MXene-Decorated Nanofibrous Membrane with Programmed Antibacterial and Anti-Inflammatory Effects via Steering NF-κB Pathway for Infectious Cutaneous Regeneration.

Although antibiotic is still the main choice for antibacteria both in hospital and community, phototherapy has become a possibly one of the alternative approaches in the treatment of microbe-associated infections nowadays because of its considerable potential in effective eradication of pathogenic bacteria. However, overwhelming reactive oxygen species (ROS) generated from phototherapy inevitably provoke an inflammatory response, complicating the healing process. To address this outstanding issue, a MXene-decorated nanofibrious is devised that not only yield localized heat but also elevate ROS levels under near-infrared laser exposure ascribed to the synergistic photothermal/photodynamic effect, for potent bacterial inactivation. After being further loaded with aspirin, the nanofibrous membranes exhibit benign cytocompatibility, boosting cell growth and suppressing the (nuclear factor kappa-B ( NF-κB) signaling pathways through RNA sequencing analysis, indicating an excellent anti-inflammatory effect. Interestingly, in vivo investigations also corroborate that the nanofibrous membranes accelerate infectious cutaneous regeneration by efficiently killing pathogenic bacteria, promoting collagen deposition, boosting angiogenesis, and dampening inflammatory reaction via steering NF-κB pathway. As envisaged, this work furnishes a decorated nanofibrous membrane with programmed antibacterial and anti-inflammatory effects for remedy of refractory bacteria-invaded wound regeneration.

What exactly does the PfK13 C580Y mutation in Plasmodium falciparum influence?

BACKGROUND: The emergence and spread of artemisinin resistance threaten global malaria control and elimination goals, and encourage research on the mechanisms of drug resistance in malaria parasites. Mutations in Plasmodium falciparum Kelch 13 (PfK13) protein are associated with artemisinin resistance, but the unique or common mechanism which results in this resistance is unclear. METHODS: We analyzed the effects of the PfK13 mutation on the transcriptome and proteome of P. falciparum at different developmental stages. Additionally, the number of merozoites, hemozoin amount, and growth of P. falciparum 3D7C580Y and P. falciparum 3D7WT were compared. The impact of iron supplementation on the number of merozoites of P. falciparum 3D7C580Y was also examined. RESULTS: We found that the PfK13 mutation did not significantly change glycolysis, TCA, pentose phosphate pathway, or oxidative phosphorylation, but did reduce the expression of reproduction- and DNA synthesis-related genes. The reduced number of merozoites, decreased level of hemozoin, and slowed growth of P. falciparum 3D7C580Y were consistent with these changes. Furthermore, adding iron supply could increase the number of the merozoites of P. falciparum 3D7C580Y. CONCLUSIONS: These results revealed that the PfK13 mutation reduced hemoglobin ingestion, leading to artemisinin resistance, likely by decreasing the parasites' requirement for haem and iron. This study helps elucidate the mechanism of artemisinin resistance due to PfK13 mutations.

Engineered Bio-Heterojunction with Infection-Primed H2 S Liberation for Boosted Angiogenesis and Infectious Cutaneous Regeneration.

Photodynamic therapy (PDT) acts as a powerful weapon against infectious diseases for its enormous antimicrobial activity that quickly elicits storms of reactive oxygen species (ROS). Nevertheless, redundant ROS during treatment inevitably bring detriments in revascularization. To address this dilemma, an innovative P-N bio-heterojunction (bio-HJ) material consisting of p-type copper sulfide (p-CuS), n-type bismuth sulfide (n-Bi2 S3 ), and lactate oxidase (LOx) for effective treatment of recalcitrant infectious wounds by promoting angiogenesis is devised. LOx exhausts lactic acid accumulated in infection environment and converts it to hydrogen peroxide (H2 O2 ), which subsequently yields bactericidal hydroxyl radicals (·OH) via Fenton-like reactions. Ultimately, the P-N bio-HJs exert synergistic photothermal, photodynamic, and chemodynamic effects for rapid bacterial annihilation. Moreover, in vitro and RNA-seq analyses reveal that the crafted bio-HJs dramatically expedite the proliferation of L929 cells and promote angiogenesis by up-regulating angiogenic gene expression in hypoxia-inducible factor-1 (HIF-1) signaling pathway, which may ascribe to the evolution of H2 S in response to the infection microenvironment. Critically, results of in vivo experiments have authenticated that the bio-HJs significantly boost healing rates of full-thickness wounds by slaughtering bacteria, elevating angiogenesis, and promoting cytothesis. As envisioned, this work furnishes a novel tactic for the effective treatment of bacteria-invaded wound using H2 S-liberating P-N bio-HJs.

Metabolomics-based investigation of SARS-CoV-2 vaccination (Sinovac) reveals an immune-dependent metabolite biomarker.

SARS-CoV-2 and its mutant strains continue to rapidly spread with high infection and fatality. Large-scale SARS-CoV-2 vaccination provides an important guarantee for effective resistance to existing or mutated SARS-CoV-2 virus infection. However, whether the host metabolite levels respond to SARS-CoV-2 vaccine-influenced host immunity remains unclear. To help delineate the serum metabolome profile of SARS-CoV-2 vaccinated volunteers and determine that the metabolites tightly respond to host immune antibodies and cytokines, in this study, a total of 59 sera samples were collected from 30 individuals before SARS-CoV-2 vaccination and from 29 COVID-19 vaccines 2 weeks after the two-dose vaccination. Next, untargeted metabolomics was performed and a distinct metabolic composition was revealed between the pre-vaccination (VB) group and two-dose vaccination (SV) group by partial least squares-discriminant and principal component analyses. Based on the criteria: FDR < 0.05, absolute log2 fold change greater than 0.25, and VIP >1, we found that L-glutamic acid, gamma-aminobutyric acid (GABA), succinic acid, and taurine showed increasing trends from SV to VB. Furthermore, SV-associated metabolites were mainly annotated to butanoate metabolism and glutamate metabolism pathways. Moreover, two metabolite biomarkers classified SV from VB individuals with an area under the curve (AUC) of 0.96. Correlation analysis identified a positive association between four metabolites enriched in glutamate metabolism and serum antibodies in relation to IgG, IgM, and IgA. These results suggest that the contents of gamma-aminobutyric acid and indole in serum could be applied as biomarkers in distinguishing vaccinated volunteers from the unvaccinated. What's more, metabolites such as GABA and taurine may serve as a metabolic target for adjuvant vaccines to boost the ability of the individuals to improve immunity.

Genomic alterations in KMT2 family predict outcome of immune checkpoint therapy in multiple cancers.

Immune checkpoint therapy (ICT) can produce durable antitumor responses in various cancer types; however, the responses are not universal, and the predictive biomarkers are urgently needed. Growing evidence points to a link between epigenetic regulation and anti-tumor immunity, while clinical data on the association of genomic alterations in transcriptional dysregulation-related genes and ICT clinical benefit are lacking. Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility, which is associated with tumorigenesis, mutagenesis, and immune tolerance in various cancers, indicating its possible correlation with the output of immune checkpoint therapy. We hypothesized that genomic mutations in the KMT2 family have the potential to be a novel predictor of immunotherapeutic efficacy. Through integrative cancer genomic analyses of baseline tumor tissues from multiple cohorts involving immunotherapeutic patients, we uncovered a remarkable correlation between KMT2 family mutation and better immune checkpoint therapy responses in multiple patient cohorts. Then, we gathered all the independent ICT-treated datasets as a combination cohort consisted of 418 patients. Significant enrichment of KMT2 family genomic alterations in responding tumors was observed (odds ratio = 2.60, P value = 1.67e-04). This work distinguished the mutations in the KMT2 family as a potential predictor of favorable ICT response in multiple cancers, highlighting the importance of genomic profiling in immunotherapy.

Mechanisms of the antiangiogenic effects of aspirin in cancer.

Aspirin is an old drug extracted from willow bark and is widely used for the prevention and treatment of cardiovascular diseases. Accumulating evidence has shown that aspirin use may significantly reduce the angiogenesis of cancer; however, the mechanism of the association between angiogenesis and aspirin is complex. Although COX-1 is widely known as a target of aspirin, several studies reveal other antiangiogenic targets of aspirin, such as angiotensin II, glucose transporter 1, heparanase, and matrix metalloproteinase. In addition, some data indicates that aspirin may produce antiangiogenic effects after acting in different cell types, such as endothelial cells, platelets, pericytes, and macrophages. In this review, we concentrate on research regarding the antiangiogenic effects of aspirin in cancer, and we discuss the molecular mechanisms of aspirin and its metabolites. Moreover, we discuss some mechanisms through which aspirin treatment may normalize existing blood vessels, including preventing the disintegration of endothelial adheres junctions and the recruitment of pericytes. We also address the antiangiogenic effects and the underlying mechanisms of aspirin derivatives, which are aimed at improving safety and efficacy.

Transcriptome profiling reveals the molecular processes for survival of Lysinibacillus fusiformis strain 15-4 in petroleum environments.

A bacterial strain designated Lysinibacillus fusiformis 15-4 was isolated from oil-free soil on the Qinghai-Tibet Plateau, which can grow well utilizing petroleum hydrocarbons as a carbon source at a lower temperature. To deeply characterize the molecular adaptations and metabolic processes of this strain when grown in a petroleum-containing environment, transcriptome analysis was performed. A total of 4664 genes and the expression of 3969 genes were observed in strain 15-4. When the strain was grown in petroleum-containing medium, 2192 genes were significantly regulated, of which 1312 (60%) were upregulated and 880 (40%) were downregulated. This strain degraded and adapted to petroleum via modulation of diverse molecular processes, including improvements in transporter activity, oxidoreductase/dehydrogenase activity, two-component system/signal transduction, transcriptional regulation, fatty acid catabolism, amino acid metabolism, and environmental stress responses. Many strain-specific genes were involved in the oxidation of hydrocarbon compounds, such as several luciferase family alkane monooxygenase genes, flavin-utilizing monooxygenase family genes, and flavoprotein-like family alkanesulfonate monooxygenase genes. Several cold shock protein genes were also induced suggesting adaptation to cold environments and the potential for petroleum degradation at low temperatures. The results obtained in this study may broaden our understanding of molecular adaptation of bacteria to hydrocarbon-containing environments and may provide valuable data for further study of L. fusiformis.

Inhibition effect of Zedoary turmeric oil on Listeria monocytogenes and Staphylococcus aureus growth and exotoxin proteins production.

PURPOSE: Zedoary turmeric oil (ZTO), the steam extract of Curcuma zedoaria Rosc was researched for its chemical composition, antibacterial activity, and mechanism for countering two major food-borne pathogenic species, Listeria monocytogenes and Staphylococcus aureus. METHODOLOGY: Gas chromatography-mass spectrometry (GC-MS) was used to analyse and characterize the chemical composition of ZTO. Its MICs for the two bacterial species and growth curves were measured. Western blot and real-time reverse-transcription (RT)-PCR assays were utilized to elaborate the mechanism of the antibacterial effect of ZTO by examining the expression levels of virulence-related extracellular proteins. ELISA was used to explore the biological relevance. RESULTS: GC-MS revealed high contents of curzerene, eucalyptol, germacrone and (-)-g-elemene representing 28.45, 10.94, 10.77 and 10.54  %, respectively, of the whole components. The MICs of ZTO that combatted L. monocytogenes and S. aureus were similar (1-2 mg ml-1 ). After adding ZTO at increasing concentrations, there was an evident reduction in the transcription of hly, iap, hla, sea, seb and agrA in a dose-dependent manner. Furthermore, TNF-α accumulation in RAW264.7 cells stimulated by L. monocytogenes and S. aureus supernatants was restricted by a 1/4 MIC of ZTO. CONCLUSION: Overall, L. monocytogenes and S. aureus were comparably susceptible to ZTO. These data demonstrated that ZTO's antimicrobial property was mediated by the repression of the production of virulence factors involved in L. monocytogenes and S. aureus pathogenesis, a finding that can potentially further progress in the development of new anti-virulence drugs.

Analysing the correlations of long-term seasonal water quality parameters, suspended solids and total dissolved solids in a shallow reservoir with meteorological factors.

To explore the correlations among water quality parameters, suspended solids (SS) and total dissolved solids (TDS) with meteorological factors in a shallow reservoir in China, the long-term variations of water quality were considered. A non-parametric regression method, generalized additive models (GAM), was used to analyse the correlations among eleven physicochemical and biological parameters as well as three meteorological factors (wind speed, rainfall and solar radiation) which we collected from 2000 to 2011. The results indicate that the three meteorological factors may have positive effects on SS. Moreover, statistically significant correlations between many water quality parameters and SS or TDS were exhibited seasonally. The correlations between electrical conductivity (EC) and SS were opposite to correlations between EC and TDS. This finding reveals that TDS have a positive impact on EC, while EC negatively affects SS. The results indicated that many parameters, such as total nitrogen, total phosphorus, biological oxygen demand (BOD) and chemical oxygen demand (COD), were related to SS due to the adsorption of SS. Moreover, both positive and negative correlations between COD and TDS were observed in this freshwater reservoir. The positive correlation between chlorophyll a and SS suggested that the change of SS concentration in autumn was caused by the growth of algae. Meanwhile, significant correlations between SS and meteorological factors were also observed, indicating that meteorological factors had effects on SS dynamics. This study provides useful information regarding the correlations among water quality parameters, SS and TDS with meteorological factors in a freshwater reservoir.

Impedance spectroscopy analysis of human odorant binding proteins immobilized on nanopore arrays for biochemical detection.

Human odorant-binding proteins (hOBPs) not only can bind and transport odorants in the surrounding environment for sensing smells, but also play important roles in transmitting lots of biomolecules in different organs. Utilizing the properties of hOBPs, an electrochemical biosensor with nanopore array was developed to detect specific biomolecular ligands, such as aldehydes and fatty acids. The highly ordered nanopores of anodic aluminum oxide with diameter of 20-40 nm were fabricated with two-step oxidation. Through 2-carboxyethyl phosphonic acid, hOBPs were self-assembled on nanopores as the sensing membrane. With nanopore arrays, the impedance spectra showed quite different electron transfer processes in the frequency spectra, which could be characterized by the electron transfer resistance and electrical resistance of the porous membrane. Under stimulation of biomolecular ligands, series resistance of nanopores and hOBPs increased and showed a concentration-dependence feature, while the electron transfer resistance hardly changed. The nanopore based biosensor could sensitively detect biological ligands of benzaldehyde, docosahexaenoic acid, and lauric acid, which were closely related to or were potential biomarkers for cancers and other serious diseases. Equipped with hOBPs, the sensor exhibited promising potentials both in odorant and biomolecule detection for olfactory biosensing and in disease diagnosis and evaluation for biochemical detection.

Tubeimoside-1 inhibits the proliferation and activation of mouse T lymphocytes through signal transduction pathways.

Tubeimoside-1 (TBMS1) is one of the important components in Bolbostemma paniculatum (Maxim.) Franque. In the study, its immunosuppressive effects on murine T lymphocyte responses were evaluated in vitro and in vivo. The data showed that TBMS1 inhibited ConA-induced T lymphocyte proliferation, decreased the ratio of CD4(+)/CD8(+), suppressed IL-2, IFN-γ, IL-4 and IL-6 production and mRNA expression, down-regulate activation of NF-κB, NFAT2 and AP-1 signal transduction pathways in vitro. In addition, administration of TBMS1 significantly inhibited T cell-mediated DTH response in vivo. These findings indicated that TBMS1 inhibits the proliferation and activation of T lymphocytes in mice.