Junctional adhesion molecule (JAM) binds to PAR-3: a possible mechanism for the recruitment of PAR-3 to tight junctions

At tight junctions (TJs), claudins with four transmembrane domains are incorporated into TJ strands. Junctional adhesion molecule (JAM), which belongs to the immunoglobulin superfamily, is also localized at TJs, but it remains unclear how JAM is integrated into TJs. Immunoreplica electron microscopy revealed that JAM showed an intimate spatial relationship with TJ strands in epithelial cells. In L fibroblasts expressing exogenous JAM, JAM was concentrated at cell–cell adhesion sites, where there were no strand-like structures, but rather characteristic membrane domains free of intramembranous particles were detected. These domains were specifically labeled with anti-JAM polyclonal antibody, suggesting that JAM forms planar aggregates through their lateral self-association. Immunofluorescence microscopy and in vitro binding assays revealed that ZO-1 directly binds to the COOH termini of claudins and JAM at its PDZ1 and PDZ3 domains, respectively. Furthermore, another PDZ-containing polarity-related protein, PAR-3, was directly bound to the COOH terminus of JAM, but not to that of claudins. These findings led to a molecular architectural model for TJs: small aggregates of JAM are tethered to claudin-based strands through ZO-1, and these JAM aggregates recruit PAR-3 to TJs. We also discuss the importance of this model from the perspective of the general molecular mechanisms behind the recruitment of PAR proteins to plasma membranes

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

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/

Genetic Predisposition to Ischemic Stroke

Background and Purpose—The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk.Methods—We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets).Results—In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33–2.31) and 1.99 (95% confidence interval, 1.19–3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001).Conclusions—The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target