Methods and approaches to improving the emotional health and well being of children: A briefing paper concerning interventions to prevent internalising disorders

This paper presents a summary of the prevalence of somatic, anxiety and depressive disorders in children and of the known risk and protective factors associated with these problems. It then reviews the evidence for successful treatments and prevention programmes, focusing on psychological therapies rather than pharmacological interventions, with particular emphasis on interventions for children of primary school age

The effects of new firm formation on regional development over time: The case of Great Britain

This paper re-examines the link between new firm formation and subsequent employment growth. It investigates whether it is possible to have the 'wrong type of entrepreneurship'�defined as new firm formation which leads to zero or even negative subsequent employment growth. It uses a very similar approach to that of Fritsch and Mueller (2004), confirming their findings that the employment impact of new firm formation is in three discrete phases. Then, using data for Great Britain, the paper shows the employment impact of new firm formation is significantly positive in England, but zero in Scotland where formation rates are much lower. It also shows that, in the low enterprise counties of GB, new firm formation has a negative effect on employment, implying that we find that the 'wrong type of entrepreneurship' is possible.

FGF Signalling Regulates Chromatin Organisation during Neural Differentiation via Mechanisms that Can Be Uncoupled from Transcription

Changes in higher order chromatin organisation have been linked to transcriptional regulation; however, little is known about how such organisation alters during embryonic development or how it is regulated by extrinsic signals. Here we analyse changes in chromatin organisation as neural differentiation progresses, exploiting the clear spatial separation of the temporal events of differentiation along the elongating body axis of the mouse embryo. Combining fluorescence in situ hybridisation with super-resolution structured illumination microscopy, we show that chromatin around key differentiation gene loci Pax6 and Irx3 undergoes both decompaction and displacement towards the nuclear centre coincident with transcriptional onset. Conversely, down-regulation of Fgf8 as neural differentiation commences correlates with a more peripheral nuclear position of this locus. During normal neural differentiation, fibroblast growth factor (FGF) signalling is repressed by retinoic acid, and this vitamin A derivative is further required for transcription of neural genes. We show here that exposure to retinoic acid or inhibition of FGF signalling promotes precocious decompaction and central nuclear positioning of differentiation gene loci. Using the Raldh2 mutant as a model for retinoid deficiency, we further find that such changes in higher order chromatin organisation are dependent on retinoid signalling. In this retinoid deficient condition, FGF signalling persists ectopically in the elongating body, and importantly, we find that inhibiting FGF receptor (FGFR) signalling in Raldh2−/− embryos does not rescue differentiation gene transcription, but does elicit both chromatin decompaction and nuclear position change. These findings demonstrate that regulation of higher order chromatin organisation during differentiation in the embryo can be uncoupled from the machinery that promotes transcription and, for the first time, identify FGF as an extrinsic signal that can direct chromatin compaction and nuclear organisation of gene loci

Wnt regulates amino-acid transporter <i>Slc7a5</i> and so constrains the integrated stress response in mouse embryos

Amino-acids are essential for cellular metabolism and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis. Here we show that the amino-acid transporter Slc7a5/Lat1 is highly expressed in tissues undergoing morphogenesis and that Slc7a5-null mouse embryos have profound neural and limb-bud outgrowth defects. Slc7a5-null neural tissue exhibited aberrant mTORC1 activity and cell proliferation; transcriptomics, protein phosphorylation and apoptosis analyses further indicated induction of the integrated stress response as a potential cause of observed defects. The pattern of stress-response gene expression induced in Slc7a5 null embryos was also detected at low-level in wildtype embryos and identified stress-vulnerability specifically in tissues undergoing morphogenesis. The Slc7a5-null phenotype is reminiscent of Wnt-pathway mutants and we show that Wnt/β-catenin loss inhibits Slc7a5 expression and induces this stress response. Wnt-signalling therefore normally supports the metabolic demands of morphogenesis and constrains cellular stress. Moreover, operation in the embryo of the integrated stress response, which is triggered by pathogen mediated as well as metabolic stress, may provide a mechanistic explanation for a range of developmental defects

Sr-Nd-Pb-Hf isotope results from ODP Leg 187: Evidence for mantle dynamics of the Australian-Antarctic Discordance and origin of the Indian MORB source

New high precision PIMMS Hf and Pb isotope data for 14–28 Ma basalts recovered during ODP Leg 187 are compared with zero-age dredge samples from the Australian-Antarctic Discordance (AAD). These new data show that combined Nd-Hf isotope systematics can be used as an effective discriminant between Indian and Pacific MORB source mantle domains. In particular, Indian mantle is displaced to lower εNd and higher εHf ratios compared to Pacific mantle. As with Pb isotope plots, there is almost no overlap between the two mantle types in Nd-Hf isotope space. On the basis of our new Nd-Hf isotope data, we demonstrate that Pacific MORB-source mantle was present near the eastern margin of the AAD from as early as 28 Ma, its boundary with Indian MORB-source mantle coinciding with the eastern edge of a basin-wide arcuate depth anomaly that is centered on the AAD. This observation rules out models requiring rapid migration of Pacific MORB mantle into the Indian Ocean basin since separation of Australia from Antarctica. Although temporal variations in isotopic composition can be discerned relative to the fracture zone boundary of the modern AAD at 127°E, the distribution of different compositional groups appears to have remained much the same relative to the position of the residual depth anomaly for the past 30 m.y. Thus significant lateral flow of mantle along the ridge axis toward the interface appears unlikely. Instead, the dynamics that maintain both the residual depth anomaly and the isotopic boundary between Indian and Pacific mantle are due to eastward migration of the Australian and Antarctic plates over a stagnated, but slowly upwelling, slab oriented roughly orthogonal to the ridge axis. Temporal and spatial variations in the compositions of Indian MORB basalts within the AAD can be explained by progressive displacement of shallower Indian MORB-source mantle by deeper mantle having a higher εHf composition ascending ahead of the upwelling slab. Models for the origin of the distinctive composition of the Indian MORB-source based on recycling of a heterogeneous enriched component that consist of ancient altered ocean crust plus<10% pelagic sediment are inconsistent with Nd-Hf isotope systematics. Instead, the data can be explained by a model in which Indian mantle includes a significant proportion of material that was processed in the mantle wedge above a subduction zone and was subsequently mixed back into unprocessed upper mantle

The role of a second RGD motif in the ID protein of a Namibian SATI foot-and-mouth disease virus for target cell attachment

Foot-and-mouth disease virus (FMDV), which is a member of the Aphthovirus genus of Picornaviridae, is an economically important animal virus that infects cloven-hoofed animals. At least two families of cell-surface receptors have been identified that mediate binding of FMDV to susceptible cells, i.e. integrins and heparan sulfate proteoglycans (HSPG). Whereas several tissue culture-adapted FMD viruses use heparan sulfate proteoglycans for internalization, field isolates of FMDV use integrins as receptors. A conserved amino acid sequence Arg-Gly-Asp (RGD), located in the surface-exposed flexible ƒÒG-ƒÒH loop of the viral outer capsid protein 1D, participates in binding FMDV to integrin receptors on the surface of susceptible cells. Sequence analyses of the 1D-encoding genome region of a SAT1 type FMDV field isolate, NAM/307/98, indicated the presence of a second RGD sequence upstream of the conserved G-H loop RGD sequence. Since FMDV is capable of binding to RGD-binding integrin receptors, the aim of this study was to investigate whether the second RGD motif in capsid protein 1D of NAM/307/98 may function as a ligand for receptor-binding in baby hamster kidney (BHK) cells. Towards this end, a cDNA copy of the genomic region encoding the external capsid proteins (1B-1D) of NAM/307/98 was cloned into pSAT2, a genome-length cDNA clone derived from the SAT2 strain ZIM/7/83. Transfection of BHK-21 cells with in vitro-transcribed RNA derived from the chimeric pNAM/SAT2 clone resulted in the recovery of infectious chimeric virus particles. The availability of such an infectious chimeric cDNA clone greatly facilitated the introduction of specific, targeted mutations in the 1D capsid-encoding region of NAM/307/98 in order to investigate the functional role of the second RGD sequence. Using the chimeric SAT1/SAT2 cDNA clone as template, the RGD codons in the G-H loop of NAM/307/98 were replaced with codons specifying a KGE sequence by a polymerase chain reaction (PCR)-based method of site-directed mutagenesis. The mutated DNA fragment was introduced into the pSAT2 infectious cDNA clone, transcribed in vitro, and the resulting RNA transfected into BHK-21 cells. The transfected cells were analyzed for cytopathic effect (CPE). In contrast to cells transfected with non-mutated RNA transcripts, from which infectious virus could be recovered, cells transfected with the mutant RNA transcripts showed cell lysis, but no CPE could be observed upon subsequent passaging of the resultant viruses on BHK cells. Notably, subsequent replacement of the KGE sequence with an RGD sequence in the mutant clones led to recovery of infectious viruses. Furthermore, RNA replication could be demonstrated with the mutant and non-mutant chimeric viruses, suggesting that virus particles were indeed present in the tissue culture supernatants of all transfected cells. Based on the results obtained during the course of this investigation, it was therefore concluded that the second RGD motif, situated upstream of the conserved RGD motif in the G-H loop of capsid protein 1D of NAM/307/98, does not function as a ligand for receptor-binding in BHK-21 cells.Dissertation (MSc (Microbiology))--University of Pretoria, 2007.Microbiology and Plant Pathologyunrestricte