Effect of the changes of NMDA receptor in hypothalamic paraventricular nucleus on cardiac function and sympathetic nervous activity in rats with heart failure.

OBJECTIVE: To observe the effect of the changes of n-methyl-d-aspartate receptor 1 (NMDAR1), tyrosine hydroxylase (TH), and glutamic acid decarboxylase 67 (GAD67) in the hypothalamic paraventricular nucleus (PVN) on cardiac function and sympathetic nervous activity in rats with heart failure (HF). METHODS: Thirty-six adult male SD rats were randomly divided into the heart failure group (HF), the heart failure + NMDA receptors agonist AP5 intervention group (HF-AP5), and the Sham-operation group (SO) (n = 12). HF model in SD rats was induced by ligation of left coronary artery. AP5 (0.02 µg/h) was administrated by the paraventricular nucleus subsequently for 4 weeks. The cardiac function, renal sympathetic nerve activity (RSNA), lung/body weight ratio (L/BW), and right ventricle/body weight ratio (RV/BW), as well as the plasma noradrenaline (NE) and Angiotensin II (Ang II) level and the expressions of NMDAR1, GAD67, and TH in PVN, in different groups were recorded 4 weeks after the establishment of HF model. RESULTS: After the coronary artery was ligated, LVEDP was increased, ±dp/dt max and LVEF were decreased, lung/BW and RV/BW were raised. RSNA, Ang II and NE were raised. Expression of NMDAR1 and TH were increased, but GAD67 was decreased. The levels of LVEDP, lung/BW, and RV/BW in group HF-AP5 were reduced while ± dp/dtmax was increased after the treatment. The blood Ang II and NE content was decreased, RSNA was reduced, expression of NMDAR1 and TH were downregulated, but GAD67 was upregulated. CONCLUSIONS: NMDAR1 is significantly activated in PVN of HF rats, the activity of TH is increased, GAD67 is downregulated, RSNA is increased, and the heart function is decreased. NMDA receptor blockers can alleviate HF.

Antigen-specific T cell response from dendritic cell vaccination using side population cell-associated antigens targets hepatocellular carcinoma.

Dendritic cell (DC) vaccination targeting cancer stem cells is an effective way to suppress tumor progression and reduce the metastasis and recurrence. In the present study, we explored the suitability of side population (SP) cells as source of antigens for DC vaccination against hepatocellular carcinoma (HCC) in a mouse model. In this study, we identified the "stem-like" characteristics of SP cells in the MHCC97 and Hepa 1-6 HCC cell lines. We found that SP cells express high levels of tumor-associated antigens and MHC class I molecules. Although loading with cell lysates did not change the characteristics of DCs, SP cell lysate-pulsed DCs induced antigen-specific T cell responses, including T cell proliferation and increased IFN-γ production by stimulated CD8(+) T cells. We investigated the cytotoxicity of T cells stimulated by SP cell lysate-pulsed DCs in nude mice co-injected with MHCC97 cells. To mimic the in vivo environment, we also confirmed the result in mouse HCC cell line Hepa 1-6 induced tumor-bearing C57/BL6 immune competent mice, and we demonstrated that vaccination with DCs loaded with Hepa 1-6 SP cell lysates could induce a T cell response in vivo and suppress the tumor growth. Our results may have applications for anti-HCC immunotherapy by targeting the cancer stem cells and may provide new insight for cancer vaccines.

Single-cell RNA sequencing reveals S100a9hi macrophages promote the transition from acute inflammation to fibrotic remodeling after myocardial ischemia‒reperfusion.

Rationale: The transition from acute inflammation to fibrosis following myocardial ischemia‒reperfusion (MIR) significantly affects prognosis. Macrophages play a pivotal role in inflammatory damage and repair after MIR. However, the heterogeneity and transformation mechanisms of macrophages during this transition are not well understood. Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) and mass cytometry to examine murine monocyte-derived macrophages after MIR to investigate macrophage subtypes and their roles in the MIR process. S100a9-/- mice were used to establish MIR model to clarify the mechanism of alleviating inflammation and fibrosis after MIR. Reinfusion of bone marrow-derived macrophages (BMDMs) after macrophage depletion (MD) in mice subjected to MIR were performed to further examine the role of S100a9hi macrophages in MIR. Results: We identified a unique subtype of S100a9hi macrophages that originate from monocytes and are involved in acute inflammation and fibrosis. These S100a9hi macrophages infiltrate the heart as early as 2 h post-reperfusion and activate the Myd88/NFκB/NLRP3 signaling pathway, amplifying inflammatory responses. As the tissue environment shifts from proinflammatory to reparative, S100a9 activates transforming growth factor-ß (Tgf-ß)/p-smad3 signaling. This activation not only induces the transformation of myocardial fibroblasts to myofibroblasts but also promotes fibrosis via the macrophage-to-myofibroblast transition (MMT). Targeting S100a9 with a specific inhibitor could effectively mitigate acute inflammatory damage and halt the progression of fibrosis, including MMT. Conclusion: S100a9hi macrophages are a promising therapeutic target for managing the transition from inflammation to fibrosis after MIR.

Effects of Childhood Maltreatment on Self-Compassion: A Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review aims to estimate the extent to which childhood maltreatment influences self-compassion in later life. METHOD: Four English databases (Web of Science, PsycINFO, PubMed, and PsycARTICLES) and three Chinese databases (China National Knowledge Infrastructure, Wanfang, and Weipu) were systematically searched. We extracted data related to the associations between child maltreatment and self-compassion and pooled them using random effect models. FINDINGS: A total of 20 eligible studies were included involving 6,877 participants in the analyses. Overall child maltreatment was negatively related to self-compassion (r = -.28, p < .001); emotional abuse and neglect were negatively related to self-compassion (r = -.28, p < .01; r = -.31, p < .01, respectively) at a moderate level; and physical abuse, sexual abuse, and physical neglect were negatively related to self-compassion (r = -.12, p < .01; r = -.10, p < .01; and r = -.22, p < .001, respectively) at a small level. CONCLUSION: The results indicate that overall and subtypes of maltreatment are associated with decreased self-compassion, and child intervention programs focused on self-compassion should be designed to protect the well-being of individuals with a history of childhood maltreatment.

Scalable and Parallel Deep Bayesian Optimization on Attributed Graphs.

We propose a general and scalable global optimization framework directly operating on annotated graph data by introducing a Bayesian graph neural network to approximate the expensive-to-evaluate objectives. It prevents the cubical complexity of Gaussian processes and can scale linearly with the number of observations. Its parallelized variant makes it scalable. We provide strict theoretical support on its convergence. Intensive experiments conducted on both artificial and real-world problems, including molecular discovery and urban road network design, demonstrate the effectiveness of the proposed methods compared with the current state of the art.

IGFBP-3 Is the Key Target of Sanguinarine in Promoting Apoptosis in Hepatocellular Carcinoma.

INTRODUCTION: Chemotherapeutic treatment of hepatocellular carcinoma (HCC) has always been plagued by nonspecific and side effects. Plant extracts have potential anticancer capabilities with low cytotoxicity and few side effects, but their detailed mechanisms are still unclear, thus limiting their clinical applications. METHODS: In this study, five plant extracts were chosen, their inhibition on HCC cell viability was compared by CCK-8 assay and sanguinarine (SAN) was selected. Then, wound healing assay, transwell assay, and apoptosis assay were carried out in Hep3B cells. Bioinformatics methods were performed and IGFBP-3 was predicted the targets of SAN in HCC. The mechanism of SAN regulating IGFBP-3 was explored using qRT-PCR, Western blotting, cell viability assay and apoptosis assay. Meanwhile, knockdown of IGFBP-3 were used by small interfering RNA (siRNA). RESULTS: In five plant extracts, SAN inhibited the proliferation of HCC cell lines most considerably. In addition, apoptosis was promoted, and invasion and migration were inhibited in the Hep3B cell line by treatment with SAN at 2 µM. Bioinformatics indicated that SAN could affect HCC apoptosis through the TP53/IGFBP-3 pathway, and further verification experiments showed that SAN upregulated the expression of insulin-like growth factor binding protein-3 (IGFBP-3) in the Hep3B cell line; SAN also inhibited the expression of Bcl-2 and promoted the expression of BAX and caspase-3. After using siRNA to inhibit the expression of IGFBP-3, the effect of SAN was blocked. CONCLUSION: Our study further reveals a novel mechanism that IGFBP-3 is an important target of SAN, by upregulating expression of IGFBP-3, SAN promotes apoptosis in HCC.

A Multi-Objective Compounded Local Mobile Cloud Architecture Using Priority Queues to Process Multiple Jobs.

As a result of the greatly increased use of mobile devices, the disadvantages of portable devices have gradually begun to emerge. To solve these problems, the use of mobile cloud computing assisted by cloud data centers has been proposed. However, cloud data centers are always very far from the mobile requesters. In this paper, we propose an improved multi-objective local mobile cloud model: Compounded Local Mobile Cloud Architecture with Dynamic Priority Queues (LMCpri). This new architecture could briefly store jobs that arrive simultaneously at the cloudlet in different priority positions according to the result of auction processing, and then execute partitioning tasks on capable helpers. In the Scheduling Module, NSGA-II is employed as the scheduling algorithm to shorten processing time and decrease requester cost relative to PSO and sequential scheduling. The simulation results show that the number of iteration times that is defined to 30 is the best choice of the system. In addition, comparing with LMCque, LMCpri is able to effectively accommodate a requester who would like his job to be executed in advance and shorten execution time. Finally, we make a comparing experiment between LMCpri and cloud assisting architecture, and the results reveal that LMCpri presents a better performance advantage than cloud assisting architecture.