Transforming growth factor-beta 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages

Matrix metalloproteinases (MMP) have been identified in vulnerable areas of atherosclerotic plaques and may contribute to plaque instability through extracellular matrix degradation. Human metalloelastase (MMP-12) is a macrophage-specific MMP with broad substrate specificity and is capable of degrading proteins found in the extracellular matrix of atheromas. Despite its potential importance, little is known about the regulation of MMP-12 expression in the context of atherosclerosis. In this study, we report that in human peripheral blood-derived macrophages, MMP-12 mRNA was markedly up-regulated by several pro-atherosclerotic cytokines and growth factors including interleukin-1beta, tumor necrosis factor-alpha, macrophage colony-stimulating factor, vascular endothelial growth factor, and platelet-derived growth factor-BB. In contrast, the pleiotropic anti-inflammatory growth factor transforming growth factor-beta1 (TGF-beta1) inhibited cytokine-mediated induction of MMP-12 mRNA, protein, and enzymatic activity. Analyses of MMP-12 promoter through transient transfections and electrophoretic mobility shift assays indicated that both its induction by cytokines and its inhibition by TGF-beta1 depended on signaling through an AP-1 site at -81 base pairs. Moreover, the inhibitory effect of TGF-beta1 on MMP-12 was dependent on Smad3. Taken together, MMP-12 is induced by several factors implicated in atherosclerosis. The inhibition of MMP-12 expression by TGF-beta1 suggests that TGF-beta1, acting via Smad3, may promote plaque stability.     

Identification of new mutations in Israeli patients with X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by impaired peroxisomal betaoxidation of very-long-chain fatty acids (VLCFAs). This is probably due to reduced activation of the VLCFAs and results in demyelination of the nervous system and adrenocortical insufficiency. The ALD gene is localized on Xq28, has 10 exons and encodes a protein of 745 amino acids with significant homology to the membrane peroxisomal protein PMP70. Characterizing the disease causing mutations is of importance in prenatal diagnosis because 12-20% of women who are obligatory carriers show false-negative results when tested for VLCFA in plasma. We have analyzed DNA from blood samples of 7 Jewish (5 Sephardi and 2 Ashkenazi) and 3 Arab Israeli families suffering from ALD. Five missense-type mutations were identified: R104H, Y174C, L229P, R401Q, and G512C. A single mutation, R464X, was nonsense, and two, Y171 frameshift and E471 frameshift, were frameshift. Interestingly, a single mutation was identified in three families of Moroccan Jewish descent, probably due to a founder effect.     

A Genetic Strategy to Measure Circulating Drosophila Insulin Reveals Genes Regulating Insulin Production and Secretion

Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.     

Sentinel node biopsy should be supplemented by axillary sampling in patients with small breast cancers

Axillary clearance provides important prognostic information but is associated with significant morbidity. Sentinel node biopsy can provide staging .141 patients with node negative early breast cancers-tumour size less than 1.5 cm measured clinically or by imaging had guided axillary sampling (sentinel lymph node biopsy in combination with axillary sampling). Four node axillary sampling improved the detection rate of axillary node metastases by 13.6% as compared to blue dye sentinel node biopsy alone. Positive sampled nodes strongly indicated the likelihood of further metastatic being revealed by axillary dissection (67%). Negative sampled nodes in combination with a positive sentinel node biopsy were associated with a much lower rate of further nodal involvement in the axillary clearance (8%).     

A Position Paper on the Electronic Publication of Nematode Taxonomic Manuscripts

Several nematode species have now attained ‘model organism’ status, yet there remain many niches in basic biological inquiry for which nematodes would be ideal model systems of study. However, furthering the model system approach is hindered by lack of information on nematode biodiversity. The shortage of taxonomic resources to inventory and characterize biodiversity hinders research programs in invasion biology, ecosystem functioning, conservation biology, and many others. The disproportion between numbers of species to be described and numbers of available taxonomic specialists is greater for Nematoda than for any other metazoan phylum. A partial solution to the taxonomic impediment is the adoption of recent advances in electronic publishing. Electronic publishing has the potential to increase the rate at which taxonomic papers are published, the breadth of their distribution, and the type, quantity, quality, and accessibility of data. We propose that the Journal of Nematology implement the advantageous aspects of electronic publication as a means to help ameliorate the limitations of an underdeveloped taxonomy and empower the nematological disciplines currently hindered by it.     

Is EGF a physiological inhibitor of mouse mammary casein synthesis? Unphysiological responses to pharmacological levels of hormones

It has been observed that EGF inhibits the induction of casein synthesis by mouse mammary tissue in vitro in addition to acting as a promoter of mammary epithelial proliferation. However, since the circulating level of EGF increases during lactation, and since functional EGF receptors are retained by the lactating cells, it seemed unlikely that EGF is an inhibitor of mammary differentiation in vivo. The current studies demonstrate, in fact, that EGF inhibits the induction of casein synthesis in vitro only when insulin is present in the culture medium at unphysiologically high concentrations. Other artifactual responses to high levels of hormones are described.     

An essential role for glucocorticoid in casein gene expression in rat mammary explants

It is demonstrated that the accumulation of 42 K casein mRNA in mammary tissue from adrenalectomized, virgin rats is almost 20x higher in the presence of exogenous hydrocortisone than in its absence. Accumulation of 25 K casein mRNA in this tissue is totally dependent on the steroid. The results indicate a much greater dependency on hydrocortisone than was appreciated previously, and also show that this dependency does not reflect a loss of cell viability in the absence of the steroid.