Spatio-temporal regulation of Wnt and retinoic acid signaling by tbx16/spadetail during zebrafish mesoderm differentiation

<p>Abstract</p> <p>Background</p> <p>A complex network of signaling pathways and transcription factors regulates vertebrate mesoderm development. Zebrafish mutants provide a powerful tool for examining the roles of individual genes in such a network. <it>spadetail (spt) </it>is a mutant with a lesion in <it>tbx16</it>, a T-box transcription factor involved in mesoderm development; the mutant phenotype includes disrupted primitive red blood cell formation as well as disrupted somitogenesis. Despite much recent progress, the downstream targets of <it>tbx16 </it>remain incompletely understood. The current study was carried out to test whether any of the five major signaling pathways are regulated by <it>tbx16 </it>during two specific stages of mesoderm development: primitive red blood cell formation in the intermediate mesoderm and somite formation in the tail paraxial mesoderm. This test was performed using Gene Set Enrichment Analysis, which identifies coordinated changes in expression among <it>a priori </it>sets of genes associated with biological features or processes.</p> <p>Results</p> <p>Our Gene Set Enrichment Analysis results identify Wnt and retinoic acid signaling as likely downstream targets of <it>tbx16 </it>in the developing zebrafish intermediate mesoderm, the site of primitive red blood cell formation. In addition, such results identify retinoic acid signaling as a downstream target of <it>tbx16 </it>in the developing zebrafish posterior somites. Finally, using candidate gene identification and <it>in situ </it>hybridization, we provide expression domain information for 25 additional genes downstream of <it>tbx16 </it>that are outside of both pathways; 23 were previously unknown downstream targets of <it>tbx16</it>, and seven had previously uncharacterized expression in zebrafish.</p> <p>Conclusions</p> <p>Our results suggest that (1) <it>tbx16 </it>regulates Wnt signaling in the developing zebrafish intermediate mesoderm, the site of primitive red blood cell formation, and (2) <it>tbx16 </it>regulates retinoic acid signaling at two distinct embryonic locations and developmental stages, which may imply ongoing spatio-temporal regulation throughout mesoderm development.</p

Assessing Regulatory Impact Analyses: The Failure of Agencies to Comply With Executive Order 12,866

None.Environment, Health and Safety, Regulatory Reform

Assessing the Quality of Regulatory Impact Analyses

This study provides the most comprehensive evaluation of the quality of recent economic analyses that agencies conduct before finalizing major regulations. We construct a new dataset that includes analyses of forty-eight major health, safety, and environmental regulations from mid-1996 to mid-1999. This dataset provides detailed information on a variety of issues, including an agency's treatment of benefits, costs, net benefits, discounting, and uncertainty. We use this dataset to assess the quality of recent economic analyses and to determine the extent to which they are consistent with President Clinton's Executive Order 12866 and the benefit-cost guidelines issued by the Office of Management and Budget (OMB). We find that economic analyses prepared by regulatory agencies typically do not provide enough information to make decisions that will maximize the efficiency or effectiveness of a rule. Agencies quantified net benefits for only 29 percent of the rules. Agencies failed to discuss alternatives in 27 percent of the rules and quantified costs and benefits of alternatives in only 31 percent of the rules. Our findings strongly suggest that agencies generally failed to comply with the executive order and adhere to the OMB guidelines. We offer specific suggestions for improving the quality of analysis and the transparency of the regulatory process, including writing clear executive summaries, making analyses available on the Internet, providing more careful consideration of alternatives to a regulation, and estimating net benefits of a regulation when data on costs and benefits are provided.

Too Much Interference: Injection of Double-Stranded RNA Has Nonspecific Effects in the Zebrafish Embryo

AbstractWe have investigated the ability of double-stranded RNA (dsRNA) to inhibit gene expression in a vertebrate, the zebrafish, Danio rerio. Injection of dsRNA corresponding to the T-box gene tbx16/spadetail (spt) into early wild-type embryos caused a rapid and dramatic loss of tbx16/spt mRNA in the blastula. mRNAs from the papc, tbx6, and gata1 genes, which depend on tbx16/spt function for their expression, were reduced, apparently mimicking the spt mutant phenotype. However, mRNAs from a number of genes that are unaffected by the spt mutation, such as β catenin, stat3, and no tail, were also lost, indicating that the “interference” effect of tbx16/spt dsRNA was not restricted to the endogenous tbx16/spt mRNA. We compared the effects of injecting dsRNA from the zebrafish tbx16/spadetail, nieuwkoid/bozozok, and Brachyury/no tail genes with dsRNA from the bacterial lacZ gene. In each case the embryos displayed a variable syndrome of abnormalities at 12 and 24 h postfertilization. In blind studies, we could not distinguish between the effects of the various dsRNAs. Consistent with a common effect of dsRNA, regardless of sequence, injection of dsRNA from the lacZ gene was likewise effective in strongly reducing tbx16/spt and β catenin mRNA in the blastula. These findings indicate that, despite published reports, the current methodology of double-stranded RNA interference is not a practical technique for investigating zygotic gene function during early zebrafish development

Learning Rewards from Linguistic Feedback

We explore unconstrained natural language feedback as a learning signal for artificial agents. Humans use rich and varied language to teach, yet most prior work on interactive learning from language assumes a particular form of input (e.g., commands). We propose a general framework which does not make this assumption, using aspect-based sentiment analysis to decompose feedback into sentiment about the features of a Markov decision process. We then perform an analogue of inverse reinforcement learning, regressing the sentiment on the features to infer the teacher's latent reward function. To evaluate our approach, we first collect a corpus of teaching behavior in a cooperative task where both teacher and learner are human. We implement three artificial learners: sentiment-based "literal" and "pragmatic" models, and an inference network trained end-to-end to predict latent rewards. We then repeat our initial experiment and pair them with human teachers. All three successfully learn from interactive human feedback. The sentiment models outperform the inference network, with the "pragmatic" model approaching human performance. Our work thus provides insight into the information structure of naturalistic linguistic feedback as well as methods to leverage it for reinforcement learning.Comment: 9 pages, 4 figures. AAAI '2

Polarized Narrow-Line Emission from the Nucleus of NGC 4258

The detection of polarized continuum and line emission from the nucleus of NGC 4258 by Wilkes et al. (1995) provides an intriguing application of the unified model of Seyfert nuclei to a galaxy in which there is known to be an edge-on, rotating disk of molecular gas surrounding the nucleus. Unlike most Seyfert nuclei, however, NGC 4258 has strongly polarized narrow emission lines. To further investigate the origin of the polarized emission, we have obtained spectropolarimetric observations of the NGC 4258 nucleus at the Keck-II telescope. The narrow-line polarizations range from 1.0% for [S II] 6716 to 13.9% for the [O II] 7319,7331 blend, and the position angle of polarization is oriented nearly parallel to the projected plane of the masing disk. A correlation between critical density and degree of polarization is detected for the forbidden lines, indicating that the polarized emission arises from relatively dense (n_e > 10^4 cm^-3) gas. An archival Hubble Space Telescope narrow-band [O III] image shows that the narrow-line region has a compact, nearly unresolved core, implying a FWHM size of <2.5 pc. We discuss the possibility that the polarized emission might arise from the accretion disk itself and become polarized by scattering within the disk atmosphere. A more likely scenario is an obscuring torus or strongly warped disk surrounding the inner portion of a narrow-line region which is strongly stratified in density. The compact size of the narrow-line region implies that the obscuring structure must be smaller than ~2.5 pc in diameter.Comment: To appear in the Astronomical Journal. 13 pages, including 1 table and 4 figures. Uses emulateapj.st

Origin of intermittent accretion-powered X-ray oscillations in neutron stars with millisecond spin periods

We have shown previously that many of the properties of persistent accretion-powered millisecond pulsars can be understood if their X-ray emitting areas are near their spin axes and move as the accretion rate and structure of the inner disk vary. Here we show that this "nearly aligned moving spot model" may also explain the intermittent accretion-powered pulsations that have been detected in three weakly magnetic accreting neutron stars. We show that movement of the emitting area from very close to the spin axis to about 10 degrees away can increase the fractional rms amplitude from less than about 0.5 percent, which is usually undetectable with current instruments, to a few percent, which is easily detectable. The second harmonic of the spin frequency usually would not be detected, in agreement with observations. The model produces intermittently detectable oscillations for a range of emitting area sizes and beaming patterns, stellar masses and radii, and viewing directions. Intermittent oscillations are more likely in stars that are more compact. In addition to explaining the sudden appearance of accretion-powered millisecond oscillations in some neutron stars with millisecond spin periods, the model explains why accretion-powered millisecond oscillations are relatively rare and predicts that the persistent accretion-powered millisecond oscillations of other stars may become undetectable for brief intervals. It suggests why millisecond oscillations are frequently detected during the X-ray bursts of some neutron stars but not others and suggests mechanisms that could explain the occasional temporal association of intermittent accretion-powered oscillations with thermonuclear X-ray bursts.Comment: 5 pages, 1 figure; includes additional discussion and updated references; accepted for publication in ApJ