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Background A total of 10%–20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. Methods We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10−8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. Results Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10−10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10−10), and rs11122573 with hematuria (Pmeta = 1.8 × 10−8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10−6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. Conclusions This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

This paper presents a phase description of chaotic dynamics for the study of chaotic phase synchronization. A prominent feature of the proposed description is that it systematically incorporates the dynamics of the non-phase variables inherent in the system. Taking these non-phase dynamics into account is essential for capturing the complicated nature of chaotic phase synchronization, even in a qualitative manner. We numerically verified the validity of the proposed description in application to the R\"{o}ssler and Lorenz oscillators, and we found that our method provides an accurate description of the characteristic distorted shapes of the synchronization regions for these chaotic oscillators. Furthermore, the proposed description allows us to systematically identify and describe the origin of this distortion.

Additional file 7. Generation and genotyping a P. falciparum mutant line lacking expression of CSP (PfΔcsp). A. The PfΔcsp line was generated using CRISPR/Cas9 methodology. The pfcsp gene was replaced by insertion of a mCherry expression cassette (mCherry under control of the of the constitutive gapdh promoter) using donor-DNA plasmids pLf0086. A schematic representation of the pfcsp locus before and after insertion of the construct showing the location of the restriction sites (A: AvaII), sizes (in bp) of restriction fragments (red for Southern blot analysis), location of primers (p), PCR amplicons and sizes of the fragments (in black) used to analyse correct disruption of the pfcsp and insertion of the mCherry cassette (B, C). HR1, HR2: pfcsp homology (targeting) regions. The figure is not shown to scale. Primer sequences can be found in Additional file 8. B. Diagnostic PCR confirming correct integration of the mCherry cassette into the PfCSP locus. 5′ integration PCR (lane 2; primers p15/p19); pfcsp open reading frame (lane 3; primers p17/p18); P. falciparum sequestrin as a control gene (lane 1; primers p22/p23); mCherry gene (lane 4; primers P20/P21) of cloned parasites of PfΔcsp (cl3) and WT. C. Southern blot analysis of AvaII/XhoI restricted DNA of WT and PfΔcsp parasites confirms the specific integration of the mCherry cassette into the pfcsp gene locus. DNA was hybridized with a probe targeting the homology region 2 (upper panels; HR2; primers p3/p4; see (A) of pfcsp. The hybridization pattern observed with the HR2 probe identified the expected different-sized DNA fragments in WT and pf-pvcsp parasites (2057 bp and 4105 bp). In addition to show absence of donor-DNA plasmid and presence of single cross-over events DNA was hybridized with a probe for the ampicillin gene (lower panels; intermediate donor-DNA plasmid pLf0040 digested with AatII and PvuI).

Additional file 2. List of primers used in this study.

Local spectral functions and Nuclear Magnetic Relaxation (NMR) rates, 1/T1, for the spin-half Heisenberg antiferromagnet on the Kagome Lattice are calculated using Moriyas Gaussian approximation, as well as through an extrapolation of multiple frequency moments. The temperature dependence of the calculated rates is compared with the oxygen 1/T1 NMR data in Herbertsmithite. We find that the Gaussian approximation for 1/T1 shows behavior qualitatively similar to experiments with a sharp drop in rates at low temperatures, consistent with a spin-gapped behavior. However, this approximation significantly underestimates the magnitude of 1/T1 even at room temperature. Rates obtained from extrapolation of multiple frequency moments give very good agreement with the room temperature NMR data with J = 195 +/- 20 K and hyperfine couplings determined independently from other measurements. The use of multiple frequency moments also leads to additional low frequency weight in the local structure factors. The convergence of our calculations with higher frequency moments breaks down at low temperatures suggesting the existence of longer range dynamic correlations in the system despite the very short-range static correlations., Comment: 5 pages 4 figures

We successfully isolated the $^{17}$O NMR signals at the planar sites in La$_{1.885}$Sr$_{0.115}$CuO$_4$ ($T_{c}=30$ K) by applying an external magnetic field along the Cu-O-Cu bond direction of a single crystal. We demonstrate that charge order enhances incommensurate Cu spin fluctuations below $T_{charge} \simeq 80$ K., Short Note published in J. Phys. Soc. Jpn

菜種原油からラジカル捕捉活性物質であるCanololを効率的に回収し，精製油に添加することで機能性の優れた新規菜種油を製造することを試みた．Canololの回収法については，回収率が高くリン脂質などの不純物の混入が少ない水蒸気蒸留が適していることがわかった．Canololを高濃度に含む焙煎菜種原油から水蒸気蒸留により回収したものを菜種精製油に添加し評価した結果，酸化安定性および熱安定性は優れていたが，光安定性に若干の問題点があることがわかった．味や香りに関しては，独特の焙煎臭が感じられるが，特に悪いと感じるものではなかった．上述したように揚げ物用油としての可能性のほかに，風味を生かしたテーブルオイルとしての利用にも期待がもたれた．

In order to search tissue-specific elements in the 5′-upstream promoter region, gene gun was used to transfect in vivo plasmid DNAs with varying lengths of truncated ovalbumin promoter fused to the CAT reporter gene to the oviduct and liver of laying hens. The results indicated that in the oviduct, consistently high reporter gene expression was observed irrespective of the length of the truncated ovalbumin gene promoters, whereas in the liver the ovalbumin promoter extending from -3200 to +8 bp suppressed substantially the reporter gene expression compared with consistently high gene expression obtained by the ovalbumin promoters from -2800 to +8 bp or shorter length. It was concluded, therefore, that a tissue-specific silencer-like element might reside most likely in the ovalbumin gene promoter region between -3200 and -2800 bp which represses the ovalbumin gene transcription in the liver, but not in the oviduct of laying hens.

Additional file 8. Chimeric rodent parasite lines pb-pvcsp(vk210) and pb-pvcsp(vk247) are able to produce salivary gland sporozoites that are infectious to mice. A. Upper panel, left: Light microscope pictures of wild type P. berghei (WT) and pb-pvcsp oocyst at days 7, 10 and 14 after feeding of An. stephensi mosquitoes. Black arrows indicate oocyst with sporozoite formation and white arrows indicate degenerated, vacuolated oocyst without sporozoite formation (scale bar, 10 µm). Upper panel, right, Percentage of degenerated oocyst in An. stephensi mosquitoes (n = 5) at day 14 after feeding (***P =

Additional file 8. Chimeric rodent parasite lines pb-pvcsp(vk210) and pb-pvcsp(vk247) are able to produce salivary gland sporozoites that are infectious to mice. A. Upper panel, left: Light microscope pictures of wild type P. berghei (WT) and pb-pvcsp oocyst at days 7, 10 and 14 after feeding of An. stephensi mosquitoes. Black arrows indicate oocyst with sporozoite formation and white arrows indicate degenerated, vacuolated oocyst without sporozoite formation (scale bar, 10 µm). Upper panel, right, Percentage of degenerated oocyst in An. stephensi mosquitoes (n = 5) at day 14 after feeding (***P =

Additional file 4. Growth of asexual blood stages and mCherry expression in blood stages. Growth of asexual blood stages of two chimeric P. falciparum parasite lines (pf-pvcsp(vk210) and pf-pvcsp(vk247), a P. falciparum line lacking expression of CSP (PfΔcsp) and P. falciparum wild type (WT) parasites. Parasites of the different cloned lines were cultured in semi-automated culture system for a period of 7 days. Cultures were initiated with a parasitaemia of 0.5%. Arrows indicate the dilution of the cultures with fresh red blood cells to have a final parasitaemia of 1%. B. mCherry-expressing blood stages of PfΔcsp parasites where the csp gene has been disrupted by insertion of an mCherry expression cassette (see Additional file 5 for details of the generation of PfΔcsp). Scale bar, 7 µm.

BACKGROUND: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

Additional file 3. Sequence analysis of the P. vivax csp genes introduced into P. falciparum. Long-range PCR fragments (see Fig. 1) were cloned into pET TOPO TA (Invitrogen) and sequenced. See Additional file 2 for primer sequences used for sequencing the complete fragment. A. LR-PCR fragment of parasites of pf-pvcsp(vk210). B. LR-PCR fragment of parasites of pf-pvcsp(vk247).

Additional file 1. Vector maps of the P. vivax csp genes introduced into P. falciparum. A. Vector maps of the different plasmids used to generate two chimeric P. falciparum parasite lines (pf-pvcsp) expressing P. vivax CSP(VK210) of CSP(VK247) and a P. falciparum line lacking expression of CSP (PfÎ csp). See â Methodsâ section for description and details of the generation of these plasmids.

Additional file 5. Degenerated oocysts of two chimeric P. falciparum parasite lines (pf-pvcsp) and a PfCSP knockout line (PfΔcsp). Light microscope pictures of degenerated oocysts at day 10 after feeding gametocytes to Anopheles stephensi mosquitoes. These oocysts are classified as degenerate based on the absence of sporozoite formation and vacuolated cytoplasm. See Fig. 2 for pf-pvcsp and wild type P. falciparum (WT) oocyst in which sporozoite formation occurred. No sporozoite formation was observed in PfΔcsp oocysts. Scale bar, 20 µm.

Additional file 4. Growth of asexual blood stages and mCherry expression in blood stages. Growth of asexual blood stages of two chimeric P. falciparum parasite lines (pf-pvcsp(vk210) and pf-pvcsp(vk247), a P. falciparum line lacking expression of CSP (PfΔcsp) and P. falciparum wild type (WT) parasites. Parasites of the different cloned lines were cultured in semi-automated culture system for a period of 7 days. Cultures were initiated with a parasitaemia of 0.5%. Arrows indicate the dilution of the cultures with fresh red blood cells to have a final parasitaemia of 1%. B. mCherry-expressing blood stages of PfΔcsp parasites where the csp gene has been disrupted by insertion of an mCherry expression cassette (see Additional file 5 for details of the generation of PfΔcsp). Scale bar, 7 µm.

Additional file 5. Degenerated oocysts of two chimeric P. falciparum parasite lines (pf-pvcsp) and a PfCSP knockout line (PfΔcsp). Light microscope pictures of degenerated oocysts at day 10 after feeding gametocytes to Anopheles stephensi mosquitoes. These oocysts are classified as degenerate based on the absence of sporozoite formation and vacuolated cytoplasm. See Fig. 2 for pf-pvcsp and wild type P. falciparum (WT) oocyst in which sporozoite formation occurred. No sporozoite formation was observed in PfΔcsp oocysts. Scale bar, 20 µm.

Additional file 1. Vector maps of the P. vivax csp genes introduced into P. falciparum. A. Vector maps of the different plasmids used to generate two chimeric P. falciparum parasite lines (pf-pvcsp) expressing P. vivax CSP(VK210) of CSP(VK247) and a P. falciparum line lacking expression of CSP (PfÎ csp). See â Methodsâ section for description and details of the generation of these plasmids.

Additional file 3. Sequence analysis of the P. vivax csp genes introduced into P. falciparum. Long-range PCR fragments (see Fig. 1) were cloned into pET TOPO TA (Invitrogen) and sequenced. See Additional file 2 for primer sequences used for sequencing the complete fragment. A. LR-PCR fragment of parasites of pf-pvcsp(vk210). B. LR-PCR fragment of parasites of pf-pvcsp(vk247).