A Coupled Experimental and Computational Approach to Quantify Deleterious Hemodynamics, Vascular Alterations, and Mechanisms of Long-Term Morbidity in Response to Aortic Coarctati

Introduction Coarctation of the aorta (CoA) is associated with morbidity despite treatment. Although mechanisms remain elusive, abnormal hemodynamics and vascular biomechanics are implicated. We present a novel approach that facilitates quantification of coarctation-induced mechanical alterations and their impact on vascular structure and function, without genetic or confounding factors. Methods Rabbits underwent thoracic CoA at 10 weeks of age (~ 9 human years) to induce a 20 mm Hg blood pressure (BP) gradient using permanent or dissolvable suture thereby replicating untreated and corrected CoA. Computational fluid dynamics (CFD) was performed using imaging and BP data at 32 weeks to quantify velocity, strain and wall shear stress (WSS) for comparison to vascular structure and function as revealed by histology and myograph results. Results Systolic and mean BP was elevated in CoA compared to corrected and control rabbits leading to vascular thickening, disorganization and endothelial dysfunction proximally and distally. Corrected rabbits had less severe medial thickening, endothelial dysfunction, and stiffening limited to the proximal region despite 12 weeks of normal BP (~ 4 human years) after the suture dissolved. WSS was elevated distally for CoA rabbits, but reduced for corrected rabbits. Discussion These findings are consistent with alterations in humans. We are now poised to investigate mechanical contributions to mechanisms of morbidity in CoA using these methods

Chronology of dune development in the White River Badlands, northern Great Plains, USA

Aeolian dune field chronologies provide important information on drought history on the Great Plains. The White River Badlands (WRB) dunes are located approximately 60 km north of the Nebraska Sand Hills (NSH), in the western section of the northern Great Plains. Clifftop dunes, sand sheets, and stabilized northwest-southeast trending parabolic dunes are found on upland mesas and buttes, locally called tables. The result of this study is a dune stabilization history determined from samples collected from stratigraphic exposures and dune crests. Thirty-seven OSL ages, from this and previous investigations, show three periods of dune activity: 1) ~21,000 years ago to 12,000 years ago (a), 2) ~9 to 6 ka, and 3) post-700 a. Stratigraphic exposures and low-relief dune forms preserve evidence of late Pleistocene and middle Holocene dune development, while high-relief dune crests preserve evidence of late Holocene dune development. Results of 12 OSL ages from the most recent dune activation event indicate that Medieval Climate Anomaly (MCA) droughts and Little Ice Age (LIA) droughts caused dune reactivation on the tables. Dune reactivation was accompanied by other drought-driven geomorphological responses in the WRB, including fluvial incision of the prairie and formation of sod tables. Regional significance of the MCA and LIA droughts is supported by similarities in the aeolian chronologies of the NSH at 700–600 a and some western Great Plains dune fields at 420–210 a. Aerial photographs of the WRB show little activity during the Dust Bowl droughts of the 1930s

Mapping the Galactic Halo I. The `Spaghetti' Survey

We describe a major survey of the Milky Way halo designed to test for kinematic substructure caused by destruction of accreted satellites. We use the Washington photometric system to identify halo stars efficiently for spectroscopic followup. Tracers include halo giants (detectable out to more than 100 kpc), blue horizontal branch stars, halo stars near the main sequence turnoff, and the ``blue metal-poor stars'' of Preston et al (1994). We demonstrate the success of our survey by showing spectra of stars we have identified in all these categories, including giants as distant as 75 kpc. We discuss the problem of identifying the most distant halo giants. In particular, extremely metal-poor halo K dwarfs are present in approximately equal numbers to the distant giants for V fainter than 18, and we show that our method will distinguish reliably between these two groups of metal-poor stars. We plan to survey 100 square degrees at high galactic latitude, and expect to increase the numbers of known halo giants, BHB stars and turnoff stars by more than an order of magnitude. In addition to the strong test that this large sample will provide for the question `was the Milky Way halo accreted from satellite galaxies?', we will improve the accuracy of mass measurements of the Milky Way beyond 50 kpc via the kinematics of the many distant giants and BHB stars we will find. We show that one of our first datasets constrains the halo density law over galactocentric radii of 5-20 kpc and z heights of 2-15 kpc. The data support a flattened power-law halo with b/a of 0.6 and exponent -3.0. More complex models with a varying axial ratio may be needed with a larger dataset.Comment: 55 pages, 22 figures, to appear in the Astronomical Journa

DBS Under FCC and International Regulation

This Article examines the legal and technological development of DBS in both the domestic and international fora. Part II examines the development of DBS and information policy concerning DBS in the United States. The Article then in part III discusses the international positions of the developed nations, the developing countries, and the Soviet bloc on the DBS issues and reveals the results thus far in the policy debate among these nations and the United States. Part IV concludes the Article with a brief outline of the possibilities for international cooperation to solve the DBS controversy

Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p= 4.89 x 10 - 57) , high mitotic index (p= 5.25 x 10 - 28), pleomorphism (p= 6.31 x 10-19), ER negative (p= 9.02 x 10-35 ), PR negative (p= 9.24 x 10-24 ), triple negative phenotype (p= 6.67 x 10-21) , PAM50.Her2 (p=5.19 x 10-13 ), PAM50.Basal (p=2.7 x 10-41), PAM50.LumB (p=1.56 x 10-26), integrative molecular cluster 1 (intClust.1) ( p=7.47 x 10-12), intClust.5 (p=4.05 x 10-12) and intClust. 10 (p=7.59 x 10-38 ) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p=4.4 x 10-16) and multivariate analysis (p=9.19 x 10-7). At the protein level, in ER positive tumours , FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps< 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps<0.05). In ER positive as well as in ER negative tumours, FEN1 protein over expression is associated with poor survival in univariate and multivariate analysis (ps<0.01). In ovarian epithelial cancers , similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps<0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer

Assessment of algorithms for mitosis detection in breast cancer histopathology images

The proliferative activity of breast tumors, which is routinely estimated by counting of mitotic figures in hematoxylin and eosin stained histology sections, is considered to be one of the most important prognostic markers. However, mitosis counting is laborious, subjective and may suffer from low inter-observer agreement. With the wider acceptance of whole slide images in pathology labs, automatic image analysis has been proposed as a potential solution for these issues. In this paper, the results from the Assessment of Mitosis Detection Algorithms 2013 (AMIDA13) challenge are described. The challenge was based on a data set consisting of 12 training and 11 testing subjects, with more than one thousand annotated mitotic figures by multiple observers. Short descriptions and results from the evaluation of eleven methods are presented. The top performing method has an error rate that is comparable to the inter-observer agreement among pathologists