Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIMS: Cell-cell interactions between hepatocytes and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes hepatocyte (Hep) dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of NO. Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression. RESULTS: NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into neighboring hepatocytes to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout (Cygb-/-) mouse liver mitochondria. It's inhibitory action towards CcO specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through formation of excessive reactive oxygen species. Treating Cygb-/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo. INNOVATION AND CONCLUSION: Our findings provide a biochemical link between CYGB-absence in HSC and neighboring hepatocyte dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO.

DOI： 10.1089/ars.2021.0279

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT.

DOI： 10.1016/j.jiac.2022.10.020

PubMed

Publishing type：Research paper (scientific journal)  

B細胞標的治療を受けたリンパ球系腫瘍患者におけるSARS-CoV-2ワクチンの免疫原性を前向きに監視した。2回目のBNT162b2 mRNAワクチン接種を受けた参加者から血清を採取し、抗スパイクIgGとIgAの抗体陽転率と抗体保有率を調べた。リンパ腫/白血病の患者12例中11例はリツキシマブを含むレジメン(RTX)、1例はブルトン型チロシンキナーゼ阻害薬(BTKi)によるB細胞標的療法を受けた。RTX/BTKi治療群は他のリンパ球系腫瘍患者(他群、n=5)と比べて有意に減弱した抗スパイク抗体を示した。RTX/BTKi群と他群の間の幾何平均抗スパイクIgG抗体価には280倍の差があった。RTX/BTKi群のIgG抗体陽転率33%(4/12)は他群の100%(5/5)より有意に低かった。更に、他群のIgG抗体保有率が20%(1/5)であったのに対してRTX/BTKi群では0%(0/12)であった。RTX/BTKi群のIgA抗体陽転率が8%(1/12)まで減少したことから、RTX/BTKi曝露患者におけるIgGからIgAへのクラススイッチ異常が示唆された。直近のRTX/BTKi投与からワクチン接種までの期間中央値は5.3ヵ月であった。ワクチン接種時にRTX/BTKi群で推奨リンパ球数を超えたのは抗体陽転者が75%(3/4)、非抗体陽転者は63%(5/8)であった。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Vaccines having aided in escaping the majority of the population from immunological naïvety, our strategies are now shifting towards an increased focus on identifying and protecting the extremely vulnerable. We here describe the results of testing 12 patients, those with lymphoid malignancies having been targeted their B-cells for therapy with rituximab-containing regimens or a Bruton tyrosine kinase inhibitor, for anti-SARS-CoV-2 spike antibodies after receiving the BNT162b2 mRNA vaccine doses. The interval from last dosing of B-cell depletion therapy to SARS-CoV-2 vaccination was at median 5.3 (range 3.1-6.6) months. Using the 'seroprotection' threshold of 775 [BAU/mL] for the anti-spike antibody titer, our finding points out the crucial unresponsiveness of the targeted population with 0/12 (0%) achieving 'seroprotection'. Although IgG seroconversion was observed in 4/12 (33%), supporting the overall benefit of vaccination, the figures still point out a potential need for optimization of practice. IgA was further less responsive (unsuccessful 'seroconversion' in 11/12 (92%)), implicating an underlying class switch defect. Those with depletion on B-cells are caught at a dilemma between, being too early and too late on receiving SARS-CoV-2 vaccines. They wish to get over their immunological naïvety at the earliest, while, in order to assure quality immune memory, are also required to hold the patience for their B-cells to repopulate. Although it remains an issue whether intensified vaccine schedules and/or regimens will lead to stronger immunogenicity or more effective boosters for non-responders, we shall take advantage of every increasing evidence in order to optimize current options.

DOI： 10.1016/j.jiac.2022.09.018

PubMed

Authorship：Last author   Publishing type：Research paper (scientific journal)  

More people with a history of prior infection are receiving SARS-CoV-2 vaccines. Understanding the level of protection granted by ‘hybrid immunity’, the combined response of infection- and vaccine-induced immunity, may impact vaccination strategies through tailored dosing. A total of 36 infected (‘prior infection’) and 33 SARS-CoV-2 ‘naïve’ individuals participated. Participants provided sera six months after completing a round of BNT162b2 vaccination, to be processed for anti-spike antibody measurements and the receptor binding domain-ACE2 binding inhibition assays. The relationships between antibody titer, groups and age were explored. Anti-spike antibody titers at 6 months post-vaccination were significantly higher, reaching 13- to 17-fold, in the ‘prior infection’ group. Semi-log regression models showed that participants with ‘prior infection’ demonstrated higher antibody titer compared with the ‘naïve’ even after adjusting for age. The enhancement in antibody titer attributable to positive infection history increased from 8.9- to 9.4- fold at age 30 to 19- to 32-fold at age 60. Sera from the ‘prior infection’ group showed higher inhibition capacity against all six analyzed strains, including the Omicron variant. Prior COVID-19 led to establishing enhanced humoral immunity at 6 months after vaccination. Antibody fold-difference attributed to positive COVID-19 history increased with age, possibly because older individuals are prone to symptomatic infection accompanied by potentiated immune responses. While still pending any modifications of dosing recommendations (i.e. reduced doses for individuals with prior infection), our observation adds to the series of real-world data demonstrating the enhanced and more durable immune response evoked by booster vaccinations following prior infection.

DOI： 10.3389/fimmu.2023.1087473

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12916-022-02695-5

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

This study assessed the immunogenicity and safety of the BNT162b2 mRNA vaccine in lung cancer patients receiving anticancer treatment. We enrolled lung cancer patients receiving anticancer treatment and non-cancer patients; all participants were fully vaccinated with the BNT162b2 vaccine. Blood samples were collected before the first and second vaccinations and 4 ± 1 weeks after the second vaccination. Anti-severe respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein S1 subunit receptor-binding domain antibody titers were measured using the Architect SARS-CoV-2 IgG II Quant and Elecsys Anti-SARS-CoV-2 S assays. Fifty-five lung cancer patients and 38 non-cancer patients were included in the immunogenicity analysis. Lung cancer patients showed significant increase in the geometric mean antibody concentration, which was significantly lower than that in the non-cancer patients after the first (30 vs. 121 AU/mL, p < .001 on Architect; 4.0 vs 1.2 U/mL, p < .001 on Elecsys) and second vaccinations (1632 vs. 3472 AU/mL, p = .005 on Architect; 213 vs 573 A/mL, p = .002 on Elecsys). The adjusted odds ratio (aOR) for seroprotection was significantly lower (p < .05) in lung cancer patients than that in non-cancer patients. Analysis of the anticancer treatment types showed that the aOR for seroprotection was significantly lower (p < .05) in lung cancer patients receiving cytotoxic agents. They showed no increase in adverse reactions. BNT162b2 vaccination in lung cancer patients undergoing anticancer treatment significantly increased (p < .05) antibody titers and showed acceptable safety. Immunogenicity in these patients could be inadequate compared with that in non-cancer patients.

DOI： 10.1080/21645515.2022.2140549

PubMed

Publishing type：Research paper (scientific journal)  

健康人の唾液蛋白質(SP)がアンジオテンシン変換酵素2(ACE2)に結合する能力を評価し、新型コロナウイルス(SARS-CoV-2)スパイク蛋白質S1(S1)受容体結合ドメインとACE2の間の結合に及ぼすSPの影響を測定した。SPはACE2に結合し、S1のACE2への結合を妨害し、S1-ACE2相互作用を阻害するカチオン性ヒストンH2Aと好中球エラスターゼを含む4種類のACE2結合性SPを同定した。ウシ胸腺ヒストン(CTH)もH2Aと同じく効果的に結合を阻害した。CTHはACE2発現宿主細胞へのSARS-CoV-2偽ウイルス性侵入を抑制した。ε-ポリ-L-リジンなどの合成ポリペプチドもS1-ACE2結合を妨害し、ACE2結合におけるSPの重要性が示された。以上より、正荷電のSPはACE2の負荷電表面をクローキングしてSARS-CoV-2の侵入に対する障壁になり、カチオン性ポリペプチドは新型コロナウイルス感染症に対する予防的・治療的手法になり得ると考えられた。

Publishing type：Research paper (scientific journal)  

新型コロナウイルス(SARS-CoV-2)に対するmRNA COVID-19ワクチン接種後に自己免疫性血球減少を発症することが知られているが,成熟B細胞腫瘍患者のワクチン接種が腫瘍随伴症状へ与える影響を調べた報告はない。症例は71歳男性。数年前に成熟B細胞腫瘍を疑う症状があったが自然軽快し経過観察されていた。BNT162b2 mRNA COVID-19ワクチン2回目接種10日後に温式自己免疫性溶血性貧血を発症した。貧血はステロイドで改善したが,脾腫,IgM-M蛋白血症,腎障害が増悪した。診断・治療目的に脾臓摘出術を施行し,脾辺縁帯リンパ腫と診断され,M蛋白血症,腎障害は改善した。本症例でSARS-CoV-2特異的抗体の獲得は障害されていた。ワクチン接種後の非特異的な免疫賦活が,成熟B細胞腫瘍の腫瘍随伴症状を増悪させる可能性が示唆されたが,病態解明のためにさらなる症例集積が必要である。(著者抄録)

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

DOI： 10.1186/s12916-022-02518-7

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Although several assays are used to measure anti-receptor-binding domain (RBD) antibodies induced after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, the assays are not fully comparable in practice. This study evaluated the immunogenicity of the BNT162b2 mRNA vaccine in healthy adults using two immunoassays. METHODS: This prospective cohort study included SARS-CoV-2-naïve adults, predominantly healthcare workers, aged 20-64 years, who received two BNT162b2 vaccine doses between March and May 2021. Blood samples were collected before the first vaccination (S0), before the second vaccination (S1), 4 weeks after the second vaccination (S2), and 6 months after the second vaccination (S3). anti-RBD antibodies were measured using the Architect SARS-CoV-2 IgG II Quant (Abbott Laboratory) and Elecsys anti-SARS-CoV-2 S (Roche Diagnostics) assays. RESULTS: Among the 385 participants, the geometric mean antibody titers (GMTs) on the Architect assay (AU/mL) were 7.5, 693, 7007, and 1030 for S0, S1, S2, and S3, respectively. The corresponding GMTs on the Elecsys assay (U/mL) were 0.40, 24, 928, and 659, respectively. The GMT ratio (S3/S2) was 0.15 on the Architect and 0.71 on the Elecsys assay. The correlation between antibody titers measured with the two assays were strong at all time points after vaccination (Spearman's correlation coefficient: 0.74 to 0.86, P < 0.01 for all). GMT was significantly lower in the older age group after vaccination (P < 0.01), with no significant differences according to sex. Seroprotection (≥5458 AU/mL on the Architect assay and ≥ 753 U/mL on the Elecsys) at each time point was 0 %, 1 %, 67 %, and 1 % on the Architect assay and 0 %, 1 %, 62 %, and 43 % on the Elecsys, respectively. CONCLUSIONS: Two BNT162b2 vaccine doses resulted in adequate anti-RBD antibody response, which varied by age. As the two assays showed different kinetics, the results of single immunoassays should be interpreted with caution.

DOI： 10.1016/j.vaccine.2022.08.018

PubMed

Publishing type：Research paper (scientific journal)  

国際共同研究グループは、シャーガス病の原因である媒介昆虫による感染リスクを評価するため、2年間にわたり中米エルサルバドル全域にて調査を行いました。シャーガス病は、WHOが定義する顧みられない熱帯病(Neglected Tropical Diseases, NTDs)の一つであり、クルーズトリパノソーマ(Trypanosoma cruzi)と呼ばれる原虫に感染している媒介昆虫によりヒトに感染します。主にラテンアメリカで猛威をふるう感染症で、エルサルバドルは流行国の中でも特に感染者が多く深刻な状況であるにもかかわらず、媒介昆虫がどの程度、病原体に寄生されておりヒトへの感染源となっているかについて、十分な調査や報告がなされていませんでした。そこで本研究グループは、エルサルバドル全域で同国保健省や地方自治体等と協力し家屋への立ち入り調査を行い、媒介昆虫の侵入状況や感染率をもとに、リスクの高い地域を層別することができました。本研究成果により、今後特に感染リスクの高い地域を対象とした対策の効率化が期待できます。

Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Since the late twentieth century, Chagas disease gained global attention to suppress the vector burden as a main control strategy in endemic countries. In Central America, multi-national initiative successfully achieved significant reduction in the estimated disease prevalence as well as elimination of the region's principal vector species at the time in 2012. While the last decade has witnessed significant changes in ecosystem-such as urbanization and replacement of the main vector species-that can possibly affect the vector's habitation and residual transmission, the up-to-date vector burden in the region has not been evaluated thoroughly due to the cessation of active vector surveillance. The aim of this study was to update the risk of vector-borne Trypanosoma cruzi infection in El Salvador, the top Chagas disease-endemic country in Central America. METHODS: A nationwide vector survey was conducted in the domestic environment of El Salvador from September 2018 to November 2020. The selection of the houses for inspection was based on expert purposeful sampling. Infection for T. cruzi was examined by microscopic observation of the insects' feces, followed by a species confirmation using PCR. The data were analyzed using R software version 4.1.3. Proportion estimates with 95% confidence intervals were inferred using the Jeffrey's method provided under the epiR package. RESULTS: A total of 1529 Triatoma dimidiata was captured from 107 houses (infestation rate, 34.4%; 107/311) in all the fourteen departments of the country visited within the period; prevalence of T. cruzi infection was as high as 10% (153/1529). In the country, domestic T. dimidiata infestation was distributed ubiquitously, while T. cruzi infection rates varied across the departments. Five out of fourteen departments showed higher infection rates than the average, suggesting sporadic high-risk areas in the country. CONCLUSIONS: Our comprehensive study revealed substantial T. cruzi infection of T. dimidiata across the country, indicating potential active transmission of the disease. Therefore, strengthened surveillance for both vector and human infection is required to truly eliminate the risk of T. cruzi transmission in Central America.

DOI： 10.1186/s40249-022-01008-5

PubMed

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)  

DOI： 10.1128/spectrum.00986-22

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jb/mvac054

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10875-022-01308-3

PubMed

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.cmi.2022.06.020

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Recently, immune response to coronavirus disease (COVID-19) has attracted attention where an association between higher antibody titer and worsening disease severity has been reported. However, our experiences with severe COVID-19 patients with low antibody titers led to hypothesizing that suppressed humoral immune response may be associated with poorer prognosis in severe COVID19. In this study, antibody titers in severe COVID19 patients were measured at 7, 10, 12, and 14 days after onset. Patients were divided into survivors and non-survivors. SARS-CoV-2 IgM in survivors and non-survivors were 0.06 AU and 0.02 AU (P = 0.048) at 10 days, 0.1 AU and 0.03 AU (P = 0.02) at 12 days, and 0.17 AU and 0.06 AU (P = 0.02) at 14 days. IgG in survivors and non-survivors were 0.01 AU and 0.01 AU (P = 0.04) at 7 days, 0.42 AU and 0.01 AU (P = 0.04) at 12 days, and 0.42 AU and 0.01 AU (P = 0.02) at 14 days. Multivariate analysis showed better survival among patients with IgM positivity at 12 days (P = 0.04), IgG positivity at 12 days (P = 0.04), IgM positivity at 14 days (P = 0.008), and IgG positivity at 14 days (P = 0.005). In severe COVID-19, low antibody titers on days 12 and 14 after onset were associated with poorer prognosis.

DOI： 10.1038/s41598-022-12834-w

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Cryptosporidium spp. are protozoan parasites that are transmitted via fecal-oral routes and can exhibit chemical resistance. Chlorine resistance makes it very difficult to eliminate parasites present in contaminated drinking water. While the efficacy of ultraviolet light-emitting diodes (UV-LEDs) against microorganisms has been reported, the efficacy of UV-LEDs against Cryptosporidium spp. has not been fully evaluated. Here, we assessed the efficacy of UV-LEDs with peak wavelengths of 268, 275, 284, and 289 nm against Cryptosporidium parvum at various exposure times, with a fixed exposure distance, using two in vitro methods. Consequently, the time required for 2 log10 inactivation through the excystation method by UV-LEDs of 268, 275, 284, and 289 nm was estimated as 115.5, 104.1, 37.4, and 30.7 min, respectively. The propidium iodide (PI) and 4',6-diamidino-2-phenylindole (DAPI) staining assays estimated the inactivation time as 311.3, 275.2, 60.6, and 39.1 min, respectively. Our results showed that UV-LED irradiation at longer wavelengths produced higher inactivation activity against C. parvum, which corroborates our previously reported in vivo assay results, although further study is needed to clarify the mechanism.

DOI： 10.1016/j.parint.2022.102557

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.21203/rs.3.rs-1430985/v1

PubMed

Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Serial antibody measurements using an array of SARS-CoV-2 immunoassays have demonstrated differing kinetics among assay platforms (1).….

DOI： 10.1128/JCM.02262-21

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

We report on a 52-year-old Brazilian immigrant woman with past histories of chronic kidney disease and uveitis, presenting with symptomatic atrioventricular block. Her country of origin being endemic for Trypanosoma cruzi infection, we suspected Chagas disease as the aetiology, diagnosis of which was confirmed by serological tests. Further systemic workup identified an emerging nodular lesion in the lung, which turned out to be a sarcoid epithelioid granuloma on biopsy. Involvement of the kidneys and eyes was suggestive of systemic extension of the lung sarcoidosis. Although imaging modalities did not detect inflammatory foci in the myocardium, the rare coexistence of histologically proven sarcoidosis raised the intriguing concept of cardiac manifestation having arisen from two possibly overlapping aetiologies: Chagas disease and cardiac sarcoidosis. The case highlights a treatment dilemma increasingly likely to be encountered in this globalized world, and also raises the potential, but intriguing, association of these two diseases.

DOI： 10.1002/ehf2.13771

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.2491/jjsth.33.338

Publishing type：Research paper (scientific journal)  

<p>There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient’s symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient’s serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.</p>

DOI： 10.11406/rinketsu.63.1379

PubMed

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

The prompt rollout of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine is facilitating population immunity, which is becoming more dominant than natural infection-mediated immunity. In the midst of coronavirus disease 2019 (COVID-19) vaccine deployment, understanding the epitope profiles of vaccine-elicited antibodies will be the first step in assessing the functionality of vaccine-induced immunity. In this study, the high-resolution linear epitope profiles of Pfizer-BioNTech COVID-19 mRNA vaccine recipients and COVID-19 patients were delineated by using microarrays mapped with overlapping peptides of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The vaccine-induced antibodies targeting the RBD had a broader distribution across the RBD than that induced by the natural infection. Half-maximal neutralization titers were measured in vitro by live virus neutralization assays. As a result, relatively lower neutralizability was observed in vaccine recipient sera, when normalized to a total anti-RBD IgG titer. However, mutation panel assays targeting the SARS-CoV-2 variants of concern have shown that the vaccine-induced epitope variety, rich in breadth, may grant resistance against future viral evolutionary escapes, serving as an advantage of vaccine-induced immunity. IMPORTANCE Establishing vaccine-based population immunity has been the key factor in attaining herd protection. Thanks to expedited worldwide research efforts, the potency of mRNA vaccines against the coronavirus disease 2019 (COVID-19) is now incontestable. The next debate is regarding the coverage of SARS-CoV-2 variants. In the midst of vaccine deployment, it is of importance to describe the similarities and differences between the immune responses of COVID-19 vaccine recipients and naturally infected individuals. In this study, we demonstrated that the antibody profiles of vaccine recipients are richer in variety, targeting a key protein of the invading virus, than those of naturally infected individuals. Vaccine-elicited antibodies included more nonneutralizing antibodies than infection-elicited antibodies, and their breadth in antibody variations suggested possible resilience against future SARS-CoV-2 variants. The antibody profile achieved by vaccinations in naive individuals provides important insight into the first step toward vaccine-based population immunity.

DOI： 10.1128/Spectrum.00965-21

PubMed

Publishing type：Research paper (scientific journal)  

症例は73歳男性で、食道の粘膜関連リンパ組織リンパ腫と診断され、リツキシマブを8回投与後、局所照射を行った。最終リツキシマブ投与の12週後、発熱と呼吸症状が出現し、SARS-CoV-2陽性が判明した。呼吸検体だけでなく血清もSARS-CoV-2陽性であったことから、SARS-CoV-2播種によるRNA血症が示唆された。胸部CT所見から、新型コロナウイルス感染症(COVID-19)H型が示唆された。重度呼吸障害のために機械的換気を行い、ファビピラビルとクロロキンによる併用療法を行ったが、明らかな有効性は得られなかった。高用量メチルプレドニゾロンにより換気パラメータが軽度に改善したが、一過性であった。イベルメクチン単回投与を行ったが、発症24日目の喀痰PCRは、依然としてSARS-CoV-2陽性であった。発症25日目の血清SARS-CoV-2特異的抗体検査では矛盾した結果が得られ、スパイク標的ウイルス中和抗体は検出レベル未満であったが、抗ヌクレオカプシド結合抗体の程度と動態は他の免疫正常重度COVID-19患者と同等であった。発症29日目、酸素化不良により死亡した。

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

We describe the results of testing health care workers, from a tertiary care hospital in Japan that had experienced a coronavirus disease 2019 (COVID-19) outbreak during the first peak of the pandemic, for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody seroconversion. Using two chemiluminescent immunoassays and a confirmatory surrogate virus neutralization test, serological testing revealed that a surprising 42% of overlooked COVID-19 diagnoses (27/64 cases) occurred when case detection relied solely on SARS-CoV-2 nucleic acid amplification testing (NAAT). Our results suggest that the NAAT-positive population is only the tip of the iceberg and the portion left undetected might potentially have led to silent transmissions and triggered the spread. A questionnaire-based risk assessment was further indicative of exposures to specific aerosol-generating procedures (i.e., noninvasive ventilation and airway suctioning) having mediated transmission and served as the origins of the outbreak. Our observations are supportive of a multitiered testing approach, including the use of serological diagnostics, in order to accomplish exhaustive case detection along the whole COVID-19 spectrum. IMPORTANCE We describe the results of testing frontline health care workers, from a hospital in Japan that had experienced a COVID-19 outbreak, for SARS-CoV-2-specific antibodies. Antibody testing revealed that a surprising 42% of overlooked COVID-19 diagnoses occurred when case detection relied solely on PCR-based viral detection. COVID-19 clusters have been continuously striking the health care system around the globe. Our findings illustrate that such clusters are lined with hidden infections eluding detection with diagnostic PCR and that the cluster burden in total is more immense than actually recognized. The mainstays of diagnosing infectious diseases, including COVID-19, generally consist of two approaches, one aiming to detect molecular fragments of the invading pathogen and the other to measure immune responses of the host. Considering antibody testing as one trustworthy option to test our way through the pandemic can aid in the exhaustive case detection of COVID-19 patients with variable presentations.

DOI： 10.1128/Spectrum.01082-21

PubMed

Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.1186/s13054-021-03768-2

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Beside diagnostic uncertainties due to the lack of a perfect gold standard test for Helicobacter pylori infection, the diagnosis and the prevalence estimation for this infection encounter particular challenges in Africa including limited diagnostic tools and specific genetic background. We developed and evaluated the accuracy of an enzyme-linked immunosorbent assay (ELISA) system tailored for H. pylori genetics in Africa (HpAfr-ELISA). Strains belonging to main genetic populations infecting Africans were exploited as sources for whole-cell antigens to establish in-house the ELISA system. A phase II unmatched case-control study explored the diagnostic accuracy of the HpAfr-ELISA using a training set of samples collected from dyspeptic patients from Kinshasa, the Democratic Republic of Congo (DRC) who had been tested with invasive standard tests (i.e., histology, culture, and rapid urease test) in 2017. Then the assay was cross-validated through a community-based survey assessing the prevalence of H. pylori and associated factors in 425 adults from Mbujimayi, DRC in 2018. Bayesian inferences were used to deal with statistical uncertainties of estimates (true prevalence, sensitivity, and specificity) in the study population. At its optimal cut-off-value 20.2 U/mL, the assay achieved an estimated sensitivity of 97.6% (95% credible interval [95%CrI]: 89.2; 99.9%) and specificity of 90.5% (95%CrI: 78.6; 98.5). Consistent outcomes obtained at repeated tests attested the robustness of the assay (negative and positive agreements always > 70%). The true prevalence of H. pylori was estimated 53.8% [95%CrI: 42.8; 62.7%]. Increasing age (adjusted odds ratio [aOR] > 1.0 [95% confidence interval (CI): > 1.0; 1.1]; p<0.001), overcrowding households (aOR = 3.2 [95%CI: 2.0; 5.1]; p<0.001), and non-optimal hand hygiene (aOR = 4.5 [95%CI: 2.0; 11.4]; p = 0.001) were independently associated with the H. pylori-seropositivity. The novel ELISA system has demonstrated good diagnostic accuracy and potential usefulness for management and mitigation strategies for H. pylori infection in African settings.

DOI： 10.1371/journal.pntd.0009763

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Healthcare workers (HCWs) who manage patients with the novel coronavirus disease 2019 (COVID-19) are at an increased risk and fear of contracting the infection themselves. Hospitals must reduce both the physical and mental burden of HCWs on the front lines and ensure their safety. No prospective study has focused on the physical health complaints among HCWs engaged in the care of critically ill COVID-19 patients. This study aimed to evaluate the prevalence of various physical symptoms experienced by HCWs following their exposure to COVID-19 patients and investigate the association between occupation and the manifestation of physical symptoms among HCWs at a tertiary hospital in Japan during the current ongoing COVID-19 pandemic. METHODS: A twice-weekly questionnaire targeting HCWs who care for COVID-19 patients was performed at Osaka City University Hospital from April 30 to May 31, 2020. The demographic characteristics of the participants, frequency of exposure to at-risk care, and physical complaints were evaluated. RESULTS: Seventy-six HCWs participated in this study, of whom 24 (31.6%) were doctors, 43 (56.6%) were nurses, and 9 (11.8%) were technicians. The frequency of experiencing any physical symptom was 25.0% among HCWs. Exposure to at-risk care was significantly higher among nurses than among doctors (p < 0.001). Notably, the frequency of physical symptoms among the nurses was very high at 39.5% and obviously higher than that of physical symptoms among the doctors (p < 0.01). CONCLUSIONS: Our results indicate that hospital occupational health care must be provided to HCWs who are engaged in the care of COVID-19 patients and are thus highly exposed to at-risk care.

DOI： 10.1016/j.jiph.2021.08.023

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis and infects almost one-third of the global human population. A lack of effective drugs and vaccines and the emergence of drug resistant parasites highlight the need for the development of new drugs. The mitochondrial electron transport chain (ETC) is an essential pathway for energy metabolism and the survival of T. gondii. In apicomplexan parasites, malate:quinone oxidoreductase (MQO) is a monotopic membrane protein belonging to the ETC and a key member of the tricarboxylic acid cycle, and has recently been suggested to play a role in the fumarate cycle, which is required for the cytosolic purine salvage pathway. In T. gondii, a putative MQO (TgMQO) is expressed in tachyzoite and bradyzoite stages and is considered to be a potential drug target since its orthologue is not conserved in mammalian hosts. As a first step towards the evaluation of TgMQO as a drug target candidate, in this study, we developed a new expression system for TgMQO in FN102(DE3)TAO, a strain deficient in respiratory cytochromes and dependent on an alternative oxidase. This system allowed, for the first time, the expression and purification of a mitochondrial MQO family enzyme, which was used for steady-state kinetics and substrate specificity analyses. Ferulenol, the only known MQO inhibitor, also inhibited TgMQO at IC50 of 0.822 μM, and displayed different inhibition kinetics compared to Plasmodium falciparum MQO. Furthermore, our analysis indicated the presence of a third binding site for ferulenol that is distinct from the ubiquinone and malate sites.

DOI： 10.3390/ijms22157830

PubMed

Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: The gold standard for coronavirus disease (COVID-19) diagnosis has been the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA by nucleic acid amplification testing (NAAT). On the other hand, serological testing for COVID-19 may offer advantages in detecting possibly overlooked infections by NAAT. METHODS: To evaluate seroconversion of NAAT-negative pneumonia patients, immunoglobulin M (IgM) and IgG targeting the spike protein of SARS-CoV-2 were semiquantified by an immunofluorescence assay. Seroconversion was confirmed by another serological method, targeting the nucleocapsid protein. RESULTS: Eight suspected but unconfirmed COVID-19 pneumonia patients (median age, 39 years; range, 21-55) were included. The median period between symptom onset and NAAT sample collection was 6 days (2-27 days). None of them had tested positive for SARS-CoV-2 by NAAT. In contrast, all eight patients revealed seropositivity with the two serological methods, indicating actual seroconversion against SARS-CoV-2. The median period between onset and blood sampling was 26.5 days (7-51 days). CONCLUSION: Eight patients with COVID-19 pneumonia, initially tested negative for SARS-CoV-2 by NAAT, were finally confirmed of the diagnosis by serological testing. To cover the whole spectrum of this heterogenous infectious disease, serology testing should be implemented to the multitiered diagnostic algorithm for COVID-19.

DOI： 10.1002/jmv.26949

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Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: USA300 produces Panton-Valentin leucocidin (PVL) and is known as a predominant community-associated methicillin-resistant Staphylococcus aureus (MRSA) strain in the United States, but it was extremely rare in Japan. We report here an outbreak of USA300 in people with HIV (PWH) in Tokyo, Japan. METHODS: We analyzed the cases of PVL-MRSA infection between 2010 and 2020 and screened for nasal colonization of PVL-MRSA in PWH who visited an HIV/AIDS referral hospital from December 2019 to March 2020. Whole-genome sequencing-based single nucleotide polymorphism (SNP) analysis was performed on these isolates. RESULTS: During the study period, a total of 21 PVL-MRSA infections in 14 patients were identified after 2014. The carriage prevalence was 4.3% (12/277) and PVL-MRSA carriers were more likely to have sexually transmitted infections (STIs) within a year compared with patients who had neither a history of PVL-MRSA infection nor colonization (33.3% [4/12] vs 10.1% [26/258]; P = .03). SNP analysis showed that all 26 isolates were ST8-SCCmecIVa-USA300. Twenty-four isolates were closely related (≤100 SNP differences) and had the nonsynonymous SNPs associated with carbohydrate metabolism and antimicrobial tolerance. CONCLUSIONS: An outbreak of USA300 has been occurring among PWH in Tokyo and a history of STI was a risk of colonization.

DOI： 10.1093/infdis/jiaa651

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Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.1016/j.jmii.2020.09.005

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

DOI： 10.1002/jmv.26495

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

We used 2 commercially available antibody tests to estimate seroprevalence of severe acute respiratory syndrome coronavirus 2 infection in Japan during June 2020. Of 7,950 samples, 8 were positive by both assays. Using 2 reliable antibody tests in conjunction is an effective method for estimating seroprevalence in low prevalence settings.

DOI： 10.3201/eid2702.204088

PubMed

Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

<p>A 73-year-old man previously treated with rituximab for his mucosa-associated lymphoid tissue lymphoma suffered a suboptimal humoral immune response against an acquired SARS-CoV-2 infection. A detailed serological description revealed discrepant antigen-specific humoral immune responses. The titer of spike-targeting, "viral-neutralizing" antibodies remained below the detection level, in contrast to the anti-nucleocapsid, "binding" antibody response, which was comparable in both magnitude and kinetics. Accordingly, viral neutralizability and clearance was delayed, leading to prolonged RNAemia and persistent pneumonia. The present case highlights the need to closely monitor this unique population of recipients of B-cell-targeted therapies for their neutralizing antibody responses against SARS-CoV-2. </p>

DOI： 10.2169/internalmedicine.7884-21

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CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Previous studies have shown that HIV-infected individuals were less susceptible to chronic gastritis and Helicobacter pylori infection. Th1 and Th17 cells are important components of the immune response to H. pylori in adults. We investigated the relative importance of Th1 versus Th17 responses for mucosal inflammation and protection. We conducted a prospective cross-sectional study to evaluate the relationship among the peripheral blood gut-homing CD4+ T cell subset, the severity of chronic H. pylori gastritis, and H. pylori amount in the gastric mucosa. Biopsy specimens were obtained at the time of gastroendoscopy, which was used for classification of histological gastritis by updated-Sydney system. Peripheral blood mononuclear cells were collected at the same point to determine the frequency of peripheral blood gut homing CD4+ T cells (CCR9+integrin β7+) and CD4+ memory T cells subsets by flow cytometry. H. pylori amount in the gastric mucosa was measured using 16S ribosomal RNA gene amplicon sequencing. Peripheral blood gut-homing CD4+ T cells were significantly higher in individuals with histological gastritis compared with those without chronic gastritis (median 16.8 cells/μL vs. 9.7 cells/μL; p = .0307). In particular, there were significant differences in gut-homing Th1 (median 1.3 cells/μL vs. 0.5 cells/μL; p = .0061) and nonconventional Th1 (median 0.4 cells/μL vs. 0.2 cells/μL; p = .0196). In addition, there was a significant positive correlation between H. pylori amount in the gastric mucosa measured using 16S ribosomal RNA gene amplicon sequencing and gut-homing Th1 subsets. Our findings suggested that gut Th1 may play a key role in the development of chronic gastritis in HIV-infected individuals.

DOI： 10.1089/AID.2020.0086

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Publishing type：Research paper (scientific journal)  

各種波長のUV-LEDによるCryptosporidium parvum不活化作用を、重症複合免疫不全症(SCID)マウスを用いて評価した。5週齢の雌SCIDマウスを7群に割り付けた(5〜6頭/群)。A群には未処理オーシスト10^5、B群には未処理オーシスト10^3、C群にはUVランプ照射(波長253.7nm)オーシスト10^6、D〜G群にはUV-LED(ピーク波長268、275、284、289nm)照射オーシスト10^6を腹腔内投与した。1日当たりのオーシスト排出量(OPD)を算出した。全ての処理群のOPD値は対照(未処理オーシスト)群と同様に、10^7のプラトーに達した。未処理オーシスト群の増殖曲線の標準偏差は比較的小さかったのに対して、UV/UV-LED処理オーシスト群では大きな分散を示した。OPDが10^4、10^5、10^6に達する推定日数については、波長284nmと289nmのUV-LEDで処理した場合の方がUVランプ処理の場合より有意に長かった。10^3対照群における40日後の死亡率は0%、10^5対照群で66.7%(4/6)、UVランプ群では40%(2/5)、UV-LED群では波長268nmが60%(3/5)、275nmが0%、284nmが20%(1/5)、289nmが0%であった。波長約280nmのUV-LED照射はオーシストからの脱嚢を阻害するものと推測された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

As an alternative to using ultraviolet (UV) lamps, which are made with mercury that is toxic to the environment and human health, UV light-emitting diodes (UV-LEDs) are expected to be effective for inactivating microorganisms in water. Although UV-LEDs have been reported to be effective against bacteria and viruses, the effectiveness of UV-LEDs against Cryptosporidium parasites has not been fully evaluated. As we report here, we have developed an in vivo quantitative inactivation assay for C. parvum oocysts using immunodeficient mice. Using the assay, we evaluated the effectiveness of treatment by UV lamp (254 nm) at approximately 1000 μJ/cm2 (for 3 s at a distance of 95 mm) compared to inactivation by commercially available UV-LEDs (with peak wavelengths of 268, 275, 284, and 289 nm). The shed patterns of oocysts after treatment with 284- and 289-nm wavelength UV-LEDs were significantly delayed compared to that after treatment with a UV lamp. These findings provide the first suggestion that UV-LEDs are effective against these parasites, as assessed using commercially available 350-mA UV-LEDs under conditions of fixed exposure distance and time.

DOI： 10.1016/j.parint.2020.102108

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Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Antimicrobial susceptibility testing (AST) is increasingly needed to guide the Helicobacterpylori (H. pylori) treatment but remains laborious and unavailable in most African countries. To assess the clinical relevance of bacterial whole genome sequencing (WGS)-based methods for predicting drug susceptibility in African H. pylori, 102 strains isolated from the Democratic Republic of Congo were subjected to the phenotypic AST and next-generation sequencing (NGS). WGS was used to screen for the occurrence of genotypes encoding antimicrobial resistance (AMR). We noted the broad-spectrum AMR of H. pylori (rates from 23.5 to 90.0%). A WGS-based method validated for variant discovery in AMR-related genes (discovery rates of 100%) helped in identifying mutations of key genes statistically related to the phenotypic AMR. These included mutations often reported in Western and Asian populations and, interestingly, several putative AMR-related new genotypes in the pbp1A (e.g., T558S, F366L), gyrA (e.g., A92T, A129T), gyrB (e.g., R579C), and rdxA (e.g., R131_K166del) genes. WGS showed high performance for predicting AST phenotypes, especially for amoxicillin, clarithromycin, and levofloxacin (Youden's index and Cohen's Kappa > 0.80). Therefore, WGS is an accurate alternative to the phenotypic AST that provides substantial decision-making information for public health policy makers and clinicians in Africa, while providing insight into AMR mechanisms for researchers.

DOI： 10.3390/microorganisms8060887

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Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00430-019-00634-5

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Currently, Western-type CagA is used in most commercial Helicobacter pylori CagA ELISA kits for CagA detection rather than East Asian-type CagA. We evaluated the ability of the East Asian-type CagA ELISA developed by our group to detect anti-CagA antibody in patients infected with different cagA genotypes of H. pylori from four different countries in South Asia and Southeast Asia. The recombinant CagA protein was expressed and later purified using GST-tag affinity chromatography. The East Asian-type CagA-immobilized ELISA was used to measure the levels of anti-CagA antibody in 750 serum samples from Bhutan, Indonesia, Myanmar, and Bangladesh. The cutoff value of the serum antibody in each country was determined via Receiver-Operating Characteristic (ROC) analysis. The cutoff values were different among the four countries studied (Bhutan, 18.16 U/mL; Indonesia, 6.01 U/mL; Myanmar, 10.57 U/mL; and Bangladesh, 6.19 U/mL). Our ELISA had better sensitivity, specificity, and accuracy of anti-CagA antibody detection in subjects predominantly infected with East Asian-type CagA H. pylori (Bhutan and Indonesia) than in those infected with Western-type CagA H. pylori predominant (Myanmar and Bangladesh). We found positive correlations between the anti-CagA antibody and antral monocyte infiltration in subjects from all four countries. There was no significant association between bacterial density and the anti-CagA antibody in the antrum or the corpus. The East Asian-type CagA ELISA had improved detection of the anti-CagA antibody in subjects infected with East Asian-type CagA H. pylori. The East Asian-type CagA ELISA should, therefore, be used in populations predominantly infected with East Asian-type CagA.

DOI： 10.1007/s00430-019-00634-5

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Toxoplasma gondii is a neurotropic protozoan parasite, which is linked to neurological manifestations in immunocompromised individuals as well as severe neurodevelopmental sequelae in congenital toxoplasmosis. While the complement system is the first line of host defense that plays a significant role in the prevention of parasite dissemination, Toxoplasma artfully evades complement-mediated clearance via recruiting complement regulatory proteins to their surface. On the other hand, the details of Toxoplasma and the complement system interaction in the brain parenchyma remain elusive. In this study, infection-induced changes in the mRNA levels of complement components were analyzed by quantitative PCR using a murine Toxoplasma infection model in vivo and primary glial cells in vitro. In addition to the core components C3 and C1q, anaphylatoxin C3a and C5a receptors (C3aR and C5aR1), as well as alternative complement pathway components properdin (CFP) and factor B (CFB), were significantly upregulated 2 weeks after inoculation. Two months post-infection, CFB, C3, C3aR, and C5aR1 expression remained higher than in controls, while CFP upregulation was transient. Furthermore, Toxoplasma infection induced significant increase in CFP, CFB, C3, and C5aR1 in mixed glial culture, which was abrogated when microglial activation was inhibited by pre-treatment with minocycline. This study sheds new light on the roles for the complement system in the brain parenchyma during Toxoplasma infection, which may lead to the development of novel therapeutic approaches to Toxoplasma infection-induced neurological disorders.

DOI： 10.3389/fimmu.2020.603924

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CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1096/fj.201901342R

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

African trypanosomiasis, sleeping sickness in humans or nagana in animals, is a potentially fatal neglected tropical disease and a threat to 65 million human lives and 100 million small and large livestock animals in sub-Saharan Africa. Available treatments for this devastating disease are few and have limited efficacy, prompting the search for new drug candidates. Simultaneous inhibition of the trypanosomal glycerol kinase (TGK) and trypanosomal alternative oxidase (TAO) is considered a validated strategy toward the development of new drugs. Our goal is to develop a TGK-specific inhibitor for coadministration with ascofuranone (AF), the most potent TAO inhibitor. Here, we report on the identification of novel compounds with inhibitory potency against TGK. Importantly, one of these compounds (compound 17) and its derivatives (17a and 17b) killed trypanosomes even in the absence of AF. Inhibition kinetics revealed that derivative 17b is a mixed-type and competitive inhibitor for TGK and TAO, respectively. Structural data revealed the molecular basis of this dual inhibitory action, which, in our opinion, will aid in the successful development of a promising drug to treat trypanosomiasis. Although the EC50 of compound 17b against trypanosome cells was 1.77 µM, it had no effect on cultured human cells, even at 50 µM.-Balogun, E. O., Inaoka, D. K., Shiba, T., Tsuge, C., May, B., Sato, T., Kido, Y., Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue, M., Matsuoka, S., Michels, P. A. M., Watanabe, Y.-I., Moore, A. L., Harada, S., Kita, K. Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei.

DOI： 10.1096/fj.201901342R

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jphs.2019.09.005

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Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Volume overloadによる心室機能不全モデルを用いて、ミトコンドリア活性酸素種(ROS)産生の分子メカニズムとROSの機能について検討した。VOL誘発性心室機能障害の基本的特徴を再現した動静脈瘻(AVF)マウスモデルを用いた。心臓ミトコンドリアの酵素アッセイにて、クエン酸シンターゼ-NADH-キノンレダクターゼ(complex I)の活性がAVF心臓内では維持されていた。一方、NADHオキシダーゼ超複合体の活性は顕著に障害され、ROS産生が増加していた。また、抗酸化物質のN-アセチルシステインは心室拡張と心機能障害を予防したことから、透析関連心筋症におけるROSの役割が示唆された。心保護効果はメトフォルミン(MET)処置マウスでも観察され、透析糖尿病患者の複合的心不全の管理におけるMETの有用性が示された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Concomitant heart failure is associated with poor clinical outcome in dialysis patients. The arteriovenous shunt, created as vascular access for hemodialysis, increases ventricular volume-overload, predisposing patients to developing cardiac dysfunction. The integral function of mitochondrial respiration is critically important for the heart to cope with hemodynamic overload. The involvement, however, of mitochondrial activity or reactive oxygen species (ROS) in the pathogenesis of ventricular-overload-induced heart failure has not been fully elucidated. We herein report that disorganization of mitochondrial respiration increases mitochondrial ROS production in the volume-overloaded heart, leading to ventricular dysfunction. We adopted the murine arteriovenous fistula (AVF) model, which replicates the cardinal features of volume-overload-induced ventricular dysfunction. Enzymatic assays of cardiac mitochondria revealed that the activities of citrate synthase and NADH-quinone reductase (complex Ⅰ) were preserved in the AVF heart. In contrast, the activity of NADH oxidase supercomplex was significantly compromised, resulting in elevated ROS production. Importantly, the antioxidant N-acetylcysteine prevented the development of ventricular dilatation and cardiac dysfunction, suggesting a pathogenic role for ROS in dialysis-related cardiomyopathy. A cardioprotective effect was also observed in metformin-treated mice, illuminating its potential use in the management of heart failure complicating diabetic patients on dialysis.

DOI： 10.1016/j.jphs.2019.09.005

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbabio.2019.03.008

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Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

The alternative oxidase (AOX) is a monotopic diiron carboxylate protein which catalyzes the four-electron reduction of dioxygen to water by ubiquinol. Although we have recently determined the crystal structure of Trypanosoma brucei AOX (TAO) in the presence and absence of ascofuranone (AF) derivatives (which are potent mixed type inhibitors) the mechanism by which ubiquinol and dioxygen binds to TAO remain inconclusive. In this article, ferulenol was identified as the first competitive inhibitor of AOX which has been used to probe the binding of ubiquinol. Surface plasmon resonance reveals that AF is a quasi-irreversible inhibitor of TAO whilst ferulenol binding is completely reversible. The structure of the TAO-ferulenol complex, determined at 2.7 Å, provided insights into ubiquinol binding and has also identified a potential dioxygen molecule bound in a side-on conformation to the diiron center for the first time.

DOI： 10.1016/j.bbabio.2019.03.008

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Publishing type：Research paper (scientific journal)  

DOI： 10.1073/pnas.1819254116

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Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Ascofuranone (AF) and ascochlorin (AC) are meroterpenoids produced by various filamentous fungi, including Acremonium egyptiacum (synonym: Acremonium sclerotigenum), and exhibit diverse physiological activities. In particular, AF is a promising drug candidate against African trypanosomiasis and a potential anticancer lead compound. These compounds are supposedly biosynthesized through farnesylation of orsellinic acid, but the details have not been established. In this study, we present all of the reactions and responsible genes for AF and AC biosyntheses in A. egyptiacum, identified by heterologous expression, in vitro reconstruction, and gene deletion experiments with the aid of a genome-wide differential expression analysis. Both pathways share the common precursor, ilicicolin A epoxide, which is processed by the membrane-bound terpene cyclase (TPC) AscF in AC biosynthesis. AF biosynthesis branches from the precursor by hydroxylation at C-16 by the P450 monooxygenase AscH, followed by cyclization by a membrane-bound TPC AscI. All genes required for AC biosynthesis (ascABCDEFG) and a transcriptional factor (ascR) form a functional gene cluster, whereas those involved in the late steps of AF biosynthesis (ascHIJ) are present in another distantly located cluster. AF is therefore a rare example of fungal secondary metabolites requiring multilocus biosynthetic clusters, which are likely to be controlled by the single regulator, AscR. Finally, we achieved the selective production of AF in A. egyptiacum by genetically blocking the AC biosynthetic pathway; further manipulation of the strain will lead to the cost-effective mass production required for the clinical use of AF.

DOI： 10.1073/pnas.1819254116

PubMed

Publishing type：Research paper (scientific journal)  

症例1は39歳男性で、排便後に長さ約2mの白色紐状物を排泄したため当院感染症内科外来を受診した。虫卵検査の結果より裂頭条虫症と判断し、プラジカンテルを用いて駆虫した。駆虫後、長さ約5m、最大幅約8mmで正中に1列の生殖器を有する虫体を1隻排泄した。症例2は31歳女性で、排便後に長さ約20cmと約30cmの白色紐状物を排泄した。駆虫を希望し、当院感染症内科外来を受診した。虫体の写真より裂頭条虫症と判断した。患者の駆虫希望が強く、プラジカンテルを用いて駆虫を行ったが虫体は排泄されなかった。さらに、日本海裂頭条虫卵の発生実験を行ったところ、実験第34日にごく一部の虫卵内に6本の鉤を有するコラシジウムを確認した。実験第40日頃より小蓋が開き内部が空となった虫卵を散見したが、孵化したコラシジウムは確認できなかった。

Publishing type：Research paper (scientific journal)  

症例1は39歳男性で、排便後に長さ約2mの白色紐状物を排泄したため当院感染症内科外来を受診した。虫卵検査の結果より裂頭条虫症と判断し、プラジカンテルを用いて駆虫した。駆虫後、長さ約5m、最大幅約8mmで正中に1列の生殖器を有する虫体を1隻排泄した。症例2は31歳女性で、排便後に長さ約20cmと約30cmの白色紐状物を排泄した。駆虫を希望し、当院感染症内科外来を受診した。虫体の写真より裂頭条虫症と判断した。患者の駆虫希望が強く、プラジカンテルを用いて駆虫を行ったが虫体は排泄されなかった。さらに、日本海裂頭条虫卵の発生実験を行ったところ、実験第34日にごく一部の虫卵内に6本の鉤を有するコラシジウムを確認した。実験第40日頃より小蓋が開き内部が空となった虫卵を散見したが、孵化したコラシジウムは確認できなかった。

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms19103043

PubMed

Publishing type：Research paper (scientific journal)  

Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure-activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9 were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment.

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fphar.2018.00997

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbagen.2017.07.028

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.18926/AMO/55309

PubMed

Publishing type：Research paper (scientific journal)  

新生児におけるグルコース-6-リン酸デヒドロゲナーゼ(G6PD)欠損症の調査を、ベトナム南部ホーチミン市内のTu Du病院で実施した。その結果、Kinh族85例、中国人4例および少数民族のK'Ho族1例を含む、全90例のG6PD欠損例の新生児が認められた。また、Kinh族では、32例にG6PD Viangchan、11例にKaiping、8例にCanton、7例にChinese-5、5例にUnion、4例にQuing YuanなどのG6PD変異体が検出され、17例には1311 C>TおよびIVS11 nt 93 T>Cにサイレント変異を保有する変異体も検出された。また、Kinh族の新生児女児と女児の父親には、 58 Asp>Glyのアミノ酸変異が予測されるエクソン4新規変異173 A>Gが認められ、本報ではこれをG6PD Ho Chi Minhと命名した。これら知見から、ベトナム南部Kinh族は8種類のG6PD変異体を保有し、Kinh族はG6PD変異体に関して、東南アジア、中国およびオセアニアから多くの祖先をもつことが示された。また、Kinh族集団のG6PD変異体の頻度分布を他の東南アジア集団と比較したところ、Kinh族集団分布はタイ人集団分布と極めて類似していたが、G6PD-Mahidol変異が検出されないことから、タイ人集団とは異なると考えられた。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

新生児におけるグルコース-6-リン酸デヒドロゲナーゼ(G6PD)欠損症の調査を、ベトナム南部ホーチミン市内のTu Du病院で実施した。その結果、Kinh族85例、中国人4例および少数民族のK'Ho族1例を含む、全90例のG6PD欠損例の新生児が認められた。また、Kinh族では、32例にG6PD Viangchan、11例にKaiping、8例にCanton、7例にChinese-5、5例にUnion、4例にQuing YuanなどのG6PD変異体が検出され、17例には1311 C>TおよびIVS11 nt 93 T>Cにサイレント変異を保有する変異体も検出された。また、Kinh族の新生児女児と女児の父親には、 58 Asp>Glyのアミノ酸変異が予測されるエクソン4新規変異173 A>Gが認められ、本報ではこれをG6PD Ho Chi Minhと命名した。これら知見から、ベトナム南部Kinh族は8種類のG6PD変異体を保有し、Kinh族はG6PD変異体に関して、東南アジア、中国およびオセアニアから多くの祖先をもつことが示された。また、Kinh族集団のG6PD変異体の頻度分布を他の東南アジア集団と比較したところ、Kinh族集団分布はタイ人集団分布と極めて類似していたが、G6PD-Mahidol変異が検出されないことから、タイ人集団とは異なると考えられた。

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/toxins9030101

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/ja.2016.132

PubMed

Publishing type：Research paper (scientific journal)  

血清CKが基準値上限の1.5倍以上に上昇したHIV感染者110例144件(男性141件、女性3件、20〜81歳)を対象とした。CK上昇と関連する合併症や薬剤変更、生活習慣などに関するエピソードがカルテ上に記載されていたものは116件(81%)あった。最も多かったのは運動や多忙で62件(43%)に認めた。急性HIV感染症は2件(1.4%)あった。その他の感染症は31件(22%)、胸部症状を有したものは5件(3.5%)、原因不明2件であった。CK上昇直前に精神疾患に関する記載があったものは15件(10%)あった。その他の非感染性急性疾患を合併していたものは37件(26%)あった。外傷は7件(4.9%)、薬剤変更は20件(14%)、大量飲酒・薬物乱用は4件(2.8%)、特別なエピソードの記載がなかった28件(19%)であった。転帰は、CK上昇に対して特別な介入をしないまま自然軽快したものが113件(78%)と最も多かった。調査期間終了までCK上昇が続いたものが19件(13%)あった。薬剤を変更して軽快したものは6件(4.2%)、薬剤変更以外の介入を行って軽快したものは6件(4.2%)であった。

Publishing type：Research paper (scientific journal)  

DOI： 10.3748/wjg.v23.i1.48

PubMed

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DOI： 10.1016/j.rmcr.2017.01.007

PubMed

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13099-016-0137-x

PubMed

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DOI： 10.2169/internalmedicine.55.7246

PubMed

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DOI： 10.1159/000446513

PubMed

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DOI： 10.1017/S095026881400154X

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/mmi.12831

PubMed

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DOI： 10.1016/j.mito.2014.03.002

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13099-014-0042-0

PubMed

Publishing type：Research paper (scientific journal)  

The cyanide-insensitive alternative oxidase （AOX） is a diiron carboxylate protein that catalyzes the four-electron reduction of dioxygen to water by ubiquinol. In <i>Trypanosoma brucei</i>, a parasite that causes human African sleeping sickness, AOX plays a critical role in the survival of the parasite in its bloodstream form. Since AOX is absent from mammals, this protein represents a novel and promising therapeutic target. We determined the first crystal structures of the trypanosomal alternative oxidase in the absence and presence of ascofuranone and its derivatives, which are drug candidates for African trypanosomiasis. All structures reveal that AOX is a homodimer with a non-haem diiron carboxylate active-site buried within a four-helix bundle.

DOI： 10.5940/jcrsj.55.254

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jb/mvt037

PubMed

Publishing type：Research paper (scientific journal)  

組み替えDNA技術を用いて大容量のグリセロールキナーゼ(GK)の精製タンパク質を取得する方法を確立し、最適化した。さらに、GKの酵素学的な生化学データを明らかにした。本タンパク質は25-70℃の温度範囲でpH6.8で最も活性が高く、活性化エネルギーは34.02±0.31kJ/molであった。酵素は可逆的な2種の基質(ADPとグリセロール3-リン酸(G3P))の反応を触媒し、ATPとグリセロールを産生した。ADPとG3Pに対するKm値はそれぞれ0.90と5.54mMであり、Vmax値はそれぞれ25.3と20μmol/min/mgであった。10mM MgSO4を含むpH6.8の0.1Mリン酸ナトリウム緩衝液に4℃で48時間保存すると活性の50%以上が失われた。しかし、天然のリガンドと共役因子を共存させることでGKを4週間以上、完全に安定化して保存することが可能であった。この安定化したタンパク質を用いて高解像度のトリパノソーマGKの結晶を取得した。

Publishing type：Research paper (scientific journal)  

組み替えDNA技術を用いて大容量のグリセロールキナーゼ(GK)の精製タンパク質を取得する方法を確立し、最適化した。さらに、GKの酵素学的な生化学データを明らかにした。本タンパク質は25-70℃の温度範囲でpH6.8で最も活性が高く、活性化エネルギーは34.02±0.31kJ/molであった。酵素は可逆的な2種の基質(ADPとグリセロール3-リン酸(G3P))の反応を触媒し、ATPとグリセロールを産生した。ADPとG3Pに対するKm値はそれぞれ0.90と5.54mMであり、Vmax値はそれぞれ25.3と20μmol/min/mgであった。10mM MgSO4を含むpH6.8の0.1Mリン酸ナトリウム緩衝液に4℃で48時間保存すると活性の50%以上が失われた。しかし、天然のリガンドと共役因子を共存させることでGKを4週間以上、完全に安定化して保存することが可能であった。この安定化したタンパク質を用いて高解像度のトリパノソーマGKの結晶を取得した。

Publishing type：Research paper (scientific journal)  

DOI： 10.1073/pnas.1218386110

PubMed

Publishing type：Research paper (scientific journal)  

アフリカ睡眠病の病原体であるTrypanosoma bruceiの呼吸は,シアン耐性末端酸化酵素であるTrypanosome Alternative Oxidase(TAO)に依存しており,生存に必須である.本論文では,TAOを薬剤標的としたアフリカ睡眠病の新規治療薬開発に向けて,本酵素に対する特異的阻害剤Ascofuranoneの詳細な構造活性相関研究を行い,その薬理学的活性中心を明らかにした.(著者抄録)

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jb/mvs135

PubMed

Publishing type：Research paper (scientific journal)  

アフリカ睡眠病の病原体であるTrypanosoma bruceiの呼吸は,シアン耐性末端酸化酵素であるTrypanosome Alternative Oxidase(TAO)に依存しており,生存に必須である.本論文では,TAOを薬剤標的としたアフリカ睡眠病の新規治療薬開発に向けて,本酵素に対する特異的阻害剤Ascofuranoneの詳細な構造活性相関研究を行い,その薬理学的活性中心を明らかにした.(著者抄録)

Publishing type：Research paper (scientific journal)  

Wild isolates of malaria parasites were preserved in wet ice for 2–12 days and cultivated by a candle jar method. In four isolates of <i>Plasmodium falciparum</i> collected from Myanmar and preserved for 12 days, all failed to grow. In 31 isolates preserved for 5–10 days, nine were transformed to young gametocytes, but 22 isolates grew well. From Ranong, Thailand, nine isolates preserved for 7 days were examined, and six grew well. On the other hand, all of the 59 isolates collected from eastern Indonesian islands failed to establish as culture-adapted isolates, even most of them were preserved only for 2–3 days: 10 isolates stopped to grow, and 49 isolates were transformed to sexual stages by Day 10. These results indicated that a great difference in adaptation to in vitro culture may exist between wild isolates distributed in continental Southeast Asia and in eastern Indonesia and that gametocytogenesis might be easily switched on in Indonesian isolates. In wild isolates of <i>P. vivax</i>, <i>P. malariae</i> and <i>P. ovale</i> preserved for 2–9 days, ring forms or young trophozoites survived, but adaptation to in vitro culture failed. These results indicate that wild isolates can be preserved in wet ice for 9–10 days.

DOI： 10.2149/tmh.2012-07o

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)  

マラリア寄生虫の野生分離株をwet ice内で2-12日間保存し、キャンドルジャー法で培養した。ミャンマーで収集し12日間保存したPlasmodium falciparumのうち4分離株は全て成長不能だった。5-10日間保存した31分離株の内、9は若い生殖母細胞に転換したが、22は良好に成長した。タイのRanongで収集し7日間保存した9分離株の内、6株が良好に成長した。インドネシア島東部で収集した59分離株は大部分が2-3日保存であったが、全て培養適応分離株として樹立不能であり、10分離株は成長が停止し、49分離株は10日までに有性ステージに転換した。

Publishing type：Research paper (scientific journal)  

マラリア寄生虫の野生分離株をwet ice内で2-12日間保存し、キャンドルジャー法で培養した。ミャンマーで収集し12日間保存したPlasmodium falciparumのうち4分離株は全て成長不能だった。5-10日間保存した31分離株の内、9は若い生殖母細胞に転換したが、22は良好に成長した。タイのRanongで収集し7日間保存した9分離株の内、6株が良好に成長した。インドネシア島東部で収集した59分離株は大部分が2-3日保存であったが、全て培養適応分離株として樹立不能であり、10分離株は成長が停止し、49分離株は10日までに有性ステージに転換した。

Publishing type：Research paper (scientific journal)  

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

African trypanosome species are causative agents for sleeping sickness in humans and nagana disease in cattle. <i>Trypanosoma brucei</i> can generate ATP via a reverse reaction with glycerol kinase (GK) when alternative oxidase (AOX) is inhibited; thus, GK is considered to be a crucial target for chemotherapy combined with AOX. However, the energy metabolism systems of African trypanosome species other than <i>T. brucei</i> are poorly understood. Thus, GK genes were surveyed from genome databases and cloned by PCR from <i>T. vivax</i> and <i>T. congolense</i>. Then, recombinant GK proteins (rGK) of <i>T. vivax, T. congolense</i> and <i>T. brucei</i> were expressed and purified. Kinetic analysis of these rGK proteins revealed that the <i>K</i>_m values of <i>T. congolense</i> rGK for ADP and G-3-P substrates were lower than those of <i>T. vivax </i>and <i>T. brucei</i>. The expression level of GK molecules was highest in <i>T. congolense</i> cells and lowest in <i>T. vivax</i> cells. Based on these results, effective combination dosages of ascofuranone, a specific inhibitor of AOX, and glycerol, an inhibitor of the GK reverse reaction, were determined by using <i>in vitro</i>-cultured trypanosome cells.<br>

DOI： 10.1292/jvms.10-0481

CiNii Article

Publishing type：Research paper (scientific journal)  

CiNii Article

Publishing type：Research paper (scientific journal)  

T.brucei rhodesienseおよびT.b.gambienseは治療しなければ死に至るアフリカトリパノソーマ病(HAT)または眠り病の原因として知られている。著者等は、トリパノソーマ代替オキシダーゼ(TAO)の特異的阻害剤アスコフラノンがin vtroでアフリカトリパノソーマを速やかに死滅させ、in vivo実験ではヒトに非感染性のT.b.brucei感染マウスを治癒させることを報告した。TAOはトリパノソーマ生存に必須の因子であるため、哺乳動物宿主における薬物治療の標的となる。HATを生じさせるトリパノソーマに発現しているTAOのアミノ酸配列はヒトに非感染性のT.b.bruceiのTAOと同じであった。HAT治療薬の研究において、TAOの三次元構造とTAO阻害物質に関する生化学的知見をT.brucei亜種3種に応用できた。T.b.bruceiを用いたin vitro試験から、ヒト非感染性株培養においてアスコフラノンがトリパノソーマを排除できることを確認した。

Publishing type：Research paper (scientific journal)  

東部インドネシアにおけるグルコース-6-リン酸デヒドロゲナーゼ(G6PD)欠損について現地調査を行い、G6PD変異を分子的に分析した。G6PD欠損の発生率はFlores島とPalue島の5民族が他の先住民族(Sikka)や非先住民族(Riung)より低かった。分子分析では、Sikkaの19例はG6PD変異の度数分布が前回の調査と同等であったが、Riungの8例は異なっていた。西チモール、Sumba、Sulawesi、Muna、Bangkaの島の8民族での現地調査からは全部で49例の欠損症例が検出された。このうち39例はメラネシア起源のG6PD Vanua Lava(383T>C)であった。前回の調査ではG6PD Vanua Lavaが他の東部インドネシア諸島で多数見つかった。以上の結果から、G6PD Vanua LavaはSikkaを除く東部インドネシア住民における最も一般的な変異であることが示唆された。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.parint.2010.07.006

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.18926/AMO/41322

PubMed

Publishing type：Research paper (scientific journal)  

東部インドネシアにおけるグルコース-6-リン酸デヒドロゲナーゼ(G6PD)欠損について現地調査を行い、G6PD変異を分子的に分析した。G6PD欠損の発生率はFlores島とPalue島の5民族が他の先住民族(Sikka)や非先住民族(Riung)より低かった。分子分析では、Sikkaの19例はG6PD変異の度数分布が前回の調査と同等であったが、Riungの8例は異なっていた。西チモール、Sumba、Sulawesi、Muna、Bangkaの島の8民族での現地調査からは全部で49例の欠損症例が検出された。このうち39例はメラネシア起源のG6PD Vanua Lava(383T>C)であった。前回の調査ではG6PD Vanua Lavaが他の東部インドネシア諸島で多数見つかった。以上の結果から、G6PD Vanua LavaはSikkaを除く東部インドネシア住民における最も一般的な変異であることが示唆された。

Publishing type：Research paper (scientific journal)  

T.brucei rhodesienseおよびT.b.gambienseは治療しなければ死に至るアフリカトリパノソーマ病(HAT)または眠り病の原因として知られている。著者等は、トリパノソーマ代替オキシダーゼ(TAO)の特異的阻害剤アスコフラノンがin vtroでアフリカトリパノソーマを速やかに死滅させ、in vivo実験ではヒトに非感染性のT.b.brucei感染マウスを治癒させることを報告した。TAOはトリパノソーマ生存に必須の因子であるため、哺乳動物宿主における薬物治療の標的となる。HATを生じさせるトリパノソーマに発現しているTAOのアミノ酸配列はヒトに非感染性のT.b.bruceiのTAOと同じであった。HAT治療薬の研究において、TAOの三次元構造とTAO阻害物質に関する生化学的知見をT.brucei亜種3種に応用できた。T.b.bruceiを用いたin vitro試験から、ヒト非感染性株培養においてアスコフラノンがトリパノソーマを排除できることを確認した。

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DOI： 10.1016/j.bbabio.2009.12.021

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DOI： 10.1107/S1744309109054062

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DOI： 10.1107/S1744309110000369

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DOI： 10.1371/journal.ppat.1000761

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DOI： 10.1074/jbc.M109.059980

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DOI： 10.1128/AAC.00378-07

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DOI： 10.1016/j.bbrc.2005.06.131

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DOI： 10.1111/j.1550-7408.2005.00050.x

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