Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning

Sonic hedgehog (Shh) acts as a morphogen to mediate the specification of distinct cell identities in the ventral neural tube through a Gli-mediated (Gli1-3) transcriptional network. Identifying Gli targets in a systematic fashion is central to the understanding of the action of Shh. We examined this issue in differentiating neural progenitors in mouse. An epitope-tagged Gli-activator protein was used to directly isolate cis-regulatory sequences by chromatin immunoprecipitation (ChIP). ChIP products were then used to screen custom genomic tiling arrays of putative Hedgehog (Hh) targets predicted from transcriptional profiling studies, surveying 50-150 kb of non-transcribed sequence for each candidate. In addition to identifying expected Gli-target sites, the data predicted a number of unreported direct targets of Shh action. Transgenic analysis of binding regions in Nkx2.2, Nkx2.1 (Titf1) and Rab34 established these as direct Hh targets. These data also facilitated the generation of an algorithm that improved in silico predictions of Hh target genes. Together, these approaches provide significant new insights into both tissue-specific and general transcriptional targets in a crucial Shh-mediated patterning process

Apoptosis is a prominent feature of acute anterior uveitis in the Fischer 344 rat

AIMS: To examine the hypothesis that apoptosis of infiltrating cells contributes to spontaneous resolution of uveitis in clinically relevant rodent models. METHODS: Experimental melanin induced uveitis (EMIU) was induced in Fischer 344 rats by immunisation with 250 microg bovine ocular melanin. Endotoxin induced uveitis (EIU) was induced by injection of 200 microg Escherichia coli lipopolysaccharide. Formalin fixed, paraffin embedded ocular cross sections were stained by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick end labelling (TUNEL) to identify apoptotic cells. Indirect immunoperoxidase staining of paraformaldehyde lysine periodate fixed tissue cross sections was used to demonstrate expression of inducible nitric oxide synthase (iNOS). RESULTS: TUNEL positive mononuclear cells were observed in the anterior uvea during both EMIU and EIU at all selected time points. However, whereas the majority of mononuclear cells appeared apoptotic from the outset of disease, neutrophils were notably TUNEL negative at all time points examined. Many infiltrating neutrophils expressed iNOS. CONCLUSION: Apoptosis occurs early in the course of rat EMIU and EIU, and may contribute to resolution of these diseases. In general, infiltrating mononuclear cells die rapidly, while neutrophils survive, producing inducible nitric oxide synthase which may contribute to disease pathogenesis

Fetal testosterone and autistic traits

Studies of amniotic testosterone in humans suggest that fetal testosterone (fT) is related to specific (but not all) sexually dimorphic aspects of cognition and behaviour. It has also been suggested that autism may be an extreme manifestation of some male-typical traits, both in terms of cognition and neuroanatomy. In this paper, we examine the possibility of a link between autistic traits and fT levels measured in amniotic fluid during routine amniocentesis. Two instruments measuring number of autistic traits (the Childhood Autism Spectrum Test (CAST) and the Child Autism Spectrum Quotient (AQ-Child)) were completed by these women about their children (N = 235), ages 6-10 years. Intelligence Quotient (IQ) was measured in a subset of these children (N = 74). fT levels were positively associated with higher scores on the CAST and AQ-Child. This relationship was seen within sex as well as when the sexes were combined, suggesting this is an effect of fT rather than of sex per se. No relationships were found between overall IQ and the predictor variables, or between IQ and CAST or AQ-Child. These findings are consistent with the hypothesis that prenatal androgen exposure is related to children exhibiting more autistic traits. These results need to be followed up in a much larger sample to test if clinical cases of ASC have elevated fT.</p

The Oryza BAC resource: A genus-wide and genome scale tool for exploring rice genome evolution and leveraging useful genetic diversity from wild relatives

Rice was the first crop to have a high-quality reference genome sequence and is now at the forefront of intense functional and evolutionary research for two reasons-its central role in world food security, and its status as a model system for grasses. A thorough characterization of the rice genome cannot be accomplished without a deep understanding of its evolutionary history. The genus Oryza contains two cultivated and 22 wild rice species that represent 10 distinct genome types embedded within a robust phylogeny spanning a ~15 million year time span. The genus contains an untapped reservoir of agriculturally important traits and a historical record of genomic changes (especially those related to domestication, polyploidy, speciation and adaption).The two main objectives of the 'Oryza Map Alignment Project' (OMAP) were to functionally characterize the rice genome from a comparative standpoint and to provide essential tools to leverage the novel genetic diversity from wild relatives for rice improvement. The objective of this review is to summarize our efforts towards developing the most comprehensive genus-wide set of publicly available BAC resources for the genus Oryza, the first of its kind among plants (and perhaps higher eukaryotes), and their applications

Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction

Importance  The angiotensin receptor neprilysin inhibitor sacubitril/valsartan was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Sacubitril/valsartan has been approved for use in heart failure (HF) with reduced ejection fraction in the United States and cost has been suggested as 1 factor that will influence the use of this agent. Objective  To estimate the cost-effectiveness of sacubitril/valsartan vs enalapril in the United States. Design, Setting, and Participants  Data from US adults (mean [SD] age, 63.8 [11.5] years) with HF with reduced ejection fraction and characteristics similar to those in the PARADIGM-HF trial were used as inputs for a 2-state Markov model simulated HF. Risks of all-cause mortality and hospitalization from HF or other reasons were estimated with a 30-year time horizon. Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and enalapril. A discount rate of 3% was used. Sensitivity analyses were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates. Main Outcomes and Measures  Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained. Results  The 2-state Markov model of US adult patients (mean age, 63.8 years) calculated that there would be 220 fewer hospital admissions per 1000 patients with HF treated with sacubitril/valsartan vs enalapril over 30 years. The incremental costs and QALYs gained with sacubitril/valsartan treatment were estimated at $35 512 and 0.78, respectively, compared with enalapril, equating to an incremental cost-effectiveness ratio (ICER) of$45 017 per QALY for the base-case. Sensitivity analyses demonstrated ICERs ranging from $35 357 to$75 301 per QALY. Conclusions and Relevance  For eligible patients with HF with reduced ejection fraction, the Markov model calculated that sacubitril/valsartan would increase life expectancy at an ICER consistent with other high-value accepted cardiovascular interventions. Sensitivity analyses demonstrated sacubitril/valsartan would remain cost-effective vs enalapril

Tobacco retailer density surrounding schools and youth smoking behaviour: a multi-level analysis

<p>Abstract</p> <p>Background</p> <p>Youth smoking prevention should be a public health priority. It is not only vital to prevent youth from smoking but also to prevent non-smoking youth from becoming susceptible to smoking. Past research has examined factors associated with youth's susceptibility to become a future smoker, but research has yet to examine tobacco retailer density and susceptibility to smoking among never smokers. The objectives of this study are to examine how tobacco retailer density surrounding schools and social smoking influences are associated with smoking susceptibility among youth of never smokers, and occasional and daily smoking among youth of current smokers.</p> <p>Methods</p> <p>Data were collected in 2005-2006 from grade 9 to 12 students attending 76 secondary schools in Ontario, Canada, as part of the SHAPES-On study. A series of multi-level logistic regression analyses were performed to understand how student- and school-level factors are associated with three smoking behaviour outcomes: smoking susceptibility among never smokers, occasional smoking, and daily smoking.</p> <p>Results</p> <p>The number of tobacco retailers surrounding a school was found to be associated with the likelihood of a never smoker being susceptible to future smoking (OR 1.03, 95CI% 1.01, 1.05). We also identified that being surrounded by smoking social influences, specifically family and close friends, can substantially increase the likelihood that never smokers are at risk for future smoking or that youth are already occasional or daily smokers.</p> <p>Conclusions</p> <p>We identified that the number of tobacco retailers surrounding a school was associated with an increased odds of being susceptible to future smoking among male never smokers. Smoking social models surrounding youth also appears to have an important impact on their smoking behaviour regardless of their smoking status. It is important for youth smoking prevention programs to begin early, interrupt youths' susceptibility to future smoking, and focus on subgroups that are at higher risk of smoking. The government should consider the impact of tobacco retailer density on youth smoking behaviour, and be cautious when granting licenses for establishments to sell tobacco products.</p

Jet production in charged current deep inelastic e⁺p scatteringat HERA

The production rates and substructure of jets have been studied in charged current deep inelastic e⁺p scattering for Q² > 200 GeV² with the ZEUS detector at HERA using an integrated luminosity of 110.5 pb⁻¹. Inclusive jet cross sections are presented for jets with transverse energies E_{T}^{jet} > 5 GeV. Measurements of the mean subjet multiplicity, 〈n_{sbj}〉, of the inclusive jet sample are presented. Predictions based on parton-shower Monte Carlo models and next-to-leading-order QCD calculations are compared to the measurements. The value of α_{s} (M_{z}), determined from 〈n_{sbj}〉 at y_{cut} = 10⁻² for jets with 25 < E_{T}^{jet} < 119 GeV, is α_{s} (M_{z}) = 0.1202 ± 0.0052 (stat.)_{-0.0019}^{+0.0060} (syst.)_{-0.0053}^{+0.0065} (th.). The mean subjet multiplicity as a function of Q² is found to be consistent with that measured in NC DIS

Faint High Latitude Carbon Stars Discovered by the Sloan Digital Sky Survey: Methods and Initial Results

We report the discovery of 39 Faint High Latitude Carbon Stars (FHLCs) from Sloan Digital Sky Survey commissioning data. The objects, each selected photometrically and verified spectroscopically, range over 16.6 < r* < 20.0, and show a diversity of temperatures as judged by both colors and NaD line strengths. At the completion of the Sloan Survey, there will be many hundred homogeneously selected and observed FHLCs in this sample. We present proper motion measures for each object, indicating that the sample is a mixture of extremely distant (>100 kpc) halo giant stars, useful for constraining halo dynamics, plus members of the recently-recognized exotic class of very nearby dwarf carbon (dC) stars. Motions, and thus dC classification, are inferred for 40-50 percent of the sample, depending on the level of statistical significance invoked. The new list of dC stars presented here, although selected from only a small fraction of the final SDSS, doubles the number of such objects found by all previous methods. (Abstract abridged).Comment: Accepted for publication in The Astronomical Journal, Vol. 124, Sep. 2002, 40 pages, 7 figures, AASTeX v5.

Abundances of the elements in the solar system

A review of the abundances and condensation temperatures of the elements and their nuclides in the solar nebula and in chondritic meteorites. Abundances of the elements in some neighboring stars are also discussed.Comment: 42 pages, 11 tables, 8 figures, chapter, In Landolt- B\"ornstein, New Series, Vol. VI/4B, Chap. 4.4, J.E. Tr\"umper (ed.), Berlin, Heidelberg, New York: Springer-Verlag, p. 560-63