The Heparan Sulfate Proteoglycans Dally-like and Syndecan Have Distinct Functions in Axon Guidance and Visual-System Assembly in Drosophila

SummaryHeparan sulfate proteoglycans (HSPGs), a class of glycosaminoglycan-modified proteins, control diverse patterning events via their regulation of growth-factor signaling and morphogen distribution [1]. In C. elegans, zebrafish, and the mouse, heparan sulfate (HS) biosynthesis is required for normal axon guidance [2–4], and mutations affecting Syndecan (Sdc), a transmembrane HSPG, disrupt axon guidance in Drosophila embryos [5, 6]. Glypicans, a family of glycosylphosphatidylinositol (GPI)-linked HSPGs, are expressed on axons and growth cones in vertebrates, but their role in axon guidance has not been determined [7, 8]. We demonstrate here that the Drosophila glypican Dally-like protein (Dlp) is required for proper axon guidance and visual-system function. Mosaic studies revealed that Dlp is necessary in both the retina and the brain for different aspects of visual-system assembly. Sdc mutants also showed axon guidance and visual-system defects, some that overlap with dlp and others that are unique. dlp+ transgenes were able to rescue some sdc visual-system phenotypes, but sdc+ transgenes were ineffective in rescuing dlp abnormalities. Together, these findings suggest that in some contexts HS chains provide the biologically critical component, whereas in others the structure of the protein core is also essential

Understanding how children are coping with climate change anxiety by exploring coping strategies and supportive interventions.

Climate change presents a significant threat to both the planet and human prosperity which impacts our physical health and mental well-being. There is an imminent requirement for significant global action. This means (a) our children have been born into unprecedented times and (b) as future adults, they will find themselves facing the major consequences of climate change. These can negatively affect their mental health and well-being. This paper reports the effect of climate anxiety on this population group through an exploration of coping strategies and supportive interventions. Empowering children to engage in climate action has been identified as a coping strategy. Whilst equipping them with knowledge and resources on climate change and providing safe spaces and experiences in nature are identified as supportive interventions. However, further empirical research evidence is needed to determine the next steps to address the extent of the impact of climate anxiety and prepare our children for the future

Patient engagement with antibiotic messaging in secondary care: a qualitative feasibility study of the ‘review & revise’ experience

Background: We aimed to investigate and optimise the acceptability and usefulness of a patient leaflet about antibiotic prescribing decisions made during hospitalisation, and to explore individual patient experiences and preferences regarding the process of antibiotic prescription ‘review & revise’ which is a key strategy to minimise antibiotic overuse in hospitals. Methods: In this qualitative study, run within the feasibility study of a large, cluster-randomised stepped wedge trial of 36 hospital organisations, a series of semi-structured, think-aloud telephone interviews were conducted and data were analysed using thematic analysis. Fifteen adult patients who had experienced a recent acute medical hospital admission during which they had been prescribed antimicrobials and offered a patient leaflet about antibiotic prescribing were recruited to the study. Results: Participants reacted positively to the leaflet, reporting that it was both an accessible and important source of information which struck the appropriate balance between informing and reassuring. Participants all valued open communication with clinicians, and were keen to be involved in antibiotic prescribing decisions, with individuals reporting positive experiences regarding antibiotic prescription changes or stopping. Many participants had prior experience or knowledge of antibiotics and resistance, and generally welcomed efforts to reduce antibiotic usage. Overall, there was a feeling that healthcare professionals (HCPs) are trusted experts providing the most appropriate treatment for individual patient conditions. Conclusions: This study offers novel insights into how patients within secondary care are likely to respond to messages advocating a reduction in the use of antibiotics through the ‘review & revise’ approach. Due to the level of trust that patients place in their care provider, encouraging HCPs within secondary care to engage patients with greater communication and information provision could provide great advantages in the drive to reduce antibiotic use. It may also be beneficial for HCPs to view patient experiences as cumulative events that have the potential to impact future behaviour around antibiotic use. Finally, pre-testing messages about antibiotic prescribing and resistance is vital to dispelling any misconceptions either around effectiveness of treatment for patients, or perceptions of how messages may be received

Anisotropic crack propagation and deformation in dentin observed by four-dimensional X-ray nano-computed tomography

Understanding the cracking behaviour of biological composite materials is of practical importance. This paper presents the first study to track the interplay between crack initiation, microfracture and plastic deformation in three dimensions (3D) as a function of tubule and collagen fibril arrangement in elephant dentin using in situ X-ray nano-computed tomography (nano-CT). A nano-indenter with a conical tip has been used to incrementally indent three test-pieces oriented at 0°, 45° and 70° to the long axis of the tubules (i.e. radial to the tusk). For the 0° sample two significant cracks formed, one of which linked up with microcracks in the axial-radial plane of the tusk originating from the tubules and the other one occurred as a consequence of shear deformation at the tubules. The 70° test-piece was able to bear the greatest loads despite many small cracks forming around the indenter. These were diverted by the microstructure and did not propagate significantly. The 45° test-piece showed intermediate behaviour. In all cases strains obtained by digital volume correlation were well in excess of the yield strain (0.9%), indeed some plastic deformation could even be seen through bending of the tubules. The hoop strains around the conical indenter were anisotropic with the smallest strains correlating with the primary collagen orientation (axial to the tusk) and the largest strains aligned with the hoop direction of the tusk

Electrochemical analysis of gold nanoparticles multifunctionalised withCytochrome c and a zinc Porphyrin

Cytochrome c (Cyt c), known for its functional redox capabilities, plays a pivotal role in biologicalprocesses such as the electron transport chain and apoptosis. However, understanding how differentconjugation strategies impact its structural and redox characteristics is limited. To fill this gap, weinvestigated the effects of conjugating Cyt c and a zinc(II) porphyrin (Zn Porph) to gold nanoparticles(AuNPs). We used circular dichroism (CD) spectroscopy to detect structural conformational changesin Cyt c upon conjugation and time-of-flight secondary ion mass spectrometry (TOF-SIMS) toidentify protein orientation. Cyt c was predicted to have different orientations depending on the sizeof AuNPs and methods used to conjugate the protein, it was hypothesised that the orientation of Cythttps://doi.org/10.26434/chemrxiv-2023-rsrwv ORCID: https://orcid.org/0000-0002-4872-8928 Content not peer-reviewed by ChemRxiv. License: CC BY 4.02c may influence the redox properties of the protein. The electrochemical properties of Cyt c wereassessed using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). We used DPVbasedto determine the heterogeneous rate constant (k0). The results show a lower k0 for conjugatedCyt c than free Cyt c, likely due to structural changes in the protein. The spatial orientation of Cyt chad minimal influence on k0, while ligand density and AuNP size had an effect. The k0 value of ZnPorph did not decrease on conjugation. Despite these changes, Cyt c and Zn Porph maintained theirelectrochemical capabilities after conjugation.</p

Missed opportunities for shared decision making in antimicrobial stewardship: The potential consequences of a lack of patient engagement in secondary care

Background: Within infectious diseases in secondary care, understanding of the potential for behavioural changes arising from patient involvement in antimicrobial decision making is lacking. Shared decision making is becoming part of international policy. The United States have passed it into legislation and the United Kingdom has implemented a number of national interventions across healthcare pathways. This study aims to understand the level of patient involvement in decision making around antimicrobial use in secondary care and the potential consequences associated with it. Methods & Materials: Fourteen members of the public who had received antimicrobials from secondary care in the preceding 12 months were recruited to participate in group interviews. Group interactions were audio-recorded, transcribed verbatim, and thematically analysed. Results: Participants reported feelings of disempowerment during episodes of infection in secondary care. Information is currently communicated in a unilateral manner with individuals ‘told’ that they have an infection and will receive an antimicrobial (often unnamed), leading to loss of ownership, frustration, anxiety and ultimately distancing them from participation in decision making. This poor communication drives individuals to seek information from alternative sources, including on-line resources, which are associated with concerns over reliability and individualisation. This failure of communication and information provision from clinicians in secondary care influences individual's future ideas about infections and their management. This alters their future actions towards infections and antimicrobials and can drive non-adherence to prescribed antimicrobial regimes and loss-to-follow-up after discharge from secondary care. Conclusion: Current infection management and antimicrobial prescribing practices in secondary care may be failing to engage patients in the decision making process. It is vital that secondary care physicians do not view infection management episodes as discrete events, but as cumulative experiences which have the potential to drive future non-adherence to prescribed antimicrobial regimes and thus poor individual outcomes and antimicrobial resistance. This lesson is transferable to all settings of healthcare, where poor communication and information provision having the potential to influence future health seeking behaviours. We call for the development of clear, pragmatic mechanism to support healthcare professionals and patients engage in infection related decision making during consultations

Patient engagement with infection management in secondary care: a qualitative investigation of current experiences.

OBJECTIVE: To understand patient engagement with decision-making for infection management in secondary care and the consequences associated with current practices. DESIGN: A qualitative investigation using in-depth focus groups. PARTICIPANTS: Fourteen members of the public who had received antimicrobials from secondary care in the preceding 12 months in the UK were identified for recruitment. Ten agreed to participate. All participants had experience of infection management in secondary care pathways across a variety of South-East England healthcare institutes. Study findings were subsequently tested through follow-up focus groups with 20 newly recruited citizens. RESULTS: Participants reported feelings of disempowerment during episodes of infection in secondary care. Information is communicated in a unilateral manner with individuals 'told' that they have an infection and will receive an antimicrobial (often unnamed), leading to loss of ownership, frustration, anxiety and ultimately distancing them from engaging with decision-making. This poor communication drives individuals to seek information from alternative sources, including online, which is associated with concerns over reliability and individualisation. Failures in communication and information provision by clinicians in secondary care influence individuals' future ideas about infections and their management. This alters their future actions towards antimicrobials and can drive prescription non-adherence and loss to follow-up. CONCLUSIONS: Current infection management and antimicrobial prescribing practices in secondary care fail to engage patients with the decision-making process. Secondary care physicians must not view infection management episodes as discrete events, but as cumulative experiences which have the potential to shape future patient behaviour and understanding of antimicrobial use

Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review

Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl--dependent Cr transporter (CRT). Once within cells, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4-]2- and Cr to produce phosphocreatine (PCr) and [Mg2+:ADP3-]-. We aimed to perform a comprehensive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states