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Recent studies found that non‐coding RNAs (ncRNAs) played crucial roles in drug addiction through epigenetic regulation of gene expression and underlying drug‐induced neuroadaptations. In this study, we characterized lncRNA transcriptome profiles in the nucleus accumbens (NAc) of mice exhibiting morphine‐conditioned place preference (CPP) and explored the prospective roles of novel differentially expressed lncRNA, lncLingo2 and its derived miR‐876‐5p in the acquisition of opioids‐associated behaviours. We found that the lncLingo2 was downregulated within the NAc core (NAcC) but not in the NAc shell (NAcS). This downregulation was found to be associated with the development of morphine CPP and heroin intravenous self‐administration (IVSA). As Mfold software revealed that the secondary structures of lncLingo2 contained the sequence of pre‐miR‐876, transfection of LV‐lncLingo2 into HEK293 cells significantly upregulated miR‐876 expression and the changes of mature miR‐876 are positively correlated with lncLingo2 expression in NAcC of morphine CPP trained mice. Delivering miR‐876‐5p mimics into NAcC also inhibited the acquisition of morphine CPP. Furthermore, bioinformatics analysis and dual‐luciferase assay confirmed that miR‐876‐5p binds to its target gene, Kcnn3, selectively and regulates morphine CPP training‐induced alteration of Kcnn3 expression. Lastly, the electrophysiological analysis indicated that the currents of small conductance calcium‐activated potassium (SK) channel was increased, which led to low neuronal excitability in NAcC after CPP training, and these changes were reversed by lncLingo2 overexpression. Collectively, lncLingo2 may function as a precursor of miR‐876‐5p in NAcC, hence modulating the development of opioid‐associated behaviours in mice, which may serve as an underlying biomarker and therapeutic target of opioid addiction. [ABSTRACT FROM AUTHOR]

Model predictive control (MPC) technology for multi-phase electric drives has received increasing attention in modern industries, especially in electric vehicles, marine electrical propulsion, and wind power generation. However, MPC has several challenges in controlling multi-phase electric drives, including the design of weighting factors, high computational complexity, large harmonic currents, heavy reliance on the system model, fault-tolerant control operation, common-mode voltage, and zero-sequence current hazards. Therefore, this paper gives a comprehensive review of the latest and most effective solutions to the existing major technical challenges and prospects for the future trends of MPC for multi-phase electric drives. [ABSTRACT FROM AUTHOR]

Exposure to a catastrophic event or intense stimulation can trigger fear memories, and the threatening memories persist even over a lifetime. Exposure therapy is based on extinction learning and is widely used to treat fear-related disorders, but its effect on remote fear memory is modest. Berberine, an isoquinoline alkaloid derived from Coptis chinensis or Berberis spp., has been recently reported to exert a diversity of pharmacological effects on the central nervous system, such as facilitating extinction of drug memory. Here, we explored the effect of berberine on extinction of fear memory using a classical contextual fear conditioning (CFC) paradigm, which is Pavlovian conditioning, can rapidly create fear memories related to contexts. Twenty-four hours or 30 days after CFC training, mice were subjected to context extinction (10 days) to extinguish their behaviors and treated with 12.5 or 25 mg/kg berberine intragastrically 1 or 6 h after each extinction session, followed by reinstatement and spontaneous recovery tests. The results showed that intragastric administration of 25 mg/kg berberine 1 h after extinction significantly promoted the extinction of recent and remote fear memories and prevented reinstatement and spontaneous recovery of extinguished fear in mice. These findings indicate that berberine combined with extinction training could serve as a promising novel avenue for the treatment of fear-related disorders. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO), a byproduct of heme catalyzed by heme oxygenase (HO), has been reported to exert antioxidant and anti-inflammatory actions, and to produce significant neuroprotective effects. The potential effects of CO and even HO on depressive-like behaviors are still poorly understood. Utilizing several approaches including adeno-associated virus (AAV)-mediated overexpression of HO-1, systemic CO-releasing molecules (CO-RMs), CO-rich saline or CO gas treatment procedures in combination with hydrogen peroxide (H2O2)-induced PC12 cell injury model, and lipopolysaccharide (LPS)-induced depression mouse model, the present study aimed to investigate the potential antidepressant- and anxiolytic-like effects of endogenous and exogenous CO administration in vivo and in vitro. The results of in vitro experiments showed that both CO-RM-3 and CO-RM-A1 pretreatment blocked H2O2-induced cellular injuries by increasing cell survival and decreasing cell apoptosis and necrosis. Similar to the effects of CO-RM-3 and CO-RM-A1 pretreatment, AAV-mediated HO-1 overexpression in the dorsal hippocampus produced significant antidepressant-like activities in mice under normal conditions. Further investigation showed that the CO gas treatment significantly blocked LPS-induced depressive- and anxiety-like behaviors in mice. Taken together, our results suggest that the activation of HO-1 and/or exogenous CO administration produces protective effects and exerts antidepressant- and anxiolytic-like effects. These data uncover a novel function of the HO-1/CO system that appears to be a promising therapeutic target for the treatment of depression and anxiety. [ABSTRACT FROM AUTHOR]

Persistent traces of drug reward memories contribute to intense craving and often trigger relapse. A number of pharmacological interventions on drug-associated memories have shown significant benefits in relapse prevention at a preclinical level but their translational potential is limited due to deleterious side effects. Propranolol, a non-specific β-adrenergic receptors antagonist, is known for its ability to erase maladaptive memories associated with nicotine or cocaine in rodents and humans. However, little is known about its effect on reconsolidation of heroin memory and heroin seeking. In the present study, rats with a history of intravenous heroin self-administration received the propranolol treatment (10 mg/kg; i.p.) at different time windows with or without CS (conditioned stimulus) exposure. Our results showed that propranolol, when administered immediately after CS exposure but not 6 h later, can significantly attenuate cue-induced and drug-primed reinstatement of heroin seeking, suggesting that propranolol has the ability to disrupt heroin memory and reduce relapse. The propranolol treatment without retrieval of drug memory had no effect on subsequent reinstatement of heroin seeking, suggesting that its interfering effects are retrieval-dependent. Importantly, the effects of propranolol were long lasting as rats showed diminished drug seeking even 28 days after the treatment. Altogether, our study suggests that propranolol can interfere with reconsolidation of heroin memory and reduce subsequent drug seeking, making it an attractive therapeutic candidate for the treatment of opioid addiction and relapse prevention. [ABSTRACT FROM AUTHOR]

This article proposes a novel model predictive control for a three-phase permanent-magnet synchronous motor (PMSM) with enhanced robustness against parameter variation and higher current control precision. First, the extended set of voltage vectors are adopted to increase the current control precision. Then, the parameter sensitivity problem is avoided in the first stage using an indirect reference vector strategy for the sake of computation time reduction. Subsequently, the inductance disturbance observer is adopted in the current prediction process to enhance the robustness against machine parameter mismatch. The intrinsic connection between the discrete control sets precision and disturbance observer is analyzed. The proposed method improves the robustness against parameter mismatch and current control precision simultaneously. Experimentations are conducted to verify the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

A high rate of relapse is a major clinical problem among drug-addicted individuals. Persistent traces of drug-associated reward memories contribute to intense craving and often trigger relapse. A number of interventions on drug-associated memories have shown significant benefits in relapse prevention. Among them are pre- or post-extinction pharmacological manipulations that facilitate the extinction of drug-associated behavior. Berberine, a bioactive isoquinoline alkaloid, has been recently reported to provide therapeutic benefits for a number of central nervous system (CNS) disorders, including morphine addiction. The present study aimed to investigate whether berberine could serve as a post-extinction pharmacological intervention agent to reduce risks of reinstatement of drug seeking. We found that an intragastric administration of berberine at doses of 25 and 50 mg/kg during the critical time window significantly facilitated the extinction of morphine-reward related behavior in free access and confined conditioned place preference (CPP) extinction paradigms, and subsequently, it prevented reinstatement and spontaneous recovery of morphine-induced CPP in mice. Intriguingly, the berberine treatment with or without extinction training altered expression of plasticity-related proteins such as brain-derived neurotrophic factor (BDNF), AMPA receptors (GluA1 and GluA2) in the nucleus accumbens (NAc). Moreover, the post-extinction berberine treatment significantly reduced reinstatement of cocaine-induced CPP and operant intravenous self-administration (IVSA) memories in rats. Altogether, our findings suggest that extinction training combined with the post-extinction berberine treatment can facilitate extinction of drug-associated behavior making it an attractive therapeutic candidate in relapse prevention. [ABSTRACT FROM AUTHOR]

This paper presents a model predictive control for a six-phase permanent magnet synchronous machine (PMSM) with a reduced-dimension cost function. Only the variables in the harmonic subspace are included into the cost function, while the energy conversion related variables are excluded. This is achieved by using the deadbeat direct torque and flux control method to obtain a reference voltage vector and then to track the torque and stator flux properly in the energy conversion related subspace. Then, according to the position of the reference vector, the appropriate prediction vectors can be determined. Subsequently, a reduced-dimension cost function including only the harmonic constraints is defined to evaluate the feasible prediction vectors. In this way, the predictive model and the cost function are simplified without redundant constraints. Meanwhile, the torque and flux can be regulated satisfactorily, and the harmonic currents are suppressed effectively. Finally, experimental results of the proposed method and the conventional model predictive torque control are presented in this paper to verify the validity of the proposed method. [ABSTRACT FROM AUTHOR]

This paper proposes a multi-vector-based model predictive torque control with fixed switching frequency for a six-phase permanent-magnet synchronous machine to improve its steady-state performance. First, two active vectors are synthesized in each control period to suppress the stator current harmonics in x–y subspace. For the sake of easy implementation in the real-time system, the vectors are artfully synthesized in two different manners. Second, to achieve the fixed switching frequency, two null vectors are inserted along with the synthesized vector. The duty ratio of the null vectors is determined based on the principle of deadbeat torque control. In the meantime, the synthesized vector and its duty ratio are evaluated simultaneously by the cost function. In this way, the torque ripple can be reduced considerably. Thus, with the proposed method, both the current harmonics and the torque ripple are reduced effectively. Also, the proposed methodology can be readily implemented practically under the constant switching frequency. Finally, the experimentation is carried out to verify the validity of the proposed method. [ABSTRACT FROM AUTHOR]

This paper proposes a low-complexity model predictive flux control (MPFC) with current harmonics and torque ripple reduced for a six-phase permanent magnet synchronous machine (PMSM) motor. First, the virtual vectors in two different magnitudes are adopted for the sake of harmonic currents and torque ripple reduction, as well as simplifying the predictive model by eliminating the z1–z2 variables from the cost function. Then, a look-up table is developed to exclude the useless voltage vectors in advance. In this way, the number of prediction vectors is reduced and heavy computation burden is alleviated. Moreover, to avoid the tedious tuning work of the weighting factor in the cost function, the torque and flux amplitude are transformed into an equivalent reference flux vector. Thus, the complexity of the cost function is significantly reduced. Meanwhile, the current and torque performance are highly improved using the proposed method. Also, the fast dynamic response of predictive control is retained. Finally, simulation and experimental results are offered to verify the effectiveness of the proposed MPFC method. [ABSTRACT FROM AUTHOR]

This paper proposes a novel deadbeat current control (DBCC)-based model predictive control for an asymmetrical six-phase permanent magnet synchronous machine. First, the solution of DBCC is adopted to obtain the expected reference voltage vector (RVV). Then, two groups of virtual vectors, in the total number of 24 with different magnitudes, are defined for the sake of current harmonics suppression. Subsequently, two in-phase virtual vectors which are closest to the RVV are selected as the prediction vectors. The next step is to define a cost function which is composed of the error between the RVV and the available prediction vectors. Then, the selected two virtual vectors are evaluated and the one that minimizes the cost function will be applied in the next instant. In this way, only two prediction vectors need to be evaluated and the computation burden is highly alleviated. In the meantime, the weighting factor involved in predictive torque control is avoided. In addition, to achieve the readily implementation with standard pulsewidth modulation switching sequence, 18 virtual vectors are artfully replaced by their corresponding equivalent virtual vectors. Finally, the proposed method is comparatively studied and compared with other benchmark methods. Simulation and experimental results are offered to confirm the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

This paper presents a novel model predictive torque control with discrete duty ratio optimization for a six-phase PMSM machine with high robustness against weighting factor variation. First, a two-step lookup table is developed to initially select the optimal voltage vector, which is to regulate the torque and flux in the energy conversion related subspace, as well as suppress the harmonic currents in the x–y subspace. Then, a null vector is inserted along with the selected optimal voltage vector to adjust the duty ratio with a set of value to avoid the complicated derivation. Subsequently, the optimal duty ratio is determined by a cost function to minimize the torque and flux error. So by using the proposed method, the torque ripple is reduced and even applying an improper weighting factor will not deteriorate the machine performance severely. Finally, experimentations are carried out to verify the validity of the proposed method. [ABSTRACT FROM AUTHOR]

This paper proposes a model predictive control scheme based remedial control for the single-phase open-circuit fault of an asymmetrical six-phase PMSM machine. The proposed strategy adopts the normal vector space decomposition transformation matrix without reconfiguring the controller topology. The key is to derive the perturbation term of the prediction vectors in α-β and x-y subspace, which is based on the difference of the faulty phase voltage under healthy and faulty condition. Through the compensation of the prediction vectors, the predictive model can be accurately described in the faulty condition. Thus, the current variables in the next instant is accurately predicted and the torque fluctuation is suppressed. Finally, the experimental results are provided to verify the validity of the proposed method on pre- and post-fault tolerant operation. [ABSTRACT FROM AUTHOR]

This study presents a finite‐control‐set model predictive current control (FCS‐MPCC) with phase shift compensation for a cost‐effective voltage source inverter. Firstly, the FCS‐MPCC algorithm uses the discrete‐time model of the inverter to predict the coming value of the load current. In addition, a cost function is defined to evaluate all possible voltage vectors from the inverter, where the cost function is selected. Moreover, a pulse computation module is developed to obtain the final switching signals for insulated‐gate bipolar transistors. In addition, the problem of current distortion caused by phase shift is solved by employing a time interval compensation factor. Furthermore, a comparison between the hysteresis control, pulse‐width modulation control, and proposed predictive control is presented in terms of the steady‐state and dynamic performances. Both simulation and experiment are conducted, which confirm the validity of the proposed control scheme of FCS‐MPCC. [ABSTRACT FROM AUTHOR]

Stress in adolescence has been widely demonstrated to have a lasting impact in humans and animal models. Developmental risk and protective factors play an important role in the responses to stress in adulthood. Mild-to-moderate stress in adolescence may resist the negative impacts of adverse events in adulthood. However, little research on resilience has been conducted. In this study, we used a predictable chronic mild stress (PCMS) procedure (5 min of daily restraint stress for 28 days) in adolescent rats (postnatal days (PNDs) 28-55) to test the resilience effect of PCMS on depressive-like behavior in the sucrose preference test and forced swim test and anxiety-like behavior in the novelty-suppressed feeding test and elevated plus maze in adulthood. We also investigated the role of mammalian target of rapamycin (mTOR) signaling in the brain during the PCMS procedure in adolescence. Moreover, we investigated the effect of PCMS in adolescence on subsequent responses to chronic unpredictable stress (CUS; PNDs 63-83) in adulthood. The results demonstrated that PCMS during adolescence produced antidepressant- and anxiolytic-like effects and increased mTOR signaling activity in the prefrontal cortex in early adulthood. Either systemic administration or intra-PFC infusion of the mTOR inhibitor rapamycin completely blocked the behavioral effects produced by PCMS in adolescence. PCMS during adolescence resisted depressive- and anxiety-like behavior caused by CUS in adulthood. These findings indicate that PCMS in adolescence can contribute to resilience against depression and anxiety caused by stress in adulthood. [ABSTRACT FROM AUTHOR]

β-delayed proton decays of Tz = 1/2 series nuclei81Zr and85Mo have been studied in detail by using p-γ coincidence measurement. The β-delayed proton spectra populating the first excited states of the daughter nuclei have been obtained. Half-life of81Zr has been measured tobe5.3s ± 0.5 s and that of85Mo 3.2 s ± 0.2 S. By using statistical model calculations and systematic analyses, spins and parities for the ground states of81Zr and85Mo have been tentatively assigned to be 3/2− and 1/2−, respectively. Mass excess of81Zris -58.3 MeV± 0.2 MeV and that of85Mo-59.1 MeV ± 0.4 MeV. Combining the measured half-lives with the calculated partial ones yields the branches of β-de-layed proton decay for81zr and85Mo of (1.2 ± 0.2) × 10-3 and (1.4 ± 0.2) × 10-3, respectively. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that gut microbiota and its metabolites can influence the brain function and the related behaviors. Trimethylamine N-oxide (TMAO), an indirect metabolite of gut microbiota, has been linked to aging, cognitive impairment, and many brain disorders. However, the potential effects of TMAO on social behaviors remain elusive. The present study investigated the effects of early life systemic TMAO exposure and intra-hippocampal TMAO infusion during adulthood on social behaviors in mice. We also analyzed the effects of intra-hippocampus infusion of TMAO during adulthood on levels of metabolites. The results showed that both systemic TMAO exposure in the post-weaning period and intra-hippocampal TMAO infusion during adulthood decreased social rank and reduced sexual preference in adult mice. Data from LC-MS metabolomics analysis showed that intra-hippocampal TMAO infusion induced a total 207 differential metabolites, which belongs to several metabolic or signaling pathways, especially FoxO signaling pathway and retrograde endocannabinoid signaling pathway. These data suggest that TMAO may affect social behaviors by regulating metabolites in the hippocampus, which may provide a new insight into the role of gut microbiota in regulating social behaviors. • Long-lasting effects of postweaning TMAO exposure on mice were observed. • Intra-hippocampal TMAO infusion affects social behaviors of adult mice. • TMAO can induce abnormal sexual preference and lower social dominance of mice. • Hippocampal metabolism is involved in behavioral abnormalities caused by TMAO. [ABSTRACT FROM AUTHOR]

Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific. [ABSTRACT FROM AUTHOR]

A new transuranium neutron-deficient isotope235Am was produced by 35 MeV proton to bombard the rare radioactive238Pu target. The products were transported and collected by the He-jet system. The Am isotopes were separated and purified by radiochemistry method and the y-ray, X-ray and y-X(y) coincidence of the samples was measured. The synthesis of235Am was definitely identified. Its measured half-life is (15±5) min. [ABSTRACT FROM AUTHOR]

Proposes a laser ion source based on laser resonant ionization at the outlet of a helium jet for on-line isotope separator of the Heavy Ion Research Facility in Lanzhou, China. Description of in-beam ionization; Classification of the proposal in three categories; Sodium atoms introduced into vacuum at reduced water density.

Background Drug memories that associate drug-paired stimuli with the effects of abused drugs contribute to relapse. Exposure to drug-associated contexts causes consolidated drug memories to be in a labile state, during which manipulations can be given to impair drug memories. Although substantial evidence demonstrates the crucial role of neuronal signaling in addiction, little is known about the contribution of astrocyte-neuron communication. Methods Rats were trained for cocaine-induced conditioned place preference (CPP) or self-administration and microinjected with the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol into the basolateral amygdala (BLA) immediately after retrieval. The concentration of lactate was measured immediately after retrieval via microdialysis, and the CPP score and number of nosepokes were recorded 24 hours later. Furthermore, we used antisense oligodeoxynucleotides to disrupt the expression of astrocytic lactate transporters (monocarboxylate transporters 1 and 2) in the BLA after retrieval, tested the expression of CPP 1 day later, and injected L-lactate into the BLA 15 minutes before retrieval to rescue the effects of the oligodeoxynucleotides. Results Injection of 1,4-dideoxy-1,4-imino-D-arabinitol into the BLA immediately after retrieval prevented the subsequent expression of cocaine-induced CPP, decreased the concentration of lactate in the BLA, and reduced the number of nosepokes for cocaine self-administration. Disrupting the expression of monocarboxylate transporters 1 and 2 in the BLA also caused subsequent deficits in the expression of cocaine-induced CPP, which was rescued by pretreatment with L-lactate. Conclusions Our results suggest that astrocyte-neuron lactate transport in the BLA is critical for the reconsolidation of cocaine memory. [ABSTRACT FROM AUTHOR]

Background Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. Conclusions These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. [ABSTRACT FROM AUTHOR]

• Atractylenolide III produces antidepressant- and anxiolytic-like effects in rat models. Atractylenolide III, a major component of the atractylodes macrocephala Koidz, derived from the rhizoma atractylodes , has been reported to produce various pharmacological effects including anti-aging, anti-inflammation, anti-tumor, and other effects. Growing evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α, are increased in depressed patients. The present study was aimed at investigating the antidepressant- and anxiolytic-like effects of atractylenolide III in lipopolysaccharide (LPS) challenge and chronic unpredictable mild stress (CUMS) rat model. We found that 30 mg/kg of atractylenolide III administered by oral gavage for 14 days, significantly reduced the immobility time in a forced swimming test (FST), but did not alter the number of crossings in an open field test (OFT), respectively. The results indicated that atractylenolide III has an antidepressant-like effect without affecting locomotor activity. We then used the LPS-induced depression model to assess the effects of atractylenolide III on behaviors in FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT). Interestingly, in addition to the antidepressant-like effects, 30 mg/kg of atractylenolide III also produced an anxiolytic-like effect. To further identify the antidepressant- and anxiolytic-like effects of atractylenolide III, we used the CUMS model with 28 consecutive days of the atractylenolide III treatment, followed by the SPT, FST, and NSFT. Atractylenolide III prevented CUMS-induced depressive- and anxiety-like behaviors in rats. To illustrate the underlying possible mechanisms of action of atractylenolide III, we measured the proinflammatory cytokines levels. The results showed that atractylenolide III decreased the proinflammatory cytokines levels in the hippocampus of CUMS exposed rats. In summary, our findings demonstrated that atractylenolide III produces antidepressant- and anxiolytic-like effects in rats, and these effects appear to be mediated by inhibition of hippocampal neuronal inflammation. [ABSTRACT FROM AUTHOR]

A progressive increase in drug craving following drug exposure is an important trigger of relapse. CircularRNAs (CircRNAs), key regulators of gene expression, play an important role in neurological diseases. However, the role of circRNAs in drug craving is unclear. In the present study, we trained mice to morphine conditioned place preference (CPP) and collected the nucleus accumbens (NAc) sections on abstinence day 1 (AD1) and day 14 (AD14) for RNA-sequencing. CircTmeff-1, which was highly expressed in the NAc core, was associated with incubation of context-induced morphine craving. The gain- and loss- of function showed that circTmeff-1 was a positive regulator of incubation. Simultaneously, the expression of miR-541–5p and miR-6934–3p were down-regulated in the NAc core during the incubation period. The dual luciferase reporter, RNA pulldown, and fluorescence insitu hybridization assays confirmed that miR-541–5p and miR-6934–3p bind to circTmeff-1 selectively. Furthermore, bioinformatics and western blot analysis suggested that vesicle-associated membrane protein 1 (VAMP1) and neurofascin (NFASC), both overlapping targets of miR-541–5p and miR-6934–3p, were highly expressed during incubation. Lastly, AAV-induced down-regulation of circTmeff-1 decreased VAMP1 and NFASC expression and incubation of morphine craving. These findings suggested that circTmeff-1, a novel circRNA, promotes incubation of context-induced morphine craving by sponging miR-541/miR-6934 in the NAc core. Thus, circTmeff-1 represents a potential therapeutic target for context-induced opioid craving, following prolonged abstinence. [Display omitted] [ABSTRACT FROM AUTHOR]

The persistence of drug memory contributes to relapse to drug seeking. The association between repeated drug exposure and drug-related cues leads to cravings triggered by drug-paired cues. The erasure of drug memories has been considered a promising way to inhibit cravings and prevent relapse. The re-exposure to drug-related cues destabilizes well-consolidated drug memories, during which a de novo protein synthesis-dependent process termed "reconsolidation" occurs to restabilize the reactivated drug memory. Disrupting reconsolidation of drug memories leads to the attenuation of drug-seeking behavior in both animal models and people with addictions. Additionally, epigenetic mechanisms regulated by DNA methyltransferase (DNMT) are involved in the reconsolidation of fear and cocaine reward memory. In the present study, we investigated the role of DNMT in the reconsolidation of heroin reward memory. In the heroin self-administration model in rats, we tested the effects of DNMT inhibition during the reconsolidation process on cue-induced reinstatement, heroin-priming-induced reinstatement, and spontaneous recovery of heroin-seeking behavior. We found that the bilateral infusion of 5-azacytidine (5-AZA) inhibiting DNMT into the basolateral amygdala (BLA) immediately after heroin reward memory retrieval, but not delayed 6 h after retrieval or without retrieval, decreased subsequent cue-induced and heroin-priming-induced reinstatement of heroin-seeking behavior. These findings demonstrate that inhibiting the activity of DNMT in BLA during the reconsolidation of heroin reward memory attenuates heroin-seeking behavior, which may provide a potential strategy for the therapeutic of heroin addiction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BX declared a past co-authorship with the author YL to the handling editor., (Copyright © 2022 Qian, Shi, Huang, Yang and Luo.)

TGFβ is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFβ signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFβ-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFβ signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFβR1 at K268, which is critical to activate TGFβ signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFβR1 ubiquitination and Th9 differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti-PD-1-mediated checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFβ-regulated gene to fine-tune TGFβ signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Pei et al.)

Background: Targeted therapeutic strategies for advanced colorectal cancer (CRC) have been limited. STING is crucial to the antitumor immunotherapy, for it stimulates IFN signaling to mediate the crosstalk between innate and adaptive immune responses. Emerging evidence suggests that STING also contributes to the prognosis of CRC. However, prognostic models relating to STING have not yet been explored., Methods: A total of 431 CRC samples from the TCGA database were analyzed to explore the prognostic value of STING-related genes. We trained prognostic models using the multivariate Cox regression. A STING-related prognostic score (SPS) was calculated as the gene expression multiplied by the corresponding coefficients of the final model. A backward stepAIC strategy was adopted to select the optimal model. A nomogram was used to personalize medical decisions for CRC., Results: The expression level of STING was upregulated in the CMS1 subtype (P=0.036). Among STING-related genes, DHX9 (HR =0.72, P=0.01), IRF2 (HR =1.34, P=0.022), and POLR1D (HR =1.23, P=0.038) showed significant prognostic value. The SPS was proven to be an independent risk factor (training: HR =2.9, P=0.00013; validation: HR =3.02, P=0.01), and outperformed random classifiers in identifying high-risk CRC. The high SPS group was characterized by less genomic aberrations, upregulated IL6-JAK-STAT3 and IL2-STAT5 signaling pathways, increased expression of TIM-3, increased infiltration of regulatory T (Treg) cells and T helper 17 (Th17) cells, and decreased infiltration of M0 macrophages. Finally, the nomogram based on the SPS and clinical factors showed good performance in CRC., Conclusions: SPS is an independent risk factor that could identify high-risk CRC. While ICBs may benefit patients of the CMS1 subtype, for the CMS2, CMS3, and CMS4 subtypes in the high SPS group, STING agonists and immunotherapies targeting the Th17 axis may be beneficial. Finally, the SPS-based nomogram could help advance personalized medical decisions for CRC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-2430). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: The prevalence of HER2 alterations in pan-cancer indicates a broader range of application of HER2-targeted therapies; however, biomarkers for such therapies are still insufficient and limited to breast cancer and gastric cancer., Methods: Using multi-omics data from The Cancer Genome Atlas (TCGA), the landscape of HER2 alterations was exhibited across 33 tumor types. A HER2 index was constructed using one-class logistic regression (OCLR). With the predictive value validated in GEO cohorts and pan-cancer cell lines, the index was then applied to evaluate the HER2-enriched expression pattern across TCGA pan-cancer types., Findings: Increased HER2 somatic copy number alterations (SCNAs) could be divided into two patterns, focal- or arm-level. The expression-based HER2 index successfully distinguished the HER2-enriched subtype from the others and provided a stable and superior performance in predicting the response to HER2-targeted therapies both in breast tumor tissue and pan-cancer cell lines. With frequencies varying from 12.0% to 0.9%, tumors including head and neck squamous tumors, gastrointestinal tumors, bladder cancer, lung cancer and uterine tumors exhibited high HER2 indices together with HER2 amplification or overexpression, which may be more suitable for HER2-targeted therapies. The BLCA.3 and HNSC.Basal were the most distinguishable subtypes within bladder cancer and head and neck cancer respectively by HER2 index, implying their potential benefits from HER2-targeted therapies., Interpretation: As a pan-cancer predictive biomarker of HER2-targeted therapies, the HER2 index could help identify potential candidates for such treatment in multiple tumor types by combining with HER2 multi-omics features. The discoveries of our study highlight the importance of incorporating transcriptional pattern into the assessment of HER2 status for better patient selection., Funding: The National Key Research and Development Program of China; Clinical Research and Cultivation Project of Shanghai ShenKang Hospital Development Center., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphate-activated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation.

The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.

Repeated exposure to nicotine increases psychomotor activity. Long-lasting neural plasticity changes that contribute to the nicotine-induced development of locomotor sensitization have been identified. The mammalian target of rapamycin complex 1 (mTORC1) signalling pathway is involved in regulating the neuroplasticity of the central nervous system. In this study, we examined the role of mTORC1 in the amygdala in nicotine-induced locomotor sensitization. Rapamycin, an inhibitor of mTORC1, was infused into the basolateral amygdala (BLA) and central amygdala (CeA) or systemically administered to investigate the role of the mTORC1 in the development and expression of nicotine-induced locomotor sensitization. We found that locomotor activity progressively increased during the initiation of nicotine-induced locomotor sensitization and the expression of nicotine sensitization was induced by nicotine challenge injection (0.35 mg/kg s.c.) after five days of withdrawal. The initiation of nicotine-induced locomotor sensitization was accompanied by the increased phosphorylated level of mTORC1 downstream target proteins including p-p70s6k and p-4EBP in the BLA, but not CeA. Intra-BLA infusion or systemic administration of rapamycin blocked locomotor activity. Increased p-p70s6k and p-4EBP were also observed in the expression of nicotine sensitization, which was demonstrated to be inhibited by systemic rapamycin administration. Our findings indicated that mTORC1 activity in the BLA, but not the CeA, mediated the initiation and expression of nicotine-induced locomotor sensitization, and may become a potential target for the treatment of nicotine addiction.

Posttraumatic stress disorder (PTSD) is characterized by acute and chronic changes in the stress response, manifested as conditioned fear memory. Previously formed memories that are susceptible to disruption immediately after retrieval undergo a protein synthesis-dependent process to become persistent, termed reconsolidation, a process that is regulated by many distinct molecular mechanisms that control gene expression. Increasing evidence supports the participation of the transcription factor NF-κB in the different phases of memory. Here, we demonstrate that inhibition of NF-κB in the basolateral amygdala (BLA), but not central nucleus of the amygdala, after memory reactivation impairs the retention of amygdala-dependent auditory fear conditioning (AFC). We used two independent pharmacological strategies to disrupt the reconsolidation of AFC. Bilateral intra-BLA infusion of sulfasalazine, an inhibitor of IκB kinase that activates NF-κB, and bilateral intra-BLA infusion of SN50, a direct inhibitor of the NF-κB DNA-binding complex, immediately after retrieval disrupted the reconsolidation of AFC. We also found that systemic pretreatment with sodium butyrate, a histone deacetylase inhibitor that enhances histone acetylation, in the amygdala rescued the disruption of reconsolidation induced by NF-κB inhibition in the BLA. These findings indicate that NF-κB activity in the BLA is required for memory reconsolidation in AFC, suggesting that NF-κB might be a potential pharmacotherapy target for posttraumatic stress disorder.