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Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases., (© 2024. The Author(s).)

A counter-propagating laser-beam platform using a spherical plasma mirror was developed for the kilojoule-class petawatt LFEX laser. The temporal and spatial overlaps of the incoming and redirected beams were measured with an optical interferometer and an x-ray pinhole camera. The plasma mirror performance was evaluated by measuring fast electrons, ions, and neutrons generated in the counter-propagating laser interaction with a Cu-doped deuterated film on both sides. The reflectivity and peak intensity were estimated as ∼50% and ∼5 × 10 18 W/cm 2 , respectively. The platform could enable studies of counter-streaming charged particles in high-energy-density plasmas for fundamental and inertial confinement fusion research.

Aims/introduction: Understanding morning-evening variation in metabolic state is critical for managing metabolic disorders. We aimed to characterize this variation from the viewpoints of insulin secretion and insulin sensitivity, including their relevance to the circadian rhythm., Materials and Methods: A total of 14 and 10 people without diabetes were enrolled, and underwent a 75-g oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp study, respectively. Participants completed the OGTT or hyperinsulinemic-euglycemic clamp at 08.00 hours and 20.00 hours in random order. Before each study, hair follicles were collected. In mice, phosphorylation levels of protein kinase B were examined in the liver and muscle by western blotting., Results: Glucose tolerance was better at 08 .00 hours, which was explained by the higher 1-h insulin secretion on OGTT and increased skeletal muscle insulin sensitivity on hyperinsulinemic-euglycemic clamp. Hepatic insulin sensitivity, estimated by the hepatic insulin resistance index on OGTT, was better at 20.00 hours. The 1-h insulin secretion and hepatic insulin resistance index correlated significantly with Per2 messenger ribonucleic acid expression. The change (evening value - morning value) in the glucose infusion rate correlated significantly with the change in non-esterified fatty acid, but not with clock gene expressions. The change in non-esterified fatty acid correlated significantly with E4bp4 messenger ribonucleic acid expression and the change in cortisol. In mice, phosphorylation of protein kinase B was decreased in the liver and increased in muscle in the beginning of the active period as, expected from the human study., Conclusions: Glucose metabolism in each tissue differed between the morning and evening, partly reflecting lipid metabolism, clock genes and cortisol levels. Deeper knowledge of these associations might be useful for ameliorating metabolic disorders., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Organizing pneumonia (OP) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a manifestation of peripheral airway/alveolar inflammation. Recently, alveolar nitric oxide concentration (Calv) has been revealed as a noninvasive marker of peripheral airway inflammation; however, whether Calv levels are associated with OP and peripheral airway in patients after allo-HSCT remains unclear. Herein, we evaluated whether Calv levels could reflect the presence of OP and structural airway changes in patients after allo-HSCT. We measured the eNO levels of 38 patients (6 with OP and 32 without OP) who underwent allo-HSCT. Three-dimensional computed tomography (CT) analysis of the airway was performed in 19 patients. We found that in patients with OP, Calv levels were significantly higher than in those without OP (10.6 vs. 5.5 ppb, p < 0.01). Receiver-operating characteristic analyses revealed a Calv cut-off value for OP detection of 10.2 ppb. No significant differences in the patient characteristics, except for the presence of OP (p < 0.01), were noted between the two groups stratified by the Calv cut-off value. Three-dimensional CT images of the airway revealed gradually increasing positive correlations between Calv levels and airway wall area of the third-, fourth-, and fifth-generation bronchi (r = 0.20, 0.31, 0.38; p = 0.42, 0.19, 0.038, respectively), indicating that Calv levels are strongly correlated with the wall thickness of the distal bronchi. Our results suggest that the Calv level may be a useful noninvasive detectable marker for OP after an allo-HSCT., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The liver is the major organ maintaining metabolic homeostasis in animals during shifts between fed and fasted states. Circadian oscillations in peripheral tissues including the liver are connected with feeding-fasting cycles. We generated transgenic mice with hepatocyte specific E4BP4, D-box negative regulator, overexpression. Liver-specific E4BP4 overexpression was also achieved by adenoviral gene transfer. Interestingly, hepatic E4BP4 overexpression induced marked insulin resistance, that was rescued by DBP, a competing D-box positive regulator, overexpression. At basal conditions hepatocyte E4BP4 transgenic mice exhibited increased gluconeogenesis with reduced AKT phosphorylation in liver. In muscle, AKT phosphorylation was impaired after insulin stimulation. Such muscle insulin resistance was associated with elevated free fatty acid flux from the liver and reduced fatty acid utilization as an energy source during the inactive phase. E4BP4, one of the clock-controlled output genes, are key metabolic regulators in liver adjusting liver and muscle metabolism and insulin sensitivity in the feeding-fasting cycles. Its tuning is critical for preventing metabolic disorders., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Our previous study demonstrated that the soluble interleukin-2 receptor (sIL-2R) index, defined as the ratio of serum sIL-2R levels at neutrophil engraftment to that before conditioning, is a biomarker that can predict acute graft-vs-host disease (GVHD) after unrelated bone marrow transplantation. In the present study, we evaluated the significance of the sIL-2R index among patients who underwent cord blood transplantation (CBT)., Methods: We retrospectively analyzed 31 patients who underwent single-unit CBT as their first transplantation for hematologic malignancies., Results: The median sIL-2R index was 4.2. The cumulative incidence of grade II to IV acute GVHD was not associated with the sIL-2R index. However, the cumulative incidence of relapse at 3 years after transplantation was significantly lower, with an sIL-2R index ≥ 3.7 than with an index < 3.7 (12.8% vs 50.0%; P = .04). As a result, the probability of overall survival at 3 years after transplantation was significantly higher in the former group than in the latter (79.8% vs 20.0%; P < .01). Only the dose of corticosteroid administered in the pre-engraftment period influenced the sIL-2 index., Conclusion: The sIL-2R index can predict the incidence of relapse and probability of survival after CBT, possibly reflecting a graft-vs-leukemia effect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are often characterized by specific somatic mutations in any of the three genes: JAK2, CALR, or MPL. A single nucleotide polymorphism (SNP), rs2736100, in the reverse transcriptase gene (TERT) and a germline JAK2 46/1 haplotype have been associated with MPNs in North American and European patients. We examined 201 Japanese MPN patients, including 52 with PV, 131 with ET, and 18 with PMF, as well as 366 control individuals for TERT rs2736100 and JAK2 rs10974944, a tagging SNP of the 46/1 haplotype. Furthermore, correlations between the JAK2 V617F allele burden at diagnosis and TERT rs2736100 or JAK2 rs10974944 were evaluated using a digital PCR assay for accurate quantitation. The JAK2 46/1 haplotype, but not the TERT rs2736100 SNP, was correlated to the JAK2 V617F mutant allele burden in JAK2 V617F-positive MPN patients. In conclusion, we demonstrated that both TERT rs2736100&#95;C and JAK2 46/1 haplotype are predisposing factors for MPNs in Japanese patients. While TERT rs2736100&#95;C tended to have a more general, non-specific effect on all MPNs, the JAK2 46/1 haplotype was essentially predisposed to the JAK2 V617F-positive MPNs.

A 30-year-old primigravid woman without a history of thrombocytopenia was referred to our hospital because of severe thrombocytopenia (<1,000 thrombocytes/µl) at 16 weeks of gestation and diagnosed with idiopathic thrombocytopenic purpura (ITP). There was no improvement in the platelet count after treatment with 0.5-1.0 mg/kg/day prednisolone, and the 400 mg/day intravenous immunoglobulin (IVIg) administered for 5 days gradually became ineffective; therefore, a laparoscopic splenectomy was performed at 25 weeks of gestation. The increase in the platelet count after the splenectomy was temporary, but the effects of IVIg therapy improved, and the patient received IVIg therapy seven times in total during her pregnancy. Her platelet count ranged between 10,000 and 70,000/µl after the splenectomy, compared with <5,000/µl before the surgery. The patient underwent an elective cesarean section at 34 weeks of gestation without any significant bleeding. The baby was diagnosed with thrombocytopenia at birth (34,000 thrombocytes/µl) and was administered only one dose of IVIg, which increased the baby's platelet count to a normal level after 14 days. The patient's platelet count also increased after delivery. Splenectomy and repeated IVIg therapy can be considered for refractory severe ITP during pregnancy.

We report an experimental demonstration of controlling plasma flow direction with a magnetic nozzle consisting of multiple coils. Four coils are controlled separately to form an asymmetric magnetic field to change the direction of laser-produced plasma flow. The ablation plasma deforms the topology of the external magnetic field, forming a magnetic cavity inside and compressing the field outside. The compressed magnetic field pushes the plasma via the Lorentz force on a diamagnetic current: j × B in a certain direction, depending on the magnetic field configuration. Plasma and magnetic field structure formations depending on the initial magnetic field were simultaneously measured with a self-emission gated optical imager and B-dot probe, respectively, and the probe measurement clearly shows the difference of plasma expansion direction between symmetric and asymmetric initial magnetic fields. The combination of two-dimensional radiation hydrodynamic and three-dimensional hybrid simulations shows the control of the deflection angle with different number of coils, forming a plasma structure similar to that observed in the experiment.

We isolated four strains of bacteria producing antifungal antibiotics from the rhizosphere of garlic with basal rot caused by the plant pathogenic fungal strain Fusarium oxysporum. Among them, Bacillus subtilis FR-2 was found to produce new antifungal antibiotics, named bacillopeptins A, B, and C. Their structures have been determined by 1D and 2D NMR and MS experiments, and amino acid analysis coupled with chiral HPLC, to be cyclic lipopeptides each containing a long-chain beta-amino acid. Another bacterial strain, Bacillus polymyxa KT-8, was shown to produce new antifungal antibiotics named fusaricidins A, B, C, and D which are more potent than bacillopeptins in their antimicrobial activity. The structures of the fusaricidins have been elucidated similarly as bacillopeptins to be cyclic hexadepsipeptides all containing 15-guanidino-3-hydroxypentadecanoic acid as a side chain. Fusaricidins strongly inhibit the growth of various kinds of fungi and moreover surprisingly show strong inhibitory activity against Gram-positive bacteria such as Staphylococcus aureus or Micrococcus luteus.

Fusaricidins B, C and D, new depsipeptide antibiotics, have been isolated as minor components from the culture broth of Bacillus polymyxa KT-8 which was obtained from the rhizosphere of garlic suffering from the basal rot caused by Fusarium oxysporum. The structure of fusaricidin B has been elucidated mainly by various NMR experiments coupled with amino acid analysis in relation to fusaricidin A, the main component of the complex, whose structure was reported previously. The fraction consisting of fusaricidins C and D was unsuccessfully separated, giving roughly a 4:1 mixture of the two, respectively. The structures of fusaricidins C and D have been determined within the mixture by detailed analyses of the 2D NMR spectra. Fusaricidins B, C and D are active against fungi and Gram-positive bacteria almost as well as fusaricidin A.

Determination of gamma-glutamyl peptides, alliin, and fructan during growth of Allium sativum L. was carried out by HPLC. The contents of gamma-glutamyl peptides and alliin in garlic bulbs remarkably increased during one month before the garlic leaves withered.

Fusaricidin A, a new depsipeptide antibiotic, was isolated from the culture broth of Bacillus polymyxa KT-8 obtained from the rhizosphere of garlic suffering from the basal rot caused by Fusarium oxysporum. The structure of fusaricidin A was determined by 1D and 2D NMR and MS experiments coupled with amino acid analysis to be a hexadepsipeptide containing 15-guanidino-3-hydroxypentadecanoic acid as a side chain. The absolute configuration of each amino acid residue was determined by chiral HPLC. Fusaricidin A is active against fungi and Gram-positive bacteria.

Bacilopeptins, new iturin-group antifungal antibiotics, were isolated from the culture broth of Bacillus subtilis FR-2 obtained from the rhizosphere of garlic suffering from the basal rot caused by Fusarium oxysporum. Their structures were elucidated to be cyclic lipopeptides similar to bacillomycin L by NMR and mass spectral studies coupled with amino acid analysis. The absolute configuration of each amino acid residue was determined by chiral HPLC.

Two different lengths of long unique synthetic oligonucleotide probes (37- and 48-mers) specific for human major histocompatibility complex (MHC) class II beta genes were synthesized. These oligonucleotides were utilized to examine factors influencing hybridization specificity. Both probe length and stringency of washing conditions were found to be crucial factors for sequence-specific hybridization.

The recent development of the amino acid microsequence technique allows us to obtain partial sequence information using an extremely small amount of protein. Two sets of mixed oligonucleotide probes were chemically synthesized using the amino acid sequence information for the heavy chain of human HLA-DR antigen obtained by the microsequence technique. These two hybridization probes were used to screen cDNA clones constructed from cytoplasmic poly(A)+ mRNA from a human B lymphoblastoid homozygous cell line (LG-2). Of the 10,000 clones screened, two clones hybridized with the probes. DNA sequence analysis showed that the longer one of the two cDNA clones was 1183 nucleotides long, including the entire coding region, the signal peptide region, and the complete 3'-noncoding region. The deduced amino acid sequence of the HLA-DR alpha chain is identical to that of other cell lines with a different HLA-DR typing. However, several nucleotide differences are found in the 3'-untranslated region compared with that of other DR haplotypes.