Novel lines of Pax6-/- embryonic stem cells exhibit reduced neurogenic capacity without loss of viability

<p>Abstract</p> <p>Background</p> <p>Embryonic stem (ES) cells can differentiate into all cell types and have been used extensively to study factors affecting neuronal differentiation. ES cells containing mutations in known genes have the potential to provide useful in vitro models for the study of gene function during neuronal differentiation. Recently, mouse ES cell lines lacking the neurogenic transcription factor Pax6 were reported; neurons derived from these <it>Pax6</it>^-/-ES cells died rapidly after neuronal differentiation in vitro.</p> <p>Results</p> <p>Here we report the derivation of new lines of <it>Pax6</it>^-/-ES cells and the assessment of their ability to survive and differentiate both in vitro and in vivo. Neurons derived from our new <it>Pax6</it>^-/-lines were viable and continued to elaborate processes in culture under conditions that resulted in the death of neurons derived from previously reported <it>Pax6</it>^-/-ES cell lines. The new lines of <it>Pax6</it>^-/-ES cells showed reduced neurogenic potential, mimicking the effects of loss of Pax6 in vivo. We used our new lines to generate <it>Pax6</it>^-/-↔ <it>Pax6</it>^+/+chimeras in which the mutant cells survived and displayed the same phenotypes as <it>Pax6</it>^-/-cells in <it>Pax6</it>^-/-↔ <it>Pax6</it>^+/+chimeras made by embryo aggregation.</p> <p>Conclusions</p> <p>We suggest that loss of Pax6 from ES cells reduces their neurogenic capacity but does not necessarily result in the death of derived neurons. We offer these new lines as additional tools for those interested in the generation of chimeras and the analysis of in vitro ES cell models of Pax6 function during neuronal differentiation, embryonic and postnatal development.</p

The Metagalactic Ionizing Radiation Field at Low Redshift

We compute the ionizing radiation field at low redshift, arising from Seyferts, QSOs, and starburst galaxies. This calculation combines recent Seyfert luminosity functions, extrapolated ultraviolet fluxes from our IUE-AGN database, and a new intergalactic opacity model based on Hubble Space Telescope and Keck Ly-alpha absorber surveys. At z = 0 for AGN only, our best estimate for the specific intensity at 1 Ryd is I_0 = 1.3 (+0.8/-0.5) x 10^-23 ergs/cm^2/s/Hz/sr, independent of H_0, Omega_0, and Lambda. The one-sided ionizing photon flux is Phi_ion = 3400 (+2100/-1300) photons/cm^2/s, and the H I photoionization rate is Gamma_HI = 3.2 (+2.0/-1.2) x 10^-14 s^-1 for alpha_s = 1.8. We also derive Gamma_ HI for z = 0 - 4. These error ranges reflect uncertainties in the spectral indexes for the ionizing EUV (alpha_s = 1.8 +/- 0.3) and the optical/UV (alpha_UV = 0.86 +/- 0.05), the IGM opacity model, the range of Seyfert luminosities (0.001 - 100 L*) and the completeness of the luminosity functions. Our estimate is a factor of three lower than the most stringent upper limits on the ionizing background (Phi_ion < 10^4 photons/cm^2/s) obtained from H-alpha observations in external clouds, and it lies within the range implied by other indirect measures. Starburst galaxies with a sufficiently large Lyman continuum escape fraction, f_ esc > 0.05, may provide a comparable background to AGN, I_0 (z=0) = 1.1 (+1.5/-0.7) x 10^{-23). An additional component of the ionizing background of this magnitude would violate neither upper limits from H-alpha observations nor the acceptable range from other measurements.Comment: 30 pages, 9 figures, accepted for Astronomical J. (Oct. 1999

The Galaxy Luminosity Function and Luminosity Density at Redshift z=0.1

Using a catalog of 147,986 galaxy redshifts and fluxes from the Sloan Digital Sky Survey (SDSS), we measure the galaxy luminosity density at z = 0.1 in five optical bandpasses corresponding to the SDSS bandpasses shifted to match their rest-frame shape at z = 0.1. We denote the bands (0.1)u, (0.1)g, (0.1)r, (0.1)i, (0.1)z with lambda(eff) = (3216; 4240; 5595; 6792; 8111 Angstrom), respectively. To estimate the luminosity function, we use a maximum likelihood method that allows for a general form for the shape of the luminosity function,fits for simple luminosity and number evolution, incorporates the flux uncertainties, and accounts for the flux limits of the survey. We find luminosity densities at z = 0.1 expressed in absolute AB magnitudes in a Mpc(3) to be (-14.10 +/- 0.15, -15.18 +/- 0.03, - 15.90 +/- 0.03, -16.24 +/- 0.03, -16.56 +/- 0.02) in ((0.1)u, (0.1)g, (0.1)r, (0.1)i, (0.1)z), respectively, for a cosmological model with Omega(0) = 0.3, Omega(Lambda) = 0.7, and h = 1 and using SDSS Petrosian magnitudes. Similar results are obtained using Sersic model magnitudes, suggesting that flux from outside the Petrosian apertures is not a major correction. In the (0.1)r band, the best-fit Schechter function to our results has phi* = (1.49 +/- 0.04) x 10(-2) h(3) Mpc(-3), M-* - 5 log(10) h = - 20.44 +/- 0.01, and alpha = - 1.05 +/- 0.01. In solar luminosities, the luminosity density in (0.1)r is (1.84 +/- 0.04) x 10(8) h L-0.1r,L-. Mpc(-3). Our results in the (0.1)g band are consistent with other estimates of the luminosity density, from the Two-Degree Field Galaxy Redshift Survey and the Millennium Galaxy Catalog. They represent a substantial change ( similar to 0.5 mag) from earlier SDSS luminosity density results based on commissioning data, almost entirely because of the inclusion of evolution in the luminosity function model

Pharmacovigilance in hospice/palliative care: Net effect of haloperidol for delirium

Introduction: Prescribing practice in hospice/palliative care is largely extrapolated from other areas of clinical practice, with few studies of net medication effects (benefits and harms) in hospice/palliative care to guide prescribing decisions. Hospice/palliative care patients differ in multiple ways from better studied participant groups, hence the applicability of studies in other participant groups is uncertain. Haloperidol, a butyrophenone derivative and dopamine antagonist, is commonly prescribed for nausea, vomiting, and delirium in hospice/palliative care. Its frequent use in delirium occurs despite little evidence of the effect of antipsychotics on the untreated course of delirium. The aim of this study was to examine the immediate and short-term clinical benefits and harms of haloperidol for delirium in hospice/palliative care patients. Method: A consecutive cohort of participants from 14 centers across four countries who had haloperidol commenced for delirium were recruited. Data were collected at three time points: baseline, 48 hours (clinical benefits), and day 10 (clinical harms). Investigators were also able to report clinical harms at any time up to 14 days after it was commenced. Results: Of the 119 participants included, the average dose was 2.1 mg per 24 hours; 42 of 106 (35.2%) reported benefit at 48 hours. Harm was reported in 14 of 119 (12%) at 10 days, the most frequent being somnolence (n=11) and urinary retention (n=6). Seven participants had their medication ceased due to harms (2 for somnolence and 2 for rigidity). Approximately half (55/119) were still being treated with haloperidol after 10 days. Conclusion: Overall, 1 in 3 participants gained net clinical benefit at 10 days. © Copyright 2013, Mary Ann Liebert, Inc. 2013

Brief of Corporate Law Professors as Amici Curie in Support of Respondents

The Supreme Court has looked to the rights of corporate shareholders in determining the rights of union members and non-members to control political spending, and vice versa. The Court sometimes assumes that if shareholders disapprove of corporate political expression, they can easily sell their shares or exercise control over corporate spending. This assumption is mistaken. Because of how capital is saved and invested, most individual shareholders cannot obtain full information about corporate political activities, even after the fact, nor can they prevent their savings from being used to speak in ways with which they disagree. Individual shareholders have no “opt out” rights or practical ability to avoid subsidizing corporate political expression with which they disagree. Nor do individuals have the practical option to refrain from putting their savings into equity investments, as doing so would impose damaging economic penalties and ignore conventional financial guidance for individual investors

A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection

Funder: Isaac Newton Trust; funder-id: http://dx.doi.org/10.13039/501100004815Funder: Li Ka Shing Foundation; funder-id: http://dx.doi.org/10.13039/100007421Funder: Division of Intramural Research, National Institute of Allergy and Infectious Diseases; funder-id: http://dx.doi.org/10.13039/100006492Funder: Helsingin Yliopisto; funder-id: http://dx.doi.org/10.13039/100007797In the absence of effective antiviral therapy, HIV-1 evolves in response to the within-host environment, of which the immune system is an important aspect. During the earliest stages of infection, this process of evolution is very rapid, driven by a small number of CTL escape mutations. As the infection progresses, immune escape variants evolve under reduced magnitudes of selection, while competition between an increasing number of polymorphic alleles (i.e., clonal interference) makes it difficult to quantify the magnitude of selection acting upon specific variant alleles. To tackle this complex problem, we developed a novel multi-locus inference method to evaluate the role of selection during the chronic stage of within-host infection. We applied this method to targeted sequence data from the p24 and gp41 regions of HIV-1 collected from 34 patients with long-term untreated HIV-1 infection. We identify a broad distribution of beneficial fitness effects during infection, with a small number of variants evolving under strong selection and very many variants evolving under weaker selection. The uniquely large number of infections analysed granted a previously unparalleled statistical power to identify loci at which selection could be inferred to act with statistical confidence. Our model makes no prior assumptions about the nature of alleles under selection, such that any synonymous or non-synonymous variant may be inferred to evolve under selection. However, the majority of variants inferred with confidence to be under selection were non-synonymous in nature, and in most cases were have previously been associated with either CTL escape in p24 or neutralising antibody escape in gp41. We also identified a putative new CTL escape site (residue 286 in gag), and a region of gp41 (including residues 644, 648, 655 in env) likely to be associated with immune escape. Sites inferred to be under selection in multiple hosts have high within-host and between-host diversity although not all sites with high between-host diversity were inferred to be under selection at the within-host level. Our identification of selection at sites associated with resistance to broadly neutralising antibodies (bNAbs) highlights the need to fully understand the role of selection in untreated individuals when designing bNAb based therapies

Kepler-16: A Transiting Circumbinary Planet

We report the detection of a planet whose orbit surrounds a pair of low-mass stars. Data from the Kepler spacecraft reveal transits of the planet across both stars, in addition to the mutual eclipses of the stars, giving precise constraints on the absolute dimensions of all three bodies. The planet is comparable to Saturn in mass and size, and is on a nearly circular 229-day orbit around its two parent stars. The eclipsing stars are 20% and 69% as massive as the sun, and have an eccentric 41-day orbit. The motions of all three bodies are confined to within 0.5 degree of a single plane, suggesting that the planet formed within a circumbinary disk.Comment: Science, in press; for supplemental material see http://www.sciencemag.org/content/suppl/2011/09/14/333.6049.1602.DC1/1210923.Doyle.SOM.pd

Five Kepler target stars that show multiple transiting exoplanet candidates

We present and discuss five candidate exoplanetary systems identified with the Kepler spacecraft. These five systems show transits from multiple exoplanet candidates. Should these objects prove to be planetary in nature, then these five systems open new opportunities for the field of exoplanets and provide new insights into the formation and dynamical evolution of planetary systems. We discuss the methods used to identify multiple transiting objects from the Kepler photometry as well as the false-positive rejection methods that have been applied to these data. One system shows transits from three distinct objects while the remaining four systems show transits from two objects. Three systems have planet candidates that are near mean motion commensurabilities---two near 2:1 and one just outside 5:2. We discuss the implications that multitransiting systems have on the distribution of orbital inclinations in planetary systems, and hence their dynamical histories; as well as their likely masses and chemical compositions. A Monte Carlo study indicates that, with additional data, most of these systems should exhibit detectable transit timing variations (TTV) due to gravitational interactions---though none are apparent in these data. We also discuss new challenges that arise in TTV analyses due to the presence of more than two planets in a system.Comment: Accepted to Ap

Inosine can increase DNA's susceptibility to photo-oxidation by a Ru(II) complex due to structural change in the minor groove

Key to the development of DNA-targeting phototherapeutic drugs is determining the interplay between the photoactivity of the drug and its binding preference for a target sequence. For the photo- oxidising lambda-[Ru(TAP)2(dppz)]2+ (Ʌ-1) complex bound to either d{T1C2G3G4C5G6C7C8G9A10}2 (G9) or d{TCGGCGCCIA}2 (I9), the X- ray crystal structures shows the dppz intercalated at the terminal T1C2;G9A10 step or T1C2;I9A10 step. Thus substitution of the G9 nucleobase by inosine does not affect intercalation in the solid state although with I9 the dppz is more deeply inserted. In solution it is found that the extent of guanine photo-oxidation, and the rate of back electron transfer, as determined by ps and ns time-resolved infrared and transient visible absorption spectroscopy, is enhanced in I9, despite it containing the less oxidisable inosine. This is attributed to the nature of the binding in the minor groove due to the absence of an NH2 group. Similar behaviour and the same binding site in the crystal.are found for d{TTGGCGCCAA}2 (A9), In solution we propose that intercalation occurs at the C2G3;C8I9 or T2G3;C8A9 steps, respectively, with G3 the likely target for photo-oxidation. This demonstrates how changes in the minor groove (in this case removal of an NH2 group) can facilitate binding of Ru(II)dppz complexes and hence influence any sensitised reactions occurring at these sites. No similar enhancement of photooxidation on binding to I9 is found for the delta enantiomer

Can online self-reports assist in real-time identification of influenza vaccination uptake? A cross-sectional study of influenza vaccine-related tweets in the USA, 2013-2017

The Centers for Disease Control and Prevention (CDC) spend significant time and resources to track influenza vaccination coverage each influenza season using national surveys. Emerging data from social media provide an alternative solution to surveillance at both national and local levels of influenza vaccination coverage in near real time. This study aimed to characterise and analyse the vaccinated population from temporal, demographical and geographical perspectives using automatic classification of vaccination-related Twitter data. In this cross-sectional study, we continuously collected tweets containing both influenza-related terms and vaccine-related terms covering four consecutive influenza seasons from 2013 to 2017. We created a machine learning classifier to identify relevant tweets, then evaluated the approach by comparing to data from the CDC's FluVaxView. We limited our analysis to tweets geolocated within the USA. We assessed 1 124 839 tweets. We found strong correlations of 0.799 between monthly Twitter estimates and CDC, with correlations as high as 0.950 in individual influenza seasons. We also found that our approach obtained geographical correlations of 0.387 at the US state level and 0.467 at the regional level. Finally, we found a higher level of influenza vaccine tweets among female users than male users, also consistent with the results of CDC surveys on vaccine uptake. Significant correlations between Twitter data and CDC data show the potential of using social media for vaccination surveillance. Temporal variability is captured better than geographical and demographical variability. We discuss potential paths forward for leveraging this approach.</p