Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype

Techniques for measuring aerosol attenuation using the Central Laser Facility at the Pierre Auger Observatory

The Pierre Auger Observatory in Malargüe, Argentina, is designed to study the properties of ultra-high energy cosmic rays with energies above 10(18) eV. It is a hybrid facility that employs a Fluorescence Detector to perform nearly calorimetric measurements of Extensive Air Shower energies. To obtain reliable calorimetric information from the FD, the atmospheric conditions at the observatory need to be continuously monitored during data acquisition. In particular, light attenuation due to aerosols is an important atmospheric correction. The aerosol concentration is highly variable, so that the aerosol attenuation needs to be evaluated hourly. We use light from the Central Laser Facility, located near the center of the observatory site, having an optical signature comparable to that of the highest energy showers detected by the FD. This paper presents two procedures developed to retrieve the aerosol attenuation of fluorescence light from CLF laser shots. Cross checks between the two methods demonstrate that results from both analyses are compatible, and that the uncertainties are well understood. The measurements of the aerosol attenuation provided by the two procedures are currently used at the Pierre Auger Observatory to reconstruct air shower data

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

Depth Of Maximum Of Air-shower Profiles At The Pierre Auger Observatory. I. Measurements At Energies Above 1017.8ev

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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

Ultrahigh energy neutrinos at the pierre auger observatory

The observation of ultrahigh energy neutrinos (UHEs) has become a priority in experimental astroparticle physics. UHEs can be detected with a variety of techniques. In particular, neutrinos can interact in the atmosphere (downward-going ) or in the Earth crust (Earth-skimming ), producing air showers that can be observed with arrays of detectors at the ground. With the surface detector array of the Pierre Auger Observatory we can detect these types of cascades. The distinguishing signature for neutrino events is the presence of very inclined showers produced close to the ground (i.e., after having traversed a large amount of atmosphere). In this work we review the procedure and criteria established to search for UHEs in the data collected with the ground array of the Pierre Auger Observatory.This includes Earth-skimming as well as downward-going neutrinos. No neutrino candidates have been found, which allows us to place competitive limits to the diffuse flux of UHEs in the EeV range and above

Description of Atmospheric Conditions at the Pierre Auger Observatory using the Global Data Assimilation System (GDAS)

Atmospheric conditions at the site of a cosmic ray observatory must be known for reconstructing observed extensive air showers. The Global Data Assimilation System (GDAS) is a global atmospheric model predicated on meteorological measurements and numerical weather predictions. GDAS provides altitude-dependent profiles of the main state variables of the atmosphere like temperature, pressure, and humidity. The original data and their application to the air shower reconstruction of the Pierre Auger Observatory are described. By comparisons with radiosonde and weather station measurements obtained on-site in Malarg\"ue and averaged monthly models, the utility of the GDAS data is shown

Search for patterns by combining cosmic-ray energy and arrival directions at the Pierre Auger Observatory

Energy-dependent patterns in the arrival directions of cosmic rays are searched for using data of the Pierre Auger Observatory. We investigate local regions around the highest-energy cosmic rays with E > = 6×1019 eV by analyzing cosmic rays with energies above E > = 5×1018 eV arriving within an angular separation of approximately 15°. We characterize the energy distributions inside these regions by two independent methods, one searching for angular dependence of energy-energy correlations and one searching for collimation of energy along the local system of principal axes of the energy distribution. No significant patterns are found with this analysis. The comparison of these measurements with astrophysical scenarios can therefore be used to obtain constraints on related model parameters such as strength of cosmic-ray deflection and density of point sources

Ultrahigh energy neutrinos at the Pierre Auger observatory

The observation of ultrahigh energy neutrinos (UHEνs) has become a priority in experimental astroparticle physics. UHEνs can be detected with a variety of techniques. In particular, neutrinos can interact in the atmosphere (downward-going ν) or in the Earth crust (Earth-skimming ν), producing air showers that can be observed with arrays of detectors at the ground. With the surface detector array of the Pierre Auger Observatory we can detect these types of cascades. The distinguishing signature for neutrino events is the presence of very inclined showers produced close to the ground (i.e., after having traversed a large amount of atmosphere). In this work we review the procedure and criteria established to search for UHEνs in the data collected with the ground array of the Pierre Auger Observatory. This includes Earth-skimming as well as downward-going neutrinos. No neutrino candidates have been found, which allows us to place competitive limits to the diffuse flux of UHEνs in the EeV range and above.P. Abreu ... K. B. Barber ... J. A. Bellido ... R. W. Clay ... M. J. Cooper ... B. R. Dawson ... T. A. Harrison ... A. E. Herve ... V. C. Holmes ... J. Sorokin ... P. Wahrlich ... B. J. Whelan ... et al

An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach

Acyl-CoA dehydrogenase 9 (ACAD9), linked to chromosome 3q21.3, is one of a family of multimeric mitochondrial flavoenzymes that catalyze the degradation of fatty acyl-CoA from the carnitine shuttle via β-oxidation (He et al. 2007). ACAD9, specifically, is implicated in the processing of palmitoyl-CoA and long-chain unsaturated substrates, but unlike other acyl-CoA dehydrogenases (ACADs), it has a significant role in mitochondrial complex I assembly (Nouws et al. 2010 & 2014). Mutations in this enzyme typically cause mitochondrial complex I deficiency, as well as a mild defect in long chain fatty acid metabolism (Haack et al. 2010, Kirby et al. 2004, Mcfarland et al. 2003, Nouws et al. 2010 & 2014). The clinical phenotype of ACAD9 deficiency and the associated mitochondrial complex I deficiency reflect this unique duality, and symptoms are variable in severity and onset. Patients classically present with cardiac dysfunction due to hypertrophic cardiomyopathy. Other common features include Leigh syndrome, macrocephaly, and liver disease (Robinson et al. 1998). We report the case of an 11-month old girl presenting with microcephaly, dystonia, and lactic acidosis, concerning for a mitochondrial disorder, but atypical for ACAD9 deficiency. Muscle biopsy showed mitochondrial proliferation, but normal mitochondrial complex I activity. The diagnosis of ACAD9 deficiency was not initially considered, due both to these findings and to her atypical presentation. Biochemical assay for ACAD9 deficiency is not clinically available. Family trio-based whole exome sequencing (WES) identified 2 compound heterozygous mutations in the ACAD9 gene. This discovery led to optimized treatment of her mitochondrial dysfunction, and supplementation with riboflavin, resulting in clinical improvement. There have been fewer than 25 reported cases of ACAD9 deficiency in the literature to date. We review these and compare them to the unique features of our patient. ACAD9 deficiency should be considered in the differential diagnosis of patients with lactic acidosis, seizures, and other symptoms of mitochondrial disease, including those with normal mitochondrial enzyme activities. This case demonstrates the utility of WES, in conjunction with biochemical testing, for the appropriate diagnosis and treatment of disorders of energy metabolism