In the age of failing small-molecule antibiotics, tapping the near-infinite structural and chemical repertoire of antimicrobial peptides (AMPs) offers one of the most promising routes toward developing next-generation antibacterial compounds. One of the key impediments en route is the lack of methodologies for systematic rational design and optimization of new AMPs. Here we present a new simulation-guided rational design approach and apply it to develop a potent new AMP. We show that unbiased atomic detail molecular dynamics (MD) simulations are able to predict structures formed by evolving peptide designs enabling structure-based rational fine-tuning of functional properties. Starting from a 14-residue poly leucine template we demonstrate the design of a minimalistic potent new AMP. Consisting of only four types of amino acids (LDKA), this peptide forms large pores in microbial membranes at very low peptide-to-lipid ratios (1:1000) and exhibits low micromolar activity against common Gram-positive and Gram-negative pathogenic bacteria. Remarkably, the four amino acids were sufficient to encode preferential poration of bacterial membranes with negligible damage to red blood cells at bactericidal concentrations. As the sequence is too short to span cellular membranes, pores are formed by stacking of channels in each bilayer leaflet.

Voltage-gated sodium channels are transmembrane proteins involved in generating action potentials for nerve signalling and muscle contractions. They are of a great deal of interest, as mutations in voltage-gated sodium channels are responsible for a variety of disorders, including epilepsy and chronic pain. Designing better inhibitors and treatments, including ones which are

Drug development for the treatment of central nervous system (CNS) diseases is extremely challenging, in large part due to the difficulty in crossing the blood-brain barrier (BBB). Here we develop and experimentally validate a new in silico method to predict quantitatively the BBB permeability for small-molecule drugs. We show accurate prediction of solute permeabilities at physiological temperature using high-temperature unbiased atomic detail molecular dynamics simulations of spontaneous drug diffusion across BBB bilayers. These simulations provide atomic detail insights into the transport mechanisms, as well as converged kinetics and thermodynamics. The method is validated computationally against physiological temperature simulations for fast-diffusing compounds, as well as experimentally by direct determination of the compound permeabilities using a transwell assay as an in vitro BBB model. The overall agreement of the predicted values with both direct simulations at physiological temperatures and experimental data is excellent. This new tool has the potential to replace current semi-empirical in silico screening and in vitro permeability measurements in CNS drug discovery.

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.

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The retina has a complex structure with a diverse collection of component cells that work together to facilitate vision. The retinal capillaries supplying the nutritional requirements to the inner retina have an intricate system of neural, glial and vascular elements that interconnect to form the neurovascular unit (NVU). The retina has no autonomic nervous system and so relies on the NVU as an interdependent, physical

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had an unprecedented impact on the people of Ireland as waves of infection spread across the island during the global coronavirus disease 2019 (COVID-19) pandemic. Viral whole-genome sequencing (WGS) has provided insights into SARS-CoV-2 molecular mechanisms of pathogenicity and evolution and contributed to the development of anti-virals and vaccines. High levels of WGS have enabled effective SARS-CoV-2 genomic surveillance on the island of Ireland, leading to the generation of a sizeable data set with potential to provide additional insights into viral epidemiology. Because Ireland is an island, accurate documentation of travel rates to and from other regions, both by air and by sea, are available. Furthermore, the two distinct political jurisdictions on the island allow comparison of the impact of varying public health responses on viral dynamics, including SARS-CoV-2 introduction events. Using phylogenomic analysis incorporating sample collection date and location metadata, we identify multiple introduction and spreading events for all major viral lineages to the island of Ireland during the period studied (March 2020-June 2022). The majority of SARS-CoV-2 introductions originated from England, with frequent introductions from USA and northwestern Europe. The clusters of sequences predicted to derive from discrete introduction events ("introduction clusters") vary greatly in size, with some involving only one or two cases and others comprising thousands of samples. When introduction cluster samples are mapped sequentially by collection date, they appear predominantly in previously affected or adjacent areas. This mirroring of the phylogenetic relationships by the geospatiotemporal propagation of SARS-CoV-2 validates our analytic approach. By downsampling, we estimate the power to detect introductions to Ireland as a function of sequencing levels. Per capita normalisation of both sequencing levels and detected introductions accounts for biases due to differing sequencing efforts and total populations. This approach showed similar rates of introductions for all major lineages into Northern Ireland (NI) and Republic of Ireland (RoI) with the exception of Delta, which was higher in NI which is likely attributable to higher travel per capita. However, there were similar rates of Delta infection within NI and RoI, suggesting that although travel restrictions will reduce risk of introducing novel variants to the region, they may not substantially decrease total incidence. Our generalisable methodology to study introduction dynamics and optimal sequencing levels will assist public health authorities to select the most appropriate control measures and viral sequencing strategy.