126 research outputs found

    Madurella mycetomatis, the main causative agent of eumycetoma, is highly susceptible to olorofim

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    OBJECTIVES: Eumycetoma is currently treated with a combination of itraconazole therapy and surgery, with limited success. Recently, olorofim, the lead candidate of the orotomides, a novel class of antifungal agents, entered a Phase II trial for the treatment of invasive fungal infections. Here we determined the activity of olorofim against Madurella mycetomatis, the main causative agent of eumycetoma. METHODS: Activity of olorofim against M. mycetomatis was determined by in silico comparison of the target gene, dihydroorotate dehydrogenase (DHODH), and in vitro susceptibility testing. We also investigated the in vitro interaction between olorofim and itraconazole against M. mycetomatis. RESULTS: M. mycetomatis and Aspergillus fumigatus share six out of seven predicted binding residues in their DHODH DNA sequence, predicting susceptibility to olorofim. Olorofim demonstrated excellent potency against M. mycetomatis in vivo with MICs ranging from 0.004 to 0.125 mg/L and an MIC90 of 0.063 mg/L. Olorofim MICs were mostly one dilution step lower than the itraconazole M

    F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase

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    There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≀0.06 ”g/mL—greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals

    Review of interventions to encourage SMEs to make environmental improvements

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    Small and medium-sized enterprises (SMEs) are an important part of the world economy but they are thought to be responsible for around 60% of all carbon dioxide emissions and 70% of all pollution. SMEs often have major problems with limited resources, limited knowledge, and limited technical capabilities to deal with their own negative environmental impact. SMEs exhibit widely differing characteristics and commitment where environmental issues are concerned. Yet under these conditions they are all expected to engage in environmental improvement. Interventions that encourage environmental improvement are often polarised between regulation and legislation at one extreme and voluntary environmental agreement at the other. It is clear that a holistic mixture of interventions is necessary to achieve maximum engagement and environmental improvement by all SMEs. In this paper we categorise the different levels of environmental commitment observed in SMEs and develop a selection or &lsquo;toolkit&rsquo; of intervention strategies that might be deployed within each category of SME.<br /

    Comparative Genome Analysis of Filamentous Fungi Reveals Gene Family Expansions Associated with Fungal Pathogenesis

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    Fungi and oomycetes are the causal agents of many of the most serious diseases of plants. Here we report a detailed comparative analysis of the genome sequences of thirty-six species of fungi and oomycetes, including seven plant pathogenic species, that aims to explore the common genetic features associated with plant disease-causing species. The predicted translational products of each genome have been clustered into groups of potential orthologues using Markov Chain Clustering and the data integrated into the e-Fungi object-oriented data warehouse (http://www.e-fungi.org.uk/). Analysis of the species distribution of members of these clusters has identified proteins that are specific to filamentous fungal species and a group of proteins found only in plant pathogens. By comparing the gene inventories of filamentous, ascomycetous phytopathogenic and free-living species of fungi, we have identified a set of gene families that appear to have expanded during the evolution of phytopathogens and may therefore serve important roles in plant disease. We have also characterised the predicted set of secreted proteins encoded by each genome and identified a set of protein families which are significantly over-represented in the secretomes of plant pathogenic fungi, including putative effector proteins that might perturb host cell biology during plant infection. The results demonstrate the potential of comparative genome analysis for exploring the evolution of eukaryotic microbial pathogenesis

    Report of the Working Group on Commercial Catches (WGCATCH)

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    The Working Group on Commercial Catches (WGCATCH), chaired by Mike Arm- strong (UK) and Hans Gerritsen (Ireland), met in ICES HQ, Copenhagen, Denmark, 10–14 November 2014. The meeting was attended by 34 experts from 21 laboratories or organizations, covering 16 countries. Currently, an important task for WGCATCH is to improve and review sampling sur- vey designs for commercial fisheries, particularly those for estimating quantities and size or age compositions of landings and discards and providing data quality indica- tors. However, the scope of WGCATCH is broader than this, covering many other aspects of collection and analysis of data on fishing activities and catches. This will be end-user driven, and coordinated with the work of other ICES data EGs such as the Working Group on Biological Parameters (WGBIOP), the Planning Group on Data Needs for Assessments and Advice (PGDATA) and the Working Group on Recrea- tional Fisheries Surveys (WGRFS) to ensure synergy and efficiency. The report of the meeting commences with background information on the formation of WGCATCH and its overall role. The remainder of the report provides the out- comes for each of the Terms of Reference (ToRs) and responses to external requests, the proposed future work plan and the ToRs for the 2015 meeting. The group formed two large subgroups to deal with the two major terms of reference which are the development of guidelines for carrying out sampling of catches on shore and the provision of advice on adapting sampling programmes to deal with the landing obligation. In order to evaluate methods and develop guidelines for best practice in carrying out sampling of commercial sampling of commercial fish catches onshore, a question- naire was circulated before the meeting. This questionnaire was structured around guidelines developed by the ICES Workshop on Practical Implementation of Statisti- cally Sound Catch Sampling Programmes (WKPICS) for best practice at each stage of the sampling process, and asked for a description of current practices at each of these stages. Based on these questionnaires, common and specific problems were cata- logued and potential solutions were identified. At the same time, the discussion of the questionnaires provided a form of peer-review of the sampling designs and iden- tified where improvements could be made. WGCATCH provided guidelines for de- signing a sampling survey and summarized earlier guidelines provided by the 2010 Workshop on methods for merging mĂ©tiers for fishery based sampling (WKMERGE) The other main subject addressed by WGCATCH concerns the provision of advice on adapting sampling protocols to deal with the impact of the introduction of the land- ing obligation, which will alter discarding practices and result in additional catego- ries of catch being landed. A second questionnaire was circulated before the meeting to allow the group to identify the fleets that will be affected and possible issues that are anticipated, as well as to propose solutions to adapt existing monitoring and sampling schemes and to quantify bias resulting from the introduction of this regula- tion. WGCATCH outlined a range of likely scenarios and the expected effects of these on fishery sampling programmes, and developed guidelines for adapting sam- pling schemes. The group also explored a range of analyses that could be conducted in order to quantify bias resulting from the introduction of the landing obligation. Finally a number of pilot studies/case studies were summarized, highlighting the practical issues involve

    Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

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    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∌38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

    First measurement of the C P -violating phase in B s 0 → J / ψ ( → e + e - ) ϕ decays

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    Abstract: A flavour-tagged time-dependent angular analysis of Bs0→J/ψϕ decays is presented where the J/ψ meson is reconstructed through its decay to an e+e- pair. The analysis uses a sample of pp collision data recorded with the LHCb experiment at centre-of-mass energies of 7 and 8\,Te V, corresponding to an integrated luminosity of 3\,fb-1. The CP-violating phase and lifetime parameters of the Bs0 system are measured to be ϕs=0.00±0.28±0.07\,rad, ΔΓs=0.115±0.045±0.011\,ps-1 and Γs=0.608±0.018±0.012\,ps-1 where the first uncertainty is statistical and the second systematic. This is the first time that CP-violating parameters are measured in the Bs0→J/ψϕ decay with an e+e- pair in the final state. The results are consistent with previous measurements in other channels and with the Standard Model predictions

    Search for the doubly charmed baryon Ω cc +

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    Abstract: A search for the doubly charmed baryon Ωcc+ with the decay mode Ωcc+ → Ξc+K−π+ is performed using proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the LHCb experiment from 2016 to 2018, corresponding to an integrated luminosity of 5.4 fb−1. No significant signal is observed within the invariant mass range of 3.6 to 4.0GeV/c2. Upper limits are set on the ratio R of the production cross-section times the total branching fraction of the Ωcc+ → Ξc+K−π+ decay with respect to the Ξcc++→Λc+K−π+π+ decay. Upper limits at 95% credibility level for R in the range 0.005 to 0.11 are obtained for different hypotheses on the Ωcc+ mass and lifetime in the rapidity range from 2.0 to 4.5 and transverse momentum range from 4 to 15 GeV/c

    Measurement of the CKM angle γγ in B±→DK±B^\pm\to D K^\pm and B±→Dπ±B^\pm \to D π^\pm decays with D→KS0h+h−D \to K_\mathrm S^0 h^+ h^-

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    A measurement of CPCP-violating observables is performed using the decays B±→DK±B^\pm\to D K^\pm and B±→Dπ±B^\pm\to D \pi^\pm, where the DD meson is reconstructed in one of the self-conjugate three-body final states KSπ+π−K_{\mathrm S}\pi^+\pi^- and KSK+K−K_{\mathrm S}K^+K^- (commonly denoted KSh+h−K_{\mathrm S} h^+h^-). The decays are analysed in bins of the DD-decay phase space, leading to a measurement that is independent of the modelling of the DD-decay amplitude. The observables are interpreted in terms of the CKM angle Îł\gamma. Using a data sample corresponding to an integrated luminosity of 9 fb−19\,\text{fb}^{-1} collected in proton-proton collisions at centre-of-mass energies of 77, 88, and 13 TeV13\,\text{TeV} with the LHCb experiment, Îł\gamma is measured to be (68.7−5.1+5.2)∘\left(68.7^{+5.2}_{-5.1}\right)^\circ. The hadronic parameters rBDKr_B^{DK}, rBDπr_B^{D\pi}, ÎŽBDK\delta_B^{DK}, and ÎŽBDπ\delta_B^{D\pi}, which are the ratios and strong-phase differences of the suppressed and favoured B±B^\pm decays, are also reported
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