Pitx1 Regulates Cement Gland Development in Xenopus laevis through Activation of Transcriptional Targets and Inhibition of BMP Signaling

The cement gland in Xenopus laevis has long been used as a model to study the interplay of cell signaling and transcription factors during embryogenesis. It has been shown that an intermediate level of Bone Morphogenetic Protein (BMP) signaling is essential for cement gland formation. In addition, several transcription factors have been linked to cement gland development. One of these, the homeodomain-containing protein Pitx1, can generate ectopic cement gland formation; however, the mechanisms underlying this process remain obscure. We report here, for the first time, a requirement for Pitx proteins in cement gland formation, in vivo: knockdown of both pitx1 and the closely related pitx2c inhibit endogenous cement gland formation. Pitx1 transcriptionally activates cement gland differentiation genes through both direct and indirect mechanisms, and functions as a transcriptional activator to inhibit BMP signaling. This inhibition, required for the expression of pitx genes, is partially mediated by Pitx1-dependent follistatin expression. Complete suppression of BMP signaling inhibits induction of cement gland markers by Pitx1; furthermore, we find that Pitx1 physically interacts with Smad1, an intracellular transducer of BMP signaling. We propose a model of cement gland formation in which Pitx1 limits local BMP signaling within the cement gland primordium, and recruits Smad1 to activate direct downstream targets

Cloning and spatiotemporal expression of Xenopus laevis Apolipoprotein CI

Apolipoprotein CI (ApoCI) belongs to the Apolipoprotein superfamily, members of which are involved in lipid transport, uptake and homeostasis. Excessive ApoCI has been implicated in atherosclerosis and Alzheimer’s disease in humans. In this study we report the isolation of Xenopus laevis apoCI and describe the expression pattern of this gene during early development, using reverse transcription polymerase chain reaction and whole mount in situ hybridization. Xenopus apoCI is enriched in the dorsal ectoderm during gastrulation, and is subsequently expressed in sensory placodes, neural tube and cranial neural crest. These data suggest as yet uncharacterized roles for ApoCI during early vertebrate embryogenesis

Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability to Predict Progression to American College of Rheumatology-Classified Systemic Lupus Erythematosus.

ObjectiveTo evaluate the frequency of cell-bound complement activation products (CB-CAPs) as a marker of complement activation in patients with suspected systemic lupus erythematosus (SLE) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology (ACR) criteria.MethodsPatients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria, patients with primary Sjögren's syndrome (SS), and patients with other rheumatic diseases. Individual CB-CAPs were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. Probable SLE cases were followed up prospectively.ResultsThe 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE, and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB-CAPs (28%) or MAP (40%) than had low complement levels (9%) (P = 0.0001 for each). In probable SLE, MAP scores of >0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P < 0.01).ConclusionComplement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB-CAPs and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria

Patient- and population-level health consequences of discontinuing antiretroviral therapy in settings with inadequate HIV treatment availability

Background In resource-limited settings, HIV budgets are flattening or decreasing. A policy of discontinuing antiretroviral therapy (ART) after HIV treatment failure was modeled to highlight trade-offs among competing policy goals of optimizing individual and population health outcomes. Methods In settings with two available ART regimens, we assessed two strategies: (1) continue ART after second-line failure (Status Quo) and (2) discontinue ART after second-line failure (Alternative). A computer model simulated outcomes for a single cohort of newly detected, HIV-infected individuals. Projections were fed into a population-level model allowing multiple cohorts to compete for ART with constraints on treatment capacity. In the Alternative strategy, discontinuation of second-line ART occurred upon detection of antiretroviral failure, specified by WHO guidelines. Those discontinuing failed ART experienced an increased risk of AIDS-related mortality compared to those continuing ART. Results At the population level, the Alternative strategy increased the mean number initiating ART annually by 1,100 individuals (+18.7%) to 6,980 compared to the Status Quo. More individuals initiating ART under the Alternative strategy increased total life-years by 15,000 (+2.8%) to 555,000, compared to the Status Quo. Although more individuals received treatment under the Alternative strategy, life expectancy for those treated decreased by 0.7 years (−8.0%) to 8.1 years compared to the Status Quo. In a cohort of treated patients only, 600 more individuals (+27.1%) died by 5 years under the Alternative strategy compared to the Status Quo. Results were sensitive to the timing of detection of ART failure, number of ART regimens, and treatment capacity. Although we believe the results robust in the short-term, this analysis reflects settings where HIV case detection occurs late in the disease course and treatment capacity and the incidence of newly detected patients are stable. Conclusions In settings with inadequate HIV treatment availability, trade-offs emerge between maximizing outcomes for individual patients already on treatment and ensuring access to treatment for all people who may benefit. While individuals may derive some benefit from ART even after virologic failure, the aggregate public health benefit is maximized by providing effective therapy to the greatest number of people. These trade-offs should be explicit and transparent in antiretroviral policy decisions

Efficient Photometric Selection of Quasars from the Sloan Digital Sky Survey: 100,000 z<3 Quasars from Data Release One

We present a catalog of 100,563 unresolved, UV-excess (UVX) quasar candidates to g=21 from 2099 deg^2 of the Sloan Digital Sky Survey (SDSS) Data Release One (DR1) imaging data. Existing spectra of 22,737 sources reveals that 22,191 (97.6%) are quasars; accounting for the magnitude dependence of this efficiency, we estimate that 95,502 (95.0%) of the objects in the catalog are quasars. Such a high efficiency is unprecedented in broad-band surveys of quasars. This ``proof-of-concept'' sample is designed to be maximally efficient, but still has 94.7% completeness to unresolved, g<~19.5, UVX quasars from the DR1 quasar catalog. This efficient and complete selection is the result of our application of a probability density type analysis to training sets that describe the 4-D color distribution of stars and spectroscopically confirmed quasars in the SDSS. Specifically, we use a non-parametric Bayesian classification, based on kernel density estimation, to parameterize the color distribution of astronomical sources -- allowing for fast and robust classification. We further supplement the catalog by providing photometric redshifts and matches to FIRST/VLA, ROSAT, and USNO-B sources. Future work needed to extend the this selection algorithm to larger redshifts, fainter magnitudes, and resolved sources is discussed. Finally, we examine some science applications of the catalog, particularly a tentative quasar number counts distribution covering the largest range in magnitude (14.2<g<21.0) ever made within the framework of a single quasar survey.Comment: 35 pages, 11 figures (3 color), 2 tables, accepted by ApJS; higher resolution paper and ASCII version of catalog available at http://sdss.ncsa.uiuc.edu/qso/nbckde

International Society for Pharmacoeconomics and Outcomes Research Comments on the American Society of Clinical Oncology Value Framework

As members of the International Society for Pharmacoeconomics and Outcomes Research, we read with great interest the new American Society of Clinical Oncology (ASCO) conceptual framework to assess the value of cancer treatment options.1 We applaud the Value in Cancer Care Task Force for proposing a conceptual framework to support clinicians and patients in assessing the value of new cancer treatments. We acknowledge the challenges facing clinician–patient decision making, particularly concerning cancer treatments. Like ASCO, we recognize that the cost of treatments is increasingly being placed on patients through cost sharing and that engaging patients as part of making individual treatment decisions is of high importance. The ASCO framework highlights the growing tension among patients, insurance companies, and product manufacturers in a dynamic health care environment. In that light, the framework deserves a field test, and we look forward to seeing the outcome of that experience. We also appreciate the opportunity to offer comments and suggestions on the ASCO framework at this early stage, and our membership stands ready to support ASCO in future enhancements

Photometric redshifts from reconstructed QSO templates

From SDSS commissioning photometric and spectroscopic data, we investigate the utility of photometric redshift techniques to the task of estimating QSO redshifts. We consider empirical methods (e.g. nearest-neighbor searches and polynomial fitting), standard spectral template fitting and hybrid approaches (i.e. training spectral templates from spectroscopic and photometric observations of QSOs). We find that in all cases, due to the presence of strong emission-lines within the QSO spectra, the nearest-neighbor and template fitting methods are superior to the polynomial fitting approach. Applying a novel reconstruction technique, we can, from the SDSS multicolor photometry, reconstruct a statistical representation of the underlying SEDs of the SDSS QSOs. Although, the reconstructed templates are based on only broadband photometry the common emission lines present within the QSO spectra can be recovered in the resulting spectral energy distributions. The technique should be useful in searching for spectral differences among QSOs at a given redshift, in searching for spectral evolution of QSOs, in comparing photometric redshifts for objects beyond the SDSS spectroscopic sample with those in the well calibrated photometric redshifts for objects brighter than 20th magnitude and in searching for systematic and time variable effects in the SDSS broad band photometric and spectral photometric calibrations.Comment: 21 pages, 9 figures, LaTeX AASTeX, submitted to A

Phenomenological Consequences of Singlet Neutrinos

In this paper, we study the phenomenology of right-handed neutrino isosinglets. We consider the general situation where the neutrino masses are not necessarily given by $m_D^2/M$, where $m_D$ and $M$ are the Dirac and Majorana mass terms respectively. The consequent mixing between the light and heavy neutrinos is then not suppressed, and we treat it as an independent parameter in the analysis. It turns out that $\mu-e$ conversion is an important experiment in placing limits on the heavy mass scale ($M$) and the mixing. Mixings among light neutrinos are constrained by neutrinoless double beta decay, as well as by solar and atmospheric neutrino experiments. Detailed one-loop calculations for lepton number violating vertices are provided.Comment: Revtex file,TRI-PP-94-1,VPI-IHEP-94-1, 23 pages, a compressed for 8 figures is appende

Optical and Radio Properties of Extragalactic Sources Observed by the FIRST and SDSS Surveys

We discuss the optical and radio properties of 30,000 FIRST sources positionally associated with an SDSS source in 1230 deg$^2$ of sky. The majority (83%) of the FIRST sources identified with an SDSS source brighter than r=21 are optically resolved. We estimate an upper limit of 5% for the fraction of quasars with broad-band optical colors indistinguishable from those of stars. The distribution of quasars in the radio flux -- optical flux plane supports the existence of the "quasar radio-dichotomy"; 8% of all quasars with i<18.5 are radio-loud and this fraction seems independent of redshift and optical luminosity. The radio-loud quasars have a redder median color by 0.08 mag, and a 3 times larger fraction of objects with red colors. FIRST galaxies represent 5% of all SDSS galaxies with r<17.5, and 1% for r<20, and are dominated by red galaxies. Magnitude and redshift limited samples show that radio galaxies have a different optical luminosity distribution than non-radio galaxies selected by the same criteria; when galaxies are further separated by their colors, this result remains valid for both blue and red galaxies. The distributions of radio-to-optical flux ratio are similar for blue and red galaxies in redshift-limited samples; this similarity implies that the difference in their luminosity functions, and resulting selection effects, are the dominant cause for the preponderance of red radio galaxies in flux-limited samples. We confirm that the AGN-to-starburst galaxy number ratio increases with radio flux, and find that radio emission from AGNs is more concentrated than radio emission from starburst galaxies (abridged).Comment: submitted to AJ, color gif figures, PS figures available from [email protected]

β-Catenin-Independent Activation of TCF1/LEF1 in Human Hematopoietic Tumor Cells through Interaction with ATF2 Transcription Factors

The role of Wnt signaling in embryonic development and stem cell maintenance is well established and aberrations leading to the constitutive up-regulation of this pathway are frequent in several types of human cancers. Upon ligand-mediated activation, Wnt receptors promote the stabilization of β-catenin, which translocates to the nucleus and binds to the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to regulate the expression of Wnt target genes. When not bound to β-catenin, the TCF/LEF proteins are believed to act as transcriptional repressors. Using a specific lentiviral reporter, we identified hematopoietic tumor cells displaying constitutive TCF/LEF transcriptional activation in the absence of β-catenin stabilization. Suppression of TCF/LEF activity in these cells mediated by an inducible dominant-negative TCF4 (DN-TCF4) inhibited both cell growth and the expression of Wnt target genes. Further, expression of TCF1 and LEF1, but not TCF4, stimulated TCF/LEF reporter activity in certain human cell lines independently of β-catenin. By a complementary approach in vivo, TCF1 mutants, which lacked the ability to bind to β-catenin, induced Xenopus embryo axis duplication, a hallmark of Wnt activation, and the expression of the Wnt target gene Xnr3. Through generation of different TCF1-TCF4 fusion proteins, we identified three distinct TCF1 domains that participate in the β-catenin-independent activity of this transcription factor. TCF1 and LEF1 physically interacted and functionally synergized with members of the activating transcription factor 2 (ATF2) family of transcription factors. Moreover, knockdown of ATF2 expression in lymphoma cells phenocopied the inhibitory effects of DN-TCF4 on the expression of target genes associated with the Wnt pathway and on cell growth. Together, our findings indicate that, through interaction with ATF2 factors, TCF1/LEF1 promote the growth of hematopoietic malignancies in the absence of β-catenin stabilization, thus establishing a new mechanism for TCF1/LEF1 transcriptional activity distinct from that associated with canonical Wnt signaling