Attenuating the emergence of anti-fungal drug resistance by harnessing synthetic lethal interactions in a model organism

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: All relevant data are within the manuscript and its Supporting Information files.Drug resistance is a rapidly emerging concern, thus prompting the development of novel therapeutics or combinatorial therapy. Currently, combinatorial therapy targets are based on knowledge of drug mode of action and/or resistance mechanisms, constraining the number of target proteins. Unbiased genome-wide screens could reveal novel genetic components within interaction networks as potential targets in combination therapies. Testing this, in the context of antimicrobial resistance, we implemented an unbiased genome-wide screen, performed in Saccharomyces cerevisiae expressing a Candida glabrata PDR1+ gain-of-function allele. Gain-of-function mutations in this gene are the principal mediators of fluconazole resistance in this human fungal pathogen. Eighteen synthetically lethal S. cerevisiae genetic mutants were identified in cells expressing C. glabrata PDR1+. One mutant, lacking the histone acetyltransferase Gcn5, was investigated further. Deletion or drug-mediated inhibition of Gcn5 caused a lethal phenotype in C. glabrata cells expressing PDR1+ alleles. Moreover, deletion or drug-mediated inactivation of Gcn5, inhibited the emergence of fluconazole-resistant C. glabrata isolates in evolution experiments. Thus, taken together, the data generated in this study provides proof of concept that synthetically lethal genetic screens can identify novel candidate proteins that when therapeutically targeted could allow effective treatment of drug-resistant infections

The frequency and properties of young tidal dwarf galaxies in nearby gas-rich groups

We present high-resolution Giant Metrewave Radio Telescope (GMRT) HI observations and deep Canada-France-Hawaii Telescope (CFHT) optical imaging of two galaxy groups: NGC 4725/47 and NGC 3166/9. These data are part of a multi-wavelength unbiased survey of the gas-rich dwarf galaxy populations in three nearby interacting galaxy groups. The NGC 4725/47 group hosts two tidal knots and one dIrr. Both tidal knots are located within a prominent HI tidal tail, appear to have sufficient mass (M_gas~10^8 M_sol) to evolve into long-lived tidal dwarf galaxies (TDGs) and are fairly young in age. The NGC 3166/9 group contains a TDG candidate, AGC 208457, at least three dIrrs and four HI knots. Deep CFHT imaging confirms that the optical component of AGC 208457 is bluer -- with a 0.28 mag g-r colour -- and a few Gyr younger than its purported parent galaxies. Combining the results for these groups with those from the NGC 871/6/7 group reported earlier, we find that the HI properties, estimated stellar ages and baryonic content of the gas-rich dwarfs clearly distinguish tidal features from their classical counterparts. We optimistically identify four potentially long-lived tidal objects associated to three separate pairs of interacting galaxies, implying that TDGs are not readily produced during interaction events as suggested by some recent simulations. The tidal objects examined in this survey also appear to have a wider variety of properties than TDGs of similar mass formed in current simulations of interacting galaxies, which could be the result of pre- or post-formation environmental influences.Comment: 18 pages, 14 figures, accepted for publication in MNRA

Impaired interferon-γ responses, increased interleukin-17 expression, and a tumor necrosis factor–α transcriptional program in invasive aspergillosis

This article is available open access through the publisher’s website. Copyright @ 2009 Oxford University Press.Background - Invasive aspergillosis (IA) is the most common cause of death associated with fungal infection in the developed world. Historically, susceptibility to IA has been associated with prolonged neutropenia; however, IA has now become a major problem in patients on calcineurin inhibitors and allogenic hematopoetic stem cell transplant patients following engraftment. These observations suggest complex cellular mechanisms govern immunity to IA. Methods - To characterize the key early events that govern outcome from infection with Aspergillus fumigatus we performed a comparative immunochip microarray analysis of the pulmonary transcriptional response to IA between cyclophosphamide-treated mice and immunocompetent mice at 24 h after infection. Results - We demonstrate that death due to infection is associated with a failure to generate an incremental interferon-γ response, increased levels of interleukin-5 and interleukin-17a transcript, coordinated expression of a network of tumor necrosis factor–α-related genes, and increased levels of tumor necrosis factor–α. In contrast, clearance of infection is associated with increased expression of a number genes encoding proteins involved in innate pathogen clearance, as well as apoptosis and control of inflammation. Conclusion - This first organ-level immune response transcriptional analysis for IA has enabled us to gain new insights into the mechanisms that govern fungal immunity in the lung.The BBSRC, CGD Research Trust, and the MRC

Modeling of intrinsic electron and hole trapping in crystalline and amorphous ZnO

Recent advances in ultrafast liquid quenching and deposition of thin films on cold substrates make growing amorphous (a)‐ZnO films increasingly feasible. The electronic structure and electron and hole trapping properties of amorphous ZnO are predicted using density functional theory (DFT) simulations with a hybrid density functional (h‐DFT). An ensemble of fifty 324‐atom structures is employed to obtain the distribution of structural and electronic properties of a‐ZnO. The results demonstrate that electrons do not localize in a‐ZnO, but holes form deep localized states with average trapping energy of about 0.9 eV. It is also shown that dispersion at the conduction band minimum (CBM) is not affected upon amorphization, suggesting that high electron mobility should be retained. An average value of a‐ZnO band gap of 3.36 eV is calculated with no states splitting into the band gap, which accounts for no substantial detrimental effect on the optical transparency upon amorphization. These findings may have important implications for future applications of a‐ZnO as a transparent conductor and photocatalyst

The representation of abstract task rules in the human prefrontal cortex

We have previously reported sustained activation in the ventral prefrontal cortex while participants prepared to perform 1 of 2 tasks as instructed. But there are studies that have reported activation reflecting task rules elsewhere in prefrontal cortex, and this is true in particular when it was left to the participants to decide which rule to obey. The aim of the present experiment was to use functional magnetic resonance imaging (fMRI) to find whether there was activation in common, irrespective of the way that the task rules were established. On each trial, we presented a word after a variable delay, and participants had to decide either whether the word was abstract or concrete or whether it had 2 syllables. The participants either decided before the delay which task they would perform or were instructed by written cues. Comparing the self-generated with the instructed trials, there was early task set activation during the delay in the middle frontal gyrus. On the other hand, a conjunction analysis revealed sustained activation in the ventral prefrontal and polar cortex for both conditions. We argue that the ventral prefrontal cortex is specialized for handling conditional rules regardless of how the task rules were established

The complex network of global cargo ship movements

Transportation networks play a crucial role in human mobility, the exchange of goods, and the spread of invasive species. With 90% of world trade carried by sea, the global network of merchant ships provides one of the most important modes of transportation. Here we use information about the itineraries of 16,363 cargo ships during the year 2007 to construct a network of links between ports. We show that the network has several features which set it apart from other transportation networks. In particular, most ships can be classified in three categories: bulk dry carriers, container ships and oil tankers. These three categories do not only differ in the ships' physical characteristics, but also in their mobility patterns and networks. Container ships follow regularly repeating paths whereas bulk dry carriers and oil tankers move less predictably between ports. The network of all ship movements possesses a heavy-tailed distribution for the connectivity of ports and for the loads transported on the links with systematic differences between ship types. The data analyzed in this paper improve current assumptions based on gravity models of ship movements, an important step towards understanding patterns of global trade and bioinvasion.Comment: 7 figures Accepted for publication by Journal of the Royal Society Interface (2010) For supplementary information, see http://www.icbm.de/~blasius/publications.htm

AGC 226067: A possible interacting low-mass system

We present Arecibo, GBT, VLA and WIYN/pODI observations of the ALFALFA source AGC 226067. Originally identified as an ultra-compact high velocity cloud and candidate Local Group galaxy, AGC 226067 is spatially and kinematically coincident with the Virgo cluster, and the identification by multiple groups of an optical counterpart with no resolved stars supports the interpretation that this systems lies at the Virgo distance (D=17 Mpc). The combined observations reveal that the system consists of multiple components: a central HI source associated with the optical counterpart (AGC 226067), a smaller HI-only component (AGC 229490), a second optical component (AGC 229491), and extended low surface brightness HI. Only ~1/4 of the single-dish HI emission is associated with AGC 226067; as a result, we find M_HI/L_g ~ 6 Msun/Lsun, which is lower than previous work. At D=17 Mpc, AGC 226067 has an HI mass of 1.5 x 10^7 Msun and L_g = 2.4 x 10^6 Lsun, AGC 229490 (the HI-only component) has M_HI = 3.6 x 10^6 Msun, and AGC 229491 (the second optical component) has L_g = 3.6 x 10^5 Lsun. The nature of this system of three sources is uncertain: AGC 226067 and AGC 229490 may be connected by an HI bridge, and AGC 229490 and AGC 229491 are separated by only 0.5'. The current data do not resolve the HI in AGC 229490 and its origin is unclear. We discuss possible scenarios for this system of objects: an interacting system of dwarf galaxies, accretion of material onto AGC 226067, or stripping of material from AGC 226067.Comment: Accepted for publication in A&A. 6 pages, 4 figure

EarthN: A new Earth System Nitrogen Model

The amount of nitrogen in the atmosphere, oceans, crust, and mantle have important ramifications for Earth's biologic and geologic history. Despite this importance, the history and cycling of nitrogen in the Earth system is poorly constrained over time. For example, various models and proxies contrastingly support atmospheric mass stasis, net outgassing, or net ingassing over time. In addition, the amount available to and processing of nitrogen by organisms is intricately linked with and provides feedbacks on oxygen and nutrient cycles. To investigate the Earth system nitrogen cycle over geologic history, we have constructed a new nitrogen cycle model: EarthN. This model is driven by mantle cooling, links biologic nitrogen cycling to phosphate and oxygen, and incorporates geologic and biologic fluxes. Model output is consistent with large (2-4x) changes in atmospheric mass over time, typically indicating atmospheric drawdown and nitrogen sequestration into the mantle and continental crust. Critical controls on nitrogen distribution include mantle cooling history, weathering, and the total Bulk Silicate Earth+atmosphere nitrogen budget. Linking the nitrogen cycle to phosphorous and oxygen levels, instead of carbon as has been previously done, provides new and more dynamic insight into the history of nitrogen on the planet.Comment: 36 pages, 12 figure