Netrin-1 controls colorectal tumorigenesis by regulating apoptosis

The expression of the protein DCC (deleted in colorectal cancer) is lost or markedly reduced in numerous cancers and in the majority of colorectal cancers due to loss of heterozygosity in chromosome 18q, and has therefore been proposed to be a tumour suppressor. However, the rarity of mutations found in DCC, the lack of cancer predisposition of DCC mutant mice, and the presence of other tumour suppressor genes in 18q have raised doubts about the function of DCC as a tumour suppressor. Unlike classical tumour suppressors, DCC has been shown to induce apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless DCC is engaged by its ligand, netrin-1 (ref. 3). Here we show that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract leads to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engenders aggressive adenocarcinomatous malignancies. These data demonstrate that netrin-1 can promote intestinal tumour development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumour suppressors.     

Beating the superparamagnetic limit with exchange bias

Interest in magnetic nanoparticles has increased in the past few years by virtue of their potential for applications in fields such as ultrahigh-density recording and medicine. Most applications rely on the magnetic order of the nanoparticles being stable with time. However, with decreasing particle size the magnetic anisotropy energy per particle responsible for holding the magnetic moment along certain directions becomes comparable to the thermal energy. When this happens, the thermal fluctuations induce random flipping of the magnetic moment with time, and the nanoparticles lose their stable magnetic order and become superparamagnetic. Thus, the demand for further miniaturization comes into conflict with the superparamagnetism caused by the reduction of the anisotropy energy per particle: this constitutes the so-called 'superparamagnetic limit' in recording media. Here we show that magnetic exchange coupling induced at the interface between ferromagnetic and antiferromagnetic systems can provide an extra source of anisotropy, leading to magnetization stability. We demonstrate this principle for ferromagnetic cobalt nanoparticles of about 4 nm in diameter that are embedded in either a paramagnetic or an antiferromagnetic matrix. Whereas the cobalt cores lose their magnetic moment at 10 K in the first system, they remain ferromagnetic up to about 290 K in the second. This behaviour is ascribed to the specific way ferromagnetic nanoparticles couple to an antiferromagnetic matrix.     

Loss of collagenase-2 confers increased skin tumor susceptibility to male mice

Matrix metalloproteinases (MMPs) have fundamental roles in tumor progression, but most clinical trials with MMP inhibitors have not shown improvements in individuals with cancer. This may be partly because broad-range inhibitors also reduce host-protective antitumor properties of individual MMPs. We generated mice deficient in collagenase-2 (Mmp8), an MMP mainly produced by neutrophils in inflammatory reactions and detected in some malignant tumors. Loss of Mmp8 did not cause abnormalities during embryonic development or in adult mice. Contrary to previous studies with MMP-deficient mice, however, the absence of Mmp8 strongly increased the incidence of skin tumors in male Mmp8(-/-)mice. Female Mmp8(-/-)mice whose ovaries were removed or were treated with tamoxifen were also more susceptible to tumors compared with wild-type mice. Bone marrow transplantation experiments confirmed that Mmp8 supplied by neutrophils was sufficient to restore the natural protection against tumor development mediated by this protease in male mice. Histopathological analysis showed that mutant mice had abnormalities in the inflammatory response induced by carcinogens. Our study identifies a paradoxical protective role for Mmp8 in cancer and provides a genetic model to evaluate the molecular basis of gender differences in cancer susceptibility.     

The contribution of noncatalytic phosphate-binding subsites to the mechanism of bovine pancreatic ribonuclease A

The enzymatic catalysis of polymeric substrates such as proteins, polysaccharides or nucleic acids requires precise alignment between the enzyme and the substrate regions flanking the region occupying the active site. In the case of ribonucleases, enzyme-substrate binding may be directed by electrostatic interactions between the phosphate groups of the RNA molecule and basic amino acid residues on the enzyme. Specific interactions between the nitrogenated bases and particular amino acids in the active site or adjacent positions may also take place. The substrate-binding subsites of ribonuclease A have been characterized by structural and kinetic studies. In addition to the active site (p₁ ), the role of other noncatalytic phosphate-binding subsites in the correct alignment of the polymeric substrate has been proposed. p₂ and p₀ have been described as phosphate-binding subsites that bind the phosphate group adjacent to the 3′ side and 5′ side, respectively, of the phosphate in the active site. In both cases, basic amino acids (Lys-7 and Arg-10 in p₂ , and Lys-66 in p₀ ) are involved in binding. However, these binding sites play different roles in the catalytic process of ribonuclease A. The electrostatic interactions in p₂ are important both in catalysis and in the endonuclease activity of the enzyme, whilst the p₀ electrostatic interaction contributes only to binding of the RNA.     

The roots of reductionism: A counter-ontoepistemology for a systems approach

Both an ontoepistemology for reductionist modern science (counter-ontoepistemology) and an ontology for interpretive Systemology have been outlined in the two preceding papers in this special issue ofSystems Practice. In the present article, the notion of truth is interpreted in terms of both the ontoepistemology of reductionism and the ontology of interpretive systemology. Both interpretations are discussed. Such a discussion represents the objective of this paper, that is, to outline the epistemological face of the ontoepistemology of interpretive systemology. In order to design that epistemological face, the relation between ontology and epistemology must be clarified. Such a relation is seen from the standpoint already provided by the ontology. After the discussion on the notion of truth, the general shape of a systemic-interpretive inquiring process is outlined.     

Characterization of a thermosensitive protein from human milk whey

Summary A human milk whey protein, which aggregates at room temperature and resolubilizes when cooled, was purified by chromatography on hydroxyapatite. The present study demonstrated that the thermosensitive protein is a nonphosphorylated form of -casein.We thank Dr J.J. Pahud for preparation of anti Na-caseinate antiserum and Miss D. Fumeaux for technical assistance.     

Integrative taxonomy of the gymnophthalmid lizard Neusticurus rudis Boulenger, 1900 identifies a new species in the eastern Pantepui region,north-eastern South America

ABSTRACT

The gymnophthalmid lizard genus Neusticurus Duméril and Bibron, 1839 currently contains six described species. One of them, Neusticurus rudis Boulenger, 1900 has a long history of taxonomic confusion, and uncertainty remains about the number of species involved under that name, especially in the Pantepui region. Our molecular phylogenetic (concatenation and species tree) and morphological (morphometrics, external and hemipenial morphology) analyses confirm Neusticurus rudis as a species complex with several candidate species in the eastern Pantepui region. Neusticurus rudis is here redescribed based on the re-examination of the holotype and 10 specimens from the vicinity of the type locality (ca. 15 km airline) in Guyana. The geographic distribution of N. rudis sensu stricto is restricted to east of the Venezuelan Gran Sabana, extending from the slopes of Mount Roraima in Venezuela through the slopes of Maringma-tepui and Wayalayeng to Mount Ayanganna in Guyana, between 678 and 1500 m elevation. Populations tentatively assigned to N. rudis also occur from Mount Wokomung in the Pakaraima Mountains of Guyana to the Iwokrama Forest Reserve in Guyana, between 159 and 1234 m elevation. A new Neusticurus species is described from the uplands and highlands of the eastern Pantepui region, west of the Venezuelan Gran Sabana in Brazil and Venezuela, between 900 and 2200 m elevation. Populations provisionally assigned to the new species were also found from the La Escalera region to Chivatón, the summit of Abakapá-tepui and the slopes and summit of Auyán-tepui, Venezuela, between 1100 and 2203 m elevation. Our results suggest the Gran Sabana as a possible recent biogeographical barrier for the genus in the region and indicate that tepui-summit Neusticurus populations derive from uplands populations that shifted their habitat preference.

www.zoobank.org/lsid:zoobank.org:pub:33DCF862-11CF-4FD0-B4D6-706E2C6A339E     

CDK5 downregulation enhances synaptic plasticity

CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity—such as long-term potentiation (LTP)—have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca²⁺ signaling and BDNF/CREB activation.     

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis

Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.