Heme oxygenase activates calcium release from the endoplasmic reticulum of bovine mammary epithelial cells to promote TFEB entry into the nucleus to reduce the intracellular load of Mycoplasma bovis.

Heme oxygenase HO-1 (HMOX) regulates cellular inflammation and apoptosis, but its role in regulation of autophagy in Mycoplasma bovis infection is unknown. The objective was to determine how the HO-1/CO- Protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Ca2+- transcription factor EB (TFEB) signaling axis induces autophagy and regulates clearance of M. bovis by bovine mammary epithelial cells (bMECs). M. bovis inhibited autophagy and lysosomal biogenesis in bMECs and suppressed HO-1 protein and expression of related proteins, namely nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (keap1). Activation of HO-1 and its production of carbon monoxide (CO) were required for induction of autophagy and clearance of intracellular M. bovis. Furthermore, when HO-1 was deficient, CO sustained cellular autophagy. HO-1 activation increased intracellular calcium (Ca2+) and cytosolic localization activity of TFEB via PERK. Knockdown of PERK or chelation of intracellular Ca2+ inhibited HO-1-induced M. bovis autophagy and clearance. M. bovis infection affected nuclear localization of lysosomal TFEB in the MiT/TFE transcription factor subfamily, whereas activation of HO-1 mediated dephosphorylation and intranuclear localization of TFEB, promoting autophagy, lysosomal biogenesis and autophagic clearance of M. bovis. Nuclear translocation of TFEB in HO-1 was critical to induce M. bovis transport and survival of infected bMECs. Furthermore, the HO-1/CO-PERK-Ca2+-TFEB signaling axis induced autophagy and M. bovis clearance, providing a viable approach to treat persistent M. bovis infections.

An Adjuvant Micelle-Based Multifunctional Nanosystem for Tumor Immunotherapy by Remodeling Three Types of Immunosuppressive Cells.

Immunotherapy is restricted by a complex tumor immunosuppressive microenvironment (TIM) and low drug delivery efficiency. Herein, a multifunctional adjuvant micelle nanosystem (PPD/MPC) integrated with broken barriers and re-education of three classes of immune-tolerant cells is constructed for cancer immunotherapy. The nanosystem significantly conquers the penetration barrier via the weakly acidic tumor microenvironment-responsive size reduction and charge reversal strategy. The detached core micelle MPC could effectively be internalized by tumor-associated macrophages (TAMs), tumor-infiltrating dendritic cells (TIDCs), and myeloid-derived suppressor cells (MDSCs) via mannose-mediated targeting endocytosis and electrostatic adsorption pathways, promoting the re-education of immunosuppressive cells for allowing them to reverse from pro-tumor to antitumor phenotypes by activating TLR4/9 pathways. This process in turn leads to the remodeling of TIM. In vitro and in vivo studies collectively indicate that the adjuvant micelle-based nanosystem not only relieves the intricate immune tolerance and remodels TIM via reprogramming the three types of immunosuppressive cells and regulating the secretion of relevant cytokines/immunity factors but also strengthens immune response and evokes immune memory, consequently suppressing the tumor growth and metastasis.

Atmospheric deposition and river runoff stimulate the utilization of dissolved organic phosphorus in coastal seas.

In coastal seas, the role of atmospheric deposition and river runoff in dissolved organic phosphorus (DOP) utilization is not well understood. Here, we address this knowledge gap by combining microcosm experiments with a global approach considering the relationship between the activity of alkaline phosphatases and changes in phytoplankton biomass in relation to the concentration of dissolved inorganic phosphorus (DIP). Our results suggest that the addition of aerosols and riverine water stimulate the biological utilization of DOP in coastal seas primarily by depleting DIP due to increasing nitrogen concentrations, which enhances phytoplankton growth. This "Anthropogenic Nitrogen Pump" was therefore identified to make DOP an important source of phosphorus for phytoplankton in coastal seas but only when the ratio of chlorophyll a to DIP [Log10 (Chl a / DIP)] is larger than 1.20. Our study therefore suggests that anthropogenic nitrogen input might contribute to the phosphorus cycle in coastal seas.

Multifunctional Fe-based coordination polymer nano-bomb modified with ß-lapachone and CaO2 for targeted tumor dual chemodynamic therapy with enhanced ferroptosis and H2O2 self-supply.

Chemodynamic therapy (CDT) is seriously limited by the inadequacy of exogenous catalytic ions and endogenous H2O2 in tumors. Herein, a multifunction nano-bomb integrated with calcium peroxide (CaO2) and ß-lapachone as donors of H2O2 and GSH-sensitive Fe-based coordination polymer as provider of catalytic ions was constructed for dual cascade-amplified tumor CDT. This hyaluronic acid (HA)-modified nano-bomb could be specially endocytosed by breast cancer cells through a targeting pathway, degraded and released cargoes in response to the GSH-rich cytoplasm. Furthermore, the released CaO2 and ß-lapachone could significantly self-generated sufficient H2O2, which could dual-cascade amplify CDT and induce severe oxidative to tumors via cooperating with the delivered iron ions from nano-bombs. Moreover, the unloaded iron and calcium ions could further accelerate tumor damage by overloading Ca2+ and ferroptosis, as accompanied by good magnetic resonance imaging (MRI). In vitro and in vivo studies collectively reveal that this nano-bomb not only self-initiates double cascade-amplified CDT via self-generation of H2O2, but also efficiently activates ferroptosis and initiates Ca2+ overloading, consequently significantly tumor growth suppression. This study offers a novel tumor-initiated nano-bomb for dual cascade-amplified CDT and bioimaging with activated ferroptosis and self-supplying H2O2.

Correlation analysis between Raman spectral signature and transcriptomic features of carbapenem-resistant Klebsiella pneumoniae.

The Raman microspectroscopy technology has been successfully applied to evaluate the molecular composition of living cells for identifying cell types and states, but the rationale behind it was not well investigated. In this study, we acquired single-cell Raman spectra (SCRS) of three Klebsiella pneumoniae (K. pneumoniae) strains with different Carbapenem resistant mechanisms and analyzed them with machine learning algorithm. Two carbapenem resistant Klebsiella pneumoniae (CRKP) strains can be successfully distinguished from susceptible strain and CRKP with KPC or IMP carbapenemases can be classified with an overall accuracy achieving 100 %. Furthermore, we performed a correlation analysis between transcriptome and Raman spectra, and found that Raman shifts such as 752 and 1039 cm-1 highly correlated with drug resistance genes expression and could be regarded as Raman biomarkers for CRKP with different mechanisms. The findings of the study provide a theoretical basis for identifying the relationship between Raman spectra and transcriptome of bacteria, as well as a novel method for rapid identification of CRKP and their carbapenemases types.

Effect of Epichloë Endophyte on the Growth and Carbon Allocation of Its Host Plant Stipa purpurea under Hemiparasitic Root Stress.

Epichloë endophytes not only affect the growth and resistance of their host plants but also confer nutrient benefits to parasitized hosts. In this study, we used Pedicularis kansuensis to parasitize Stipa purpurea, both with and without endophytic fungi, and to establish a parasitic system. In this study, endophytic fungal infection was found to increase the dry weight of the leaf, stem, and leaf sheath, as well as the plant height, root length, tiller number, aboveground biomass, and underground biomass of S. purpurea under root hemiparasitic stress. Meanwhile, the 13C allocation of the leaf sheaths and roots of S. purpurea increased as the density of P. kansuensis increased, while the 13C allocation of the leaf sheaths and roots of E+ S. purpurea was lower than that of E- S. purpurea. The 13C allocation of the stem, leaf sheath, and root of E+ S. purpurea was higher than that of its E- counterpart. Furthermore, the content of photosynthetic 13C and the 13C partition rate of the stems, leaves, roots, and entire plant of S. purpurea and P. kansuensis transferred from S. purpurea increased as the density of P. kansuensis increased. These results will generate new insights into the potential role of symbiotic microorganisms in regulating the interaction between root hemiparasites and their hosts.

Detachable MOF-Based Core/Shell Nanoreactor for Cancer Dual-Starvation Therapy With Reversing Glucose and Glutamine Metabolisms.

Tumor-dependent glucose and glutamine metabolisms are essential for maintaining survival, while the accordingly metabolic suppressive therapy is limited by the compensatory metabolism and inefficient delivery efficiency. Herein, a functional metal-organic framework (MOF)-based nanosystem composed of the weakly acidic tumor microenvironment-activated detachable shell and reactive oxygen species (ROS)-responsive disassembled MOF nanoreactor core is designed to co-load glycolysis and glutamine metabolism inhibitors glucose oxidase (GOD) and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES) for tumor dual-starvation therapy. The nanosystem excitingly improves tumor penetration and cellular uptake efficiency via integrating the pH-responsive size reduction and charge reversal and ROS-sensitive MOF disintegration and drug release strategy. Furthermore, the degradation of MOF and cargoes release can be self-amplified via additional self-generation H2 O2 mediated by GOD. Last, the released GOD and BPTES collaboratively cut off the energy supply of tumors and induce significant mitochondrial damage and cell cycle arrest via simultaneous restriction of glycolysis and compensatory glutamine metabolism pathways, consequently realizing the remarkable triple negative breast cancer killing effect in vivo with good biosafety via the dual starvation therapy.

Cultureless enumeration of live bacteria in urinary tract infection by single-cell Raman spectroscopy.

Urinary tract infections (UTIs) are the most common outpatient infections. Obtaining the concentration of live pathogens in the sample is crucial for the treatment. Still, the enumeration depends on urine culture and plate counting, which requires days of turn-around time (TAT). Single-cell Raman spectra combined with deuterium isotope probing (Raman-DIP) has been proven to identify the metabolic-active bacteria with high accuracy but is not able to reveal the number of live pathogens due to bacteria replication during the Raman-DIP process. In this study, we established a new approach of using sodium acetate to inhibit the replication of the pathogen and applying Raman-DIP to identify the active single cells. By combining microscopic image stitching and recognition, we could further improve the efficiency of the new method. Validation of the new method on nine artificial urine samples indicated that the exact number of live pathogens obtained with Raman-DIP is consistent with plate-counting while shortening the TAT from 18 h to within 3 h, and the potential of applying Raman-DIP for pathogen enumeration in clinics is promising.

A Novel Two-Dimensional Liquid Chromatography Combined with Ultraviolet Detection Method for Quantitative Determination of Pyridoxal 5'-Phosphate, 4-Pyridoxine Acid and Pyridoxal in Animal Plasma.

Vitamin B6 is an indispensable micronutrient in organisms and is widely distributed in blood, tissues, and organs. Changes in the content and ratio of vitamin B6 can affect the entire physiological condition of the body, so it becomes particularly important to reveal the relationship between changes in its content and disease by monitoring vitamin B6 levels in the organism. In this study, a two-dimensional liquid chromatography-UV detector (2D-LC-UV) was used to establish a method for the simultaneous detection of PLP, PA, and PL for the first time. First, PLP, PA, and PL were extracted with plasma: 0.6 M TCA: ultrapure water = 1:2:3 (v/v/v) and then derivatized. Enrichment and preliminary separation were performed on a one-dimensional column and automatically entered into a two-dimensional column for further separation. This method exhibited good selectivity, and the correlation coefficients for the analyte calibration curves were >0.99. The detection limits for PLP, PA, and PL were 0.1, 0.2, and 4 nmol/L, respectively. The results showed that the system has high loading capacity, excellent resolution, and a good peak shape. This method is expected to provide applicability for the determination of PLP, PA, and PL in pharmacological, pharmaceutical, and clinical research.

Biomass Derived, Hierarchically Porous, Activated Starbons® as Adsorbents for Volatile Organic Compounds.

The use of potassium hydroxide activated Starbons® derived from starch and alginic acid as adsorbents for 29 volatile organic compounds (VOCs) was investigated. In every case, the alginic acid derived Starbon (A800K2) was found to be the optimal adsorbent, significantly outperforming both commercial activated carbon and starch derived, activated Starbon (S800K2). The saturated adsorption capacity of A800K2 depends on both the size of the VOC and the functional groups it contains. The highest saturated adsorption capacities were obtained with small VOCs. For VOC's of similar size, the presence of polarizable electrons in lone pairs or π-bonds within non-polar VOCs was beneficial. Analysis of porosimetry data suggests that the VOC's are being adsorbed within the pore structure of A800K2 rather than just on its surface. The adsorption was completely reversible by thermal treatment of the saturated Starbon under vacuum.

Cascade amplification of tumor chemodynamic therapy and starvation with re-educated TAMs via Fe-MOF based functional nanosystem.

Tumor microenvironment is characterized by the high concentration of reactive oxygen species (ROS), which is an effective key used to open the Pandora's Box against cancer. Herein, a tumor-targeted nanosystem HFNP@GOX@PFC composed of ROS-cleaved Fe-based metal-organic framework, hyaluronic acid (HA), glucose oxidase (GOX) and perfluorohexane (PFC) has been developed for tumor cascade amplified starvation and chemodynamic therapy (CDT). In response to the high concentration of hydrogen peroxide (H2O2) intratumorally, HFNP@GOX@PFC endocytosed by tumor cells can specially be disassembled and release GOX, PFC and Fe2+, which can collectively starve tumor and self-produce additional H2O2 via competitively glucose catalyzing, supply oxygen to continuous support GOX-mediated starvation therapy, initiate CDT and cascade amplify oxidative stress via Fe2+-mediated Fenton reaction, leading to the serious tumor damage with activated p53 signal pathway. Moreover, HFNP@GOX@PFC also significantly initiates antitumor immune response via re-educating tumor-associated macrophages (TAMs) by activating NF-κB and MAPK signal pathways. In vitro and in vivo results collectively demonstrate that nanosystem not only continuously initiates starvation therapy, but also pronouncedly cascade-amplify CDT and polarize TAMs, consequently efficiently inhibiting tumor growth with good biosafety. The functional nanosystem combined the cascade amplification of starvation and CDT provides a new nanoplatform for tumor therapy.

In vitro antifungal activity of lasiodiplodin, isolated from endophytic fungus Lasiodiplodia pseudotheobromae J-10 associated with Sarcandra glabra and optimization of culture conditions for lasiodiplodin production.

A macrolide antibiotic, lasiodiplodin was isolated from the endophytic fungus (EF) Lasiodiplodia pseudotheobromae J-10 associated with the medicinal plant Sarcandra glabra. In vitro antifungal assay demonstrated the inhibitory activity of lasiodiplodin against the growth of six phytopathogenic fungi, with the IC50 values ranging between 15.50 and 52.30 µg/mL. The highest antifungal activities were recorded against Exserohilum turcicum, Colletotrichum capsici, and Pestalotiopsis theae, with IC50 values of 15.50, 15.90, and 17.55 µg/mL, respectively. The underlying mechanism of the antifungal activity of lasiodiplodin against E. turcicum included the alteration of its colony morphology and disturbance of its cell membrane integrity. In addition, the optimization of L. pseudotheobromae J-10 culture conditions increased lasiodiplodin yield to 52.33 mg/L from 0.59 mg/L at pre-optimization. This is the first report on the isolation and identification of antifungal compound from the EF L. pseudotheobromae J-10 associated with S. glabra, as well as on the optimization of L. pseudotheobromae J-10 culture conditions to increase lasiodiplodin yield. The results of this study support that lasiodiplodin is a natural compound with high potential bioactivity against phytopathogens, and provide a basis for further study of the EF associated with S. glabra.

Leveraging single-cell Raman spectroscopy and single-cell sorting for the detection and identification of yeast infections.

Invasive fungal infection serves as a great threat to human health. Discrimination between fungal and bacterial infections at the earliest stage is vital for effective clinic practice; however, traditional culture-dependent microscopic diagnosis of fungal infection usually requires several days, meanwhile, culture-independent immunological and molecular methods are limited by the detectable type of pathogens and the issues with high false-positive rates. In this study, we proposed a novel culture-independent phenotyping method based on single-cell Raman spectroscopy for the rapid discrimination between fungal and bacterial infections. Three Raman biomarkers, including cytochrome c, peptidoglycan, and nucleic acid, were identified through hierarchical clustering analysis of Raman spectra across 12 types of most common yeast and bacterial pathogens. Compared to those of bacterial pathogens, the single cells of yeast pathogens demonstrated significantly stronger Raman peaks for cytochrome c, but weaker signals for peptidoglycan and nucleic acid. A two-step protocol combining the three biomarkers was established and able to differentiate fungal infections from bacterial infections with an overall accuracy of 94.9%. Our approach was also used to detect ten raw urinary tract infection samples. Successful identification of fungi was achieved within half an hour after sample obtainment. We further demonstrated the accurate fungal species taxonomy achieved with Raman-assisted cell ejection. Our findings demonstrate that Raman-based fungal identification is a novel, facile, reliable, and with a breadth of coverage approach, that has a great potential to be adopted in routine clinical practice to reduce the turn-around time of invasive fungal disease (IFD) diagnostics.

Tumor-targeted dual-starvation therapy based on redox-responsive micelle nanosystem with co-loaded LND and BPTES.

The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, HPPPH@L@B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.

Effects of Ultra-High Pressure on Endogenous Enzyme Activities, Protein Properties, and Quality Characteristics of Shrimp (Litopenaeus vannamei) during Iced Storage.

The present study aimed to explore the effects of ultra-high pressure (UHP) on the cathepsin (B, D, H, and L) activities, protein oxidation, and degradation properties as well as quality characteristics of iced shrimp (Litopenaeus vannamei). Fresh shrimps were vacuum-packed, treated with UHP (100-500 MPa for 5 min), and stored at 0 °C for 15 days. The results showed that the L* (luminance), b* (yellowness), W (whiteness), ΔE (color difference), hardness, shear force, gumminess, chewiness, and resilience of shrimp were significantly improved by UHP treatment. Moreover, the contents of surface hydrophobicity, myofibril fragmentation index (MFI), trichloroacetic acid (TCA)-soluble peptides, carbonyl, dityrosine, and free sulfhydryl of myofibrillar protein (MP) were significantly promoted by UHP treatment. In addition, UHP (above 300 MPa) treatment enhanced the mitochondrial membrane permeability but inhibited the lysosomal membrane stability, and the cathepsin (B, D, H, and L) activities. UHP treatment notably inhibited the activities of cathepsins, delayed protein oxidation and degradation, as well as texture softening of shrimp during storage. Generally, UHP treatment at 300 MPa for 5 min effectively delayed the protein and quality deterioration caused by endogenous enzymes and prolonged the shelf life of shrimp by 8 days.

Stain-free Gram staining classification of pathogens via single-cell Raman spectroscopy combined with machine learning.

Gram staining (GS) is one of the routine microbiological operations to classify bacteria based on the cell wall structure. Accurate GS classification of pathogens is of great significance since it helps correct administration of antimicrobial treatment. The laborious procedure and low sensitivity results related to conventional GS have resulted in reluctance among clinicians. In this study, we integrate confocal Raman spectroscopy and machine learning techniques to distinguish Gram-negative (GN) or Gram-positive (GP) bacteria. A single-cell Raman database including seven most common clinical pathogens (three GP strains and four GN strains) was constructed. Machine learning algorithms including the support-vector machine (SVM), k-nearest neighbors' algorithm (k-NN), gradient boosting machine (GBM), linear discriminant analysis (LDA), and t-distributed stochastic neighbor embedding (t-SNE) were trained to achieve the binary classification for GS. With such a relatively small database, the SVM model achieved the highest accuracy of 98.1%. The molecular signatures of GN and GP embedded in their Raman fingerprints were identified with hierarchical cluster analysis (HCA). The results indicated that Raman peaks for peptidoglycan and teichoic acid were the most significant factors that contributed to accurate classification. The Raman machine learning approach could greatly enhance the diagnosis of pathogenic infections.

Preoperative CECT-based Radiomic Signature for Predicting the Response of Transarterial Chemoembolization (TACE) Therapy in Hepatocellular Carcinoma.

PURPOSE: To evaluate the efficiency of radiomics signatures in predicting the response of transarterial chemoembolization (TACE) therapy based on preoperative contrast-enhanced computed tomography (CECT). MATERIALS: This study consisted of 111 patients with intermediate-stage hepatocellular carcinoma who underwent CECT at both the arterial phase (AP) and venous phase (VP) before and after TACE. According to mRECIST 1.1, patients were divided into an objective-response group (n = 38) and a non-response group (n = 73). Among them, 79 patients were assigned as the training dataset, and the remaining 32 cases were assigned as the test dataset. METHODS: Radiomics features were extracted from CECT images. Two feature ranking methods and three classifiers were used to find the best single-phase radiomics signatures for both AP and VP on the training set. Meanwhile, multi-phase radiomics signatures were built upon integration of images from two CECT phases by decision-level fusion and feature-level fusion. Finally, multivariable logistic regression was used to develop a nomogram by combining radiomics signatures and clinic-radiologic characteristics. The prediction performance was evaluated by AUC on the test dataset. RESULTS: The multi-phase radiomics signature (AUC = 0.883) performed better in predicting TACE therapy response compared to the best single-phase radiomics signature (AUC = 0.861). The nomogram (AUC = 0.913) showed better performance than any radiomics signatures. CONCLUSION: The radiomics signatures and nomogram were developed and validated for predicting responses to TACE therapy, and the radiomics model may play a positive role in identifying patients who may benefit from TACE therapy in clinical practice.

Multifunctional metal-organic framework-based nanoreactor for starvation/oxidation improved indoleamine 2,3-dioxygenase-blockade tumor immunotherapy.

Inhibited immune response and low levels of delivery restrict starvation cancer therapy efficacy. Here, we report on the co-delivery of glucose oxidase (GOx) and indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan using a metal-organic framework (MOF)-based nanoreactor, showing an amplified release for tumor starvation/oxidation immunotherapy. The nanosystem significantly overcomes the biobarriers associated with tumor penetration and improves the cargo bioavailability owing to the weakly acidic tumor microenvironment-activated charge reversal and size reduction strategy. The nanosystem rapidly disassembles and releases cargoes in response to the intracellular reactive oxygen species (ROS). GOx competitively consumes glucose and generates ROS, further inducing the self-amplifiable MOF disassembly and drug release. The starvation/oxidation combined IDO-blockade immunotherapy not only strengthens the immune response and stimulates the immune memory through the GOx-activated tumor starvation and recruitment of effector T cells, but also effectively relieves the immune tolerance by IDO blocking, remarkably inhibiting the tumor growth and metastasis in vivo.

The Use of Internet of Things and Cloud Computing Technology in the Performance Appraisal Management of Innovation Capability of University Scientific Research Team.

This study aims to speed up the progress of scientific research projects in colleges and universities, continuously improve the innovation ability of scientific research teams in colleges and universities, and optimize the current management methods of performance appraisal of college innovation ability. Firstly, the needs of the innovation performance evaluation system are analyzed, and the corresponding innovation performance evaluation index system of scientific research team is constructed. Secondly, the Internet of Things (IoT) combines the Field Programmable Gate Array (FPGA) to build an innovation capability performance appraisal management terminal. Thirdly, the lightweight deep network has been built into the innovation ability performance assessment management network of university scientific research teams, which relates to the innovation performance assessment index system of scientific research teams. Finally, the system performance is tested. The results show that the proposed method has different degrees of compression for MobileNet, which can significantly reduce the network computation and retain the original recognition ability. Models whose Floating-Point Operations (FLOPs) are reduced by 70% to 90% have 3.6 to 14.3 times fewer parameters. Under different pruning rates, the proposed model has higher model compression rate and recognition accuracy than other models. The results also show that the output of the results is closely related to the interests of the research team. The academic influence score of Team 1 is 0.17, which is the highest among the six groups in this experimental study, indicating that Team 1 has the most significant academic influence. These results provide certain data support and method reference for evaluating the innovation ability of scientific research teams in colleges and universities and contribute to the comprehensive development of efficient scientific research teams.

TGF-ß blockade-improved chemo-immunotherapy with pH/ROS cascade-responsive micelle via tumor microenvironment remodeling.

Immunosuppressive tumor microenvironment and low delivery efficiency severely impede the tumor chemotherapy effect. To address this issue, we develop a pH/ROS cascade-responsive prodrug micelle to deliver siTGF-ß with size-shrinkage and charge-reversal property, leading to synergistical tumor microenvironment remodeling. The nanosystem highly improved endocytosis efficiency and tumor penetration depth through charge reversal and size reduction upon exposure to weakly acidic tumor microenvironment. Moreover, the nanocarrier would rapidly escape from endo/lysosome, disassemble and release siTGF-ß and hydroxycamptothecin in response to high intracellular ROS. Furthermore, the nanosystem significantly boosted antitumor immune response and reduced immune tolerance with remodeling tumor microenvironment, which significantly prolonged the survival time of tumor-bearing mice (75% survival rate upon 35 days). It is realized by the combined effects of chemotherapy-enhanced immunogenicity and recruitment of effector T cells, TGF-ß-blockade immunotherapy-activated inhibition immunosuppressive tumor microenvironment and epithelial-to-mesenchymal transition (EMT), and regulation physical tumor microenvironment via reducing the dense tumor extracellular matrix and the high tumor interstitial pressure obstacles. To this end, the nanosystem not only overcame biobarriers and reinforced antitumor immune response, but also effectively inhibited tumor growth, metastasis and recurrence in vivo.