線虫Caenorhabditis elegansの低温耐性における精子から神経へのフィードバック制御

全ての生物にとって、環境温度は生存と繁殖に非常に重要な環境情報である。そのため、全ての生物には環境温度に適応するための生体メカニズムが存在する。動物の温度耐性メカニズムには多くの組織が関与するが、それらの組織間の相互作用による統合的な制御メカニズムは詳細がまだ明らかとなっていない。そこで、シンプルなモデル動物である線虫Caenorhabditis elegansの低温耐性現象をモデルとして、動物の温度耐性メカニズムの解明を目指した。線虫の低温耐性とは、20℃で飼育した個体は2℃に置かれると死滅するのに対し、15℃で飼育した個体は2℃に置かれても生存することができる現象である。これまでの研究から、頭部の温度受容ニューロンASJが温度を受容することでインスリンを分泌し、インスリンを受容した腸や神経系が遺伝子の発現を変化させることで低温耐性を制御することが明らかとなっている。本研究では、新たに低温耐性に関与することが明らかとなった精子から温度受容ニューロンASJへのフィードバックが存在し、その神経活動に影響を与えることを示した。まず、腸のインスリン経路の下流で機能する遺伝子の解析から、精子が低温耐性に影響を与えることが示唆された。さらに、精子の遺伝子と他の組織の遺伝子との関係を遺伝学的解析で調べたところ、精子の遺伝子変異が温度受容ニューロンASJの遺伝子変異より遺伝学的に優位であるという予想外の結果が得られた。また、カルシウムイメージング解析で温度受容ニューロンASJの神経活動を光学的に計測した結果、精子特異的プロテインホスファターゼPP1/GSP-4の変異体で、温度に対する応答性が低下していた。さらに、gsp-4変異体の精子特異的にgsp-4遺伝子を発現させた遺伝子導入系統において、ASJの温度応答性が回復したことから、精子が温度受容ニューロンASJに影響を与えることが示唆された。低温耐性において、精子、神経、そして腸という組織間の情報伝達を行う分子を同定するために、DNAマイクロアレイ解析で同定された飼育温度で発現変動する核内受容体 (Nuclear Hormone Receptor、NHR) の変異体の低温耐性を解析したところ、nhr-88とnhr-114変異体で強い異常が見られた。遺伝学的解析から、既知のインスリン経路とは独立に、神経からNHRを介して腸に温度情報を送っていることが示唆された。以上の結果から、動物の温度耐性において、精子が関与すること、そして、精子が頭部温度受容ニューロンをフィードバック制御することが示唆された。甲南大学平成28年(2016年度

New readout and data-acquisition system in an electron-tracking Compton camera for MeV gamma-ray astronomy (SMILE-II)

For MeV gamma-ray astronomy, we have developed an electron-tracking Compton camera (ETCC) as a MeV gamma-ray telescope capable of rejecting the radiation background and attaining the high sensitivity of near 1 mCrab in space. Our ETCC comprises a gaseous time-projection chamber (TPC) with a micro pattern gas detector for tracking recoil electrons and a position-sensitive scintillation camera for detecting scattered gamma rays. After the success of a first balloon experiment in 2006 with a small ETCC (using a 10$\times$10$\times$15 cm$^3$ TPC) for measuring diffuse cosmic and atmospheric sub-MeV gamma rays (Sub-MeV gamma-ray Imaging Loaded-on-balloon Experiment I; SMILE-I), a (30 cm)$^{3}$ medium-sized ETCC was developed to measure MeV gamma-ray spectra from celestial sources, such as the Crab Nebula, with single-day balloon flights (SMILE-II). To achieve this goal, a 100-times-larger detection area compared with that of SMILE-I is required without changing the weight or power consumption of the detector system. In addition, the event rate is also expected to dramatically increase during observation. Here, we describe both the concept and the performance of the new data-acquisition system with this (30 cm)$^{3}$ ETCC to manage 100 times more data while satisfying the severe restrictions regarding the weight and power consumption imposed by a balloon-borne observation. In particular, to improve the detection efficiency of the fine tracks in the TPC from $\sim$10\% to $\sim$100\%, we introduce a new data-handling algorithm in the TPC. Therefore, for efficient management of such large amounts of data, we developed a data-acquisition system with parallel data flow.Comment: 11 pages, 24 figure

The impact of human leukocyte antigen mismatch on recipient outcomes in living‐donor liver transplantation

Donor–recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990–2020). The primary and secondary endpoints were recipient survival and the incidence of T cell–mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0–10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21–5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11–5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor–recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children

Spectral evolution of GRB 060904A observed with Swift and Suzaku -- Possibility of Inefficient Electron Acceleration

We observed an X-ray afterglow of GRB 060904A with the Swift and Suzaku satellites. We found rapid spectral softening during both the prompt tail phase and the decline phase of an X-ray flare in the BAT and XRT data. The observed spectra were fit by power-law photon indices which rapidly changed from $\Gamma = 1.51^{+0.04}_{-0.03}$ to $\Gamma = 5.30^{+0.69}_{-0.59}$ within a few hundred seconds in the prompt tail. This is one of the steepest X-ray spectra ever observed, making it quite difficult to explain by simple electron acceleration and synchrotron radiation. Then, we applied an alternative spectral fitting using a broken power-law with exponential cutoff (BPEC) model. It is valid to consider the situation that the cutoff energy is equivalent to the synchrotron frequency of the maximum energy electrons in their energy distribution. Since the spectral cutoff appears in the soft X-ray band, we conclude the electron acceleration has been inefficient in the internal shocks of GRB 060904A. These cutoff spectra suddenly disappeared at the transition time from the prompt tail phase to the shallow decay one. After that, typical afterglow spectra with the photon indices of 2.0 are continuously and preciously monitored by both XRT and Suzaku/XIS up to 1 day since the burst trigger time. We could successfully trace the temporal history of two characteristic break energies (peak energy and cutoff energy) and they show the time dependence of $\propto t^{-3} \sim t^{-4}$ while the following afterglow spectra are quite stable. This fact indicates that the emitting material of prompt tail is due to completely different dynamics from the shallow decay component. Therefore we conclude the emission sites of two distinct phenomena obviously differ from each other.Comment: 19 pages, 9 figures, accepted for publication in PASJ (Suzaku 2nd Special Issue

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA)

PURPOSE: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer

Sperm Affects Head Sensory Neuron in Temperature Tolerance of Caenorhabditis elegans

Tolerance to environmental temperature change is essential for the survival and proliferation of animals. The process is controlled by various body tissues, but the orchestration of activity within the tissue network has not been elucidated in detail. Here, we show that sperm affects the activity of temperature-sensing neurons (ASJ) that control cold tolerance in Caenorhabditis elegans. Genetic impairment of sperm caused abnormal cold tolerance, which was unexpectedly restored by impairment of temperature signaling in ASJ neurons. Calcium imaging revealed that ASJ neuronal activity in response to temperature was decreased in sperm mutant gsp-4 with impaired protein phosphatase 1 and rescued by expressing gsp-4 in sperm. Genetic analysis revealed a feedback network in which ASJ neuronal activity regulates the intestine through insulin and a steroid hormone, which then affects sperm and, in turn, controls ASJ neuronal activity. Thus, we propose that feedback between sperm and a sensory neuron mediating temperature tolerance

Successful Rotational Atherectomy for an Angulated Calcified Lesion in an Anomalous Right Coronary Artery Using the “Mother-and-Child” Technique

Percutaneous coronary intervention (PCI) involving the anomalous coronary artery is challenging with respect to difficulty in achieving stable catheterization. Rotational atherectomy (RA) can facilitate severely calcified lesions to improve stent delivery and stent expansion; however, its utility in tortuous and angulated coronary arteries is limited with difficulty in delivery of the RA burr. The mother-and-child technique is effective for complex PCIs with increased backup force for device delivery in such complicated cases. We report a case of successful rotational atherectomy using the “mother-and-child” technique with a Dio thrombus aspiration catheter for an angulated calcified lesion in an anomalous origin of the right coronary artery