Antiviral activity of Vigna radiata extract against feline coronavirus in vitro.

Feline infectious peritonitis (FIP) is a fatal illness caused by a mutated feline coronavirus (FCoV). This disease is characterized by its complexity, resulting from systemic infection, antibody-dependent enhancement (ADE), and challenges in accessing effective therapeutics. Extract derived from Vigna radiata (L.) R. Wilczek (VRE) exhibits various pharmacological effects, including antiviral activity. This study aimed to investigate the antiviral potential of VRE against FCoV, addressing the urgent need to advance the treatment of FIP. We explored the anti-FCoV activity, antiviral mechanism, and combinational application of VRE by means of in vitro antiviral assays. Our findings reveal that VRE effectively inhibited the cytopathic effect induced by FCoV, reduced viral proliferation, and downregulated spike protein expression. Moreover, VRE blocked FCoV in the early and late infection stages and was effective under in vitro ADE infection. Notably, when combined with VRE, the polymerase inhibitor GS-441524 or protease inhibitor GC376 suppressed FCoV more effectively than monotherapy. In conclusion, this study characterizes the antiviral property of VRE against FCoV in vitro, and VRE possesses therapeutic potential for FCoV treatment.

Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs.

Engineering human enzymes for therapeutic applications is attractive but introducing new amino acids may adversely affect enzyme stability and immunogenicity. Here we used a mammalian membrane-tethered screening system (ECSTASY) to evolve human lysosomal beta-glucuronidase (hBG) to hydrolyze a glucuronide metabolite (SN-38G) of the anticancer drug irinotecan (CPT-11). Three human beta-glucuronidase variants (hBG3, hBG10 and hBG19) with 3, 10 and 19 amino acid substitutions were identified that display up to 40-fold enhanced enzymatic activity, higher stability than E. coli beta-glucuronidase in human serum, and similar pharmacokinetics in mice as wild-type hBG. The hBG variants were two to three orders of magnitude less immunogenic than E. coli beta-glucuronidase in hBG transgenic mice. Intravenous administration of an immunoenzyme (hcc49-hBG10) targeting a sialyl-Tn tumor-associated antigen to mice bearing human colon xenografts significantly enhanced the anticancer activity of CPT-11 as measured by tumor suppression and mouse survival. Our results suggest that genetically-modified human enzymes represent a good alternative to microbially-derived enzymes for therapeutic applications.

Pulmonary Hypertension Induces Serotonin Hyperreactivity and Metabolic Reprogramming in Coronary Arteries via NOX1/4-TRPM2 Signaling Pathway.

BACKGROUND: Clinical evidence revealed abnormal prevalence of coronary artery (CA) disease in patients with pulmonary hypertension (PH). The mechanistic connection between PH and CA disease is unclear. Serotonin (5-hydroxytryptamine), reactive oxygen species, and Ca2+ signaling have been implicated in both PH and CA disease. Our recent study indicates that NOXs (NADPH [nicotinamide adenine dinucleotide phosphate] oxidases) and TRPM2 (transient receptor potential cation channel subfamily M member 2) are key components of their interplay. We hypothesize that activation of the NOX-TRPM2 pathway facilitates the remodeling of CA in PH. METHODS: Left and right CAs from chronic hypoxia and monocrotaline-induced PH rats were collected to study vascular reactivity, gene expression, metabolism, and mitochondrial function. Inhibitors or specific siRNA were used to examine the pathological functions of NOX1/4-TRPM2 in CA smooth muscle cells. RESULTS: Significant CA remodeling and 5-hydroxytryptamine hyperreactivity in the right CA were observed in PH rats. NOX1/4-mediated reactive oxygen species production coupled with TRPM2-mediated Ca2+ influx contributed to 5-hydroxytryptamine hyperresponsiveness. CA smooth muscle cells from chronic hypoxia-PH rats exhibited increased proliferation, migration, apoptosis, and metabolic reprogramming in an NOX1/4-TRPM2-dependent manner. Furthermore, the NOX1/4-TRPM2 pathway participated in mitochondrial dysfunction, involving mitochondrial DNA damage, reactive oxygen species production, elevated mitochondrial membrane potential, mitochondrial Ca2+ accumulation, and mitochondrial fission. In vivo knockdown of NOX1/4 alleviated PH and suppressed CA remodeling in chronic hypoxia rats. CONCLUSIONS: PH triggers an increase in 5-hydroxytryptamine reactivity in the right CA and provokes metabolic reprogramming and mitochondrial disruption in CA smooth muscle cells via NOX1/4-TRPM2 activation. This signaling pathway may play an important role in CA remodeling and CA disease in PH.

Genetic exploration of roles of acid-sensing ion channel subtypes in neurosensory mechanotransduction including proprioception.

Although acid-sensing ion channels (ASICs) are proton-gated ion channels responsible for sensing tissue acidosis, accumulating evidence has shown that ASICs are also involved in neurosensory mechanotransduction. However, in contrast to Piezo ion channels, evidence of ASICs as mechanically gated ion channels has not been found using conventional mechanoclamp approaches. Instead, ASICs are involved in the tether model of mechanotransduction, with the channels gated via tethering elements of extracellular matrix and intracellular cytoskeletons. Methods using substrate deformation-driven neurite stretch and micropipette-guided ultrasound were developed to reveal the roles of ASIC3 and ASIC1a, respectively. Here we summarize the evidence supporting the roles of ASICs in neurosensory mechanotransduction in knockout mouse models of ASIC subtypes and provide insight to further probe their roles in proprioception.

Nucleus accumbens deep brain stimulation improves depressive-like behaviors through BDNF-mediated alterations in brain functional connectivity of dopaminergic pathway.

Major depressive disorder (MDD), a common psychiatric condition, adversely affects patients' moods and quality of life. Despite the development of various treatments, many patients with MDD remain vulnerable and inadequately controlled. Since anhedonia is a feature of depression and there is evidence of leading to metabolic disorder, deep brain stimulation (DBS) to the nucleus accumbens (NAc) might be promising in modulating the dopaminergic pathway. To determine whether NAc-DBS alters glucose metabolism via mitochondrial alteration and neurogenesis and whether these changes increase neural plasticity that improves behavioral functions in a chronic social defeat stress (CSDS) mouse model. The Lab-designed MR-compatible neural probes were implanted in the bilateral NAc of C57BL/6 mice with and without CSDS, followed by DBS or sham stimulation. All animals underwent open-field and sucrose preference testing, and brain resting-state functional MRI analysis. Meanwhile, we checked the placement of neural probes in each mouse by T2 images. By confirming the placement location, mice with incorrect probe placement (the negative control group) showed no significant therapeutic effects in behavioral performance and functional connectivity (FC) after receiving electrical stimulation and were excluded from further analysis. Western blotting, seahorse metabolic analysis, and electron microscopy were further applied for the investigation of NAc-DBS. We found NAc-DBS restored emotional deficits in CSDS-subjected mice. Concurrent with behavioral amelioration, the CSDS DBS-on group exhibited enhanced FC in the dopaminergic pathway with increased expression of BDNF- and NeuN-positive cells increased dopamine D1 receptor, dopamine D2 receptors, and TH in the medial prefrontal cortex, NAc, ventral hippocampus, ventral tegmental area, and amygdala. Increased pAMPK/total AMPK and PGC-1α levels, functions of oxidative phosphorylation, and mitochondrial biogenesis were also observed after NAc-DBS treatment. Our findings demonstrate that NAc-DBS can promote BDNF expression, which alters FC and metabolic profile in the dopaminergic pathway, suggesting a potential strategy for ameliorating emotional processes in individuals with MDD.

Prediction of extranodal extension in head and neck squamous cell carcinoma by CT images using an evolutionary learning model.

BACKGROUND: Extranodal extension (ENE) in head and neck squamous cell carcinoma (HNSCC) correlates to poor prognoses and influences treatment strategies. Deep learning may yield promising performance of predicting ENE in HNSCC but lack of transparency and interpretability. This work proposes an evolutionary learning method, called EL-ENE, to establish a more interpretable ENE prediction model for aiding clinical diagnosis. METHODS: There were 364 HNSCC patients who underwent neck lymph node (LN) dissection with pre-operative contrast-enhanced computerized tomography images. All the 778 LNs were divided into training and test sets with the ratio 8:2. EL-ENE uses an inheritable bi-objective combinatorial genetic algorithm for optimal feature selection and parameter setting of support vector machine. The diagnostic performances of the ENE prediction model and radiologists were compared using independent test datasets. RESULTS: The EL-ENE model achieved the test accuracy of 80.00%, sensitivity of 81.13%, and specificity of 79.44% for ENE detection. The three radiologists achieved the mean diagnostic accuracy of 70.4%, sensitivity of 75.6%, and specificity of 67.9%. The features of gray-level texture and 3D morphology of LNs played essential roles in predicting ENE. CONCLUSIONS: The EL-ENE method provided an accurate, comprehensible, and robust model to predict ENE in HNSCC with interpretable radiomic features for expanding clinical knowledge. The proposed transparent prediction models are more trustworthy and may increase their acceptance in daily clinical practice.

Assessing traffic-related air pollution-induced fiber-specific white matter degradation associated with motor performance declines in aged rats.

Fine particulate matter (PM2.5) is thought to exacerbate Parkinson's disease (PD) in the elderly, and early detection of PD progression may prevent further irreversible damage. Therefore, we used diffusion tensor imaging (DTI) for probing microstructural changes after late-life chronic traffic-related PM2.5 exposure. Herein, 1.5-year-old Fischer 344 rats were exposed to clean air (control), high-efficiency particulate air (HEPA)-filtered ambient air (HEPA group), and ambient traffic-related PM2.5 (PM2.5 group, 9.933 ± 1.021 µg/m3) for 3 months. Rotarod test, DTI tractographic analysis, and immunohistochemistry were performed in the end of study period. Aged rats exposed to PM2.5 exhibited motor impairment with decreased fractional anisotropy and tyrosine hydroxylase expression in olfactory and nigrostriatal circuits, indicating disrupted white matter integrity and dopaminergic (DA) neuronal loss. Additionally, increased radial diffusivity and lower expression of myelin basic protein in PM2.5 group suggested ageing progression of demyelination exacerbated by PM2.5 exposure. Significant production of tumor necrosis factor-α was also observed after PM2.5 exposure, revealing potential inflammation of injury to multiple fiber tracts of DA pathways. Microstructural changes demonstrated potential links between PM2.5-induced inflammatory white matter demyelination and behavioral performance, with indication of pre-manifestation of DTI-based biomarkers for early detection of PD progression in the elderly.

Study of vacuole glycerate transporter NPF8.4 reveals a new role of photorespiration in C/N balance.

The photorespiratory intermediate glycerate is known to be shuttled between the peroxisome and chloroplast. Here, localization of NPF8.4 in the tonoplast, together with the reduced vacuolar glycerate content displayed by an npf8.4 mutant and the glycerate efflux activity detected in an oocyte expression system, identifies NPF8.4 as a tonoplast glycerate influx transporter. Our study shows that expression of NPF8.4 and most photorespiration-associated genes, as well as the photorespiration rate, is upregulated in response to short-term nitrogen (N) depletion. We report growth retardation and early senescence phenotypes for npf8.4 mutants specifically upon N depletion, suggesting that the NPF8.4-mediated regulatory pathway for sequestering the photorespiratory carbon intermediate glycerate in vacuoles is important to alleviate the impact of an increased C/N ratio under N deficiency. Thus, our study of NPF8.4 reveals a novel role for photorespiration in N flux to cope with short-term N depletion.

Pediatric Cardiac Lymphoblastic Lymphoma: A Case Report and Review of the Literature.

Cardiac lymphoma is rare in children. Treatment typically includes chemotherapy, combination of radiotherapy, or surgery. We report a case of stage IV precursor B lymphoblastic lymphoma with secondary involvement of the heart in an 11-year-old girl who was treated with acute lymphoblastic leukemia-based chemotherapy. Also, we review the literature on this uncommon malignancy.

Antibodies against Poly(ethylene glycol) Activate Innate Immune Cells and Induce Hypersensitivity Reactions to PEGylated Nanomedicines.

Nanomedicines and macromolecular drugs can induce hypersensitivity reactions (HSRs) with symptoms ranging from flushing and breathing difficulties to hypothermia, hypotension, and death in the most severe cases. Because many normal individuals have pre-existing antibodies that bind to poly(ethylene glycol) (PEG), which is often present on the surface of nanomedicines and macromolecular drugs, we examined if and how anti-PEG antibodies induce HSRs to PEGylated liposomal doxorubicin (PLD). Anti-PEG IgG but not anti-PEG IgM induced symptoms of HSRs including hypothermia, altered lung function, and hypotension after PLD administration in C57BL/6 and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Hypothermia was significantly reduced by blocking FcγRII/III, by depleting basophils, monocytes, neutrophils, or mast cells, and by inhibiting secretion of histamine and platelet-activating factor. Anti-PEG IgG also induced hypothermia in mice after administration of other PEGylated liposomes, nanoparticles, or proteins. Humanized anti-PEG IgG promoted binding of PEGylated nanoparticles to human immune cells and induced secretion of histamine from human basophils in the presence of PLD. Anti-PEG IgE could also induce hypersensitivity reactions in mice after administration of PLD. Our results demonstrate an important role for IgG antibodies in induction of HSRs to PEGylated nanomedicines through interaction with Fcγ receptors on innate immune cells and provide a deeper understanding of HSRs to PEGylated nanoparticles and macromolecular drugs that may facilitate development of safer nanomedicines.

Mouse Abdominal Aortic Aneurysm Model Induced by Periarterial Incubation of Papain.

For decades, numerous experimental animal models have been developed to examine the pathophysiologic mechanisms and potential treatments for abdominal aortic aneurysms (AAAs) in diverse species with varying chemical or surgical approaches. This study aimed to create an AAA mouse model by the periarterial incubation with papain, which can mimic human AAA with advantages such as simplicity, convenience, and high efficiency. Eighty C57BL/6J male mice were randomly assigned to 1 of the 4 groups: papain (1.0 or 2.0 mg), porcine pancreatic elastase, and phosphate-buffered solution. The aortic segment was wrapped for 20 minutes, and the diameter was measured using ultrasound preoperatively and postoperative days 7 and 14. Then, the mice were killed for histomorphometric and immunohistochemical analyses. According to ultrasound measurements and histomorphometric analyses, on postoperative day 7, 65% of mice in the 1.0-mg papain group and 60% of mice in the 2.0-mg papain group developed AAA. In both papain groups, 100% of mice developed AAA, and 65% of mice in the porcine pancreatic elastase group developed AAA on postoperative day 14. Furthermore, hematoxylin/eosin, elastin van Gieson, and Masson staining of tissues from the papain group revealed thickened media and intimal hyperplasia, collagen sediments, and elastin destruction, indicating that AAA histochemical alteration was similar to that of humans. In addition, the immunohistochemical analysis was conducted to detect infiltrated inflammatory cells, such as macrophages and leukocytes, in the aortic wall and hyperplasic adventitia. The expression of matrix metalloproteinase 2 and 9 was significantly upregulated in papain and human AAA tissues. Periarterial incubation with 1.0 mg of papain for 20 minutes can successfully create an experimental AAA model in mice for 14 days, which can be used to explore the mechanism and treatment of human AAA.

Motivating Individuals to Take Responsible Ocean Action: The Mediatory Effects of Attitude toward the Ocean.

When considering how to improve public literacy and behavior related to specific themes, top priority is usually given to strategies that enhance relevant knowledge. Fostering attitude comes later. Understanding the mechanisms of behavior may help us develop better policy and educational strategies. However, how knowledge and attitude impact behavior is still under investigation. The aim of this study is to explore the relationships among ocean knowledge, attitude toward the ocean, and the intention to behave responsibly in the marine setting. Specifically, we investigated a potential mediation mechanism by recruiting a total of 266 participants, whose ocean knowledge, attitudes toward the ocean, and intention to behave responsibly were evaluated using questionnaires. The results indicate that a person's attitude toward the ocean may indeed be a mediating factor between ocean knowledge and their intention to show positive marine behavior. In order to engage people in responsible ocean behavior, other forms of assistance from marine policy and education are recommended. Additionally, it would be of interest for future studies to investigate the effects of attitude and attitude-related knowledge in the development of ocean actions.

[Oral Care to Prevent Ventilator-Associated Pneumonia].

Ventilator-associated pneumonia (VAP), one of the most common nosocomial infections in critical care units, has been associated with adverse outcomes such as higher medical expenses, prolonged hospital stays, and higher mortality rates. Although studies have demonstrated the effectiveness of oral care in reducing VAP incidence and enhancing patient comfort, few critically ill patients are able to perform oral care independently. Moreover, related evaluations and execution require specialized nursing techniques that rely on well-trained nurses. Unfortunately, descriptions of oral evaluations, caring practices, and hygiene related to pathogenic mechanisms in critically ill patients are scarce in both textbooks and the scientific literature. Based on a review of the related literature, this article discusses: the pathogenic mechanism of VAP; the purpose, principals, and steps of providing oral care to endotracheal tube ventilated patients, with particular emphasis on current evidence on the effect of chlorhexidine on oral care; and the major factors impacting oral care effectiveness. This article is expected to raise awareness of oral care, update the current evidence-based knowledge base, and increase the quality of nursing care provided to critically ill populations.

Accelerated clearance by antibodies against methoxy PEG depends on pegylation architecture.

Methoxy polyethylene glycol (mPEG) is attached to many proteins, peptides, nucleic acids and nanomedicines to improve their biocompatibility. Antibodies that bind PEG are present in many individuals and can be generated upon administration of pegylated therapeutics. Anti-PEG antibodies that bind to the PEG "backbone" can accelerate drug clearance and detrimentally affect drug activity and safety, but no studies have examined how anti-methoxy PEG (mPEG) antibodies, which selectively bind the terminus of mPEG, affect pegylated drugs. Here, we investigated how defined IgG and IgM monoclonal antibodies specific to the PEG backbone (anti-PEG) or terminal methoxy group (anti-mPEG) affect pegylated liposomes or proteins with a single PEG chain, a single branched PEG chain, or multiple PEG chains. Large immune complexes can be formed between all pegylated compounds and anti-PEG antibodies but only pegylated liposomes formed large immune complexes with anti-mPEG antibodies. Both anti-PEG IgG and IgM antibodies accelerated the clearance of all pegylated compounds but anti-mPEG antibodies did not accelerate clearance of proteins with a single or branched PEG molecule. Pegylated liposomes were primarily taken up by Kupffer cells in the liver, but both anti-PEG and anti-mPEG antibodies directed uptake of a heavily pegylated protein to liver sinusoidal endothelial cells. Our results demonstrate that in contrast to anti-PEG antibodies, immune complex formation and drug clearance induced by anti-mPEG antibodies depends on pegylation architecture; compounds with a single or branched PEG molecule are unaffected by anti-mPEG antibodies but are increasingly affected as the number of PEG chain in a structure increases.

Neuroplasticity of peripheral axonal properties after ischemic stroke.

OBJECTIVE: This study investigated how peripheral axonal excitability changes in ischemic stroke patients with hemiparesis or hemiplegia, reflecting the plasticity of motor axons due to corticospinal tract alterations along the poststroke stage. METHODS: Each subject received a clinical evaluation, nerve conduction study, and nerve excitability test. Nerve excitability tests were performed on motor median nerves in paretic and non-paretic limbs in the acute stage of stroke. Control nerve excitability test data were obtained from age-matched control subjects. Some patients underwent excitability examinations several times in subacute or chronic stages. RESULTS: A total of thirty patients with acute ischemic stroke were enrolled. Eight patients were excluded due to severe entrapment neuropathy in the median nerve. The threshold current for 50% compound muscle action potential (CMAP) was higher in paretic limbs than in control subjects. Furthermore, in the cohort with severe patients (muscle power ≤ 3/5 in affected hands), increased threshold current for 50% CMAP and reduced subexcitability were noted in affected limbs than in unaffected limbs. In addition, in the subsequent study of those severe patients, threshold electrotonus increased in the hyperpolarization direction: TEh (100-109 ms), and the minimum I/V slope decreased. The above findings suggest the less excitable and less accommodation in lower motor axons in the paretic limb caused by ischemic stroke. CONCLUSION: Upper motor neuron injury after stroke can alter nerve excitability in lower motor neurons, and the changes are more obvious in severely paretic limbs. The accommodative changes of axons progress from the subacute to the chronic stage after stroke. Further investigation is necessary to explore the downstream effects of an upper motor neuron insult in the peripheral nerve system.

Wound-Dressing-Based Antenna Inkjet-Printed Using Nanosilver Ink for Wireless Medical Monitoring.

In this paper, we present a wound-dressing-based antenna fabricated via screen-printed and inkjet-printed technologies. To inkjet print a conductive film on wound dressing, it must be screen-printed, UV-curable-pasted, and hard-baked to provide appropriate surface wettability. Two passes were UV-curable-pasted and hard-baked at 100 °C for 2 h on the wound dressing to obtain 65° WCA for silver printing. The silver film was printed onto the wound dressing at room-tempature with 23 µm droplet spacing for three passes, then sintered at 120 °C for 1 h. By optimizing the inkjet printing conditions by modifying the surface morphologies and electrical properties, three-pass printed silver films with 3.15 µm thickness and 1.05 × 107 S/m conductivity were obtained. The insertion losses at the resonant frequency (17 and 8.85 GHz) were -2.9 and -2.1 dB for the 5000 and 10,000 µm microstrip transmission lines, respectively. The material properties of wound dressing with the relative permittivity and loss-tangent of 3.15-3.25 and 0.04-0.05, respectively, were determined by two transmission line methods and used for antenna design. A quasi-Yagi antenna was designed and implemented on the wound-dressing with an antenna bandwidth of 3.2-4.6 GHz, maximal gain of 0.67 dBi, and 42% radiation efficiency. The bending effects parallel and perpendicular to the dipole direction of three fixtures were also examined. The gain decreased from 0.67 to -1.22 dBi and -0.44 dBi for a flat to curvature radius of 5 cm fixture after parallel and perpendicular bending, respectively. Although the maximal gain was reduced with the bending radius, the directivity of the radiation pattern remained unchanged. The feasibility of a wound-dressing antenna demonstrates that inkjet-printed technology enables fast fabrication with low cost and environmental friendliness. Additionally, inkjet-printed technology can be combined with sensing technology to realize remote medical monitoring, such as with smart bandages, for assessment of chronic wound status or basic physical conditions.

[Using the Model of Motivation to Improve the Accuracy of Nurses Conducting Aerosol Therapy in Mechanically Ventilated Patients].

ACKGROUND & PROBLEMS: Aerosol therapy is increasingly used in pulmonary critical care and in patients with respiratory disease. However, improper application of the aerosol delivery device will decrease the therapeutic effect as well as increase the incidence of pulmonary infection. An initial assessment conducted in our intensive care unit found an accuracy rate for nursing staff aerosol-therapy execution of only 55.9%. Possible reasons identified for this low rate included lack of learning experience and resources, lack of related standard operating procedures, lack of related performance assessments, complicated / unfamiliar device assembly procedure, diffuse storage of device components, and a lack of illustrations. PURPOSE: This project was developed to increase the accuracy rate of performing aerosol therapy to over 90% in our intensive care unit. METHODS: We designed diverse learning materials using the model of motivation, developed an evaluation system, simplified the assembly of components based on evidence-based research, improved the storage situation, and added reference illustrations. RESULTS: The accuracy rate in aerosol therapy execution for our nursing staff increased from 55.9% to 95.0% after the intervention. CONCLUSIONS: This project used the model of motivation to develop the teaching materials. By using diverse teaching methods, including both in-person classes and online interactive quizzes, we realized high learning satisfaction and efficacy. Along with simplifying equipment handling, improving the working environment, enhancing nurses' aerosol therapy techniques, establishing standard operating procedure guidelines, and adding an evaluation system, we standardized the entire procedure for potential promotion to other intensive care units.

Reduced CircSMOC1 Level Promotes Metabolic Reprogramming via PTBP1 (Polypyrimidine Tract-Binding Protein) and miR-329-3p in Pulmonary Arterial Hypertension Rats.

BACKGROUND: Pulmonary arterial hypertension maintains rapid cell proliferation and vascular remodeling through metabolic reprogramming. Recent studies suggested that circRNAs play important role in pulmonary vascular remodeling and pulmonary arterial smooth muscle cells proliferation. However, the relationship between circRNA, cell proliferation, and metabolic reprogramming in pulmonary arterial hypertension has not been investigated. METHODS: RNA-seq and qRT-PCR reveal the differential expression profile of circRNA in pulmonary arteries of pulmonary arterial hypertension rat models. Transfection was used to examine the effects of circSMOC1 on pulmonary artery smooth muscle cells, and the roles of circSMOC1 in vivo were investigated by adenoassociated virus. Mass spectrometry, RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assay were performed to investigate the signaling pathway of circSMOC1 regulating the metabolic reprogramming. RESULTS: CircSMOC1 was significantly downregulated in pulmonary arteries of pulmonary arterial hypertension rats. CircSMOC1 knockdown promoted proliferation and migration and enhanced aerobic glycolysis of pulmonary artery smooth muscle cells. CircSMOC1 overexpression in vivo alleviates pulmonary vascular remodeling, right ventricular pressure, and right heart hypertrophy. In the nucleus, circSMOC1 directly binds to PTBP1 (polypyrimidine tract-binding protein), competitively inhibits the specific splicing of PKM (pyruvate kinase M) premRNA, resulting in the upregulation of PKM2 (pyruvate kinase M2), the key enzyme of aerobic glycolysis, to enhance glycolysis. In the cytoplasm, circSMOC1 acted as a miR-329-3p sponge, and its reduction in pulmonary arterial hypertension suppressed PDHB (pyruvate dehydrogenase E1 subunit beta) expression, leading to the impairment of mitochondrial oxidative phosphorylation. CONCLUSIONS: circSMOC1 is crucially involved in the metabolic reprogramming of pulmonary artery smooth muscle cells through PTBP1 and miR-329-3p to regulate pulmonary vascular remodeling in pulmonary arterial hypertension.

Neuro-Inspired Reinforcement Learning to Improve Trajectory Prediction in Reward-Guided Behavior.

Hippocampal pyramidal cells and interneurons play a key role in spatial navigation. In goal-directed behavior associated with rewards, the spatial firing pattern of pyramidal cells is modulated by the animal's moving direction toward a reward, with a dependence on auditory, olfactory, and somatosensory stimuli for head orientation. Additionally, interneurons in the CA1 region of the hippocampus monosynaptically connected to CA1 pyramidal cells are modulated by a complex set of interacting brain regions related to reward and recall. The computational method of reinforcement learning (RL) has been widely used to investigate spatial navigation, which in turn has been increasingly used to study rodent learning associated with the reward. The rewards in RL are used for discovering a desired behavior through the integration of two streams of neural activity: trial-and-error interactions with the external environment to achieve a goal, and the intrinsic motivation primarily driven by brain reward system to accelerate learning. Recognizing the potential benefit of the neural representation of this reward design for novel RL architectures, we propose a RL algorithm based on [Formula: see text]-learning with a perspective on biomimetics (neuro-inspired RL) to decode rodent movement trajectories. The reward function, inspired by the neuronal information processing uncovered in the hippocampus, combines the preferred direction of pyramidal cell firing as the extrinsic reward signal with the coupling between pyramidal cell-interneuron pairs as the intrinsic reward signal. Our experimental results demonstrate that the neuro-inspired RL, with a combined use of extrinsic and intrinsic rewards, outperforms other spatial decoding algorithms, including RL methods that use a single reward function. The new RL algorithm could help accelerate learning convergence rates and improve the prediction accuracy for moving trajectories.

Ganoderic acid A from Ganoderma lucidum protects against alcoholic liver injury through ameliorating the lipid metabolism and modulating the intestinal microbial composition.

Alcoholic liver injury is mainly caused by long-term excessive alcohol consumption and has become a global public threat to human health. It is well known that Ganoderma lucidum has excellent beneficial effects on liver function and lipid metabolism. The object of this study was to investigate the hepatoprotective effects of ganoderic acid A (GAA, one of the main triterpenoids in G. lucidum) against alcohol-induced liver injury and reveal the underlying mechanisms of its protective effects. The results showed that oral administration of GAA significantly inhibited the abnormal elevation of the liver index, serum total triglyceride (TG), cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in mice exposed to alcohol intake, and also significantly protected the liver against alcohol-induced excessive lipid accumulation and pathological changes. Besides, alcohol-induced oxidative stress in the liver was significantly ameliorated by the dietary intervention of GAA through decreasing the hepatic levels of lactate dehydrogenase (LDH) and malondialdehyde (MDA), and increasing hepatic activities of catalase (CAT), superoxide dismutase (SOD), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and hepatic levels of glutathione (GSH). In addition, GAA intervention evidently ameliorated intestinal microbial disorder by markedly increasing the abundance of Muribaculaceae, Prevotellaceae, Jeotgalicoccus, Bilophila, Family_XIII_UCG_001, Aerococcus, Ruminococcaceae_UCG_005, Harryflintia, Christensenellaceae, Rumonpcpccaceae, Prevotelaceae_UCG_001, Clostridiales_vadinBB60_group, Parasutterella and Bifidobacterium, but decreasing the proportion of Lactobacillus, Burkholderia_Caballeroria_Paraburkholderia, Escherichia_Shigella and Erysipelatoclostridium. Furthermore, liver metabolomics based on UPLC-QTOF/MS demonstrated that oral administration of GAA had a significant regulatory effect on the composition of liver metabolites in mice exposed to alcohol intake, especially the levels of the biomarkers involved in the metabolic pathways of riboflavin metabolism, glycine, serine and threonine metabolism, pyruvate metabolism, glycolysis/gluconeogenesis, biosynthesis of unsaturated fatty acids, synthesis and degradation of ketone bodies, fructose and mannose metabolism. Moreover, dietary supplementation of GAA significantly regulated the hepatic mRNA levels of lipid metabolism and inflammatory response related genes. Conclusively, these findings demonstrate that GAA has beneficial effects on alleviating alcohol-induced liver injury and is expected to become a new functional food ingredient for the prevention of alcoholic liver injury.