Plans for a 10-m Submillimeter-wave Telescope at the South Pole

A 10 meter diameter submillimeter-wave telescope has been proposed for the NSF Amundsen-Scott South Pole Station. Current evidence indicates that the South Pole is the best submillimeter-wave telescope site among all existing or proposed ground-based observatories. Proposed scientific programs place stringent requirements on the optical quality of the telescope design. In particular, reduction of the thermal background and offsets requires an off-axis, unblocked aperture, and the large field of view needed for survey observations requires shaped optics. This mix of design elements is well-suited for large scale (square degree) mapping of line and continuum radiation from submillimeter-wave sources at moderate spatial resolutions (4 to 60 arcsecond beam size) and high sensitivity (milliJansky flux density levels). the telescope will make arcminute angular scale, high frequency Cosmic Microwave Background measurements from the best possible ground-based site, using an aperture which is larger than is currently possible on orbital or airborne platforms. Effective use of this telescope will require development of large (1000 element) arrays of submillimeter detectors which are background-limited when illuminated by antenna temperatures near 50 K.Comment: 12 pages, 3 figure

SNLS Spectroscopy: Testing for Evolution in Type Ia Supernovae

Aims: We present a quantitative study of a new data set of high redshift Type Ia supernovae spectra, observed at the Gemini telescopes during the first 34 months of the Supernova Legacy Survey. During this time 123 supernovae candidates were observed, of which 87 have been identified as SNe Ia at a median redshift of z=0.720. Spectra from the entire second year of the survey and part of the third year (59 total SNe candidates with 46 confirmed SNe Ia) are published here for the first time. The spectroscopic measurements made on this data set are used determine if these distant SNe comprise a population similar to those observed locally. Methods: Rest-frame equivalent width and ejection velocity measurements are made on four spectroscopic features. Corresponding measurements are presented for a set of 167 spectra from 24 low-z SNe Ia from the literature. Results: We show that there exists a sample at high redshift with properties similar to nearby SNe. No significant difference was found between the distributions of measurements at low and high redsift for three of the features. The fourth feature displays a possible difference that should be investigated further. Correlations between Type Ia SNe properties and host galaxy morphology were also found to be similar at low and high z, and within each host galaxy class we see no evidence for redshift-evolution in SN properties. A new correlation between SNe Ia peak magnitude and the equivalent width of SiII absorption is presented. We demonstrate that this correlation reduces the scatter in SNe Ia luminosity distances in a manner consistent with the lightcurve shape-luminosity corrections that are used for Type Ia SNe cosmology. Conclusions: We show that this new sample of SNLS SNe Ia has spectroscopic properties similar to nearby objects. (Abridged)Comment: Accepted for publication in Astronomy and Astrophysic

Revised Thickness of the Lunar Crust from GRAIL Data: Implications for Lunar Bulk Composition

High-resolution gravity data from GRAIL have yielded new estimates of the bulk density and thickness of the lunar crust. The bulk density of the highlands crust is 2550 kg m-3. From a comparison with crustal composition measured remotely, this density implies a mean porosity of 12%. With this bulk density and constraints from the Apollo seismic experiment, the average global crustal thickness is found to lie between 34 and 43 km, a value 10 to 20 km less than several previous estimates. Crustal thickness is a central parameter in estimating bulk lunar composition. Estimates of the concentrations of refractory elements in the Moon from heat flow, remote sensing and sample data, and geophysical data fall into two categories: those with refractory element abundances enriched by 50% or more relative to Earth, and those with abundances the same as Earth. Settling this issue has implications for processes operating during lunar formation. The crustal thickness resulting from analysis of GRAIL data is less than several previous estimates. We show here that a refractory-enriched Moon is not require

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Functional and perceptive differences between conventional and advanced ankle foot orthoses in community ambulators post-limb trauma: the injuries managed with advanced bracing of the lower extremity (IM ABLE) study

IntroductionMany military service members and civilians suffer from lower extremity trauma. Despite recent advancements in lower limb bracing technology, it remains unclear whether these newer advanced braces offer improved comfort and functionality compared to conventional options. The IDEO (Intrepid Dynamic Exoskeletal Orthosis), a type of “advanced” orthosis was developed to assist in maintaining high functional performance in patients who have experienced high-energy lower extremity trauma and underwent limb salvage surgeries.MethodsA cross-sector multi-site initiative was completed to study the efficacy of advanced ankle foot orthoses (AFO) for lower limb trauma and injury compared to a conventional AFO. Following fitting, training, and accommodation, the subjects were assessed in each AFO system for mobility, self-reported function, safety and pain, and preference.ResultsThey preferred the advanced over the conventional AFO and the mobility and exertion perception improved with the advanced AFO with no difference in pain or overall health status scores.DiscussionThus, an advanced AFO is an option for trauma affecting the lower limb. Long-term studies are required to better understand the accommodation and learning process of using an advanced AFO

Analysis of RNA splicing defects in PITX2 mutants supports a gene dosage model of Axenfeld-Rieger syndrome

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is associated with mutations in the PITX2 gene that encodes a homeobox transcription factor. Several intronic PITX2 mutations have been reported in Axenfeld-Rieger patients but their effects on gene expression have not been tested. METHODS: We present two new families with recurrent PITX2 intronic mutations and use PITX2c minigenes and transfected cells to address the hypothesis that intronic mutations effect RNA splicing. Three PITX2 mutations have been analyzed: a G>T mutation within the AG 3' splice site (ss) junction associated with exon 4 (IVS4-1G>T), a G>C mutation at position +5 of the 5' (ss) of exon 4 (IVS4+5G>C), and a previously reported A>G substitution at position -11 of 3'ss of exon 5 (IVS5-11A>G). RESULTS: Mutation IVS4+5G>C showed 71% retention of the intron between exons 4 and 5, and poorly expressed protein. Wild-type protein levels were proportionally expressed from correctly spliced mRNA. The G>T mutation within the exon 4 AG 3'ss junction shifted splicing exclusively to a new AG and resulted in a severely truncated, poorly expressed protein. Finally, the A>G substitution at position -11 of the 3'ss of exon 5 shifted splicing exclusively to a newly created upstream AG and resulted in generation of a protein with a truncated homeodomain. CONCLUSION: This is the first direct evidence to support aberrant RNA splicing as the mechanism underlying the disorder in some patients and suggests that the magnitude of the splicing defect may contribute to the variability of ARS phenotypes, in support of a gene dosage model of Axenfeld-Rieger syndrome

Structure and Evolution of the Lunar Procellarum Region as Revealed by GRAIL Gravity Data

The Procellarum region is a broad area on the nearside of the Moon that is characterized by low elevations, thin crust, and high surface concentrations of the heat-producing elements uranium, thorium, and potassium. The Procellarum region has been interpreted as an ancient impact basin approximately 3200 km in diameter, though supporting evidence at the surface would have been largely obscured as a result of the great antiquity and poor preservation of any diagnostic features. Here we use data from the Gravity Recovery and Interior Laboratory (GRAIL) mission to examine the subsurface structure of Procellarum. The Bouguer gravity anomalies and gravity gradients reveal a pattern of narrow linear anomalies that border the Procellarum region and are interpreted to be the frozen remnants of lava-filled rifts and the underlying feeder dikes that served as the magma plumbing system for much of the nearside mare volcanism. The discontinuous surface structures that were earlier interpreted as remnants of an impact basin rim are shown in GRAIL data to be a part of this continuous set of quasi-rectangular border structures with angular intersections, contrary to the expected circular or elliptical shape of an impact basin. The spatial pattern of magmatic-tectonic structures bounding Procellarum is consistent with their formation in response to thermal stresses produced by the differential cooling of the province relative to its surroundings, coupled with magmatic activity driven by the elevated heat flux in the region

Greater white matter degeneration and lower structural connectivity in non-amnestic vs. amnestic Alzheimer’s disease

IntroductionMultimodal evidence indicates Alzheimer’s disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypothesized each non-amnestic AD syndrome would exhibit WM differences from amnestic and other non-amnestic syndromes.Materials and methodsParticipants included 45 cognitively normal (CN) individuals; 41 amnestic AD patients; and 67 patients with non-amnestic AD syndromes including logopenic-variant primary progressive aphasia (lvPPA, n = 32), posterior cortical atrophy (PCA, n = 17), behavioral variant AD (bvAD, n = 10), and corticobasal syndrome (CBS, n = 8). All had T1-weighted MRI and 30-direction diffusion-weighted imaging (DWI). We performed whole-brain deterministic tractography between 148 cortical and subcortical regions; connection strength was quantified by tractwise mean generalized fractional anisotropy. Regression models assessed effects of group and phenotype as well as associations with grey matter volume. Topological analyses assessed differences in persistent homology (numbers of graph components and cycles). Additionally, we tested associations of topological metrics with global cognition, disease duration, and DWI microstructural metrics.ResultsBoth amnestic and non-amnestic patients exhibited lower WM connection strength than CN participants in corpus callosum, cingulum, and inferior and superior longitudinal fasciculi. Overall, non-amnestic patients had more WM disease than amnestic patients. LvPPA patients had left-lateralized WM degeneration; PCA patients had reductions in connections to bilateral posterior parietal, occipital, and temporal areas. Topological analysis showed the non-amnestic but not the amnestic group had more connected components than controls, indicating persistently lower connectivity. Longer disease duration and cognitive impairment were associated with more connected components and fewer cycles in individuals’ brain graphs.DiscussionWe have previously reported syndromic differences in GM degeneration and tau accumulation between AD syndromes; here we find corresponding differences in WM tracts connecting syndrome-specific epicenters. Determining the reasons for selective WM degeneration in non-amnestic AD is a research priority that will require integration of knowledge from neuroimaging, biomarker, autopsy, and functional genetic studies. Furthermore, longitudinal studies to determine the chronology of WM vs. GM degeneration will be key to assessing evidence for WM-mediated tau spread

SNP genotyping to screen for a common deletion in CHARGE Syndrome

BACKGROUND: CHARGE syndrome is a complex of birth defects including coloboma, choanal atresia, ear malformations and deafness, cardiac defects, and growth delay. We have previously hypothesized that CHARGE syndrome could be caused by unidentified genomic microdeletion, but no such deletion was detected using short tandem repeat (STR) markers spaced an average of 5 cM apart. Recently, microdeletion at 8q12 locus was reported in two patients with CHARGE, although point mutation in CHD7 on chromosome 8 was the underlying etiology in most of the affected patients. METHODS: We have extended our previous study by employing a much higher density of SNP markers (3258) with an average spacing of approximately 800 kb. These SNP markers are diallelic and, therefore, have much different properties for detection of deletions than STRs. RESULTS: A global error rate estimate was produced based on Mendelian inconsistency. One marker, rs431722 exceeded the expected frequency of inconsistencies, but no deletion could be demonstrated after retesting the 4 inconsistent pedigrees with local flanking markers or by FISH with the corresponding BAC clone. Expected deletion detection (EDD) was used to assess the coverage of specific intervals over the genome by deriving the probability of detecting a common loss of heterozygosity event over each genomic interval. This analysis estimated the fraction of unobserved deletions, taking into account the allele frequencies at the SNPs, the known marker spacing and sample size. CONCLUSIONS: The results of our genotyping indicate that more than 35% of the genome is included in regions with very low probability of a deletion of at least 2 Mb

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts