Qualitative exploration of recovery following first episode psychosis: a grounded theory approach & Clinical research portfolio

Specialist Early Intervention (E.I.) services are becoming increasingly accepted as the most effective way of working with people experiencing first episode psychosis. Although there have been a wealth of studies looking at the clinical outcomes of E.I. services, there remains relatively little research on the subjective experiences of recovery following a first episode of psychosis (FEP). This study explored the individual’s experiences of recovery following a first episode of psychosis, in the context of a specialist E. I. Service. Grounded Theory methodology was employed to explore the individual experiences of people involved with an E.I. service. A total of 9 individuals selected from a group of E.I. service users approaching the end of their care were interviewed. Data from the transcribed interviews were analysed using Grounded Theory methodology, where themes emerged from the coding process. The study identified 7 key themes: Build Up of experiences, Awareness, Acceptance, Shame, Family and Friends, Loss and Re-building. Themes were often expressed as continuums and all appeared to overlap. This study provided an initial understanding of the predominant experiences of recovery following FEP for E.I. service-users. Future research might consider the experiences of those in other service settings

Pupils' use of visual mathematical problem solving strategies

An exploration of how the Y1 children used visualisation to understand and work through activities involving telling the time to the hour. The Year 1 class had been exposed to some formal mathematical methods, but were encouraged to explore and present problems in their own ways during carpet discussions. The aim was to find out whether the children would choose to present their ideas visually if provided with the opportunity and resources with which to do so

Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis.

During epithelial ovarian cancer (EOC) progression, intraperitoneally disseminating tumor cells and multicellular aggregates (MCAs) present in ascites fluid adhere to the peritoneum and induce retraction of the peritoneal mesothelial monolayer prior to invasion of the collagen-rich submesothelial matrix and proliferation into macro-metastases. Clinical studies have shown heterogeneity among EOC metastatic units with respect to cadherin expression profiles and invasive behavior; however, the impact of distinct cadherin profiles on peritoneal anchoring of metastatic lesions remains poorly understood. In the current study, we demonstrate that metastasis-associated behaviors of ovarian cancer cells and MCAs are influenced by cellular cadherin composition. Our results show that mesenchymal N-cadherin-expressing (Ncad+) cells and MCAs invade much more efficiently than E-cadherin-expressing (Ecad+) cells. Ncad+ MCAs exhibit rapid lateral dispersal prior to penetration of three-dimensional collagen matrices. When seeded as individual cells, lateral migration and cell-cell junction formation precede matrix invasion. Neutralizing the Ncad extracellular domain with the monoclonal antibody GC-4 suppresses lateral dispersal and cell penetration of collagen gels. In contrast, use of a broad-spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) to block endogenous membrane type 1 matrix metalloproteinase (MT1-MMP) activity does not fully inhibit cell invasion. Using intact tissue explants, Ncad+ MCAs were also shown to efficiently rupture peritoneal mesothelial cells, exposing the submesothelial collagen matrix. Acquisition of Ncad by Ecad+ cells increased mesothelial clearance activity but was not sufficient to induce matrix invasion. Furthermore, co-culture of Ncad+ with Ecad+ cells did not promote a 'leader-follower' mode of collective cell invasion, demonstrating that matrix remodeling and creation of invasive micro-tracks are not sufficient for cell penetration of collagen matrices in the absence of Ncad. Collectively, our data emphasize the role of Ncad in intraperitoneal seeding of EOC and provide the rationale for future studies targeting Ncad in preclinical models of EOC metastasis

HYDROGEN BONDING IN betabeta-NITRO ALCOHOLS. III. PYRIDINE COMPLEXES

BETA -Nitro alcohols form stable 1:1 complexes with pyridine, examples of which were prepared. In solvents such as dichloromethane and carbon tetrachloride the complexes partially dissociate into their components. The dissociation constants for the equilibria were determined by infrared methods and may be used as a measure of the strength of the complex hydrogen bond. The dissociation constants decrease with increasing number of BETA -nitro groups. Some reactions of the pyridine complexes are described. (auth

Enhancing the magneto-optical Kerr effect through the use of a plasmonic antenna (article)

This is the final version of the article. Available from Optical Society of America via the DOI in this record.The dataset associated with this article is located in ORE at: http://hdl.handle.net/10871/31354We employ an extended finite-element model as a design tool capable of incorporating the interaction between plasmonic antennas and magneto-optical effects, specifically the magneto-optical Kerr effect (MOKE). We first test our model in the absence of an antenna and show that for a semi-infinite thin-film, good agreement is obtained between our finite-element model and analytical calculations. The addition of a plasmonic antenna is shown to yield a wavelength dependent enhancement of the MOKE. The antenna geometry and its separation from the magnetic material are found to impact the strength of the observed MOKE signal, as well as the antenna's resonance wavelength. Through optimization of these parameters we achieved a MOKE enhancement of more than 100 when compared to a magnetic film alone. These initial results show that our modeling methodology offers a tool to guide the future fabrication of hybrid plasmonic magneto-optical devices and plasmonic antennas for magneto-optical sensing.UK Engineering and Physical Science Research Council (EPSRC) (EP/1038470/I

Translational autoregulation of BZW1 and BZW2 expression by modulating the stringency of start codon selection.

The efficiency of start codon selection during ribosomal scanning in eukaryotic translation initiation is influenced by the context or flanking nucleotides surrounding the AUG codon. The levels of eukaryotic translation initiation factors 1 (eIF1) and 5 (eIF5) play critical roles in controlling the stringency of translation start site selection. The basic leucine zipper and W2 domain-containing proteins 1 and 2 (BZW1 and BZW2), also known as eIF5-mimic proteins, are paralogous human proteins containing C-terminal HEAT domains that resemble the HEAT domain of eIF5. We show that translation of mRNAs encoding BZW1 and BZW2 homologs in fungi, plants and metazoans is initiated by AUG codons in conserved unfavorable initiation contexts. This conservation is reminiscent of the conserved unfavorable initiation context that enables autoregulation of EIF1. We show that overexpression of BZW1 and BZW2 proteins enhances the stringency of start site selection, and that their poor initiation codons confer autoregulation on BZW1 and BZW2 mRNA translation. We also show that overexpression of these two proteins significantly diminishes the effect of overexpressing eIF5 on stringency of start codon selection, suggesting they antagonize this function of eIF5. These results reveal a surprising role for BZW1 and BZW2 in maintaining homeostatic stringency of start codon selection, and taking into account recent biochemical, genetic and structural insights into eukaryotic initiation, suggest a model for BZW1 and BZW2 function

A platform for time-resolved scanning Kerr microscopy in the near-field

This is the author accepted manuscript. The final version is available from AIP Publishing via the DOI in this record.Time-resolved scanning Kerr microscopy (TRSKM) is a powerful technique for the investigation of picosecond magnetization dynamics at sub-micron length scales by means of the magneto-optical Kerr effect (MOKE). The spatial resolution of conventional (focused) Kerr microscopy using a microscope objective lens is determined by the optical diffraction limit so that the nanoscale character of the magnetization dynamics is lost. Here we present a platform to overcome this limitation by means of a near-field TRSKM that incorporates an atomic force microscope (AFM) with optical access to a metallic AFM probe with a nanoscale aperture at its tip. We demonstrate the near-field capability of the instrument through the comparison of time-resolved polar Kerr images of magnetization dynamics within a microscale NiFe rectangle acquired using both near-field and focused TRSKM techniques at a wavelength of 800 nm. The flux-closure domain state of the in-plane equilibrium magnetization provided the maximum possible dynamic polar Kerr contrast across the central domain wall and enabled an assessment of the magneto-optical spatial resolution of each technique. Line profiles extracted from the Kerr images demonstrate that the near-field spatial resolution was enhanced with respect to that of the focused Kerr images. Furthermore, the near-field polar Kerr signal (∼1 mdeg) was more than half that of the focused Kerr signal, despite the potential loss of probe light due to internal reflections within the AFM tip. We have confirmed the near-field operation by exploring the influence of the tip-sample separation and have determined the spatial resolution to be ∼550 nm for an aperture with a sub-wavelength diameter of 400 nm. The spatial resolution of the near-field TRSKM was in good agreement with finite element modeling of the aperture. Large amplitude electric field along regions of the modeled aperture that lie perpendicular to the incident polarization indicate that the aperture can support plasmonic excitations. The comparable near-field and focused polar Kerr signals suggest that such plasmonic excitations may lead to an enhanced near-field MOKE. This work demonstrates that near-field TRSKM can be performed without significant diminution of the polar Kerr signal in relatively large, sub-wavelength diameter apertures, while development of a near-field AFM probe utilizing plasmonic antennas specifically designed for measurements deeper into the nanoscale is discussed.The authors gratefully acknowledge the financial support of the UK Engineering and Physical Sciences Research Council under Grant No. EP/I038470/1 “A plasmonic antenna for magneto-optical imaging at the deep nanoscale.

Insights into the mechanisms of eukaryotic translation gained with ribosome profiling

The development of Ribosome Profiling (RiboSeq) has revolutionized functional genomics. RiboSeq is based on capturing and sequencing of the mRNA fragments enclosed within the translating ribosome and it thereby provides a â snapshotâ of ribosome positions at the transcriptome wide level. Although the method is predominantly used for analysis of differential gene expression and discovery of novel translated ORFs, the RiboSeq data can also be a rich source of information about molecular mechanisms of polypeptide synthesis and translational control. This review will focus on how recent findings made with RiboSeq have revealed important details of the molecular mechanisms of translation in eukaryotes. These include mRNA translation sensitivity to drugs affecting translation initiation and elongation, the roles of upstream ORFs in response to stress, the dynamics of elongation and termination as well as details of intrinsic ribosome behavior on the mRNA after translation termination. As the RiboSeq method is still at a relatively early stage we will also discuss the implications of RiboSeq artifacts on data interpretation

TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response

Translation initiation is the rate-limiting step of protein synthesis that is downregulated during the Integrated Stress Response (ISR). Previously, we demonstrated that most human mRNAs that are resistant to this inhibition possess translated upstream open reading frames (uORFs), and that in some cases a single uORF is sufficient for the resistance. Here we developed a computational model of Initiation Complexes Interference with Elongating Ribosomes (ICIER) to gain insight into the mechanism. We explored the relationship between the flux of scanning ribosomes upstream and downstream of a single uORF depending on uORF features. Paradoxically, our analysis predicts that reducing ribosome flux upstream of certain uORFs increases initiation downstream. The model supports the derepression of downstream translation as a general mechanism of uORF-mediated stress resistance. It predicts that stress resistance can be achieved with long slowly decoded uORFs that do not favor translation reinitiation and that start with initiators of low leakiness

Design and fabrication of plasmonic cavities for magneto-optical sensing (article)

This is the author accepted manuscript. The final version is available from AIP Publishing via the DOI in this record.The dataset associated with this article is located in ORE at: http://hdl.handle.net/10871/32604The design and fabrication of a novel plasmonic cavity, intended to allow far-field recovery of signals arising from near field magneto-optical interactions, is presented. Finite element modeling is used to describe the interaction between a gold film, containing cross-shaped cavities, with a nearby magnetic under-layer. The modeling revealed strong electric field confinement near the center of the cross structure for certain optical wavelengths, which may be tuned by varying the length of the cross through a range that is compatible with available fabrication techniques. Furthermore, the magneto optical Kerr effect (MOKE) response of the composite structure can be enhanced with respect to that of the bare magnetic film. To confirm these findings, cavities were milled within gold films deposited upon a soluble film, allowing relocation to a ferromagnetic film using a float transfer technique. Cross cavity arrays were fabricated and characterized by optical transmission spectroscopy prior to floating, revealing resonances at optical wavelengths in good agreement with the finite element modeling. Following transfer to the magnetic film, circular test apertures within the gold film yielded clear magneto-optical signals even for diameters within the sub-wavelength regime. However, no magneto-optical signal was observed for the cross cavity arrays, since the FIB milling process was found to produce nanotube structures within the soluble under-layer that adhered to the gold. Further optimization of the fabrication process should allow recovery of magneto-optical signal from cross cavity structures.Financial support from the UK Engineering and Physical Science Research Council (EPSRC) grants EP/1038470/I and EP/1038411/1 is gratefully acknowledged. We also acknowledge the support of Seagate Technology (Ireland) under SOW 00077300.0. RMB contribution to project was supported by the Royal Academy of Engineering under the Research Chairs and Senior Research Fellowships Scheme