Proceedings of the Japan Academy, Series B

Reviews

Use of gnotobiotic mice to identify and characterize key microbes responsible for the development of the intestinal immune system

Yoshinori UMESAKI

2014 Volume 90 Issue 9 Pages 313-332
Published: November 11, 2014
Released on J-STAGE: November 11, 2014

DOIhttps://doi.org/10.2183/pjab.90.313

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Symbiosis between intestinal microbiota and the host animal plays an important role in the homeostasis of host physiology. Since the first production of germ-free rodents in 1945, it has become increasingly clear that the intestinal immune system and the biochemical characteristics of epithelial cells differ greatly between conventional and germ-free rodents. However, questions remain about the types of microbes involved and the precise mechanism by which these microbes affect the host physiology. Here, we review experiments designed to answer these questions with the use of gnotobiotic mice. We have determined suitable biochemical and immunological markers for monitoring microbial effects in these mice. Using these markers, we have found clear differences in epithelial cell glycolipid biosynthesis and intraepithelial lymphocyte dynamics between germ-free and conventional mice. Furthermore, we have identified a key microbe that activates the mucosal immune system in the small intestine. This indigenous bacteria, called segmented filamentous bacteria, is a key symbiont in the host-microbiota interplay, including Th17 cell-inducing activity.

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Reminiscence of phospholipase B in Penicillium notatum

Kunihiko SAITO

2014 Volume 90 Issue 9 Pages 333-346
Published: November 11, 2014
Released on J-STAGE: November 11, 2014

DOIhttps://doi.org/10.2183/pjab.90.333

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Since the phospholipase B (PLB) was reported as a deacylase of both lecithin and lysolecithin yielding fatty acids and glycerophosphocholine (GPC), there was a question as to whether it is a single enzyme or a mixture of a phospholipase A₂ (PLA₂) and a lysophospholipase (LPL). We purified the PLB in Penicillium notatum and showed that it catalyzed deacylation of sn-1 and sn-2 fatty acids of 1,2-diacylphospholipids and also sn-1 or sn-2 fatty acids of 1- or 2-monoacylphospholipids (lysophospholipids). Further, it also has a monoacyllipase activity. The purified PLB is a glycoprotein with m.w. of 91,300. The sugar moiety is M₉ only and the protein moiety consists of 603 amino acids. PLB, different from PLA₂, shows other enzymatic activities, such as transacylase, lipase and acylesterase. PLB activity is influenced by various substances, e.g. detergents, deoxycholate, diethylether, Fe³⁺, and endogenous protease. Therefore, PLB might have broader roles than PLA₂ in vivo. The database shows an extensive sequence similarity between P. notatum PLB and fungal PLB, cPLA₂ and patatin, suggesting a homologous relationship. The catalytic triad of cPLA₂, Ser, Asp and Arg, is also present in P. notatum PLB. Other related PLBs, PLB/Lipases are discussed.

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Original Articles

Cause and risk of catastrophic eruptions in the Japanese Archipelago

Yoshiyuki TATSUMI, Keiko SUZUKI-KAMATA

2014 Volume 90 Issue 9 Pages 347-352
Published: November 11, 2014
Released on J-STAGE: November 11, 2014

DOIhttps://doi.org/10.2183/pjab.90.347

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The Japanese Archipelago is characterized by active volcanism with variable eruption styles. The magnitude (M)-frequency relationships of catastrophic caldera-forming eruptions (M ≥ 7) are statistically different from those of smaller eruptions (M ≤ 5.7), suggesting that different mechanisms control these eruptions. We also find that volcanoes prone to catastrophic eruptions are located in regions of low crustal strain rate (<0.5 × 10⁸/y) and propose, as one possible mechanism, that the viscous silicic melts that cause such eruptions can be readily segregated from the partially molten lower crust and form a large magma reservoir in such a tectonic regime. Finally we show that there is a ∼1% probability of a catastrophic eruption in the next 100 years based on the eruption records for the last 120 ky. More than 110 million people live in an area at risk of being covered by tephra >20 cm thick, which would severely disrupt every day life, from such an eruption on Kyushu Island, SW Japan.

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Novel plasma biomarker surrogating cerebral amyloid deposition

Naoki KANEKO, Akinori NAKAMURA, Yukihiko WASHIMI, Takashi KATO, Takash ...

2014 Volume 90 Issue 9 Pages 353-364
Published: November 11, 2014
Released on J-STAGE: November 11, 2014

DOIhttps://doi.org/10.2183/pjab.90.353

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Alzheimer’s disease (AD) is the most common and devastating dementia. Simple and practical biomarkers for AD are urgently required for accurate diagnosis and to facilitate the development of disease-modifying interventions. The subjects for the study were selected on the basis of PiB amyloid imaging by PET. Forty PiB-positive (PiB+) individuals, including cognitively healthy controls (HC), and mild cognitive impairment and AD individuals, and 22 PiB-negative (PiB−) HC participated. Employing our novel highly sensitive immunoprecipitation-mass spectrometry, we measured plasma amyloid β-proteins (Aβs; Aβ1-40 and Aβ1-42) and Aβ-approximate peptides (AβAPs), which were cleaved from amyloid precursor protein (APP). Among the AβAPs, APP669-711 appeared to be a good reference for deciphering pathological change of Aβ1-42. We evaluated the performance of the ratio of APP669-711 to Aβ1-42 (APP669-711/Aβ1-42) as a biomarker. APP669-711/Aβ1-42 significantly increased in the PiB+ groups. The sensitivity and specificity to discriminate PiB+ individuals from PiB− individuals were 0.925 and 0.955, respectively. Our plasma biomarker precisely surrogates cerebral amyloid deposition.

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Ionizing radiation-induced XRCC4 phosphorylation is mediated through ATM in addition to DNA-PK

Shoji IMAMICHI, Mukesh Kumar SHARMA, Radhika Pankaj KAMDAR, Mikoto FUK ...

2014 Volume 90 Issue 9 Pages 365-372
Published: November 11, 2014
Released on J-STAGE: November 11, 2014

DOIhttps://doi.org/10.2183/pjab.90.365

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XRCC4 (X-ray cross-complementation group 4) is a protein associated with DNA ligase IV, which is thought to join two DNA ends at the final step of DNA double-strand break repair through non-homologous end-joining. It has been shown that, in response to irradiation or treatment with DNA damaging agents, XRCC4 undergoes phosphorylation, requiring DNA-PK. Here we explored possible role of ATM, which is structurally related to DNA-PK, in the regulation of XRCC4. The radiosensitizing effects of DNA-PK inhibitor and/or ATM inhibitor were dependent on XRCC4. DNA-PK inhibitor and ATM inhibitor did not affect the ionizing radiation-induced chromatin recruitment of XRCC4. Ionizing radiation-induced phosphorylation of XRCC4 in the chromatin-bound fraction was largely inhibited by DNA-PK inhibitor but further diminished by the combination with ATM inhibitor. The present results indicated that XRCC4 phosphorylation is mediated through ATM as well as DNA-PK, although DNA-PK plays the major role. We would propose a possible model that DNA-PK and ATM acts in parallel upstream of XRCC4, regulating through phosphorylation.

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