J Biol Chem

Collagen XXIII is a member of the transmembranous subfamily of collagens containing a cytoplasmic domain, a membrane-spanning hydrophobic domain, and three extracellular triple helical collagenous domains interspersed with non-collagenous domains. We cloned mouse, chicken, and human{alpha}1(XXIII) collagen cDNAs and showed that this non-abundant collagen has a limited tissue distribution in non-tumor tissues. Lung, cornea, brain, skin, tendon, and kidney are the major sites of expression. In contrast, five transformed cell lines were tested for collagen XXIII expression, and all expressed the mRNA. In vivo the {alpha}1(XXIII) mRNA is found in mature and developing organs, the latter demonstrated using stages of embryonic chick cornea and mouse embryos. Polyclonal antibodies were generated in guinea pig and rabbit and showed that collagen XXIII has a transmembranous form and a shed form. Comparison of collagen XXIII with its closest relatives in the transmembranous subfamily of collagens, types XIII and XXV, which have the same number of triple helical and non-collagenous regions, showed that there is a discontinuity in the alignment of domains but that striking similarities remain despite this

Field induced stationary state for an accelerated tracer in a bath

Our interest goes to the behavior of a tracer particle, accelerated by a constant and uniform external field, when the energy injected by the field is redistributed through collision to a bath of unaccelerated particles. A non equilibrium steady state is thereby reached. Solutions of a generalized Boltzmann-Lorentz equation are analyzed analytically, in a versatile framework that embeds the majority of tracer-bath interactions discussed in the literature. These results --mostly derived for a one dimensional system-- are successfully confronted to those of three independent numerical simulation methods: a direct iterative solution, Gillespie algorithm, and the Direct Simulation Monte Carlo technique. We work out the diffusion properties as well as the velocity tails: large v, and either large -v, or v in the vicinity of its lower cutoff whenever the velocity distribution is bounded from below. Particular emphasis is put on the cold bath limit, with scatterers at rest, which plays a special role in our model.Comment: 20 pages, 6 figures v3:minor corrections in sec.III and added reference

Re-Assembly of the Genome of Francisella tularensis Subsp. holarctica OSU18

Francisella tularensis is a highly infectious human intracellular pathogen that is the causative agent of tularemia. It occurs in several major subtypes, including the live vaccine strain holarctica (type B). F. tularensis is classified as category A biodefense agent in part because a relatively small number of organisms can cause severe illness. Three complete genomes of subspecies holarctica have been sequenced and deposited in public archives, of which OSU18 was the first and the only strain for which a scientific publication has appeared [1]. We re-assembled the OSU18 strain using both de novo and comparative assembly techniques, and found that the published sequence has two large inversion mis-assemblies. We generated a corrected assembly of the entire genome along with detailed information on the placement of individual reads within the assembly. This assembly will provide a more accurate basis for future comparative studies of this pathogen

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival

Background: Proteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. Anchorage-independent survival is induced by growth factor receptor hyperactivation in many cell types. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival. Methods and Results: We conducted a high-throughput siRNA screen and identified PTK6 as a critical component of IGF-1 receptor (IGF-1R)-induced anchorage-independent survival of mammary epithelial cells. PTK6 downregulation induces apoptosis of breast and ovarian cancer cells deprived of matrix attachment, whereas its overexpression enhances survival. Reverse-phase protein arrays and subsequent analyses revealed that PTK6 forms a complex with IGF-1R and the adaptor protein IRS-1, and modulates anchorage-independent survival by regulating IGF-1R expression and phosphorylation. PTK6 is highly expressed not only in the previously reported Her2$^+$ breast cancer subtype, but also in high grade ER$^+$, Luminal B tumors and high expression is associated with adverse outcomes. Conclusions: These findings highlight PTK6 as a critical regulator of anchorage-independent survival of breast and ovarian tumor cells via modulation of IGF-1 receptor signaling, thus supporting PTK6 as a potential therapeutic target for multiple tumor types. The combined genomic and proteomic approaches in this report provide an effective strategy for identifying oncogenes and their mechanism of action

Evaluation of efalizumab using safe psoriasis control

BACKGROUND: Safe Psoriasis Control (SPC) is an important comprehensive measure that is validated for the assessment of benefit:risk of psoriasis treatments, combining efficacy, quality of life, and safety measures. The objective of this analysis was to assess the benefit:risk of efalizumab, a novel biologic agent indicated for the treatment of moderate-to-severe plaque psoriasis, by applying the SPC to data from randomized, placebo-controlled clinical studies of efalizumab. METHODS: SPC was applied to week 12 data from four placebo-controlled, Phase III studies: three retrospective and one prospective, the latter including a cohort of "high-need" patients for whom existing therapies were inadequate or unsuitable. RESULTS: In the retrospective analysis, 39.4% of patients achieved SPC after 12 weeks of treatment with efalizumab, compared with 10.4% for placebo. In the prospective analysis, 34.3% of patients achieved SPC after 12 weeks of treatment with efalizumab, compared with 7.3% on placebo. Among high-need patients, 33.0% achieved SPC, compared with 3.4% on placebo. CONCLUSION: Efalizumab has a favorable benefit:risk profile using the comprehensive outcome measure SPC

RNF43 is frequently mutated in colorectal and endometrial cancers

We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers.National Human Genome Research Institute (U.S.) (Grant U54HG003067

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on childre

Towards concolic testing for hybrid systems

Hybrid systems exhibit both continuous and discrete behavior. Analyzing hybrid systems is known to be hard. Inspired by the idea of concolic testing (of programs), we investigate whether we can combine random sampling and symbolic execution in order to effectively verify hybrid systems. We identify a sufficient condition under which such a combination is more effective than random sampling. Furthermore, we analyze different strategies of combining random sampling and symbolic execution and propose an algorithm which allows us to dynamically switch between them so as to reduce the overall cost. Our method has been implemented as a web-based checker named HYCHECKER. HYCHECKER has been evaluated with benchmark hybrid systems and a water treatment system in order to test its effectiveness.CPCI-S(ISTP)[email protected]; [email protected]

Search for Electroweak Production of Single Top Quarks in ppbar Collisions

We present a search for electroweak production of single top quarks in the electron+jets and muon+jets decay channels. The measurements use ~90 pb^-1 of data from Run 1 of the Fermilab Tevatron collider, collected at 1.8 TeV with the DZero detector between 1992 and 1995. We use events that include a tagging muon, implying the presence of a b jet, to set an upper limit at the 95% confidence level on the cross section for the s-channel process ppbar->tb+X of 39 pb. The upper limit for the t-channel process ppbar->tqb+X is 58 pb.Comment: 11 pages, 2 figures. This is the published versio