A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics

Probing the Dawn of Galaxies at z~9-12: New Constraints from HUDF12/XDF and CANDELS Data

We present a comprehensive analysis of z>8 galaxies based on ultra-deep WFC3/IR data. We constrain the evolution of the UV luminosity function (LF) and luminosity densities from z~11 to z~8 by exploiting all the WFC3/IR data over the Hubble Ultra-Deep Field from the HUDF09 and the new HUDF12 program, in addition to the HUDF09 parallel field data, as well as wider area WFC3/IR imaging over GOODS-South. Galaxies are selected based on the Lyman Break Technique in three samples centered around z~9, z~10 and z~11, with seven z~9 galaxy candidates, and one each at z~10 and z~11. We confirm a new z~10 candidate (with z=9.8+-0.6) that was not convincingly identified in our first z~10 sample. The deeper data over the HUDF confirms all our previous z>~7.5 candidates as genuine high-redshift candidates, and extends our samples to higher redshift and fainter limits (H_160~29.8 mag). We perform one of the first estimates of the z~9 UV LF and improve our previous constraints at z~10. Extrapolating the lower redshift UV LF evolution should have revealed 17 z~9 and 9 z~10 sources, i.e., a factor ~3x and 9x larger than observed. The inferred star-formation rate density (SFRD) in galaxies above 0.7 M_sun/yr decreases by 0.6+-0.2 dex from z~8 to z~9, in good agreement with previous estimates. The low number of sources found at z>8 is consistent with a very rapid build-up of galaxies across z~10 to z~8. From a combination of all current measurements, we find a best estimate of a factor 10x decrease in the SFRD from z~8 to z~10, following (1+z)^(-11.4+-3.1). Our measurements thus confirm our previous finding of an accelerated evolution beyond z~8, and signify a rapid build-up of galaxies with M_UV<-17.7 within only ~200 Myr from z~10 to z~8, in the heart of cosmic reionization.Comment: 21 pages, 13 figures, 6 tables; submitted to Ap

'I Sat Filling in This Form While Smoking and It Was Divine'. An Analysis of Free-Text Comments from Smokers Who Report They Have No Intention of Quitting in the Next Six Months

INTRODUCTION: Smokers unmotivated to quit are neglected by smoking cessation research. Free-text comment analysis is a potentially useful way to gain insight into this group's beliefs. AIMS: To analyse the free-text comments provided by smokers unmotivated to quit as part of a randomized controlled trial of computer-tailored feedback for smoking cessation. METHOD: A random sample of 58,660 smokers were sent a smoking behaviour questionnaire (SBQ). The responses and follow-up outcomes of those providing free-text comments were compared to those who did not to assess the representativeness of the former group of smokers. The comments of participants unmotivated to quit (631) were thematically analysed. RESULTS: Those who provided a comment differed from those who did not on variables including education level and quit attempts at six-month follow-up. Emergent themes included; justification of smoking and restricting smoking instead of quitting. CONCLUSIONS: The findings illustrate the value of free-text comments in identifying issues important to respondents. The identified themes highlight areas for future research in smokers unmotivated to quit including cutting down as a path to quitting and explicit messages regarding the inability of positive health behaviours to balance out the negative impact of smoking on health. Trial registration: Current Controlled Trials ISRCTN05385712

A Rest-frame Optical View on z~4 Galaxies I: Color and Age Distributions from Deep IRAC Photometry of the IUDF10 and GOODS Surveys

We present a study of rest-frame UV-to-optical color distributions for z~4 galaxies based on the combination of deep HST/ACS+WFC3/IR data with Spitzer/IRAC imaging. In particular, we use new, ultra-deep data from the IRAC Ultradeep Field program (IUDF10). Our sample contains a total of ~2600 galaxies selected as B-dropout Lyman Break Galaxies (LBGs) in the HUDF and one of its deep parallel fields, the HUDF09-2, as well as GOODS-North and South. This sample is used to investigate the UV continuum slopes beta and Balmer break colors (J_125-[4.5]) as a function of rest-frame optical luminosity. The [4.5] filter is chosen to avoid potential contamination by strong rest-frame optical emission lines. We find that galaxies at M_z<-21.5 (roughly corresponding to L*[z~4]) are significantly redder than their lower luminosity counterparts. The UV continuum slopes and the J_125-[4.5] colors are well correlated. The most simple explanation for this correlation is that the dust reddening at these redshifts is better described by an SMC-like extinction curve, rather than the typically assumed Calzetti reddening. After correcting for dust, we find that the galaxy population shows mean stellar population ages in the range 10^8.5 to 10^9 yr, with a dispersion of ~0.5 dex, and only weak trends as a function of luminosity. In contrast to some results from the literature, we find that only a small fraction of galaxies shows Balmer break colors which are consistent with extremely young ages, younger than 100 Myr. Under the assumption of smooth star-formation histories, this fraction is only 12-19% for galaxies at M_z<-19.75. Our results are consistent with a gradual build-up of stars and dust in galaxies at z>4, with only a small fraction of stars being formed in short, intense bursts of star-formation.Comment: 11 pages, 10 figures; submitted to Ap

Helical structures from an isotropic homopolymer model

We present Monte Carlo simulation results for square-well homopolymers at a series of bond lengths. Although the model contains only isotropic pairwise interactions, under appropriate conditions this system shows spontaneous chiral symmetry breaking, where the chain exists in either a left- or a right-handed helical structure. We investigate how this behavior depends upon the ratio between bond length and monomer radius.Comment: 10 pages, 3 figures, accepted for publication by Physical Review Letter