Settling the thymus: immigration requirements

Thymus settling by precursor cells is essential for the production of T cells, yet the immigration requirements are poorly defined. P-selectin and CC chemokine receptor-9 (CCR9) are involved, and settling is favored when existing residents have moved on. A new study strengthens the correlation between niche emptying and the induction of thymic P-selectin and CCR9 ligand, and provides evidence for feedback from the periphery to thymic P-selectin expression via sphingosine-1-phosphate

Mutation of Directed Graphs -- Corresponding Regular Expressions and Complexity of Their Generation

Directed graphs (DG), interpreted as state transition diagrams, are traditionally used to represent finite-state automata (FSA). In the context of formal languages, both FSA and regular expressions (RE) are equivalent in that they accept and generate, respectively, type-3 (regular) languages. Based on our previous work, this paper analyzes effects of graph manipulations on corresponding RE. In this present, starting stage we assume that the DG under consideration contains no cycles. Graph manipulation is performed by deleting or inserting of nodes or arcs. Combined and/or multiple application of these basic operators enable a great variety of transformations of DG (and corresponding RE) that can be seen as mutants of the original DG (and corresponding RE). DG are popular for modeling complex systems; however they easily become intractable if the system under consideration is complex and/or large. In such situations, we propose to switch to corresponding RE in order to benefit from their compact format for modeling and algebraic operations for analysis. The results of the study are of great potential interest to mutation testing

Interaction and flocculation of spherical colloids wetted by a surface-induced corona of paranematic order

Particles dispersed in a liquid crystal above the nematic-isotropic phase transition are wetted by a surface-induced corona of paranematic order. Such coronas give rise to pronounced two-particle interactions. In this article, we report details on the analytical and numerical study of these interactions published recently [Phys. Rev. Lett. 86, 3915 (2001)]. We especially demonstrate how for large particle separations the asymptotic form of a Yukawa potential arises. We show that the Yukawa potential is a surprisingly good description for the two-particle interactions down to distances of the order of the nematic coherence length. Based on this fact, we extend earlier studies on a temperature induced flocculation transition in electrostatically stabilized colloidal dispersions [Phys. Rev. E 61, 2831 (2000)]. We employ the Yukawa potential to establish a flocculation diagram for a much larger range of the electrostatic parameters, namely the surface charge density and the Debye screening length. As a new feature, a kinetically stabilized dispersion close to the nematic-isotropic phase transition is found.Comment: Revtex v4.0, 16 pages, 12 Postscript figures. Accepted for publication in Phys. Rev.

Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 μ in MCF-7 cells and IC 50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society

Genome-wide copy number variation (CNV) in patients with autoimmune Addison's disease

<p>Abstract</p> <p>Background</p> <p>Addison's disease (AD) is caused by an autoimmune destruction of the adrenal cortex. The pathogenesis is multi-factorial, involving genetic components and hitherto unknown environmental factors. The aim of the present study was to investigate if gene dosage in the form of copy number variation (CNV) could add to the repertoire of genetic susceptibility to autoimmune AD.</p> <p>Methods</p> <p>A genome-wide study using the Affymetrix GeneChip^®Genome-Wide Human SNP Array 6.0 was conducted in 26 patients with AD. CNVs in selected genes were further investigated in a larger material of patients with autoimmune AD (n = 352) and healthy controls (n = 353) by duplex Taqman real-time polymerase chain reaction assays.</p> <p>Results</p> <p>We found that low copy number of <it>UGT2B28 </it>was significantly more frequent in AD patients compared to controls; conversely high copy number of <it>ADAM3A </it>was associated with AD.</p> <p>Conclusions</p> <p>We have identified two novel CNV associations to <it>ADAM3A </it>and <it>UGT2B28 </it>in AD. The mechanism by which this susceptibility is conferred is at present unclear, but may involve steroid inactivation (<it>UGT2B28</it>) and T cell maturation (<it>ADAM3A</it>). Characterization of these proteins may unravel novel information on the pathogenesis of autoimmunity.</p

Sequence History Analysis (SHA) : Estimating the Effect of Past Trajectories on an Upcoming Event

In this article, we propose an innovative method which is a combination of Sequences Analysis and Event History Analysis. We called this method Sequence History Analysis (SHA). We start by identifying typical past trajectories of individuals over time by using Sequence Analysis. We then estimate the effect of these typical past trajectories on the event under study using discrete-time models. The aim of this approach is to estimate the effect of past trajectories on the chances of experiencing an event. We apply the proposed methodological approach to an original study of the effect of past childhood co-residence structures on the chances of leaving the parental home in Switzerland. The empirical research was based on the LIVES Cohort study, a panel survey that started in autumn 2013 in Switzerland. Analyses show that it is not only the occurrence of an event that increases the risk of experiencing another event, but also the order in which various states occurred. What is more, it seems that two features have a significant influence on departure from the parental home: the co-residence structures and the arrival or departure of siblings from the parental home

Photocontrolled DNA binding of a receptor-targeted organometallic ruthenium(II) complex

A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as “tumor-targeting devices” since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium–peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV–vis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(η6-p-cym)Ru(bpm)(H2O)]2+, reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, 5′dCATGGCT and 5′dAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptide–oligonucleotide hybrid, Phac-His-Gly-Met-linker-p5′dCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids