Tumour-microenvironment-responsive Na2S2O8 nanocrystals encapsulated in hollow organosilica-metal-phenolic networks for cycling persistent tumour-dynamic therapy.

Traditional tumour-dynamic therapy still inevitably faces the critical challenge of limited reactive oxygen species (ROS)-generating efficiency due to tumour hypoxia, extreme pH condition for Fenton reaction, and unsustainable mono-catalytic reaction. To fight against these issues, we skilfully develop a tumour-microenvironment-driven yolk-shell nanoreactor to realize the high-efficiency persistent dynamic therapy via cascade-responsive dual cycling amplification of •SO4 -/•OH radicals. The nanoreactor with an ultrahigh payload of free radical initiator is designed by encapsulating the Na2S2O8 nanocrystals into hollow tetra-sulphide-introduced mesoporous silica (HTSMS) and afterward enclosed by epigallocatechin gallate (EG)-Fe(II) cross-linking. Within the tumour microenvironment, the intracellular glutathione (GSH) can trigger the tetra-sulphide cleavage of nanoreactors to explosively release Na+/S2O8 2 - /Fe2+ and EG. Then a sequence of cascade reactions will be activated to efficiently generate •SO4 - (Fe2+-catalyzed S2O8 2 - oxidation), proton (•SO4 --catalyzed H2O decomposition), and •OH (proton-intensified Fenton oxidation). Synchronously, the oxidation-generated Fe3+ will be in turn recovered into Fe2+ by excessive EG to circularly amplify •SO4 -/•OH radicals. The nanoreactors can also disrupt the intracellular osmolarity homeostasis by Na+ overload and weaken the ROS-scavenging systems by GSH exhaustion to further amplify oxidative stress. Our yolk-shell nanoreactors can efficiently eradicate tumours via multiple oxidative stress amplification, which will provide a perspective to explore dynamic therapy.

Analysis of pulmonary microecology and clinical characteristics of patients carrying human herpesvirus.

Aim: To investigate the impact of human herpes virus (HHV) carriage on lung microbiota, and its correlation with clinical features and laboratory indicators in patients. Methods: Retrospective analysis was conducted on 30 outpatient lung infection cases, which were divided into HHV (n = 15) and non-HHV (n = 15) groups. mNGS detected microbial composition. Microbial diversity and abundance were tested using Shannon and Chao1 indices. Their relationship with laboratory indicators were explored. Results: Significant differences in microbial abundance and distribution were found between two groups (p < 0.05). Moreover, HHV group showed negative correlations (p < 0.05) between Prevotella, Porphyromonas, Streptococcus and basophil/eosinophil percentages. Conclusion: HHV carriage impacts lung microbiota, emphasizing the need for clinicians to pay attention to HHV reactivation in outpatient lung infection patients.

This study looked at how a common virus called human herpesvirus (HHV) affects the bacteria in our lungs. We wanted to see if HHV is linked to how sick we feel and what tests show. We split 30 people who had lung infections into two groups ­ 15 with HHV and 15 without ­ and checked how sick they felt, did some tests, and looked at the types of bacteria in their lungs. Both groups felt similarly sick and got better with medicine, but people with HHV had fewer of a certain type of blood cell. People with and without HHV also had different types of bacteria in their lungs. This study helps us understand why people get sick with lung infections and how to make them better. It might also help doctors decide how to treat people with lung infections.

Oxygen-Evolving Radiotherapy-Radiodynamic Therapy Synergized with NO Gas Therapy by Cerium-Based Rare-Earth Metal-Porphyrin Framework.

The efficacy of traditional radiotherapy (RT) has been severely limited by its significant side effects, as well as tumor hypoxia. Here, the nanoscale cerium (Ce)-based metaloxo clusters (Ce(IV)6)-porphyrin (meso-tetra (4-carboxyphenyl) porphyrin, TCPP) framework loaded with L-arginine (LA) (denoted as LA@Ce(IV)6-TCPP) is developed to serve as a multifarious radio enhancer to heighten X-ray absorption and energy transfer accompanied by O2/NO generation for hypoxia-improved RT-radiodynamic therapy (RDT) and gas therapy. Within tumor cells, LA@Ce(IV)6-TCPP will first react with endogenous H2O2 and inducible NO synthase (iNOS) to produce O2 and NO to respectively increase the oxygen supply and reduce oxygen consumption, thus alleviating tumor hypoxia. Then upon X-ray irradiation, LA@Ce(IV)6-TCPP can significantly enhance hydroxyl radical (•OH) generation from Ce(IV)6 metaloxo clusters for RT and synchronously facilitate singlet oxygen (1O2) generation from adjacently-coordinated TCPP for RDT. Moreover, both the •OH and 1O2 can further react with NO to generate more toxic peroxynitrite anions (ONOO-) to inhibit tumor growth for gas therapy. Benefitting from the alleviation of tumor hypoxia and intensified RT-RDT synergized with gas therapy, LA@Ce(IV)6-TCPP elicited superior anticancer outcomes. This work provides an effective RT strategy by using low doses of X-rays to intensify tumor suppression yet reduce systemic toxicity.

N6-Methyladenosine reader HNRNPC-mediated downregulation of circITCH prevents miR-224-3p sequestering and contributes to tumorigenesis in nasopharyngeal carcinoma.

BACKGROUND: N6-Methyladenosine (m6A) RNA methylation modulators are implicated in nasopharyngeal carcinoma (NPC). Circular RNAs (circRNAs) stimulate/inhibit the development of NPC by sponging microRNAs (miRNAs). Herein, m6A modifications affecting the circRNA/miRNA axis in NPC were explored. METHODS: Twenty prognostic m6A RNA methylation regulators were identified from 504 head/neck squamous cell carcinoma and 44 normal samples from The Cancer Genome Atlas (TCGA). Differentially expressed miRNAs were screened from the TCGA and Gene Expression Omnibus (GEO) databases. RNA-binding protein (RBP)-circRNA and circRNA-miRNA interactive pairs were verified using RBPmap and RNAhybrid, respectively. The RBP/circRNA/miRNA network was constructed using Cytoscape. Furthermore, CircITCH (hsa_circ_00059948), HNRNPC, and miR-224-3p expressions were detected by western blotting and quantitative polymerase chain reaction. The role of circITCH in NPC was examined using apoptosis, scratch wound healing, transwell invasion, and cell counting kit-8 assays. Finally, CircITCH-miR-224-3p and circITCH-HNRNPC interactions were assessed by dual-luciferase reporter and RNA-immunoprecipitation (RIP) assays, respectively. RESULTS: Bioinformatics analysis revealed that high pathological grade, late-stage tumors, and low survival were associated with increased HNRNPC expression. MiR-224-3p was upregulated in NPC and sequestered by circITCH. Construction of the RBP/circRNA/miRNA network highlighted the HNRNPC/circITCH/miR-224-3p axis. In vitro experiments demonstrated decreased circITCH expression and increased HNRNPC and miR-224-3p expressions in NPC. In NPC cells overexpressing circITCH, HNRNPC and miR-224-3p expressions were significantly decreased. Dual-luciferase assays demonstrated a targeting relationship between circITCH and miR-224-3p, and RIP assays demonstrated interaction of HNRNPC targets with circITCH. CONCLUSION: CircITCH overexpression inhibited NPC progression by sequestering miR-224-3p, and HNRNPC reduced circITCH expression through direct interaction.

Tumor-Microenvironment-Responsive Cerium-Enriched Copper Nanozyme with O2 Supply and Oxidative Stress Amplification for In Situ Disulfiram Chemotherapy and Chemodynamic Therapy Intensification.

Traditional chemotherapy has faced tough challenges of systemic toxicity, hypoxia resistance, and inadequacy of monotherapy. Developing the tumor-specific O2-supply-enhanced chemotherapy without toxic drugs while combing other precise treatments can substantially improve therapeutic efficacy. Herein, a CeO2-enriched CuO nanozyme with O2 supply and oxidative stress amplification for tumor-specific disulfiram (DSF) chemotherapy and intensified chemodynamic therapy by synergistic in situ "nontoxicity-toxicity" activation is developed. Notably, CeO2 can not only act as a morphological "regulator," but also serve as a cascaded enzyme-mimetic catalyst via tumor-microenvironment-responsive cascaded-logical programmable valence conversion. Once internalized inside tumor cells, the nanozyme can be degraded by lysosomal acidity to release nontoxic DSF and Cu2+, which can trigger in situ "Cu2+-DSF" chelation, generating a highly toxic Cu(DTC)2 for in situ chemotherapy. Moreover, the enriched CeO2 with catalase-mimetic activity can decompose the endogenous H2O2 into O2, which can relieve the hypoxia to enhance the chemotherapeutic efficacy. Furthermore, the simultaneously generated Ce3+ can exert peroxidase-mimetic activity to catalyze H2O2 into hydroxyl radicals (•OH) for chemodynamic therapy. This Fenton-like chemistry is accompanied by the regeneration of Ce4+, which can deplete the intracellular overproduced GSH to amplify the oxidative stress. Therefore, this nanozyme can provide an alternative to precise cancer treatment.

Urinary peptidome analysis in CKD and IgA nephropathy.

Background: Chronic kidney disease (CKD) has emerged as a significant challenge to human health and economic stability in aging societies worldwide. Current clinical practice strategies remain insufficient for the early identification of kidney dysfunction, and the differential diagnosis of immunoglobulin A nephropathy (IgAN) predominantly relies on invasive kidney biopsy procedures. Methods: First, we assessed a case-control cohort to obtain urine samples from healthy controls and biopsy-confirmed CKD patients. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) was applied to detect urinary peptide and then these urinary peptide profiles were used to construct diagnostic models to distinguish CKD patients from controls and identify IgAN patients from other nephropathy patients. Furthermore, we assessed the robustness of the diagnostic models and their reproducibility by applying different algorithms. Results: A rapid and accurate working platform for detecting CKD and its IgAN subtype based on urinary peptide pattern detected by MALDI-TOF MS was established. Naturally occurring urinary peptide profiles were used to construct a diagnostic model to distinguish CKD patients from controls and identify IgAN patients from other nephropathy patients. The performance of several algorithms was assessed and demonstrated that the robustness of the diagnostic models as well as their reproducibility were satisfactory. Conclusions: The present findings suggest that the CKD-related and IgAN-specific urinary peptides discovered facilitate precise identification of CKD and its IgAN subtype, offering a dependable framework for screening conditions linked to renal dysfunction. This will aid in comprehending the pathogenesis of nephropathy and identifying potential protein targets for the clinical management of nephropathy.

Tailoring Electrolyte Distributions to Enable High-performance Li3 PS4 -based All-solid-state Batteries under Different Operating Temperatures.

Li3 PS4 shows great potential as solid electrolyte for all-solid-state lithium batteries (ASSLBs) due to its high Li-ion conductivity and excellent mechanical properties. However, its poor interfacial stability with bare high-nickel active materials in the cathode mixture inhibits the energy density and electrochemical performances of the corresponding LiNi0.6 Mn0.2 Co0.2 O2 /Li3 PS4 /Li-In battery. The Li3 InCl6 electrolyte with good electrochemical/chemical stability with bare LiNi0.6 Mn0.2 Co0.2 O2 (NCM622), which acts both as a Li-ion additive in the cathode mixture and as an isolation layer to isolate the direct contact between the sulfide electrolytes and active materials, providing superior solid/solid interface stabilities in the assembled battery. XPS and TEM results confirm that this strategy can mitigate the side reactions between the bare NCM622 and Li3 PS4 electrolytes. In-situ EIS and DRT results prove that this grading utilization of different solid electrolytes can greatly alleviate the poor electrochemical stability between those two materials, yielding smaller interfacial resistances. The corresponding battery delivers high discharge capacities at various C-rates under different operating temperatures. It delivers a much higher initial discharge capacity of 187.7 mAh g-1 (vs. 92.5 mAh g-1 ) at 0.1 C with a coulombic efficiency of 87.6% (vs. 71.1%) at room temperature. Moreover, this battery can even show highly reversible capacity with excellent cyclability when the operating temperature lowers to 0 and -20 °C. This work provides a hierarchical utilization strategy to fabricate sulfide electrolytes-based ASSLBs with high energy density and superior cycling performance combined with highly-oxidation cathode materials.

The Clinical Features and Management of Empyema Caused by Streptococcus constellatus.

Background: Streptococcus constellatus, a commensal, plays an important role in purulent infections. It has been reported as aggressive pathogen causing pleural empyema. But the role of S. constellatus in empyema has not been taken seriously. There are no studies about clinical characteristics of empyema caused by S. constellatus domestically and abroad. This study aimed to explore the clinical features and management of empyema caused by S. constellatus. Methods: A retrospective review of 9 patients diagnosed with empyema caused by S. constellatus in a hospital between January 2010 and August 2021 was performed. Results: S. constellatus empyema were mostly seen in old males (66.7%) with comorbid diseases. The high-risk factors include diabetes mellitus, oral infection, and oral surgery. All were unilateral encapsulated empyema (right-side, 55.6%), diagnosed with pneumonia (bilateral pneumonia, 88.9%; ipsilateral lung abscess, 44.4%). 33.3% of patients had S. constellatus and anaerobes co-isolated. S. constellatus were sensitive to penicillin G, linezolid, levofloxacin, vancomycin, ceftriaxone, and chloramphenicol, resistant to erythromycin, tetracycline, and clindamycin. 33.3% of the patients needed ventilator support. The primary treatment to S. constellatus empyema was timely pus drainage, intravenous antibiotics, and enough nutrition support, intrapleural fibrinolytics and surgery (VAST recommended first) in necessity. Conclusion: S. constellatus may cause pneumonia and lung abscess first and then spread to cause empyema mainly in old males with comorbid diseases. S. constellatus often co-isolated with anaerobes in empyema. Antibiotics should cover simultaneously both S. constellatus and anaerobes.

Tumor Microenvironment-Responsive Yolk-Shell NaCl@Virus-Inspired Tetrasulfide-Organosilica for Ion-Interference Therapy via Osmolarity Surge and Oxidative Stress Amplification.

Ion-interference therapy, which utilizes ions to disturb intracellular biological processes, provides inspiration for tumor therapy. Artificially reversing osmotic pressure by transporting large amounts of physiological ions to tumor cells is a straightforward yet low-toxic strategy for ion-interference therapy. However, it is hard to achieve due to the serious limitations of single-ion delivery. Herein, we skillfully deliver NaCl nanocrystals to tumor sites and sequentially realize the explosive release of Na+/Cl- inside tumor cells by utilizing a virus-mimicking and glutathione (GSH)-responsive hollow mesoporous tetrasulfide-bridged organosilica (ssss-VHMS). Once the ssss-VHMS-wrapped NaCl nanocrystals (NaCl@ssss-VHMS) accumulate in the tumors, they would rapidly invade tumor cells via spike surface-assisted endocytosis, thus bypassing Na+/K+-ATPase transmembrane ion transporters. Afterward, the intracellular overproduced GSH of tumor cells would trigger the rapid degradation of ssss-VHMS via thiol-tetrasulfide exchange, which could not only remarkably deplete the GSH but also explosively release the Na+/Cl-, leading to the osmolarity surge accompanied by reactive oxygen species (ROS) generation. The cell swelling, ROS storm, and GSH exhaustion of NaCl@ssss-VHMS effectively eradicated tumor cells by caspase-1-dependent pyroptosis, caspase-3-dependent apoptosis, and GPX4-dependent ferroptosis, respectively, thus synergistically inhibiting tumor growth. We believe that NaCl@ssss-VHMS would be a potential cancer therapeutic agent, and this discovery could provide a perspective for exploring synergistic ion-interference therapy.

Gut Microbiome Alterations and Hepatic Metabolic Flexibility in the Gansu Zokor, Eospalax cansus: Adaptation to Hypoxic Niches.

The Gansu zokor (Eospalax cansus), a typical subterranean rodent endemic to the Chinese Loess Plateau, spends almost its whole life in its self-constructed underground burrows and has strong adaptability to ambient hypoxia. Energy adaptation is the key to supporting hypoxia tolerance, and recent studies have shown that the intestinal microbiota has an evident effect on energy metabolism. However, how the gut microbiome of Gansu zokor will change in response to hypoxia and the metabolic role played by the microbiome have not been reported. Thus, we exposed Gansu zokors to severe hypoxia of 6.5% of O2 (6 or 44 h) or moderate hypoxia of 10.5% of O2 (44 h or 4 weeks), and then analyzed 16S rRNA sequencing, metagenomic sequencing, metagenomic binning, liver carbohydrate metabolites, and the related molecular levels. Our results showed that the hypoxia altered the microbiota composition of Gansu zokor, and the relative contribution of Ileibacterium to carbohydrate metabolism became increased under hypoxia, such as glycolysis and fructose metabolism. Furthermore, Gansu zokor liver enhanced carbohydrate metabolism under the short-term (6 or 44 h) hypoxia but it was suppressed under the long-term (4 weeks) hypoxia. Interestingly, under all hypoxia conditions, Gansu zokor liver exhibited enhanced fructose-driven metabolism through increased expression of the GLUT5 fructose transporter, ketohexokinase (KHK), aldolase B (ALDOB), and aldolase C (ALDOC), as well as increased KHK enzymatic activity and fructose utilization. Overall, our results suggest that the altered gut microbiota mediates the carbohydrate metabolic pattern under hypoxia, possibly contributing to the hepatic metabolic flexibility in Gansu zokor, which leads to better adaptation to hypoxic environments.

Identification of Hub Genes Associated with Abnormal Endothelial Function in Early Coronary Atherosclerosis.

Abnormal coronary endothelial function is an important step in the development of atherosclerosis. Coronary atherosclerosis is one of the main causes of death worldwide. We constructed a co-expression network to identify hub genes associated with abnormal coronary endothelial function in early coronary atherosclerosis. In brief, we used the GSE132651 dataset from the gene expression omnibus database. The top 5000 genes with greatest variances were used for weighted gene co-expression network analysis, and the module most strongly correlated with abnormal coronary endothelial function was chosen as key module. Functional enrichment analysis was performed for genes in the key module, a protein-protein interaction network was constructed to find hub genes, and gene set enrichment analysis (GSEA) was also performed. Genes were classified into 7 modules, with the midnightblue module being the one that was most related to abnormal coronary endothelial function and containing genes enriched in DNA replication, cell cycle, nucleotide excision repair, and Human T-cell leukemia virus 1 infection. We identified nine hub genes (HOXC5, PRND, PADI3, RC3H1, DAPP1, SIT1, DRICH1, GPRIN2, and RHO), which differently expressed in abnormal and normal coronary endothelial function samples. GSEA suggested that samples associated with abnormal coronary endothelial function and highly expressed hub genes were linked with immune, coagulation, hypoxia, and angiogenesis processes. These hub genes, their expression pattern, and pathways may be involved in the development of abnormal coronary endothelial function and promotion of early coronary atherosclerosis.

Natural Killer Cell Membrane-Cloaked Virus-Mimicking Nanogenerator with NIR-Triggered Shape Reversal and •C/•OH Storm for Synergistic Thermodynamic-Chemodynamic Therapy.

Free radical-based anticancer modality has been widely applied to cancer therapies. However, it still faces challenges of low delivery efficiency and poor selectivity of free radical generation specifically toward tumors. Herein, a virus-mimicking hollow mesoporous disulfide-bridged organosilica is designed to encapsulate •C precursor 2, 2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), which is then enclosed by tannic acid (TA)/FeIII photothermal assembly and further cloaked by natural killer (NK) cell membrane to achieve synergistic thermodynamic-chemodynamic therapy. The nanogenerator can first evade immune surveillance via NK cell membrane "cloaking" mechanism to strongly accumulate in tumors. Interestingly, the NIR laser-induced heat can trigger NK cell membrane rupture for "shape reversal" to expose a virus-like surface to amplify the cellular uptake, and simultaneously break the azo bonds of AIPH for in situ controlled •C generation. Then upon glutathione (GSH) triggering, the nanogenerator disintegrates via disulfide-thiol exchange and efficiently generates •OH by lysosomal pH-initiated TA-FeIII reaction; notably, the consumption of GSH can amplify oxidative stress to enhance free radical therapy by weakening the self-defense mechanism of tumor cells. It is envisioned that the NK cell membrane-cloaked virus-mimicking and NIR/GSH sequentially activated •C/•OH radical nanogenerator can provide a promising strategy for oxidative stress-based anticancer therapy.

Artificial Intelligence to Detect Meibomian Gland Dysfunction From in-vivo Laser Confocal Microscopy.

Background: In recent years, deep learning has been widely used in a variety of ophthalmic diseases. As a common ophthalmic disease, meibomian gland dysfunction (MGD) has a unique phenotype in in-vivo laser confocal microscope imaging (VLCMI). The purpose of our study was to investigate a deep learning algorithm to differentiate and classify obstructive MGD (OMGD), atrophic MGD (AMGD) and normal groups. Methods: In this study, a multi-layer deep convolution neural network (CNN) was trained using VLCMI from OMGD, AMGD and healthy subjects as verified by medical experts. The automatic differential diagnosis of OMGD, AMGD and healthy people was tested by comparing its image-based identification of each group with the medical expert diagnosis. The CNN was trained and validated with 4,985 and 1,663 VLCMI images, respectively. By using established enhancement techniques, 1,663 untrained VLCMI images were tested. Results: In this study, we included 2,766 healthy control VLCMIs, 2,744 from OMGD and 2,801 from AMGD. Of the three models, differential diagnostic accuracy of the DenseNet169 CNN was highest at over 97%. The sensitivity and specificity of the DenseNet169 model for OMGD were 88.8 and 95.4%, respectively; and for AMGD 89.4 and 98.4%, respectively. Conclusion: This study described a deep learning algorithm to automatically check and classify VLCMI images of MGD. By optimizing the algorithm, the classifier model displayed excellent accuracy. With further development, this model may become an effective tool for the differential diagnosis of MGD.

Potential Role and Clinical Value of PPP2CA in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Protein phosphatase 2A (PP2A) is associated with many cancers. This study aimed to clarify whether PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, plays a role in hepatocellular carcinoma (HCC) and to identify the potential underlying molecular pathways. METHODS: Based on bioinformatics, public databases and our in-house RNA-Seq database, we analyzed the clinical value and molecular mechanism of PPP2CA in HCC. RESULTS: Data were analyzed from 2,545 patients with HCC and 1,993 controls without HCC indexed in The Cancer Genome Atlas database, the Gene Expression Omnibus database and our in-house RNA-Seq database. PPP2CA expression was significantly higher in HCC tissue than in non-cancerous tissues (standardized mean difference: 0.69, 95% confidence interval [CI]: 0.50-0.89). PPP2CA expression was able to differentiate HCC from non-HCC, with an area under the summary receiver operator characteristic curve of 0.79 (95% CI: 0.75-0.83). Immunohistochemistry of tissue sections confirmed that PPP2CA protein was up-regulated in HCC tissues. High PPP2CA expression in HCC patients was associated with shorter overall, progression-free and disease-free survival. Potential molecular pathways through which PPP2CA may be involved in HCC were determined using miRWalk 2.0 as well as analysis of Gene Ontology categories, Kyoto Encyclopedia of Genes and Genomes pathways, and protein-protein interaction networks. CONCLUSIONS: PPP2CA is up-regulated in HCC and higher expression correlates with worse prognosis. PPP2CA shows potential as a diagnostic marker for HCC. Future studies should examine whether PPP2CA contributes to HCC through the candidate microRNAs, pathways and hub genes identified in this study.

Identification of Hub Genes and MicroRNAs Associated With Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Analyses.

OBJECTIVE: The aim of this study is the identification of hub genes associated with idiopathic pulmonary arterial hypertension (IPAH). MATERIALS AND METHODS: GSE15197 gene expression data was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by screening IPAH patients and controls. The 5,000 genes with the greatest variances were analyzed using a weighted gene co-expression network analysis (WGCNA). Modules with the strongest correlation with IPAH were chosen, followed by a functional enrichment analysis. Protein-protein interaction (PPI) networks were constructed to identify hub gene candidates using calculated degrees. Real hub genes were found from the overlap of DEGs and candidate hub genes. microRNAs (miRNAs) targeting real hub genes were found by screening miRNet 2.0. The most important IPAH miRNAs were identified. RESULTS: There were 4,395 DEGs identified. WGCNA indicated that green and brown modules associated most strongly with IPAH. Functional enrichment analysis showed that green and brown module genes were mainly involved in protein digestion and absorption and proteoglycans in cancer, respectively. The top ten candidate hub genes in green and brown modules were identified, respectively. After overlapping with DEGs, 11 real hub genes were identified: EP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1. These genes were expressed with significant differences in IPAH versus controls, indicating a high diagnostic ability. The miRNA-gene network showed that hsa-mir-1-3p could associate with IPAH. CONCLUSION: EP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1 may play essential roles in IPAH. Predicted miRNA hsa-mir-1-3p could regulate gene expression in IPAH. Such hub genes may contribute to the pathology and progression in IPAH, providing potential diagnostic and therapeutic opportunities for IPAH patients.

Virus-like mesoporous silica-coated plasmonic Ag nanocube with strong bacteria adhesion for diabetic wound ulcer healing.

The Gram-positive bacterium Staphylococcus aureus (MRSA) and the Gram-negative bacillus Escherichia coli (E. coli) can be commonly found in diabetic foot ulcers. However, the multi-drug resistant pathogenic bacteria infection is often difficult to eradicate by the conventional antibiotics and easy to spread which can lead to complications such as gangrene or sepsis. In this work, in order to pull through the low cell wall adhesion capability of typical antibacterial Ag nanoparticles, we fabricated biomimic virus-like mesoporous silica coated Ag nanocubes with gentamicin loading, and then the core-shell nanostructure was entrapped in the FDA approved hydrogel dressing. Interestingly, the Ag nanocubes with virus-like mesoporous silica coating are capable of effectively adsorbing on the rigid cell wall of both E. coli and MRSA. The intracellular H2S in natural bacterial environment can induce generation of small Ag nanospheres, which are the ideal antibacterial nanoagents. Combined with the gentamicin delivery, the pathogenic bacteria in diabetic wound can be completely eradicated by our dressing to improve the wound healing procedure. This virus-like core-shell nanostructure sheds light for the future wound healing dressing design to promote the clinical applications on antibacterial eradication.

The mTORC1/eIF4E/HIF-1α Pathway Mediates Glycolysis to Support Brain Hypoxia Resistance in the Gansu Zokor, Eospalax cansus.

The Gansu zokor (Eospalax cansus) is a subterranean rodent species that is unique to China. These creatures inhabit underground burrows with a hypoxia environment. Metabolic energy patterns in subterranean rodents have become a recent focus of research; however, little is known about brain energy metabolism under conditions of hypoxia in this species. The mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) coordinates eukaryotic cell growth and metabolism, and its downstream targets regulate hypoxia inducible factor-1α (HIF-1α) under conditions of hypoxia to induce glycolysis. In this study, we compared the metabolic characteristics of hypoxia-tolerant subterranean Gansu zokors under hypoxic conditions with those of hypoxia-intolerant Sprague-Dawley rats with a similar-sized surface area. We exposed Gansu zokors and rats to hypoxia I (44 h at 10.5% O2) or hypoxia II (6 h at 6.5% O2) and then measured the transcriptional levels of mTORC1 downstream targets, the transcriptional and translational levels of glycolysis-related genes, glucose and fructose levels in plasma and brain, and the activity of key glycolysis-associated enzymes. Under hypoxia, we found that hif-1α transcription was upregulated via the mTORC1/eIF4E pathway to drive glycolysis. Furthermore, Gansu zokor brain exhibited enhanced fructose-driven glycolysis under hypoxia through increased expression of the GLUT5 fructose transporter and ketohexokinase (KHK), in addition to increased KHK enzymatic activity, and utilization of fructose; these changes did not occur in rat. However, glucose-driven glycolysis was enhanced in both Gansu zokor and rat under hypoxia II of 6.5% O2 for 6 h. Overall, our results indicate that on the basis of glucose as the main metabolic substrate, fructose is used to accelerate the supply of energy in Gansu zokor, which mirrors the metabolic responses to hypoxia in this species.

Correction: Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy.

Correction for 'Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy' by Kaihang Xue et al., Biomater. Sci., 2021, DOI: 10.1039/D0BM01864C.

Tumor acidity-responsive carrier-free nanodrugs based on targeting activation via ICG-templated assembly for NIR-II imaging-guided photothermal-chemotherapy.

Carrier-free nanodrugs composed of photosensitizers and chemotherapeutic drugs show great potential in synergistic photothermal-chemotherapy. However, the targeting specificity to tumor cells is still a major obstacle for carrier-free nanodrugs. Meanwhile, almost all exogenous tumor-targeting ligands show no therapeutic effect by themselves. Here, a tumor microenvironment-driven self-targeting supramolecular nanodrug was successfully constructed via an indocyanine green (ICG)-templated small-molecule self-assembly strategy with methotrexate (MTX, folic acid-like antitumor drug) followed by post-insertion of weak acidity-responsive PEG for synergistic photothermal-chemotherapy. Interestingly, the size and morphology could be adjusted by changing the ICG-to-MTX ratio. Notably, the dynamic introduction of PEG not only could temporarily shield self-targeting function in blood to prolong the circulation time, but also could trigger the activation of self-targeting via re-exposing MTX ligands within the tumor microenvironment to enhance cellular uptake. Furthermore, the dePEGylated nanodrug would be disassembled to release MTX on-demand for chemotherapy via both stimuli of stronger lysosomal acidity and an external NIR laser. Moreover, the elimination of tumors could be realized through NIR-II fluorescence/PA imaging-guided synergistic photothermal-chemotherapy. The tumor microenvironment-driven carrier-free nanodrug based on self-targeting activation via ICG-templated assembly might provide a brand-new idea for synergistic photothermal-chemotherapy.