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

Model-based design of AM components to enable decentralized digital manufacturing systems

Additive manufacturing (AM) is a versatile technology that could add flexibility in manufacturing processes, whether implemented alone or along other technologies. This technology enables on-demand production and decentralized production networks, as production facilities can be located around the world to manufacture products closer to the final consumer (decentralized manufacturing). However, the wide adoption of additive manufacturing technologies is hindered by the lack of experience on its implementation, the lack of repeatability among different manufacturers and a lack of integrated production systems. The later, hinders the traceability and quality assurance of printed components and limits the understanding and data generation of the AM processes and parameters. In this article, a design strategy is proposed to integrate the different phases of the development process into a model-based design platform for decentralized manufacturing. This platform is aimed at facilitating data traceability and product repeatability among different AM machines. The strategy is illustrated with a case study where a car steering knuckle is manufactured in three different facilities in Sweden and Italy

Early life vitamin C deficiency does not alter morphology of hippocampal CA1 pyramidal neurons or markers of synaptic plasticity in a Guinea pig model

Approximately 15% of the Western world population, including pregnant women and their children, is characterized as vitamin C (vitC) deficient. In guinea pigs, early life vitC deficiency causes spatial memory deficits, decreased hippocampal volume and neuron numbers, in otherwise clinically healthy animals. We hypothesized that vitC deficiency leads to decreased brain-derived neurotrophic factor and synaptic plasticity markers in selected brain areas (frontal cortex, hippocampus and striatum) and cause morphological changes in cornu ammonis 1 pyramidal neurons of the hippocampus either through a direct effect or indirectly by increased oxidative stress. Fifty-seven female guinea pigs were allocated to three groups receiving either 1390, 100 or 0–50 mg vitC/kg feed for 11 weeks. Dietary vitC levels were reflected in the plasma, cortical and adrenal gland levels, however, redox imbalance was only present in the adrenal glands allowing for the investigation of a direct influence of vitC deficiency on the chosen parameters in the brain. Synaptic plasticity markers were not affected in the investigated brain areas and no differences in isolated pyramidal neuron morphology was recorded. Based on our findings, it appears that vitC deficiency may primarily elicit impaired neuronal function through increased levels of oxidative stress

The response of four calcium hydroxides on monkey pulps

. Dentinal bridge formation and pulpal responses of four calcium hydroxide materials, pulp capping medicaments, MFC®, Experimental MFC-12, Dycal® and Pulpdent®, were evaluated in primary and permanent monkey teeth. A total of 60 primary and 60 permanent teeth were used with each material placed in a Class V cavity exposure in Rhesus monkey teeth. The materials were placed on the exposed pulp tissue and were histologically evaluated at 3 days, 5 weeks and 8 weeks. After perfusion the teeth were processed using routine histological procedures. The 3-day pulpal responses in both primary and permanent teeth were moderate, characterized by disruption of the pulpal tissue directly beneath the exposure site and a zone of acute inflammation and hemorrhage in the underlying pulp. The 5-week response showed histological differences between the four medicaments, with Dycal producing the least amount of pulpal irritation with reparative dentin bridges occurring in 50% of the permanent teeth. Experimental MFC-12 stimulated one reparative dentin bridge, while Pulpdent and MFC showed no evidence of bridge formation. Pulpal responses to Dycal were moderate and moderate to severe for the other calcium hydroxide compounds. No reparative dentin bridges were seen in the primary teeth at 5 weeks with any of the materials, and the pulpal responses were of a moderate degree at that time. Eight-week responses were similar to the 5-week responses. Dycal provoked a slight to moderate pulpal response with 50% success at bridging. Experimental MFC-12 initiated pulpal responses in the moderate to severe range with some bridging evident. Pulpdent incited moderate to severe histological responses with three teeth demonstrating bridge formation, and MFC provoked severe pulpal responses with no bridging. Primary teeth showed some bridging for all compounds except those treated with MFC, in which no evidence of bridging occurred, and moderate to severe pulpal responses were present.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72823/1/j.1600-0714.1980.tb00393.x.pd

The Risk of Exposure to Diagnostic Ultrasound in Postnatal Subjects

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135382/1/jum2008274565.pd

Crystallisation and preliminary X-ray analysis of the receptor-binding domain of human and bovine α2-macroglobulin

AbstractThe receptor-binding domains (RBDs) of human and bovine α2-macroglobulin (α2M) have been isolated after limited proteolysis of methylamine-treated α2M with papain. Single crystals of the RBDs have been grown by vapour diffusion. Crystals of human RBD are very thin plates unsuited for data collection. However, crystals of RBD from bovine α2M give diffraction patterns suitable for X-ray analysis, and a complete dataset with a maximum resolution of 2.3 Å has been collected with synchrotron radiation at cryogenic temperature. The crystals belong to spacegroup P3121 or P3221 with cell parameters a = b = 106.8 Å, c = 72.2 Å

Changes in rod and frame test scores recorded in schoolchildren during development--a longitudinal study.

The Rod and Frame Test has been used to assess the degree to which subjects rely on the visual frame of reference to perceive vertical (visual field dependence-independence perceptual style). Early investigations found children exhibited a wide range of alignment errors, which reduced as they matured. These studies used a mechanical Rod and Frame system, and presented only mean values of grouped data. The current study also considered changes in individual performance. Changes in rod alignment accuracy in 419 school children were measured using a computer-based Rod and Frame test. Each child was tested at school Grade 2 and retested in Grades 4 and 6. The results confirmed that children displayed a wide range of alignment errors, which decreased with age but did not reach the expected adult values. Although most children showed a decrease in frame dependency over the 4 years of the study, almost 20% had increased alignment errors suggesting that they were becoming more frame-dependent. Plots of individual variation (SD) against mean error allowed the sample to be divided into 4 groups; the majority with small errors and SDs; a group with small SDs, but alignments clustering around the frame angle of 18°; a group showing large errors in the opposite direction to the frame tilt; and a small number with large SDs whose alignment appeared to be random. The errors in the last 3 groups could largely be explained by alignment of the rod to different aspects of the frame. At corresponding ages females exhibited larger alignment errors than males although this did not reach statistical significance. This study confirms that children rely more heavily on the visual frame of reference for processing spatial orientation cues. Most become less frame-dependent as they mature, but there are considerable individual differences

Supersymmetric Monojets at the Large Hadron Collider

Supersymmetric monojets may be produced at the Large Hadron Collider by the process qg -> squark neutralino_1 -> q neutralino_1 neutralino_1, leading to a jet recoiling against missing transverse momentum. We discuss the feasibility and utility of the supersymmetric monojet signal. In particular, we examine the possible precision with which one can ascertain the neutralino_1-squark-quark coupling via the rate for monojet events. Such a coupling contains information on the composition of the neutralino_1 and helps bound dark matter direct detection cross-sections and the dark matter relic density of the neutralino_1. It also provides a check of the supersymmetric relation between gauge couplings and gaugino-quark-squark couplings.Comment: 46 pages, 10 figures. The appendix has been rewritten to correct an error that appears in all previous versions of the appendix. This error has no effect on the results in the main body of the pape