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Certain point mutations within gene for ribosomal protein S12, rpsL, are known to dramatically change physiological traits of bacteria, most prominently antibiotic resistance and production of various metabolites. The rpsL mutants are usually searched among spontaneous mutants resistant to aminoglycoside antibiotics, such as streptomycin or paromomycin. The shortcomings of traditional selection are as follows: random rpsL mutants may carry undesired genome alterations; many rpsL mutations cannot be isolated because they are either not associated with increased antibiotic resistance or non-viable in the absence of intact rpsLWT gene. Introduction of mutant rpsL alleles in the rpsLWT background can be used to circumvent these obstacles. Here we take the latter approach and report the generation and properties of a set of stable rpsL merodiploids for Streptomyces albus J1074. We identified several rpsL alleles that enhance endogenous and heterologous antibiotic production by this strain and show that rpsLWTrpsLK88E merodiploid displays increased streptomycin resistance. We further tested several promising rpsL alleles in two more strains, Streptomyces cyanogenus S136 and Streptomyces ghanaensis ATCC14672. In S136, plasmid-borne rpsLK88E+P91S and rpsLK88R led to elevated landomycin production; no changes were detected for ATCC14672 merodiploids. Our data outline the prospects for and limitations to rpsL merodiploids as a tool for rapid enhancement of secondary metabolism in Streptomyces.

Although transcriptional activation of pathwayspecific positive regulatory genes and/or biosynthetic genes is primarily important for enhancing secondary metabolite production, reinforcement of substrate supply, as represented by primary metabolites, is also effective. For example, partial inhibition of fatty acid synthesis with ARC2 (an analog of triclosan) was found to enhance polyketide antibiotic production. Here, we demonstrate that this approach is effective even for industrial high-producing strains, for example enhancing salinomycin production by 40%, reaching 30.4 g/l of salinomycin in an industrial Streptomyces albus strain. We also hypothesized that a similar approach would be applicable to another important antibiotic group, nonribosomal peptide (NRP) antibiotics. We therefore attempted to partially inhibit protein synthesis by using ribosome-targeting drugs at subinhibitory concentrations (1/50∼1/2 of MICs), which may result in the preferential recruitment of intracellular amino acids to the biosynthesis of NRP antibiotics rather than to protein synthesis. Among the ribosome-targeting drugs examined, chloramphenicol at subinhibitory concentrations was most effective at enhancing the production by Streptomyces of NRP antibiotics such as actinomycin, calcium-dependent antibiotic (CDA), and piperidamycin, often resulting in an almost 2-fold increase in antibiotic production. Chloramphenicol activated biosynthetic genes at the transcriptional level and increased amino acid pool sizes 1.5- to 6-fold, enhancing the production of actinomycin and CDA. This “metabolic perturbation” approach using subinhibitory concentrations of ribosome-targeting drugs is a rational method of enhancing NRP antibiotic production, being especially effective in transcriptionally activated (e.g., rpoB mutant) strains. Because this approach does not require prior genetic information, it may be widely applicable for enhancing bacterial production of NRP antibiotics and bioactive peptides.

Streptomyces rochei 7434AN4 produces two structurally unrelated polyketide antibiotics, lankacidin and lankamycin, and carries three linear plasmids, pSLA2-L (211 kb), -M (113 kb), and -S (18 kb), whose nucleotide sequences were previously reported. The complete nucleotide sequence of the S. rochei chromosome has now been determined using the long-read PacBio RS-II sequencing together with short-read Illumina Genome Analyzer IIx sequencing and Roche 454 pyrosequencing techniques. The assembled sequence revealed an 8,364,802-bp linear chromosome with a high G + C content of 71.7% and 7,568 protein-coding ORFs. Thus, the gross genome size of S. rochei 7434AN4 was confirmed to be 8,706,406 bp including the three linear plasmids. Consistent with our previous study, a tap-tpg gene pair, which is essential for the maintenance of a linear topology of Streptomyces genomes, was not found on the chromosome. Remarkably, the S. rochei chromosome contains seven ribosomal RNA ( rrn ) operons (16S-23S-5S), although Streptomyces species generally contain six rrn operons. Based on 2ndFind and antiSMASH platforms, the S. rochei chromosome harbors at least 35 secondary metabolite biosynthetic gene clusters, including those for the 28-membered polyene macrolide pentamycin and the azoxyalkene compound KA57-A.

Streptomyces spp. are well-known producers of secondary metabolites with diverse biological activities. We screened the substances that regulate polyp-to-jellyfish transition, called strobilation, of the moon jellyfish ( Aurelia coerulea ) from the Streptomyces culture library. Among the culture extracts of the strains tested, Streptomyces albus HUT6047 inhibited the strobilation of A. coerulea . The active component in strain HUT6047 was purified. Based on structure elucidation, this component was identified as 4-methoxy-2,2′-bipyrrole-5-carbaldehyde (MBC), a possible common biosynthetic intermediate of pyrrole-containing natural products including prodigiosins and tambjamines. Synthetic MBC arrested strobilation without inducing cytotoxicity and generated abnormal tentacle-like structures in a dose-dependent manner. Synthetic MBC also exhibited a minimum activity of 6.3 µM. To our knowledge, this study provides the first example of a biological activity of MBC.

We present the first clear detection of ionized Fe-K emission and absorption components in the nearby radio galaxy Centaurus A, revealed by the high-resolution XRISM/Resolve detector. In the 6.5–6.9 keV band, XRISM reveals multiple Fe xxv and Fe xxvi emission components. One is a broad (with a width of σ = 3000 km s−1) and redshifted (+3400 km s−1) component, originating at D = 0.02 pc from the central black hole. The other two components are narrow (with a width of σ = 500 km s−1) and exhibit redshifted and blueshifted velocities (+2600 and −1500 km s−1), originating from more distant regions (D = 0.1 pc). The photoionized model explains the broader component, while the two narrower components can be explained by either photoionization or collisional ionization. One interpretation is that the broader component is an outflow at ∼102RS (Schwarzschild radius) and the narrow component is a shock-heated plasma close to the torus, with a possible connection to the JWST-discovered outflow outside the torus. Two blueshifted absorption lines are detected at ∼7.1 keV (∼104 km s−1) and ∼10.6 keV (∼105 km s−1). The line significance of the 10.6 keV line is above 98%. The absorption line components might be attributed to the broad emission component. These results demonstrate the high potential of XRISM/Resolve to characterize ionized emission and absorption features in the Fe-K band. Our findings establish a new benchmark in the study of circumnuclear environments in low-luminosity radio galaxies, thereby contributing to a broader understanding of active galactic nuclei unification.

We report results from the simultaneous XRISM (183 ks) and NuSTAR (62 ks) observations of the Seyfert 2 galaxy NGC 4388. This active galactic nucleus has the brightest Fe Kα line among Compton-thin, obscured sources. To model the reflection continuum and fluorescent lines, we employ an updated version of XCLUMPY and a broad-line region (BLR) model with a disk-like geometry. The profile of the neutral Fe K fluorescent line is well described as the sum of three components convolved with Gaussians with FWHM values of ∼290 km s−1, ∼1470 km s−1, and ∼11,100 km s−1. These line widths correspond to radii of 1.5 pc, 0.060 pc, and 1.0 × 10−3 pc by assuming Keplerian motion, which we interpret as the dusty torus, its inner edge region, and the BLR, respectively. The data suggest that the Fe Kα BLR component is larger than that of Hα (FWHM of 4500 km s−1) in the polarized optical spectrum, implying that the velocity field of the BLR is dominated by that parallel to the equatorial plane. In addition, Fe XXVI Lyα and Fe XXV absorption lines are detected, characterized by logξ∼3.50ergcms−1 , logNH∼22.1cm−2 , vout ∼ 40 km s−1, and σv ∼ 160 km s−1. We infer that the absorber is gravitationally bound and is possibly associated with a failed wind, consistent with a radiation-driven fountain flow.

We are developing the Gamma-Ray Astro-Imager with Nuclear Emulsion project, designed for 10 MeV–100 GeV cosmic γ-ray observations with a high angular resolution (5′/0.°08 at 1–2 GeV) and a polarization-sensitive large-aperture (∼10 m2) emulsion telescope for repeated long-duration balloon flights. In 2018, a balloon-borne experiment was carried out in Australia with a 0.38 m2 sensitive area and a flight duration of 17.4 hr, including 6.7 hr of Vela observations. Significant improvements compared with the 2015 balloon-borne experiment were achieved by a factor of 5, including both an increase in effective area × time and a reduction in the background contribution. We aimed to demonstrate the telescope’s overall performance based on detection and imaging of a known γ-ray source, the Vela pulsar. A robust detection of the Vela pulsar was achieved with a 68% containment radius of 0.°42, at a significance of 6σ, at energies above 80 MeV. The resulting angular profile is consistent with that of a pointlike source. We achieved the current best imaging performance of the Vela pulsar using an emulsion γ-ray telescope with the highest angular resolution of any γ-ray telescope to date.

Background Inappropriate dosing of direct oral anticoagulants (DOACs) has been associated with clinical safety and efficacy; however, little is known about clinical data associated with an inappropriate DOAC dosing in Japan. In addition, there is no report in which the appropriateness of DOAC dosing between prescription for inpatients and for outpatients was examined. In this study, we aimed to investigate the prevalence and factors associated in the inappropriate dosing of DOACs in patients with atrial fibrillation (AF). Methods The retrospective cohort study was conducted at a single Japanese university hospital. Both inpatients and outpatients, who were diagnosed with AF and for whom treatment with either dabigatran, rivaroxaban, apixaban, or edoxaban was initiated between April 1, 2014 and March 31, 2018, were enrolled in the study. Appropriateness of DOAC dosing was assessed according to the manufacturer’s labeling recommendations (dose reduction criteria) of each DOAC. Inappropriate reduced dose, namely, underdosing, was defined as prescription of a reduced dose of DOAC despite the patient not meeting the dose reduction criteria. Inappropriate standard dose, namely, overdosing, was defined as prescription of a standard dose of DOAC despite the patient meeting the dose reduction criteria. Inappropriate DOAC dosing was defined as a deviation of the recommended dose (both underdosing and overdosing). Results A total of 316 patients (dabigatran, 28; rivaroxaban, 107; apixaban, 116; and edoxaban, 65) were included, with a median (interquartile range) age of 75 (66–81) years and 62.3% male. DOACs were prescribed at an appropriate standard dose in 39.2% of patients, an appropriate reduced dose in 36.7%, an inappropriate standard dose in 2.5%, and an inappropriate reduced dose in 19.3%. Multivariate analysis revealed that the inappropriate dosing of DOACs was significantly associated with prescriptions for outpatients (vs. inpatients; odds ratio [OR] 2.87, 95% confidence interval [CI] 1.53–5.62, p  < 0.001) and those with higher HAS-BLED scores (OR 1.87, 95% CI 1.42–2.51, p < 0.001). Conclusions Our results demonstrated that the inappropriate dosing of DOACs occurred in approximately 20% of AF patients, and was more frequent in outpatients (vs. inpatients) and in those with a higher risk of bleeding. It is recommended that pharmacists play a greater role in assisting in the prescription process to help physicians make better decisions.

Leaf spot caused by Corynespora cassiicola was observed on plants of Assam indigo (Strobilanthes flaccidifolius) in Higashi village in Okinawa Prefecture, Japan, in October 2019. The fungus isolated from diseased leaves was identified based on morphological characteristics and molecular analysis of the rDNA-ITS region. Inoculation tests using the isolated fungus confirmed Corynespora cassiicola as the causative agent of the disease. To the best of our knowledge, this is the first report of leaf spot disease in Assam indigo caused by C. cassiicola in Japan. Leaf spot, “hanten-byo” in Japanese, is the proposed name of the disease.

Disulfiram is an FDA approved drug for the treatment of alcoholism. The drug acts by inhibiting aldehyde dehydrogenase, an enzyme essential to alcohol metabolism. However, a recent study has demonstrated that disulfiram also potently inhibits the cytoplasmic protein FROUNT, a common regulator of chemokine receptor CCR2 and CCR5 signaling. Several studies have reported that chemokine receptors are associated with the regulation of emotional behaviors in rodents, such as anxiety. Therefore, this study was performed to clarify the effect of disulfiram on emotional behavior in rodents. The anxiolytic-like effects of disulfiram were investigated using an elevated plus-maze (EPM) test, a typical screening model for anxiolytics. Disulfiram (40 or 80 mg/kg) significantly increased the amount of time spent in the open arms of the maze and the number of open arm entries without affecting the total open arms entries. Similar results were obtained in mice treated with a selective FROUNT inhibitor, disulfiram-41 (10 mg/kg). These disulfiram-associated behavioral changes were similar to those observed following treatment with the benzodiazepine anxiolytic diazepam (1.5 mg/kg). Moreover, disulfiram (40 mg/kg) significantly and completely attenuated increased extracellular glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) during stress exposure on the elevated open-platform. However, no effect in the EPM test was seen following administration of the selective aldehyde dehydrogenase inhibitor cyanamide (40 mg/kg). In contrast to diazepam, disulfiram caused no sedation effects in the open-field, coordination disorder on a rotarod, or amnesia in a Y-maze. This is the first report suggesting that disulfiram produces anxiolytic-like effects in rodents. We found that the presynaptic inhibitory effects on glutaminergic neurons in the PL-PFC may be involved in its underlying mechanism. Disulfiram could therefore be an effective and novel anxiolytic drug that does not produce benzodiazepine-related adverse effects, such as amnesia, coordination disorder, or sedation, as found with diazepam. We propose that the inhibitory activity of disulfiram against FROUNT function provides an effective therapeutic option in anxiety.