Search

Abstract Thioredoxin Related Transmembrane Protein 1 (TMX1) encodes a thiol-disulfide oxidoreductase and regulates cleavage, formation, or isomerization of disulfide bonds among cysteine residues in proteins. Using bioinformatic analysis, we firstly prove TMX1 is significantly upregulated in lower-grade gliomas (LGGs) and associated with poor prognosis of LGG patients. Besides, it’s also highly expressed in higher WHO grade, 1p/19q non-co-deleted and isocitrate dehydrogenase (IDH) wildtype LGGs, thus we established a TMX1-based nomogram model, which exhibits a strong and stable predictive ability in the prognosis of LGG patients. Then, we also noticed that TMX1 was significantly associated with the immune cell infiltrations in LGGs, especially in B cell, CD8+ T cell, CD4+T cell, dendritic cell, macrophage and neutrophil. Meanwhile, it was also highly correlated to the expressions of MKI67, PCNA, PROM1 and SOX2 in LGGs, and that higher TMX1 LGGs showed a stronger resistance to temozolomide (TMZ). Finally, in our in vitro and in vivo experiments, we verified that TMX1 is highly expressed in LGG patients clinically, and it not only regulates the proliferative ability of SW1088 and SW1783 cells both in vitro and in vivo, it can also be inhibited to increase the TMZ therapy sensitivity in vivo. These results revealed that TMX1 acts as a strong prognostic biomarker in LGGs, and targeting TMX1 can be an efficient way to increase the TMZ therapy in LGG patients.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Four major genes associated with ALS—SOD1, TARDBP, FUS, and C9orf72—have been identified, with the fused in sarcoma (FUS) gene demonstrating considerable genetic heterogeneity. Our research group has previously established an induced pluripotent stem (iPS) cell line harboring the c.1562G > A mutation in the FUS gene. The objective of this study is to create another iPS cell line featuring the pathogenic c.1126C > T mutation in the FUS gene. This research aims not only to establish a disease model for ALS linked to FUS mutations but also to pave the way for potential therapeutic interventions.

N7-methylguanosine (m7G) modification is one of the most prevalent forms of chemical modification in RNA molecules, which plays an important role in biological processes such as RNA stability, translation regulation and ribosome recognition. Methyl-transferation of m7G modification is catalyzed by the enzyme complex of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4), and Quaking (QKI) recognizes internal m7G methylated mRNA and regulates mRNA translation and stabilization. Recent studies have found that m7G modification - related enzymes are associated with the onset and progression of digestive cancer, such as colorectal cancer, liver cancer, and other digestive diseases such as ulcerative colitis. This review will focus on the latest research progress on the roles of m7G methyltransferase METTL1/WDR4 and recognized enzyme QKI in digestive diseases.

Cardiac organoids offer sophisticated 3D structures that emulate key aspects of human heart development and function. This review traces the evolution of cardiac organoid technology, from early stem cell differentiation protocols to advanced bioengineering approaches. We discuss the methodologies for creating cardiac organoids, including self-organization techniques, biomaterial-based scaffolds, 3D bioprinting, and organ-on-chip platforms, which have significantly enhanced the structural complexity and physiological relevance of in vitro cardiac models. We examine their applications in fundamental research and medical innovations, highlighting their potential to transform our understanding of cardiac biology and pathology. The integration of multiple cell types, vascularization strategies, and maturation protocols has led to more faithful representations of the adult human heart. However, challenges remain in achieving full functional maturity and scalability. We critically assess the current limitations and outline future directions for advancing cardiac organoid technology. By providing a comprehensive analysis of the field, this review aims to catalyze further innovation in cardiac tissue engineering and facilitate its translation to clinical applications.

Porous materials are integral to numerous aspects of daily life, from metabolic processes in the human body to various industrial applications. Significant efforts have been directed toward the synthesis of single-crystalline reticular materials with well-defined architectures and enhanced performance by reticulating organic units into extended frameworks. However, the development of these materials for diverse applications is substantially impeded by the limitations of current preparation strategies and the unclear mechanisms underlying single-crystal formation. This review provides a comprehensive summary of recent advancements in the design and synthetic methodologies of single-crystal framework materials, emphasizing solvothermal-induced direct synthesis, template-assisted synthesis, and modulator-assisted preparation. Detailed insights into the challenges of modulating crystal growth are presented. Furthermore, the review discusses the potential large-scale applications of single-crystal frameworks, including catalysis, adsorption/separation, sensing, polarized optics, and life sciences, thereby broadening the scope of their utility across various fields.

Abstract Background This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development. Methods By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes. Results The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P

Abstract Objective To assess renal interstitial fibrosis (IF) using diffusion MRI approaches, and explore whether corticomedullary difference (CMD) of diffusion parameters, combination among MRI parameters, or combination with estimated glomerular filtration rate (eGFR) benefit IF evaluation. Methods Forty-two patients with chronic kidney disease were included, undergoing MRI examinations. MRI parameters from apparent diffusion coefficient (ADC), intra-voxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), and diffusion-relaxation correlated spectrum imaging (DR-CSI) were obtained both for renal cortex and medulla. CMD of these parameters was calculated. Pathological IF scores (1–3) were obtained by biopsy. Patients were divided into mild (IF = 1, n = 23) and moderate-severe fibrosis (IF = 2–3, n = 19) groups. Group comparisons for MRI parameters were performed. Diagnostic performances were assessed by the receiver operator’s curve analysis for discriminating mild from moderate-severe IF patients. Results Significant inter-group differences existed for cortical ADC, IVIM-D, IVIM-f, DKI-MD, DR-CSI V B, and DR-CSI V C. Significant inter-group differences existed in ΔADC, ΔMD, ΔV B, ΔV C, ΔQ B, and ΔQ C. Among the cortical MRI parameters, V B displayed the highest AUC = 0.849, while ADC, f, and MD also showed AUC > 0.8. After combining cortical value and CMD, the diagnostic performances of the MRI parameters were slightly improved except for IVIM-D. Combining V B with f brings the best performance (AUC = 0.903) among MRI bi-variant models. A combination of cortical V B, ΔADC, and eGFR brought obvious improvement in diagnostic performance (AUC 0.963 vs 0.879, specificity 0.826 vs 0.896, and sensitivity 1.000 vs 0.842) than eGFR alone. Conclusion Our study shows promising results for the assessment of renal IF using diffusion MRI approaches. Critical relevance statement Our study explores the non-invasive assessment of renal IF, an independent and effective predictor of renal outcomes, by comparing and combining diffusion MRI approaches including compartmental, non-compartmental, and model-free approaches. Key Points Significant difference exists for diffusion parameters between mild and moderate-severe IF. Generally, cortical parameters show better performance than corresponding CMD. Bi-variant model lifts the diagnostic performance for assessing IF. Graphical Abstract

The present study designed and prepared a novel platinum alloy system Pt-xAu-5Ni (x = 0, 2, 5, wt.%) with high strength and good electrical resistivity. The mechanical, electrical properties and related microstructure during the cold deformation and subsequent aging process were investigated. The cold-deformed Pt–5Ni alloy obtained the yield strength of 581 MPa, the ultimate tensile strength of 828 MPa, the hardness of 283 HV, and the electrical resistivity of 23.9 μΩ⋅cm. The subsequent aging process and the Au addition into Pt–5Ni alloy were found to both enhance the mechanical properties. Therefore, with the dual strengthening effect of the subsequent aging and the Au addition, Pt–5Au–5Ni alloy achieved the high yield strength of 889 MPa, the high ultimate tensile strength of 1117 MPa, the high hardness of 361 HV with the electrical resistivity of 26.7 μΩ⋅cm. The precipitation of L12-type Pt3Ni nanoparticles and L11-type CSRO dominated the age-strengthening behavior of Pt–2Au–5Ni and Pt–5Au–5Ni alloys after cold deformation. The Au addition refined the grains via the experimental observations, and predictably favored the L12-type Pt3Ni nanoprecipitation based on the thermodynamical calculations, thus the Au addition effectively strengthened Pt–5Ni alloy. This study provides a novel platinum alloy system with excellent mechanical and electrical properties, which has potential application in the electrical contact field.

Abstract Primary membranous nephropathy (PMN) is one of the leading causes of end‐stage renal disease, and the most frequent cause of massive proteinuria in nondiabetic adults, resulting in fatal complications. However, the underlying pathomechanisms of PMN remain largely unclear. Here, single‐cell RNA sequencing is employed to analyze kidney biopsies from eleven PMN patients and seven healthy subjects. Profiling 44 060 cells from patients allowed us to characterize the cellular composition and cell‐type‐specific gene expression in the PMN kidney. The complement‐induced BMP2/pSMAD1/COL4 pathway is identified as the pathogenic pathway in podocytes, bridging two key events, i.e., complement system activation and glomerular basement membrane thickening in PMN. Augmented infiltration and activation of myeloid leukocytes and B lymphocytes are found, profiling delicate crosstalk of immune cells in PMN kidneys. Overall, these results provide valuable insights into the roles of podocytes and immune cells in PMN, and comprehensive resources toward the complete understanding of PMN pathophysiology.

Abstract Background Autoimmune responses have been suggested to involvement in patients with Behcet’s syndrome (BS). There has been growing attention towards the roles of cutaneous lymphocyte antigen (CLA)+ regular T cells (Tregs) in autoimmune diseases. The role of CLA+ Tregs in BS is still uncertain. This study aims to clarify the impact of CLA+ Tregs on BS. Methods We collected peripheral blood from a total of 107 patients with BS and 114 healthy controls (HCs). The number of CLA+ Tregs, natural killer (NK) cells, B cells, and several subtypes of CD4+ T cells were detected using flow cytometry and compared between patients and HCs. Results The absolute number and proportion of CLA+ Tregs among CD4+ T lymphocytes and CD4+ Tregs were lower in patients with BS than in HCs. CLA+ Tregs were positively related with NK cells (r = 0.500, P

As the volume of Chinese electronic medical records (EMRs) experiences an explosive growth, the application of clinical named entity recognition (CNER) technology becomes crucial for the effective utilization of EMR data and practical implementation of evidence-based medicine. While mainstream models excel in capturing global contextual information, their feature extraction mechanisms tend to be unidimensional, limiting their information retrieval capabilities. To address this issue, this paper proposes a Dual-Channel Model for CNER (DCM-CNER), which enhances feature extraction through the introduction of a customized convolutional stack, denoted as emConvNet (embedded ConvNet), for local feature extraction. The model further addresses the vanishing gradient issue by employing a newly designed Gated Dilated Convolutional Neural Network (GDCNN) module with a residual structure. Sequential and contextual information is extracted from the text using a Bidirectional Long Short-Term Memory (BiLSTM) layer. Additionally, a multi-head bilinear attention mechanism is introduced for parallel dynamic feature fusion. Experimental results demonstrate the superiority of the proposed DCM-CNER model, in comparison to the existing mainstream models and state-of-the-art models, achieving F1 scores of 94.15%, 85.26%, and 84.21% on the CCKS2017, CCKS2019, and CLUENER2020 datasets, respectively, thereby validating its effectiveness in performing the task of Chinese CNER in EMRs.

Abstract Background To classify the different clinical phenotypes and compare the distinct prognoses of microscopic polyangiitis (MPA). Methods A retrospective analysis of 436 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) from 2015 to 2022 was conducted in our center, of which 90 patients were diagnosed with MPA and underwent renal biopsy. Results Among the 90 MPA patients, 63% were female, and the median age at onset was 63 years (25th–75th percentile: 58–68). The median follow-up time was 26 months (25th–75th percentile: 10–53). We identified four subtypes: renal impairment type (cluster 1, 39%), pure type (cluster 2, 22%), systemic inflammation type (cluster 3, 26%), and rapid progress type (cluster 4, 13%). Cluster 1, characterized by renal dysfunction at onset (80%), demonstrated poor prognoses with only 26% achieved complete remission (CR), 11% dying, and 19% developing renal failure. In contrast, patients in cluster 2, exclusively female, most had only kidney involvement showed the best prognoses with 55% achieving CR and none experiencing death or renal failure within 10 years. Cluster 3 mostly consisted of males; high fever and C-reactive protein levels were the primary characteristics. These cases exhibited moderate prognoses with 53% achieving CR, 9% dying, and 4% developing renal failure. Finally, patients in cluster 4, which was characterized by rapidly progressive glomerulonephritis, had the worst prognoses, with none achieving CR, 8% dying, and 75% developing renal failure despite aggressive treatment. Conclusions MPA is classified into four subtypes with distinct clinical manifestations and prognoses.

INF2 mutations cause Charcot-Marie-Tooth disease (CMT), and /or focal segmental glomerulosclerosis (FSGS) in an autosomal dominant inheritance mode, whose underlying mechanism remains unclear. Here, we report the generation of an iPSC line from a female patient with CMT and FSGS. The iPSC line from the patient's PBMCs carried a heterozygous INF2 deletion mutation (c.315_323delGCGCGCCGT) within the conserved E2. This line exhibited a normal karyotype, high expression of pluripotency markers, and trilineage differentiation potential. This line can be used to dissect the complex pathomechanism through further induction of differentiation into related cells and as a drug screening tool for INF2-associated diseases.

Abstract Background Extraglomerular immune complex deposition is rare and only a few membranous nephropathy cases with tubular basement membrane deposits have been reported following allogeneic hematopoietic stem cell transplantation. Case presentation We reported a 56-year-old man with increased serum creatinine after allogeneic hematopoietic stem cell transplantation who underwent a renal biopsy. Tubular interstitial nephritis was identified on light microscope. The unique histologic features were diffuse tubular basement membrane immune complex deposition detected by both immunofluorescence and electron microscopy, while the glomerular involvement was inconspicuous. The differential diagnosis from other forms of tubular basement membrane deposition is discussed. Conclusion Diffuse granular tubular basement membrane immune complex deposition with minimal glomerular involvement is also a manifestation of renal complication in hematopoietic stem cell transplantation recipient. However, the exact mechanism and target antigen remains unknown.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Affected patients experience gradual loss of their spinal cord and cortical motor neurons with consequent muscle weakness and emaciation, and eventual respiratory failure. The pathogenesis of ALS remains largely unknown although the FUS (sarcoma fusion gene) gene is known to be one of the major pathogenic genes. We have generated an induced pluripotent stem cell line SMUSHi002-A from an ALS patient who carries a heterozygous mutation c.1562G > A in FUS. This cell line will serve as a useful model to investigate disease pathogenesis and develop potential therapeutic approaches for ALS.

Chronic pain can induce not only nociceptive but also depressive emotions. A previous study demonstrated that betaine, a commonly used nutrient supplement, has an anti-nociceptive effect, but whether betaine can alleviate chronic pain-induced depressive emotion is elusive. Our current study found that betaine administration significantly eliminated complete Freund’s adjuvant (CFA)-induced pain-related depressive-like behaviour. Mechanistically, betaine treatment inhibited microglia and astrocyte activation. Furthermore, betaine significantly promoted the transition of microglia from the M1 to the M2 phenotype, as well as the transition of astrocytes from the A1 to the A2 phenotype. Additionally, the release of pro-inflammatory factors such as IL-18, IL-1β and IL-6 and anti-inflammatory factors such as IL-10 in the hippocampus induced by CFA were also reversed by betaine administration. Overall, betaine has therapeutic effects on pain-related depressive-like phenotypes caused by CFA, possibly through altering the polarization of microglia and astrocytes to reduce neuroinflammation.

Abstract Background Impaired renal function was not a recognized indication for renal biopsy. The effects of receiving renal biopsy on the renal functional prognosis for chronic kidney disease (CKD) patients with impaired renal function need to be explored. Methods This study retrospectively enrolled 300 renal function impaired CKD patients in Renji Hospital from January 2015 to December 2017, 150 of them received percutaneous renal biopsy while the others did not. The endpoint was ≥ 50% estimated glomerular filtration rate (eGFR) decline from baseline or development of end-stage renal disease (ESRD). Kaplan-Meier analysis with log-rank test was performed to compare the renal survival probability between patients receiving renal biopsy or not. Univariate and multivariate analysis with Cox regression were conducted with predictors of poor renal outcomes in the study cohort. Results The median follow-up period was 37.6 months. During the follow-up period, the eGFR of the biopsy group increased from 52.2 ± 14.4 to 67.4 ± 37.8 ml/min/1.73 m², but decreased from 55.3 ± 17.1 to 29.8 ± 19.1 ml/min/1.73 m² in the non-biopsy group. Patients who received renal biopsy had significantly higher renal survival probability (P

Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice. Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regeneration without uneven surface, graft necrosis and sclerosis. However, poor gap integration is a serious concern, which eventually leads to deterioration of joint function. To deal with such complications, this study has developed a strategy to effectively enhance integration of the gap region following mosaicplasty by applying injectable bioactive supramolecular nanofiber-enabled gelatin methacryloyl (GelMA) hydrogel (BSN-GelMA). A rabbit osteochondral defect model demonstrated that BSN-GelMA achieved seamless osteochondral healing in the gap region between plugs of osteochondral defects following mosaicplasty, as early as six weeks. Moreover, the International Cartilage Repair Society score, histology score, glycosaminoglycan content, subchondral bone volume, and collagen II expression were observed to be the highest in the gap region of BSN-GelMA treated group. This improved outcome was due to bio-interactive materials, which acted as tissue fillers to bridge the gap, prevent cartilage degeneration, and promote graft survival and migration of bone marrow mesenchymal stem cells by releasing bioactive supramolecular nanofibers from the GelMA hydrogel. This study provides a powerful and applicable approach to improve gap integration after autologous mosaicplasty. It is also a promising off-the-shelf bioactive material for cell-free in situ tissue regeneration.

Abstract Background Early metastasis is a key factor contributing to poor breast cancer (BC) prognosis. Circulating tumor cells (CTCs) are regarded as the precursor cells of metastasis, which are ultimately responsible for the main cause of death in BC. However, to date molecular mechanisms underlying CTC formation in BC have been insufficiently defined. Methods RNA-seq was carried out in primary tissues from early-stage BC patients (with CTCs≥5 and CTCs = 0, respectively) and the validation study was conducted in untreated 80 BC patients. Multiple in vitro and in vivo models were used in functional studies. Luciferase reporter, ChIP-seq, CUT&Tag-seq, and GST-pulldown, etc. were utilized in mechanistic studies. CTCs were counted by the CanPatrol™ CTC classification system or LiquidBiospy™ microfluidic chips. ERK1/2 inhibitor SCH772984 was applied to in vivo treatment. Results Highly expressed FOXD1 of primary BC tissues was observed to be significantly associated with increased CTCs in BC patients, particularly in early BC patients. Overexpressing FOXD1 enhanced the migration capability of BC cells, CTC formation and BC metastasis, via facilitating epithelial-mesenchymal transition of tumor cells. Mechanistically, FOXD1 was discovered to induce RalA expression by directly bound to RalA promotor. Then, RalA formed a complex with ANXA2 and Src, promoting the interaction between ANXA2 and Src, thus increasing the phosphorylation (Tyr23) of ANXA2. Inhibiting RalA-GTP form attenuated the interaction between ANXA2 and Src. This cascade culminated in the activation of ERK1/2 signal that enhanced metastatic ability of BC cells. In addition, in vivo treatment with SCH772984, a specific inhibitor of ERK1/2, was used to dramatically inhibit the CTC formation and BC metastasis. Conclusion Here, we report a FOXD1-dependent RalA-ANXA2-Src complex that promotes CTC formation via activating ERK1/2 signal in BC. FOXD1 may serve as a prognostic factor in evaluation of BC metastasis risks. This signaling cascade is druggable and effective for overcoming CTC formation from the early stages of BC.

Abstract Background Chronic kidney disease (CKD) is a common complication after liver transplantation and is traditionally considered to be secondary to calcineurin inhibitors (CNIs). However, several studies have reported that the etiology of CKD after liver transplantation is broad and may only be assessed accurately by renal biopsy. The current study aimed to explore the usefulness of renal biopsies in managing CKD after liver transplantation in daily clinical practice. Method This retrospective analysis enrolled all post-liver transplantation patients who had a renal biopsy in a single center from July 2018 to February 2021. Results Fourteen renal biopsies were retrieved for review from 14 patients at a median of 35.7 (minimum-maximum: 2.80–134.73) months following liver transplantation. The male-to-female ratio was 13:1 (age range, 31–75 years). The histomorphological alterations were varied. The predominant glomerular histomorphological changes included focal segmental glomerular sclerosis (FSGS) (n = 4), diabetic glomerulopathy (n = 4), and membranoproliferative glomerulonephritis (n = 4). Thirteen (92.9%) patients had renal arteriolar sclerosis. Immune complex nephritis was present in six patients, of whom only two had abnormal serum immunological indicators. Despite interstitial fibrosis and tubular atrophy being present in all the patients, only six (42.9%) presented with severe interstitial injury. No major renal biopsy-related complications occurred. After a mean follow-up of 11.8 months (range: 1.2–29.8), three patients progressed to end-stage renal disease (ESRD). Conclusion The etiology of CKD after liver transplantation might be more complex than originally thought and should not be diagnosed simply as calcineurin inhibitors(CNI)-related nephropathy. Renal biopsy plays a potentially important role in the diagnosis and treatment of CKD after liver transplantation and might not be fully substituted by urine or blood tests. It may help avoid unnecessary changes to the immunosuppressants and inadequate treatment of primary diseases.

Abstract Articular cartilage damage is a universal health problem. Despite recent progress, chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration. Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions, but the characteristics and intermediate molecular mechanisms remain unclear. In this study, we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation. We performed various assays, such as single-cell RNA sequencing (scRNA-seq), live-cell metabolic assays, and assays for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages. Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation, whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling. Using the chemical inhibitor BTB06584, we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss. Notably, this two-stage transition was also validated in human chondrocytes. An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers. Overall, this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.

Abstract Tendon heterotopic ossification (HO) is characterized by bone formation inside tendon tissue, which severely debilitates people in their daily life. Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis. Here, we investigate the pathological mechanism and propose a potential treatment method for HO. Immunofluorescence assays showed that the Mohawk (MKX) expression level was decreased in human tendon HO tissue, coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx −/− mice. Single-cell RNA sequencing analyses of wild-type and Mkx −/− tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx −/− tendon cells. Single-cell analysis revealed that the gene expression program of angiogenesis, which is strongly associated with bone formation, was activated in all cell types during HO. Moreover, inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO. These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.

Chondroitin sulfate (CS) derivatives are useful biomacromolecules for fabrication of biomaterials. However, chemical modifications of CS molecular structure during processing may alter its physicochemical and biological properties. Here, we studied these changes in molecular and biological functions following CS oxidation to different oxidation. Under ultraviolet visible (UV–Vis) spectroscopy, CS exhibited a blue shift in characteristic absorption peaks after the oxidation. The thermo-stability of the modified CS was also weaker than its original molecular form. Both FTIR and NMR results demonstrated distinct structural changes at the molecular level after oxidation. In vitro study showed that rabbit bone marrow stromal cells cultured with oxidized CS (CSA) containing cell culture medium exhibited viability comparable to normal cell culture medium for CSA concentration less than 125 mg/mL. However, CSA may also inhibit proliferation of these cells. Besides, unmodified CS could induce a chondrogenesis of stem cells, but this function was weakened after chemical modification. Interestingly, chemical modification altered physicochemical and biological properties in substitution degree-dependent manner with the highly oxidized CS exhibiting the lowest stability and chondrogenic induction. These results indicated that chemical modification of biomacromolecules, such as CS, could change both their physicochemical properties and biological functions, suggesting the need to carefully control parameters during biomaterial processing and fabrication.

Cartilage defects are one of the most common symptoms of osteoarthritis (OA), a degenerative disease that affects millions of people world-wide and places a significant socio-economic burden on society. Hydrogels, which are a class of biomaterials that are elastic, and display smooth surfaces while exhibiting high water content, are promising candidates for cartilage regeneration. In recent years, various kinds of hydrogels have been developed and applied for the repair of cartilage defects in vitro or in vivo, some of which are hopeful to enter clinical trials. In this review, recent research findings and developments of hydrogels for cartilage defects repair are summarized. We discuss the principle of cartilage regeneration, and outline the requirements that have to be fulfilled for the deployment of hydrogels for medical applications. We also highlight the development of advanced hydrogels with tailored properties for different kinds of cartilage defects to meet the requirements of cartilage tissue engineering and precision medicine.

Vulnerable carotid plaque is closely related to the occurrence of Ischemic stroke. Therefore, accurate and rapid identification of the nature of carotid plaques is essential. AS is a chronic immune inflammatory process. Systemic immune-inflammation index (SII) is a novel index of immune inflammation obtained from routine whole blood cell count analysis, which comprehensively reflects the state of inflammation and immune balance in the body. This study sought to explore the relationship between SII level and carotid plaque vulnerability, plaque composition characteristics, and acute ischemic stroke (AIS) severity. A total of 131 patients diagnosed with AIS presenting with a carotid atherosclerotic plaque were enrolled in this study. Using carotid ultrasound (CDU) to assess the carotid-responsible plaque properties, we divided the patients into stable plaques group and vulnerable plaques group, and analyzed the correlation between SII levels and plaque vulnerability. And we further analyzed to evaluate the correlation between high SII levels and plaque characteristics and AIS severity. In addition, Cohen's Kappa statistics was used to detect the consistency of Carotid ultrasound (US) and cervical High-resolution magnetic resonance imaging (HRMRI) in evaluating plaque vulnerability. The findings showed that the vulnerable group had higher levels of SII compared with the stable group. The high SII group had more vulnerable plaques and a high frequency of plaque fibrous cap rupture compared with the low SII group. Logistic analysis showed that a high SII level was an independent risk factor for vulnerable plaques (odds ratio [OR] = 2.242) and plaque fibrous cap rupture (OR=3.462). The results also showed a high consistency between Carotid US and HRMRI methods in the assessment of plaque vulnerability [Cohen's kappa value was 0.89 (95% CI = 0.78–0.97)] and the level of SII was positively associated with NIHSS score (r = 0.473, P < 0.001). Our study suggests that elevated levels of SII may have adverse effects on the vulnerability of carotid plaques, especially in stroke patients with vulnerable plaques with ruptured fibrous caps, which may aggravate the severity of AIS.

Abstract Stem cell therapies are unsatisfactory due to poor cell survival and engraftment. Stem cell used for therapy must be properly “tuned” for a harsh in vivo environment. Herein, we report that transfer of exogenous mitochondria (mito) to adipose‐derived mesenchymal stem cells (ADSCs) can effectively boost their energy levels, enabling efficient cell engraftment. Importantly, the entire process of exogeneous mitochondrial endocytosis is captured by high‐content live‐cell imaging. Mitochondrial transfer leads to acutely enhanced bioenergetics, with nearly 17% of higher adenosine 5′‐triphosphate (ATP) levels in ADSCs treated with high mitochondrial dosage and further results in altered secretome profiles of ADSCs. Mitochondrial transfer also induced the expression of 334 mRNAs in ADSCs, which are mainly linked to signaling pathways associated with DNA replication and cell division. We hypothesize that increase in ATP and cyclin‐dependent kinase 1 and 2 expression might be responsible for promoting enhanced proliferation, migration, and differentiation of ADSCs in vitro. More importantly, mito‐transferred ADSCs display prolonged cell survival, engraftment and horizontal transfer of exogenous mitochondria to surrounding cells in a full‐thickness skin defect rat model with improved skin repair compared with nontreated ADSCs. These results demonstrate that intracellular mitochondrial transplantation is a promising strategy to engineer stem cells for tissue regeneration.

In the era of immune checkpoint blockade cancer therapy, cytokines have become an attractive immune therapeutics to increase response rates. Interleukin 21 (IL21) as a single agent has been evaluated for cancer treatment with good clinical efficacy. However, the clinical application of IL21 is limited by a short half-life and concern about potential immune suppressive effect on dendritic cells. Here, we examined the antitumor function of a half-life extended IL21 alone and in combination with PD-1 blockade using preclinical mouse tumor models. We also determined the immune mechanisms of combination therapy. We found that combination therapy additively inhibited the growth of mouse tumors by increasing the effector function of type 1 lymphocytes. Combination therapy also increased the fraction of type 1 dendritic cells (DC1s) and M1 macrophages in the tumor microenvironment (TME). However, combination therapy also induced immune regulatory mechanisms, including the checkpoint molecules Tim-3, Lag-3, and CD39, as well as myeloid derived suppressor cells (MDSC). This study reveals the mechanisms of IL21/PD-1 cooperation and shed light on rational design of novel combination cancer immunotherapy.

Bearing compression from adjacent joints, the articular cartilage is cumulatively pressured in daily life, thus making it prone to injuries; however, once damaged, the self-healing capacity of articular cartilage is limited owing to its low metabolic property. Autologous chondrocyte implantation, a three-step repairing technique for articular lesions, has received satisfactory short-term clinical outcomes, whereas its long-term effect remains controversial. Currently, improved stem-cell therapies and novel biomaterials have shed new lights on autologous chondrocyte implantation. We would, therefore, synthesize these optimization strategies in order of their presences in the three-step protocol, seeking to find and amplify synergic effects between these strategies. The translational potential of this article: Autologous chondrocytes implantation serves as an alternative for the treatment of articular cartilage lesions to avoid potentially detrimental effects of applying microfracture. The optimized ACI should improve the cost-effectiveness of repairing articular cartilage while circumventing latent complications like osteophyte. This article synthesized optimization strategies for ACI and provided appropriate applying approaches to maximize their synergic effects. It will be a pioneering trial for combinedly using stem cells and nanotechnology to regenerate cartilage. Keywords: Autologous chondrocyte implantation, Scaffold, Stem cell, Nanotechnology

Background: Shear wave elastography ultrasound (SWE) is an emerging non-invasive candidate for assessing kidney stiffness. However, its prognostic value regarding kidney injury is unclear. Methods: A prospective cohort was created from kidney biopsy patients in our hospital from May 2019 to June 2020. The primary outcome was the initiation of renal replacement therapy or death, while the secondary outcome was eGFR < 60 mL/min/1.73 m2. Ultrasound, biochemical, and biopsy examinations were performed on the same day. Radiomics signatures were extracted from the SWE images. Results: In total, 187 patients were included and followed up for 24.57 ± 5.52 months. The median SWE value of the left kidney cortex (L_C_median) is an independent risk factor for kidney prognosis for stage 3 or over (HR 0.890 (0.796–0.994), p < 0.05). The inclusion of 9 out of 2511 extracted radiomics signatures improved the prognostic performance of the Cox regression models containing the SWE and the traditional index (chi-square test, p < 0.001). The traditional Cox regression model had a c-index of 0.9051 (0.8460–0.9196), which was no worse than the machine learning models, Support Vector Machine (SVM), SurvivalTree, Random survival forest (RSF), Coxboost, and Deepsurv. Conclusions: SWE can predict kidney injury progression with an improved performance by radiomics and Cox regression modeling.

Immunoglobulin A nephropathy (IgAN) is a known cause of end-stage kidney disease, but the pathogenesis and factors affecting prognosis are not fully understood. In the present study, we carried out weighted gene correlation network analysis (WGCNA) to identify hub genes related to the occurrence of IgAN and validated candidate genes in experiments using mouse mesangial cells (MMCs) and clinical specimens (kidney tissue from IgAN patients and healthy controls). We screened the GSE37460 and GSE104948 differentially expressed genes common to both datasets and identified periostin (POSTN) as one of the five key genes using the cytoHubba plugin of Cytoscape software and by receiver-operating characteristic curve analysis. The top 25% of genes in the GSE93798 dataset showing variable expression between IgAN and healthy tissue were assessed by WGCNA. The royalblue module in WGCNA was closely related to creatinine and estimated glomerular filtration rate (eGFR) in IgAN patients. POSTN had very high module membership and gene significance values for creatinine (0.82 and 0.66, respectively) and eGFR (0.82 and −0.67, respectively), indicating that it is a co-hub gene. In MMCs, POSTN was upregulated by transforming growth factor β1, and stimulation of MMCs with recombinant POSTN protein resulted in an increase in the level of proliferating cell nuclear antigen (PCNA) and a decrease in that of B cell lymphoma-associated X protein, which were accompanied by enhanced MMC proliferation. POSTN gene knockdown had the opposite effects. Immunohistochemical analysis of kidney tissue specimens showed that POSTN and PCNA levels were elevated, whereas the rate of apoptosis was reduced in IgAN patients relative to healthy controls. POSTN level in the kidney tissue of IgAN patients was positively correlated with creatinine level and negatively correlated with eGFR. Thus, POSTN promotes the proliferation of MCs to promote renal dysfunction in IgAN.

Complement 3a (C3a) and complement 5a (C5a), small cleavage fragments generated by complement activation, has been previously shown to be obviously up-regulated in highly metastatic hepatocellular carcinoma (HCC) cells. However, their functional roles in HCC cells remains unclear. Here, we investigated the biological function of G protein-coupled receptor C3aR/C5aR using small interference RNA in HCC cells. Our data showed that C3aR and C5aR knockdown significantly inhibited the proliferation, migration and invasion of HCC cells using CCK-8, colony formation and transwell assays. Flow cytometry assay showed C3aR and C5aR knockdown induced cell cycle G0/G1 phase arrest and apoptosis in HCC cells. Moreover, we found down-regulation of C3aR/C5aR obviously down-regulated the expression of PCNA, Ki-67 and suppressed the epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) in HCC cells. Collectively, our data demonstrated that targeting C3aR/C5aR may hold promise for the treatment of HCC.

Abstract High product return rates are an increasingly pressing challenge for many e-retailers around the world. To address this problem, this paper offers a new perspective by focusing on the critical moment of the package-opening process. Going beyond previous research, which has primarily focused on website information and the product itself, we examine the effects of the outside appearance (i.e., the color of the delivery package) and contents of the delivery package (i.e., extra gifts, coupons, and preprinted return labels) on consumer return behavior. Our findings across two experimental studies and an observational field study show that a well-considered package design, including colorful packaging and extra gifts, significantly lowers consumers’ return intentions and actual returns. We also explore the process of consumers’ cognitive–affective reactions after opening a delivery package. During this two-stage reaction process, pleasure plays a crucial role in the consumer’s return choice.

Cancer stem-like cells, possessing “stemness” properties, play crucial roles in progression, metastasis, and drug resistance in various cancers. Viral microRNAs (such as EBV-miR-BART7-3p), as exogenous regulators, have been discovered to regulate malignant progression of nasopharyngeal carcinoma (NPC), suggesting a possible role of viral microRNAs in imposing stemness. In this study, we found that EBV-miR-BART7-3p induce stemness of NPC cells. We firstly reported that EBV-miR-BART7-3p increased the percentage of side population cells, the development of tumor spheres, and the expression level of stemness markers in vitro. This viral microRNA also enhanced stem-like or cancer-initiating properties of NPC cells in vivo. Besides, we identified SMAD7 as a novel target gene of EBV-miR-BART7-3p in addition to PTEN gene we previously reported; this viral microRNA suppressed SMAD7, led to activation of TGF-β signaling, and eventually enhanced the stemness of NPC cells. Silencing of SMAD7 resembled the effects generated by EBV-miR-BART7-3p in NPC cells. After reconstitution of SMAD7, EBV-miR-BART7-3p-expressing cells underwent a phenotypic reversion. EBV-positive NPC cells were used to enable experimental validation. Finally, we further discovered that EBV-miR-BART7-3p increased chemo-resistance of NPC in vitro and in vivo, supporting that EBV-miR-BART7-3 resulted in increased stemness of NPC cells and lead to drug resistance and cancer recurrence. Overall, this study uncovered a novel mechanism underlying viral microRNA-associated stemness of NPC cells. This viral microRNA and its associated cellular genes may be potential therapeutic targets for restraining chemo-resistance and recurrence of NPC.

Contrast-induced acute kidney injury (CI-AKI) occurs in more than 30% of patients after intravenous iodinated contrast media and causes serious complications, including renal failure and mortality. Recent research has demonstrated that routine antioxidant and alkaline therapy failed to show benefits in CI-AKI patients with high risk for renal complications. Mitophagy is a mechanism of selective autophagy, which controls mitochondrial quality and mitochondrial reactive oxygen species (ROS) through degradation of damaged mitochondria. The role of mitophagy and its regulation of apoptosis in CI-AKI are poorly understood. In this study, we demonstrated that mitophagy was induced in renal tubular epithelial cells (RTECs) during CI-AKI, both in vivo and in vitro. Meanwhile, contrast media–induced mitophagy was abolished when silencing PINK1 or PARK2 (Parkin), indicating a dominant role of the PINK1-Parkin pathway in mitophagy. Moreover, mitochondrial damage, mitochondrial ROS, RTEC apoptosis, and renal injury under contrast exposure were more severe in PINK1- or PARK2-deficient cells and mice than in wild-type groups. Functionally, PINK1-Parkin–mediated mitophagy prevented RTEC apoptosis and tissue damage in CI-AKI through reducing mitochondrial ROS and subsequent NLRP3 inflammasome activation. These results demonstrated that PINK1-Parkin–mediated mitophagy played a protective role in CI-AKI by reducing NLRP3 inflammasome activation. Keywords: Acute kidney injury, Contrast media, Mitophagy, Mitochondrial ROS, NLRP3 inflammasome, Apoptosis

Arthroscopic lavage and arthrocentesis, performed with different inner-diameter lavage needles, are the current minimally invasive techniques used in temporomandibular joint disc displacement (TMJ-DD) for pain reduction and functional improvement. In the current study, we aimed to explore the biomechanical influence and explain the diverse clinical outcomes of these two approaches with computational fluid dynamics. Data was retrospectively analyzed from 78 cases that had undergone arthroscopic lavage or arthrocentesis for TMJ-DD from 2002 to 2010. Four types of finite volume models, featuring irrigation needles of different diameters, were constructed based on computed tomography images. We investigated the flow pattern and pressure distribution of lavage fluid secondary to caliber-varying needles. Our results demonstrated that the size of outflow portal was the critical factor in determining irrigated flow rate, with a larger inflow portal and a smaller outflow portal leading to higher intra-articular pressure. This was consistent with clinical data suggesting that increasing the mouth opening and maximal contra-lateral movement led to better outcomes following arthroscopic lavage. The findings of this study could be useful for choosing the lavage apparatus according to the main complaint of pain, or limited mouth opening, and examination of joint movements.