ALBERT

Description: The 5'-AMP-activated protein kinase (AMPK) functions as a cellular energy sensor. 5-Aminoimidazole-4-carboxyamide-1-β-D-ribofranoside (AICAR) is a chemical activator of AMPK. In the liver, AICAR suppresses expression of the phosphoenolpyruvate carboxykinase ( PEPCK ) gene. The rat enhancer of split- and hairy-related protein-2 (SHARP-2) is an insulin-inducible transcriptional repressor and its target is the PEPCK gene. In this study, we examined an issue of whether the SHARP-2 gene expression is regulated by AICAR via the AMPK. AICAR increased the level of SHARP-2 mRNA in H4IIE cells. Whereas an AMPK inhibitor, compound-C, had no effects on the AICAR-induction, inhibitors for both phosphoinositide 3-kinase (PI 3-K) and protein kinase C (PKC) completely diminished the effects of AICAR. Western blot analyses showed that AICAR rapidly activated atypical PKC lambda (aPKC). In addition, when a dominant negative form of aPKC was expressed, the induction of SHARP-2 mRNA level by AICAR was inhibited. Calcium ion is not required for the activation of aPKC. A calcium ion-chelating reagent had no effects on the AICAR-induction. Furthermore, the AICAR-induction was inhibited by treatment with an RNA polymerase inhibitor or a protein synthesis inhibitor. Thus, we conclude that the AICAR-induction of the SHARP-2 gene is mediated at transcription level by a PI 3-K/aPKC pathway.

Description: Small nucleolar RNAs (snoRNAs) function mainly as guides for the post-transcriptional modification of ribosomal RNAs (rRNAs). In recent years, several studies have identified a wealth of small fragments (〈35 nt) derived from snoRNAs (termed sdRNAs) that stably accumulate in the cell, some of which may regulate splicing or translation. A comparison of human small RNA deep sequencing data sets reveals that box C/D sdRNA accumulation patterns are conserved across multiple cell types although the ratio of the abundance of different sdRNAs from a given snoRNA varies. sdRNA profiles of many snoRNAs are specific and resemble the cleavage profiles of miRNAs. Many do not show characteristics of general RNA degradation, as seen for the accumulation of small fragments derived from snRNA or rRNA. While 53% of the sdRNAs contain an snoRNA box C motif and boxes D and D' are also common in sdRNAs (54%), relatively few (12%) contain a full snoRNA guide region. One box C/D snoRNA, HBII-180C, was analysed in greater detail, revealing the presence of C' box-containing sdRNAs complementary to several pre-messenger RNAs (pre-mRNAs) including FGFR3. Functional analyses demonstrated that this region of HBII-180C can influence the alternative splicing of FGFR3 pre-mRNA, supporting a role for some snoRNAs in the regulation of splicing.

Description: Author(s): I. Nishi, M. Ishikado, S. Ideta, W. Malaeb, T. Yoshida, A. Fujimori, Y. Kotani, M. Kubota, K. Ono, M. Yi, D. H. Lu, R. Moore, Z.-X. Shen, A. Iyo, K. Kihou, H. Kito, H. Eisaki, S. Shamoto, and R. Arita We have performed an angle-resolved photoemission spectroscopy (ARPES) study of the iron-based superconductor PrFeAsO 0.7 and examined the Fermi surfaces and band dispersions near the Fermi level. Heavily hole-doped electronic states have been observed due to the polar nature of the cleaved surfaces.... [Phys. Rev. B 84, 014504] Published Mon Jul 18, 2011

Description: Cardio-facio-cutaneous (CFC) syndrome is one of the ‘RASopathies’, a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS–MAPK pathway. Germline mutations in BRAF cause CFC syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we here generated new knockin mice (here Braf Q241R/+ ) expressing the Braf Q241R mutation, which corresponds to the most frequent mutation in CFC syndrome, Q257R. Braf Q241R/+ mice manifested embryonic/neonatal lethality, showing liver necrosis, edema and craniofacial abnormalities. Histological analysis revealed multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects. Braf Q241R/+ embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels, demonstrating lymphatic defects in RASopathy knockin mice for the first time. Prenatal treatment with a MEK inhibitor, PD0325901, rescued the embryonic lethality with amelioration of craniofacial abnormalities and edema in Braf Q241R/+ embryos. Unexpectedly, one surviving pup was obtained after treatment with a histone 3 demethylase inhibitor, GSK-J4, or NCDM-32b. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality, ameliorating enlarged cardiac valves. These results suggest that our new Braf knockin mice recapitulate major features of RASopathies and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome.

Description: Author(s): L. Liu, T. Mikami, S. Ishida, K. Koshiishi, K. Okazaki, T. Yoshida, H. Suzuki, M. Horio, L. C. C. Ambolode, II, J. Xu, H. Kumigashira, K. Ono, M. Nakajima, K. Kihou, C. H. Lee, A. Iyo, H. Eisaki, T. Kakeshita, S. Uchida, and A. Fujimori We have studied the anisotropy in the in-plane resistivity and the electronic structure of isovalent Ru-substituted BaFe 2 As 2 in the antiferromagnetic-orthorhombic phase using well-annealed crystals. The anisotropy in the residual resistivity component increases in proportion to the Ru dopant concent… [Phys. Rev. B 92, 094503] Published Tue Sep 01, 2015

Description: Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2 -related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G〉C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the ‘knock-in’ Crouzon mouse model Fgfr2c C342Y/C342Y carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2c C342Y/– mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.

Description: Context. Massive stars end their lives in catastrophic supernova (SN) explosions. Key information on the explosion processes and on the progenitor stars can be extracted from observations of supernova remnants (SNRs), which are the outcome of SNe. Deciphering these observations, however, is challenging because of the complex morphology of SNRs. Aims. We aim to link the dynamical and radiative properties of the remnant of SN 1987A to the geometrical and physical characteristics of the parent aspherical SN explosion and to the internal structure of its progenitor star. Methods. We performed comprehensive three-dimensional hydrodynamic simulations which describe the long-term evolution of SN 1987A from the onset of the SN to the full-fledged remnant at the age of 50 years, accounting for the pre-SN structure of the progenitor star. The simulations include all physical processes relevant for the complex phases of SN evolution and for the interaction of the SNR with the highly inhomogeneous ambient environment around SN 1987A. Furthermore, the simulations follow the life cycle of elements from the synthesis in the progenitor star through the nuclear reaction network of the SN to the enrichment of the circumstellar medium as a result of the mixing of chemically homogeneous layers of ejecta. From the simulations, we synthesize observables that are to be compared with observations. Results. By comparing the model results with observations, we constrained the initial SN anisotropy causing Doppler shifts, observed in the emission lines of heavy elements from ejecta, and leading to the remnant evolution observed in the X-ray band in the last thirty years. In particular, we found that the high mixing of ejecta unveiled by high redshifts and broadenings of [Fe II] and 44Ti lines require a highly asymmetric SN explosion channeling a significant fraction of energy along an axis that is almost lying in the plane of the central equatorial ring around SN 1987A, roughly along the line-of-sight, but with an offset of 40°, with the lobe propagating away from the observer slightly more energetic than the other. Furthermore, we found unambiguously that the observed distribution of ejecta and the dynamical and radiative properties of the SNR can be best reproduced if the structure of the progenitor star was that of a blue supergiant which had resulted from the merging of two massive stars.

Description: Aims. We investigate the role played by a pre-supernova (SN) ambient magnetic field in the dynamics of the expanding remnant of SN 1987A, and the origin and evolution of the radio emission from the remnant, in particular during the interaction of the blast wave with the nebula surrounding the SN. Methods. We modeled the evolution of SN 1987A from the breakout of the shock wave at the stellar surface to the expansion of its remnant through the surrounding nebula using three-dimensional magnetohydrodynamic simulations. The model considers the radiative cooling, the deviations from equilibrium of ionization, the deviation from temperature-equilibration between electrons and ions, and a plausible configuration of the pre-SN ambient magnetic field. We explore the strengths of the pre-SN magnetic field ranging between 1 and 100 μG at the inner edge of the nebula and we assume an average field strength at the stellar surface B0 ≈ 3 kG. From the simulations, we synthesize the thermal X-ray and the non-thermal radio emission and compare the model results with observations. Results. The presence of an ambient magnetic field with strength in the range considered does not change significantly the overall evolution of the remnant. Nevertheless, the magnetic field reduces the erosion and fragmentation of the dense equatorial ring after the impact of the SN blast wave. As a result, the ring survives the passage of the blast, at least during the time covered by the simulations (40 yr). Our model is able to reproduce the morphology and lightcurves of SN 1987A in both X-ray and radio bands. The model reproduces the observed radio emission if the flux originating from the reverse shock is heavily suppressed. In this case, the radio emission originates mostly from the forward shock traveling through the H II region and this may explain why the radio emission seems to be insensitive to the interaction of the blast with the ring. Possible mechanisms for the suppression of emission from the reverse shock are investigated. We find that synchrotron self-absorption and free–free absorption have negligible effects on the emission during the interaction with the nebula. We suggest that the emission from the reverse shock at radio frequencies might be limited by highly magnetized ejecta.

Description: Context. The manifold phases in the evolution of a core-collapse (CC) supernova (SN) play an important role in determining the physical properties and morphology of the resulting supernova remnant (SNR). Thus, the complex morphology of SNRs is expected to reflect possible asymmetries and structures developed during and soon after the SN explosion. Aims. The aim of this work is to bridge the gap between CC SNe and their remnants by investigating how post-explosion anisotropies in the ejecta influence the structure and chemical properties of the remnant at later times. Methods. We performed three-dimensional magneto-hydrodynamical simulations starting soon after the SN event and following the evolution of the system in the circumstellar medium, which includes the wind of the stellar progenitor, for 5000 yr, obtaining the physical scenario of a SNR. Here we focused the analysis on the case of a progenitor red supergiant of 19.8 M⊙. We also investigated how a post-explosion large-scale anisotropy in the SN affects the ejecta distribution and the matter mixing of heavy elements in the remnant during the first 5000 yr of evolution. Results. In the case of a spherically symmetric SN explosion without large-scale anisotropies, the remnant roughly keeps memory of the original onion-like layering of ejecta soon after the SN event. Nevertheless, as the reverse shock hits the ejecta, the element distribution departs from a homologous expansion because of the slowing down of the outermost ejecta layers due to interaction with the reverse shock. In the case of a large-scale anisotropy developed after the SN, we found that the chemical stratification in the ejecta can be strongly modified and the original onion-like layering is not preserved. The anisotropy may cause spatial inversion of ejecta layers, for instance leading to Fe/Si-rich ejecta outside the O shell, and may determine the formation of Fe/Si-rich jet-like features that may protrude the remnant outline. The level of matter mixing and the properties of the jet-like feature are sensitive to the initial physical (density and velocity) and geometrical (size and position) initial characteristics of the anisotropy.