Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries.

The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRß). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRß has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.

Selective Modulation of the Human Glucocorticoid Receptor Compromises GR Chromatin Occupancy and Recruitment of p300/CBP and the Mediator Complex.

Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts for the treatment of solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the differential transcriptional activity of GR following treatment with the selective GR agonist and modulator dagrocorat compared to classic (ant)agonists, we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that dagrocorat and the antagonist RU486 both reduced GR interaction with CREB-binding protein/p300 and the mediator complex compared to the full GR agonist dexamethasone. Chromatin immunoprecipitation assays revealed that these changes in GR interactome were accompanied by reduced GR chromatin occupancy with dagrocorat and RU486. Our data offer new insights into the role of differential coregulator recruitment in shaping ligand-specific GR-mediated transcriptional responses.

The taste of vitamin C in Drosophila.

Vitamins are essential micronutrients, but the mechanisms of vitamin chemoreception in animals are poorly understood. Here, we provide evidence that vitamin C doubles starvation resistance and induces egg laying in Drosophila melanogaster. Our behavioral analyses of genetically engineered and anatomically ablated flies show that fruit flies sense vitamin C via sweet-sensing gustatory receptor neurons (GRNs) in the labellum. Using a behavioral screen and in vivo electrophysiological analyses of ionotropic receptors (IRs) and sweet-sensing gustatory receptors (GRs), we find that two broadly tuned IRs (i.e., IR25a and IR76b) and five GRs (i.e., GR5a, GR61a, GR64b, GR64c, and GR64e) are essential for vitamin C detection. Thus, vitamin C is directly detected by the fly labellum and requires at least two distinct receptor types. Next, we expand our electrophysiological study to test attractive tastants such as sugars, carboxylic acids, and glycerol. Our analysis elucidates the molecular basis of chemoreception in sweet-sensing GRNs.

The Prl3d1-Cre mouse line selectively induces the expression of Cre recombinase in parietal trophoblast giant cells.

The placenta plays a pivotal role in the maintenance of normal pregnancy, but how it forms, matures, and performs its function remains poorly understood. Here, we describe a novel mouse line (Prl3d1-iCre) that expresses iCre recombinase under the control of the endogenous prl3d1 promoter. Prl3d1 has been proposed as a marker for distinguishing trophoblast giant cells (TGCs) from other trophoblast cells in the placenta. The in vivo efficiency and specificity of the Cre line were analyzed by interbreeding Prl3d1-iCre mice with B6-G/R reporter mice. Through anatomical studies of the placenta and other tissues of Prl3d1-iCre/+; B6-G/R mouse mice, we found that the tdTomato signal was expressed in parietal trophoblast giant cells (P-TGCs). Thus, we report a mouse line with ectopic Cre expression in P-TGCs, which provides a valuable tool for studying human pathological pregnancies caused by implantation failure or abnormal trophoblast secretion due to aberrant gene regulation.

The mTORC2/AKT/VCP axis is associated with quality control of the stalled translation of poly(GR) dipeptide repeats in C9-ALS/FTD.

Expansion of G4C2 hexanucleotide repeats in the chromosome 9 ORF 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (C9-ALS/FTD). Dipeptide repeats generated by unconventional translation, especially the R-containing poly(GR), have been implicated in C9-ALS/FTD pathogenesis. Mutations in other genes, including TAR DNA-binding protein 43 KD (TDP-43), fused in sarcoma (FUS), and valosin-containing protein, have also been linked to ALS/FTD, and upregulation of amyloid precursor protein (APP) is observed at the early stage of ALS and FTD. Fundamental questions remain as to the relationships between these ALS/FTD genes and whether they converge on similar cellular pathways. Here, using biochemical, cell biological, and genetic analyses in Drosophila disease models, patient-derived fibroblasts, and mammalian cell culture, we show that mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling is activated by APP, TDP-43, and FUS and that mTORC2/AKT and its downstream target valosin-containing protein mediate the effect of APP, TDP-43, and FUS on the quality control of C9-ALS/FTD-associated poly(GR) translation. We also find that poly(GR) expression results in reduction of global translation and that the coexpression of APP, TDP-43, and FUS results in further reduction of global translation, presumably through the GCN2/eIF2α-integrated stress response pathway. Together, our results implicate mTORC2/AKT signaling and GCN2/eIF2α-integrated stress response as common signaling pathways underlying ALS/FTD pathogenesis.

Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective cure. GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD. A key pathological feature of C9orf72 related ALS/FTD is the presence of abnormal dipeptide repeat proteins translated from GGGGCC repeat expansion, including poly Glycine-Arginine (GR). In this study, we observed that (GR)50 conferred significant mitochondria damage and cytotoxicity. Metformin, the most widely used clinical drug, successfully relieved (GR)50 induced mitochondrial damage and inhibited (GR)50 related cytotoxicity. Further research revealed metformin effectively restored mitochondrial function by upregulating AKT phosphorylation in (GR)50 expressed cells. Taken together, our results indicated restoring mitochondrial function with metformin may be a rational therapeutic strategy to reduce poly(GR) toxicity in C9orf72 ALS/FTD patients.

The Nonvolatile Memory and Neuromorphic Simulation of ReS2/h-BN/Graphene Floating Gate Devices Under Photoelectrical Hybrid Modulations.

The floating gate devices, as a kind of nonvolatile memory, obtain great application potential in logic-in-memory chips. The 2D materials have been greatly studied due to atomically flat surfaces, higher carrier mobility, and excellent photoelectrical response. The 2D ReS2 flake is an excellent candidate for channel materials due to thickness-independent direct bandgap and outstanding optoelectronic response. In this paper, the floating gate devices are prepared with the ReS2/h-BN/Gr heterojunction. It obtains superior nonvolatile electrical memory characteristics, including a higher memory window ratio (81.82%), tiny writing/erasing voltage (±8 V/2 ms), long retention (>1000 s), and stable endurance (>1000 times) as well as multiple memory states. Meanwhile, electrical writing and optical erasing are achieved by applying electrical and optical pulses, and multilevel storage can easily be achieved by regulating light pulse parameters. Finally, due to the ideal long-time potentiation/depression synaptic weights regulated by light pulses and electrical pulses, the convolutional neural network (CNN) constructed by ReS2/h-BN/Gr floating gate devices can achieve image recognition with an accuracy of up to 98.15% for MNIST dataset and 91.24% for Fashion-MNIST dataset. The research work adds a powerful option for 2D materials floating gate devices to apply to logic-in-memory chips and neuromorphic computing.

Fluorinated Co-Solvents Enable Excellent Performances of Practical Cells Comprising LixSiO-Graphite Composite Anodes and LiNi0.89Co0.05Mn0.05Al0.01O2 (NCMA) Cathodes.

Li-ion batteries based on high specific capacity LixSiO-Graphite anodes and LiNi0.89Co0.05 Mn0.05Al0.01O2 (NCMA) cathodes may have numerous practical applications owing to high energy density without a necessary compromise on safety. SiO, which is an attractive Li insertion anode material, offers more cycling stability than Si and a higher capacity than graphite. Therefore, a new trend has emerged for developing composite C-Si anodes, possessing the excellent cyclability of graphite coupled with high capacity SiO. The composite structure described herein prevents the volume expansion of SiO and maintains the structural integrity during prolonged cycling. However, graphite electrodes suffer from exfoliation in propylene carbonate (PC) based electrolyte solutions, which avoids well known safety benefits related to a possible use of PC based electrolyte solutions in all kinds of Li batteries. Herein, it is reported that trifluoro propylene carbonate (TFPC) is compatible with graphite anodes. New electrolyte formulations are developed and tested containing fluorinated co-solvents and compared the performance of several electrolyte solutions, including conventional alkyl carbonates-based solutions in full Li-ion cells, which included LixSiO-Graphite anodes and LiNi0.89Co0.05Mn0.05Al0.01O2 (NCMA) cathodes. Cells with new electrolyte solutions developed herein demonstrated nearly twice capacity retention in prolonged cycling experiments compared to similar reference cells containing conventional electrolyte solutions.

Strigolactone deficiency induces jasmonate, sugar and flavonoid phytoalexin accumulation enhancing rice defense against the blast fungus Pyricularia oryzae.

Strigolactones (SLs) are carotenoid-derived phytohormones that regulate plant growth and development. While root-secreted SLs are well-known to facilitate plant symbiosis with beneficial microbes, the role of SLs in plant interactions with pathogenic microbes remains largely unexplored. Using genetic and biochemical approaches, we demonstrate a negative role of SLs in rice (Oryza sativa) defense against the blast fungus Pyricularia oryzae (syn. Magnaporthe oryzae). We found that SL biosynthesis and perception mutants, and wild-type (WT) plants after chemical inhibition of SLs, were less susceptible to P. oryzae. Strigolactone deficiency also resulted in a higher accumulation of jasmonates, soluble sugars and flavonoid phytoalexins in rice leaves. Likewise, in response to P. oryzae infection, SL signaling was downregulated, while jasmonate and sugar content increased markedly. The jar1 mutant unable to synthesize jasmonoyl-l-isoleucine, and the coi1-18 RNAi line perturbed in jasmonate signaling, both accumulated lower levels of sugars. However, when WT seedlings were sprayed with glucose or sucrose, jasmonate accumulation increased, suggesting a reciprocal positive interplay between jasmonates and sugars. Finally, we showed that functional jasmonate signaling is necessary for SL deficiency to induce rice defense against P. oryzae. We conclude that a reduction in rice SL content reduces P. oryzae susceptibility by activating jasmonate and sugar signaling pathways, and flavonoid phytoalexin accumulation.

Caged Dexamethasone to Photo-control the Development of Embryos through Activation of the Glucocorticoid Receptor.

Efficient tools for controlling molecular functions with exquisite spatiotemporal resolution are much in demand to investigate biological processes in living systems. Here we report an easily synthesized caged dexamethasone for photo-activating cytoplasmic proteins fused to the glucocorticoid receptor. In the dark, it is stable in vitro as well as in vivo in both zebrafish (Danio rerio) and Xenopus sp, two significant models of vertebrates. In contrast, it liberates dexamethasone upon UV illumination, which has been harnessed to interfere with developmental steps in embryos of these animals. Interestingly, this new system is biologically orthogonal to the one for photo-activating proteins fused to the estrogen ERT receptor, which brings great prospect for activating two distinct proteins down to the single cell level.

Manipulation of a social signal affects DNA methylation of a stress-related gene in a free-living bird.

Social status directly affects the health of humans and other animals. Low status individuals receive more antagonistic encounters, have fewer supportive relationships and have worse health outcomes. However, the physiological and cellular processes that mediate the relationship between the social environment and health are incompletely known. Epigenetic regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine pathway that activates in response to stressors, may be one process that is sensitive to the social environment. Here, we experimentally manipulated plumage, a key social signal in female tree swallows (Tachycineta bicolor) and quantified methylation of four genes in the HPA axis before and after treatment. We found that dulling the white breast plumage affected methylation in one gene, CRHR1; however, the effect depended on the original brightness of the bird. Methylation in this gene was correlated with baseline corticosterone levels, suggesting that DNA methylation of CRHR1 helps regulate glucocorticoid production in this species. Methylation in two other genes, FKBP5 and GR, changed over the course of the experiment, independent of treatment. These results show that methylation of these genes is labile into adulthood and suggest that epigenetic regulation of the HPA axis could help birds respond to current environmental conditions.

Innovations in HbA1c analysis: finding the balance between speed and accuracy. An investigation of a potential new Secondary Reference Measurement Procedure for the IFCC.

OBJECTIVES: The escalating prevalence of diabetes worldwide has resulted in a dramatic increase in the number of people who need testing, which in turn necessitates faster HbA1c measurement. The Tosoh GR01 addresses the need for fast turnaround times of whilst offering pragmatic steps to maintain result accuracy in a single instrument by offering two distinct operating modes: Short Mode (SM) and Long Mode (LM). The aim of this study was to evaluate all relevant aspects of the performance of the Tosoh GR01 with a view to accepting the instrument as a future Secondary Reference Measurement Procedure (SRMP) for the IFCC. METHODS: Certified Clinical & Laboratory Standards Institute (CLSI) Evaluation Protocols (EP) were used to evaluate precision (EP-5), accuracy (EP-9), linearity (EP-6), carry-over (EP-10) and the effect of hemoglobin variants and other potential interferences. RESULTS: Both modes demonstrated CVs <0.6 % in SI units and <0.4 % in NGSP units at 46 mmol/mol (6.4 %) and 75 mmol/mol (9.0 %) and passed both National Glycohemoglobin Standardization Program (NGSP) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) certification procedures when compared with 7 IFCC Certified Secondary Reference Measurement Procedures (SRMP). Sigma for both modes was >6 when using the results of EP-5 and EP-9 at an HbA1c concentration of 50 mmol/mol (6.7 %). Neither mode showed any interference with common Hb-variants except for HbAE when HbA1c was >65 mmol/mol. In the SM HbAS, HbAD and HbAC were recognized but no result was reported. CONCLUSIONS: There is a good balance between speed and accuracy for determining HbA1c with the Tosoh GR01 in both analytical modes and the device is suitable for use as an IFCC SRMP.

IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease.

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice.

INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible. METHODS: To do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs. RESULTS: Each model set consists of a control line with a wild-type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high-impact pathogenic mutation or risk variant.

An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer's Disease.

Both the brain-derived neurotrophic factor (BDNF) and glucocorticoids (GCs) play multiple roles in various aspects of neurons, including cell survival and synaptic function. BDNF and its receptor TrkB are extensively expressed in neurons of the central nervous system (CNS), and the contribution of the BDNF/TrkB system to neuronal function is evident; thus, its downregulation has been considered to be involved in the pathogenesis of Alzheimer's disease (AD). GCs, stress-related molecules, and glucocorticoid receptors (GRs) are also considered to be associated with AD in addition to mental disorders such as depression. Importantly, a growing body of evidence suggests a close relationship between BDNF/TrkB-mediated signaling and the GCs/GR system in the CNS. Here, we introduce the current studies on the interaction between the neurotrophic system and stress in CNS neurons and discuss their involvement in the pathophysiology of AD.

Citrus Flavanone Effects on the Nrf2-Keap1/GSK3/NF-κB/NLRP3 Regulation and Corticotroph-Stress Hormone Loop in the Old Pituitary.

Oxidative stress and inflammation are significant causes of aging. At the same time, citrus flavanones, naringenin (NAR), and hesperetin (HES) are bioactives with proven antioxidant and anti-inflammatory properties. Nevertheless, there are still no data about flavanone's influence and its potential effects on the healthy aging process and improving pituitary functioning. Thus, using qPCR, immunoblot, histological techniques, and biochemical assays, our study aimed to elucidate how citrus flavanones (15 mg/kg b.m. per os) affect antioxidant defense, inflammation, and stress hormone output in the old rat model. Our results showed that HES restores the redox environment in the pituitary by down-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein while increasing kelch-like ECH-associated protein 1 (Keap1), thioredoxin reductase (TrxR1), and superoxide dismutase 2 (SOD2) protein expression. Immunofluorescent analysis confirmed Nrf2 and Keap1 down- and up-regulation, respectively. Supplementation with NAR increased Keap1, Trxr1, glutathione peroxidase (Gpx), and glutathione reductase (Gr) mRNA expression. Decreased oxidative stress aligned with NLRP3 decrement after both flavanones and glycogen synthase kinase-3 (GSK3) only after HES. The signal intensity of adrenocorticotropic hormone (ACTH) cells did not change, while corticosterone levels in serum decreased after both flavanones. HES showed higher potential than NAR in affecting a redox environment without increasing the inflammatory response, while a decrease in corticosterone level has a solid link to longevity. Our findings suggest that HES could improve and facilitate redox and inflammatory dysregulation in the rat's old pituitary.

The Role of Glutathione in Age-Related Macular Degeneration (AMD).

Age-related macular degeneration (AMD) is a chronic disease that usually develops in older people. Pathogenetic changes in this disease include anatomical and functional complexes. Harmful factors damage the retina and macula. These changes may lead to partial or total loss of vision. The disease can occur in two clinical forms: dry (the progression is slow and gentle) and exudative (wet-progression is acute and severe), which usually starts in the dry form; however, the coexistence of both forms is possible. The etiology of AMD is not fully understood, and the precise mechanisms of the development of this illness are still unknown. Extensive genetic studies have shown that AMD is a multi-factorial disease and that genetic determinants, along with external and internal environmental and metabolic-functional factors, are important risk factors. This article reviews the role of glutathione (GSH) enzymes engaged in maintaining the reduced form and polymorphism in glutathione S-transferase theta-1 (GSTT1) and glutathione S-transferase mu-1 (GSTM1) in the development of AMD. We only chose papers that confirmed the influence of the parameters on the development of AMD. Because GSH is the most important antioxidant in the eye, it is important to know the influence of the enzymes and genetic background to ensure an optimal level of glutathione concentration. Numerous studies have been conducted on how the glutathione system works till today. This paper presents the current state of knowledge about the changes in GSH, GST, GR, and GPx in AMD. GST studies clearly show increased activity in ill people, but for GPx, the results relating to activity are not so clear. Depending on the research, the results also suggest higher and lower GPx activity in patients with AMD. The analysis of polymorphisms in GST genes confirmed that mutations lead to weaker antioxidant barriers and may contribute to the development of AMD; unfortunately, a meta-analysis and some research did not confirm that connection. Unspecific results of many of the parameters that make up the glutathione system show many unknowns. It is so important to conduct further research to understand the exact mechanism of defense functions of glutathione against oxidative stress in the human eye.

Decolorization and detoxification of Brilliant Crocein GR by a newly enriched thermophilic consortium.

The environmental pollution caused by azo dyes at high temperatures has become an urgent problem. However, little attention has been paid to decolorizing azo dyes by thermophilic consortiums. In this study, a thermophilic bacterial consortium (BCGR-T) mainly composed of two genera, namely, Caldibacillus (70.90%) and Aeribacillus (17.63%) was first enriched, which can decolorize Brilliant Crocein GR (BCGR) at high temperatures (50-75 °C), pH values of 6∼8, dye concentrations (100-400 mg/L) and salinities (1-5%, w/v). The enzyme activity results showed that the azoreductase activity was nearly 8.8 times that of the control (p < 0.01), and the intracellular lignin peroxidase was also highly expressed with enzyme activity of 5.64 U (min-1 mg-1 protein) (p < 0.05), indicated that both azoreductase and intracellular lignin peroxidase played an important part in the decolorization process. Furthermore, seven new intermediate metabolic products, including aniline, phthalic acid, 2-carboxy benzaldehyde, phenylacetic acid, benzoic acid, toluene, and 4-methyl-hexanoic acid, were identified. In addition, functional genes related with the azo dye decolorization, such as those encoding the azoreductase, laccase, FMN reductase, NADPH-/NADH-quinone oxidoreductases and NADPH-/NADH dehydrogenases, catechol dioxygenase, homogentisate 1,2-dioxygenase, protocatechuate 3,4-dioxygenase, gentisate 1,2-dioxygenase, azobenzene reductase, naphthalene 1,2-dioxygenase, benzoate/toluate 1,2-dioxygenase, and anthranilate 1,2-dioxygenase and so on were found in the metagenome of the consortium BCGR-T. Finally, a new decolorization pathway of the thermophilic consortium BCGR-T was proposed. In addition, the phototoxicity of BCGR decreased after decolorization. Overall, the thermophilic consortium BCGR-T could be a promising candidate in the treatment of high concentration azo dye wastewater at high temperatures.

[On the formation of Russian pulmonology: the development of the doctrine of lung diseases (first half of the 20th century)].

The articles on the history of Russian pulmonology presented in the historical, medical and therapeutic literature contain materials for this history, but their authors did not solve the problem of its consistent presentation, highlighting the stages of formation and founders. The authors of this study critically reviewed the literary and archival primary sources, for the first time proposed the identification of three stages in the development of Russian pulmonology and indicated eight of its founders at these stages. The abundance of material did not allow us to present it in one article. This article is devoted to the 1st stage of the history of pulmonology - the formation of the doctrine of lung diseases. The second (development of pulmonology as an independent scientific direction in internal diseases) and the third (organizational design of pulmonology as a new independent clinical scientific and educational discipline and medical specialty, i.e. its institutionalization) stages will be discussed in the next articles.

Zaxinone synthase controls arbuscular mycorrhizal colonization level in rice.

The Oryza sativa (rice) carotenoid cleavage dioxygenase OsZAS was described to produce zaxinone, a plant growth-promoting apocarotenoid. A zas mutant line showed reduced arbuscular mycorrhizal (AM) colonization, but the mechanisms underlying this behavior are unknown. Here, we investigated how OsZAS and exogenous zaxinone treatment regulate mycorrhization. Micromolar exogenous supply of zaxinone rescued root growth but not the mycorrhizal defects of the zas mutant, and even reduced mycorrhization in wild-type and zas genotypes. The zas line did not display the increase in the level of strigolactones (SLs) that was observed in wild-type plants at 7 days post-inoculation with AM fungus. Moreover, exogenous treatment with the synthetic SL analog GR24 rescued the zas mutant mycorrhizal phenotype, indicating that the lower AM colonization rate of zas is caused by a deficiency in SLs at the early stages of the interaction, and indicating that during this phase OsZAS activity is required to induce SL production, possibly mediated by the Dwarf14-Like (D14L) signaling pathway. OsZAS is expressed in arbuscule-containing cells, and OsPT11prom::OsZAS transgenic lines, where OsZAS expression is driven by the OsPT11 promoter active in arbusculated cells, exhibit increased mycorrhization compared with the wild type. Overall, our results show that the genetic manipulation of OsZAS activity in planta leads to a different effect on AM symbiosis from that of exogenous zaxinone treatment, and demonstrate that OsZAS influences the extent of AM colonization, acting as a component of a regulatory network that involves SLs.