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Benign prostatic hyperplasia (BPH), characterized by the non-malignant enlargement of the prostate, exhibits a pronounced association with inflammation resulting from androgen receptor (AR) deficiency. Ferroptosis, a cell death mechanism triggered by iron-dependent lipid peroxidation and closely linked to inflammation, has yet to be fully understood in the context of BPH. Using RNA sequencing, we observed a significant elevation of taurine-upregulated gene 1 (TUG1) long noncoding RNA (lncRNA) in BPH tissues compared to normal prostate tissue. High levels of TUG1 exhibited a discernible correlation with both prostate volume and the extent of inflammatory infiltration in BPH patients. The suppression of TUG1 not only led to a reduction in prostate size but also ameliorated AR-deficiency-induced prostatic hyperplasia. Mechanistically, a decrease in AR in prostate luminal cells prompted macrophage aggregation and the release of IL-1β, subsequently fostering the transcription of TUG1 via MYC. Induced TUG1, through competitive binding with miR-188-3p, facilitated the expression of GPX4, thereby diminishing intracellular ROS levels and impeding ferroptosis in prostate luminal cells. Notably, the ferroptosis inducer JKE-1674 alleviated inflammation-induced prostatic hyperplasia in vivo. Together, these findings suggest that AR deficiency crucially inhibits ferroptosis, promoting BPH via the TUG1/miR-188-3p/GPX4 signaling axis, and making ferroptosis induction a promising therapeutic strategy for BPH patients with AR deficiency.

Purpose: To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status. Methods: The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-β) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro. Results: The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-β ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1. Conclusion: Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.

Hepatopancreatic necrosis disease (HPND) is a highly lethal disease that first emerged in 2015 in Jiangsu Province, China. So far, most researchers believe that this disease is caused by abiotic factors. However, its true pathogenic mechanism remains unknown. In this study, the effects of HPND on the metabolism and other biological indicators of the Chinese mitten crab (Eriocheir sinensis) were evaluated by integrating transcriptomics and metabolomics. Our findings demonstrate that the innate immunity, antioxidant activity, detoxification ability, and nervous system of the diseased crabs were affected. Additionally, metabolic pathways such as lipid metabolism, nucleotide metabolism, and protein metabolism were dysregulated, and energy production was slightly increased. Moreover, the IL-17 signaling pathway was activated and high levels of autophagy and apoptosis occurred in diseased crabs, which may be related to hepatopancreas damage. The abnormal mitochondrial function and possible anaerobic metabolism observed in our study suggested that functional hypoxia may be involved in HPND progression. Furthermore, the activities of carboxylesterase and acetylcholinesterase were significantly inhibited, indicating that the diseased crabs were likely stressed by pesticides such as pyrethroids. Collectively, our findings provide new insights into the molecular mechanisms altered in diseased crabs, as well as the etiology and pathogenic mechanisms of HPND.

The role of high-fat diet (HFD) induced gut microbiota alteration and Ghrelin as well as their correlation in benign prostatic hyperplasia (BPH) were explored in our study. The gut microbiota was analyzed by 16s rRNA sequencing. Ghrelin levels in serum, along with Ghrelin and Ghrelin receptor in prostate tissue of mice and patients with BPH were measured. The effect of Ghrelin on cell proliferation, apoptosis, and induction of BPH in mice was explored. Our results indicated that BPH mice have the highest ratio of Firmicutes and Bacteroidetes induced by HFD, as well as Ghrelin level in serum and prostate tissue was significantly increased compared with control. Elevated Ghrelin content in the serum and prostate tissue of BPH patients was also observed. Ghrelin promotes cell proliferation while inhibiting cell apoptosis of prostate cells. The effect of Ghrelin on enlargement of the prostate was found almost equivalent to that of testosterone propionate (TP) which may be attenuated by Ghrelin receptor antagonist YIL-781. Ghrelin could up-regulate Jak2/pJak2/Stat3/pStat3 expression in vitro and in vivo. Our results suggested that Gut microbiota may associate with Ghrelin which plays an important role in activation of Jak2/Stat3 in BPH development. Gut microbiota and Ghrelin might be pathogenic factors for BPH and could be used as a target for mediation.

Aims: Probucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator of mitochondrial ROS production in renal cells under high-glucose (HG) ambience. We previously showed that p66Shc can serve as a biomarker for renal oxidative injury in DN patients and that p66Shc up-regulation is correlated with renal damage in vivo and in vitro. Here, we determined whether probucol ameliorates renal injury in DN by inhibiting p66Shc expression. Results: We found that the expression of SIRT1, Ac-H3 and p66Shc in kidneys of DN patients was altered. Also, probucol reduced the levels of serum creatinine, urine protein and LDL-c and attenuated renal oxidative injury and fibrosis in STZ induced diabetic mice. In addition, probucol reversed p-AMPK, SIRT1, Ac-H3 and p66Shc expression. Correlation analyses showed that p66Shc expression was correlated with p-AMPK and Sirt1 expression and severity of renal injury. In vitro pretreatment of HK-2 cells with p-AMPK and SIRT1 siRNA negated the beneficial effects of probucol. Furthermore, we noted that probucol activates p-AMPK and Sirt1 and inhibits p66shc mRNA transcription by facilitating the binding of Sirt1 to the p66Shc promoter and modulation of Ac-H3 expression in HK-2 cells under HG ambience. Innovation and conclusion: Our results suggest for the first time that probucol ameliorates renal damage in DN by epigenetically suppressing p66Shc expression via the AMPK-SIRT1-AcH3 pathway.

Due to the stratified nature of the manufacturing process, material extrusion (ME) parts have lower mechanical properties than those fabricated by traditional technology. This is one of the most significant defects hindering the development and application of this rapid prototyping technique. In this paper, vibration was applied to the ME process by using piezoelectric ceramics for the first time to improve the mechanical properties of the built parts. The vibrating ME equipment was established, and the specimens processed in different build directions were individually fabricated without applied vibration and with different applied vibrations. To quantify the effect of applied vibration on their mechanical properties and to summarize the influencing rule, a series of experimental tests were then performed on these specimens. A comparison between the testing results shows that the tensile strength and plasticity of the specimens, especially those processed in the Z direction, can be obviously improved by applied vibration. The orthogonal anisotropy is decreased obviously. The improvement becomes greater with increasing vibration frequency or amplitude. From the microscopic point of view, it can be seen that applied vibration can reduce the part’s defects of porosity and inclusion as well as separation between layers and, thereby, improve the bonding strength.

Previous studies have suggested that breast cancer stem cells (BCSCs) mediate metastasis, are resistant to radiation and chemotherapy, and contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSCs. Here, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition [EMT]) and epithelial-like (mesenchymal-epithelial transition [MET]) states. Mesenchymal-like BCSCs characterized as CD24−CD44+ are primarily quiescent and localized at the tumor invasive front, whereas epithelial-like BCSCs express aldehyde dehydrogenase (ALDH), are proliferative, and are located more centrally. The gene-expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across different molecular subtypes of breast cancer, and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.

Abstract Background Bioactive peptides are important bioactive molecules composed of short-chain amino acids that play various crucial roles in the body, such as regulating physiological processes and promoting immune responses and antibacterial effects. Due to their significance, bioactive peptides have broad application potential in drug development, food science, and biotechnology. Among them, understanding their biological mechanisms will contribute to new ideas for drug discovery and disease treatment. Results This study employs generative adversarial capsule networks (CapsuleGAN), gated recurrent units (GRU), and convolutional neural networks (CNN) as base classifiers to achieve ensemble learning through voting methods, which not only obtains high-precision prediction results on the angiotensin-converting enzyme (ACE) inhibitory peptides dataset and the anticancer peptides (ACP) dataset but also demonstrates effective model performance. For this method, we first utilized the protein language model—evolutionary scale modeling (ESM-2)—to extract relevant features for the ACE inhibitory peptides and ACP datasets. Following feature extraction, we trained three deep learning models—CapsuleGAN, GRU, and CNN—while continuously adjusting the model parameters throughout the training process. Finally, during the voting stage, different weights were assigned to the models based on their prediction accuracy, allowing full utilization of the model's performance. Experimental results show that on the ACE inhibitory peptide dataset, the balanced accuracy is 0.926, the Matthews correlation coefficient (MCC) is 0.831, and the area under the curve is 0.966; on the ACP dataset, the accuracy (ACC) is 0.779, and the MCC is 0.558. The experimental results on both datasets are superior to existing methods, demonstrating the effectiveness of the experimental approach. Conclusion In this study, CapsuleGAN, GRU, and CNN were successfully employed as base classifiers to implement ensemble learning, which not only achieved good results in the prediction of two datasets but also surpassed existing methods. The ability to predict peptides with strong ACE inhibitory activity and ACPs more accurately and quickly is significant, and this work provides valuable insights for predicting other functional peptides. The source code and dataset for this experiment are publicly available at https://github.com/Zhou-Jianren/bioactive-peptides .

Sarcodon mushrooms are esteemed as a rare and highly valuable resource for both culinary and medicinal purposes. Ancient medical classics have documented their beneficial effects on conditions such as indigestion, loss of appetite, and neurological disorders. Modern phytochemical research into their secondary metabolites has led to the discovery of numerous bioactive compounds with significant biological activities. Despite notable achievements in the study of the chemical composition and bioactivity of Sarcodon mushrooms, a comprehensive understanding of these findings has been lacking. This review provides an exhaustive summary of the advancements in the phytochemistry of Sarcodon mushrooms, as well as the biological and pharmacological activities of the isolated compounds and crude extracts derived from Sarcodon over the past nine decades. A total of 100 secondary metabolites isolated from these mushrooms have been classified into five major categories based on their chemical structures, which exhibit bioactivities such as anti-tumour, neurotrophic, and neuroprotective, antioxidant, anti-inflammatory, antimicrobial, and hypoglycaemic properties. The aim of this study is to establish a scientific foundation for future research in drug discovery, biotechnological development, and the exploration of functional foods involving Sarcodon mushrooms.

Alzheimer's disease (AD) is characterized by progressive cognitive decline due to neuronal damage and impaired neurogenesis. Preserving neuronal integrity and stimulating neurogenesis are promising therapeutic strategies to combat AD-related cognitive dysfunction. In this study, we synthesized metformin carbon dots (CMCDs) using a hydrothermal method with metformin hydrochloride and citric acid as precursors. Notably, we found that CMCDs were significantly more effective than metformin in promoting the differentiation of neural stem cells (NSCs) into functional neurons under amyloid-beta (Aβ) conditions. Moreover, CMCDs fostered NSCs proliferation, enhanced neurogenesis, reduced Aβ deposition, and inhibited glial cell activation. We also examined neuronal structure by assessing Map2/NF-H/PSD95/SYN expression in the hippocampus, finding that CMCDs robustly strengthened neuronal structure. These results suggest that CMCDs can cognitive dysfunction in AD and promote the proliferation and neurogenesis of NSCs, as well as ameliorate neuronal injury. Hence, CMCDs emerge as promising candidates for AD therapy, demonstrating superior efficacy compared to metformin alone, and offering novel insights into small molecule drug interventions for AD.

Alzheimer’s disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

Mesenchymal stem cell derived exosomes (MSC-Exos) demonstrate beneficial effects on wound healing via anti-inflammatory and angiogenic properties. Chitosan (CS) exhibits excellent biocompatibility and accelerates cellular migration, adhesion, and proliferation. The ions released from bioactive glass (BG) and titanium dioxide (TiO2) nanoparticles exhibit sustained angiogenic and antibacterial potency. In this study, CMCS-CEBT hydrogel was synthesized from exosomes encapsulated carboxymethyl chitosan (CMCS), chitosan nanoparticles (CS-NPs), BG, and TiO2 nanoparticles for a preliminary evaluation of its impacts on the treatment of full-thickness skin defects, diabetic wounds, and burn skin injury due to burns. In vitro analysis indicated that the hydrogel exhibits excellent cell compatibility, stimulates endothelial cell adhesion and proliferation, and presents anti-inflammatory, angiogenic, and antibacterial activities. In vivo, the composite hydrogel dressing accelerated a wound healing acceleration effect, stimulated angiogenesis, and increased collagen deposition and the expression of anti-inflammatory factors. This innovative composite hydrogel dressing as a potential clinical therapy, utilizing bioactive materials, holds promise as a potential clinical therapy that aims to facilitate the regeneration of acute and chronically damaged skin tissue.

Noncoding RNA plays a pivotal role as novel regulators of endothelial cell function. Type 2 diabetes, acknowledged as a primary contributor to cardiovascular diseases, plays a vital role in vascular endothelial cell dysfunction due to induced abnormalities of glucolipid metabolism and oxidative stress. In this study, aberrant expression levels of circHMGCS1 and MIR4521 were observed in diabetes-induced human umbilical vein endothelial cell dysfunction. Persistent inhibition of MIR4521 accelerated development and exacerbated vascular endothelial dysfunction in diabetic mice. Mechanistically, circHMGCS1 upregulated arginase 1 by sponging MIR4521, leading to decrease in vascular nitric oxide secretion and inhibition of endothelial nitric oxide synthase activity, and an increase in the expression of adhesion molecules and generation of cellular reactive oxygen species, reduced vasodilation and accelerated the impairment of vascular endothelial function. Collectively, these findings illuminate the physiological role and interacting mechanisms of circHMGCS1 and MIR4521 in diabetes-induced cardiovascular diseases, suggesting that modulating the expression of circHMGCS1 and MIR4521 could serve as a potential strategy to prevent diabetes-associated cardiovascular diseases. Furthermore, our findings provide a novel technical avenue for unraveling ncRNAs regulatory roles of ncRNAs in diabetes and its associated complications.

BackgroundStudies on the relationships between diseases of the urinary system and human plasma proteomes have identified several potential biomarkers. However, none of these studies have elucidated the causal relationships between plasma proteins and urolithiasis.ObjectiveThe objective of the study was to investigate the potential risks of plasma metabolites in urolithiasis using a two-sample Mendelian randomization (MR) study.MethodsA total of 1,400 metabolites were identified in the most comprehensive genome-wide association study (GWAS) of plasma metabolomics in a European population to date, and single-nucleotide polymorphisms (SNPs) were used as the instrumental variables for the plasma metabolites. The European GWAS data for urinary calculi included 482,123 case samples and 6,223 control samples (ebi-a-GCST90018935). The associations between the plasma metabolites and risk of urolithiasis were evaluated by inverse variance weighting (IVW) and supplemented by sensitivity analyses of the MR-Egger and MR-PRESSO tests.ResultsFor the first time, we found a causal relationship between two plasma metabolites (p < 1.03 × 10−4) and urolithiasis (p < 0.05). The chemical 4-hydroxychlorothalonil, which is an intermediate product of the pesticide hydroxychlorothalonil, could promote urolithiasis (odds ratio (OR) = 1.12) as a risk factor. Moreover, 1-stearoyl-2-arachidonoyl-GPC, which is an important component of phospholipid metabolism in the human body, can inhibit urolithiasis (OR = 0.94).Conclusions Our results suggest that blood metabolites can be used as blood markers and drug targets in the prevention, diagnosis, and treatment of urolithiasis; furthermore, our results can provide a basis for policy makers to formulate prevention and treatment policies for urolithiasis.

Semen is a complex fluid that contains spermatozoa and also functions as a dynamic bacterial microecosystem, comprising probiotics, pathogenic bacteria, and natural antimicrobial substances. Probiotic bacteria, such as Lactobacillus and Bifidobacterium, along with pathogenic bacteria like Pseudomonas aeruginosa and Escherichia coli, play significant roles in semen preservation and reproductive health. Studies have explored the impact of pathogenic bacteria on sperm quality, providing insights into the bacterial populations in mammalian semen and their influence on sperm function. These reviews highlight the delicate balance between beneficial and harmful bacteria, alongside the role of natural antimicrobial substances that help maintain this equilibrium. Moreover, we discuss the presence and roles of antimicrobial substances in semen, such as lysozyme, secretory leukocyte peptidase inhibitors, lactoferrin, and antimicrobial peptides, as well as emerging antibacterial substances like amyloid proteins. Understanding the interactions among probiotics, pathogens, and antimicrobial agents is crucial for elucidating semen preservation and fertility mechanisms. Additionally, the potential for adding probiotic bacteria with recombinant antibacterial properties presents a promising avenue for the development of new semen extenders. This review offers updated insights to understand the equilibrium of the bacterial microecosystem in semen and points toward innovative approaches for improving semen preservation.

Early and highly precise detection is essential for delaying the progression of coronary artery disease (CAD). Previous methods primarily based on single-modal data inherently lack sufficient information that compromises detection precision. This paper proposes a novel multi-modal learning method aimed to enhance CAD detection by integrating ECG, PCG, and coupling signals. A novel coupling signal is initially generated by operating the deconvolution of ECG and PCG. Then, various entropy features are extracted from ECG, PCG, and its coupling signals, as well as recurrence deep features also encoded by integrating recurrence plots and a parallel-input 2-D CNN. After feature reduction and selection, final classification is performed by combining optimal multi-modal features and support vector machine. This method was validated on simultaneously recorded standard lead-II ECG and PCG signals from 199 subjects. The experimental results demonstrate that the proposed multi-modal method by integrating all signals achieved a notable enhancement in detection performance with best accuracy of 95.96%, notably outperforming results of single-modal and joint analysis with accuracies of 80.41%, 86.51%, 91.44%, and 90.42% using ECG, PCG, coupling signal, and joint ECG and PCG, respectively. This indicates that our multi-modal method provides more sufficient information for CAD detection, with the coupling information playing an important role in classification.

Owing to the tissue characteristics of tendons with few blood vessels and cells, the regeneration and repair of injured tendons can present a considerable challenge, which considerably affects the motor function of limbs and leads to serious physical and mental pain, along with an economic burden on patients. Herein, we designed and fabricated a dipeptide hydrogel (DPH) using polypeptides P11-4 and P11-8. This hydrogel exhibited self-assembly characteristics and could be administered in vitro. To endow the hydrogel with differentiation and regeneration abilities, we added different concentrations of growth differentiation factor 5 (GDF5) to form GDF5@DPH. GDF5@DPH promoted the aggregation and differentiation of tendon stem/progenitor cells and promoted the regeneration and repair of tendon cells and collagen fibers in injured areas. In addition, GDF5@DPH inhibited inflammatory reactions in the injured area. Owing to its injectable properties, DPH can jointly inhibit adhesion and scar hyperplasia between tissues caused by endogenous inflammation and exogenous surgery and can provide a favorable internal environment for the regeneration and repair of the injured area. Overall, the GDF5@DPH system exhibits considerable promise as a novel approach to treating tendon injury.

Background: Platelets have the hemostatic function, and their aberrant activation is associated with occlusive thrombus formation. Plasma exosomes are rich in platelets containing ubiquitin-specific peptidase 15 (USP15). Herein, we aim to explore the effect of USP15 on thrombosis, as well as expounding whether USP15 acts as an upstream target of FK506 binding protein 5 (FKBP5) to regulate occlusive thrombus formation. Methods: Washed human platelets were treated with thrombin for measurement of USP15 and FKBP5 expressions. USP15 loss/gain-of-function variant in HEK293 cells was performed by cell transfection, and the interaction between USP15 and FKBP5 was examined using immunoprecipitation and ubiquitination assays. Mice with USP15-knockout platelets (Plt USP15-/-) were modeled, and subjected to calculation of bleeding time, artery thrombosis imaging and clot retraction assay. FKBP5 expression and the inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE)/phosphatidylinositol 3-kinase (PI3K)/Rap1 pathway in wild-type and Plt USP15-/- mice-derived platelets were detected using Western blot. The activation of αIIbβ3 in washed platelets was analyzed using flow cytometry. Results: USP15 and FKBP5 expressions were upregulated in platelets after thrombin treatment. Following transfection of USP15 knockdown and USP15 overexpression plasmids into HEK293 cells, FKBP5 protein expression was downregulated by USP15 knockdown while being upregulated by USP15 overexpression. USP15 bound to FKBP5 and protected FKBP5 against ubiquitination. Knockdown of platelet USP15 prolonged bleeding time, inhibited arterial thrombosis and delayed clot retraction in mice. Knockdown of platelet USP15 also decreased protein expressions of FKBP5, IKBKE and Rap1, p-PI3K/PI3K ratio, and activation of αIIbβ3 in mice. Conclusion: USP15 knockdown in platelets affects thrombosis in mice by promoting the instability of FKBP5 to repress the activation of IKBKE/PI3K/Rap1 pathway-mediated αIIbβ3.

This study aimed to compare the effects of 8 weeks (24 sessions) between flywheel complex training with eccentric overload and traditional complex training of well-trained volleyball players on muscle adaptation, including hypertrophy, strength, and power variables. Fourteen athletes were recruited and randomly divided into the flywheel complex training with an eccentric-overload group (FCTEO, n = 7) and the control group (the traditional complex training group, TCT, n = 7). Participants performed half-squats using a flywheel device or Smith machine and drop jumps, with three sets of eight repetitions and three sets of 12 repetitions, respectively. The variables assessed included the muscle thickness at the proximal, mid, and distal sections of the quadriceps femoris, maximal half-squats strength (1RM-SS), squat jump (SJ), countermovement jump (CMJ), and three-step approach jump (AJ). In addition, a two-way repeated ANOVA analysis was used to find differences between the two groups and between the two testing times (pre-test vs. post-test). The indicators of the FCTEO group showed a significantly better improvement (p

Abstract Background Deep learning has been extensively used in digital histopathology. The purpose of this study was to test deep learning (DL) algorithms for predicting the vital status of whole-slide image (WSI) of uveal melanoma (UM). Methods We developed a deep learning model (Google-net) to predict the vital status of UM patients from histopathological images in TCGA-UVM cohort and validated it in an internal cohort. The histopathological DL features extracted from the model and then were applied to classify UM patients into two subtypes. The differences between two subtypes in clinical outcomes, tumor mutation, and microenvironment, and probability of drug therapeutic response were investigated further. Results We observed that the developed DL model can achieve a high accuracy of > = 90% for patches and WSIs prediction. Using 14 histopathological DL features, we successfully classified UM patients into Cluster1 and Cluster2 subtypes. Compared to Cluster2, patients in the Cluster1 subtype have a poor survival outcome, increased expression levels of immune-checkpoint genes, higher immune-infiltration of CD8 + T cell and CD4 + T cells, and more sensitivity to anti-PD-1 therapy. Besides, we established and verified prognostic histopathological DL-signature and gene-signature which outperformed the traditional clinical features. Finally, a well-performed nomogram combining the DL-signature and gene-signature was constructed to predict the mortality of UM patients. Conclusions Our findings suggest that DL model can accurately predict vital status in UM patents just using histopathological images. We found out two subgroups based on histopathological DL features, which may in favor of immunotherapy and chemotherapy. Finally, a well-performing nomogram that combines DL-signature and gene-signature was constructed to give a more straightforward and reliable prognosis for UM patients in treatment and management.

Background: The treatment options for third-trimester musculoskeletal issues are limited. This study aims to examine how heel height affects gait biomechanics and provides heel height recommendations for various musculoskeletal problems. Methods: Five third-trimester gravidas were recruited wearing uniform footwear with four heel heights (0 mm, 15 mm, 30 mm, and 45 mm). Lower-limb muscle forces, joint angles, joint torques, joint contact forces, and ground reaction forces (GRF) at specific moments (the first peak, valley, and second peak of GRF) were collected for one-way analysis of variance with repeated measures. Results: The soleus, gastrocnemius, tibialis posterior, plantaris, obturator externus, gluteus maximus, gemellus superior, and obturator internus were the smallest at heel heights of 45 mm and 15 mm at the valley of GRF. Hip extension and knee flexion displayed the smallest joint angle and joint torques at a height of 15 mm. Ankle joint contact force decreased with increased heel height. Conclusions: The height of the heel significantly impacts muscle force, joint angles, joint torques, and joint contact force. A heel of 15 mm might be the most suitable heel height to potentially avoid or alleviate musculoskeletal problems during the third trimester.

The Changzhou ship lock is approaching its capacity limit. In order to quantitatively analyze the influencing factors that restrict the capacity of the Changzhou ship lock, this study proposes an influencing factor analysis method based on principal component analysis (PCA). This method estimates the confidence interval of ship passing time by fitting a lognormal distribution curve, eliminates redundancy in navigability data by combining the hydrological data and cargo load data, and quantitatively analyzes the influencing factors of ship lock capacity under saturated operating conditions. The results show that the influencing factors of Changzhou ship lock capacity are classified according to their influence contribution rate as minimum water depth above the lock sill, operation direction, ship dimensions, draft, loading capacity, and actual load. The research results can provide a theoretical basis for improving the ship lock capacity and have application value for lock scheduling management.

Bone marrow lesion (BML) volume is a potential biomarker of knee osteoarthritis (KOA) as it is associated with cartilage degeneration and pain. However, segmenting and quantifying the BML volume is challenging due to the small size, low contrast, and various positions where the BML may occur. It is also time-consuming to delineate BMLs manually. In this paper, we proposed a fully automatic segmentation method for BMLs without requiring human intervention. The model takes intermediate weighted fat-suppressed (IWFS) magnetic resonance (MR) images as input, and the output BML masks are evaluated using both regular 2D Dice similarity coefficient (DSC) of the slice-level area metric and 3D DSC of the subject-level volume metric. On a dataset with 300 subjects, each subject has a sequence of 36 IWFS MR images approximately. We randomly separated the dataset into training, validation, and testing sets with a 70%/15%/15% split at the subject level. Since not every subject or image has a BML, we excluded the images without a BML in each subset. The ground truth of the BML was labeled by trained medical staff using a semi-automatic tool. Compared with the ground truth, the proposed segmentation method achieved a Pearson’s correlation coefficient of 0.98 between the manually measured volumes and automatically segmented volumes, a 2D DSC of 0.68, and a 3D DSC of 0.60 on the testing set. Although the DSC result is not high, the high correlation of 0.98 indicates that the automatically measured BML volume is strongly correlated with the manually measured BML volume, which shows the potential to use the proposed method as an automatic measurement tool for the BML biomarker to facilitate the assessment of knee OA progression.

Cyclin D1 is a key regulator of cell cycle progression, which forms a complex with CDK4/6 to regulate G1/S transition during cell cycle progression. Cyclin D1 has been recognized as an oncogene since it was upregulated in several different types of cancers. It is known that the post-translational regulation of cyclin D1 is controlled by ubiquitination/proteasome degradation system in a phosphorylation-dependent manner. Several cullin-associated F-box E3 ligases have been shown to regulate cyclin D1 degradation; however, it is not known if additional cullin-associated E3 ligases participate in the regulation of cyclin D1 protein stability. In this study, we have screened an siRNA library containing siRNAs specific for 154 ligase subunits, including F-box, SOCS, BTB-containing proteins, and DDB proteins. We found that multiple cullin-associated E3 ligases regulate cyclin D1 activity, including Keap1, DDB2, and WSB2. We found that these E3 ligases interact with cyclin D1, regulate cyclin D1 ubiquitination and proteasome degradation in a phosphorylation-dependent manner. These E3 ligases also control cell cycle progression and cell proliferation through regulation of cyclin D1 protein stability. Our study provides novel insights into the regulatory mechanisms of cyclin D1 protein stability and function.

Murine chondrocyte hypertrophy was found to require IGF2-regulated bioenergetic reprogramming, in which glucose utilization shifts from glycolysis to oxidative phosphorylation as chondrocytes mature.

Hydnum is a well-characterized genus in the family Hydnaceae of Cantharellales and is characterized by spinose hymenophores. In this study, an ITS phylogenetic overview and a multilocus (ITS-nrLSU-tef1) phylogenetic tree of Hydnum were carried out. On the basis of morphological characteristics and phylogenetic results, seven species from China were confirmed, described, illustrated, and compared with similar species, including three new species, i.e., H. longipes, H. microcarpum, and H. sinorepandum, and four known species, i.e., H. cremeoalbum, H. melitosarxm, H. orientalbidum, and H. pinicola were recorded for the first time in China. A key to the species of Hydnum in China was provided.

Species of Gyroporus from southern China were studied in this study. Based on morphology and molecular phylogenetic analyses of DNA sequences from the nuclear ribosomal internal transcribed spacer (ITS), the nuclear ribosomal large subunit (nrLSU), and the mitochondrial adenosine triphosphate ATP synthase subunit 6 (atp6), Gyroporus was divided into four main branches in the phylogenetic tree, and four sections were firstly proposed i.e. Gyroporus sect. Castaneus, G. sect. Cyanescens, G. sect. Longicystidiatus and G. sect. Pallidus. Five new species, i.e. G. alboluteus, G. atrocyanescens, G. pseudolongicystidiatus, G. pallidus and G. subcaerulescens, were revealed from China, and their phylogenetic positions were also analysed. Among them, G. alboluteus and G. pallidus were nested into the sect. Pallidus, although morphologically similar to G. castaneus; G. atrocyanescens and G. subcaerulescens, with obvious cyanescent oxidation reactions, were nested into the sect. Cyanescens; and G. pseudolongicystidiatus characterised by its long cystidia and was nested into the sect. Longicystidiatus. The new species were formally described and illustrated in the present study, and a key to the sections and species of Gyroporus in China was provided.

Summary: Osteoarthritis (OA) is the most common degenerative disorder, affecting approximately half of the elderly population. In this study, we find that the expressions of long noncoding RNA (lncRNA) IGFBP7-OT and its maternal gene, IGFBP7, are upregulated and positively correlated in osteoarthritic cartilage. Overexpression of IGFBP7-OT significantly inhibits chondrocyte viability, promotes chondrocyte apoptosis, and reduces extracellular matrix components, whereas IGFBP7-OT knockdown has the opposite effects. IGFBP7-OT overexpression promotes cartilage degeneration and markedly aggravates the monosodium iodoacetate-induced OA phenotype in vivo. Further mechanistic research reveals that IGFBP7-OT promotes OA progression by upregulating IGFBP7 expression. Specifically, IGFBP7-OT suppresses the occupancy of DNMT1 and DNMT3a on the IGFBP7 promoter, thereby inhibiting methylation of the IGFBP7 promoter. The upregulation of IGFBP7-OT in OA is partially controlled by METTL3-mediated N6-methyladenosine (m6A) modification. Collectively, our findings reveal that m6A modification of IGFBP7-OT promotes OA progression by regulating the DNMT1/DNMT3a-IGFBP7 axis and provide a potential therapeutical target for OA treatment.

Influenza A viruses in animal reservoirs repeatedly cross species barriers to infect humans. Dogs are the closest companion animals to humans, but the role of dogs in the ecology of influenza viruses is unclear. H3N2 avian influenza viruses were transmitted to dogs around 2006 and have formed stable lineages. The long-term epidemic of avian-origin H3N2 virus in canines offers the best models to investigate the effect of dogs on the evolution of influenza viruses. Here, we carried out a systematic and comparative identification of the biological characteristics of H3N2 canine influenza viruses (CIVs) isolated worldwide over 10 years. We found that, during adaptation in dogs, H3N2 CIVs became able to recognize the human-like SAα2,6-Gal receptor, showed gradually increased hemagglutination (HA) acid stability and replication ability in human airway epithelial cells, and acquired a 100% transmission rate via respiratory droplets in a ferret model. We also found that human populations lack immunity to H3N2 CIVs, and even preexisting immunity derived from the present human seasonal influenza viruses cannot provide protection against H3N2 CIVs. Our results showed that canines may serve as intermediates for the adaptation of avian influenza viruses to humans. Continuous surveillance coordinated with risk assessment for CIVs is necessary.

Abstract Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic. We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice. Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice, whereas knockout of the progesterone receptor PGR has opposite effects. Mechanistically, stimulation of PGR by progesterone activates the tyrosine kinase SRC, which phosphorylates the transcriptional factor IRF3 at Y107, leading to its activation and induction of antiviral genes. SARS-CoV-2-infected patients have increased progesterone levels, and which are co-related with decreased severity of COVID-19. Our findings reveal how progesterone modulates host innate antiviral response, and point to progesterone as a potential immunomodulatory reagent for infectious and inflammatory diseases.

The genus Laccaria is a type of cosmopolitan and ecologically important fungal group. Members can form ectomycorrhizal associations with numerous trees, and some species are common edible fungi in local markets. Although some new species from China are recently published, the species diversity of Laccaria is still unclear in China. In this study, some samples of Laccaria were collected from southern China, and morphological characteristics and phylogenetic analyses based on the multilocus dataset of ITS-LSU-tef1-rpb2 confirmed five new species. Laccaria miniata, L. nanlingensis and L. neovinaceoavellanea were collected from subtropical broad-leaved forests, and L. rufobrunnea and L. umbilicata were collected from subtropical mixed forests of southwest China. Full descriptions, illustrations, comparisons with similar species and phylogenetic analysis are provided.

Background: Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor of the urinary system characterized by abundant immunocytes infiltration. The impact of guanosine triphosphatases (GTPases) of immunity-associated proteins (GIMAPs) on the tumor immune microenvironment (TIME) and prognosis of ccRCC is unclear. Methods: The expression of GIMAPs in ccRCC was determined through multiple datasets (ONCOMINE, TCGA and UALCAN). The relationship between GIMAP family members was analyzed through Spearman correlation analysis. The interaction among the GIMAPs protein was analyzed using STRING. Prognostic values of GIMAPs were evaluated by Survival analysis, Lasso and Cox regression analysis; Prognostic risk model and nomogram were constructed. The correlation between GIMAPs and TIME was explored using TIMER, Cibersort and Pearson correlation analysis. Gene set enrichment analysis (GSEA) was performed to discuss their function and mechanism in ccRCC. Results: GIMAPs were over-expressed in ccRCC and significantly related to overall survival (OS) of the patients. GIMAPs were positively correlated with each other, the risk model based on GIMAPs had good prognostic value in ccRCC. GIMAPs mainly expressed in TIME and were associated with abundant immunocytic infiltration in ccRCC, the risk model also had close correlation with TIME. Our results showed GIMAPs may affect the development of ccRCC by regulating the amount and antitumor activity of immunocytes in TIME. Conclusions: GIMAPs were over-expressed in ccRCC, and their expression levels were significantly related to the OS of patients and immunocytic infiltration in TIME. GIMAPs are potential therapeutic targets and prognostic biomarkers for ccRCC.

To investigate the hysteretic behavior of an X-shaped metal damper (XMD) with an oblique angle, cyclic loading tests were carried out on nine specimens, including two XMDs without buckling-restrained devices, four XMDs with stiffening ribs, and three XMDs with cover plates as references. The test results showed that the oblique angle could effectively increase the stiffness, strength, and energy dissipation of the XMD. When the oblique angle of an XMD with stiffening ribs increased from 0° to 30° at the applied displacement of 8.4 mm, the mean strengths and cumulative energy dissipation of specimens increased by about 80.77% and 80.57%, respectively. Although asymmetric hysteretic loops were also observed in specimens with an oblique angle and buckling-restrained devices, stable hysteretic curves were obtained. This indicated that the stiffening ribs and cover plates can effectively constrain the buckling behavior of XMDs. Additionally, the mean strengths of specimens with stiffening ribs were a little higher than those of specimens with cover plates. Subsequently, the finite element analysis models of the XMDs were proposed, in which the metal plasticity model considering isotropic and kinematical hardening was used to model the material properties of steel, and the simulation results matched well with the test results. Finally, the theoretical calculation method was proposed to predict the elastic stiffness of specimens, and the theoretical elastic stiffness matched well with the test results.

Coronary heart disease leading to myocardial ischemia is a major cause of heart failure. A hallmark of heart failure is myocardial fibrosis. Using a murine model of myocardial ischemia/reperfusion injury (IRI), we showed that, following IRI, in mice genetically deficient in the central factor of complement system, C3, myocardial necrosis was reduced compared with WT mice. Four weeks after the ischemic period, the C3−/− mice had significantly less cardiac fibrosis and better cardiac function than the WT controls. Overall, our results suggest that innate immune response through complement C3 plays an important role in necrotic cell death, which contributes to the cardiac fibrosis that underlies post-infarction heart failure.

The tooth arrangements of human beings are challenging to accurately observe when relying on dentists’ naked eyes, especially for dental caries in children, which is difficult to detect. Cone-beam computer tomography (CBCT) is used as an auxiliary method to measure patients’ teeth, including children. However, subjective and irreproducible manual measurements are required during this process, which wastes much time and energy for the dentists. Therefore, a fast and accurate tooth segmentation algorithm that can replace repeated calculations and annotations in manual segmentation has tremendous clinical significance. This study proposes a local contextual enhancement model for clinical dental CBCT images. The local enhancement model, which is more suitable for dental CBCT images, is proposed based on the analysis of the existing contextual models. Then, the local enhancement model is fused into an encoder–decoder framework for dental CBCT images. At last, extensive experiments are conducted to validate our method.

This study delves into the effects of sample height on consolidation behaviour, utilising the automatic air pressure consolidometer. Extensive tests were conducted on three varieties of dredged silt samples of varying heights from Qianwan, Shenzhen, China. The salient findings can be summarised as follows: (1) Compression curves for samples of different dimensions transitioned through three distinct phases: minimal load disturbance, elastic deformation, and plastic deformation. Notably, the void ratio during the latter two phases diminished as sample height increased. (2) A rising sample height corresponded to a reduced stable strain and compression index. Furthermore, the consolidation coefficient notably diminished with an escalation in the sample height, whereas the structural yield stress remained largely unaffected. (3) Given the disparate formation processes, stress histories, and material compositions between dredged and marine silts, the permeability coefficient of dredged silt was found to be superior to that of marine silt. Within the typical preloading pressure scope (50~300 kPa), the consolidation coefficient of dredged silt was lower compared to marine silt. However, as the consolidation pressure significantly surpassed this threshold, the coefficient disparity between the two silts narrowed.

To address the issue of insufficient testing caused by the continuous reduction of software development cycles, many organizations maintain bug repositories and bug tracking systems to ensure real-time updates of bugs. However, each day, a large number of bugs is discovered and sent to the repository, which imposes a heavy workload on bug fixers. Therefore, effective bug deduplication and triage are of great significance in software development. This paper provides a comprehensive investigation and survey of the recent developments in bug deduplication and triage. The study begins by outlining the roadmap of the existing literature, including the research trends, mathematical models, methods, and commonly used datasets in recent years. Subsequently, the paper summarizes the general process of the methods from two perspectives—runtime information-based and bug report-based perspectives—and provides a detailed overview of the methodologies employed in relevant works. Finally, this paper presents a detailed comparison of the experimental results of various works in terms of usage methods, datasets, accuracy, recall rate, and F1 score. Drawing on key findings, such as the need to improve the accuracy of runtime information collection and refine the description information in bug reports, we propose several potential future research directions in the field, such as stack trace enrichment and the combination of new NLP models.

Two new Melanoleuca species, Melanoleuca subgriseoflava and M. substridula, are originally reported and described in China based on both morphological and molecular methods. Melanoleuca subgriseoflava, collected in Liaoning province, is mainly characterized by its greyish-brown to yellowish-grey pileus, creamy to light orange lamellae, greyish-yellow context, round and warted basidiospores and fusiform hymenial cystidia. Melanoleuca substridula, discovered in Sichuan province, is mainly characterized by its light brown to dark brown pileus, whitish lamellae, light brown to greyish-brown stipe, round and warted basidiospores and lack of any forms of cystidia. The phylogenetic relationships as well as divergence-time estimation were analyzed using the combined data set (ITS-nrLSU-RPB2), and the results showed that the two Melanoleuca species formed two distinct lineages. Based on the combination of morphological and molecular data, M. subgriseoflava and M. substridula are confirmed as two new species to science. A theoretical basis is provided for the species diversity of Melanoleuca.

Esophageal cancer is the sixth leading cause of cancer mortalities globally with a high incidence rate. Apelin (APLN) plays regulatory roles in different organs. However, its role in esophageal cancer remains unknown. Therefore, our study aims to explore the effect of APLN on esophageal cancer. One hundred and eighty-four (184) esophageal tumor tissues samples from patients with esophageal cancer, and 11 esophageal tissues samples from healthy volunteers were analyzed for the expression of APLN. APLN was highly expressed in the tumor of patients with esophageal cancer and esophageal cancer cells. Patients with high expressions of APLN had a lower survival rate than the ones with low to medium expressions of APLN. Human esophageal carcinoma cell lines, TE-1 and ECA-109 cells were transfected with APLN siRNA to knockdown APLN, or transfected with pcDNA-APLN to overexpress APLN. Inhibition of APLN by siRNA-APLN reduced proliferative, migrative, and invasive abilities of esophageal cancer cells and promoted cell apoptosis, which could be all restored by pcDNA-APLN. Moreover, knocking down APLN by siRNA-APLN suppressed the PI3K/mTOR signaling pathway. These findings identify that APLN inhibition might ameliorate esophageal cancer through activating the PI3K/mTOR signaling pathway, thus APLN could be a potential target for esophageal cancer.

Healthy lifestyle is reported to reduce the prevalence of gestational diabetes mellitus (GDM). The association between Mediterranean diet (MD) and GDM incidence remains unclear in China. Therefore, we aim to establish a Chinese-habit-based MD recipe and explore its effects on GDM. This study recruited gestational age women who were planning a pregnancy in the near future with at least one risk factor for GDM. The participants were randomly allocated into the control and MD groups. They were required to follow diet interventions at least 6 months prior to pregnancy until delivery. Average dietary intake, glucose and insulin metabolism in 26–28-week of gestation, and maternal and neonatal outcomes were analyzed to assess the effects of MD. The clinical outcomes of 580 participants, with 294 in the MD group and 286 in the control group, were analyzed. It was revealed that the MD group had a high intake of protein, vitamins, and dietary fibers, whereas low intake of fat, resulting in improved insulin and glucose metabolism. Meanwhile, women and their newborns in the MD group showed a reduced proportion of complications. The modified MD intervention started before pregnancy shows a preventive effect against GDM and also benefits the mother and their newborns in other outcomes.

Autologous bone marrow-derived mesenchymal stem cells (BMSCs) are more easily available and frequently used for bone regeneration in clinics. Osteogenic differentiation of BMSCs involves complex regulatory networks affecting bone formation phenomena. Non-coding RNAs (ncRNAs) refer to RNAs that do not encode proteins, mainly including microRNAs, long non-coding RNAs, circular RNAs, piwi-interacting RNAs, transfer RNA-derived small RNAs, etc. Recent in vitro and in vivo studies had revealed the regulatory role of ncRNAs in osteogenic differentiation of BMSCs. NcRNAs had both stimulatory and inhibitory effects on osteogenic differentiation of BMSCs. During the physiological condition, osteo-stimulatory ncRNAs are upregulated and osteo-inhibitory ncRNAs are downregulated. The opposite effects might occur during bone degenerative disease conditions. Intracellular ncRNAs and ncRNAs from neighboring cells delivered via exosomes participate in the regulatory process of osteogenic differentiation of BMSCs. In this review, we summarize the recent advances in the regulatory role of ncRNAs on osteogenic differentiation of BMSCs during physiological and pathological conditions. We also discuss the prospects of the application of modulation of ncRNAs function in BMSCs to promote bone tissue regeneration in clinics.

Abstract Ten-eleven translocation (TET) proteins, encoding dioxygenase for DNA hydroxymethylation, are important players in nervous system development and disease. In addition to their proverbial enzymatic role, TET proteins also possess non-enzymatic activity and function in multiple protein–protein interaction networks, which remains largely unknown during oligodendrocyte differentiation. To identify partners of TET1 in the myelinating cells, we performed proteome-wide analysis using co-immunoprecipitation coupled to mass spectrometry (IP-MS) in purified oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (mOLs), respectively. Following a stringent selection of MS data based on identification reliability and protein enrichment, we identified a core set of 1211 partners that specifically interact with TET1 within OPCs and OLs. Analysis of the biological process and pathways associated with TET1-interacting proteins indicates a significant enrichment of proteins involved in regulation of cellular protein localization, cofactor metabolic process and regulation of catabolic process, et al. We further validated TET1 interactions with selected partners. Overall, this comprehensive analysis of the endogenous TET1 interactome during oligodendrocyte differentiation suggest its novel mechanism in regulating oligodendrocyte homeostasis and provide comprehensive insight into the molecular pathways associated with TET1.

Vulnerable atherosclerotic plaques of the artery wall that pose a significant risk of cardio-cerebral vascular accidents remain the global leading cause of morbidity and mortality. Thus, early delineation of vulnerable atherosclerotic plaques is of clinical importance for prevention and treatment. The currently available imaging technologies mainly focus on the structural assessment of the vascular wall. Unfortunately, several disadvantages in these strategies limit the improvement in imaging effect. Nanoparticle technology is a novel diagnostic strategy for targeting and imaging pathological biomarkers. New functionalized nanoparticles that detect hallmarks of vulnerable plaques are promising for advance further control of this critical illness. The review aims to address the current opportunities and challenges for the use of nanoparticle technology in imagining vulnerable plaques.

Many cellular genes and networks induced in human lung epithelial cells infected with the influenza virus remain uncharacterized. Here, we find that p21 levels are elevated in response to influenza A virus (IAV) infection, which is independent of p53. Silencing, pharmacological inhibition or deletion of p21 promotes virus replication in vitro and in vivo, indicating that p21 is an influenza restriction factor. Mechanistically, p21 binds to the C-terminus of IAV polymerase subunit PA and competes with PB1 to limit IAV polymerase activity. Besides, p21 promotes IRF3 activation by blocking K48-linked ubiquitination degradation of HO-1 to enhance type I interferons expression. Furthermore, a synthetic p21 peptide (amino acids 36 to 43) significantly inhibits IAV replication in vitro and in vivo. Collectively, our findings reveal that p21 restricts IAV by perturbing the viral polymerase complex and activating the host innate immune response, which may aid the design of desperately needed new antiviral therapeutics.

Many of the current methods for enzyme purification and immobilization suffer from several drawbacks, such as requiring tedious multistep procedures or long preparation, and being environmentally unfriendly, due to the chemicals and conditions involved. Thus, a simple technique for direct purification and immobilization of target enzymes from cell lysates was proposed. The elastin-like polypeptides (ELPs)-SpyCatcher chimera could mediate the formation of silica carriers within seconds and the target enzymes were then covalently immobilized on silica carriers via SpyCatcher/SpyTag spontaneous reaction. These tailor-made carriers were easily prepared, with precisely controlled morphology and size, as well as none-consuming surface modification needed, which could specifically immobilize the SpyTag-fused target enzymes from the cell lysate without pre-purification.

Background: Iliotibial band syndrome (ITBS) is one of the most prevalent overuse injuries in runners. The strain rate in the iliotibial band (ITB) has been theorized to be the primary causative factor in the development of ITBS. Running speed and exhaustion might lead to an alteration in the biomechanics that influence the strain rate in the iliotibial band. Objectives: To identify how exhaustion states and running speeds affect the ITB strain and strain rate. Methods: A total of 26 healthy runners (including 16 males and 10 females) ran at a normal preferred speed and a fast speed. Then, participants performed a 30 min exhaustive treadmill run at a self-selected speed. Afterward, participants were required to run at similar speeds to those of the pre-exhaustion state. Results: Both the exhaustion and running speeds were revealed to have significant influences on the ITB strain rate. After exhaustion, an increase of approximately 3% in the ITB strain rate was observed for both the normal speed (p = 0.001) and the fast speed (p = 0.008). Additionally, a rapid increase in the running speed could lead to an increase in the ITB strain rate for both the pre- (9.71%, p = 0.000) and post-exhaustion (9.87%, p = 0.000) states. Conclusions: It should be noted that an exhaustion state could lead to an increase in the ITB strain rate. In addition, a rapid increase in running speed might cause a higher ITB strain rate, which is proposed to be the primary cause of ITBS. The risk of injury should also be considered due to the rapid increase in the training load involved. Running at a normal speed in a non-exhaustive state might be beneficial for the prevention and treatment of ITBS.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the high ratio of recurrence and metastasis remains the main cause of its poor prognosis. Vascular invasion of HCC includes microvascular invasion (MVI) and portal vein tumor thrombosis (PVTT) and is regarded as a common roadmap of intrahepatic metastasis in HCC. However, the molecular mechanism underlying vascular invasion of HCC is largely unknown. Here, we analyzed the transcriptomes of primary tumors, PVTT tissues, and tumor tissues with or without MVI. We found that extracellular matrix-related pathways were involved in vascular invasion of HCC and that decorin secreted by cancer-associated fibroblasts was gradually downregulated from normal to tumor tissues and more so in PVTT tissues. We also established that low-level decorin expression is an independent risk factor for MVI and it is associated with a poor prognosis. Decorin downregulated integrin β1 and consequently inhibited HCC cell invasion and migration in vitro. Co-staining DCN and integrin β1 revealed that DCN dynamically regulated integrin β1 protein expression. Integrin β1 knockdown significantly inhibited HCC invasion and migration, and decorin combined with such knockdown synergistically augmented the anti-metastatic effects. Co-IP assay confirmed the direct interaction of decorin with integrin β1. Our findings showed that targeting cancer-associated fibroblast-related decorin is not only a promising strategy for inhibiting HCC vascular invasion and metastasis but also provides insight into the clinical treatment of patients with PVTT.

Coronary artery disease (CAD) is a major atherosclerotic cardiovascular disease and the leading cause of mortality globally. Long non-coding RNAs (lncRNAs) play crucial roles in CAD development. To date, the effect of lncRNA non-coding RNA activated by DNA damage (NORAD) on atherosclerosis in CAD remains unclear. The primary aim of this study was to investigate the effect of lncRNA NORAD on vascular endothelial cell injury and atherosclerosis. Here, ox-LDL-treated human umbilical vein endothelial cells (HUVECs) and high-fat-diet (HFD)-fed ApoE–/– mice were utilized as in vitro and in vivo models. The present study found that lncRNA NORAD expression was increased in ox-LDL-treated HUVECs and thoracic aorta of atherosclerotic mice, and knockdown of lncRNA NORAD alleviated vascular endothelial cell injury and atherosclerosis development in vitro and in vivo. Knockdown of lncRNA NORAD aggravated ox-LDL-reduced or atherosclerosis-decreased vascular endothelial growth factor (VEGF) expression in HUVECs and thoracic aorta of mice to ameliorate vascular endothelial cell injury and atherosclerosis development. Moreover, nucleus lncRNA NORAD suppressed VEGF gene transcription through enhancing H3K9 deacetylation via recruiting HDAC6 to the VEGF gene promoter in ox-LDL-treated HUVECs. In addition, VEGF reduced FUS (FUS RNA binding protein) expression by a negative feedback regulation in HUVECs. In summary, lncRNA NORAD enhanced vascular endothelial cell injury and atherosclerosis through suppressing VEGF gene transcription via enhancing H3K9 deacetylation by recruiting HDAC6. The findings could facilitate discovering novel diagnostic markers and therapeutic targets for CAD.