ALBERT

Beschreibung: Background: Recent advance in genetic analysis has revealed that many mutations are associated with the development, progression and/or prognosis of core-binding factor acute myeloid leukemia (CBF-AML). Although KIT mutation is the most frequently identified in CBF-AML, its prognostic relevance remains controversial. We conducted the prospective, multicenter cooperative study (JALSG CBF-AML209-KIT, UMIN Clinical Trials Registry UMIN000003434, http://www.umin.ac.jp/ctr/) to evaluate the prognostic impact of KIT mutation, the incidence and clinical relevance of the other gene mutations and prognostic impact of the minimal residual disease (MRD) in CBF-AML. Methods: A total of 199 patients 16 to 64 years of age with newly diagnosed de novo AML were enrolled in this study if they had a RUNX1-RUNX1T1 or CBFB-MYH11 chimeric transcript and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received 3 courses of high-dose cytarabine therapy (2 g/m2 by 3-hour infusion every 12 hours for 5 days) and no further chemotherapy until relapse. MRD level was evaluated in BM after the completion of the 3-course of consolidation therapy by the quantitation of RUNX1-RUNX1T or CBFB-MYH11 transcript in 112 patients. Target sequencing of 56 genes frequently identified in myeloid malignancies including exons 8, 10, 11 and 17 of the KIT gene were analyzed using the preserved DNA extracted from AML cells at diagnosis. Results: A total of 68 KIT mutations were identified in 63 of 199 patients (31.7%); 42 of 132 (31.8%) and 21 of 67 (31.3%) patients with RUNX1-RUNX1T1 and CBFB-MYH11, respectively. Mutation in exon 17 was the most frequently identified (73.5%), followed by in exon 8 (20.6%) and in exon 10-11 (5.9%). Mutation in exon 8 was more frequent in AML with CBFB-MYH11 (37.5%) than that with RUNX1-RUNX1T1 (11.4%, P=0.014). Although mutation at N822 residue in exon 17 was identified in 13/44 (29.5%) KIT mutations of the patients with RUNX1-RUNX1T1, no patient with CBFB-MYH11 had this mutation (P=0.008); however, mutation at the D816 residue was equally identified in patients with RUNX1-RUNX1T1 (21/44, 47.7%) and CBFB-MYH11 (13/24, 54.1%). The median BM blast percentage of the KIT mutation positive-patients (73.5%) was significantly higher than that of negative-patients (53.8%, P

Beschreibung: The generation and evolution of basaltic magmas at Usu volcano, located at the junction between the NE Japan arc and the Kuril arc, have been investigated. The mafic products, which form the somma edifice of the volcano, consist of basalt (49·6–51·3 wt % SiO 2 ) and basaltic andesite (52·0–54·9 wt % SiO 2 ) lavas. The basaltic lavas show relatively tight compositional trends, and 87 Sr/ 86 Sr ratios tend to decrease with increasing whole-rock SiO 2 content. The water content of the basaltic magmas was determined to be ~4·8 wt % based on plagioclase–melt thermodynamic equilibrium. Using this information and an olivine maximum fractionation model, the water content of the primary Usu magma was estimated to be 3·9 wt %. Multi-component thermodynamic calculations suggest that the primary magma was generated by ~23% melting of the source mantle with ~0·94 wt % H 2 O at ~1300°C and ~1·4 GPa. The 0·94 wt % water content of the source mantle is significantly higher than that beneath volcanoes in the main NE Japan arc (generally 〈0·7 wt % H 2 O); this implies that the wedge mantle at the arc–arc junction is intensively hydrated. The temperature of the wedge mantle of ~1300°C at ~1·4 GPa is also significantly higher than that of the mantle in the main NE Japan arc. Unlike the basaltic lavas, the whole-rock compositions of the basaltic andesite lavas are scattered in Harker variation diagrams. This observation suggests that the compositional diversity was produced by at least two independent processes. To elucidate the processes responsible for this compositional diversity, principal component analysis was applied to the major element compositions of the samples. This suggests that 47% of the diversity of the whole-rock compositions can be explained by mixing with partial melts of lower crustal materials, 25% is explained by redistribution of plagioclase phenocrysts, and 16% is explained by fractionation of accessory minerals.

Beschreibung: Redshifted 21 cm signal is a promising tool to investigate the state of intergalactic medium (IGM) in the cosmic dawn (CD) and epoch of reionization (EoR). In our previous work, we studied the variance and skewness of the 21 cm fluctuations to give a clear interpretation of the 21 cm power spectrum and found that skewness is a good indicator of the epoch when X-ray heating becomes effective. Thus, the non-Gaussian feature of the spatial distribution of the 21 cm signal is expected to be useful to investigate the astrophysical effects in the CD and EoR. In this paper, in order to investigate such a non-Gaussian feature in more detail, we focus on the bispectrum of the 21 cm signal. It is expected that the 21 cm brightness temperature bispectrum is produced by non-Gaussianity due to the various astrophysical effects such as the Wouthuysen–Field effect, X-ray heating and reionization. We study the various properties of 21 cm bispectrum such as scale dependence, shape dependence and redshift evolution. And also we study the contribution from each component of 21 cm bispectrum. We find that the contribution from each component has characteristic scale-dependent feature. In particular, we find that the bulk of the 21 cm bispectrum at z = 20 comes from the matter fluctuations, while in other epochs it is mainly determined by the spin and/or neutral fraction fluctuations and it is expected that we could obtain more detailed information on the IGM in the CD and EoR by using the 21 cm bispectrum in the future experiments, combined with the power spectrum and skewness.

Beschreibung: The redshifted 21cm line signal from neutral hydrogens is a promising tool to probe the cosmic dawn and the epoch of reionization. Ongoing and future low-frequency radio experiments are expected to detect its fluctuations, especially through the power spectrum. In this paper, we give a physical interpretation of the time evolution of the power spectrum of the 21cm brightness temperature fluctuations, which can be decomposed into dark matter density, spin temperature and neutral fraction of hydrogen fluctuations. From the one-point statistics of the fluctuations, such as variance and skewness, we find that the peaks and dips in the time evolution are deeply related to X-ray heating of the intergalactic gas, which controls the spin temperature. We suggest the skewness of the brightness temperature distribution is a key observable to identify the onset of X-ray heating.

Beschreibung: Selenocysteine (Sec), the 21 st amino acid in translation, uses its specific tRNA (tRNA Sec ) to recognize the UGA codon. The Sec-specific elongation factor SelB brings the selenocysteinyl-tRNA Sec (Sec-tRNA Sec ) to the ribosome, dependent on both an in-frame UGA and a Sec-insertion sequence (SECIS) in the mRNA. The bacterial SelB binds mRNA through its C-terminal region, for which crystal structures have been reported. In this study, we determined the crystal structure of the full-length SelB from the bacterium Aquifex aeolicus , in complex with a GTP analog, at 3.2-Å resolution. SelB consists of three EF-Tu-like domains (D1–3), followed by four winged-helix domains (WHD1–4). The spacer region, connecting the N- and C-terminal halves, fixes the position of WHD1 relative to D3. The binding site for the Sec moiety of Sec-tRNA Sec is located on the interface between D1 and D2, where a cysteine molecule from the crystallization solution is coordinated by Arg residues, which may mimic Sec binding. The Sec-binding site is smaller and more exposed than the corresponding site of EF-Tu. Complex models of Sec-tRNA Sec , SECIS RNA, and the 70S ribosome suggest that the unique secondary structure of tRNA Sec allows SelB to specifically recognize tRNA Sec and characteristically place it at the ribosomal A-site.

Beschreibung: Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P- value of 4.03 x 10 –9 . Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium ( r 2 = 1) with rs11543198, was also associated with bladder cancer risk in Europeans ( P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1 , APOBEC3A , PSCA and MYC , with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer.

Beschreibung: The immutability of the genetic code has been challenged with the successful reassignment of the UAG stop codon to non-natural amino acids in Escherichia coli . In the present study, we demonstrated the in vivo reassignment of the AGG sense codon from arginine to l -homoarginine. As the first step, we engineered a novel variant of the archaeal pyrrolysyl-tRNA synthetase (PylRS) able to recognize l -homoarginine and l - N 6 -(1-iminoethyl)lysine ( l -NIL). When this PylRS variant or HarRS was expressed in E. coli , together with the AGG-reading tRNA Pyl CCU molecule, these arginine analogs were efficiently incorporated into proteins in response to AGG. Next, some or all of the AGG codons in the essential genes were eliminated by their synonymous replacements with other arginine codons, whereas the majority of the AGG codons remained in the genome. The bacterial host's ability to translate AGG into arginine was then restricted in a temperature-dependent manner. The temperature sensitivity caused by this restriction was rescued by the translation of AGG to l -homoarginine or l -NIL. The assignment of AGG to l -homoarginine in the cells was confirmed by mass spectrometric analyses. The results showed the feasibility of breaking the degeneracy of sense codons to enhance the amino-acid diversity in the genetic code.

Beschreibung: Crystal structures of 5-aminoimidazole ribonucleotide (AIR) synthetase, also known as PurM, from Thermus thermophilus ( Tt ) and Geobacillus kaustophilus ( Gk ) were determined. For Tt PurM, the maximum resolution was 2.2 Å and the space group was P 2 1 2 1 2 with four dimers in an asymmetric unit. For Gk PurM, the maximum resolution was 2.2 Å and the space group was P 2 1 2 1 2 with one monomer in asymmetric unit. The biological unit is dimer for both Tt PurM and Gk PurM and the dimer structures were similar to previously determined structures of PurM in general. For Tt PurM, ~50 residues at the amino terminal were disordered in the crystal structure whereas, for Gk PurM, the corresponding region covered the ATP-binding site forming an α helix in part, suggesting that the N-terminal region of PurM changes its conformation upon binding of ligands. FGAM binding site was predicted by the docking simulation followed by the MD simulation based on the SO 4 2– binding site found in the crystal structure of Tt PurM.

Beschreibung: The redshifted 21cm line signal from neutral hydrogens is a promising tool to probe the cosmic dawn and the epoch of reionization. Ongoing and future low-frequency radio experiments are expected to detect its fluctuations, especially through the power spectrum. In this paper, we give a physical interpretation of the time evolution of the power spectrum of the 21cm brightness temperature fluctuations, which can be decomposed into dark matter density, spin temperature and neutral fraction of hydrogen fluctuations. From the one-point statistics of the fluctuations, such as variance and skewness, we find that the peaks and dips in the time evolution are deeply related to X-ray heating of the intergalactic gas, which controls the spin temperature. We suggest the skewness of the brightness temperature distribution is a key observable to identify the onset of X-ray heating.

Beschreibung: Inference of globally averaged eustatic sea level (ESL) rise since the Last Glacial Maximum (LGM) highly depends on the interpretation of relative sea level (RSL) observations at Barbados and Bonaparte Gulf, Australia, which are sensitive to the viscosity structure of Earth's mantle. Here we examine the RSL changes at the LGM for Barbados and Bonaparte Gulf ( ${\rm{RSL}}_{\rm{L}}^{{\rm{Bar}}}$ and ${\rm{RSL}}_{\rm{L}}^{{\rm{Bon}}}$ ), differential RSL for both sites ( $\Delta {\rm{RSL}}_{\rm{L}}^{{\rm{Bar}},{\rm{Bon}}})$ and rate of change of degree-two harmonics of Earth's geopotential due to glacial isostatic adjustment (GIA) process (GIA-induced 2 ) to infer the ESL component and viscosity structure of Earth's mantle. Differential RSL, $\Delta {\rm{RSL}}_{\rm{L}}^{{\rm{Bar}},{\rm{Bon}}}$ and GIA-induced 2 are dominantly sensitive to the lower-mantle viscosity, and nearly insensitive to the upper-mantle rheological structure and GIA ice models with an ESL component of about (120–130) m. The comparison between the predicted and observationally derived $\Delta {\rm{RSL}}_{\rm{L}}^{{\rm{Bar}},{\rm{Bon}}}$ indicates the lower-mantle viscosity higher than ~2  x  10 22 Pa s, and the observationally derived GIA-induced 2 of –(6.0–6.5)  x  10 –11 yr –1 indicates two permissible solutions for the lower mantle, ~10 22 and (5–10)  x  10 22 Pa s. That is, the effective lower-mantle viscosity inferred from these two observational constraints is (5–10)  x  10 22 Pa s. The LGM RSL changes at both sites, ${\rm{RSL}}_{\rm{L}}^{{\rm{Bar}}}$ and ${\rm{RSL}}_{\rm{L}}^{{\rm{Bon}}}$ , are also sensitive to the ESL component and upper-mantle viscosity as well as the lower-mantle viscosity. The permissible upper-mantle viscosity increases with decreasing ESL component due to the sensitivity of the LGM sea level at Bonaparte Gulf ( ${\rm{RSL}}_{\rm{L}}^{{\rm{Bon}}}$ ) to the upper-mantle viscosity, and inferred upper-mantle viscosity for adopted lithospheric thicknesses of 65 and 100 km is (1–3)  x  10 20 Pa s for ESL~130 m and (4–10)  x  10 20 Pa s for ESL~125 m. The former solution of (1–3)  x  10 20 Pa s is consistent with the inferences from the postglacial differential RSL changes in the Australian region and also inversion study of far-field sea-level data. The inference of the viscosity structure based on these four observational constraints is, however, relatively insensitive to the viscosity structure of D'' layer.