Rational Design of Tetrahedral Derivatives as Efficient Light-Emitting Materials Based on "Super Atom" Perspective.

Traditional semiconductor quantum dots of groups II-VI are key ingredients of next-generation display technology. Yet, the majority of them contain toxic heavy-metal elements, thus calling for alternative light-emitting materials. Herein, we have explored three novel categories of multicomponent compounds, namely, tetragonal II-III2-VI4 porous ternary compounds, cubic I2-II3-VI4 ternary compounds, and cubic I-II-III3-V4 quaternary compounds. This is achieved by judicious introduction of a "super atom" perspective and concurrently varying the solid-state lattice packing of involved super atoms or the population of surrounding counter cations. Based on first-principles calculations of 392 candidate materials with designed crystal structures, 53 highly stable materials have been screened. Strikingly, 34 of them are direct-bandgap semiconductors with emitting wavelengths covering the near-infrared and visible-light regions. This work provides a comprehensive database of highly efficient light-emitting materials, which may be of interest for a broad field of optoelectronic applications.

Rotor-based image-guided therapy of glioblastoma.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.

External Stimuli-Responsive Strategies for Surface Modification of Orthopedic Implants: Killing Bacteria and Enhancing Osteogenesis.

Bacterial infection and insufficient osteogenic activity are the main causes of orthopedic implant failure. Conventional surface modification methods are difficult to meet the requirements for long-term implant placement. In order to better regulate the function of implant surfaces, especially to improve both the antibacterial and osteogenic activity, external stimuli-responsive (ESR) strategies have been employed for the surface modification of orthopedic implants. External stimuli act as "smart switches" to regulate the surface interactions with bacteria and cells. The balance between antibacterial and osteogenic capabilities of implant surfaces can be achieved through these specific ESR manifestations, including temperature changes, reactive oxygen species production, controlled release of bioactive molecules, controlled release of functional ions, etc. This Review summarizes the recent progress on different ESR strategies (based on light, ultrasound, electric, and magnetic fields) that can effectively balance antibacterial performance and osteogenic capability of orthopedic implants. Furthermore, the current limitations and challenges of ESR strategies for surface modification of orthopedic implants as well as future development direction are also discussed.

Theoretical Insights on the Charge State and Bifunctional OER/ORR Electrocatalyst Activity in 4d-Transition-Metal-Doped g-C3N4 Monolayers.

Exploring efficient and stable electrocatalysts for the bifunctional oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) is vital to developing renewable energy technologies. However, due to the substantial and intricate design space associated with these bifunctional OER/ORR electrocatalysts, their development presents a formidable challenge, resulting in their cost-prohibitive nature in both experimental and computational studies. Herein, using the defect physics method, we systematically investigate the formation energies and bifunctional overpotential (ηBi) of 4d-transition-metal (4d-TM, 4d-TM = Zr, Nb, Mo, Ru, Rh, Pd, and Ag)-doped monolayer supercell g-C3N4 (4d-TM@C54N72) based on the density functional theory (DFT) calculations. Under N-rich and C-rich conditions, we find that the formation energies of RhN@C54N71 (Rh occupation N) and PdN@C54N71 (Pd occupation N) are smaller than that of other 4d-TMN@C54N71 (4d-TM occupation N site); for the 4d-TMint@C54N72 (4d-TM interstitial site occupation), the lowest-formation energy defects are Pdint@C54N72. These results indicate that they have better stabilities. Interestingly, for these formation energy lower systems, Pd0int@C54N72 (ηBi = 1.00 V) and Rh1+N@C54N71 (ηBi = 0.73 V) have ultralow overpotential and can be great candidates for bifunctional OER/ORR electrocatalysts. We find the reason is that adjusting the charge states of 4d-TM@C54N72 can tune the interaction strength between the oxygenated intermediates and the 4d-TM@C54N72, which plays a crucial role in the activity of reactions. Additionally, the data obtained through machine learning (ML) application suggest that the electronegativity (Nm) and bond length of 4d-TM and coordination atoms (dTM-OOH) are primary descriptors characterizing the OER and ORR activities, respectively. The charged defect tuning of the bifunctional OER/ORR activity for 4d-TM@C54N72 would enable electrocatalytic performance optimization and the development of potential electrocatalysts for renewable energy applications.

The role of pulmonary rehabilitation in idiopathic pulmonary fibrosis: An overview of systematic reviews.

BACKGROUND: The role of pulmonary rehabilitation (PR) in idiopathic pulmonary fibrosis (IPF) has been studied in several systematic reviews (SRs), but no definitive conclusions have been drawn due to the wide variation in the quality and outcomes of the studies. And there are no studies to assess the quality of relevant published SRs. This overview aims to determine the effectiveness of PR in patients with IPF and to summarize and critically evaluate the risk of bias, methodological, and evidence quality of SRs on this related topic. METHODS: With no language restrictions, eight databases were searched from inception to March 10, 2023. The literature search, screening, and data extraction were carried out separately by two reviewers. We assessed the risk of bias using the ROBIS tool, the reporting quality using PRISMA statements, the methodological quality using AMSTAR-2, and the evidence quality using Grades of Recommendations, Assessment, Development, and Evaluation (GRADE). RESULTS: Seven SRs from 2018-2023 (including 1836 participants) on PR for the treatment of IPF were selected, all of which included patients with a definitive diagnosis of IPF. After strict evaluation by the ROBIS tool and AMSTAR-2 tool, 42.86% of the SRs had a high risk of bias and 85.71% of the SRs had critically low methodological quality in this overview. PR might be effective for patients with IPF on exercise capacity, quality of life, and pulmonary function-related outcomes, but we did not find high quality evidence to confirm the effectiveness. CONCLUSION: PR may appear to be an effective and safe treatment for patients with IPF, but the results of this overview should be interpreted dialectically and with caution. Further high-quality, rigorous studies are urgently needed to draw definitive conclusions and provide scientific evidence.

Amino-Functionalized Zirconium-Based Metal-Organic Frameworks as Bifunctional Nanomaterials to Treat Bone Tumors and Promote Osteogenesis.

Bone tumor patients often encounter challenges associated with cancer cell residues and bone defects postoperation. To address this, there is an urgent need to develop a material that can enable tumor treatment and promote bone repair. Metal-organic frameworks (MOFs) have attracted the interest of many researchers due to their special porous structure, which has great potential in regenerative medicine and drug delivery. However, few studies explore MOFs with dual antitumor and bone regeneration properties. In this study, we investigated amino-functionalized zirconium-based MOF nanoparticles (UiO-66-NH2 NPs) as bifunctional nanomaterials for bone tumor treatment and osteogenesis promotion. UiO-66-NH2 NPs loading with doxorubicin (DOX) (DOX@UiO-66-NH2 NPs) showed good antitumor efficacy both in vitro and in vivo. Additionally, DOX@UiO-66-NH2 NPs significantly reduced lung injury compared to free DOX in vivo. Interestingly, the internalized UiO-66-NH2 NPs notably promoted the osteogenic differentiation of preosteoblasts. RNA-sequencing data revealed that PI3K-Akt signaling pathways or MAPK signaling pathways might be involved in this enhanced osteogenesis. Overall, UiO-66-NH2 NPs exhibit dual functionality in tumor treatment and bone repair, making them highly promising as a bifunctional material with broad application prospects.

hsa_circ_0129047 Upregulates LYVE1 to Inhibit Hepatocellular Carcinoma Progression by Sponging miR-492.

Compelling evidence indicates the regulatory role of circular RNAs in cancers, including hepatocellular carcinoma (HCC). Our study aimed to elucidate the regulatory function of circ_0129047 in HCC progression. A reverse transcription-quantitative polymeric chain reaction was conducted to detect the expression of circ_0129047, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1), and miR-492 in HCC tissues and cells. The characteristics of circ_0129047 were determined by evaluating the nuclear and cytoplasmic fractions and by RNase R digestion assays. The cell counting kit-8 assay, scratch wound, and transwell invasion assays were used to examine the effects of circ_0129047 overexpression, miR-492 mimic, and LYVE1 overexpression on the proliferation, migration, and invasion abilities of HCC cells in vitro. A mouse xenograft model was also established. The relationship between miR-492 and circ_0129047 or LYVE1 was clarified using luciferase reporter and Argonaute-2 RNA immunoprecipitation assays. We found that circ_0129047 and LYVE1 were poorly expressed in HCC tissues and cells, whereas miR-492 was upregulated. Overexpression of circ_0129047 inhibits HCC cell proliferation, migration, and invasion and delays in vivo tumor growth. Furthermore, circ_0129047 sponged miR-492, and 3'UTR LYVE1 was a direct target of miR-492. Additionally, LYVE1 overexpression reduced the oncogenic activity of the miR-492 mimic, whereas the miR-492 mimic abolished the antimigratory, antiproliferative, and anti-invasive effects of circ_0129047 overexpression in HCC cells. These data suggest that circ_0129047 exerts a tumor-suppressive role in HCC by sponging miR-492 away from LYVE1 and that the circ_0129047/miR-492/LYVE1 axis may be a promising target for HCC treatment.

An acid-responsive MOF nanomedicine for augmented anti-tumor immunotherapy via a metal ion interference-mediated pyroptotic pathway.

Pyroptosis is an inflammatory form of programmed cell death (PCD) that is regulated by the Gasdermin protein family in response to various stimuli, playing a critical role in the development of tumor therapy strategies. However, cancers are generally known to escape from PCD via immunosuppressive pathways or other resistant mechanisms. In this study, an acid-responsive Fe/Mn bimetal-organic framework nanosystem carrying metal ions and immune adjuvant R848 (FeMn@R@H) was designed for combining pyroptosis and augmented immunotherapy. The FeMn@R@H would be triggered to disintegrate and release Fe3+ and Mn2+ ions in response to the acidic tumor microenvironment (TME), thereby initiating Fenton-like reactions for ROS-mediated pyroptosis. On the one hand, the pyroptosis-caused cell rupture would induce the release of proinflammatory cytokines and immunogenic constituents from tumor cells, further resulting in immunogenic cell death (ICD) to promote antitumor immune responses. On the other hand, the co-delivered R848 could reverse suppressive tumor immune microenvironment (TIME) and induce inflammatory responses by activating the TLR7/8 pathway. In conclusion, this tumor-specific therapy system can co-deliver metal ions and R848 to tumor tissues to perform pyroptosis-mediated PCD and augmented anti-tumor immunotherapy.

Structural insights into the transcription activation mechanism of the global regulator GlnR from actinobacteria.

In actinobacteria, an OmpR/PhoB subfamily protein called GlnR acts as an orphan response regulator and globally coordinates the expression of genes responsible for nitrogen, carbon, and phosphate metabolism in actinobacteria. Although many researchers have attempted to elucidate the mechanisms of GlnR-dependent transcription activation, progress is impeded by lacking of an overall structure of GlnR-dependent transcription activation complex (GlnR-TAC). Here, we report a co-crystal structure of the C-terminal DNA-binding domain of GlnR (GlnR_DBD) in complex with its regulatory cis-element DNA and a cryo-EM structure of GlnR-TAC which comprises Mycobacterium tuberculosis RNA polymerase, GlnR, and a promoter containing four well-characterized conserved GlnR binding sites. These structures illustrate how four GlnR protomers coordinate to engage promoter DNA in a head-to-tail manner, with four N-terminal receiver domains of GlnR (GlnR-RECs) bridging GlnR_DBDs and the RNAP core enzyme. Structural analysis also unravels that GlnR-TAC is stabilized by complex protein-protein interactions between GlnR and the conserved ß flap, σAR4, αCTD, and αNTD domains of RNAP, which are further confirmed by our biochemical assays. Taken together, these results reveal a global transcription activation mechanism for the master regulator GlnR and other OmpR/PhoB subfamily proteins and present a unique mode of bacterial transcription regulation.

Breast cancer-related lymphedema and recurrence of breast cancer: Protocol for a prospective cohort study in China.

INTRODUCTION: The primary aim is to determine the factors associated with breast cancer-related lymphedema and to identify new associated factors for the recurrence of breast cancer and depression. The secondary objective is to investigate the incidence of breast cancer-related events (breast cancer-related lymphedema, recurrence of breast cancer, and depression). Finally, we want to explore and validate the complex relationship among multiple factors influencing breast cancer complications and breast cancer recurrence. PATIENTS AND METHODS: A cohort study of females with unilateral breast cancer will be conducted in West China Hospital between February 2023 and February 2026. Breast cancer survivors in the age range of 17-55 will be recruited before breast cancer surgery. We will recruit 1557 preoperative patients with a first invasive breast cancer diagnosis. Consenting breast cancer survivors will complete demographic information, clinicopathological factors, surgery information, baseline information, and a baseline depression questionnaire. Data will be collected at four stages: the perioperative stage, chemotherapy therapy stage, radiation therapy stage, and follow-up stage. Data including the incidence and correlation of breast cancer-related lymphedema, breast cancer recurrence, depression, and medical cost will be collected and computed through the four stages above. For every statistical analysis, the participants will be classified into two groups based on whether they develop secondary lymphedema. Incidence rates of breast cancer recurrence and depression will be calculated separately for groups. Multivariate logistic regression will be used to determine whether secondary lymphedema and other parameters can predict breast cancer recurrence. DISCUSSION: Our prospective cohort study will contribute to establishing an early detection program for breast cancer-related lymphedema and recurrence of breast cancer, which are both associated with poor quality of life and reduced life expectancy. Our study can also provide new insights into the physical, economic, treatment-related and mental burdens of breast cancer survivors.

Inhibiting Osteolytic Breast Cancer Bone Metastasis by Bone-Targeted Nanoagent via Remodeling the Bone Tumor Microenvironment Combined with NIR-II Photothermal Therapy.

Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.

In vitro antifungal and antibiofilm activities of auranofin against itraconazole-resistant Aspergillus fumigatus.

BACKGROUND: Infections caused by azole-resistant Aspergillus are a rising public health threat with high mortality rates, high treatment costs and limited available antifungals, indicating an urgent need for new antifungals or strategies. Our aim was to investigate antifungal and antibiofilm activities of auranofin, an FDA-approved anti-antirheumatic drug. METHODS: Fungal susceptibility testing for auranofin was carried out by the broth-based microdilution methods. Cell viability treated by auranofin was tested by resazurin dye testing. The synergistic effect of auranofin and antifungal drugs was evaluated using checkboard assay. The inhibitory of biofilms were measured by crystal violet staining. Gene expression level analysis and enzyme activity was investigated with qRT-PCR analysis and DTNB assay. The key amino acid residues in the binding of auranofin with A. fumigatus thioredoxin reductase (AfTrxR) were indicated by structural analyses, site-directed mutagenesis, and microscale thermophoresis (MST) assays. RESULTS: Auranofin has fungicidal activity and in vitro antifungal spectrum including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, even itraconazole (ITC)-resistant A. fumigatus. Additionally, it has antibiofilm activities against ITC-resistant A. fumigatus by reducing the expression level of SomA and MedA. Moreover, we discovered a synergistic effect of auranofin and ITC or amphotericin B against ITC-resistant A. fumigatus. Auranofin downregulated the gene transcription of AfTrxR, and strongly inhibited the enzyme activity of AfTrxR through interacting with residues C145 and C148. CONCLUSIONS: Auranofin has fungicidal and antibiofilm activities in Aspergillus spp. and is also a potentiator of ITC or amphotericin B in vitro.

Facile synthesis of flower-like sandwich-structured molecularly imprinted polymers for efficient recognition of target protein from egg white.

In this work, a facile method for synthesis of flower-like sandwich-structured molecularly imprinted polymers (NiO@PDA/MIPs) was proposed for protein recognition. Polydopamine modified flower-like NiO was used as substrate to immobilize the target protein (ovalbumin, OVA), and dopamine was utilized as functional monomer to form the imprinted layer. The whole preparation process was conducted in aqueous solution at room temperature. The key preparation conditions were studied systematically. Owing to the large surface-to-volume of the flower-like structure and the multifunctional groups on the polydopamine layer, the NiO@PDA/MIPs showed large binding capacity (143.2 mg/g), efficient adsorption kinetics (60 min) and excellent selectivity toward OVA. Meanwhile, the NiO@PDA/MIPs possessed satisfactory stability and reusability. Finally, successful capture of OVA from egg white suggested its potential value in practical applications.

The charge effects on the hydrogen evolution reaction activity of the defected monolayer MoS2.

Doping engineering has proven to be an effective way to tune the hydrogen evolution reaction (HER) activity of MoS2. Introducing these defects could cause the overall charge imbalance of MoS2, which makes MoS2 charged. In order to understand the effect of charge on the HER activity of the defected MoS2, we systematically investigate the formation energies, hydrogen adsorption Gibbs free energy (), and electronic structures of 3d, 4d, and 5d transition metal (TM) doped monolayer MoS2 with S vacancies (Svac) based on the density functional theory (DFT) calculations. According to the formation energy calculation, Svac in the 0 and -1 charge states (S0vac and Svac1-) is found to be stable. of Svac1- is -0.16 eV, suggesting its HER catalytic activity is lower than that of Pt (), which is consistent with the experimental results. By substituting the Mo atom with TM atoms, we found that the TM atoms in groups VB-VIIB can promote the generation of Svac, forming defect complexes (TMMoSvac). is greatly affected by the charge state of defects; TMMoSvac defects (TM = V, Nb, Ta, Cr, W, Mn, and Re) in -1 charge states exhibited excellent HER activity (). Significantly, W and Re doping can promote the HER activity of MoS2 independent of the charge state and the Fermi level, which suggests that W and Re doping are most beneficial to improve the HER activity of MoS2. Therefore, the HER activity of defected MoS2 is not only influenced by as previously thought, but also by formation energies, charge state and Fermi level position of defects. The underlying physics could be deduced from the charge-induced changes in electronic structures. Our work highlights the defect charge effects on the electrochemical reactions and offers plausible mechanisms of defect charge effects.

Effects of exercise-based pulmonary rehabilitation on severe/very severe COPD: a systematic review and meta-analysis.

OBJECTIVE: Pulmonary rehabilitation (PR) has been considered to be an effective treatment method for various respiratory diseases. However, the effects of exercise-based PR on patients with severe/very severe chronic obstructive pulmonary disease (COPD) are unclear. This review aimed to investigate the effects of exercise-based PR on patients with severe/very severe COPD. METHODS: PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases were searched from inception to December 23, 2022, without language restrictions. Randomized controlled trials (RCTs) investigating the effects of exercise-based PR on patients with severe/very severe COPD were included. Study selection, data extraction, and risk of bias assessment were conducted independently. RevMan software (version 5.3) was used for meta-analysis. The quality of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Six studies (263 patients) were identified. Compared with the control group, the 6-min walking distance [MD = 52.91, 95% CI (3.80, 102.03)], the St. George's Respiratory Questionnaire total scores [MD = -7.70, 95% CI (-14.32, -1.08)] and the Borg scale scores [MD = -0.68, 95% CI (-1.28, -0.08)] in the experimental group improved, respectively. The St. George's Respiratory Questionnaire and Borg scale scores were rated as 'moderate quality' and 'low quality', respectively, and the 6-min walking distance was rated as 'very low quality'. CONCLUSIONS: Exercise-based PR may improve the exercise capacity, quality of life and dyspnea of patients with severe/very severe COPD, which can be regarded as an adjuvant treatment. High quality and large sample RCTs are needed. REGISTRATION: This systematic review and meta-analysis protocol was prospectively registered with PROSPERO (No. CRD42022294085).

[Distribution characteristics of traditional Chinese medicine syndromes in 4 367 adult influenza patients: a Meta-analysis].

OBJECTIVE: To systematically evaluate the distribution characteristics of traditional Chinese medicine (TCM) syndromes in adult influenza patients and to provide a basis for the TCM syndrome differentiation of influenza. METHODS: The CNKI, CBM, Wanfang, VIP, PubMed, Embase, Cochrane Library databases were searched to collect cross-sectional studies on the distribution pattern of TCM syndromes in adult patients with influenza. The risk of bias assessment tool for cross-sectional studies developed by the Joanna Briggs Institute (JBI) evidence-based health care center was used to evaluate the literature quality, and the Stata 15.1 software was used to conduct a Meta-analysis of the pooled effect sizes of the included studies. RESULTS: A total of 11 studies with 4 367 influenza patients were included. Quality assessment results of JBI showed that the risk bias was higher in the sample size calculation, and the description of sampling modalities and response rate was unclear. There were 17 influenza syndromes after specification, and a single group rate Meta-analysis was performed of the syndromes with ≥ 50 incident cases showed that there were 9 syndromes with an incidence ≥ 10% and statistical significance, the top 5 syndromes were syndrome of wind and heat invading the defense [n = 1 583, RATE = 34.3%, 95% confidence interval (95%CI) was 22.2%-46.3%], syndrome of exterior cold and interior heat (n = 1 122, RATE = 36.1%, 95%CI was 21.2%-51.1%), syndrome of wind-cold fettering the exterior (n = 860, RATE = 19.4%, 95%CI was 10.7%-28.0%), syndrome of heat and toxin in the lung (n = 217, RATE = 17.1%, 95%CI was 9.1%-25.0%), and syndrome of disease involving both defense phase and qi phase (n = 184, RATE = 38.8%, 95%CI was 14.2%-63.5%). The results of the subgroup analysis in different geographical regions showed that the frequency of distribution of syndrome of wind and heat invading the defense and heat and toxin in the lung was higher in the South (RATE: 36.5%, 18.6%) than in the North (RATE: 30.9%, 15.4%), and the frequency of distribution of syndrome of wind-cold fettering the exterior and exterior cold and interior heat in the North (RATE: 23.8%, 40.1%) was higher than that in the South (RATE: 15.7%, 32.3%). CONCLUSIONS: There are 9 common TCM syndromes of influenza, including wind and heat invading the defense syndrome, exterior cold and interior heat syndrome, wind-cold fettering the exterior syndrome, heat and toxin in the lung syndrome, disease involving both defense phase and qi phase syndrome, wind and heat complicated by dampnessinvading the surface syndrome, wind and cold complicated by dampnessinvading the surface syndrome, defense phase syndrome and dampness and heatinvading the surface syndrome, which can provide a reference for the TCM syndrome differentiation and treatment of influenza.

Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy.

The immunotherapeutic effect elicited by photodynamic therapy (PDT) is attenuated by tumor defense mechanisms associated with glutamine metabolism, including the metabolic regulation of redox homeostasis and the limitation of the immunosuppressive tumor microenvironment (ITM). Herein, a carrier-free immunotherapeutic nanobooster C9SN with dual synergistic effects was constructed by the self-assembly of glutaminase (GLS) inhibitor compound 968 (C968) and photosensitizer Chlorin e6. C968-mediated GSH deprivation through inhibiting glutamine metabolism prevented PDT-generated reactive oxygen species from being annihilated by GSH, amplifying intracellular oxidative stress, which caused severe cell death and also enhanced the immunogenic cell death (ICD) effect. In addition, genome-wide analysis was carried out using RNA-sequencing to evaluate the changes in cell transcriptome induced by amplifying oxidative stress. Thereafter, neoantigens generated by the enhanced ICD effect promoted the maturation of dendritic cells, thereby recruiting and activating cytotoxic T lymphocytes (CTLs). Meanwhile, C9SN remodeled the ITM by blocking glutamine metabolism to polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which further recruited and activated the CTLs. Ultimately, this immunotherapeutic nanobooster suppressed primary and distant tumors. This "kill two birds with one stone" strategy would shed light on enhancing tumor immunogenicity and alleviating tumor immunosuppression to improve the immunotherapeutic effect of PDT.

Deep-Learning-Enhanced Diffusion Imaging Assay for Resolving Local-Density Effects on Membrane Receptors.

G-protein-coupled receptor (GPCR) density at the cell surface is thought to regulate receptor function. Spatially resolved measurements of local-density effects on GPCRs are needed but technically limited by density heterogeneity and mobility of membrane receptors. We now develop a deep-learning (DL)-enhanced diffusion imaging assay that can measure local-density effects on ligand-receptor interactions in the plasma membrane of live cells. In this method, the DL algorithm allows the transformation of 100 ms exposure images to density maps that report receptor numbers over any specified region with ∼95% accuracy by 1 s exposure images as ground truth. With the density maps, a diffusion assay is further established for spatially resolved measurements of receptor diffusion coefficient as well as to express relationships between receptor diffusivity and local density. By this assay, we scrutinize local-density effects on chemokine receptor CXCR4 interactions with various ligands, which reveals that an agonist prefers to act with CXCR4 at low density while an inverse agonist dominates at high density. This work suggests a new insight into density-dependent receptor regulation as well as provides an unprecedented assay that can be applicable to a wide variety of receptors in live cells.

A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy.

Ovarian cancer (OC) is one of the most common and recurring malignancies in gynecology. Patients with relapsed OC always develop "cascade drug resistance" (CDR) under repeated chemotherapy, leading to subsequent failure of chemotherapy. To overcome this challenge, amphiphiles (P1) carrying a nitric oxide (NO) donor (Isosorbide 5-mononitrate, ISMN) and high-density disulfide are synthesized for encapsulating mitochondria-targeted tetravalent platinum prodrug (TPt) to construct a nanocomposite (INP@TPt). Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum, depleting glutathione, and preventing apoptosis escape through generating highly toxic peroxynitrite anion (ONOO-). To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor, an OC patient-derived tumor xenograft (PDXOC) model in BALB/c nude mice was established. INP@TPt showed the best therapeutic effects in the PDXOC model. The corresponding tumor tissues contained high ONOO- levels, which were attributed to the simultaneous release of O2•- and NO in tumor tissues. Taken together, INP@TPt-based systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR, providing practical applications for ovarian therapy.

Prediction of the Ibuprofen Loading Capacity of MOFs by Machine Learning.

Metal-organic frameworks (MOFs) have been widely researched as drug delivery systems due to their intrinsic porous structures. Herein, machine learning (ML) technologies were applied for the screening of MOFs with high drug loading capacity. To achieve this, first, a comprehensive dataset was gathered, including 40 data points from more than 100 different publications. The organic linkers, metal ions, and the functional groups, as well as the surface area and the pore volume of the investigated MOFs, were chosen as the model's inputs, and the output was the ibuprofen (IBU) loading capacity. Thereafter, various advanced and powerful machine learning algorithms, such as support vector regression (SVR), random forest (RF), adaptive boosting (AdaBoost), and categorical boosting (CatBoost), were employed to predict the ibuprofen loading capacity of MOFs. The coefficient of determination (R2) of 0.70, 0.72, 0.66, and 0.76 were obtained for the SVR, RF, AdaBoost, and CatBoost approaches, respectively. Among all the algorithms, CatBoost was the most reliable, exhibiting superior performance regarding the sparse matrices and categorical features. Shapley additive explanations (SHAP) analysis was employed to explore the impact of the eigenvalues of the model's outputs. Our initial results indicate that this methodology is a well generalized, straightforward, and cost-effective method that can be applied not only for the prediction of IBU loading capacity, but also in many other biomaterials projects.