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One-dimensional (1D) supramolecular polymers are commonly found in natural and synthetic systems to prompt functional responses that capitalise on hierarchical molecular ordering. Despite amphiphilic self-assembly being significantly studied in the context of aqueous encapsulation and autopoiesis, very little is currently known about the physico-chemical consequences and functional role of 1D supramolecular polymerisation confined in aqueous compartments. Here, we describe the different phenomena that resulted from the chemically triggered supramolecular fibrillation of synthetic peptide amphiphiles inside water microdroplets. The confined connection of suitable dormant precursors triggered a physically autocatalysed chemical reaction that resulted in functional environmental responses such as molecular uptake, fusion and chemical exchange. These results demonstrate the potential of minimalistic 1D supramolecular polymerisation to modulate the behaviour of individual aqueous entities with their environment and within communities. One-dimensional (1D) supramolecular polymers are commonly found in natural and synthetic systems but very little is currently known about the physico-chemical consequences and functional role of 1D supramolecular polymerisation confined in aqueous compartments. Here, the authors describe the different phenomena that resulted from the chemically triggered supramolecular fibrillation of synthetic peptide amphiphiles inside water microdroplets.

As in natural cytoskeletons, the cooperative assembly of fibrillar networks can be hosted inside compartments to engineer biomimetic functions, such as mechanical actuation, transport, and reaction templating. Coacervates impose an optimal liquid-liquid phase separation within the aqueous continuum, functioning as membrane-less compartments that can organise such self-assembling processes as well as the exchange of information with their environment. Furthermore, biological fibrillation can often be controlled or assisted by intracellular compartments. Thus, the reconstitution of analogues of natural filaments in simplified artificial compartments, such as coacervates, offer a suitable model to unravel, mimic, and potentially exploit cellular functions. This perspective summarises the latest developments towards assembling fibrillar networks under confinement inside coacervates and related compartments, including a selection of examples ranging from biological to fully synthetic monomers. Comparative analysis between coacervates, lipid vesicles, and droplet emulsions showcases the interplay between supramolecular fibres and the boundaries of the corresponding compartment. Combining inspiration from natural systems and the custom properties of tailored synthetic fibrillators, rational monomer and compartment design will contribute towards engineering increasingly complex and more realistic artificial protocells. The bottom-up reconstitution of natural filaments within simplified artificial cellular compartments, such as coacervates, offer a model to study, mimic, and potentially exploit cellular functions. Here, the authors summarize the latest developments towards assembling confined fibrillar networks inside coacervates and related compartments, including a selection of examples ranging from biological to fully synthetic building blocks.

To increase granularity in human neuroimaging science, we designed and built a next-generation 7 Tesla magnetic resonance imaging scanner to reach ultra-high resolution by implementing several advances in hardware. To improve spatial encoding and increase the image signal-to-noise ratio, we developed a head-only asymmetric gradient coil (200 mT m −1 , 900 T m −1 s −1 ) with an additional third layer of windings. We integrated a 128-channel receiver system with 64- and 96-channel receiver coil arrays to boost signal in the cerebral cortex while reducing g-factor noise to enable higher accelerations. A 16-channel transmit system reduced power deposition and improved image uniformity. The scanner routinely performs functional imaging studies at 0.35–0.45 mm isotropic spatial resolution to reveal cortical layer functional activity, achieves high angular resolution in diffusion imaging and reduces acquisition time for both functional and structural imaging. A combination of hardware developments has increased the achievable spatial resolution in 7 Tesla human neuroimaging to about 0.4 mm.

Here, we describe the preparation and characterisation of polyion complex (PIC) nanoparticles containing last resort antimicrobial polymyxin B (Pol-B). PIC nanoparticles were prepared with poly(styrene sulphonate) (PSS) as an inert component, across a range of degrees of polymerisation to evaluate the effect that multivalency of this electrolyte has on the stability and antimicrobial activity of these nanoparticles. Our results demonstrate that while nanoparticles prepared with longer polyelectrolytes are more stable under simulated physiological conditions, those prepared with shorter polyelectrolytes have a higher antimicrobial activity. Tailoring the degree of polymerisation and the ratio of the components we have been able to identify a formulation that shows a sustained inhibitory effect on the growth of P . aeruginosa and can reduce the number of viable colonies of this pathogen over 10,000 times more effectively than our previously reported formulation.

Antibiotic resistance is a serious worldwide threat. Alternative solutions to the limited pipeline of new antibiotics are urgently needed. Nanotechnology and drug delivery can be used to develop new therapies from old antimicrobials by controlling their distribution in the body. The goal of this thesis was to investigate the formation and activity of polyion complex (PIC) nanoparticles as vehicles for the delivery of two cationic antibiotics: poly(ethylene imine), used as model to develop these nanomaterials, and the FDA-approved antimicrobial peptide polymyxin B. These antibiotics were combined with two types of polyanions to form PIC particles with distinct antimicrobial properties: 1) Anionic peptides, degradable by bacterial enzymes led to bacteria-targeted nanoparticles; 2) Acidic polymers assembled particles for passive release, which tuned the activity of the antibiotic in the absence of a specific trigger. All the PIC particles prepared were characterised, and their physiological stability and antimicrobial properties evaluated. To improve the stability and activity of these nanoparticles, several characteristics of their anionic components were optimised: 1) their multivalency, as a function of the peptide’s anionic residues and polymer’s DP; 2) the acidity of the polymers; and 3) the number of cross-linking residues in the peptides.

Abstract Opportunistic infections by environmental fungi are a growing clinical problem, driven by an increasing population of people with immunocompromising conditions. Spores of the Mucorales order are ubiquitious in the environment but can also cause acute invasive infections in humans through germination and evasion of the mammalian host immune system. How they achieve this, and the evolutionary drivers underlying the acquisition of virulence mechanisms, are poorly understood. Here we show that a clinical isolate of Rhizopus microsporus contains a Ralstonia pickettii bacterial endosymbiont required for virulence in both zebrafish and mice, and that this endosymbiosis enables secretion of factors that potently suppress growth of the soil amoeba Dictyostelium discoideum, as well as their ability to engulf and kill other microbes. As amoebae are natural environmental predators of both bacteria and fungi, we propose this tri-kingdom interaction contributes to establishing the endosymbiosis, and acquisition of anti-phagocyte activity. Importantly, we show this activity also protects fungal spores from phagocytosis and clearance by human macrophages, and endosymbiont removal renders the fungal spores avirulent in vivo. Together, these findings describe a novel role for a bacterial endosymbiont in Rhizopus microsporus pathogenesis in animals, and suggest a mechanism of virulence acquisition through environmental interactions with amoebae. In brief How environmental fungi evolved the mechanisms that enable them to cause opportunistic infections in humans is unclear. Here, we identify a novel tri-kingdom interaction, whereby a bacterial endosymbiont, living within a clinical isolate of the ubiquitous environmental fungus Rhizopus microsporus, causes the generation of a secreted activity that blocks the growth and predatory activity of amoebae. We suggest this provides a new evolutionary driver for the establishment of bacterial/fungal endosymbiosis and demonstrate this is critical for fungal pathogenicity in vivo. Competing Interest Statement The authors have declared no competing interest. Footnotes * Revised to reflect reviewer feedback

Vibrio cholerae, the causative agent of cholera, is an abundant environmental bacterium that can efficiently colonize the intestinal tract and trigger severe diarrheal illness. Motility, and the production of colonization factors and cholera toxin, are fundamental for the establishment of disease. In the aquatic environment, V. cholerae persists by forming avirulent biofilms on zooplankton, phytoplankton and chitin debris. Here, we describe the formation of artificial, biofilm-like communities, driven by exposure of planktonic bacteria to synthetic polymers. This recruitment is extremely rapid and charge-driven, and leads to the formation of initial 'seed clusters' which then recruit additional bacteria to extend in size. Bacteria that become entrapped in these 'forced communities' undergo transcriptional changes in motility and virulence genes, and phenotypically mimic features of environmental biofilm communities by forming a matrix that contains polysaccharide and extracellular DNA. As a result of this lifestyle transition, pathogenicity and in vivo host colonization decrease. These findings highlight the potential of synthetic polymers to disarm pathogens by modulating their lifestlye, without creating selective pressure favoring the emergence of antimicrobial resistant strains.

[Abstract] The present study provides an energy, exergy and economic analysis of a seawater regasification system (open loop) combining stages of simple organic Rankine cycles (ORCs) arranged in series with an open organic Rankine cycle (OC) in order to exploit the cold energy of liquefied natural gas (LNG). The proposed system, termed ORC-OC, is implemented in a Floating Storage Regasification Unit (FSRU) to achieve the objective of zero greenhouse emissions during the regasification process. Configurations of up to three stages of ORCs and the use of zeotropic mixtures of ethane/propane and n-butane/propane as working fluids are considered in the study of the novel regasification system. Only the two-stage ORC-OC (2ORC-OC) and three-stage (3ORC-OC) configurations accomplish the objective of zero emissions, attaining exergy efficiencies of 61.80% and 62.04%, respectively. The overall cost rate of the latter, however, is 20.85% greater, so the 2ORC-OC results as being more cost-effective. A comparison with conventional regasification systems installed on board shows that the 2ORC-OC yields a lower total cost rate if the LNG price exceeds 8.903 USD/MMBtu. This value could be reduced, however, if the electrical power that exceeds the FSRU’s demand is exported and if compact heat exchangers are implemented.

The type-1 cannabinoid receptor (CB 1 R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB 1 R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C -terminal, intracellular domain of CB 1 R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB 1 R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB 1 R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB 1 R that hampers CB 1 R-mediated effects on hippocampal circuit function. Cannabis impacts our brain by engaging the CB 1 receptor. Here, the authors identify a protein called GAP43 that interacts with CB 1 and blocks its synaptic functions. This finding provides a conceptual view to understand how CB 1 acts in the brain.

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.