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Symbiotic nitrogen fixation is a highly coordinated process involving legume plants and nitrogen-fixing bacteria known as rhizobia. In this study, we investigated a novel Fix - mutant of the model legume Lotus japonicus that develops root nodules with endosymbiotic rhizobia but fails in nitrogen fixation. Map-based cloning identified the causal gene encoding the filamentation temperature-sensitive H (FtsH) protein, designated as LjFtsH4. The LjFtsH4 gene was expressed in all plant organs without increased levels during nodulation. Subcellular localization revealed that LjFtsH4, fused with a fluorescent protein, localized in mitochondria. The Ljftsh4 mutant nodules showed signs of premature senescence, including symbiosome membrane collapse and bacteroid disintegration. Additionally, nodule cells of Ljftsh4 mutant displayed mitochondria with indistinct crista structures. Grafting and complementation tests confirmed that the Fix - phenotype was determined by the root genotype, and that protease activity of LjFtsH4 was essential for nodule nitrogen fixation. Furthermore, the ATP content in Ljftsh4 mutant roots and nodules was lower than in the wild-type, suggesting reduced mitochondrial function. These findings underscore the critical role of LjFtsH4 in effective symbiotic nitrogen fixation in root nodules., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Case 1: A 68-year-old woman was diagnosed with advanced HER2-positive breast cancer(T2N2aM0, cStage ⅢA). She was treated with 4 courses of preoperative chemotherapy with pertuzumab, trastuzumab, and docetaxel. She was diagnosed to have achieved partial remission(PR), and subsequently underwent a mastectomy and axillary dissection. Pathological examination revealed smaller than 1 mm(Grade 2b). Case 2: A 59-year-old woman was diagnosed with advanced HER2-positive breast cancer(T4bN1M0, cStage ⅢB). She was treated with 4 courses of preoperative chemotherapy with pertuzumab, trastuzumab, and docetaxel. She was diagnosed to have achieved PR(primary lesion: complete remission), and subsequently underwent a mastectomy and axillary dissection. Pathological examination revealed complete pathological response(Grade 3). Combination therapy with pertuzumab, trastuzumab, and docetaxel appears to be a useful preoperative chemotherapy regimen for locally advanced HER2-positive breast cancer.

Leguminous plants establish endosymbiotic associations with rhizobia and form root nodules in which the rhizobia fix atmospheric nitrogen. The host plant and intracellular rhizobia strictly control this symbiotic nitrogen fixation. We recently reported a Lotus japonicus Fix - mutant, apn1 ( aspartic peptidase nodule-induced 1 ), that impairs symbiotic nitrogen fixation. APN1 encodes a nodule-specific aspartic peptidase involved in the Fix - phenotype in a rhizobial strain-specific manner. This host-strain specificity implies that some molecular interactions between host plant APN1 and rhizobial factors are required, although the biological function of APN1 in nodules and the mechanisms governing the interactions are unknown. To clarify how rhizobial factors are involved in strain-specific nitrogen fixation, we explored transposon mutants of Mesorhizobium loti strain TONO, which normally form Fix - nodules on apn1 roots, and identified TONO mutants that formed Fix + nodules on apn1 The identified causal gene encodes an autotransporter, part of a protein secretion system of Gram-negative bacteria. Expression of the autotransporter gene in M. loti strain MAFF3030399, which normally forms Fix + nodules on apn1 roots, resulted in Fix - nodules. The autotransporter of TONO functions to secrete a part of its own protein (a passenger domain) into extracellular spaces, and the recombinant APN1 protein cleaved the passenger protein in vitro. The M. loti autotransporter showed the activity to induce the genes involved in nodule senescence in a dose-dependent manner. Therefore, we conclude that the nodule-specific aspartic peptidase, APN1, suppresses negative effects of the rhizobial autotransporter in order to maintain effective symbiotic nitrogen fixation in root nodules., Competing Interests: The authors declare no competing interest.

To develop biofertilizers for rice in Afghanistan, 98 plant growth-promoting rhizobacteria were isolated from rice plants and their morphological and physiological characteristics, such as indole-3-acetic acid production, acetylene reduction, phosphate and potassium solubilization, and siderophore production, were evaluated. The genetic diversity of these bacteria was also analyzed based on 16S rRNA gene sequences. Of 98 bacteria, 89.7% produced IAA, 54.0% exhibited nitrogenase activity, and 40% showed phosphate solubilization and siderophore production. Some isolates assigned to Pseudomonas (brassicacearum, chengduensis, plecoglossicida, resinovorans, and straminea) formed a relationship with rice, and P. resinovorans and P. straminea showed nitrogen fixation. Rhizobium borbori and R. rosettiformans showed a relationship with rice plants and nitrogen fixation. Among the isolates examined, AF134 and AF137 belonging to Enterobacter ludwigii and P. putida produced large amounts of IAA (92.3 μg mL -1 ) and exhibited high nitrogenase activity (647.4 nmol C 2 H 4 h -1 ), respectively. In the plant growth test, more than 70% of the inoculated isolates showed significantly increased root and shoot dry weights. Highly diverse bacterial isolates showing promising rice growth-promoting traits were obtained from Afghanistan alkaline soils.

Pancreatic cancer in young adults is very rare. We report a case of young-onset poorly differentiated pancreatic ductal adenocarcinoma with rapid progression and poor prognosis in a 31-year-old Japanese man with no obvious family history of malignancy. Preoperative examinations revealed a mass lesion in the body of the pancreas, accompanied by a slightly dilated main pancreatic duct distal to the mass lesion. Pancreatic cancer with acute pancreatitis was suspected because of an elevation of serum pancreatic enzyme and tumor marker, along with imaging findings. Distal pancreatectomy with resection of the common hepatic artery and splenectomy along with lymph node dissection was performed. Microscopically, the tumor was mainly composed of poorly differentiated ductal adenocarcinoma. The postoperative course was uneventful, but the patient had multiple liver metastases 2 months postoperatively, in spite of adjuvant chemotherapy, and died 8 months postoperatively. This case may represent a rare instance of young-onset poorly differentiated ductal adenocarcinoma with rapid progression and may indicate potential risk factors of pancreatic cancer in young adults.

Background: Adiponectin (ADPN) prevents the development/recurrence of cardiovascular events via its anti-atherogenic effects. However, few long-term studies have examined the changes in serum ADPN levels and arterial calcification seen in renal allograft recipients., Subjects and Methods: The effects of the serum ADPN level on arterial calcification were examined in 51 Japanese renal allograft recipients. Abdominal aorta calcification was evaluated on computed tomography using the aortic calcification area index (ACAI). The change in the ACAI and serum high-molecular-weight (HMW)-ADPN fractions were studied over an 8-year period. The arterial expression of ADPN, ADPN receptors (AdipoR)1 and 2, and T-cadherin (cadherin-13) were also examined by immunohistochemistry., Results: The change in the ACAI were grouped into quartiles and compared with the alterations in the serum levels of each ADPN fraction over an 8-year period. The change in the ACAI was much lower in the patients with highly elevated HMW-ADPN levels.Multiple regression analysis demonstrated that an advanced age at transplant and a history of cardiovascular complications were associated with an increased change in the ACAI, while higher HMW-ADPN concentrations were associated with improvements in the ACAI. Serum HDL-C level was also identified as a positive factor to increase serum HMW-ADPN level.In immunohistochemical examinations, ADPN was detected on CD31-positive arterial endothelial cells from renal allograft biopsy samples. ADPN co-localized with T-cadherin and AdipoR1, but only partially co-localized with AdipoR2., Conclusion: Both HMW-ADPN and HDL-C might inhibit the progression of vascular calcification by promoting ADPN binding to vascular endothelial cells via T-cadherin and AdipoR in Japanese renal allograft recipients.

Problem: If universal health coverage (UHC) is to be achieved globally, it needs sustained promotion and political awareness and support., Approach: During its presidency of the Group of Seven (G7) industrialized nations in 2016, Japan aimed to raise the issue of UHC to the top of the global health agenda., Local Setting: Japan has promoted a health agenda at all of the G7 summits since 2000 that it has hosted. Human security has been the core foundation of Japan's foreign diplomacy for several decades and, consequently, there was no apparent opposition within Japan to the inclusion of UHC on the agenda of the summit in 2016. Other G7 governments appeared keen to promote such coverage., Relevant Changes: Since the 2016 summit, UHC has remained a central agenda item for the United Nations and World Health Organization, even though the leaders of both these global organizations have changed. In 2017, Japan hosted the UHC Forum in Tokyo. The participants, who were the heads of United Nations agencies, politicians and other decision-makers from all over the world, showed their continued commitment towards UHC., Lessons Learnt: In the raising of awareness of an item on the global health agenda, high-level champions are critical. Although they may be very diverse, all relevant stakeholders need to be connected and allowed to discuss policies with each other. Having too many allies can, however, lead to policy fragmentation, especially when there is commitment from the highest echelons within each country.

Background: The M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as intrinsic antigens in primary membranous nephropathy (MN). Complement activation via the lectin pathway in intrinsic antigen-related MN is still unclear., Methods: We retrospectively enrolled 60 primary Japanese MN patients and detected activated complement pathways by staining complement proteins in glomerular deposition. According to the findings of PLA2R and THSD7A staining in glomeruli, they were classified into intrinsic antigen-related or -unrelated MN. We evaluated clinicopathological characteristics and predictors of clinical outcomes in intrinsic antigen-related MN., Results: Thirty-nine (65%) patients had PLA2R in glomerular deposits and two (3.3%) patients had THSD7A. One of them had both PLA2R and THSD7A (double positive). Forty patients were classified into the intrinsic antigen-related group. The other 20 patients were negative for both antigens (unrelated group). The prevalence and staining intensity of mannose-binding lectin (MBL) deposits were much higher in the intrinsic antigen-related group [55% versus 20%, P < 0.010, 1.0 (interquartile range 1.0-2.0) versus 1.0 (0.0-1.0), P = 0.01, respectively]. The staining intensity of MBL in glomeruli also correlated with the IgG4 staining intensity. In intrinsic antigen-related MN, MBL staining intensity was an unfavorable predictor for remission of proteinuria [hazard ratio (HR) 0.40, P < 0.01] and renal dysfunction (HR 3.81, P = 0.01) in Cox proportional hazards analysis. Moreover, the glomerular MBL-positive group showed more severe interstitial fibrosis and worse clinical outcomes., Conclusions: Intrinsic antigen-related MN was more strongly associated with complement activation by the lectin pathway, which may contribute to a less favorable clinical outcome.

In the present study, the cell viability and cluster of differentiation (CD)38 mRNA expression were evaluated in radioresistant (Res)-HL60 acute promyelocytic leukemia (APL) cells. Cell viability in Res-HL60 cells was higher compared with wild-type HL60 cells, but did not differ between high and mid/low CD38 antigen expression groups in Res-HL60 cells. A higher expression of CD38 mRNA in Res-HL60 cells was observed, particularly in the CD38 high cell subpopulation. Furthermore, the expression of CD38 mRNA was upregulated following exposure to X-irradiation. In contrast, the characteristic expression of CD45 and CCAAT/enhancer-binding protein α mRNA were not altered. These results suggest that the accumulation of CD38 protein in radioresistant APL cells, resulting from the constant expression of CD38 mRNA induced by X-irradiation, is a characteristic response of the radioresistant-surviving fraction; however, the accumulation of CD38 did not influence the extent of radioresistant behavior.

The nitrogen-fixing symbiosis of legumes and Rhizobium bacteria is established by complex interactions between the two symbiotic partners. Legume Fix - mutants form apparently normal nodules with endosymbiotic rhizobia but fail to induce rhizobial nitrogen fixation. These mutants are useful for identifying the legume genes involved in the interactions essential for symbiotic nitrogen fixation. We describe here a Fix - mutant of Lotus japonicus, apn1, which showed a very specific symbiotic phenotype. It formed ineffective nodules when inoculated with the Mesorhizobium loti strain TONO. In these nodules, infected cells disintegrated and successively became necrotic, indicating premature senescence typical of Fix - mutants. However, it formed effective nodules when inoculated with the M. loti strain MAFF303099. Among nine different M. loti strains tested, four formed ineffective nodules and five formed effective nodules on apn1 roots. The identified causal gene, ASPARTIC PEPTIDASE NODULE-INDUCED 1 (LjAPN1), encodes a nepenthesin-type aspartic peptidase. The well characterized Arabidopsis aspartic peptidase CDR1 could complement the strain-specific Fix - phenotype of apn1. LjAPN1 is a typical late nodulin; its gene expression was exclusively induced during nodule development. LjAPN1 was most abundantly expressed in the infected cells in the nodules. Our findings indicate that LjAPN1 is required for the development and persistence of functional (nitrogen-fixing) symbiosis in a rhizobial strain-dependent manner, and thus determines compatibility between M. loti and L. japonicus at the level of nitrogen fixation., (© 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.)

Background: The impact of hepatitis C virus (HCV) infections on patient long-term survival after renal transplants is unclear., Method: To clarify the long-term outcomes of Japanese renal allograft recipients with HCV infections, we studied the cases of 187 patients (118 males and 69 females; 155 living donor cases, and 32 deceased donor cases; median follow-up period: 250 months) who underwent an initial renal transplant at Kanazawa Medical University from 1974 onwards., Result: In this cohort, 35 patients (18.7%) were HCV core antigen (Ag)-positive, and 13 of them (37.1%) died (due to liver cirrhosis (4 cases), hepatocellular carcinoma (1 case), fibrosing cholestatic hepatitis due to HCV (1 case), and infections complicated with chronic hepatitis (6 cases)). However, only 14 of the 145 (9.7%) recipients died in the HCV-Ag/HCV antibody (Ab)-negative group. The Kaplan-Meier life table method indicated that the HCV-infected group exhibited significantly lower patient and death-censored allograft survival rates (log-rank test; patient survival: Chi-square: 11.2, p = 0.004; graft survival: Chi-square: 25.7, p < 0.001). The survival rate of the HCV-Ag-positive recipients decreased rapidly at 240 months after the renal transplant procedure. In addition, a Cox proportional hazards model indicated that positivity for the HCV-Ag was the most important independent risk factor for post-renal transplant survival and allograft function [survival: hazard ratio (HR) 3.93 (1.54-10.03), p = 0.004; graft function: HR 2.09 (1.14-3.81), p = 0.016]., Conclusion: HCV infection is a harmful risk factor for patient survival (especially at ≥20 years post-renal transplant) and renal allograft function in allograft recipients.

Background: Although the risk of acute rejection has been studied in renal transplanted patients, there is little data about the long-term renal survival effects of non-classical human leukocyte antigen class I (HLA-G) in Japanese patients., Method: We investigated the changes in the estimated glomerular filtration rate (eGFR) for Japanese, and factors affecting the eGFR in 141 adult Japanese subjects whose allografts had survived for at least 1 year. Clinical background data, gender, HLA matching status, the total ischemic time, ABO incompatibility, immunosuppressive therapy, and the serum soluble(s) HLA-G5 level were examined. In addition, renal biopsy specimens from 32 cases, which were obtained before, or 2-4 weeks or one year after the transplant were also evaluated for HLA-G1/5 expression using monoclonal anti-HLA-G antibodies (clone 87G or 4H84)., Results: The rates of change per year in the median eGFR (ΔeGFR) and sHLA-G5 were -1.5 ml/min/1.73 m 2 /year and 11.8 ng/ml, respectively. A positive correlation was detected between the ΔeGFR and sHLA-G5 (r = 0.188, p = 0.025). In multivariate regression analysis, sHLA-G5 and HLA-matching were significant predictors of an improvement in eGFR (beta for sHLA-G: 0.374, p = 0.009; beta for mismatching: -1.135, p = 0.045). The renal tubular epithelial cells (TEC) in 11 cases showed a perinuclear HLA-G1/5 expression after renal transplantation. The renal HLA-G1/5-positive patients displayed much better ΔeGFR (p < 0.05). In conclusion, the sHLA-G5 level and HLA matching status are independent predictors of renal allograft function, as determined by the ΔeGFR, in Japanese patients. HLA-G1/5 was also detected on TEC in the patients with favorable renal function.

Competing Interests: Compliance with ethical standards Financial sources and conflict of interest The funds used in producing the guideline were supported by a Health and Labour Science Research Grant from the Ministry of Health, Labour, and Welfare and the Japan AMED for Practical Research Project for Renal Diseases. All committee members involved in producing the Clinical Practice Guideline submitted conflict-of-interest statements based on academic society rules, which are managed by the Japanese Society of Nephrology (JSN). Opinions were sought from related academic societies, including JSN, The Japanese Society of Nephrology and pharmacotherapy, The Japanese Society of Clinical Pharmacology and Therapeutics, and The Japan Geriatrics Society to prevent the guidelines from being influenced by any conflicts of interest. Drafts were shown to the society members, and revisions were made based on their opinions (public comments).

Background and Objectives: Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects., Methods: In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II)., Results: After single oral doses, maximum plasma concentrations (C max ) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed., Conclusion: Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies., Competing Interests: Compliance with Ethical StandardsFundingThis study was funded by TAIHO Pharmaceutical Co. Ltd.Conflict of interestM Togawa, and H. Yamaya are paid employees of TAIHO Pharmaceutical Co. Ltd. Dr. Monica Rodríguez carried out PK/PD modeling, and Dr. Nagashima was the principal investigator in this study, for which they received financial compensation from TAIHO. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.EthicsAll procedures in this study were performed in accordance with the ethical standards of the institutional and/or the institutional review board, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Informed consentInformed consent was obtained from all individual participants prior to their inclusion in the study.

Background: A few studies have investigated the role of adiponectin fraction for cardiovascular disease (CVD) in RTx recipients., Subjects and Methods: We studied 57 adult subjects (39 males, 18 females; 10 cadaveric donors) with at least three years of allograft survival (median 251 months). We examined clinical backgrounds such as treated drugs, blood pressure (BP, mmHg), body mass index (BMI), and blood chemistry including cholesterol (total, LDL-C, HDL-C), glucose, glycated hemoglobin (HbA1c), and serum high and low-molecular-weight (HMW/LMW) ADPN fractions with regard to the associations of the visceral and subcutaneous fat areas on CT scan. We also analyzed the associations of CVD and post-transplant diabetes (PTDM) with ADPN fractions and the fat areas., Results: The visceral fat area was inversely correlated with serum HMW and LMW ADPN levels and HMW ADPN ratio (r = -0.400, p = 0.002 and r = -0.296, p = 0.025 and r = -0.444, p<0.001, respectively). Furthermore, the visceral fat area was positively with the LMW ADPN ratio (r = 0.467, p<0.001), but no significant correlation was noted between the subcutaneous fat area and the ADPN ratio. On multiple regression analysis, eGFR and the visceral fat area were significant reducing factors of HMW ADPN levels, and the alteration of eGFR was identified as an increasing factor of HMW ADPN levels. Patients with CVD had larger visceral fat area (p = 0.004), lower HMW ADPN ratio (p = 0.022) and higher LMW ADPN ratio (p = 0.049). In addition, the higher HMW ADPN ratio and statin treatment were identified as reducing factors of the development of CVD, but the LDL-C level was an aggravating factor. Moreover, the higher LMW ADPN ratio and the visceral fat area were aggravating factors of PTDM., Conclusion: Even in Japanese renal transplant recipients, visceral fat area and ADPN fractions were significant factors for the development of both CVD and PTDM., Competing Interests: The authors have declared that no competing interests exist.

Previous transcriptome analyses have suggested that a gene cluster including a transcriptional regulator (blr7984) of the tetracycline repressor family was markedly down-regulated in symbiosis. Since blr7984 is annotated to be the transcriptional repressor, we hypothesized that it is involved in the repression of genes in the genomic cluster including blr7984 in symbiotic bacteroids. In order to examine the function and involvement of the blr7984 gene in differentiation into bacteroids, we compared the free-living growth/symbiotic phenotype and gene expression between a blr7984-knockout mutant and the wild-type strain of Bradyrhizobium diazoefficiens USDA110. The mutant transiently increased the cell growth rate under free-living conditions and nodule numbers over those with the wild-type strain USDA110. The expression of three genes adjacent to the disrupted blr7984 gene was strongly up-regulated in the mutant in free-living and symbiotic cells. The mutant also induced the expression of genes for glutathione S-transferase, cytochrome c oxidases, ABC transporters, PTS sugar transport systems, and flagella synthesis under free-living conditions. bll7983 encoding glutathione S-transferase was up-regulated the most by the blr7984 disruption. Since redox regulation by glutathione is known to be involved in cell division in prokaryotes and eukaryotes, the strong expression of glutathione S-transferase encoded by the bll7983 gene may have caused redox changes in mutant cells, which resulted in higher rates of cell division.

The screening of mini-core collection of azuki bean accessions (Vigna angularis (Willd.) Ohwi & Ohashi) for comparative uptake of (137)Cs in their edible portions was done in field trials on land contaminated by the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. Ninety seven azuki bean accessions including their wild relatives from a Japanese gene bank, were grown in a field in the Fukushima prefecture, which is located approximately 51 km north of FDNPP. The contamination level of the soil was 3665 ± 480 Bq kg(-1) dry weight ((137)Cs, average ± SD). The soil type comprised clay loam, where the sand: silt: clay proportion was 42:21:37. There was a significant varietal difference in the biomass production, radiocaesium accumulation and transfer factor (TF) of radiocaesium from the soil to edible portion. Under identical agricultural practice, the extent of (137)Cs accumulation by seeds differed between the accessions by as much as 10-fold. Inter-varietal variation was expressed at the ratio of the maximum to minimum observed (137)Cs transfer factor for seeds ranged from 0.092 to 0.009. The total biomass, time to flowering and maturity, and seed yield had negative relationship to (137)Cs activity concentration in seeds. The results suggest that certain variety/varieties of azuki bean which accumulated less (137)Cs in edible portion with preferable agronomic traits are suitable to reduce the (137)Cs accumulation in food chain on contaminated land., (Copyright © 2016 Elsevier Ltd. All rights reserved.)