Inhibition of high-mobility group box 1 protein (HMGB1) enhances bacterial clearance and protects against Pseudomonas Aeruginosa pneumonia in cystic fibrosis

Pulmonary infection with Pseudomonas aeruginosa and neutrophilic lung inflammation significantly contribute to morbidity and mortality in cystic fibrosis (CF). High-mobility group box 1 protein (HMGB1), a ubiquitous DNA binding protein that promotes inflammatory tissue injury, is significantly elevated in CF sputum. However, its mechanistic and potential therapeutic implications in CF were previously unknown. We found that HMGB1 levels were significantly elevated in bronchoalveolar lavage fluids (BALs) of CF patients and cystic fibrosis transmembrane conductance regulator (CFTR )(-/-) mice. Neutralizing anti-HMGB1 monoclonal antibody (mAb) conferred significant protection against P. aeruginosa-induced neutrophil recruitment, lung injury and bacterial infection in both CFTR(-/-) and wild-type mice. Alveolar macrophages isolated from mice treated with anti-HMGB1 mAb had improved phagocytic activity, which was suppressed by direct exposure to HMGB1. In addition, BAL from CF patients significantly impaired macrophage phagocytotic function, and this impairment was attenuated by HMGB1-neutralizing antibodies. The HMGB1-mediated suppression of bacterial phagocytosis was attenuated in macrophages lacking toll-like receptor (TLR)-4, suggesting a critical role for TLR4 in signaling HMGB1-mediated macrophage dysfunction. These studies demonstrate that the elevated levels of HMGB1 in CF airways are critical for neutrophil recruitment and persistent presence of P. aeruginosa in the lung. Thus, HMGB1 may provide a therapeutic target for reducing bacterial infection and lung inflammation in CF.     

Synthesis and antioxidant, cytotoxicity and antimicrobial activities of novel curcumin mimics

Claisen-Schmidt condensation of 3-(1,2,3,6-tetrahydro-1-methylpyridin-4-yl)-2,4,5- trimethoxybenzaldehyde 3 and various aromatic, heterocyclic and alicyclic amides of 3- aminoacetophenone 6(a-s) afforded novel curcumin mimics. All the synthesized compounds were characterized by IR, (1)H NMR, Mass spectroscopy and evaluated for antioxidant, cytotoxicity and antimicrobial activity. Out of the 20 compounds screened, compounds 7i, 7l, 7q, and 7n have shown excellent radical scavenging activity, compounds 7o, 7t, 7f, and 7r have shown significant xanthine oxidase inhibition, and compounds 7a, 7k and 7l were found to be potent inhibitors of selected cancer cell lines. Compounds 7h, 7t, 7l, 7i, and 7e have shown good antibacterial activity, whereas compounds 7j, 7f, 7o, 7h, and 7t exhibited significant antifungal activity.     

Cytotoxicity and DNA binding studies of several platinum (II) and palladium (II) complexes of the 2,2'-bipyridine and an anion of 2-pyridinecarboxylic/2-pyrazinecarboxylic acid.

Four water soluble complexes of the type [M(bpy)(a-x)]NO3, where M is Pd(II) or Pt(II), bpy is 2,2-bipyridine, and a-x is anion of 2-pyridinecarboxylic acid or 2-pyrazinecarboxylic acid, have been found to bind calf thymus DNA, possibly through hydrogen binding. [M(bpy)(2-py)]NO3 complexes (2-py is an anion of 2-pyridinecarboxylic acid) show I.D.50 values smaller than cisplatin whereas [M(bpy)(2-pyz)]NO3 complexes (2-pyz is an anion of 2-pyrazinecarboxylic acid) show I.D.50 values larger than cisplatin against P388 cancer cells.     

Light-altering cover materials and sustainable greenhouse production of vegetables: a review

Plant Growth Regulation - Greenhouse horticulture (protected cropping) is essential in meeting increasing global food demand under climate change scenarios by ensuring sustainability, efficiency,...     

Potential of constructed wetland in reducing total nitrogen loading into the Truckee River

A pilot-scale wetland was constructed along Steamboat Creek (SBC) at the Truckee Meadows Water Reclamation Facility (TMWRF), Sparks, Nevada. SBC is a major non-point source of total nitrogen (TN) for the Truckee River. In this study, four (16.2 m²) parallel wetland trains with two different experimental designs were utilized to assess seasonal variations in TN. The experimental designs included: (1) SBC water and SBC sediments (Configuration-1) and (2) TMWRF effluent and SBC sediments (Configuration-2). Over a period of 2 years, the TN in both designs was routinely monitored. TN was reduced by an average of 47% (0.60 mg/l) in Configuration-1 and an average of 24% (0.39 mg/l) in Configuration-2. Nitrogen speciation was an important factor influencing the effectiveness of nitrogen removal within the wetland system. Ammonia-N (NH₃-N) and nitrate plus nitrite nitrogen ((NO₃ + NO₂)-N) were removed more effectively than organic nitrogen. The results obtained from this pilot-scale wetland system suggest that a proposed large-scale constructed wetlands system along SBC would be expected to overall reduce TN loading into the Truckee River from 19 to 30% on an annual basis. This research was jointly funded by the Environmental Protection Agency (EPA) Region 9 and the Nevada Division of Environmental Protection.     

Iron-histidine resonance raman band of deoxyheme proteins: effects of anharmonic coupling and glass-liquid phase transition

Weak anharmonic coupling of two soft molecular vibrations is shown to cause pronounced temperature dependence of the corresponding resonance Raman bands. The developed theory is used to interpret the temperature dependence of the iron-histidine band of deoxyheme proteins and model compounds. It is shown that anharmonic coupling of the iron-histidine and heme doming vibrations must cause pronounced broadening of the band, its asymmetry, and shift of its maximum to the red upon heating. It also can lead to a structured shape of this band at room temperature. Proper consideration of the anharmonic coupling allows simulation of the temperature dependence of the iron-histidine band shape of horse heart myoglobin in the temperature interval of 10-300 K, using the minimum number of necessary parameters. Analysis of this temperature dependence clearly shows that the iron-histidine band of deoxyheme proteins is sensitive to the glass-liquid phase transition in the protein hydration shell, which takes place at 160-190 K.     

Morphological and Molecular Differentiation of Sporidiobolus johnsonii ATCC 20490 and Its Coenzyme Q10 Overproducing Mutant Strain UF16

Coenzyme Q₁₀ (CoQ₁₀) is an industrially important molecule having nutraceutical and cosmeceutical applications. CoQ₁₀ is mainly produced by microbial fermentation and the process demands the use of strains with high productivity and yields of CoQ₁₀. During strain improvement program consisting of sequential induced mutagenesis, rational selection and screening process, a mutant strain UF16 was generated from Sporidiobolus johnsonii ATCC 20490 with 2.3-fold improvements in CoQ₁₀ content. EMS and UV rays were used as mutagenic agents for generating UF16 and it was rationally selected based on atorvastatin resistance as well as survival at free radicals exposure. We investigated the genotypic and phenotypic changes in UF16 in order to differentiate it from wild type strain. Morphologically it was distinct due to reduced pigmentation of colony, reduced cell size and significant reduction in mycelial growth forms with abundance of yeast forms. At molecular level, UF16 was differentiated based on PCR fingerprinting method of RAPD as well as large and small-subunit rRNA gene sequences. Rapid molecular technique of RAPD analysis using six primers showed 34 % polymorphic fragments with mean genetic distance of 0.235. The partial sequences of rRNA-gene revealed few mutation sites on nucleotide base pairs. However, the mutations detected on rRNA gene of UF16 were less than 1 % of total base pairs and its sequence showed 99 % homology with the wild type strain. These mutations in UF16 could not be linked to phenotypic or genotypic changes on CoQ₁₀ biosynthetic pathway that resulted in improved yield. Hence, investigating the mutations responsible for deregulation of CoQ₁₀ pathway is essential to understand the cause of overproduction in UF16. Phylogenetic analysis based on RAPD bands and rRNA gene sequences coupled with morphological variations, exhibited the novelty of mutant UF16 having potential for improved CoQ₁₀ production.     

Prediction of protein-mannose binding sites using random forest

Mannose is an abundant cell surface monosaccharide and has an important role in many biochemical processes. It binds to a great diversity of receptor proteins. In this study we have employed Random Forest for prediction of mannose binding sites. Mannosebinding site is taken to be a sphere around the centroid of the ligand and the sphere is subdivided into different layers and atom wise and residue wise features were extracted for each layer. The method achieves 95.59 % of accuracy using Random Forest with 10 fold cross validation. Prediction of mannose binding site analysis will be quite useful in drug design.