Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for treating fungal infectious disease that evades resistance

Prospects for dark matter detection with IceCube in the context of the CMSSM

We study in detail the ability of the nominal configuration of the IceCube neutrino telescope (with 80 strings) to probe the parameter space of the Constrained MSSM (CMSSM) favoured by current collider and cosmological data. Adopting conservative assumptions about the galactic halo model and the expected experiment performance, we find that IceCube has a probability between 2% and 12% of achieving a 5sigma detection of dark matter annihilation in the Sun, depending on the choice of priors for the scalar and gaugino masses and on the astrophysical assumptions. We identify the most important annihilation channels in the CMSSM parameter space favoured by current constraints, and we demonstrate that assuming that the signal is dominated by a single annihilation channel canlead to large systematic errors in the inferred WIMP annihilation cross section. We demonstrate that ~ 66% of the CMSSM parameter space violates the equilibrium condition between capture and annihilation in the center of the Sun. By cross-correlating our predictions with direct detection methods, we conclude that if IceCube does detect a neutrino flux from the Sun at high significance while direct detection experiments do not find a signal above a spin-independent cross section sigma_SI^p larger than 5x10^{-9} pb, the CMSSM will be strongly disfavoured, given standard astrophysical assumptions for the WIMP distribution. This result is robust with respect to a change of priors. We argue that the proposed low-energy DeepCore extension of IceCube will be an ideal instrument to focus on relevant CMSSM areas of parameter space.Comment: 32 pages, 12 figures. Updated discussion of comparison with direct detection. References added. Main results unchanged. Matches version accepted by JCA

Methodologies for <i>in vitro</i> and <i>in vivo</i> evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms.

Unlike superficial fungal infections of the skin and nails, which are the most common fungal diseases in humans, invasive fungal infections carry high morbidity and mortality, particularly those associated with biofilm formation on indwelling medical devices. Therapeutic management of these complex diseases is often complicated by the rise in resistance to the commonly used antifungal agents. Therefore, the availability of accurate susceptibility testing methods for determining antifungal resistance, as well as discovery of novel antifungal and antibiofilm agents, are key priorities in medical mycology research. To direct advancements in this field, here we present an overview of the methods currently available for determining (i) the susceptibility or resistance of fungal isolates or biofilms to antifungal or antibiofilm compounds and compound combinations; (ii) the &lt;i&gt;in vivo&lt;/i&gt; efficacy of antifungal and antibiofilm compounds and compound combinations; and (iii) the &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; performance of anti-infective coatings and materials to prevent fungal biofilm-based infections

Is Ocean Reflectance Acquired by Citizen Scientists Robust for Science Applications?

Monitoring the dynamics of the productivity of ocean water and how it affects fisheries is essential for management. It requires data on proper spatial and temporal scales, which can be provided by operational ocean colour satellites. However, accurate productivity data from ocean colour imagery is only possible with proper validation of, for instance, the atmospheric correction applied to the images. In situ water reflectance data are of great value due to the requirements for validation and reflectance is traditionally measured with the Surface Acquisition System (SAS) solar tracker system. Recently, an application for mobile devices, &ldquo;HydroColor&rdquo;, was developed to acquire water reflectance data. We examined the accuracy of the water reflectance measures acquired by HydroColor with the help of both trained and untrained citizens, under different environmental conditions. We used water reflectance data acquired by SAS solar tracker and by HydroColor onboard the BC ferry Queen of Oak Bay from July to September 2016. Monte Carlo permutation F tests were used to assess whether the differences between measurements collected by SAS solar tracker and HydroColor with citizens were significant. Results showed that citizen HydroColor measurements were accurate in red, green, and blue bands, as well as red/green and red/blue ratios under different environmental conditions. In addition, we found that a trained citizen obtained higher quality HydroColor data especially under clear skies at noon

Mechanisms of Antifungal Drug Resistance.

Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug- resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance

A contact tracing SIR model for randomly mixed populations

Contact tracing is an important intervention measure to control infectious diseases. We present a new approach that borrows the edge dynamics idea from network models to track contacts included in a compartmental SIR model for an epidemic spreading in a randomly mixed population. Unlike network models, our approach does not require statistical information of the contact network, data that are usually not readily available. The model resulting from this new approach allows us to study the effect of contact tracing and isolation of diagnosed patients on the control reproduction number and number of infected individuals. We estimate the effects of tracing coverage and capacity on the effectiveness of contact tracing. Our approach can be extended to more realistic models that incorporate latent and asymptomatic compartments