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Maosheng Lee,1,2 Huilin Li,2 Hengxia Zhao,2 Miao Suo,1,2 Deliang Liu2 1The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 2Department of Endocrinology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, People’s Republic of ChinaCorrespondence: Huilin Li Tel/Fax +86 755-8839368Email sztcmlhl@163.comBackground and Aim: Type 2 diabetes mellitus (T2DM), a complex metabolic disease, has become a major public health issue around the world. Hydroxysafflor yellow A (HSYA) is the major active chemical ingredient of Carthamus tinctorius L. (safflower), which is widely used in patients with cardiovascular and cerebrovascular diseases in China. The aim of this study was to investigate the anti-diabetic effect and potential mechanism of HSYA on the high-fat diet (HFD) and streptozotocin (STZ-)-induced T2DM rats.Materials and Methods: T2DM rats were induced by feeding HFD (60% fat) for four weeks followed by intraperitoneal injection of a low dose of streptozocin (35mg/kg). The T2DM rats were treated with HSYA (120mg/kg) or metformin (90mg/kg) for eight weeks. Biochemical analysis, histological analysis and Western blot analysis were conducted after 8 weeks of intervention.Results: The treatment with HSYA evidently reduced fasting-blood glucose and insulin resistance in T2DM rats, indicated by results from fasting-blood glucose, oral glucose tolerance test, fasting insulin levels and histology of pancreas islets. The Western blot results revealed that HSYA reversed the down-regulation of PI3K and AKT in liver. The TUNEL assay analysis of pancreatic tissue showed that HSYA could inhibit the apoptosis of pancreatic β-cells to a certain extent. Moreover, HSYA-treatment increased the levels of glycogen synthase and hepatic glycogen and improved lipid metabolism by reducing the triglyceride, total and low-density lipoprotein cholesterol levels, even though it did not change the rats’ body weights.Conclusion: The results of this study suggested that HSYA could promote PI3K/Akt activation and inhibit the apoptosis of pancreatic β-cells directly or indirectly, which might be the underlying mechanisms in HSYA to improve insulin resistance and regulate glycolipid metabolism in T2DM rats.Keywords: hydroxysafflor yellow A, insulin resistance, PI3K/AKT pathway, apoptosis, type 2 diabetes mellitus, traditional Chinese medicine

NHX proteins are transmembrane antiporters belonging to the cation/proton antiporter gene family, with a conserved Na+ (K+)/H+ exchange (PF00999) protein domain. NHXs play a prominent role in plant growth, development, and defense. However, the role of NHX gene family in potato (Solanum tuberosum L.) is yet to be known. In this study, we conducted a genome-wide analysis of the potato NHX gene family. A total of 25 StNHX family members were identified to be unevenly distributed on 10 chromosomes. The proteins ranged in length from 252 to 1,153 amino acids, with molecular masses ranging from 27516.32 to 127860.87 kD, and isoelectric points (pI) ranging from 4.96 to 9.3. Analyses of gene structures and conserved motifs indicated that StNHX genes in the same phylogenetic cluster are conserved. Phylogenetic analysis divided the StNHX genes into three subfamilies (Classes I, II, and III). Synteny analysis indicated that StNHX gene family Class III of NHX and all Arabidopsis thaliana NHXs shared a close evolutionary relationship. Analysis of cis-acting elements in the upstream 1,500 bp promoter region of potato NHX genes showed that these genes could be regulated by light, stress, and hormones such as abscisic acid and gibberellic acid. Protein-protein interaction network analysis indicated that StNHX proteins may participate in the regulation of potato growth and stress response. Besides, To determine a potential role of these genes in tissue development and drought response, we analyzed the RNA-seq data of different DM potato tissues. The results showed that NHX genes exhibited distinct tissue-specific expression patterns. We further examined the expression patterns of StNHX in different tissues (leaves, roots, shoots, tubers, stolons, and flowers) during the flowering stage in ‘Jizhangshu NO.8.’ potato. The qRT-PCR results further confirmed the importance of StNHX genes in potato plant growth and development. We further analyzed the RNA-seq data (DM potato) under different abiotic stresses (salt, drought, and heat), and found that the expression of StNHX genes was induced under abiotic stress. qRT-PCR analysis of shoots and roots of ‘Jizhangshu NO.8.’ potato treated for 0, 6, 12, and 24 h with 15% PEG6000 confirmed that the 25 StNHX genes are involved in the response to drought stress in potato. The results of this study may be useful for selecting appropriate candidate genes for the breeding of new drought-tolerant potato varieties. Furthermore, this study lays a foundation for prospective analysis of StNHX gene functions.

[Objective] The temporal and spatial evolution characteristics of ecological sensitivity in a typical coal mine resource city (Liupanshui City in Guizhou Province) in a karst region from 2000 to 2020 were analyzed in order to provide a basis for the ecological protection of coal mine resource cities in karst regions. [Methods] We chose a remote sensing ecological index, a water loss and soil erosion sensitivity index, a rocky desertification sensitivity index, a landscape development intensity index, and an index of carbon emissions to build an integrated ecological sensitivity index, and analyzed the ecological sensitivity of Liupanshui City with the aid of spatial autocorrelation analysis. [Results] ① From 2000 to 2020, the extremely sensitive, highly sensitive, mildly sensitive, and moderately sensitive areas in Liupanshui City showed a trend of fluctuation and decline, while the insensitive areas continued to rise. The ecological environment of Liupanshui City improved significantly over time. ② From 2000 to 2020, the spatial evolution trend of extremely sensitive and highly sensitive areas in Liupanshui City was scattered over the entire city, shifted to the southeast, and spread to the northwest, and the area continued to shrink. Except for the slight spread in the south of Zhongshan District, other areas showed a continuous or fluctuating shrinking trend, and the environment tended to improve. ③ From 2000 to 2020, the Global Moran's I values for Liupanshui City were 0.525, 0.570 and 0.476, respectively, indicating that the ecological sensitivity of Liupanshui City had a positive spatial correlation, and the correlation gradually weakened with time. The LISA diagram showed that the high and low aggregation areas decreased, and the degree of ecological sensitivity aggregation decreased. [Conclusion] The ecological sensitivity of Liupanshui City is mainly mild, mainly distributed in the northwest region with better ecological conditions. The proportion of extremely sensitive areas was small, concentrated in the southeast where the natural conditions are more fragile. With the passage of time, afforestation and other engineering measures in Liupanshui City have alleviated the environmental deterioration caused by excessive human intervention to a certain extent, reducing the area of extremely sensitive and highly sensitive areas in the region and significantly improving the ecological environment.

Abstract Background Chronic lymphocytic leukemia (CLL) results in increased susceptibility to infections. T cell dysfunction is not associated with CLL in all patients; therefore, it is important to identify CLL patients with T cell defects. The role of B-cell lymphoma-2 (BCL-2) in CLL has been explored; however, few studies have examined its role in T cells in CLL patients. Herein, we have investigated the regulatory role of BCL-2 in T cells in the CLL tumor microenvironment. Methods The expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored. Results We found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2+CD4+ T cells had the gene signature of increased regulatory T cells (Treg); BCL-2+CD8+ T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2+CD4+ T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2−CD4+ T cells. BCL-2 expression in CD8+T cells was associated with exhausted cells (PD-1+Tim-3+) and weak expression of granzyme B and perforin. T cell–associated cytokine profiling revealed a negative association between BCL-2+ T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2+T cells were observed in CLL patients in complete remission after treatment with venetoclax. Conclusion BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.

Diabetes is a systemic disease, and its progression involves multiple organ dysfunction. However, the exact mechanisms underlying pathological progression remain unclear. Small extracellular vesicles (sEVs) mediate physiological and pathological signaling communication between organs and have been shown to have important regulatory roles in diabetes and its complications in recent years. In particular, the majority of studies in the diabetes-related research field have focused on the noncoding RNAs carried by sEVs. Researchers found that noncoding RNA sorting into sEVs is not random but selective. Both tissue origin differences and environmental variations affect the cargo of sEVs. In addition, the function of sEVs differs according to the tissue they derive from; for example, sEVs derived from adipose tissue regulate insulin sensitivity in the periphery, while sEVs derived from bone marrow promote β-cell regeneration. Therefore, understanding the roles of sEVs from different tissues is important for elucidating their molecular mechanisms and is necessary for the application of sEVs as therapeutic agents for diabetes treatment in the future. In this review, we summarized current studies on the mechanisms of noncoding RNA sorting into sEVs, as well as the research progress on the effects of sEVs from different tissue origins and noncoding RNAs in diabetes and diabetic complications. The knowledge of noncoding RNAs in sEVs will help us better understand the role of sEVs in the diabetes progression.

In order to accurately predict the industrial water demand of Handan City,based on the residual error correction GM(1,1) model and the equivalent dimensions addition,this paper proposes an equal-dimension-addition residual error correction GM(1,1) model to effectively predict the industrial water demand of each region in Handan city in 2025,as well as based on this,calculates the industrial water-saving correction value in 2025 according to the indicators of water consumption per ten thousand yuan of value-added by industry in Handan city issued by the Department of Water Resources of Hebei Province,and apply it to correct the predictive value.The results show that compared with the GM(1,1) model and residual error correction GM(1,1) model,the relative error of equal-dimension-addition residual error correction GM(1,1) model decreases by 33.9% and 12.5% respectively,and the relative error further reduces by 4.0% after the water saving correction value is used to correct the prediction results of the model,because of which it can be concluded that equal-dimension-addition residual error correction GM(1,1) model is more applicable for the prediction of industrial water demand in Handan City.Through the analysis of the calculation result from the equal-dimension-addition residual error correction GM(1,1) model and water saving correction value,the industrial water demand of Handan city in 2025 will be 34,799.90×104 m3,which would be helpful for the decision-making of the industrial sustainable development in Handan and also the prediction of water demand in other regions.

Dyslipidemia has been widely proven to contribute to cardiovascular diseases and other metabolic disorders, especially in insulin resistance and type 2 diabetes. The overproduction of VLDL is a significant characteristic of dyslipidemia, indicating the dysfunction of hepatic lipid metabolism, from triglyceride synthesis to transport. The fructose-fed Syrian golden hamster is an established animal model for the study of VLDL assembly with insulin resistance, however, it remains unknown how VLDL production is regulated at the transcriptional level due to the absence of a complete hamster genome. Here, we performed deep sequencing and constructed an mRNA-miRNA-lncRNA interaction network of Syrian golden hamster liver in order to reveal the global transcription profile and find potential RNA molecular regulation of VLDL production. We identified 4,450 novel multi-exon hamster lncRNAs and 755 miRNAs expressed in liver. Additionally, 146 differentially expressed coding genes, 27 differentially expressed lncRNA genes, as well as 16 differentially expressed miRNAs were identified. We then constructed an mRNA-miRNA-lncRNA interaction network that may potentially regulate VLDL production, and interestingly found several microRNA-centered regulatory networks. In order to verify our interpretation, miR-486 was selected for further experiments. Overexpression or down-regulation of miR-486 in fructose-fed hamsters resulted in altered hepatic expression of proteins involved in VLDL production, and in modulated levels of circulating VLDL. Our findings implicated that miR-486 is a potential regulator of circulating VLDL levels. These results provide new insights and a valuable resource for further study of the molecular mechanisms of VLDL secretion.

Intervertebral disk degeneration (IDD) is a common clinical spinal disease and one of the main causes of low back pain (LBP). Generally speaking, IDD is considered a natural degenerative process with age. However, with the deepening of research, people have discovered that IDD is not only related to age, but also has many factors that can induce and accelerate its progression. In addition, the pathogenesis of IDD remains unclear, resulting in limited traditional treatment methods that cannot effectively prevent and treat IDD. Conservative treatment may lead to patients' dependence on drugs, and the pain relief effect is not obvious. Similarly, surgical treatment is highly invasive, with a longer recovery time and a higher recurrence rate. With the deepening of exploration, people have discovered that intestinal microorganisms are an important symbiotic microbial community in the human body and are closely related to the occurrence and development of various diseases. Changes in intestinal microorganisms and their metabolites may affect the body's inflammatory response, immune regulation, and metabolic processes, thereby affecting the health of the intervertebral disk. In this context, the gut microbiota has received considerable attention as a potential target for delaying or treating IDD. This article first introduces the impact of gut microbes on common distal organs, and then focuses on three potential mechanisms by which gut microbes and their metabolites influence IDD. Finally, we also summarized the methods of delaying or treating IDD by interfering with intestinal microorganisms and their metabolites. Further understanding of the potential mechanisms between intestinal microorganisms and IDD will help to formulate reasonable IDD treatment strategies to achieve ideal therapeutic effects., 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 © 2024 Wang, Liu, Huang, Suo, Wang, Liu, Zhang, Chen and Li.)

Photothermal therapy (PTT) holds considerable clinical promise. However, insufficient PTT-induced tumor recurrence and metastasis is an urgent practical problem that needs to be solved. Herein, a biomimetic mesoporous organosilicon nano-system called PSAB is designed to precisely deplete cancer stem cells (CSCs) and prevent tumor recurrence and metastasis after PTT. The PSAB system is made up of Aggregation-induced emission (AIE)-active photothermal agent, 2TT-oC26B, and SO 2 prodrug, benzothiazole sulfinate (BTS), within mesoporous organosilicon nanoparticles (MON) enclosed by an exterior platelet membrane. PSAB effectively targets CSCs both in vitro and in vivo by P-selectin/CD44 interaction. The degradation of MON and subsequent release of BTS and AIE molecules are facilitated by intracellular glutathione (GSH). Subsequently, the acidic tumor environment triggers the SO 2 gas therapy from BTS. This process leads to the depletion of GSH and CSCs elimination. After combining PSAB with photothermal therapy, there is no significant tumor recurrence or metastasis. These results indicate that SO 2 gas therapy and AIE-mediated PTT act synergistically to offer a unique approach for preventing tumor recurrence and metastasis after PTT, thus holding significant promise for clinical applications in cancer PTT., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Rational design of plant cis -regulatory DNA sequences without expert intervention or prior domain knowledge is still a daunting task. Here, we developed PhytoExpr, a deep learning framework capable of predicting both mRNA abundance and plant species using the proximal regulatory sequence as the sole input. PhytoExpr was trained over 17 species representative of major clades of the plant kingdom to enhance its generalizability. Via input perturbation, quantitative functional annotation of the input sequence was achieved at single-nucleotide resolution, revealing an abundance of predicted high-impact nucleotides in conserved noncoding sequences and transcription factor binding sites. Evaluation of maize HapMap3 single-nucleotide polymorphisms (SNPs) by PhytoExpr demonstrates an enrichment of predicted high-impact SNPs in cis -eQTL. Additionally, we provided two algorithms that harnessed the power of PhytoExpr in designing functional cis -regulatory variants, and de novo creation of species-specific cis -regulatory sequences through in silico evolution of random DNA sequences. Our model represents a general and robust approach for functional variant discovery in population genetics and rational design of regulatory sequences for genome editing and synthetic biology., Competing Interests: Competing interests statement:The authors declare no competing interest.

Surface electromyography (sEMG) has emerged as a valuable tool for assessing muscle activity in various clinical and research settings. This review focuses on the application of sEMG specifically in the context of paraspinal muscles. The paraspinal muscles play a critical role in providing stability and facilitating movement of the spine. Dysfunctions or alterations in paraspinal muscle activity can lead to various musculoskeletal disorders and spinal pathologies. Therefore, understanding and quantifying paraspinal muscle activity is crucial for accurate diagnosis, treatment planning, and monitoring therapeutic interventions. This review discusses the clinical applications of sEMG in paraspinal muscles, including the assessment of low back pain, spinal disorders, and rehabilitation interventions. It explores how sEMG can aid in diagnosing the potential causes of low back pain and monitoring the effectiveness of physical therapy, spinal manipulative therapy, and exercise protocols. It also discusses emerging technologies and advancements in sEMG techniques that aim to enhance the accuracy and reliability of paraspinal muscle assessment. In summary, the application of sEMG in paraspinal muscles provides valuable insights into muscle function, dysfunction, and therapeutic interventions. By examining the literature on sEMG in paraspinal muscles, this review offers a comprehensive understanding of the current state of research, identifies knowledge gaps, and suggests future directions for optimizing the use of sEMG in assessing paraspinal muscle activity.

Intervertebral disc degeneration (IDD) due to multiple causes is one of the major causes of low back pain (LBP). A variety of traditional treatments and biologic therapies are currently used to delay or even reverse IDD; however, these treatments still have some limitations. Finding safer and more effective treatments is urgent for LBP patients. With increasing reports it has been found that the intervertebral disc (IVD) can convert pressure loads from the spine into electrical stimulation in a variety of ways, and that this electrical stimulation is of great importance in modulating cell behavior, the immune microenvironment and promoting tissue repair. However, when intervertebral disc degeneration occurs, the normal structures within the IVD are destroyed. This eventually leads to a weakening or loss of self-powered. Currently various piezoelectric materials with unique crystal structures can mimic the piezoelectric effect of normal tissues. Based on this, tissue-engineered scaffolds prepared using piezoelectric materials have been widely used for regenerative repair of various types of tissues, however, there are no reports of their use for the treatment of IDD. For this reason, we propose to utilize tissue-engineered scaffolds prepared from piezoelectric biomaterials with excellent biocompatibility and self-powered properties to be implanted into degenerated IVD to help restore cell type and number, restore extracellular matrix, and modulate immune responses. It provides a feasible and novel therapeutic approach for the clinical treatment of IDD., 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 © 2024 Huang, Wang, Liu, Wang, Suo, Liu and Li.)

Background: Stem cell-based therapy (SCT) is an important component of regenerative therapy that brings hope to many patients. After decades of development, SCT has made significant progress in the research of various diseases, and the market size has also expanded significantly. The transition of SCT from small-scale, customized experiments to routine clinical practice requires the assistance of standards. Many countries and international organizations around the world have developed corresponding SCT standards, which have effectively promoted the further development of the SCT industry., Methods: We conducted a comprehensive literature review to introduce the clinical application progress of SCT and focus on the development status of SCT standardization., Results: We first briefly introduced the types and characteristics of stem cells, and summarized the current clinical application and market development of SCT. Subsequently, we focused on the development status of SCT-related standards as of now from three levels: the International Organization for Standardization (ISO), important international organizations, and national organizations. Finally, we provided perspectives and conclusions on the significance and challenges of SCT standardization., Conclusions: Standardization plays an important role in the sustained, rapid and healthy development of SCT., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Aims: With an aging population and better survival rates, coronary artery disease (CAD) with multimorbidity has become more prevalent, complicating treatment and impacting life quality and longevity. This study identifies multimorbidity patterns in CAD patients and their effect on clinical outcomes, emphasizing treatment strategies., Methods and Results: The study analysed data from the DCEM registry (173 459 patients) and BleeMACS cohort (15 401 patients) to categorize CAD patients into three multimorbidity patterns. The focus was on how these patterns influence outcomes, especially concerning the efficacy and safety of dual antiplatelet therapy (DAPT). The study identified three distinct multimorbidity patterns: Class 1 encompassed cardiovascular-kidney-metabolic comorbidities indicating the highest risk; Class 2 included hypertension-dyslipidaemia comorbidities, reflecting intermediate risk; and Class 3 involved non-specific comorbidities, indicating the lowest risk. Class 1 patients demonstrated a six-fold increase in in-hospital mortality and a four-fold increase in severe in-hospital complications compared with Class 3. Over a 1-year period, Class 1 was associated with the highest risk, displaying a significant increase in all-cause mortality [adjusted hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.52-2.31, P < 0.001] and a notable risk for major bleeding (adjusted HR 1.74, 95% CI 1.36-2.24, P < 0.001) compared with Class 3. The use of DAPT, particularly aspirin combined with clopidogrel, significantly reduced the 1-year all-cause mortality in Class 1 patients (adjusted HR 0.60, 95% CI 0.37-0.98, P = 0.04) without increasing in major bleeding., Conclusion: Coronary artery disease patients with a cardiovascular-kidney-metabolic profile face the highest mortality risk. Targeted DAPT, especially aspirin and clopidogrel, effectively lowers mortality without significantly raising bleeding risks., Registration: DCEM registry (NCT05797402) and BleeMACS registry (NCT02466854)., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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.

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)