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PDF file - 236K, 4NQO-water consumptions

PDF file - 48K, Hematological indices of wild-type and Nrf2-KO mice treated with 4NQO

PDF file - 31K, Sequences of primers and probes for RT-PCR

PDF file - 725K, The effects of 4NQO treatment on the body weights of wild-type, Keap1-KD and Nrf2-KO mice

PDF file - 78K

PDF file - 720K, A model for the role of the Keap1-Nrf2 system in upper aerodigestive tract carcinogenesis induced by 4NQO

PDF file - 1357K, Representative hematoxylin-eosin-stained sections of esophageal tumors after experiments with 4NQO

Methane hydrate and subsea minerals have been found in the deepwater within Japan’s exclusive economic zone. However, their development has not reached the commercialization stage because many technical issues still need to be solved. Gas-lift pumping systems are one of the promising methods for methane hydrate transport from the seafloor to the sea surface. Since the internal flow in pipes becomes a three-phase flow for gas-lift pumping systems, flow assurance for the three-phase flow is essential to design the actual systems. Gas supplied into pipes deep in the sea expands as it returns to the surface. Thus, the void fractions of the gas phase in lines would be larger near sea surface than near seafloor. In addition, there are few studies on flow assurance in the conditions of a high void fraction of the gas phase. We conducted the experiment of gas-lift pumping systems using clear polyvinyl chloride pipes and resin balls as solid particles. As a result, we obtained mass flux data, void fractions, and frictional pressure drops in those conditions. Furthermore, we investigated whether the methods previously proposed clould calculate the void fractions and the frictional pressure drops in three-phase flow by comparing the calculated results with experimental data obtained from the present experiment.

Methane hydrate has been found below the seafloor in Japan’s Exclusive Economic Zone (EEZ) in a large amount. During the methane hydrate transportation, it is concerned that the riser pipe or the flowline can be plugged by the hydrate reformation and the freezing of seawater. The degradation and reformation kinetics of methane hydrate are mainly controlled by temperature, pressure, and methane concentration in the system, however, it is difficult to predict these factors in the multiphase flow because they are affected by fluid dynamics and heat transfer. Therefore, we are currently constructing an evaluation model for the slurry transportation, including the formation and dissociation processes of the hydrate in a riser pipe at dynamic conditions. Then, the characteristics of the phase change by the hydrate’s formation and dissociation have been investigated using experimental apparatus simulating the flow situations in a riser pipe. This paper reports some data obtained in two preliminary experiments on the heat transfer effect of pipes and the hydrate formation process. The formation processes of gas hydrate at a gas-liquid interface under high-pressure conditions were observed by using a probe-type video camera. The experimental results showed that the formation of gas hydrate requires enough amount of gas injection, including the dissolved gas in seawater, in addition to temperature-pressure condition.

For subsea mining, it is important to predict the pressure loss in oscillating pipes with pulsating flow for the safe and reliable operation of ore lifting. In the present paper, the authors focused on the pulsating internal flow in static vertical pipe and carried out slurry transport experiment to investigate the effects of flow fluctuation on the pressure loss. The alumina beads and glass beads were used as the solid particles in the experiment, and the fluctuating periods and amplitudes of pulsating water flow were varied. The time-averaged pressure losses calculated by the prediction method for the steady flow proposed in the past by the authors agreed well with the experimental ones. As for the fluctuating component of pressure loss, the calculation results using the quasi-steady expression of a mixture model were compared with the experimental data. The calculated results were different from experimental ones for alumina beads of which densities are almost same as those of the ores of Seafloor Massive Sulfides. It suggests that the expression is insufficient to predict the pressure loss for heavy solid particles. The calculated ones, however, provided those in the safety side. On the other hand, the calculated results for light solid particles such as glass beads agreed well with the experimental ones. It means that the expression would be applicable to the prediction of pressure loss for the mining of manganese nodules which are lighter than the ores of Seafloor Massive Sulfides.

Subsea minerals exist in the deep water within Japan’s exclusive economic zone. There are many technical issues which should be addressed for subsea mining. The air-lift pumping systems are one of promising methods for subsea minerals transport. Flow assurance for three-phase flow is important to design the air-lift pumping system for subsea mining. It is important to establish methods for estimating void fractions and frictional pressure drops. To establish the methods for three-phase flow, we reviewed previous studies for two- or three-phase flow. There are some models to estimate the void fractions such as slip flow model and drift flux model. There are also some models to estimate the frictional pressure drops such as homogeneous model and separated flow model. We calculated void fractions and frictional pressure drops by existing correlation and compared calculated results with experimental data in two- or three-phase flow. In addition, we proposed the methods for estimating the void fractions and frictional pressure drops in three-phase flow. These had fewer number of experimental constants than existing correlations, these could calculate void fractions and frictional pressure drops in more various conditions than existing correlations.

Methane hydrate has been found below the seafloor in the Exclusive Economic Zone (EEZ) of Japan in a large amount. During the methane hydrate transportation, it is concerned that the riser pipe or the flowline can be plugged by the hydrate reformation and the freezing of seawater. The degradation and reformation kinetics of methane hydrate are mainly controlled by temperature, pressure, and methane concentration in the system; however, it is difficult to predict these factors in the multiphase flow because they are affected by fluid dynamics and heat transfer. To obtain the experimental data of the degradation kinetics, we developed a closed-loop experimental apparatus consisting of jacketed tubings used as heat exchangers, three acrylic units to observe the flow, and a slurry pump. The flow rate, salinity, temperature, and pressure in the apparatus were continuously measured in the circulation experiments. The experiment results showed that the freezing condition of the fluid in the pipe is affected by the temperature of the outside of the pipe or the particle in the fluid. This paper reports some experimental data obtained in several cases, including those conducted under freezing conditions.

For subsea mining, it is important to predict the pressure loss in oscillating pipes for the safe and reliable operation of ore lifting as well as the design of lifting system. In the present paper, the authors focused on the internal flow in vertical lifting pipe oscillating in the axial direction and carried out slurry transport experiment to investigate the effects of pipe oscillation on the pressure loss. The spherical alumina beads and glass beads were used as the solid particles in the experiment, and the oscillating periods and amplitudes of pipe model as well as the solid concentrations and the mean slurry velocities were varied. The time-averaged components of hydraulic gradient calculated by the prediction method for the steady flow proposed in the past by the authors agreed well with the experimental ones. As for the fluctuating components of hydraulic gradient, the calculation results using a homogeneous mixture model were compared with the experimental data. The comparison result indicated that the homogeneous mixture model would be applicable to the prediction of pressure loss in the vertical pipe oscillating in the axial direction.

The background of this study is to develop a method to improve the fluidity of high viscosity oil left in sunken ships. We focused on emulsification to control the rheological properties of the oil. As a first step towards the goal, experiments and modeling were conducted to understand the viscosity properties of oil-water emulsions. In the experiments, oil-water emulsions were prepared using several surfactants to measure viscosity properties. The results showed a continuous change in viscosity with increasing water content as well as a discontinuous change in viscosity due to phase inversion that occurs at a certain water content. In the theoretical modelling, a new layer-stacking model was developed and applied to the experimental results. This model, though extremely simplifying the structure of the emulsion, was found to be able to well explain the continuous and discontinuous viscosity characteristics of the emulsion.

While the vascular healing process after drug-eluting stent implantation is not fully elucidated, it is generally accepted that macrophages play an important role in inflammation. It is also known that macrophages involved in the pathogenesis of atherosclerosis may stem from several origins, that is, monocyte-derived macrophages versus resident macrophages. However, little is known about the role of human macrophages on reperfusion of culprit coronary arteries in patients with atherosclerotic disease who have sustained acute coronary syndrome. In this present case report, we describe the presence of cluster of differentiation (CD) 163-positive macrophages in close proximity to the stent struts at the luminal site 72 hours after drug-eluting stent implantation in the culprit coronary lesion for ST elevation myocardial infarction by postmortem examination.

This paper describes experiments to circulate a mixture of synthetic seawater and ice particles, in other words, an ice slurry, in a flow-loop apparatus consisted of double-tube heat exchangers with acrylic tubes placed along the loop to observe the inner flow. As a method to prepare ice slurry, the ice injection method and stepwise cooling method were tried. In the experiments by the ice injection method, ice in the slurry was gradually melted due to heat transfer from the outer fluid, which was circulated in the annulus of the heat exchangers, because the temperature of the slurry became lower than that of the outer fluid. On the other hand, in experiments by the stepwise cooling method, the seawater was gradually frozen to form ice slurry with flaky ice, and finally, ice layers were formed in the wall of the inner tube in the heat exchangers. The observation of the ice layers implied that iron rusts were contained in the flow to affect the formation of flaky ice. These results suggest that the formation of methane hydrate in a flow of seawater through pipes could be affected by muddiness or turbidity in seawater.

Subsea minerals exist in the deep water within Japanese exclusive economic zone. However, the development of subsea minerals is not commercialized. The Air-lift pump is the promising method for subsea minerals transport. It is significant to estimate the amount of lifting ore when the conditions of submergence ratio and supplying air volume are changed. The estimation of the amount of lifting ore needs the void fraction in three phase flow and friction loss in pipe. Therefore, the empirical methods to estimate the void fraction and friction loss in mainly vertical pipe were proposed in the previous studies. However, the lifting system for subsea minerals has not only vertical pipe but inclined pipe. There are few works for flow assurance on three phase flow in inclined pipe. Then we conducted the scale model experiment to investigate void fraction and friction loss. The experiment was conducted in the conditions of the five kinds of inclination angles. We used the glass beads as solid particles in the experiment. The glass beads were 4mm in diameter and 2553kg/m3 in density. The internal diameter of pipe was 26mm. We applied the empirical method for vertical or horizontal pipe proposed in previous researches to the present experimental condition. Then we compared the experimental results with the calculated ones on void fraction and friction loss. As the results, the calculated results were in good agreement with the experimental ones. Therefore, it was suggested that the void fraction and friction loss in the inclined pipe could be calculated by the empirical method based on the experiment on the vertical or horizontal pipe.

For the exploitation of seafloor massive sulfides, we have investigated the dynamic behavior of the jumper, a piece of flexible pipe that connects the seafloor mining tool to the subsea slurry pump. In this article, we present the results of the experiment using a 1/5 reduced-scale model of the jumper. This experiment was carried out in Deep-Sea Basin. During the experiment, a slurry fluid was conveyed throughout the jumper’s model. In addition, an oscillator generated harmonic motion on the top end of the model. In terms of instrumentation, we installed load cells on the top and bottom ends of the model and a 3D visual measurement system tracked the motion of measurement stations attached to the model. We present the experimental results measured by the 3D visual measurement system, loads cells, and differential pressure gauges in the cases where a vertically forced oscillation is imposed on the top of the jumper. In this experiment, we could observe the effects of slurry on the jumper reduced-scale model. Since the slurry has a larger density than the single liquid phase, the slurry flow changed, as expected, the static shape of the jumper compared to a jumper conveying only water. The vertical top force average and differential pressure average increase with the volume concentration of solid, while their amplitudes increase quadratically with the forced oscillation frequency.

In the robust control of systems with dynamic uncertainty, there are mainly two methodologies: one based on the gain bound of uncertainty and the other based on the phase bound. The well-known small-gain approach belongs to the former and is able to conduct nonconservative robust performance design by using $\mu$ -synthesis. Meanwhile, the study on the latter case is still under way, and only a positive-real method was proposed by the authors recently to handle the robust performance synthesis. This paper aims at improving the positive-real method. The key idea is to model a passive uncertainty not only by its phase bound but also utilizing its largest gain. This is achieved by applying the notion of output strict passivity well known in nonlinear control. Furthermore, the negative-imaginary uncertainty can be treated in this framework more naturally. A case study on a vibration system validates the advantage of the present method.

This paper addresses the robust performance synthesis problem for systems with positive-real or negative-imaginary uncertainty. The conventional robust performance design methods are mostly based on the gain information of uncertainty, which is not suitable for uncertainties characterized by the phase information. The approach taken here is based on the input–output relation of systems in the frequency-domain, which enables a less conservative yet numerically tractable solution to the robust performance synthesis. The effectiveness is validated through a detailed case study on the head positioning control of hard disk drives. The results and comparison demonstrate that the proposed method can achieve a much higher robust performance than existing methods.

In the Deep-Sea Mining, the seafloor mining tool is connected to the subsea slurry pump by a piece of flexible pipe named jumper. The jumper’s shape is similar to a steep-wave flexible riser. Compared to a flexible riser, the jumper is a reinforced hose and has a shorter length. Numerous studies shed light on the dynamic behavior of flexible riser; however, all studies were carried out by the way of numerical analysis. We carried out, in the Deep-Sea Basin, an experiment using 1/5 reduced scale model of the jumper. Unhappily, the model’s bending stiffness had to be distorted. During the experiment, an oscillator generated harmonic motion on the top end of the model and a centrifugal pump circulated water throughout the model. In addition, we installed load cells on the top and bottom ends of the model. Our Basin is equipped with a visual measurement system. Thus, we measured the displacement of targets attached to the model. The initial results show that axial tension amplitude increases with the frequency of the top end oscillation. This response is due to the drag force on the lower bend increases with the frequency of top motion. We also could observe that the internal flow may increase the vertical motion amplitude. The jumper’s motion generates an oscillation on the internal differential pressure between both ends and the flow velocity. The differential pressure amplitude increases with the top oscillation frequency, but it is proportional to the top end oscillation amplitude. We will use these experimental results to validate our numerical models. Further, it is important to understand the internal flow effects to design the actual pump used to convey the slurry through the jumper.

The gyroscopic g factor, g ′ , of FeCo nanogranules embedded in a matrix of MgF 2 (FeCo-MgF 2 ) was determined by measuring the magnetic-field generation from a rotating sample due to the Barnett effect. The g ′ value of the FeCo-MgF 2 is estimated to be 1.76 ± 0.11. The orbital contribution to the magnetic moment in the FeCo nanogranules was found to be quite large compared with that in bulk FeCo, being consistent with a density-functional-theory calculation that shows that the orbital magnetic moment may increase at the FeCo/MgF 2 interfaces. The result suggests that the orbital magnetic moment is enhanced by symmetry breaking at the surface of the FeCo nanogranules.

The air-lift pumping system is one of the promising method for subsea mineral lifting. It is significant to figure out the relation between water flux and injected air volume or submergence ratio. In this paper, the authors conducted the experiment to obtain basic data for vertical air-lift pumping. As the results of the experiment, the water flux increased with increasing the submergence ratio. Then the water flux increased with increasing the injected air volume up to a value. In addition, the authors calculated the solid flux using large internal diameter of pipe. The calculated results are in good agreement with the experimental ones.

We report direct observation of gyromagnetic reversal, which is the sign change of gyromagnetic ratio in a ferrimagnet Ho$_3$Fe$_5$O$_{12}$, by using the Barnett effect measurement technique at low temperatures. The Barnett effect is a phenomenon in which magnetization is induced by mechanical rotation through the coupling between rotation and total angular momentum $J$ of electrons. The magnetization of Ho$_3$Fe$_5$O$_{12}$ induced by mechanical rotation disappears at 135~K and 240~K. The temperatures correspond to the magnetization compensation temperature $T_{\rm M}$ and the angular momentum compensation temperature $T_{\rm A}$, respectively. Between $T_{\rm M}$ and $T_{\rm A}$, the magnetization flips over to be parallel against the angular momentum due to the sign change of gyromagnetic ratio. This study provides an unprecedented technique to explore the gyromagnetic properties., 4pages,4figures

Magnetohydrodynamic generators use magnetic fields to convert the kinetic energy of conducting fluids into electricity. Fluid motion is now shown to generate spin currents, which can induce electric voltages without applying magnetic fields. Magnetohydrodynamic generation1,2,3,4 is the conversion of fluid kinetic energy into electricity. Such conversion, which has been applied to various types of electric power generation, is driven by the Lorentz force acting on charged particles and thus a magnetic field is necessary3,4. On the other hand, recent studies of spintronics5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 have revealed the similarity between the function of a magnetic field and that of spin–orbit interactions in condensed matter. This suggests the existence of an undiscovered route to realize the conversion of fluid dynamics into electricity without using magnetic fields. Here we show electric voltage generation from fluid dynamics free from magnetic fields; we excited liquid-metal flows in a narrow channel and observed longitudinal voltage generation in the liquid. This voltage has nothing to do with electrification or thermoelectric effects, but turned out to follow a universal scaling rule based on a spin-mediated scenario. The result shows that the observed voltage is caused by spin-current6 generation from a fluid motion: spin hydrodynamic generation. The observed phenomenon allows us to make mechanical spin-current and electric generators, opening a door to fluid spintronics.

Subsea minerals exist in the deep water within Japanese exclusive economic zone. Development of slurry pump passing large particles is required for lifting ore. In design of slurry pump, it is significant to estimate the pressure loss in a riser pipe for large particle slurry transport. Therefore the authors have been studied the slurry flow model for large particle slurry transport. In addition, the authors developed the model for the static pipe including the inclined configurations. Since the lifting pipe will be oscillated due to the connected ship motion and VIV (Vortex Induced Vibration), the authors conducted the scaled model experiment to investigate the effects of pipe oscillation on the pressure loss. The model scale was 1/8. Alumina beads and glass beads were used as solid particles in the experiment. The pipe was vertical, and oscillated in horizontal or vertical direction. The experimental results showed that the horizontal and vertical oscillation had little influence on the static pressure loss in most of the experimental conditions. However the influence was observed for the horizontally oscillating pipe in the low slurry velocity and short oscillation period condition. On the other hand, the significant fluctuation components of pressure loss and flow rate were observed in vertically oscillating pipe. The results also indicated that the density of slurry and amplitude of oscillation had influence on the fluctuation components of pressure loss and flow rate but the particle diameters had little influence on them.

For subsea mining, the prediction of pressure loss due to the hydraulic transport of solid particles in the flexible pipe to connect the mining tool and the lifting system is important for the design of mining system. The configuration of the flexible pipe is expected to have an inclined part. In the present paper, the authors developed a mathematical model to predict the pressure loss in inclined pipes. The total pressure loss is expressed by the summation of the loss due to a liquid single-phase flow and the additional loss due to the existence of solid particles. The additional pressure loss can be divided into the variation in static pressure due to the existence of solid particles, the loss due to the particle-to-pipe wall friction and collisions, and the loss due to the particle-to-particle collisions. The empirical formula in horizontal pipes proposed by the other researchers was applied to the model of the last two losses. Furthermore, we carried out the experiment on hydraulic transport of solid particles in a pipe. In the experiment, alumina beads, glass beads, and gravel were used as the solid particles, and the inclination angles of the pipe were varied to investigate the effect of the pipe inclination on the pressure loss. The calculated pressure loss using the model was compared with the experimental data. As the results of the comparison, it was confirmed that the developed model could be applied to the prediction of the pressure loss in inclined pipes.

SH2D1A, also known as signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), is an adaptor protein. Recently, it was reported that SAP deficient mice were protected from systemic lupus erythematosus (SLE). In this study, we postulated SH2D1A gene to be a candidate susceptibility gene for SLE and analyzed its association with SLE. A case-control association study was conducted on 5 tag single nucleotide polymorphisms (SNPs) in SH2D1A region in 506 Japanese female SLE patients and 330 healthy female controls. The luciferase assay was performed to determine the functional role of the SNP associated with SLE. One SNP in the intron 2, rs2049995, showed association with SLE ( p = 0.0110, odds ratio (OR) 1.97, 95% confidence interval (CI) 1.16–3.34, under the dominant model). The association of rs2049995 seemed to be stronger in the subset with the age of onset less than 20 years ( p = 0.0067, OR 2.65, 95% CI 1.28–5.46). Functional evaluation of rs2049995 showed that reporter gene activity was increased 1.9-fold for the susceptible allele compared with the resistant allele. An intronic SNP of SH2D1A is associated with SLE.

Although costimulatory molecules have been shown to play crucial roles in the immune response, their involvement in the pathogenesis of Sjögren's syndrome is incompletely understood. In this study, we evaluated the relationship between the severity of spontaneous Sjögren's syndrome-like autoimmune sialadenitis in MRL/MpJ-lpr/lpr (MRL-Fas(lpr)) mice and the expression of 6 costimulatory molecules that play important roles in the immune response: CD80, CD86, OX40 ligand (OX40L), 4-1BB ligand (4-1BBL), glucocorticoid-induced TNF receptor-related protein ligand (GITRL), and B cell-activating factor of the tumor necrosis factor family (BAFF). Expression of the costimulatory molecules in the submandibular salivary glands of age-matched autoimmune MRL-Fas(lpr) mice and non-autoimmune MRL/MpJ-+/+(MRL/+) and C3H/HeJ-lpr/lpr (C3H-Fas(lpr)) mice was examined immunohistochemically and scored on a scale of 0 to 3. The severity of sialadenitis was evaluated histologically and scored on a scale of 0 to 3. We found that all of the costimulatory molecules were expressed in duct epithelial cells of salivary glands from MRL-Fas(lpr) mice, whereas immunoreactivity was absent or weak in the MRL/+ mice. The staining intensity for all 6 costimulatory molecules was significantly higher in the MRL-Fas(lpr) than in the MRL/+ mice. Partial correlation analysis was performed to assess the degree of association between costimulatory molecule staining scores and disease scores, which clearly revealed a significant correlation for only GITRL and 4-1BBL. These molecules showed negligible immunoreactivity in the submandibular glands of C3H-Fas(lpr) mice, suggesting that their expression was independent of the Fas(lpr) mutation. In conclusion, the expression of GITRL and 4-1BBL in salivary gland duct epithelial cells is associated with background genes in the MRL strain, but not with the Fas(lpr) mutation itself, and contributes significantly to the pathogenesis of autoimmune sialadenitis in MRL-Fas(lpr) mice. These results suggest that GITRL and 4-1BBL may be effective targets for the development of therapies for Sjögren's syndrome.

Objectives With the aim of searching for novel oncofetal tumor biomarkers of lung adenocarcinoma other than carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP), we developed a strategy involving monoclonal antibodies generated from embryonic tissue of miniature swine. Materials and methods Using immunohistochemistry, we selected suitable hybridoma clones that were reactive against swine fetal lung but not adult lung using tissue microarray loading of human normal lung, lung cancer, and fetal and adult swine tissues. Results The selected clones included several that were uniquely reactive against both swine fetal lung and human lung adenocarcinoma, and protein microarray revealed that the antigen they recognized was "drebrin" ( DBN1 ). We then examined the association between the pattern of drebrin expression and the clinicopathological characteristics of lung adenocarcinoma using surgically resected samples of human lung adenocarcinoma. Two hundred formalin-fixed and paraffin-embedded tumor samples were immunostained for drebrin using clone B246, one of the clones that were reactive against drebrin. The cases were divided into those with strong (n=85) and weak (n=115) drebrin expression. In terms of disease-free survival, cases showing strong drebrin expression had a significantly poorer prognosis than those with weak drebrin expression (p=0.033). Conclusion The present findings indicate that "drebrin" is a unique oncofetal protein that can be applied as a new biomarker of lung adenocarcinoma.

Background: Limited information is available regarding the lymphatic vasculature during pneumonia. Objective: To characterize lymphatic vasculatures in autopsied cadavers with pneumonia. Methods: Paraffin-embedded lung tissues obtained from 20 autopsied cadavers with complicated pneumonia and 10 control cadavers without pneumonia were used for immunohistochemical analyses using primary antibodies against podoplanin, vascular endothelial growth factor receptor-3 (VEGFR-3), CD34, vascular endothelial growth factor (VEGF)-C, VEGF-D, CD73, and CD163. Results: There was no difference in the vascular density of podoplanin+ usual lymphatics between the individuals with and without pneumonia. In half of the cadavers with pneumonia, however, a network of podoplanin+ cells lying together in a side-by-side bead-like arrangement appeared along the alveolar septa; however, this was absent in the control cadavers. The podoplanin+ cells in the network were characterized by a weaker expression of podoplanin, rel...

Homogeneous Bi-Pb alloy samples in the ε-phase are treated under mega-gravity centrifugal acceleration field. Atomic sedimentation in solid and associated partial crystallization occurs during the treatment. Small differences of densities in the ε-phase are enhanced under the mega-gravity, and they cause the separation of the ε-phase between fully packed hcp structure of the Bi3Pb7and partially defected hcp structure of the Bi3Pb7-δ. The compositional graded superconducting alloy is obtained in the latter. Partially melt-growth occurs in the latter and microstructure of Pb is formed along the gravity field associating with the formation of highly oriented the (211) phase of Bi3Pb7-δ. The superconductivity parallel to gravity is Pb, and perpendicular to gravity is Bi3Pb7-δas the result. Superconducting properties differs between the separated two phases.

Objective Fcγ receptor type IIb (FcγRIIb) is a major negative regulator of B cells, and the lack of FcγRIIb expression has been reported to induce systemic lupus erythematosus (SLE) in mice of the C57BL/6 (B6) genetic background. The 129 strain–derived Sle16 locus on the telomeric region of chromosome 1 including polymorphic Fcgr2b confers the predisposition to systemic autoimmunity when present on the B6 background. We undertook this study to examine the effect of the Sle16 locus on autoimmune disease in FcγRIIb-deficient B6 mice. Methods We established 2 lines of FcγRIIb-deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed FcγRIIb-deficient mice on a hybrid (129 × B6) background into a B6 background. Although both lack FcγRIIb expression, the KO1 and KO2 strains carry different lengths of the 129 strain–derived telomeric chromosome 1 segment flanked to the null-mutated Fcgr2b gene; the KO1 strain carries a 129 strain–derived ∼6.3-Mb interval distal from the null-mutated Fcgr2b gene within the Sle16 locus, while this interval in the KO2 strain is of B6 origin. Results Unexpectedly, both strains failed to develop SLE; instead, the KO1 strain, but not the KO2 strain, spontaneously developed severe rheumatoid arthritis (RA) with an incidence reaching >90% at age 12 months. Conclusion The current study shows evidence that the epistatic interaction between the Fcgr2b-null mutation and a polymorphic gene(s) in the 129 strain–derived interval located in the distal Sle16 locus contributes to RA susceptibility in a new mouse model with the B6 genetic background, although the participation of other genetic polymorphisms cannot be totally excluded.

The chicken Ig-β locus is organized by three cell-type-specific genes and two ubiquitously expressed genes. B-cell-specific DNase I hypersensitive sites (DHS) in that locus, including three present inside the flanking gene, were grouped into six regions and deleted. The deletions decreased Ig-β mRNA content to

Recent studies indicate that several transcription units assemble to form a 'transcription factory' where active transcription occurs in the nuclei. Previously, we generated chicken B-lymphocyte-derived DT40 cells lacking six transcriptional regulatory regions scattered in and around the immunoglobulin (Ig)-β gene. The deletions caused a complete shut down of transcription and epigenetic regulation of the Ig-β gene, demonstrating that the scattered regulatory regions cooperated in the transcriptional and epigenetic regulation of the gene. However, the in vivo 3-dimensional spatial relationships between the Ig-β promoter and these six regulatory regions were not investigated. In this study, we used chromosome conformation capture (3C) technology and demonstrated that the Ig-β promoter physically interacted with the scattered regulatory regions. We found that the Ig-β promoter also interacted with two downstream promoters of ubiquitously expressed genes, rad motif 1 (RDM1) and Plekhm1, to form a transcription factory, but not with three ubiquitously expressed genes, BAF60b, p45/SUG, and RRMJ3, located upstream of the Ig-β gene. In this factory, the chromatin from the three promoters and the scattered regulatory regions of the Ig-β gene formed a complex structure with many chromatin loops.

OBJECTIVE Fc? receptor type IIb (Fc?RIIb) is a major negative regulator of B cells and the lack of Fc?RIIb expression has been reported to induce systemic lupus erythematosus (SLE) in mice of the C57BL/6 (B6) genetic background. The 129 strain derived Sle16 locus on the telomeric region of chromosome 1 including polymorphic Fcgr2b confers the predisposition to systemic autoimmunity when present on the B6 background. We undertook this study to examine the effect of the Sle16 locus on autoimmune disease in Fc?RIIb deficient B6 mice. METHODS We established 2 lines of Fc?RIIb deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed Fc?RIIb deficient mice on a hybrid (129×B6) background into a B6 background. Although both lack Fc?RIIb expression the KO1 and KO2 strains carry different lengths of the 129 strain derived telomeric chromosome 1 segment flanked to the null mutated Fcgr2b gene; the KO1 strain carries a 129 strain derived ~6.3 Mb interval distal from the null mutated Fcgr2b gene within the Sle16 locus while this interval in the KO2 strain is of B6 origin. RESULTS Unexpectedly both strains failed to develop SLE; instead the KO1 strain but not the KO2 strain spontaneously developed severe rheumatoid arthritis (RA) with an incidence reaching >90 at age 12 months. CONCLUSION The current study shows evidence that the epistatic interaction between the Fcgr2b null mutation and a polymorphic gene(s) in the 129 strain derived interval located in the distal Sle16 locus contributes to RA susceptibility in a new mouse model with the B6 genetic background although the participation of other genetic polymorphisms cannot be totally excluded.