Development of an information management knowledge transfer framework for evidence-based occupational therapy

Purpose - Digital technology has changed how people interact with information and each other. Being able to access and share information ensures healthcare practitioners can keep abreast of new and ever changing information and improve services. The purpose of this paper is to present an Information Management - Knowledge Transfer (IM-KT) Framework which emerged from a study looking at digital literacy in the occupational therapy profession. Design/methodology/approach - The research was undertaken in three stages. First an in-depth literature review was undertaken, which enabled the creation of an initial conceptual framework which in turn, informed the second stage of the research: the development of a survey about the use of digital technologies. Occupational therapy students, academics and practitioners across five different countries completed the survey, after which refinements to the framework were made. The IM-KT framework presented in this paper emerged as a result of the third stage of the study, which was completed using the Delphi technique where 18 experts were consulted over four rounds of qualitative questionnaires. Findings - The IM-KT framework assists individuals and groups to better understand how information management and knowledge transfer occurs. The framework highlights the central role of information literacy and digital literacy and the influence of context on knowledge transfer activities. Originality/value - The IM-KT framework delineates clearly between information and knowledge and demonstrates the essential role of information literacy and digital literacy in the knowledge era. This framework was developed for the occupational therapy profession and may be applicable to other professions striving to keep up to date with best evidence

Lysosome Morphology, Exocytosis and Immunity

Many types of immune cells rely on secretory lysosomes to execute their function. These specialised organelles perform the catabolic function of conventional lysosomes and possess the added capacity to undergo regulated exocytosis. In particular, the cytotoxic function of natural killer (NK) cells depends on the rapid, polarised secretion of secretory lysosomes, known as lytic granules, for the targeted destruction of malignant and virally infected cells. Dysregulation of the biogenesis and exocytosis of secretory lysosomes is the cause of several severe immunological diseases such as Chédiak-Higashi syndrome (CHS). In CHS, mutations in the LYST gene result in enlarged secretory lysosomes that cannot undergo exocytosis. However, the mechanisms underlying LYST function remain elusive. Here, characterisation of the giant lysosome phenotype of beige cells reveals altered phosphoinositide metabolism and increased autophagy, indicating a potential role for LYST in regulating these pathways. Furthermore, RNA interference of LYST recapitulated the giant lysosome phenotype, suggesting a strategy for analysis of the pathways in which LYST functions. Pharmacological inhibition of the phosphoinositide kinase PIKfyve induces a giant vesicle phenotype resembling that in beige cells. However, on further analysis PIKfyve inhibition was shown to induce giant endosomes as opposed to the giant lysosomes found in beige cells. Despite these differences, PIKfyve inhibition, like LYST mutations, reduced NK cell granule exocytosis at a late stage in the pathway. Thus, LYST and PIKfyve act upon different intracellular compartments but inhibit the formation and exocytosis of NK cell granules. These results extend our knowledge of the exocytosis of secretory lysosomes within the immune system and suggest future strategies to define the pathways by which lysosomal biogenesis and exocytosis is regulated

Development of an in vitro cytotoxicity model for aerosol exposure using 3D reconstructed human airway tissue; application for assessment of e-cigarette aerosol

AbstractDevelopment of physiologically relevant test methods to analyse potential irritant effects to the respiratory tract caused by e-cigarette aerosols is required. This paper reports the method development and optimisation of an acute in vitro MTT cytotoxicity assay using human 3D reconstructed airway tissues and an aerosol exposure system. The EpiAirway™ tissue is a highly differentiated in vitro human airway culture derived from primary human tracheal/bronchial epithelial cells grown at the air–liquid interface, which can be exposed to aerosols generated by the VITROCELL® smoking robot. Method development was supported by understanding the compatibility of these tissues within the VITROCELL® system, in terms of airflow (L/min), vacuum rate (mL/min) and exposure time. Dosimetry tools (QCM) were used to measure deposited mass, to confirm the provision of e-cigarette aerosol to the tissues. EpiAirway™ tissues were exposed to cigarette smoke and aerosol generated from two commercial e-cigarettes for up to 6h. Cigarette smoke reduced cell viability in a time dependent manner to 12% at 6h. E-cigarette aerosol showed no such decrease in cell viability and displayed similar results to that of the untreated air controls. Applicability of the EpiAirway™ model and exposure system was demonstrated, showing little cytotoxicity from e-cigarette aerosol and different aerosol formulations when compared directly with reference cigarette smoke, over the same exposure time

The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

The cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, levels of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts have been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis

Sustainable food consumption across Western and Non-Western cultures: A scoping review considering the theory of planned behaviour

The theory of planned behaviour (TPB) states that food consumption is preceded by an intention, which is shaped by behavioural beliefs and attitudes. To mitigate criticism of the TPB's lack of cultural context, researchers have tested extended models with culturally specific variables included. This scoping review maps the use of the extended TPB across Western and Non-Western cultures in the context of sustainable food consumption, which includes meat consumption, food waste and organic food purchases. 3924 abstracts and 241 articles were screened. The final review included 95 articles. The number of Western and Non-Western studies was similar, but sample sizes were larger in Western cultures. Generally, the inclusion of culturally specific variables improved models that predicted organic food purchases and food waste, but not for meat consumption. The current findings highlight a lack of consensus regarding the selection of culturally specific variables. Instead, future cross-cultural research that explores similar factors could facilitate the development of a universal model of sustainable food. This model is required to drive a global approach towards encouraging sustainable diets. Incorporating cultural nuances and targeting common core values and attitudes may improve generalisability and efficacy of subsequent interventions that target sustainable food consumption across cultures

Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness

Background. Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo- and radio-therapy. A deeper understanding of the mechanisms invoked by GMB to infiltrate the brain is needed to develop approaches to contain the disease and reduce recurrence. The aim of this study was to discover mechanisms through which extracellular vesicles (EVs) released by GBM influence the brain microenvironment to facilitate infiltration, and to determine how altered extracellular matrix (ECM) deposition by glial cells might contribute to this. Methods. CRISPR was used to delete genes, previously established to drive carcinoma invasiveness and EV production, from patient-derived primary and GBM cell lines. We purified and characterised EVs released by these cells, assessed their capacity to foster pro-migratory microenvironments in mouse brain slices, and evaluated the contribution made by astrocyte-derived extracellular matrix (ECM) to this. Finally, we determined how CRISPR-mediated deletion of genes, which we had found to control EV-mediated communication between GBM cells and astrocytes, influenced GBM infiltration when orthotopically injected into CD1-nude mice. Results. GBM cells expressing a p53 mutant (p53 273H) with established pro-invasive gain-of-function release EVs containing a sialomucin, podocalyxin (PODXL), which encourages astrocytes to deposit ECM with increased levels of hyaluronic acid (HA). This HA-rich ECM, in turn, promotes migration of GBM cells. Consistently, CRISPR-mediated deletion of PODXL opposes infiltration of GBM in vivo. Conclusions This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue. Conclusions. This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue

Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion

Signals are relayed from receptor tyrosine kinases (RTKs) at the cell surface to effector systems in the cytoplasm and nucleus, and coordination of this process is important for the execution of migratory phenotypes, such as cell scattering and invasion. The endosomal system influences how RTK signalling is coded, but the ways in which it transmits these signals to the nucleus to influence gene expression are not yet clear. Here we show that hepatocyte growth factor, an activator of MET (an RTK), promotes Rab17- and clathrin-dependent endocytosis of EphA2, another RTK, followed by centripetal transport of EphA2-positive endosomes. EphA2 then mediates physical capture of endosomes on the outer surface of the nucleus; a process involving interaction between the nuclear import machinery and a nuclear localisation sequence in EphA2’s cytodomain. Nuclear capture of EphA2 promotes RhoG-dependent phosphorylation of the actin-binding protein, cofilin to oppose nuclear import of G-actin. The resulting depletion of nuclear G-actin drives transcription of Myocardin-related transcription factor (MRTF)/serum-response factor (SRF)-target genes to implement cell scattering and the invasive behaviour of cancer cells

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten BRF1 ) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten BRF1 tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Setting a baseline for global urban virome surveillance in sewage

The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective