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.

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.

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.

[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.

Berberin sustained-release nanoparticles were enriched in infarcted rat myocardium and resolved inflammation.

Inflammatory regulation induced by macrophage polarization is essential for cardiac repair after myocardial infarction (MI). Berberin (BBR) is an isoquinoline tetrasystemic alkaloid extracted from plants. This study analyzes the most likely mechanism of BBR in MI treatment determined via network pharmacology, showing that BBR acts mainly through inflammatory responses. Because platelets (PLTs) can be enriched in the infarcted myocardium, PLT membrane-coated polylactic-co-glycolic acid (PLGA) nanoparticles (BBR@PLGA@PLT NPs) are used, which show enrichment in the infarcted myocardium to deliver BBR sustainably. Compared with PLGA nanoparticles, BBR@PLGA@PLT NPs are more enriched in the infarcted myocardium and exhibit less uptake in the liver. On day three after MI, BBR@PLGA@PLT NPs administration significantly increases the number of repaired macrophages and decreases the number of inflammatory macrophages and apoptotic cells in infarcted rat myocardium. On the 28th day after MI, the BBR@PLGA@PLT group exhibits a protective effect on cardiac function, reduced cardiac collagen deposition, improved scar tissue stiffness, and an excellent angiogenesis effect. In addition, BBR@PLGA@PLT group has no significant impact on major organs either histologically or enzymologically. In summary, the therapeutic effect of BBR@PLGA@PLT NPs on MI is presented in detail from the perspective of the resolution of inflammation, and a new solution for MI treatment is proposed.

Chlorin e6-loaded goat milk-derived extracellular vesicles for Cerenkov luminescence-induced photodynamic therapy.

PURPOSE: Photodynamic therapy (PDT) is a promising cancer treatment strategy with rapid progress in preclinical and clinical settings. However, the limitations in penetration of external light and precise delivery of photosensitizers hamper its clinical translation. As such, the internal light source such as Cerenkov luminescence (CL) from decaying radioisotopes offers new opportunities. Herein, we show that goat milk-derived extracellular vesicles (GEV) can act as a carrier to deliver photosensitizer Chlorin e6 (Ce6) and tumor-avid 18F-FDG can activate CL-induced PDT for precision cancer theranostics. METHODS: GEV was isolated via differential ultracentrifugation of commercial goat milk and photosensitizer Ce6 was loaded by co-incubation to obtain Ce6@GEV. Tumor uptake of Ce6@GEV was examined using confocal microscopy and flow cytometry. To demonstrate the ability of 18F-FDG to activate photodynamic effects against cancer cells, apoptosis rates were measured using flow cytometry, and the production of 1O2 was measured by reactive oxygen species (ROS) monitoring kit. Moreover, we used the IVIS device to detect Cherenkov radiation and Cerenkov radiation energy transfer (CRET). For animal experiments, a small-animal IVIS imaging system was used to visualize the accumulation of the GEV drug delivery system in tumors. PET/CT and CL images of the tumor site were performed at 0.5, 1, and 2 h. For in vivo antitumor therapy, changes of tumor volume, survival time, and body weight in six groups of tumor-bearing mice were monitored. Furthermore, the blood sample and organs of interest (heart, liver, spleen, lungs, kidneys, and tumor) were collected for hematological analysis, immunohistochemistry, and H&E staining. RESULTS: Confocal microscopy of 4T1 cells incubated with Ce6@GEV for 4 h revealed strong red fluorescence signals in the cytoplasm, which demonstrated that Ce6 loaded in GEV could be efficiently delivered into tumor cells. When Ce6@GEV and 18F-FDG co-existed incubated with 4T1 cells, the cell viability plummeted from more than 88.02 ± 1.30% to 23.79 ± 1.59%, indicating excellent CL-induced PDT effects. In vivo fluorescence images showed a peak tumor/liver ratio of 1.36 ± 0.09 at 24 h after Ce6@GEV injection. For in vivo antitumor therapy, Ce6@GEV + 18F-FDG group had the best tumor inhibition rate (58.02%) compared with the other groups, with the longest survival rate (35 days, 40%). During the whole treatment process, neither blood biochemical analysis nor histological observation revealed vital organ damage, suggesting the biosafety of this treatment strategy. CONCLUSIONS: The simultaneous accumulation of 18F-FDG and Ce6 in tumor tissues is expected to overcome the deficiency of traditional PDT. This strategy has the potential to extend PDT to a variety of tumors, including metastases, using targeted radiotracers to provide internal excitation of light-responsive therapeutics. We expect that our method will play a critical role in precision treatment of deep solid tumors.

Non-Ischemic, Non-Hypoxic Myocardial Injury, and Long-Term Mortality in Patients with Coronavirus Disease 2019: A Retrospective Cohort Study.

Objective: Cardiac damage is commonly reported in patients with coronavirus disease 2019 (COVID-19) but its prevalence and impact on the long-term survival of patients remain uncertain. This study aimed to explore the prevalence of myocardial injury and assess its prognostic value in patients with COVID-19. Methods: A single-center, retrospective cohort study was performed at the Affiliated Hospital of Jianghan University. Data from 766 patients with confirmed COVID-19 who were hospitalized from December 27, 2019 to April 25, 2020 were collected. Demographic, clinical, laboratory, electrocardiogram, treatment data and all-cause mortality during follow-up were collected and analyzed. Results: Of the 766 patients with moderate to critically ill COVID-19, 86 (11.2%) died after a mean follow-up of 72.8 days. Myocardial injury occurred in 94 (12.3%) patients. The mortality rate was 64.9% (61/94) and 3.7% (25/672) in patients with and without myocardial injury, respectively. Cox regression showed that myocardial injury was an independent risk factor for mortality (hazard ratio: 8.76, 95% confidence interval: 4.76-16.11, P < 0.001). Of the 90 patients with myocardial injury with electrocardiogram results, sinus tachycardia was present in 29, bundle branch block in 26, low voltage in 10, and abnormal T-wave in 53. Conclusions: COVID-19 not only involves pneumonia but also cardiac damage. Myocardial injury is a common complication and an independent risk factor for mortality in COVID-19 patients.

An artificial neural network chip based on two-dimensional semiconductor.

Recently, research on two-dimensional (2D) semiconductors has begun to translate from the fundamental investigation into rudimentary functional circuits. In this work, we unveil the first functional MoS2 artificial neural network (ANN) chip, including multiply-and-accumulate (MAC), memory and activation function circuits. Such MoS2 ANN chip is realized through fabricating 818 field-effect transistors (FETs) on a wafer-scale and high-homogeneity MoS2 film, with a gate-last process to realize top gate structured FETs. A 62-level simulation program with integrated circuit emphasis (SPICE) model is utilized to design and optimize our analog ANN circuits. To demonstrate a practical application, a tactile digit sensing recognition was demonstrated based on our ANN circuits. After training, the digit recognition rate exceeds 97%. Our work not only demonstrates the protentional of 2D semiconductors in wafer-scale integrated circuits, but also paves the way for its future application in AI computation.

Nacre-inspired magnetically oriented micro-cellulose fibres/nano-hydroxyapatite/chitosan layered scaffold enhances pro-osteogenesis and angiogenesis.

In situ regeneration of large-segment bone defects is a difficult clinical problem. Here, we innovatively developed magnetically oriented micro-cellulose fibres using nano-hydroxyapatite/chitosan (CEF/Fe3O4/HA/CS) and loaded an NFκB pathway inhibitor on the surface of magnetically oriented cellulose fibres (CEF/Fe3O4/HA/CS/PQQ) prepared as a layered bioscaffold. CEF/Fe3O4/HA/CS/PQQ was constructed by layering HA/CS sheets. Nano-hydroxyapatite was deposited on the surface of cellulose fibres, then the magnetic nanoparticles on the cellulose fibres were aligned on the surface of chitosan under a magnetic field. Oriented cellulose fibres enhanced the compressive properties of the scaffold, with an average maximum compressive strength of 1.63 â€‹MPa. The CEF/Fe3O4/HA/CS/PQQ layered scaffold was filled into the body, and the acute inflammatory response (IL-1ß and TNF-α) was suppressed through the early sustained release of PQQ. The CEF/Fe3O4/HA/CS/PQQ-layered scaffold further inhibited the osteoclasts differentiation. It was further found that the nano-hydroxyapatite on the surface of oriented cellulose fibres promoted the formation and migration of new blood vessels, accelerated the processing of collagen-I fibres to cartilage, and endochondral ossification. Hence, the development of the CEF/Fe3O4/HA/CS/PQQ layered scaffold with oriented fibres guides bone growth direction and pro-osteogenesis activity and provides a novel strategy for the in situ regeneration of large segmental bone defects.

The earlier, the better? A review of neoadjuvant immunotherapy in resectable non-small-cell lung cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the approach to advanced and locally advanced non-small-cell lung cancer (NSCLC). Antibodies blocking inhibitory immune checkpoints, such as programmed death 1 (PD-1) and its ligand (PD-L1), have remarkable antitumor efficacy and have been approved as a standard first- or second-line treatment in non-oncogene-addicted advanced NSCLC. The successful application of immunotherapy in advanced lung cancer has motivated researchers to further evaluate its clinical role as a neoadjuvant setting for resectable NSCLC and for improved long-term overall survival and curative rates. In this review, we discuss the efforts that incorporate ICIs into the treatment paradigm for surgically resectable lung cancer. We reviewed the early-phase results from neoadjuvant clinical trials, the landscape of the majority of ongoing phase III trials, and discuss the prospects of ICIs as a curative therapy for resectable lung cancer. We also summarized the potential biomarkers and beneficiaries involved in the current study, as well as the remaining unresolved challenges for neoadjuvant immunotherapy.