A low-cost tebuconazole-based screening test for azole-resistant aspergillus fumigatus.

The global emergence of azole resistance in Aspergillus fumigatus is resulting in health and food security concerns. Rapid diagnostics and environmental surveillance methods are key to understanding the distribution and prevalence of azole resistance. However, such methods are often associated with high costs and are not always applicable to laboratories based in the least-developed countries. Here, we present and validate a low-cost screening protocol that can be used to differentiate between azole-susceptible "wild-type" and azole-resistant A. fumigatus isolates. © 2020 The Authors. Basic Protocol 1: Preparation of Tebucheck multi-well plates Basic Protocol 2: Inoculation of Tebucheck multi-well plates

A coherent middle Pliocene magnetostratigraphy, Wanganui Basin, New Zealand

We document magnetostratigraphies for three river sections (Turakina, Rangitikei, Wanganui) in Wanganui Basin and interpret them as corresponding to the Upper Gilbert, the Gauss and lower Matuyama Chrons of the Geomagnetic Polarity Timescale, in agreement with foraminiferal biostratigraphic datums. The Gauss-Gilbert transition (3.58 Ma) is located in both the Turakina and Wanganui River sections, while the Gauss-Matuyama transition (2.58 Ma) is located in all three sections, as are the lower and upper boundaries of the Mammoth (3.33–3.22 Ma) and Kaena (3.11–3.04 Ma) Subchrons. Our interpretations are based in part on the re-analysis of existing datasets and in part on the acquisition and analysis of new data, particularly for the Wanganui River section. The palaeomagnetic dates of these six horizons provide the only numerical age control for a thick (up to 2000 m) mudstone succession (Tangahoe Mudstone) that accumulated chiefly in upper bathyal and outer neritic palaeoenvironments. In the Wanganui River section the mean sediment accumulation rate is estimated to have been about 1.8 m/k.y., in the Turakina section it was about 1.5 m/k.y., and in the Rangitikei section, the mean rate from the beginning of the Mammoth Subchron to the Hautawa Shellbed was about 1.1 m/k.y. The high rates may be associated with the progradation of slope clinoforms northward through the basin. This new palaeomagnetic timescale allows revised correlations to be made between cyclothems in the Rangitikei River section and the global Oxygen Isotope Stages (OIS) as represented in Ocean Drilling Program (ODP) Site 846. The 16 depositional sequences between the end of the Mammoth Subchron and the Gauss-Matuyama Boundary are correlated with OIS MG2 to 100. The cyclothems average 39 k.y. in duration in our age model, which is close to the 41 k.y. duration of the orbital obliquity cycles. We support the arguments advanced recently in defence of the need for local New Zealand stages as a means of classifying New Zealand sedimentary successions, and strongly oppose the proposal to move stage boundaries to selected geomagnetic polarity transitions. The primary magnetisation of New Zealand mudstone is frequently overprinted with secondary components of diagenetic origin, and hence it is often difficult to obtain reliable magnetostratigraphic records. We suggest specific approaches, analytical methods, and criteria to help ensure robustness and coherency in the palaeomagnetic identification of chron boundaries in typical New Zealand Cenozoic mudstone successions

Quantitative characterization of plastic deformation of single diamond crystals: A high pressure high temperature (HPHT) experimental deformation study combined with electron backscatter diffraction (EBSD)

We report the results of a high-pressure high-temperature (HPHT) experimental investigation into the deformation of diamonds using the D-DIA apparatus. Electron backscatter diffraction (EBSD) data confirm that well-defined 300–700 nm wide {111} slip lamellae are in fact deformation micro-twins with a 60° rotation around a axis. Such twins formed at high confining pressures even without any apparatus-induced differential stress; mechanical anisotropy within the cell assembly was sufficient for their formation with very little subsequent lattice bending ( slip system dominates as expected for the face-centred cubic (FCC) structure of diamond. Slip occurs on multiple {111} planes resulting in rotation around axes. Deformation microstructure characteristics depend on the orientation of the principal stress axes and finite strain but are independent of confining pressure and nitrogen content. All of the uniaxially deformed samples took on a brown colour, irrespective of their initial nitrogen characteristics. This is in contrast to the two quasi-hydrostatic experiments, which retained their original colour (colourless for nitrogen free diamond, yellow for single substitutional nitrogen, Type Ib diamond) despite the formation of {111} twin lamellae. Comparison of our experimental data with those from two natural brown diamonds from Finsch mine (South Africa) shows the same activation of the dominant slip system. However, no deformation twin lamellae are present in the natural samples. This difference may be due to the lower strain rates experienced by the natural samples investigated. Our study shows the applicability and potential of this type of analysis to the investigation of plastic deformation of diamonds under mantle conditions

The re-emergence of natural products for drug discovery in the genomics era

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery

Rapid Global Expansion of the Fungal Disease Chytridiomycosis into Declining and Healthy Amphibian Populations

Published versio

Methylome of human skeletal muscle after acute & chronic resistance exercise training, detraining & retraining

DNA methylation is an important epigenetic modification that can regulate gene expression following environmental encounters without changes to the genetic code. Using Infinium MethylationEPIC BeadChip Arrays (850,000 CpG sites) we analysed for the first time, DNA isolated from untrained human skeletal muscle biopsies (vastus lateralis) at baseline (rest) and immediately following an acute (single) bout of resistance exercise. In the same participants, we also analysed the methylome following a period of muscle growth (hypertrophy) evoked via chronic (repeated bouts-3 sessions/wk) resistance exercise (RE) (training) over 7-weeks, followed by complete exercise cessation for 7-weeks returning muscle back to baseline levels (detraining), and finally followed by a subsequent 7-week period of RE-induced hypertrophy (retraining). These valuable methylome data sets described in the present manuscript and deposited in an open-access repository can now be shared and re-used to enable the identification of epigenetically regulated genes/ networks that are modified after acute anabolic stimuli and hypertrophy, and further investigate the phenomenon of epigenetic memory in skeletal muscle

Criticality in correlated quantum matter

At quantum critical points (QCP) \cite{Pfeuty:1971,Young:1975,Hertz:1976,Chakravarty:1989,Millis:1993,Chubukov:1 994,Coleman:2005} there are quantum fluctuations on all length scales, from microscopic to macroscopic lengths, which, remarkably, can be observed at finite temperatures, the regime to which all experiments are necessarily confined. A fundamental question is how high in temperature can the effects of quantum criticality persist? That is, can physical observables be described in terms of universal scaling functions originating from the QCPs? Here we answer these questions by examining exact solutions of models of correlated systems and find that the temperature can be surprisingly high. As a powerful illustration of quantum criticality, we predict that the zero temperature superfluid density, $\rho_{s}(0)$, and the transition temperature, $T_{c}$, of the cuprates are related by $T_{c}\propto\rho_{s}(0)^y$, where the exponent $y$ is different at the two edges of the superconducting dome, signifying the respective QCPs. This relationship can be tested in high quality crystals.Comment: Final accepted version not including minor stylistic correction

Appetite suppressants and valvular heart disease - a systematic review

Background Although appetite suppressants have been implicated in the development of valvular heart disease, the exact level of risk is still uncertain. Initial studies suggested that as many as 1 in 3 exposed patients were affected, but subsequent research has yielded substantially different figures. Our objective was to systematically assess the risk of valvular heart disease with appetite suppressants. Methods We accepted studies involving obese patients treated with any of the following appetite suppressants: fenfluramine, dexfenfluramine, and phentermine. Three types of studies were reviewed: controlled and uncontrolled observational studies, and randomized controlled trials. Outcomes of interest were echocardiographically detectable aortic regurgitation of mild or greater severity, or mitral regurgitation of moderate or greater severity. Results Of the 1279 patients evaluated in seven uncontrolled cohort studies, 236 (18%) and 60 (5%) were found to have aortic and mitral regurgitation, respectively. Pooled data from six controlled cohort studies yielded, for aortic regurgitation, a relative risk ratio of 2.32 (95% confidence intervals 1.79 to 3.01, p < 0.00001) and an attributable rate of 4.9%, and for mitral regurgitation, a relative risk ratio of 1.55 (95% confidence intervals 1.06 to 2.25, p = 0.02) with an attributable rate of 1.0%. Only one case of valvular heart disease was detected in 57 randomized controlled trials, but this was judged unrelated to drug therapy. Conclusions The risk of valvular heart disease is significantly increased by the appetite suppressants reviewed here. Nevertheless, when considering all the evidence, valvulopathy is much less common than suggested by the initial, less methodologically rigorous studies

Hidden Orbital Order in URu2Si2URu_{2}Si_{2}

When matter is cooled from high temperatures, collective instabilities develop amongst its constituent particles that lead to new kinds of order. An anomaly in the specific heat is a classic signature of this phenomenon. Usually the associated order is easily identified, but sometimes its nature remains elusive. The heavy fermion metal $URu_2Si_2$ is one such example, where the order responsible for the sharp specific heat anomaly at $T_0=17 K$ has remained unidentified despite more than seventeen years of effort. In $URu_{2}Si_{2}$, the coexistence of large electron-electron repulsion and antiferromagnetic fluctuations in $URu_2Si_2$ leads to an almost incompressible heavy electron fluid, where anisotropically paired quasiparticle states are energetically favored. In this paper we use these insights to develop a detailed proposal for the hidden order in $URu_2Si_2$. We show that incommensurate orbital antiferromagnetism, associated with circulating currents between the uranium ions, can account for the local fields and entropy loss observed at the $17 K$ transition; furthermore we make detailed predictions for neutron scattering measurements

Citizen science reveals landscape-scale exposures to multiazole-resistant Aspergillus fumigatus bioaerosols.

Using a citizen science approach, we identify a country-wide exposure to aerosolized spores of a human fungal pathogen, Aspergillus fumigatus, that has acquired resistance to the agricultural fungicide tebuconazole and first-line azole clinical antifungal drugs. Genomic analysis shows no distinction between resistant genotypes found in the environment and in patients, indicating that at least 40% of azole-resistant A. fumigatus infections are acquired from environmental exposures. Hotspots and coldspots of aerosolized azole-resistant spores were not stable between seasonal sampling periods. This suggests a high degree of atmospheric mixing resulting in an estimated per capita cumulative annual exposure of 21 days (±2.6). Because of the ubiquity of this measured exposure, it is imperative that we determine sources of azole-resistant A. fumigatus to reduce treatment failure in patients with aspergillosis