F11R RNA trinucleotide over-edited by ADAR in gastric and colorectal cancers: Cross-cohort validation, gene expression regulation, and diagnostic significance.

The F11 receptor (F11R) gene encoding junctional adhesion molecule A has been associated with gastric cancer (GC) and colorectal cancer (CRC), in which its role and regulation remain to be further elucidated. Recently F11R was also identified as a potential target of adenosine-to-inosine (A-to-I) mediated by the adenosine deaminases acting on RNA (ADARs). Herein, using RNA-Seq and experimental validation, our current study revealed an F11R RNA trinucleotide over-edited by ADAR, with its regulation of gene expression and clinical significance in four GC and three CRC cohorts. Our results found an over-edited AAA trinucleotide in an AluSg located in the F11R 3'-untranslated region (3'-UTR), which showed editing levels correlated with elevated ADAR expression across all GC and CRC cohorts in our study. Overexpression and knockdown of ADAR in GC and CRC cells, followed by RNA-Seq and Sanger sequencing, confirmed the ADAR-mediated F11R 3'-UTR trinucleotide editing, which potentially disrupted an RBM45 binding site identified by crosslinking immunoprecipitation sequencing (CLIP-seq) and regulated F11R expression in luciferase reporter assays. Moreover, the F11R trinucleotide editing showed promising predictive performance for diagnosing GC and CRC across GC and CRC cohorts. Our findings thus highlight both the potential biological and clinical significance of an ADAR-edited F11R trinucleotide in GC and CRC, providing new insights into its application as a novel diagnostic biomarker for both cancers.

Modeling defensive resource allocation in multilayered systems under probabilistic and strategic risks.

Confronting the continuing risk of an attack, security systems have adopted target-hardening strategies through the allocation of security measures. Most previous work on defensive resource allocation considers the security system as a monolithic architecture. However, systems such as schools are typically characterized by multiple layers, where each layer is interconnected to help prevent single points of failure. In this paper, we study the defensive resource allocation problem in a multilayered system. We develop two new resource allocation models accounting for probabilistic and strategic risks, and provide analytical solutions and illustrative examples. We use real data for school shootings to illustrate the performance of the models, where the optimal investment strategies and sensitivity analysis are presented. We show that the defender would invest more in defending outer layers over inner layers in the face of probabilistic risks. While countering strategic risks, the defender would split resources in each layer to make the attacker feel indifferent between any individual layer. This paper provides new insights on resource allocation in layered systems to better enhance the overall security of the system.

Automatic detection of the third molar and mandibular canal on panoramic radiographs based on deep learning.

PURPOSE: This study aims to develop a deep learning framework for the automatic detection of the position relationship between the mandibular third molar (M3) and the mandibular canal (MC) on panoramic radiographs (PRs), to assist doctors in assessing and planning appropriate surgical interventions. METHODS: Datasets D1 and D2 were obtained by collecting 253 PRs from a hospitals and 197 PRs from online platforms. The RPIFormer model proposed in this study was trained and validated on D1 to create a segmentation model. The CycleGAN model was trained and validated on both D1 and D2 to develop an image enhancement model. Ultimately, the segmentation and enhancement models were integrated with an object detection model to create a fully automated framework for M3 and MC detection in PRs. Experimental evaluation included calculating Dice coefficient, IoU, Recall, and Precision during the process. RESULTS: The RPIFormer model proposed in this study achieved an average Dice coefficient of 92.56 % for segmenting M3 and MC, representing a 3.06 % improvement over the previous best study. The deep learning framework developed in this research enables automatic detection of M3 and MC in PRs without manual cropping, demonstrating superior detection accuracy and generalization capability. CONCLUSION: The framework developed in this study can be applied to PRs captured in different hospitals without the need for model fine-tuning. This feature is significant for aiding doctors in accurately assessing the spatial relationship between M3 and MC, thereby determining the optimal treatment plan to ensure patients' oral health and surgical safety.

Clinical characteristics and outcomes associated with culture-negative status in limb osteomyelitis patients.

Aims: This study aimed to investigate the clinical characteristics and outcomes associated with culture-negative limb osteomyelitis patients. Methods: A total of 1,047 limb osteomyelitis patients aged 18 years or older who underwent debridement and intraoperative culture at our clinic centre from 1 January 2011 to 31 December 2020 were included. Patient characteristics, infection eradication, and complications were analyzed between culture-negative and culture-positive cohorts. Results: Of these patients, 264 (25.2%) had negative cultures. Patients with a culture-negative compared with a culture-positive status were more likely to have the following characteristics: younger age (≤ 40 years) (113/264 (42.8%) vs 257/783 (32.8%); p = 0.004), a haematogenous aetiology (75/264 (28.4%) vs 150/783 (19.2%); p = 0.002), Cierny-Mader host A (79/264 (29.9%) vs 142/783 (18.1%); p < 0.001), antibiotic use before sampling (34/264 (12.9%) vs 41/783 (5.2%); p＜0.001), fewer taken samples (n＜3) (48/264 (18.2%) vs 60/783 (7.7%); p＜0.001), and less frequent presentation with a sinus (156/264 (59.1%) vs 665/783 (84.9%); p < 0.001). After initial treatments of first-debridement and antimicrobial, infection eradication was inferior in culture-positive osteomyelitis patients, with a 2.24-fold increase (odds ratio 2.24 (95% confidence interval 1.42 to 3.52)) in the redebridement rate following multivariate analysis. No statistically significant differences were found in long-term recurrence and complications within the two-year follow-up. Conclusion: We identified several factors being associated with the culture-negative result in osteomyelitis patients. In addition, the data also indicate that culture negativity is a positive prognostic factor in early infection eradication. These results constitute the basis of optimizing clinical management and patient consultations.

Effects of low-molecular-weight organic acids on the transformation and phosphate retention of iron (hydr)oxides.

The retention and mobilization of phosphate in soils are closely associated with the adsorption of iron (hydr)oxides and root exudation of low-molecular-weight organic acids (LMWOAs). This study investigated the role of LMWOAs in phosphate mobilization under incubation and field conditions. LMWOAs-mediated iron (hydr)oxide transformation and phosphate adsorption experiments revealed that the presence of LMWOAs decreased the phosphate adsorption capacity of iron (hydr)oxides by up to ~74 % due to the competition effect, while LMWOAs-induced iron mineral transformation resulted in an approximately six-fold increase in phosphate retention by decreasing the crystallinity and increasing the surface reactivity. Root simulation in rhizobox experiments demonstrated that LMWOAs can alter the contents of different extractable phosphate species and iron components, leading to 10 % ~ 30 % decreases in available phosphate in the near root region of two tested soils. Field experiments showed that crop covering between mango tree rows promoted the exudation of LMWOAs from mango roots. In addition, crop covering increased the contents of total phosphate and available phosphate by 9.08 % ~ 61.20 % and 34.33 % ~ 147.33 % in the rhizosphere soils of mango trees, respectively. These findings bridge the microscale and field scale to understand the delicate LMWOAs-mediated balance between the retention and mobilization of phosphate on iron (hydr)oxide surface, thereby providing important implications for mitigating the low utilization efficiency of phosphate in iron-rich soils.

Whether weekend warriors (WWs) achieve equivalent benefits in lipid accumulation products (LAP) reduction as other leisure-time physical activity patterns? -Results from a population-based analysis of NHANES 2007-2018.

BACKGROUND: Obesity is characterized by excessive fat accumulation in the body. Physical activity (PA) is an effective intervention to combat obesity, but the effectiveness of different PA patterns on controlling obesity is unclear. Lipid accumulation product (LAP), derived from waist circumference and triglycerides, is a novel indicator for obesity evaluation. However, the association between PA patterns (i.e., weekend warriors and regularly active) and LAP remains unexplored. This study aims to elucidate the relationship between PA patterns and LAP in US adult population. METHODS: Adult individuals with complete data on LAP, PA patterns, and other covariates from the National Health and Nutrition Examination Survey (NHANES) database (2007-2018) were included in this study. Multivariate linear regression models were utilized to explore the association between PA patterns and LAP. Subgroup analyses, interaction tests, restricted cubic spline (RCS) regression analyses, and threshold and saturation effect analyses were also performed to investigate the stability and nonlinearity of PA-LAP association, respectively. RESULTS: A total of 11,212 participants were included in this study. After adjusting for all potential covariates, being regularly active (RA) (ß=-8.85, P < 0.05) obtained significantly higher LAP reduction as opposed to being weekend warriors (WWs) (ß=-4.70, P = 0.3841). Furthermore, subgroup analyses and interaction tests indicated that the PA-LAP association was more pronounced in individuals with higher education levels (P interaction = 0.0084) and diabetes (P interaction = 0.0062). Additionally, a significant, non-linear, and negative correlation between weekly total PA and LAP in non-inactive individuals was identified by RCS analysis (P for overall < 0.001, P for nonlinearity = 0.009). A threshold of 440 min in weekly total PA was found to arouse favorable LAP reduction. CONCLUSIONS: Being regularly active obtained better LAP reduction as opposed to being WWs. For non-inactive adults, engaging in more than 440 min of PA per week helps to reduce LAP effectively.

Exploration of the core pathway of inflammatory bowel disease complicated with metabolic fatty liver and two-sample Mendelian randomization study of the causal relationships behind the disease.

Background: Inflammatory bowel disease (IBD) is often associated with complex extraintestinal manifestations. The incidence of nonalcoholic fatty liver disease (NAFLD) in IBD populations is increasing yearly. However, the mechanism of interaction between NAFLD and IBD is not clear. Consequently, this study aimed to explore the common genetic characteristics of IBD and NAFLD and identify potential therapeutic targets. Materials and methods: Gene chip datasets for IBD and NAFLD were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules in those datasets related to IBD and NAFLD. ClueGO was used for biological analysis of the shared genes between IBD and NAFLD. Based on the Human MicroRNA Disease Database (HMDD), microRNAs (miRNAs) common to NAFLD and IBD were obtained. Potential target genes for the miRNAs were predicted using the miRTarbase, miRDB, and TargetScan databases. Two-sample Mendelian randomization (MR) and two-way MR were used to explore the causal relationship between Interleukin-17 (IL-17) and the risk of IBD and NAFLD using data from GWAS retrieved from an open database. Results: Through WGCNA, gene modules of interest were identified. GO enrichment analysis using ClueGO suggested that the abnormal secretion of chemokines may be a common pathophysiological feature of IBD and NAFLD, and that the IL-17-related pathway may be a common key pathway for the pathological changes that occur in IBD and NAFLD. The core differentially expressed genes (DEGs) in IBD and NAFLD were identified and included COL1A1, LUM, CCL22, CCL2, THBS2, COL1A2, MMP9, and CXCL8. Another cohort was used for validation. Finally, analysis of the miRNAs identified potential therapeutic targets. The MR results suggested that although there was no causal relationship between IBD and NAFLD, there were causal relationships between IL-17 and IBD and NAFLD. Conclusion: We established a comorbid model to explain the potential mechanism of IBD with NAFLD and identified the chemokine-related pathway mediated by cytokine IL-17 as the core pathway in IBD with NAFLD, in which miRNA also plays a role and thus provides potential therapeutic targets.

The induced membrane technique for the management of infected segmental bone defects.

Aims: The aim of the present study was to assess the outcomes of the induced membrane technique (IMT) for the management of infected segmental bone defects, and to analyze predictive factors associated with unfavourable outcomes. Methods: Between May 2012 and December 2020, 203 patients with infected segmental bone defects treated with the IMT were enrolled. The digital medical records of these patients were retrospectively analyzed. Factors associated with unfavourable outcomes were identified through logistic regression analysis. Results: Among the 203 enrolled patients, infection recurred in 27 patients (13.3%) after bone grafting. The union rate was 75.9% (154 patients) after second-stage surgery without additional procedures, and final union was achieved in 173 patients (85.2%) after second-stage surgery with or without additional procedures. The mean healing time was 9.3 months (3 to 37). Multivariate logistic regression analysis of 203 patients showed that the number (≥ two) of debridements (first stage) was an independent risk factor for infection recurrence and nonunion. Larger defect sizes were associated with higher odds of nonunion. After excluding 27 patients with infection recurrence, multivariate analysis of the remaining 176 patients suggested that intramedullary nail plus plate internal fixation, smoking, and an allograft-to-autograft ratio exceeding 1:3 adversely affected healing time. Conclusion: The IMT is an effective method to achieve infection eradication and union in the management of infected segmental bone defects. Our study identified several risk factors associated with unfavourable outcomes. Some of these factors are modifiable, and the risk of adverse outcomes can be reduced by adopting targeted interventions or strategies. Surgeons can fully inform patients with non-modifiable risk factors preoperatively, and may even use other methods for bone defect reconstruction.

Complexation mechanism of Pb2+ on Al-substituted hematite: A modeling study and theoretical calculation.

Hematite nanoparticles commonly undergoes isomorphic substitution of Al3+ in nature, while how the Al-substitution-induced morphological change, defective structure and newly generated Al-OH sites affect the adsorption behavior of hematite for contaminants remains poorly understood. Herein, the interfacial reactions between Al-substituted hematite and Pb2+ was investigated via CD-MUSIC modeling and DFT calculations. As the Al content increased from 0% to 9.4%, Al-substitution promoted the proportion of (001) facets and caused Fe vacancies on hematite, which increased the total active site density of hematite from 5.60 to 17.60 sites/nm2. The surface positive charge of hematite significantly increased from 0.096 to 0.418 C/m2 at pH 5.0 due to the increases in site density and proton affinity (logKH) of hematite under Al-substitution. The adsorption amount of hematite for Pb2+ increased from 3.92 to 9.74 mmol/kg at pH 5.0 and 20 µmol/L initial Pb2+ concentration with increasing Al content. More Fe vacancies may lead to a weaker adsorption energy (Ead) of hematite for Pb2+, while the Ead was enhanced at higher Al content. The adsorption affinity (logKPb) of bidentate Pb complexes slightly increased while that of tridentate Pb complexes decreased with increasing Al content due to the presence of ≡ AlOH-0.5 and ≡ Fe2AlO-0.5 sites. Tridentate Pb complexes were dominant species on the surface of pure hematite, while bidentate ones became more dominant with increasing Al content. The obtained model parameters and molecular scale information are of great importance for better describing and predicting the environmental fate of toxic heavy metals in terrestrial and aquatic environments.

How would autonomous vehicles behave in real-world crash scenarios?

Autonomous Vehicles (AVs) have the potential to revolutionize transportation systems by enhancing traffic safety. Safety testing is undoubtedly a critical step for enabling large-scale deployment of AVs. High-risk scenarios are particularly important as they pose significant challenges and provide valuable insights into the driving capabilities of AVs. This study presents a novel approach to assess the safety of AVs using in-depth crash data, with a particular focus on real-world crash scenarios. First, based on the high-definition video recording of the whole process prior to the crash occurrences, 453 real-world crashes involving 596 passenger cars from China In-depth Mobility Safety Study-Traffic Accident (CIMSS-TA) database were reconstructed. Pertinent static and dynamic elements needed for the construction of the testing scenarios were extracted. Subsequently, 596 testing scenarios were created via each passenger car's perspective within the simulation platform. Following this, each of the crash-involved passenger cars was replaced with Baidu Apollo, a famous automated driving system (ADS), for counterfactual simulation. Lastly, the safety performance of the AV was assessed using the simulation results. A logit model was utilized to identify the fifteen crucial scenario elements that have significant impacts on the test results. The findings demonstrated that the AV could avoid 363 real-world crashes, accounting for approximately 60.91% of the total, and effectively mitigated injuries in the remaining 233 unavoidable scenarios compared to a human driver. Moreover, the AV maintain a smoother speed in most of the scenarios. The common feature of these unavoidable scenarios is that the AV is in a passive state, and the crashes are not caused by the AV violating traffic rules, but rather caused by abnormal behavior exhibited by the human drivers. Additionally, seven specific scenarios have been identified wherein AVs are unable to avoid a crash. These findings demonstrate that, compared to human drivers, AVs can avoid crashes that are difficult for humans to avoid, thereby enhancing traffic safety.

SNF472: a novel therapeutic agent for vascular calcification and calciphylaxis.

Vascular calcification is a common complication in patients with chronic kidney disease (CKD) and is strongly associated with an increased risk of cardiovascular events and all-cause mortality. Calciphylaxis is a specific and life-threatening manifestation of vascular calcifications that usually affects individuals with advanced kidney function impairment or those undergoing dialysis. Currently, the treatment of vascular calcification and calciphylaxis in CKD lacks approved treatments and focuses on controlling risk factors. SNF472, the intravenous formulation of myo-inositol hexaphosphate, is a novel vascular calcification inhibitor currently undergoing phase 3 clinical trials, demonstrating its ability to directly inhibit the formation of calcium and phosphorus crystals, thereby blocking the production and deposition of ectopic calcium. The efficacy and safety of SNF472 in inhibiting vascular calcification have been confirmed in recent clinical studies. This review summarizes the results of studies related to SNF472 to provide a comprehensive overview of its mechanism of action, efficacy, safety, and ongoing clinical studies.

Preparation of Matrix Product States with Log-Depth Quantum Circuits.

We consider the preparation of matrix product states (MPS) on quantum devices via quantum circuits of local gates. We first prove that faithfully preparing translation-invariant normal MPS of N sites requires a circuit depth T=Ω(logN). We then introduce an algorithm based on the renormalization-group transformation to prepare normal MPS with an error ε in depth T=O[log(N/ε)], which is optimal. We also show that measurement and feedback leads to an exponential speedup of the algorithm to T=O[loglog(N/ε)]. Measurements also allow one to prepare arbitrary translation-invariant MPS, including long-range non-normal ones, in the same depth. Finally, the algorithm naturally extends to inhomogeneous MPS.

ADAR-mediated RNA editing regulates PVR immune checkpoint in colorectal cancer.

Recent studies have revealed that tumor immunotherapy resistance is influenced by ADAR-mediated RNA editing, but its targets remain unelucidated. Our current study identified the poliovirus receptor (PVR) oncogene, which encodes an immune checkpoint in colorectal cancer (CRC), as a potential target for RNA editing. We performed transcriptome sequencing analysis and experimental validation in two Chinese CRC cohorts. PVR and ADAR expressions significantly increased in CRC tumors and showed positive correlations in both cohorts, coupled with upregulated PVR RNA editing in CRC tumors. Manipulation of ADAR expression by over-expression or knockdown substantially changed PVR expression and RNA editing in HTC116 CRC cells. Luciferase reporter and actinomycin D assays further revealed that RNA editing in PVR 3'-UTR could upregulate PVR RNA expression, probably by increasing the RNA stability. By increasing PVR expression, ADAR-mediate RNA editing might contribute to tumor- and immune-related gene functions and pathways in CRC. Moreover, a signature combining PVR RNA editing and expression showed promising predictive performance in CRC diagnosis in both Chinese CRC cohorts. Our findings thus highlight the importance of ADAR-mediated RNA editing in PVR up-regulation in CRC tumors and provide new insight into the application of PVR RNA editing as a novel diagnostic biomarker for CRC.

Comparative Analysis of Molecular Landscape in Mouse Models and Patients Reveals Conserved Inflammation Pathways in Age-Related Macular Degeneration.

Purpose: The purpose of this study was to identify key genes and their regulatory networks that are conserved in mouse models of age-related macular degeneration (AMD) and human AMD. Methods: Retinal RNA-Seq was performed in laser-induced choroidal neovascularization (CNV) mice at day 3 and day 7 after photocoagulation. Mass spectrometry-based proteomic analysis was performed with retinas collected at day 3. Retinal RNA-Seq data was further compared among mouse models of laser-induced CNV and NaIO3-induced retinal degeneration (RD) and a large AMD cohort. Results: Retinal RNA-Seq revealed upregulated genes and pathways related to innate immunity and inflammation in mice with CNV, with more profound changes at the early stage (day 3). Proteomic analysis further validated these differentially expressed genes and their networks in retinal inflammation during CNV. Notably, the most evident overlap in the retina of mice with laser-induced CNV and NaIO3-induced RD was the upregulation of inflammation-related genes, pointing to a common vital role of retinal inflammation in the early stage for both mouse AMD models. Further comparative transcriptomic analysis of the mouse AMD models and human AMD identified 48 conserved genes mainly involved in inflammation response. Among them, B2M, C3, and SERPING1 were upregulated in all stages of human AMD and the mouse AMD models compared to controls. Conclusions: Our study demonstrates conserved molecular changes related to retinal inflammation in mouse AMD models and human AMD and provides new insight into the translational application of these mouse models in studying AMD mechanisms and treatments.

STAT3 and SOX-5 induce BRG1-mediated chromatin remodeling of RORCE2 in Th17 cells.

Retinoid-related orphan receptor gamma t (RORγt) is the lineage-specific transcription factor for T helper 17 (Th17) cells. Our previous study demonstrated that STAT3 likely participates in the activation of RORCE2 (a novel enhancer of the RORγt gene) in Th17 cells. However, the detailed mechanism is still unclear. Here, we demonstrate that both STAT3 and SOX-5 mediate the enhancer activity of RORCE2 in vitro. Deletion of the STAT3 binding site (STAT3-BS) in RORCE2 impaired RORγt expression and Th17 differentiation, resulting in reduced severity of experimental autoimmune encephalomyelitis (EAE). Mechanistically, STAT3 and SOX-5 bind the RORCE2 region and recruit the chromatin remodeling factor BRG1 to remodel the nucleosomes positioned at this region. Collectively, our data suggest that STAT3 and SOX-5 mediate the differentiation of Th17 cells through the induction of BRG1-mediated chromatin remodeling of RORCE2 in Th17 cells.

Donor-π-Acceptor Porphyrin-Assisted Bifunctional Defect Passivation for Enhanced Temporal Domain-/Wavelength-Dependent Nonlinear Absorption Properties in Perovskite Films.

Perovskite layer defects are a primary inhibiting factor for their optical nonlinearity, which restricts their use in nonlinear photonics devices. Nevertheless, due to the variety of defect types, the passivation and repair of these defects remain challenging. Herein, a novel bifunctional passivation strategy was proposed, and the porphyrin with a donor-π-acceptor structure was designed to bifunctionally repair perovskite defects by linking different types of functional groups via acetylenic π-conjugated linkage bridges on both sides, thus improving the nonlinear optical (NLO) absorption properties of porphyrin-perovskite hybrid materials. Research results indicate that the amino and carboxyl groups of porphyrins endow the ability to bifunctionally passivate charged defects via effective coordination interactions. The nonlinear absorption properties of all porphyrin-passivated MAPbI3 films were remarkably enhanced compared to that of the MAPbI3 film across multiple wavelengths and temporal domains. Particularly, the Por3-passivated perovskite film (MAPbI3/Por3) exhibited optimized strongest NLO performance, including reverse saturable absorption (RSA) under 800 nm femtosecond (fs) and 1064 nm nanosecond (ns) laser irradiations, as well as saturable absorption (SA) with 515 and 532 nm ns laser excitations. The value of the NLO absorption coefficient (ß = 266.23 cm GW-1) is 1 order of magnitude higher than that of the pristine perovskite film (ß = 12.93 cm GW-1), also outperforming other porphyrin-passivated perovskite films and some reported materials. The bifunctional passivation mechanism of porphyrin not only intensifies the perovskite's photoinduced ground-state dipole moment in the two-photon absorption (TPA) process and the free carrier absorption ability to deepen the RSA properties under 800 nm fs and 1064 nm ns lasers, respectively, but also enables the improvement of SA responses under 515 nm fs and 532 nm ns lasers by expediting the Pauli blocking effect of perovskite. Our study offers a viable paradigm, which aims at exploiting high-performance NLO perovskite materials across wide spectral regions and time scales.

The age-related characteristics in bone microarchitecture, osteoclast distribution pattern, functional and transcriptomic alterations of BMSCs in mice.

Deteriorated age-related bone loss is the hallmarks of skeletal aging. However, how the aging of bone marrow mesenchymal stem cells (BMSCs) and osteoclasts are linked to the bone microstructure degeneration is not yet very clear. In this study, the characteristics of age-related bone loss, distribution patterns of osteoclasts, functional and transcriptomic alterations of BMSCs, hub genes responsible for BMSCs senescence, were analyzed. Our study revealed an age-related declined trends in trabecular and cortical bones of femur, tibia and lumbar vertebra in mice, which was accompanied by a shift from the trabecular to cortical bones in osteoclasts. Additionally, middle-aged or aged mice exhibited remarkably reduced dynamic bone formation capacities, along with reversed osteogenic-adipogenic differentiation potentials in BMSCs. Finally, transcriptomic analysis indicated that aging-related signaling pathways were significantly activated in BMSCs from aged mice (e.g., cellular senescence, p53 signaling pathway, etc.). Also, weighted correlation network analysis (WGCNA) and venn diagram analysis based on our RNA-Seq data and GSE35956 dataset revealed the critical role of PTPN1 in BMSCs senescence. Targeted inhibition of PTP1B with AAV-Ptpn1-RNAi dramatically postponed age-related bone loss in middle-aged mice. Collectively, our study has uncovered the age-dependent cellular characteristics in BMSCs and osteoclasts underlying progressive bone loss with advancing age.

Discovery of multipotent progenitor cells from human induced membrane: Equivalent to periosteum-derived stem cells in bone regeneration.

Background: The periosteum stem cells (PSCs) plays a critical role in bone regeneration and defect reconstruction. Insertion of polymethyl methacrylate (PMMA) bone cement can form an induced membrane(IM) and showed promising strategy for bone defect reconstruction, the underlying mechanism remains unclear. Our study sought to determine whether IM-derived cells(IMDCs) versus PSCs have similar characteristics in bone regeneration. Methods: IM and periosteum were harvested from ten bone defect patients treated with PMMA, the IMDCs and PSCs were isolated respectively. Morphological, functional and molecular evaluation was performed and matched for comparison. Results: Both progenitor-like IMDCs and PSCs were successfully isolated. In vitro, we found IMDCs were similar to PSCs in morphology, colony forming capacity and expression of surface marker(CD90+, CD73+, CD105+, CD34-/CD45-). Meanwhile, these IMSCs displayed multipotency with chondrogenic, adipogenic and osteogenic differentiation, but differed in some IMSCs(3/10) population showing relatively poor osteogenic differentiation. The molecular profiles suggests that cell cycle and DNA replication signaling pathways were associated with these varying osteogenic potential. In vivo, we established a cell-based tissue-engineered bone by seeding IMDSs/PSCs to demineralized bone matrix (DBM) scaffold and demonstrated both IMDSs and PSCs enhanced bone regeneration in SCID mice bone defect model compared with DBM alone. Conclusion: Our data demonstrated IM containing multipotent progenitor cells similar to that periosteum promoting bone regeneration, and indicated the existence of multiple subsets in osteogenic differentiation. Overall, the study provided a cellular and molecular insights in understanding the successful or failed outcome of bone defect healing.The translational potential of this article: This study confirmed IMDCs and PSCs share similar regeneration capacity and inform a translation potential of that cellular therapy applying IMDCs in bone defect repair.

Deep-learning and conventional radiomics to predict IDH genotyping status based on magnetic resonance imaging data in adult diffuse glioma.

Objectives: In adult diffuse glioma, preoperative detection of isocitrate dehydrogenase (IDH) status helps clinicians develop surgical strategies and evaluate patient prognosis. Here, we aim to identify an optimal machine-learning model for prediction of IDH genotyping by combining deep-learning (DL) signatures and conventional radiomics (CR) features as model predictors. Methods: In this study, a total of 486 patients with adult diffuse gliomas were retrospectively collected from our medical center (n=268) and the public database (TCGA, n=218). All included patients were randomly divided into the training and validation sets by using nested 10-fold cross-validation. A total of 6,736 CR features were extracted from four MRI modalities in each patient, namely T1WI, T1CE, T2WI, and FLAIR. The LASSO algorithm was performed for CR feature selection. In each MRI modality, we applied a CNN+LSTM-based neural network to extract DL features and integrate these features into a DL signature after the fully connected layer with sigmoid activation. Eight classic machine-learning models were analyzed and compared in terms of their prediction performance and stability in IDH genotyping by combining the LASSO-selected CR features and integrated DL signatures as model predictors. In the validation sets, the prediction performance was evaluated by using accuracy and the area under the curve (AUC) of the receiver operating characteristics, while the model stability was analyzed by using the relative standard deviation of the AUC (RSDAUC). Subgroup analyses of DL signatures and CR features were also individually conducted to explore their independent prediction values. Results: Logistic regression (LR) achieved favorable prediction performance (AUC: 0.920 ± 0.043, accuracy: 0.843 ± 0.044), whereas support vector machine with the linear kernel (l-SVM) displayed low prediction performance (AUC: 0.812 ± 0.052, accuracy: 0.821 ± 0.050). With regard to stability, LR also showed high robustness against data perturbation (RSDAUC: 4.7%). Subgroup analyses showed that DL signatures outperformed CR features (DL, AUC: 0.915 ± 0.054, accuracy: 0.835 ± 0.061, RSDAUC: 5.9%; CR, AUC: 0.830 ± 0.066, accuracy: 0.771 ± 0.051, RSDAUC: 8.0%), while DL and DL+CR achieved similar prediction results. Conclusion: In IDH genotyping, LR is a promising machine-learning classification model. Compared with CR features, DL signatures exhibit markedly superior prediction values and discriminative capability.