Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer

Dispersive stabilization of the inverse cascade for the Kolmogorov flow

It is shown by perturbation techniques and numerical simulations that the inverse cascade of kink-antikink annihilations, characteristic of the Kolmogorov flow in the slightly supercritical Reynolds number regime, is halted by the dispersive action of Rossby waves in the beta-plane approximation. For beta tending to zero, the largest excited scale is proportional to the logarithm of one over beta and differs strongly from what is predicted by standard dimensional phenomenology which ignores depletion of nonlinearity.Comment: 4 pages, LATEX, 3 figures. v3: revised version with minor correction

Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder

OBJECTIVE: To describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia. METHODS: We performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures. RESULTS: Twenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days–13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance. CONCLUSION: MBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management

Superior Neuroprotective Efficacy of LAU-0901, a Novel Platelet-Activating Factor Antagonist, in Experimental Stroke

Platelet-activating factor (PAF) accumulates during cerebral ischemia, and inhibition of this process plays a critical role in neuronal survival. Recently, we demonstrated that LAU-0901, a novel PAF receptor antagonist, is neuroprotective in experimental stroke. We used magnetic resonance imaging in conjunction with behavior and immunohistopathology to expand our understanding of this novel therapeutic approach. Sprague–Dawley rats received 2 h middle cerebral artery occlusion (MCAo) and were treated with LAU-0901 (60 mg/kg) or vehicle 2 h from MCAo onset. Behavioral function, T2-weighted imaging (T2WI), and apparent diffusion coefficients were performed on days 1, 3, and 7 after MCAo. Infarct volume and number of GFAP, ED-1, and NeuN-positive cells were conducted on day 7. Behavioral deficit was significantly improved by LAU-0901 treatment compared to vehicle on days 1, 3, and 7. Total lesion volumes computed from T2WI were significantly reduced by LAU-0901 on days 1, 3, and 7 (by 83%, 90%, and 96%, respectively), which was consistent with decreased edema formation. Histopathology revealed that LAU-0901 treatment resulted in significant reduction of cortical and subcortical infarct volumes, attenuated microglial infiltration, and promoted astrocytic and neuronal survival. These findings suggest LAU-0901 is a promising neuroprotectant and provide the basis for future therapeutics in patients suffering ischemic stroke

Fermi LAT Observations of the Supernova Remnant W28 (G6.4-0.1)

We present detailed analysis of the two gamma-ray sources,1FGL J1801.3-2322c and 1FGL J1800.5-2359c,that have been found toward the supernova remnant(SNR) W28 with the Large Area Telescope(LAT) on board the Fermi Gamma-ray Space Telescope.1FGL J1801.3-2322c is found to be an extended source within the boundary of SNR W28,and to extensively overlap with the TeV gamma-ray source HESS J1801-233,which is associated with a dense molecular cloud interacting with the supernova remnant.The gamma-ray spectrum measured with LAT from 0.2--100 GeV can be described by a broken power-law function with a break of ~1GeV,and photon indices of 2.09$\pm$0.08(stat)$\pm$0.28(sys) below the break and 2.74$\pm$0.06(stat)$\pm$0.09(sys) above the break.Given the clear association between HESS J1801-233 and the shocked molecular cloud and a smoothly connected spectrum in the GeV--TeV band,we consider the origin of the gamma-ray emission in both GeV and TeV ranges to be the interaction between particles accelerated in the SNR and the molecular cloud.The decay of neutral pions produced in interactions between accelerated hadrons and dense molecular gas provide a reasonable explanation for the broadband gamma-ray spectrum. 1FGL J1800.5-2359c, located outside the southern boundary of SNR W28, cannot be resolved.An upper limit on the size of the gamma-ray emission was estimated to be ~16$'$ using events above ~2GeV under the assumption of a circular shape with uniform surface brightness. It appears to coincide with the TeV source HESS J1800-240B,which is considered to be associated with a dense molecular cloud that contains the ultra compact HII region W28A2(G5.89-0.39).We found no significant gamma-ray emission in the LAT energy band at the positions of TeV sources HESS J1800-230A and HESS J1800-230C.The LAT data for HESS J1800-230A combined with the TeV data points indicate a spectral break between 10GeV and 100GeV.Comment: 23 pages, 6 figures. Accepted for publication in the Astrophysical Journal. Corresponding authors: H. Katagiri, H. Tajima, T. Tanaka, and Y. Uchiyam

GeV Gamma-ray Flux Upper Limits from Clusters of Galaxies

The detection of diffuse radio emission associated with clusters of galaxies indicates populations of relativistic leptons infusing the intracluster medium. Those electrons and positrons are either injected into and accelerated directly in the intracluster medium, or produced as secondary pairs by cosmic-ray ions scattering on ambient protons. Radiation mechanisms involving the energetic leptons together with decay of neutral pions produced by hadronic interactions have the potential to produce abundant GeV photons. Here, we report on the search for GeV emission from clusters of galaxies using data collected by the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope (Fermi) from August 2008 to February 2010. Thirty-three galaxy clusters have been selected according to their proximity and high mass, X-ray flux and temperature, and indications of non-thermal activity for this study. We report upper limits on the photon flux in the range 0.2-100 GeV towards a sample of observed clusters (typical values 1-5 x 10^-9 ph cm^-2 s^-1) considering both point-like and spatially resolved models for the high-energy emission, and discuss how these results constrain the characteristics of energetic leptons and hadrons, and magnetic fields in the intracluster medium. The volume-averaged relativistic-hadron-to-thermal energy density ratio is found to be < 5-10% in several clusters.Comment: 9 pages, 3 tables, 1 figure, accepted for publication in ApJ Letter

Searches for Cosmic-Ray Electron Anisotropies with the Fermi Large Area Telescope

The Large Area Telescope on board the \textit{Fermi} satellite (\textit{Fermi}-LAT) detected more than 1.6 million cosmic-ray electrons/positrons with energies above 60 GeV during its first year of operation. The arrival directions of these events were searched for anisotropies of angular scale extending from $\sim$ 10 $^\circ$ up to 90$^\circ$, and of minimum energy extending from 60 GeV up to 480 GeV. Two independent techniques were used to search for anisotropies, both resulting in null results. Upper limits on the degree of the anisotropy were set that depended on the analyzed energy range and on the anisotropy's angular scale. The upper limits for a dipole anisotropy ranged from $\sim0.5$ to $\sim10$.Comment: 16 pages, 10 figures, accepted for publication in Physical Review D - contact authors: M.N. Mazziotta and V. Vasileio

Fermi-LAT observations of the exceptional gamma-ray outbursts of 3C 273 in September 2009

We present the light curves and spectral data of two exceptionally luminous gamma-ray outburts observed by the Large Area Telescope (LAT) experiment on board Fermi Gamma-ray Space Telescope from 3C 273 in September 2009. During these flares, having a duration of a few days, the source reached its highest gamma-ray flux ever measured. This allowed us to study in some details their spectral and temporal structures. The rise and decay are asymmetric on timescales of 6 hours, and the spectral index was significantly harder during the flares than during the preceding 11 months. We also found that short, very intense flares put out the same time-integrated energy as long, less intense flares like that observed in August 2009.Comment: Corresponding authors: E. Massaro, [email protected]; G. Tosti, [email protected]. 15 pages, 4 figures, published in The Astrophysical Journal Letters, Volume 714, Issue 1, pp. L73-L78 (2010

Fermi observations of high-energy gamma-ray emission from GRB 090217A

The Fermi observatory is advancing our knowledge of Gamma-Ray Bursts (GRBs) through pioneering observations at high energies, covering more than 7 decades in energy with the two on-board detectors, the Large Area Telescope (LAT) and the Gamma-ray Burst Monitor (GBM). Here we report on the observation of the long GRB 090217A which triggered the GBM and has been detected by the LAT with a significance greater than 9 sigma. We present the GBM and LAT observations and on-ground analyses, including the time-resolved spectra and the study of the temporal profile from 8 keV up to 1 GeV. All spectra are well reproduced by a Band model. We compare these observations to the first two LAT-detected, long bursts GRB 080825C and GRB 080916C. These bursts were found to have time-dependent spectra and exhibited a delayed onset of the high-energy emission, which are not observed in the case of GRB 090217A. We discuss some theoretical implications for the high-energy emission of GRBs.Comment: 17 pages, 4 figures. Contact Authors: Fred, Piron; Sara, Cutini; Andreas, von Kienli

Fermi Large Area Telescope Observations of the Cosmic-Ray Induced gamma-ray Emission of the Earth's Atmosphere

We report on measurements of the cosmic-ray induced gamma-ray emission of Earth's atmosphere by the Large Area Telescope onboard the Fermi Gamma-ray Space Telescope. The LAT has observed the Earth during its commissioning phase and with a dedicated Earth-limb following observation in September 2008. These measurements yielded 6.4 x 10^6 photons with energies >100MeV and ~250hours total livetime for the highest quality data selection. This allows the study of the spatial and spectral distributions of these photons with unprecedented detail. The spectrum of the emission - often referred to as Earth albedo gamma-ray emission - has a power-law shape up to 500 GeV with spectral index Gamma = 2.79+-0.06.Comment: Accepted for publication in PR