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AbstractObjectiveTo determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression.DesignRandomised, double blind, placebo controlled trial with two parallel arms.SettingFive tertiary care hospitals in China, 19 June 2020 to 3 August 2022.Participants364 mothers aged ≥18 years who had at least mild prenatal depression as indicated by Edinburgh postnatal depression scale scores of ≥10 (range 0-30, with higher scores indicating worse depression) and who were admitted to hospital for delivery.InterventionsParticipants were randomly assigned 1:1 to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth once the umbilical cord had been clamped.Main outcome measuresThe primary outcome was prevalence of a major depressive episode at 42 days post partum, diagnosed using the mini-international neuropsychiatric interview. Secondary outcomes included the Edinburgh postnatal depression scale score at seven and 42 days post partum and the 17 item Hamilton depression rating scale score at 42 days post partum (range 0-52, with higher scores indicating worse depression). Adverse events were monitored until 24 hours after childbirth.ResultsA total of 364 mothers (mean age 31.8 (standard deviation 4.1) years) were enrolled and randomised. At 42 days post partum, a major depressive episode was observed in 6.7% (12/180) of participants in the esketamine group compared with 25.4% (46/181) in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P<0.001). Edinburgh postnatal depression scale scores were lower in the esketamine group at seven days (median difference −3, 95% CI −4 to −2; P<0.001) and 42 days (−3, −4 to −2; P<0.001). Hamilton depression rating scale scores at 42 days post partum were also lower in the esketamine group (−4, −6 to −3; P<0.001). The overall incidence of neuropsychiatric adverse events was higher in the esketamine group (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than a day and none required drug treatment.ConclusionsFor mothers with prenatal depression, a single low dose of esketamine after childbirth decreases major depressive episodes at 42 days post partum by about three quarters. Neuropsychiatric symptoms were more frequent but transient and did not require drug intervention.Trial registrationClinicalTrials.gov NCT04414943.

Low temperature is a key factor limiting the rubber plantation extending to high latitude area. Previous work has shown that cold-induced DNA demethylation was coordinated with the expression of cold-responsive ( COR ) genes in Hevea brasiliensis . In this work, reduced representation bisulphite sequencing analysis of H. brasiliensis showed that cold treatment induced global genomic DNA demethylation and altered the sequence contexts of methylated cytosines, but the levels of mCG methylation in transposable elements were slightly enhanced by cold treatment. Integrated analysis of the DNA methylome and transcriptome revealed 400 genes whose expression correlated with altered DNA methylation. DNA demethylation in the upstream region of gene seems to correlate with higher gene expression, whereas demethylation in the gene body has less association. Our results suggest that cold treatment globally change the genomic DNA methylation status of the rubber tree, which might coordinate reprogramming of the transcriptome.

Key messageAn ICE-like transcription factor mediates jasmonate-regulated cold tolerance in the rubber tree (Hevea brasiliensis), and confers cold tolerance in transgenic Arabidopsis.The rubber tree (Hevea brasiliensis) is susceptible to low temperatures, and understanding the mechanisms regulating cold stress is of great potential value for enhancing tolerance to this environmental variable. In this study, we find that treatment with exogenous methyl jasmonate (MeJA) could significantly enhance Hevea brasiliensis cold tolerance. In addition, yeast two-hybrid and bimolecular fluorescence complementation (BiFC) experiments show that JASMONATE ZIM-DOMAIN(JAZ) proteins, HbJAZ1 and HbJAZ12, key repressors of JA signaling pathway, interact with HbICE2, a novel ICE (Inducer of CBF Expression)-like protein. HbICE2 was nuclear-localised and bound to the MYC recognition (MYCR) sequence. The transcriptional activation activity of HbICE2 in yeast cells was dependent on the N-terminus, and overexpression of HbICE2 in Arabidopsis resulted in elevated tolerance to chilling stress. Furthermore, dual-luciferase transient assay reveals that HbJAZ1 and HbJAZ12 proteins inhibit the transcriptional function of HbICE2. The expression of C-repeat-binding factor (CBF) signalling pathway genes including HbCBF1, HbCBF2 and HbCOR47 were up-regulated by MeJA. Taken together, our data suggest that the new ICE-like transcription factor HbICE2 is involved in jasmonate-regulated cold tolerance in Hevea brasiliensis.

Salicylic acid (SA) acts antagonistically to jasmonic acid (JA) in plant immunity. We previously reported that CATALASE2 (CAT2) promotes JA‐biosynthetic acyl‐CoA oxidase (ACX) activity to enhance plant resistance to necrotrophic Botrytis cinerea, and SA represses JA biosynthesis through inhibiting CAT2 activity, while the underlying mechanism remains to be further elucidated. Here, we report that the truncated CAT2 N‐terminus (CAT2‐N) interacts with and promotes ACX2/3, and CAT2‐N‐overexpressing plants have increased JA accumulation and enhanced resistance to B. cinerea B05.10, but compromised antagonism of SA on JA. Catalase inhibitor treatment or mutating CAT2 active amino acids abolished CAT2 H2O2‐decomposing activity but did not affect its promotion of ACX2/3 activity via interaction. CAT2‐N, a truncated protein with no catalase activity, interacted with and promoted ACX2/3. Overexpressing CAT2‐N in Arabidopsis plants resulted in increased ACX activity, higher JA accumulation, and stronger resistance to B. cinerea B05.10 infection. Additionally, SA dramatically repressed JA biosynthesis and resistance to B. cinerea in the wild type but not in the CAT2‐N‐overexpressing plants. Together, our study reveals that CAT2‐N can be utilized as an accelerator for JA biosynthesis during plant resistance to B. cinerea B05.10, and this truncated protein partly relieves SA repression of JA biosynthesis in plant defence responses. N‐terminal fragment of CATALASE2 interacts with and promotes acyl‐CoA oxidases implicated in JA biosynthesis and enhances plant resistance to Botrytis cinerea, thus CATALASE2‐N could be a genetic tool conferring plant resistance.

Cold stress poses significant limitations on the growth, latex yield, and ecological distribution of rubber trees (Hevea brasiliensis). The GSK3-like kinase plays a significant role in helping plants adapt to different biotic and abiotic stresses. However, the functions of GSK3-like kinase BR-INSENSITIVE 2 (BIN2) in Hevea brasiliensis remain elusive. Here, we identified HbBIN2s of Hevea brasiliensis and deciphered their roles in cold stress resistance. The transcript levels of HbBIN2s are upregulated by cold stress. In addition, HbBIN2s are present in both the nucleus and cytoplasm and have the ability to interact with the INDUCER OF CBF EXPRESSION1(HbICE1) transcription factor, a central component in cold signaling. HbBIN2 overexpression in Arabidopsis displays decreased tolerance to chilling stress with a lower survival rate and proline content but a higher level of electrolyte leakage (EL) and malondialdehyde (MDA) than wild type under cold stress. Meanwhile, HbBIN2 transgenic Arabidopsis treated with cold stress exhibits a significant increase in the accumulation of reactive oxygen species (ROS) and a decrease in the activity of antioxidant enzymes. Further investigation reveals that HbBIN2 inhibits the transcriptional activity of HbICE1, thereby attenuating the expression of C-REPEAT BINDING FACTOR (HbCBF1). Consistent with this, overexpression of HbBIN2 represses the expression of CBF pathway cold-regulated genes under cold stress. In conclusion, our findings indicate that HbBIN2 functions as a suppressor of cold stress resistance by modulating HbICE1 transcriptional activity and ROS homeostasis.

Low temperature remarkably limits rubber tree (Hevea brasiliensis Muell. Arg.) growth, latex production, and geographical distribution, but the underlying mechanisms of Hevea brasiliensis cold stress response remain elusive. Here, we identified HbSnRK2.6 as a key component in ABA signaling functions in phytohormone abscisic acid (ABA)-regulated cold stress response in Hevea brasiliensis. Exogenous application of ABA enhances Hevea brasiliensis cold tolerance. Cold-regulated (COR) genes in the CBF pathway are upregulated by ABA. Transcript levels of all five HbSnRK2.6 members are significantly induced by cold, while HbSnRK2.6A, HbSnRK2.6B, and HbSnRK2.6C can be further activated by ABA under cold conditions. Additionally, HbSnRK2.6s are localized in the cytoplasm and nucleus, and can physically interact with HbICE2, a crucial positive regulator in the cold signaling pathway. Overexpression of HbSnRK2.6A or HbSnRK2.6B in Arabidopsis extensively enhances plant responses to ABA and expression of COR genes, leading to increased cold stress tolerance. Furthermore, HbSnRK2.6A and HbSnRK2.6B can promote transcriptional activity of HbICE2, thus, increasing the expression of HbCBF1. Taken together, we demonstrate that HbSnRK2.6s are involved in ABA-regulated cold stress response in Hevea brasiliensis by regulating transcriptional activity of HbICE2.

Sepsis-associated encephalopathy (SAE) is a potentially irreversible acute cognitive dysfunction with unclear mechanism. Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase which normally opposes synaptic strengthening by regulating key signaling molecules involved in synaptic plasticity and neuronal function. Thus, we hypothesized that abnormal STEP signaling pathway was involved in sepsis-induced cognitive impairment evoked by lipopolysaccharides (LPS) injection. The levels of STEP, phosphorylation of GluN2B (pGluN2B), the kinases extracellular signal-regulated kinase 1/2 (pERK), cAMP-response element binding protein (CREB), synaptophysin, brain derived neurotrophic factor (BDNF), and post-synaptic density protein 95 (PSD95) in the hippocampus, prefrontal cortex, and striatum were determined at the indicated time points. In the present study, we found that STEP levels were significantly increased in the hippocampus, prefrontal cortex, and striatum following LPS injection, which might resulted from the disruption of the ubiquitin–proteasome system. Notably, a STEP inhibitor TC-2153 treatment alleviated sepsis-induced memory impairment by increasing phosphorylation of GluN2B and ERK1/2, CREB/BDNF, and PSD95. In summary, our results support the key role of STEP in sepsis-induced memory impairment in a mouse model of SAE, whereas inhibition of STEP may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.

Rubber trees ( ) were successfully introduced to south China in the 1950s on a large-scale; however, due to the climate, are prone to cold injury during the winter season. Increased cold tolerance is therefore an important goal, yet the mechanism underlying rubber tree responses to cold stress remains unclear. This study carried out functional characterization of (Inducer of Expression 1) from . A nucleic protein with typical features of ICEs, HbICE1 was able to bind to MYC recognition sites and had strong transactivation activity. was constitutively expressed in all tested tissues, with highest levels in the bark, and was up-regulated when subjected to various stresses including cold, dehydration, salinity and wounding. When overexpressed in plants showed enhanced cold resistance with increased proline content, reduced malondialdehyde (MDA) metabolism and electrolyte leakage, and decreased reactive oxygen species (ROS) accumulation. Expression of the cold responsive genes ( , and ) was also significantly promoted in compared to wild-type plants under cold stress. Differentially expressed genes (DEGs) analysis showed that cold treatment changed genes expression profiles involved in many biological processes and phytohormones perception and transduction. Ethylene, JA, ABA, as well as ICE-CBF signaling pathways might work synergistically to cope with cold tolerance in rubber tree. Taken together, these findings suggest that is a member of the gene family and a positive regulator of cold tolerance in .

Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, yet the precise mechanisms underlying PTSD remains largely to be determined. Using an animal model of PTSD induced by a single prolonged stress (SPS), we assessed the role of hippocampal nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and parvalbumin (PV) interneurons in the development of PTSD symptoms. In the present study, behavioral tests were performed by the open field (day 13 after SPS) and fear conditioning tests (days 13 and 14 after SPS). For the interventional study, rats were chronically treated with a NADPH oxidase inhibitor apocynin either by early or delayed administration. The levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, malondialdehyde, superoxide dismutase, NOX2, 4-hydroxynonenal, and PV in the hippocampus were measured at the indicated time points. In the present study, we showed that SPS rats displayed anxiety-like and enhanced fear learning behavior, which was accompanied by the increased expressions of malondialdehyde, IL-6, NOX2, 4-hydroxynonenal, and decreased PV expression. Notably, early but not delayed treatment with apocynin reversed all these abnormalities after SPS. In conclusion, our results provided evidence that NOX2 activation in the hippocampus, at least in part, contributes to oxidative stress and neuroinflammation, which further results in PV interneuron loss and consequent PTSD symptoms in a rat model of PTSD induced by SPS.

Transthoracic echocardiographic evaluation of the right ventricle is more difficult than the left ventricle and has not been well characterised in the parturient during delivery. As a preliminary investigation, our goal was to use bedside transthoracic echocardiography to evaluate right ventricular myocardial function before and after caesarean delivery. Term parturients undergoing caesarean delivery under spinal anaesthesia were enrolled. Echocardiography was performed pre- and postoperatively. Assessment of myocardial function included longitudinal myocardial strain using 2D-speckle tracking for both ventricles, and fractional area change for the right ventricle. Troponin-T, creatine kinase-muscle/brain and brain natriuretic peptide were measured pre- and postoperatively. One hundred patients were enrolled; 98 completed the study. Adequate images from both timepoints (pre- and postoperatively) were obtained in 85 patients for left ventricle assessment, and 66 for the right ventricle. Right ventricular fractional area change (mean (standard deviation)) (24.9% (8.9%) to 24.9% (9.2%); P1/40.99) and strain (-19.7% (6.8%) to -18.1% (6.5%); P1/40.08) measurements suggested mild baseline dysfunction and did not change after delivery. Left ventricular strain values were normal and unchanged after delivery (-23.8% (7.4%) to -24.3% (6.7%); P1/40.51). One patient had elevated troponin-T and demonstrated worse biventricular function. Elevation of brain natriuretic peptide (n1/47) was associated with mildly decreased left ventricular strain, but creatine kinase-muscle/brain (n1/44) was not associated with consistent changes in cardiac function. Further investigations into peripartum right ventricular function are required to validate the findings in this preliminary study. Findings of baseline mild right ventricular dysfunction and functional changes associated with troponin-T and brain natriuretic peptide warrant rigorous investigation.