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Background: Atherosclerotic cardiovascular disease (ASCAD) is recognized as a chronic subclinical systemic inflammatory condition. The platelet-albumin ratio (PAR) has shown promise in prognosticating various inflammation-related disorders. Our study aimed to assess the connection between PAR and major adverse cardiovascular events (MACE) in percutaneous coronary intervention (PCI)-treated patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS)., Methods: PAR, derived from platelet and albumin counts, categorized participants into four quartiles. The primary outcome was composite MACE, encompassing all-cause mortality, non-fatal myocardial infarction (MI), and ischemia-driven revascularization. Secondary outcomes comprised individual MACE components. Multivariate Cox regression evaluated PAR's independent impact on adverse events. The non-linear relationship between the PAR value and MACE was explored using a restricted cubic spline (RCS). Receiver operating characteristic (ROC) analysis was conducted and the area under the curve (AUC) was calculated. Subgroup analysis was used to determine the effect of PAR on MACE in different subgroups., Results: Enrolling 1391 NSTE-ACS patients, high PAR quartiles were correlated with elevated MACE rates (quartile 4 vs. quartile 1: 33.5% vs. 10.2%, p < 0.001). PAR was revealed to be independently related to an increased risk of MACE (quartile 4 vs. quartile 1: HR, 2.04 [95% CI, 1.34-3.08], p = 0.001). RCS indicated a positive PAR-MACE relationship. The AUC of PAR for the 3-year MACE was 0.659 (95% CI: 0.626-0.677, P<0.001). Subgroup analysis showed no significant interactions across subsets., Conclusion: PAR independently predicted MACE risk in PCI-treated NSTE-ACS patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.

As a global public health problem, low back pain (LBP) caused by intervertebral disc degeneration (IDD) seriously affects patients' quality of life. In addition, the prevalence of IDD tends to be younger, which brings a huge burden to individuals and society economically. Current treatments do not delay or reverse the progression of IDD. The emergence of biologic therapies has brought new hope for the treatment of IDD. Among them, extracellular vesicles (EVs), as nanoscale bioactive substances that mediate cellular communication, have now produced many surprising results in the research of the treatment of IDD. This article reviews the mechanisms and roles of EVs in delaying IDD and describes the prospects and challenges of EVs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The pore-forming S. aureus α-toxin (Hla) contributes to virulence and disease pathogenesis. While high concentrations of toxin induce cell death, neutrophils exhibit relative resistance to lysis, suggesting that the action of Hla may not be solely conferred by lytic susceptibility. Using intravital microscopy, we observed that Hla disrupts neutrophil localization and clustering early in infection. Hla forms a narrow, ion-selective pore, suggesting that Hla may dysregulate calcium or other ions to impair neutrophil function. We found that sub-lytic Hla did not permit calcium influx but caused rapid membrane depolarization. Depolarization decreases the electrogenic driving force for calcium, and concordantly, Hla suppressed calcium signaling in vitro and in vivo and calcium-dependent leukotriene B4 (LTB4) production, a key mediator of neutrophil clustering. Thus, Hla disrupts the early patterning of the neutrophil response to infection, in part through direct impairment of neutrophil calcium signaling. This early mis-localization of neutrophils may contribute to establishment of infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Accumulating evidence has underscored the prognostic value of tumor-infiltrating immune cells in the tumor microenvironment of colon cancer (CC). In this retrospective study, based on publicly available transcriptome profiles and clinical data from the Gene Expression Omnibus and The Cancer Genome Atlas databases, we derived and verified an activated dendritic cell (aDC)-related gene signature (aDCRS) for predicting the survival outcomes and chemotherapy and immunotherapy response of CC patients. We quantified the infiltration abundance of 22 immune cell subtypes via the "CIBERSORT" R script. Univariate Cox proportional hazards (PHs) regression was used to identify aDC as the most robust protective cell type for CC prognosis. After selecting differentially expressed genes (DEGs) significantly correlated with aDC infiltration, we performed univariate Cox-PH regression, LASSO regression, and stepwise multivariate Cox-PH regression successively to screen out prognosis-related genes from selected DEGs for constructing the aDCRS. Receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analysis were employed to assess the discriminatory ability and risk-stratification capacity. The "oncoPredict" package, Cancer Treatment Response gene signature DataBase, and Tumor Immune Dysfunction and Exclusion algorithm were utilized to estimate the practicability of the aDCRS in predicting response to chemotherapy and immune checkpoint blockade. Gene set enrichment analysis and single-cell RNA sequencing analysis were also implemented. Furthermore, an aDCRS-based nomogram was constructed and validated via ROC curves, calibration plots and decision curve analysis. In conclusion, aDCRS and an aDCRS-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions, thus improving the survival outcomes of CC patients in the future.

There are many debates regarding the risk factors of surgical site infection (SSI) following posterior cervical surgery in previous studies. And, till now there is no such a study to examine cervical laminoplasty surgery. From January 2011 through October 2021, a total of 405 patients who were treated with unilateral open-door laminoplasty surgeries were enrolled in this study. We divided the patients into the SSI group and the non-SSI group and compared their patient-specific and procedure-specific factors. Univariate and multiple logistic regression analysis were performed to determine the risk factors. Of the 405 patients, 20 patients had SSI. The rate of SSI found to be 4.93%. There were significant differences between groups in the thicker subcutaneous fat thickness (FT) (p < 0.001), the higher ratio of subcutaneous FT to muscle thickness (MT) (p < 0.001), the higher preoperative Japanese Orthopaedic Association (JOA) Scores (p < 0.003), the decreased preoperative serum albumin (p < 0.001), the more postoperative drainage (p < 0.05) and the longer time of draining (p < 0.001). Logistic regression analysis of these differences showed that the higher ratio of subcutaneous FT/MT, the higher preoperative JOA scores, the decreased preoperative serum albumin and the longer time of draining were significantly related to SSI (p < 0.05). The higher ratio of subcutaneous FT/MT, the higher preoperative JOA scores, the decreased preoperative serum albumin and the longer time of draining are identified as the independent risk factors of SSI in cervical laminoplasty. Identification of these risk factors could be useful in reducing the SSI incidence and patients counselling., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Despite advances in cancer therapy, the existence of self-renewing cancer stem cells (CSC) can lead to tumor recurrence and radiation resistance, resulting in treatment failure and high mortality in patients. To address this issue, a near-infrared (NIR) laser-induced synergistic therapeutic platform has been developed by incorporating aggregation-induced emission (AIE)-active phototheranostic agents and sulfur dioxide (SO 2 ) prodrug into a biocompatible hydrogel, namely TBH, to suppress malignant CSC growth. Outstanding hydroxyl radical (·OH) generation and photothermal effect of the AIE phototheranostic agent actualizes Type I photodynamic therapy (PDT) and photothermal therapy through 660 nm NIR laser irradiation. Meanwhile, a large amount of SO 2 is released from the SO 2 prodrug in thermo-sensitive TBH gel, which depletes upregulated glutathione in CSC and consequentially promotes ·OH generation for PDT enhancement. Thus, the resulting TBH hydrogel can diminish CSC under 660 nm laser irradiation and finally restrain tumor recurrence after radiotherapy (RT). In comparison, the tumor in the mice that were only treated with RT relapsed rapidly. These findings reveal a double-boosting ·OH generation protocol, and the synergistic combination of AIE-mediated PDT and gas therapy provides a novel strategy for inhibiting CSC growth and cancer recurrence after RT, which presents great potential for clinical treatment., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The epithelial-mesenchymal transition (EMT) is an important process during metastasis in various tumors, including colorectal cancer (CRC). Thus, the study of its characteristics and related genes is of great significance for CRC treatment. In this study, 26 EMT-related gene sets were used to score each sample from The Cancer Genome Atlas program (TCGA) colon adenocarcinoma (COAD) database. Based on the 26 EMT enrichment scores for each sample, we performed unsupervised cluster analysis and classified the TCGA-COAD samples into three EMT clusters. Then, weighted gene co-expression network analysis (WGCNA) was used to investigate the gene modules that were significantly associated with these three EMT clusters. Two gene modules that were strongly positively correlated with the EMT cluster 2 (worst prognosis) were subjected to Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Then, a prognosis-related risk model composed of three hub genes GPRC5B , LSAMP , and PDGFRA was established. The TCGA rectal adenocarcinoma (READ) dataset and a CRC dataset from the Gene Expression Omnibus (GEO) were used as the validation sets. A novel nomogram that incorporated the risk model and clinicopathological features was developed to predict the clinical outcomes of the COAD patients. The risk model served as an independent prognostic factor. It showed good predictive power for overall survival (OS), immunotherapy efficacy, and drug sensitivity in the COAD patients. Our study provides a comprehensive evaluation of the clinical relevance of this three-gene risk model for COAD patients and a deeper understanding of the role of EMT-related genes in COAD.

Intervertebral disc degeneration is thought to be a major contributor to low back pain, the etiology of which is complex and not yet fully understood. To compensate for the lack of drug and surgical treatment, mesenchymal stem cells have been proposed for regenerative treatment of intervertebral discs in recent years, and encouraging results have been achieved in related trials. Mesenchymal stem cells can be derived from different parts of the body, among which mesenchymal stem cells isolated from the fetal umbilical cord have excellent performance in terms of difficulty of acquisition, differentiation potential, immunogenicity and ethical risk. This makes it possible for umbilical cord derived mesenchymal stem cells to replace the most widely used bone marrow-derived and adipose tissue derived mesenchymal stem cells as the first choice for regenerating intervertebral discs. However, the survival of umbilical cord mesenchymal stem cells within the intervertebral disc is a major factor affecting their regenerative capacity. In recent years biomaterial scaffolds in tissue engineering have aided the survival of umbilical cord mesenchymal stem cells by mimicking the natural extracellular matrix. This seems to provide a new idea for the application of umbilical cord mesenchymal stem cells. This article reviews the structure of the intervertebral disc, disc degeneration, and the strengths and weaknesses of common treatment methods. We focus on the cell source, cell characteristics, mechanism of action and related experiments to summarize the umbilical cord mesenchymal stem cells and explore the feasibility of tissue engineering technology of umbilical cord mesenchymal stem cells. Hoping to provide new ideas for the treatment of disc degeneration., 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 Huang, Liu, Wang, Suo, Zhang, Sun, Zhang and Li.)

Due to the high prevalence and rates of disability associated with musculoskeletal system diseases, more thorough research into diagnosis, pathogenesis, and treatments is required. One of the key contributors to the emergence of diseases of the musculoskeletal system is thought to be changes in the biomechanics of the human musculoskeletal system. However, there are some defects concerning personal analysis or dynamic responses in current biomechanical research methodologies. Digital twin (DT) was initially an engineering concept that reflected the mirror image of a physical entity. With the application of medical image analysis and artificial intelligence (AI), it entered our lives and showed its potential to be further applied in the medical field. Consequently, we believe that DT can take a step towards personalized healthcare by guiding the design of industrial personalized healthcare systems. In this perspective article, we discuss the limitations of traditional biomechanical methods and the initial exploration of DT in musculoskeletal system diseases. We provide a new opinion that DT could be an effective solution for musculoskeletal system diseases in the future, which will help us analyze the real-time biomechanical properties of the musculoskeletal system and achieve personalized medicine.

Background: Depression, a serious public health disorder, is increasingly prevalent worldwide. An association between alkaline phosphatase (ALP) and neurological disorders has been reported. However, data on ALP and depression risk are scarce, which warrants attention., Methods: We assessed the association between ALP and risk of depression in adults from the 2007-2014 National Health and Nutrition Examination Survey (NHANES). Depression was assessed using the Patient Health Questionnaire-9. Univariate and multivariate logistic regression were used to assess the association between ALP and risk of depression, and subgroup analyses were also performed., Results: A total of 17,485 participants were included. The prevalence of depression was 9.3% (1,631/17,485) and ALP was significantly associated with the risk of depression when ALP was a categorical variable (quadratic or categorized by 79 U/L) in a multivariate logistic regression model after adjusting for confounding factors (≥79 U/L vs. <79 U/L, adjusted OR, 1.15; 95%CI, 1.02-1.29). Each 1-unit increase in ALP (log 2 ) was associated with a 20% increase in depression prevalence (adjusted OR, 1.20; 95%CI, 1.06-1.36) when ALP was used as a continuous variable. Subgroup analysis showed that ALP was positively associated with the risk of depression with different characteristics., Conclusion: Our findings suggest that higher alkaline phosphatase levels, even within the normal range, are significantly associated with a higher risk of depression in US adults. Such findings require further prospective studies to provide more evidence., 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 Liang, Mao, Liang, Liang, Suo, Xue and Yang.)

Background and Objectives: Full waveform inversion (FWI) has been widely applied for the reconstruction of underground medium parameters in seismic communities and has made a great success. It is also a promising way to image hard tissues such as bones by ultrasonic FWI algorithm. However, the ultrasonic FWI methods for bone parameters imaging reported in literature so far are limited to the time domain and/or Fourier domain, and can only achieve quantitative imaging with acoustic velocity of bone less than 3000 m/s. Because the acoustic velocity of actual cortical bones can be as high as 4200 m/s, it is still a challenge for FWI to achieve higher parameter contrast bone imaging., Methods: Here, we proposed an ultrasonic FWI algorithm in Laplace-Fourier domain (LFDFWI) for high-contrast bone quantitative imaging. Compared to Time domain and Fourier domain, the LFDFWI algorithm is more appropriate for dealing with the presence of high contrast between bone tissues, reducing the possibility of inversion falling into a local minimum, and obtaining better inversion results. We adapted the seismic FWI algorithm to make it suitable for high-frequency ultrasonic sources and small-sized bone parameter imaging., Results: We conducted a series of bone models to evaluate the effectiveness of the proposed algorithm, including four kinds of bone model derived from micro computed tomography (Micro-CT) image of rat. We evaluated the experimental results based on visual analysis, error analysis and structural similarity (SSIM). The numerical simulation results showed that, when acoustic approximation is used, the proposed method can obtain accurate high-contrast images of the velocity and density parameters of bone structure, the mean relative error (MRE) in the region of interest (ROI) were all less than 2%, and the SSIM is up to 98%; when the viscoelastic approximation is used, this method can also obtain the desired high-contrast bone parameter distribution, with MRE less than 4% and SSIM higher than 74%, both of which are better than FDFWI in Fourier domain (FDFWI)., Conclusion: The results demonstrated that the proposed FWI algorithm can obtain high resolution bone parameter models close to the Micro-CT image, which proves its clinical application potential., Competing Interests: Conflict of 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 Elsevier B.V. All rights reserved.)

The regulation of detached ripening is significant for prolonging fruit shelf life. Although light quality and sucrose affecting strawberry fruit ripening have been widely reported, little information is available about how they co-regulate the strawberry detached ripening process. In this study, different light qualities (red light-RL, blue light-BL, and white light-WL) and 100 mM sucrose were applied to regulate the ripening of initial red fruits detached from the plant. The results showed RL-treated samples (RL + H 2 O, RL + 100 mM sucrose) had brighter and purer skin color with a higher L*, b*, and C* value, and promoted the ascorbic acid. Almost all light treatments significantly decreased TSS/TA (total soluble solid/titratable acid) and soluble sugar/TA ratio, which is exacerbated by the addition of sucrose. Blue or red light in combination with sucrose notably increased total phenolic content and decreased malondialdehyde (MDA) accumulation. In addition, blue or red light combined with sucrose increased abscisic acid (ABA) content and promoted ABA signaling by inducing ABA-INSENSITIVE 4 ( ABI4 ) expression and inhibiting SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE 2.6 ( SnRK2.6 ) expression. The strawberries exposed to blue and red light significantly improved auxin (IAA) content compared to the control (0 d), whereas the addition of sucrose inhibited IAA accumulation. Moreover, sucrose treatment suppressed the AUXIN/INDOLE-3-ACETIC ACID 11 ( AUX/IAA11 ) and AUXIN RESPONSE FACTOR 6 ( ARF6 ) expression under different light qualities. Overall, these results indicated that RL/BL + 100 mM sucrose might promote the detached ripening of strawberries by regulating abscisic acid and auxin signaling.

The present protocol describes an observational cohort study that was designed to propose a therapeutic scheme and formulate an individualized treatment strategy for frail elderly patients diagnosed with multiple diseases in a Chinese, multicenter setting. Over a 3-year period, we will recruit 30,000 patients from 10 hospitals and collect baseline data including patient demographic information, comorbidity characteristic, FRAIL scale, age-adjusted Charlson comorbidity index (aCCI), relevant blood tests, the results of imaging examination, prescription of drugs, length of hospital stay, number of overall re-hospitalizations and death. Elderly patients (≥ 65 years old) with multimorbidity and receiving hospital care are eligible for this study. Data collection is being performed at baseline and 3, 6, 9 and 12 months after discharge. Our primary analysis was all-cause death, readmission rate and clinical events (including emergency visits, stroke, heart failure, myocardial infarction, tumor, acute chronic obstructive pulmonary disease, etc). The study is approved by the National Key R & D Program of China (2020YFC2004800). Data will be disseminated in manuscripts submitted to medical journals and in abstracts submitted to international geriatric conferences. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR2200056070]., (© 2023 JGC All rights reserved; www.jgc301.com.)

Background: Spinal disorders affect millions of people worldwide, and can cause significant disability and pain. The paraspinal muscles, located on either side of the spinal column, play a crucial role in the movement, support, and stabilization of the spine. Many spinal disorders can affect paraspinal muscles, as evidenced by changes in their morphology, including hypertrophy, atrophy, and degeneration., Objectives: The objectives of this review were to examine the current literature on the relationship between the paraspinal muscles and spinal disorders, summarize the methods used in previous studies, and identify areas for future research., Methods: We reviewed studies on the morphological characteristics of the paravertebral muscle and discussed their relationship with spinal disorders, as well as the current limitations and future research directions., Results: The paraspinal muscles play a critical role in spinal disorders and are important targets for the treatment and prevention of spinal disorders. Clinicians should consider the role of the paraspinal muscles in the development and progression of spinal disorders and incorporate assessments of the paraspinal muscle function in clinical practice., Conclusion: The findings of this review highlight the need for further research to better understand the relationship between the paraspinal muscles and spinal disorders, and to develop effective interventions to improve spinal health and reduce the burden of spinal disorders.

Acute myeloid leukemia (AML) is the second most common hematological malignancy after lymphoma in the world. Long non-coding RNAs (LncRNAs) have been suggested as key regulators of cancer development and progression in AML. As a member of lncRNA family, the biological role and mechanisms of tyrosine kinase non receptor 2 antisense RNA 1 (TNK2-AS1) in AML is still unclear. The expression of TNK2-AS1 was measured with RT-qPCR in AML cell lines. The changes of the proliferation, apoptosis, and differentiation in TNK2-AS1 shRNA-transfected HL-60 and THP-1 cells were detected with CCK-8, EdU, flow cytometry, Western blot, and NBT assays. Molecular control of TNK2-AS1 on CUGBP Elav-like family member 2 (CELF2) and ETS domain-containing protein-1 (ELK1) on TNK2-AS1 was assessed by chromatin immunoprecipitation (ChIP), RT-qPCR, Western blot, and RNA immunoprecipitation (RIP) assays. TNK2-AS1 expression was upregulated in AML cell lines and negatively correlated with survival patients. Knockdown of TNK2-AS1 markedly reduced AML cell proliferation and promoted apoptosis and differentiation. Likewise, TNK2-AS1 knockdown significantly suppressed tumor growth in vivo. Mechanistically, the upregulation of TNK2-AS1 was activated by transcription factor ELK1. We also uncovered that TNK2-AS1 exerted tumor-promoting effect through silencing CELF2 via binding with EZH2, thus activating PI3K/Akt pathway in AML cells. Elevated expression of TNK2-AS1 was induced by ELK1 and facilitated AML progression by suppressing CELF2 expression via EZH2-mediated epigenetic silencing, suggesting TNK2-AS1 may be a promising therapeutic target and prognostic marker for AML patients.

Background: The associations between the long-term triglyceride-glucose (TyG) index level and variability and clinical outcomes in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) have not been well studied., Methods: A total of 1,694 ACS patients with at least three postbaseline TyG index measurements within 2 years after PCI were included in the present study. The TyG index was defined as ln (fasting triglycerides [mg/dL] × fasting plasma glucose [mg/dL]/2). Multivariable-adjusted Cox proportional hazard models were used to examine the association between baseline and mean TyG index levels and TyG index variability and the risk of major adverse cardiovascular and cerebrovascular events (MACCEs)., Results: During the median follow-up of 31 months, the overall incidence of MACCE was 5.9%. Both high baseline and mean TyG index levels were independently associated with an increased risk of MACCEs after adjustment for multiple potential confounders (hazard ratio [HR) 1.76 95% confidence interval [CI] 1.06-2.93; and HR 2.73 95% CI 1.57-4.74). Similarly, higher TyG index variability by successive variation (SD) was well related to a higher prevalence of MACCEs (HR 2.17 95% CI 1.28-3.68). In addition, the mean TyG index level showed a stronger risk prediction for MACCEs than the baseline TyG index level and TyG index-SD (AUCs 0.618 vs 0.566 vs 0.566)., Conclusions: The risk of MACCEs significantly increased with higher baseline and mean TyG index levels, as well as TyG index variability, in patients with ACS undergoing PCI. In particular, the mean TyG index level exhibited the highest predicting ability for MACCEs. Therefore, monitoring the long-term pattern of the TyG index deserves attention in clinical practice., (© 2022. The Author(s).)

Single cell analysis is crucial for elucidating cellular diversity and heterogeneity as well as for medical diagnostics operating at the ultimate detection limit. Although superbly sensitive biosensors have been developed using the strongly enhanced evanescent fields provided by optical microcavities, real-time quantification of intracellular molecules remains challenging due to the extreme low quantity and limitations of the current techniques. Here, we introduce an active-mode optical microcavity sensing stage with enhanced sensitivity that operates via Förster resonant energy transferring (FRET) mechanism. The mutual effects of optical microcavity and FRET greatly enhances the sensing performance by four orders of magnitude compared to pure Whispering gallery mode (WGM) microcavity sensing system. We demonstrate distinct sensing mechanism of FRET-WGM from pure WGM. Predicted lasing wavelengths of both donor and acceptor by theoretical calculations are in perfect agreement with the experimental data. The proposed sensor enables quantitative molecular analysis at single cell resolution, and real-time monitoring of intracellular molecules over extended periods while maintaining the cell viability. By achieving high sensitivity at single cell level, our approach provides a path toward FRET-enhanced real-time quantitative analysis of intracellular molecules., (© 2022. The Author(s).)

Background: Syndromic congenital heart disease (CHD) is among the most severe conditions in the pediatric population. Copy number variant (CNV) is an important cause of syndromic CHD, but few studies focused on CNVs related to these patients in China. The present study aimed to identify pathogenic CNVs associated with syndromic CHD in the Chinese population., Methods: A total of 109 sporadic patients with syndromic CHD were applied chromosomal microarray analysis (CMA). Phenotype spectrum of pathogenic or likely pathogenic CNVs was analyzed. CHD-related genes were prioritized from genes within pathogenic or likely pathogenic CNVs by VarElect, OVA, AMELIE, and ToppGene., Results: Using CMA, we identified 43 candidate CNVs in 37/109 patients. After filtering CNVs present in the general population, 29 pathogenic/likely pathogenic CNVs in 24 patients were identified. The diagnostic yield of CMA for pathogenic/likely pathogenic CNVs was 23.1% (24/104), excluding 5 cases with aneuploidies or gross chromosomal aberrations. The overlapping analysis of CHD-related gene lists from different prioritization tools highlighted 16 CHD candidate genes., Conclusion: As the first study focused on CNVs in syndromic CHD from the Chinese population, this study reveals the importance of CMA in exploring the genetic etiology of syndromic CHD and expands our understanding of these complex diseases. The bioinformatic analysis of candidate genes suggests several CHD-related genes for further functional research., (© 2022. The Author(s).)

Background: No meta-analysis has been conducted to compare the long-term clinical outcomes of intravascular ultrasound (IVUS)-guided versus angiographic-guided drug-eluting stent implantation in patients with long de novo coronary lesions. We attempted to compare the efficacy and safety of IVUS guidance versus angiography guidance in percutaneous coronary intervention (PCI) for long de novo coronary lesions., Materials and Methods: We performed a detailed meta-analysis from four randomized controlled trials (RCTs) and one observational study to compare long outcomes of IVUS versus angiography in guiding coronary stent implantation with long de novo coronary lesions defined as coronary stenosis which need stent implantation >28 mm in length. Data were aggregated for the endpoints measure using the fixed-effects model as pooled odds ratio (OR) with 95% confidence intervals. Clinical outcomes included major adverse cardiovascular events (MACE), all revascularization, including target lesion revascularization (TLR) and target vessel revascularization (TVR), all myocardial infarction (MI), all-cause death, and stent thrombosis (ST). Cochrane Library, Embase, PubMed, and Web of Science were searched., Results: Four RCTs and one observational study were included in our study with 3,349 patients (IVUS guidance = 1,708; Angiography guidance = 1,641). With mean follow-up of 2 years, the incidence of MACE, all myocardial infarction, all revascularization and stent thrombosis were significantly lower in IVUS-guided DES implantation of patients with long de novo coronary lesions than in angiography-guided patients; MACE [OR 0.41; 95% confidence interval (CI), 0.29-0.58; p < 0.00001], all myocardial infarction (OR 0.23; 95% CI, 0.09-0.58; p = 0.002), all revascularization (OR 0.48; 95% CI, 0.36-0.66; p < 0.00001), stent thrombosis (OR 0.32; 95% CI, 0.11-0.89; p = 0.03). There was no significant difference in all-cause mortality between the two groups (OR 0.82; 95% CI, 0.55-1.23; p = 0.34)., Conclusion: During mean follow-up of 2 years, the incidence of MACE, stent thrombosis, all myocardial infarction and revascularization in patients with long de novo coronary lesions under IVUS-guided PCI were significantly lower than angiography-guided PCI, and there were no statistically significant differences in all-cause mortality., 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 © 2022 Wang, Liang, Wang, Sun, Wang, Suo, Ye, Li, Liu, Zhang and Wu.)

Background: The optimal P2Y 12 inhibitor in high bleeding risk (HBR) patients with acute coronary syndrome (ACS) remains unclear. We compared the in-hospital efficacy and safety of ticagrelor versus clopidogrel in ACS patients at HBR., Methods: We identified 22,120 hospitalized ACS patients with HBR treated with aspirin combined with either clopidogrel (n = 17,420) or ticagrelor (n = 4700) in the Improving Care for Cardiovascular Disease in China-ACS (CCC-ACS) project between November 2014 and December 2019., Results: The median length of hospital stay was 10 days (interquartile range, 7-14 days). Compared with clopidogrel, ticagrelor was associated with a higher risk of in-hospital TIMI major or minor bleeding (4.8% vs 3.8%; adjusted OR 1.20; 95% CI 1.03-1.41; P = 0.022). The incidence of TIMI major bleeding (1.7% vs 1.1%, P = 0.005) and intracranial bleeding (0.8% vs 0.5%, P = 0.005) were also higher in the ticagrelor group than in the clopidogrel group. There was no significant difference in the rate of in-hospital major adverse cardiovascular and cerebrovascular event (MACCE) (a composite of all-cause death, myocardial infarction, stent thrombosis, or ischemic stroke) with ticagrelor compared with clopidogrel therapy (4.2% vs 4.3%; adjusted OR 1.08; 95% CI 0.90-1.28; P = 0.411). Outcomes in the propensity-matched cohorts and in sensitivity analyses were consistent with the those of the main analysis., Conclusions: Among ACS patients with HBR, ticagrelor as compared with clopidogrel was associated with an increased risk of in-hospital major bleeding without a significant reduction in in-hospital MACCE., Clinical Trial Registration: https://www., Clinicaltrials: gov. Unique identifier: NCT02306616., (Copyright © 2022. Published by Elsevier Ltd.)

Plant-associated microbes play important roles in plant health and disease. Mortierella is often found in the plant rhizosphere, and its possible functions are not well known, especially in medical plants. Mortierella alpina isolated from ginseng soil was used to investigate its effects on plant disease. The promoting properties and interactions with rhizospheric microorganisms were investigated in a medium. Further, a pot experiment was conducted to explore its effects on ginseng root rot disease. Physicochemical properties, high-throughput sequencing, network co-occurrence, distance-based redundancy analysis (db-RDA), and correlation analysis were used to evaluate their effects on the root rot pathogen. The results showed that Mortierella alpina YW25 had a high indoleacetic acid production capacity, and the maximum yield was 141.37 mg/L at 4 days. The growth of M. alpina YW25 was inhibited by some probiotics ( Bacillus , Streptomyces , Brevibacterium , Trichoderma , etc.) and potential pathogens ( Cladosporium , Aspergillus , etc.), but it did not show sensitivity to the soil-borne pathogen Fusarium oxysporum . Pot experiments showed that M. alpina could significantly alleviate the diseases caused by F. oxysporum , and increased the available nitrogen and phosphorus content in rhizosphere soil. In addition, it enhanced the activities of soil sucrase and acid phosphatase. High-throughput results showed that the inoculation of M. alpina with F. oxysporum changed the microbial community structure of ginseng, stimulated the plant to recruit more plant growth-promoting bacteria, and constructed a more stable microbial network of ginseng root. In this study, we found and proved the potential of M. alpina as a biocontrol agent against F. oxysporum , providing a new idea for controlling soil-borne diseases of ginseng by regulating rhizosphere microorganisms., 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 © 2022 Wang, Wang, Suo, Qiu, Wu, Zhao and Yang.)

Relative to traditional photosensitizer (PS) agents, those that exhibit aggregation-induced emission (AIE) properties offer key advantages in the context of photodynamic therapy (PDT). At present, PDT efficacy is markedly constrained by the hypoxic microenvironment within tumors and the limited depth to which lasers can penetrate in a therapeutic context. Herein, we developed platelet-mimicking MnO 2 nanozyme/AIEgen composites (PMD) for use in the interventional PDT treatment of hypoxic tumors. The resultant biomimetic nanoparticles (NPs) exhibited excellent stability and were able to efficiently target tumors. Moreover, they were able to generate O 2 within the tumor microenvironment owing to their catalase-like activity. Notably, through an interventional approach in which an optical fiber was introduced into the abdominal cavity of mice harboring orthotopic colon tumors, good PDT efficacy was achieved. We thus propose that a novel strategy consisting of a combination of an AIEgen-based bionic nanozyme and a biomimetic cell membrane coating represents an ideal therapeutic platform for targeted antitumor PDT. This study is the first to have combined interventional therapy and AIEgen-based PDT, thereby overcoming the limited light penetration that typically constrains the therapeutic efficacy of this technique, highlighting a promising new AIEgen-based PDT treatment strategy.

Heart failure caused by pressure overload is one of the leading causes of heart failure worldwide, but its pathological origin remains poorly understood. It remains critical to discover and find new improvements and treatments for pressure overload-induced heart failure. According to previous studies, mitochondrial dysfunction and myocardial interstitial fibrosis are important mechanisms for the development of heart failure. The oligopeptide Szeto-Schiller Compound 31 (SS31) can specifically interact with the inner mitochondrial membrane and affect the integrity of the inner mitochondrial membrane. Whether SS31 alleviates pressure overload-induced heart failure through the regulation of mitochondrial fusion has not yet been confirmed. We established a pressure-overloaded heart failure mouse model through TAC surgery and found that SS31 can significantly improve cardiac function, reduce myocardial interstitial fibrosis, and increase the expression of optic atrophy-associated protein 1 (OPA1), a key protein in mitochondrial fusion. Interestingly, the role of SS31 in improving heart failure and reducing fibrosis is inseparable from the presence of sirtuin3 (Sirt3). We found that in Sirt3KO mice and fibroblasts, the effects of SS31 on improving heart failure and improving fibroblast transdifferentiation were disappeared. Likewise, Sirt3 has direct interactions with proteins critical for mitochondrial fission and fusion. We found that SS31 failed to increase OPA1 expression in both Sirt3KO mice and fibroblasts. Thus, SS31 can alleviate pressure overload-induced heart failure through Sirt3-mediated mitochondrial fusion. This study provides new directions and drug options for the clinical treatment of heart failure caused by pressure overload., 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 © 2022 Suo, Qi, Liu, Zhang, Li, Yan, Zhang, Ti, Chen and Bu.)

Increasing evidence links metabolism, protein synthesis, and growth signaling to impairments in the function of hematopoietic stem and progenitor cells (HSPCs) during aging. The Lin28b/Hmga2 pathway controls tissue development, and the postnatal downregulation of this pathway limits the self-renewal of adult vs fetal hematopoietic stem cells (HSCs). Igf2bp2 is an RNA binding protein downstream of Lin28b/Hmga2, which regulates messenger RNA stability and translation. The role of Igf2bp2 in HSC aging is unknown. In this study, an analysis of wild-type and Igf2bp2 knockout mice showed that Igf2bp2 regulates oxidative metabolism in HSPCs and the expression of metabolism, protein synthesis, and stemness-related genes in HSCs of young mice. Interestingly, Igf2bp2 expression and function strongly declined in aging HSCs. In young mice, Igf2bp2 deletion mimicked aging-related changes in HSCs, including changes in Igf2bp2 target gene expression and impairment of colony formation and repopulation capacity. In aged mice, Igf2bp2 gene status had no effect on these parameters in HSCs. Unexpectedly, Igf2bp2-deficient mice exhibited an amelioration of the aging-associated increase in HSCs and myeloid-skewed differentiation. The results suggest that Igf2bp2 controls mitochondrial metabolism, protein synthesis, growth, and stemness of young HSCs, which is necessary for full HSC function during young adult age. However, Igf2bp2 gene function is lost during aging, and it appears to contribute to HSC aging in 2 ways: the aging-related loss of Igf2bp2 gene function impairs the growth and repopulation capacity of aging HSCs, and the activity of Igf2bp2 at a young age contributes to aging-associated HSC expansion and myeloid skewing., (© 2022 The American Society of Hematology.)

As one of the most fascinating confined water/ice phenomena, two-dimensional square ice has been extensively studied and experimentally confirmed in recent years. Apart from the unidirectional homogeneous square icing patterns considered in previous studies, the multidirectional partitioned square icing patterns are discovered in this study and characterized by molecular dynamics (MD) simulations. Square icing parameters are proposed to quantitatively distinguish the partitioned patterns from the homogeneous patterns and the liquid water. The number of graphene monolayers n is varied in this study, and the results show that it is more energetically favorable to form partitioned square icing patterns when the water molecules are confined between graphite sheets (n ≥ 2) compared to graphene (n = 1). This phenomenon is insensitive to n as long as n ≥ 2 because of the short-range nature of the interaction between water molecules and the carbon substrate. Moreover, it is energetically unfavorable to form partitioned square icing patterns for a single layer of water molecules even for n ≥ 2, verifying that the interaction between layers of water molecules is another dominant factor in the formation of partitioned structures. The conversion from partitioned structure to homogeneous square patterns is investigated by changing the pressure and the temperature. Based on the comprehensive MD simulations, this study unveils the formation mechanism of the partitioned square icing patterns.

Abnormal expression of circular RNAs (circRNAs) in cancer-associated fibroblasts (CAFs) is involved in the tumor-promoting ability of CAFs. Hsa&#95; circ&#95; 0056686 has been reported to affect leiomyoma size. The purpose of this study is to investigate the regulatory role of hsa&#95;circ&#95;0056686 in CAFs on uterine leiomyoma (ULM). The primary CAFs and corresponding normal fibroblasts (NFs) were isolated from the tumor zones of ULM tissues and adjacent, respectively. Hsa&#95;circ&#95;0056686 level was higher in CAFs than NFs, and also higher in ULM tissues than in adjacent tissues. CAFs-CM significantly increased the proliferation and migration and inhibited apoptosis of ULM cells, as confirmed by CCK-8, transwell, and flow cytometry assays. Moreover, conditioned medium (CM) from CAFs transfected with hsa&#95;circ&#95;0056686 shRNA (CAFssh-circ&#95;0056686-CM) abolished CAFs-mediated proliferation, migration and apoptosis of ULM cells. CAFs-CM suppressed the expression of endoplasmic reticulum stress (ERS) marker proteins and induced the expression of extracellular matrix (ECM) marker proteins, thus suppressing ERS and increasing ECM accumulation, which could be declined by CAFssh-circ&#95;0056686-CM. Meanwhile, knockdown of hsa&#95;circ&#95;0056686 reversed the inhibitory effects of CAFs-CM on brefeldin A-induced cell apoptosis. Luciferase gene reporter and RNA pull-down assays indicated that miR-515-5p directly bound with hsa&#95;circ&#95;0056686. MiR-515-5p overexpression restored the hsa&#95;circ&#95;0056686-shRNA-mediated malignant biological behaviors of ULM cells. Hsa&#95;circ&#95;0056686 contributed to tumor-promoting effects of CAFs in ULM, manifested by promoting ULM cell proliferation and migration and reducing ERS-induced apoptosis through sponging miR-515-5p., Competing Interests: The authors have declared that no competing interests exist.

Although promising, the efficiency of aggregation-induced emission luminogens (AIEgens)-based photodynamic therapy (PDT) is limited by cellular glutathione (GSH). GSH is not a terminal reducing agent but it can be oxidized and subsequently reduced to its original state by reductases to further participate in antioxidant activity. It is therefore imperative to control GSH for effectively inducing oxidation within tumor cells. Recent studies showed that tumor cell metabolism depends mainly on glutamine, which is also the nitrogen and ATP source for GSH synthesis. Therefore, glutamine-based starvation therapy may be effective in enhancing photodynamic therapy. In this work, tumor-derived exosomes were developed for co-delivering AIEgens and proton pump inhibitors (PPI) for tumor combination therapy. Tumor-derived exosomes could specifically deliver drugs to the tumor sites, where PPI inhibited cell glutamine metabolism, suppressed tumor cell GSH and ATP production, and improved the effect of type-I PDT from AIEgens. When used in the treatment of MGC803 gastric cancer subcutaneous model, our system shows a high tumor growth inhibition rate, and even promoting tumor immunogenic death. This is the first work which combine inhibition of glutamine metabolism with PDT, and it has the potential to be applied for future designs of new tumor metabolic therapies and photodynamic systems., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Intestinal flora plays an important role in atherosclerosis. Tongxinluo, as a multi-target Chinese medicine to improve atherosclerosis, whether it can improve atherosclerosis by affecting the intestinal flora is worth exploring. We established a vulnerable plaque model of atherosclerosis in New Zealand white rabbits by high cholesterol diet and balloon injury (HCB), and performed Tongxinluo intervention. We detected the level of inflammation by immunohistochemistry, Western Blot, and ELISA, analyzed plaque characteristics by calculating the vulnerability index, and analyzed the changes of gut microbiota and metabolites by 16S rRNA gene sequencing and untargeted metabolomic sequencing. The results showed that Tongxinluo intervention improved plaque stability, reduced inflammatory response, inhibited NLRP3 inflammatory pathway, increased the relative abundance of beneficial bacteria such as Alistipes which reduced by HCB, and increased the content of beneficial metabolites such as trans-ferulic acid in feces. Through correlation analysis, we found that some metabolites were significantly correlated with some bacteria and some inflammatory factors. In particular, the metabolite trans-ferulic acid was also significantly positively correlated with plaque stability. Our further studies showed that trans-ferulic acid could also inhibit the NLRP3 inflammatory pathway. In conclusion, Tongxinluo can improve plaque stability and reduce inflammation in atherosclerotic rabbits, which may be achieved by modulating intestinal flora and intestinal metabolism. Our study provides new views for the role of Tongxinluo in improving atherosclerotic vulnerable plaque, which has important clinical significance., 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 © 2022 Qi, Liu, Yan, Zhang, Zhang, Liu, Zheng, Suo, Ti, Ni, Zhang and Bu.)

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart malformation accounting for ~10% of cases. Although the pathogenesis of TOF is complex and largely unknown, epigenetics plays a huge role, specifically DNA methylation. The protein δ like non‑canonical Notch ligand 1 (DLK1) gene encodes a non‑canonical ligand of the Notch signaling pathway, which is involved in heart development. However, the epigenetic mechanism of DLK1 in the pathogenesis of TOF is yet to be elucidated. Therefore, the present study aimed to clarify its specific mechanism. In this study, immunohistochemistry was used to detect the protein expression of DLK1 and the methylation status of the DLK1 promoter was measured via bisulfite sequencing PCR. Dual‑luciferase reporter assays were performed to examine the influence of transcription factor ETS proto‑oncogene 1 (ETS1) on DLK1 gene expression. The electrophoretic mobility shift assay and chromatin immunoprecipitation assay, both in vivo and in vitro , were used to verify the binding of the ETS1 transcription factor to the DLK1 promoter as well as the influence of methylation status of DLK1 promoter on this binding affinity. The expression of DLK1 in the right ventricular outflow tract was significantly lower in patients with Tetralogy of Fallot (TOF) than that in controls (P<0.001). Moreover, the methylation level of CpG site 10 and CpG site 11 in the DLK1&#95;R region was significantly decreased in TOF cases compared with controls (P<0.01). The integral methylation levels of DLK1&#95;R and the methylation status of the CpG site 11 were both positively associated with DLK1 protein expression in TOF cases. ETS1 was found to inhibit DLK1 transcriptional activity by binding to the CpG site 11 and this affinity could be influenced by the methylation level of the DLK1 promoter. These findings demonstrated that the hypomethylation of the DLK1 promoter could increase the binding affinity of ETS1 transcription factor, which in turn inhibited DLK1 gene transcriptional activity and contributed to the development of TOF.

It remains unclear whether low-dose ticagrelor offers better safety and similar efficacy for Asian patients with acute coronary syndromes (ACS). We aimed to compare the safety and effectiveness of low-dose ticagrelor vs standard-dose ticagrelor in Chinese patients with ACS undergoing percutaneous coronary intervention (PCI). In this observational cohort study, a total of 2110 ACS patients who were event-free at 3 months after the index PCI were divided into standard-dose ticagrelor (90 mg twice daily) (n = 1830) or low-dose ticagrelor (45 mg twice daily) (n = 280) on a background of aspirin 100 mg once daily for at least another 9 months. The primary end point was type 2, 3, or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) criteria over a 1-year follow-up period post-PCI. Predictors of the primary end point were identified. Both Cox regression and propensity score matching analyses were used. The cumulative incidence of BARC type 2, 3, or 5 bleeding was lower in the low-dose ticagrelor group vs the standard-dose group either before (adjusted HR 0.24; 95% CI 0.07-0.77; p = .016) or after matching (HR 0.25; 95% CI 0.08-0.85; p = .026). A composite of cardiac death, myocardial infarction, or stroke was not significantly different between the two groups (0.4% vs 0.9%, respectively). By multivariate analysis, only low-dose ticagrelor was a protected predictor of BARC type 2, 3, or 5 bleeding either before (HR 0.28, 95% CI 0.09-0.89) or after matching (HR 0.24, 95% CI 0.07-0.82). A low-dose regimen of ticagrelor might provide better safety than standard-dose ticagrelor in Chinese patients with ACS undergoing PCI.

The association between tinnitus and psychological resilience is an underdeveloped area of research. This cross-sectional study investigated such associations and factors potentially affecting resilience in 61 patients. Demographic and psychometric data were collected by questionnaires. The Connor-Davidson Resilience Scale (CD-RISC), Medical Coping Modes Questionnaire (MCMQ), Satisfaction with Life Scale (SWLS), General Self-Efficacy Scale (GSES), Big Five Inventory (BFI) and Perceived Social Support Scale (PSSS) were completed by participants. Data were analyzed using independent t- test and Pearson's correlation analysis and multiple linear regression modeling. The CD-RISC score was relatively low (66.97 ± 15.71), negatively correlated with tinnitus (r = -0.276, p  < 0.001) and associated with age (r = 0.270，P＜0.001). As protective factors, SWLS (r = 0.486, p  < 0.001), GSES (r = 0.555, p  < 0.001), PSSS (r = 0.538, p  < 0.001) and extraversion were positively correlated with CD-RISC and BFI scores (r = 0.287, p  < 0.001). We also detected a negative correlation with neuroticism (r = -0.395, p  < 0.001), which is a known risk factor for worse CD-RISC scores. Identifying protective and risk factors for psychological resilience can be used to predict treatment outcomes in tinnitus patients, which will help devise personalized solutions and improve patients' quality of life., Competing Interests: Feng Xin, Fangling Guan and Qingfeng Li drafted the manuscript; Feng Xin retrieved literatures; Fangling Guan and Qingfeng Li selected the scales; Jie Yang and Dan Li collected data; Minli Suo analyzed the data; Changqing Zhao conceived the study, participated in study design and coordination and helped draft the manuscript. All authors have read and approved the final manuscript., (© 2021 PLA General Hospital Department of Otolaryngology Head and Neck Surgery. Production and hosting by Elsevier (Singapore) Pte Ltd.)

Background: Obstructive sleep apnea is an atherogenesis factor of which chronic intermittent hypoxia is a prominent feature. Chronic intermittent hypoxia (CIH) exposure can sufficiently activate the sympathetic system, which acts on the β3 adrenergic receptors of brown adipose tissue (BAT). However, the activity of BAT and its function in CIH-induced atherosclerosis have not been fully elucidated. Methods: This study involved ApoE -/- mice which were fed with a high-fat diet for 12 weeks and grouped into control and CIH group. During the last 8 weeks, mice in the CIH group were housed in cages to deliver CIH (12 h per day, cyclic inspiratory oxygen fraction 5-20.9%, 180 s cycle). Atherosclerotic plaques were evaluated by Oil Red O, hematoxylin and eosin, Masson staining, and immunohistochemistry. Afterward, we conducted immunohistochemistry, western blotting, and qRT-PCR of uncoupling protein 1 (UCP1) to investigate the activation of BAT. The level of serum total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and free fatty acid (FFA) were measured. Finally, RNA-Sequencing was deployed to explore the differentially expressed genes (DEGs) and their enriched pathways between control and CIH groups. Results: Chronic intermittent hypoxia exposure promoted atherosclerotic plaque area with increasing CD68, α-SMA, and collagen in plaques. BAT activation was presented during CIH exposure with UCP1 up-regulated. Serum TC, triglyceride, LDL-c, and FFA were increased accompanied by BAT activation. HDL-c was decreased. Mechanistically, 43 lipolysis and lipid metabolism-associated mRNA showed different expression profiling between the groups. Calcium, MAPK, and adrenergic signaling pathway included the most gene number among the significantly enriched pathways. Conclusion: This study first demonstrated that BAT activation is involved in the progression of CIH-induced atherosclerosis, possibly by stimulating lipolysis., 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 © 2021 Wang, Jiang, Liu, Chen, Wang, Liu, Suo and Wu.)

Lymphangiogenesis is possibly capable of attenuating hypertension-induced cardiac injury. Sirtuin 3 (SIRT3) is an effective mitochondrial deacetylase that has the potential to modulate this process; however, its role in hypertension-induced cardiac lymphangiogenesis to date has not been investigated. Our experiments were performed on 8-week-old wild-type (WT), SIRT3 knockout (SIRT3-KO) and SIRT3 overexpression (SIRT3-LV) mice infused with angiotensin II (Ang II) (1000 ng/kg per minute) or saline for 28 days. After Ang II infusion, SIRT3-KO mice developed a more severe cardiac remodelling, less lymphatic capillaries and lower expression of lymphatic marker when compared to wild-type mice. In comparison, SIRT3-LV restored lymphangiogenesis and attenuated cardiac injury. Furthermore, lymphatic endothelial cells (LECs) exposed to Ang II in vitro exhibited decreased migration and proliferation. Silencing SIRT3 induced functional decrease in LECs, while SIRT3 overexpression LECs facilitated. Moreover, SIRT3 may up-regulate lymphangiogenesis by affecting vascular endothelial growth factor receptor 3 (VEGFR3) and ERK pathway. These findings suggest that SIRT3 could promote lymphangiogenesis and attenuate hypertensive cardiac injury., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Diabetic cardiomyopathy (DCM) is one of the leading causes of heart failure in patients with diabetes mellitus, with limited effective treatments. The cardioprotective effects of sodium-glucose cotransporter 2(SGLT2) inhibitors have been supported by amounts of clinical trials, which largely fills the gap. However, the underlying mechanism still needs to be further explored, especially in terms of its protection against cardiac fibrosis, a crucial pathophysiological process during the development of DCM. Besides, endothelial-to-mesenchymal transition (EndMT) has been reported to play a pivotal role in fibroblast multiplication and cardiac fibrosis. This study aimed to evaluate the effect of SGLT2 inhibitor dapagliflozin (DAPA) on DCM especially for cardiac fibrosis and explore the underlying mechanism. In vivo, the model of type 2 diabetic rats was built with high-fat feeding and streptozotocin injection. Untreated diabetic rats showed cardiac dysfunction, increased myocardial fibrosis and EndMT, which was attenuated after treatment with DAPA and metformin. In vitro, HUVECs and primary cardiac fibroblasts were treated with DAPA and exposed to high glucose (HG). HG-induced EndMT in HUVECs and collagen secretion of fibroblasts were markedly inhibited by DAPA. Up-regulation of TGF-β/Smad signalling and activity inhibition of AMPKα were also reversed by DAPA treatment. Then, AMPKα siRNA and compound C abrogated the anti-EndMT effects of DAPA in HUVECs. From above all, our study implied that DAPA can protect against DCM and myocardial fibrosis through suppressing fibroblast activation and EndMT via AMPKα-mediated inhibition of TGF-β/Smad signalling., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Purpose: This study aimed to test the hypothesis that long noncoding RNA (lncRNA) AL110200 exerts a proinflammatory effect on atherosclerosis and that the variant rs901681 contributes to ischaemic stroke incidence and recurrence., Methods: The expression of AL110200 was analyzed in THP-1 cells treated with oxidized low-density lipoprotein and in human peripheral blood in a coronary heart disease and control population to determine the role of AL110200 in atherosclerosis. The effect of AL110200 on cell adhesion and invasion was tested. The plasma level of leukotriene B4 and rs901681 genotype distribution were assessed in 220 participants. In 1004 ischaemic stroke patients and 1434 controls, the association between rs901681 and stroke incidence was analyzed by logistic regression, and the association of rs901681 and stroke prognosis was analyzed using Kaplan-Meier analysis and the Cox proportional hazards model., Results: Increased expression of AL110200 was observed in THP-1 cells under oxidized low-density lipoprotein treatment. Knockdown of AL110200 reduced the adhesive and invasive ability of THP-1 cells. AL110200 expression in peripheral blood was significantly higher in the coronary heart disease group than in the controls. The GG genotype of rs901681 is associated with reduced plasma leukotriene B4. In the ischaemic stroke population, rs901681 was not associated with ischaemic stroke incidence (p = 0.686). Patients carrying rs901681 GG had a lower risk for stroke recurrence at age ≥60 years (p = 0.001), cardiovascular stroke death (p = 0.022) and all-cause mortality (p = 0.034) in the all-age group., Conclusions: AL110200 might exert a proinflammatory effect on atherosclerosis, and the variant rs901681 might be a strong predictor of stroke prognosis in ischaemic stroke patients., (© 2021 European Academy of Neurology.)

Oxidative stress and apoptosis play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). The purpose of our study was to investigate the protective effects and mechanisms of melatonin against CI-AKI in a CI-AKI mouse model and NRK-52E cells. We established the CI-AKI model in mice, and the animals were pretreated with melatonin (20 mg/kg). Our results demonstrated that melatonin treatment exerted a renoprotective effect by decreasing the level of serum creatinine (SCr) and blood urea nitrogen (BUN), lessening the histological changes of renal tubular injuries, and reducing the expression of neutrophil gelatinase-associated lipid (NGAL), a marker of kidney injury. We also found that pretreatment with melatonin remarkably increased the expression of Sirt3 and decreased the ac-SOD2 K68 level. Consequently, melatonin treatment significantly decreased the oxidative stress by reducing the Nox4, ROS, and malondialdehyde (MDA) content and by increasing the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity levels. The antiapoptotic effect of melatonin on CI-AKI was revealed by decreasing the ratio of Bax/Bcl2 and the cleaved caspase3 level and by reducing the number of apoptosis-positive tubular cells. In addition, melatonin treatment remarkably reduced the inflammatory cytokines of interleukin-1 β (IL-1 β ), tumor necrosis factor α (TNF α ), and transforming growth factor β (TGF β ) in vivo and in vitro. Sirt3 deletion and specific Sirt3 siRNA abolished the above renoprotective effects of melatonin in mice with iohexol-induced acute kidney injury and in NRK-52E cells. Thus, our results demonstrated that melatonin exhibited the renoprotective effects of antioxidative stress, antiapoptosis, and anti-inflammation by the activation of Sirt3 in the CI-AKI model in vivo and in vitro. Melatonin may be a potential drug to ameliorate CI-AKI in clinical practice., Competing Interests: All authors declare that no conflicts of interest exist., (Copyright © 2021 Chunmei Zhang et al.)

Sonodynamic therapy (SDT), as an efficient way of tumor treatment, has the advantages of deep tumor penetration and high therapeutic efficacy. However, developing efficient sonosensitizers are still challenging. AIEgen-based SDT is rarely reported and it is urgent to develop novel AIEgen-active sonosensitizers. Furthermore, the AIEgen-based theranostic system is promisingly needed to be proved on PDX models to be closer to the clinic. Herein, we constructed a novel AIEgen based SDT system and found that DCPy has advantages over traditional sonosensitizers in SDT. Then, a patient-derived MVs/AIEgen hybrid system (AMVs) prepared by electroporation was used for personalized SDT in bladder cancer patient-derived xenograft (PDX) models. Impressively, AMVs displayed the superior tumor targeting ability and efficient personalized SDT therapy on PDX models, both of which were much more improved compared with PLGA/AIEgens nanoparticles and cell line-derived micro vesicles. This work provides new ideas for both the design of AIE-active sonosensitizers and the SDT treatment of cancers, further expanding the potential clinical application of AIEgens in the future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Propofol is an oily liquid widely used for rapid onset of anaesthesia via intravenous route, which shows major limitations of hypersensitivity, anaphylactic reactions and pain. The aim of the present work was to bypass the above issues by formulating tailored niosomal gel to deliver propofol via non-invasive transdermal route. The niosomes were prepared by film hydration method and sonication using cholesterol and Span 80. The Box Behnken design (BBD) was applied to optimize the size (93.5 nm) and the entrapment efficacy (81.5%) of the niosomes by selecting cholesterol at 139 mg, Span 80 at 0.525% and sonication time at 5.13 min. The scanning electron microscopy image showed spherical shape niosomes with smooth surface without aggregation. The ex vivo release data showed significant improvement in the propofol release (92.2% after 10 h) using niosomes in comparison to the control propofol gel (with 30% methanol) without niosomes (25.3% after 10 h). The in vivo pharmacokinetic parameters in the rat model confirmed the improvement in the relative bioavailability with optimized niosomal gel (relative bioavailability = 12.12) in comparison to the control propofol gel. In conclusion, the niosomal gel offered a potential alternative non-invasive route to deliver propofol for procedural sedation especially in pediatric population.

Significant progress has been made in the use of phycocyanin (PC) as a photosensitizer (PS) agent for photodynamic therapy (PDT). The clinical use of PC, however, has been limited by its poor stability, unfavorable pharmacokinetics, limited tumor cell uptake, and the hypoxic nature of the tumor microenvironment. In this study, a novel biomimetic mineralization approach is described for encapsulating PC using zeolitic imidazolate framework-8 (ZIF-8), after which MPEG 2000 -COOH is further utilized as an anchor on the ZIF/PC complex in order to yield MPEG 2000 -ZIF/PC composites (PMs). These PMs are then used as a stable reinforced PS for PDT, effectively improving the intracellular delivery of this protein PS. In contrast to prior studies that have sought to overcome intratumoral hypoxia via increasing oxygen delivery to the tumor site, the mitochondrial complex I inhibitor papaverine (PPV) is instead utilized to reduce intratumor oxygen consumption in an effort to augment the PDT efficacy of the PMs. It is found that this combination treatment strategy markedly improves the antitumor properties of these PMs both in vitro and in patient-derived xenograft (PDX) models without inducing significant side effects. It is therefore proposed that the "armor-plating" of protein PS agents with ZIF-8 in combination with PPV may be a promising approach to precision medicine-mediated tumor treatment., (© 2020 Wiley-VCH GmbH.)

Air quality prediction is a global hot issue, and PM 2.5 is an important factor affecting air quality. Due to complicated causes of formation, PM 2.5 prediction is a thorny and challenging task. In this paper, a novel deep learning model named temperature-based deep belief networks (TDBN) is proposed to predict the daily concentrations of PM 2.5 for the next day. Firstly, the location of PM 2.5 concentration prediction is Chaoyang Park in Beijing of China from January 1, 2018 to October 27, 2018. The auxiliary variables are selected as input variables of TDBN by Partial Least Square (PLS), and the corresponding data is divided into three independent sections: training samples, validating samples and testing samples. Secondly, the TDBN is composed of temperature-based restricted Boltzmann machine (RBM), where temperature is considered as an effective physical parameter in energy balance of training RBM. The structural parameters of TDBN are determined by minimizing the error in the training process, including hidden layers number, hidden neurons and value of temperature. Finally, the testing samples are used to test the performance of the proposed TDBN on PM 2.5 prediction, and the other similar models are tested by the same testing samples for convenience of comparison with TDBN. The experimental results demonstrate that TDBN performs better than its peers in root mean square error (RMSE), mean absolute error (MAE) and coefficient of determination (R 2 )., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A previously well and immunocompetent 64-year-old woman presented with fever of unknown origin and acute hepatitis. Besides headache and nausea, she had no other symptoms. Her clinical examination was unremarkable with no clear focus of infection. She was thoroughly investigated and her biochemical profile suggested a viral or autoimmune aetiology. Multiple imaging modalities gave no further insight. Her serology and subsequent nucleic acid amplification indicated reactivation of latent cytomegalovirus (CMV). Her symptoms resolved with supportive care and no anti-viral therapy was needed. This case report highlights CMV reactivation leading to acute hepatitis in a well, immunocompetent patient., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Radiotherapy (RT) is a potent approach to cancer treatment, but the tumor microenvironment (TME) in solid tumors is often highly hypoxic and contains high levels of antioxidant enzymes, thereby reducing the RT efficacy. In this study, we developed an oxidative stress amplifier (termed CFM) capable of self-sufficient H2O2 and O2 delivery that can be used in concert with RT and chemodynamic therapy (CDT) to treat tumors in patient-derived xenograft (PDX) model systems. Upon exposure to the hypoxic and acidic TME, CFM undergoes rapid degradation that results in the release of Fe3+, Ca2+, O2, and H2O2. Glutathione can subsequently reduce Fe3+ to Fe2+, which is then able to react with H2O2via the Fenton reaction to yield high levels of hydroxyl radicals which subsequently damage mitochondria. CaO2-derived O2 also modulates intratumoral hypoxia, while excessive Ca2+ levels within mitochondria result in apoptotic cell death. Altogether, these properties sensitize PDX tumors to RT. Importantly, the Fe, Zn, and Ca generated by CFM degradation are essential elements in humans. Altogether, these properties make this approach to oxidative stress amplification a promising means of amplifying oxidative stress within tumors while overcoming hypoxia-related resistance to RT, thereby providing a framework for the design of potent radiosensitizing therapeutic approaches.

Objectives To assess perinatal outcomes of COVID-19 infections during pregnancy and the possibility of vertical transmission. Methods An analysis was performed using Stata 15.0, and Q-test was used to evaluate the heterogeneity of the included studies. Results The most common symptoms were found to be fever (64.78%), cough (59.81%) and shortness of breath or dyspnea (23.86%). Of this 88.73% patients demonstrated typical COVID-19 signs on chest CT or X-ray. Intubation was carried out in 35.87% of patients, and 4.95% of mothers were admitted to the intensive care unit, where the rate of maternal death was <0.01% and that of premature delivery was 25.32%. The rate of the birth weight being <2,500 g was 30.65% and that of Neonatal intensive care unit (NICU) admission was 24.41%. Positive nasopharynx swabs or sputum from newborns was <0.01%. Conclusions Pregnant patients with COVID-19 most commonly presented with fever, cough, shortness of breath and dyspnea, most of which possessed imaging manifestations. The risk of intubation and admission to intensive care unit were high. The risk of premature delivery was higher, leading to a high risk of NICU admission and low neonatal birthweight. Vertical transmission of SARS-CoV-2 from mother to child was found to be unlikely.

Multifunctional gold (Au)-based nanomaterials with high atomic number (symbol Z) and strong absorbance in the second near-infrared window (NIR-II) property are emerging as promising candidates for tumor thermo-radiotherapy. The main limitations of applying Au-based nanomaterials to biomedical studies include the absence of active tumor-targeting ability, penetrating efficiency, and stability. In this study, we present a novel type of tumor cell-derived stellate plasmonic exosomes (TDSP-Exos) for penetrative targeted tumor NIR-II thermo-radiotherapy and photoacoustic imaging. The TDSP-Exos are abundantly and easily produced by the incubation of tumor cells with gold nanostars, based on which gold nanostars promote the exocytosis of exosomes from tumor cells. Compared with bare gold nanostars, the TDSP-Exos exhibit pronounced accumulation in deep tumor tissues and perform well in both PA imaging and NIR-II thermo-radiotherapy against the tumor. Moreover, the TDSP-Exos improve tumor hypoxia to enhanced radiotherapy by NIR-II photothermal therapy. This work indicates that the tumor cell-derived exosomes have the potential to function as a universal carrier of photothermal agents for targeted tumor NIR-II thermo-radiotherapy.

The development of novel photosensitizing agents with aggregation-induced emission (AIE) properties has fueled significant advances in the field of photodynamic therapy (PDT). An electroporation method was used to prepare tumor-exocytosed exosome/AIE luminogen (AIEgen) hybrid nanovesicles (DES) that could facilitate efficient tumor penetration. Dexamethasone was then used to normalize vascular function within the tumor microenvironment (TME) to reduce local hypoxia, thereby significantly enhancing the PDT efficacy of DES nanovesicles, and allowing them to effectively inhibit tumor growth. The hybridization of AIEgen and biological tumor-exocytosed exosomes was achieved for the first time, and combined with PDT approaches by normalizing the intratumoral vasculature as a means of reducing local tissue hypoxia. This work highlights a new approach to the design of AIEgen-based PDT systems and underscores the potential clinical value of AIEgens., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Preeclampsia (PE), a common obstetrical disorder, is characterized by impaired migration and invasion abilities of trophoblastic cells. MicroRNA-183-5p (miR-183) was reported to regulate cell migration and invasion in various types of human cancers; however, its role in the pathogenesis of PE remains elusive. Herein, we investigated the role of miR-183 in HTR-8/SVneo trophoblast cells invasion and migration and explored the underlying mechanism. Our results showed that miR-183 was significantly up-regulated in placental tissues from pregnant women compared with that in normal pregnant women. Overexpression of miR-183 inhibited proliferation, migration and invasion, as well as induced apoptosis in HTR-8/SVneo cells. Otherwise, down-regulation of miR-183 achieved the opposite effects. Bioinformatics prediction and luciferase reporter assay confirmed that matrix metalloproteinase-9 (MMP-9) is a target of miR-183. In addition, MMP-9 expression was significantly down-regulated, and inversely correlated with the miR-183 level in placental tissues from pregnant women with severe PE. Down-regulation of MMP-9 suppressed the trophoblast cell invasion and migration, whereas overexpression of MMP-9 promoted cell invasion and migration in HTR-8/SVneo cells. More importantly, up-regulation of MMP-9 reversed the inhibitory effects of miR-183 on cell invasion and migration in trophoblast cells. Collectively, our findings suggested that miR-183 may play critical roles in the pathogenesis of PE and serve as a potential biomarker for severe PE., (© 2020 The Author(s).)

Although radiotherapy (RT) has been an effective therapeutic regimen against most solid tumors, its effect is limited by the hypoxic tumor microenvironment and radio-tolerance of tumor cells to a large extent. Here we have designed a biomimetic nanozyme/camptothecin hybrid system for synergistically enhanced radiotherapy, which consists of an internal camptothecin (CPT)-loaded hollow MnO2 core and an external tumor cell membrane. The tumor cell membrane endows the system with excellent tumor targeting ability. The hollow MnO2 core can deliver the hydrophobic drug CPT and catalyze the production of oxygen from hydrogen peroxide in tumor tissues, which was finally degraded into Mn2+, a T1-weighted contrast agent. The anti-tumor mechanism of this system includes two aspects: (i) the generated oxygen can improve the hypoxic state of the tumor microenvironment and enhance the radiotherapy sensitivity and (ii) CPT can induce cell cycle arrest in the S-phase at a low dose, which further increases the radio-sensitivity of tumor cells and augmented radiation-induced tumor damage. The results of in vivo experiments showed that the biomimetic nanozyme drug delivery system improved the hypoxic microenvironment of the tumor tissue with a high tumor inhibition rate in a murine model. This platform achieved synergistic radiotherapy sensitization and provided a novel idea for the design of a radiotherapy sensitization system.

Objective: To differentiate the value of hemoglobin A1c (HbA1c), glycated albumin (GA) and glycosylated serum protein (GSP) in monitoring blood glucose of patients with aplastic anemia., Methods: 42 patients with aplastic anemia (AA) and 30 patients with AA and Type 2 diabetes mellitus (T2DM) were enrolled in the study, in comparison with 114 healthy subjects and 88 subjects with T2DM. HbA1c, GA, GSP, fasting plasma glucose (FPG), hemoglobin (Hb) and albumin (ALB) were measured, and group comparison and correlation analysis were carried out., Results: Compared with the non-diabetes patients while ALB were <30 g/l or 30-40 g/l, the HbA1c and GSP values in AA, T2DM and AA+T2DM patients were significantly higher while the GA values were lower. Moreover, no differences in FPG levels. The AA+T2DM patients with ALB >40 g/l had higher HbA1c level, with no difference in GA, GSP and FPG levels. There was a positive correlation between HbA1c and GA in healthy group (ALB ≥ 40 g/l), AA patients (ALB 30-40 g/l and ≥40 g/l), T2DM patients (ALB 30-40 g/l and ≥40 g/l) and AA+T2DM patients (ALB 30-40 g/l and ≥40 g/l) but not in those with ALB < 30 g/l., Conclusion: The HbA1c results were affected by moderate-to-severe anemia, but not mild anemia. HbA1c is not recommended to detect blood glucose levels in AA patients (Hb < 90 g/l) or AA patients (ALB < 30 g/l). FPG and GSP are not suitable for AA patients., (© 2020 The Author(s).)

Objective: To apply biological variation and six Sigma models to evaluate analysis performance of 6 HbA 1c analyzers and design the new quality control strategy. Method: We collected data of imprecision and inaccuracy from routine internal quality control (June 2017-December 2017) and proficiency test of NGSP, respectively. The coefficient of variance (CV)% and bias% were plotted in the biological variation and six sigma models. The new quality control strategy was designed by the sigma value and OPSpecs. The quality improvement was guided by the QGI. Results: The analytical performance of 6 HbA 1c analyzers in our laboratory were good in the routine model, However, 50% (3/6) and 67% (4/6) of the HbA 1c analyzers reached the acceptable level in the biological variation and six Sigma model, respectively. We also design personalized control strategy and promote quality improvement by combining the sigma value, OPSpecs, and QGI. Conclusions: Biological variation model and six sigma model could visually display the performance of 6 HbA 1c analyzers and personalized control strategy could be designed based on the sigma value, OPSpecs, and QGI.