Antiparasitic nitazoxanide potentiates colistin against colistin-resistant Acinetobacter baumannii and Escherichia coli in vitro and in vivo.

IMPORTANCE: Colistin is used as a last resort in many infections caused by multidrug-resistant Gram-negative bacteria; however, colistin-resistant (COL-R) is on the rise. Hence, it is critical to develop new antimicrobial strategies to overcome COL-R. We found that nitazoxanide (NTZ) combined with colistin showed notable synergetic antibacterial activity. These findings suggest that the NTZ/colistin combination may provide an effective alternative route to combat COL-R A. baumannii and COL-R Escherichia coli infections.

Surface Phonon Polariton-Mediated Near-Field Radiative Heat Transfer at Cryogenic Temperatures.

Recent experiments, at room temperature, have shown that near-field radiative heat transfer (NFRHT) via surface phonon polaritons (SPhPs) exceeds the blackbody limit by several orders of magnitude. Yet, SPhP-mediated NFRHT at cryogenic temperatures remains experimentally unexplored. Here, we probe thermal transport in nanoscale gaps between a silica sphere and a planar silica surface from 77-300 K. These experiments reveal that cryogenic NFRHT has strong contributions from SPhPs and does not follow the T^{3} temperature (T) dependence of far-field thermal radiation. Our modeling based on fluctuational electrodynamics shows that the temperature dependence of NFRHT can be related to the confinement of heat transfer to two narrow frequency ranges and is well accounted for by a simple analytical model. These advances enable detailed NFRHT studies at cryogenic temperatures that are relevant to thermal management and solid-state cooling applications.

Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.

BACKGROUND: Ceftazidime-avibactam (CZA) improves treatment outcomes for infections caused by carbapenem-resistant organisms, but has led to serious bacterial resistance. Acetylcysteine (NAC) is an approved medication that protects the respiratory tract through antioxidant and anti-inflammatory effects. RESULTS: This study found that NAC combined with CZA effectively inhibits the growth of CZA-resistant clinical Enterobacterales strains. The CZA/NAC combination inhibits biofilm formation in vitro and decreases bacterial burden in a mouse thigh infection model. The combination is biocompatible and primarily increases cell membrane permeability to cause bacterial death. CONCLUSIONS: These findings prove that the CZA/NAC combination has potential as a treatment for CZA-resistant Enterobacterales infections.

FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing.

Mesenchymal glioblastoma (GBM) is highly resistant to radio-and chemotherapy and correlates with worse survival outcomes in GBM patients; however, the underlying mechanism determining the mesenchymal phenotype remains largely unclear. Herein, it is revealed that FBXO7, a substrate-recognition component of the SCF complex implicated in the pathogenesis of Parkinson's disease, confers mesenchymal properties and chemoresistance in GBM by controlling Rbfox2-mediated alternative splicing. Specifically, FBXO7 ubiquitinates Rbfox2 Lys249 through K63-linked ubiquitin chains upon arginine dimethylation at Arg341 and Arg441 by PRMT5, leading to Rbfox2 stabilization. FBXO7 controls Rbfox2-mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion of FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, thereby upregulates CD44, CD9, and ID1 levels, resulting in GBM stem cell self-renewal and mesenchymal transformation. Moreover, FBXO7 is stabilized by temozolomide, and FBXO7 depletion sensitizes tumor xenografts in mice to chemotherapy. The findings demonstrate that the FBXO7-Rbfox2 axis-mediated splicing contributes to mesenchymal transformation and tumorigenesis, and targeting FBXO7 represents a potential strategy for GBM treatment.

Complete-genome sequencing and comparative genomic characterization of blaNDM-5 carrying Citrobacter freundii isolates from a patient with multiple infections.

BACKGROUND: The emergence and wide spread of carbapenemase-producing Enterobacteriaceae (CPE) poses a growing threat to global public health. However, clinically derived carbapenemase-producing Citrobacter causing multiple infections has rarely been investigated. Here we first report the isolation and comparative genomics of two blaNDM-5 carrying Citrobacter freundii (C. freundii) isolates from a patient with bloodstream and urinary tract infections. RESULTS: Antimicrobial susceptibility testing showed that both blaNDM-5 carrying C. freundii isolates were multidrug-resistant. Positive modified carbapenem inactivation method (mCIM) and EDTA-carbapenem inactivation method (eCIM) results suggested metallo-carbapenemase production. PCR and sequencing confirmed that both metallo-carbapenemase producers were blaNDM-5 positive. Genotyping and comparative genomics analyses revealed that both isolates exhibited a high level of genetic similarity. Plasmid analysis confirmed that the blaNDM-5 resistance gene is located on IncX3 plasmid with a length of 46,161 bp, and could successfully be transferred to the recipient Escherichia coli EC600 strain. A conserved structure sequence (ISAba125-IS5-blaNDM-5-trpF-IS26-umuD-ISKox3) was found in the upstream and downstream of the blaNDM-5 gene. CONCLUSIONS: The data presented in this study showed that the conjugative blaNDM-5 plasmid possesses a certain ability to horizontal transfer. The dissemination of NDM-5-producing C. freundii isolates should be of close concern in future clinical surveillance. To our knowledge, this is the first study to characterize C. freundii strains carrying the blaNDM-5 gene from one single patient with multiple infections.

Heterogenous profiles between primary lung cancers and paired brain metastases reveal tumor evolution.

Background: Brain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary lung cancers and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary lung cancers and BMs, and the evolutionary process remains little known. Methods: To deeply insight into the extent of inter-tumor heterogeneity at a single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 10 patients with matched primary lung cancers and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary lung cancers and BMs were evaluated by utilizing whole-exome sequencing (WESeq) and immunohistochemical analysis. Results: In addition to inheriting genomic phenotype and molecular phenotype from the primary lung cancers, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at a single-patient level. By analysis of a multi-metastases case (Case 3) of cancer cells' subclonal composition, we found similar multiple subclonal clusters in the four spatial and temporal isolated brain metastatic focus, with the characteristics of polyclonal dissemination. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0002) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary lung cancers. Additionally, tumor microvascular density (MVD) also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity. Conclusion: Our study revealed the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary lung cancers and BMs, which also provided novel insight for formulating individualized treatment strategies for BMs.

Inorganically Connecting Colloidal Nanocrystals Significantly Improves Mechanical Properties.

Understanding and characterizing the mechanical behavior of colloidal nanocrystal (NC) assemblies are important for developing nanocrystalline materials with exceptional mechanical properties for robust electronic, thermoelectric, photovoltaic, and optoelectronic devices. However, the limited ranges of Young's modulus, hardness, and fracture toughness (≲1-10 GPa, ≲50-500 MPa, and ≲10-50 kPa m1/2, respectively) in as-synthesized NC assemblies present challenges for their mechanical stability and therefore their practical applications. In this work, we demonstrate using a combination of nanoindentation measurements and coarse-grained modeling that the mechanical response of assemblies of as-synthesized NCs is governed by the van der Waals interactions of the organic surface ligands. More importantly, we report tremendous ∼60× enhancements in Young's modulus and hardness and an ∼80× enhancement in fracture toughness of CdSe NC assemblies through a simple inorganic Sn2S64- ligand exchange process. Moreover, our observation of softening in nanocrystalline materials with decreasing CdSe NC diameter is consistent with atomistic simulations.

Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view.

Cerebral cavernous malformations (CCMs) are common vascular anomaly diseases in the central nervous system associated with seizures, cerebral microbleeds, or asymptomatic mostly. CCMs can be classified as sporadic or familial, with familial cerebral cavernous malformations (fCCMs) being the autosomal dominant manner with incomplete penetrance. Germline mutations of KRIT1, CCM2, and PDCD10 are associated with the pathogenesis of fCCMs. Till now, little is known about the fCCMs mutation spectrum in the Han Chinese population. In this study, we enrolled a large, aggregated family, 11/26 of the family members were diagnosed with CCMs by pathological or neuroradiological examination, with a high percentage (5/9) of focal spinal cord involvement. Genomic DNA sequencing verified a novel duplication mutation (c.1119dupT, p.L374Sfs*9) in exon 9 of the Krev interaction trapped 1 (KRIT1) gene. The mutation causes a frameshift and is predicted to generate a truncated KRIT1/CCM1 protein of 381 amino acids. All our findings confirm that c.1119dupT mutation of KRIT1 is associated with fCCMs, which enriched the CCM genes' mutational spectrum in the Chinese population and will be beneficial for deep insight into the pathogenesis of Chinese fCCMs. Additionally, with a retrospective study, we analyzed the molecular genetic features of Chinese fCCMs, most of the Chinese fCCMs variants are in the KRIT1 gene, and all these variants result in the functional deletion or insufficiency of the C-terminal FERM domain of the KRIT1 protein.

A novel transposon Tn7540 carrying blaNDM-9 and fosA3 in chromosome of a pathogenic multidrug-resistant Salmonella enterica serovar Indiana isolated from human faeces.

OBJECTIVES: Emergence of multidrug-resistant (MDR) Salmonella enterica serovar Indiana has raised global concern. Mobile genetic elements (MGEs) play vital roles in accelerating the dissemination of resistance genes in bacteria communities. The study aims to improve our understanding of the underlying resistance mechanisms and characterize the MGEs in a MDR S. Indiana isolate. METHODS: Here, we report the characteristics of a MDR pathogenic S. Indiana isolate. The antimicrobial susceptibility pattern of S. Indiana QT6365 was determined. The genomic structure of the chromosome and the plasmid, serotype, and multi-locus sequence type were analysed by whole genome sequencing. The circular form derived from IS26-flanked transposon was confirmed by reverse polymerase chain reaction and sequencing. RESULTS: S. Indiana QT6365 exhibited resistance to all tested antimicrobials except for aztreonam, amikacin, polymyxin, and tigecycline, was defined as MDR, and belonged to ST17. S. Indiana QT6365 was closely related with food resource S. Indiana C629 with similar resistance gene profiles. Multiple resistance genes are mainly carried by a novel transposon Tn7540 located on the chromosome and an IncHI2/HI2A/N plasmid. Sequence analysis and the formed circular intermediate suggested Tn7540 might be generated through homologous recombination by IS26-bounded translocatable units (IS26-fosA-IS26-intI1-dfrA12-aadA2-sul1-ISCR1-blaNDM-9-IS26). CONCLUSIONS: To the best of our knowledge, this is the first report of the novel chromosomal transposon possessing blaNDM-9 and fosA3 in S. Indiana isolated from human specimen, which might facilitate the dissemination of resistance genes and should arouse serious awareness.

A newly isolated bacteriophage vB8388 and its synergistic effect with aminoglycosides against multi-drug resistant Klebsiella oxytoca strain FK-8388.

The bacteriophage vB8388 can lyse multi-drug resistant Klebsiella oxytoca strain FK-8388 and maintain stability in a wide range of temperatures (from 4 °C to 80 °C) and pHs (3-11). Bioinformatics analysis showed that vB8388 is a linear double-stranded DNA virus that is 39,750 long with 50.65% G + C content and 44 putative open reading frames (ORFs). Phage vB8388 belongs to the family Autographviridae and possesses a non-contractile tail. The latency period of vB8388 was approximately 20 min. The combination of phage vB8388 and gentamicin, amikacin, or tobramycin could effectively inhibit the growth of K. oxytoca strain FK-8388, with a decrease of more than 4 log units within 12 h in vitro. Phage vB8388 showed a strong synergistic effect with gentamicin that could enhance the anti-biofilm effect of vB8388. The phage + gentamicin combination also showed synergy in vivo in the larval infection model of Galleria mellonella. In conclusion, the findings of this study suggest the potential of phage + antibiotic combination therapy to be used as an alternative therapeutic approach for treating infectious diseases caused by multidrug-resistant bacteria.

Novel Insight of Transcription Factor PtrA on Pathogenicity and Carbapenems Resistance in Pseudomonas aeruginosa.

Introduction: Globally, Pseudomonas aeruginosa (PA) is emerging as a predominant nosocomial pathogen that often induces aggressive and even deadly infections. Pseudomonas type III repressor A (PtrA) can be activated specifically by copper ions and interacts with type-III transcriptional activator ExsA. This study aims to provide insight into the PtrA-mediated regulation of the pathogenicity and antibiotics resistance of PA. Methods and Results: The results of transcriptome sequencing analyses and real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) showed that PtrA plays a dual regulatory role in the virulence systems of PA: negatively regulates the type-III secretion system (T3SS) and positively regulates the quorum-sensing system (QS). The ptrA mutant attenuated extracellular virulence related to QS like pyocyanin, elastase, rhamnolipids, proteolytic activity, and biofilm production. According to adhesion and invasion experiments, PtrA can not only contribute to the adhesiveness but also the invasive of PA. Moreover, the PtrA-mediated regulation of PA pathogenicity was determined both in vivo and in vitro through cytotoxicity and Galleria mellonella survival experiments. In addition, apart from virulence, PtrA was found to influence the carbapenems resistance of PA. After deleting ptrA, the minimum inhibitory concentration (MIC) of carbapenems antibiotics was decreased by 2-fold, while a 2-8 fold increase was noted for the complemented strain. Conclusion: Our findings establish that PtrA exerts a regulatory role in both pathogenicity and carbapenems resistance of PA. This work may shed light on a novel target for the clinical treatment of PA.

Case report: ISL2 is involved in malignant transformation in a patient with multiple relapsed oligodendroglioma.

The majority of oligodendrogliomas exhibit an intrinsic tendency to develop into malignant high-grade tumors. Angiogenesis is a major factor contributing to the malignant transformation of oligodendroglioma, and its molecular regulatory mechanism needs further study. We provide a case report of an oligodendroglioma patient with two recurrences whose disease progressed from WHO grade II to grade III. We showed that the expression of insulin gene enhancer protein (ISL2) and its angiogenic ability were positively correlated with the progression of oligodendroglioma. In Low-grade glioma (LGG) patients, including oligodendroglioma patients, overexpression of ISL2 was correlated with poor prognosis, and this correlation was not affected by gender or isocitrate dehydrogenase 1(IDH1) mutation status. ISL2 expression and ISL2-mediated angiogenic pathway activity are ideal biomarkers for the malignant transformation of oligodendroglioma. Anti-ISL2 therapy is also a potential treatment option for malignantly transformed oligodendroglioma.

Metagenomic analysis of the dynamical conversion of photosynthetic bacterial communities in different crop fields over different growth periods.

Photosynthetic bacteria are beneficial to plants, but knowledge of photosynthetic bacterial community dynamics in field crops during different growth stages is scarce. The factors controlling the changes in the photosynthetic bacterial community during plant growth require further investigation. In this study, 35 microbial community samples were collected from the seedling, flowering, and mature stages of tomato, cucumber, and soybean plants. 35 microbial community samples were assessed using Illumina sequencing of the photosynthetic reaction center subunit M (pufM) gene. The results revealed significant alpha diversity and community structure differences among the three crops at the different growth stages. Proteobacteria was the dominant bacterial phylum, and Methylobacterium, Roseateles, and Thiorhodococcus were the dominant genera at all growth stages. PCoA revealed clear differences in the structure of the microbial populations isolated from leaf samples collected from different crops at different growth stages. In addition, a dissimilarity test revealed significant differences in the photosynthetic bacterial community among crops and growth stages (P<0.05). The photosynthetic bacterial communities changed during crop growth. OTUs assigned to Methylobacterium were present in varying abundances among different sample types, which we speculated was related to the function of different Methylobacterium species in promoting plant growth development and enhancing plant photosynthetic efficiency. In conclusion, the dynamics observed in this study provide new research ideas for the detailed assessments of the relationship between photosynthetic bacteria and different growth stages of plants.

Analysis of the key prognostic genes and potential traditional Chinese medicine therapeutic targets in glioblastoma based on bioinformatics and network pharmacology methods.

Background: To analyze the key prognostic genes and potential traditional Chinese medicine targets in glioblastoma (GBM) by bioinformatics and network pharmacology. Methods: GBM datasets were obtained from the Gene Expression Omnibus (GEO) database to clarify the differentially-expressed genes (DEGs) in the carcinoma and paracancerous tissues. The molecular functions (MF) and signaling pathways of enriched DEGs were analyzed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The STRING database and Cytoscape software were used to construct the protein-protein interaction (PPI) network and screen hub genes to focus on genes with greater clinical significance. The transcription expression and prognosis of hub genes were analyzed using the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) database. The important compounds and target molecules were obtained via the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) database. We identified the active ingredients by setting the property values of pharmacokinetic attribute values. We constructed the network of "Chinese medicine ingredients-DEGs target" and screened out the target genes and active ingredients with high correlation scores. Finally, molecular docking verification was carried out using AutoDock Tools and PyMOL. Results: We obtained 271 DEGs, including 212 up-regulated genes and 59 down-regulated genes and screened ten hub genes. GO and KEGG analyses suggested that the hub genes were mainly involved in the following biological processes: the cell cycle, cell division, and cell adhesion, as well as extracellular matrix adhesion-related pathways, the p53 signaling pathways, and cadherin binding involved in cell-cell adhesion. We established the interaction network between the components and DEGs to screen out the traditional Chinese medicine active component (luteolin) and target genes (BIRC5 and CCNB1) for the treatment of GBM. The molecular docking results showed that the bindings of protein receptors, BIRC5 and CCNB1, with the compound ligand, luteolin, were stable and formed by hydrogen bonding interaction. Conclusions: In this study, we determined that luteolin potentially inhibits glioblastoma proliferation and migration through key target genes, BIRC5 and CCNB1, via bioinformatics and network pharmacology analysis, and affects the prognosis of GBM patients, providing new ideas for clinical targeted therapy and new drug development.

Nanocrystal Ordering Enhances Thermal Transport and Mechanics in Single-Domain Colloidal Nanocrystal Superlattices.

Colloidal nanocrystal (NC) assemblies are promising for optoelectronic, photovoltaic, and thermoelectric applications. However, using these materials can be challenging in actual devices because they have a limited range of thermal conductivity and elastic modulus, which results in heat dissipation and mechanical robustness challenges. Here, we report thermal transport and mechanical measurements on single-domain colloidal PbS nanocrystal superlattices (NCSLs) that have long-range order as well as measurements on nanocrystal films (NCFs) that are comparatively disordered. Over an NC diameter range of 3.0-6.1 nm, we observe that NCSLs have thermal conductivities and Young's moduli that are up to ∼3 times higher than those of the corresponding NCFs. We also find that these properties are more sensitive to NC diameter in NCSLs relative to NCFs. Our measurements and computational modeling indicate that stronger ligand-ligand interactions due to enhanced ligand interdigitation and alignment in NCSLs account for the improved thermal transport and mechanical properties.

New prognostic biomarker CMTM3 in low grade glioma and its immune infiltration.

Background: The CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3) is differentially expressed in a variety of tumors and closely related to tumor occurrence and progression. The expression of CMTM3 was significantly elevated in glioma compared with normal brain tissue, to explore the potential function of CMTM3 in the prognosis and immune infiltration of glioma has certain clinical significance. Methods: The tumor data in this study were derived from the sequencing data of various tumors in The Cancer Genome Atlas (TCGA) database. Low-grade glioma (LGG) data in the TCGA database include sequencing and clinical data. Clinical data mainly include survival time, survival outcome, age, WHO classification and other information. Sequencing data for normal tissues were obtained from the Genotype Tissue Expression (GTEx) database. Statistical analyses were mainly performed using bioinformatics tools and the corresponding R software (version 3.6.3). The Mann-Whitney U test (Wilcoxon rank sum test) was used to compare the expression differences between the tumor group and the normal group. Survival analysis was conducted using log-rank test to compare whether the overall survival (OS) time was statistically different between the CMTM3 high and low expression groups. The Tumor Immunity Estimation Resource (TIMER) database was used for immune infiltration analysis. Results: The results showed that the expression of CMTM3 in World Health Organization (WHO) II and WHO III gliomas was significantly higher than that of normal tissues (P<0.05). Glioma with high CMTM3 expression showed a lower overall survival (OS) (P<0.05). Gene enrichment analysis showed that CMTM3 was significantly enriched in 4 pathways (FDR <0.25, P<0.05). A high correlation was detected between CMTM3 and a variety of immune cells. CMTM3 is highly correlated with macrophages (r=0.536, P=1.31e-36), dendritic cells (r=0.546, P=2.85e-38), CD4+ T cells (r=0.517, P=6.17e-34). Conclusions: The CMTM3 gene can be used as a potential prognostic marker for WHO grade II and WHO grade III glioma, is related to the immune infiltration in glioma microenvironment, and may became a new immunotherapy target.

Molecular Mechanisms and Epidemiology of Carbapenem-Resistant Enterobacter cloacae Complex Isolated from Chinese Patients During 2004-2018.

BACKGROUND: The emergence and spread of carbapenem-resistant Enterobacter cloacae complex (ECC) have posed a serious threat to human health worldwide. This study aimed to investigate the molecular mechanism of carbapenem resistance and its prevalence among ECC in China. METHODS: A total of 1314 ECC clinical isolates were collected from the First Affiliated Hospital of Wenzhou Medical University from 2004 to 2018. Sensitivity to antibiotics was determined using the agar dilution method. The production of carbapenemases and the prevalence of resistance-associated genes were investigated using PCR. The expression of outer membrane porin (OMP) genes (ompC/ompF) and cephalosporinase gene ampC was analyzed by quantitative real-time PCR. The effect of efflux pump mechanism on carbapenem resistance was tested. ECC was typed by multilocus sequence typing (MLST). RESULTS: In this study, 113 carbapenem-nonsusceptible ECC strains were identified. The prevalence rates of carbapenemase genes bla KPC-2 and bla NDM were 12.4% (14/113) and 17.7% (20/113), and that of the extended-spectrum ß-lactamase (ESBL) genes bla CTX-M, bla TEM, and bla SHV were 28.3% (32/113), 27.4% (31/113), and 14.2% (16/113), respectively. Among 67 carbapenem-nonsusceptible ECC isolates producing non-carbapenemase, low expression of ompC/ompF and overexpression of ampC were found in 46 and 40 strains, respectively. In addition, the carbapenem resistance was related to the overexpression of the efflux pump in the study. Finally, the 113 carbapenem-nonsusceptible ECC strains were categorized into 39 different sequence types using MLST. CONCLUSION: Carbapenem-nonsusceptible ECC strains producing non-carbapenemase were predominant. The low expression of OMP with the overexpression of cephalosporinase or production of ESBLs and overexpression of efflux pump might contribute to the resistance to carbapenem for carbapenem-nonsusceptible ECC strains producing non-carbapenemase. The bla NDM and bla KPC comprised the principal resistance mechanism of carbapenemase-producing ECC in the hospital, causing a threat to public health. Therefore, monitoring programs to prevent the emergence and further spread of antibiotic resistance are urgently needed.

Integrative analysis of TP73 profile prognostic significance in WHO grade II/III glioma.

Due to the extremely intrinsic heterogeneity among glioma patients, the outcomes of these patients are tremendously different. Therefore, the exploitation of novel biomarker classification of glioma is vitally important for deep insight into the essence and predicting the prognosis of glioma. We aim to analyze the correlation between TP73 mRNA expression, DNA methylated alteration and the prognosis of WHO grade II/III glioma, utilizing bioinformatics to evaluate its significance as a risk-factor in predicting the prognosis of these glioma patients. The analysis found that TP73 expression was positively correlated with the grade of glioma, and showed a strong correlation with glioma molecular classification, which revealed significantly higher TP73 expression in IDH-wildtype than in IDH-mutant subtype of WHO grade II/III glioma. Cox regression analysis indicated that high expression of TP73 shared an independent high-risk factor impacting the prognosis of WHO grade II/III glioma. We discovered 8 DNA promoter methylation sites with prognostic significance, which were negatively associated with TP73 expression, and positively associated with beneficial overall survival (OS) and progression-free survival (PFS). Integrating with four independent glioma datasets, subsequent Meta-analysis verified that low expression of TP73 was closely related to favorable OS, especially in IDH-mutant subtype. Moreover, we found that 1p/19qCodel /TP73low subgroup shared the most favorable OS, 1p/19qNon-codel /TP73high subgroup suffered the worst OS. Meanwhile, the enrichment analysis of TP73-related differential mRNAs demonstrated that TP73 aberration in WHO grade II/III glioma might be closely related to cell cycle and P53 signaling pathways. Finally, TP73 expression of 53 glioma specimens was measured by qRT-PCR, which was consistent with the previous analytical result, and TP73 high-expression subgroup suffered worse PFS than TP73 low-expression subgroup. In summary, our funding supports that TP73 gene can perform as a reliable biomarker to evaluate the survival outcome of patients diagnosed with WHO grade II/III glioma.

Antibacterial and Anti-biofilm Efficacy of Chinese Dragon's Blood Against Staphylococcus aureus Isolated From Infected Wounds.

Chinese dragon's blood (CDB), a characteristic red resin, is an important traditional Chinese medicine (TCM), and empiric therapy of infected wounds with CDB is performed in clinical settings. For the first time, we herein report the antibacterial and anti-biofilm efficacy of CDB against Staphylococcus aureus (S. aureus). Antimicrobial susceptibility testing, growth curve assay, time-kill curve assay, crystal violet biofilm assay, scanning electron microscope (SEM) analysis, cell membrane tests, and quantitative real-time polymerase chain reaction (qRT-PCR) were used for this purpose. The results suggested that the minimum inhibitory concentration (MIC) values of CDB against S. aureus ranged from 32 to 128 µg/mL. Growth curves and time-kill curves confirmed that CDB could inhibit the growth of S. aureus. The biofilm formation ability and the expression levels of saeR, saeS, and hla of S. aureus in the presence and absence of CDB were statistically significant (P < 0.01). The results of SEM analysis and cell membrane tests revealed that exposure to CDB had some destructive effects on S. aureus cells. In conclusion, CDB exhibits positive antibacterial activity against S. aureus. Moreover, CDB could reduce the biofilm formation and the virulence factors of S. aureus by downregulating the expression levels of saeR, saeS, and hla genes. These findings indicated that CDB has immense potential to serve as a viable alternative for the treatment of infected wounds caused by S. aureus in clinical settings.

PSMD12 promotes glioma progression by upregulating the expression of Nrf2.

BACKGROUND: Glioma is the most common and aggressive primary brain tumor in adults. Proteasome 26S subunit, non-ATPase 12 (PSMD12), an important subunit in the 26S proteasome, is known to be involved in the growth and apoptosis of breast cancer cells. However, its exact function and underlying molecular mechanisms in glioma remain unknown. METHODS: PSMD12 expression was detected in glioma tissue specimens by immunohistochemistry (IHC) and TCGA database. Overexpression and down-regulation of PSMD12 and Nrf2 were induced in glioma cell lines, and CCK-8 and Transwell assays were used to detect cell proliferation and invasion evaluation, respectively. Xenograft model was used to observe the effect of knockdown of PSMD12 on tumor growth. Immunohistochemical assays and TCGA database were conducted to reveal the relationships between PSMD12 expression and Nrf2. Finally, Western blot and related biological function experiments were used to explore the mechanism of PSMD12 regulating the glioma progression and Nrf2. RESULTS: We revealed that PSMD12 is upregulated in glioma, especially in high-grade glioma, by analyzing bioinformatics data and clinical specimens. PSMD12 upregulation was associated with poor prognosis in glioma patients. Knockdown of PSMD12 inhibited the growth of glioma cells in vitro and in vivo and decreased their invasion ability, whereas PSMD12 overexpression had the opposite effect. Mechanistic analysis revealed that PSMD12 increased the expression of nuclear factor E2-related factor 2 (Nrf2), which functions as a tumor promoter in the development of glioma. Similar to PSMD12, Nrf2, which exhibited a strong positive correlation with PSMD12, was abnormally elevated in glioma tissues and contributed to worse overall survival (OS). Nrf2 overexpression reversed the inhibitory effects induced by PSMD12 knockdown. Finally, PSMD12 enhanced the proliferation and invasion of glioma cells via Akt signaling-mediated Nrf2 expression. CONCLUSIONS: These results suggest that PSMD12 is considered to be a crucial regulator of the development and progression of glioma and may serve as a potential biomarker or therapeutic target for the treatment of glioma.