Anti-pyroptosis biomimetic nanoplatform loading puerarin for myocardial infarction repair: From drug discovery to drug delivery.

Pyroptosis is a critical pathological mechanism implicated in myocardial damage following myocardial infarction (MI), and the crosstalk between macrophages and pyroptotic cardiomyocytes presents a formidable challenge for anti-pyroptosis therapies of MI. However, as single-target pyroptosis inhibitors frequently fail to address this crosstalk, the efficacy of anti-pyroptosis treatment post-MI remains inadequate. Therefore, the exploration of more potent anti-pyroptosis approaches is imperative for improving outcomes in MI treatment, particularly in addressing the crosstalk between macrophages and pyroptotic cardiomyocytes. Here, in response to this crosstalk, we engineered an anti-pyroptosis biomimetic nanoplatform (NM@PDA@PU), employing polydopamine (PDA) nanoparticles enveloped with neutrophil membrane (NM) for targeted delivery of puerarin (PU). Notably, network pharmacology is deployed to discern the most efficacious anti-pyroptosis drug (puerarin) among the 7 primary active monomers of TCM formulations widely applied in clinical practice and reveal the effect of puerarin on the crosstalk. Additionally, targeted delivery of puerarin could disrupt the malignant crosstalk between macrophages and pyroptotic cardiomyocytes, and enhance the effect of anti-pyroptosis by not only directly inhibiting cardiomyocytes pyroptosis through NLRP3-CASP1-IL-1ß/IL-18 signal pathway, but reshaping the inflammatory microenvironment by reprogramming macrophages to anti-inflammatory M2 subtype. Overall, NM@PDA@PU could enhance anti-pyroptosis effect by disrupting the crosstalk between M1 macrophages and pyroptotic cardiomyocytes to protect cardiomyocytes, ameliorate cardiac function and improve ventricular remodeling, which providing new insights for the efficient treatment of MI.

Diphasic CeO2 Nanocrystal/Bioactive Glass Nanosphere-Based Composite Hydrogel for Diabetic Wound Healing by Reactive Oxygen Species Scavenging and Inflammation Regulation.

Background: Antioxidant therapy aimed at reducing excessive local oxidative stress is one of the most important strategies for promoting diabetic wound repair. The reversible transformation of Ce3+/Ce4+ in ceria (CeO2) can reduce excessive local oxidative stress. However, inducing angiogenesis, local anti-inflammatory effects, and other positive effects are challenging. Therefore, ideal dressings for chronic diabetic wound management must concurrently reduce excessive oxidative stress, promote angiogenesis, and have anti-inflammatory effects. Methods: In this study, Ce-doped borosilicate bioactive glasses (BGs) were prepared using the sol-gel method, and CeO2 nanocrystals (CeO2-NCs) were precipitated on the glass surface by heat treatment to obtain BG-xCe composite glass nanospheres. Subsequently, nanospheres were modified by amino group and combined with dopamine and acrylamide to obtain BG-xCe/polydopamine/polyacrylamide (PDA/PAM) composite hydrogel. Then, the morphology and properties of composite hydrogels were detected, and the properties to treat the diabetic wounds were also evaluated. Results: The results demonstrated that the BG-10Ce/PDA/PAM composite hydrogel possessed excellent tensile and adhesive properties. In vitro, the migration and angiogenesis of human umbilical vein endothelial cells (HUVECs) and fibroblasts (L929) were enhanced by reducing reactive oxygen species (ROS) levels in the conditioned medium. Animal experiments have shown that CeO2-NCs in hydrogels effectively scavenge ROS in diabetic wounds, and Sr dissolved from the glassy phase can modulate macrophage polarization to the M2 phenotype. Conclusions: The synergistic effect of both amorphous materials and nanocrystals provides the BG-10Ce/PDA/PAM composite hydrogel with great potential for diabetic wound healing.

Decreased plasma docosahexaenoic acid concentration in chronic obstructive pulmonary disease patients with pulmonary Hypertension: Findings from human lipidomics and transcriptomics analysis.

Oxylipins derived from polyunsaturated fatty acids (PUFAs) are important endogenous signaling molecules, but are little characterized in pulmonary hypertension (PH) due to chronic obstructive pulmonary disease (COPD). In this study, we identified novel plasma oxylipins associated with PH risk in COPD patients. The plasma oxylipin profiles of COPD patients without PH (COPD-noPH) or with PH (COPD-PH) were obtained from discovery and validation cohort, using the process of LC-MS/MS analysis. There was a significant decrease in the plasma levels of both free docosahexaenoic acid (DHA) and DHA-derived oxylipins in the COPD-PH group. The multivariable logistic regression model identified DHA and four DHA-derived oxylipins (13-HDHA, 10-HDHA, 8-HDHA and 16-HDHA) exhibited significant differences between the two groups after adjusting for sex, BMI, FEV1% predicted, and smoking status. The diagnostic value of these metabolites was further evaluated through ROC curve analysis. The transcriptome profiles in peripheral blood mononuclear cells (PBMCs) of COPD-PH patients and COPD-PH patients were detected through high-throughput sequencing. The enrichment analysis revealed that the upregulated differentially expressed genes (DEGs) were highly enriched in the interferon signaling pathway. In addition, DHA supplementation proved that DHA may inhibit the development of pH by reducing the secretion of interferons derived from PBMCs. This conjecture was further confirmed by the higher level of serum interferon-γ and interferon-α2 of COPD-PH patients than that of COPD-noPH patients. The present study highlights that decreased DHA and DHA-derived oxylipins levels are suggestive of a higher risk of pH development in COPD cases.

Clinical and radiological features associated with rupture of pulmonary artery pseudoaneurysm: a retrospective study.

BACKGROUND: Hemoptysis resulting from rupture of the pulmonary artery pseudoaneurysm (PAP) is massive and fatal, while factor contributing to the rupture of pseudoaneurysm remains elusive. This study aimed to elucidate the clinical and radiological features of PAP and identify the risk factors associated with rupture. METHODS: Patients who developed hemoptysis with PAP were collected from January 2019 to December 2022 retrospectively. Clinical data of the demographic characteristics, radiological findings, treatment strategies, and prognosis were collected. A comparative analysis was performed on the characteristics in the ruptured and non-ruptured cases. RESULTS: A total of 58 PAPs were identified in the 50 patients. The most common causes were infection (86%) and cancer (8%). The PAPs were located predominantly in the upper lobes of both lungs, and 57 (99.3%) were distributed in the segmental or subsegmental pulmonary arteries. The median diameter was 6.1(4.3-8.7) mm. A total of 29 PAPs were identified adjacent to pulmonary cavitations, with the median diameter of the cavity being 18.9 (12.4-34.8) mm. Rupture of pseudoaneurysm occurred in 21 cases (42%). Compared to unruptured group, the ruptured group had a significantly higher proportion of massive hemoptysis (57.1% vs. 6.9%, p < 0.001), larger pseudoaneurysm diameter (8.1 ± 3.2 mm vs. 6.0 ± 2.3 mm, p = 0.012), higher incidence of pulmonary cavitation (76.2% vs. 44.8%, p = 0.027), and larger cavitation diameters (32.9 ± 18.8 mm vs. 15.7 ± 8.4 mm, p = 0.005). The mean pulmonary artery pressure (mPAP) in the ruptured group was also significantly higher than that in the unruptured group [23.9 ± 7.4 mmHg vs. 19.2 ± 5.0 mmHg, p = 0.011]. Endovascular treatment was successfully performed in all 21 patients with ruptured PAP, of which the clinical success rate was 96.0%. Five patients experienced recurrent hemoptysis within one year. CONCLUSIONS: Massive hemoptysis, pseudoaneurysm diameter, pulmonary cavitation, and elevated mPAP were the risk factors for rupture of pseudoaneurysm. Our findings facilitate early identification and timely intervention of PAP at high risk of rupture.

Peptide-based PET tracer targeting LAG-3 for evaluating the efficacy of immunotherapy in melanoma.

BACKGROUND: Lymphocyte activation gene 3 (LAG-3) is expressed on activated immune cells and has emerged as a promising target for immune checkpoints blockade. However, conflicting findings have been reported regarding the association between LAG-3 expression in tumors and patient prognosis, indicating the need for further investigation into the significance of LAG-3 expression levels in tumor therapies. In this study, 68Ga-NOTA-XH05, a novel peptide-based positron emission tomography (PET) tracer targeting LAG-3, was constructed to non-invasively detect LAG-3 expression in melanoma after CpG oligonucleotide (CpG) treatment and explore the relationship between LAG-3 expression and therapeutic effect. METHODS: The tracer 68Ga-NOTA-XH05 was identified by high-performance liquid chromatography after being prepared and purified. Cell uptake and blocking essays were performed to verify the specificity of the tracer in vitro. The expression of LAG-3 in B16-F10 subcutaneous tumors was monitored by flow cytometry, and its correlation with the tracer uptake was analyzed to evaluate the tracer specificity. PET imaging and biodistribution studies were conducted after CpG treatment of unilateral or bilateral B16-F10 subcutaneous tumor models to assess the ability of 68Ga-NOTA-XH05 in monitoring immunotherapy efficacy and the abscopal effect of CpG. RESULTS: Following purification, 68Ga-NOTA-XH05 exhibited high radiochemical purity and specificity. Flow cytometry analysis revealed a positive correlation between LAG-3 expression in tumors and the uptake of 68Ga-NOTA-XH05. In B16-F10 bearing mice treated with CpG, PET imaging using 68Ga-NOTA-XH05 demonstrated a higher tumor to blood ratio (TBR) compared with the control group. Furthermore, TBR values obtained from CpG-treated mice allowed for differentiation between responders and non-responders. In a bilateral subcutaneous tumor model where only right-sided tumors were treated with intratumoral injection of CpG, TBR values of left-sided tumors were significantly higher than those in the control group, indicating that 68Ga-NOTA-XH05 could effectively monitor the systemic effect of local CpG injection. CONCLUSION: Our findings highlight the detection capability of 68Ga-NOTA-XH05 in assessing LAG-3 expression levels within tumors and evaluating response to immunotherapy, thereby suggesting promising clinical translational prospects.

Cell Membrane Hybrid Lipid Nanovesicles Enhance Innate Immunity for Synergistic Immunotherapy by Promoting Immunogenic Cell Death and cGAS Activation.

Immunotherapy shows great therapeutic potential for long-term protection against tumor relapse and metastasis. Innate immune sensors, such as cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), dissolve DNA and induce type I interferon. Through activation of the cGAS/STING pathway, chemotherapy drugs and reversine (REV) may provide synergetic anti-tumor effects. Here, we prepared drug-loaded cell membrane hybrid lipid nanovesicles (LEVs) (designated LEV@DOX@REV) by fusion of cell membranes, phospholipids, doxorubicin (DOX), and REV, to realize accurate delivery to tumors and chemo-immunotherapy. The cell membranes of LEVs confer "homing" abilities. DOX can induce immunogenic cell death as a result of its specific immunomodulatory effects, which promotes the maturation of immune cells and improves the microenvironment of the immune system. REV is proven to efficiently activate cGAS/STING signaling, thereby enhancing the immune system. The antitumor efficacy of LEV@DOX@REV was evaluated in a 4T1 subcutaneous tumor xenograft model, a distant metastatic tumor model, and a liver metastatic tumor model. LEV@DOX@REV facilitated the infiltration of cytotoxic T lymphocytes within tumors, increased the secretion of proinflammatory cytokines, and modified the tumor microenvironment. In conclusion, LEV@DOX@REV displayed favorable antitumor effects and extended the survival of tumor-bearing mice. We therefore successfully developed nanoparticles capable of enhancing immune activation that have potential therapeutic applications for cancer immunotherapy.

Enhanced osteogenesis and physicochemical properties of PMMA bone cement with SrBG/HA porous core-shell microspheres.

Artificial bone graft with osteoconductivity, angiogenesis, and immunomodulation is promising clinical therapeutics for the reluctant healing process of bone defects. Among various osteogenic substitutes, polymethyl methacrylate (PMMA) bone cement is a quit competitive platform due to its easy deployment to the bone defects with irregular shape and biomimetic mechanical properties. However, the biologically inert essence of PMMA is reliant on the passive osseointegration and cannot provide sufficient biologic cues to induce fast bone repair. Bioactive glass could serve as an efficient platform for the active osteogenesis of PMMA via ionic therapy and construction of alkaline microenvironment. However, the direct of deployment of bioactive glass into PMMA may trigger additional cytotoxicity and hinder cell growth on its surface. Hence we incorporated ionic therapy as osteogenic cue into the PMMA to enhance the biomedical properties. Specifically, we synthesized core-shell microspheres with a strontium-doped bioactive glass (SrBG) core and hydroxyapatite (HA) shell, and then composited them with PMMA to introduce multifunctional effects of HA incorporation, alkaline microenvironment construction, and functional ion release by adding microsphere. We preparedxSrBG@HA/PMMA cements (x= 30, 40, 50) with varied microsphere content and evaluated impacts on mechanical/handling properties, ion release, and investigated the impacts of different composite cements on proliferation, osteogenic differentiation, angiogenic potential, and macrophage polarization. These findings provide new perspectives and methodologies for developing advanced bone biomaterials to promote tissue regeneration.

Enhanced ·OH-Scavenging Activity of Cu-CeOx Nanozyme via Resurrecting Macrophage Nrf2 Transcriptional Activity Facilitates Diabetic Wound Healing.

Diabetic wounds are a prevalent and devastating complication of diabetes, which may impede their healing and regeneration. In diabetic wounds, excess reactive oxygen species (ROS) activate the nuclear factor kappa-B pathway, leading to transcriptional silencing of nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in a vicious cycle of oxidative stress and inflammation. Conventional nanozymes have limitations in preventing the continuous production of ROS, including the most oxidizing reactive hydroxyl radical (·OH), although they can remove pre-existing ROS. Herein, a novel antioxidant nanoplatform addresses this challenge by incorporating JSH-23 into the mesoporous of cupric-doped cerium oxide nanozymes. Additionally, for rapid wound adaptability and durable tissue adhesion, a nanozyme hydrogel spray consisting of oxidized sodium alginate and methacrylate gelatin is constructed, named OG@CCJs. This platform resurrects Nrf2 transcriptional activity of macrophages in vitro, curbing the production of ROS at its source, particularly ·OH, while enabling the nanozymes to scavenge previously generated ROS. OG@CCJs significantly alleviate oxidative stress in diabetic wounds in vivo, promoting wound healing. Overall, the proposed nanozyme-hydrogel spray with enhanced ·OH-scavenging activity uses a "two-track" antioxidant strategy to rebuild the antioxidant defense barrier of macrophages. This pioneering approach highlights the tremendous potential of OG@CCJs for facilitating diabetic wound healing.

Spatiotemporal characteristics of meteorological drought events in 34 major global river basins during 1901-2021.

Meteorological drought is a crucial driver of various types of droughts; thus, identifying the spatiotemporal characteristics of meteorological drought at the basin scale has implications for ecological and water resource security. However, differences in drought characteristics between river basins have not been clearly elucidated. In this study, we identify and compare meteorological drought events in 34 major river basins worldwide using a three-dimensional drought-clustering algorithm based on the standardised precipitation evapotranspiration index on a 12-month scale from 1901 to 2021. Despite synchronous increases in precipitation and potential evapotranspiration (PET), with precipitation increasing by more than three times the PET, 47 % (16/34) of the basins showed a tendency towards drought in over half their basin areas. Drought events occurred frequently, with more than half identified as short-term droughts (lasting less than or equal to three months). Small basins had a larger drought impact area, with major drought events often originating from the basin boundaries and migrating towards the basin centre. Meteorological droughts were driven by changes in sea surface temperature (SST), especially the El Niño Southern Oscillation (ENSO) or other climate indices. Anomalies in SST and atmospheric circulation caused by ENSO events may have led to altered climate patterns in different basins, resulting in drought events. These results provide important insights into the characteristics and mechanisms of meteorological droughts in different river basins worldwide.

Decreasing trends of mean and extreme snowfall in High Mountain Asia.

Intense warming profoundly alters precipitation phase patterns and intensity in High Mountain Asia (HMA). While snowfall climatology and precipitation extremes have been studied, there is a lack of understanding of snowfall extremes within HMA. Here, we investigate the spatial and temporal variability of non-extreme and extreme snowfall in hydrological years 1979-2020 using multi-source meteorological data, compare weather systems during extreme and non-extreme snowfall events, and identify key circulation factors that influence fluctuations in mean annual snowfall and extreme snowfall. The snowfall amount (-0.13 d/mm), days (-0.56 d/a), and fraction (-0.0012) were significantly reduced in HMA, with a shorter snowfall season (-0.52 d/a). Some extreme snowfall metrics (maximum 1-day snowfall and maximum 3-day snowfall) were insensitive to climate change, whereas the maximum consecutive snowfall days (-0.007 d/a), snowfall amount (-0.0023 mm/a), heavy snowfall days (S95pD; 0.0087 d/a), and extremely heavy snowfall days (S99pD; -0.1019 d/a) showed significant decreases. Synthetic analyses show that extreme snowfall events were more likely to occur within a narrow temperature range (-5 °C to 3 °C) with higher relative humidity and precipitation compared to non-extreme events. A stepwise regression method was used to determine that the fluctuation in the average annual snowfall was closely related to the Atlantic Multidecadal Oscillation, whereas the variation in extreme snowfall was mainly influenced by the Southern Oscillation Index. Our research provides a reference for assessing the potential impacts of climate change on a regional scale for risk management and disaster adaptation.

[Comparison of Pb2+ Adsorption Properties of Biochars Modified Through CO2 Atmosphere Pyrolysis and Nitric Acid].

Acid modification has been widely used to modify the structural properties of biochars. However, acid modification led to the large consumption of acid, increased difficulty of waste effluent disposal, and a high application cost. To evaluate the advantages and application potential of biochars prepared under CO2, utilizing pyrolysis to directly modify biochars to improve heavy metal removal efficiency and reduce production cost, would be an important prerequisite for the broad application of biochars. The sorption performance of Pb2+ with CO2-modified biochars was compared with that of HNO3-modified biochar. The elemental compositions and structural properties of biochars were characterized through elemental analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The results revealed that for biochars produced at 500℃, HNO3 modification produced abundant carboxylic groups and -NO2 (asy) and -NO2 (sym) groups, promoting the surface activities and complexing abilities of biochars. The CO2-modified biochars contained abundant carbonate minerals, which could remove Pb2+ by electrostatic ion exchange and coprecipitation or complex. In addition, compared to that of HNO3-modified biochars, CO2-modified biochars had the larger specific surface area and better microporous structures, which were beneficial to the diffusion of Pb2+ and further promoted surface sorption. CO2 modification increased the maximum Pb2+ sorption capacity of W500CO2 and W700CO2, which were 60.14 mg·g-1 and 71.69 mg·g-1. By contrast, HNO3-modified biochars W500N2-A and W700N2-A showed the lower Pb2+ sorption capacities, which were 42.26 mg·g-1 and 68.3 mg·g-1, respectively. The increasing of the specific surface area and functional groups simultaneously promoted the sorption capacity of CO2-modified biochars. Consequently, the CO2-modified biochar had the advantages of low cost, environmental friendliness, and high heavy metal removal efficiency, which is a modification method worthy of promotion and application.

Biomimetic Targeting Nanoadjuvants for Sonodynamic and Chronological Multi-Immunotherapy against Holistic Biofilm-Related Infections.

Biofilm-related infections (BRIs) present significant challenges owing to drug resistance, adverse immune responses, and implant failure; however, current approaches inadequately cater to the diverse therapeutic requirements at different stages of infection. To address this issue, a multi-immunotherapy strategy in combination with sonodynamic therapy is proposed for the chronological treatment of BRIs. Macrophage membrane-decorated targeting sonosensitive nanoadjuvants are fabricated to load cytosine-phosphate-guanine oligodeoxynucleotide (CPG-ODN) or microRNA (miR)-21-5p. In the early stages of BRI (Stage I), CPG-ODN-loaded nanoadjuvants (CPG@HMPN@M) promote the formation of neutrophil extracellular traps to capture and neutralize detached microbes. During the late stage of infection (Stage II), CPG-ODNs redirect macrophage polarization into the M1 phase to combat infections via TLR9/Myd88/TRAF6 pathway. During these stages, CPG@HMPN@M generates singlet oxygen through sonodynamic processes, eradicating the biofilms under US irradiation. Once the BRIs are eliminated, miR-21-5p-loaded nanoadjuvants (miR@HMPN@M) are delivered to the lesions to suppress excessive inflammation and promote tissue integration by evoking macrophage M2 polarization during the repair phase (Stage III) through PTEN/PI3K/Akt pathway. This innovative approach aims to provide comprehensive treatment strategies for the chronological treatment of BRI by effectively eliminating infections, promoting tissue restoration, and implementing different immune regulations at different stages, thus demonstrating promising clinical value.

A Novel High Entropy Hydroxide Electrode Material for Promoting Energy Density of Supercapacitors and Its Efficient Synthesis Strategy.

In this work, a novel high entropy hydroxide NiCoMoMnZn-layered double hydroxide(LDH) is synthesized as an electrode material for supercapacitors using a novel template re-etching method to promote the energy density. As a positive electrode material for supercapacitors, NiCoMoMnZn-LDH has the advantage of a uniform distribution of elements, high specific surface area, porous and stable structure. More importantly, the specific capacitance can reach 1810.2 F g-1 at the current density of 0.5 A g-1 , and the NiCoMoMnZn-LDH//AC HSC assembled from the material has an energy density of up to 62.1 Wh kg-1 at a power density of 475 W kg-1 . Moreover, the influence of different compositions on their morphological, structural, and electrochemical properties is investigated based on the characterization results. Then, the synergistic mechanism among the components of the high entropy NiCoMoMnZn-LDH is revealed in detail by DFT calculations. In addition, the synthesis strategy proposed in this work for high-entropy hydroxides exhibits universality. Experimental results show that the proposed strategy successfully avoids not only phase separation and element aggregation in the formation of high entropy materials, but also reduces structural distortion, which is beneficial for efficient and large-scale synthesis of high entropy hydroxides.

Triptolide with hepatotoxicity and nephrotoxicity used in local delivery treatment of myocardial infarction by thermosensitive hydrogel.

Myocardial infarction (MI) resulting from coronary artery occlusion is the leading global cause of cardiovascular disability and mortality. Anti-inflammatory treatment plays an important role in MI treatment. Triptolide (TPL), as a Chinese medicine monomer, has a variety of biological functions, including anti-inflammatory, anti-tumor, and immunoregulation. However, it has been proved that TPL is poorly water soluble, and has clear hepatotoxicity and nephrotoxicity, which seriously limits its clinical application. Herein, we designed a long-acting hydrogel platform (TPL@PLGA@F127) for MI treatment by intramyocardial injection. First, we found that the inflammatory response and immune regulation might be the main mechanisms of TPL against MI by network pharmacology. Subsequently, we prepared the hydrogel platform (TPL@PLGA@F127) and tested its effects and toxicity on normal organs in the early stage of MI (3 days after MI-operation). The results showed that TPL@PLGA@F127 could not only promote "repair" macrophages polarization (to M2 macrophage) by day 3 after MI, but also has a long-lasting anti-inflammatory effect in the later stage of MI (28 days after MI-operation). Additionally, we proved that TPL@PLGA@F127 could attenuate the toxicity of TPL by releasing it more slowly and stably. Finally, we observed the long-term effects of TPL@PLGA@F127 on MI and found that it could improve cardiac function, depress the myocardial fibrosis and protect the cardiomyocytes. In summary, this study indicated that TPL@PLGA@F127 could not only enhance the therapeutic effects of TPL on MI, but also attenuate the hepatotoxicity and nephrotoxicity, which established a strong foundation for the clinical application of TPL for MI.

What makes vertical femoral neck fracture with posterior inferior comminution different? An analysis of biomechanical features and optimal internal fixation strategy.

BACKGROUND AND PURPOSE: Fracture comminution occurs in 83.9%-94% of vertical femoral neck fractures (VFNFs), the majority of which were located in posterior-inferior region, and poses a clinical challenge in fixation stability. We conducted a subject-specific finite element analysis to determine the biomechanical features and optimal fixation selection for treating VFNF with posterior-inferior comminution. PATIENTS AND METHODS: Eighteen models with three fracture types (VFNF without comminution [NCOM], with comminution [COM], with comminution + osteoporosis [COMOP]) and six internal fixation types (alpha [G-ALP], buttress [G-BUT], rhomboid [G-RHO], dynamic hip screw [G-DHS], invert triangle [G-ITR], femoral neck system (G-FNS)) were created based on the computed tomography data. By using the subject-specific finite element analysis method, stiffness, implant stress, yielding rate (YR) were compared. Additionally, in order to elucidate distinct biomechanical characters of different fracture types and fixation strategies, we calculated interfragmentary movement (IFM), detached interfragmentary movement (DIM), shear interfragmentary movement (SIM) of all fracture surface nodes. RESULTS: Generally, in comparison with NCOM, COM showed a 30.6% reduction of stiffness and 1.46-times higher mean interfragmentary movement. Besides, COM had a 4.66-times (p = 0.002) higher DIM at the superior-middle position, but similar SIM across fracture line, which presented as varus deformation. In COM and COMOP, among all six fixation strategies, G-ALP had significantly the lowest IFM (p<0.001) and SIM (p<0.001). Although G-FNS had significantly highest IFM and SIM (p<0.001), it had the highest stiffness and lowest DIM (p<0.001). In COMOP, YR was the lowest in G-FNS (2.67%). CONCLUSIONS: Posterior-inferior comminution primarily increases superior-middle detached interfragmentary movement in VFNF, which results in varus deformation. For comminuted VFNF with or without osteoporosis, alpha fixation has the best interfragmentary stability and anti-shear property among six current mainstream fixation strategies, but a relatively weaker stiffness and anti-varus property compared to fixed-angle devices. FNS is advantageous owing to stiffness, anti-varus property and bone yielding rate in osteoporosis cases, but is insufficient in anti-shear property.

Aggregation-induced emission photosensitizer/bacteria biohybrids enhance Cerenkov radiation-induced photodynamic therapy by activating anti-tumor immunity for synergistic tumor treatment.

Cerenkov radiation-induced photodynamic therapy (CR-PDT) gets rid of the limited tissue penetration depth of the external light source and provides a feasible scheme for the PDT excited by the internal light. However, due to the low luminescence intensity of Cerenkov radiation, CR-PDT alone cannot effectively inhibit tumor growth, curbing the potential clinical translation of CR-PDT. Herein, we reported an AIE-PS/bacteria biohybrid (EcN@TTVP) composed of Escherichia coli Nissle 1917 (EcN) loaded with aggregation-induced emission photosensitizer (AIE-PS) termed TTVP, which enhanced CR-PDT by activating anti-tumor immunity for synergistic tumor treatment. The preferential tumor-colonized EcN@TTVP and radiopharmaceutical 18F-fluorodeoxyglucose (18F-FDG) were administered sequentially to enable them to co-enrich in the tumor site, thereby triggering CR-PDT and promoting immunogenic tumor cell death. Most importantly, EcN acting as immunoadjuvants enhanced the maturation of dendritic cells (DCs) and priming of cytotoxic T cells (CTLs). Therefore, under the synergistic treatment of CR-PDT and immunotherapy, AIE-PS/bacteria biohybrids resulted in either efficient tumor remission or a survival prolongation in tumor-bearing mice, which presented significant advantages over single CR-PDT. Remarkably, no obvious toxic effects were observed during the treatment. In this study, we proposed a synergistic therapeutic strategy based on EcN@TTVP for combined CR-PDT and immunotherapy against tumors. Moreover, this strategy may have great potential in clinical translation and provide references for deep-seated tumor treatment. STATEMENT OF SIGNIFICANCE: PDT is restricted due to the shallow penetration depth of light into tumor tissues. Using CR as the excitation light source for PDT can overcome the aforementioned issue and greatly expand the application of PDT. However, the low efficacy of single CR-PDT limits further its applications. Therefore, the design and development of feasible strategies to improve the efficacy of CR-PDT are of immediate importance. Introducing probiotics to our study can be used not only as tumor-targeting carriers of photosensitizers but also as immunoadjuvants. Under co-stimulation by immunogenic tumor cell death triggered by CR-PDT and probiotics acting as immunoadjuvants, anti-tumor immune responses were effectively activated, thus remarkably enhancing the efficacy of CR-PDT.

Tuning the lattice thermal conductivity of Sb2Te3 by Cr doping: a deep potential molecular dynamics study.

Element doping is a prominent method for reducing the lattice thermal conductivity and optimizing the thermoelectric performance of materials in the thermoelectric field. However, determination of the thermal conductivity of element-doped systems is a challenging task, especially when the elements are randomly doped. In this work, a first-principles based deep neural network potential (NNP) is developed to investigate the lattice thermal transport properties of Cr-doped Sb2Te3 using molecular dynamics simulations. Compared with pure Sb2Te3, the thermal conductivity of orderly Cr-doped Sb2Te3 with Cr atoms locating at specific atomic layer positions decreases slightly in the in-plane direction, but sharply in the out-of-plane direction. The decrease of the low frequency phonon density of states and the enhancement of phonon scattering near 2.5 THz are the primary reasons for the decrease in the thermal conductivity of Cr-doped Sb2Te3, while the decrease of phonon velocity due to band flattening is the reason for the sharp decrease of thermal conductivity in the out-of-plane direction. Moreover, the thermal conductivities of randomly Cr-doped Sb2Te3 with different Cr concentrations are also investigated using the NNP. It is found that the thermal conductivities in both the in-plane and out-of-plane directions are reduced by 76% and 80%, respectively, for Sb36Cr36Te108. Furthermore, the influence of different Cr dopant arrays on the thermal conductivity of Sb2Te3 is also predicted using the NNP. Our work provides a good example for predicting the thermal conductivity of element-doped systems using the NNP combined with molecular dynamics simulations.

Peptide-based PET imaging agent of tumor TIGIT expression.

BACKGROUND: Accumulating studies have demonstrated that elevated TIGIT expression in tumor microenvironment correlates with better therapeutic response to TIGIT-based immunotherapy in pre-clinical studies. Therefore, a non-invasive method to detect tumor TIGIT expression is crucial to predict the therapeutic effect. METHODS: In this study, a peptide-based PET imaging agent, 68Ga-DOTA-DTBP-3, was developed to non-invasively detect TIGIT expression by micro-PET in tumor-bearing BALB/c mice. DTBP-3, a D-peptide comprising of 12 amino acids, was radiolabeled with 68Ga through a DOTA chelator. In vitro studies were performed to evaluate the affinity of 68Ga-DOTA-DTBP-3 to TIGIT and its stability in fetal bovine serum. In vivo studies were assessed by micro-PET, biodistribution, and immunohistochemistry on tumor-bearing BALB/c mice. RESULTS: The in vitro studies showed the equilibrium dissociation constant of 68Ga-DOTA-DTBP-3 for TIGIT was 84.21 nM and its radiochemistry purity was 89.24 ± 1.82% in FBS at 4 h in room temperature. The results of micro-PET, biodistribution and immunohistochemistry studies indicated that 68Ga-DOTA-DTBP-3 could be specifically targeted in 4T1 tumor-bearing mice, with a highest uptake at 0.5 h. CONCLUSION: 68Ga-DOTA-DTBP-3 holds potential for non-invasively detect tumor TIGIT expression and for timely assessment of the therapeutic effect of immune checkpoint blockade.

Regulated contribution of local and systemic immunity to new bone regeneration by modulating B/Sr concentration of bioactive borosilicate glass.

The local immune response induced by bioactive borosilicate glass (BG) plays a vital role in bone regeneration, but its effect in the systemic immune response of distal tissues, such as spleen, remains unknown. In this study, the network structures and the relative theoretical structural descriptors (Fnet) of the novel BG composition containing boron (B) and strontium (Sr) were calculated and stimulated by molecular dynamics (MD) simulation, and the linear relationships of Fnet and B and Sr releasing rate in pure water and simulate body fluid were built. Next, the synergistic effects of the released B and Sr on promoting osteogenic differentiation, angiogenesis, and macrophage polarization were analyzed in vitro and convinced in rats skull models in vivo. Results show that the optimal synergistic effects of B and Sr both in vitro and in vivo released from 1393B2Sr8 BG increased vessel regeneration, modulated M2 macrophages polarization and promoted new-bone formation. Interestingly, the 1393B2Sr8 BG was found to mobilize monocytes from the spleen to the defects and subsequently modulate them into M2 macrophages. Then, these modulated cells cycled from the bone defects back to the spleen. To analyze the necessity of spleen-derived immune cells in bone regeneration, two contrasting rat models (with/without spleen) of skull defects were furtherly established. As results, rats without spleen had fewer M2 macrophages surrounding skull defects and the bone tissues recovered more slowly, indicating the beneficial effects on bone regeneration of circulating monocytes and polarized macrophages provided by spleen. The present study provides a new approach and strategy in optimizing complex composition of novel BG and sheds light on the importance of spleen through modulating systemic immune response to contribute to local bone regeneration.