Identification of Elg1 interaction partners and effects on post-replication chromatin re-formation

We thank members of the Donaldson, Kubota, and Lorenz labs for helpful discussion, Sophie Shaw at the University of Aberdeen for data upload to Array Express and Shin-ichiro Hiraga for help with Bioinformatic analysis. This work was supported by BBSRC Grant BB/K006304/1 and Cancer Research UK Programme Award A19059 to ADD, and Wellcome Trust Grant 095062 to TOH. KS was supported by Grant-in-Aid for Scientific Research on Priority Areas (15H05970 and 15K21761) from Ministry of Education, Culture, Sports, Science and Technology, Japan All raw-data files for MNase-Seq and ChIP-Seq data are uploaded to Array Express under accession number: E-MTAB-6985.Peer reviewedPublisher PD

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.

BACKGROUND: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. METHODS: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. FINDINGS: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. INTERPRETATION: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. FUNDING: This study was supported by RIKEN (RIKEN President\u27s Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report

重傷外傷の認識が遅れ救急外来で緊急開腹術を行った１例

An８１-year-old man fell down and bruised his left abdomen. After a while the back pain got worse, and he admitted to the Emergency Department. At hospitals admission, several signs of shock were observed, and contrast-enhanced CT revealed a splenic injury. However, it took an hour and a half to diagnose and convene the trauma team because of the lack of information shared among medical staffs and the delay of the recognition as a severe traumatic injury. Since there was no available operation room at the time, nor there wasn’t time to transfer to another hospital, he was forced to undergo emergency open splenectomy at the Emergency Department. That decision saved his life as a result. In ２００２, it revealed that the deaths of about ４０％ of expired trauma patients who arrived at emergency centers were probably preventable. Since then, much progress has been made in establishing and generalizing the trauma care and evaluation guidelines. Our hospital is also making progress in organizing a trauma team and the massive transfusion protocol. However, even if they are well maintained, we won’t be able to decrease the number of preventable trauma deaths（PTD）unless we diagnose it. Improving clinical management as well as making efforts on teamwork, leads to a rapid definitive care in trauma patients

An Arabidopsis Homolog of Yeast ATG6/VPS30 Is Essential for Pollen Germination

Yeast (Saccharomyces cerevisiae) Atg6/Vps30 is required for autophagy and the sorting of vacuolar hydrolases, such as carboxypeptidase Y. In higher eukaryotes, however, roles for ATG6/VPS30 homologs in vesicle sorting have remained obscure. Here, we show that AtATG6, an Arabidopsis (Arabidopsis thaliana) homolog of yeast ATG6/VPS30, restored both autophagy and vacuolar sorting of carboxypeptidase Y in a yeast atg6/vps30 mutant. In Arabidopsis cells, green fluorescent protein-AtAtg6 protein localized to punctate structures and colocalized with AtAtg8, a marker protein of the preautophagosomal structure. Disruption of AtATG6 by T-DNA insertion resulted in male sterility that was confirmed by reciprocal crossing experiments. Microscopic analyses of AtATG6 heterozygous plants (AtATG6/atatg6) crossed with the quartet mutant revealed that AtATG6-deficient pollen developed normally, but did not germinate. Because other atatg mutants are fertile, AtAtg6 likely mediates pollen germination in a manner independent of autophagy. We propose that Arabidopsis Atg6/Vps30 functions not only in autophagy, but also plays a pivotal role in pollen germination

Advanced turning maneuver of a multi-legged robot using pitchfork bifurcation

Legged robots have excellent terrestrial mobility for traversing diverse environments and thus have the potential to be deployed in a wide variety of scenarios. However, they are susceptible to falling and leg malfunction during locomotion. Although the use of a large number of legs can overcome these problems, it makes the body long and leads to many legs being constrained to contact with the ground to support the long body, which impedes maneuverability. To improve the locomotion maneuverability of such robots, the present study focuses on dynamic instability, which induces rapid and large movement changes, and uses a 12-legged robot with a flexible body axis. Our previous work found that the straight walk of the robot becomes unstable through Hopf bifurcation when the body axis flexibility is changed, which induces body undulations. Furthermore, we developed a simple controller based on the Hopf bifurcation and showed that the instability facilitates the turning of the robot. In this study, we newly found that the straight walk becomes unstable through pitchfork bifurcation when the body-axis flexibility is changed in a way different from that in our previous work. In addition, the pitchfork bifurcation induces a transition into a curved walk, whose curvature can be controlled by the body-axis flexibility. We developed a simple controller based on the pitchfork-bifurcation characteristics and demonstrated that the robot can perform a turning maneuver superior to that with the previous controller. This study provides a novel design principle for maneuverable locomotion of many-legged robots using intrinsic dynamic properties