Specialised information processing deficits and distinct metabolomics profiles following TM-domain disruption of Nrg1

While there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signalling in schizophrenia. The present study focused on specialised behavioural and characterisation of hitherto un-characterised information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across two different sites and protocols, Nrg1 mutants demonstrated deficits in pre-pulse inhibition, a measure of sensorimotor gating that is disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second-, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in the ‘what-where-when’ cognitive paradigm, Nrg1 mutants displayed sex-specific (males only) disruption of ‘what-when’ performance, indicative of impaired episodic memory. Differential metabolomic profiling revealed that these behavioural phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioural changes in adulthood

Systemic Membrane Defect in the Proximal Muscular Dystrophies

Abstract We studied lymphocyte capping in 61 patients with Duchenne, Becker, limb-girdle, facioscapulohumeral and congenital muscular dystrophies. All showed a markedly diminished percentage of capped cells when compared with 86 normal controls, providing support for previous evidence that an alteration in membrane fluidity may be a common pathogenic feature in several genetically distinct forms of proximal muscular dystrophy. Heterozygous carriers of Duchenne muscular dystrophy showed diminished capping that was indistinguishable from that of afflicted males and was often present even when serum enzyme levels were normal. Studies in 25 families with 16 suspected sporadic cases indicated that no more than four out of 30 afflicted males may represent new mutations. These findings imply that most cases of Duchenne dystrophy might be prevented by a population screening program for carrier females combined with prenatal detection of afflicted males. (N Engl J Med 299:841–846, 1978

An experimental study of residual fiber strains in Ti-15-3 continuous fiber composites

A simplified experimental technique to determine the axial fiber residual strain in continuously-reinforced metal matrix composites is described. The residual fiber strains in two Ti-15V-3Cr-3Al-3Sn/SiC metal matrix composites have been measured with this technique. Residual fiber strains on the order of 0.2% are measured in the as-processed condition, and the residual stresses approach zero after testing the composite in tension to failure at room temperature. A conceptual description of the effect of tensile testing on the residual stresses is provided. The experimental results are consistent with predictions based on a concentric cylinder iso-strain analysis of thermal strains. Measurement errors result in a residual fiber strain error that is typically less than ±0.05%. Periodic fiber bending induced by cross-weave fibers is also analyzed, and may contribute significantly to measurement errors

Pleiotropic actions of mIR-21 highlight the critical role of deregulated stromal microRNA's during colorectal cancer progression

The oncogene microRNA-21 (miRNA; miR-21) is overexpressed in most solid organ tumours; however, a recent examination of stage II colorectal cancer (CRC) specimens suggests this may be a stromal phenomenon and not only a feature of cancer cells. In vitro and in vivo studies show that miR-21 has potent pro-metastatic effects in various malignant carcinoma cell lines. The tumour microenvironment has also been identified as a key actor during the metastatic cascade; however to date the significance of deregulated miR-21 expression within the cancer-associated stroma has not been examined. In the present study, a quantitative RT-PCR-based analysis of laser microdissected tissue confirmed that miR-21 expression is associated with a four-fold mean increase in CRC stroma compared with normal tissue. In situ hybridisation using locked nucleic acid probes localised miR-21 expression predominantly to fibroblasts within tumour-associated stroma. To study the molecular and biological impact of deregulated stromal miR-21 in CRC, stable ectopic expression was induced in immortalised fibroblasts. This resulted in upregulated ?-smooth muscle actin expression implying miR-21 overexpression is driving the fibroblast-to-myofibroblast transdifferentiation. Conditioned medium from miR-21-overexpressing fibroblasts protected CRC cells from oxaliplatin-induced apoptosis and increased their proliferative capacity. 3D organotypic co-cultures containing fibroblasts and CRC cells revealed that ectopic stromal miR-21 expression was associated with increased epithelial invasiveness. Reversion-inducing cysteine-rich protein with kazal motifs, an inhibitor of matrix-remodelling enzyme MMP2, was significantly downregulated by ectopic miR-21 in established and primary colorectal fibroblasts with a reciprocal rise in MMP2 activity. Inhibition of MMP2 abrogated the invasion-promoting effects of ectopic miR-21. This data, which characterises a novel pro-metastatic mechanism mediated by miR-21 in the CRC stroma, highlights the importance of miRNA deregulation within the tumour microenvironment and identifies a potential application for stromal miRNAs as biomarkers in cancer

Genomic Organization and FISH Mapping of Human Pmel 17, the Putative Silver Locus

The Pmel 17 gene is expressed preferentially in pigment cells. It has been mapped to human chromosome 12 pter-q21 and mouse chromosome 10, near the silver locus. The Pmel 17 gene contains an insertional mutation at its carboxyl terminus in the silver mouse, suggesting that the silver locus might correspond to the gene. In the current studies, we have isolated and characterized human Pmel 17 genomic clones and employed FISH mapping for a precise localization of this gene in the human chromosome. The FISH mapping placed the Pmel 17 gene at human chromosome 12 q12-q13. The human gene consists of nine exons and eight introns, and the entire coding region of the gene spans approximately 7.9 kb of the human chromosome 12. The putative functional domains, such as the signal sequence, histidine-rich, 26-amino acid repeats, cysteine-rich, transmembrane and cytoplasmic domains, were encoded by separate exons. Cis-transcription elements such as a TATA, a CAT and other potential elements for pigment cell-specific gene expression were found within 1100 base pairs of the 5'flanking region

Genomic organization and FISH mapping of human Pmel 17, the putative silver locus

The Pmel 17 gene is expressed preferentially in pigment cells. It has been mapped to human chromosome 12 pter-q21 and mouse chromosome 10, near the silver locus. The Pmel 17 gene contains an insertional mutation at its carboxyl terminus in the silver mouse, suggesting that the silver locus might correspond to the gene. In the current studies, we have isolated and characterized human Pmel 17 genomic clones and employed FISH mapping for a precise localization of this gene in the human chromosome. The FISH mapping placed the Pmel 17 gene at human chromosome 12 q12-q13. The human gene consists of nine exons and eight introns, and the entire coding region of the gene spans approximately 7.9 kb of the human chromosome 12. The putative functional domains, such as the signal sequence, histidine-rich, 26-amino acid repeats, cysteine-rich, transmembrane and cytoplasmic domains, were encoded by separate exons. Cis-transcription elements such as a TATA, a CAT and other potential elements for pigment cell-specific gene expression were found within 1100 base pairs of the 5' flanking region.This work was supported by NIH Grant R01 AR-40248 (BSK). Kack-Kyun Kim is supported by a fund from the Cancer Research Center, SNU, Korea (KOSEF-SRC-56-crc-21).