A non-canonical function of Plk4 in centriolar satellite integrity and ciliogenesis through PCM1 phosphorylation

Centrioles are the major constituents of the animal centrosome, in which Plk4 kinase serves as a master regulator of the duplication cycle. Many eukaryotes also contain numerous peripheral particles known as centriolar satellites. While centriolar satellites aid centriole assembly and primary cilium formation, it is unknown whether Plk4 plays any regulatory roles in centriolar satellite integrity. Here we show that Plk4 is a critical determinant of centriolar satellite organisation. Plk4 depletion leads to the dispersion of centriolar satellites and perturbed ciliogenesis. Plk4 interacts with the satellite component PCM1, and its kinase activity is required for phosphorylation of the conserved S372. The nonphosphorylatable PCM1 mutant recapitulates phenotypes of Plk4 depletion, while the phosphomimetic mutant partially rescues the dispersed centriolar satellite patterns and ciliogenesis in cells depleted of PCM1. We show that S372 phosphorylation occurs during the G1 phase of the cell cycle and is important for PCM1 dimerisation and interaction with other satellite components. Our findings reveal that Plk4 is required for centriolar satellite function, which may underlie the ciliogenesis defects caused by Plk4 dysfunction

The conserved Wdr8-hMsd1/SSX2IP complex localises to the centrosome and ensures proper spindle length and orientation

The centrosome plays a pivotal role in a wide range of cellular processes and its dysfunction is causally linked to many human diseases including cancer and developmental and neurological disorders. This organelle contains more than one hundred components, and yet many of them remain uncharacterised. Here we identified a novel centrosome protein Wdr8, based upon the structural conservation of the fission yeast counterpart. We showed that Wdr8 constitutively localises to the centrosome and super resolution microscopy uncovered that this protein is enriched at the proximal end of the mother centriole. Furthermore, we identified hMsd1/SSX2IP, a conserved spindle anchoring protein, as one of Wdr8 interactors by mass spectrometry. Wdr8 formed a complex and partially colocalised with hMsd1/SSX2IP. Intriguingly, knockdown of Wdr8 or hMsd1/SSX2IP displayed very similar mitotic defects, in which spindle microtubules became shortened and misoriented. Indeed, Wdr8 depletion resulted in the reduced recruitment of hMsd1/SSX2IP to the mitotic centrosome, though the converse is not true. Together, we propose that the conserved Wdr8-hMsd1/SSX2IP complex plays a critical role in controlling proper spindle length and orientation.T.T. and A.P.S were supported by Cancer Research UK.Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.bbrc.2015.10.169

Dual phase regulation of experimental allergic encephalomyelitis by platelet-activating factor

Experimental allergic encephalomyelitis (EAE) serves as a model for multiple sclerosis and is considered to be a CD4+ Th1 cell–mediated autoimmune disease. To investigate the role of platelet-activating factor (PAF) in this disease, PAF receptor (PAFR) KO (PAFR-KO) and wild-type (WT) mice, on a C57BL/6 genetic background, were immunized with myelin oligodendrocyte glycoprotein 35–55. The levels of PAF production and PAFR mRNA expression in the spinal cord (SC) correlated with the EAE symptoms. PAFR-KO mice showed lower incidence and less severe symptoms in the chronic phase of EAE than WT mice. However, no difference was observed in T cell proliferation, Th1-cytokine production, or titer of IgG2a between both genotypes. Before onset, as revealed by microarray analysis, mRNAs of inflammatory mediators and their receptors—including IL-6 and CC chemokine receptor 2—were down-regulated in the SC of PAFR-KO mice compared with WT mice. Moreover, in the chronic phase, the severity of inflammation and demyelination in the SC was substantially reduced in PAFR-KO mice. PAFR-KO macrophages reduced phagocytic activity and subsequent production of TNF-α. These results suggest that PAF plays a dual role in EAE pathology in the induction and chronic phases through the T cell–independent pathways

The Aggregation Inhibitor Peptide QBP1 as a Therapeutic Molecule for the Polyglutamine Neurodegenerative Diseases

Misfolding and abnormal aggregation of proteins in the brain are implicated in the pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. In the polyQ diseases, an abnormally expanded polyQ stretch triggers misfolding and aggregation of the disease-causing proteins, eventually resulting in neurodegeneration. In this paper, we introduce our therapeutic strategy against the polyQ diseases using polyQ binding peptide 1 (QBP1), a peptide that we identified by phage display screening. We showed that QBP1 specifically binds to the expanded polyQ stretch and inhibits its misfolding and aggregation, resulting in suppression of neurodegeneration in cell culture and animal models of the polyQ diseases. We further demonstrated the potential of protein transduction domains (PTDs) for in vivo delivery of QBP1. We hope that in the near future, chemical analogues of aggregation inhibitor peptides including QBP1 will be developed against protein misfolding-associated neurodegenerative diseases

Plasmacytoid DCs help lymph node DCs to induce anti-HSV CTLs

Antiviral cell–mediated immunity is initiated by the dendritic cell (DC) network in lymph nodes (LNs). Plasmacytoid DCs (pDCs) are known to migrate to inflamed LNs and produce interferon (IFN)-α, but their other roles in antiviral T cell immunity are unclear. We report that LN-recruited pDCs are activated to create local immune fields that generate antiviral cytotoxic T lymphocytes (CTLs) in association with LNDCs, in a model of cutaneous herpes simplex virus (HSV) infection. Although pDCs alone failed to induce CTLs, in vivo depletion of pDCs impaired CTL-mediated virus eradication. LNDCs from pDC-depleted mice showed impaired cluster formation with T cells and antigen presentation to prime CTLs. Transferring circulating pDC precursors from wild-type, but not CXCR3-deficient, mice to pDC-depleted mice restored CTL induction by impaired LNDCs. In vitro co-culture experiments revealed that pDCs provided help signals that recovered impaired LNDCs in a CD2- and CD40L-dependent manner. pDC-derived IFN-α further stimulated the recovered LNDCs to induce CTLs. Therefore, the help provided by pDCs for LNDCs in primary immune responses seems to be pivotal to optimally inducing anti-HSV CTLs

インドネシア ノ チュウトウ キョウイク ニ オケル 「レッスン・ スタディ」 ノ ココロミ -ジッセン カラ マナビ、 ジュギョウ ノ カイゼン ヘ ツナグ-

インドネシアでは、中等教育における日本語学習者の増加に伴って、教師の育成が課題とされて久しい。国際交流基金ジャカルタ日本文化センターは課題解決へ向けて様々な支援を続けてきたが、とりわけ政府と共催で行ってきた教師研修による高校日本語教師育成への貢献は大きい。一方で、当該研修に残された課題や教師の育成をめぐる議論のパラダイム・シフトに鑑みると、「教師の成長」を促す新たなアプローチが求められてもいる。本稿では、その方策のひとつとして、インドネシア中学校・高等学校日本語教師会とともに試みた「レッスン・スタディ」について報告する。「レッスン・スタディ」を通じて高校教師たちが得た学び、その学びがもたらした成果と課題を振り返り、インドネシアの中等教育機関での日本語教育における「レッスン・スタディ」の意義や課題を検討することで、教師の育成に関する議論の活性化が期待される。Teacher training of Japanese language education has been a big problem for a long time according to the increase of Japanese learners in secondary education in Indonesia. Japan Foundation Jakarta (JFJ) hasbeen supporting a variety programs toward solving this problem, especially in teacher training, cooperated with the government. On the other hand, along with the paradigm shift of discussion about the teacher training, a new approach is in need to encourage "Teacher Development". In this paper, we report on an attempt of "Lesson Study" as a new approach at secondary schools by the JFJ and the Association of Secondary School Teachers in Indonesia. The findings suggest that all participants have benefit from "Lesson Study", and reveal some challenges. Learning the significanceand challenges of "Lesson study" through this observation, this report contributes to stimulate the discussion of teacher training in Indonesia

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私達の看護活動は,患者(人間)の反応として起ってくる問題,特に治療・検査上・日常生活面その他の問題を明確にし,これを解決すべくケア・支援に日夜努力している。当第一内科病棟は,胃腸・肝疾患・コントロール困難な糖尿病患者が入院している。治療目的が,胃腸・肝疾患でも糖尿病を合併しているケースが多い。従来,看護計画を立案する時に主疾患に関連する問題を上げ,糖尿病に関する問題を上げる事が少なかった。そこで,糖尿病教室の指導内容を基にしたアンケートを作成し,これを使用した問題点と従来の看護記録からの問題点を比較検討した結果,アンケート用紙使用による問題点が,知識や自己管理の段階をとらえた個別的な問題として把握する事が出来,アンケートの有用性を見い出した