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A distinctive feature of the Gram-negative bacterial cell envelope is the asymmetric outer membrane (OM), where lipopolysaccharides and phospholipids (PLs) reside in the outer and inner leaflets, respectively. This unique lipid asymmetry renders the OM impermeable to external insults, including antibiotics and bile salts. In Escherichia coli, the complex comprising osmoporin OmpC and the OM lipoprotein MlaA is believed to maintain lipid asymmetry by removing mislocalized PLs from the outer leaflet of the OM. How this complex performs this function is unknown. Here, we defined the molecular architecture of the OmpC?MlaA complex to gain insights into its role in PL transport. Using in vivo photo-cross-linking and molecular dynamics simulations, we established that MlaA interacts extensively with OmpC and is located entirely within the lipid bilayer. In addition, MlaA forms a hydrophilic channel, likely enabling PL translocation across the OM. We further showed that flexibility in a hairp ...

Amyloids are associated with many neurodegenerative diseases, motivating investigations into their structure and function. Although not linked to a specific disease, albumins have been reported to form many structural aggregates. We were interested in investigating host immune responses to amyloid fibrils assembled from the model protein ovalbumin. Surprisingly, upon subjecting ovalbumin to standard denaturing conditions, we encountered giant protein nanosheets harboring amyloid-like features and hypothesized that these nanosheets might have potential in clinical or therapeutic applications. We found that the nanosheets, without the administration of any additional adjuvant, evoked a strong antibody response in mice that was higher than that observed for native ovalbumin. This suggests that amyloid nanosheets have a self-adjuvanting property. The nanosheet-induced immune response was helper T cell 2 (Th2) biased and negligibly inflammatory. While testing whether the nanosheets might fo ...

Dysregulation of the circadian rhythm is associated with many diseases, including diabetes, obesity, and cancer. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (Arntl or Bmal1) is the only clock gene whose loss disrupts circadian locomotor behavior in constant darkness. BMAL1 levels are affected by proteasomal inhibition and by several enzymes in the ubiquitin?proteasome system, but the exact molecular mechanism remains unclear. Here, using immunoprecipitation and MS analyses, we discovered an interaction between BMAL1 and ubiquitin-conjugating enzyme E2 O (UBE2O), an E3-independent E2 ubiquitin?conjugating enzyme (i.e. hybrid E2/E3 enzyme). Biochemical experiments with cell lines and animal tissues validated this specific interaction and uncovered that UBE2O expression reduces BMAL1 levels by promoting its ubiquitination and degradation. Moreover, UBE2O expression/knockdown diminished/increased, respectively, BMAL1-mediated transcriptional activity but did not affect BM ...

Microtubule-based molecular motors mediate transport of intracellular cargo to subdomains in neurons. Previous evidence has suggested that the anesthetic propofol decreases the average run-length potential of the major anterograde transporters kinesin-1 and kinesin-2 without altering their velocity. This effect on kinesin has not been observed with other inhibitors, stimulating considerable interest in the underlying mechanism. Here, we used a photoactive derivative of propofol, meta-azipropofol (AziPm), to search for potential propofol-binding sites in kinesin. Single-molecule motility assays confirmed that AziPm and propofol similarly inhibit kinesin-1 and kinesin-2. We then applied AziPm in semiquantitative radiolabeling and MS microsequencing assays to identify propofol-binding sites within microtubule?kinesin complexes. The radiolabeling experiments suggested preferential AziPm binding to the ATP-bound microtubule?kinesin complex. The photolabeled residues were contained within th ...

The genus Salmonella is responsible for many illnesses in humans and other vertebrate animals. We report here that Salmonella enterica serovar Typhimurium harbors three transketolases that support the non-oxidative branch of the pentose phosphate pathway. BLAST analysis identified two genes, STM14_2885 and STM14_2886, that together encode a putative transketolase (TktC) with 46?47% similarity to the known TktA and TktB isoforms. Assessing the mRNA and protein expression for each of the three transketolases, we determined that all are expressed in WT cells and regulated to varying extents by the alternative sigma factor RpoS. Enzyme assays with lysates from WT and transketolase-knockout strains established that TktA is responsible for > 88% of the transketolase activity in WT cells. We purified recombinant forms of each isoenzyme to assess the kinetics for canonical transketolase reactions. TktA and TktB had comparable values for Vmax (539?1362 ?m NADH consumed/s), Km (80?739 ?m), and c ...

Neuronal Per-Arnt-Sim (PAS) domain?containing protein 4 (NPAS4) is a basic helix?loop?helix (bHLH)-PAS transcription factor first discovered in neurons in the neuronal layer of the mammalian hippocampus and later discovered in pancreatic ?-cells. NPAS4 has been proposed as a therapeutic target not only for depression and neurodegenerative diseases associated with synaptic dysfunction but also for type 2 diabetes and pancreas transplantation. The ability of bHLH-PAS proteins to fulfil their function depends on their intracellular trafficking, which is regulated by specific sequences, i.e. the nuclear localization signal (NLS) and the nuclear export signal (NES). However, until now, no study examining the subcellular localization signals of NPAS4 has been published. We show here that Rattus norvegicus NPAS4 was not uniformly localized in the nuclei of COS-7 and N2a cells 24 h after transfection. Additionally, cytoplasmic localization of NPAS4 was leptomycin B-sensitive. We demonstrate th ...

日本歴史 2018年8月号について

該当時期に高崎に大きな被害をもたらした地震としては大正12年の関東大震災が、またお探しの時期とは若干ずれますが、昭和6年の西埼玉地震があります。「群馬の噴火災害草軽縣令」には災害時の新聞記事が再録されており、当時の報道を知ることができます。また「群馬県気象災害史」「群馬の自然災害」には風水害・火山爆発・地震などの県内の自然災害の一覧が掲載されています。以下、当館所蔵の参考資料になります。新編高崎市史 通史編4 p.310-312,312-314 関東大震災の被災状況について 西埼玉地震について新編高崎市史 資料編10 p.310-311,315-316 関東大震災の被害の状況 西埼玉地震の被害状況群馬県気象災害史群馬の噴火災害草軽縣令 p.132,141 当時の新聞の災害等に関わる切抜きを掲載した資料たかさき100年 第20回 関東大震災と高崎 ...

高崎が受けた空襲は昭和20年7月10日と7月30日の機銃掃射と、8月5日と8月15日のB29による爆撃です。北通町、田町、羅漢町等が銃撃され、宮元町、鞘町、連雀町、通町等が爆撃にあいました。高崎空襲について記載している資料は何点かありましたが、空襲に遭った際の写真が掲載されている資料は見当たりませんでした。以下、当館所蔵の参考資料になります。新編高崎市史 通史編4 p328-330 空襲について罹災場所・人数等の記載あり。群馬の20世紀 p.190-191 空襲についての上毛新聞記事。高崎市教育史 下巻 高崎市の戦災と学校被災 p.290-298 終戦前後の学校施設の状況 p.307-311新編高崎市史 資料編10 p.359-362 高崎の空襲について上毛新聞記事他記載。戦災と復興 p.86-87 県内空襲について市町村別被害状況一覧あり。群馬県戦災誌 p.157-169 高崎市の機 ...

2018年07月20日「双葉町ありがとうメッセージ」プロジェクト！-双葉町からありがとうの気持ちを全国へ伝えます-2018年07月20日タブレット教室（個別相談会）8月開催スケジュール2018年07月20日コンビニエンスストア等における住民票などの各種証明書の自動交付サービス