The peroxisomal membrane protein import receptor Pex3p is directly transported to peroxisomes by a novel Pex19p- and Pex16p-dependent pathway

Two distinct pathways have recently been proposed for the import of peroxisomal membrane proteins (PMPs): a Pex19p- and Pex3p-dependent class I pathway and a Pex19p- and Pex3p-independent class II pathway. We show here that Pex19p plays an essential role as the chaperone for full-length Pex3p in the cytosol. Pex19p forms a soluble complex with newly synthesized Pex3p in the cytosol and directly translocates it to peroxisomes. Knockdown of Pex19p inhibits peroxisomal targeting of newly synthesized full-length Pex3p and results in failure of the peroxisomal localization of Pex3p. Moreover, we demonstrate that Pex16p functions as the Pex3p-docking site and serves as the peroxisomal membrane receptor that is specific to the Pex3p–Pex19p complexes. Based on these novel findings, we suggest a model for the import of PMPs that provides new insights into the molecular mechanisms underlying the biogenesis of peroxisomes and its regulation involving Pex3p, Pex19p, and Pex16p

Lie derivatives of homogeneous structures of real hypersurfaces in a complex space form

In this paper we calculate the Lie derivatives of homogeneous structure tensors of homogeneous real hypersurfaces in nonflat complex space forms in the direction of the structure vector field. Using these results, we give two characterization theorems of a homogeneous real hypersurface of type (A) in a nonflat complex space form

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

Long-term exposure to methylmercury and psychiatric symptoms in residents of Minamata, Japan

Introduction: It is well-known that prenatal or postnatal exposure to methylmercury can produce neurological signs in adults and children, exemplified by a case of large-scale poisoning in Minamata, Japan, in the 1950s. However, evidence regarding whether pre- or postnatal exposure to methylmercury causes psychiatric symptoms (e.g., impairment of intelligence and mood and behavioral dysfunction) is still limited-excluding cases of fetal Minamata disease patients. Methods: We evaluated the effects of pre- or postnatal exposure to methylmercury on psychiatric symptoms using data derived from a 1971 population-based survey in Minamata and neighboring communities. We adopted residential areas as an exposure indicator and psychiatric symptoms as the outcome. Then, we estimated the adjusted prevalence odds ratio (POR) and confidence interval (Cl) of psychiatric symptoms in relation to residential area. Results: There were 904 participants in Minamata (high exposure area), 1700 in Goshonoura (middle exposure area), and 913 in Ariake (low exposure area). Compared to the Ariake area, participants in the Minamata area manifested psychiatric symptoms more frequently: PORs for impairment of intelligence and mood and behavioral dysfunction were 5.2 (95% Cl: 3.7-7.3) and 4.4 (95% Cl: 2.9-6.7), respectively. Furthermore, participants with psychiatric symptoms in the Minamata area more frequently had neurological signs. Peaks in prevalence of psychiatric symptoms occurred around age 20 and in older age adults in the area. These findings did not change when we excluded those who had been officially certified as Minamata disease patients by that time. Conclusions: The present study suggests a relationship between pre- or postnatal exposure to methylmercury and psychiatric symptoms among the general population in Minamata even after excluding officially certified patients

A Comparative Analysis of Changes of Student’s Attitude Before and After an International Virtual Learning Class

The purpose of this study was to investigate the effects of international virtual learning classes. For the purpose, the class implemented using multipoint communication system which was constructed high quality video transfer systems on a cross-border infrastructure (gigabit bandwidth) between Japan to South Korea. In order to reveal the effects of the class, a questionnaire was composed of five categories; Consciousness to Foreign Countries, Nationality, Acquisition of View Point, Motivation, Recognition to the partner country. The results of 2x2 mixed two-way ANOVA showed differences of characteristics of two countries and changes of student’s attitude. The results revealed that an international virtual learning class has a possibility to develop and enhance student\u27s awareness of humanity and the world. Future implementation will depend on growth and sustenance of the international relationship for a prolonged period

RETRACTED: The Chromatin-Remodeling Complex WINAC Targets a Nuclear Receptor to Promoters and Is Impaired in Williams Syndrome

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.Our paper reported that a chromatin-remodeling complex, WINAC, recruited the unliganded vitamin D receptor to promoters in cooperation with the transcription factor implicated in Williams syndrome, WSTF. The findings provided insights into the coordination between chromatin remodelers and sequence-specific transcription factors and pointed to a role of chromatin remodeling defects in Williams syndrome. We recently identified errors affecting several figure panels where original data were processed inappropriately such that the figure panels do not accurately report the original data. We believe that the most responsible course of action is to retract the paper. We sincerely apologize to the scientific community for any inconvenience that this might cause. The first author, H.K., declined to sign the retraction notice

IL-12 and IL-18 Induction and Subsequent NKT Activation Effects of the Japanese Botanical Medicine Juzentaihoto

In this study, we first measured some cytokine concentrations in the serum of patients treated with Juzentaihoto (JTT). Of the cytokines measured interleukin (IL) -18 was the most prominently up-regulated cytokine in the serum of patients under long term JTT administration. We next evaluated the effects of JTT in mice, focusing especially on natural killer T (NKT) cell induction. Mice fed JTT were compared to control group ones. After sacrifice, the liver was fixed, embedded and stained. Transmission electron microscope (TEM) observations were performed. Although the mice receiving the herbal medicine had same appearance, their livers were infiltrated with massive mononuclear cells, some of which were aggregated to form clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of IL-12 and IL-18 in the liver of JTT treated mice. To clarify what the key molecules that induce immunological restoration with JTT might be, we next examined in vitro lymphocyte cultures. Mononuclear cells isolated and prepared from healthy volunteers were cultured with and without JTT. Within 24 hours, JTT induced the IL-12 and IL-18 production and later (72 hours) induction of interferon (IFN)-gamma. Oral administration of JTT may induce the expression of IL-12 in the early stage, and IL-18 in the chronic stage, followed by NKT induction. Their activation, following immunological restoration could contribute to anti-tumor effects

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

Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model.

BACKGROUND: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. METHODS: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34 FINDINGS: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. INTERPRETATION: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD