Antifungal Activity of Natural Naphthoquinones and Anthraquinones against Madurella mycetomatis

Eumycetoma, the fungal form of the neglected tropical disease mycetoma, is a crippling infectious disease with low response rates to currently available antifungal drugs. In this study, a series of natural naphthoquinones and anthraquinones was evaluated for their activity against Madurella mycetomatis, which is the most common causative agent of eumycetoma. The metabolic activity of Madurella mycetomatis as well as the viability of Galleria mellonella larvae upon treatment with quinones was investigated. Several hydroxy-substituted naphthoquinones exhibited activity against Madurella mycetomatis. In particular, naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) was identified as a considerably active antifungal compound against Madurella mycetomatis (IC50=1.4 μM), while it showed reduced toxicity to Galleria mellonella larvae, which is a well-established in vivo invertebrate model for mycetoma drug studies

A <i>Falciformispora senegalensis</i> grain model in <i>Galleria mellonella</i> larvae

Eumycetoma is a subcutaneous implantation mycosis often found in the foot. One of the hallmarks of eumycetoma is the formation of grains. These grains are either black or white, and the consistency and morphology differs per causative agent. The two most common causative agents of black-grain eumycetoma are Madurella mycetomatis and Falciformispora senegalensis. Since grains cannot be formed in vitro, in vivo models are needed to study grain formation. Here, we used the invertebrate Galleria mellonella to establish an in vivo grain model for F. senegalensis. Three different F. senegalensis strains were selected, and four different inocula were used to infect G. mellonella larvae, ranging from 0.04 mg/larvae to 10 mg/larvae. Larval survival was monitored for 10 days. Grain formation was studied macroscopically and histologically. The efficacy of antifungal therapy was determined for itraconazole, amphotericin B, and terbinafine. A concentration of 10 mg F. senegalensis per larva was lethal for the majority of the larvae within 10 days. At this inoculum, grains were formed within 24 h after infection. The grains produced in the larvae resembled those formed in human patients. Amphotericin B given at 1 mg/kg 4 h, 28 h, and 52 h after infection prolonged larval survival. No enhanced survival was noted for itraconazole or terbinafine. In conclusion, we developed a F. senegalensis grain model in G. mellonella larvae in which grains were formed that were similar to those formed in patients. This model can be used to monitor grain formation over time and study antifungal efficacy.</p

Measurements of Low Temperature Rate Coefficients for the Reaction of CH with CH₂O and Application to Dark Cloud and AGB Stellar Wind Models

Rate coefficients have been measured for the reaction of CH radicals with formaldehyde, CH₂O, over the temperature range of 31–133 K using a pulsed Laval nozzle apparatus combined with pulsed laser photolysis and laser-induced fluorescence spectroscopy. The rate coefficients are very large and display a distinct decrease with decreasing temperature below 70 K, although classical collision rate theory fails to reproduce this temperature dependence. The measured rate coefficients have been parameterized and used as input for astrochemical models for both dark cloud and Asymptotic Giant Branch stellar outflow scenarios. The models predict a distinct change (up to a factor of two) in the abundance of ketene, H₂CCO, which is the major expected molecular product of the CH + CH₂O reaction

ImageNet Large Scale Visual Recognition Challenge

The ImageNet Large Scale Visual Recognition Challenge is a benchmark in object category classification and detection on hundreds of object categories and millions of images. The challenge has been run annually from 2010 to present, attracting participation from more than fifty institutions. This paper describes the creation of this benchmark dataset and the advances in object recognition that have been possible as a result. We discuss the challenges of collecting large-scale ground truth annotation, highlight key breakthroughs in categorical object recognition, provide a detailed analysis of the current state of the field of large-scale image classification and object detection, and compare the state-of-the-art computer vision accuracy with human accuracy. We conclude with lessons learned in the five years of the challenge, and propose future directions and improvements.Comment: 43 pages, 16 figures. v3 includes additional comparisons with PASCAL VOC (per-category comparisons in Table 3, distribution of localization difficulty in Fig 16), a list of queries used for obtaining object detection images (Appendix C), and some additional reference

A dynamical model for longitudinal wave functions in light-front holographic QCD

We construct a Schrodinger-like equation for the longitudinal wave function of a meson in the valence qq-bar sector, based on the 't Hooft model for large-N two-dimensional QCD, and combine this with the usual transverse equation from light-front holographic QCD, to obtain a model for mesons with massive quarks. The computed wave functions are compared with the wave function ansatz of Brodsky and De Teramond and used to compute decay constants and parton distribution functions. The basis functions used to solve the longitudinal equation may be useful for more general calculations of meson states in QCD.Comment: 12 pages, 2 figures, RevTeX 4.1; expanded discussion, with calculation details moved to appendice

A New Basis Function Approach to 't Hooft-Bergknoff-Eller Equations

We analytically and numerically investigate the 't Hooft-Bergknoff-Eller equations, the lowest order mesonic Light-Front Tamm-Dancoff equations for U(N_C) and SU(N_C) gauge theories. We find the wavefunction can be well approximated by new basis functions and obtain an analytic formula for the mass of the lightest bound state. Its value is consistent with the precedent results.Comment: 16 pages, 3 figure

Phylogenetic Analysis of the Complete Mitochondrial Genome of Madurella mycetomatis Confirms Its Taxonomic Position within the Order Sordariales

Background: Madurella mycetomatis is the most common cause of human eumycetoma. The genus Madurella has been characterized by overall sterility on mycological media. Due to this sterility and the absence of other reliable morphological and ultrastructural characters, the taxonomic classification of Madurella has long been a challenge. Mitochondria are of monophyletic origin and mitochondrial genomes have been proven to be useful in phylogenetic analyses. Results: The first complete mitochondrial DNA genome of a mycetoma-causative agent was sequenced using 454 sequencing. The mitochondrial genome of M. mycetomatis is a circular DNA molecule with a size of 45,590 bp, encoding for the small and the large subunit rRNAs, 27 tRNAs, 11 genes encoding subunits of respiratory chain complexes, 2 ATP synthase subunits, 5 hypothetical proteins, 6 intronic proteins including the ribosomal protein rps3. In phylogenetic analyses using amino acid sequences of the proteins involved in respiratory chain complexes and the 2 ATP synthases it appeared that M. mycetomatis clustered together with members of the order Sordariales and that it was most closely related to Chaetomium thermophilum. Analyses of the gene order showed that within the order Sordariales a similar gene order is found. Furthermore also the tRNA order seemed mostly conserved. Conclusion: Phylogenetic analyses of fungal mitochondrial genomes confirmed that M. mycetomatis belongs to the order of Sordariales and that it was most closely related to Chaetomium thermophilum, with which it also shared a comparable gene and tRNA order

Prognostic Factors in Arthroplasty in the Rheumatoid Shoulder

Total shoulder arthroplasty is commonly considered a good option for treatment of the rheumatoid shoulder. However, when the rotator cuff and glenoid bone stock are not preserved, the clinical outcome of arthroplasty in the rheumatoid patients remains unclear. Aim of the study is to explore the prognostic value of multiple preoperative and peroperative variables in total shoulder arthroplasty and shoulder hemiarthroplasty in rheumatoid patients. Clinical Hospital for Special Surgery Shoulder score was determined at different time points over a mean period of 6.5 years in 66 rheumatoid patients with total shoulder arthroplasty and 75 rheumatoid patients with shoulder hemiarthroplasty. Moreover, radiographic analysis was performed to assess the progression of humeral head migration and glenoid loosening. Advanced age and erosions or cysts at the AC joint at time of surgery were associated with a lower postoperative Clinical Hospital for Special Surgery Shoulder score. In total shoulder arthroplasty, status of the rotator cuff and its repair at surgery were predictive of postoperative improvement. Progression of proximal migration during the period after surgery was associated with a lower clinical score over time. However, in hemiarthroplasty, no relation was observed between the progression of proximal or medial migration during follow-up and the clinical score over time. Status of the AC joint and age at the time of surgery should be taken into account when considering shoulder arthroplasty in rheumatoid patients. Total shoulder arthroplasty in combination with good cuff repair yields comparable clinical results as total shoulder arthroplasty when the cuff is intact

Host Genetic Factors and Vaccine-Induced Immunity to Hepatitis B Virus Infection

BACKGROUND: Vaccination against hepatitis B virus infection (HBV) is safe and effective; however, vaccine-induced antibody level wanes over time. Peak vaccine-induced anti-HBs level is directly related to antibody decay, as well as risk of infection and persistent carriage despite vaccination. We investigated the role of host genetic factors in long-term immunity against HBV infection based on peak anti-HBs level and seroconversion to anti-HBc. METHODS: We analyzed 715 SNP across 133 candidate genes in 662 infant vaccinees from The Gambia, assessing peak vaccine-induced anti-HBs level and core antibody (anti-HBc) status, whilst adjusting for covariates. A replication study comprised 43 SNPs in a further 393 individuals. RESULTS: In our initial screen we found variation in IFNG, MAPK8, and IL10RA to affect peak anti-HBs level (GMTratio of 1.5 and P < or = 0.001) and lesser associations in other genes. Odds of core-conversion was associated with variation in CD163. A coding change in ITGAL (R719V) with likely functional relevance showed evidence of association with increased peak anti-HBs level in both screens (1st screen: s595_22 GMTratio 1.71, P = 0.013; 2nd screen: s595_22 GMTratio 2.15, P = 0.011). CONCLUSION: This is to our knowledge the largest study to date assessing genetic determinants of HBV vaccine-induced immunity. We report on associations with anti-HBs level, which is directly related to durability of antibody level and predictive of vaccine efficacy long-term. A coding change in ITGAL, which plays a central role in immune cell interaction, was shown to exert beneficial effects on induction of peak antibody level in response to HBV vaccination. Variation in this gene does not appear to have been studied in relation to immune responses to viral or vaccine challenges previously. Our findings suggest that genetic variation in loci other than the HLA region affect immunity induced by HBV vaccination