A kernel-based dose calculation algorithm for kV photon beams with explicit handling of energy and material dependencies.

Objective Mimicking state-of-the-art patient radiotherapy with high-precision irradiators for small animals is expected to advance the understanding of dose-effect relationships and radiobiology in general. We work on the implementation of intensity-modulated radiotherapy-like irradiation schemes for small animals. As a first step, we present a fast analytical dose calculation algorithm for keV photon beams.Methods We follow a superposition-convolution approach adapted to kV X-rays, based on previous work for microbeam therapy. We assume local energy deposition at the photon interaction point due to the short electron ranges in tissue. This allows us to separate the dose calculation into locally absorbed primary dose and the scatter contribution, calculated in a point kernel approach. We validate our dose model against Geant4 Monte Carlo (MC) simulations and compare the results to Muriplan (XStrahl Ltd, Camberley, UK).Results For field sizes of (1 mm)2 to (1 cm)2 in water, the depth dose curves show a mean disagreement of 1.7% to MC simulations, with the largest deviations in the entrance region (4%) and at large depths (5% at 7 cm). Larger discrepancies are observed at water-to-bone boundaries, in bone and at the beam edges in slab phantoms and a mouse brain. Calculation times are in the order of 5 s for a single beam.Conclusion The algorithm shows good agreement with MC simulations in an initial validation. It has the potential to become an alternative to full MC dose calculation. Advances in knowledge: The presented algorithm demonstrates the potential of kernel-based dose calculation for kV photon beams. It will be valuable in intensity-modulated radiotherapy and inverse treatment planning for high precision small-animal radiotherapy

Autoimmune hepatitis triggered by nitrofurantoin: a case series

<p>Abstract</p> <p>Introduction</p> <p>Drugs can occasionally trigger the onset of autoimmune liver disease.</p> <p>Case presentation</p> <p>Three Caucasian women (aged 65, 42 and 74 years old) who were receiving long-term nitrofurantoin as prophylaxis against recurrent urinary tract infections developed hepatitic liver disease. Serological auto-antibody profiles and liver histology appearances were consistent with autoimmune hepatitis. Two of the patients presented with jaundice, and one required a prolonged hospital admission for liver failure. In all three patients nitrofurantoin was withdrawn, and long-term immunosuppressive therapy with prednisolone and azathioprine or mycophenolate was given. The patients responded well, with liver biochemistry returning to normal within a few months.</p> <p>Conclusions</p> <p>Although nitrofurantoin rarely causes autoimmune hepatitis, this antimicrobial is increasingly used as long-term prophylaxis against recurrent urinary tract infection. General practitioners and urologists who prescribe long-term nitrofurantoin therapy should be aware of this adverse effect.</p

Unique and conserved MicroRNAs in wheat chromosome 5D revealed by next-generation sequencing

MicroRNAs are a class of short, non-coding, single-stranded RNAs that act as post-transcriptional regulators in gene expression. miRNA analysis of Triticum aestivum chromosome 5D was performed on 454 GS FLX Titanium sequences of flow sorted chromosome 5D with a total of 3,208,630 good quality reads representing 1.34x and 1.61x coverage of the short (5DS) and long (5DL) arms of the chromosome respectively. In silico and structural analyses revealed a total of 55 miRNAs; 48 and 42 miRNAs were found to be present on 5DL and 5DS respectively, of which 35 were common to both chromosome arms, while 13 miRNAs were specific to 5DL and 7 miRNAs were specific to 5DS. In total, 14 of the predicted miRNAs were identified in wheat for the first time. Representation (the copy number of each miRNA) was also found to be higher in 5DL (1,949) compared to 5DS (1,191). Targets were predicted for each miRNA, while expression analysis gave evidence of expression for 6 out of 55 miRNAs. Occurrences of the same miRNAs were also found in Brachypodium distachyon and Oryza sativa genome sequences to identify syntenic miRNA coding sequences. Based on this analysis, two other miRNAs: miR1133 and miR167 were detected in B. distachyon syntenic region of wheat 5DS. Five of the predicted miRNA coding regions (miR6220, miR5070, miR169, miR5085, miR2118) were experimentally verified to be located to the 5D chromosome and three of them : miR2118, miR169 and miR5085, were shown to be 5D specific. Furthermore miR2118 was shown to be expressed in Chinese Spring adult leaves. miRNA genes identified in this study will expand our understanding of gene regulation in bread wheat

Plant–soil feedback of native and range-expanding plant species is insensitive to temperature

Temperature change affects many aboveground and belowground ecosystem processes. Here we investigate the effect of a 5°C temperature increase on plant–soil feedback. We compare plant species from a temperate climate region with immigrant plants that originate from warmer regions and have recently shifted their range polewards. We tested whether the magnitude of plant–soil feedback is affected by ambient temperature and whether the effect of temperature differs between these groups of plant species. Six European/Eurasian plant species that recently colonized the Netherlands (non-natives), and six related species (natives) from the Netherlands were selected. Plant–soil feedback of these species was determined by comparing performance in conspecific and heterospecific soils. In order to test the effect of temperature on these plant–soil feedback interactions, the experiments were performed at two greenhouse temperatures of 20/15°C and 25/20°C, respectively. Inoculation with unconditioned soil had the same effect on natives and non-natives. However, the effect of conspecific conditioned soil was negative compared to heterospecific soil for natives, but was positive for non-natives. In both cases, plant–soil interactions were not affected by temperature. Therefore, we conclude that the temperature component of climate change does not affect the direction, or strength of plant–soil feedback, neither for native nor for non-native plant species. However, as the non-natives have a more positive soil feedback than natives, climate warming may introduce new plant species in temperate regions that have less soil-borne control of abundance

Dependence of cancer cell adhesion kinetics on integrin ligand surface density measured by a high-throughput label-free resonant waveguide grating biosensor

A novel high-throughput label-free resonant waveguide grating (RWG) imager biosensor, the Epic® BenchTop (BT), was utilized to determine the dependence of cell spreading kinetics on the average surface density (vRGD) of integrin ligand RGD-motifs. vRGD was tuned over four orders of magnitude by co-adsorbing the biologically inactive PLL-g-PEG and the RGD-functionalized PLL-g-PEG-RGD synthetic copolymers from their mixed solutions onto the sensor surface. Using highly adherent human cervical tumor (HeLa) cells as a model system, cell adhesion kinetic data of unprecedented quality were obtained. Spreading kinetics were fitted with the logistic equation to obtain the spreading rate constant (r) and the maximum biosensor response (Δλmax), which is assumed to be directly proportional to the maximum spread contact area (Amax). r was found to be independent of the surface density of integrin ligands. In contrast, Δλmax increased with increasing RGD surface density until saturation at high densities. Interpreting the latter behavior with a simple kinetic mass action model, a 2D dissociation constant of 1753 ± 243 μm−2 (corresponding to a 3D dissociation constant of ~30 μM) was obtained for the binding between RGD-specific integrins embedded in the cell membrane and PLL-g-PEG-RGD. All of these results were obtained completely noninvasively without using any labels

Identification and Differential Expression of MicroRNAs during Metamorphosis of the Japanese Flounder (Paralichthys olivaceus)

BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs of 20-25 nucleotides that play a key role in diverse biological processes. Japanese flounder undergo dramatic metamorphosis in their early development. The metamorphosis is characterized by morphological transformation from a bilaterally symmetrical to an asymmetrical body shape concomitant with extensive morphological and physiological remodeling of organs. So far, only a few miRNAs have been identified in fish and there are very few reports about the Japanese flounder miRNA. METHODOLOGY/PRINCIPAL FINDINGS: Solexa sequencing technology was used to perform high throughput sequencing of the small RNA library from the metamorphic period of Japanese flounder. Subsequently, aligning these sequencing data with metazoan known miRNAs, we characterized 140 conserved miRNAs and 57 miRNA: miRNA* pairs from the small RNA library. Among these 57 miRNA: miRNA* pairs, twenty flounder miRNA precursors were amplified from genomic DNA. We also demonstrated evolutionary conservation of Japanese flounder miRNAs and miRNA* in the animal evolution process. Using miRNA microarrays, we identified 66 differentially expressed miRNAs at two metamorphic stages (17 and 29 days post hatching) of Japanese flounder. The results show that miRNAs might play a key role in regulating gene expression during Japanese flounder metamorphosis. CONCLUSIONS/SIGNIFICANCE: We identified a large number of miRNAs during flounder metamorphosis, some of which are differentially expressed at two different metamorphic stages. The study provides an opportunity for further understanding of miRNA function in the regulation of flounder metamorphosis and gives us clues for further studies of the mechanisms of metamorphosis in Japanese flounder

Toxicity in mice expressing short hairpin RNAs gives new insight into RNAi

Short hairpin RNAs can provide stable gene silencing via RNA interference. Recent studies have shown toxicity in vivo that appears to be related to saturation of the endogenous microRNA pathway. Will these findings limit the therapeutic use of such hairpins

MIR-99a and MIR-99b Modulate TGF-β Induced Epithelial to Mesenchymal Plasticity in Normal Murine Mammary Gland Cells

Epithelial to mesenchymal transition (EMT) is a key process during embryonic development and disease development and progression. During EMT, epithelial cells lose epithelial features and express mesenchymal cell markers, which correlate with increased cell migration and invasion. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that induces EMT in multiple cell types. The TGF-β pathway is regulated by microRNAs (miRNAs), which are small non-coding RNAs regulating the translation of specific messenger RNAs