Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients

© 2012 Joksic et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Background: Fanconi anemia (FA) is characterized by sensitivity to DNA cross-linking agents, mild cellular, and marked clinical radio sensitivity. In this study we investigated telomeric abnormalities of non-immortalized primary cells (lymphocytes and fibroblasts) derived from FA patients of the FA-D2 complementation group, which provides a more accurate physiological assessment than is possible with transformed cells or animal models. Results: We analyzed telomere length, telomere dysfunction-induced foci (TIFs), sister chromatid exchanges (SCE), telomere sister chromatid exchanges (T-SCE), apoptosis and expression of shelterin components TRF1 and TRF2. FANCD2 lymphocytes exhibited multiple types of telomeric abnormalities, including premature telomere shortening, increase in telomeric recombination and aberrant telomeric structures ranging from fragile to long-string extended telomeres. The baseline incidence of SCE in FANCD2 lymphocytes was reduced when compared to control, but in response to diepoxybutane (DEB) the 2-fold higher rate of SCE was observed. In contrast, control lymphocytes showed decreased SCE incidence in response to DEB treatment. FANCD2 fibroblasts revealed a high percentage of TIFs, decreased expression of TRF1 and invariable expression of TRF2. The percentage of TIFs inversely correlated with telomere length, emphasizing that telomere shortening is the major reason for the loss of telomere capping function. Upon irradiation, a significant decrease of TIFs was observed at all recovery times. Surprisingly, a considerable percentage of TIF positive cells disappeared at the same time when incidence of γ-H2AX foci was maximal. Both FANCD2 leucocytes and fibroblasts appeared to die spontaneously at higher rate than control. This trend was more evident upon irradiation; the percentage of leucocytes underwent apoptosis was 2.59- fold higher than that in control, while fibroblasts exhibited a 2- h delay before entering apoptosis. Conclusion: The results of our study showed that primary cells originating from FA-D2 patients display shorten telomeres, elevated incidence of T-SCEs and high frequency of TIFs. Disappearance of TIFs in early response to irradiation represent distinctive feature of FANCD2 cells that should be examined further.This article is made available through the Brunel Open Access Publishing Fund. This work was supported by the Ministry of Education and Science of the Republic of Serbia (Project No.173046)

The impact of pulsed irradiation upon neutron activation calculations for inertial and magnetic fusion energy power plants

Inertial fusion energy (IFE) and magnetic fusion energy (MFE) power plants will probably operate in a pulsed mode. The two different schemes, however, will have quite different time periods. Typical repetition rates for IFE power plants will be 1-5 Hz. MFE power plants will ramp up in current for about 1 hour, shut down for several minutes, and repeat the process. Traditionally, activation calculations for IFE and MFE power plants have assumed continuous operation and used either the ``steady state`` (SS) or ``equivalent steady state`` (ESS) approximations. It has been suggested recently that the SS and ESS methods may not yield accurate results for all radionuclides of interest. The present work expands that of Sisolak, et al. by applying their formulae to conditions which might be experienced in typical IFE and MFE power plants. In addition, complicated, multi-step reaction/decay chains are analyzed using an upgraded version of the ACAB radionuclide generation/depletion code. Our results indicate that the SS method is suitable for application to MFE power plant conditions. We also find that the ESS method generates acceptable results for radionuclides with half-lives more than a factor of three greater than the time between pulses. For components that are subject to 0.05 Hz (or more frequent) irradiation (such as coolant), use of the ESS method is recommended. For components or materials that are subject to less frequent irradiation (such as high-Z target materials), pulsed irradiation calculations should be used

Pancreatic pseudocyst eroding into the splenoportal venous confluence and mimicking an arterial aneurysm

We report the case of a 62-year-old man with chronic pancreatitis who presented with increasing abdominal pain. Sonography, magnetic resonance imaging, contrast-enhanced computed tomography, and ultimately catheter angiography demonstrated a pancreatic pseudocyst that had eroded into the splenoportal venous confluence, mimicking an arterial aneurysm. The diagnostic was confirmed at the time of surgical treatment. This case demonstrates the use of imaging to diagnose complications of pancreatitis, and the difficulty of distinguishing an eroding pseudocyst from an arterial aneurysm

Radiation shielding and patient organ dose study for an accelerator- based BNCT Facility at LBNL

This study considers the radiation safety aspects of several designs discussed in a previous report of an accelerator-based source of neutrons, based on the [sup 7]Li(p,n) reaction, for a Boron Neutron Capture Therapy (BNCT) Facility at Lawrence Berkeley National Laboratory (LBNL). determines the optimal radiation shield thicknesses for the patient treatment room. Since this is an experimental facility no moderator or reflector is considered in the bulk wall shield design. This will allow the flexibility of using any postulated moderator/reflector design and assumes sufficient shielding even in the absence of a moderator/reflector. In addition the accelerator is assumed to be capable of producing 100 mA of 2.5 MeV proton beam current. The addition of 1% and 2% [sup 10]B (by weight) to the concrete is also investigated. The second part of this paper determines the radiation dose to the major organs of a patient during a treatment. Simulations use the MIRD 5 anthropomorphic phantom to calculate organ doses from a 20 mA proton beam assuming various envisioned moderator/reflector in place. Doses are tabulated by component and for a given uniform [sup 10]B loading in all organs. These are presented in for a BeO moderator and for an Al/AlF[sub 3] moderator. Dose estimates for different [sup 10]B loadings may be scaled

Simulations of lattice animals and trees

The scaling behaviour of randomly branched polymers in a good solvent is studied in two to nine dimensions, using as microscopic models lattice animals and lattice trees on simple hypercubic lattices. As a stochastic sampling method we use a biased sequential sampling algorithm with re-sampling, similar to the pruned-enriched Rosenbluth method (PERM) used extensively for linear polymers. Essentially we start simulating percolation clusters (either site or bond), re-weigh them according to the animal (tree) ensemble, and prune or branch the further growth according to a heuristic fitness function. In contrast to previous applications of PERM, this fitness function is {\it not} the weight with which the actual configuration would contribute to the partition sum, but is closely related to it. We obtain high statistics of animals with up to several thousand sites in all dimension 2 <= d <= 9. In addition to the partition sum (number of different animals) we estimate gyration radii and numbers of perimeter sites. In all dimensions we verify the Parisi-Sourlas prediction, and we verify all exactly known critical exponents in dimensions 2, 3, 4, and >= 8. In addition, we present the hitherto most precise estimates for growth constants in d >= 3. For clusters with one site attached to an attractive surface, we verify the superuniversality of the cross-over exponent at the adsorption transition predicted by Janssen and Lyssy. Finally, we discuss the collapse of animals and trees, arguing that our present version of the algorithm is also efficient for some of the models studied in this context, but showing that it is {\it not} very efficient for the `classical' model for collapsing animals.Comment: 17 pages RevTeX, 29 figures include

Structural basis for potency differences between GDF8 and GDF11.

BACKGROUND: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. RESULTS: Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. CONCLUSIONS: These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined

Beam Interaction Measurements with a Retarding Field Analyzer in a High-Current High-Vacuum Positively-Charged Particle Accelerator

A Retarding Field Analyzer (RFA) was inserted in a drift region of a magnetic transport section of the high-current experiment (HCX) that is at high-vacuum to measure ions and electrons resulting from beam interaction with background gas and walls. The ions are expelled during the beam by the space-charge potential and the electrons are expelled mainly at the end of the beam, when the beam potential decays. The ion energy distribution shows the beam potential of {approx} 2100 V and the beam-background gas total cross-section of 1.6x10{sup -20} m{sup 2}. The electron energy distribution reveals that the expelled electrons are mainly desorbed from the walls and gain {approx} 22 eV from the beam potential decaying with time before entering the RFA. Details of the RFA design and of the measured energy distributions are presented and discussed