A targeted gene panel that covers coding, non-coding and short tandem repeat regions improves the diagnosis of patients with neurodegenerative diseases

Genetic testing for neurodegenerative diseases (NDs) is highly challenging because of genetic heterogeneity and overlapping manifestations. Targeted-gene panels (TGPs), coupled with next-generation sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes. Due to the technical limitations inherent in NGS and TGPs, short tandem repeat (STR) variations are often ignored. However, STR expansions are known to cause such NDs as Huntington\u27s disease and spinocerebellar ataxias type 3 (SCA3). Here, we studied the clinical utility of a custom-made TGP that targets 199 NDs and 311 ND-associated genes on 118 undiagnosed patients. At least one known or likely pathogenic variation was found in 54 patients; 27 patients demonstrated clinical profiles that matched the variants; and 16 patients whose original diagnosis were refined. A high concordance of variant calling were observed when comparing the results from TGP and whole-exome sequencing of four patients. Our in-house STR detection algorithm has reached a specificity of 0.88 and a sensitivity of 0.82 in our SCA3 cohort. This study also uncovered a trove of novel and recurrent variants that may enrich the repertoire of ND-related genetic markers. We propose that a combined comprehensive TGPs-bioinformatics pipeline can improve the clinical diagnosis of NDs

Watson Brake, A Middle Archaic Mound Complex in Northeast Louisiana

Middle Archaic earthen mound complexes in the lower Mississippi valley are remote antecedents of the famous but much younger Poverty Point earthworks. Watson Brake is the largest and most complex of these early mound sites. Wry extensive coring and stratigraphic studies, aided by 25 radiocarbon dates and six huninescence dates, show that minor earthworks were begun here at ca. 3500 B.C. in association with an oval arrangement of burned rock middens at the edge of a stream terrace. The full extent of the first earthworks is not yet known. Substantial moundraising began ca. 3350 B.C. and continued in stages until some time after 3000 B.C. when the site was abandoned. All 11 mounds and their connecting ridges were occupied between building bursts. Soils,formed on some of these temporary surfaces, while lithics. fire-cracked rock. and,fired clay/loam objects became scattered throughout the mound fills. Faunal and floral remains from a basal midden indicate all-season occupation, supported by broad-spectrum foraging centered on nuts, fish, and deer All the overlying fills are so acidic that organics have not survived. The area enclosed by the mounds was kept clean of debris, suggesting its use as ritual space. The reasons why such elaborate activities first occurred here remain elusive. However some building bursts covary with very well-documented increases in El Nino/Southern Oscillation events. During such rapid increases in ENSO frequencies, rainfall becomes extremely erratic and unpredictable. It may be that early moundraising was a communal response to new stresses of droughts and flooding that created a suddenly more unpredictable food base

Hubble Space Telescope NICMOS Polarization Observations of Three Edge-on Massive YSOs

Massive young stellar objects (YSOs), like low-mass YSOs, appear to be surrounded by optically thick envelopes and/or disks and have regions, often bipolar, that are seen in polarized scattered light at near-infrared wavelengths. We are using the 0.2'' spatial resolution of NICMOS on Hubble Space Telescope to examine the structure of the disks and outflow regions of massive YSOs in star-forming regions within a few kpc of the Sun. Here we report on 2 micron polarimetry of NGC 6334 V and S255 IRS1. NGC 6334 V consists of a double-lobed bright reflection nebula seen against a dark region, probably an optically thick molecular cloud. Our polarization measurements show that the illuminating star lies ~ 2'' south of the line connecting the two lobes; we do not detect this star at 2 micron, but there are a small radio source and a mid-infrared source at this location. S255 IRS1 consists of two YSOs (NIRS1 and NIRS3) with overlapping scattered light lobes and luminosities corresponding to early B stars. Included in IRS1 is a cluster of stars from whose polarization we determine the local magnetic field direction. Neither YSO has its scattered light lobes aligned with this magnetic field. The line connecting the scattered light lobes of NIRS1 is twisted symmetrically around the star; the best explanation is that the star is part of a close binary and the outflow axis of NIRS1 is precessing as a result of non-coplanar disk and orbit. The star NIRS3 is also offset from the line connecting its two scattered light lobes. We suggest that all three YSOs show evidence of episodic ejection of material as they accrete from dense, optically thick envelopes.Comment: 39 pages, 7 figures, 4 tables To be published in The Astrophysical Journa

A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe