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Tricholoma matsutake is an ectomycorrhizal agaricomycete that produces matsutake mushrooms in association with conifers. Here, we isolated a pleiotropic mutant, designated as G1, following 7-ray irradiation of T. matsutake NBRC 33136. In addition to exhibiting increased cellulose- and amylose-degrading activities and altered mycelial morphology, G1 degenerated lateral roots and caused stunting or fatal wilting of seedlings of its symbiotic partner, Pinus densiflora, in vitro. A mutant, designated Ar 59, previously isolated after argon-ion beam irradiation, exhibited the same phenotypes as G1, but without its detrimental effects. Ar 59, like NBRC 33136, developed a Hartig net around healthy cortical cells that was composed of uniseriate hyphae. In G1-inoculated seedlings, the Hartig net was composed of heavily bundled hyphae penetrating the intercellular space, and it was accompanied by somewhat unusual forms of plant cortical cells. Sequences of rRNA gene-related markers, including four single nucleotide polymorphisms present within each strain, were 100% identical among NBRC 33136, G1, and Ar 59, indicating that they are mutants of the wild-type. Thus, 7-ray irradiation can convert the fungus from a beneficial to a harmful agent. These findings suggest the presence of an unknown mechanism in the fungal genome that can transform mutualism into parasitism. Key words: degrading enzymes, 7-ray irradiation mutagenesis, heavy-ion beam, phenotypic transformation, plant-microbe interactions. Tricholoma matsutake est un agaromycète ectomycorhize qui produit les champignons matsutake en association avec les conifères. Les auteurs ont isolé ici un mutant pléiotropique qu'ils ont désigné G1, à la suite d'une irradiation [gamma] de T. matsutake NBRC 33136. En plus de présenter une activité accrue de dégradation de la cellulose et de l'amylose et une morphologie mycéliale modifiée, G1 provoquait la dégénérescence des racines latérales et un retard de croissance ou une flétrissure fatale des jeunes plants de son partenaire symbiotique, Pinus densiflora, in vitro. Un mutant désigné Ar 59, isolé précédemment après une irradiation à un faisceau d'argon ionisé, présentait le même phénotype que G1, mais sans les effets néfastes. Ar 59, comme NBRC 33136, développait un réseau de Hartig autour des cellules corticales saines, composé d'hyphes unisériées. Chez les plantules inoculées avec G1, le réseau de Hartig était composé d'hyphes en faisceau pénétrant l'espace intercellulaire et était accompagné par des cellules corticales végétales de formes quelque peu inhabituelles. Les séquences de marqueurs reliés aux gènes de l'ARNr, y compris quatre polymorphismes de nucléotides uniques présents dans chaque souche, étaient 100% identiques entre NBRC 33136, G1 et Ar 59, indiquant qu'ils constituent des mutants de la souche sauvage. Ainsi, l'irradiation gamme peut convertir le champignon d'une forme bénéfique en un agent pathogène. Ces données suggèrent la présence d'un mécanisme inconnu dans le génome fongique qui peut transformer le mutualisme en parasitisme. [Traduit par la Rédaction] Mots-clés : enzymes de dégradation, mutagenèse par irradiation gamma, faisceau d'ions lourds, transformation phénotypique, interactions plante-microbe., Introduction Ectomycorrhizal symbiosis occurs belowground between woody plants, belonging mostly to Caesalpinioideae, Dipterocarpaceae, Fagaceae, and Pinaceae, and filamentous fungi, belonging mostly to Ascomycota and Basidiomycota, greatly contributing to healthy forest [...]

Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin -A, a molecule that normally transduces TGF-[beta] signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high -throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs). Two different HO mouse models, an FOP model mouse expressing FOP-ACVR1 and an FOP-iPSC-based HO model mouse, revealed critical roles for mTOR signaling in vivo. Moreover, we identified ENPP2, an enzyme that generates lysophosphatidic acid, as a linker of FOP-ACVR1 and mTOR signaling in chondrogenesis. These results uncovered the crucial role of the Activin-A/FOP-ACVR1/ ENPP2/mTOR axis in FOP pathogenesis., Introduction Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation in soft tissue, where bone normally does not exist. Ectopic bones are formed through endochondral [...]

For pluripotent stem cell (PSC)-based regenerative therapy against diabetes, the differentiation efficiency to pancreatic lineage cells needs to be improved based on the mechanistic understanding of pancreatic differentiation. Here, we aimed to elucidate the molecular mechanisms underlying pancreatic endoderm differentiation by searching for factors that regulate a crucial pancreatic endoderm marker gene, NKX6.1. Unbiasedly screening an siRNA knockdown library, we identified a candidate transcription factor, HHEX. HHEX knockdown suppressed the expression of another pancreatic endoderm marker gene, PTF1A, as well as NKX6.1, independently of PDX1, a known regulator of NKX6.1 expression. In contrast, the overexpression of HHEX upregulated the expressions of NKX6.1 and PTF1A. RNA-seq analysis showed decreased expressions of several genes related to pancreatic development, such as NKX6.1, PTF1A, ONECUT1 and ONECUT3, in HHEX knockdown pancreatic endoderm. These results suggest that HHEX plays a key role in pancreatic endoderm differentiation. [ABSTRACT FROM AUTHOR]

The third-order intermodulation distortions (IM3s) of class-F and inverse class-F heterojunction bipolar transistor amplifiers were compared experimentally. It was revealed that the IM3 of inverse class F is lower than that of class F at high input power ([P.sub.in]), although the better class for IM3 at low [P.sub.in] changes from class F to inverse class F according to the increase of the quiescent current ([I.sub.q]). The different IM3 behaviors are mainly caused by the different gain variations in both amplifiers. At a low [P.sub.in], the gain of class F is larger than that of inverse class F. The larger gain in class F causes a gradual gain decrease and a steep gain rise at high and low [I.sub.q], respectively. On the other hand, the gain of inverse class F is larger than that of class F at a high [P.sub.in]. The larger gain in inverse class F causes a gradual gain decrease at all [I.sub.q] values. These gradual gain decreases are one of main causes of a lower IM3. These phenomena can be explained by the output current ([I.sub.out]) and voltage ([V.sub.out]) waveforms, which differ according to the harmonic loads. The [I.sub.out] and [V.sub.out] positive half-sinusoidal waveforms, which consist of in-phase second harmonics, are effective for large-gain operations. The positive half-sinusoidal [I.sub.out] waveform of the class-F amplifier prevents a gain decrease at a low [P.sub.in] and high [I.sub.q], and the similar [V.sub.out] waveform in inverse class F prevents a gain decrease at a high [P.sub.in]. Index Terms--Code division multiple access (CDMA), hetero-junction bipolar transistor (HBT), intermodulation distortion, power amplifiers.

Human pathogenic RNA viruses are threats to public health because they are prone to escaping the human immune system through mutations of genomic RNA, thereby causing local outbreaks and global pandemics of emerging or re‐emerging viral diseases. While specific therapeutics and vaccines are being developed, a broad‐spectrum therapeutic agent for RNA viruses would be beneficial for targeting newly emerging and mutated RNA viruses. In this study, we conducted a screen of repurposed drugs using Sendai virus (an RNA virus of the family Paramyxoviridae), with human‐induced pluripotent stem cells (iPSCs) to explore existing drugs that may present anti‐RNA viral activity. Selected hit compounds were evaluated for their efficacy against two important human pathogens: Ebola virus (EBOV) using Huh7 cells and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) using Vero E6 cells. Selective estrogen receptor modulators (SERMs), including raloxifene, exhibited antiviral activities against EBOV and SARS‐CoV‐2. Pioglitazone, a PPARγ agonist, also exhibited antiviral activities against SARS‐CoV‐2, and both raloxifene and pioglitazone presented a synergistic antiviral effect. Finally, we demonstrated that SERMs blocked entry steps of SARS‐CoV‐2 into host cells. These findings suggest that the identified FDA‐approved drugs can modulate host cell susceptibility against RNA viruses. [ABSTRACT FROM AUTHOR]

Curative therapeutic options for a number of immunological disorders remain to be established, and approaches for identifying drug candidates are relatively limited. Furthermore, phenotypic screening methods using induced pluripotent stem cell (iPSC)-derived immune cells or hematopoietic cells need improvement. In the present study, using immortalized monocytic cell lines derived from iPSCs, we developed a high-throughput screening (HTS) system to detect compounds that inhibit IL-1β secretion and NLRP3 inflammasome activation from activated macrophages. The iPSCs were generated from a patient with neonatal onset multisystem inflammatory disease (NOMID) as a model of a constitutively activated NLRP3 inflammasome. HTS of 4,825 compounds including FDA-approved drugs and compounds with known bioactivity identified 7 compounds as predominantly IL-1β inhibitors. Since these compounds are known inflammasome inhibitors or derivatives of, these results prove the validity of our HTS system, which can be a versatile platform for identifying drug candidates for immunological disorders associated with monocytic lineage cells. [ABSTRACT FROM AUTHOR]