ALBERT

Description: The Advanced Laser Interferometer Gravitational-Wave Observatory (aLIGO) has detected direct signals of gravitational waves (GWs) from GW150914. The event was a merger of binary black holes whose masses are $36^{+5}_{-4}\,\mathrm{M}_{{\odot }}$ and $29^{+4}_{-4}\,\mathrm{M}_{{\odot }}$ . Such binary systems are expected to be directly evolved from stellar binary systems or formed by dynamical interactions of black holes in dense stellar environments. Here we derive the binary black hole merger rate based on the nearby ultra-luminous X-ray source (ULX) luminosity function (LF) under the assumption that binary black holes evolve through X-ray emitting phases. We obtain the binary black hole merger rate as 5.8( t ULX /0.1 Myr) – 1 – 0.6 exp ( – 0.30) Gpc – 3 yr – 1 , where t ULX is the typical duration of the ULX phase and is the Eddington ratio in luminosity. This is coincident with the event rate inferred from the detection of GW150914 as well as the predictions based on binary population synthesis models. Although we are currently unable to constrain the Eddington ratio of ULXs in luminosity due to the uncertainties of our models and measured binary black hole merger event rates, further X-ray and GW data will allow us to narrow down the range of the Eddington ratios of ULXs. We also find the cumulative merger rate for the mass range of 5 M ≤ M BH ≤ 100 M inferred from the ULX LF is consistent with that estimated by the aLIGO collaboration considering various astrophysical conditions such as the mass function of black holes.

Description: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. However, the combined use of synthetic disease-modifying anti-rheumatic drug (DMARD) such as methotrexate and a biological DMARD targeting tumour necrosis factor (TNF) has revolutionized treatment of RA. Clinical remission is a realistic target to treat and the maintenance of remission has produced significant improvements in structural and function outcomes. However, biological DMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. The multiple cytokines and cell surface molecules bind to receptors, resulting in the activation of various signalling, including phosphorylation of kinase proteins. Among multiple kinases, Janus kinase (JAK) plays pivotal roles in the pathological processes of RA. Tofacitinib, a small product targeting JAK, inhibits phosphorylation of JAK1 and JAK3, subsequent Stat1 and expression of Stat1-inducible genes, which contribute to efficient propagation of its anti-inflammatory effects for the treatment of RA. The primary targets of tofacitinib are dendritic cells, CD4 + T cells such as Th1 and Th17 and activated B cells which leads to multi-cytokine targeting. Six global phase 3 studies revealed that oral administration of 5 or 10 mg tofacitinib was significantly effective than placebo with or without methotrexate in active RA patients with methotrexate-naïve, inadequately responsive to methotrexate or TNF-inhibitors. Therapeutic efficacy of tofacitinib was observed in a short term after administration and was as strong as adalimumab, a TNF-inhibitor. The most commonly observed adverse events were related to infection, hematologic, hepatic and renal disorders and association of tofacitinib with carcinogenicity and infections remains debated. Further investigation on post-marketing survey would help us understand the positioning of this drug.

Description: To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P -values of 〈10 –4 in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level ( P 〈 5 x 10 –8 ). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 x 10 –10 ). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes ( r 2 = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.

Description: Developing applications for metal-mediated base pairs (metallo-base-pair) has recently become a high-priority area in nucleic acid research, and physicochemical analyses are important for designing and fine-tuning molecular devices using metallo-base-pairs. In this study, we characterized the Hg II -mediated T-T (T-Hg II -T) base pair by Raman spectroscopy, which revealed the unique physical and chemical properties of Hg II . A characteristic Raman marker band at 1586 cm –1 was observed and assigned to the C4=O4 stretching mode. We confirmed the assignment by the isotopic shift ( 18 O-labeling at O4) and density functional theory (DFT) calculations. The unusually low wavenumber of the C4=O4 stretching suggested that the bond order of the C4=O4 bond reduced from its canonical value. This reduction of the bond order can be explained if the enolate-like structure (N3=C4-O4 – ) is involved as a resonance contributor in the thymine ring of the T-Hg II -T pair. This resonance includes the N-Hg II -bonded state (Hg II -N3-C4=O4) and the N-Hg II -dissociated state (Hg II+ N3=C4-O4 – ), and the latter contributor reduced the bond order of N-Hg II . Consequently, the Hg II nucleus in the T-Hg II -T pair exhibited a cationic character. Natural bond orbital (NBO) analysis supports the interpretations of the Raman experiments.

Description: Rett syndrome (RTT) is one of the most prevalent female mental disorders. De novo mutations in methyl CpG-binding protein 2 (MeCP2) are a major cause of RTT. MeCP2 regulates gene expression as a transcription regulator as well as through long-range chromatin interaction. Because MeCP2 is present on the X chromosome, RTT is manifested in an X-linked dominant manner. Investigation using murine MeCP2 null models and post-mortem human brain tissues has contributed to understanding the molecular and physiological function of MeCP2. In addition, RTT models using human induced pluripotent stem cells derived from RTT patients (RTT-iPSCs) provide novel resources to elucidate the regulatory mechanism of MeCP2. Previously, we obtained clones of female RTT-iPSCs that express either wild-type or mutant MECP2 due to the inactivation of one X chromosome. Reactivation of the X chromosome also allowed us to have RTT-iPSCs that express both wild-type and mutant MECP2 . Using these unique pluripotent stem cells, we investigated the regulation of gene expression by MeCP2 in pluripotent stem cells by transcriptome analysis. We found that MeCP2 regulates genes encoding mitochondrial membrane proteins. In addition, loss of function in MeCP2 results in de-repression of genes on the inactive X chromosome. Furthermore, we showed that each mutation in MECP2 affects a partly different set of genes. These studies suggest that fundamental cellular physiology is affected by mutations in MECP2 from early development, and that a therapeutic approach targeting to unique forms of mutant MeCP2 is needed.

Description: Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129 - LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 x 10 –13 ; odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 x 10 –10 ; OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 x 10 –13 ; OR = 1.20) . This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

Description: We have determined the three-dimensional (3D) structure of DNA duplex that includes tandem Hg II -mediated T–T base pairs (thymine–Hg II –thymine, T–Hg II –T) with NMR spectroscopy in solution. This is the first 3D structure of metallo-DNA (covalently metallated DNA) composed exclusively of ‘NATURAL’ bases. The T–Hg II –T base pairs whose chemical structure was determined with the 15 N NMR spectroscopy were well accommodated in a B-form double helix, mimicking normal Watson–Crick base pairs. The Hg atoms aligned along DNA helical axis were shielded from the bulk water. The complete dehydration of Hg atoms inside DNA explained the positive reaction entropy ( S ) for the T–Hg II –T base pair formation. The positive S value arises owing to the Hg II dehydration, which was approved with the 3D structure. The 3D structure explained extraordinary affinity of thymine towards Hg II and revealed arrangement of T–Hg II –T base pairs in metallo-DNA.

Description: Riboswitches are RNA elements that regulate gene expression in response to their ligand. Although these regulations are thought to be performed without any aid of other factors, recent studies suggested the participation of protein factors such as transcriptional termination factor Rho and RNase in some riboswitch regulations. However, to what extent these protein factors contribute to the regulation was unclear. Here, we studied the regulatory mechanism of the flavin mononucleotide (FMN) riboswitch of Corynebacterium glutamicum which controls the expression of downstream ribM gene. Our results showed that this riboswitch downregulates both ribM mRNA and RibM protein levels in FMN-rich cells. Analysis of mRNA stability and chromatin immunoprecipitation–real-time PCR analysis targeting RNA polymerase suggested the involvement of the mRNA degradation and premature transcriptional termination in this regulation, respectively. Simultaneous disruption of RNase E/G and Rho function completely abolished the regulation at the mRNA level. Also, the regulation at the protein level was largely diminished. However, some FMN-dependent regulation at the protein level remained, suggesting the presence of other minor regulatory mechanisms. Altogether, we demonstrated for the first time that two protein factors, Rho and RNase E/G, play a central role in the riboswitch-mediated gene expression control.

Description: AML1/RUNX1 is an essential transcription factor involved in the differentiation of hematopoietic cells. AML1 binds to the Runt-binding double-stranded DNA element (RDE) of target genes through its N-terminal Runt domain. In a previous study, we obtained RNA aptamers against the AML1 Runt domain by systematic evolution of ligands by exponential enrichment and revealed that RNA aptamers exhibit higher affinity for the Runt domain than that for RDE and possess the 5'-GCGMGNN-3' and 5'-N'N'CCAC-3' conserved motif (M: A or C; N and N' form Watson–Crick base pairs) that is important for Runt domain binding. In this study, to understand the structural basis of recognition of the Runt domain by the aptamer motif, the solution structure of a 22-mer RNA was determined using nuclear magnetic resonance. The motif contains the AH + –C mismatch and base triple and adopts an unusual backbone structure. Structural analysis of the aptamer motif indicated that the aptamer binds to the Runt domain by mimicking the RDE sequence and structure. Our data should enhance the understanding of the structural basis of DNA mimicry by RNA molecules.

Description: Global navigation satellite systems (GNSSs) have revealed that a mega-thrust earthquake that occurs in an island-arc trench system causes post-seismic crustal deformation. Such crustal deformation data have been interpreted by combining three mechanisms: afterslip, poroelastic rebound and viscoelastic relaxation. It is seismologically important to determine the contribution of each mechanism because it provides frictional properties between the plate boundaries and viscosity estimates in the asthenosphere which are necessary to evaluate the stress behaviour during earthquake cycles. However, the observation sites of GNSS are mostly deployed over land and can detect only a small part of the large-scale deformation, which precludes a clear separation of the mechanisms. To extend the spatial coverage of the deformation area, recent studies started to use satellite gravity data that can detect long-wavelength deformations over the ocean. To date, compared with theoretical models for calculating the post-seismic crustal deformation, a few models have been proposed to interpret the corresponding gravity variations. Previous approaches have adopted approximations for the effects of compressibility, sphericity and self-gravitation when computing gravity changes. In this study, a new spectral-finite element approach is presented to consider the effects of material compressibility for Burgers viscoelastic earth model with a laterally heterogeneous viscosity distribution. After the basic principles are explained, it is applied to the 2004 Sumatra–Andaman earthquake. For this event, post-seismic deformation mechanisms are still a controversial topic. Using the developed approach, it is shown that the spatial patterns of gravity change generated by the above three mechanisms clearly differ from one another. A comparison of the theoretical simulation results with the satellite gravity data obtained from the Gravity Recovery and Climate Experiment reveals that both afterslip and viscoelastic relaxation are occurring. Considering the spatial patterns in satellite gravity fields is an effective method for investigating post-seismic deformation mechanisms.