HIF2A mediates lineage transition to aggressive phenotype of cancer-associated fibroblasts in lung cancer brain metastasis.

Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets.

The clinical efficacy of Medial Sustain Nail(MSN) and Proximal femoral nail anti-rotation(PFNA) for fixation of medial comminuted trochanteric fractures: a prospective randomized controlled trial.

PURPOS: To evaluate the clinical efficacy of the Medial Sustain Nail (MSN) for medial comminuted trochanteric fractures fixation in comparison to Proximal Femoral Nail Antirotation (PFNA) through a clinical study. METHODS: A non-inferiority randomized controlled trial was conducted at a single centre between July 2019 and July 2020. Fifty patients diagnosed comminuted trochanteric fractures were randomly assigned to either the MSN group (n = 25) or the PFNA group (n = 25). A total of forty-three patients were included in the final study analysis. The primary outcome measure was Short Form 36 health surgery physical component summary (SF-36 PCS) score. Secondary outcomes included the Oxford Hip Scores (OHS), weight bearing, complication relate to implant and so on. This study was not blined to surgeons, but to patients and data analysts. RESULTS: The MSN demonstrated significantly better functional outcomes as measured by SF-36 PCS and OHS at six months postoperative compared to PFNA (p < 0.05). Union of fractures in the MSN group reached 90.9% at three months after surgery, whereas the PFNA group achieved a union rate of 57.1% (p < 0.05). Furthermore, weight-bearing time of MSN group was earlier than PFNA group (p < 0.05). Additionally, complications related to implant usage were more prevalent in the PFNA group (33.3%) compared to the MSN group (4.5%) (p < 0.05). CONCLUSION: MSN exhibited superior quality of life outcomes compared to PFNA at six months postoperative. This indicates that MSN effectively reconstructs medial femoral support in patients with comminuted trochanteric fractures, which facilitates early weight-bearing and accelerates the recovery process. TRIAL REGISTRATION: Trial registration number: NCT01437176, Date of the trial registration:2011-9-1, Date of commencement of the study:2011-9, Date of enrolment/recruitment of the study subjects:2019-7.

Establishment and validation of an artificial intelligence web application for predicting postoperative in-hospital mortality in patients with hip fracture: a National cohort study of 52,707 cases.

BACKGROUND: In-hospital mortality following hip fractures is a significant concern, and accurate prediction of this outcome is crucial for appropriate clinical management. Nonetheless, there is a lack of effective prediction tools in clinical practice. By utilizing artificial intelligence and machine learning techniques, this study aims to develop a predictive model that can assist clinicians in identifying geriatric hip fracture patients at a higher risk of in-hospital mortality. METHODS: A total of 52,707 geriatric hip fracture patients treated with surgery from 90 hospitals were included in this study. The primary outcome was postoperative in-hospital mortality. The patients were randomly divided into two groups, with a ratio of 7:3. The majority of patients, assigned to the training cohort, were used to develop the AI models. The remaining patients, assigned to the validation cohort, were used to validate the models. Various machine learning algorithms, including logistic regression (LR), decision tree (DT), naïve Bayesian (NB), neural network (NN), eXGBoosting machine (eXGBM), and random forest (RF), were employed for model development. A comprehensive scoring system, incorporating 10 evaluation metrics, was developed to assess the prediction performance, with higher scores indicating superior predictive capability. Based on the best machine learning-based model, an AI application was developed on the Internet. In addition, a comparative testing of prediction performance between doctors and the AI application. FINDINGS: The eXGBM model exhibited the best prediction performance, with an AUC of 0.908 (95% CI: 0.881-0.932), as well as the highest accuracy (0.820), precision (0.817), specificity (0.814), and F1 score (0.822), and the lowest Brier score (0.120) and log loss (0.374). Additionally, the model showed favorable calibration, with a slope of 0.999 and an intercept of 0.028. According to the scoring system incorporating 10 evaluation metrics, the eXGBM model achieved the highest score (56), followed by the RF model (48) and NN model (41). The LR, DT, and NB models had total scores of 27, 30, and 13, respectively. The AI application has been deployed online at https://in-hospitaldeathinhipfracture-l9vhqo3l55fy8dkdvuskvu.streamlit.app/ , based on the eXGBM model. The comparative testing revealed that the AI application's predictive capabilities significantly outperformed those of the doctors in terms of AUC values (0.908 vs. 0.682, P <0.001). CONCLUSIONS: The eXGBM model demonstrates promising predictive performance in assessing the risk of postoperative in-hospital mortality among geriatric hip fracture patients. The developed AI model serves as a valuable tool to enhance clinical decision-making.

Novel biomimetic macromolecules system for highly efficient lubrication, ROS scavenging and osteoarthritis treatment.

The early stages of osteoarthritis (OA) in the joints are typically characterized by two key factors: the dysfunction of articular cartilage lubrication and inflammation resulting from the excessive production of reactive oxygen species (ROS). Synthetic injectable macromolecular materials present great potential for preventing the progression of early OA. In this study, to mimic the excellent lubricity of brush-like aggregates found in natural synovial fluid, we develop a novel macromolecular biolubricant (CS-PS-DA) by integrating adhesion and hydration groups onto backbone of natural biomacromolecules. CS-PS-DA exhibits a strong affinity for cartilage surfaces, enabling the formation of a stable lubrication layer at the sliding interface of degraded cartilages to restore joint lubrication performance. In vitro results from ROS scavenging and anti-inflammatory experiments indicate the great advantage of CS-PS-DA to decrease the levels of proinflammatory cytokines by inhibiting ROS overproduction. Finally, in vivo rats OA model demonstrates that intra-cavitary injection of CS-PS-DA could effectively resist cartilage wear and mitigated inflammation in the joints. This novel biolubricant provides a new and timely strategy for the treatment of OA.

Inhibiting the "isolated island" effect in simulated bone defect repair using a hollow structural scaffold design.

The treatment of bone tissue defects remains a complicated clinical challenge. Recently, the bone tissue engineering (BTE) technology has become an important therapeutic approach for bone defect repair. Researchers have improved the scaffolds, cells, and bioactive factors used in BTE through various existing bone repair material preparation strategies. However, due to insufficient vascularization, inadequate degradation, and fibrous wrapping, most BTE scaffolds impede new bone ingrowth and the reconstruction of grid-like connections in the middle and late stages of bone repair. These non-degradable scaffolds become isolated and disordered like independent "isolated islands", which leads to the failure of osteogenesis. Consequently, we hypothesized that the "island effect" prevents successful bone repair. Accordingly, we proposed a new concept of scaffold modification-osteogenesis requires a bone temporary shelter (also referred to as the empty shell osteogenesis concept). Based on this concept, we consider that designing hollow structural scaffolds is the key to mitigating the "isolated island" effect and enabling optimal bone regeneration and reconstruction.

Evolution of Musculoskeletal Electronics.

The musculoskeletal system, constituting the largest human physiological system, plays a critical role in providing structural support to the body, facilitating intricate movements, and safeguarding internal organs. By virtue of advancements in revolutionized materials and devices, particularly in the realms of motion capture, health monitoring, and postoperative rehabilitation, "musculoskeletal electronics" has actually emerged as an infancy area, but has not yet been explicitly proposed. In this review, the concept of musculoskeletal electronics is elucidated, and the evolution history, representative progress, and key strategies of the involved materials and state-of-the-art devices are summarized. Therefore, the fundamentals of musculoskeletal electronics and key functionality categories are introduced. Subsequently, recent advances in musculoskeletal electronics are presented from the perspectives of "in vitro" to "in vivo" signal detection, interactive modulation, and therapeutic interventions for healing and recovery. Additionally, nine strategy avenues for the development of advanced musculoskeletal electronic materials and devices are proposed. Finally, concise summaries and perspectives are proposed to highlight the directions that deserve focused attention in this booming field.

Three-Dimensional-Printed Spherical Hollow Structural Scaffolds for Guiding Critical-Sized Bone Regeneration.

The treatment of bone tissue defects continues to be a complex medical issue. Recently, three-dimensional (3D)-printed scaffold technology for bone tissue engineering (BTE) has emerged as an important therapeutic approach for bone defect repair. Despite the potential of BTE scaffolds to contribute to long-term bone reconstruction, there are certain challenges associated with it including the impediment of bone growth within the scaffolds and vascular infiltration. These difficulties can be resolved by using scaffold structural modification strategies that can effectively guide bone regeneration. This study involved the preparation of biphasic calcium phosphate spherical hollow structural scaffolds (SHSS) with varying pore sizes using 3D printing (photopolymerized via digital light processing). The chemical compositions, microscopic morphologies, mechanical properties, biocompatibilities, osteogenic properties, and impact on repairing critical-sized bone defects of SHSS were assessed through characterization analyses, in vitro cytological assays, and in vivo biological experiments. The results revealed the biomimetic properties of SHSS and their favorable biocompatibility. The scaffolds stimulated cell adhesion, proliferation, differentiation, and migration and facilitated the expression of osteogenic genes and proteins, including Col-1, OCN, and OPN. Furthermore, they could effectively repair a critical-sized bone defect in a rabbit femoral condyle by establishing an osteogenic platform and guiding bone regeneration in the defect region. This innovative strategy presents a novel therapeutic approach for assessing critical-sized bone defects.

CHRONIC CRITICAL ILLNESS-INDUCED MUSCLE ATROPHY: INSIGHTS FROM A TRAUMA MOUSE MODEL AND POTENTIAL MECHANISM MEDIATED VIA SERUM AMYLOID A.

ABSTRACT: Background: Chronic critical illness (CCI), which was characterized by persistent inflammation, immunosuppression, and catabolism syndrome (PICS), often leads to muscle atrophy. Serum amyloid A (SAA), a protein upregulated in critical illness myopathy, may play a crucial role in these processes. However, the effects of SAA on muscle atrophy in PICS require further investigation. This study aims to develop a mouse model of PICS combined with bone trauma to investigate the mechanisms underlying muscle weakness, with a focus on SAA. Methods: Mice were used to examine the effects of PICS after bone trauma on immune response, muscle atrophy, and bone healing. The mice were divided into two groups: a bone trauma group and a bone trauma with cecal ligation and puncture group. Tibia fracture surgery was performed on all mice, and PICS was induced through cecal ligation and puncture surgery in the PICS group. Various assessments were conducted, including weight change analysis, cytokine analysis, hematological analysis, grip strength analysis, histochemical staining, and immunofluorescence staining for SAA. In vitro experiments using C2C12 cells (myoblasts) were also conducted to investigate the role of SAA in muscle atrophy. The effects of inhibiting receptor for advanced glycation endproducts (RAGE) or JAK2 on SAA-induced muscle atrophy were examined. Bioinformatic analysis was conducted using a dataset from the GEO database to identify differentially expressed genes and construct a coexpression network. Results: Bioinformatic analysis confirmed that SAA was significantly upregulated in muscle tissue of patients with intensive care unit-induced muscle atrophy. The PICS animal models exhibited significant weight loss, spleen enlargement, elevated levels of proinflammatory cytokines, and altered hematological profiles. Evaluation of muscle atrophy in the animal models demonstrated decreased muscle mass, grip strength loss, decreased diameter of muscle fibers, and significantly increased expression of SAA. In vitro experiment demonstrated that SAA decreased myotube formation, reduced myotube diameter, and increased the expression of muscle atrophy-related genes. Furthermore, SAA expression was associated with activation of the FOXO signaling pathway, and inhibition of RAGE or JAK2/STAT3-FOXO signaling partially reversed SAA-induced muscle atrophy. Conclusions: This study successfully develops a mouse model that mimics PICS in CCI patients with bone trauma. Serum amyloid A plays a crucial role in muscle atrophy through the JAK2/STAT3-FOXO signaling pathway, and targeting RAGE or JAK2 may hold therapeutic potential in mitigating SAA-induced muscle atrophy.

Extracellular vesicles produced by 3D cultured MSCs promote wound healing by regulating macrophage activation through ANXA1.

The conundrum of wound healing has transformed into an imminent medical challenge. Presently, cell-free therapy centered around extracellular vesicles (EVs) has become a pivotal and promising research avenue. EVs generated from three-dimensional (3D) cell cultures have been previously established to possess enhanced tissue regeneration potential, although the underlying mechanisms remain elusive. In this study, we observed higher expression of annexin ANXA1 in 3D-cultured EVs. Remarkably, 3D-EVs with elevated ANXA1 expression demonstrated a more potent capacity to promote macrophage polarization from the M1 phenotype to the M2 phenotype. Concurrently, they exhibited superior abilities to enhance cell migration and tube formation, facilitating expedited wound healing in animal experiments. Conversely, the application of an ANXA1 inhibitor counteracted the positive effects of 3D-EVs. Taken together, our data validate that extracellular vesicles derived from 3D-cultured MSCs regulate macrophage polarization via ANXA1, thereby fostering wound healing.

Biomechanical Research of Three Parallel Cannulated Compression Screws in Oblique Triangle Configuration for Fixation of Femoral Neck Unstable Fractures.

OBJECTIVE: Surgical treatment with internal fixation, specifically percutaneous fixation with three cannulated compression screws (CCSs), is the preferred choice for young and middle-aged patients. The mechanical advantage of the optimal spatial configuration with three screws provides maximum dispersion and cortical support. We suspect that the spatial proportion of the oblique triangle configuration (OTC) in the cross-section of the femoral neck isthmus (FNI) may significantly improve shear and fatigue resistance of the fixed structure, thereby stabilizing the internal fixation system in femoral neck fracture (FNF). This study aims to explore the mechanical features of OTC and provide a mechanical basis for its clinical application. METHODS: Twenty Sawbone femurs were prepared as Pauwels type III FNF models and divided equally into two fixation groups: OTC and inverted equilateral triangle configuration (IETC). Three 7.3 mm diameter cannulated compression screws (CCSs) were used for fixation. The specimens of FNF after screw internal fixation were subjected to static loading and cyclic loading tests, respectively, with five specimens for each test. Axial stiffness, 5 mm failure load, ultimate load, shear displacement, and frontal rotational angle of two fragments were evaluated. In the cyclic loading test, the load sizes were 700 N, 1400 N, and 2100 N, respectively, and the fracture end displacement was recorded. Results were presented as means ± SD. Data with normal distributions were compared by the Student's t test. RESULTS: In the static loading test, the axial stiffness, ultimate load, shear displacement, and frontal rotational angle of two fragments were (738.64 vs. 620.74) N/mm, (2957.61 vs. 2643.06) N, (4.67 vs. 5.39) mm, and (4.01 vs. 5.52)° (p < 0.05), respectively. Comparison between the femoral head displacement after 10,000 cycles of 700N cyclic loading and total displacement after 20,000 cycles of 700-1400N cyclic loading showed the OTC group was less than the IETC group (p < 0.05). A comparison of femoral head displacement after 10,000 cycles of 1400N and 2100N cycles and total displacement after 30,000 cycles of 700-2100N cycles showed the OTC group was less than another group, but the difference was not significant (p > 0.05). CONCLUSION: When three CCSs are inserted in parallel to fix FNF, the OTC of three screws has obvious biomechanical advantages, especially in shear resistance and early postoperative weight-bearing, which provides a mechanical basis for clinical selection of ideal spatial configuration for unstable FNF.

Head-to-head comparison of [68Ga]Ga-FAPI PET and [18F]FDG PET in the detection of bone and lymph node metastasis in various cancers: A systematic review and meta-analysis.

PURPOSE: The aim of our meta-analysis and systematic review was to contrast the positivity rates of [68Ga]Ga-FAPI PET and [18F]FDG PET in detecting bone and lymph node metastases across diverse cancer types. METHODS: We conducted a comprehensive search for eligible articles up until August 2023, utilizing databases including PubMed, Embase, and Web of Science. Studies focusing on the positivity rate of [68Ga]Ga-FAPI PET vs. [18F]FDG PET for bone and lymph metastasis were included. Using random-effect model, the positivity rate for [68Ga]Ga-FAPI PET and [18F]FDG PET were generated. In order to gauge the heterogeneity among aggregated studies, we utilized the I2 statistic. Additionally, we applied the Quality Assessment of Diagnostic Performance Studies (QUADAS-2) methodology to evaluate the caliber of the studies encompassed in our analysis. RESULTS: A total of 430 publications were initially identified in the search. Eventually, 25 studies, involving 779 patients, met the inclusion criteria. In terms of bone metastasis, the findings indicate no statistically significant difference between the use of [68Ga]Ga-FAPI PET and [18F]FDG PET (P = 0.34). However, concerning lymph node metastasis, the results demonstrate significant difference between the two imaging agents (P = 0.04). CONCLUSIONS: This systematic review suggests that [68Ga]Ga-FAPI PET appears to outperform [18F]FDG PET in detecting lymph node metastases. However, when it comes to bone metastasis, no statistically significant difference was observed. It is crucial to acknowledge that the insights concerning bone metastasis stem from studies with comparatively modest sample sizes. Consequently, there is a pressing demand for further, expansive prospective studies in this field.

Deciphering Immune Landscape Remodeling Unravels the Underlying Mechanism for Synchronized Muscle and Bone Aging.

Evidence from numerous studies has revealed the synchronous progression of aging in bone and muscle; however, little is known about the underlying mechanisms. To this end, human muscles and bones are harvested and the aging-associated transcriptional dynamics of two tissues in parallel using single-cell RNA sequencing are surveyed. A subset of lipid-associated macrophages (triggering receptor expressed on myeloid cells 2, TREM2+ Macs) is identified in both aged muscle and bone. Genes responsible for muscle dystrophy and bone loss, such as secreted phosphoprotein 1 (SPP1), are also highly expressed in TREM2+ Macs, suggesting its conserved role in aging-related features. A common transition toward pro-inflammatory phenotypes in aged CD4+ T cells across tissues is also observed, activated by the nuclear factor kappa B subunit 1 (NFKB1). CD4+ T cells in aged muscle experience Th1-like differentiation, whereas, in bone, a skewing toward Th17 cells is observed. Furthermore, these results highlight that degenerated myocytes produce BAG6-containing exosomes that can communicate with Th17 cells in the bone through its receptor natural cytotoxicity triggering receptor 3 (NCR3). This communication upregulates CD6 expression in Th17 cells, which then interact with TREM2+ Macs through CD6-ALCAM signaling, ultimately stimulating the transcription of SPP1 in TREM2+ Macs. The negative correlation between serum exosomal BCL2-associated athanogene 6 (BAG6) levels and bone mineral density further supports its role in mediating muscle and bone synchronization with aging.

ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3.

BACKGROUND: Activating signal cointegrator 3 (ASCC3) has been identified as an oncogenic factor that impairs host immune defense. However, the underlying mechanisms of carcinogenesis and its impact on the antitumor immune response remain unclear. In this study, we aimed to investigate the molecular mechanisms of ASCC3 in the progression of non-small cell lung cancer (NSCLC). METHODS: Single-cell sequencing data from the Gene Expression Omnibus and gene expression profiles from The Cancer Genome Atlas database were analyzed. The expression, clinical relevance and biological functions of ASCC3 in NSCLC were explored. Then, RNA sequencing, immunoprecipitation, mass spectrometry, immunofluorescence, and flow cytometry analyses were conducted to explore the underlying molecular mechanisms. In addition, in vivo experiments in mouse models were conducted to explore the probability of ASCC3 knockdown to improve the efficacy of anti-Programmed Death-1 (PD-1) therapy in NSCLC. RESULTS: ASCC3 was significantly upregulated in NSCLC and correlated with poor pathological characteristics and prognosis in patients with NSCLC. Overexpression of ASCC3 promoted malignant phenotypes of NSCLC cells and induced an immunosuppressive tumor microenvironment, which was characterized by a decrease in CD8+ T cells, natural killer cells and dendritic cells but an increase in regulatory T(Treg) cells. Mechanistically, ASCC3 stabilized signal transducer and activator of transcription (STAT)3 signaling by recruiting Cullin-associated and neddylation dissociated 1 (CAND1), which inhibited ubiquitin-mediated degradation of STAT3, thereby impairing the type I interferon response of tumor cells and promoting the immunosuppression and progression of NSCLC. Furthermore, high expression of ASCC3 impaired the efficacy of anti-PD-1 therapy, and an anti-PD-1 antibody combined with ASCC3 knockdown exerted promising synergistic efficacy in a preclinical mouse model. CONCLUSION: ASCC3 could stabilize the STAT3 pathway via CAND1, reshaping the tumor microenvironment and inducing resistance to anti-PD-1 therapy, which promotes the progression of NSCLC. It is a reliable prognostic indicator and can be a target in combination therapy for NSCLC.

Effect of denosumab on glucose metabolism in postmenopausal osteoporotic women with prediabetes: a study protocol for a 12-month multicenter, open-label, randomized controlled trial.

BACKGROUND: Participants with prediabetes are at a high risk of developing type 2 diabetes (T2D). Recent studies have suggested that blocking the receptor activator of nuclear factor-κB ligand (RANKL) may improve glucose metabolism and delay the development of T2D. However, the effect of denosumab, a fully human monoclonal antibody that inhibits RANKL, on glycemic parameters in the prediabetes population is uncertain. We aim to examine the effect of denosumab on glucose metabolism in postmenopausal women with osteoporosis and prediabetes. METHODS: This is a 12-month multicenter, open-label, randomized controlled trial involving postmenopausal women who have been diagnosed with both osteoporosis and prediabetes. Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density T score of ≤ - 2.5, as measured by dual-energy X-ray absorptiometry (DXA). Prediabetes is defined as (i) a fasting plasma glucose level of 100-125 mg/dL, (ii) a 2-hour plasma glucose level of 140-199 mg/dL, or (iii) a glycosylated hemoglobin A1c (HbA1c) level of 5.7-6.4%. A total of 346 eligible subjects will be randomly assigned in a 1:1 ratio to receive either subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg every week for 12 months. The primary outcome is the change in HbA1c levels from baseline to 12 months. Secondary outcomes include changes in fasting and 2-hour blood glucose levels, serum insulin levels, C-peptide levels, and insulin sensitivity from baseline to 12 months, and the incidence of T2D at the end of the study. Follow-up visits will be scheduled at 3, 6, 9, and 12 months. DISCUSSION: This study aims to provide evidence on the efficacy of denosumab on glucose metabolism in postmenopausal women with osteoporosis and prediabetes. The results derived from this clinical trial may provide insight into the potential of denosumab in preventing T2D in high-risk populations. TRIAL REGISTRATION: This study had been registered in the Chinese Clinical Trials Registry. REGISTRATION NUMBER: ChiCTR2300070789 on April 23, 2023. https://www.chictr.org.cn .

Comparison between Novel Anatomical Locking Guide Plate and Conventional Locking Plate for Acetabular Fractures: A Finite Element Analysis.

The treatment of complex acetabular fractures remains a complicated clinical challenge. Our self-designed novel anatomical locking guide plate (NALGP) has previously shown promising potential in T-shaped acetabular fractures (TAF), but a direct comparison with conventional fixations is yet to be made. The TAF model was established based on a volunteer's computer tomography data and then fixed with double column locking plates (DLP), a posterior column locking plate with anterior column screws (LPACS), and our NALGP. Forces of 200 N, 400 N, and 600 N were then loaded on the model vertically downward, respectively. The stress distribution and peaks and maximum displacements at three sites were assessed. We found that the stress area of all three plates was mainly concentrated around the fracture line, while only the matching screws of the NALGP showed no obvious stress concentration points. In addition, the NALGP and DLP showed significantly less fracture fragment displacement than the LPACS at the three main fracture sites. The NALGP was found to have less displacement than DLP at the posterior column and ischiopubic branch sites, especially under the higher loading forces of 400 N and 600 N. The fixation stability of the NALGP for TAF was similar to that of DLP but better than that of LPACS. Moreover, the NALGP and its matching screws have a more reasonable stress distribution under different loads of force and the same strength as the LPACS.

Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning.

MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration. However, whether myofibers-expressed MyoD exerts its metabolic function in regulating whole body energy homeostasis in vivo remains largely unknown. Here, we report that genetic deletion of Myod in male mice enhances the oxidative metabolism of muscle and, intriguingly, renders the male mice resistant to high fat diet-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identify 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in male Myod KO mice. Functionally, the administration of DLPC significantly ameliorates HFD-induced obesity in male mice. Mechanistically, DLPC is found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in male mice. Collectively, our findings not only uncover a novel function of MyoD in controlling systemic energy homeostasis through the muscle-derived lipokine DLPC but also suggest that the DLPC might have clinical potential for treating obesity in humans.

Replenishing decoy extracellular vesicles inhibits phenotype remodeling of tissue-resident cells in inflammation-driven arthritis.

The interleukin 6 (IL6) signaling pathway plays pleiotropic roles in regulating the inflammatory milieu that contributes to arthritis development. Here, we show that activation of IL6 trans-signaling induces phenotypic transitions in tissue-resident cells toward an inflammatory state. The establishment of arthritis increases the serum number of extracellular vesicles (EVs), while these EVs express more IL6 signal transducer (IL6ST, also known as gp130) on their surface. Transferring these EVs can block IL6 trans-signaling in vitro by acting as decoys that trap hyper IL6 and prevent inflammatory amplification in recipient arthritic mice. By genetically fusing EV-sorting domains with extracellular domains of receptors, we engineered EVs that harbor a higher quantity of signaling-incompetent decoy receptors. These exogenous decoy EVs exhibit significant potential in eliciting efficient anti-inflammatory effects in vivo. Our findings suggest an inherent resistance of decoy EVs against inflammation, highlighting the therapeutic potential of efficient decoy EVs in treating inflammatory diseases.

The dual role of microglia in neuropathic pain after spinal cord injury: Detrimental and protective effects.

Spinal cord injury (SCI) is a debilitating condition that is frequently accompanied by neuropathic pain, resulting in significant physical and psychological harm to a vast number of individuals globally. Despite the high prevalence of neuropathic pain following SCI, the precise underlying mechanism remains incompletely understood. Microglia are a type of innate immune cell that are present in the central nervous system (CNS). They have been observed to have a significant impact on neuropathic pain following SCI. This article presents a comprehensive overview of recent advances in understanding the role of microglia in the development of neuropathic pain following SCI. Specifically, the article delves into the detrimental and protective effects of microglia on neuropathic pain following SCI, as well as the mechanisms underlying their interconversion. Furthermore, the article provides a thorough overview of potential avenues for future research in this area.

Identification and characterization of BES1 genes involved in grain size development of Oryza sativa L.

BES1 (BRI1-EMS-SUPPRESSOR1) defines a unique class of plant-specific transcription factors that plays an essential role in response to Brassinosteroids (BRs) signal induction pathways. In our study, we conducted genome-wide scanning and comprehensive characterization of the BES1 gene family in rice and other eukaryotes, leading to valuable findings. Molecular docking experiments showed that all OsBES1 genes in rice could directly bind to BR small molecules. Among the identified genes, OsBES1-4 exhibited a remarkable response as it consistently showed induction upon exposure to various phytohormones after treatment. Further functional verification of OsBES1-4 revealed its impact on grain size. Overexpression of OsBES1-4 resulted in increased grain size, as confirmed by cytological observations showing an increase in cell length and cell number. Moreover, we identified that OsBES1-4 plays a role in rice grain size development by binding to the BR response element in the promoter region of the OsBZR1 gene. Evolutionary analysis indicated differentiation of OsBES1-4 between indica and japonica rice varieties, suggesting natural selection during the domestication process of cultivated rice. Therefore, we conclude that OsBES1-4 plays a crucial role in regulating rice grain size and has the potential to be an important target in rice breeding programs, and haplotype analysis found that all OsBES1 genes were associated with grain size development, either thousand-grain weight, grain length, or grain width. Overall, these findings suggest that the BES1 genes are involved in the regulation of grain size development in rice, and the utilization of SNPs in the OsBES1-4 gene promoter could be a favorable option for distinguishing indica and japonica.