Model Building by Coset Space Dimensional Reduction Scheme Using Twelve-Dimensional Coset Spaces

We investigate the twelve-dimensional gauge-Higgs unification models with an eight-dimensional coset space. For each model, we apply the coset space dimensional reduction procedure and examine the particle contents of the resulting four-dimensional theory. Then, some twelve-dimensional SO(18) gauge theories lead to models of the SO(10)\times U(1) grand unified theory in four dimensions, where fermions of the Standard Model appear in multiple generations along with scalars that may break the electroweak symmetry. The representations of the obtained scalars and fermions are summarized.Comment: 17 pages, 4 table

High‐Density Lipoprotein Engineering for Eye‐Drop Treatment of Age‐Related Macular Degeneration

Eye-drop treatments of age-related macular degeneration (AMD) are desirable; however, no clinically approved eye drop has been reported to date. This study aim to evaluate the therapeutic activity of eye-drop instillation of a high-density lipoprotein (HDL) variant bearing a cell-penetrating peptide and neovasculature-targeted peptide (AsnGlyArg [NGR] peptide) in a mouse model at a dose of 0.6–0.85 µg protein/eye drop. The results reveal that the activity of the abovementioned variant was >10-fold higher than that of the previous variant lacking an NGR peptide. In addition, the anti-inflammatory activity, cholesterol-efflux capacity, and antiangiogenic activity of reconstituted HDL are significantly augmented by the attachment of these two peptides. The mechanism underlying this dramatic improvement is likely the expression of CD13, an NGR peptide receptor, on the cornea and conjunctiva in mice. CD13 mRNA/protein expression is also detected in cultured human corneal and conjunctival cells. These results demonstrate that NGR peptide is an unprecedented class of an absorption enhancer on the eye surface. Thus, HDL engineering is a potential strategy for developing eye drops to treat neovascular AMD by enhancing the ocular surface absorption and HDL functionalities

粘液性嚢胞腺腫の悪性化との鑑別に苦慮した膵未分化癌の1例

症例は70歳代の女性．7年前に膵尾部単純性嚢胞と診断され，経過観察中であった．4ヶ月持続する発熱と心窩部痛の精査を目的として入院した．入院時のCTでは多発肝腫瘍を認め，嚢胞内には結節病変を，嚢胞周囲には出血・感染を示唆する所見を認めた．以上より，嚢胞性病変が癌化して転移・浸潤をきたし，嚢胞周囲に膿瘍を形成したものと考えて対症的に治療したが，第15病日に死亡した．剖検所見から嚢胞の癌化は否定され，嚢胞に近接して発生した膵未分化癌と，肝転移，肺転移等の多臓器転移，腹膜播種と診断された

Comparative Analyses Define Differences Between Bhd-Associated Renal Tumour and Sporadic Chromophobe Renal Cell Carcinoma

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research

Association of melanocortin 1 receptor gene (MC1R) polymorphisms with skin reflectance and freckles in Japanese.

Most studies on the genetic basis of human skin pigmentation have focused on people of European ancestry and only a few studies have focused on Asian populations. We investigated the association of skin reflectance and freckling with genetic variants of melanocortin 1 receptor (MC1R) gene in Japanese. DNA samples were obtained from a total of 653 Japanese individuals (ages 19-40 years) residing in Okinawa; skin reflectance was measured using a spectrophotometer and freckling status was determined for each individual. Lightness index (L*) and freckling status were not correlated with age, body mass index or ancestry (Ryukyuan or Main Islanders of Japan). Among the 10 nonsynonymous variants that were identified by direct sequencing of the coding region of MC1R, two variants--R163Q and V92M--with the derived allele frequencies of 78.6 and 5.5%, respectively, were most common. Multiple regression analysis showed that the 163Q allele and the presence of nonsynonymous rare variants (allele frequencies <5%) were significantly associated with an increase in sex-standardized skin lightness (L* of CIELAB (CIE 1976 (L*a*b*) color space)) of the inner upper arm. Relative to the 92V allele, the 92M allele was significantly associated with increased odds of freckling. This is the first study to show an association between the 163Q allele and skin reflectance values; this association indicated that light-toned skin may have been subjected to positive selection in East Asian people

Model building by coset space dimensional reduction scheme using eight-dimensional coset spaces

Abstract We investigate the twelve-dimensional gauge-Higgs unification models with an eight- dimensional coset space as the extra space. For each model, we apply the coset space dimensional reduction procedure and examine the particle contents of the resulting four-dimensional theory. All combinations of inputs to the procedure are exhaustively analyzed under several assumptions. As a result, some twelve-dimensional SO(18) gauge theories lead to models of the SO(10) × U(1) grand unified theory in four dimensions, where fermions of the Standard Model appear in multiple generations along with scalars that may break the electroweak symmetry. The representations of the obtained scalars and fermions are summarized

Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Dextran Sulfate Sodium-Induced Severe Colitis in Rats

Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of human amnion-derived MSCs (AMSCs) in rats with severe colitis. Colitis was induced by the administration of 8% dextran sulfate sodium (DSS) from day 0 to day 5, and AMSCs (1 x 10(6) cells) were transplanted intravenously on day 1. Rats were sacrificed on day 5, and the colon length and histological colitis score were evaluated. The extent of inflammation was evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. The effect of AMSCs on the inflammatory signals was investigated in vitro. AMSC transplantation significantly ameliorated the disease activity index score, weight loss, colon shortening, and the histological colitis score. mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and migration inhibitory factor (MIF) were significantly decreased in the rectums of AMSC-treated rats. In addition, the infiltration of monocytes/macrophages was significantly decreased in AMSC-treated rats. In vitro experiments demonstrated that activation of proinflammatory signals induced by TNF-alpha or lipopolysaccharide (LPS) in immortalized murine macrophage cells (RAW264.7) was significantly attenuated by coculturing with AMSCs or by culturing with a conditioned medium obtained from AMSCs. Although the phosphorylation of I kappa B induced by TNF-alpha or LPS was not inhibited by the conditioned medium, nuclear translocation of NF-kappa B was significantly inhibited by the conditioned medium. Taken together, AMSC transplantation provided significant improvement in rats with severe colitis, possibly through the inhibition of monocyte/macrophage activity and through inhibition of NF-kappa B activation. AMSCs could be considered as a new cell source for the treatment of severe colitis

Minimally invasive plate osteosynthesis for humeral shaft nonunion: A report of two cases

Introduction: We treated two cases of humeral shaft nonunion by minimally invasive plate osteosynthesis (MIPO) without autogenous bone grafting. Presntation of case: Case 1: An osteosynthesis with intramedullary nailing (IMN) was performed on a 17-year-old female for a humeral shaft fracture at another hospital; however, bony union was not obtained. We removed the nail and screws, then performed MIPO without autogenous bone grafting. At the final follow-up of 4 years after the surgery, she had obtained full range of motion. Case 2: Osteosynthesis with Rush pins had been performed in a 73-year-old female for a humeral shaft fracture at another hospital. Five months later, a revision surgery using IMN was performed at the same hospital; however, this led to nonunion. We removed the IMN and performed MIPO without autogenous bone grafting. At the final follow-up 2 years after surgery, she had obtained full range of motion. Discussion: The cause of nonunion is the lack of mechanical instability and/or biological activity. In these cases, from the findings of radiography and bone scintigraphy, mechanical instability was thought to be the primary cause; therefore, in order to enhance stability, we used a locking plate. Because we can see that these cases are biologically active, we decided not to use bone grafting. Both our cases successfully achieved bony union and excellent functional recovery using this method. Conclusion: We performed MIPO without exposure of the nonunion site and autogenous bone grafting in two cases of humeral shaft nonunion, and obtained successful clinical outcomes

Final height and cardiometabolic outcomes in young adults with very low birth weight (<1500 g).

OBJECTIVE: Individuals with very low birth weight (VLBW; <1500 g) are known to be predisposed to both short final height and cardiometabolic disorders. However, associations between final height and cardiometabolic outcomes including glucose metabolism in VLBW individuals in young adulthood are not fully investigated. METHODS: We investigated glucose metabolism and other cardiometabolic outcomes such as lipid profiles, blood pressure, renal function, urinary albumin, and thyroid function in young adults with VLBW born between 1980 and 1990. Short stature was defined as a final height <10th percentile. Glucose intolerance [diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG)] was determined using 75-g oral glucose tolerance tests. Associations between final height and cardiometabolic outcomes were examined using logistic or multiple linear regression. RESULTS: A total of 628 VLBW individuals were screened and 111 young adults with VLBW (19-30 years) participated in the study. Of the participants, 40 subjects (36%) had short stature with a final height <10th percentile. Eight subjects (7.2%) had glucose intolerance (1, diabetes; 6, IGT; 1, IFG). Short stature was correlated with glucose intolerance (odds ratio 11.1; 95% CI 1.92, 99.7; P = 0.006). Final height was inversely associated with the homeostatic model assessment (HOMA) of insulin resistance, HOMA-β, insulinogenic index, and total/LDL-cholesterol. The associations of final height with insulin sensitivity and lipid profiles remained after adjustment for target height and age at puberty onset. CONCLUSIONS: Shorter final height was associated with less favorable metabolic profiles in young adults with VLBW, and may be partly mediated by reduced insulin sensitivity. These associations were independent of target height or age at puberty onset

A new technology for increasing therapeutic protein levels in the brain over extended periods.

Effective delivery of protein therapeutics into the brain remains challenging because of difficulties associated with crossing the blood-brain barrier (BBB). To overcome this problem, many researchers have focused on antibodies binding the transferrin receptor (TfR), which is expressed in endothelial cells, including those of the BBB, and is involved in receptor-mediated transcytosis (RMT). RMT and anti-TfR antibodies provide a useful means of delivering therapeutics into the brain, but the anti-TfR antibody has a short half-life in blood because of its broad expression throughout the body. As a result, anti-TfR antibodies are only maintained at high concentrations in the brain for a short time. To overcome this problem, we developed a different approach which slows down the export of therapeutic antibodies from the brain by binding them to a brain-specific antigen. Here we report a new technology, named AccumuBrain, that achieves both high antibody concentration in the brain and a long half-life in blood by binding to myelin oligodendrocyte glycoprotein (MOG), which is specifically expressed in oligodendrocytes. We report that, using our technology, anti-MOG antibody levels in the brains of mice (Mus musculus) and rats (Rattus norvegicus) were increased several tens of times for a period of one month. The mechanism of this technology is different from that of RMT technologies like TfR and would constitute a breakthrough for central nervous system disease therapeutics