Distinct phosphorylation clusters determines the signalling outcome of the free fatty acid receptor FFA4/GPR120

It is established that long-chain free fatty acids including ω-3 fatty acids mediate an array of biological responses through members of the free fatty acid receptor family, which includes FFA4. However, the signalling mechanisms and modes of regulation of this receptor class remain unclear. Here we employ mass spectrometry to determine that phosphorylation of mouse (m)FFAR4 occurs at five serine and threonine residues clustered in two separable regions of the C terminal tail, designated cluster 1 (Thr347, Thr349 and Ser350) and cluster 2 (Ser357 and Ser361). Mutation of these phospho-acceptor sites to alanine completely prevented phosphorylation of mFFA4 but did not limit receptor coupling to ERK1/2 activation. Rather an inhibitor of Gq/11 proteins completely prevented receptor signalling to ERK1/2. In contrast, the recruitment of arrestin 3, receptor internalization and activation of Akt were regulated by mFFA4 phosphorylation. The analysis of mFFA4 phosphorylation-dependent signalling was extended further by selective mutations of the phospho-acceptor sites. Mutations within cluster 2 did not affect agonist activation of Akt but instead significantly compromised receptor internalization and arrestin 3 recruitment. Distinctly, mutation of the phospho-acceptor sites within cluster 1 had no effect on receptor internalization and a less extensive effect on arrestin 3 recruitment, but significantly uncoupled the receptor from Akt activation. These unique observations define differential effects on signalling mediated by phosphorylation at distinct locations. This hallmark feature supports the possibility that the signalling outcome of mFFA4 activation can be determined by the pattern of phosphorylation (phosphorylation barcode) at the C-terminus of the receptor

The evaluation of brine prospects and the requirement for modifications to filing standards

The recent increase in demand for lithium has led to the development of new brine prospects, particularly in the Central Andes. The brines are hosted in closed basin aquifers of two types: mature, halite dominant, and immature, clastic dominant. The estimate of elemental resources in these salars depends on a detailed knowledge of aquifer geometry, porosity, and brine grade. The geometry of the aquifers can be evaluated by classical geophysical and drilling techniques, but because the resource is a fluid, with the attendant problems of in-aquifer mixing and reorganization, existing codes for filing resource and reserve estimates need modification. Total porosity is relatively straightforward to measure, but effective porosity and specific yield, which are required to estimate the resource, are more difficult. Recovery factors are low compared with most metalliferous and industrial mineral deposits due to reliance on pumping of the brine from wells for extraction. These and related issues lead us to believe that modifications to the existing standards for reporting mineral resources and reserves are required for these prospects

The UK Cardiac and Vascular Surgery Interventional Anaemia Response (CAVIAR) Study: protocol for an observational cohort study to determine the impact and effect of preoperative anaemia management in cardiac and vascular surgical patients.

INTRODUCTION: Preoperative anaemia is linked to poor postsurgical outcome, longer hospital stays, greater risk of complications and mortality. Currently in the UK, some sites have developed anaemia clinics or pathways that use intravenous iron to correct iron deficiency anaemia prior to surgery as their standard of care. Although intravenous iron has been observed to be effective in a variety of patient settings, there is insufficient evidence in its use in cardiac and vascular patients. The aim of this study is to observe the impact and effect of anaemia and its management in patients undergoing cardiac and vascular surgery. In addition, the UK Cardiac and Vascular Surgery Interventional Anaemia Response (CAVIAR) Study is also a feasibility study with the aim to establish anaemia management pathways in the preoperative setting to inform the design of future randomised controlled trials. METHODS AND ANALYSIS: The UK CAVIAR Study is a multicentre, stepped, observational study, in patients awaiting major cardiac or vascular surgery. We will be examining different haematological variables (especially hepcidin), functional capacity and patient outcome. Patients will be compared based on their anaemia status, whether they received intravenous iron in accordance to their hospital's preoperative pathway, and their disease group. The primary outcomes are the change in haemoglobin levels from baseline (before treatment) to before surgery; and the number of successful patients recruited and consented (feasibility). The secondary outcomes will include changes in biomarkers of iron deficiency, length of stay, quality of life and postoperative recovery. ETHICS AND DISSEMINATION: The study protocol was approved by the London-Westminster Research Ethics Committee (15/LO/1569, 27 November 2015). NHS approval was also obtained with each hospital trust. The findings of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Clinical Trials registry (NCT02637102) and the ISRCTN registry (ISRCTN55032357)

Groundwater in Cretaceous carbonates: KG@B field trip 21st June 2015

The Upper Cretaceous Chalk of southern England is the UK’s most important aquifer, providing more than 75% of the public supply for southeast England, including London. The aquifer also sustains rivers and wetlands, and their associated groundwater dependent ecosystems. However, the aquifer is facing a multitude of threats including over-abstraction, nitrate pollution, and climate change. The Chalk is a complex aquifer in which groundwater flow is through the matrix, fractures and karstic dissolutional voids. The Chalk matrix has a porosity of around 35% (Bloomfield et al., 1995). The matrix is thought to provide an important contribution to storage, although the size of the pore throats is very small, and therefore the permeability is very low (Price et al., 1993). The average permeability of 977 core samples was only 6.3 x 10-4 m/day (Allen et al., 1997). The matrix is particularly important in solute transport, because solutes move between the matrix and the more permeable parts of the aquifer via diffusion (Foster 1975). The unmodified fracture network provides an important contribution to storage and flow, and has a hydraulic conductivity of about 0.1 m/d, and a transmissivity of about 20 m2/day (Price, 1987). However, it is the dissolutionally enlarged fissures and conduits that make the Chalk such a good aquifer. The median transmissivity from 2100 pumping tests is 540 m2/day, and the 25th and 75th percentiles are 190 and 1500 m2/day respectively (MacDonald and Allen, 2001). Borehole packer testing, logging and imaging have shown that most of this transmissivity comes from a small number of dissolutional voids (e.g. Tate et al., 1970; Schurch and Buckley, 2002). Laterally extensive lithostratigraphical horizons including marl seams, bedding planes, sheet and tabular flint bands, and hard-grounds have an important influence on these groundwater flows. They are all horizons where downward percolation of water may be impeded. Dissolution often occurs where flow is concentrated along these horizons, creating conduits or fissures, especially where they are intersected by joint sets

Antimicrobial treatment improves mycobacterial survival in nonpermissive growth conditions

Antimicrobials targeting cell wall biosynthesis are generally considered inactive against nonreplicating bacteria. Paradoxically, we found that under nonpermissive growth conditions, exposure of Mycobacterium bovis BCG bacilli to such antimicrobials enhanced their survival. We identified a transcriptional regulator, RaaS (for regulator of antimicrobial-assisted survival), encoded by bcg1279 (rv1219c) as being responsible for the observed phenomenon. Induction of this transcriptional regulator resulted in reduced expression of specific ATP-dependent efflux pumps and promoted long-term survival of mycobacteria, while its deletion accelerated bacterial death under nonpermissive growth conditions in vitro and during macrophage or mouse infection. These findings have implications for the design of antimicrobial drug combination therapies for persistent infectious diseases, such as tuberculosis

The effectiveness of functional family therapy in substance-involved family preservation clients

Abuse and neglect of children has been a recognized problem in America for many years. Recent developments in the child welfare system have introduced intensive, family-based services, otherwise known as family preservation services. The aim is to preserve the family and provide reasonable efforts to avoid out of home placement. State and private family preservation programs across the country have been faced with the challenge of evaluating program effectiveness and to better meet the needs of client populations by enhancing treatment models and programs; The Nevada State Division of Child and Family Services (DCFS) has utilized valuable resources to evaluate their Intensive Family Preservation (IFP) service program to discover its effectiveness. The program has been the subject of a longitudinal study. Research data from the 1999 fiscal year was used to examine the effectiveness of the Functional Family Therapy (FFT) model on substance-involved families. This secondary analysis discovered that the preservation services in Las Vegas are effective but that substance involved families have significantly lower outcome scores. The data revealed that substance-involved families also have larger households and less income than non-substance users

The role of Tribbles 1 and Tribbles 3 in cartilage turnover

PhD ThesisArthritis is a term which encompasses a number of diseases characterised by cartilage degradation and joint destruction which represents an enormous and growing healthcare burden. Matrix metalloproteinases (MMPs) are a family of enzymes involved in cleavage of extracellular matrix proteins. They have many roles in both development and normal tissue homeostasis. As well as this they have been shown to be important in a number of diseases, including arthritis. MMP-1 and -13 in particular have been shown to be important in arthritis, due to their ability to cleave type II collagen, a key component of cartilage. A greater understanding of the regulation of these MMPs could lead to the potential for new therapeutic arthritis treatments. Tribbles (Trb) 1-3 are a group of proteins linked with diseases including diabetes, multiple sclerosis and cancer. Trb 1-3 are reported to play a role in regulating many cellular signalling pathways, such as mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase/Akt (PI3K/Akt) and nuclear factor kappa B (NFκB). These pathways are considered important in mediating gene expression changes, including MMPs. Both Trb1 and Trb3 were shown to regulate MMPs in chondrocytes, with a greater effect being on MMP-13 regulation. Trb1 and Trb3 were both shown to regulate the major MMP transcription factor AP-1, as well as the ATF3 and NFκB transcription factors. Both Trb1 and Trb3 interacted with MAP2Ks MEK1, MKK4, MKK6 and MKK7, and in addition were shown to regulate MAPK activation, with Trb3 protein levels appearing to be affected by MAP2K levels. Trb3 also had the ability to affect both Akt and STAT activation. These data demonstrate that Trb1 and Trb3 can regulate signalling pathways that have the ability to alter MMP expression and transcription factors within chondrocytes. This would suggest that Trb1 and Trb3 have the ability to affect cartilage degradation. This greater understanding of MMP regulation by Trb1 and Trb3 may help in the development of potential future therapeutic targets for arthritic disease.Oliver Bird and Nuffield foundatio

Evidence-Based Indications of Cone Beam Computed Tomography in Children with maxillary impacted canines - A literary review

Prosjektoppgåve/masteroppgåveOD3PROSJMAOD-ODON