Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57

BackgroundTransient neonatal diabetes mellitus 1 (TNDM1) is a rare imprinting disorder characterized by intrautering growth retardation and diabetes mellitus usually presenting within the first six weeks of life and resolves by the age of 18 months. However, patients have an increased risk of developing diabetes mellitus type 2 later in life. Transient neonatal diabetes mellitus 1 is caused by overexpression of the maternally imprinted genes PLAGL1 and HYMAI on chromosome 6q24. One of the mechanisms leading to overexpression of the locus is hypomethylation of the maternal allele of PLAGL1 and HYMAI. A subset of patients with maternal hypomethylation at PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2 (PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57, a transcription factor involved in establishment and maintenance of methylation of imprinted loci. Our objective was to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers.MethodsGenome-wide DNA methylation analysis was performed on four individuals with homozygous or compound heterozygous ZFP57 mutations, three relatives with heterozygous ZFP57 mutations and five controls. Methylation status of selected regions showing aberrant methylation in the patients was verified using bisulfite-sequencing.ResultsWe found large variability among the patients concerning the number and identity of the differentially methylated regions, but more than 60 regions were aberrantly methylated in two or more patients and a novel region within PPP1R13L was found to be hypomethylated in all the patients. The hypomethylated regions in common between the patients are enriched for the ZFP57 DNA binding motif.ConclusionsWe have expanded the epimutational spectrum of TNDM1 associated with ZFP57 mutations and found one novel region within PPP1R13L which is hypomethylated in all TNDM1 patients included in this study. Functional studies of the locus might provide further insight into the etiology of the disease.<br/

Collective Intelligence for Control of Distributed Dynamical Systems

We consider the El Farol bar problem, also known as the minority game (W. B. Arthur, ``The American Economic Review'', 84(2): 406--411 (1994), D. Challet and Y.C. Zhang, ``Physica A'', 256:514 (1998)). We view it as an instance of the general problem of how to configure the nodal elements of a distributed dynamical system so that they do not ``work at cross purposes'', in that their collective dynamics avoids frustration and thereby achieves a provided global goal. We summarize a mathematical theory for such configuration applicable when (as in the bar problem) the global goal can be expressed as minimizing a global energy function and the nodes can be expressed as minimizers of local free energy functions. We show that a system designed with that theory performs nearly optimally for the bar problem.Comment: 8 page

First Results of a Study of TeV Emission from GRBs in Milagrito

Milagrito, a detector sensitive to gamma-rays at TeV energies, monitored the northern sky during the period February 1997 through May 1998. With a large field of view and high duty cycle, this instrument was used to perform a search for TeV counterparts to gamma-ray bursts. Within the Milagrito field of view 54 gamma-ray bursts at keV energies were observed by the Burst And Transient Satellite Experiment (BATSE) aboard the Compton Gamma-Ray Observatory. This paper describes the results of a preliminary analysis to search for TeV emission correlated with BATSE detected bursts. Milagrito detected an excess of events coincident both spatially and temporally with GRB 970417a, with chance probability $2.8 \times 10^{-5}$ within the BATSE error radius. No other significant correlations were detected. Since 54 bursts were examined the chance probability of observing an excess with this significance in any of these bursts is $1.5 \times 10^{-3}$. The statistical aspects and physical implications of this result are discussed.Comment: 6 pages, 5 figures, to appear in "GeV-TeV Astrophysics: Toward a Major Atmospheric Cherenkov Telescope VI," Snowbird, Utah (August, 1999

First results of a study of TeV emission from GRBs in Milagrito

Milagrito, a detector sensitive to γ-rays at TeV energies, monitored the northern sky during the period February 1997 through May 1998. With a large field of view and high duty cycle, this instrument was used to perform a search for TeV counterparts to γ-ray bursts. Within the Milagrito field of view 54 γ-ray bursts at keV energies were observed by the Burst And Transient Satellite Experiment (BATSE) aboard the Compton Gamma-Ray Observatory. This paper describes the results of a preliminary analysis to search for TeV emission correlated with BATSE detected bursts. Milagrito detected an excess of events coincident both spatially and temporally with GRB 970417a, with chance probability 2.8×10−5 within the BATSE error radius. No other significant correlations were detected. Since 54 bursts were examined the chance probability of observing an excess with this significance in any of these bursts is 1.5×10−3. The statistical aspects and physical implications of this result are discussed

Milagro: A TeV observatory for gamma-ray bursts

Observation of prompt TeV γ-rays from GRBs requires a new type of detector to overcome the low duty factor and small field of view of current TeV observatories. Milagro is such a new type of very high energy (\u3e a few 100 GeV) gamma-ray observatory, which has a large field of view of \u3e1 steradian and 24 hours/day operation. Milagrito, a prototype for Milagro, was operated from February 1997 to May 1998. During the summer of 1998, Milagrito was dismantled and Milagro was built. Both detectors use a 80 m×60 m×8 m pond of water in which a 3 m×3 m grid of photomultiplier tubes detects the Cherenkov light produced in the water by the relativistic particles in extensive air showers. Milagrito was smaller and had only one layer of photomultipliers, but allowed the technique to be tested. Milagrito observations of the Moon’s shadow and Mrk 501 are consistent with the Monte Carlo prediction of the telescope’s parameters, such as effective area and angular resolution. Milagro will have improved flux sensitivity over Milagrito due to larger effective area, better angular resolution and cosmic-ray background rejection

The high-energy gamma-ray fluence and energy spectrum of GRB 970417a from observations with Milagrito

Evidence of TeV emission from GRB970417a has been previously reported using data from the Milagrito detector. Constraints on the TeV fluence and the energy spectrum are now derived using additional data from a scaler system that recorded the rate of signals from the Milagrito photomultipliers. This analysis shows that if emission from GRB970417a has been observed, it must contain photons with energies above 650 GeV. Some consequences of this observation are discussed.Comment: Submitted to the Astrophysical Journa

Development and testing of a fiber/multianode photomultiplier system for use on FiberGLAST

A scintillating fiber detector is currently being studied for the NASA Gamma-Ray Large Area Space Telescope (GLAST) mission. This detector utilizes modules composed of a thin converter sheet followed by an x, y plane of scintillating fibers to examine the shower of particles created by high energy gamma-rays interacting in the converter material. The detector is composed of a tracker with 90 such modular planes and a calorimeter with 36 planes. The two major component of this detector are the scintillating fibers and their associated photodetectors. Here we present current status of development and test result of both of these. The Hamamatsu R5900-00-M64 multianode photomultiplier tube (MAPMT) is the baseline readout device. A characterization of this device has been performed including noise, cross- talk, gain variation, vibration, and thermal/vacuum test. A prototype fiber/MAPMT system has been tested at the Center for Advanced Microstructures and Devices at Louisiana State University with a photon beam and preliminary results are presented

A Survey of the Northern Sky for TeV Point Sources

A search for steady TeV point sources anywhere in the northern sky has been made with data from the Milagrito air-shower-particle detector. Over 3 x 10**9 events collected from 1997 February to 1998 May have been used in this study. No statistically significant excess above the background from the isotropic flux of cosmic rays was found for any direction of the sky with declination between -5 degrees and 71.7 degrees. Upper limits are derived for the photon flux above 1 TeV from any steady point source in the northern sky.Comment: 2 Figure

Milagro: A TeV gamma-ray monitor of the Northern Hemisphere Sky

A new type of very high energy (\u3e a few 100 GeV) gamma-ray observatory, Milagro, has been built with a large field of view of \u3e1 steradian and nearly 24 hours/day operation. Milagrito, a prototype for Milagro, was operated from February 1997 to May 1998. During the summer of 1998, Milagrito was dismantled and Milagro was built. Both detectors use a 80 m×60 m×8 mpond of water in which a 3 m×3 m grid of photomultiplier tubes detects the Cherenkov light produced in the water by the relativistic particles in extensive air showers. Milagrito was smaller and had only one layer of photomultipliers, but allowed the technique to be tested. Milagrito observations of the Moon’s shadow and Mrk 501 are consistent with the Monte Carlo prediction of the telescopes parameters, such as effective area and angular resolution. Milagro is larger and consists of two layers of photomultiplier tubes. The bottom layer detects penetrating particles that are used to reject the background of cosmic-ray initiated showers