Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?

Signal peptide peptidase (SPIP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the,gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPIP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/ SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2, and spp13 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNF(x intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article,we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others

Effectiveness and micro-costing of the KiVa school-based bullying prevention programme in Wales: study protocol for a pragmatic definitive parallel group cluster randomised controlled trial

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Bullying refers to verbal, physical or psychological aggression repeated over time that is intended to cause harm or distress to the victims who are unable to defend themselves. It is a key public health priority owing to its widespread prevalence in schools and harmful short- and long-term effects on victims' well-being. There is a need to strengthen the evidence base by testing innovative approaches to preventing bullying. KiVa is a school-based bullying prevention programme with universal and indicated elements and an emphasis on changing bystander behaviour. It achieved promising results in a large trial in Finland, and now requires testing in other countries. This paper describes the protocol for a cluster randomised controlled trial (RCT) of KiVa in Wales. METHODS/DESIGN: The study uses a two-arm waitlist control pragmatic definitive parallel group cluster RCT design with an embedded process evaluation and calculation of unit cost. Participating schools will be randomised a using a 1:1 ratio to KiVa plus usual provision (intervention group) or usual provision only (control group). The trial has one primary outcome, child self-reported victimisation from bullying, dichotomised as 'victimised' (bullied at least twice a month in the last couple of months) versus 'not victimised'. Secondary outcomes are: bullying perpetration; aspects of child social and emotional well-being (including emotional problems, conduct, peer relations, prosocial behaviour); and school attendance. Follow-up is at 12 months post-baseline. Implementation fidelity is measured through teacher-completed lesson records and independent school-wide observation. A micro-costing analysis will determine the costs of implementing KiVa, including recurrent and non-recurrent unit costs. Factors related to the scalability of the programme will be examined in interviews with head teachers and focus groups with key stakeholders in the implementation of school-based bullying interventions. DISCUSSION: The results from this trial will provide evidence on whether the KiVa programme is transportable from Finland to Wales in terms of effectiveness and implementation. It will provide information about the costs of delivery and generate insights into factors related to the scalability of the programme. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23999021 Date 10-6-13.BIG Lottery Wales (REF: B/l/1/010430196) is funding the costs of the trial, including recruitment conferences, provision of programme resources for schools, translation of resources into Welsh, support and feedback sessions, and central organisational meetings. The design, management, statistical analysis and dissemination of the trial are fully independent of the BIG Lottery and KiVa Finland. The programme is delivered by teachers and other school staff during school hours and no supply costs are provided to schools for staff training

Review: Attachment and attachment-related outcomes in preschool children – a review of recent evidence

Background Secure attachment is associated with optimal outcomes across all domains in childhood, and both insecure and disorganised attachment are associated with a range of later psychopathologies. Insecure and disorganised attachment are common, particularly in disadvantaged populations, pointing to the need to identify effective methods of addressing such problems. Aims This paper presents the findings of a review of secondary and primary studies evaluating the effectiveness of interventions aimed at improving attachment and attachment-related outcomes on a universal, targeted or indicated basis, which was undertaken as part of an update of the evidence base for a UK-based national programme targeting children aged 0–5 years (Healthy Child Programme). Method A systematic search of key electronic databases was undertaken to identify secondary and primary sources of data that addressed the research question and that had been published between 2008 and 2014; search sources included Cochrane Collaboration, NICE, EPPI Centre, Campbell Collaboration and PubMed, PsychInfo, CINAHL databases. Findings Six systematic reviews and 11 randomised controlled trials were identified that had evaluated the effectiveness of universal, selective or indicated interventions aimed at improving attachment and attachment-related outcomes in children aged 0–5 years. Potentially effective methods of improving infant attachment include parent–infant psychotherapy, video feedback and mentalisation-based programmes. Methods that appear to be effective in improving attachment-related outcomes include home visiting and parenting programmes. Conclusions A number of methods of working to promote attachment and attachment-related outcomes in preschool children are now being recommended as part of the Healthy Child Programme. The implications in terms of the role and contribution of practitioners working in child and adolescent mental health service are discusse

Modified f(R) gravity from scalar-tensor theory and inhomogeneous EoS dark energy

The reconstruction of f(R)-gravity is showed by using an auxiliary scalar field in the context of cosmological evolution, this development provide a way of reconstruct the form of the function f (R) for a given evolution of the Hubble parameter. In analogy, f(R)-gravity may be expressed by a perfect fluid with an inhomogeneous equation of state that depends on the Hubble parameter and its derivatives. This mathematical equivalence that may confuse about the origin of the mechanism that produces the current acceleration, and possibly the whole evolution of the Hubble parameter, is shown here.Comment: 8 page

Economic-demographic interactions in long-run growth

Cliometrics confirms that Malthus’ model of the pre-industrial economy, in which increases in productivity raise population but higher population drives down wages, is a good description for much of demographic/economic history. A contributor to the Malthusian equilibrium was the Western European Marriage Pattern, the late age of female first marriage, which promised to retard the fall of living standards by restricting fertility. The demographic transition and the transition from Malthusian economies to modern economic growth attracted many Cliometric models surveyed here. A popular model component is that lower levels of mortality over many centuries increased the returns to, or preference for, human capital investment so that technical progress eventually accelerated. This initially boosted birth rates and population growth accelerated. Fertility decline was earliest and most striking in late eighteenth century France. By the 1830s the fall in French marital fertility is consistent with a response to the rising opportunity cost of children. The rest of Europe did not begin to follow until end of the nineteenth century. Interactions between the economy and migration have been modelled with Cliometric structures closely related to those of natural increase and the economy. Wages were driven up by emigration from Europe and reduced in the economies receiving immigrants

Fossil energy in economic growth: A study of the energy direction of technical change, 1950-2012

Climate change mitigation challenges national economies to increase productivity while reducing fossil energy consumption. Fossil energy-saving technical change has been assumed to accomplish this, yet empirical evidence is scarce. This paper investigates the long-run relationship between the rate and direction of technical change with respect to fossil energy and labor in the world economy. Growth rates of labor productivity and the fossil energy-labor ratio are examined for more than 95 of world output between 1950 and 2012. The average elasticity of the energy-labor ratio with respect to labor productivity is close to one, implying highly energy-using technical change, but no trade-o between factor productivity growth rates. This stylized fact suggests the importance of a cheap, abundant energy supply for robust global growth, and a more important role for renewable energy. Integrated assessment models do not incorporate this restriction which may result in poorly speci ed baseline scenarios

The Status of Dosage Compensation in the Multiple X Chromosomes of the Platypus

Dosage compensation has been thought to be a ubiquitous property of sex chromosomes that are represented differently in males and females. The expression of most X-borne genes is equalized between XX females and XY males in therian mammals (marsupials and “placentals”) by inactivating one X chromosome in female somatic cells. However, compensation seems not to be strictly required to equalize the expression of most Z-borne genes between ZZ male and ZW female birds. Whether dosage compensation operates in the third mammal lineage, the egg-laying monotremes, is of considerable interest, since the platypus has a complex sex chromosome system in which five X and five Y chromosomes share considerable genetic homology with the chicken ZW sex chromosome pair, but not with therian XY chromosomes. The assignment of genes to four platypus X chromosomes allowed us to examine X dosage compensation in this unique species. Quantitative PCR showed a range of compensation, but SNP analysis of several X-borne genes showed that both alleles are transcribed in a heterozygous female. Transcription of 14 BACs representing 19 X-borne genes was examined by RNA-FISH in female and male fibroblasts. An autosomal control gene was expressed from both alleles in nearly all nuclei, and four pseudoautosomal BACs were usually expressed from both alleles in male as well as female nuclei, showing that their Y loci are active. However, nine X-specific BACs were usually transcribed from only one allele. This suggests that while some genes on the platypus X are not dosage compensated, other genes do show some form of compensation via stochastic transcriptional inhibition, perhaps representing an ancestral system that evolved to be more tightly controlled in placental mammals such as human and mouse