A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensivity in a patient with xeroderma pigmentosum

Background: Radiotherapy-induced DNA double-strand breaks (DSBs) are critical cytotoxic lesions. Inherited defects in DNA DSB repair pathways lead to hypersensitivity to ionising radiation, immunodeficiency and increased cancer incidence. A patient with xeroderma pigmentosum complementation group C, with a scalp angiosarcoma, exhibited dramatic clinical radiosensitivity following radiotherapy, resulting in death. A fibroblast cell line from non-affected skin (XP14BRneo17) was hypersensitive to ionising radiation and defective in DNA DSB repair. Aim: To determine the genetic defect causing cellular radiation hypersensitivity in XP14BRneo17 cells. Methods: Functional genetic complementation whereby copies of human chromosomes containing genes involved in DNA DSB repair (chromosomes 2, 5, 8 10, 13 and 22) were individually transferred to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Clonogenic survival assays and g-H2AX immunofluorescence were conducted to measure radiation sensitivity and repair of DNA DSBs. DNA sequencing of defective DNA repair genes was performed. Results: Transfer of chromosome 8 (location of DNAPKcs gene) and transfection of a mammalian expression construct containing the DNA-PKcs cDNA restored normal ionising radiation sensitivity and repair of DNA DSBs in XP14BRneo17 cells. DNA sequencing of the DNA-PKcs coding region revealed a 249-bp deletion (between base pairs 3656 and 3904) encompassing exon 31 of the gene. Conclusion: We provide evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a patient with xeroderma pigmentosum and report the first double mutant in distinct DNA repair pathways being consistent with viability

Degradation and forgone removals increase the carbon impact of intact forest loss by 626%

Intact tropical forests, free from substantial anthropogenic influence, store and sequester large amounts of atmospheric carbon but are currently neglected in international climate policy. We show that between 2000 and 2013, direct clearance of intact tropical forest areas accounted for 3.2% of gross carbon emissions from all deforestation across the pantropics. However, full carbon accounting requires the consideration of forgone carbon sequestration, selective logging, edge effects, and defaunation. When these factors were considered, the net carbon impact resulting from intact tropical forest loss between 2000 and 2013 increased by a factor of 6 (626%), from 0.34 (0.37 to 0.21) to 2.12 (2.85 to 1.00) petagrams of carbon (equivalent to approximately 2 years of global land use change emissions). The climate mitigation value of conserving the 549 million ha of tropical forest that remains intact is therefore significant but will soon dwindle if their rate of loss continues to accelerate

Timelike and null focusing singularities in spherical symmetry: a solution to the cosmological horizon problem and a challenge to the cosmic censorship hypothesis

Extending the study of spherically symmetric metrics satisfying the dominant energy condition and exhibiting singularities of power-law type initiated in SI93, we identify two classes of peculiar interest: focusing timelike singularity solutions with the stress-energy tensor of a radiative perfect fluid (equation of state: $p={1\over 3} \rho$) and a set of null singularity classes verifying identical properties. We consider two important applications of these results: to cosmology, as regards the possibility of solving the horizon problem with no need to resort to any inflationary scenario, and to the Strong Cosmic Censorship Hypothesis to which we propose a class of physically consistent counter-examples.Comment: 26 pages, 2 figures, LaTeX file. Submitted to Phys. Rev.

Isoforms of transferrin in psoriasis patients abusing alcohol

The different isoforms of transferrin have been quantified by isoelectric focusing in the sera of psoriasis patients with and without a history of abusing alcohol. In both male and female psoriasis subjects abusing alcohol, there were significant increases in the 2-sialylated forms by comparison to the control subjects. Psoriasis patients who had no evidence of alcohol abuse had similar profile for the isoforms of transferrin to that of the controls. Other groups of patients with alcohol-induced tissue damage, i.e. liver, brain or muscle, used as positive controls, similarly showed significant increases in the 2-sialylated forms, by comparison to controls. These results substantiate the current use of carbohydrate-deficient transferrin as a sensitive marker of alcohol abuse, particularly in subjects not drinking in excess of 60 g of ethanol/day but showing alcohol-related psoriasis

The Power of Proofs: New Algorithms for Timed Automata Model Checking (with Appendix)

This paper presents the first model-checking algorithm for an expressive modal mu-calculus over timed automata, $L^{\mathit{rel}, \mathit{af}}_{\nu,\mu}$, and reports performance results for an implementation. This mu-calculus contains extended time-modality operators and can express all of TCTL. Our algorithmic approach uses an "on-the-fly" strategy based on proof search as a means of ensuring high performance for both positive and negative answers to model-checking questions. In particular, a set of proof rules for solving model-checking problems are given and proved sound and complete; we encode our algorithm in these proof rules and model-check a property by constructing a proof (or showing none exists) using these rules. One noteworthy aspect of our technique is that we show that verification performance can be improved with \emph{derived rules}, whose correctness can be inferred from the more primitive rules on which they are based. In this paper, we give the basic proof rules underlying our method, describe derived proof rules to improve performance, and compare our implementation of this model checker to the UPPAAL tool.Comment: This is the preprint of the FORMATS 2014 paper, but this is the full version, containing the Appendix. The final publication is published from Springer, and is available at http://link.springer.com/chapter/10.1007%2F978-3-319-10512-3_9 on the Springer webpag

Extremism propagation in social networks with hubs

One aspect of opinion change that has been of academic interest is the impact of people with extreme opinions (extremists) on opinion dynamics. An agent-based model has been used to study the role of small-world social network topologies on general opinion change in the presence of extremists. It has been found that opinion convergence to a single extreme occurs only when the average number of network connections for each individual is extremely high. Here, we extend the model to examine the effect of positively skewed degree distributions, in addition to small-world structures, on the types of opinion convergence that occur in the presence of extremists. We also examine what happens when extremist opinions are located on the well-connected nodes (hubs) created by the positively skewed distribution. We find that a positively skewed network topology encourages opinion convergence on a single extreme under a wider range of conditions than topologies whose degree distributions were not skewed. The importance of social position for social influence is highlighted by the result that, when positive extremists are placed on hubs, all population convergence is to the positive extreme even when there are twice as many negative extremists. Thus, our results have shown the importance of considering a positively skewed degree distribution, and in particular network hubs and social position, when examining extremist transmission

Root biomass in cereals, catch crops and weeds can be reliably estimated without considering aboveground biomass

Reliable information on belowground plant biomass is essential to estimate belowground carbon inputs to soils. Estimations of belowground plant biomass are often based on a fixed allometric relationship of plant biomass between aboveground and belowground parts. However, environmental and management factors may affect this allometric relationship making such estimates uncertain and biased. Therefore, we aimed to explore how root biomass for typical cereal crops, catch crops and weeds could most reliably be estimated. Published and unpublished data on aboveground and root biomass (corrected to 0–25 cm depth) of cereal crops (wheat and barley), catch crops and weeds were collected from studies in Denmark. Leave one out cross validation was used to determine the model that could best estimate root biomass. Root biomass varied with year, farming system (organic versus conventional) and cereal species. Shoot and root biomass of catch crops were higher than for weeds (sampled in late autumn), and farming system significantly affected root biomass of catch crops and weeds. The use of fixed root biomass based on the most influential factors (farming system and species) provided the lowest error of prediction for estimation of root biomass, compared with the use of fixed allometric relations, such as root/shoot ratio. For cereal crops, the average root dry matter in organic farming systems was 218 g m−2 (243 and 193 g m−2 for wheat and barley, respectively), but in conventional systems only 139 g m−2 (142 and 129 g m−2 for wheat and barley, respectively). For catch crops and weeds, the root dry matter in organic farming systems were around 127 and 35 g m−2, and in conventional farming systems 75 and 28 g m−2, respectively. In conclusion, the present analysis indicates that root biomass in cereals, catch crops and weeds can be reliably estimated without considering aboveground biomass, and it may be better estimated using fixed values based on species and farming systems than using fixed allometric ratios