Alternative splicing of REGULATOR OF LEAF INCLINATION 1 modulates phosphate starvation signaling and growth in plants.

Phosphate (Pi) limitation represents a primary constraint on crop production. To better cope with Pi deficiency stress, plants have evolved multiple adaptive mechanisms for phosphorus acquisition and utilization, including the alteration of growth and the activation of Pi starvation signaling. However, how these strategies are coordinated remains largely unknown. Here, we found that the alternative splicing (AS) of REGULATOR OF LEAF INCLINATION 1 (RLI1) in rice (Oryza sativa) produces two protein isoforms: RLI1a, containing MYB DNA binding domain and RLI1b, containing both MYB and coiled-coil (CC) domains. The absence of a CC domain in RLI1a enables it to activate broader target genes than RLI1b. RLI1a, but not RLI1b, regulates both brassinolide (BL) biosynthesis and signaling by directly activating BL-biosynthesis and signaling genes. Both RLI1a and RLI1b modulate Pi starvation signaling. RLI1 and PHOSPHATE STARVATION RESPONSE 2 function redundantly to regulate Pi starvation signaling and growth in response to Pi deficiency. Furthermore, the AS of RLI1-related genes to produce two isoforms for growth and Pi signaling is widely present in both dicots and monocots. Together, these findings indicate that the AS of RLI1 is an important and functionally conserved strategy to orchestrate Pi starvation signaling and growth to help plants adapt to Pi-limitation stress.

[Research advances of prostaglandin E2 receptor 1 (EP1)].

Prostaglandin E2 (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the inhibition of inflammatory PGE2 production, non-steroidal anti-inflammatory drugs (NSAIDs) are considered as the most commonly used drugs to treat inflammatory diseases and to relieve fever and pain symptoms. PGE2 mediates its functions via four different G protein-coupled receptors, named EP1-EP4. Though the limited distribution and low PGE2 affinity of EP1, it plays important roles in the maintenance of many physiological functions and homeostasis. Moreover, EP1 is widely involved in the inflammatory response, pain perception and multisystem pathological function regulation. In this review, we will briefly summarize the recent advances on the physiological and pathophysiological function of EP1 and its targeted drugs development.

The effect of thermal treatment on the transformation and transportation of arsenic and cadmium in soil.

Thermal treatment can effectively decontaminate soils but alter their properties. Previous research mainly focused on volatile organic compounds and metals, i.e. Hg, neglecting non-volatile metal(loid)s. This study aimed to investigate Cd and As transformation during aerobic and anaerobic calcination. The results showed that both aerobic and anaerobic calcination increased soil pH by reducing soil organic matter (SOM) content, which also influenced the cation exchange capacity (CEC) and the leaching behavior of Cd and As in the soil. The total concentrations of Cd and As in the calcined soils varied depending on the calcination temperature and atmosphere. When the aerobic calcination temperature exceeded 700 °C, Cd volatilized as CdCl2, while anaerobic calcination at relatively low temperatures (600 °C) involved reductive reactions, resulting in the formation of metallic Cd with a lower boiling point. Similarly, As volatilized at 800 °C aerobically and 600 °C anaerobically. The formation of As-based minerals, particularly Ca3(AsO4)2, hindered its gasification, whereas anaerobic calcination promoted volatilization efficiency through the generation of C-As(III) based gaseous components with lower boiling points. Contrasting trends were observed in the TCLP-extractable Cd and As contents of the calcined soils. Over 70% of TCLP-extractable Cd contents were suppressed after thermal treatment, attributed to the elevated pH and reduced CEC of the soil, as well as volatilization. However, TCLP-extractable As contents increased with elevated temperatures, likely due to the desorption of AsO43- and re-adsorption of gaseous As2O3 during cooling. These findings have implications for assessing the environmental impact of thermal treatment and provide insights for remediation strategies concerning Cd and As-contaminated soils.

Insights into the Selective Transformation of Ceria Sulfation and Iron/Manganese Mineralization for Enhancing the Selective Recovery of Rare Earth Elements.

To cope with the urgent and unprecedented demands for rare earth elements (REEs) in sophisticated industries, increased attention has been paid to REE recovery from recycled streams. However, the similar geochemical behaviors of REEs and transition metals often result in poor separation performance due to nonselectivity. Here, a unique approach based on the selective transformation between ceria sulfation and iron/manganese mineralization was proposed, leading to the enhancement of the selective separation of REEs. The mechanism of the selective transformation of minerals could be ascribed to the distinct geochemical and metallurgical properties of ions, resulting in different combinations of cations and anions. According to hard-soft acid-base (HSAB) theory, the strong Lewis acid of Ce(III) was inclined to combine with the hard base of sulfates (SO42-), while the borderline acid of Fe(II)/Mn(II) prefers to interact with oxygen ions (O2-). Both in situ characterization and density functional theory (DFT) calculation further revealed that such selective transformation might trigger by the generation of an oxygen vacancy on the surface of CeO2, leading to the formation of Ce2(SO4)3 and Fe/Mn spinel. Although the electron density difference of the configurations (CeO2-x-SO4, Fe2O3-x-SO4, and MnO2-x-SO4) shared a similar direction of the electron transfer from the metals to the sulfate-based oxygen, the higher electron depletion of Ce (QCe = -1.91 e) than Fe (QFe = -1.66 e) and Mn (QMn = -1.64 e) indicated the higher stability in the Ce-O-S complex, resulting in the larger adsorption energy of CeO2-x-SO4 (-6.88 eV) compared with Fe2O3-x-SO4 (-3.10 eV) and MnO2-x-SO4 (-2.49 eV). This research provided new insights into the selective transformation of REEs and transition metals in pyrometallurgy and thus offered a new approach for the selective recovery of REEs from secondary resources.

NIGT1 represses plant growth and mitigates phosphate starvation signaling to balance the growth response tradeoff in rice.

Inorganic phosphate (Pi) availability is an important factor which affects the growth and yield of crops, thus an appropriate and effective response to Pi fluctuation is critical. However, how crops orchestrate Pi signaling and growth under Pi starvation conditions to optimize the growth defense tradeoff remains unclear. Here we show that a Pi starvation-induced transcription factor NIGT1 (NITRATE-INDUCIBLE GARP-TYPE TRANSCRIPTIONAL REPRESSOR 1) controls plant growth and prevents a hyper-response to Pi starvation by directly repressing the expression of growth-related and Pi-signaling genes to achieve a balance between growth and response under a varying Pi environment. NIGT1 directly binds to the promoters of Pi starvation signaling marker genes, like IPS1, miR827, and SPX2, under Pi-deficient conditions to mitigate the Pi-starvation responsive (PSR). It also directly represses the expression of vacuolar Pi efflux transporter genes VPE1/2 to regulate plant Pi homeostasis. We further demonstrate that NIGT1 constrains shoot growth by repressing the expression of growth-related regulatory genes, including brassinolide signal transduction master regulator BZR1, cell division regulator CYCB1;1, and DNA replication regulator PSF3. Our findings reveal the function of NIGT1 in orchestrating plant growth and Pi starvation signaling, and also provide evidence that NIGT1 acts as a safeguard to avoid hyper-response during Pi starvation stress in rice.

An SPX-RLI1 Module Regulates Leaf Inclination in Response to Phosphate Availability in Rice.

Leaf erectness is one of the key traits of plant architecture; in grains, plants with upright leaves can be planted close together, thus benefiting yield/unit area. Many factors, such as hormones, affect leaf inclination; however, how nutrition status, in particular phosphate (Pi) availability, affects leaf inclination remains largely unexplained. Here, we show that in rice (Oryza sativa), Pi deficiency stress inhibits lamina joint cell elongation, thus restricting lamina joint size and inducing leaf erectness in rice. The Pi starvation-induced proteins SPX1 (for Syg1/Pho81/XPR1) and SPX2 play a negative role in the regulation of leaf inclination. We further identified an SPX1-interacting protein, REGULATOR OF LEAF INCLINATION1 (RLI1), which positively regulates leaf inclination by affecting lamina joint cell elongation in rice. The rli1 mutants showed reduced leaf inclination and the RLI1 overexpressors showed increased leaf inclination. RLI1 directly activates the downstream genes BRASSINOSTEROID UPREGULATED1 (BU1) and BU1-LIKE 1 COMPLEX1 to control elongation of the lamina joint cells, therefore enhancing leaf inclination. We also found that Pi deficiency repressed the expression of RLI1 SPX1 protein interacts directly with RLI1, which could prevent RLI1 binding to the promoters of downstream genes. Therefore, SPX and RLI1 form a module to regulate leaf inclination in response to external Pi availability in rice.

Selective Leaching of Rare Earth Elements from Ion-Adsorption Rare Earth Tailings: A Synergy between CeO2 Reduction and Fe/Mn Stabilization.

The increasing demand for rare earth elements (REEs) motivates the development of novel strategies for cost-effective REE recovery from secondary sources, especially rare earth tailings. The biggest challenges in recovering REEs from ion-adsorption rare earth tailings are incomplete extraction of cerium (Ce) and the coleaching of iron (Fe) and manganese (Mn). Here, a synergistic process between reduction and stabilization was proposed by innovatively using elemental sulfur (S) as reductant for converting insoluble CeO2 into soluble Ce2(SO4)3 and transforming Fe and Mn oxides into inert FeFe2O4 and MnFe2O4 spinel minerals. After the calcination at 400 °C, 97.0% of Ce can be dissolved using a diluted sulfuric acid, along with only 3.67% of Fe and 23.3% of Mn leached out. Thermodynamic analysis reveals that CeO2 was indirectly reduced by the intermediates MnSO4 and FeS in the system. Density functional theory calculations indicated that Fe(II) and Mn(II) shared similar outer electron arrangements and coordination environments, favoring Mn(II) over Ce(III) as a replacement for Fe(II) in the FeO6 octahedral structure of FeFe2O4. Further investigation on the leaching process suggested that 0.5 mol L-1 H2SO4 is sufficient for the recovery of REEs (97.0%). This research provides a promising strategy to selectively recover REEs from mining tailings or secondary sources via controlling the mineral phase transformation.

[Research advances of prostaglandin E2 synthases and receptors in cardiovascular diseases].

Prostaglandin E2 (PGE2) is an important lipid mediator derived from arachidonic acid. It is widely distributed in various tissues and involved in numerous physiological and pathophysiological processes. Based on the inhibition of inflammatory PGE2 production, non-steroidal anti-inflammatory drugs (NSAIDs) are considered as the most commonly used drugs to treat pain and inflammation. However, clinical trials have revealed that NSAIDs, especially cyclooxygenase-2 (COX-2) selective inhibitors, may predispose patients to a remarkably increased cardiovascular risk, including hypertension, myocardial infarction, and heart failure. This promotes scientists to develop new drugs to not only afford pain relief but also have cardiovascular efficacy. Microsomal prostaglandin E synthase-1 (mPGES-1), the key terminal enzyme catalyzing the synthesis of inflammatory PGE2, and the four PGE2 receptors (EP1-4) have gained more attention as the promising alternative drug targets for the development of novel NSAIDs. The role of mPGES-1 and EP receptors in cardiovascular diseases also has been widely studied. In this review, we highlight the most recent advances from our and other studies on the role of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular diseases.

Inhibition of expression of glucocorticoids receptors may contribute to postpartum depression.

Although postpartum depression (PPD) is the leading cause of disability worldwide, its molecular mechanisms are poorly understood. Recent evidence has suggested that impaired glucocorticoid receptor (GR), the signaling of key molecules of the HPA axis, plays a key role in the behavioral and neuroendorcrine alterations of major depression. However, the role of GR in postpartum period, which following with the abrupt withdrawal of placental corticotropin releasing hormone (CRH) and resulting in a re-equilibration of the maternal HPA axis in the days of post-delivery, is still not entirely clear. Previously, a hormone-simulated pregnancy (HSP), and the subsequent 'postpartum' withdrawal in estrogen has been employed to mimic the fluctuations in estradiol associated with pregnancy and postpartum. Using the HSP model, we investigated here the effect of 'postpartum' withdrawal in estrogen as well as depression- and anxiety-like behavior by intra-hippocampal infusion with GR inhibitor-RU486. Following the successful acquisition of PPD model by withdrawal in estrogen, reduced GR expression was observed in hippocampus. Further, HSP-rats suffered intra-hippocampal RU486 infusion presented depression- and anxiety-like behavior as postpartum depression. Together, these results suggest an important, though complex, role for GR in the behavioral regulation of postpartum depression.

PGC-1α regulate critical period plasticity via gene × environment interaction in the developmental trajectory to schizophrenia.

Genes and environmental conditions are thought to interact in the development of postnatal brain in schizophrenia (SZ). Genome wide association studies have identified that PPARGC1A being one of the top candidate genes for SZ. We previously reported GABAergic neuron-specific PGC-1α knockout mice (Dlx5/6-Cre:PGC-1αfl/fl) presented some characteristic features of SZ. However, there is a fundamental gap of the molecular mechanism by which PGC-1α gene involved in the developmental trajectory to SZ. To explore whether PGC-1α regulates environmental factors interacting with genetic susceptibility to trigger symptom onset and disease progression, PGC-1α deficient mice were utilized to model genetic effect and an additional oxidative stress was induced by GBR injection. We confirm that PGC-1α gene deletion prolongs critical period (CP) timing, as revealed by delaying maturation of PV interneurons (PVIs), including their perineuronal nets (PNNs). Further, we confirm that gene × environment (G × E) influences CP plasticity synergistically and the interaction varies as a function of age, with the most sensitive period being at preweaning stage, and the least sensitive one at early adult age in PGC-1α deficient mice. Along this line, we find that the synergic action of G × E is available in ChABC-infusion PGC-1α KO mice, even though during the adulthood, and the neuroplasticity seems to remain open to fluctuate. Altogether, these results refine the observations made in the PGC-1α deficient mice, a potential mouse model of SZ, and illustrate how PGC-1α regulates CP plasticity via G × E interaction in the developmental trajectory to SZ.

Accumulation and fractionation of rare earth elements (REEs) in the naturally grown Phytolacca americana L. in southern China.

The widespread use of rare earth elements (REEs) has resulted in problems for soil and human health. Phytolacca americana L. is a herbaceous plant widely distributed in Dingnan county of Jiangxi province, China, which is a REE mining region (ion absorption rare earth mine) and the soil has high levels of REEs. An investigation of REE content of P. americana growing naturally in Dingnan county was conducted. REE concentrations in the roots, stems, and leaves of P. americana and in their rhizospheric soils were determined. Results showed that plant REEs concentrations varied among the sampling sites and can reach 1040 mg/kg in the leaves. Plant REEs concentrations decreased in the order of leaf > root > stem and all tissues were characterized by a light REE enrichment and a heavy REE depletion. However, P. americana exhibited preferential accumulation of light REEs during the absorption process (from soil to root) and preferential accumulation of heavy REEs during the translocation process (from stem to leaf). The ability of P. americana to accumulate high REEs in the shoot makes it a potential candidate for understanding the absorption mechanisms of REEs and for the phytoremediation of REEs contaminated soil.

Phosphate starvation induced OsPHR4 mediates Pi-signaling and homeostasis in rice.

KEY MESSAGE: OsPHR4 mediates the regulation of Pi-starvation signaling and Pi-homeostasis in a PHR1-subfamily dependent manner in rice. Phosphate (Pi) starvation response is a sophisticated process for plant in the natural environment. In this process, PHOSPHATE STARVATION RESPONSE 1 (PHR1) subfamily genes play a central role in regulating Pi-starvation signaling and Pi-homeostasis. Besides the three PHR1 orthologs in Oryza sativa L. (Os) [(Os) PHR1, (Os) PHR2, and (Os) PHR3], which were reported to regulated Pi-starvation signaling and Pi-homeostasis redundantly, a close related PHR1 ortholog [designated as (Os) PHR4] is presented in rice genome with unknown function. In this study, we found that OsPHR4 is a Pi-starvation induced gene and mainly expresses in vascular tissues through all growth and development periods. The expression of OsPHR4 is positively regulated by OsPHR1, OsPHR2 and OsPHR3. The nuclear located OsPHR4 can respectively interact with other three PHR1 subfamily members to regulate downstream Pi-starvation induced genes. Consistent with the positive role of PHR4 in regulating Pi-starvation signaling, the OsPHR4 overexpressors display higher Pi accumulation in the shoot and elevated expression of Pi-starvation induced genes under Pi-sufficient condition. Besides, moderate growth retardation and repression of the Pi-starvation signaling in the OsPHR4 RNA interfering (RNAi) transgenic lines can be observed under Pi-deficient condition. Together, we propose that OsPHR4 mediates the regulation of Pi-starvation signaling and Pi-homeostasis in a PHR1-subfamily dependent manner in rice.

Integrative Comparison of the Role of the PHOSPHATE RESPONSE1 Subfamily in Phosphate Signaling and Homeostasis in Rice.

Phosphorus (P), an essential macronutrient for all living cells, is indispensable for agricultural production. Although Arabidopsis (Arabidopsis thaliana) PHOSPHATE RESPONSE1 (PHR1) and its orthologs in other species have been shown to function in transcriptional regulation of phosphate (Pi) signaling and Pi homeostasis, an integrative comparison of PHR1-related proteins in rice (Oryza sativa) has not previously been reported. Here, we identified functional redundancy among three PHR1 orthologs in rice (OsPHR1, OsPHR2, and OsPHR3) using phylogenetic and mutation analysis. OsPHR3 in conjunction with OsPHR1 and OsPHR2 function in transcriptional activation of most Pi starvation-induced genes. Loss-of-function mutations in any one of these transcription factors (TFs) impaired root hair growth (primarily root hair elongation). However, these three TFs showed differences in DNA binding affinities and messenger RNA expression patterns in different tissues and growth stages, and transcriptomic analysis revealed differential effects on Pi starvation-induced gene expression of single mutants of the three TFs, indicating some degree of functional diversification. Overexpression of genes encoding any of these TFs resulted in partial constitutive activation of Pi starvation response and led to Pi accumulation in the shoot. Furthermore, unlike OsPHR2-overexpressing lines, which exhibited growth retardation under normal or Pi-deficient conditions, OsPHR3-overexpressing plants exhibited significant tolerance to low-Pi stress but normal growth rates under normal Pi conditions, suggesting that OsPHR3 would be useful for molecular breeding to improve Pi uptake/use efficiency under Pi-deficient conditions. We propose that OsPHR1, OsPHR2, and OsPHR3 form a network and play diverse roles in regulating Pi signaling and homeostasis in rice.

Genetic manipulation of a high-affinity PHR1 target cis-element to improve phosphorous uptake in Oryza sativa L.

Phosphorus (P) is an essential macronutrient for crop development and production. Phosphate starvation response 1 (PHR1) acts as the central regulator for Pi-signaling and Pi-homeostasis in plants by binding to the cis-element PHR1 binding sequence (P1BS; GNATATNC). However, how phosphate starvation-induced gene expression is regulated remains obscure. In this work, we investigated the DNA binding affinity of the PHR1 ortholog OsPHR2 to its downstream target genes in Oryza sativa (rice). We confirmed that a combination of P1BS and P1BS-like motifs are essential for stable binding by OsPHR2. Furthermore, we report that variations in P1BS motif bases affected the binding affinity of OsPHR2 and that the highest affinity motif was GaATATtC (designated the A-T-type P1BS). We also found that a combination of two A-T-type P1BS elements in tandem, namely HA-P1BS, was very efficient for binding of OsPHR2. Using the cis-regulator HA-P1BS, we modified the promoters of Transporter Traffic Facilitator 1 (PHF1), a key factor controlling endoplasmic reticulum-exit of phosphate transporters to the plasma membrane, for efficient uptake of phosphorous in an energetically neutral way. Transgenic plants with the modified promoters showed significantly enhanced tolerance to low phosphate stress in both solution and soil conditions, which provides a new strategy for crop improvement to enhance tolerance of nutrient deficiency.

Myeloid Cell mPGES-1 Deletion Attenuates Calcium Phosphate-induced Abdominal Aortic Aneurysm in Male Mice.

Microsomal PGE2 synthase (mPGES)-1 is the key enzyme responsible for synthesizing inflammatory prostaglandin E2 (PGE2). Our previous studies have shown that deletion mPGES-1 in myeloid cells hinders atherogenesis, suppresses vascular proliferative response to injury and enhances survival after myocardial infarction. Here we aimed to further explore the influence of myeloid cell mPGES-1 deletion in abdominal aortic aneurysm (AAA) formation. The AAA was triggered by applying 0.5 M calcium phosphate (CaPO4) to the infrarenal aorta of both myeloid mPGES-1 knockout (Mac-mPGES-1-KO) and their littermate control Mac-mPGES-1-WT mice. AAA induction was assessed by calculating the expansion of the infrarenal aortic diameter 4 weeks after CaPO4 application. The maximum diameters of the aortas were measured by morphometry and the mean maximal diameters were calculated. Paraffin sections of the infrarenal aortas were examined for morphological analysis and immunohistochemical staining. The results showed that myeloid cell mPGES-1 deletion significantly mitigated AAA formation, including reducing expansion of the infrarenal aorta, preventing elastic lamellar degradation, and decreasing aortic calcium deposition. Immunohistochemical staining further indicated that macrophage infiltration and matrix metalloproteinase 2 (MMP2) expression was attenuated in the Mac-mPGES-1-KO aortas. Consistently, in vitro experiments showed that expression of pro-inflammatory cytokines and MMPs was significantly reduced when mPGES-1 was lacking in the primary cultured peritoneal macrophages. These data altogether demonstrated that deletion of mPGES-1 in myeloid cells may attenuate AAA formation and targeting myeloid cell mPGES-1 could potentially offer an effective strategy for the treatment and prevention of vascular inflammatory diseases.

Enhancing singlet oxygen production of dioxygen activation on the carbon-supported rare-earth oxide nanocluster and rare-earth single atom catalyst to remove antibiotics.

Singlet oxygen (1O2) is extensively employed in the fields of chemical, biomedical and environmental. However, it is still a challenge to produce high- concentration 1O2 by dioxygen activation. Herein, a system of carbon-supported rare-earth oxide nanocluster and single atom catalysts (named as RE2O3/RE-C, RE=La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Sc and Y) with similar morphology, structure, and physicochemical characteristic are constructed to activate dissolved oxygen (DO) to enhance 1O2 production. The catalytic activity trends and mechanisms are revealed experimentally and are also proven by theoretical analyses and calculations. The 1O2 generation activity trend is Gd2O3/Gd-C>Er2O3/Er-C>Sm2O3/Sm-C>pristine carbon (C). More than 95.0% of common antibiotics (ciprofloxacin, ofloxacin, norfloxacin and carbamazepine) can be removed in 60 min by Gd2O3/Gd-C. Density functional theory calculations indicate that Gd2O3 nanoclusters and Gd single atoms exhibit the moderate adsorption energy of ·O2- to enhance 1O2 production. This study offers a universal strategy to enhance 1O2 production in dioxygen activation for future application and reveals the natural essence of basic mechanisms of 1O2 production via rare-earth oxide nanoclusters and rare-earth single atoms.

Visualizing plant intracellular inorganic orthophosphate distribution.

Intracellular inorganic orthophosphate (Pi) distribution and homeostasis profoundly affect plant growth and development. However, its distribution patterns remain elusive owing to the lack of efficient cellular Pi imaging methods. Here we develop a rapid colorimetric Pi imaging method, inorganic orthophosphate staining assay (IOSA), that can semi-quantitatively image intracellular Pi with high resolution. We used IOSA to reveal the alteration of cellular Pi distribution caused by Pi starvation or mutations that alter Pi homeostasis in two model plants, rice and Arabidopsis, and found that xylem parenchyma cells and basal node sieve tube element cells play a critical role in Pi homeostasis in rice. We also used IOSA to screen for mutants altered in cellular Pi homeostasis. From this, we have identified a novel cellular Pi distribution regulator, HPA1/PHO1;1, specifically expressed in the companion and xylem parenchyma cells regulating phloem Pi translocation from the leaf tip to the leaf base in rice. Taken together, IOSA provides a powerful method for visualizing cellular Pi distribution and facilitates the analysis of Pi signalling and homeostasis from the level of the cell to the whole plant.

Deletion of Cyclic GMP-AMP Synthase Aggravates Concanavalin A-Induced Acute Hepatic Injury by Facilitating Leukocyte Chemotaxis.

Growing evidence demonstrates that cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, is essential for activating innate immunity and regulating inflammatory response against cellular damage. However, its role in immune-mediated hepatitis remains unclear. Here by challenging the cGAS knockout (KO) and their littermate wide-type (WT) mice with intravenous ConA injection to induce acute immune-mediated liver injury, we found that lack of cGAS drastically aggravated liver damage post ConA treatment for 24 h, reflected by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and amplified hepatic necrosis. The number of apoptotic hepatocytes was also significantly increased in the KO mice. RNA-sequencing analysis revealed that leukocyte chemotaxis and migration-related genes were remarkably upregulated in the KO livers. Consistently, immunofluorescence assays illustrated that the infiltrating F4/80-positive macrophages, Ly6G-positive neutrophils, and CD3-positive T cells were all significantly increased in the KO liver sections. The hepatic expression of the pro-inflammatory genes was elevated as well. Supporting the in vivo findings, the knockdown of cGAS in cultured macrophages showed promoted migration potential and enhanced pro-inflammatory gene expression. These results collectively demonstrated that deletion of cGAS could aggravate ConA-induced acute liver injury, at least at the 24-h time point, and its mechanism might be related to facilitating leukocyte chemotaxis and promoting liver inflammatory response.

An ethylene-induced NAC transcription factor acts as a multiple abiotic stress responsor in conifer.

The proper response to various abiotic stresses is essential for plants' survival to overcome their sessile nature, especially for perennial trees with very long-life cycles. However, in conifers, the molecular mechanisms that coordinate multiple abiotic stress responses remain elusive. Here, the transcriptome response to various abiotic stresses like salt, cold, drought, heat shock and osmotic were systematically detected in Pinus tabuliformis (P. tabuliformis) seedlings. We found that four transcription factors were commonly induced by all tested stress treatments, while PtNAC3 and PtZFP30 were highly up-regulated and co-expressed. Unexpectedly, the exogenous hormone treatment assays and the content of the endogenous hormone indicates that the upregulation of PtNAC3 and PtZFP30 are mediated by ethylene. Time-course assay showed that the treatment by ethylene immediate precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), activated the expression of PtNAC3 and PtZFP30 within 8 hours. We further confirm that the PtNAC3 can directly bind to the PtZFP30 promoter region and form a cascade. Overexpression of PtNAC3 enhanced unified abiotic stress tolerance without growth penalty in transgenic Arabidopsis and promoted reproductive success under abiotic stress by shortening the lifespan, suggesting it has great potential as a biological tool applied to plant breeding for abiotic stress tolerance. This study provides novel insights into the hub nodes of the abiotic stresses response network as well as the environmental adaptation mechanism in conifers, and provides a potential biofortification tool to enhance plant unified abiotic stress tolerance.

Circadian control of ConA-induced acute liver injury and inflammatory response via Bmal1 regulation of Junb.

Background & Aims: Circadian rhythms play significant roles in immune responses, and many inflammatory processes in liver diseases are associated with malfunctioning molecular clocks. However, the significance of the circadian clock in autoimmune hepatitis (AIH), which is characterised by immune-mediated hepatocyte destruction and extensive inflammatory cytokine production, remains unclear. Methods: We tested the difference in susceptibility to the immune-mediated liver injury induced by concanavalin A (ConA) at various time points throughout a day in mice and analysed the effects of global, hepatocyte, or myeloid cell deletion of the core clock gene, Bmal1 (basic helix-loop-helix ARNT-like 1), on liver injury and inflammatory responses. Multiple molecular biology techniques and mice with macrophage-specific knockdown of Junb, a Bmal1 target gene, were used to investigate the involvement of Junb in the circadian control of ConA-induced hepatitis. Results: The susceptibility to ConA-induced liver injury is highly dependent on the timing of ConA injection. The treatment at Zeitgeber time 0 (lights on) triggers the highest mortality as well as the severest liver injury and inflammatory responses. Further study revealed that this timing effect was driven by macrophage, but not hepatocyte, Bmal1. Mechanistically, Bmal1 controls the diurnal variation of ConA-induced hepatitis by directly regulating the circadian transcription of Junb and promoting M1 macrophage activation. Inhibition of Junb in macrophages blunts the administration time-dependent effect of ConA and attenuates liver injury. Moreover, we demonstrated that Junb promotes macrophage inflammation by regulating AKT and extracellular signal-regulated kinase (ERK) signalling pathways. Conclusions: Our findings uncover a critical role of the Bmal1-Junb-AKT/ERK axis in the circadian control of ConA-induced hepatitis and provide new insights into the prevention and treatment of AIH. Impact and Implications: This study unveils a critical role of the Bmal1-Junb-AKT/ERK axis in the circadian control of ConA-induced liver injury, providing new insights into the prevention and treatment of immune-mediated hepatitis, including autoimmune hepatitis (AIH). The findings have scientific implications as they enhance our understanding of the circadian regulation of immune responses in liver diseases. Furthermore, clinically, this research offers opportunities for optimising treatment strategies in immune-mediated hepatitis by considering the timing of therapeutic interventions.