Lymph Node Stromal Cell Subsets

The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRb, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different fromCXCL12highLepRhigh FSCs in themedullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN

Reversal of neuroinflammation in novel GS model mice by single i.c.v. administration of CHO-derived rhCTSA precursor protein

Galactosialidosis (GS) is a lysosomal cathepsin A (CTSA) deficiency. It associates with a simultaneous decrease of neuraminidase 1 (NEU1) activity and sialylglycan storage. Central nervous system (CNS) symptoms reduce the quality of life of juvenile/adult-type GS patients, but there is no effective therapy. Here, we established a novel GS model mouse carrying homozygotic Ctsa IVS6+1g→a mutation causing partial exon 6 skipping with concomitant deficiency of Ctsa/Neu1. The GS mice developed juvenile/adult GS-like symptoms, such as gargoyle-like face, edema, proctoprosia due to sialylglycan accumulation, and neurovisceral inflammation, including activated microglia/macrophage appearance and increase of inflammatory chemokines. We produced human CTSA precursor proteins (proCTSA), a homodimer carrying terminal mannose 6-phosphate (M6P)-type N-glycans. The CHO-derived proCTSA was taken up by GS patient-derived fibroblasts via M6P receptors and delivered to lysosomes. Catalytically active mature CTSA showed a shorter half-life due to intralysosomal proteolytic degradation. Following single i.c.v. administration, proCTSA was widely distributed, restored the Neu1 activity, and reduced the sialylglycans accumulated in brain regions. Moreover, proCTSA suppressed neuroinflammation associated with reduction of activated microglia/macrophage and up-regulated Mip1α. The results show therapeutic effects of intracerebrospinal enzyme replacement utilizing CHO-derived proCTSA and suggest suppression of CNS symptoms

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies

CO Multi-line Imaging of Nearby Galaxies (COMING). III. Dynamical effect on molecular gas density and star formation in the barred spiral galaxy NGC 4303

We present the results of $^{12}$CO($J$=1-0) and $^{13}$CO($J$=1-0) simultaneous mappings toward the nearby barred spiral galaxy NGC 4303 as a part of the CO Multi-line Imaging of Nearby Galaxies (COMING) project. Barred spiral galaxies often show lower star-formation efficiency (SFE) in their bar region compared to the spiral arms. In this paper, we examine the relation between the SFEs and the volume densities of molecular gas $n(\rm{H}_2)$ in the eight different regions within the galactic disk with CO data combined with archival far-ultraviolet and 24 $\mu$m data. We confirmed that SFE in the bar region is lower by 39% than that in the spiral arms. Moreover, velocity-alignment stacking analysis was performed for the spectra in the individual regions. The integrated intensity ratios of $^{12}$CO to $^{13}$CO ($R_{12/13}$) range from 10 to 17 as the results of stacking. Fixing a kinetic temperature of molecular gas, $n(\rm{H}_2)$ was derived from $R_{12/13}$ via non-local thermodynamic equilibrium (non-LTE) analysis. The density $n(\rm{H}_2)$ in the bar is lower by 31-37% than that in the arms and there is a rather tight positive correlation between SFEs and $n(\rm{H}_2)$, with a correlation coefficient of $\sim 0.8$. Furthermore, we found a dependence of $n(\rm{H}_2)$ on the velocity dispersion of inter-molecular clouds ($\Delta V/ \sin i$). Specifically, $n(\rm{H}_2)$ increases as $\Delta V/ \sin i$ increases when $\Delta V/ \sin i < 100$ km s$^{-1}$. On the other hand, $n(\rm{H}_2)$ decreases as $\Delta V/ \sin i$ increases when $\Delta V/ \sin i > 100$ km s$^{-1}$. These relations indicate that the variations of SFE could be caused by the volume densities of molecular gas, and the volume densities could be governed by the dynamical influence such as cloud-cloud collisions, shear and enhanced inner-cloud turbulence.Comment: 15 pages, 8 figures, accepted for publication in PAS

A Distinct Subset of Fibroblastic Stromal Cells Constitutes the Cortex-Medulla Boundary Subcompartment of the Lymph Node

The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRβ, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12highLepRhigh FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN

Hayabusa2’s superior solar conjunction mission operations: planning and post-operation results

Abstract In late 2018, the asteroid Ryugu was in the Sun’s shadow during the superior solar conjunction phase. As the Sun-Earth-Ryugu angle decreased to below 3°, the Hayabusa2 spacecraft experienced 21 days of planned blackout in the Earth-probe communication link. This was the first time a spacecraft had experienced solar conjunction while hovering around a minor body. For the safety of the spacecraft, a low energy transfer trajectory named Ayu was designed in the Hill reference frame to increase its altitude from 20 to 110 km. The trajectory was planned with the newly developed optNEAR tool and validated with real time data. This article shows the results of the conjunction operation, from planning to flight data.</jats:p

CO Multi-line Imaging of Nearby Galaxies (COMING) IV. Overview of the Project

Observations of the molecular gas in galaxies are vital to understanding the evolution and star-forming histories of galaxies. However, galaxies with molecular gas maps of their whole discs having sufficient resolution to distinguish galactic structures are severely lacking. Millimeter wavelength studies at a high angular resolution across multiple lines and transitions are particularly needed, severely limiting our ability to infer the universal properties of molecular gas in galaxies. Hence, we conducted a legacy project with the 45 m telescope of the Nobeyama Radio Observatory, called the CO Multi-line Imaging of Nearby Galaxies (COMING), which simultaneously observed 147 galaxies with high far-infrared flux in $^{12}$CO, $^{13}$CO, and C$^{18}$O $J=1-0$ lines. The total molecular gas mass was derived using the standard CO-to-H$_2$ conversion factor and found to be positively correlated with the total stellar mass derived from the WISE $3.4 \mu$m band data. The fraction of the total molecular gas mass to the total stellar mass in galaxies does not depend on their Hubble types nor the existence of a galactic bar, although when galaxies in individual morphological types are investigated separately, the fraction seems to decrease with the total stellar mass in early-type galaxies and vice versa in late-type galaxies. No differences in the distribution of the total molecular gas mass, stellar mass, and the total molecular gas to stellar mass ratio was observed between barred and non-barred galaxies, which is likely the result of our sample selection criteria, in that we prioritized observing FIR bright (and thus molecular gas-rich) galaxies.Comment: Accepted for publication in PASJ; 47 pages, 5 tables, 29 figures. On-line supplementary images are available at this URL (https://astro3.sci.hokudai.ac.jp/~radio/coming/publications/). CO data is available at the Japanese Virtual Observatory (JVO) website (https://jvo.nao.ac.jp/portal/nobeyama/coming.do) and the project website (https://astro3.sci.hokudai.ac.jp/~radio/coming/data/

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10’s of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation