Tyrosine phosphorylation of SGEF regulates RhoG activity and cell migration

SGEF and Ephexin4 are members of the Ephexin subfamily of RhoGEFs that specifically activate the small GTPase RhoG. It is reported that Ephexin1 and Ephexin5, two well-characterized Ephexin subfamily RhoGEFs, are tyrosine-phosphorylated by Src, and that their phosphorylation affect their activities and functions. In this study, we show that SGEF, but not Ephexin4, is tyrosine-phosphorylated by Src. Tyrosine phosphorylation of SGEF suppresses its interaction with RhoG, the elevation of RhoG activity, and SGEF-mediated promotion of cell migration. We identified tyrosine 530 (Y530), which is located within the Dbl homology domain, as a major phosphorylation site of SGEF by Src, and Y530F mutation blocked the inhibitory effect of Src on SGEF. Taken together, these results suggest that the activity of SGEF is negatively regulated by tyrosine phosphorylation of the DH domain

Single Balloon Enteroscopy-Assisted ERCP Using Rendezvous Technique for Sharp Angulation of Roux-en-Y Limb in a Patient with Bile Duct Stones

The acute angulation of Roux-en-Y (R-Y) limb precludes endoscopic access for endoscopic retrograde cholangiopancreatography (ERCP) even using a balloon enteroscopy. Here, we describe a case of successful single balloon enteroscopy (SBE)-assisted ERCP using a rendezvous technique in a patient with sharply angulated R-Y limb in a 79-year-old woman who had bile duct stones. Method. At first, a guidewire was passed antegradely through the major papilla after the needle puncture using percutaneous transhepatic biliary drainage technique. A hydrophilic guidewire with an ERCP catheter was antegradely advanced beyond the Roux limb. After a guidewire was firmly grasped by a snare forceps, it was pulled out of the body, resulting that the enteroscope could advance to the papilla. After papillary dilation, complete removal of bile duct stones was achieved without any procedure-related complication. In conclusion, although further study is needed, SBE-assisted ERCP using a rendezvous technique may have a potential for selected patients

The Type Ic Hypernova SN 2002ap

Photometric and spectroscopic data of the energetic Type Ic supernova (SN) 2002ap are presented, and the properties of the SN are investigated through models of its spectral evolution and its light curve. The SN is spectroscopically similar to the "hypernova" SN 1997ef. However, its kinetic energy [$\sim (4-10) \times 10^{51}$ erg] and the mass ejected (2.5-5 $M_{\odot}$) are smaller, resulting in a faster-evolving light curve. The SN synthesized $\sim 0.07 M_{\odot}$ of $^{56}$Ni, and its peak luminosity was similar to that of normal SNe. Brightness alone should not be used to define a hypernova, whose defining character, namely very broad spectral features, is the result of a high kinetic energy. The likely main-sequence mass of the progenitor star was 20-25 $M_{\odot}$, which is also lower than that of both hypernovae SNe 1997ef and 1998bw. SN 2002ap appears to lie at the low-energy and low-mass end of the hypernova sequence as it is known so far. Observations of the nebular spectrum, which is expected to dominate by summer 2002, are necessary to confirm these values.Comment: 10 pages, 4 figures, accepted for publication in ApJL, 30 April 2002 (minor changes to match the accepted version, with figures being colored

EMPRESS. IX. Extremely Metal-Poor Galaxies are Very Gas-Rich Dispersion-Dominated Systems: Will JWST Witness Gaseous Turbulent High-z Primordial Galaxies?

We present kinematics of 6 local extremely metal-poor galaxies (EMPGs) with low metallicities ($0.016-0.098\ Z_{\odot}$) and low stellar masses ($10^{4.7}-10^{7.6} M_{\odot}$). Taking deep medium-high resolution ($R\sim7500$) integral-field spectra with 8.2-m Subaru, we resolve the small inner velocity gradients and dispersions of the EMPGs with H$\alpha$ emission. Carefully masking out sub-structures originated by inflow and/or outflow, we fit 3-dimensional disk models to the observed H$\alpha$ flux, velocity, and velocity-dispersion maps. All the EMPGs show rotational velocities ($v_{\rm rot}$) of 5--23 km s$^{-1}$ smaller than the velocity dispersions ($\sigma_{0}$) of 17--31 km s$^{-1}$, indicating dispersion-dominated ($v_{\rm rot}/\sigma_{0}=0.29-0.80<1$) systems affected by inflow and/or outflow. Except for two EMPGs with large uncertainties, we find that the EMPGs have very large gas-mass fractions of $f_{\rm gas}\simeq 0.9-1.0$. Comparing our results with other H$\alpha$ kinematics studies, we find that $v_{\rm rot}/\sigma_{0}$ decreases and $f_{\rm gas}$ increases with decreasing metallicity, decreasing stellar mass, and increasing specific star-formation rate. We also find that simulated high-$z$ ($z\sim 7$) forming galaxies have gas fractions and dynamics similar to the observed EMPGs. Our EMPG observations and the simulations suggest that primordial galaxies are gas-rich dispersion-dominated systems, which would be identified by the forthcoming James Webb Space Telescope (JWST) observations at $z\sim 7$.Comment: Submitted to ApJ; After revisio

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

A short splicing isoform of afadin suppresses the cortical axon branching in a dominant-negative manner

Precise wiring patterns of axons are among the remarkable features of neuronal circuit formation, and establishment of the proper neuronal network requires control of outgrowth, branching, and guidance of axons. R-Ras is a Ras-family small GTPase that has essential roles in multiple phases of axonal development. We recently identified afadin, an F-actin-binding protein, as an effector of R-Ras mediating axon branching through F-actin reorganization. Afadin comprises two isoforms-l-afadin, having the F-actin-binding domain, and s-afadin, lacking the F-actin-binding domain. Compared with l-afadin, s-afadin, the short splicing variant of l-afadin, contains RA domains but lacks the F-actin-binding domain. Neurons express both isoforms; however, the function of s-afadin in brain remains unknown. Here we identify s-afadin as an endogenous inhibitor of cortical axon branching. In contrast to the abundant and constant expression of l-afadin throughout neuronal development, the expression of s-afadin is relatively low when cortical axons branch actively. Ectopic expression and knockdown of s-afadin suppress and promote branching, respectively. s-Afadin blocks the R-Ras-mediated membrane translocation of l-afadin and axon branching by inhibiting the binding of l-afadin to R-Ras. Thus s-afadin acts as a dominant-negative isoform in R-Ras-afadin-regulated axon branching