UBC9-mediated SUMOylation of Lamin B1 enhances DNA-damage-induced nuclear DNA leakage and autophagy after spinal cord injury.

Recent studies have shown that nucleophagy can mitigate DNA damage by selectively degrading nuclear components protruding from the nucleus. However, little is known about the role of nucleophagy in neurons after spinal cord injury (SCI). Western blot analysis and immunofluorescence were performed to evaluate the nucleophagy after nuclear DNA damage and leakage in SCI neurons in vivo and NSC34 expression in primary neurons cultured with oxygen-glucose deprivation (OGD) in vitro, as well as the interaction and colocalization of autophagy protein LC3 with nuclear lamina protein Lamin B1. The effect of UBC9, a Small ubiquitin-related modifier (SUMO) E2 ligase, on Lamin B1 SUMOylation and nucleophagy was examined by siRNA transfection or 2-D08 (a small-molecule inhibitor of UBC9), immunoprecipitation, and immunofluorescence. In SCI and OGD injured NSC34 or primary cultured neurons, neuronal nuclear DNA damage induced the SUMOylation of Lamin B1, which was required by the nuclear Lamina accumulation of UBC9. Furthermore, LC3/Atg8, an autophagy-related protein, directly bound to SUMOylated Lamin B1, and delivered Lamin B1 to the lysosome. Knockdown or suppression of UBC9 with siRNA or 2-D08 inhibited SUMOylation of Lamin B1 and subsequent nucleophagy and protected against neuronal death. Upon neuronal DNA damage and leakage after SCI, SUMOylation of Lamin B1 is induced by nuclear Lamina accumulation of UBC9. Furthermore, it promotes LC3-Lamin B1 interaction to trigger nucleophagy that protects against neuronal DNA damage.

Establishment and validation of a nomogram predicting the risk of deep vein thrombosis before total knee arthroplasty.

PURPOSE: This study aimed to analyze the independent risk factors contributing to preoperative DVT in TKA and constructed a predictive nomogram to accurately evaluate its occurrence based on these factors. METHODS: The study encompassed 496 patients who underwent total knee arthroplasty at our hospital between June 2022 and June 2023. The dataset was randomly divided into a training set (n = 348) and a validation set (n = 148) in a 7:3 ratio. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analysis were used to screen the predictors of preoperative DVT occurrence in TKA and construct a nomogram. The performance of the predictive models was evaluated using the concordance index (C-index), calibration curves, and the receiver operating characteristic (ROC) curves. Decision curve analysis was used to analyze the clinical applicability of nomogram. RESULTS: A total of 496 patients who underwent TKA were included in this study, of which 28 patients were examined for lower extremity DVT preoperatively. Platelet crit, Platelet distribution width, Procalcitonin, prothrombin time, and D-dimer were predictors of preoperative occurrence of lower extremity DVT in the nomograms of the TKA patients. In addition, the areas under the curve of the ROC of the training and validation sets were 0.935 (95%CI: 0.880-0.990) and 0.854 (95%CI: 0.697-1.000), and the C-indices of the two sets were 0.919 (95%CI: 0.860-0.978) and 0.900 (95%CI: 0.791-1.009). The nomogram demonstrated precise risk prediction of preoperative DVT occurrence in TKA as confirmed by the calibration curve and decision curve analysis. CONCLUSIONS: This Nomogram demonstrates great differentiation, calibration and clinical validity. By assessing individual risk, clinicians can promptly detect the onset of DVT, facilitating additional life monitoring and necessary medical interventions to prevent the progression of DVT effectively.

Ezrin inhibition alleviates oxidative stress and pyroptosis via regulating TRPML1-calcineurin axis mediated enhancement of autophagy in spinal cord injury.

Spinal cord injury (SCI) presents profound ramifications for patients, leading to diminished motor and sensory capabilities distal to the lesion site. Once SCI occurs, it not only causes great physical and psychological problems for patients but also imposes a heavy economic burden. Ezrin is involved in various cellular processes, including signal transduction, cell death, inflammation, chemotherapy resistance and the stress response. However, whether Ezrin regulates functional repair after SCI and its underlying mechanism has not been elucidated. Here, our results showed that there is a marked augmentation of Ezrin levels within neurons and Ezrin inhibition markedly diminished glial scarring and bolstered functional recuperation after SCI. RNA sequencing indicated the potential involvement of pyroptosis, oxidative stress and autophagy in the enhancement of functional recovery upon reduced Ezrin expression. Moreover, the inhibition of Ezrin expression curtailed pyroptosis and oxidative stress by amplifying autophagy. Our studies further demonstrated that Ezrin inhibition promoted autophagy by increasing TFEB activity via the Akt-TRPML1-calcineurin pathway. Finally, we concluded that inhibiting Ezrin expression alleviates pyroptosis and oxidative stress by enhancing TFEB-driven autophagy, thereby promoting functional recovery after SCI, which may be a promising therapeutic target for SCI treatment.

Identification of autophagy-associated circRNAs in sepsis-induced cardiomyopathy of mice.

Circular RNAs (circRNAs) play a role in sepsis-related autophagy. However, the role of circRNAs in autophagy after sepsis-induced cardiomyopathy (SICM) is unknown, so we explored the circRNA expression profiles associated with autophagy in an acute sepsis mouse model. At a dose of 10 mg/kg, mice were intraperitoneally administered with lipopolysaccharides. The myocardial tissue was harvested after 6 h for microarray analysis, qRT-PCR, and western blotting. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were evaluated, and a competing endogenous RNA network was constructed, to evaluate the role of circRNAs related to autophagy in SICM. In total, 1,735 differently expressed circRNAs were identified in the LPS-treated group, including 990 upregulated and 745 downregulated circRNAs. The expression level of the autophagy-specific protein p62 decreased, while the ratio of LC3 II to LC3 I increased. Additionally, 309 mRNAs and 187 circRNAs were correlated with autophagy in myocardial tissue after SICM. Of these, 179 circRNAs were predicted to function as "miRNA sponges". Some distinctive circRNAs and mRNAs found by ceRNA analysis might be involved in autophagy in SICM. These findings provide insights into circRNAs and identified new research targets that may be used to further explore the pathogenesis of SICM.

New insights into the biological roles of immune cells in neural stem cells in post-traumatic injury of the central nervous system.

Traumatic injuries in the central nervous system, such as traumatic brain injury and spinal cord injury, are associated with tissue inflammation and the infiltration of immune cells, which simultaneously affect the self-renewal and differentiation of neural stem cells. However, the tissue repair process instigated by endogenous neural stem cells is incapable of restoring central nervous system injuries without external intervention. Recently, resident/peripheral immune cells have been demonstrated to exert significant effects on neural stem cells. Thus, the restoration of traumatic injuries in the central nervous system by the immune intervention in neural stem cells represents a potential therapeutic method. In this review, we discuss the roles and possible mechanisms of immune cells on the self-renewal and differentiation of neural stem cells along with the prognosis of central nervous system injuries based on immune intervention. Finally, we discuss remaining research challenges that need to be considered in the future. Further elucidation of these challenges will facilitate the successful application of neural stem cells in central nervous system injuries.

3D Bioprinting Using Synovium-Derived MSC-Laden Photo-Cross-Linked ECM Bioink for Cartilage Regeneration.

In this study, inspired by the components of cartilage matrix, a photo-cross-linked extracellular matrix (ECM) bioink composed of modified proteins and polysaccharides was presented, including gelatin methacrylate, hyaluronic acid methacrylate, and chondroitin sulfate methacrylate. The systematic experiments were performed, including morphology, swelling, degradation, mechanical and rheological tests, printability analysis, biocompatibility and chondrogenic differentiation characterization, and RNA sequencing (RNA-seq). The results indicated that the photo-cross-linked ECM hydrogels possessed suitable degradation rate and excellent mechanical properties, and the three-dimensional (3D) bioprinted ECM scaffolds obtained favorable shape fidelity and improved the basic properties, biological properties, and chondrogenesis of synovium-derived MSCs (SMSCs). The strong stimulation of transforming growth factor-beta 1 (TGF-ß1) enhanced the aggregation, proliferation, and differentiation of SMSCs, thereby enhancing chondrogenic ECM deposition. In vivo animal experiments and gait analysis further confirmed that the ECM scaffold combined with TGF-ß1 could effectively promote cartilage regeneration and functional recovery of injured joints. To sum up, the photo-cross-linked ECM bioink for 3D printing of functional cartilage tissue may become an attractive strategy for cartilage regeneration.

The status and trends of mitochondrial dynamics research: A global bibliometric and visualized analysis.

BACKGROUND: Mitochondria are remarkably dynamic organelles encapsulated by bilayer membranes. The dynamic properties of mitochondria are critical for energy production. AIMS: The aim of our study is to investigate the global status and trends of mitochondrial dynamics research and predict popular topics and directions in the field. METHODS: Publications related to the studies of mitochondrial dynamics from 2002 to 2021 were retrieved from Web of Science database. A total of 4,576 publications were included. Bibliometric analysis was conducted by visualization of similarities viewer and GraphPadPrism 5 software. RESULTS: There is an increasing trend of mitochondrial dynamics research during the last 20 years. The cumulative number of publications about mitochondrial dynamics research followed the logistic growth model [Formula: see text]. The USA made the highest contributions to the global research. The journal Biochimica et Biophysica Acta (BBA)-Molecular Cell Research had the largest publication numbers. Case Western Reserve University is the most contributive institution. The main research orientation and funding agency were cell biology and HHS. All keywords related studies could be divided into three clusters: "Related disease research", "Mechanism research" and "Cell metabolism research". CONCLUSIONS: Attention should be drawn to the latest popular research and more efforts will be put into mechanistic research, which may inspire new clinical treatments for the associated diseases.

Single-cell RNA sequencing analysis reveals the relationship of bone marrow and osteopenia in STZ-induced type 1 diabetic mice.

INTRODUCTION: Type 1 diabetes (T1D) is a multifactorial autoimmune disease. Broad knowledge about the genetics, epidemiology and clinical management of T1D has been achieved, but understandings about the cell varieties in the bone marrow during T1D remain limited. OBJECTIVES: We aimed to present a profile of the bone marrow cells and reveal the relationship of bone marrow and osteopenia in streptozotocin (STZ)-induced T1D mice. METHODS: The whole bone marrow cells from the femurs and tibias of healthy (group C) and STZ-induced T1D mice (group D) were collected for single-cell RNA sequencing analysis. Single-cell flow cytometry and immunohistochemistry were performed to confirm the proportional changes among bone marrow neutrophils (BM-neutrophils) (Cxcr2+, Ly6g+) and B lymphocytes (Cd19+). X-ray and micro-CT were performed to detect bone mineral density. The correlation between the ratio of BM-neutrophils/B lymphocytes and osteopenia in STZ-induced T1D mice was analyzed by nonparametric Spearman correlation analysis. RESULTS: The bone marrow cells in groups C and D were divided into 12 clusters, and 249 differentially expressed genes were found. The diversity of CD45+ immune cells between groups C and D were greatly affected: the proportion of BM-neutrophils showed a significant increase while the proportion of B lymphocytes in group D showed a significant decrease. X-ray and micro-CT analyses confirmed that osteopenia occurred in group D mice. In addition, the results of single-cell flow cytometry and correlation analysis showed that the ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice. CONCLUSION: A single-cell RNA sequencing analysis revealed the profile and heterogeneity of bone marrow immune cells in STZ-induced T1D mice for the first time. The ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice, which may enhance understanding for treating T1D and preventing T1D-induced osteopenia.

A simple method for restoring the femoral head center in hip arthroplasty: a 3-dimensional analysis in the Chinese population.

BACKGROUND: Various authors have successfully demonstrated that the distance from the greater trochanter to the femoral head center (GTFHC) and the distance from the lesser trochanter to the femoral head center (LTFHC) can be used as parameters to determine the recovery of the femoral head center (FHC) during hip arthroplasty. It is necessary to undertake an anatomical study concerning the correlations between the greater trochanter (GT), the lesser trochanter (LT), and the FHC using data obtained from the 3D-CT reconstruction method. METHODS: The study comprised 293 patients (151 males and 142 females), with an average age of 65.06 years. The femoral head diameter(FHD), the linear distance from FHC to GT (GTFHC), and the linear distance from FHC to LT(LTFHC) were all measured and recorded data. The correlation between FHD with LTFHC and GTFHC was assessed using Pearson correlation coefficients, and the ratio of LTFHC and GTFHC to FHD was calculated from this ratio. All measured parameters were compared between the left and right sides and the sexes of the participants. RESULTS: The average ratios of GTFHC/FHD and LTFHC/FHD were 0.99 and 0.95, respectively .96% of the LTFHC had absolute lateral differences of < 4 mm . 92% of the GTFHC had absolute lateral differences of < 4 mm. CONCLUSION: LTFHC and GTFHC are reliable reference parameters for preoperative planning and reconstruction of FHC of hip arthroplasty. The ratio displayed in this research may yield insight into a practical and straightforward method for orthopedic surgeons to perform hip arthroplasty in patients with femoral neck fractures. Ratios from studies based on the same race may be desirable for future work.

Comparison of Walking Quality Variables between End-Stage Osteonecrosis of Femoral Head Patients and Healthy Subjects by a Footscan Plantar Pressure System.

Background and Objectives: Osteonecrosis of the femoral head (ONFH) is a progressive disease with a complex etiology and unknown pathogenesis. Gait analysis can objectively assess the functional behavior of the foot, thus revealing essential aspects and influencing factors of gait abnormalities. The aim of this study was to evaluate the differences in spatiotemporal parameters, static and dynamic plantar pressure parameters, and symmetry indices between patients with ONFH and healthy subjects. Materials and Methods: The study population consisted of 31 ONFH patients and 31 healthy volunteers. Gait parameters were obtained from the plantar pressure analysis system for both the ONFH and healthy groups. The symmetry index was calculated according to a formula, including spatiotemporal parameters, static and dynamic plantar pressure distribution, percentage of regional impulse, and percentage of the restricted contact area. Results: Compared with healthy controls, patients with ONFH had slower walking speed, shorter step length and stride length, and increased stride time, stance time, and percentage of stance. patients with ONFH had lower plantar static pressure on the affected side and higher contralateral plantar static pressure during stance than controls. During walking, the peak pressures in all regions on the affected side and the peak pressure in the toe 1 and metatarsal 3 regions on the healthy side were lower in ONFH patients than in controls. The percentage of contact area and regional impulse in the heel of both limbs were higher in ONFH patients than in the control group. The symmetry indexes of stride time, stance time, step length, maximum force, impulse and contacted area were significantly increased in ONFH patients compared to controls, with decreased symmetry. Conclusions: Osteonecrosis of the femoral head leads to characteristic changes in plantar pressure distribution. These changes may be interpreted as an attempt by patients with ONFH to reduce the load on the affected limb. Plantar pressure analysis may assist in the diagnosis of ONFH and can provide an objective quantitative indicator for the assessment of subsequent treatment outcomes.

Biological roles and therapeutic potential of circular RNAs in osteoarthritis.

Osteoarthritis (OA) is a common and disabling joint disorder that is mainly characterized by cartilage degeneration and narrow joint spaces. The regulatory functions of non-coding RNAs (long non-coding RNAs, microRNAs [miRNAs], and circular RNAs [circRNAs]) in OA progression have attracted considerable attention, and the function of circular RNAs in the context of OA has been an increasingly popular research topic in the last 6 years. Recent studies have reported that various circRNAs can delay or aggravate diverse aspects of the OA process, including extracellular matrix formation, apoptosis, proliferation, inflammation, and autophagy, via circRNA/miRNA/mRNA pathways. Thus, circRNAs and related pathways are potential therapeutic targets for OA. Our review provides comprehensive information about circRNAs, including their biogenesis, functions, and characteristics, and it reveals their critical roles in the pathogenesis of OA via a large regulatory network of sponges. Considering their regulatory functions and characteristics, we hypothesize that circRNAs not only can be transferred through bodily fluids to serve as diagnostic biomarkers, but they can also be released from mesenchymal stem cell-derived exosomes and delivered to OA chondrocytes acting as therapeutic circRNAs. Further investigations of the in-depth molecular mechanisms of action of circRNAs in OA are expected to provide effective and safe OA treatment strategies.

miR-135a Reduces Osteosarcoma Pulmonary Metastasis by Targeting Both BMI1 and KLF4.

Because of the modest response rate after surgery and chemotherapy, treatment of osteosarcoma (OS) remains challenging due to tumor recurrence and metastasis. miR-135a has been reported to act as an anticarcinogenic regulator of several cancers. However, its expression and function in osteosarcoma remain largely unknown. Here, we reported that abridged miR-135a expression in OS cells and tissues, and its expression is inversely correlated with the expression of BMI1 and KLF4, which are described as oncogenes in several cancers. Ectopic expression of miR-135a inhibited cell invasion and expression of BMI1 and KLF4 in OS cells. In vivo investigation confirmed that miR-135a acts as a tumor suppressor in OS to inhibit tumor growth and lung metastasis in xenograft nude mice. BMI1 and KLF4 were revealed to be direct targets of miR-135a, and miR-135a had a similar effect as the combination of si-BMI1 and si-KLF4 on inhibiting tumor progression and the expression of BMI1 and KLF4 in vivo. Altogether, our results demonstrate that the targeting of BMI1/KLF4 with miR-135a may provide an applicable strategy for exploring novel therapeutic approaches for OS.

An accurate method for locating the joint line during revision total knee arthroplasty: A radiologic study in the Chinese population.

BACKGROUND: The systems for precisely locating the joint line during primary and revision total knee arthroplasty are still controversial, and they should be better evaluated in the Chinese population. METHODS: A total of 451 standard anteroposterior knee radiographs from 451 healthy Chinese people (283 males and 168 females, the average age of 33.26 years, range 20-50 years) were included to measure the femoral width (FW) and the distances from the adductor tubercle (AT), the medial epicondyle (ME), the lateral epicondyle (LE), and the fibular head (FH) to the joint line (JL). Correlation between FW and distances from landmarks to the joint line was evaluated using Pearson correlation coefficient, and the ratios of ATJL, MEJL, LEJL, FHJL to FW were calculated. RESULTS: The average distances from the AT, the ME, the LE, the FH to the JL were 49.4 ± 5.0 mm, 28.3 ± 3.1 mm, 26.9 ± 2.9 mm, 20.0 ± 4.0 mm, respectively. An excellent linear correlation was found between FW and the distance from AT to the joint line (R = 0.836, R2 = 0.698); it was more reliable than the LE (R = 0.686, R2 = 0.471) and the ME (R = 0.672, R2 = 0.452). The average ratios of ATJL/FW, MEJL/FW, LEJL/FW were 0.553, 0.317, and 0.302, respectively. There were significant differences between our results and the studies based on the Western people. CONCLUSION: The AT can be used as a reliable landmark to locate the JL precisely by the formula (ATJL = 0.548 × FW in males; ATJL = 0.562 × FW in females) in the Chinese population. The LE and ME can be the second choices. Moreover, it may be better to use ratios from the research based on the same race.

Mitochondria: Potential Targets for Osteoarthritis.

Osteoarthritis (OA) is a common and disabling joint disorder that is mainly characterized by cartilage degeneration and narrow joint spaces. The role of mitochondrial dysfunction in promoting the development of OA has gained much attention. Targeting endogenous molecules to improve mitochondrial function is a potential treatment for OA. Moreover, research on exogenous drugs to improve mitochondrial function in OA based on endogenous molecular targets has been accomplished. In addition, stem cells and exosomes have been deeply researched in the context of cartilage regeneration, and these factors both reverse mitochondrial dysfunctions. Thus, we hypothesize that biomedical approaches will be applied to the treatment of OA. Furthermore, we have summarized the global status of mitochondria and osteoarthritis research in the past two decades, which will contribute to the research field and the development of novel treatment strategies for OA.

The status and trends of coronavirus research: A global bibliometric and visualized analysis.

OBJECTIVES: The infectious pneumonia caused by the Coronavirus Disease 2019 (COVID-19) occurred in Wuhan, Hubei Province, China, from December 2019 and spread the whole country and even other 24 countries. Coronavirus research is of significance to overcome the epidemic. Our study aims to investigate the global status and trends of coronavirus research. METHOD: Publications related to the studies of coronavirus research from January 1, 2003 to February 6, 2020 were retrieved from the Science Citation Index-Expanded (SCI-E) of the Web of Science database. A total of 9294 publications were included. The data source was studied and indexed by bibliometric methodology. For visualized study, bibliographic coupling analysis, co-authorship analysis, co-citation analysis, co-occurrence analysis and the analysis of publication trends in coronavirus research were conducted by VOS (visualization of similarities) viewer and GraphPadPrism 6 software. RESULTS: The number of publications about coronavirus research increased sharply in 2004 for SARS outbreak and increased again in 2012 for MERS outbreak. The USA made the highest contributions to the global research with the most total number of publications, total citation frequency, and the highest H-index, while Netherlands had the highest average citation per item. Journal of Virology had the largest publication numbers. The University of Hong Kong is the most contributive institution with the most publications. The main research orientation and funding agency were virology and United States Department of Health Human Services. Keywords of all related studies could be divided into 4 clusters: "Pathological research," "Epidemiology research," "Clinical research," and "Mechanism research." CONCLUSIONS: The outbreak of the epidemic could promote coronavirus research, meanwhile, coronavirus research contributes to overcoming the epidemic. Attention should be drawn to the latest popular research, including "Spike protein," "Receptor binding domain," and "Vaccine." Therefore, more and more efforts will be put into mechanism research and vaccine research and development, which can be helpful to deal with the epidemic.

A global bibliometric and visualized analysis in the status and trends of subchondral bone research.

BACKGROUND: Structural and functional changes in subchondral bone have been recognized as a key factor in the development of related disease, and subchondral bone may be a new target for the treatment of osteoarthritis. The purpose of our present study is to investigate the global status and trends of subchondral bone research. METHOD: Publications related to the studies of subchondral bone from 1993 to 2018 were retrieved from the Science Citation Index-Expanded Web of Science database. The data source was studied and indexed by using bibliometric methodology. For visualized study, bibliographic coupling analysis, co-authorship analysis, co-citation analysis, co-occurrence analysis and the analysis of publication trends in subchondral bone research were conducted by VOS viewer and GraphPadPrism 5 software. RESULTS: A total of 4780 publications were included. There is an increasing trend of the relative research interests and number of publications per year globally. The cumulative number of publications about subchondral bone research followed the logistic growth model (Equation is included in full-text article.). The USA made the highest contributions to the global research with the most citations, the highest H-index, and the most total link strength, while Denmark had the highest average citation per item. The journal Osteoarthritis and Cartilage had the largest publication number. Boston University is the most contributive institution. Studies could be divided into 4 clusters: "Mechanism research", "Animal study", "Clinical study" and "Pathological features". Less efforts were put into clinical study. CONCLUSION: The number of publications about subchondral bone research would be increasing in the next years based on the current global trends. Attention should be drawn to the latest popular research, including "Mesenchymal stem-cells", "Autologous chondrocyte implantation", "Microfracture" and "Pain". Therefore, more and more efforts will be put into mechanism research on subchondral bone, which may inspire new clinical treatments for osteoarthritis and other related diseases based on subchondral bone.