LATENT RANK CHANGE DETECTION FOR ANALYSIS OF SPLICE-JUNCTION MICROARRAYS WITH NONLINEAR EFFECTS

Alternative splicing of gene transcripts greatly expands the functional capacity of the genome, and certain splice isoforms may indicate specific disease states such as cancer. Splice junction microarrays interrogate thousands of splice junctions, but data analysis is difficult and error prone because of the increased complexity compared to differential gene expression analysis. We present Rank Change Detection (RCD) as a method to identify differential splicing events based upon a straightforward probabilistic model comparing the over-or underrepresentation of two or more competing isoforms. RCD has advantages over commonly used methods because it is robust to false positive errors due to nonlinear trends in microarray measurements. Further, RCD does not depend on prior knowledge of splice isoforms, yet it takes advantage of the inherent structure of mutually exclusive junctions, and it is conceptually generalizable to other types of splicing arrays or RNA-Seq. RCD specifically identifies the biologically important cases when a splice junction becomes more or less prevalent compared to other mutually exclusive junctions. The example data is from different cell lines of glioblastoma tumors assayed with Agilent microarrays.

Association Between Increased Platelet P-Selectin Expression and Obesity in Patients With Type 2 Diabetes A BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) substudy

OBJECTIVE- To determine whether obesity increases platelet reactivity and thrombin activity in patients with type 2 diabetes plus stable coronary artery disease. RESEARCH DESIGN AND METHODS- We assessed platelet reactivity and markers of thrombin generation and activity in 193 patients from nine clinical sites of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). Blood taken at the time of enrollment was used for assay of the concentration of prothrombin fragment 1.2 (PT1.2, released when prothrombin is activated) and fibrinopeptide A (FPA, released when fibrinogen is cleaved). Platelet activation was identified with the use of flow cytometry in response to 0, 0.2, and 1 mu mol/l adenosine diphosphate (ADP). RESULTS- Concentrations of FPA, PT1.2, and platelet activation in the absence of agonist were low. Greater BMI was associated with higher platelet reactivity in response to 1 mu m ADP as assessed by surface expression of P-selectin (r = 0.29, P < 0.0001) but not reflected by the binding of fibrinogen to activated glycoprotein IIb-IIIa. BMI was not associated with concentrations of FPA or PT1.2. Platelet reactivity correlated negatively with A1C (P < 0.04), was not related to the concentration Of triglycerides in blood, and did not correlate with the concentration of C-reactive peptide. CONCLUSIONS- Among patients enrolled in this substudy of BARI 2D, a greater BMI was associated with higher platelet reactivity at the time of enrollment. Our results suggest that obesity and insulin resistance that accompanies obesity may influence platelet reactivity in patients with type 2 diabetes.

Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss

We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling.

Hemostatic changes and clinical sequelae after on-pump compared with off-pump coronary artery bypass surgery: a prospective randomized study

Objective To delineate the effects of extracorporeal bypass on biomarkers of hemostasis, fibrinolysis, and inflammation and clinical sequelae. Methods Patients were assigned prospectively and randomly to either on-pump (n=41) or off-pump (n=51) coronary bypass surgery. The concentrations of C-reactive protein, fibrinogen, D-dimer, and plasminogen activator inhibitor type-1 in blood were quantified before and after (1 and 24 h) surgery. Similar surgical and anesthetic procedures were used for both groups. Clinical events were assessed during initial hospitalization and at the end of I year. Results The concentrations of plasminogen activator inhibitor type-1 and D-dimer were greater compared with preoperative values 1 and 24 h after surgery in both groups, but their concentrations increased to a greater extent 24 h after surgery in the on-pump group (P<0.01). The concentration of C-reactive protein did not change appreciably immediately after surgery in either group but increased in a parallel manner 24 h after either on-pump or off-pump surgery (P<0.01). Bypass surgery in the on-pump group was associated with greater blood loss during surgery and more bleeding after surgery (P <= 0.01). The incidence of all other complications was similar in the two groups. Conclusion On-pump surgery was associated with biochemical evidence of a prothrombotic state early after surgery but no greater incidence of thrombotic events was observed. The prothrombotic state might be a consequence of extracorporeal bypass, compensation in response to more bleeding, or both in patients undergoing on-pump surgery. Coron Artery Dis 20:100-105 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans

The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge-rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector -based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4(+) T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.

Upper limit on the cosmic-ray photon flux above 10(19) eV using the surface detector of the Pierre Auger Observatory

A method is developed to search for air showers initiated by photons using data recorded by the surface detector of the Auger Observatory. The approach is based on observables sensitive to the longitudinal shower development, the signal risetime and the curvature of the shower front. Applying this method to the data, tipper limits on the flux of photons of 3.8 x 10(-3), 2.5 x 10(-3), and 2.2 x 10(-3) km(-2) sr(-1) yr(-1) above 10(19) eV, 2 x 10(19) eV, and 4 x 10(19) eV are derived, with corresponding limits on the fraction of photons being 2.0%, 5.1%, and 31% (all limits at 95% c.l.). These photon limits disfavor certain exotic models of sources of cosmic rays. The results also show that the approach adopted by the Auger Observatory to calibrate the shower energy is not strongly biased by a contamination from photons. (C) 2008 Elsevier B.V. All rights reserved.

Correlation of the highest-energy cosmic rays with the positions of nearby active galactic nuclei

Data collected by the Pierre Auger Observatory provide evidence for anisotropy in the arrival directions of the cosmic rays with the highest-energies, which are correlated with the positions of relatively nearby active galactic nuclei (AGN) [Pierre Auger Collaboration, Science 318 (2007) 938]. The correlation has maximum significance for cosmic rays with energy greater than similar to 6 x 10(19) eV and AGN at a distance less than similar to 75 Mpc. We have confirmed the anisotropy at a confidence level of more than 99% through a test with parameters specified a priori, using an independent data set. The observed correlation is compatible with the hypothesis that cosmic rays with the highest-energies originate from extra-galactic sources close enough so that their flux is not significantly attenuated by interaction with the cosmic background radiation (the Greisen-Zatsepin-Kuz`min effect). The angular scale of the correlation observed is a few degrees, which suggests a predominantly light composition unless the magnetic fields are very weak outside the thin disk of our galaxy. Our present data do not identify AGN as the sources of cosmic rays unambiguously, and other candidate sources which are distributed as nearby AGN are not ruled out. We discuss the prospect of unequivocal identification of individual sources of the highest-energy cosmic rays within a few years of continued operation of the Pierre Auger Observatory. (C) 2008 Elsevier B.V. All rights reserved.

Advanced functionality for radio analysis in the Offline software framework of the Pierre Auger Observatory

The advent of the Auger Engineering Radio Array (AERA) necessitates the development of a powerful framework for the analysis of radio measurements of cosmic ray air showers. As AERA performs ""radio-hybrid"" measurements of air shower radio emission in coincidence with the surface particle detectors and fluorescence telescopes of the Pierre Auger Observatory, the radio analysis functionality had to be incorporated in the existing hybrid analysis solutions for fluorescence and surface detector data. This goal has been achieved in a natural way by extending the existing Auger Offline software framework with radio functionality. In this article, we lay out the design, highlights and features of the radio extension implemented in the Auger Offline framework. Its functionality has achieved a high degree of sophistication and offers advanced features such as vectorial reconstruction of the electric field, advanced signal processing algorithms, a transparent and efficient handling of FFTs, a very detailed simulation of detector effects, and the read-in of multiple data formats including data from various radio simulation codes. The source code of this radio functionality can be made available to interested parties on request. (C) 2011 Elsevier B.V. All rights reserved.

Longitudinal scaling property of the charge balance function in Au plus Au collisions at root s(NN)=200 GeV

We present measurements of the charge balance function, from the charged particles, for diverse pseudorapidity and transverse momentum ranges in Au + Au collisions at root S(NN) = 200 GeV using the STAR detector at RHIC. We observe that the balance function is boost-invariant within the pseudorapidity coverage vertical bar-1.3, 1.3 vertical bar. The balance function properly scaled by the width of the observed pseudorapidity window does not depend on the position or size of the pseudorapidity window. This scaling property also holds for particles in different transverse momentum ranges. In addition, we find that the width of the balance function decreases monotonically with increasing transverse momentum for all centrality classes. (c) 2010 Elsevier B.V. All rights reserved.

Observation of an Antimatter Hypernucleus

Nuclear collisions recreate conditions in the universe microseconds after the Big Bang. Only a very small fraction of the emitted fragments are light nuclei, but these states are of fundamental interest. We report the observation of antihypertritons-comprising an antiproton, an antineutron, and an antilambda hyperon-produced by colliding gold nuclei at high energy. Our analysis yields 70 +/- 17 antihypertritons (3/Lambda(H) over bar) and 157 +/- 30 hypertritons ((3)(Lambda)H). The measured yields of (3)(Lambda)H (3/Lambda(H) over bar) and (3)He ((3)(He) over bar) are similar, suggesting an equilibrium in coordinate and momentum space populations of up, down, and strange quarks and antiquarks, unlike the pattern observed at lower collision energies. The production and properties of antinuclei, and of nuclei containing strange quarks, have implications spanning nuclear and particle physics, astrophysics, and cosmology.

System size dependence of associated yields in hadron-triggered jets STAR Collaboration

We present results on the system size dependence of high transverse momentum di-hadron correlations at root s(NN) = 200 GeV as measured by STAR at RHIC. Measurements in d + Au, Cu + Cu and Au + Au collisions reveal similar jet-like near-side correlation yields (correlations at small angular separation Delta phi similar to 0, Delta eta similar to 0) for all systems and centralities. Previous measurements have shown Chat the away-side (Delta phi similar to pi) yield is suppressed in heavy-ion collisions. We present measurements of the away-side Suppression as a function of transverse momentum and centrality in Cu + Cu and Au + Au collisions. The suppression is found to be similar in Cu + Cu and An + An collisions at a similar number of participants. The results are compared to theoretical calculations based on the patron quenching model and the modified fragmentation model. The observed differences between data and theory indicate that the correlated yields presented here will further constrain dynamic energy loss models and provide information about the dynamic density profile in heavy-ion collisions. (C) 2009 Elsevier B.V. All rights reserved.

Center of mass energy and system-size dependence of photon production at forward rapidity at RHIC

We present the multiplicity and pseudorapidity distributions of photons produced in Au + Au and Cu + Cu collisions at root(s)NN = 62.4 and 200 GeV. The photons are measured in the region -3.7 < eta < -2.3 using the photon Multiplicity detector in the STAR experiment at RHIC. The number of photons produced per average number of participating nucleon pairs increases with the beam energy and is independent of (lie collision centrality. For collisions with similar average numbers of participating nucleons the photon multiplicities are observed to be similar for An + Au and Cu + Cu collisions at a given beam energy. The ratios of the number of charged particles to photons in the measured pseudorapidity range are found to be 1.4 +/- 0.1 and 1.2 +/- 0.1 for root(s)NN = 62.4 and 200 GeV, respectively. The energy dependence of this ratio could reflect varying contributions from baryons to charged particles, while mesons are the dominant contributors to photon production in the given kinematic region. The photon pseudorapidity distributions normalized by average number of participating nucleon pairs, when plotted as a function of eta-Y(beam), are found to follow a longitudinal scaling independent of centrality and colliding ion species at both beam energies. (C) 2009 Elsevier B.V. All rights reserved.

Observation of the antimatter helium-4 nucleus

High-energy nuclear collisions create an energy density similar to that of the Universe microseconds after the Big Bang(1); in both cases, matter and antimatter are formed with comparable abundance. However, the relatively short-lived expansion in nuclear collisions allows antimatter to decouple quickly from matter, and avoid annihilation. Thus, a high-energy accelerator of heavy nuclei provides an efficient means of producing and studying antimatter. The antimatter helium-4 nucleus ((4)(He) over bar), also known as the anti-alpha ((alpha) over bar), consists of two antiprotons and two antineutrons (baryon number B = -4). It has not been observed previously, although the alpha-particle was identified a century ago by Rutherford and is present in cosmic radiation at the ten per cent level(2). Antimatter nuclei with B -1 have been observed only as rare products of interactions at particle accelerators, where the rate of antinucleus production in high-energy collisions decreases by a factor of about 1,000 with each additional antinucleon(3-5). Here we report the observation of (4)<(He) over bar, the heaviest observed antinucleus to date. In total, 18 (4)(He) over bar counts were detected at the STAR experiment at the Relativistic Heavy Ion Collider (RHIC; ref. 6) in 10(9) recorded gold-on-gold (Au+Au) collisions at centre-of-mass energies of 200 GeV and 62 GeV per nucleon-nucleon pair. The yield is consistent with expectations from thermodynamic(7) and coalescent nucleosynthesis(8) models, providing an indication of the production rate of even heavier antimatter nuclei and a benchmark for possible future observations of (4)(He) over bar in cosmic radiation.

Energy and system size dependence of phi meson production in Cu plus Cu and Au plus Au collisions

We study the beam-energy and system-size dependence of phi meson production (using the hadronic decay mode phi -> K(+) K(-)) by comparing the new results from Cu + Cu collisions and previously reported Au + Au collisions at root s(NN) = 62.4 and 200 GeV measured in the STAR experiment at RHIC. Data presented in this Letter are from mid-rapidity (vertical bar y vertical bar < 0.5) for 0.4 < p(T) < 5 GeV/c. At a given beam energy, the transverse momentum distributions for phi mesons are observed to be similar in yield and shape for Cu + Cu and Au + Au colliding systems with similar average numbers of participating nucleons. The phi meson yields in nucleus-nucleus collisions, normalized by the average number of participating nucleons, are found to be enhanced relative to those from p + p collisions. The enhancement for phi mesons lies between strange hadrons having net strangeness = 1 (K(-) and <(A)over bar>) and net strangeness = 2 (Xi). The enhancement for phi mesons is observed to be higher at root s(NN) = 200 GeV compared to 62.4 GeV. These observations for the produced phi(s (s) over bar) mesons clearly suggest that, at these collision energies, the source of enhancement of strange hadrons is related to the formation of a dense partonic medium in high energy nucleus-nucleus collisions and cannot be alone due to canonical suppression of their production in smaller systems. (C) 2009 Elsevier B.V. All rights reserved.

Trigger and aperture of the surface detector array of the Pierre Auger Observatory

The surface detector array of the Pierre Auger Observatory consists of 1600 water-Cherenkov detectors, for the study of extensive air showers (EAS) generated by ultra-high-energy cosmic rays. We describe the trigger hierarchy, from the identification of candidate showers at the level of a single detector, amongst a large background (mainly random single cosmic ray muons), up to the selection of real events and the rejection of random coincidences. Such trigger makes the surface detector array fully efficient for the detection of EAS with energy above 3 x 10(18) eV, for all zenith angles between 0 degrees and 60 degrees, independently of the position of the impact point and of the mass of the primary particle. In these range of energies and angles, the exposure of the surface array can be determined purely on the basis of the geometrical acceptance. (C) 2009 Elsevier B.V. All rights reserved.