Oligomeric Conjugated Polyelectrolytes Display Site-Preferential Binding to an MS2 Viral Capsid.

Opportunistic bacteria and viruses are a worldwide health threat prompting the need to develop new targeting modalities. A class of novel synthetic poly(phenylene ethynylene) (PPE)-based oligomeric conjugated polyelectrolytes (OPEs) have demonstrated potent wide-spectrum biocidal activity. A subset of cationic OPEs display high antiviral activity against the MS2 bacteriophage. The oligomers have been found to inactivate the bacteriophage and perturb the morphology of the MS2 viral capsid. However, details of the initial binding and interactions between the OPEs and the viruses are not well understood. In this study, we use a multiscale computational approach, including random sampling, molecular dynamics, and electronic structure calculations, to gain an understanding of the molecular-level interactions of a series of OPEs that vary in length, charge, and functional groups with the MS2 capsid. Our results show that OPEs strongly bind to the MS2 capsid protein assembly with binding energies of up to -30 kcal/mol. Free-energy analysis shows that the binding is dominated by strong van der Waals interactions between the hydrophobic OPE backbone and the capsid surface and strong electrostatic free energy contributions between the OPE charged moieties and charged residues on the capsid surface. This knowledge provides molecular-level insight into how to tailor the OPEs to optimize viral capsid disruption and increase OPE efficacy to target amphiphilic protein coats of icosahedral-based viruses.

Cationic oligo-p-phenylene ethynylenes form complexes with surfactants for long-term light-activated biocidal applications.

Cationic oligo-p-phenylene ethynylenes are highly effective light-activated biocides that deal broad-spectrum damage to a variety of pathogens, including bacteria. A potential problem arising in the long-term usage of these compounds is photochemical breakdown, which nullifies their biocidal activity. Recent work has shown that these molecules complex with oppositely-charged surfactants, and that the resulting complexes are protected from photodegradation. In this manuscript, we determine the biocidal activity of an oligomer and a complex formed between it and sodium dodecyl sulfate. The complexes are able to withstand prolonged periods of irradiation, continuing to effectively kill both Gram-negative and Gram-positive bacteria, while the oligomer by itself loses its biocidal effectiveness quickly in the presence of light. In addition, damage and stress responses induced by these biocides in both E. coli and S. aureus are discussed. This work shows that complexation with surfactants is a viable method for long-term light-activated biocidal applications.

Structural basis for aggregation mode of oligo-p-phenylene ethynylenes with ionic surfactants.

In this letter, the aggregation modes of two classes of ionic p-phenylene ethynylene oligomers with oppositely charged surfactants are studied. The location of the ionic side chains was found to influence the type of aggregate formed when an equivalent number of surfactant molecules are added to solution. When the charged groups were located at the terminal ends of the molecule, strong H-aggregates were observed to form. Alternatively, when the ionic groups were both located on opposite sides of the central phenyl ring, the formation of J-aggregates was observed. Interestingly, as the surfactant concentration approaches the critical micelle concentration, the weakly bound aggregates are dissociated and the absorbance spectrum returns to what is observed in water. This study reveals the structural basis for aggregation effects between molecules based on the p-phenylene ethynylene backbone, and gives an understanding of how to influence the aggregation mode of similar compounds.

Recruitment and retention in dentistry in the UK: a scoping review to explore the challenges across the UK, with a particular interest in rural and coastal areas.

Introduction There is currently reduced access to NHS dental services in the UK, particularly in England, with rural and coastal areas significantly affected. Recruitment and retention in dentistry has been highlighted as an issue contributing to the problem.Objectives To explore what is known or unknown about recruitment and retention of the dental workforce in the UK, with a particular focus on rural and coastal areas. We were keen to gain information relating to factors affecting recruitment and retention, geographical distribution of the workforce, anticipated challenges, strategies or proposals to assist workforce planning and the extent of empirical research.Methods Searches for peer-reviewed literature and reports were undertaken and included when they met the eligibility criteria. Data were extracted and the findings narratively synthesised.Discussion The findings suggested wide ranging recruitment and retention issues of the dental workforce in the UK. Most issues were associated with NHS dentists, followed by dental nurses across both the NHS and private sectors. The worst affected parts of the country were rural and coastal areas.Conclusion It appears from the evidence that there are many dental professionals discussing recruitment and retention issues, followed by stakeholders. However, there is limited research and data to initiate change.

Dental practice workforce challenges in rural England: survey into recruitment and retention in Devon and Cornwall.

Introduction Devon and Cornwall have been identified as 'dental deserts' with limited NHS dental access and high levels of oral health inequality. Challenges around recruitment and retention of the dental workforce have been acknowledged as an important contributory factor.Aims The aim of this research was to explore the experiences of dental practices within Devon and Cornwall in relation to recruitment and retention of the dental workforce.Method A self-administered, online questionnaire was used to explore various aspects of workforce recruitment and retention. The questionnaire included categorical rating scale and free-text question formats providing quantitative and qualitative data.Results In total, 106 dental practices responded to the survey, providing a response rate of 36%. The vast majority of respondents (94%) considered recruitment and retention to be a major barrier to delivering NHS services. Additionally, 77% of practices had a current staff vacancy, 57% had a dentist vacancy and 48% had a vacancy for dental nurses. Thematic analysis led to identification of four main themes which were considered to influence recruitment and retention: NHS system; economic challenges; logistics; and support networks.Conclusion A large number of dental practices in Devon and Cornwall are failing to operate at capacity due to workforce shortages, which is affecting access to services in both NHS and private practices. Recruitment and retention of dentists and dental nurses appears to be the most challenging factor, with NHS practices affected more than the private sector.

The dental workforce recruitment and retention crisis in the UK.

The precarious state of NHS dentistry is widely acknowledged, yet there is limited progress in addressing the underlying issues. Further delays will undoubtedly impact patient care, leading to oral health deterioration and unnecessary suffering. This will predominantly affect the most vulnerable in society, resulting in greater oral health inequalities.The underlying issues contributing to the current NHS dental crisis are many, and they include: prolonged delays in contract reform; long-term underinvestment; private sector growth; and fewer dentists working full-time and/or in the NHS. In England, an NHS dental contract that fails to promote prevention or equality of access continues to have a deep and pernicious impact on the future of NHS dentistry. The devastating impact of the COVID-19 pandemic on access cannot be underestimated and neither should the effect of Brexit on the availability of workforce.The recruitment and retention of dentists, and other members of the dental team, is undoubtedly a major issue in terms of capacity and access to NHS dental care. These problems, seen across the UK, are a particular issue in England, with acute challenges within rural and coastal areas.There is an urgent necessity to develop coherent, multifaceted strategies, aided by the collection of clear and accurate workforce data, to tackle these issues.

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 10(6)-fold improvement over comparable liposomes.

Computational study of bacterial membrane disruption by cationic biocides: structural basis for water pore formation.

The development of biocides as disinfectants that do not induce bacterial resistance is crucial to health care since hospital-acquired infections afflict millions of patients every year. Recent experimental studies of a class of cationic biocides based on the phenylene ethynylene backbone, known as OPEs, have revealed that their biocidal activity is accompanied by strong morphology changes to bacterial cell membranes. In vitro studies of bacterial membrane mimics have shown changes to the lipid phase that are dependent on the length and orientation of the cationic moieties on the backbone. This study uses classical molecular dynamics to conduct a comprehensive survey of how oligomers with different chemical structures interact with each other and with a bacterial cell membrane mimic. In particular, the ability of OPEs to disrupt membrane structure is studied as a function of the length of the biocides and the orientation of their cationic moieties along the backbone of the molecule. The simulation results show that the structure of OPEs radically affects their interactions with a lipid bilayer. Biocides with branched cationic groups form trans-membrane water pores regardless of their backbone length, while only 1-1.5 nm of membrane thinning is observed with biocides with cationic groups on their terminal ends. The molecular dynamics simulations provide mechanistic details at the molecular level of the interaction of these biocidal oligomers and the lipid bilayer and corroborate experimental findings regarding observed differences in membrane disruption by OPEs with different chemical structures.