A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance

In the initial scale-up batches of the experimental drug substance AMG 517, a pair of unexpected impurities was observed by HPLC. Analysis of data from initial LC-MS experiments indicated the presence of two dimer-like molecules. One impurity had an additional sulfur atom incorporated into its structure relative to the other impurity. Isolation of the impurities was performed, and further structural elucidation experiments were conducted with high-resolution LC-MS and 2D NMR. The dimeric structures were confirmed, with one of the impurities having an unexpected C-S-C linkage. Based on the synthetic route of AMG 517, it was unlikely that these impurities were generated during the last two steps of the process. Stress studies on the enriched impurities were carried out to further confirm the existence of the C-S-C linkage in the benzothiazole portion of AMG 517. Further investigation revealed that these two dimeric impurities originated from existing impurities in the AMG 517 starting material, N-acetyl benzothiazole. The characterization of these two dimeric impurities allowed for better quality control of new batches of the N-acetyl benzothiazole starting material. As a result, subsequent batches of AMG 517 contained no reportable levels of these two impuritie

Benchtop flow-NMR for rapid online monitoring of RAFT and free radical polymerisation in batch and continuous reactors

A “Benchtop” NMR spectrometer is used for detailed monitoring of controlled and free radical polymerisations performed in batch and continuous reactors both offline and in real-time. This allows detailed kinetic analysis with unprecedented temporal resolution for reactions which reach near completion in under five minutes

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

A search for point sources of EeV photons

Measurements of air showers made using the hybrid technique developed with the fluorescence and surface detectors of the Pierre Auger Observatory allow a sensitive search for point sources of EeV photons anywhere in the exposed sky. A multivariate analysis reduces the background of hadronic cosmic rays. The search is sensitive to a declination band from -85{\deg} to +20{\deg}, in an energy range from 10^17.3 eV to 10^18.5 eV. No photon point source has been detected. An upper limit on the photon flux has been derived for every direction. The mean value of the energy flux limit that results from this, assuming a photon spectral index of -2, is 0.06 eV cm^-2 s^-1, and no celestial direction exceeds 0.25 eV cm^-2 s^-1. These upper limits constrain scenarios in which EeV cosmic ray protons are emitted by non-transient sources in the Galaxy.Comment: 28 pages, 10 figures, accepted for publication in The Astrophysical Journa

Reconstruction of inclined air showers detected with the Pierre Auger Observatory

We describe the method devised to reconstruct inclined cosmic-ray air showers with zenith angles greater than $60^\circ$ detected with the surface array of the Pierre Auger Observatory. The measured signals at the ground level are fitted to muon density distributions predicted with atmospheric cascade models to obtain the relative shower size as an overall normalization parameter. The method is evaluated using simulated showers to test its performance. The energy of the cosmic rays is calibrated using a sub-sample of events reconstructed with both the fluorescence and surface array techniques. The reconstruction method described here provides the basis of complementary analyses including an independent measurement of the energy spectrum of ultra-high energy cosmic rays using very inclined events collected by the Pierre Auger Observatory.Comment: 27 pages, 19 figures, accepted for publication in Journal of Cosmology and Astroparticle Physics (JCAP

The rapid atmospheric monitoring system of the Pierre Auger Observatory

The Pierre Auger Observatory is a facility built to detect air showers produced by cosmic rays above 10(17) eV. During clear nights with a low illuminated moon fraction, the UV fluorescence light produced by air showers is recorded by optical telescopes at the Observatory. To correct the observations for variations in atmospheric conditions, atmospheric monitoring is performed at regular intervals ranging from several minutes (for cloud identification) to several hours (for aerosol conditions) to several days (for vertical profiles of temperature, pressure, and humidity). In 2009, the monitoring program was upgraded to allow for additional targeted measurements of atmospheric conditions shortly after the detection of air showers of special interest, e. g., showers produced by very high-energy cosmic rays or showers with atypical longitudinal profiles. The former events are of particular importance for the determination of the energy scale of the Observatory, and the latter are characteristic of unusual air shower physics or exotic primary particle types. The purpose of targeted (or 'rapid') monitoring is to improve the resolution of the atmospheric measurements for such events. In this paper, we report on the implementation of the rapid monitoring program and its current status. The rapid monitoring data have been analyzed and applied to the reconstruction of air showers of high interest, and indicate that the air fluorescence measurements affected by clouds and aerosols are effectively corrected using measurements from the regular atmospheric monitoring program. We find that the rapid monitoring program has potential for supporting dedicated physics analyses beyond the standard event reconstruction

The Rapid Atmospheric Monitoring System of the Pierre Auger Observatory

The Pierre Auger Observatory is a facility built to detect air showers produced by cosmic rays above 10^17 eV. During clear nights with a low illuminated moon fraction, the UV fluorescence light produced by air showers is recorded by optical telescopes at the Observatory. To correct the observations for variations in atmospheric conditions, atmospheric monitoring is performed at regular intervals ranging from several minutes (for cloud identification) to several hours (for aerosol conditions) to several days (for vertical profiles of temperature, pressure, and humidity). In 2009, the monitoring program was upgraded to allow for additional targeted measurements of atmospheric conditions shortly after the detection of air showers of special interest, e.g., showers produced by very high-energy cosmic rays or showers with atypical longitudinal profiles. The former events are of particular importance for the determination of the energy scale of the Observatory, and the latter are characteristic of unusual air shower physics or exotic primary particle types. The purpose of targeted (or "rapid") monitoring is to improve the resolution of the atmospheric measurements for such events. In this paper, we report on the implementation of the rapid monitoring program and its current status. The rapid monitoring data have been analyzed and applied to the reconstruction of air showers of high interest, and indicate that the air fluorescence measurements affected by clouds and aerosols are effectively corrected using measurements from the regular atmospheric monitoring program. We find that the rapid monitoring program has potential for supporting dedicated physics analyses beyond the standard event reconstruction

Production of sexuals in a fission-performing ant: Dual effects of queen pheromones and colony size

Models based on the kin selection theory predict that in social hymenopterans, queens may favor a lower investment in the production of sexuals than workers. However, in perennial colonies, this conflict may be tuned down by colony-level selection because of the trade off between colony survival and reproductive allocation. In this study, we present a survey of sexual production in colonies of Aphaenogaster senilis, a common species of ant in the Iberian Peninsula. Similar to most species that reproduce by fission, males were found in large excess compared to gynes (172:1). Sexuals were more likely to be found in queenless than in queenright (QR) field colonies. However, we also found a few gynes and numerous males in very large QR colonies. We compared these data with those available in the literature for A. rudis, a congeneric species from North America that has independent colony founding. The sex ratio in this species was only five males for each female, and sexuals were mostly found in QR nests, irrespective of colony size. We confirmed queen inhibition of sexual production in A. senilis in laboratory experiments and provide evidence that this inhibition is mediated by a nonvolatile pheromone. To seek the potential source of such a queen pheromone, we analyzed the secretions of two conspicuous exocrine glands, the Dufour's and postpharyngeal glands (DG and PPG, respectively) in both queens and workers. Both secretions were composed of hydrocarbons, but that of DG also contained small quantities of tetradecanal and hexadecanal. The hydrocarbon profile of the DG and PPG showed notable caste specificity suggesting a role in caste-related behavior. The PPG secretions also differed between colonies suggesting its role in colony-level recognition. We suggest that in A. senilis, there are two modes of colony fission: First, in very large colonies, gynes are produced, probably because of the dilution of the queen pheromone, and consequently one or more gynes leave the mother colony with workers and brood to found a new nest. This is beneficial at the colony level because it avoids the production of costly sexuals in small colonies. However, because the queen and workers have different optima for sexual production, we hypothesize that queens tend to overproduce the pheromone to delay their production. This in turn may drive workers to leave the mother colony during nest relocation and to produce sexuals once they are away from the queen's influence, creating a second mode of colony fission. © 2007 Springer-Verlag.Peer Reviewe

Identifying clouds over the Pierre Auger Observatory using infrared satellite data

We describe a new method of identifying night-time clouds over the Pierre Auger Observatory using infrared data from the Imager instruments on the GOES-12 and GOES-13 satellites. We compare cloud. identifications resulting from our method to those obtained by the Central Laser Facility of the Auger Observatory. Using our new method we can now develop cloud probability maps for the 3000 km(2) of the Pierre Auger Observatory twice per hour with a spatial resolution of similar to 2.4 km by similar to 5.5 km. Our method could also be applied to monitor cloud cover for other ground-based observatories and for space-based observatories. (C) 2013 Elsevier B.V. All rights reserved.The successful installation, commissioning, and operation of the Pierre Auger Observatory would not have been possible without the strong commitment and effort from the technical and adminis- trative staff in Malargüe. We are very grateful to the following agencies and organiza- tions for financial support: Comisión Nacional de Energía Atómica, Fundación Antorchas, Gobierno De La Provincia de Mendoza, Municipalidad de Malargüe, NDM Holdings and Valle Las Leñas, in gratitude for their continuing cooperation over land access, Argentina; the Australian Research Council; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundação de Amparo à Pesquisa do Estado de Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Ministério de Ciência e Tecnolo- gia (MCT), Brazil; AVCR AV0Z10100502 and AV0Z10100522, GAAV KJB100100904, MSMT-CR LA08016, LG11044, MEB111003, MSM0021620859, LA08015, TACR TA01010517 and GA UK 119810, Czech Republic; Centre de Calcul IN2P3/CNRS, Centre Na- tional de la Recherche Scientifique (CNRS), Conseil Régional Ile-de- France, Département Physique Nucléaire et Corpusculaire (PNC- IN2P3/CNRS), Département Sciences de l’Univers (SDU-INSU/ CNRS), France; Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Finanzministeri- um Baden-Württemberg, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen, Ministerium für Wissenschaft, Forschung und Kunst, Baden-Württemberg, Germany; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), Italy; Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico; Ministerie van Ond- erwijs, Cultuur en Wetenschap, Nederlandse Organisatie voor Wet- enschappelijk Onderzoek (NWO), Stichting voor Fundamenteel Onderzoek der Materie (FOM), Netherlands; Ministry of Science and Higher Education, Grant Nos. N N202 200239 and N N202 207238, Poland; Portuguese national funds and FEDER funds with- in COMPETE - Programa Operacional Factores de Competitividade through Fundação para a Ciência e a Tecnologia, Portugal; Roma- nian Authority for Scientific Research ANCS, CNDI-UEFISCDI part- nership projects nr.20/2012 and nr.194/2012, project nr.1/ ASPERA2/2012 ERA-NET and PN-II-RU-PD-2011-3-0145-17, Roma- nia; Ministry for Higher Education, Science, and Technology, Slove- nian Research Agency, Slovenia; Comunidad de Madrid, FEDER funds, Ministerio de Ciencia e Innovación and Consolider-Ingenio 2010 (CPAN), Xunta de Galicia, Spain; The Leverhulme Foundation, Science and Technology Facilities Council, United Kingdom; Department of Energy, Contract Nos. DE-AC02-07CH11359, DE- FR02-04ER41300, DE-FG02-99ER41107, National Science Founda- tion, Grant No. 0450696, The Grainger Foundation USA; NAFO- STED, Vietnam; Marie Curie-IRSES/EPLANET, European Particle Physics Latin American Network, European Union 7th Framework Program, Grant No. PIRSES-2009-GA-246806; and UNESCO. We would like to thank the former Michigan Tech students: Nathan Kelley-Hoskins, Kyle Luck and Arin Nelson for their impor- tant contribution to the development of this paper. We would like to thank NOAA for the GOES satellite data that we freely down- loaded from their website. Also, we would like to mention in these acknowledgments Dr. Steve Ackerman and Dr. Tony Schreiner for very valuable conversationsPeer reviewe

Constraints on the origin of cosmic rays above 101810^{18} eV from large scale anisotropy searches in data of the Pierre Auger Observatory

A thorough search for large scale anisotropies in the distribution of arrival directions of cosmic rays detected above $10^{18}$ eV at the Pierre Auger Observatory is reported. For the first time, these large scale anisotropy searches are performed as a function of both the right ascension and the declination and expressed in terms of dipole and quadrupole moments. Within the systematic uncertainties, no significant deviation from isotropy is revealed. Upper limits on dipole and quadrupole amplitudes are derived under the hypothesis that any cosmic ray anisotropy is dominated by such moments in this energy range. These upper limits provide constraints on the production of cosmic rays above $10^{18}$ eV, since they allow us to challenge an origin from stationary galactic sources densely distributed in the galactic disk and emitting predominantly light particles in all directions.Peer Reviewe