Central Regulator Research Articles

Plasmacytoid dendritic cells are central regulators of the humoral ChAdOx1 nCoV-19 vaccine response in a human tonsil organoid model

Abstract Studying human vaccine responses is limited by the difficulty of access to secondary lymphoid tissues. To overcome this, we have optimized a human tonsil organoid model to investigate the processes that regulate the humoral responses to the ChAdOx1 nCoV-19 vaccine. Stimulation of tonsil cultures with ChAdOx1 nCoV-19 induced broad innate immune activation and cytokine secretion within 24 hours. This induced (global and antigen-specific) B cell activation and spike-specific antibody secretion over the following 14-day culture period. Stimulation with an irrelevant ChAdOx1 GFP vector did not induce spike-specific antibody secretion. Plasmacytoid dendritic cells (pDCs) showed the highest rate of transduction and activation. Critically, pDC-depletion decreased both innate and humoral responses. IFN-⍺ blockade phenocopied pDC depletion while supplementing IFN-⍺ to pDC-depleted cultures rescued humoral responses. IL-6 was also critical for optimal humoral responses, and its production was modulated in an IFN-⍺-dependent manner even in the absence of pDCs, suggesting cross-talk of multiple key signaling pathways. Overall, this model reveals a critical role for pDCs in inducing humoral responses to ChAdOx1 nCoV-19, primarily through IFN-⍺. IFN-⍺ appears to act directly and indirectly through IFN-induced IL-6 secretion to augment the humoral response. This model has the potential for studying other vaccine platforms.

Estrogenic re-mapping of the metabolic response to an energy deficit

Endothermy is an adaptation that can be traced back hundreds of millions of years and is critical for nearly every aspect of mammalian biology. Despite the advantages associated with a stable internal temperature, endothermy is energetically expensive. To conserve energy when food is scarce, mice have evolved the ability to reversibly enter a regulated state of hypothermia and hypometabolism, known as torpor. We have found that circulating 17β-estradiol, a potent estrogen, inhibits fasting-induced torpor in ovariectomized female mice, yet the signaling mechanisms underlying this estrogenic re-mapping of the metabolic response to an energy deficit remain largely unknown. Recent studies have identified the medial preoptic area of the hypothalamus (MPO) as the central regulator of torpor. MPO neurons that express estrogen receptor alpha have been identified as central coordinators of torpor, and MPO neurons that are activated during torpor broadly express estrogen receptors, suggesting that circulating estrogens may directly modulate torpor-driving neurons in the MPO. To test the hypothesis that circulating estrogens inhibit torpor by acting directly on estrogen-sensitive neurons in the MPO, we delivered 17β-estradiol (E2) directly to the MPO before inducing torpor with a 48-hour fast. Surprisingly, we found that E2 delivered to the MPO was suffcient to inhibit fasting-induced torpor in gonad-intact, but not ovariectomized, female mice. These data demonstrate that E2 signaling in the MPO is insuffcient to inhibit torpor on its own and that there are likely MPO-independent nodes in the body that circulating estrogens act on to inhibit torpor. However, our data also demonstrate that E2 signaling in the MPO does play a role in tuning the torpor response when endogenous gonadal hormones are present, suggesting that the MPO can sense estrogens and engage the appropriate effector circuits to inhibit torpor in certain physiological contexts. Together, these data advance our understanding of how circulating estrogens inhibit torpor in mice — a critical step towards the broader goal of understanding how circulating estrogens influence energy expenditure, and how these pathways can be manipulated to improve metabolic health. NIH RO1 (R01AG066821) - "Estrogenic modulation of neural circuits that control temperature" AHA Predoctoral Fellowship (23PRE1019923) - Estrogenic modulation of hypothalamic neurons that control energy expenditure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

MAP kinase MKK: A central regulator in the development, toxigenic potential, and pathogenesis of Penicillium expansum infecting pears

Penicillium expansum is one of the primary pathogens causing postharvest blue mold of pears, which leads to the spoiling of pulp and produces patulin, endangering food security. Mitogen-activated protein kinase (MAPK) signaling pathway regulates the growth and development, cell wall integrity, and pathogenicity of fungi. Mitogen-activated protein kinase kinase (MKK) in the MAPK signaling pathway has been reflected to be associated with fungal cell wall integrity. Nevertheless, the pivotal function of MKK in the process of P. expansum infection remained unexplored. In this study, MKK was knocked out and repaired by the Agrobacterium-mediated homologous recombination technology to explore the function of MKK in P. expansum infection process. It has been found that the deletion of MKK induces morphological changes in the mutant strain and delayed mycelium and spore growth. Further studies showed that the mutant strain was susceptible to cell wall interference compounds and showed a significant decrease in decay diameters and virulence during the infection of the pears. RT-qPCR analysis showed that the deletion of MKK affected the relative expression levels of its upstream and downstream genes. Our results suggest that MKK is essential in the growth and development, cell wall integrity, pathogenicity, and toxigenic capacity of P. expansum.

OsPHR2-mediated recruitment of Pseudomonadaceae enhances rice phosphorus uptake

Plants can shape their root microbiome to promote growth and nutrient uptake. PHOSPHATE STARVATION RESPONSE 2 (OsPHR2) is a central regulator of phosphate signaling in rice, but whether OsPHR2 can shape the root microbiome to promote phosphorus uptake is unclear. Here, we investigate the role of OsPHR2 in recruiting microbiota for phosphorus uptake using high-throughput sequencing and metabolite analysis. OsPHR2-overexpressing (OsPHR2 OE) rice showed 69.8% greater shoot P uptake in natural soil compared with sterilized soil under high-phosphorus (HP) conditions, but there was only a 54.8% increase in the wild-type (WT). The abundance of the family Pseudomonadaceae was significantly enriched in OsPHR2 OE roots relative to those of WT rice. Compared with the WT, OsPHR2 OE rice had a relatively higher abundance of succinic acid and methylmalonic acid, which could stimulate the growth of Pseudomonas sp. (P6). After inoculation with P6, phosphorus uptake in WT and OsPHR2 OE rice was higher than that in uninoculated rice under low-phosphorus (LP) conditions. Taken together, our results suggest that OsPHR2 can increase phosphorus use in rice through root exudate-mediated recruitment of Pseudomonas. This finding reveals a cooperative contribution of the OsPHR2-modulated root microbiome, which is important for improving phosphorus use in agriculture.

Design and Implementation of an Iot-Based Safety and Energy Efficient System

The paper provides a safe and power-efficient Internet of Things (IoT)-based solution. With the growing concerns about environmental sustainability and the demand for improved safety measures in today’s society, it has become critical to focus on building systems that decrease energy consumption and assure the safety of humans and the environment. The proposed system employs cutting-edge technologies and novel approaches that will result in optimal energy usage with minimal or no human involvement thereby assuring the safety of people. The proposed system leverages on existing IoT technologies and is comprised of smart sensors, energy-efficient gadgets, and a centralized control unit. Therefore, it is able to demonstrate cutting edge power control strategies including power gating and dynamic central power regulation which control the usage of gadgets to operate at optimal power levels vis-a-vis the real-time demand to achieve energy efficiency. The system is also able to collect data on occupancy, lighting, temperature, and power consumption trends which can assist in making data-driven choices that improve the usage of energy. The proposed system provides large energy savings without sacrificing user comfort by dynamically altering lighting, and cooling systems based on occupants and ambient factors. Multiple simulations and real-world trials in homes and institutions’ buildings were used to assess the efficacy of the suggested system. The findings revealed substantial reductions in energy consumption without jeopardizing safety.

Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer

BackgroundGinsenoside Rh2 (G-Rh2), a steroidal compound extracted from roots of ginseng, has been extensively studied in tumor therapy. However, its specific regulatory mechanism in non-small cell lung cancer (NSCLC) is not well understood. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in various malignant tumors. We investigated the impact of G-Rh2 on the malignant progression of NSCLC and how it regulated PDK4 to influence tumor aerobic glycolysis and mitochondrial function.MethodWe examined the inhibitory effect of G-Rh2 on NSCLC through I proliferation assay, migration assay and flow cytometry in vitro. Subsequently, we verified the ability of G-Rh2 to inhibit tumor growth and metastasis by constructing subcutaneous tumor and metastasis models in nude mice. Proteomics analysis was conducted to analyze the action pathways of G-Rh2. Additionally, we assessed glycolysis and mitochondrial function using seahorse, PET-CT, Western blot, and RT-qPCR.ResultTreatment with G-Rh2 significantly inhibited tumor proliferation and migration ability both in vitro and in vivo. Furthermore, G-Rh2 inhibited the tumor’s aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/PDK4 pathway. Overexpression of PDK4 demonstrated that G-Rh2 targeted the inhibition of PDK4 expression, thereby restoring mitochondrial function, promoting reactive oxygen species (ROS) accumulation, and inducing apoptosis. When combined with sodium dichloroacetate, a PDK inhibitor, it complemented the inhibitory capacity of PDKs, acting synergistically as a detoxifier.ConclusionG-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes.

Interactions Between HDL and CD4+ T Cells: A Novel Understanding of HDL Anti-Inflammatory Properties.

Several studies in animal models and human cohorts have recently suggested that HDLs (high-density lipoproteins) not only modulate innate immune responses but also adaptative immune responses, particularly CD4+ T cells. CD4+ T cells are central effectors and regulators of the adaptive immune system, and any alterations in their homeostasis contribute to the pathogenesis of cardiovascular diseases, autoimmunity, and inflammatory diseases. In this review, we focus on how HDLs and their components affect CD4+ T-cell homeostasis by modulating cholesterol efflux, immune synapsis, proliferation, differentiation, oxidative stress, and apoptosis. While the effects of apoB-containing lipoproteins on T cells have been relatively well established, this review focuses specifically on new connections between HDL and CD4+ T cells. We present a model where HDL may modulate T cells through both direct and indirect mechanisms.

P4HA2 activates mTOR via hydroxylation and targeting P4HA2-mTOR inhibits lung adenocarcinoma cell growth

,Mammalian target of rapamycin (mTOR) kinase functions as a central regulator of cell growth and metabolism, and its complexes mTORC1 and mTORC2 phosphorylate distinct substrates. Dysregulation of mTOR signaling is commonly implicated in human diseases, including cancer. Despite three decades of active research in mTOR, much remains to be determined. Here, we demonstrate that prolyl 4-hydroxylase alpha-2 (P4HA2) binds directly to mTOR and hydroxylates one highly conserved proline 2341 (P2341) within a kinase domain of mTOR, thereby activating mTOR kinase and downstream effector proteins (e.g. S6K and AKT). Moreover, the hydroxylation of P2341 strengthens mTOR stability and allows mTOR to accurately recognize its substrates such as S6K and AKT. The growth of lung adenocarcinoma cells overexpressing mTORP2341A is significantly reduced when compared with that of cells overexpressing mTORWT. Interestingly, in vivo cell growth assays show that targeting P4HA2-mTOR significantly suppresses lung adenocarcinoma cell growth. In summary, our study reveals an undiscovered hydroxylation-regulatory mechanism by which P4HA2 directly activates mTOR kinase, providing insights for therapeutically targeting mTOR kinase-driven cancers.

Ang-1 and VEGF: central regulators of angiogenesis.

Angiopoietin-1 (Ang-1) and Vascular Endothelial Growth Factor (VEGF) are central regulators of angiogenesis and are often inactivated in various cardiovascular diseases. VEGF forms complexes with ETS transcription factor family and exerts its action by downregulating multiple genes. Among the target genes of the VEGF-ETS complex, there are a significant number encoding key angiogenic regulators. Phosphorylation of the VEGF-ETS complex releases transcriptional repression on these angiogenic regulators, thereby promoting their expression. Ang-1 interacts with TEK, and this phosphorylation release can be modulated by the Ang-1-TEK signaling pathway. The Ang-1-TEK pathway participates in the transcriptional activation of VEGF genes. In summary, these elements constitute the Ang-1-TEK-VEGF signaling pathway. Additionally, Ang-1 is activated under hypoxic and inflammatory conditions, leading to an upregulation in the expression of TEK. Elevated TEK levels result in the formation of the VEGF-ETS complex, which, in turn, downregulates the expression of numerous angiogenic genes. Hence, the Ang-1-dependent transcriptional repression is indirect. Reduced expression of many target genes can lead to aberrant angiogenesis. A significant overlap exists between the target genes regulated by Ang-1-TEK-VEGF and those under the control of the Ang-1-TEK-TSP-1 signaling pathway. Mechanistically, this can be explained by the replacement of the VEGF-ETS complex with the TSP-1 transcriptional repression complex at the ETS sites on target gene promoters. Furthermore, VEGF possesses non-classical functions unrelated to ETS and DNA binding. Its supportive role in TSP-1 formation may be exerted through the VEGF-CRL5-VHL-HIF-1α-VH032-TGF-β-TSP-1 axis. This review assesses the regulatory mechanisms of the Ang-1-TEK-VEGF signaling pathway and explores its significant overlap with the Ang-1-TEK-TSP-1 signaling pathway.

Capitalist, Evolution, Financial Innovations and Financial Literacy: A Study of their Dynamics in Shaping Modern Capitalism

Finance has had its root in human history since human being started a settled civilized life. As production for trade took a shape, various means of transactions and storage of value kept on evolving. Gradually, finance took the center stage with the evolution of modern capitalism. In early stages the financial instruments remained a scattered individual means of financial practice, no central regulation existed in the early era. Hence the acquaintance with these instruments was also confined to individual users, the traders, particularly. Since economic productivity was quite low, ordinary individuals had little surplus to save, not many had much to do with financial literacy. The modern capitalism required industrial workers, surplus of agricultural products, more consumers for market, more means of production to produce trade surplus and more financial savings and instruments to channelize investments. Also the producers were required to be alienated from the product of labour so that the trade of commodities could be taken in control by the trading class. Also the means of production, which was otherwise the ownership of the households, was to be turned marketable to facilitate the transfer the ownership from ordinary owners to the trading class. The trinity of commodity production, wage labour and market system altogether had to evolve for capitalism to come into existence. Accordingly, various financial instruments took shape, the traditional ones became more formalized and many new ones were invented. The evolution of different forms of business, the 'company' form particularly, helped this process in a big way. Simultaneously, the financial anarchy put the systems in turmoil and hence regulatory bodies became a compulsion. These regulatory bodies assumed the twin role of regulation of financial markets, financial facilitation, as well as creating financial literacy among ordinary people to link their savings to the mainstream trade and commerce lines. The paper attempts to portray the evolution of modern financial system and find out how this evolution has been linked to the financial literacy of the common masses. Also the paper would throw lights on imminent market and systemic hazards caused by excess leliance on financialisation of economic system.

Функціональні перебудови кардіогемодинаміки людини при морському кінетозі

Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kyiv; e-mail: moiseyenkoev@gmail.com The purpose of the study was to determine the functional changes in cardiohemodynamics during dosed physical activity of a person in the conditions of sea storm kinetosis and features of cerebral biorhythms, this may indicate the development of modification rearrangements of the mechanisms of central regulation of the body’s functional systems. The research was carried out with the participation of 23 specialists of the Antarctic expedition (men aged 24 to 45 years). They crossed the Drake Passage by sea: sea turbulence - 7 points, the ship’s roll angle - 120, the duration of the crossing was 4 days. It was determined that a person’s stay in the conditions of a sea wave leads to changes in the mechanisms of vasoconstrictor regulation, this was indicated by inadequate blood pressure fluctuations during functional diagnostics and an increase in the load on the heart’s activity due to an increase in pulse and diastolic pressure and the lack of recovery dynamics after performing physical work. It was shown that as a result of marine kinetosis in the structure of cerebral biorhythms, the power of β1 and β2 rhythms in the projections of the cerebral cortex increases. Such changes may indicate a certain participation of central mechanisms in the reorganization of the regulation of functional reserves of cardiohemodynamics. It is assumed that when using medical devices for patients with a cardiac profile in conditions of seasickness, it is advisable to take into account the presence of features of changes in the central and regional regulation of blood circulation function.

QRFP43 modulates the activity of the hypothalamic appetite regulatory centre in sheep

QRFP43 modulates the activity of the hypothalamic appetite regulatory centre in sheep

Acute nicotine activates orectic and inhibits anorectic brain regions in rats exposed to chronic nicotine

Nicotine use produces psychoactive effects, and chronic use is associated with physiological and psychological symptoms of addiction. However, chronic nicotine use is known to decrease food intake and body weight gain, suggesting that nicotine also affects central metabolic and appetite regulation. We recently showed that acute nicotine self-administration in nicotine-dependent animals produces a short-term increase in food intake, contrary to its long-term decrease of feeding behavior. As feeding behavior is regulated by complex neural signaling mechanisms, this study aimed to test the hypothesis that nicotine intake in animals exposed to chronic nicotine may increase activation of pro-feeding regions and decrease activation of pro-satiety regions to produce the acute increase in feeding behavior. FOS immunohistochemistry revealed that acute nicotine intake in nicotine self-administering animals increased activation of the pro-feeding arcuate and lateral hypothalamic nuclei and decreased activation of the pro-satiety parabrachial nucleus. Regional correlational analysis also showed that acute nicotine changes the functional connectivity of the hunger/satiety network. Further dissection of the role of the arcuate nucleus using electrophysiology found that putative POMC neurons in animals given chronic nicotine exhibited decreased firing following acute nicotine application. These brain-wide central signaling changes may contribute to the acute increase in feeding behavior we see in rats after acute nicotine and provide new areas of focus for studying both nicotine addiction and metabolic regulation.

Interaction with B-type lamin reveals the function of Drosophila Keap1 xenobiotic response factor in nuclear architecture.

The Keap1-Nrf2 pathway serves as a central regulator that mediates transcriptional responses to xenobiotic and oxidative stimuli. Recent studies have shown that Keap1 and Nrf2 can regulate transcripts beyond antioxidant and detoxifying genes, yet the underlying mechanisms remain unclear. Our research has uncovered that Drosophila Keap1 (dKeap1) and Nrf2 (CncC) proteins can control high-order chromatin structure, including heterochromatin. In this study, we identified the molecular interaction between dKeap1 and lamin Dm0, the Drosophila B-type lamin responsible for the architecture of nuclear lamina and chromatin. Ectopic expression of dKeap1 led to an ectopic localization of lamin to the intra-nuclear area, corelated with the spreading of the heterochromatin marker H3K9me2 into euchromatin regions. Additionally, mis-regulated dKeap1 disrupted the morphology of the nuclear lamina. Knocking down of dKeap1 partially rescued the lethality induced by lamin overexpression, suggesting their genetic interaction during development. The discovered dKeap1-lamin interaction suggests a novel role for the Keap1 oxidative/xenobiotic response factor in regulating chromatin architecture.

Cadmium modulates intestinal Wnt/β-catenin signaling ensuing intestinal barrier disruption and systemic inflammation

The intricate architecture of the intestinal epithelium, crucial for nutrient absorption, is constantly threatened by environmental factors. The epithelium undergoes rapid turnover, which is essential for maintaining homeostasis, under the control of intestinal stem cells (ISCs). The central regulator, Wnt/β-catenin signaling plays a key role in intestinal integrity and turnover. Despite its significance, the impact of environmental factors on this pathway has been largely overlooked. This study, for the first time, investigates the influence of Cd on the intestinal Wnt signaling pathway using a mouse model. In this study, male BALB/c mice were administered an environmentally relevant Cd dose (0.98 mg/kg) through oral gavage to investigate the intestinal disruption and Wnt signaling pathway. Various studies, including histopathology, immunohistochemistry, RT-PCR, western blotting, ELISA, intestinal permeability assay, and flow cytometry, were conducted to study Cd-induced changes in the intestine. The canonical Wnt signaling pathway experienced significant downregulation as a result of sub-chronic Cd exposure, which caused extensive damage throughout the small intestine. Increased intestinal permeability and a skewed immune response were also observed. To confirm that Wnt signaling downregulation is the key driver of Cd-induced gastrointestinal toxicity, mice were co-exposed to LiCl (a recognized Wnt activator) and Cd. The results clearly showed that the harmful effects of Cd could be reversed, which is strong evidence that Cd mostly damages the intestine through the Wnt/β-catenin signalling axis. In conclusion, this research advances the current understanding of the role of Wnt/β catenin signaling in gastrointestinal toxicity caused by diverse environmental pollutants.

Regulation of the d-band center of metal–organic frameworks for energy-saving hydrogen generation coupled with selective glycerol oxidation

The hybrid electrolyzer coupled glycerol oxidation (GOR) with hydrogen evolution reaction (HER) is fascinating to simultaneously generate H2 and high value-added chemicals with low energy input, yet facing a challenge. Herein, Cu-based metal-organic frameworks (Cu-MOFs) are reported as model catalysts for both HER and GOR through doping of atomically dispersed precious and nonprecious metals. Remarkably, the HER activity of Ru-doped Cu-MOF outperformed a Pt/C catalyst, with its Faradaic efficiency for formate formation at 90% at a low potential of 1.40 V. Furthermore, the hybrid electrolyzer only needed 1.36 V to achieve 10 mA cm-2, 340 mV lower than that for splitting pure water. Theoretical calculations demonstrated that electronic interactions between the host and guest (doped) metals shifted downward the d-band centers (εd) of MOFs. This consequently lowered water adsorption and dissociation energy barriers and optimized hydrogen adsorption energy, leading to significantly enhanced HER activities. Meanwhile, the downshift of εd centers reduced energy barriers for rate-limiting step and the formation energy of OH*, synergistically enhancing the activity of MOFs for GOR. These findings offered an effective means for simultaneous productions of hydrogen fuel and high value-added chemicals using one hybrid electrolyzer with low energy input.

A FLOWERING LOCUS T ortholog is associated with photoperiod-insensitive flowering in hemp (Cannabis sativa L.).

Hemp (Cannabis sativa L.) is an extraordinarily versatile crop, with applications ranging from medicinal compounds to seed oil and fibre products. Cannabis sativa is a short-day plant, and its flowering is highly controlled by photoperiod. However, substantial genetic variation exists for photoperiod sensitivity in C. sativa, and photoperiod-insensitive ("autoflower") cultivars are available. Using a bi-parental mapping population and bulked segregant analysis, we identified Autoflower2, a 0.5 Mbp locus significantly associated with photoperiod-insensitive flowering in hemp. Autoflower2 contains an ortholog of the central flowering time regulator FLOWERING LOCUS T (FT) from Arabidopsis thaliana which we termed CsFT1. We identified extensive sequence divergence between alleles of CsFT1 from photoperiod-sensitive and insensitive cultivars of C. sativa, including a duplication of CsFT1 and sequence differences, especially in introns. Furthermore, we observed higher expression of one of the CsFT1 copies found in the photoperiod-insensitive cultivar. Genotyping of several mapping populations and a diversity panel confirmed a correlation between CsFT1 alleles and photoperiod response, affirming that at least two independent loci involved in the photoperiodic control of flowering, Autoflower1 and Autoflower2, exist in the C. sativa gene pool. This study reveals the multiple independent origins of photoperiod insensitivity in C. sativa, supporting the likelihood of a complex domestication history in this species. By integrating the genetic relaxation of photoperiod sensitivity into novel C. sativa cultivars, expansion to higher latitudes will be permitted, thus allowing the full potential of this versatile crop to be reached.

Integrating multi-omics data reveals energy and stress signaling activated by abscisic acid in Arabidopsis.

Phytohormones are essential signaling molecules regulating various processes in growth, development, and stress responses. Genetic and molecular studies, especially using Arabidopsis thaliana (Arabidopsis), have discovered many important players involved in hormone perception, signal transduction, transport, and metabolism. Phytohormone signaling pathways are extensively interconnected with other endogenous and environmental stimuli. However, our knowledge of the huge and complex molecular network governed by a hormone remains limited. Here we report a global overview of downstream events of an abscisic acid (ABA) receptor, REGULATORY COMPONENTS OF ABA RECEPTOR (RCAR) 6 (also known as PYRABACTIN RESISTANCE 1 [PYR1]-LIKE [PYL] 12), by integrating phosphoproteomic, proteomic and metabolite profiles. Our data suggest that the RCAR6 overexpression constitutively decreases the protein levels of its coreceptors, namely clade A protein phosphatases of type 2C, and activates sucrose non-fermenting-1 (SNF1)-related protein kinase 1 (SnRK1) and SnRK2, the central regulators of energy and ABA signaling pathways. Furthermore, several enzymes in sugar metabolism were differentially phosphorylated and expressed in the RCAR6 line, and the metabolite profile revealed altered accumulations of several organic acids and amino acids. These results indicate that energy- and water-saving mechanisms mediated by the SnRK1 and SnRK2 kinases, respectively, are under the control of the ABA receptor-coreceptor complexes.

A plant NLR receptor employs ABA central regulator PP2C-SnRK2 to activate antiviral immunity

Defence against pathogens relies on intracellular nucleotide-binding, leucine-rich repeat immune receptors (NLRs) in plants. Hormone signaling including abscisic acid (ABA) pathways are activated by NLRs and play pivotal roles in defence against different pathogens. However, little is known about how hormone signaling pathways are activated by plant immune receptors. Here, we report that a plant NLR Sw-5b mimics the behavior of the ABA receptor and directly employs the ABA central regulator PP2C-SnRK2 complex to activate an ABA-dependent defence against viral pathogens. PP2C4 interacts with and constitutively inhibits SnRK2.3/2.4. Behaving in a similar manner as the ABA receptor, pathogen effector ligand recognition triggers the conformational change of Sw-5b NLR that enables binding to PP2C4 via the NB domain. This receptor-PP2C4 binding interferes with the interaction between PP2C4 and SnRK2.3/2.4, thereby releasing SnRK2.3/2.4 from PP2C4 inhibition to activate an ABA-specific antiviral immunity. These findings provide important insights into the activation of hormone signaling pathways by plant immune receptors.

Prelimbic cortex-nucleus accumbens core projection positively regulates itch and itch-related aversion

Itch is one of the most common clinical symptoms in patients with diseases of the skin, liver, or kidney, and it strongly triggers aversive emotion and scratching behavior. Previous studies have confirmed the role of the prelimbic cortex (Prl) and the nucleus accumbens core (NAcC), which are reward and motivation regulatory centers, in the regulation of itch. However, it is currently unclear whether the Prl-NAcC projection, an important pathway connecting these two brain regions, is involved in the regulation of itch and its associated negative emotions. In this study, rat models of acute neck and cheek itch were established by subcutaneous injection of 5-HT, compound 48/80, or chloroquine. Immunofluorescence experiments determined that the number of c-Fos-immunopositive neurons in the Prl increased during acute itch. Chemogenetic inhibition of Prl glutamatergic neurons or Prl-NAcC glutamatergic projections can inhibit both histaminergic and nonhistaminergic itch-scratching behaviors and rectify the itch-related conditioned place aversion (CPA) behavior associated with nonhistaminergic itch. The Prl-NAcC projection may play an important role in the positive regulation of itch-scratching behavior by mediating the negative emotions related to itch.