関節リウマチ発症におけるCTRPファミリーの役割の解析

学位の種別:課程博士University of Tokyo(東京大学

Are Two z~6 Quasars Gravitationally Lensed ?

Several high-z (z > 5.7) quasars have been found in the course of Sloan Digital Sky Survey. The presence of such very high-z quasars is expected to give constraints on early structure formation. On one hand, it is suggested that these most luminous objects at high redshift are biased toward the highly magnified objects by gravitational lensing. To clarify the effect of gravitational lensing on the high-z quasars, we began the imaging survey of intervening lensing galaxies. Indeed our previous optical image showed that SDSSp J104433.04+012502.2 at z=5.74 is gravitationally magnified by a factor 2. In this paper, we report our new optical imaging of other two high-z quasars, SDSSp J103027.10+052455.0 at z=6.28 and SDSSp J130608.26+035626.3 at z=5.99. Since we find neither intervening galaxy nor counter image with i^{\prime} < 25.4-25.8 around each quasar, we conclude that they are not strongly magnified regardless that a lens galaxy is dusty.Comment: 10 pages, 8 figures, Accepted for PAS

Optical Recording of Neuronal Activity with a Genetically-Encoded Calcium Indicator in Anesthetized and Freely Moving Mice

Fluorescent calcium (Ca2+) indicator proteins (FCIPs) are promising tools for functional imaging of cellular activity in living animals. However, they have still not reached their full potential for in vivo imaging of neuronal activity due to limitations in expression levels, dynamic range, and sensitivity for reporting action potentials. Here, we report that viral expression of the ratiometric Ca2+ sensor yellow cameleon 3.60 (YC3.60) in pyramidal neurons of mouse barrel cortex enables in vivo measurement of neuronal activity with high dynamic range and sensitivity across multiple spatial scales. By combining juxtacellular recordings and two-photon imaging in vitro and in vivo, we demonstrate that YC3.60 can resolve single action potential (AP)-evoked Ca2+ transients and reliably reports bursts of APs with negligible saturation. Spontaneous and whisker-evoked Ca2+ transients were detected in individual apical dendrites and somata as well as in local neuronal populations. Moreover, bulk measurements using wide-field imaging or fiber-optics revealed sensory-evoked YC3.60 signals in large areas of the barrel field. Fiber-optic recordings in particular enabled measurements in awake, freely moving mice and revealed complex Ca2+ dynamics, possibly reflecting different behavior-related brain states. Viral expression of YC3.60 – in combination with various optical techniques – thus opens a multitude of opportunities for functional studies of the neural basis of animal behavior, from dendrites to the levels of local and large-scale neuronal populations

Streptococcal infection and autoimmune diseases

Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. Streptococcus species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A Streptococcus (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases

Innate immune responses in Behçet disease and relapsing polychondritis

Behçet disease (BD) and relapsing polychondritis (RP) are chronic multisystem disorders characterized by recurrent flare-ups of tissue inflammation. Major clinical manifestations of BD are oral aphthae, genital aphthous ulcers, skin lesions, arthritis, and uveitis. Patients with BD may develop rare but serious neural, intestinal, and vascular complications, with high relapse rates. Meanwhile, RP is characterized by the inflammation of the cartilaginous tissues of the ears, nose, peripheral joints, and tracheobronchial tree. Additionally, it affects the proteoglycan-rich structures in the eyes, inner ear, heart, blood vessels, and kidneys. The mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome is a common characteristic of BD and RP. The immunopathology of these two diseases may be closely related. It is established that the genetic predisposition to BD is related to the human leukocyte antigen (HLA)-B51 gene. Skin histopathology demonstrates the overactivation of innate immunity, such as neutrophilic dermatitis/panniculitis, in patients with BD. Monocytes and neutrophils frequently infiltrate cartilaginous tissues of patients with RP. Somatic mutations in UBA1, which encodes a ubiquitylation-related enzyme, cause vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) with severe systemic inflammation and activation of myeloid cells. VEXAS prompts auricular and/or nasal chondritis, with neutrophilic infiltration around the cartilage in 52–60% of patients. Thus, innate immune cells may play an important role in the initiation of inflammatory processes underlying both diseases. This review summarizes the recent advances in our understanding of the innate cell-mediated immunopathology of BD and RP, with a focus on the common and distinct features of these mechanisms

The Subaru Deep Field Project: Lymanα\alpha Emitters at Redshift of 6.6

We present new results of a deep optical imaging survey using a narrowband filter ($NB921$) centered at $\lambda =$ 9196 \AA ~ together with $B$, $V$, $R$, $i^\prime$, and $z^\prime$ broadband filters in the sky area of the Subaru Deep Field which has been promoted as one of legacy programs of the 8.2m Subaru Telescope. We obtained a photometric sample of 58 Ly$\alpha$ emitter candidates at $z \approx$ 6.5 -- 6.6 among $\sim 180$ strong $NB921$-excess ($z^\prime - NB921 > 1.0$) objects together with a color criterion of $i^\prime - z^\prime > 1.3$. We then obtained optical spectra of 20 objects in our $NB921$-excess sample and identified at least nine Ly$\alpha$ emitters at $z \sim 6.5$ -- 6.6 including the two emitters reported by Kodaira et al. (2003). Since our Ly$\alpha$ emitter candidates are free from strong amplification of gravitational lensing, we are able to discuss their observational properties from a statistical point of view. Based on these new results, we obtain a lower limit of the star formation rate density of $\rho_{\rm SFR} \simeq 5.5 \times 10^{-4}$ $h_{0.7}$ $M_\odot$ yr$^{-1}$ Mpc$^{-3}$ at $z \approx 6.6$, being consistent with our previous estimate. We discuss the nature of star-formation activity in galaxies beyond $z=6$.Comment: 49 pages, 16 figures, PASJ, Vol. 57, No. 1, in pres

On the Origin of Lyman-α\alpha Blobs at High Redshift: Kinematic Evidence for a Hyperwind Galaxy at z = 3.1

We present deep optical spectroscopy of an extended Ly$\alpha$ emission-line blob located in an over-dense region at redshift $z \approx 3.1$; `blob 1' of Steidel et al. (2000). The origin of such Ly$\alpha$ blobs has been debated for some time; two of the most plausible models are (1) that it comes from a dust-enshrouded, extreme starburst galaxy with a large-scale galactic outflow (superwind/hyperwind) or (2) that it is the cooling radiation of proto-galaxies in dark matter halos. Examination of the kinematic properties of the Ly$\alpha$ emission-line gas should allow us to determine its nature. With this motivation, we performed optical spectroscopy of `blob 1' using the Subaru Telescope, and found that its kinematic properties can be well explained in terms of superwind activity.Comment: 12 pages, including 4 figures, accepted for publication in ApJ

Two distinct prions in fatal familial insomnia and its sporadic form

Abstract Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human–mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt–Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia

Expression of human mutant cyclin dependent kinase 4, Cyclin D and telomerase extends the life span but does not immortalize fibroblasts derived from loggerhead sea turtle (Caretta caretta)

Conservation of the genetic resources of endangered animals is crucial for future generations. The loggerhead sea turtle (Caretta caretta) is a critically endangered species, because of human hunting, hybridisation with other sea turtle species, and infectious diseases. In the present study, we established primary fibroblast cell lines from the loggerhead sea turtle, and showed its species specific chromosome number is 2n = 56, which is identical to that of the hawksbill and olive ridley sea turtles. We first showed that intensive hybridization among multiple sea turtle species caused due to the identical chromosome number, which allows existence of stable hybridization among the multiple sea turtle species. Expressions of human-derived mutant Cyclin-dependent kinase 4 (CDK4) and Cyclin D dramatically extended the cell culture period, when it was compared with the cell culture period of wild type cells. The recombinant fibroblast cell lines maintained the normal chromosome condition and morphology, indicating that, at the G1/S phase, the machinery to control the cellular proliferation is evolutionally conserved among various vertebrates. To our knowledge, this study is the first to demonstrate the functional conservation to overcome the negative feedback system to limit the turn over of the cell cycle between mammalian and reptiles. Our cell culture method will enable the sharing of cells from critically endangered animals as research materials