Metabolic profiling unveils enhanced antibacterial synergy of polymyxin B and teixobactin against multi-drug resistant Acinetobacter baumannii.

This untargeted metabolomics study investigated the synergistic antibacterial activity of polymyxin B and Leu-teixobactin, a depsipeptide inhibitor of cell wall biosynthesis. Checkerboard microdilution assays revealed a significant synergy against polymyxin-susceptible and -resistant A. baumannii, excluding lipopolysaccharide-deficient variants.

Adaptation to zinc restriction in : role of the ribosomal protein and zinc-importers regulated by AdcR.

Unlabelled: Zinc (Zn) is an essential cofactor for numerous bacterial proteins and altering Zn availability is an important component of host innate immunity. During infection, adaptation to both Zn deprivation and excess is critical for pathogenic bacteria development. To understand the adaptive responses to Zn availability of , a pathogen causing invasive infections of neonates, global transcriptional profiling was conducted.

Supporting General Practitioners and people with hypertension to maximise medication use to control blood pressure: the contribution of Collective Intelligence to the development of the 'Maximising Adherence, Minimising Inertia' (MIAMI) intervention.

Background: Hypertension remains one of the most important modifiable risk factors for stroke and heart disease. Anti-hypertensive medications are effective, but are often not used to maximum benefit. Sub-optimal dosing by prescribers and challenges with medication-taking for patients remain barriers to effective blood pressure control.

evolution of ciprofloxacin resistance in commensals and derived mutation population dynamics in natural populations.

Commensal are members of a healthy human oropharyngeal microbiome; however, they also serve as a reservoir of antimicrobial resistance for their pathogenic relatives. Despite their known importance as sources of novel genetic variation for pathogens, we still do not understand the full suite of resistance mutations commensal species can harbor. Here, we use selection to assess the mutations that emerge in response to ciprofloxacin selection in commensal by passaging 4 replicates of 4 different species in the presence of a selective antibiotic gradient for 20 days; then categorized derived mutations with whole genome sequencing.

Physics-informed neural network simulation of thermal cavity flow.

Physics-informed neural networks (PINNs) are an emerging technology that can be used both in place of and in conjunction with conventional simulation methods. In this paper, we used PINNs to perform a forward simulation without leveraging known data. Our simulation was of a 2D natural convection-driven cavity using the vorticity-stream function formulation of the Navier-Stokes equations.

Hfe Permease and Manganese Homeostasis.

is a commensal of the human upper respiratory tract that can infect diverse host niches due, at least in part, to its ability to withstand both endogenous and host-mediated oxidative stresses. Here, we show that , a gene previously linked to iron import, is essential for manganese recruitment the HfeBCD transporter. Structural analyses show that metal binding in HfeA uses a unique mechanism that involves substantial rotation of the C-terminal lobe of the protein.

Maternal selenium dietary supplementation alters sociability and reinforcement learning deficits induced by in utero exposure to maternal immune activation in mice.

Maternal immune activation (MIA) during pregnancy increases the risk for the unborn foetus to develop neurodevelopmental conditions such as autism spectrum disorder and schizophrenia later in life. MIA mouse models recapitulate behavioural and biological phenotypes relevant to both conditions, and are valuable models to test novel treatment approaches. Selenium (Se) has potent anti-inflammatory properties suggesting it may be an effective prophylactic treatment against MIA.

Spatial distribution of trace metals and associated transport proteins during bacterial infection.

Innate immune systems alter the concentrations of trace elements in host niches in response to invading pathogens during infection. This work reports the interplay between d-block metal ions and their associated biomolecules using hyphenated elemental techniques to spatially quantify both elemental distributions and the abundance of specific transport proteins. Here, lung tissues were collected for analyses from naïve and Streptococcus pneumoniae-infected mice fed on a zinc-restricted or zinc-supplemented diet.

Runaway electron current reconstitution after a nonaxisymmetric magnetohydrodynamic flush.

Benign termination of mega-ampere (MA) level runaway current has been convincingly demonstrated in recent JET and DIII-D experiments, establishing it as a leading candidate for runaway mitigation on ITER. This comes in the form of a runaway flush by parallel streaming loss along stochastic magnetic field lines formed by global magnetohydrodynamic instabilities, which are found to correlate with a low-Z injection that purges the high-Z impurities from a post-thermal-quench plasma. Here, we show the competing physics that govern the postflush reconstitution of the runaway current in an ITER-like reactor where significantly higher current is expected.

Integrated Transcriptomic and Metabolomic Mapping Reveals the Mechanism of Action of Ceftazidime/Avibactam against Pan-Drug-Resistant .

Here, we employed an integrated metabolomics and transcriptomics approach to investigate the molecular mechanism(s) of action of ceftazidime/avibactam against a pan-drug-resistant clinical isolate from a patient with urinary tract infection. Ceftazidime/avibactam induced time-dependent perturbations in the metabolome and transcriptome of the bacterium, mainly at 6 h, with minimal effects at 1 and 3 h. Metabolomics analysis revealed a notable reduction in essential lipids involved in outer membrane glycerolipid biogenesis.

The two-component system WalKR provides an essential link between cell wall homeostasis and DNA replication in .

The opportunistic human pathogen uses an array of protein sensing systems called two-component systems (TCS) to sense environmental signals and adapt its physiology in response by regulating different genes. This sensory network is key to versatility and success as a pathogen. Here, we reveal for the first time the full extent of the regulatory network of WalKR, the only staphylococcal TCS that is indispensable for survival under laboratory conditions.

Comparison of contemporary invasive and non-invasive isolates reveals new insights into circulating anti-microbial resistance determinants.

is a major human pathogen with a high burden of disease. Non-invasive isolates (those found in non-sterile sites) are thought to be a key source of invasive isolates (those found in sterile sites) and a reservoir of anti-microbial resistance (AMR) determinants. Despite this, pneumococcal surveillance has almost exclusively focused on invasive isolates.

Host subversion of bacterial metallophore usage drives copper intoxication.

During infection, bacteria must overcome the dual threats of metal starvation and intoxication. This work reveals that the zinc-withholding response of the host sensitizes to copper intoxication. In response to zinc starvation, utilizes the metallophore staphylopine.

Copper(II) Complexes of 2,2'-dipyrrins: Synthesis, Characterization, Cell Uptake, and Radiolabeling with Copper-64.

Complexes prepared with positron-emitting copper-64 are of interest as imaging agents for positron emission tomography (PET). This work investigates the potential of using acyclic tetrapyrrolic 2,2'-dipyrrins as ligands to prepare charge-neutral, lipophilic, cell-permeable, redox active complexes with positron-emitting copper-64. The synthesis and characterization of a series of tetrapyrrolic 2,2'-dipyrrin copper(II) complexes are reported.

Human Tim8a, Tim8b and Tim13 are auxiliary assembly factors of mature Complex IV.

Human Tim8a and Tim8b are paralogous intermembrane space proteins of the small TIM chaperone family. Yeast small TIMs function in the trafficking of proteins to the outer and inner mitochondrial membranes. This putative import function for hTim8a and hTim8b has been challenged in human models, but their precise molecular function(s) remains undefined.

The role of CopA in Streptococcus pyogenes copper homeostasis and virulence.

Maintenance of intracellular metal homeostasis during interaction with host niches is critical to the success of bacterial pathogens. To prevent infection, the mammalian innate immune response employs metal-withholding and metal-intoxication mechanisms to limit bacterial propagation. The first-row transition metal ion copper serves critical roles at the host-pathogen interface and has been associated with antimicrobial activity since antiquity.

Host-Mediated Copper Stress Is Not Protective against Streptococcus pneumoniae D39 Infection.

Metal ions are required by all organisms for the chemical processes that support life. However, in excess they can also exert toxicity within biological systems. During infection, bacterial pathogens such as Streptococcus pneumoniae are exposed to host-imposed metal intoxication, where the toxic properties of metals, such as copper, are exploited to aid in microbial clearance.

Time-Dependent Studies of Oxaliplatin and Other Nucleolar Stress-Inducing Pt(II) Derivatives.

The properties of small molecule Pt(II) compounds that drive specific cellular responses are of interest due to their broad clinical use as chemotherapeutics as well as to provide a better mechanistic understanding of bioinorganic processes. The chemotherapeutic compound cisplatin causes cell death through DNA damage, while oxaliplatin may induce cell death through inhibition of ribosome biogenesis, also referred to as nucleolar stress induction. Previous work has found a subset of oxaliplatin derivatives that cause nucleolar stress at 24 h drug treatment.

The Impact of Chromate on Molybdenum Homeostasis.

Acquisition of the trace-element molybdenum the high-affinity ATP-binding cassette permease ModABC is essential for respiration in anaerobic and microaerophilic environments. This study determined the X-ray crystal structures of the molybdenum-recruiting solute-binding protein ModA from PAO1 in the metal-free state and bound to the group 6 metal oxyanions molybdate, tungstate, and chromate. PAO1 ModA has a non-contiguous dual-hinged bilobal structure with a single metal-binding site positioned between the two domains.

Influence of Ring Modifications on Nucleolar Stress Caused by Oxaliplatin-Like Compounds.

Oxaliplatin, a platinum compound in broad clinical use, can induce cell death through a nucleolar stress pathway rather than the canonical DNA damage response studied for other Pt(II) compounds. Previous work has found that the oxaliplatin 1,2-diaminocyclohexane (DACH) ring but not the oxalate leaving group is important to the ability to induce nucleolar stress. Here we study the influence of DACH ring substituents at the 4-position on the ability of DACH-Pt(II) compounds to cause nucleolar stress.