Arhgef16, a novel Elmo1 binding partner, promotes clearance of apoptotic cells via RhoG-dependent Rac1 activation

AbstractElmo is an evolutionarily conserved mammalian ortholog of Caenorhabditis elegans CED-12 with proposed roles during the removal of apoptotic cells, cell migration, neurite outgrowth, and myoblast fusion (Katoh and Negishi (2003) [1], Park and Tosello (2007) [2], Grimsley et al. (2004) [3], Hamoud et al. (2014) [4]). Elmo mediates these cellular processes by interacting with various proteins located in the plasma membrane, cytoplasm and nucleus, and by modulating their activities although it has no intrinsic catalytic activity (Park and Tosello (2007) [2], Hamoud et al. (2014) [4], Li et al. (2013) [5], Margaron, Fradet and Cote (2013) [6], and Mauldin et al. (2013)[7]). Because there are a limited number of proteins known to interact with Elmo, we performed a yeast two-hybrid screen using Elmo1 as bait to identify Elmo1-interacting proteins and to evaluate their mode of regulation. Arhgef16 was one of the proteins identified through the screen and subsequent analyses revealed that Arhgef16 interacted with Elmo1 in mammalian cells as well. Expression of Arhgef16 in phagocytes promoted engulfment of apoptotic cells, and engulfment mediated by Arhgef16 increased synergistically in the presence of Elmo1 but was abrogated in the absence of Elmo1. In addition, Arhgef16-mediated removal of apoptotic cells was dependent on RhoG, but independent of Dock1. Taken together, this study suggests that the newly identified Elmo1-interacting protein, Arhgef16, functions synergistically with Elmo1 to promote clearance of apoptotic cells in a RhoG-dependent and Dock1-independent manner

A new concept for controlling tiny-scale insect pest in green house – noval technology to apply liquid ethyl formate: Poster

As increased agricultural insecticide uses and trends in insecticide resistance, increased labor cost to apply insecticide and limited its application to fertility season in green house. There is a need of a safe, labor-saving and confined space application concept to manage control tiny-scale insect pest such as thrips and whitefly. Fumigation with ethyl formate (EF), which is considered as effective to various insect pest and safely use in quarantine treatment, was evaluated in the confined space (glass house) and semi-confined space (vinyl house). The new application technology for application of liquid EF could be the one of the key options for control of tiny flying insects in greenhouses that would save labor and operation costs. It could be connected to smartfarm technologies in the near future.As increased agricultural insecticide uses and trends in insecticide resistance, increased labor cost to apply insecticide and limited its application to fertility season in green house. There is a need of a safe, labor-saving and confined space application concept to manage control tiny-scale insect pest such as thrips and whitefly. Fumigation with ethyl formate (EF), which is considered as effective to various insect pest and safely use in quarantine treatment, was evaluated in the confined space (glass house) and semi-confined space (vinyl house). The new application technology for application of liquid EF could be the one of the key options for control of tiny flying insects in greenhouses that would save labor and operation costs. It could be connected to smartfarm technologies in the near future

FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation

Abstract Background BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor (TKI) resistance remain unclear. Methods In silico bioinformatic analysis was performed to identify the most active transcription factor and its inducer that contribute to BCR-ABL-independent TKI resistance. Tandem mass spectrometry analysis was performed to identify the receptor for the noncanonical NF-κB activator FAM167A. In vitro and in vivo mouse experiments revealed detailed molecular insights into the functional role of the FAM167A-desmoglein-1 (DSG1) axis in BCL-ABL-independent TKI resistance. CML cells derived from CML patients were analyzed using quantitative reverse transcription PCR and flow cytometry. Results We found that NF-κB had the greatest effect on differential gene expression of BCR-ABL-independent TKI-resistant CML cells. Moreover, we found that the previously uncharacterized protein FAM167A activates the noncanonical NF-κB pathway and induces BCR-ABL-independent TKI resistance. Molecular analyses revealed that FAM167A activates the noncanonical NF-κB pathway by binding to the cell adhesion protein DSG1 to upregulate NF-κB-inducing kinase (NIK) by blocking its ubiquitination. Neutralization of FAM167A in a mouse tumor model reduced noncanonical NF-κB activity and restored sensitivity of cells to TKIs. Furthermore, FAM167A and surface DSG1 levels were highly upregulated in CD34+ CML cells from patients with BCR-ABL-independent TKI-resistant disease. Conclusions These results reveal that FAM167A acts as an essential factor for BCR-ABL-independent TKI resistance in CML by activating the noncanonical NF-κB pathway. In addition, FAM167A may serve as an important target and biomarker for BCR-ABL-independent TKI resistance

The Kinase PDK1 Is Essential for B-Cell Receptor Mediated Survival Signaling

Phosphoinositide-dependent kinase 1 (PDK1) plays an important role in integrating the T cell antigen receptor (TCR) and CD28 signals to achieve efficient NF-κB activation. PDK1 is also an important regulator of T cell development, mediating pre-TCR induced proliferation signals. However, the role of PDK1 in B cell antigen receptor (BCR) signaling and B cell development remains largely unknown. In this study we provide genetic evidence supporting the role of PDK1 in B cell survival. We found PDK1 is required for BCR mediated survival in resting B cells, likely through regulation of Foxo activation. PDK1-dependent signaling to NF-κB is not crucial to resting B cell viability. However, PDK1 is necessary for triggering NF-κB during B cell activation and is required for activated B cell survival. Together these studies demonstrate that PDK1 is essential for BCR-induced signal transduction to Foxo and NF-κB and is indispensable for both resting and activated B cell survival

A test of the submentalizing hypothesis : apes' performance in a false belief task inanimate control

Financial support came from Ministry of Education, Culture, Sports, Science and Technology (K-CONNEX to FK), Japan Society for Promotion of Science (KAKENHI 26885040, 16K21108 to FK), JSPS (KAKENHI 26245069, 24000001 to SH), and European Research Council (Synergy grant 609819 SOMICS to JC).Much debate concerns whether any nonhuman animals share with humans the ability to infer others' mental states, such as desires and beliefs. In a recent eye-tracking false-belief task, we showed that great apes correctly anticipated that a human actor would search for a goal object where he had last seen it, even though the apes themselves knew that it was no longer there. In response, Heyes proposed that apes' looking behavior was guided not by social cognitive mechanisms but rather domain-general cueing effects, and suggested the use of inanimate controls to test this alternative submentalizing hypothesis. In the present study, we implemented the suggested inanimate control of our previous false-belief task. Apes attended well to key events but showed markedly fewer anticipatory looks and no significant tendency to look to the correct location. We thus found no evidence that submentalizing was responsible for apes' anticipatory looks in our false-belief task.Publisher PDFPeer reviewe

Myeloid-Derived Suppressor Cells Are Controlled by Regulatory T Cells via TGF-β during Murine Colitis

Myeloid-derived suppressor cells (MDSCs) are well known regulators of regulatory T cells (Treg cells); however, the direct regulation of MDSCs by Treg cells has not been well characterized. We find that colitis caused by functional deficiency of Treg cells leads to altered expansion and reduced function of MDSCs. During differentiation of MDSCs in vitro from bone marrow cells, Treg cells enhanced MDSC function and controlled their differentiation through a mechanism involving transforming growth factor-β (TGF-β). TGF-β-deficient Treg cells were not able to regulate MDSC function in an experimentally induced model of colitis. Finally, we evaluated the therapeutic effect of TGF-β-mediated in-vitro-differentiated MDSCs on colitis. Adoptive transfer of MDSCs that differentiated with TGF-β led to better colitis prevention than the transfer of MDSCs that differentiated without TGF-β. Our results demonstrate an interaction between Treg cells and MDSCs that contributes to the regulation of MDSC proliferation and the acquisition of immunosuppressive functions

Pilot KaVA monitoring on the M87 jet: confirming the inner jet structure and superluminal motions at sub-pc scales

We report the initial results of our high-cadence monitoring program on the radio jet in the active galaxy M87, obtained by the KVN and VERA Array (KaVA) at 22 GHz. This is a pilot study that preceded a larger KaVA-M87 monitoring program, which is currently ongoing. The pilot monitoring was mostly performed every two to three weeks from December 2013 to June 2014, at a recording rate of 1 Gbps, obtaining the data for a total of 10 epochs. We successfully obtained a sequence of good quality radio maps that revealed the rich structure of this jet from <~1 mas to 20 mas, corresponding to physical scales (projected) of ~0.1-2 pc (or ~140-2800 Schwarzschild radii). We detected superluminal motions at these scales, together with a trend of gradual acceleration. The first evidence for such fast motions and acceleration near the jet base were obtained from recent VLBA studies at 43 GHz, and the fact that very similar kinematics are seen at a different frequency and time with a different instrument suggests these properties are fundamental characteristics of this jet. This pilot program demonstrates that KaVA is a powerful VLBI array for studying the detailed structural evolution of the M87 jet and also other relativistic jets.Comment: 10 pages, 9 figures, accepted for publication in PAS

Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer’s Disease in Amnestic Mild Cognitive Impairment

Background/Aims: Disease-modifying therapy for Alzheimer’s disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD. Methods: We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Positron emission tomography was performed using florbetaben as a probe. We analyzed the concentration of Aβ1–42, total tau protein (t-Tau), and tau protein phosphorylated at threonine 181 (p-Tau181) in CSF with INNOTEST enzyme-linked immunosorbent assay. Results: For the detection of prodromal AD in patients with aMCI, the cutoff values of CSF Aβ1–42, t-Tau, and p-Tau181 were 749.5 pg/mL, 225.6 pg/mL, and 43.5 pg/mL, respectively. To discriminate prodromal AD in patients with aMCI, the t-Tau/Aβ1–42 and ­p-Tau181/Aβ1–42 ratios defined cutoff values at 0.298 and 0.059, respectively. Conclusions: CSF biomarkers are very useful tools for the differential diagnosis of prodromal AD in aMCI patients. The concentration of CSF biomarkers is well correlated with the stages of the AD spectrum

The First Very Long Baseline Interferometry Image of 44 GHz Methanol Maser with the KVN and VERA Array (KaVA)

We have carried out the first very long baseline interferometry (VLBI) imaging of 44 GHz class I methanol maser (7_{0}-6_{1}A^{+}) associated with a millimeter core MM2 in a massive star-forming region IRAS 18151-1208 with KaVA (KVN and VERA Array), which is a newly combined array of KVN (Korean VLBI Network) and VERA (VLBI Exploration of Radio Astrometry). We have succeeded in imaging compact maser features with a synthesized beam size of 2.7 milliarcseconds x 1.5 milliarcseconds (mas). These features are detected at a limited number of baselines within the length of shorter than approximately 650 km corresponding to 100 Mlambda in the uv-coverage. The central velocity and the velocity width of the 44 GHz methanol maser are consistent with those of the quiescent gas rather than the outflow traced by the SiO thermal line. The minimum component size among the maser features is ~ 5 mas x 2 mas, which corresponds to the linear size of ~ 15 AU x 6 AU assuming a distance of 3 kpc. The brightness temperatures of these features range from ~ 3.5 x 10^{8} to 1.0 x 10^{10} K, which are higher than estimated lower limit from a previous Very Large Array observation with the highest spatial resolution of ~ 50 mas. The 44 GHz class I methanol maser in IRAS 18151-1208 is found to be associated with the MM2 core, which is thought to be less evolved than another millimeter core MM1 associated with the 6.7 GHz class II methanol maser.Comment: 19 pages, 3 figure