High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of β2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts.

Key pointsPatients with diabetes show a blunted cardiac inotropic response to β-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs β-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac β2 -adrenergic receptor signalling and the impacts on cardiac contractile function. We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β-adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2 -adrenergic receptor phosphorylation at protein kinase A and G-protein receptor kinase sites in the myocardium. The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications.AbstractPatients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high-fat diet (HFD) on the insulin-adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD-fed mice displayed a significant elevation of phosphorylation of the β2 -adrenergic receptor (β2 AR) at both the protein kinase A site serine 261/262 and the G-protein-coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD-fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β2 AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD-fed mice. Together, these data indicate that HFD promotes phosphorylation of the β2 AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin-adrenergic signalling network might be effective in prevention of cardiac complications in diabetes

In Search of the Long-Tail: Systematic Generation of Long-Tail Knowledge via Logical Rule Guided Search

Since large language models have approached human-level performance on many tasks, it has become increasingly harder for researchers to find tasks that are still challenging to the models. Failure cases usually come from the long-tail distribution - data that an oracle language model could assign a probability on the lower end of its distribution. Current methodology such as prompt engineering or crowdsourcing are insufficient for creating long-tail examples because humans are constrained by cognitive bias. We propose a Logic-Induced-Knowledge-Search (LINK) framework for systematically generating long-tail knowledge statements. Grounded by a symbolic rule, we search for long-tail values for each variable of the rule by first prompting a LLM, then verifying the correctness of the values with a critic, and lastly pushing for the long-tail distribution with a reranker. With this framework we construct a dataset, Logic-Induced-Long-Tail (LINT), consisting of 200 symbolic rules and 50K knowledge statements spanning across four domains. Human annotations find that 84% of the statements in LINT are factually correct. In contrast, ChatGPT and GPT4 struggle with directly generating long-tail statements under the guidance of logic rules, each only getting 56% and 78% of their statements correct. Moreover, their "long-tail" generations in fact fall into the higher likelihood range, and thus are not really long-tail. Our findings suggest that LINK is effective for generating data in the long-tail distribution while enforcing quality. LINT can be useful for systematically evaluating LLMs' capabilities in the long-tail distribution. We challenge the models with a simple entailment classification task using samples from LINT. We find that ChatGPT and GPT4's capability in identifying incorrect knowledge drop by ~3% in the long-tail distribution compared to head distribution

Oriental melon roots metabolites changing response to the pathogen of Fusarium oxysporum f. sp. melonis mediated by Trichoderma harzianum

IntroductionTrichoderma spp. is a recognized bio-control agent that promotes plant growth and enhances resistance against soil-borne diseases, especially Fusarium wilt. It is frequently suggested that there is a relationship between resistance to melon wilt and changes in soil microbiome structures in the rhizosphere with plant metabolites. However, the exact mechanism remains unclear.MethodThis study aims to investigate the effects of Trichoderma application on the metabolic pathway of oriental melon roots in response to Fusarium oxysporum f. sp. melonis in a pot experiment. The experiment consisted of three treatments, namely water-treated (CK), FOM-inoculated (KW), and Trichoderma-applied (MM) treatments, that lasted for 25 days. Ultra-performance liquid chromatography-electron spray ionization-mass spectrometry (UPLC-ESI-MS) was used to analyze the compounds in melon roots.ResultsThe results show that Trichoderma harzianum application resulted in a reduction in the severity of oriental melon Fusarium wilt. A total of 416 distinct metabolites, categorized into four groups, were detected among the 886 metabolites analyzed. Additionally, seven differential metabolites were identified as key compounds being accumulated after inoculation with Fusarium oxysporum f. sp. melonis (FOM) and Trichoderma. The mechanism by which Trichoderma enhanced melon's resistance to Fusarium wilt was primarily associated with glycolysis/gluconeogenesis, phenylpropanoid biosynthesis, flavone and flavonol biosynthesis, and the biosynthesis of cofactors pathway. In comparison with the treatments of CK and MM, the KW treatment increased the metabolites of flavone and flavonol biosynthesis, suggesting that oriental melon defended against pathogen infection by increasing flavonol biosynthesis in the KW treatment, whereas the application of Trichoderma harzianum decreased pathogen infection while also increasing the biosynthesis of glycolysis/gluconeogenesis and biosynthesis of cofactors pathway, which were related to growth. This study also aims to enhance our understanding of how melon responds to FOM infection and the mechanisms by which Trichoderma harzianum treatment improves melon resistance at the metabolic level

NAT10 Maintains OGA mRNA Stability Through ac4C Modification in Regulating Oocyte Maturation

In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase(OGA) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA, we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein–coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a, Gm7788, Gm41780, Trpc7, Gm29036, and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation

Deacetylation of p53 induces autophagy by suppressing Bmf expression

Interferon γ (IFN-γ)–induced cell death is mediated by the BH3-only domain protein, Bik, in a p53-independent manner. However, the effect of IFN-γ on p53 and how this affects autophagy have not been reported. The present study demonstrates that IFN-γ down-regulated expression of the BH3 domain-only protein, Bmf, in human and mouse airway epithelial cells in a p53-dependent manner. p53 also suppressed Bmf expression in response to other cell death–stimulating agents, including ultraviolet radiation and histone deacetylase inhibitors. IFN-γ did not affect Bmf messenger RNA half-life but increased nuclear p53 levels and the interaction of p53 with the Bmf promoter. IFN-γ–induced interaction of HDAC1 and p53 resulted in the deacetylation of p53 and suppression of Bmf expression independent of p53’s proline-rich domain. Suppression of Bmf facilitated IFN-γ–induced autophagy by reducing the interaction of Beclin-1 and Bcl-2. Furthermore, autophagy was prominent in cultured bmf−/− but not in bmf+/+ cells. Collectively, these observations show that deacetylation of p53 suppresses Bmf expression and facilitates autophagy

Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts

Zhang J., Li J., Qu X., et al. Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts. Stem Cell Research and Therapy 14, 380 (2023); https://doi.org/10.1186/s13287-023-03560-9.Background: Heart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair. Methods: We applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling. Results: In vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group. Conclusions: We developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model

Agent-based Operation Strategy for Active Distribution Network Considering Energy Storage and Flexible Load

With the development of distributed energy resources (DERs) and the increasing flexibility in active distribution networks (ADNs), the economic operation of ADN components on both generation and demand sides to improve power self-consumption capability are required to be studied. In this paper, by considering the electricity price response of energy storage (ES) and flexible load (FL), an interactive and coordinated operation strategy for ADNs is presented based on a bi-level multi-agent system (MAS) structure. In the situation of power imbalance, each active component agent will be informed by higher level ADN agent and make their own response based on the technical operability and economical consideration. ADN agent will finally coordinate each participant and develop operation strategy by using the interactive benefit prioritization principle. The simulation results indicate that the proposed interactive coordination strategy can not only maximize the consumption of renewable energy, but also reduce the power imbalance and improve the economic operation of ADN.</p

Agent-based coordinated operation strategy for active distribution network with distributed energy resources

With the development of distributed energy resources (DERs) and the increasing flexibility in active distribution networks (ADNs), the economic operation of ADN coordinating both generation and demand sides is required to be studied. In this paper, considering the electricity price response of DER, a coordinated operation strategy for ADN is presented based on a bi-level agent framework. The DER agent makes their own response based on the technical operability and economic consideration, while the ADN agent will finally coordinate each participant by using the interactive benefit prioritization (IBP) principle. The simulation results indicate that the proposed strategy cannot only reduce the power imbalance but also improve the economic operation of ADN. Moreover, consumption of renewable energy is ameliorated as well.</p