Data-driven approaches linking wastewater and source estimation hazardous waste for environmental management.

Industrial enterprises are major sources of contaminants, making their regulation vital for sustainable development. Tracking contaminant generation at the firm-level is challenging due to enterprise heterogeneity and the lack of a universal estimation method. This study addresses the issue by focusing on hazardous waste (HW), which is difficult to monitor automatically. We developed a data-driven methodology to predict HW generation using wastewater big data which is grounded in the availability of this data with widespread application of automatic sensors and the logical assumption that a correlation exists between wastewater and HW generation. We created a generic framework that used representative variables from diverse sectors, exploited a data-balance algorithm to address long-tail data distribution, and incorporated causal discovery to screen features and improve computation efficiency. Our method was tested on 1024 enterprises across 10 sectors in Jiangsu, China, demonstrating high fidelity (R² = 0.87) in predicting HW generation with 4,260,593 daily wastewater data.

A generic causality-informed neural network (CINN) methodology for quantitative risk analytics and decision support.

In this paper, we develop a generic framework for systemically encoding causal knowledge manifested in the form of hierarchical causality structure and qualitative (or quantitative) causal relationships into neural networks to facilitate sound risk analytics and decision support via causally-aware intervention reasoning. The proposed methodology for establishing causality-informed neural network (CINN) follows a four-step procedure. In the first step, we explicate how causal knowledge in the form of directed acyclic graph (DAG) can be discovered from observation data or elicited from domain experts. Next, we categorize nodes in the constructed DAG representing causal relationships among observed variables into several groups (e.g., root nodes, intermediate nodes, and leaf nodes), and align the architecture of CINN with causal relationships specified in the DAG while preserving the orientation of each existing causal relationship. In addition to a dedicated architecture design, CINN also gets embodied in the design of loss function, where both intermediate and leaf nodes are treated as target outputs to be predicted by CINN. In the third step, we propose to incorporate domain knowledge on stable causal relationships into CINN, and the injected constraints on causal relationships act as guardrails to prevent unexpected behaviors of CINN. Finally, the trained CINN is exploited to perform intervention reasoning with emphasis on estimating the effect that policies and actions can have on the system behavior, thus facilitating risk-informed decision making through comprehensive "what-if" analysis. Two case studies are used to demonstrate the substantial benefits enabled by CINN in risk analytics and decision support.

Evaluation of electrokinetic-assisted phytoremediation efficiency of dibutyl phthalate contaminated soil by maize (Zea mays L.) under different electric field intensities.

The excessive accumulation of dibutyl phthalate (DBP) in soil poses a serious threat to soil ecosystems and crop safety production. Electrokinetic-assisted phytoremediation (EKPR) has been considered as a potential technology for remediating organic contaminated soils. In order to investigate the effect of different electric fields on removal efficiency of DBP, three kinds of electric fields were set up in this study (1 V·cm-1, 2 V·cm-1 and 3 V·cm-1). The results showed that 59 % of DBP in soil was removed by maize (Zea mays L.) within 20 d in low-intensity electric field (1 V·cm-1), and the accumulation of DBP in maize tissues decreased significantly compared to the non-electrified treatment group. Interestingly, it could be observed that the low-intensity electric field could maintain ion homeostasis and improve the photosynthetic efficiency of the plant, thereby relieving the inhibition of DBP on plant growth and increasing the chlorophyll content (94.1 %) of maize. However, the removal efficiency of DBP by maize decreased significantly under the medium-intensity (2 V·cm-1) and high-intensity electric field (3 V·cm-1). Moreover, the important roles of soil enzyme and rhizosphere bacterial community in low-electric field were also investigated and discussed. This study provided a new perspective for exploring the mechanism of removing DBP through EKPR.

Mammalian IRE1α dynamically and functionally coalesces with stress granules.

Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α-SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α-XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α-SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity.

Laccase as a useful assistant for maize to accelerate the phenanthrene degradation in soil.

Polycyclic aromatic hydrocarbon (PAH) pollution has attracted much attention due to their wide distribution in soil environment and serious harm to human health. In order to establish an efficient and eco-friendly technology for remediation of PAH-contaminated soil, phytoremediation utilizing maize assisted with enzyme remediation was explored in this study. The results showed that the participation of laccase could promote the degradation of phenanthrene (PHE) from soil and significantly reduce the accumulation of PHE in maize. The degradation efficiency of PHE in soil could reach 77.19% under laccase-assisted maize remediation treatment, while the accumulation of PHE in maize roots and leaves decreased by 41.23% and 74.63%, respectively, compared to that without laccase treatment, after 24 days of maize cultivation. Moreover, it was found that laccase addition shifted the soil microbial community structure and promoted the relative abundance of some PAH degrading bacteria, such as Pseudomonas and Sphingomonas. In addition, the activities of some enzymes that were involved in PAH degradation process and soil nutrient cycle increased with the treatment of laccase enzyme. Above all, the addition of laccase could not only improve the removal efficiency of PHE in soil, but also alter the soil environment and reduce the accumulation of PHE in maize. This study provided new perspective for exploring the efficiency of the laccase-assisted maize in the remediation of contaminated soil, evaluating the way for reducing the risk of secondary pollution of plants in the phytoremediation process.

Correlation study between motor rehabilitation level and psychological state in patients with limb movement disorders after stroke.

BACKGROUND: The psychological state of patients with post stroke limb movement disorders undergoes a series of changes that affect rehabilitation training and recovery of limb motor function. AIM: To determine the correlation between motor rehabilitation and the psychological state of patients with limb movement disorders after stroke. METHODS: Eighty patients with upper and lower limb dysfunction post stroke were retrospectively enrolled in our study. Based on Hospital Anxiety and Depression Scale (HADS) scores measured before rehabilitation, patients with HADS scores ≥ 8 were divided into the psychological group; otherwise, the patients were included in the normal group. Motor function and daily living abilities were compared between the normal and psychological groups. Correlations between the motor function and psychological status of patients, and between daily living ability and psychological status of patients were analyzed. RESULTS: After 1, 2, and 3 wk of rehabilitation, both the Fugl-Meyer assessment and Barthel index scores improved compared to their respective baseline scores (P < 0.05). A greater degree of improvement was observed in the normal group compared to the psychological group (P < 0.05). There was a negative correlation between negative emotions and limb rehabilitation (-0.592 ≤ r ≤ -0.233, P < 0.05), and between negative emotions and daily living ability (-0.395 ≤ r ≤ -0.199, P < 0.05). CONCLUSION: There is a strong correlation between motor rehabilitation and the psychological state of patients with post stroke limb movement disorders. The higher the negative emotions, the worse the rehabilitation effect.

Engineering Diselenide-IR780 Homodimeric Nanoassemblies with Enhanced Photodynamic and Immunotherapeutic Effects for Triple-Negative Breast Cancer Treatment.

Photodynamic therapy (PDT) has emerged as an efficient approach for non-invasive cancer treatment. However, organic small-molecule photosensitizers are often associated with defects in hydrophobicity, poor photostability, and aggregation-caused quenching, which limit their application. Usually, the carrier-assisted drug delivery system is a common strategy to solve the above obstacles, but additional carrier material could increase the risk of potential biological toxicity. The carrier-free drug delivery system with easy preparation and high drug-loading capability is proposed subsequently as a potential strategy to develop the clinical use of hydrophobic drugs. Herein, we rationally designed three IR780-based carrier-free nanosystems formed by carbon/disulfide/diselenide bond conjugated IR780-based homodimers. The IR780-based homodimers could self-assemble to form nanoparticles (DC-NP, DS-NP, DSe-NP) and exhibited higher reactive oxygen species generation capability and photostability than free IR780, in which DSe-NP with 808 nm laser irradiation performed best and resulted in the strongest cytotoxicity to 4T1 cells. Meanwhile, the glutathione consumption ability of DSe-NP boosted its PDT effect and then induced excessive oxidative stress of 4T1 cells, increasing antitumor efficacy by enhancing immunogenic cell death further. In tumor-bearing mice, DSe-NP displayed obvious tumor site accumulation, which obviously inhibited tumor growth and metastasis, and enhanced the immunological effect by effectively inducing dendritic cells to mature and activating T lymphocytes and natural killer cells. In summary, our study presented an IR780-based carrier-free nanodelivery system for a combination of PDT and immunity therapy and established expanding the application of organic small-molecule photosensitizers by an approach of carrier-free drug delivery system.

Aspartate aminotransferase to platelet ratio at admission can predict the prognosis of patients with hemorrhagic fever with renal syndrome.

Early indicators are needed to predict the prognosis of patients with hemorrhagic fever with renal syndrome (HFRS). Aspartate aminotransferase to platelet ratio index (APRI) has been shown to be related to mortality risk of patients with various diseases. This study evaluated the prognostic value of APRI and other inflammatory scores in HFRS patients. Data of hospitalized HFRS patients from a tertiary hospital in northwest China were collected and the inflammatory scores such as APRI and neutrophil to lymphocyte count ratio (NLR) were calculated at the day of patient admission. Independent factors related to the survival of patients were determined by multivariate logistic regression. Receiver operating characteristic curve was used to analyze the predictive value, and area under the curve (AUC) and 95% confidence interval (CI) were calculated for quantification. Of the 317 HFRS patients included in study, 15 patients died. Age (OR: 1.10, 95% CI: 1.04-1.16, p = 0.001), NLR (OR: 1.11, 95% CI: 1.02-1.19, p = 0.01), and APRI (OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were quantitative objective factors independently associated with the survival of patients. APRI had an AUC of 0.95 (95% CI: 0.91-1.00, p < 0.001) for predicting the prognosis of patients, with a sensitivity of 93.3% and a specificity of 86.8%. The performance of APRI was better than that of age or NLR. Patients with an APRI ≥ 6.15 had significantly decreased survival compared with those with an APRI < 6.15. In conclusion, this simple index APRI calculated at admission can serve as a biomarker to identify HFRS patients at risk of poor prognosis.

Tissue Engineering in Neuroscience: Applications and Perspectives.

Neurological disorders have always been a threat to human physical and mental health nowadays, which are closely related to the nonregeneration of neurons in the nervous system (NS). The damage to the NS is currently difficult to repair using conventional therapies, such as surgery and medication. Therefore, repairing the damaged NS has always been a vast challenge in the area of neurology. Tissue engineering (TE), which integrates the cell biology and materials science to reconstruct or repair organs and tissues, has widespread applications in bone, periodontal tissue defects, skin repairs, and corneal transplantation. Recently, tremendous advances have been made in TE regarding neuroscience. In this review, we summarize TE's recent progress in neuroscience, including pathological mechanisms of various neurological disorders, the concepts and classification of TE, and the most recent development of TE in neuroscience. Lastly, we prospect the future directions and unresolved problems of TE in neuroscience.

Mixed whey and pea protein based cold-set emulsion gels induced by calcium chloride: Fabrication and characterization.

The cold-set gels of oil-in-water emulsions stabilized by mixtures of whey protein isolate (WPI) and pea protein isolate (PPI) with mass ratios of 10:0, 7:3, 5:5, 3:7, and 0:10 were investigated to evaluate the possibility of pea protein to replace milk protein. Particle size and surface charge of emulsions increased and decreased with raised PPI content, respectively. The redness and yellowness of emulsion gels were strengthened with elevated pea protein percentage and independent of calcium concentration applied. Considerable differences in water holding capacity were observed between samples with different mixed proteins and high percentage of pea protein gave better water retaining ability. Gradual decreases in hardness and chewiness of emulsion gels were observed at three calcium levels with the increased PPI proportion. FT-IR spectra indicated no new covalent bonds were generated between samples with different whey and pea protein mass ratios. As PPI concentration elevated, the network structure of emulsion gels gradually became loose and disordered. The established cold-set calcium-induced whey/pea protein composite gels may have the potential to be utilized as a new material to encapsulate and deliver environment sensitive bio-active substances.

The role of microplastics in the process of laccase-assisted phytoremediation of phenanthrene-contaminated soil.

Polycyclic aromatic hydrocarbons (PAHs) are highly toxic organic pollutants widely distributed in terrestrial environments and laccase was considered as an effective enzyme in PAHs bioremediation. However, laccase-assisted phytoremediation of PAHs-contaminated soil has not been reported. Moreover, the overuse of plastic films in agriculture greatly increased the risk of co-existence of PAHs and microplastics in soil. Microplastics can adsorb hydrophobic organics, thus altering the bioavailability of PAHs and ultimately affecting the removal of PAHs from soil. Therefore, this study aimed to evaluate the efficiency of laccase-assisted maize (Zea mays L.) in the remediation of phenanthrene (PHE)-contaminated soil and investigate the effect of microplastics on this remediation process. The results showed that the combined application of laccase and maize achieved a removal efficiency of 83.47 % for soil PHE, and laccase significantly reduced the accumulation of PHE in maize. However, microplastics significantly inhibited the removal of soil PHE (10.88 %) and reduced the translocation factor of PHE in maize (87.72 %), in comparison with PHE + L treatment. Moreover, microplastics reduced the laccase activity and the relative abundance of some PAHs-degrading bacteria in soil. This study provided an idea for evaluating the feasibility of the laccase-assisted plants in the remediation of PAHs-contaminated soil, paving the way for reducing the risk of secondary pollution in the process of phytoremediation.

The Evolution of Insulation Performance of Fiber-Reinforced Silica Aerogel after High-Temperature Treatment.

Fiber-reinforced silica aerogel blankets (FRABs) are an important high-temperature thermal insulation material for industry applications that have emerged in recent years. In order to better understand the performance evolution of FRABs at high temperatures, the effect of heat treatment at different temperatures on the performance of FRABs as well as their base material, hydrophobic silica aerogel powder and glass wool, was investigated. The property evolution of the hydrophobic silica aerogel powder showed two stages with an increase in thermal treatment temperatures. The skeleton structure of the aerogel remained unchanged, but the residual organic chemicals, such as hydrophobic groups, were decomposed when the heat treatment temperature was lower than 400 °C. Above 400 °C, the skeleton began to shrink with the increase in temperature, which led to an increase in thermal conductivity. The structure and room-temperature thermal conductivity of the glass wool blanket were less affected by a heat treatment temperature under 600 °C. Therefore, the performance degradation of FRABs at high temperatures is mainly due to the change in the aerogel powder. The insulation performance of the glass wool and FRAB at high temperatures was studied using a heating table which was designed to simulate working conditions. The energy savings of using FRABs instead of glass fiber were calculated and are discussed here.

Microvascularized tumor assembloids model for drug delivery evaluation in colorectal cancer-derived peritoneal metastasis.

Peritoneal metastasis (PM) is a fatal state of colorectal cancer, and only a few patients may benefit from systemic chemotherapy. Although hyperthermic intraperitoneal chemotherapy (HIPEC) brings hope for affected patients, the drug development and preclinical evaluation of HIPEC are seriously lagging behind, mainly due to the lack of an ideal in vitro PM model that makes drug development over-reliant on expensive and inefficient animal experiments. This study developed an in vitro colorectal cancer PM model [microvascularized tumor assembloids (vTA)] based on an assembly strategy of endothelialized microvessels and tumor spheroids. Our data showed that the in vitro perfusion cultured vTA could maintain a similar gene expression pattern to their parental xenografts. Also, the drug penetration pattern of the in vitro HIPEC in vTA could mimic the drug delivery behavior in tumor nodules during in vivo HIPEC. More importantly, we further confirmed the feasibility of constructing a tumor burden-controlled PM animal model using vTA. In conclusion, we propose a simple and effective strategy to construct physiologically simulated PM models in vitro, thus providing a basis for PM-related drug development and preclinical evaluation of locoregional therapies. STATEMENT OF SIGNIFICANCE: This study developed an in vitro colorectal cancer peritoneal metastasis (PM) model based on microvascularized tumor assembloids (vTA) for drug evaluation. With perfusion culture, vTA could maintain a similar gene expression pattern and tumor heterogeneity to their parental xenografts. And the drug penetration pattern in vTA was similar to the drug delivery behavior in tumor nodules under in vivo treatment. Moreover, vTA was more conducive to construct PM animal models with controllable tumor burden. In conclusion, the construction of vTA could provide a new strategy for the PM-related drug development and preclinical evaluation of locoregional therapies.

Understanding molecular interaction between thermally modified ß-lactoglobulin and curcumin by multi-spectroscopic techniques and molecular dynamics simulation.

This study elucidated the binding of curcumin (CUR) onto preliminary thermally modified ß-lactoglobulin (ß-LG). ß-LG at pH 8.1 was heated at 75 °C, 80 °C and 85 °C for 10 min to construct denatured proteins (ß-LG75, ß-LG80, ß-LG85). Steady and time-resolved fluorescence studies uncovered that CUR quenched proteins in simultaneous static and dynamic mode. Pre-heating ß-LG improved its binding with CUR and the strongest affinity occurred in ß-LG80. Fluorescence resonance energy transfer (FRET) analysis indicated that binding distance between CUR and ß-LG80 was the smallest and energy transfer was the most efficient. ß-LG80 had the highest surface hydrophobicity. Fourier-transform infrared (FT-IR) spectroscopy and differential scanning calorimeter (DSC) confirmed that CUR transferred from crystal to amorphous state after association with protein and revealed the contribution of hydrogen bonds. Combination of ß-LG80 with CUR retained the antioxidant capacity of each component. Molecular dynamics simulation demonstrated enhanced hydrophobic solvent accessible surface area of ß-LG80 compared with native protein. Data obtained from this study may provide useful information for comprehensively understanding the ability of ß-lactoglobulin to bind hydrophobic substances under different environmental conditions like high temperature and alkaline medium.

Lycopene-loaded emulsions stabilized by whey protein covalently modified with pectin or/and chlorogenic acid: Enhanced physicochemical stability and reduced bio-accessibility.

Lycopene-loaded emulsions were formulated with whey protein isolate (WPI) covalently modified with high methoxylated pectin (HMP) or/and chlorogenic acid (CA) prepared by dry heating or/and alkali grafting. Covalent WPI products were confirmed by SDS-PAGE and degree of graft/CA binding equivalent values. The α-helix and ß-sheet percentage, surface hydrophobicity and fluorescence intensity of WPI decreased significantly (p < 0.05) upon binding. Both binary and ternary complexes enhanced the stability of the emulsions, and lycopene retained more after UV irradiation, thermal treatment, storage, compared with emulsions stabilized by WPI, with the best protection by both ternary complexes. In vitro simulated digestion results showed that free fatty acids were released in the order of WPI > WPI-HMP > WPI-CA > WPI-HMP-CA ≈ WPI-CA-HMP. Bio-accessibility analysis showed the same trend as the fatty acid release rate. These results may provide a theoretical basis for applications of conjugating protein with polysaccharide or/and polyphenol emulsions.

Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy.

The use of bacteria as living vehicles has attracted increasing attentions in tumor therapy field. The combination of functional materials with bacteria dramatically facilitates the antitumor effect. Here, we presented a rationally designed living system formed by programmed Escherichia Coli MG1655 cells (Ec) and black phosphorus (BP) nanoparticles (NPs). The bacteria were genetically engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), via an outer membrane YiaT protein (Ec-T). The Ec-T cells were associated with BP NPs on their surface to acquire BP@Ec-T. The designed living system could transfer the photoelectrons produced by BP NPs after laser irradiation and triggered the reductive metabolism of nitrate to nitric oxide for the in situ release at tumor sites, facilitating the therapeutic efficacy and the polarization of tumor associated macrophages to M1 phenotype. Meanwhile, the generation of reactive oxygen species induced the immunogenic cell death to further improve the antitumor efficacy. Additionally, the living system enhanced the immunological effect by promoting the apoptosis of tumor cells, activating the effect of T lymphocytes and releasing the pro-inflammatory cytokines. The integration of BP NPs, MG1655 cells and TRAIL led to an effective tumor therapy. Our work established an approach for the multifunctional antitumor living therapy.

Clinical and laboratory features and factors predicting disease severity in pediatric patients with hemorrhagic fever with renal syndrome caused by Hantaan virus.

The clinical features and factors associated with disease severity in children with hemorrhagic fever with renal syndrome (HFRS) have not been well characterized. This study analyzed the clinical and laboratory factors associated with disease severity in children with HFRS caused by Hantaan virus. Data in pediatric patients with HFRS were retrospectively collected from Xi'an Children's Hospital over a 9-year period. Independent factors associated with disease severity were identified. Nomogram predicting disease severity was constructed based on variables filtered by feature selection. In total, 206 children with HFRS were studied. Fever, digestive tract symptoms, headache, backache, bleeding, and renal injury signs were the common symptoms. Elevated white blood cell, reduced platelet, hematuria, proteinuria, coagulation abnormalities, increased blood urea nitrogen (BUN) and procalcitonin (PCT), decreased estimated glomerular filtration rate and low serum Na+ , Cl- , and Ca2+ were the common laboratory findings. In the 206 patients, 21 patients had critical type disease and 4 patients (1.9%) died. Hydrothorax, hypotension and cerebral edema/cerebral herniation at hospital admission were independent clinical characteristics, and neutrophil %, prothrombin activity, PCT, BUN, and Ca2+ at hospital admission were independent laboratory factors associated with critical disease. Feature selection identified BUN, PCT and prothrombin time as independent factors related to critical disease. A nomogram integrating BUN and PCT at admission was constructed and calibration showed high accuracy for the probability prediction of critical disease. In conclusion, this study characterized the clinical and laboratory features and constructed a nomogram predicting disease severity in pediatric HFRS, providing references for disease severity evaluation in managing children HFRS.

Tumor microenvironment-activated Nb2C quantum dots/lactate oxidase nanocatalyst mediates lactate consumption and macrophage repolarization for enhanced chemodynamic therapy.

Chemodynamic therapy (CDT), which takes advantages of CDT agents to selectively induce tumor cells apoptosis via Fenton or Fenton-like reactions, is considered to have great potential for tumor-specific treatment. However, the therapeutic outcome of CDT still faces the challenges of the lack of efficient CDT agents and insufficient supply of endogenous H2O2. Herein, to explore highly efficient CDT agents as well as increase the H2O2 content at tumor sites to enhance the efficiency of CDT, a red blood cell (RBC) membrane encapsulated Nb2C quantum dots/lactate oxidase (LOD) nanocatalyst (Nb2C QDs/LOD@RBC) was proposed. Nb2C quantum dots are quite prospective as efficient CDT agents in CDT application due to the intrinsic merits such as abundant active catalytic sites, satisfactory hydrophilicity, and good biocompatibility. The encapsulation of Nb2C QDs and LOD into RBC membrane was to prolong the in vivo circulation time of the nanocatalyst and increase its tumor sites accumulation. The accumulated Nb2C QDs/LOD@RBC nanocatalyst could efficiently convert the endogenous H2O2 into ·OH, while the overexpressed lactate could be catalyzed into H2O2 by LOD to replenish the depletion of H2O2. The cascaded reaction between Nb2C quantum dots and LOD eventually enhanced the CDT effect of Nb2C QDs/LOD@RBC nanocatalyst for tumors growth inhibition. Moreover, the consumption of lactate at tumor sites induced by Nb2C QDs/LOD@RBC nanocatalyst leads to the increased infiltration of antitumoral M1 tumor-associated macrophages, which alleviated the immunosuppression of the tumor microenvironment and further maximized the therapeutic outcome of CDT. Taken together, the Nb2C QDs/LOD@RBC nanocatalyst provides a promising paradigm for tumor inhibition via catalytic cascaded reaction between Nb2C quantum dots and LOD.

Extracellular vesicles secreted by human periodontal ligament induced osteoclast differentiation by transporting miR-28 to osteoclast precursor cells and further promoted orthodontic tooth movement.

BACKGROUND: Osteoclast differentiation plays a key role in orthodontic tooth movement (OTM). We aimed to explore the role of human periodontal ligament (hPDL) extracellular vesicles (EVs) in osteoclast differentiation and OTM. METHODS: The hPDL cells were exposed to 4.0 g/cm2 compression force (CF) and the hPDL-EVs were collected. The peripheral blood mononuclear cells were isolated, purified, and induced osteoclast differentiation. The OTM rat model was established through excess orthodontic force. Dual-luciferase reporter gene assay verified the targeting effect of miR-28 on RUNX1. In addition, tartrate-resistant acid phosphase (TRAP) staining, immunofluorescence, western blot, and quantitative real-time PCR were also carried out. RESULTS: CF pretreated hPDL-EVs promoted osteoclast differentiation and down-regulated RUNX1 levels in in vitro and in vivo experiments. The addition of CF-hPDL-EVs also elevated tooth movement in OTM rats. Besides, miR-28 was significantly up-regulated in CF-pretreated hPDL-EVs. In addition, RUNX1 was negatively regulated by miR-28. Moreover, the addition of CF-lenti-miR-28 inhibitor-Evs down-regulated the expression of osteoclast marker genes and the number of TRAP positive (+) multinucleated cells (MNCs) in vitro. Furthermore, in vivo experiments confirmed that CF-lenti-miR-28 inhibitor-Evs injection down-regulated the number of TRAP (+) MNCs and inhibited tooth movement of OTM rats. CONCLUSION: CF-treated hPDL-EVs promoted osteoclast differentiation by transporting miR-28 and inhibiting the expression of RUNX1, which provides new insight into the specific mechanism of hPDL-Evs affecting osteoclast differentiation.

Degradable Multifunctional Porphyrin-Based Porous Organic Polymer Nanosonosensitizer for Tumor-Specific Sonodynamic, Chemo- and Immunotherapy.

Sonodynamic therapy (SDT) benefiting from its intrinsic merits, such as noninvasiveness and deep tissue penetrability, is receiving increasing considerable attention in reactive oxygen species (ROS)-based tumor treatment. However, current sonosensitizers usually suffer from low tumor lesion accumulation, insufficient ROS generation efficiency under ultrasound, and non-biodegradability, which seriously impede the therapeutic outcomes. Additionally, it is difficult that SDT alone can completely eradicate tumors because of the complex and immunosuppressive tumor microenvironment (TME). Herein, we simultaneously employ sonosensitive porphyrin building blocks and glutathione (GSH)-responsive disulfide bonds to construct a novel degradable multifunctional porphyrin-based hollow porous organic polymer (POP) nanosonosensitizer (H-Pys-HA@M/R), which combine SDT, "on-demand" chemotherapy, and immunotherapy. Taking the unique advantages of POPs with designable structures and high specific surface area, this H-Pys-HA@M/R nanosonosensitizer can achieve tumor target accumulation, GSH-triggered drug release, and low-frequency ultrasound-activating ROS generation with encouraging results. Furthermore, this multifunctional nanosonosensitizer can effectively evoke immunogenic cell death (ICD) response through the combination of SDT and chemotherapy for both primary and distal tumor growth suppression. Meanwhile, H-Pys-HA@M/R exhibits favorable biodegradation and biosafety. Therefore, this study provides a new strategy for reasonably designing and constructing POP-related sonosensitizers combining SDT/chemotherapy/immunotherapy triple treatment modalities to eradicate malignant tumors.