Flow-induced Alignment of Amyloid Protofilaments Revealed by Linear Dichroism

This research was originally published in the Journal of Biological Chemistry. Rumi Adachi, Kei-ichi Yamaguchi, Hisashi Yagi, Kazumasa Sakurai, Hironobu Naiki and Yuji Goto. Flow-induced Alignment of Amyloid Protofilaments Revealed by Linear Dichroism. J. Biol. Chem. 2007; 282, 8978-8983. © the American Society for Biochemistry and Molecular Biolog

Increased production of intestinal immunoglobulins in Syntenin-1-deficient mice

AbstractSyntenin-1 is an intracellular PDZ protein that binds multiple proteins and regulates protein trafficking, cancer metastasis, exosome production, synaptic formation, and IL-5 signaling. However, the functions of Syntenin-1 have not yet been clearly characterized in detail, especially in vivo. In this study, we generated a Syntenin-1 knock out (KO) mouse strain and analyzed the role(s) of Syntenin-1 in IL-5 signaling, because the direct interaction of Syntenin-1 with the cytoplasmic domain of the IL-5 receptor α subunit and the regulation of IL-5 signaling by Syntenin-1 have been reported. Unexpectedly, the number of IL-5-responding cells was normal and the levels of fecal immunoglobulins were rather higher in the Syntenin-1 KO mice. We also found that IgA and IgM production of splenic B cells stimulated in vitro was increased in Syntenin-1 KO mice. In addition, we showed that a distribution of intestinal microbial flora was influenced in Syntenin-1 KO mice. Our data indicate that Syntenin-1 negatively regulates the intestinal immunoglobulin production and has a function to maintain the intestinal homeostasis in vivo. The analysis of Syntenin-1 KO mice may provide novel information on not only mucosal immunity but also other functions of Syntenin-1 such as cancer metastasis and neural development

PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation

Lentiviruses have evolved to acquire an auxiliary protein Vpx to counteract the intrinsic host restriction factor SAMHD1. Although Vpx is phosphorylated, it remains unclear whether such phosphorylation indeed regulates its activity toward SAMHD1. Here we identify the PIM family of serine/threonine protein kinases as the factors responsible for the phosphorylation of Vpx and the promotion of Vpx-mediated SAMHD1 counteraction. Integrated proteomics and subsequent functional analysis reveal that PIM family kinases, PIM1 and PIM3, phosphorylate HIV-2 Vpx at Ser13 and stabilize the interaction of Vpx with SAMHD1 thereby promoting ubiquitin-mediated proteolysis of SAMHD1. Inhibition of the PIM kinases promotes the antiviral activity of SAMHD1, ultimately reducing viral replication. Our results highlight a new mode of virus–host cell interaction in which host PIM kinases facilitate promotion of viral infectivity by counteracting the host antiviral system, and suggest a novel therapeutic strategy involving restoration of SAMHD1-mediated antiviral response

LDL-C/HDL-C Ratio Predicts Carotid Intima-Media Thickness Progression Better Than HDL-C or LDL-C Alone

High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are strong predictors of atherosclerosis. Statin-induced changes in the ratio of LDL-C to HDL-C (LDL-C/HDL-C) predicted atherosclerosis progression better than LDL-C or HDL-C alone. However, the best predictor of subclinical atherosclerosis remains unknown. Our objective was to investigate this issue by measuring changes in carotid intima-media thickness (IMT). A total of 1,920 subjects received health examinations in 1999, and were followed up in 2007. Changes in IMT (follow-up IMT/baseline IMT × 100) were measured by ultrasonography. Our results showed that changes in IMT after eight years were significantly related to HDL-C (inversely, P < 0.05) and to LDL-C/HDL-C ratio (P < 0.05). When the LDL-C/HDL-C ratios were divided into quartiles, analysis of covariance showed that increases in the ratio were related to IMT progression (P < 0.05). This prospective study demonstrated the LDL-C/HDL-C ratio is a better predictor of IMT progression than HDL-C or LDL-C alone

Crystal structures of Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides imidacloprid and clothianidin

Neonicotinoid insecticides, which act on nicotinic acetylcholine receptors (nAChRs) in a variety of ways, have extremely low mammalian toxicity, yet the molecular basis of such actions is poorly understood. To elucidate the molecular basis for nAChR–neonicotinoid interactions, a surrogate protein, acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) was crystallized in complex with neonicotinoid insecticides imidacloprid (IMI) or clothianidin (CTD). The crystal structures suggested that the guanidine moiety of IMI and CTD stacks with Tyr185, while the nitro group of IMI but not of CTD makes a hydrogen bond with Gln55. IMI showed higher binding affinity for Ls-AChBP than that of CTD, consistent with weaker CH–π interactions in the Ls-AChBP–CTD complex than in the Ls-AChBP–IMI complex and the lack of the nitro group-Gln55 hydrogen bond in CTD. Yet, the NH at position 1 of CTD makes a hydrogen bond with the backbone carbonyl of Trp143, offering an explanation for the diverse actions of neonicotinoids on nAChRs

Qualitative Improvement of a Coronary Plaque after Treatment with a Strong Statin : Observation using Virtual Histology Intravascular Ultrasound

Statins are used currently for treatment and prevention of coronary artery disease, but it is difficult to assess the therapeutics effects and patient responses to different statins. Virtual histology intravascular ultrasound (VH-IVUS) has been used to evaluate detailed quantitative changes in coronary plaques, and here we report a case in which marked qualitative improvement in a coronary plaque was observed using VH-IVUS after a change in treatment from a conventional statin to a strong statin

キュウセイ シンキンエン ガ ウタガワレ, ハツネツ ニヨリ ケンザイカ シタ ムショウコウセイ Brugadaショウコウグン ノ イチレイ

Brugada症候群は,重症不整脈を発症する症候群であるが,特異な心電図所見が明らかでなく診断に苦慮することがある.今回,発熱時心電図上ST上昇を認め,心筋炎を疑われ精査でBrugada症候群と診断した1例と,本邦で報告された発熱時顕在化した本症候群16例を検討した.症例は42歳男性,感冒症状とともに心電図所見でI.aV_R, aV_L, V_(1-4)のST上昇を認め急性心筋炎を疑われ入院した.心臓超音波検査でごく軽度心機能低下,心筋生検では異常なく,冠動脈造影では有意な狭窄はなかった.pilsicainide負荷でcoved型ST上昇を示し,電気生理学検査で容易に心室細動が誘発され,植込み型除細動器の植込み術が施行された.発熱時顕在化例で,高齢者群では高率に失神を発症した.Brugada症候群は発熱時顕在化することがあり,軽快により正常化するが,発熱と同時に失神や心室性不整脈が見られることがあり,十分な配慮が必要である.Brugada syndrome is a disease associated with severe arrhythmia but without specific ECG characteristics, which makes diagnosis difficult. We report the case of a patient with Brugada syndrome who had a ST segment elevation accompanied by fever, and we investigate 16 additional Japanese patients with Brugada syndrome that was recognized by fever. The patient was a 42-year-old man who showed ST segment elevation associated with cold symptoms and was admitted after diagnosis of myocarditis. Echocardiography exhibited slight cardiac dysfunction, but a myocardial biopsy showed no abnormalities and no significant stenosis was found in coronary angiography. After administration of pilsicainide, the patient showed covedtype ST segment elevation, and ventricular fibrillation was induced during an electrophysiological study ; therefore, an implantable cardioverter defibrillator (ICD) was installed. Among the patients with Brugada syndrome recognized by fever, many elderly patients showed syncope. In conclusion, Brugada syndrome frequently appears in fever and attention should be paid to elderly patients because they frequently develop fever and syncope simultaneously