Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL.

Unlike other tumor necrosis factor family members, the cytotoxic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L contains an unpaired cysteine residue (Cys(230)) in its receptor-binding domain. Here we show that the biological activity of both soluble recombinant TRAIL and cell-associated, full-length TRAIL is critically dependent on the presence of Cys(230). Mutation of Cys(230) to alanine or serine strongly affected its ability to kill target cells. Binding to its receptors was decreased by at least 200-fold, and the stability of its trimeric structure was reduced. In recombinant TRAIL, Cys(230) was found engaged either in interchain disulfide bridge formation, resulting in poorly active TRAIL, or in the chelation of one zinc atom per TRAIL trimer in the active, pro-apoptotic form of TRAIL

Examples of mathematical modeling tales from the crypt

Mathematical modeling is being increasingly recognized within the biomedical sciences as an important tool that can aid the understanding of biological systems. The heavily regulated cell renewal cycle in the colonic crypt provides a good example of how modeling can be used to find out key features of the system kinetics, and help to explain both the breakdown of homeostasis and the initiation of tumorigenesis. We use the cell population model by Johnston et al. (2007) Proc. Natl. Acad. Sci. USA 104, 4008-4013, to illustrate the power of mathematical modeling by considering two key questions about the cell population dynamics in the colonic crypt. We ask: how can a model describe both homeostasis and unregulated growth in tumorigenesis; and to which parameters in the system is the model most sensitive? In order to address these questions, we discuss what type of modeling approach is most appropriate in the crypt. We use the model to argue why tumorigenesis is observed to occur in stages with long lag phases between periods of rapid growth, and we identify the key parameters

On the proportion of cancer stem cells in a tumour

It is now generally accepted that cancers contain a sub-population, the cancer stem cells (CSCs), which initiate and drive a tumour’s growth. At least until recently it has been widely assumed that only a small proportion of the cells in a tumour are CSCs. Here we use a mathematical model, supported by experimental evidence, to show that such an assumption is unwarranted. We show that CSCs may comprise any possible proportion of the tumour, and that the higher the proportion the more aggressive the tumour is likely to be

Modelling the consequences of interactions between tumour cells.

Classical models of tumorigenesis assume that the mutations which cause tumours to grow act in a cell-autonomous fashion. This is not necessarily true. Sometimes tumour cells may adopt genetic strategies that boost their own replication and which also influence other cells in the tumour, whether directly or as a side-effect. Tumour growth as a whole might be enhanced or retarded. We have used mathematical models to study two non-autonomous strategies that tumour cells may use. First, we have considered the production by tumour cells of an angiogenesis growth factor that benefits both the cell from which it originates and neighbouring cells. Second, we have analysed a situation in which tumour cells produce autocrine-only or paracrine-only growth factors to prevent programmed cell death. In the angiogenesis model, stable genetic polymorphisms are likely to occur between cells producing and not producing the growth factor. In the programmed cell death model, cells with autocrine growth factor production can spread throughout the tumour. Production of paracrine-only growth factor is never selected because it is 'altruistic' (that is of no benefit to the cell that makes the growth factor), despite being potentially beneficial to tumour growth as a whole. No polymorphisms can occur in the programmed cell death model. Production of angiogenesis and other growth factors in tumours may be under stable genetic, rather than epigenetic, control, with implications for therapies aimed at such targets. Many of the mutations observed in tumours may have non-autonomous effects

Evolutionary history and identification of conservation units in the giant otter, Pteronura brasiliensis.

The giant otter, Pteronura brasiliensis, occupies a range including the major drainage basins of South America, yet the degree of structure that exists within and among populations inhabiting these drainages is unknown. We sequenced portions of the mitochondrial DNA (mtDNA) cytochrome b (612 bp) and control region (383 bp) genes in order to determine patterns of genetic variation within the species. We found high levels of mtDNA haplotype diversity (h = 0.93 overall) and support for subdivision into four distinct groups of populations, representing important centers of genetic diversity and useful units for prioritizing conservation within the giant otter. We tested these results against the predictions of three hypotheses of Amazonian diversification (Pleistocene Refugia, Paleogeography, and Hydrogeology). While the phylogeographic pattern conformed to the predictions of the Refugia Hypothesis, molecular dating using a relaxed clock revealed the phylogroups diverged from one another between 1.69 and 0.84 Ma, ruling out the influence of Late Pleistocene glacial refugia. However, the role of Plio-Pleistocene climate change could not be rejected. While the molecular dating also makes the influence of geological arches according to the Paleogeography Hypothesis extremely unlikely, the recent Pliocene formation of the Fitzcarrald Arch and its effect of subsequently altering drainage pattern could not be rejected. The data presented here support the interactions of both climatic and hydrological changes resulting from geological activity in the Plio-Pleistocene, in shaping the phylogeographic structure of the giant otter

Allele loss occurs frequently at hMLH1, but rarely at hMSH2, in sporadic colorectal cancers with microsatellite instability.

Mutations at the hMSH2 and hMLH1 mismatch repair loci have been implicated in the pathogenesis of colorectal cancer. Tumours with two allelic mutations at a mismatch repair locus develop replication errors (RERs). In the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, one mutation is inherited and the other acquired somatically: in RER+ sporadic colorectal cancers, both mutations are somatic. RER+ tumours tend to have a low frequency of allele loss, presumably because they acquire most mutations through RERs. However, before a second mismatch repair mutation has occurred somatically, there is no reason to suppose that allele loss occurs less frequently in tumours that are to become RER+. Indeed, this second mutation might itself occur by allele loss. We have searched for allele loss at the hMSH2 and hMLH1 loci in RER+ and RER- sporadic colorectal cancers. Loss occurred at the hMLH1 locus in 7/17 (41%) RER+ tumours, compared with 6/40 (15%) RER- cancers (chi2=3.82, P approximately 0.05). At hMSH2, 2/22 RER+ sporadic cancers (9%) had lost an allele, compared with 2/40 (5%) RER- cancers (chi2=0.03, P>0.5). Taken together with previous studies which focused on colorectal cancers from HNPCC families, the data suggest that allele loss at hMLH1, but not at hMSH2, contributes to defective mismatch repair in inherited and sporadic colorectal cancer

Relativistic Model of Detonation Transition from Neutron to Strange Matter

We study the conversion of neutron matter into strange matter as a detonation wave. The detonation is assumed to originate from a central region in a spherically symmetric background of neutrons with a varying radial density distribution. We present self-similar solutions for the propagation of detonation in static and collapsing backgrounds of neutron matter. The solutions are obtained in the framework of general relativistic hydrodynamics, and are relevant for the possible transition of neutron into strange stars. Conditions for the formation of either bare or crusted strange stars are discussed.Comment: 16 pages, 4 figures. Submitted to IJMP

Identification of the growth factor-binding sequence in the extracellular matrix protein MAGP-1

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Strange stars in low-mass binary pulsar systems

Based on observational facts and a variety of theoretical arguments we discuss in this work the possibility that pulsars in Low-Mass Binary Pulsar systems could be strange stars rather than neutron stars. It is shown that, although subject to reasonable uncertainties, the consideration of the physics of the SQM core and thin normal crusts leads to the prediction of several observed features of the magnetic field history of these systems whitin this working hypothesis.Comment: 6 pages, no figures, PlainTex file submitted to IJMP