Gene Expression Signatures That Predict Radiation Exposure in Mice and Humans

BACKGROUND: The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. METHODS AND FINDINGS: We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. CONCLUSIONS: We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure

Control of Hox transcription factor concentration and cell-to-cell variability by an auto-regulatory switch

The variability in transcription factor concentration among cells is an important developmental determinant, yet how variability is controlled remains poorly understood. Studies of variability have focused predominantly on monitoring mRNA production noise. Little information exists about transcription factor protein variability, as this requires the use of quantitative methods with single-molecule sensitivity. Using Fluorescence Correlation Spectroscopy (FCS), we have characterized the concentration and variability of 14 endogenously tagged TFs in live Drosophila imaginal discs. For the Hox TF Antennapedia, we investigated whether protein variability results from random stochastic events or is developmentally regulated. We found that Antennapedia transitioned from low concentration/high variability early, to high concentration/low variability later, in development. FCS and temporally resolved genetic studies uncovered that Antennapedia itself is necessary and sufficient to drive a developmental regulatory switch from auto-activation to auto-repression, thereby reducing variability. This switch is controlled by progressive changes in relative concentrations of preferentially activating and repressing Antennapedia isoforms, which bind chromatin with different affinities. Mathematical modeling demonstrated that the experimentally supported auto-regulatory circuit can explain the increase of Antennapedia concentration and suppression of variability over time

Effects of butter from mountain-pasture grazing cows on risk markers of the metabolic syndrome compared with conventional Danish butter: a randomized controlled study.

BACKGROUND: There is considerable interest in dairy products from low-input systems, such as mountain-pasture grazing cows, because these products are believed to be healthier than products from high-input conventional systems. This may be due to a higher content of bioactive components, such as phytanic acid, a PPAR-agonist derived from chlorophyll. However, the effects of such products on human health have been poorly investigated. OBJECTIVE: To compare the effect of milk-fat from mountain-pasture grazing cows (G) and conventionally fed cows (C) on risk markers of the metabolic syndrome. DESIGN: In a double-blind, randomized, 12-week, parallel intervention study, 38 healthy subjects replaced part of their habitual dietary fat intake with 39 g fat from test butter made from milk from mountain-pasture grazing cows or from cows fed conventional winter fodder. Glucose-tolerance and circulating risk markers were analysed before and after the intervention. RESULTS: No differences in blood lipids, lipoproteins, hsCRP, insulin, glucose or glucose-tolerance were observed. Interestingly, strong correlations between phytanic acid at baseline and total (P<0.0001) and LDL cholesterol (P=0.0001) were observed. CONCLUSIONS: Lack of effects on blood lipids and inflammation indicates that dairy products from mountain-pasture grazing cows are not healthier than products from high-input conventional systems. Considering the strong correlation between LDL cholesterol and phytanic acid at baseline, it may be suggested that phytanic acid increases total and LDL cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0134358

Distinguishing rift-related from inversion-related anticlines: Observations from the Abu Gharadig and Gindi Basins, Western Desert, Egypt

Distinguishing the tectonic origin of anticlinal structures is problematic in regions with a complex history of rifting and inversion. We present the results of seismic mapping, in the form of time-depth (isochron) and time-thickness maps to characterize how sedimentary thickness differentials evolved in response to normal faulting and to inversion events on faults within the Abu Gharadig and Gindi Basins in the Western Desert of Egypt. Late Cretaceous rift-related faults in the Abu Gharadig Basin strike NW-SE, W-E and SW-NE. In the eastern part of the basin, a prominent SW-NE trending interbasinal saddle formed in response to preferential subsidence forming half-grabens to its north-west and southeast, during the Mid-Turonian to Santonian interval. Santonian to Palaeogene inversion in the Abu Gharadig Basin developed on its northern basin margin, the absence of SW-NE striking faults in the eastern central basin resulting in any inversion effects being minor. In the central Gindi Basin, Upper Cenomanian to Lower Turonian SW-NE striking rift faults underwent inversion as early as the Mid-Turonian. The orientation of existing rift faults and modification of the local stress fields control the extent to which inversion was taken up in each basin trough time. The Abu Gharadig and Gindi Basins are two of the rift basins developed in West and Central Africa that underwent rifting, inversion and dextral shearing during the Late Cretaceous. We emphasize the value of high-resolution stratigraphic mapping to characterize short-lived and subtle pop-up events that may have gone unnoticed

The specificities of Sex combs reduced and Antennapedia are defined by a distinct portion of each protein that includes the homeodomain

The sequence requirements for distinguishing the functional specificities of two homeodomain proteins, Antennapedia and Sex combs reduced, involved in the specification of segmental identities in Drosophila, have been determined. A series of deletions and hybrid proteins was generated and assayed for their function in vivo after heat shock-induced ectopic expression during development. A distinct portion of each protein, including the residues within and adjacent to both ends of the homeodomain, has been found to almost entirely determine its functional specificity as measured by diagnostic cuticular transformations of embryonic and adult head structures. The remaining sequences contribute to the potency with which the proteins act in different cells and are to a limited extent functionally transferable from one protein to the other