Tobacco use, self-reported professional dental cleaning habits, and lung adenocarcinoma diagnosis are associated with bronchial and lung microbiome alpha diversity.

RATIONALE: The lung microbiome is an inflammatory stimulus whose role in the development of lung malignancies is incompletely understood. We hypothesized that the lung microbiome associates with multiple clinical factors, including the presence of a lung malignancy. OBJECTIVES: To assess associations between the upper and lower airway microbiome and multiple clinical factors including lung malignancy. METHODS: We conducted a prospective cohort study of upper and lower airway microbiome samples from 44 subjects undergoing lung lobectomy for suspected or confirmed lung cancer. Subjects provided oral (2), induced sputum, nasopharyngeal, bronchial, and lung tissue (3) samples. Pathologic diagnosis, age, tobacco use, dental care history, lung function, and inhaled corticosteroid use were associated with upper and lower airway microbiome findings. MEASUREMENTS AND MAIN RESULTS: Older age was associated with greater Simpson diversity in the oral and nasopharyngeal sites (p = 0.022 and p = 0.019, respectively). Current tobacco use was associated with greater lung and bronchus Simpson diversity (p < 0.0001). Self-reported last profession dental cleaning more than 6 months prior (vs. 6 or fewer months prior) was associated with lower lung and bronchus Simpson diversity (p < 0.0001). Diagnosis of a lung adenocarcinoma (vs. other pathologic findings) was associated with lower bronchus and lung Simpson diversity (p = 0.024). Last professional dental cleaning, dichotomized as ≤ 6 months vs. >6 months prior, was associated with clustering among lung samples (p = 0.027, R2 = 0.016). Current tobacco use was associated with greater abundance of pulmonary pathogens Mycoplasmoides and Haemophilus in lower airway samples. Self-reported professional dental cleaning ≤ 6 months prior (vs. >6 months prior) was associated with greater bronchial Actinomyces and lung Streptococcus abundance. Lung adenocarcinoma (vs. no lung adenocarcinoma) was associated with lower Lawsonella abundance in lung samples. Inhaled corticosteroid use was associated with greater abundance of Haemophilus among oral samples and greater Staphylococcus among lung samples. CONCLUSIONS: Current tobacco use, recent dental cleaning, and a diagnosis of adenocarcinoma are associated with lung and bronchial microbiome α-diversity, composition (ß-diversity), and the abundance of several respiratory pathogens. These findings suggest that modifiable habits (tobacco use and dental care) may influence the lower airway microbiome. Larger controlled studies to investigate these potential associations are warranted.

Sputum microbiome α-diversity is a key feature of the COPD frequent exacerbator phenotype.

Background: The lung microbiome is an inflammatory stimulus whose role in COPD pathogenesis is incompletely understood. We hypothesised that the frequent exacerbator phenotype is associated with decreased α-diversity and increased lung inflammation. Our objective was to assess correlations between the frequent exacerbator phenotype, the microbiome and inflammation longitudinally during exacerbation-free periods. Methods: We conducted a case-control longitudinal observational study of the frequent exacerbator phenotype and characteristics of the airway microbiome. 81 subjects (41 frequent and 40 infrequent exacerbators) provided nasal, oral and sputum microbiome samples at two visits over 2-4 months. Exacerbation phenotype, relevant clinical factors and sputum cytokine values were associated with microbiome findings. Results: The frequent exacerbator phenotype was associated with lower sputum microbiome α-diversity (p=0.0031). This decrease in α-diversity among frequent exacerbators was enhanced when the sputum bacterial culture was positive (p<0.001). Older age was associated with decreased sputum microbiome α-diversity (p=0.0030). Between-visit ß-diversity was increased among frequent exacerbators and those who experienced a COPD exacerbation between visits (p=0.025 and p=0.014, respectively). Sputum cytokine values did not differ based on exacerbation phenotype or other clinical characteristics. Interleukin (IL)-17A was negatively associated with α-diversity, while IL-6 and IL-8 were positively associated with α-diversity (p=0.012, p=0.012 and p=0.0496, respectively). IL-22, IL-17A and IL-5 levels were positively associated with Moraxella abundance (p=0.027, p=0.0014 and p=0.0020, respectively). Conclusions: Even during exacerbation-free intervals, the COPD frequent exacerbator phenotype is associated with decreased sputum microbiome α-diversity and increased ß-diversity. Decreased sputum microbiome α-diversity and Moraxella abundance are associated with lung inflammation.

Fabrication of Laponite-Reinforced Dextran-Based Hydrogels for NIR-Responsive Controlled Drug Release.

Natural polymer gels with sensitivity to near-infrared (NIR) light have attracted the attention of scientists working on intelligent drug delivery systems. Compared to ultraviolet or visible light, NIR light has the advantages of strong trigger levels, deep penetration through affected tissues, and fewer side effects. Herein, we present a topical photothermal hydrogel for NIR-controlled drug delivery. The proposed DexIEM-GM-Laponite hydrogel was prepared through free radical polymerization of vinyl-functionalized dextran (DexIEM), vinyl-modified graphene oxide (GM), and Laponite; thereafter, the hydrogel was loaded with ciprofloxacin (CIP, an antibacterial drug) as a model drug. With the Laponite content increased, the density of crosslinking in the hydrogel increased, and its mechanical properties improved noticeably. Under NIR irradiation, the DexIEM-GM-Laponite hydrogel exhibited a photothermal property, where the surface temperature increased from 26.8 to 55.5 °C. The simulation of subcutaneous drug delivery experiments ex vivo showed that under the specified pork tissue thickness (2, 4, and 6 mm), the CIP release remained NIR-controllable. Additionally, the results of the antibacterial performance tests indicated the excellent antibacterial effect of the hydrogel, and the blood hemolysis ratio of the hydrogel was less than 5%, signifying good blood compatibility. This work will provide an avenue for the application of NIR light-responsive materials in antimicrobial therapy.

[Genetic diversity of protopine-6-hydroxylase in three medicinal Papaver plants].

Sanguinarine is the main active component of the Papaver plants, and protopine-6-hydroxylase(P6 H), involved in the sanguinarine biosynthetic pathway, can oxidize protopine to 6-hydroxyprotopine. The investigation on the diversity of P6 H genes in the medicinal Papaver plants contributes to the acquirement of P6 H with high activity to increase the biosynthesis of sanguinarine. Five P6 H genes in P. somniferum, P. orientale, and P. rhoeas were discovered based on the re-sequencing data of the Papaver species, followed by bioinformatics analysis. With the elongation factor 1α(EF-1α), which exhibits stable expression in the root and stem, as the internal reference gene, the transcription levels of P6H genes in roots and stems of the Papaver plants were detected by real-time fluorescent quantitative PCR. As indicated by the re-sequencing results, there were two genotypes of P6H in P. somniferum and P. orientale, respectively, and only one in P. rhoeas. The bioinformatics analysis showed that the P6 H proteins of the three Papaver plants contained the conserved domain cl12078, which is the characteristic of p450 supergene family, and transmembrane regions. The existence of signal peptide remained verification. Real-time fluorescent quantitative PCR results revealed that the transcription level of P6 H in roots of P. somniferum was about 1.44 times of that in stems(α=0.05). The present study confirmed genetic diversity of P6 H in the three medicinal Papaver plants, which lays a basis for the research on the biosynthesis pathway and mechanism of sanguinarine in Papaver species.

Mechanism Insight into Rapid Photodriven Sterilization Based on Silver Bismuth Sulfide Quantum Dots.

Microbial contamination and the prevalence of resistant bacteria is considered a worldwide public health problem. Therefore, recently, great efforts have been made to develop photoresponsive platforms for the simultaneous photodynamic antibacterial (PDA) and photothermal antibacterial (PTA) therapy processes as mediated by specific light. However, owing to the absorption mismatches of the photothermal agents and photodynamic photosensitizers, it has been discovered that many synergistic photoresponsive antibacterial platforms cannot be excited by a single-wavelength light. In this study, silver bismuth sulfide quantum dots (AgBiS2 QDs) identified from the literature as a near-infrared light (NIR) that triggers bifunctional materials with simultaneous photodynamic and photothermal effects for photoresponsive bacterial killing were used. Specifically, AgBiS2 QDs were successfully synthesized via a bottom-up approach, using polyethylenimine (PEI) as an assistant molecule. With PEI wrapping, the attachment between the negatively charged membrane surfaces of the bacterial cells and AgBiS2 QDs was enhanced via the electrostatic interactions. The photodriven antibacterial activity of AgBiS2 QDs was then investigated against both S. aureus and E. coli. The results revealed a significant reduction in bacterial survival. The killing effect was found to be independent of the AgBiS2 QDs, and redox potentials controlled the photogenerated electrons that thermodynamically favored the formation of multiple reactive oxygen species (ROS). A possible phototriggered antibacterial mechanism was then proposed in which the AgBiS2 QDs are anchored first to the bacterial surface and then induce breaking on its outer membrane by high local heat and ROS under single 808 nm NIR laser illumination to finally induce bacterial death.

Preferential Use of Public TCR during Autoimmune Encephalomyelitis.

How the TCR repertoire, in concert with risk-associated MHC, imposes susceptibility for autoimmune diseases is incompletely resolved. Due largely to recombinatorial biases, a small fraction of TCRα or ß-chains are shared by most individuals, or public. If public TCR chains modulate a TCRαß heterodimer's likelihood of productively engaging autoantigen, because they are pervasive and often high frequency, they could also broadly influence disease risk and progression. Prior data, using low-resolution techniques, have identified the heavy use of select public TCR in some autoimmune models. In this study, we assess public repertoire representation in mice with experimental autoimmune encephalomyelitis at high resolution. Saturation sequencing was used to identify >18 × 10(6) TCRß sequences from the CNSs, periphery, and thymi of mice at different stages of autoimmune encephalomyelitis and healthy controls. Analyses indicated the prominent representation of a highly diverse public TCRß repertoire in the disease response. Preferential formation of public TCR implicated in autoimmunity was identified in preselection thymocytes, and, consistently, public, disease-associated TCRß were observed to be commonly oligoclonal. Increased TCR sharing and a focusing of the public TCR response was seen with disease progression. Critically, comparisons of peripheral and CNS repertoires and repertoires from preimmune and diseased mice demonstrated that public TCR were preferentially deployed relative to nonshared, or private, sequences. Our findings implicate public TCR in skewing repertoire response during autoimmunity and suggest that subsets of public TCR sequences may serve as disease-specific biomarkers or influence disease susceptibility or progression.

The role of nuclear factor-kappaB in rats of radiocontrast-media-induced nephropathy.

This study was undertaken to examine the possible role of the DNA-binding activity of nuclear factor-kappa B (NF-kappaB) in rat of radiocontrast-media-induced nephropathy (RCIN) and to explore the characteristic of RCIN in rats and the role of NF-kappaB in its occurrence. Forty-eight adult male Sprague-Dawley (SD) rats were randomly divided into Groups A-D. Rats of Groups A and B were intravenously injected with NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg) and indomethacin (10 mg/kg), respectively. Rats of Groups C and D were intravenously injected with 1-M phosphate buffer (PH = 8.4 3 mL/kg) and normal saline (NS 2 mL/kg), respectively. After 30 min, Groups A and D were injected with NS (8 mL/kg) and Groups B and C were injected with diatrizoate (DTZ 8 mL/kg). After injected contrast media (CM) for 6 h, the serum creatinine and blood urea nitrogen of rat in Group B increased sharply as compared with Groups A, C, and D. After 48 h, the data recovered to 49.28 +/- 8.81 mumol/L and 6.72 +/- 2.75 mmol/L, respectively. Vacuolization of the tubule epithelial cells of the kidney was observed in Group A. Especially, these pathological changes were most obvious in outer medulla. Contrast to group A, the DNA-binding activity of NF-kappaB in rat kidney of Group B reached a peak at the 6th h and recovered to the normal level after the 48th h. CM mainly damages renal tubular-interstitial, which appears the earliest and most serious in the outer medulla. Activation of NF-kappaB of renal may be one of the mechanisms of RCIN occurrence.

A Cycloaddition Approach toward the Synthesis of Substituted Indolines and Tetrahydroquinolines.

The intramolecular Diels-Alder reaction of 2-substituted aminofurans (IMDAF) results in the formation of various indolines and tetrahydroquinolines. The isolation of these ring systems from the IMDAF reaction can be rationalized in terms of an initial [4 + 2]-cycloaddition that first produces an oxa-bridged cycloadduct, which was not detected since it readily underwent nitrogen-assisted ring opening. Proton exchange followed by an eventual dehydration provides the aromatic product. In certain cases, the intermediate cyclohexadienol can be isolated and independently converted to the final product in high yield. The starting 2-aminofurans were readily prepared from furanyl acyl azide by a Curtius rearrangement in the presence of an alcohol. Alkylation of the resulting N-alkyl carbamate with an alkenyl bromide allows for the synthesis of a wide variety of cycloaddition precursors. The scope of the IMDAF reaction was evaluated by using mono- and disubstituted alkenes, electron rich and electron deficient olefins, and acetylenic tethers. Cyclic 2-amidofurans were also synthesized using a related intramolecular Diels-Alder reaction of 2-amido-substituted oxazoles which contain a tethered alkyne. This transformation represents a new route to this rare heterocyclic ring system. The sequential cycloaddition method was used for a formal synthesis of the pyrrolophenanthridone alkaloid hippadine.