Function of MYB8 in larch under PEG simulated drought stress.

Larch, a prominent afforestation, and timber species in northeastern China, faces growth limitations due to drought. To further investigate the mechanism of larch's drought resistance, we conducted full-length sequencing on embryonic callus subjected to PEG-simulated drought stress. The sequencing results revealed that the differentially expressed genes (DEGs) primarily played roles in cellular activities and cell components, with molecular functions such as binding, catalytic activity, and transport activity. Furthermore, the DEGs showed significant enrichment in pathways related to protein processing, starch and sucrose metabolism, benzose-glucuronic acid interconversion, phenylpropyl biology, flavonoid biosynthesis, as well as nitrogen metabolism and alanine, aspartic acid, and glutamic acid metabolism. Consequently, the transcription factor T_transcript_77027, which is involved in multiple pathways, was selected as a candidate gene for subsequent drought stress resistance tests. Under PEG-simulated drought stress, the LoMYB8 gene was induced and showed significantly upregulated expression compared to the control. Physiological indices demonstrated an improved drought resistance in the transgenic plants. After 48 h of PEG stress, the transcriptome sequencing results of the transiently transformed LoMYB8 plants and control plants exhibited that genes were significantly enriched in biological process, cellular component and molecular function. Function analyses indicated for the enrichment of multiple KEGG pathways, including energy synthesis, metabolic pathways, antioxidant pathways, and other relevant processes. The pathways annotated by the differential metabolites mainly encompassed signal transduction, carbohydrate metabolism, amino acid metabolism, and flavonoid metabolism.

An adhesion-switchable hydrogel dressing for painless dressing removal without secondary damage.

Hydrogels with strong adhesion to wet tissues are considered promising for wound dressings. However, the clinical application of adhesive hydrogel dressing remains a challenge due to the issues of secondary damage during dressing changes. Herein, we fabricated an adhesion-switchable hydrogel formed with poly(acrylamide)-co-poly(N-isopropyl acrylamide), quaternary ammonium chitosan and tannic acid. This hydrogel forms instant and robust adhesion to the skin at body temperature. However, as the temperature rises above the lower critical solution temperature (LCST), the hydrogel loses its adhesion towards the wound area due to the temperature-dependent volume phase transition of the copolymer, occurring around 45 °C. Consequently, the designed hydrogel can be easily detached from adhered tissues upon demand, providing a facile and effective method for painless dressing changes without secondary damage. This hydrogel holds great promise for long-term application in wound dressings.

Light-Induced Conductance Potentiation and Depression in an All-Optically Controlled Memristor.

Optoelectronic memristors are new multifunctional devices with both electrically tunable and light-tunable synaptic plasticity, attracting great attention as key promising devices for optoelectronic neuromorphic computing systems. At present, the conductance modulation in most optoelectronic memristors is conducted in a hybrid photoelectric mode, suffering some problems such as heat generation and control complexity. Here, an optoelectronic memristor based on the p+-Si/n-ZnO heterojunction is proposed where the conductance can be reversibly modulated in an all-optically controlled mode. The electron detrapping/trapping mechanism at the p+-Si/n-ZnO interface barrier region is presented to explain the light-induced conductance potentiation/depression behavior. Furthermore, some synaptic functions, including excitatory postsynaptic current (EPSC), inhibitory postsynaptic current (IPSC), and paired-pulse facilitation (PPF), are successfully mimicked in the p+-Si/n-ZnO heterojunction memristor, instructing its application potential for optoelectronic neuromorphic computing.

p52-ZER6/IGF1R axis maintains cancer stem cell population to promote cancer progression by enhancing pro-survival mitophagy.

Cancer stem cells (CSCs), which are distinct subpopulations of tumor cells, have a substantially higher tumor-initiating capacity and are closely related to poor clinical outcomes. Damage to organelles can trigger CSC pool exhaustion; however, the underlying mechanisms are poorly understood. ZER6 is a zinc-finger protein with two isoforms possessing different amino termini: p52-ZER6 and p71-ZER6. Since their discovery, almost no study reported on their biological and pathological functions. Herein, we found that p52-ZER6 was crucial for CSC population maintenance; p52-ZER6-knocking down almost abolished the tumor initiation capability. Through transcriptomic analyses together with in vitro and in vivo studies, we identified insulin like growth factor 1 receptor (IGF1R) as the transcriptional target of p52-ZER6 that mediated p52-ZER6 regulation of CSC by promoting pro-survival mitophagy. Moreover, this regulation of mitophagy-mediated CSC population maintenance is specific to p52-ZER6, as p71-ZER6 failed to exert the same effect, most possibly due to the presence of the HUB1 domain at its N-terminus. These results provide a new perspective on the regulatory pathway of pro-survival mitophagy in tumor cells and the molecular mechanism underlying p52-ZER6 oncogenic activity, suggesting that targeting p52-ZER6/IGF1R axis to induce CSC pool exhaustion may be a promising anti-tumor therapeutic strategy.

Tacrolimus-loaded Drug Delivery Systems in Vascularized Composite Allotransplantation: Lessons and Opportunities for Local Immunosuppression.

Long-term systemic immunosuppression is needed for vascularized composite allotransplantation (VCA). The high rate of acute rejection episodes in the first posttransplant year, the development of chronic rejection, and the adverse effects that come along with this treatment, currently prevent a wider clinical application of VCA. Opportunistic infections and metabolic disturbances are among the most observed side effects in VCA recipients. To overcome these challenges, local immunosuppression using biomaterial-based drug delivery systems (DDS) have been developed. The aim of these systems is to provide high local concentrations of immunosuppressive drugs while reducing their systemic load. This review provides a summary of recently investigated local DDS with different mechanisms of action such as on-demand, ultrasound-sensitive, or continuous drug delivery. In preclinical models, ranging from rodent to porcine and nonhuman primate models, this approach has been shown to reduce systemic tacrolimus (TAC) load and adverse effects, while prolonging graft survival. Localized immunosuppression using biomaterial-based DDS represents an encouraging approach to enhance graft survival and reduce toxic side effects of immunosuppressive drugs in VCA patients. Preclinical models using TAC-releasing DDS have demonstrated high local immunosuppressive effects with a low systemic burden. However, to reduce acute rejection events in translational animal models or in the clinical reality, the use of additional low-dose systemic TAC treatment may be envisaged. Patients may benefit through efficient graft immunosuppression and survival with negligible systemic adverse effects, resulting in better compliance and quality of life.

Transboundary migration of Loxostege sticticalis (Lepidoptera: Crambidae) among China, Russia and Mongolia.

BACKGROUND: The beet webworm, Loxostege sticticalis, a worldwide pest of many crops, performs a seasonal migration, causing periodic outbreaks in Asia, Europe and North America. Although long-distance migration is well documented in China, patterns of transboundary migration among China, Russia and Mongolia are largely unknown. We performed a phase analysis of L. sticticalis periodic outbreaks among three countries based on 30 years of historical population data, analyzed the wind systems during migration over boundary regions, and traced the migratory routes in a case study of outbreaks in 2008 by trajectory simulation. RESULTS: Highly synchronized outbreak years of L. sticticalis were observed between China and Mongolia, China and eastern Siberia, China and western Siberia, Mongolia and eastern Siberia, eastern Siberia and western Siberia from 1978 to 2008, indicating possible transboundary migration between these regions. Winds at 300-600 m altitude, where adult migration usually occurs, also showed a high probability of northwestern winds in Haila'er (China), Chita (Russia) and Choybalsan (Mongolia), favoring successful adult migration from these areas to northern and northeastern China. Back trajectory analysis further showed that the first-generation adults that caused the severe outbreak of second-generation larvae in 2008 originated from eastern Siberia, eastern Mongolia, and the boundary regions of China-Russia and China-Mongolia. CONCLUSION: Our findings demonstrated that the source of L. sticticalis outbreaks in northern China was closely related to the outbreaks in Siberia and Mongolia via long-distance transboundary windborne migration. This information will help guide international monitoring and management strategies against this notorious pest. © 2024 Society of Chemical Industry.

The influence of social feedback on reward learning in the Iowa gambling task.

Learning, an important activity for both human and animals, has long been a focal point of research. During the learning process, subjects assimilate not only their own information but also information from others, a phenomenon known as social learning. While numerous studies have explored the impact of social feedback as a reward/punishment during learning, few studies have investigated whether social feedback facilitates or inhibits the learning of environmental rewards/punishments. This study aims to test the effects of social feedback on economic feedback and its cognitive processes by using the Iowa Gambling Task (IGT). One hundred ninety-two participants were recruited and categorized into one non-social feedback group and four social feedback groups. Participants in the social feedback groups were informed that after the outcome of each choice, they would also receive feedback from an online peer. This peer was a fictitious entity, with variations in identity (novice or expert) and feedback type (random or effective). The Outcome-Representation Learning model (ORL model) was used to quantify the cognitive components of learning. Behavioral results showed that both the identity of the peer and the type of feedback provided significantly influenced the deck selection, with effective social feedback increasing the ratio of chosen good decks. Results in the ORL model showed that the four social feedback groups exhibited lower learning rates for gain and loss compared to the nonsocial feedback group, which suggested, in the social feedback groups, the impact of the recent outcome on the update of value decreased. Parameters such as forgetfulness, win frequency, and deck perseverance in the expert-effective feedback group were significantly higher than those in the non-social feedback and expert-random feedback groups. These findings suggest that individuals proactively evaluate feedback providers and selectively adopt effective feedback to enhance learning.

Cystic adenomyoma of the uterus: Case report and literature review.

Cystic adenomyosis is a rare type of adenomyosis. The main clinical manifestation of uterine cystic adenomyoma is severe dysmenorrhoea, and the condition can be diagnosed by relevant clinical examination. The preferred treatment, with a good prognosis, is lesion resection. The clinical data of a patient with uterine cystic adenomyoma recorded at the Third Hospital of Hebei Medical University are reported herein. A 39-year-old female patient presented with tolerable menstrual pain and aggravated dysmenorrhoea, which she had experienced for 4 years, and menorrhagia, which she had had for approximately 1 year. Ultrasound and tumour marker tests suggested abnormalities, and magnetic resonance imaging confirmed a diagnosis of uterine cystic adenomyoma. A hysteroscopy and intrauterine lesion electrocision were performed, and the results of postoperative pathology tests suggested that the endometriosis cysts had returned to normal after the postoperative intervention. The analysis of the clinical manifestations and diagnosis and treatment of uterine cystic adenomyoma can improve the understanding of the disease and reduce the rates of misdiagnosis and missed diagnoses to ensure early detection with timely diagnosis and treatment.

Treatment of chromium-containing sludge using sintering and ironmaking combined technology: A risk-reducing strategy for environmental impact.

The efficient, safe and eco-friendly disposal of the chromium-containing sludge (CCS) has attracted an increasing concern. In this study, Co-processing of CCS was developed via employing sintering and ironmaking combined technology for its harmless disposal and resource utilization. Crystalline phase and valence state transformation of chromium (Cr), technical feasibility assessment, leaching risk, characteristics of sintered products, and pollutant release during CCS co-processing were investigated through a series of laboratory-scale sintering pot experiments and large scale industrial trials. The results showed that the content of Cr(VI) in sintered products first increased then decreased with increasing temperature ranges of 300 °C-800 °C, and reached a maximum of 2189.64 mg/kg at 500 °C. 99.99% of Cr(VI) can be reduced to Cr(III) at above 1000 °C, which was attributed to the transformation of the Cr(VI)-containing crystalline phases (such as, MgCrO4 and CaCrO4) to the (Mg, Fe2+)(Cr, Al, Fe3+)2O4. The industrial trial results showed that adding 0.5 wt‰ CCS to sintering feed did not have adverse effects on the properties of the sintered ore and the plant's operating stability. The tumbler index of sinter was above 78% and the leaching concentrations of TCr (0.069 mg/L) was significantly lower than the Chinese National Standard of 1.0 mg/L (GB5085.3-2007). The TCr contents of sintering dust and blast furnace gas (BFG) scrubbing water were less than 0.19 wt‰ and 0.11 mg/L, respectively, which was far below the regulatory limit (1.5 mg/L, GB13456-2012). The mass balance evaluation results indicated that at least 89.9% of the Cr in the CCS migrated into the molten iron in the blast furnace (BF), which became a useful supplement to the molten iron. This study provided a new perspective strategy for the safe disposal and resource utilization of CCS in iron and steel industry.

Promoting tissue repair using deferoxamine nanoparticles loaded biomimetic gelatin/HA composite hydrogel.

To effectively address underlying issues and enhance the healing process of hard-to-treat soft tissue defects, innovative therapeutic approaches are required. One promising strategy involves the incorporation of bioactive substances into biodegradable scaffolds to facilitate synergistic tissue regeneration, particularly in vascular regeneration. In this study, we introduce a composite hydrogel design that mimics the extracellular matrix by covalently combining gelatin and hyaluronic acid (HA), with the encapsulation of deferoxamine nanoparticles (DFO NPs) for potential tissue regeneration applications. Crosslinked hydrogels were fabricated by controlling the ratio of HA in the gelatin-based hydrogels, resulting in improved mechanical properties, enhanced degradation ability, and optimised porosity, compared with hydrogel formed by gelatin alone. The DFO NPs, synthesized using a double emulsion method with poly (D,L-lactide-co-glycolide acid), exhibited a sustained release of DFO over 12 d. Encapsulating the DFO NPs in the hydrogel enabled controlled release over 15 d. The DFO NPs, composite hydrogel, and the DFO NPs loaded hydrogel exhibited excellent cytocompatibility and promoted cell proliferationin vitro. Subcutaneous implantation of the composite hydrogel and the DFO NPs loaded hydrogel demonstrated biodegradability, tissue integration, and no obvious adverse effects, evidenced by histological analysis. Furthermore, the DFO NPs loaded composite hydrogel exhibited accelerated wound closure and promoted neovascularisation and granular formation when tested in an excisional skin wound model in mice. These findings highlight the potential of our composite hydrogel system for promoting the faster healing of diabetes-induced skin wounds and oral lesions through its ability to modulate tissue regeneration processes.

Deep multiscale convolutional feature learning for intracranial hemorrhage classification and weakly supervised localization.

Objective: This study evaluated the performance of attentional fusion model-based multiscale features in classifying intracerebral hemorrhage and the localization of bleeding focus based on weakly supervised target localization. Methods: A publicly available dataset provided by the American College of Neuroradiology (ASNR) was used, consisting of 750,000 computed tomography (CT) scans of the brain, manually marked by radiologists for intracranial hemorrhage and five hemorrhage subtypes. A multiscale feature classification and weakly supervised localization framework based on an attentional fusion mechanism were applied, which could be annotated at the slice level and provided intracranial hemorrhage classification and hemorrhage focus localization. Results: The designed framework achieved excellent performance for classification and localization. The area under the curve (AUC) for predicting bleeding was 0.973. High AUC values were observed for the five hemorrhage subtypes (epidural AUC = 0.891, subdural AUC = 0.991, subarachnoid AUC = 0.983, intraventricular AUC = 0.995, intraparenchymal AUC = 0.990). This model outperformed the average entry-level radiology trainee compared to previously reported data. Conclusion: The designed method quickly and accurately detected intracerebral hemorrhage, classifying hemorrhage subtypes and locating bleeding points with image-level annotation alone. The results indicate that this framework can significantly reduce diagnostic time while improving the detection of intracerebral hemorrhage in emergencies. It can thus be integrated into the diagnostic radiology workflow in the future.

EMPT: a sparsity Transformer for EEG-based motor imagery recognition.

Introduction: Transformer network is widely emphasized and studied relying on its excellent performance. The self-attention mechanism finds a good solution for feature coding among multiple channels of electroencephalography (EEG) signals. However, using the self-attention mechanism to construct models on EEG data suffers from the problem of the large amount of data required and the complexity of the algorithm. Methods: We propose a Transformer neural network combined with the addition of Mixture of Experts (MoE) layer and ProbSparse Self-attention mechanism for decoding the time-frequency-spatial domain features from motor imagery (MI) EEG of spinal cord injury patients. The model is named as EEG MoE-Prob-Transformer (EMPT). The common spatial pattern and the modified s-transform method are employed for achieving the time-frequency-spatial features, which are used as feature embeddings to input the improved transformer neural network for feature reconstruction, and then rely on the expert model in the MoE layer for sparsity mapping, and finally output the results through the fully connected layer. Results: EMPT achieves an accuracy of 95.24% on the MI EEG dataset for patients with spinal cord injury. EMPT has also achieved excellent results in comparative experiments with other state-of-the-art methods. Discussion: The MoE layer and ProbSparse Self-attention inside the EMPT are subjected to visualisation experiments. The experiments prove that sparsity can be introduced to the Transformer neural network by introducing MoE and kullback-leibler divergence attention pooling mechanism, thereby enhancing its applicability on EEG datasets. A novel deep learning approach is presented for decoding EEG data based on MI.

A Study on the Efficacy of Thrombectomy in Patients with Atherosclerotic and Cardioembolic Basilar Artery Occlusion.

Background Studies on basilar artery occlusion are relatively few compared with those of anterior circulation stroke. The aim of the present study was to compare the efficacy of endovascular therapy (EVT) in patients with basilar artery occlusion classified as large artery atherosclerosis (LAA) and cardioembolism (CE), and to analyze the independent risk factors affecting the prognosis of EVT. Methods A total of 123 people were assigned to the LAA and CE groups (97 to the LAA and 26 to the CE). The primary outcome was a modified Rankin Scale (mRS) score of 2 or lower at 90 days. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial hemorrhage and reinfarction. Multiple logistic regression was used to screen out independent risk factors for EVT prognosis of the LAA and CE groups. Results In the analysis, the patients with LAA stroke had better collateral circulation (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology [SIR] score of 2-4; 61.9 vs. 19.2%, p = 0.000), and higher angioplasty rate (32.0 vs. 3.8%, p = 0.002). The proportions of patients with a 90-day mRS score of 0 to 2 and 90-day mortality were not found to be statistically significant between the two groups. Multivariate logistic regression analysis indicated that age, SIR, white blood cell, blood glucose, and modified thrombolysis in cerebral infarction were independent risk factors for the poor prognosis of EVT in the LAA group. Conclusion Although there were differences in clinical characteristics and imaging features between LAA and CE, there was no evidence of a significant difference in prognosis after EVT. In addition, the National Institutes of Health Stroke Scale score was not among the independent risk factors affecting the prognosis of the LAA group.

Integrated physiological, transcriptomic and metabolomic analyses reveal the mechanism of peanut kernel weight reduction under waterlogging stress.

Waterlogging stress (WS) hinders kernel development and directly reduces peanut yield; however, the mechanism of kernel filling in response to WS remains unknown. The waterlogging-sensitive variety Huayu 39 was subjected to WS for 3 days at 7 days after the gynophores touched the ground (DAG). We found that WS affected kernel filling at 14, 21, and 28 DAG. WS decreased the average filling rate and kernel dry weight, while transcriptome sequencing and widely targeted metabolomic analysis revealed that WS inhibited the gene expression in starch and sucrose metabolism, which reduced sucrose input and transformation ability. Additionally, genes related to ethylene and melatonin synthesis and the accumulation of tryptophan and methionine were upregulated in response to WS. WS upregulated the expression of the gene encoding tryptophan decarboxylase (AhTDC), and overexpression of AhTDC in Arabidopsis significantly reduced the seed length, width, and weight. Therefore, WS reduced the kernel-filling rate, leading to a reduction in the 100-kernel weight. This survey informs the development of measures that alleviate the negative impact of WS on peanut yield and quality and provides a basis for exploring high-yield and high-quality cultivation, molecular-assisted breeding, and waterlogging prevention in peanut farming.

Picometer-Scale Atomic Shifts Governing Subdisordered Structures in Diamond.

Diamond is considered the most promising next-generation semiconductor material due to its excellent physical characteristics. It has been more than three decades since the discovery of a special structure named n-diamond. However, despite extensive efforts, its crystallographic structure and properties are still unclear. Here, we show that subdisordered structures in diamond provide an explanation for the structural feature of n-diamond. Monocrystalline diamond with subdisordered structures is synthesized via the chemical vapor deposition method. Atomic-resolution scanning transmission electron microscopy characterizations combined with the picometer-precision peak finder technology and diffraction simulations reveal that picometer-scale shifts of atoms within cells of diamond govern the subdisordered structures. First-principles calculations indicate that the bandgap of diamond decreases rapidly with increasing shifting distance, in accordance with experimental results. These findings clarify the crystallographic structure and electronic properties of n-diamond and provide new insights into the bandgap adjustment in diamond.

Spectral fusion-based machine learning classifiers for discriminating membrane breakage in multiple scenarios.

Membrane breakage can lead to filtration failure, which allows harmful substances to enter the effluent, posing potential hazards to human health and the environment. This study is an innovative combination of fluorescence and ultraviolet-visible (UV-Vis) spectroscopy to identify membrane breakage. It aims to unravel more comprehensive information, improve detection sensitivity and selectivity, and enable real-time monitoring capabilities. Fluorescence and UV-Vis data are extracted through variance partitioning analysis (VPA) and integrated through a decision tree algorithm to form a superior system with enhanced discrimination capabilities. VPA improves discrimination efficiency by extracting key information from spectral data and eliminating redundancy. The decision tree algorithm, on the other hand, can process large amounts of data simultaneously. In addition, the method has a wide range of applications and can be used in various scenarios accurately. The scenarios include domestic sewage, micropollutant water, aquaculture wastewater, and secondary treated sewage. The experimental results validate the application of machine learning classifiers in membrane breakage detection with an accuracy rate of 96.8 % to 97.4 %.

Decrease of ESKAPE virulence with a cationic heme-mimetic gallium porphyrin photosensitizer: The Trojan horse strategy that could help address antimicrobial resistance.

INTRODUCTION: Emerging antibiotic resistance among bacterial pathogens has forced an urgent need for alternative non-antibiotic strategies development that could combat drug resistant-associated infections. Suppression of virulence of ESKAPE pathogens' by targeting multiple virulence traits provides a promising approach. OBJECTIVES: Here we propose an iron-blocking antibacterial therapy based on a cationic heme-mimetic gallium porphyrin (GaCHP), which antibacterial efficacy could be further enhanced by photodynamic inactivation. METHODS: We used gallium heme mimetic porphyrin (GaCHP) excited with light to significantly reduce microbial viability and suppress both the expression and biological activity of several virulence traits of both Gram-positive and Gram-negative ESKAPE representatives, i.e., S. aureus and P. aeruginosa. Moreover, further improvement of the proposed strategy by combining it with routinely used antimicrobials to resensitize the microbes to antibiotics and provide enhanced bactericidal efficacy was investigated. RESULTS: The proposed strategy led to substantial inactivation of critical priority pathogens and has been evidenced to suppress the expression and biological activity of multiple virulence factors in S. aureus and P. aeruginosa. Finally, the combination of GaCHP phototreatment and antibiotics resulted in promising strategy to overcome antibiotic resistance of the studied microbes and to enhance disinfection of drug resistant pathogens. CONCLUSION: Lastly, considering high safety aspects of the proposed treatment toward host cells, i.e., lack of mutagenicity, no dark toxicity and mild phototoxicity, we describe an efficient alternative that simultaneously suppresses the functionality of multiple virulence factors in ESKAPE pathogens.

Hexabenzoheptacene: A Longitudinally Multihelicene Nanocarbon with Local Aromaticity and Enhanced Stability.

We report the synthesis of a longitudinally helical molecular nanocarbon, hexabenzoheptacene (HBH), along with its dimethylated derivative (HBH-Me), which are composed of six benzene rings periodically benzannulated to both zigzag edges of a heptacene core. This benzannulation pattern endows the resulting nanocarbons with a helical heptacene core and local aromaticity, imparting enhanced solubility and stability to the system. The chiral HBH-Me adopts a more highly twisted conformation with an end-to-end twist angle of 95°, enabling the separation of the enantiomers. Both HBH and HBH-Me can be facilely oxidized into their corresponding dications, which exhibit enhanced planarity and aromaticity upon loss of electrons. Notably, both longitudinally helical nanocarbons readily promote solid state packing into two-dimensional (2D) arrangement. Single-crystal microbelts of HBH-Me show hole mobility up to 0.62 cm2 V-1 s-1, illustrating the promising potential of these longitudinally helical molecules for organic electronic devices.

Genipin improves obesity through promoting bile secretion and changing bile acids composition in diet-induced obese rats.

OBJECTIVES: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. METHODS: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. KEY FINDINGS: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. CONCLUSIONS: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.

Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.