Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-Y Response to Viral Infection

Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN- and IFN- (IFN-/) have been established, their immunoregulatory functions, especially their ability to regulate IFN- production, are poorly understood. Here we show that IFN-/ activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN- production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-/ induction of IFN-. Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs.

'Dare the boist'rous main': the role of the Belfast Newsletter in the process of emigration from Ulster to North America 1760-1800

Before the mass migrations from Ireland in the nineteenth century, earlier waves of migration in the eighteenth century saw significant numbers of people leave Ireland, predominantly from Ulster, to settle in North America. This article, using as its principal data source the Belfast News Letter ( BNL), its letters, advertisements and reports, focuses firstly on reconstructing the late eighteenth-century migration process and voyage, highlighting the barriers represented by the Atlantic Ocean. In addition to the challenges of the sea, there were problems with the ships, the ever-present danger of disease and also threats from other vessels, from privateers to press gangs. The voyage was recognized as a ‘universal dread’, and the risks taken to ‘dare the boist’rous main’ were perhaps not minimized in the pages of the BNL, whose editorial stance was antipathetic to the migration for the potential harm it caused to Ulster by removing so many of its industrious young. The second part of this article goes on to consider the newspaper’s and others’ vested interests in the emigration process, demonstrates how these were manifested in the press and sets the coverage of this very significant early emigration flow within the context of contemporary religious and colonial discourses at a period of very lively transatlantic interactions.

The “re-socialization” of Gypsy women in the literacy courses aimed to the recipients of the Social Integration Revenue Policy of the Region of Madrid

This article studies the gender values that are promoted both in the literacy courses for gypsy women beneficiaries of the Social Integration Revenue Policy of the Region of Madrid and in the events that are organized for this group by public institutions and NGOs. The process of “socialization” that occurs in the educative groups for Gypsy women is focused on constructing an image of what it is to be a “Gypsy modern woman”. Through multiple mechanisms and discursive techniques a specific conception of gender equality is transmitted in these educative spaces. In addition to this, Gypsy women are continually urged to assume certain values and social practices (of gender identity, of "citizenship", of parenting, etc..), while an archetype of "Gypsy Woman" which condenses powerful stereotypes and prejudices about the "Gypsy culture" and the gender relations characteristics of this group is constructed.

Attachment Style in Adults who Failed to Thrive as Children: Outcomes of a 20 Year Follow-up Study of Factors Influencing Maintenance or Change in Attachment Style

A group of children identified as non-organic failure-to-thrive between 1977 and 1980 were investigated, assessed and provided with social work intervention and treatment. Those children and their families have been followed up for the last 20 years. The current paper examines the stability of an internal working model in a sample of individuals who had failed to thrive as children, by comparing each individual's adult attachment style with their childhood attachment to their mother. In this sample, several cases showed changes from insecure to secure attachment styles. Possible reasons are discussed for positive and negative changes, as well as cases when there was no change in attachment style. These include the effectiveness of intervention in addition to changes in life circumstances. The findings suggest that when appropriate support and intervention is provided, or when different circumstances or relationships are experienced, internal working models can change.

Comparison of genetic and morphological methods to detect the presence of American lobsters, Homarus americanus H. Milne Edwards, 1837 (Astacidea: Nephropidae) in Norwegian waters

American lobsters (Homarus americanus H. Milne Edwards, 1837) are imported live to Europe and should according regulations be kept in land-based tanks until sold. In spite of the strict regulations aimed specifically at preventing the introduction of this species into the NE Atlantic, several specimens of H. americanus have been captured in the wild, especially in Oslofjord, Norway since 1999. One of the great concerns is interbreeding between the introduced American species and the local European lobster, H. gammarus (Linnaeus, 1758). For this reason an awareness campaign was launched in 2000 focusing on morphologically "unusual" lobsters caught in local waters. Morphological characters have been based on colour and sub-ventral spines on the rostrum. Two samples of H. americanus were used for comparisons, as well as samples of European lobster from Oslofjord collected in 1992. Previous genetic analyses (allozymes, mtDNA and microsatellite DNA) have demonstrated that the American lobster is distinct from its European counterpart, with several additional alleles at many loci in addition to different allelic frequency distribution of alleles of "shared" alleles. During the present study, thirteen microsatellite loci were tested in the initial screening, and the three most discriminating loci (Hgam98, Hgam197b and Hgam47b) were used in a detailed comparison between the two species. A total of 45 unusual lobsters were reported captured from Ålesund (west) to Oslofjord (southeast) from 2001 to 2005 and these were analysed for the three microsatellite loci. Nine specimens were identified as American lobsters. Comparisons between morphological and genetic characteristics revealed that morphological differences are not reliable in discrimination the two species, or to identify hybrids. Further, some loci display almost no overlapping in allele frequency distribution for the reference samples analysed, thus providing a reliable tool to identify hybrids.

'An aid to mental health': natural history, alienists and therapeutics in Victorian Scotland

In the nineteenth century natural history was widely regarded as a rational and ‘distracting’ pursuit that countered the ill-effects, physical and mental, of urban life. This familiar argument was not only made by members of naturalists’ societies but was also borrowed and adapted by alienists concerned with the moral treatment of the insane. This paper examines the work of five long-serving superintendents in Victorian Scotland and uncovers the connections made between an interest in natural history and the management of mental disease. In addition to recovering a significant influence on the conduct of several alienists the paper explores arguments made outside the asylum walls in favour of natural history as an aid to mental health. Investigating the promotion of natural history as a therapeutic recreation in Scotland and elsewhere reveals more fully the moral and cultural significance attached to natural history pursuits in the nineteenth century.

Fast model based feature matching technique applied to airport lighting

The use of image processing techniques to assess the performance of airport landing lighting using images of it collected from an aircraft-mounted camera is documented. In order to assess the performance of the lighting, it is necessary to uniquely identify each luminaire within an image and then track the luminaires through the entire sequence and store the relevant information for each luminaire, that is, the total number of pixels that each luminaire covers and the total grey level of these pixels. This pixel grey level can then be used for performance assessment. The authors propose a robust model-based (MB) featurematching technique by which the performance is assessed. The development of this matching technique is the key to the automated performance assessment of airport lighting. The MB matching technique utilises projective geometry in addition to accurate template of the 3D model of a landing-lighting system. The template is projected onto the image data and an optimum match found, using nonlinear least-squares optimisation. The MB matching software is compared with standard feature extraction and tracking techniques known within the community, these being the Kanade–Lucus–Tomasi (KLT) and scaleinvariant feature transform (SIFT) techniques. The new MB matching technique compares favourably with the SIFT and KLT feature-tracking alternatives. As such, it provides a solid foundation to achieve the central aim of this research which is to automatically assess the performance of airport lighting.

Use of the multispecies freshwater biomonitor to assess behavioral changes of Corophium volutator (Pallas, 1766) (Crustacea, Amphipoda) in response to toxicant exposure in sediment

Automated sediment toxicity testing and biomonitoring has grown rapidly. This study tested the suitability of the marine amphipod Corophium volutator (Pallas, 1766) for sediment biomonitoring using the Multispecies Freshwater Biomonitor (MFB). Two experiments were undertaken to (1) characterize individual behaviors of C. volutator using the MFB and (2) examine behavioral changes in response to sediment spiked with the pesticide Bioban. Four behaviors were visually identified (walking, swimming, grooming and falling) and characterized in the MFB as different patterns of locomotor activity (0-2 Hz range). Ventilation was not visually observed but was detected by the MFB (2-8 Hz). No clear diel activity patterns were detected. The MFB detected an overall increase in C. volutator locomotor activity after Bioban addition to the sediments (56, 100, 121 mg kg(-1)). C. volutator was more active (both locomotion and ventilation) in the water column than the spiked sediment. C. volutator appears a sensitive and appropriate species for behavioral sediment toxicity assessment and biomonitoring. (c) 2005 Elsevier Inc. All rights reserved.

Dual adaptation to two opposing visuomotor rotations when each is associated with different regions of workspace

Studies examining dual adaptation to opposing novel environments have yielded contradictory results, with previous evidence supporting both successful dual adaptation and interference leading to poorer adaptive performance. Whether or not interference is observed during dual adaptation appears to be dependent on the method used to allow the performer of the task to distinguish between two novel environments. This experiment tested if colour cues, a separation in workspace, and presentation schedule, could be used to distinguish between two opposing visuomotor rotations and enable dual adaptation. Through the use of a purpose designed manipulandum, each visuomotor rotation was either presented in the same region of workspace and associated with colour cues (Group 1), different regions of workspace in addition to colour cues (Groups 2 and 3) or different regions of workspace only (Groups 4 and 5). We also assessed the effectiveness of the workspace separation with both randomised and alternating presentation schedules (Groups 4 and 5). The results indicated that colour cues were not effective at enabling dual adaptation when each of the visuomotor rotations was associated with the same region of workspace. When associated with different regions of workspace, however, dual adaptation to the opposing rotations was successful regardless of whether colour cues were present or the type of presentation schedule.

Advanced glycation end product (AGE) accumulation on Bruch's membrane: links to age-related RPE dysfunction.

PURPOSE: Advanced glycation end products (AGEs) accumulate during aging and have been observed in postmortem eyes within the retinal pigment epithelium (RPE), Bruch's membrane, and subcellular deposits (drusen). AGEs have been associated with age-related dysfunction of the RPE-in particular with development and progression to age-related macular degeneration (AMD). In the present study the impact of AGEs at the RPE-Bruch's membrane interface was evaluated, to establish how these modifications may contribute to age-related disease. METHODS: AGEs on Bruch's membrane were evaluated using immunohistochemistry. A clinically relevant in vitro model of substrate AGE accumulation was established to mimic Bruch's membrane ageing. Responses of ARPE-19 growing on AGE-modified basement membrane (AGE-BM) for 1 month were investigated by using a microarray approach and validated by quantitative (q)RT-PCR. In addition to identified AGE-related mRNA alterations, lysosomal enzyme activity and lipofuscin accumulation were also studied in ARPE-19 grown on AGE-BM. RESULTS: Autofluorescent and glycolaldehyde-derived AGEs were observed in clinical specimens on Bruch's membrane and choroidal extracellular matrix. In vitro analysis identified a range of dysregulated mRNAs in ARPE-19 exposed to AGE-BM. Altered ARPE-19 degradative enzyme mRNA expression was observed on exposure to AGE-BM. AGE-BM caused a significant reduction in cathepsin-D activity in ARPE-19 (P

Highly resolved absolute cross-sections for dissociative electron attachment to SF5CF3

Using two complementary experimental methods, we have measured partial (mass-resolved) cross-sections for dissociative electron attachment to the molecule trifluoromethyl sulfurpentafluoride (SF5CF3) at the gas temperature T-G = 300 K over a broad range of electron energies (E = 0.001-12 eV). The absolute scale for these cross-sections was obtained with reference to the thermal (T = 300 K) rate coefficient for anion formation (8.0(3) x 10(-8) cm(3) s(-1)). Below 1 eV, SF5- is the dominant product anion and formed through the lowest anion state which cuts the neutral SF5CF3 potential close to the S-C equilibrium distance. The highly resolved laser photoelectron attachment data exhibit a downward Wigner cusp at 86meV, indicating that the nu(4)(alpha(1)) vibrational mode is important for the primary attachment dynamics. Both SF5- and F- anions are formed with similar yields through the first excited resonance located near 3.6eV. Towards higher energies, the anions CF3-, SF4-, and SF3- are also produced. Summation of the partial cross-sections yields a total absolute cross-section for anion formation over the energy range 0.001-12 eV. This is used to calculate the dependence of the rate coefficient for dissociative electron attachment over a broad range of electron temperatures for the fixed gas temperature T-G = 300 K; good agreement is found between the calculated values and those obtained in a drift tube experiment. In addition to the experimental work, semiempirical R-matrix calculations have been Carried out for the energy dependence of the cross-section for SF5- formation. The experimental findings are semi-quantitatively recovered. (C) 2008 Elsevier B.V. All rights reserved.

Use of Digital Manufacturing to Improve Management Learning in Aerospace Assembly

The primary goal of this work is to quantify any bene?ts that the use of digital manufacturing methods can offer when used upstream from production, for manufacturing process design, and tool development. Learning at this stage of product development is referred to as management learning. Animated build simulations have been used to develop build procedures and tooling for a panel assembly for the new Bombardier CRJ1000 (Canadair Regional Jet, 100 seat). When the jig format was developed, its simulated performance was compared to that of current CRJ700/900 panel builds to identify and quantify any improvements in terms of tooling cost and panel build time. When comparing like-for-like functions between existing CRJ700/900 (Canadair Regional Jet, 70/90 seat) and the
CRJ1000 tooling, it was predicted that the digitally assisted improvements had brought about a 4.9% reduction in jig cost. An evaluation of the build process for the CRJ1000 uplock panel predicted a 5.2% reduction in the assembly time. In addition to the improvement of existing tooling functions, new jig functionality was added so that both the drilling and riveting functions could be carried out in a single jig for the new RJ1000 panel.

Drug delivery strategies for photodynamic antimicrobial chemotherapy: From benchtop to clinical practice

Light and photosensitizer-mediated killing of many pathogens, termed photodynamic antimicrobial chemotherapy (PACT), has been extensively investigated in vitro. A wide range of organisms from the Gram-positive Staphylococcus aureus to the Gram-negative Pseudomonas aeruginosa have been proven to be susceptible to PACT. Multidrug-resistant strains are just as susceptible to this treatment as their naive counterparts. Both enveloped and non-enveloped viruses have demonstrated susceptibility in vitro, in addition to fungi and protozoa. Significantly, however, no clinical treatments based on PACT are currently licensed. This paper provides a comprehensive review of work carried out to date on delivery of photosensitizers for use in PACT, including topical, intranasal and oral/buccal delivery, as well as targeted delivery. We have also reviewed photo-antimicrobial surfaces. It is hoped that, through a rational approach to formulation design and subsequent success in small-scale clinical trials, more widespread use will be made of PACT in the clinic, to the benefit of patients worldwide. (C) 2009 Elsevier B.V. All rights reserved.

Cell-collagen interactions: the use of peptide Toolkits to investigate collagen-receptor interactions

Fibrillar collagens provide the most fundamental platform in the vertebrate organism for the attachment of cells and matrix molecules. we have identified specific sites in collagens to which cells can attach, either directly or through protein intermediaries. Using Toolkits of triple-helical peptides, each peptide comprising 27 residues of collagen primary sequence and overlapping with its neighbours by nine amino acids, we have mapped the binding of receptors and other proteins on to collagens II or III. Integrin alpha 2 beta 1 binds to several GXX'GER motifs within the collagens, the affinities of which differ sufficiently to control cell adhesion and migration independently of the cellular regulation of the integrin. The platelet receptor, Gp (glycoprotein) VI binds well to GPO (where 0 is hydroxyproline)-containing model peptides, but to very few Toolkit peptides, suggesting that sequence in addition to GPO triplets is important in defining GpVI binding. The Toolkits have been applied to the plasma protein vWF (von Willebrand factor), which binds to only a single sequence, identified by truncation and amino acid substitution within Toolkit peptides, as GXRGQOGVMGFO in collagens II and III. Intriguingly, the receptor tyrosine kinase, DDR2 (discoidin domain receptor 2) recognizes three sites in collagen II, including its vWF-binding site, although the amino acids that support the interaction differ slightly within this motif. Furthermore, the secreted protein BM-40 (basement membrane protein 40) also binds well to this same region. Thus the availability of extracellular collagen-binding proteins may be important in regulating and facilitating direct collagen-receptor interaction.

The role of the active site residues in human galactokinase: implications for the mechanisms of GHMP kinases.

Galactokinase catalyses the phosphorylation of galactose at the expense of ATP. Like other members of the GHMP family of kinases it is postulated to function through an active site base mechanism in which Asp-186 abstracts a proton from galactose. This asparate residue was altered to alanine and to asparagine by site-directed mutagenesis of the corresponding gene. This resulted in variant enzyme with no detectable galactokinase activity. Alteration of Arg-37, which lies adjacent to Asp-186 and is postulated to assist the catalytic base, to lysine resulted in an active enzyme. However, alteration of this residue to glutamate abolished activity. All the variant enzymes, except the arginine to lysine substitution, were structurally unstable (as judged by native gel electrophoresis in the presence of urea) compared to the wild type. This suggests that the lack of activity results from this structural instability, in addition to any direct effects on the catalytic mechanism. Computational estimations of the pK(a) values of the arginine and aspartate residues, suggest that Arg-37 remains protonated throughout the catalytic cycle whereas Asp-186 has an abnormally high pK(a) value (7.18). Quantum mechanics/molecular mechanics (QM/MM) calculations suggest that Asp-186 moves closer to the galactose molecule during catalysis. The experimental and theoretical studies presented here argue for a mechanism in which the C-1-OH bond in the sugar is weakened by the presence of Asp-186 thus facilitating nucleophilic attack by the oxygen atom on the gamma-phosphorus of ATP.