Precocious activation of APC/C-Cdh1 at pre-anaphase causes genome instability

Faithful chromosome segregation and thereby accurate gene transmission are crucial for all organisms. Until proper attachment of the mitotic spindle to the kinetochore is established, the ubiquitin ligase (E3) Cdc20-activated APC/C (anaphase promoting complex/cyclosome) is repressed by the spindle assembly checkpoint (SAC) and sister chromatin cohesion is protected. Mutants defective in SAC fail to arrest at metaphase even in the presence of damaged microtubules. Interestingly, a similar phenomenon occurs in yeast cells defective in Bub2, a negative factor of the mitotic exit network (MEN), which is required for telophase onset, although its precise molecular mechanism is unknown. Here, we show that chromosome missegregation occurs frequently in bub2∆ cells in the presence of damaged microtubules. The loss of Bub2 caused precocious activation of APC/C-Cdh1/Hct1 at pre-anaphase, leading to securin degradation and then separase-mediated cohesin cleavage. Overexpression of CDH1 and CDC14, encoding Cdc14 phosphatase, at pre-anaphase similarly caused chromosome missegregation. Thus, sequential activation of APC/C-Cdc20 and then APC/C-Cdh1 is critical for precise chromosome segregation and precocious activation of APC/C-Cdh1 at pre-anaphase causes genomic instability. Since degradation of human securin is also mediated by APC/C-Cdc20 and APC/C-Cdh1, this study predicts that precocious activation APC/C-Cdh1 in human cells similarly causes genomic instability, and thereby cell death or tumorigenesis

Three Japanese patients with congenital pituitary hormone deficiency and ophthalmological anomalies

The clinical phenotype of congenital pituitary hormone deficiency is variable and can be associated with a number of structural abnormalities of the central nervous system. We report three Japanese patients with congenital pituitary hormone deficiency and ophthalmological anomalies. Two of the patients initially showed strabismus and unilateral optic nerve hypoplasia. Thereafter, growth failure became evident, leading to the diagnosis of pituitary hormone deficiency. The other patient had severe congenital hypopituitarism with respiratory distress and hypoglycemia from the first day of life. In addition, he had prolonged jaundice and impaired liver function with bilateral optic nerve hypoplasia. Neuroimaging of the pituitary region in all three patients demonstrated a small anterior pituitary lobe and no pituitary stalk. Our findings indicate that clinical variability of congenital hypopituitarism must be considered. In a patient with ophthalmological symptoms, endocrine evaluation and neuroimaging of the CNS including the pituitary region should be considered

Voluminous magma formation for the 30-ka Aira caldera-forming eruption in SW Japan: contributions of crust-derived felsic and mafic magmas

Understanding the origin, assembly, and evolution of voluminous magma that erupts in catastrophic caldera-forming eruptions (CCFEs) is a community imperative. A CCFE of the Aira caldera at 30 ka discharged over 350 km3 of magma, which can be grouped into petrographically and geochemically distinct types: voluminous rhyolite, small amounts of rhyodacite, and andesite magmas. To further understand the magma plumbing system of the Aira CCFE, we examined the geochemical characteristics of whole rock and plagioclase from its eruptive deposits. The trace element and 87Sr/86Sr signatures recorded in the plagioclase phenocrysts of these magmas indicate that the three magmas were originally produced by partially melting an identical source rock, which was estimated to be a mafic amphibolite with an 87Sr/86Sr signature of ∼0.7055 that comprised the lower crust. Melting of mafic amphibolite produced both felsic and mafic magmas by low and high degrees of partial melting, respectively. The mafic magma assimilated uppermost crustal materials and crystallized to produce an andesite magma type. The andesitic magma consists of phenocrysts (∼39 vol%) and melt with a dacitic (∼70 wt% SiO2) composition. The felsic magma mixed with ∼10% of the andesite magma and crystallized, forming the rhyolite magma. The mixing between the andesite and rhyolite magmas before the Aira CCFE produced the rhyodacite magma. The 30-ka Aira CCFE magmas were generated only by melting two kinds of crustal materials with different geochemical characteristics and had geochemical variations due to different conditions of partial melting and mixing between various crustal melts. The lack of definitive evidence of the mantle component mixing with the Aira CCFE magmas suggests that the mantle-derived magmas worked only as a heat source for crustal melting

Alternative splicing produces structural and functional changes in CUGBP2

<p>Abstract</p> <p>Background</p> <p>CELF/Bruno-like proteins play multiple roles, including the regulation of alternative splicing and translation. These RNA-binding proteins contain two RNA recognition motif (RRM) domains at the N-terminus and another RRM at the C-terminus. CUGBP2 is a member of this family of proteins that possesses several alternatively spliced exons.</p> <p>Results</p> <p>The present study investigated the expression of exon 14, which is an alternatively spliced exon and encodes the first half of the third RRM of CUGBP2. The ratio of exon 14 skipping product (<it>R3δ</it>) to its inclusion was reduced in neuronal cells induced from P19 cells and in the brain. Although full length CUGBP2 and the CUGBP2 <it>R3δ </it>isoforms showed a similar effect on the inclusion of the smooth muscle (SM) exon of the <it>ACTN1 </it>gene, these isoforms showed an opposite effect on the skipping of exon 11 in the <it>insulin receptor </it>gene. In addition, examination of structural changes in these isoforms by molecular dynamics simulation and NMR spectrometry suggested that the third RRM of R3δ isoform was flexible and did not form an RRM structure.</p> <p>Conclusion</p> <p>Our results suggest that CUGBP2 regulates the splicing of <it>ACTN1 </it>and <it>insulin receptor </it>by different mechanisms. Alternative splicing of <it>CUGBP2 </it>exon 14 contributes to the regulation of the splicing of the <it>insulin receptor</it>. The present findings specifically show how alternative splicing events that result in three-dimensional structural changes in CUGBP2 can lead to changes in its biological activity.</p

High-Energy X-Ray Compton Scattering Imaging of 18650-Type Lithium-Ion Battery Cell

High-energy synchrotron X-ray Compton scattering imaging was applied to a commercial 18650-type cell, which is a cylindrical lithium-ion battery in wide current use. By measuring the Compton scattering X-ray energy spectrum non-destructively, the lithiation state in both fresh and aged cells was obtained from two different regions of the cell, one near the outer casing and the other near the center of the cell. Our technique has the advantage that it can reveal the lithiation state with a micron-scale spatial resolution even in large cells. The present method enables us to monitor the operation of large-scale cells and can thus accelerate the development of advanced lithium-ion batteries