Gastrin-induced miR-222 promotes gastric tumor development by suppressing p27kip1

Background and aims Elevated circulating concentrations of the hormone gastrin contribute to the development of gastric adenocarcinoma and types-1 and 2 gastric neuroendocrine tumors (NETs). MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate proteins which in turn influence various biological processes. We hypothesised that gastrin induces the expression of specific gastric miRNAs within CCK2 receptor (CCK2R) expressing cells and that these mediate functionally important actions of gastrin.Results Gastrin increased miR-222 expression in AGSGR cells, with maximum changes observed at 10 nM G17 for 24 h. Signalling occurred via CCK2R and the PKC and PI3K pathways. miR-222 expression was increased in the serum and gastric corpus mucosa of hypergastrinemic INS-GAS mice and hypergastrinemic patients with autoimmune atrophic gastritis and type 1 gastric NETs; it decreased in patients following treatment with the CCK2R antagonist netazepide (YF476). Gastrin-induced miR-222 overexpression resulted in reduced expression and cytoplasmic mislocalisation of p27kip1, which in turn caused actin remodelling and increased migration in AGSGR cells. Materials and methods miRNA PCR arrays were used to identify changes in miRNA expression following G17 treatment of human gastric adenocarcinoma cells stably transfected with CCK2R (AGSGR). miR-222 was further investigated using primer assays and samples from hypergastrinemic mice and humans. Chemically synthesised mimics and inhibitors were used to assess cellular phenotypical changes associated with miR-222 dysregulation.Conclusions These data indicate a novel mechanism contributing to gastrin-associated gastric tumor development. miR-222 may also be a promising biomarker for monitoring gastrin induced premalignant changes in the stomach

A systematic review and meta-synthesis of the impact of low back pain on people's lives

Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives. Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach. Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly. Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U

Structure–properties relationships in fibre drawing of bioactive phosphate glasses

New bioactive phosphate glasses suitable for continuous fibre production are investigated in this work. The structure of both bulk and fibres from Na2O–CaO–MgO–P2O5 glasses has been studied by means of Raman and 31P and 23Na nuclear magnetic resonance spectroscopies, and the structural results have been correlated with the mechanical properties of the fibres and the dissolution rate of the bulk glasses. It has been observed that the mechanical properties of the phosphate glass fibres are influenced by the glass network connectivity, while the dissolution rates are governed by the Qi speciation of the PO4 units. As seen in previous studies, molar volume seems to play an important role in the fragility behaviour of phosphate glasses. Here, a lower molar volume resulting from the increase in the oxygen packing density hinders the cooperative flow of the PO4 units throughout the glass network and, therefore, causes a reduction in the kinetic fragility

Identification of 24 new microsatellite loci in the sweat bee Lasioglossum malachurum (Hymenoptera: Halictidae)

OBJECTIVE: The objective here is to identify highly polymorphic microsatellite loci for the Palaearctic sweat bee Lasioglossum malachurum. Sweat bees (Hymenoptera: Halictidae) are widespread pollinators that exhibit an unusually large range of social behaviours from non-social, where each female nests alone, to eusocial, where a single queen reproduces while the other members of the colony help to rear her offspring. They thus represent excellent models for understanding social evolution. RESULTS: 24 new microsatellite loci were successfully optimized. When amplified across 23-40 unrelated females, the number of alleles per locus ranged from 3 to 17 and the observed heterozygosities 0.45 to 0.95. Only one locus showed evidence of significant deviation from Hardy-Weinberg equilibrium. No evidence of linkage disequilibrium was found. These 24 loci will enable researchers to gain greater understanding of colony relationships within this species, an important model for the study of eusociality. Furthermore, 22 of the same loci were also successfully amplified in L. calceatum, suggesting that these loci may be useful for investigating the ecology and evolution of sweat bees in general

Genotypic characterisation and cluster analysis of Campylobacter jejuni isolates from domestic pets, human clinical cases and retail food

The genetic similarity of Campylobacter jejuni isolates from pets, compared to human clinical cases and retail food isolates collected in Ireland over 2001-2006 was investigated by cluster analysis of pulsed-field gel electrophoresis (PFGE) fingerprinting profiles. Comparison of the PFGE profiles of 60 pet isolates and 109 human isolates revealed that seven (4.1%) profiles were grouped in clusters including at least one human and one pet C. jejuni isolate. In total six (1.6%) of 60 pet and 310 food profiles were in clusters with at least one food and one pet C. jejuni isolate. The detection of only a small number of genetically indistinguishable isolates by PFGE profile cluster analysis from pets and from humans with enteritis in this study suggests that pets are unlikely to be an important reservoir for human campylobacteriosis in Ireland. However, genetically indistinguishable isolates were detected and C. jejuni from pets may circulate and may contribute to clinical infections in humans. In addition, contaminated food fed to pets may be a potential source of Campylobacter infection in pets, which may subsequently pose a risk to humans

Strong interface-induced spin-orbit coupling in graphene on WS2

Interfacial interactions allow the electronic properties of graphene to be modified, as recently demonstrated by the appearance of satellite Dirac cones in the band structure of graphene on hexagonal boron nitride (hBN) substrates. Ongoing research strives to explore interfacial interactions in a broader class of materials in order to engineer targeted electronic properties. Here we show that at an interface with a tungsten disulfide (WS2) substrate, the strength of the spin-orbit interaction (SOI) in graphene is very strongly enhanced. The induced SOI leads to a pronounced low-temperature weak anti-localization (WAL) effect, from which we determine the spin-relaxation time. We find that spin-relaxation time in graphene is two-to-three orders of magnitude smaller on WS2 than on SiO2 or hBN, and that it is comparable to the intervalley scattering time. To interpret our findings we have performed first-principle electronic structure calculations, which both confirm that carriers in graphene-on-WS2 experience a strong SOI and allow us to extract a spin-dependent low-energy effective Hamiltonian. Our analysis further shows that the use of WS2 substrates opens a possible new route to access topological states of matter in graphene-based systems.Comment: Originally submitted version in compliance with editorial guidelines. Final version with expanded discussion of the relation between theory and experiments to be published in Nature Communication

Microfabricated Physical Spatial Gradients for Investigating Cell Migration and Invasion Dynamics

We devise a novel assay that introduces micro-architectures into highly confining microchannels to probe the decision making processes of migrating cells. The conditions are meant to mimic the tight spaces in the physiological environment that cancer cells encounter during metastasis within the matrix dense stroma and during intravasation and extravasation through the vascular wall. In this study we use the assay to investigate the relative probabilities of a cell 1) permeating and 2) repolarizing (turning around) when it migrates into a spatially confining region. We observe the existence of both states even within a single cell line, indicating phenotypic heterogeneity in cell migration invasiveness and persistence. We also show that varying the spatial gradient of the taper can induce behavioral changes in cells, and different cell types respond differently to spatial changes. Particularly, for bovine aortic endothelial cells (BAECs), higher spatial gradients induce more cells to permeate (60%) than lower gradients (12%). Furthermore, highly metastatic breast cancer cells (MDA-MB-231) demonstrate a more invasive and permeative nature (87%) than non-metastatic breast epithelial cells (MCF-10A) (25%). We examine the migration dynamics of cells in the tapered region and derive characteristic constants that quantify this transition process. Our data indicate that cell response to physical spatial gradients is both cell-type specific and heterogeneous within a cell population, analogous to the behaviors reported to occur during tumor progression. Incorporation of micro-architectures in confined channels enables the probing of migration behaviors specific to defined geometries that mimic in vivo microenvironments

Incretin Receptor Null Mice Reveal Key Role of GLP-1 but Not GIP in Pancreatic Beta Cell Adaptation to Pregnancy

Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 and PC1/3 together with significant amounts of GLP-1 and GIP were detected in alpha cells. Knockout of GLP-1R abolished these islet adaptations and paradoxically decreased pancreatic insulin, GLP-1 and GIP. This was associated with abolition of normal pregnancy-induced increases in plasma GIP, L-cell numbers, and intestinal GIP and GLP-1 stores. These data indicate that GLP-1 but not GIP is a key mediator of beta cell mass expansion and related adaptations in pregnancy, triggered in part by generation of intra-islet GLP-1