The endangered northern bettong, Bettongia tropica, performs a unique and potentially irreplaceable dispersal role for truffle ectomycorrhizal fungi

Organisms that are highly connected in food webs often perform unique and vital functions within ecosystems. Understanding the unique ecological roles played by highly connected organisms and the consequences of their loss requires a comprehensive understanding of the functional redundancy among organisms. One important, yet poorly understood, food web is that between truffle‐forming ectomycorrhizal fungi and their mammalian consumers and dispersers. Mammalian fungal specialists rely on fungi as a food source, and they consume and disperse a higher diversity and abundance of fungi than do mycophagous mammals with generalist diets. Therefore, we hypothesise that mammalian fungal specialists are functionally distinct because they disperse a set of fungal taxa not fully nested within the set consumed by the combined generalist mammalian community (i.e. functional redundancy of fungal dispersal is limited). Using high‐throughput sequencing, we compared the fungal composition of 93 scats from the endangered fungal specialist northern bettong (Bettongia tropica) and 120 scats from nine co‐occurring generalist mammal species across three sites and three seasons. Compared with other generalist mammals, B. tropica consumed a more diverse fungal diet with more unique taxa. This aligns with our hypothesis that B. tropica performs a unique dispersal function for ectomycorrhizal truffle fungi. Additionally, modelling of mammalian extinctions predicted rapid loss of food web connections which could result in loss of gene flow for truffle taxa. Our results suggest that this system is sensitive to the extinction of highly connected specialist species like B. tropica and their loss could have consequences for ectomycorrhizal truffle fungal diversity. This suggests that the conservation of fungal specialists is imperative to maintaining ectomycorrhizal fungal diversity and healthy plant‐mycorrhizal relationships

Advanced resistance studies identify two discrete mechanisms in staphylococcus aureus to overcome antibacterial compounds that target biotin protein ligase

Biotin protein ligase (BPL) inhibitors are a novel class of antibacterial that target clinically important methicillin-resistant Staphylococcus aureus (S. aureus). In S. aureus, BPL is a bifunctional protein responsible for enzymatic biotinylation of two biotin-dependent enzymes, as well as serving as a transcriptional repressor that controls biotin synthesis and import. In this report, we investigate the mechanisms of action and resistance for a potent anti-BPL, an antibacterial compound, biotinyl-acylsulfamide adenosine (BASA). We show that BASA acts by both inhibiting the enzymatic activity of BPL in vitro, as well as functioning as a transcription co-repressor. A low spontaneous resistance rate was measured for the compound (<10-9) and whole-genome sequencing of strains evolved during serial passaging in the presence of BASA identified two discrete resistance mechanisms. In the first, deletion of the biotin-dependent enzyme pyruvate carboxylase is proposed to prioritize the utilization of bioavailable biotin for the essential enzyme acetyl-CoA carboxylase. In the second, a D200E missense mutation in BPL reduced DNA binding in vitro and transcriptional repression in vivo. We propose that this second resistance mechanism promotes bioavailability of biotin by derepressing its synthesis and import, such that free biotin may outcompete the inhibitor for binding BPL. This study provides new insights into the molecular mechanisms governing antibacterial activity and resistance of BPL inhibitors in S. aureus.Andrew J. Hayes, Jiulia Satiaputra, Louise M. Sternicki, Ashleigh S. Paparella, Zikai Feng, Kwang J. Lee ... et al

Dynamic Evolution Model of Isothermal Voids and Shocks

We explore self-similar hydrodynamic evolution of central voids embedded in an isothermal gas of spherical symmetry under the self-gravity. More specifically, we study voids expanding at constant radial speeds in an isothermal gas and construct all types of possible void solutions without or with shocks in surrounding envelopes. We examine properties of void boundaries and outer envelopes. Voids without shocks are all bounded by overdense shells and either inflows or outflows in the outer envelope may occur. These solutions, referred to as type $\mathcal{X}$ void solutions, are further divided into subtypes $\mathcal{X}_{\rm I}$ and $\mathcal{X}_{\rm II}$ according to their characteristic behaviours across the sonic critical line (SCL). Void solutions with shocks in envelopes are referred to as type $\mathcal{Z}$ voids and can have both dense and quasi-smooth edges. Asymptotically, outflows, breezes, inflows, accretions and static outer envelopes may all surround such type $\mathcal{Z}$ voids. Both cases of constant and varying temperatures across isothermal shock fronts are analyzed; they are referred to as types $\mathcal{Z}_{\rm I}$ and $\mathcal{Z}_{\rm II}$ void shock solutions. We apply the `phase net matching procedure' to construct various self-similar void solutions. We also present analysis on void generation mechanisms and describe several astrophysical applications. By including self-gravity, gas pressure and shocks, our isothermal self-similar void (ISSV) model is adaptable to various astrophysical systems such as planetary nebulae, hot bubbles and superbubbles in the interstellar medium as well as supernova remnants.Comment: 24 pages, 13 figuers, accepted by ApS

Diabetic gastroparesis: Therapeutic options

Gastroparesis is a condition characterized by delayed gastric emptying and the most common known underlying cause is diabetes mellitus. Symptoms include nausea, vomiting, abdominal fullness, and early satiety, which impact to varying degrees on the patient’s quality of life. Symptoms and deficits do not necessarily relate to each other, hence despite significant abnormalities in gastric emptying, some individuals have only minimal symptoms and, conversely, severe symptoms do not always relate to measures of gastric emptying. Prokinetic agents such as metoclopramide, domperidone, and erythromycin enhance gastric motility and have remained the mainstay of treatment for several decades, despite unwanted side effects and numerous drug interactions. Mechanical therapies such as endoscopic pyloric botulinum toxin injection, gastric electrical stimulation, and gastrostomy or jejunostomy are used in intractable diabetic gastroparesis (DG), refractory to prokinetic therapies. Mitemcinal and TZP-101 are novel investigational motilin receptor and ghrelin agonists, respectively, and show promise in the treatment of DG. The aim of this review is to provide an update on prokinetic and mechanical therapies in the treatment of DG

Designer D-peptides targeting the N-terminal region of α-synuclein to prevent parkinsonian-associated fibrilization and cytotoxicity

The deposition of α-synuclein (αS) aggregates in the gut and the brain is ever present in cases of Parkinson’s disease. While the central non-amyloidogenic-component (NAC) region of αS plays a critical role in fibrilization, recent studies have identified a specific sequence from within the N-terminal region (NTR, residues 36–42) as a key modulator of αS fibrilization. Due to the lack of effective therapeutics which specifically target αS aggregates, we have developed a strategy to prevent the aggregation and subsequent toxicity attributed to αS fibrilization utilizing NTR targeting peptides. In this study, L- and D-isoforms of a hexa- (VAQKTV-Aib, 77–82 NAC) and heptapeptide (GVLYVGS-Aib, 36–42 NTR) containing a self-recognition component unique to αS, as well as a Cterminal disruption element, were synthesized to target primary sequence regions of αS that modulate fibrilization. The D-peptide that targets the NTR (NTR-TP-D) was shown by ThT fluorescence assays and TEM to be the most effective at preventing fibril formation and elongation, as well as increasing the abundance of soluble monomeric αS. In addition, NTR-TP-D alters the conformation of destabilised monomers into a less aggregationprone state and reduces the hydrophobicity of αS fibrils via fibril remodelling. Furthermore, both NTR-TP isoforms alleviate the cytotoxic effects of αS aggregates in both Neuro-2a and Caco-2 cells. Together, this study highlights how targeting the NTR of αS using D-isoform peptide inhibitors may effectively combat the deleterious effects of αS fibrilization and paves the way for future drug design to utilise such an approach to treat Parkinson’s disease.John R. Horsley, Blagojce Jovcevski, Tara L. Pukala, Andrew D. Abel

Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of <em>Mycobacterium tuberculosis</em>

International audienceThe shikimate pathway is essential in Mycobacterium tuberculosis and its absence in humans makes the enzymes of this pathway potential drug targets. In this report, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from Mycobacterium tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analog of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active site subpocket inducing significant structural re-arrangement. The flexible extensions of inhibitors designed to form π-stacking interactions with the catalytic Tyr24 residue have been investigated. The high resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19-24 in MtDHQase ligand binding and catalytic mechanism and provide rationale for the design and efficacy of inhibitors