Postoperative Effusion-Synovitis is Associated With Poor Clinical Outcomes in Patients With Femoroacetabular Impingement Syndrome: a Consecutive Magnetic Resonance Imaging Study.

PURPOSE: (1) to investigate the consecutive changes in effusion-synovitis following primary arthroscopic treatment for patients with femoroacetabular impingement syndrome (FAIS), and (2) to determine the effect of postoperative effusion-synovitis on clinical outcomes. METHODS: Data between March 2021 and January 2022 was reviewed. Patients diagnosed with FAIS and undergoing hip arthroscopic treatment were included. Exclusion criteria were incomplete magnetic resonance imaging (MRI) data, prior history of hip surgery, labral reconstruction, and concomitant hip conditions. MRI (non-contrast 3.0 T) was performed preoperatively and 3, 6, 12-month postoperatively, and the measurement of the largest femoral neck fluid thickness (FTM) and cross-sectional area (CSA) of the effusion-synovitis were collected. Preoperative and a minimum of 2-year postoperative patient-reported outcome (PRO) scores including Visual Analog pain Scale (VAS), modified Harris Hip Score (mHHS), and international Hip Outcome Tool, 12-component form (iHOT-12) were collected and compared. Postoperative Tegner activity scale was also collected. The PROs and achievements of minimal clinically important difference (MCID) and patient acceptable symptom state (PASS) were compared between patients with and without postoperative effusion-synovitis. Multivariate linear regression analysis was performed to determine the effect of the effusion-synovitis size on PROs. RESULTS: A total of 61 patients (61 hips) were included in the study. The 3-month postoperative FTM, CSA and grade of effusion-synovitis presented a significant increase compared to the preoperative values (all with P < .05). No significant differences were observed in the 6-month postoperative measurements compared to the preoperative values (all with P > .05). At the 12-month follow-up, although there was a significant decrease in all measurements compared to the preoperative values (all with P < .001), 39 patients (63.9%) still presented effusion-synovitis. Compared to the other 22 patients (36.1%) without effusion-synovitis, these patients presented inferior mHHS, iHOT-12 (all with P < .05), as well as lower achievement of PASS of mHHS (82.1% vs 100%, P = .035) and iHOT-12 (38.5% vs 81.8%, P = .001). The achievement of MCID of mHHS (79.5% vs 77.3%, P = .839) and iHOT-12 (89.7% vs 95.5%, P = .839) were comparable between patients with and without effusion-synovitis. The postoperative sagittal CSA (Beta = -.302, P = .039) were negatively related to mHHS in the regression analysis. CONCLUSION: After arthroscopic treatment for FAIS, the level of effusion-synovitis presented an initial increase, then followed by a subsequent decrease. Effusion-synovitis was significantly alleviated at 12 months compared to the preoperative level. Patients with postoperative effusion-synovitis had inferior clinical outcomes and lower achievement of PASS compared to those without. LEVEL OF EVIDENCE: Level IV; retrospective case series.

The application value of 24†h Holter monitoring indices in predicting MACEs outside the hospital within three years after PCI in patients with STEMI.

Background: Evaluating cardiovascular risk in patients experiencing acute ST-elevation myocardial infarction (STEMI) and undergoing percutaneous coronary intervention (PCI) is crucial for early intervention and improving long-term outcomes. 24 h Holter monitoring provides continuous cardiac electrophysiological data, enabling the detection of arrhythmias and autonomic dysfunction that are not captured during routine examinations. This study aimed to examine the relationship between Holter monitoring metrics and the occurrence of out-of-hospital major adverse cardiovascular events (MACEs) following PCI in patients with STEMI, offering insights into cardiovascular risk evaluation. Methods: This prospective cohort study included STEMI patients undergoing PCI. 24 h Holter monitoring data were recorded, including heart rate, heart rate variability (HRV) metrics such as SDNN and SDANN index, heart rate deceleration capacity (DC) at different time scales (DC2, DC4, DC8), and the frequency of premature ventricular contractions (PVCs). Independent correlations between these indices and MACEs, as well as cardiovascular deaths, were investigated using multifactorial logistic regression. Predictive capacities were assessed through receiver operating characteristic (ROC) curves. Results: A total of 172 participants were enrolled in this study. Over the 3-year follow-up period, MACEs were observed in 57 patients, including 20 cases of cardiac death. In logistic regression models adjusted for confounding variables, SDNN [OR: 0.980; 95% CI: (0.967, 0.994); p = 0.005] and SDANN index [OR: 0.982; 95% CI: (0.969, 0.996); p = 0.009] were negatively associated with the incidence of MACEs. Conversely, the slowest heart rate [OR: 1.075; 95% CI: (1.022, 1.131); p = 0.005] and frequent PVCs [OR: 2.685; 95% CI: (1.204, 5.987); p = 0.016] demonstrated a positive association with MACEs. Furthermore, SDNN [OR: 0.957; 95% CI: (0.933, 0.981); p = 0.001], DC [OR: 0. 702; 95% CI: (0.526, 0.938); p = 0.017]) and DC4 [OR: 0.020; 95% CI: (0.001, 0.664); p = 0.029] were negatively associated with cardiac death. The ROC analysis results indicated that SDNN was an effective predictor of both MACEs [AUC: 0.688 (95% CI: 0.601-0.776)] and cardiac death [AUC: 0.752 (95% CI: 0.625-0.879)]. Conclusion: HRV, DC metrics, and frequent PVCs obtained by 24 h Holter monitoring were associated with the risk of MACEs in STEMI patients. These metrics can help clinicians identify at-risk patients early so that timely interventions.

Deciphering the role of ferroptosis in rheumatoid arthritis: Synovial transcriptome analysis and immune infiltration correlation.

The pathogenesis of rheumatoid arthritis (RA) remains elusive. The initiation of joint degeneration is characterized by the loss of self-tolerance in peripheral joints. Ferroptosis, a form of regulated cell death, holds significant importance in the pathophysiology of inflammatory arthritis, primarily due to iron accumulation and the subsequent lipid peroxidation. The present study investigated the association between synovial lesions and ferroptosis-related genes using previously published data from rheumatoid patients. Transcriptome differential gene analysis was employed to identify ferroptosis-related differentially expressed genes (FRDEGs). To validate FRDEGs and screen hub genes, we used weighted gene co-expression network analysis (WGCNA) and receiver operating characteristic (ROC) curves. Subsequently, immune infiltration analysis and single cell analysis were conducted to investigate the relationship between various synovial tissues cells and FRDEGs. The findings were further confirmed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunohistochemical staining, and immunofluorescence techniques. Upon intersecting DEGs with ferroptosis-related genes, we identified a total of 104 FRDEGs. Through the construction of a protein-protein interaction (PPI) network, we pinpointed the top 20 most highly concentrated genes as hub genes. Subsequent analyses using ROC curve and WGCNA validated eight FRDEGs: TIMP1, JUN, EGFR, SREBF1, ADIPOQ, SCD, AR, and FABP4. Immuno-infiltration analyses revealed significant infiltration of immune cell in RA synovial tissues and their correlations with the FRDEGs. Notably, TIMP1 demonstrated a positive correlation with various immune cell populations. Single-cell sequencing date of RA synovial tissue revealed predominant expression of TIMP1 is in fibroblasts. RT-qPCR, immunohistochemistry, and immunofluorescence analyses confirmed significant upregulation of TIMP1 at both mRNA and protein levels in RA synovial tissues and fibroblast-like synoviocytes (FLS). The findings provide novel insights into pathophysiology of peripheral immune tolerance deficiency in RA. The dysregulation of TIMP1, a gene associated with ferroptosis, was significantly observed in RA patients, suggesting its potential as a promising biomarker and therapeutic target.

Longitudinal Assessment of Clinical Outcomes After Arthroscopic Treatment for Hip Synovial Chondromatosis and the Effect of Residual Loose Bodies: Minimum 4-Year and 8-Year Follow-up.

BACKGROUND: Arthroscopic treatment is recommended for hip synovial chondromatosis. However, evidence regarding long-term clinical outcomes is limited. PURPOSE: To evaluate long-term patient-reported outcomes (PROs) and survival, and to determine the potential effect of residual loose bodies, as evaluated by immediate postoperative computed tomography (CT), on clinical outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A consecutive cohort of patients undergoing arthroscopic treatment and diagnosed with synovial chondromatosis between March 2010 and May 2015 were included in the study. Preoperative radiography, CT, and magnetic resonance imaging were performed. Preoperative, midterm (minimum of 4 years), and long-term (minimum of 8 years) PROs were collected for visual analog scale for pain, modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), and 12-item international Hip Outcome Tool (iHOT-12). The percentages achieving minimal clinically important difference (MCID) were calculated. PROs and survival were compared between patients with and without residual loose bodies evident on immediate postoperative CT scan. RESULTS: A total of 28 patients (20% of patients were lost to follow-up) were included in the study with a mean follow-up period of 104.9 months (range, 96-139 months). PROs including visual analog scale for pain (preoperative, 3.8 ± 1.2; midterm, 0.9 ± 1.7; long-term, 0.8 ± 1.4), mHHS (preoperative, 66.4 ± 14.4; midterm, 92.8 ± 12.3; long-term, 93.5 ± 10.5), NAHS (preoperative, 45.2 ± 16.2; midterm, 81.8 ± 15.3; long-term, 83.1 ± 12.9), and iHOT-12 (preoperative, 48.4 ± 15.6; midterm, 69.3 ± 11.7; long-term, 72.7 ± 11.4) were improved at both midterm and long-term follow-up (all with P < .001). In total, 27 (96.4%), 28 (100%), and 26 (92.9%) patients achieved MCID for mHHS, NAHS and iHOT-12, respectively, at the long-term follow-up. No significant difference was found in any of the PROs and the rate of achieving MCID between midterm and long-term follow-up (all with P > .05). One patient (3.6%) underwent revision surgery. Among the 23 patients who had loose bodies on preoperative CT or radiographs, 14 patients (60.9%) with residual loose bodies evident on immediate postoperative CT demonstrated lower NAHS (P = .045) and iHOT-12 (P = .037) scores but a comparable survival (P > .05) at long-term follow-up compared with those who did not have loose bodies. CONCLUSION: Arthroscopic treatment for hip synovial chondromatosis achieved satisfactory long-term clinical outcomes with strong survival. Most patients maintained or improved their overall functional status between midterm and long-term follow-up. Furthermore, patients with residual loose bodies had less favorable clinical outcomes, although the survival rate was comparable.

An Integrated Nanoplatform via Dual Channel Excitation for Both Precise Fluorescence Imaging and Photodynamic Therapy of Orthotopic Breast Tumor in NIR-II Region.

Although research on photodynamic therapy (PDT) of malignant tumor has made considerable progress in recent years, it is a remaining challenge to extend PDT to the second near-infrared window (NIR-II) along with real-time and accurate NIR-II fluorescence imaging to determine drug enrichment status and achieve high treatment efficacy. In this work, lanthanide nanoparticles (Ln NPs)-based nanoplatform (LCR) equipped with photosensitizer Chlorin e6 (Ce6) and targeting molecular NH2-PEG1000-cRGDfK are developed, which can achieve NIR-II photodynamic therapy (PDT) and NIR-II fluorescence imaging by dual channel excitation. Under 808 nm excitation, Nd3+ in the outer layer can absorb the energy and transfer inward to emit strong NIR-II emissions (1064 and 1525 nm). Due to the low background noise of NIR-II light and the targeting effect of NH2-PEG1000-cRGDfK, LCR can recognize tiny tumor tissue (≈3 mm) and monitor drug distribution in vivo. Under 1530 nm excitation, internal Er3+ can be self-sensitized, generating intense upconversion emission (662 nm) that can effectively activate Ce6 for in vivo PDT due to the deep tissue penetration of NIR-II light. This study provides a paradigm of theranostic nanoplatform for both real-time fluorescence imaging and PDT of orthotopic breast tumor in NIR-II window.

The interaction between physical activity and ambient particulate matters on cognitive function among Chinese community-dwelling older adults.

BACKGROUND: The interaction between physical activity (PA) and ambient particulate matters (PMs) on cognition is rarely investigated. Our study aimed to assess the interactions of PA and PMs on cognitive function in older adults. METHODS: Our study comprised 3937 Chinese community-dwelling older adults. Cognition was evaluated using the Mini-Mental State Examination. PA information was gathered using the International Physical Activity Questionnaire. The data of PMs were obtained from China High Air Pollutants (CHAP). Linear regressions model and interaction plots were applied to assess and visualize the interaction of PA and PMs on cognition, respectively. Bayesian kernel machine regression (BKMR) method was employed to visualize discernible thresholds for the interaction. RESULTS: PMs were negatively associated with MMSE scores (PM1: ß = -0.40, 95 % CI: -0.58, -0.28; PM2.5: ß = -0.46, 95 % CI: -0.64, -0.29; PM10: ß = -0.44, 95 % CI: -0.61, -0.26), and PA was positively affiliated with MMSE scores (ß = 0.18, 95 % CI: -0.01, 0.38). Interaction plots and BKMR demonstrated that adverse connotations of PMs with MMSE increased with the elevated PA levels, and the positive associations of PA with MMSE scores were attenuated by increased PMs (all Pinteraction < 0.20). Discernible thresholds for the interaction between PMs and PA on MMSE were found. CONCLUSIONS: Our findings suggest that PA should not be taken at higher PMs concentrations, and that low level of PA could be performed in PMs polluted environment to improve cognitive function. Further experimental and cohort researches are required to reproduce our discovery.

Health-Oriented Emission Control Strategy of Energy Utilization and Its Co-CO2 Benefits: A Case Study of the Yangtze River Delta, China.

Reducing air pollutants and CO2 emissions from energy utilization is crucial for achieving the dual objectives of clean air and carbon neutrality in China. Thus, an optimized health-oriented strategy is urgently needed. Herein, by coupling a CO2 and air pollutants emission inventory with response surface models for PM2.5-associated mortality, we shed light on the effectiveness of protecting human health and co-CO2 benefit from reducing fuel-related emissions and generate a health-oriented strategy for the Yangtze River Delta (YRD). Results reveal that oil consumption is the primary contributor to fuel-related PM2.5 pollution and premature deaths in the YRD. Significantly, curtailing fuel consumption in transportation is the most effective measure to alleviate the fuel-related PM2.5 health impact, which also has the greatest cobenefits for CO2 emission reduction on a regional scale. Reducing fuel consumption will achieve substantial health improvements especially in eastern YRD, with nonroad vehicle emission reductions being particularly impactful for health protection, while on-road vehicles present the greatest potential for CO2 reductions. Scenario analysis confirms the importance of mitigating oil consumption in the transportation sector in addressing PM2.5 pollution and climate change.

Short-term associations between ambient PM1, PM2.5, and PM10 and hospital admissions, length of hospital stays, and hospital expenses for patients with cardiovascular diseases in rural areas of Fuyang, East China.

Evidence on the impacts of PM1, PM2.5, and PM10 on the hospital admissions, length of hospital stays (LOS), and hospital expenses among patients with cardiovascular disease (CVD) is still limited in China, especially in rural areas. This study was performed in eight counties of Fuyang from 1 January 2015 to 30 June 2017. We use a three-stage time-series analysis to explore the effects of short-term exposure to PM1, PM2.5, and PM10 on hospital admissions, LOS, and hospital expenses for CVDs. An increment of 10 ug/m3 in PM1, PM2.5, and PM10 corresponded to an increment of 1.82% (95% CI: 1.34, 2.30), 0.96% (95% CI: 0.44, 1.48), and 0.79% (95% CI: 0.63%, 0.95%) in CVD hospital admissions, respectively. We observed that daily concentrations of PMs were associated with an increase in hospital admissions, LOS, and expenses for CVDs. Sustained endeavors are required to reduce air pollution so as to attenuate disease burdens from CVDs.

Actin-bundling protein fimbrin serves as a new auxin biosynthesis orchestrator in Arabidopsis root tips.

Plants delicately regulate endogenous auxin levels through the coordination of transport, biosynthesis, and inactivation, which is crucial for growth and development. While it is well-established that the actin cytoskeleton can regulate auxin levels by affecting polar transport, its potential role in auxin biosynthesis has remained largely unexplored. Using LC-MS/MS-based methods combined with fluorescent auxin marker detection, we observed a significant increase in root auxin levels upon deletion of the actin bundling proteins AtFIM4 and AtFIM5. Fluorescent observation, immunoblotting analysis, and biochemical approaches revealed that AtFIM4 and AtFIM5 affect the protein abundance of the key auxin synthesis enzyme YUC8 in roots. AtFIM4 and AtFIM5 regulate the auxin synthesis enzyme YUC8 at the protein level, with its degradation mediated by the 26S proteasome. This regulation modulates auxin synthesis and endogenous auxin levels in roots, consequently impacting root development. Based on these findings, we propose a molecular pathway centered on the 'actin cytoskeleton-26S proteasome-YUC8-auxin' axis that controls auxin levels. Our findings shed light on a new pathway through which plants regulate auxin synthesis. Moreover, this study illuminates a newfound role of the actin cytoskeleton in regulating plant growth and development, particularly through its involvement in maintaining protein homeostasis via the 26S proteasome.

High-resolution reconstruction of April-September precipitation and major extreme droughts in China over the past ∼530 years.

Extreme drought events have increased, causing serious losses and damage to the social economy under current warming conditions. However, short-term meteorological data limit our understanding and projection of these extremes. With the accumulation of proxy data, especially tree-ring data, large-scale precipitation field reconstruction has provided opportunities to explore underlying mechanisms further. Using point-by-point regression, we reconstructed the April-September precipitation field in China for the past ∼530 years on the basis of 590 proxy records, including 470 tree-ring width chronologies and 120 drought/flood indices. Our regression models explained average 50% of the variance in precipitation. In the statistical test on calibration and verification, our models passed the significance level that assured reconstruction quality. The reconstruction data performed well, showing consistency and better quality than previously reported reconstructions. The first three leading modes of variability in the reconstruction revealed the main distribution modes of precipitation over China. Wet/drought and extremely wet/drought years accounted for 12.81%/10.92% (68 years/58 years) and 1.69%/3.20% (9 years/17 years) of the past ∼530 years in China, respectively. Major extreme drought events can be identified explicitly in our reconstruction. The detailed features of the Chongzhen Great Drought (1637-1643), the Wanli Great Drought (1585-1590), and the Ding-Wu Great Famine (1874-1879), indicated the existence of potentially different underlying mechanisms that need further exploration. Although further improvements can be made for remote uninhabited areas and large deserts, our gridded reconstruction of April-September precipitation in China over the past ∼530 years can provide a solid database for studies on the attribution of climate change and the mechanism of extreme drought events.

An electrochemical sensor for the rapid detection of zearalenone based on the mimic peptide screened by molecular simulation.

An electrochemical sensor was developed for detecting zearalenone (ZEN) based on the mimic peptide, which was screened from the library and validated by molecular simulation and electrochemical methods. The library of the mimic peptide was constructed according to the structural analysis, molecular docking, molecular dynamics and amino acid mutation. Then, the enhanced electrical signal was attributed to gold nanoparticles (AuNPs) and reduced carboxylated graphene oxide (rGO-COOH). Under the optimal conditions, the detection limit was 0.91 pg·mL-1 (S/N = 3) with a wide linear range from 0.01 ng·mL-1 to 10 ng·mL-1. In grain samples, a good recovery rate of 84% to 105.3% was achieved, while the rate ranged from 82% to 108.8% in the commercial ELISA kits. Additionally, the electrochemical sensor exhibited the remarkable specificity, excellent stability and better reproducibility (RSD = 1.94%). This sensor has great potential for rapidly detecting ZEN in food.

Associations of toxic metals and their mixture with hyperuricemia in Chinese rural older adults.

Previous studies have related single toxic metals (TMs) to hyperuricemia (HUA) among the general population, however, the association of the TM mixture with HUA, especially in older adults, remains poorly understood. We aimed to examine the relationships between individual TMs and their mixture and HUA in Chinese rural older adults. This study consisted of 2075 rural older adults aged 60 years or over. Blood concentrations of aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), gallium (Ga), mercury (Hg), lead (Pb), thallium (Tl), and uranium (U) were detected using inductively coupled plasma mass spectrometry. The associations of single TMs with HUA were assessed using logistic regression and restricted cubic spline (RCS) models, and the association of TM mixture with HUA was explored using the elastic net with environmental risk score (ENET-ERS), quantile g-computation (QGC), and Bayesian kernel machine regression (BKMR) models, respectively. Adjusted logistic regression model showed that Cs (OR = 1.65, 95% CI 1.37-1.99) and Pb (OR = 1.46, 95% CI 1.28-1.67) were positively related to HUA, and RCS model exhibited a positive linear association of Cs and Pb with HUA. ENET-ERS and QGC models quantified a positive correlation between the TM mixture and the odds of HUA, with estimated ORs of 1.15 (95% CI 1.11-1.19) and 1.84 (95% CI 1.37-2.47), respectively, and Cs and Pb had the most weight. BKMR model demonstrated a significant linear association between the TM mixture and increased odds of HUA, with the posterior inclusion probabilities (PIPs) of both Cs and Pb being 1.00. Moreover, we observed a positive interaction between Cs and Pb on HUA. The TM mixture is associated with increased odds of HUA in rural older adults, which may mainly be driven by Cs and Pb. Subsequent studies are warranted to confirm these findings and clarify the mechanisms linking multiple TMs with HUA.

The Radiological Characteristics of Degenerative Cervical Kyphosis with Cervical Spondylotic Myelopathy.

Introduction: In this study, we aim to describe the radiological characteristics of degenerative cervical kyphosis (DCK) with cervical spondylotic myelopathy (CSM) and discuss the relationship between DCK and the pathogenesis of spinal cord dysfunction. Methods: In total, 90 patients with CSM hospitalized in our center from September 2017 to August 2022 were retrospectively examined in this study; they were then divided into the kyphosis group and the nonkyphosis group. The patients' demographics, clinical features, and radiological data were obtained, including gender, age, duration of illness, cervical Japanese Orthopaedic Association (JOA) score, cervical lordosis (CL), height of intervertebral space, degree of wedging vertebral body, degree of osteophyte formation, degree of disc herniation, degree of spinal cord compression, and anteroposterior diameter of the spinal cord. In the kyphosis group, kyphotic segments, apex of kyphosis, and segmental kyphosis angle were recorded. Radiological characteristics between the two groups were also compared. Correlation analysis was performed for different spinal cord compression types. Results: As per our findings, the patients in the kyphosis group showed more remarkable wedging of the vertebral body, more severe anterior compression of the spinal cord, and a higher degree of disc herniation, while the posterior compression of the spinal cord was relatively mild when compared with the nonkyphosis group. CL was related to the type of spinal cord compression, as cervical kyphosis is an independent risk factor for anterior spinal cord compression. Conclusions: DCK might play a vital role in the pathogenesis of spinal cord dysfunction. In patients with DCK, it was determined that the anterior column is less supported, and more severe anterior spinal cord compression is present. The anterior approach is supposed to be preferred for CSM patients with DCK.

Obscured Contribution of Oxygenated Intermediate-Volatility Organic Compounds to Secondary Organic Aerosol Formation from Gasoline Vehicle Emissions.

Secondary organic aerosol (SOA) formation from gasoline vehicles spanning a wide range of emission types was investigated using an oxidation flow reactor (OFR) by conducting chassis dynamometer tests. Aided by advanced mass spectrometric techniques, SOA precursors, including volatile organic compounds (VOCs) and intermediate/semivolatile organic compounds (I/SVOCs), were comprehensively characterized. The reconstructed SOA produced from the speciated VOCs and I/SVOCs can explain 69% of the SOA measured downstream of an OFR upon 0.5-3 days' OH exposure. While VOCs can only explain 10% of total SOA production, the contribution from I/SVOCs is 59%, with oxygenated I/SVOCs (O-I/SVOCs) taking up 20% of that contribution. O-I/SVOCs (e.g., benzylic or aliphatic aldehydes and ketones), as an obscured source, account for 16% of total nonmethane organic gas (NMOG) emission. More importantly, with the improvement in emission standards, the NMOG is effectively mitigated by 35% from China 4 to China 6, which is predominantly attributed to the decrease of VOCs. Real-time measurements of different NMOG components as well as SOA production further reveal that the current emission control measures, such as advances in engine and three-way catalytic converter (TWC) techniques, are effective in reducing the "light" SOA precursors (i.e., single-ring aromatics) but not for the I/SVOC emissions. Our results also highlight greater effects of O-I/SVOCs to SOA formation than previously observed and the urgent need for further investigation into their origins, i.e., incomplete combustion, lubricating oil, etc., which requires improvements in real-time molecular-level characterization of I/SVOC molecules and in turn will benefit the future design of control measures.

Characterizing Cellular Physiological States with Three-Dimensional Shape Descriptors for Cell Membranes.

The shape of a cell as defined by its membrane can be closely associated with its physiological state. For example, the irregular shapes of cancerous cells and elongated shapes of neuron cells often reflect specific functions, such as cell motility and cell communication. However, it remains unclear whether and which cell shape descriptors can characterize different cellular physiological states. In this study, 12 geometric shape descriptors for a three-dimensional (3D) object were collected from the previous literature and tested with a public dataset of ~400,000 independent 3D cell regions segmented based on fluorescent labeling of the cell membranes in Caenorhabditis elegans embryos. It is revealed that those shape descriptors can faithfully characterize cellular physiological states, including (1) cell division (cytokinesis), along with an abrupt increase in the elongation ratio; (2) a negative correlation of cell migration speed with cell sphericity; (3) cell lineage specification with symmetrically patterned cell shape changes; and (4) cell fate specification with differential gene expression and differential cell shapes. The descriptors established may be used to identify and predict the diverse physiological states in numerous cells, which could be used for not only studying developmental morphogenesis but also diagnosing human disease (e.g., the rapid detection of abnormal cells).

Osteogenic Induction and Anti-Inflammatory Effects of Calcium-Chlorogenic Acid Nanoparticles Remodel the Osteoimmunology Microenvironment for Accelerating Bone Repair.

Successful bone regeneration requires close cooperation between bone marrow mesenchymal stem cells (BMSCs) and macrophages, but the low osteogenic differentiation efficiency of stem cells and the excessive inflammatory response of immune cells hinder the development of bone repair. It is necessary to develop a strategy that simultaneously regulates the osteogenic differentiation of BMSCs and the anti-inflammatory polarization of macrophages for accelerating the bone regeneration. Herein, calcium-chlorogenic acid nanoparticles (Ca-CGA NPs) are synthesized by combining the small molecules of chlorogenic acid (CGA) with Ca2+. Ca-CGA NPs internalized by cells can be dissolved to release free CGA and Ca2+ under low pH conditions in lysosomes. In vitro results demonstrate that Ca-CGA NPs can not only enhance the osteogenic differentiation of BMSCs but also promote the phenotype transformation of macrophages from M1 to M2. Furthermore, in vivo experiments confirm that Ca-CGA NPs treatment facilitates the recovery of rat skull defect model through both osteoinduction and immunomodulation. This study develops a new Ca-CGA NPs-based strategy to induce the differentiation of BMSCs into osteoblasts and the polarization of macrophages into M2 phenotype, which is promising for accelerating bone repair.

Hypoalkaline Phosphatemia Dental Type: A Case Report.

Mutations in dental hypophosphatasia (HPP) have been reported less than those in other types of HPP because the symptoms are mild or the dental lesions are only partial manifestations of other types of HPP. In this case, we observe the clinical manifestation of dental hypoalkaline phosphatase by analyzing the genetic mutation and biochemical parameters in child. The clinical data of the child with odonto HPP were collected and analyzed. The blood samples of the child and his parents were sequenced and verified using Sanger through a specific probe capture and high-throughput second-generation sequencing technology. Major clinical manifestations in the patient were early loss of deciduous teeth, significantly lower serum alkaline phosphatase (ALP) levels, lower active vitamin D, and increased blood phosphorus, but no abnormality was observed in the oral X-ray. Two missense mutations-c.542C>T (p. ser181leu) and c.644 T> C (p.Ile215Thr)-were found in exon 6 of the ALPL gene from the father and mother, respectively. The clinical manifestations of odonto hypophosphatasia were early loss of deciduous teeth and significantly reduced serum ALP levels. Of 2 mutations-c.542C>T (p.ser181leu) and c.644 T> C (p.Ile215Thr)-in the ALPL gene, c.644 T> C (p.Ile215Thr) was a new mutation.

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission.

BACKGROUND: Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. MATERIALS AND METHODS: In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. RESULTS: We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. CONCLUSION: Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.

APOE ε4 allele modifies the associations of toxic metals and their mixture with cognitive impairment among older adults.

BACKGROUND: The evidence of interactive effect of the toxic metal (TM) mixture and apolipoprotein E (APOE) ε4 gene on cognitive impairment in older adults is scarce. We aimed to explore whether the associations of single TMs and their mixture with cognitive impairment depend on APOE ε4 in Chinese community-dwelling older people. METHODS: A total of 1148 older adults from a subset of the baseline survey of a cohort study were included. Blood arsenic (As), cadmium (Cd), lead (Pb), strontium (Sr), and vanadium (V) were detected by inductively coupled plasma mass spectrometry. APOE gene (rs429358, rs7412) polymorphisms were analyzed by the Polymerase Chain Reaction instrument. Mixed effects logistic regression was applied to estimate the relationships of single TMs and APOE genotype with cognitive impairment. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were performed to examine joint impacts of the TM mixture, as well as the interaction of the TM mixture with APOE ε4 genotype on cognitive impairment. RESULTS: Pb displayed a significant linear association with an increased odds of cognitive impairment after adjustment for covariates (Ptrend = 0.045). While APOE genotype did not show a significant correlation with cognitive impairment. WQS showed that the TM mixture was associated with an increased risk of cognitive impairment by 31.0% (OR=1.31, 95% CI: 0.92, 1.87) while no significance was found. BKMR exhibited a significant linear association between the TM mixture and cognitive impairment. Moreover, both WQS and BKMR indicated that Pb contributed the most to cognitive impairment within the mixture. Significant interactions of Pb or the TM mixture and APOE genotype on cognitive impairment were observed, contributing to 38.1% and 38.2% of total effects, respectively. CONCLUSIONS: APOE ε4 allele amplifies the associations of single Pb or the TM mixture with cognitive impairment. These findings may help to develop precision prevention.

Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior (RRBs). Evidence from both human and animal model studies of ASD suggest that alteration of striatal circuits, which mediate motor learning, action selection, and habit formation, may contribute to the manifestation of RRBs. CNTNAP2 is a syndromic ASD risk gene, and loss of function of Cntnap2 in mice is associated with RRBs. How loss of Cntnap2 impacts striatal neuron function is largely unknown. In this study, we utilized Cntnap2-/- mice to test whether altered striatal neuron activity contributes to aberrant motor behaviors relevant to ASD. We find that Cntnap2-/- mice exhibit increased cortical drive of striatal projection neurons (SPNs), with the most pronounced effects in direct pathway SPNs. This enhanced drive is likely due to increased intrinsic excitability of SPNs, which make them more responsive to cortical inputs. We also find that Cntnap2-/- mice exhibit spontaneous repetitive behaviors, increased motor routine learning, and cognitive inflexibility. Increased corticostriatal drive, in particular of the direct pathway, may contribute to the acquisition of repetitive, inflexible behaviors in Cntnap2 mice.