Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis

Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells and is a potential target for antifungal treatments. Glucan is synthesized from the donor uridine diphosphate glucose, with the conversion of glucose-6-phosphate to glucose-1-phosphate by the enzyme phosphoglucomutase (PGM) representing a key step in its biosynthesis. Here, we explore the possibility of selectively targeting A. fumigatus PGM (AfPGM) as an antifungal treatment strategy. Using a promoter replacement strategy, we constructed a conditional pgm mutant and revealed that pgm is required for A. fumigatus growth and cell wall integrity. In addition, using a fragment screen, we identified the thiol-reactive compound isothiazolone fragment of PGM as targeting a cysteine residue not conserved in the human ortholog. Furthermore, through scaffold exploration, we synthesized a para-aryl derivative (ISFP10) and demonstrated that it inhibits AfPGM with an IC(50) of 2 μM and exhibits 50-fold selectivity over the human enzyme. Taken together, our data provide genetic validation of PGM as a therapeutic target and suggest new avenues for inhibiting AfPGM using covalent inhibitors that could serve as tools for chemical validation

Targeting a critical step in fungal hexosamine biosynthesis

Acknowledgements We wish to thank the Dundee Drug Discovery Unit for access to the Fragment library and the European Synchrotron Radiation Facility, Grenoble and Diamond Light Source, Oxford for time at the beamline. The assistance from Mr Martin Kierans, School of Life Sciences, University of Dundee with the Electron Microscopy is gratefully acknowledged. Funding and additional information This work was supported by a Wellcome Trust Postdoctoral Research Training Fellowship for Clinicians (WT105772/A/14/Z) to DL and an MRC Programme Grant (MR/M004139/1) to DMFvA. DB was funded by a University of Aberdeen Summer Research Scholarship.Peer reviewedPostprintPublisher PD

Inhibitors against Fungal Cell Wall Remodeling Enzymes

Fungal β-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi and yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Herein we report a multidisciplinary approach based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. We demonstrate by X-ray crystallography that the compounds bind in the active site of Gas2/Gel4 and interact with the catalytic machinery. The topological analysis of noncovalent interactions demonstrates that the combination of a triazole with positively charged aromatic moieties are important for optimal interactions with Gas2/Gel4 through unusual pyridinium cation–π and face-to-face π–π interactions. The lead compound is capable of inhibiting AfGel4 with an IC value of 42 μm.This work was supported by Spanish MINECO Contracts (CTQ2016‐76155‐R to P.M., and BFU2016‐75633‐P to R.H.‐G.), and an MRC Programme Grant (M004139) to D.M.F.v.A. We also acknowledge the Government of Aragón (Spain) (Bioorganic Chemistry group E‐10 and Protein Targets group B‐89) for financial support. The European Commission is gratefully acknowledged (BioStruct‐X grant agreement no. 283570 and BIOSTRUCTX_5186).Peer Reviewe

Research on Thermosensitive Coatings for Thermal Runaway Warning in Energy Storage Power Station

[Introduction] Lithium iron phosphate battery storage power plants are an important basis for new power systems to consume large-scale new energy, however, the thermal runaway of battery cells seriously threatens the operational safety of storage power plants. It is important to conduct real-time monitoring and scientific warning of local overheating in storage power plants. [Method] In this work, a thermal microcapsule with the ability to sense overheating temperature and produce colour changes was prepared and added in appropriate amounts to an epoxy resin matrix to form a composite insulating material with the characteristics of sensing external overheating temperature fields. [Result] Test results show that the colour of the prepared thermosensitive microcapsule/epoxy insulating temperature indication coating can change sensitively with external temperature changes, with a sudden colour change occurring at around 60 °C. When the doping mass fraction of the thermosensitive microcapsules is 0.25%, the insulation strength and dielectric properties of the composite coating are comparable to those of the pure epoxy resin material, maintaining good intrinsic electrical properties. [Conclusion] The thermosensitive colour-changing composite insulation coating proposed in the study can visibly change the temperature of the external local overheating state, providing a new technical route for the application of thermal runaway warning in energy storage power plants, which has certain engineering application value

Case Report: Chronic hepatitis E virus Infection in an individual without evidence for immune deficiency

Chronic hepatitis E virus (HEV) infection occurs mainly in immunosuppressed populations. We describe an investigation of chronic HEV infection of genotype 3a in an individual without evidence for immune deficiency who presented hepatitis with significant HEV viremia and viral shedding. We monitored HEV RNA in plasma and stools, and assessed anti-HEV specific immune responses. The patient was without apparent immunodeficiency based on quantified results of white blood cell, lymphocyte, neutrophilic granulocyte, CD3+ T cell, CD4+ T cell, and CD8+ T cell counts and CD4/CD8 ratio, as well as total serum IgG, IgM, and IgA, which were in the normal range. Despite HEV specific cellular response and strong humoral immunity being observed, viral shedding persisted up to 109 IU/mL. After treatment with ribavirin combined with interferon, the indicators of liver function in the patient returned to normal, accompanied by complete suppression and clearance of HEV. These results indicate that HEV chronicity can also occur in individuals without evidence of immunodeficiency

Differences between East Asian and Indian monsoon climate records during MIS3 attributed to differences in their driving mechanisms: Evidence from the loess record in the Sichuan basin, southwestern China and other continental and marine climate records

Asian monsoons vary with global climatic change, as is well recorded by Chinese loess-paleosol sequences. A radiocarbon and OSL dated, grain size and magnetic susceptibility record of the loess-paleosol sequence from the Chengdu Basin, southwestern China, contains a greatly amplified MIS 3 Indian monsoon climate record. Comparison of this record with other continental and marine climate records in the temporal and frequency domains indicates that the high-amplitude MIS3 feature dominates the Indian monsoon region and weakens northward but is not observed in East Asian monsoon climate records. These observed differences in the amplitude of MIS 3 climate variations between the two monsoonal regions may be caused by the different effects of the precession insolation forcing on the very different monsoonal driving mechanisms. The Indian monsoon, which originates from the subtropical Mascarene High in the Southern Hemisphere, carries large precession signals from the equatorial and tropic zones, leading to the overall intensification of MIS 3 climate signals. The northward decrease of the Indian monsoon strength reduces precessional climate signals carried by the monsoon. On the other hand, the East Asian monsoon is largely generated from the Western Pacific Subtropical High in the northern subtropical zone where the impact of precessional insolation forcing and heat-vapor transport are much weaker, thus exerting a more limited spatial and temporal influence on climate records. © 2010 Elsevier Ltd and INQUA