals in China between January 2013 and September 2014 were included. Eligible patients were assigned to living alone and not living alone groups based on their living status. The primary endpoint was 2-year all-cause mortality. The secondary endpoints included in-hospital mortality and 2-year major adverse cardiac and cerebrovascular events (MACCEs; a composite of all-cause mortality, MI, or stroke). Multilevel logistic and multilevel Cox regression models were used to evaluate the effect of living status on short-term and long-term outcomes., Results: A total of 8307 consecutive AMI young and middle-aged patients were included, 192 (2.3%) patients were living alone. Of the analyzed patients, living alone was associated with 2-year all-cause mortality and MACCEs among all analyzed patients after multivariate adjustment (adjusted hazard ratio [HR] = 2.171 [1.210-3.895], P = 0.009; adjusted HR = 2.169 [1.395-3.370], P = 0.001), but not with poorer in-hospital mortality., Conclusions: The analysis suggested that living alone was associated with both 2-year all-cause mortality and MACCEs in AMI young and middle-aged patients but did not show an extra effect on the in-hospital mortality after covariate adjustment., Trial Registration: Trial registration number: NCT01874691; Registered 31 October 2012., (© 2023. The Author(s).)

Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO 2 F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor ( K i = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Aβ 1 - 42 -induced cognitive impairment, significantly prevented the effects of Aβ 1 - 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.

Background: Cardioprotection is valued in radiotherapy for patients with left-sided breast cancer. Deep inspiration breath-hold (DIBH) technique can achieve cardioprotection well. However, during DIBH, the extent to which the heart enters the radiation field is affected by the movement of the thorax and diaphragm. The aim of this study was to analyze the correlation between the maximum distance of the heart entering the field (maximum heart distance, MHD) and thoracic diameter changes and diaphragmatic descent in left-sided breast cancer patients during DIBH., Patients and Methods: Ninety-eight patients with left-sided breast cancer were included in this retrospective study. They performed simulation in Sentinel-guided DIBH, and two sets of CT images were collected under both free breathing (FB) and DIBH, and diaphragm positions, anteroposterior thoracic diameter (ATD), transverse thoracic diameter (TTD), gating window level (GWL), and MHD were measured, and the change (Δ) of each parameter in DIBH relative to that in FB were calculated. Pearson or Spearman test were used to analyze the correlation between ΔMHD and the changes in other parameters., Results: For all patients with DIBH, the average of ΔMHD was -8.3 mm, and the average of ΔATD and ΔTTD were 11.0 and 8.6 mm, and the median of both left diaphragmatic descent (LDD) and right diaphragmatic descent (RDD) were 35.0 mm, and the median of GWL was 11.1 mm. The correlation coefficients between MHD decrease (ΔMHD) and LDD, RDD, and ΔTTD were -0.430 (p = 0.000), -0.592 (p = 0.000) and 0.208 (p = 0.040), respectively, but not significantly correlated with ΔATD or GWL., Conclusions: The MHD decrease showed a moderate correlation with diaphragmatic descent In Sentinel-guided DIBH for patients with left-sided breast cancer, while there was a weak or no correlation with thoracic diameter changes or GWL. Abdominal breathing can lower diaphragm more and may be more beneficial to the heart stay away from tangential field., (© 2023 He-Gou Wu et al., published by Sciendo.)

Objectives: To develop and validate an 18F-FDG PET/CT-based clinical-radiological-radiomics nomogram and evaluate its value in the diagnosis of MYCN amplification (MNA) in paediatric neuroblastoma (NB) patients., Methods: A total of 104 patients with NB were retrospectively included. We constructed a nomogram to predict MNA based on radiomics signatures, clinical and radiological features. The multivariable logistic regression and the least absolute shrinkage and selection operator (LASSO) were used for feature selection. Radiomics models are constructed using decision trees (DT), logistic regression (LR) and support vector machine (SVM) classifiers. A clinical-radiological (C-R) model was developed using clinical and radiological features. A clinical-radiological-radiomics (C-R-R) model was developed using the C-R model of the best radiomics model. The prediction performance was verified by receiver operating characteristic (ROC) curve analysis, calibration curve analysis and decision curve analysis (DCA) in the training and validation cohorts., Results: The present study showed that four radiomics signatures were significantly correlated with MNA. The SVM classifier was the best model of radiomics signature. The C-R-R model has the best discriminant ability to predict MNA, with AUCs of 0.860 (95% CI, 0.757-0.963) and 0.824 (95% CI, 0.657-0.992) in the training and validation cohorts, respectively. The calibration curve indicated that the C-R-R model has the goodness of fit and DCA confirms its clinical utility., Conclusion: Our research provides a non-invasive C-R-R model, which combines the radiomics signatures and clinical and radiological features based on 18F-FDGPET/CT images, shows excellent diagnostic performance in predicting MNA, and can provide useful biological information with stratified therapy., Critical Relevance Statement: Radiomic signatures of 18F-FDG-based PET/CT can predict MYCN amplification in neuroblastoma., Key Points: • Radiomic signatures of 18F-FDG-based PET/CT can predict MYCN amplification in neuroblastoma. • SF, LDH, necrosis and TLG are the independent risk factors of MYCN amplification. • Clinical-radiological-radiomics model improved the predictive performance of MYCN amplification., (© 2023. The Author(s).)

Background: Dopamine and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein with an apparent Mr of 32000 (DARPP-32) is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain. However, recent studies have shown that DARPP-32 is also expressed in other tissues, including colorectal cancer (CRC), where its function is not well understood., Aim: To explore the effect of DARPP-32 on CRC progression., Methods: The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays. The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, while apoptosis was measured by flow cytometry. The migratory and invasive potential of CRC cell lines were determined using wound healing and transwell chamber assays. In vivo studies involved monitoring the growth rate of xenograft tumors. Finally, the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses., Results: DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC. Overexpression of DARPP-32 was shown to promote cancer cell proliferation, migration, and invasion and reduce apoptosis. DARPP-32 knockdown resulted in the opposite functional effects. Mechanistically, DARPP-32 may regulate the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway in order to carry out its biological function., Conclusion: DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Osteoporosis has a profound influence on public health. First-line bisphosphonates often cause osteonecrosis of the jaw meanwhile inhibiting osteoclasts. Therefore, it is important to develop effective treatments. The results of this study showed that the increased level of NFATc1 m6A methylation caused by zoledronic acid (ZOL), with 4249A as the functional site, is highly correlated with the decreased bone resorption of osteoclasts. Upstream, METTL14 regulates osteoclast bone absorption through the methylation functional site of NFATc1. Downstream, YTHDF1 and YTHDF2 show antagonistic effects on the post-transcriptional regulation of NFATc1 after the m6A methylation level is elevated by METTL14. In this study, meRIP-Seq, luciferase reporter assays, meRIP and other methods were used to elucidate the NFATc1 regulatory mechanism of osteoclasts from the perspective of RNA methylation. In addition, EphA2 overexpression on exosomes is an effective biological method for targeted delivery of METTL14 into osteoclasts. Importantly, this study shows that METTL14 released by exosomes can increase the m6A methylation level of NFATc1 to inhibit osteoclasts, help postmenopausal osteoporosis patients preserve bone mass, and avoid triggering osteonecrosis of the jaw, thus becoming a new bioactive molecule for the treatment of osteoporosis., (© 2023. The Author(s).)

Ankylosing spondylitis (AS) is a progressively worsening and disabling form of arthritis that primarily affects the axial skeleton. This disease mainly involves the spine and the sacroiliac joint. Fusion of the spine and the sacroiliac joint may occur in the later stage of the disease, resulting in spinal stiffness and kyphosis, as well as difficulty in walking, which seriously affects the quality of work and daily living activities and imposes a heavy burden on the patient, the family, and society. Increasing attention has been paid to non-pharmacotherapy as an alternative therapy for AS. Moxibustion is an ancient therapeutic technique used in Traditional Chinese Medicine (TCM). Du-moxibustion therapy, a unique and innovative external treatment developed on the basis of ordinary moxibustion, has a definite therapeutic effect on AS. Du-moxibustion skillfully combines the compatible techniques of TCM to integrate meridians, acupoints, Chinese herbal medicine, and moxibustion. This paper describes the operation procedures and precautions to be taken during Du-moxibustion in experimental mice in detail to provide an experimental basis for the study of the mechanism of Du-moxibustion in the treatment of AS.

Background: Burkitt lymphoma (BL) is an exceptionally aggressive malignant neoplasm that arises from either the germinal center or post-germinal center B cells. Patients with BL often present with rapid tumor growth and require high-intensity multi-drug therapy combined with adequate intrathecal chemotherapy prophylaxis, however, a standard treatment program for BL has not yet been established. It is important to identify biomarkers for predicting the prognosis of BLs and discriminating patients who might benefit from the therapy. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets., Aim: To identify hub genes and perform gene ontology (GO) and survival analysis in BL., Methods: Gene expression profiles and clinical traits of BL patients were collected from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was applied to construct gene co-expression modules, and the cytoHubba tool was used to find the hub genes. Then, the hub genes were analyzed using GO and Kyoto Encyclopedia of Genes and Genomes analysis. Additionally, a Protein-Protein Interaction network and a Genetic Interaction network were constructed. Prognostic candidate genes were identified through overall survival analysis. Finally, a nomogram was established to assess the predictive value of hub genes, and drug-gene interactions were also constructed., Results: In this study, we obtained 8 modules through WGCNA analysis, and there was a significant correlation between the yellow module and age. Then we identified 10 hub genes ( SRC , TLR4 , CD40 , STAT3 , SELL , CXCL10 , IL2RA , IL10RA , CCR7 and FCGR2B ) by cytoHubba tool. Within these hubs, two genes were found to be associated with OS ( CXCL10 , P = 0.029 and IL2RA , P = 0.0066) by survival analysis. Additionally, we combined these two hub genes and age to build a nomogram. Moreover, the drugs related to IL2RA and CXCL10 might have a potential therapeutic role in relapsed and refractory BL., Conclusion: From WGCNA and survival analysis, we identified CXCL10 and IL2RA that might be prognostic markers for BL., Competing Interests: Conflict-of-interest statement: All authors declare that they have no conflicts of interest and have never published the manuscript., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To evaluate the long-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) treated with different reperfusion strategies in Chinese county-level hospitals., Methods: A total of 2,514 patients with STEMI from 32 hospitals participated in the China Acute Myocardial Infarction registry between January 2013 and September 2014. The success of fibrinolysis was assessed according to indirect measures of vascular recanalization. The primary outcome was 2-year mortality., Results: Reperfusion therapy was used in 1,080 patients (42.9%): fibrinolysis ( n = 664, 61.5%) and primary percutaneous coronary intervention (PCI) ( n = 416, 38.5%). The most common reason for missing reperfusion therapy was a prehospital delay > 12 h (43%). Fibrinolysis [14.5%, hazard ratio ( HR ): 0.59, 95% confidence interval ( CI ) 0.44-0.80] and primary PCI (6.8%, HR = 0.32, 95% CI : 0.22-0.48) were associated with lower 2-year mortality than those with no reperfusion (28.5%). Among fibrinolysis-treated patients, 510 (76.8%) achieved successful clinical reperfusion; only 17.0% of those with failed fibrinolysis underwent rescue PCI. There was no difference in 2-year mortality between successful fibrinolysis and primary PCI (8.8% vs. 6.8%, HR = 1.53, 95% CI : 0.85-2.73). Failed fibrinolysis predicted a similar mortality (33.1%) to no reperfusion (33.1% vs. 28.5%, HR = 1.30, 95% CI : 0.93-1.81)., Conclusion: In Chinese county-level hospitals, only approximately 2/5 of patients with STEMI underwent reperfusion therapy, largely due to prehospital delay. Approximately 30% of patients with failed fibrinolysis and no reperfusion therapy did not survive at 2 years. Quality improvement initiativesare warranted, especially in public health education and fast referral for mechanical revascularization in cases of failed fibrinolysis., (Copyright © 2023 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

The purpose of this study is to examine how physical function, physical activity, and sleep are related to depressive symptoms in older adults using a nonlinear model. The participants were 283 Korean older adults aged 65 and older who met the study inclusion criteria. Depressive symptoms were measured using the shortened version of the Geriatric Depression Scale in Korean (SGDS-K). Physical activity and sleep time were objectively quantified by continuously monitoring participants over 20 consecutive days using a triaxial accelerometer. Physical function was evaluated using five distinct measurements: grip strength, gait speed, the Timed Up and Go Test (TUG), the Six-Minute Walk Test (SMWT), and the Five Times Sit to Stand Test (FTSST). The SMWT, gait speed, and MVPA exhibited a nonlinear relationship with depressive symptoms. However, other physical functions showed linear relationships. Also, sleep time showed a U-shaped trend starting at approximately 390 min. After adjusting for age, sex, drinking, and smoking in the logistic regression model, SMWT, MVPA, and sleep time were significantly associated with depressive symptoms. The outcomes highlight the importance of considering multiple factors in understanding depression among the elderly, particularly the intricate interactions between these elements and biological rhythms.

Oral squamous cell carcinoma (OSCC) is the most prevalent subtype of head and neck tumors, highly prone to lymph node metastasis. This study aims to examine the expression pattern of Ras-related protein Rab-27A (RAB27A) and explore its potential implications in OSCC. The expression of RAB27A was assessed through immunohistochemical analysis utilizing tissue microarrays. In vitro experiments were conducted using RAB27A-knockdown cells to investigate its impact on OSCC tumor cells. Additionally, transcriptome sequencing was performed to elucidate potential underlying mechanisms. RAB27A was significantly overexpressed in OSCC, and particularly in metastatic lymph nodes. It was positively correlated with the clinical progression and poor survival prognosis. Silencing RAB27A notably decreased the proliferation, migration, and invasion abilities of OSCC cells in vitro. A Gene Ontology (GO) enrichment analysis indicated a strong association between RAB27A and the epidermal growth factor receptor (EGFR) signaling pathway. Further investigations revealed that RAB27A regulated the palmitoylation of EGFR via zinc finger DHHC-type containing 13 (ZDHHC13). These findings provide insights into OSCC progression and highlight RAB27A as a potential therapeutic target for combating this aggressive cancer.

Objective: To screen the candidate genes in a patient with Kabuki syndrome (KS), providing basis for genetic counseling, prenatal screening, prenatal diagnosis and facilitating early treatment. Methods: This study included a 16-year-old female KS patient born of non-consanguineous Chinese parents who presented to Department of Orthognathic & Cleft Lip and Palate Plastic Surgery, School and Hospital of Stomatology, Wuhan University. Genomic DNA was extracted from the peripheral blood of the subjects and analyzed by whole-exome sequencing (WES). Sanger sequencing was performed to validate the mutation in the candidate gene. The conformational and physicochemical changes of the mutant were analyzed by Alphafold2, Antheprot and DOG.2.0.1, respectively. Distribution of KMT2D mutations in patients with KS was analyzed based on the Human Gene Mutation Database Results: The proband manifested a typical KS facial gestalt, congenital cleft palate, fifth finger deformity, hypodontia, renal hypoplasia and hydronephrosis. Two de novo mutations c.[1166A>C; 1167dupC] (NM_003482) in cis on the same allele in the KMT2D gene were identified by WES and confirmed by allele-specific PCR. Bioinformatics analysis showed that three more α-helixes were added, and a (β-) turn and a (β-) sheet were reduced in KMT2D p. Y389S, p.V390Rfs*26 compared with the wild type. Meanwhile, the interceptive mutant-KMT2D protein p.V390Rfs*26 lost all four domains (FYRN domain, FYRC domain, SET domain, and PostSET domain), which may cause functional disabilities. Conclusions: Our study is the first to identify two novel and de novo KMT2D mutations in cis on the same allele in a KS patient and extends the KMT2D mutation spectrum of KS, providing evidence for genetic susceptibility counseling, prenatal screening and diagnosis, and early treatment of KS.

Background: The immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are crucial in maintaining a delicate balance between protective effects and harmful pathological reactions that drive the progression of coronavirus disease 2019 (COVID-19). T cells play a significant role in adaptive antiviral immune responses, making it valuable to investigate the heterogeneity and diversity of SARS-CoV-2-specific T cell responses in COVID-19 patients with varying disease severity., Methods: In this study, we employed high-throughput T cell receptor (TCR) β repertoire sequencing to analyze TCR profiles in the peripheral blood of 192 patients with COVID-19, including those with moderate, severe, or critical symptoms, and compared them with 81 healthy controls. We specifically focused on SARS-CoV-2-associated TCR clonotypes., Results: We observed a decrease in the diversity of TCR clonotypes in COVID-19 patients compared to healthy controls. However, the overall abundance of dominant clones increased with disease severity. Additionally, we identified significant differences in the genomic rearrangement of variable (V), joining (J), and VJ pairings between the patient groups. Furthermore, the SARS-CoV-2-associated TCRs we identified enabled accurate differentiation between COVID-19 patients and healthy controls (AUC > 0.98) and distinguished those with moderate symptoms from those with more severe forms of the disease (AUC > 0.8). These findings suggest that TCR repertoires can serve as informative biomarkers for monitoring COVID-19 progression., Conclusions: Our study provides valuable insights into TCR repertoire signatures that can be utilized to assess host immunity to COVID-19. These findings have important implications for the use of TCR β repertoires in monitoring disease development and indicating disease severity., 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 Xu, Li, Yuan, Li, Yang, Cheng, Lu, Hou, Zhang, Hu, Qian, Liu, Li, Wang, Chu, Dong, Liu, Ge and Yang.)

Immune checkpoint molecule PD-1, expressed on the cell surface, impairs antigen-driven activation of T cells and thus plays a critical role in tumorigenesis, progression, and the poor prognosis of oral squamous cell carcinoma (OSCC). In addition, increasing evidence indicates that PD-1 carried on small extracellular vesicles (sEVs) also mediates tumor immunity, although their contributions to OSCC are yet unclear. Here, we investigated the biological functions of sEV PD-1 in patients with OSCC. The cell cycle, proliferation, apoptosis, migration, and invasion of CAL27 cell lines treated with or without sEV PD-1 were examined in vitro . We performed mass spectrometry to investigate the underlying biological process, combined with an immunohistochemical study of SCC7-bearing mice models and OSCC patient samples. In vitro data demonstrated that sEV PD-1 induced senescence and subsequent epithelial-mesenchymal transition (EMT) in CAL27 cells by ligating with tumor cell surface PD-L1 and activating the p38 mitogen-activated protein kinase (MAPK) pathway. Comprehensive immunohistochemical analysis of the xenograft mice models and OSCC patient samples revealed a very close correlation between the level of circulating sEV PD-1 and lymph node metastasis. These results demonstrate that circulating sEV PD-1 triggers senescence-initiated EMT in a PD-L1-p38 MAPK-dependent manner, contributing to tumor metastasis. It also suggests that the inhibition of sEV PD-1 may be a promising therapeutic target for the treatment of OSCC.

Objective: The poor survival rate of head and neck squamous cell carcinoma (HNSCC), one of the most prevalent human cancer, is attributed to frequent locoregional recurrence and lymph node metastases. Though it is reported that the expression of ALG-2 interacting protein X (ALIX) closely correlates with the progression of various tumors, its role in HNSCC remains unclear. The present study aims to investigate the role of ALIX in the development of HNSCC., Design: With immunohistochemical staining, the expression levels of ALIX and series of related functional proteins were compared in normal mucosal (n = 18), HNSCC tissues (n = 54), and metastatic lymph nodes (n = 11). Further, the correlation analysis was performed among the proteins detected. By knocking down ALIX in HNSCC cell lines, the correlation of ALIX with the proteins was verified in vitro. The role of ALIX in proliferation, migration, and invasion of HNSCC cells was further studied by flow cytometry, wounding healing, and transwell assays, respectively., Results: Higher expression level of ALIX was revealed in HNSCC samples, especially in metastatic lymph nodes, than in normal mucosal tissues. Accordingly, increasing levels of MMP9, MMP14, and VEGF-C were also discovered in metastatic lymph nodes and significantly correlated with the expression of ALIX. In vitro assays demonstrated that the knockdown of ALIX reduced both the transcriptional and protein levels of MMP9, MMP14, and VEGF-C, together with suppressed migration and weakened invasion of HNSCC cell lines., Conclusions: ALIX up-regulated the expression of MMP9, MMP14 and VEGF-C, and promoted migration and invasion of HNSCC cells., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Transition metal complexes exhibiting thermally activated delayed fluorescence (TADF) remain underdeveloped for organic light-emitting diodes (OLEDs). Here, we describe a design of TADF Pd(II) complexes featuring metal-perturbed intraligand charge-transfer excited states. Two orange- and red-emitting complexes with efficiencies of 82 and 89% and lifetimes of 2.19 and 0.97 μs have been developed. Combined transient spectroscopic and theoretical studies on one complex reveal a metal-perturbed fast intersystem crossing process. OLEDs using the Pd(II) complexes show maximum external quantum efficiencies of 27.5 to 31.4% and small roll-offs down to 1% at 1000 cd m -2 . Moreover, the Pd(II) complexes show exceptional operational stability with LT 95 values over 220 hours at 1000 cd m -2 , benefiting from the use of strong σ-donating ligands and the presence of multiple intramolecular noncovalent interactions beside their short emission lifetimes. This study demonstrates a promising approach for developing efficient and robust luminescent complexes without using the third-row transition metals.

The British Medical Journal published the Acupuncture research album which carried viewpoints, expert consensus, research methods and other genres of papers, providing an authoritative reference for standardizing the design of clinical randomized controlled trial (RCT) of acupuncture and improving the quality of clinical research. Based on the experts' consensus of "acupuncture album" on RCT, combining clinical practice and the related literature reports, and many existing problems existing in the design, we, in the present paper, analyzed ways to improve the design quality of clinical RCT of acupuncture, starting from improving the methodological quality and repeatability of clinica RCT, so as to provide methodological guidance for the design of clinical trials and to promote the standardization of clinical trials of acupuncture.

MYB transcription factors (TFs) play a key role in plant resistance to abiotic and biotical stresses. However, little is currently known about their involvement in the plant defense to piercing-sucking insects. Here, we studied the MYB TFs that responded to and resisted Bemisia tabaci whitefly in the model plant Nicotiana benthamiana. Firstly, a total of 453 NbMYB TFs in N. benthamiana genome were identified and 182 R2R3-MYB TFs were analyzed for molecular characteristics, phylogenetic analysis, genetic structure, motif composition, and cis-elements. Then, six stress-related NbMYB genes were selected for further study. The expression pattern shows they were highly expressed in mature leaves and intensively induced upon whitefly attack. Combined with bioinformatic analysis, overexpression, β-Glucuronidase (GUS) assay, and virus-induced silencing tests, we determined the transcriptional regulation of these NbMYBs on the genes in lignin biosynthesis and SA-signaling pathways. Meanwhile, we tested the performance of whitefly on plants with increased or silenced NbMYB genes expression and found that NbMYB42, NbMYB107, NbMYB163, and NbMYB423 were resistant to whitefly. Our results contribute to a comprehensive understanding of the MYB TFs in N. benthamiana. Furthermore, our findings will facilitate further studies on the role of MYB TFs in the interaction between plants and piercing-sucking insects., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Triclosan is a hydrophobic antimicrobial agent commonly employed in health care settings. While it exhibits broad-spectrum antibacterial properties, the gram-negative nosocomial opportunists Pseudomonas aeruginosa and Serratia marcescens are atypically refractory. Intrinsic resistance to triclosan in P. aeruginosa is largely due to its outer membrane impermeability properties for hydrophobic and bulky substances. The present study was undertaken to determine the relationship between triclosan and the outer cell envelopes of thirteen strains of ten Serratia species reported to be opportunistic pathogens in humans. General intrinsic resistance to hydrophobic and other outer membrane impermeant compounds was assessed using cultural selection, disk agar diffusion, and macrobroth dilution bioassays. Uptake of the hydrophobic fluorescent probe 1- N -phenylnapthylamine was assessed in four disparate strains of S. marcescens . Batch culture kinetics in the presence of combinations of triclosan and outer membrane permeabilizer compound 48/80 allowed analysis of outer membrane involvement in intrinsic resistance. Aggregate results revealed that individual species ranged in response to hydrophobic and bulky molecules from generally refractory to extremely susceptible. Moreover, susceptivity to triclosan sensitization by chemical disruption of outer membrane exclusionary properties differed markedly among species which exhibited intrinsic resistance to triclosan. These data suggest that disparate opportunistic pathogens within the genus Serratia differ phenotypically regarding the degree to which outer membrane exclusion contributes to intrinsic resistance for impermeant molecules in general, and triclosan specifically. Ancillary resistance mechanisms appear to contribute in some species and may involve constitutive multi-drug efflux systems. Importance A paucity of knowledge exists regarding the cellular and molecular mechanisms by which opportunistically pathogenic members of the genus Serratia are able to infect immunocompromised and otherwise susceptible individuals, and then evade chemotherapy. This is especially true for species other than Serratia marcescens and Serratia liquefaciens , although much remains to be learned with regard to the nature of key virulence factors and infection mechanisms which allow for the typically nosocomial acquisition of even these species. The research described in the present study will provide a better understanding of the contribution of outer cell envelope permeability properties to the pathogenicity of these opportunistic species in an ever-increasing susceptible patient population. It is our hope that greater knowledge of the basic biology of these organisms will contribute to the mitigation of suffering they cause in patients with underlying diseases., (©2023PublishedbyElsevierLtd.)

Husks are the main source of bran and furfural flavor in traditional Chinese light-aroma Baijiu, but they negatively affect its smell and taste. Here, bran husks were replaced with fresh bamboo to brew light-aroma Baijiu. Flavor components in Jiupei and Baijiu were detected through headspace solid-phase microextraction with gas chromatography-mass spectrometry, and physicochemical properties were assessed; flavor results were obtained from correlation, principal component, and cluster analyses. Starch and reducing sugar content in Jiupei negatively correlated with moisture, alcohol content, and acidity. Fresh bamboo reduced furfural from bran husks in Jiupei by 88.5% and increased alcohol distillation by 51%; it also improved starch efficiency (5%). Surprisingly, isovanillin was found to be present in Baijiu. Total Baijiu yield (57% ± 2.01%) was attained when crushed bamboo size was 1.5 cm × 0.3 cm × 0.3 cm. This study supports the use of fresh bamboo (an eco-friendly alternative for husks) in brewing light-aroma Baijiu. PRACTICAL APPLICATION: The use of fresh bamboo as a replacement for rice husks in brewing light-aroma Baijiu was investigated. It attenuated the chaff taste in light-aroma Baijiu and increased the liquor yield. Surprisingly, isovanillin was also present in the base Baijiu, and it added to the fragrance. This study not only supports the use of bamboo as an auxiliary material for brewing light-aroma Baijiu but also provides a reference for brewing light-aroma Baijiu with alternative auxiliary materials., (© 2023 Institute of Food Technologists.)

Objectives: To assess the correlation between triglyceride glucose (TyG) index and in-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI)., Methods: A total of 2190 patients with STEMI who underwent primary angiography within 12 h from symptom onset were selected from the prospective, nationwide, multicenter CAMI registry. TyG index was calculated with the formula: Ln [fasting triglycerides (mmol/L) × fasting glucose (mmol/L)/2]. Patients were divided into three groups according to the tertiles of TyG index. The primary endpoint was in-hospital mortality., Results: Overall, 46 patients died during hospitalization, in-hospital mortality was 1.5%, 2.2%, 2.6% for tertile 1, tertile 2, and tertile 3, respectively. However, TyG index was not significantly correlated with in-hospital mortality in single-variable logistic regression analysis. Nonetheless, after adjusting for age and sex, TyG index was significantly associated with higher mortality when regarded as a continuous variable (adjusted OR = 1.75, 95% CI: 1.16-2.63) or categorical variable (tertile 3 vs . tertile 1: adjusted OR = 2.50, 95% CI: 1.14-5.49). Furthermore, TyG index, either as a continuous variable (adjusted OR = 2.54, 95% CI: 1.42-4.54) or categorical variable (tertile 3 vs . tertile 1: adjusted OR = 3.57, 95% CI: 1.24-10.29), was an independent predictor of in-hospital mortality after adjusting for multiple confounders in multivariable logistic regression analysis. In subgroup analysis, the prognostic effect of high TyG index was more significant in patients with body mass index < 18.5 kg/m 2 ( P interaction = 0.006)., Conclusions: This study showed that TyG index was positively correlated with in-hospital mortality in STEMI patients who underwent primary angiography, especially in underweight patients., (© 2023 JGC All rights reserved; www.jgc301.com.)

Objective: To compare the therapeutic efficacy of governor vessel moxibustion combined with fluoxetine hydrochloride capsule, simple fluoxetine hydrochloride capsule and placebo moxibustion combined with fluoxetine hydrochloride capsule for mild to moderate depression with kidney- yang deficiency., Methods: A total of 126 patients with mild to moderate depression with kidney- yang deficiency were randomized into a governor vessel moxibustion group (42 cases, 2 cases dropped off), a western medication group (42 cases, 1 case dropped off) and a placebo moxibustion group (42 cases, 1 case dropped off). The western medication group was given fluoxetine hydrochloride capsule orally, 20 mg a time, once a day. On the basis of the treatment in the western medication group, governor vessel moxibustion was applied from Dazhui (GV 14) to Yaoshu (GV 2) in the governor vessel moxibustion group, once a week; placebo moxibustion was applied in the placebo moxibustion group, once a week. Treatment of 8 weeks was required in the 3 groups. Before and after treatment, the scores of Hamilton depression scale-17 (HAMD-17), Asberg's rating scale for side effects (SERS) and TCM clinical symptom were compared, and the clinical efficacy was evaluated., Results: After treatment, the scores of HAMD-17, SERS and TCM clinical symptom were decreased compared before treatment in the 3 groups ( P <0.05), the decrease ranges of above scores in the governor vessel moxibustion group were larger than those in the western medication group and the placebo moxibustion group ( P <0.05). The total effective rate was 92.5% (37/40) in the governor vessel moxibustion group, which was higher than 75.6% (31/41) in the western medication group and 80.5% (33/41) in the placebo moxibustion group ( P <0.05)., Conclusion: Governor vessel moxibustion combined with fluoxetine hydrochloride capsule can improve the degree of depression and relieve the clinical symptoms in mild to moderate depression patients with kidney- yang deficiency, the efficacy is superior to simple fluoxetine hydrochloride capsule, and can reduce the fluoxetine hydrochloride capsule-induced adverse effect to a certain extent.

This study investigated the effectiveness of electrical muscle stimulation (EMS) with resistance exercise training (ERT) and resistance exercise training (RT) on physical and brain function in middle-aged and older women. Method: Forty-eight participants were randomly allocated into three groups: (i) ERT (n = 16), (ii) RT (n = 16), and (iii) control group (n = 16). The intervention session was 50 min long and performed three times/week for four weeks. The ERT group performed quadriceps setting, straight leg raises, and ankle pump exercises while constantly receiving EMS on their quadriceps muscle on both legs. The RT group performed the same exercise without EMS. Physical function was measured using skeletal muscle mass index (SMI), handgrip strength, gait speed, five times sit-to-stand test (FTSS) and timed up-and-go test (TUG). Brain function was assessed with electroencephalogram measurement of whole brain activity. Results: After four-week intervention, significant improvements were observed in SMI (p < 0.01), phase angle (p < 0.05), and gait speed (p < 0.05) in the ERT group compared to the control group. ERT also increased muscle strength (p < 0.05) and mobility in lower limbs as observed in FTSS and TUG tests (p < 0.05) at post-intervention compared to the baseline. In the ERT group, significant positive changes were observed in Beta1 band power, Theta band power, and Alpha1 band whole brain connectivity (p < 0.005) compared to the control group. Conclusions: Our findings showed that ERT can improve muscle and brain function in middle-aged and older adults during a four-week intervention program whereas significant improvements were not observed with RT. Therefore might be one of the feasible alternative intervention to RT for the prevention of muscle loss whilst improving brain function for middle-aged and older population.

Background Acute myocardial infarction (AMI) is one of the leading causes of mortality worldwide, whereas social support is a known predictor of the prognosis after AMI. As a common factor influencing social support, the impact of marital status on care quality, in-hospital mortality, and long-term prognosis of patients with AMI remains largely unknown. Methods and Results The present study analyzed data from the CAMI (China Acute Myocardial Infarction) registry involving 19 912 patients with AMI admitted at 108 hospitals in China between January 2013 and September 2014 and aimed to evaluate marital status-based differences in acute management, medical therapies, and short-term and long-term outcomes. The primary end point was 2-year all-cause death. The secondary end points included in-hospital death and 2-year major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke). After multivariable adjustment, 1210 (6.1%) unmarried patients received less reperfusion treatment in patients with both ST-segment-elevation myocardial infarction and non-ST-segment-elevation myocardial infarction (adjusted odds ratio [OR], 0.520 [95% CI, 0.437-0.618]; P <0.0001; adjusted OR, 0.489 [95% CI, 0.364-0.656]; P <0.0001). Being unmarried was not associated with poorer in-hospital outcome but with long-term all-cause mortality and major adverse cardiac and cerebrovascular events in both ST-segment-elevation myocardial infarction (adjusted hazard ratio [HR], 1.225 [95% CI, 1.031-1.456]; P =0.0209; adjusted HR, 1.277 [95% CI, 1.089-1.498]; P =0.0027) and non-ST-segment-elevation myocardial infarction (adjusted HR, 1.302 [95% CI, 1.036-1.638]; P =0.0239; adjusted HR, 1.368 [95% CI, 1.105-1.694]; P =0.0040) populations. Conclusions The present study suggests that being unmarried is independently related to less reperfusion received, but could not explain the higher in-hospital mortality rate after covariate adjustment. Being unmarried is associated with a substantially increased risk of adverse events over at least the first 24 months after AMI. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01874691.

Whiteflies of the Bemisia tabaci complex transmit hundreds of plant viruses belonging to the genera Begomovirus and Crinivirus , among others. Tripartite interactions of whitefly-virus-plant frequently occur during virus infection and transmission. Specifically, virus transmission-related behavior of whitefly, such as preference and feeding, may be altered by viruses and thus exert significant impacts on the outcome of virus spread and epidemics. Here, we provide an overview on the current understanding of the manipulation of whitefly behavior by plant viruses. Plant viruses can significantly modulate whitefly preference and feeding behavior, either directly or in a plant-mediated manner. In general, non-viruliferous whiteflies tend to prefer virus-infected plants, and viruliferous whiteflies are more likely to prefer uninfected plants. In most cases, virus infection of plants and/or whitefly seems to exhibit positive or no effects on whitefly feeding on plants. The significance and evolution of these patterns are then discussed. Finally, we suggest several future directions of research, such as the exploration of temporal dynamics and the dissection of underlying mechanisms of virus-induced changes in whitefly behavior.

Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and h BuChE inhibition (IC 50 = 0.79 μM and 6.59 μM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of h BuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor ( K i = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the A β 1 - 42 -induced cognitive impairment, and significantly prevented the effects of A β 1 - 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.

Objective: Runt-related transcription factor 1 (RUNX1) has been proven to be over-expressed and vital in many malignancies. However, its role in cervical cancer is still unclear., Methods: Some online databases (Oncomine, GEPIA, UALCAN, LinkedOmics, and others) were used to explore the expression level, prognostic significance, and gene mutation characteristics of RUNX1 in cervical cancer. The protein levels of RUNX1 in cervical cancer were measured by immunohistochemistry (IHC). The functional changes of cervical cancer cells were measured in vitro after decreasing RUNX1., Results: Bioinformatic results revealed that RUNX1 was upregulated in cervical cancer compared to normal tissues. Moreover, over-expression of RUNX1 was significantly correlated with cervical cancer patients' clinical parameters (e.g., individual cancer stages, patients' age, nodal metastasis status, and others). Meanwhile, functional enrichment analysis of RUNX1-related genes indicated that RUNX1 was mainly involved in the epithelial-mesenchymal transition (EMT) process in cervical cancer. Furthermore, RUNX1 may be upregulated by hsamiR-616-5p and hsa-miR-766 identified by miRDB, TargetScan, and miRWalk. Finally, RUNX1 was upregulated in cervical cancer compared to normal tissues by IHC in collected cervical cancer samples. The invasion and migration abilities of cervical cancer cells were significantly reduced by repressing EMT after knocking down RUNX1 in vitro., Conclusion: RUNX1 was highly expressed in cervical cancer, and upregulated RUNX1 could significantly promote the invasive abilities of cervical cancer cells by inducing EMT. Therefore, RUNX1 may be a potential biomarker for early diagnosis and targeted therapy of cervical cancer., (© 2022. Huazhong University of Science and Technology.)

We investigated the effectiveness of virtual-reality-based cognitive training (VRCT) and exercise on the brain, cognitive, physical and activity of older adults with mild cognitive impairment (MCI)., Methods: This study included 99 participants (70.8 ± 5.4) with MCI in the VRCT, exercise, and control groups. The VRCT consisted of a series of games targeting different brain functions such as executive function, memory, and attention. Twenty-four sessions of VRCT (three days/week) were performed, and each session was 100 min long. Exercise intervention consisted of aerobic and resistance trainings performed in 24 sessions for 60 min (2 times/week for 12 weeks). Global cognitive function was measured using the Mini-Mental State Examination (MMSE) test. Resting-state electroencephalography (EEG) of the neural oscillatory activity in different frequency bands was performed. Physical function was measured using handgrip strength (HGS) and gait speed., Results: After the intervention period, VRCT significantly improved the MMSE scores ( p < 0.05), and the exercise group had significantly improved HGS and MMSE scores ( p < 0.05) compared to baseline. One-way analysis of variance (ANOVA) of resting-state EEG showed a decreased theta/beta power ratio (TBR) ( p < 0.05) in the central region of the brain in the exercise group compared to the control group. Although not statistically significant, the VRCT group also showed a decreased TBR compared to the control group. The analysis of covariance (ANCOVA) test showed a significant decrease in theta band power in the VRCT group compared to the exercise group and a decrease in delta/alpha ratio in the exercise group compared to the VRCT group., Conclusion: Our findings suggest that VRCT and exercise training enhances brain, cognitive, and physical health in older adults with MCI. Further studies with a larger population sample to identify the effect of VRCT in combination with exercise training are required to yield peak benefits for patients with MCI.

The practical use of luminescent mononuclear gold(I) complexes as optoelectronic materials has been limited by their inferior stability. Herein we demonstrate a strategy to improve the stability of gold(I) complexes which display thermally activated delayed fluorescence (TADF). A highly rigid and groove-like σ-donating aryl ligand has been used to form dual Au⋅⋅⋅H-C hydrogen bonds. The secondary metal-ligand interactions have been authenticated by single-crystal structure, NMR spectroscopy and theoretical simulations. The TADF Au I complex exhibits appealing emission properties (photoluminescence quantum yield=76 %; delayed fluorescence lifetime=1.2 μs) and much improved thermal and photo-stability. Vacuum-deposited organic light-emitting diodes (OLEDs) show promising electroluminescence with a maximum external quantum efficiency (EQE) over 23 % and negligible efficiency roll-off even at 10 000 cd m -2 . An estimated LT 50 longer than 77 000 h with initial luminance of 100 cd m -2 reveals good operational stability. This work suggests a way for design of stable luminescent gold(I) complexes., (© 2022 Wiley-VCH GmbH.)

Venous malformations (VMs), featuring localized dilated veins, are the most common developmental vascular anomalies. Aberrantly organized perivascular extracellular matrix (ECM) is one of the prominent pathological hallmarks of VMs, accounting for vascular dysfunction. Although previous studies have revealed various proteins involved in ECM remodeling, the detailed pattern and molecular mechanisms underlying the endothelium-ECM interplay have not been fully elucidated. Our previous studies revealed drastically elevated extracellular vesicle (EV) secretion in VM lesions. Here, we identified increased EV-carried MMP14 in lesion fluids of VMs and culture medium of TIE2-L914F mutant endothelial cells (ECs), along with stronger ECM degradation. Knockdown of RAB27A, a required regulator for vesicle docking and fusion, led to decreased secretion of EV-carried MMP14 in vitro. Histochemical analysis further demonstrated a highly positive correlation between RAB27A in the endothelium and MMP14 in the perivascular environment. Therefore, our results proved that RAB27A-regulated secretion of EV-MMP14, as a new pattern of endothelium-ECM interplay, contributed to the development of VMs by promoting ECM degradation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To understand that 18β-Glycyrrhetic acid 3-O-mono- β -D-glucuronide (GAMG) showed better pharmacological activity and drug-like properties than 18β-Glycyrrhizin (GL); a rapid and sensitive HPLC-MS/MS method was established for the simultaneous determination of GAMG and its metabolite 18β-Glycyrrhetinic acid (GA) in rat plasma and tissues after oral administration of GAMG or GL. This analytical method was validated by linearity, LLOQ, specificity, recovery rate, matrix effect, etc. After oral administration, GAMG exhibited excellent C max (2377.57 ng/mL), T max (5 min) and AUC 0-T (6625.54 mg/L*h), which was much higher than the C max (346.03 ng/mL), T max (2.00 h) and AUC 0-T (459.32 mg/L*h) of GL. Moreover, GAMG had wider and higher tissue distribution in the kidney, spleen, live, lung, brain, etc. These results indicated that oral GAMG can be rapidly and efficiently absorbed and be widely distributed in tissues to exert stronger and multiple pharmacological activities. This provided a physiological basis for guiding the pharmacodynamic study and clinical applications of GAMG.

Background: A growing number of cohort studies revealed an inverse association between cheese intake and cardiovascular diseases, yet the causal relationship is unclear., Objective: To assess the causal relationship between cheese intake, and cardiovascular diseases and cardiovascular biomarkers., Methods: A two-sample Mendelian randomization (MR) analysis based on publicly available genome-wide association studies was employed to infer the causal relationship. The effect estimates were calculated using the random-effects inverse-variance-weighted method., Results: Cheese intake per standard deviation increase causally reduced the risks of type 2 diabetes (odds ratio (OR) = 0.46; 95% confidence interval (CI), 0.34-0.63; p = 1.02 × 10 -6 ), heart failure (OR = 0.62; 95% CI, 0.49-0.79; p = 0.0001), coronary heart disease (OR = 0.65; 95% CI, 0.53-0.79; p = 2.01 × 10 -5 ), hypertension (OR = 0.67; 95% CI, 0.53-0.84; p = 0.001), and ischemic stroke (OR = 0.76; 95% CI, 0.63-0.91; p = 0.003). Suggestive evidence of an inverse association between cheese intake and peripheral artery disease was also observed. No associations were observed for atrial fibrillation, cardiac death, pulmonary embolism, or transient ischemic attack. The better prognosis associated with cheese intake may be explained by lower body mass index (BMI; effect estimate = -0.58; 95% CI, from -0.88 to -0.27; p = 0.0002), waist circumference (effect estimate = -0.49; 95% CI, from -0.76 to -0.23; p = 0.0003), triglycerides (effect estimate = -0.33; 95% CI, from -0.50 to -0.17; p = 4.91 × 10 -5 ), and fasting glucose (effect estimate = -0.20; 95% CI, from -0.33 to -0.07; p = 0.0003). There was suggestive evidence of a positive association between cheese intake and high-density lipoprotein. No influences were observed for blood pressure or inflammation biomarkers., Conclusions: This two-sample MR analysis found causally inverse associations between cheese intake and type 2 diabetes, heart failure, coronary heart disease, hypertension, and ischemic stroke.

Objectives: Lysine-specific demethylase1 (LSD1), an important class of histone demethylases, plays a crucial role in regulation of mammalian biology. The up-regulated LSD1 expression was frequently associated with progress and oncogenesis of multiple human cancers, including non-small cell lung cancer (NSCLC). Therefore, inhibition of LSD1 may provide an attractive strategy for cancer treatment. We investigated the effect of sanguinarine against lung cancer cells as a natural alkaloid LSD1 inhibitor., Materials and Methods: The inhibition properties of sanguinarine to the recombinant LSD1 were evaluated by a fluorescence-based method. Subsequently, assays such as viability, apoptosis, clonogenicity, wound healing, and transwell were performed on H1299 and H1975 cells after treatment with sanguinarine., Results: Upon screening our in-house natural chemical library toward LSD1, we found that sanguinarine possessed a potent inhibitory effect against LSD1 with the IC50 value of 0.4 μM in a reversible manner. Molecular docking simulation suggested that sanguinarine may inactivate LSD1 by inserting into the binding pocket of LSD1 to compete with the FAD site. In H1299 and H1975 cells, sanguinarine inhibited the demethylation of LSD1, validating its cellular activity against the enzyme. Further studies showed that sanguinarine exhibited a strong capacity to suppress colony formation, inhibit migration and invasion, as well as induce apoptosis of H1299 and H1975 cells., Conclusion: Our findings present a new chemical scaffold for LSD1 inhibitors, and also provide new insight into the anti-NSCLC action of sanguinarine., Competing Interests: The authors declare that there are no conflicts of interest associated with this manuscript.

Abstract: Dual antiplatelet therapy (DAPT) is recommended among patients with established acute coronary syndrome. In this meta-analysis, we sought to compare the clinical outcomes between de-escalation versus unchanged DAPT based on both randomized controlled trials (RCTs) and observational studies. The primary outcomes were major adverse cardiovascular events for observational studies and net clinical events for RCTs. Four RCTs and 17 observational studies with a total of 38,741 patients were included. Net clinical events were more common with unchanged DAPT than with de-escalation in RCTs [odd ratio (OR): 1.71; 95% confidence interval (CI), 1.21-2.43; I2 = 69.4%], which was mainly due to higher risks of any bleeding (OR: 1.81; 95% CI, 1.14-2.88; I2 = 75.5%) and major bleeding (OR: 1.58; 95% CI, 1.02-2.46; I2 = 0), without significant differences in ischaemic events. However, trial sequential analysis revealed that sufficient information was obtained just for net clinical events, not for respective ischaemic or bleeding events in RCTs. In the analysis based on real-world observational studies, the risks of myocardial infarction (OR: 0.77; 95% CI, 0.61-0.98; I2 = 0) and stroke (OR: 0.42; 95% CI, 0.22-0.81; I2 = 0) were lower with the unchanged DAPT group. Therefore, de-escalation of DAPT led to a marked reduction in net clinical events compared with unchanged DAPT in RCTs, which was mainly due to reduced bleeding events. However, sufficient information for ischaemic events was not obtained. In the analysis based on real-world observational studies, myocardial infarction and stroke were more common with de-escalation, which should arise our attention., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hypertension is a public health problem globally. Understanding the perceived challenges of low-income older people populations with chronic disease is an obstacle the world is facing today., Aim: To explore perceived challenges of self-management in low-income older people with hypertension., Methods: Data were collected in three communities from September 2019 to October 2019 by semi-structured interviews. Interviews were audio-taped by digital voice recorder and analysed according to Colaizzi's seven steps., Results: Participants demonstrated perceived challenges concerning hypertension self-management. Six themes were identified: hypertension belief bias, family dysfunction, deep-rooted habit, elder self-neglect, medical informatization and supportive health policy. Each theme was identified with several subthemes., Conclusions: Findings implied that most of the low-income older people lacked self-management behaviours. Future research is needed to address perceived challenges related to self-management behaviour for patients with hypertension worldwide., (© 2022 John Wiley & Sons Australia, Ltd.)

Current step-count estimation techniques use either an accelerometer or gyroscope sensors to calculate the number of steps. However, because of smartphones unfixed placement and direction, their accuracy is insufficient. It is necessary to consider the impact of the carrying position on the accuracy of the pedometer algorithm, because of people carry their smartphones in various positions. Therefore, this study proposes a carrying-position independent ensemble step-counting algorithm suitable for unconstrained smartphones in different carrying positions. The proposed ensemble algorithm comprises a classification algorithm that identifies the carrying position of the smartphone, and a regression algorithm that considers the identified carrying position and calculates the number of steps. Furthermore, a data acquisition system that collects (i) label data in the form of the number of steps estimated from the Force Sensitive Resistor (FSR) sensors, and (ii) input data in the form of the three-axis acceleration data obtained from the smartphones is also proposed. The obtained data were used to allow the machine learning algorithms to fit the signal features of the different carrying positions. The reliability of the proposed ensemble algorithms, comprising a random forest classifier and a regression model, was comparatively evaluated with a commercial pedometer application. The results indicated that the proposed ensemble algorithm provides higher accuracy, ranging from 98.1% to 98.8%, at self-paced walking speed than the commercial pedometer application, and the machine learning-based ensemble algorithms can effectively and accurately predict step counts under different smart phone carrying positions.