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Astrocytes are key components of the neurovascular unit. While we have recently identified Olig2+ astrocyte progenitors (ASPs) in the developing mouse dentate gyrus (DG), their molecular signature remains incompletely characterized. Here we demonstrate that Olig2+ ASPs predominantly express brain lipid-binding protein (BLBP), while only a small population of them expresses gfap -GFP. These Olig2+/BLBP+ ASPs co-express the transcription factors Sox3, Sox9 and the proteoglycan NG2 but not Sox10, a marker for oligodendrocyte progenitors (OLPs). Olig2+ ASPs appear from embryonic day 18 (E18) onwards and decline at postnatal day 14 (P14). Consistent with the proliferation of both Olig2+ and NG2+ glial cells after brain injury, intrauterine intermittent hypoxia (IH) led to an increase in Olig2+/NG2+/BLBP+ ASPs in the postnatal DG. IH also promoted both angiogenesis and vascular coupling of Olig2+/NG2+ ASPs. Our data suggest that IH-induced expression of HIF1a increases Olig2+/NG2+/BLBP+ ASPs in a cell non-autonomous manner. Our data also revealed increased vascular coupling of GFAP+ astrocytes following IH, while the number of GFAP+ astrocytes remains unchanged. Given that BLBP, Olig2 and NG2 are expressed in reactive astrocytes, our findings suggest that Olig2+/NG2+/BLBP+ ASPs represent a subtype of reactive astrocyte progenitors. Furthermore, the enhanced vascular coupling of Olig2+/NG2+/BLBP+ ASPs appears to be an adaptive response to hypoxic brain injury. This study provides new insights into the molecular characteristics of Olig2+/NG2+/BLBP+ ASPs and their potential role in the brain’s response to hypoxic injury, contributing to our understanding of neurovascular unit dynamics in both development and pathological conditions.

The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is, ABCA4 for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic. EYS mutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two major EYS mutations identified in this cohort. EYS mutations are the most prevalent among Japanese patients with IRD.

Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease. The USH2A gene, which accounts for approximately 74-90% of Usher syndrome type 2 (USH2) cases, is also one of the major autosomal recessive RP (arRP) causative genes among Caucasian populations. To identify disease-causing USH2A gene mutations in Japanese RP patients, all 73 exons were screened for mutations by direct sequencing. In total, 100 unrelated Japanese RP patients with no systemic manifestations were identified, excluding families with obvious autosomal dominant inheritance. Of these 100 patients, 82 were included in this present study after 18 RP patients with very likely pathogenic EYS (eyes shut homolog) mutations were excluded. The mutation analysis of the USH2A revealed five very likely pathogenic mutations in four patients. A patient had only one very likely pathogenic mutation and the others had two of them. Caucasian frequent mutations p.C759F in arRP and p.E767fs in USH2 were not found. All the four patients exhibited typical clinical features of RP. The observed prevalence of USH2A gene mutations was approximately 4% among Japanese arRP patients, and the profile of the USH2A gene mutations differed largely between Japanese patients and previously reported Caucasian populations.

Cdc10‐dependent transcript 1 (CDT1) is an essential protein for DNA replication licensing, which loads the mini‐chromosome maintenance (MCM) complex onto replication origins. We previously reported that excess CDT1 inhibits the elongation of nascent strands during DNA replication in Xenopus egg extracts. In the present study, we investigated the underlying mechanism through which CDT1 inhibits replication fork progression by expressing various CDT1 mutants in human cells. Initiation of DNA replication resulted in downregulation of CDT1, preventing MCM reloading within the same cell cycle; thus, CDT1 overexpression induces rereplication. In this study, we observed that overexpression of a mutant CDT1 lacking licensing activity induced cell cycle arrest at the S phase in human cells. An additional mutation in the MCM‐binding domain reduced this cell cycle inhibitory effect. Furthermore, overexpression of CDT1 induced DNA damage independent of its licensing activity. These results suggest that CDT1 overexpression inhibits the progression of replication forks by interacting with the MCM complex, leading to the stalling and collapse of replication forks.

A new derivation method of duality relations in stochastic processes is proposed. The current focus is on the duality between stochastic differential equations and birth-death processes. Although previous derivation methods have been based on the viewpoint of time-evolution operators, the current derivation is based on basis expansions. In addition, only the tool needed for the derivation is the integration by parts, which is rather simple and understandable. The viewpoint of basis expansions enables us to obtain various dual stochastic processes. As a demonstration, dual processes based on Taylor-type and Hermite polynomials are derived.

The authors conducted a study on superconducting magnetic bearing, which consists of superconducting rotor and stator to apply the flywheel energy-storage system for railways. In this study, high temperature bulk superconductor (HTS bulk) was combined with superconducting coils to increase the load capacity of the bearing. In the first step of the study, the thrust rolling bearing was selected for application by using liquid nitrogen cooled HTS bulk. 60mm-diameter HTS bulks and superconducting coil which generated a high gradient of magnetic field by cusp field were adopted as a rotor and a stator for superconducting magnetic bearing, respectively. The results of the static load test and the rotation test, creep of the electromagnetic forces caused by static flux penetration and AC loss due to eccentric rotation were decreased to the level without any problems in substantial use by using two HTS bulks. In the result of verification of static load capacity, levitation force (thrust load) of 8900N or more was supportable, and stable static load capacity was obtainable when weight of 460kg was levitated.

The use of biologically produced alkanes has attracted considerable attention as an alternative energy source to petroleum. In 2010, the alkane synthesis pathway in cyanobacteria was found to include two small globular proteins, acyl-(acyl carrier protein [ACP]) reductase (AAR) and aldehyde deformylating oxygenase (ADO). AAR produces fatty aldehydes from acyl-ACPs/CoAs, which are then converted by ADO to alkanes/alkenes equivalent to diesel oil. This discovery has paved the way for alkane production by genetically modified organisms. Since then, many studies have investigated the reactions catalyzed by AAR and ADO. In this review, we first summarize recent findings on structures and catalytic mechanisms of AAR and ADO. We then outline the mechanism by which AAR and ADO form a complex and efficiently transfer the insoluble aldehyde produced by AAR to ADO. Furthermore, we describe recent advances in protein engineering studies on AAR and ADO to improve the efficiency of alkane production in genetically engineered microorganisms such as Escherichia coli and cyanobacteria. Finally, the role of alkanes in cyanobacteria and future perspectives for bioalkane production using AAR and ADO are discussed. This review provides strategies for improving the production of bioalkanes using AAR and ADO in cyanobacteria for enabling the production of carbon–neutral fuels.

The kinase-inducible domain interacting (KIX) domain is an integral part of the general transcriptional coactivator CREB-binding protein, and has been associated with leukemia, cancer, and various viral diseases. Hence, the KIX domain has attracted considerable attention in drug discovery and development. Here, we rationally designed a KIX inhibitor using a peptide fragment corresponding to the transactivation domain (TAD) of the transcriptional activator, mixed-lineage leukemia protein (MLL). We performed theoretical saturation mutagenesis using the Rosetta software to search for mutants expected to bind KIX more tightly than the wild-type MLL TAD. Mutant peptides with higher helical propensities were selected for experimental characterization. We found that the T2857W mutant of the MLL TAD peptide had the highest binding affinity for KIX compared to the other 12 peptides designed in this study. Moreover, the peptide had a high inhibitory effect on the KIX–MLL interaction with a half-maximal inhibitory concentration close to the dissociation constant for this interaction. To our knowledge, this peptide has the highest affinity for KIX among all previously reported inhibitors that target the MLL site of KIX. Thus, our approach may be useful for rationally developing helical peptides that inhibit protein–protein interactions implicated in the progression of various diseases.

The transcription factor c-Myb promotes the proliferation of hematopoietic cells by interacting with the KIX domain of CREB-binding protein; however, its aberrant expression causes leukemia. Therefore, inhibitors of the c-Myb–KIX interaction are potentially useful as antitumor drugs. Since the intrinsically disordered transactivation domain (TAD) of c-Myb binds KIX via a conformational selection mechanism where helix formation precedes binding, stabilizing the helical structure of c-Myb TAD is expected to increase the KIX-binding affinity. Here, to develop an inhibitor of the c-Myb–KIX interaction, we designed mutants of the c-Myb TAD peptide fragment where the helical structure is stabilized, based on theoretical predictions using AGADIR. Three of the four initially designed peptides each had a different Lys-to-Arg substitution on the helix surface opposite the KIX-binding interface. Furthermore, the triple mutant with three Lys-to-Arg substitutions, named RRR, showed a high helical propensity and achieved three-fold higher affinity to KIX than the wild-type TAD with a dissociation constant of 80 nM. Moreover, the RRR inhibitor efficiently competed out the c-Myb–KIX interaction. These results suggest that stabilizing the helical structure based on theoretical predictions, especially by conservative Lys-to-Arg substitutions, is a simple and useful strategy for designing helical peptide inhibitors of protein–protein interactions.