The EBV-encoded oncoprotein, LMP1, induces an epithelial-to-mesenchymal transition (EMT) via Its CTAR1 domain through integrin-mediated ERK-MAPK signalling

The Epstein⁻Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) epithelial cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin⁻ligand interactions: extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK-MAPK), PI3-Kinase and tyrosine kinases, but not transforming growth factor beta (TGFβ). More detailed analysis implicated the CTAR1-mediated induction of Slug and Twist in LMP1-induced EMT. A key role for β1 integrin signalling in LMP1-mediated ERK-MAPK and focal adhesion kianse (FAK) phosphorylation was observed, and β1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in disease pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype

Ecosystem approach to harvesting in the Arctic : walking the tightrope between exploitation and conservation in the Barents Sea

Funidng: This study was supported by the Changing Arctic Ocean project MiMeMo (NE/R012679/1) jointly funded by the UKRI Natural Environment Research Council (NERC) and the German Federal Ministry of Education and Research (BMBF/03F0801A). Brierley was also supported by ArcticPRIZE (NE/P005721/1).Projecting the consequences of warming and sea-ice loss for Arctic marine food web and fisheries is challenging due to the intricate relationships between biology and ice. We used StrathE2EPolar, an end-to-end (microbes-to-megafauna) food web model incorporating ice-dependencies to simulate climate-fisheries interactions in the Barents Sea. The model was driven by output from the NEMO-MEDUSA earth system model, assuming RCP 8.5 atmospheric forcing. The Barents Sea was projected to be > 95% ice-free all year-round by the 2040s compared to > 50% in the 2010s, and approximately 2 °C warmer. Fisheries management reference points (FMSY and BMSY) for demersal fish (cod, haddock) were projected to increase by around 6%, indicating higher productivity. However, planktivorous fish (capelin, herring) reference points were projected to decrease by 15%, and upper trophic levels (birds, mammals) were strongly sensitive to planktivorous fish harvesting. The results indicate difficult trade-offs ahead, between harvesting and conservation of ecosystem structure and function.Publisher PDFPeer reviewe

How is climate change affecting marine life in the Arctic?

Rising temperature is melting the ice that covers the Arctic Ocean, allowing sunlight into waters that have been dark for thousands of years. Previously barren ice-covered regions are being transformed into productive seas. Here we explain how computer modelling can be used to predict how this transformation will affect the food web that connects plankton to fish and top-predators like whales and polar bears. Images of starving polar bears have become symbolic of the effects of warming climate. Melting of the sea-ice is expected to reduce the bears’ ability to hunt for seals. However, at the same time, the food web upon which they depend is becoming more productive, so it is not completely clear what the eventual outcome will be for the bears. Computer models help us to understand these systems and inform policy decisions on the management of newly available Arctic resources

Self-reported difficulties with everyday function, cognitive symptoms, and cognitive function in people with HIV

BACKGROUND: We determined factors associated with self-reported decline in activities of daily living (ADLs) and symptoms of cognitive impairment in HIV positive (HIV+) adults in five European clinics. METHODS: HIV+ adults underwent computerized and pen-and-paper neuropsychological tests and questionnaires of cognitive symptoms and ADLs. We considered cognitive function in five domains, psychosocial factors and clinical parameters as potentially associated with symptoms. Separate regression analyses were used to determine factors associated with decline in ADL (defined as self-reported decline affecting ≥2 ADLs and attributed to cognitive difficulties) and self-reported frequency of symptoms of cognitive impairment. We also estimated the diagnostic accuracy of both questionnaires as tests for cognitive impairment. RESULTS: 448 patients completed the assessments (mean age 45.8 years, 84% male, 87% white, median CD4 count 550 cells/mm, median time since HIV diagnosis 9.9 years, 81% virologically suppressed [HIV-1 plasma RNA <50 copies/mL]). Ninety-six (21.4%) reported decline in ADLs and attributed this to cognitive difficulties. Self-reported decline in ADLs and increased symptoms of cognitive impairment were both associated with worse performance on some cognitive tests. There were also strong associations with financial difficulties, depressive and anxiety symptoms, unemployment, and longer time since HIV diagnosis. Both questionnaires performed poorly as diagnostic tests for cognitive impairment. CONCLUSION: Patients' own assessments of everyday function and symptoms were associated with objectively-measured cognitive function. However, there were strong associations with other psychosocial issues including mood and anxiety disorders and socioeconomic hardship. This should be considered when assessing HIV-associated cognitive impairment in clinical care or research studies

The Epstein-Barr virus encoded LMP1 oncoprotein modulates cell adhesion via regulation of activin A/TGFβ and β1 integrin signalling

Approximately 20% of global cancer incidence is causally linked to an infectious agent. EpsteinBarr virus (EBV) accounts for around 1% of all virus-associated cancers and is associated with nasopharyngeal carcinoma (NPC). Latent membrane protein 1 (LMP1), the major oncoprotein encoded by EBV, behaves as a constitutively active tumour necrosis factor (TNF) receptor activating a variety of signalling pathways, including the three classic MAPKs (ERK-MAPK, p38 MAPK and JNK/SAPK). The present study identifes novel signalling properties for this integral membrane protein via the induction and secretion of activin A and TGFβ1, which are both required for LMP1’s ability to induce the expression of the extracellular matrix protein, fbronectin. However, it is evident that LMP1 is unable to activate the classic Smad-dependent TGFβ signalling pathway, but rather elicits its efects through the non-Smad arm of TGFβ signalling. In addition, there is a requirement for JNK/SAPK signalling in LMP1-mediated fbronectin induction. LMP1 also induces the expression and activation of the major fbronectin receptor, α5β1 integrin, an efect that is accompanied by increased focal adhesion formation and turnover. Taken together, these fndings support the putative role for LMP1 in the pathogenesis of NPC by contributing to the metastatic potential of epithelial cells

Multi-technique investigation of the binary fraction among A-F type candidate hybrid variable stars discovered by Kepler

Hundreds of candidate hybrid pulsators of intermediate type A-F were revealed by the recent space missions. Hybrid pulsators allow to study the full stellar interiors, where p- and g-modes are simultaneously excited. The true hybrid stars must be identified since other processes, due to stellar multiplicity or rotation, might explain the presence of (some) low frequencies observed in their periodograms. We measured the radial velocities of 50 candidate Delta Sct - Gamma Dor hybrid stars from the Kepler mission with the Hermes/Ace spectrographs over a span of months to years. We aim to derive the fraction of binary and multiple systems and to provide an independent and homogeneous determination of the atmospheric properties and vsini for all targets. The objective is to identify the physical cause of the low frequencies. We computed 1-D cross-correlation functions (CCFs) in order to find the best parameters in terms of the number of components, spectral type and vsini for each target. Radial velocities were measured from spectrum synthesis and by using a 2-D cross-correlation technique in the case of double- and triple-lined systems. Fundamental parameters were determined by fitting (composite) synthetic spectra to the normalised median spectra corrected for the appropriate Doppler shifts. We report on the analysis of 478 high-resolution Hermes and 41 Ace spectra of A/F-type candidate hybrid pulsators from the Kepler field. We determined their radial velocities, projected rotational velocities, atmospheric properties and classified our targets based on the shape of the CCFs and the temporal behaviour of the radial velocities. We derived orbital solutions for seven new systems. Three long-period preliminary orbital solutions are confirmed by a photometric time-delay analysis. Finally, we determined a global multiplicity fraction of 27% in our sample of candidate hybrid stars

A rehabilitation intervention to improve recovery after an episode of delirium in adults over 65 years (RecoverED): study protocol for a multi-centre, single-arm feasibility study

Background: Delirium affects over 20% of all hospitalised older adults. Delirium is associated with a number of adverse outcomes following hospital admission including cognitive decline, anxiety and depression, increased mortality and care needs. Previous research has addressed prevention of delirium in hospitals and care homes, and there are guidelines on short-term treatment of delirium during admission. However, no studies have addressed the problem of longer-term recovery after delirium and it is currently unknown whether interventions to improve recovery after delirium are effective and cost-effective. The primary objective of this feasibility study is to test a new, theory-informed rehabilitation intervention (RecoverED) in older adults delivered following a hospital admission complicated by delirium to determine whether (a) the intervention is acceptable to individuals with delirium and (b) a definitive trial and parallel economic evaluation of the intervention are feasible. Methods: The study is a multi-centre, single-arm feasibility study of a rehabilitation intervention with an embedded process evaluation. Sixty participants with delirium (aged > 65 years old) and carer pairs will be recruited from six NHS acute hospitals across the UK. All pairs will be offered the intervention, with follow-up assessments conducted at 3 months and 6 months post-discharge home. The intervention will be delivered in participants’ own homes by therapists and rehabilitation support workers for up to 10 intervention sessions over 12 weeks. The intervention will be tailored to individual needs, and the chosen intervention plan and goals will be discussed and agreed with participants and carers. Quantitative data on reach, retention, fidelity and dose will be collected and summarised using descriptive statistics. The feasibility outcomes that will be used to determine whether the study meets the criteria for progression to a definitive randomised controlled trial (RCT) include recruitment, delivery of the intervention, retention, data collection and acceptability of outcome measures. Acceptability of the intervention will be assessed using in-depth, semi-structured qualitative interviews with participants and healthcare professionals. Discussion: Findings will inform the design of a pragmatic multi-centre RCT of the effectiveness and cost-effectiveness of the RecoverED intervention for helping the longer-term recovery of people with delirium compared to usual care. Trial registration: The feasibility study was registered: ISRCTN1567657

Common and low frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients