Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span

Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span

Timing jitter removers of photon detectors

Among various performances of photon detectors, the timing jitter is difficult to improve because of its trade-offs with other important performances such as detection efficiency. Such trade-offs have been an issue in applications, especially for high-purity non-Gaussian-state generation necessary in optical quantum computation. Here, we introduce a method using an external fast optical switch -- Timing Jitter Remover (TJR) -- whose time window limits the photon-detectable time of photon detectors and improve the timing jitter without sacrificing other performances. By using a TJR, we experimentally improve the timing jitter of a photon-number-resolving detector based on a transition edge sensor, from 50 ns to 10 ns. Using this improved detector, we generate one of important non-Gaussian states, a Schr\"{o}dinger cat state with Wigner negativity of -0.01, which cannot be observed without TJRs. TJRs would be the key technology for the realization of ultra-fast, fault-tolerant, universal optical quantum computer.Comment: 26 pages, 6 figure

Draft genome sequence of Japanese wood mouse, Apodemus speciosus

The wood mouse (genus Apodemus) is one of the most common rodents in broad-leaf forests in the temperate zone of the Palaearctic region. Molecular studies of wood mice have critically enhanced the understanding of their evolution and ancestral biogeographic events. However, their molecular data are currently only limited to partial mitochondrial sequences and a few genes. Therefore, we sequenced the wood mouse genome to facilitate the acquisition of useful resources for inferring their molecular evolution. We sampled a wild wood mouse at Tsukuba, Japan, and sequenced its whole-genome using the Illumina Hiseq. 2000. To reduce the risk of non-randomness, three paired-end libraries (insert sizes: 150, 300, and 500 bp) and, two mate-pair reads (insert sizes: 8 and 20 kbp) were constructed. In total, we generated approximately 210 Gbp data. From these sequences, we reconstructed 336,124 scaffolds. These data will enhance our understanding of the evolution and ecological factors that affect their genetic constitution. The genome scaffolds generated are available in the National Center Biotechnology Information (NCBI) BioProject with accession number PRJDB5914. Keywords: Rodent, Mouse, Apodemus speciosus, Phylogeography, Mammal, Evolutio

Altered balance of inhibitory and active Fc gamma receptors in murine autoimmune glomerulonephritis

Mag is an MRL-derived glomerulonephritis susceptibility locus that includes the Fcgr2b and Fcgr3 genes encoding the inhibitory Fc gamma receptor IIB (FcγRIIB) and active FcγRIII, respectively. We measured changes in gene balance in three B6.MRLc1 congenic mouse strains containing the 82-86, 92–100 and 100 cM regions of the MRL chromosome 1. We found that only the strain that has 92-100 (which includes Fcgr loci) developed glomerulonephritis. These congenic mice had splenomegaly, elevated blood urea nitrogen, anti-dsDNA antibodies and higher urinary albumin excretion compared to the parental strain C57BL/6(B6). Prior to the development of glomerulonephritis, large CD3- (T cell) and B220- (B cell) positive areas were identified in the spleens of B6.MRLc1(92–100) mice. Both Fc receptors were found in mesangial and dendritic cells; important sites of immune-complex clearance and antigen presentation. The FcγRIII-positive areas were more prominent in the congenic strain. Fcgr2b mRNA was lower in the B6.MRLc1(92–100) kidney and spleen than in those organs of the B6 mice while Fcgr3 expression and the Fcgr3 to Fcgr2b mRNA ratio was higher in the congenic strain kidneys, spleen and thymus than in those of the B6 prior to and at an early stage of glomerulonephritis. We conclude that the imbalance of inhibitory and active Fc gamma receptors influences the pathogenesis of glomerulonephritis

Onset of autoimmune glomerulonephritis derived from the telomeric region of MRL-chromosome 1 is associated with the male sex hormone in mice

Female B6.MRLc1(82–100) congenic mice develop more severe autoimmune glomerulonephritis (AGN) than males. We assessed the effects of gonadectomy on the pathogenesis of AGN in these mice. One-month-old male and female mice were divided into sham-operated group (SG) and gonadectomized group (GG), and the pathological changes were investigated at 8 months. SG females showed higher spleen and thymus weights, serum total IgG and autoantibody levels, glomerular damage scores and percent IgG- and CD3-positive glomeruli as compared with SG males. Gonadectomy showed more remarkable effects in males than in females. Spleen and thymus weights, urinary albumin excretion, glomerular damage scores, percent IgG- and CD3-positive glomeruli, and CD3-positive areas in the spleen were significantly higher in GG males than in SG males. CD3-positive cells were observed in both the thymic cortex and medulla in all animals except SG males. The expression ratio of active Fc gamma receptor (Fcgr) 3 to inhibitory Fcgr2b in the kidneys, which we have previously demonstrated to have a great impact on pathogenesis in B6.MRLc1(82–100), was significantly higher in GG males than in SG males. These results suggested that the differences in the pathogenesis of AGN are primarily because of the inhibitory roles of the male sex hormones

Combined effects of treatment with trientine, a copper-chelating agent, and X-irradiaion on tumor growth in transplantation model of a murine fibrosarcoma

Combined effects of treatment with trientine, a copper-chelating agent, and X-irradiation on development of fibrosarcoma using a murine transplantation model in vivo and on cellular survival in vitro were examined. Copper contents in the tumors and serum of trientine-treated mice were significantly lower than those of untreated mice. The tumor volumes of mouse fibrosarcoma QRsp-11 cells increased more slowly in the trientine-treated and the X-irradiated mice than in the control mice from 10 to 24 days postinoculation. The extent of inhibition of tumor growth by X-irradiation at 3 Gy was similar to that obtained by treatment with trientine. A combination of trientine and X-irradiation at 3 Gy showed inhibitory effects on tumor growth similar to those obtained by X-irradiation at 6 Gy. The results showed that trientine and X-irradiation interacted additively in inhibition of tumor growth. When QRsp-11 cells and mouse and bovine endothelial cells were treated with trientine after X-irradiation, the surviving fractions of the cells with combined treatments were essentially consistent with the products of the surviving fractions of trientine-treated cells and those of X-irradiated cells. When the cells were pretreated with trientine and X-irradiated, the surviving fractions of the pretreated cells were lower than those of cells without treatment

Trientine, A Copper-Chelating Agent, Induced Apoptosis in Murine Fibrosarcoma Cells in vivo and in vitro

Anti-copper treatments have been investigated to determine whether they suppress angiogenesis and tumor development since Cu is widely accepted as being required for angiogenesis. We examined the effects of treatment with trientine, a copper-chelating agent, on tumor development in a murine xenograft model using fibrosarcoma-derived transplantable QRsp-11 cells and C57BL/6 mice and induction of apoptosis in tumor cells and endothelial cells in vivo and in vitro. The tumor volumes increased more slowly in trientine-treated mice than in untreated mice. Tumor volumes in the treated mice were significantly smaller than those in the untreated mice at 24 days postinoculation (d.p.i.) of tumor cells. A cluster of pyknotic tumor cells and morphological abnormalities in capillary endothelial cells were observed in the tumors of trientine-treated mice but not in the tumors of untreated mice. The proportions of apoptotic and necrotic cells in the tumors of treated mice were approximately 3.5-fold higher than those in the tumors of untreated mice at 14 d.p.i. When the cells were treated with trientine in vitro, mouse endothelial cells and bovine primary endothelial cells showed an approximately 10-fold higher sensitivity to trientine than QRsp-11 cells in terms of D_37. However, the proportion of apoptotic cells in endothelial cells was significantly lower than that in QRsp-11 cells after treatment with trientine. These results show that apoptosis was induced in tumor cells by treatment with trientine in vivo and in vitro