Rifampicin-manuka honey combinations are superior to other antibiotic-manuka honey combinations in eradicating Staphylococcus aureus biofilms

© 2018 Liu, Cokcetin, Lu, Turnbull, Carter, Whitchurch and Harry. Chronic wound infections are a major burden to both society and the health care industry. Bacterial biofilms are the major cause of chronic wound infections and are notoriously recalcitrant to treatments with antibiotics, making them difficult to eradicate. Thus, new approaches are required to combat biofilms in chronic wounds. One possible approach is to use drug combination therapies. Manuka honey has potent broad-spectrum antibacterial activity and has previously shown synergistic activity in combination with antibiotics against common wound pathogens, including Staphylococcus aureus. In addition, manuka honey exhibits anti-biofilm activity, thereby warranting the investigation of its potential as a combination therapy with antibiotics for the topical treatment of biofilm-related infections. Here we report the first use of MacSynergy II to investigate the response of established S. aureus (strain NCTC 8325) biofilms to treatment by combinations of Medihoney (medical grade manuka honey) and conventional antibiotics that are used for preventing or treating infections: rifampicin, oxacillin, fusidic acid, clindamycin, and gentamicin. Using checkerboard microdilution assays, viability assays and MacSynergy II analysis we show that the Medihoney-rifampicin combination was more effective than combinations using the other antibiotics against established staphylococcal biofilms. Medihoney and rifampicin were strongly synergistic in their ability to reduce both biofilm biomass and the viability of embedded S. aureus cells at a level that is likely to be significant in vivo. Other combinations of Medihoney and antibiotic produced an interesting array of effects: Medihoney-fusidic acid treatment showed minor synergistic activity, and Medihoney-clindamycin, -gentamicin, and -oxacillin combinations showed overall antagonistic effects when the honey was used at sub-inhibitory concentration, due to enhanced biofilm formation at these concentrations which could not be counteracted by the antibiotics. However, these combinations were not antagonistic when honey was used at the inhibitory concentration. Confocal scanning laser microscopy confirmed that different honey-antibiotic combination treatments could eradicate biofilms. Our results suggest that honey has potential as an adjunct treatment with rifampicin for chronic wounds infected with staphylococcal biofilms. We also show that MacSynergy II allows a comprehensive examination of the synergistic effects of honey-antibiotic combinations, and can help to identify doses for clinical use

The two PPX-GppA homologues from Mycobacterium tuberculosis have distinct biochemical activities

Inorganic polyphosphate (poly-P), guanosine pentaphosphate (pppGpp) and guanosine tetraphosphate (ppGpp) are ubiquitous in bacteria. These molecules play a variety of important physiological roles associated with stress resistance, persistence, and virulence. In the bacterial pathogen Mycobacterium tuberculosis, the identities of the proteins responsible for the metabolism of polyphosphate and (p)ppGpp remain to be fully established. M. tuberculosis encodes two PPX-GppA homologues, Rv0496 (MTB-PPX1) and Rv1026, which share significant sequence similarity with bacterial exopolyphosphatase (PPX) and guanosine pentaphosphate 5′-phosphohydrolase (GPP) proteins. Here we delineate the respective biochemical activities of the Rv0496 and Rv1026 proteins and benchmark these against the activities of the PPX and GPP proteins from Escherichia coli. We demonstrate that Rv0496 functions as an exopolyphosphatase, showing a distinct preference for relatively short-chain poly-P substrates. In contrast, Rv1026 has no detectable exopolyphosphatase activities. Analogous to the E. coli PPX and GPP enzymes, the exopolyphosphatase activities of Rv0496 are inhibited by pppGpp and, to a lesser extent, by ppGpp alarmones, which are produced during the bacterial stringent response. However, neither Rv0496 nor Rv1026 have the ability to hydrolyze pppGpp to ppGpp; a reaction catalyzed by E. coli PPX and GPP. Both the Rv0496 and Rv1026 proteins have modest ATPase and to a lesser extent ADPase activities. pppGpp alarmones inhibit the ATPase activities of Rv1026 and, to a lesser extent, the ATPase activities of Rv0496. We conclude that PPX-GppA family proteins may not possess all the catalytic activities implied by their name and may play distinct biochemical roles involved in polyphosphate and (p)ppGpp metabolic pathways. © 2012 2012 Choi et al.published_or_final_versio

Mutation Symmetries in BPS Quiver Theories: Building the BPS Spectra

We study the basic features of BPS quiver mutations in 4D $\mathcal{N}=2$ supersymmetric quantum field theory with $G=ADE$ gauge symmetries.\ We show, for these gauge symmetries, that there is an isotropy group $\mathcal{G}_{Mut}^{G}$ associated to a set of quiver mutations capturing information about the BPS spectra. In the strong coupling limit, it is shown that BPS chambers correspond to finite and closed groupoid orbits with an isotropy symmetry group $\mathcal{G}_{strong}^{G}$ isomorphic to the discrete dihedral groups $Dih_{2h_{G}}$ contained in Coxeter$(G)$ with $$ the Coxeter number of G. These isotropy symmetries allow to determine the BPS spectrum of the strong coupling chamber; and give another way to count the total number of BPS and anti-BPS states of $\mathcal{N}=2$ gauge theories. We also build the matrix realization of these mutation groups $\mathcal{G}_{strong}^{G}$ from which we read directly the electric-magnetic charges of the BPS and anti-BPS states of $\mathcal{N}=2$ QFT$_{4}$ as well as their matrix intersections. We study as well the quiver mutation symmetries in the weak coupling limit and give their links with infinite Coxeter groups. We show amongst others that $\mathcal{G}_{weak}^{su_{2}}$ is contained in ${GL}({2,}\mathbb{Z})$; and isomorphic to the infinite Coxeter ${I_{2}^{\infty}}$. Other issues such as building $\mathcal{G}$ and $\mathcal{G}_{weak}^{su_{3}}$ are also studied.Comment: LaTeX, 98 pages, 18 figures, Appendix I on groupoids adde

Positional errors in species distribution modelling are not overcome by the coarser grains of analysis

The performance of species distribution models (SDMs) is known to be affected by analysis grain and positional error of species occurrences. Coarsening of the analysis grain has been suggested to compensate for positional errors. Nevertheless, this way of dealing with positional errors has never been thoroughly tested. With increasing use of fine-scale environmental data in SDMs, it is important to test this assumption. Models using fine-scale environmental data are more likely to be negatively affected by positional error as the inaccurate occurrences might easier end up in unsuitable environment. This can result in inappropriate conservation actions. Here, we examined the trade-offs between positional error and analysis grain and provide recommendations for best practice. We generated narrow niche virtual species using environmental variables derived from LiDAR point clouds at 5 x 5 m fine-scale. We simulated the positional error in the range of 5 m to 99 m and evaluated the effects of several spatial grains in the range of 5 m to 500 m. In total, we assessed 49 combinations of positional accuracy and analysis grain. We used three modelling techniques (MaxEnt, BRT and GLM) and evaluated their discrimination ability, niche overlap with virtual species and change in realized niche. We found that model performance decreased with increasing positional error in species occurrences and coarsening of the analysis grain. Most importantly, we showed that coarsening the analysis grain to compensate for positional error did not improve model performance. Our results reject coarsening of the analysis grain as a solution to address the negative effects of positional error on model performance. We recommend fitting models with the finest possible analysis grain and as close to the response grain as possible even when available species occurrences suffer from positional errors. If there are significant positional errors in species occurrences, users are unlikely to benefit from making additional efforts to obtain higher resolution environmental data unless they also minimize the positional errors of species occurrences. Our findings are also applicable to coarse analysis grain, especially for fragmented habitats, and for species with narrow niche breadth

Exploiting attention for visual relationship detection

Visual relationship detection targets on predicting categories of predicates and object pairs, and also locating the object pairs. Recognizing the relationships between individual objects is important for describing visual scenes in static images. In this paper, we propose a novel end-to-end framework on the visual relationship detection task. First, we design a spatial attention model for specializing predicate features. Compared to a normal ROI-pooling layer, this structure significantly improves Predicate Classification performance. Second, for extracting relative spatial configuration, we propose to map simple geometric representations to a high dimension, which boosts relationship detection accuracy. Third, we implement a feature embedding model with a bi-directional RNN which considers subject, predicate and object as a time sequence. We evaluate our method on three tasks. The experiments demonstrate that our method achieves competitive results compared to state-of-the-art methods.</p

Implementation of Web-Based Respondent-Driven Sampling among Men who Have Sex with Men in Vietnam

Objective: Lack of representative data about hidden groups, like men who have sex with men (MSM), hinders an evidence-based response to the HIV epidemics. Respondent-driven sampling (RDS) was developed to overcome sampling challenges in studies of populations like MSM for which sampling frames are absent. Internet-based RDS (webRDS) can potentially circumvent limitations of the original RDS method. We aimed to implement and evaluate webRDS among a hidden population. Methods and Design: This cross-sectional study took place 18 February to 12 April, 2011 among MSM in Vietnam. Inclusion criteria were men, aged 18 and above, who had ever had sex with another man and were living in Vietnam. Participants were invited by an MSM friend, logged in, and answered a survey. Participants could recruit up to four MSM friends. We evaluated the system by its success in generating sustained recruitment and the degree to which the sample compositions stabilized with increasing sample size. Results: Twenty starting participants generated 676 participants over 24 recruitment waves. Analyses did not show evidence of bias due to ineligible participation. Estimated mean age was 22 year and 82% came from the two large metropolitan areas. 32 out of 63 provinces were represented. The median number of sexual partners during the last six months was two. The sample composition stabilized well for 16 out of 17 variables. Conclusion: Results indicate that webRDS could be implemented at a low cost among Internet-using MSM in Vietnam. WebRDS may be a promising method for sampling of Internet-using MSM and other hidden groups. Key words: Respondent-driven sampling, Online sampling, Men who have sex with men, Vietnam, Sexual risk behavio

NODIS: Neural Ordinary Differential Scene Understanding

Semantic image understanding is a challenging topic in computer vision. It requires to detect all objects in an image, but also to identify all the relations between them. Detected objects, their labels and the discovered relations can be used to construct a scene graph which provides an abstract semantic interpretation of an image. In previous works, relations were identified by solving an assignment problem formulated as Mixed-Integer Linear Programs. In this work, we interpret that formulation as Ordinary Differential Equation (ODE). The proposed architecture performs scene graph inference by solving a neural variant of an ODE by end-to-end learning. It achieves state-of-the-art results on all three benchmark tasks: scene graph generation (SGGen), classification (SGCls) and visual relationship detection (PredCls) on Visual Genome benchmark

GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity

RATIONALE: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. METHODS: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. RESULTS: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. CONCLUSION: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity

Family control, R&D expenses and firm efficiency : Evidence from Taiwanese cultural and creative industries

Purpose: First, this study assesses the link between research and development (R&D) expenses and firm efficiency. Second, this study explores how family control moderates the link between the two. Design/methodology/approach: This study uses two measures of time-based firm efficiency, namely, a window slacks-based measure (WSBM) and a window epsilon-based measure (WEBM) of data envelopment analysis (DEA). Then, 216 firm-year observations are analyzed in the Taiwanese cultural and creative industries from 2005 to 2017. Findings: This study finds that R&D expenses significantly worsen firm efficiency, and that family control positively moderates this effect. A further test separating the sample into family-controlled and nonfamily-controlled firms indicates that R&D expenses negatively affect the efficiency of nonfamily-controlled firms but positively affect that of family-controlled firms. Research limitations/implications: The existing literature has examined the link between R&D expenses and corporate performance. However, the process by which R&D expenses affect corporate performance from a production perspective remains unknown. Originality/value: Overall, this study provides insights for policymakers to scrutinize resource management and R&D expenses from the production and resource-based perspectives

Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B

BACKGROUND: Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications. METHODS: We compared the efficacy and safety of peginterferon alfa-2a (180 microg once weekly) plus placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, the percentage of patients with normalization of alanine aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as compared with 0 patients in the group given lamivudine alone. Adverse events, including pyrexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy than with peginterferon alfa-2a monotherapy or combination therapy. CONCLUSIONS: Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post-therapy response rates. Copyright 2004 Massachusetts Medical Societypublished_or_final_versio