Outcome measures for use in trials of paediatric otorrhoea:A systematic review

Introduction:Paediatric otorrhoea (PO) describes a middle ear infection that results in a perforation of the tympanic membrane and ear discharge, in children and young people (CYP). Prolonged infection may be associated with hearing loss and developmental delay. The current management of paediatric otorrhoea is variable, including non-invasive treatments (conservative, oral antibiotics, topical antibiotics) and surgery, reflecting the lack of a sufficiently strong evidence base. Outcome reporting is fundamental to producing reliable and meaningful evidence to inform best practice.Objectives:Primary objective: to determine which outcome measures are currently used to evaluate treatment success in studies of non-surgical treatments for paediatric otorrhoea. Secondary objectives: to identify outcome measurement instruments used in the literature and assess their applicability for use in clinical trials of PO.Methods:This systematic review was registered with PROSPERO (CRD42023407976). Database searches of EMBASE, MEDLINE and Cochrane was performed on June 6, 2023, covering from Jan 1995 to May 2023. Randomised controlled trials or study protocols involving CYP with PO were included following PRISMA guidelines. Risk of bias was assessed with Cochrane's tool.Results:Of the 377 papers identified, six were included in the systematic review. The primary outcome of five of the studies related to otorrhoea cessation; both time to cessation and proportion recovered at various time points were used as measures. Two measurement instruments were identified: Otitis Media-6 Questionnaire and the Institute for Medical Technology Assessment Productivity Cost Questionnaire. Both were shown to be applicable measurement instruments when used in clinical trials of PO.Conclusions:To promote homogeneity and facilitate meaningful comparison and combination of studies, we propose that time to cessation of otorrhoea from onset of otorrhoea should be used as the primary outcome in future studies. Further research is needed to establish if this is the most important outcome to children and their caregivers

Strength in diversity: enhancing learning in vocationally-orientated, master's level courses

Postgraduate education in geography, especially at the Master’s level, is undergoing significant changes in the developed world. There is an expansion of vocationally-oriented degree programmes, increasing recruitment of international students, integration of work place skills, and the engagement of non-traditional postgraduate students as departments respond to policies for a more ‘inclusive’ higher education. This paper sets the context by outlining some programmatic changes in selected countries (Australia, the UK, and the USA). We briefly reflect on how postgraduate ‘bars’ or ‘levels’ are defined and explore in detail what ‘diversity’ or ‘heterogeneity’ means in these new postgraduate settings. The paper then explores some examples of practice drawn from our own experiences, whilst recognising that relevance will vary in other contexts. Finally we consider how diversity can be harnessed as a strength that has potential to enhance taught elements of contemporary postgraduate education in and beyond the discipline

The receptor PTPRU is a redox sensitive pseudophosphatase

Abstract: The receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising an active membrane proximal (D1) domain and an inactive distal (D2) pseudophosphatase domain. Here we demonstrate that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show that this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine. Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal “backdoor” cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates

Targeting the IL-6-Yap-Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis

ACKNOWLEDGEMENTS The authors thank staff at the University of Aberdeen’s Animal Facility, Microscopy and Histology Facility, qPCR Facility, and the Iain Fraser Cytometry Centre for their expert support. The authors also thank the NHS Grampian Biorepository for facilitating the collection of human tissue samples. Additionally, thanks is given to Denis Evseenko for critical review of the manuscript. Funding This work was supported by funding from the Medical Research Council (grants MR/L020211/1, MR/L022893/1), Versus Arthritis (formerly Arthritis Research UK, grants 20775, 19429, 21156, 20050, 19667, 20865, 21800), Tenovus Scotland (grant G13/14), and European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska Curie (Grant 642414).Peer reviewedPublisher PD

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Identification of androgen receptor phosphorylation in the primate ovary in vivo

The androgen receptor (AR) is a member of the nuclear receptor superfamily, and is important for both male and female reproductive health. The receptor is a target for a number of post-translational modifications including phosphorylation, which has been intensively studied in vitro. However, little is known about the phosphorylation status of the receptor in target tissues in vivo. The common marmoset is a useful model for studying human reproductive functions, and comparison of the AR primary sequence from this primate shows high conservation of serines known to be phosphorylated in the human receptor and corresponding flanking amino acids. We have used a panel of phosphospecific antibodies to study AR phosphorylation in the marmoset ovary throughout the follicular phase and after treatment with GNRH antagonist or testosterone propionate. In normal follicular phase ovaries, total AR (both phosphorylated and non-phosphorylated forms) immunopositive staining was observed in several cell types including granulosa cells of developing follicles, theca cells and endothelial cells lining blood vessels. Receptor phosphorylation at serines 81, 308, and 650 was detected primarily in the granulosa cells of developing follicles, surface epithelium, and vessel endothelial cells. Testosterone treatment lead to a modest increase in AR staining in all stages of follicle studied, while GNRH antagonist had no effect. Neither treatment significantly altered the pattern of phosphorylation compared to the control group. These results demonstrate that phosphorylation of the AR occurs, at a subset of serine residues, in a reproductive target tissue in vivo, which appears refractory to hormonal manipulations

A deep dive into the ecology of Gamay (Botany Bay, Australia): current knowledge and future priorities for this highly modified coastal waterway

Context: Gamay is a coastal waterway of immense social, cultural and ecological value. Since European settlement, it has become a hub for industrialisation and human modification. There is growing desire for ecosystem-level management of urban waterways, but such efforts are often challenged by a lack of integrated knowledge. Aim and methods: We systematically reviewed published literature and traditional ecological knowledge (TEK), and consulted scientists to produce a review of Gamay that synthesises published knowledge of Gamay’s aquatic ecosystem to identify knowledge gaps and future research opportunities. Key results: We found 577 published resources on Gamay, of which over 70% focused on ecology. Intertidal rocky shores were the most studied habitat, focusing on invertebrate communities. Few studies considered multiple habitats or taxa. Studies investigating cumulative human impacts, long-term trends and habitat connectivity are lacking, and the broader ecological role of artificial substrate as habitat in Gamay is poorly understood. TEK of Gamay remains a significant knowledge gap. Habitat restoration has shown promising results and could provide opportunities to improve affected habitats in the future. Conclusion and implications: This review highlights the extensive amount of knowledge that exists for Gamay, but also identifies key gaps that need to be filled for effective management

In vivo polyester immobilized sortase for tagless protein purification

Background: Laboratory scale recombinant protein production and purification techniques are often complicated, involving multiple chromatography steps and specialized equipment and reagents. Here it was demonstrated that recombinant proteins can be expressed as covalently immobilized to the surface of polyester (polyhydroxyalkanoate, PHA) beads in vivo in Escherichia coli by genetically fusing them to a polyester synthase gene (phaC). The insertion of a self-cleaving module, a modified sortase A (SrtA) from Staphylococcus aureus and its five amino acid recognition sequence between the synthase and the target protein led to a simple protein production and purification method. Results: The generation of hybrid genes encoding tripartite PhaC-SrtA-Target fusion proteins, enabled immobilization of proteins of interest to the surface of PHA beads in vivo. After simple cell lysis and isolation of the PHA beads, the target proteins could be selectively and efficiently released form the beads by activating the sortase with CaCl2 and triglycine. Up to 6 mg/l of soluble proteins at a purity of ~98 % could be isolated in one step with no optimization. This process was used to produce and isolate three proteins: Green fluorescent protein, maltose binding protein and the Mycobacterium tuberculosis vaccine candidate Rv1626. Conclusions: We have developed a new technique for easy production and purification of recombinant proteins. This technique is capable of producing and purifying high yields of proteins suitable for research application in less than 2 days. No costly or specialized protein chromatography equipment, resins, reagents or expertise are required.Full Tex

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland