Inhibition of LPS-Induced Skin Inflammatory Response and Barrier Damage via MAPK/NF-κB Signaling Pathway by Houttuynia cordata Thunb Fermentation Broth.

Houttuynia cordata Thunb is rich in active substances and has excellent antioxidant and anti-inflammatory activity. Scanning electron microscopy and gel permeation chromatography were used to analyze the molecular characteristics of the fermentation broth of Houttuynia cordata Thunb obtained through fermentation with Clavispora lusitaniae (HCT-f). The molecular weight of HCT-f was 2.64265 × 105 Da, and the polydispersity coefficient was 183.10, which were higher than that of unfermented broth of Houttuynia cordata Thunb (HCT). By investigating the active substance content and in vitro antioxidant activity of HCT-f and HCT, the results indicated that HCT-f had a higher active substance content and exhibited a superior scavenging effect on 2,2-diphenyl-1-picrylhydrazyl radicals and hydroxyl radicals, with IC50 values of 11.85% and 9.01%, respectively. Our results showed that HCT-f could effectively alleviate the increase in the secretion of inflammatory factors and apoptotic factors caused by lipopolysaccharide (LPS) stimulation, and had a certain effect on repairing skin barrier damage. HCT-f could exert an anti-inflammatory effect by down-regulating signaling in the MAPK/NF-κB pathway. The results of erythrocyte hemolysis and chicken embryo experiments showed that HCT-f had a high safety profile. Therefore, this study provides a theoretical basis for the application of HCT-f as an effective ingredient in food and cosmetics.

Graph Convolutional Networks With Adaptive Neighborhood Awareness.

Graph convolutional networks (GCNs) can quickly and accurately learn graph representations and have shown powerful performance in many graph learning domains. Despite their effectiveness, neighborhood awareness remains essential and challenging for GCNs. Existing methods usually perform neighborhood-aware steps only from the node or hop level, which leads to a lack of capability to learn the neighborhood information of nodes from both global and local perspectives. Moreover, most methods learn the nodes' neighborhood information from a single view, ignoring the importance of multiple views. To address the above issues, we propose a multi-view adaptive neighborhood-aware approach to learn graph representations efficiently. Specifically, we propose three random feature masking variants to perturb some neighbors' information to promote the robustness of graph convolution operators at node-level neighborhood awareness and exploit the attention mechanism to select important neighbors from the hop level adaptively. We also utilize the multi-channel technique and introduce a proposed multi-view loss to perceive neighborhood information from multiple perspectives. Extensive experiments show that our method can better obtain graph representation and has high accuracy.

Flare: An FPGA-Based Full Precision Low Power CNN Accelerator with Reconfigurable Structure.

Convolutional neural networks (CNNs) have significantly advanced various fields; however, their computational demands and power consumption have escalated, posing challenges for deployment in low-power scenarios. To address this issue and facilitate the application of CNNs in power constrained environments, the development of dedicated CNN accelerators is crucial. Prior research has predominantly concentrated on developing low precision CNN accelerators using code generated from high-level synthesis (HLS) tools. Unfortunately, these approaches often fail to efficiently utilize the computational resources of field-programmable gate arrays (FPGAs) and do not extend well to full precision scenarios. To overcome these limitations, we integrate vector dot products to unify the convolution and fully connected layers. By treating the row vector of input feature maps as the fundamental processing unit, we balance processing latency and resource consumption while eliminating data rearrangement time. Furthermore, an accurate design space exploration (DSE) model is established to identify the optimal design points for each CNN layer, and dynamic partial reconfiguration is employed to maximize each layer's access to computational resources. Our approach is validated through the implementation of AlexNet and VGG16 on 7A100T and ZU15EG platforms, respectively. We achieve an average convolutional layer throughput of 28.985 GOP/s and 246.711 GOP/s for full precision. Notably, the proposed accelerator demonstrates remarkable power efficiency, with a maximum improvement of 23.989 and 15.376 times compared to current state-of-the-art FPGA implementations.

Adaptive Fuzzy Tracking Control With Global Prescribed-Time Prescribed Performance for Uncertain Strict-Feedback Nonlinear Systems.

For strict-feedback systems with mismatched uncertainties, adaptive fuzzy control techniques are developed to provide global prescribed performance with prescribed-time convergence. First, a class of prescribed-time prescribed performance functions are designed to quantify the performance constraints of the tracking error. Additionally, a novel error transformation function is provided to eliminate the initial value limitations and resolve the singularity issue in previous research. To ensure the convergence of the tracking error into a prescribed bounded region within a prescribed time and satisfactory transient performance, controllers with or without approximating structures are established. Notably, the settling time and initial condition of the prescribed performance function are completely independent of the initial tracking error and system parameters, thereby improving upon existing results. Furthermore, the disadvantage of the semi-global boundedness of tracking error induced by dynamic surface control can be eliminated through the use of a novel Lyapunov-like energy function. Finally, the effectiveness of the proposed strategies is validated through numerical simulations performed on practical examples.

Ginsenoside Rh2 enhances immune surveillance of natural killer (NK) cells via inhibition of ERp5 in breast cancer.

BACKGROUND: One critical component of the immune system that prevents breast cancer cells from forming distant metastasis is natural killer (NK) cells participating in immune responses to tumors. Ginsenoside Rh2 (GRh2) as one of the major active ingredients of ginseng has been employed in treatment of cancers, but the function of GRh2 in modulating the development of breast cancer remains elusive. PURPOSE: This study was to dissect the effect of GRh2 against breast cancer and its potential mechanisms associated with NK cells, both in vitro and in vivo. METHODS: MDA-MB-231 and 4T1 cells were used to establish in situ and hematogenous mouse models. MDA-MB-231 and MCF-7 were respectively co-cultured with NK92MI cells or primary NK cells in vitro. Anti-tumor efficacy of GRh2 was verified by immunohistochemistry (IHC), Cell Counting Kit-8 (CCK8), high resolution micro-computed tomography (micro-CT) scanning of lungs and hematoxylin and eosin (H&E) staining. Lactate dehydrogenase (LDH) cytotoxicity assay, flow cytometry, in vivo depletion of NK cells, enzyme-linked immunosorbent assay (ELISA), western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence and cell transfection were performed for investigating the anti-tumor mechanisms of GRh2. Molecular docking, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) were employed to determine the binding between endoplasmic reticulum protein 5 (ERp5) and GRh2. RESULTS: We demonstrated that GRh2 exerted prominent impacts on retarding the growth and metastasis of breast cancer through boosting the cytotoxic function of NK cells, as validated by the elevated release of perforin, granzyme B and interferon-γ (IFN-γ). Mechanistical studies revealed that GRh2 was capable of diminishing the expression of ERp5 and GRh2 directly bound to ERp5 in MDA-MB-231 cells as well as on a recombinant protein level. GRh2 prevented the formation of soluble MICA (sMICA) and upregulated the expression level of MICA in vivo and in vitro. Importantly, the reduced lung metastasis of breast cancer by GRh2 was almost abolished upon the depletion of NK cells. Moreover, GRh2 was able to insert into the binding pocket of ERp5 directly. CONCLUSION: We firstly demonstrated that GRh2 played a pivotal role in augmenting NK cell activity by virtue of modulating the NKG2D-MICA signaling axis via directly binding to ERp5, and may be further optimized to a therapeutic agent for the treatment of breast cancer.

Fast Determination of Optimal Transmission Rate for Wireless Blockchain Networks: A Graph Convolutional Neural Network Approach.

One of the primary challenges in wireless blockchain networks is to ensure security and high throughput with constrained communication and energy resources. In this paper, with curve fitting on the collected blockchain performance dataset, we explore the impact of the data transmission rate configuration on the wireless blockchain system under different network topologies, and give the blockchain a utility function which balances the throughput, energy efficiency, and stale rate. For efficient blockchain network deployment, we propose a novel Graph Convolutional Neural Network (GCN)-based approach to quickly and accurately determine the optimal data transmission rate. The experimental results demonstrate that the average relative deviation between the blockchain utility obtained by our GCN-based method and the optimal utility is less than 0.21%.

A Multichannel Convolutional Decoding Network for Graph Classification.

Graph convolutional networks (GCNs) have shown superior performance on graph classification tasks, and their structure can be considered as an encoder-decoder pair. However, most existing methods lack the comprehensive consideration of global and local in decoding, resulting in the loss of global information or ignoring some local information of large graphs. And the commonly used cross-entropy loss is essentially an encoder-decoder global loss, which cannot supervise the training states of the two local components (encoder and decoder). We propose a multichannel convolutional decoding network (MCCD) to solve the above-mentioned problems. MCCD first adopts a multichannel GCN encoder, which has better generalization than a single-channel GCN encoder since different channels can extract graph information from different perspectives. Then, we propose a novel decoder with a global-to-local learning pattern to decode graph information, and this decoder can better extract global and local information. We also introduce a balanced regularization loss to supervise the training states of the encoder and decoder so that they are sufficiently trained. Experiments on standard datasets demonstrate the effectiveness of our MCCD in terms of accuracy, runtime, and computational complexity.

Risk Correlation Analysis between Polycystic Ovary Syndrome (PCOS) and Serum Visfatin Levels in Middle-Aged Women: Systematic Review and Meta-Analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine disorder that occurs frequently in women of childbearing age and is associated with insulin resistance. Serum visfatin can affect insulin resistance by binding to insulin receptors and further affect the occurrence and development of PCOS. In this study, we investigated the current status of serum visfatin levels in patients with PCOS through a literature search and meta-analysis. METHODS: We searched online Pubmed, Embase, Web of Science, the Cochrane Library, CNKI (China National Knowledge Infrastructure), CBMdisc (China Biology Medicine disc) databases and registered websites such as the ICTRP (International Clinical Trial Registration Platform) and clinicaltrials.gov (https://clinicaltrials.gov/) for case-control studies on PCOS and visfatin levels, assessed the quality of the included articles with the Newcastle-Ottawa Scale (NOS scale), and combined the comparison of serum visfatin levels between patients with PCOS and healthy individuals from high-quality studies. RESULTS: 20 research papers were included in the quantitative analysis of this study. The combined analysis showed that obese patients with PCOS had statistically significantly higher visfatin levels than healthy people [MD (mean difference) = 12.94, 95% CI (confidence interval) (6.52-19.37), Z = 3.95, p < 0.0001]. Visfatin levels were higher in non-obese patients with PCOS than in healthy people and are statistically significant [MD = 14.98, 95% CI (5.80-24.16), Z = 3.20, p = 0.001]. Heterogeneity in the combined analysis was not related to study location, the publication year of the literature, source of serum samples, but was influenced by the quality of the literature. After excluding the most influential papers, the combined analysis was conducted again, and the conclusion was consistent with that before the exclusion. The results of Egger's test showed no significant publication bias. CONCLUSIONS: High serum visfatin levels are a natural feature of PCOS and are not associated with obesity; Serum visfatin levels may be a potential marker for the diagnosis of PCOS, but their relationship with PCOS and insulin resistance remains worthy of in-depth investigation.

Analysis of the relationship between supply-demand matching of selected ecosystem services and urban spatial governance: a case study of Suzhou, China.

The mismatch between the supply and demand of ecosystem services has become a critical cause of the decline of urban ecological security. Studying the supply-demand matching of ecosystem services and exploring its association with urban spatial governance are imperative for ensuring sustainable urbanization. Taking Suzhou City as a case, the supply and demand values and matching degrees of five selected ecosystem services were assessed. Additionally, we explored the relationship between ecosystem services and urban spatial governance, with a focus on urban functional zoning. The findings indicate that first, the supply value of water production, food production, carbon sequestration, and tourism and leisure fall short of the demand value, while the supply value of air purification exceeds the demand value. The spatial matching of supply and demand shows a typical circular structure, with areas in short supply predominantly located in the downtown area and its vicinity. Second, the degree of coupling coordination between the supply-demand ratio of selected ecosystem services and the intensity of ecological control is low. Urban functional zoning can affect the supply-demand relationship of selected ecosystem services, and intensified development efforts can exacerbate the mismatch between supply and demand. Third, research on the supply-demand matching of selected ecosystem services can facilitate the assessment and regulation of urban functional zoning. Urban spatial governance can be regulated based on land use, industry, and population, with a focus on achieving a better supply-demand matching of ecosystem services. Through the analysis, this paper is aimed to provide reference for mitigating urban environmental problems and formulating sustainable urban development strategies.

Pseudomonas aeruginosa isolation is an important predictor for recurrent hemoptysis after bronchial artery embolization in patients with idiopathic bronchiectasis: a multicenter cohort study.

BACKGROUND: Nearly half of bronchiectasis patients receiving bronchial artery embolization (BAE) still have recurrent hemoptysis, which may be life-threatening. Worse still, the underlying risk factors of recurrence remain unknown. METHODS: A retrospective cohort was conducted of patients with idiopathic bronchiectasis who received BAE from 2015 to 2019 at eight centers. Patients were followed up for at least 24 months post BAE. Based on the outcomes of recurrent hemoptysis and recurrent severe hemoptysis, a Cox regression model was used to identify risk factors for recurrence. RESULTS: A total of 588 individuals were included. The median follow-up period was 34.0 months (interquartile range: 24.3-53.3 months). The 1-month, 1-year, 2-year, and 5-year cumulative recurrent hemoptysis-free rates were 87.2%, 67.5%, 57.6%, and 49.4%, respectively. The following factors were relative to recurrent hemoptysis: 24-h sputum volume (hazard ratio [HR] = 1.99 [95% confidence interval [95% CI]: 1.25-3.15, p = 0.015]), isolation of Pseudomonas aeruginosa (HR = 1.50 [95% CI: 1.13-2.00, p = 0.003]), extensive bronchiectasis (HR = 2.00 [95% CI: 1.29-3.09, p = 0.002]), and aberrant bronchial arteries (AbBAs) (HR = 1.45 [95% CI: 1.09-1.93, p = 0.014]). The area under the receiver operating characteristic curve of the nomogram was 0.728 [95% CI: 0.688-0.769]. CONCLUSIONS: Isolation of Pseudomonas aeruginosa is an important independent predictor of recurrent hemoptysis. The clearance of Pseudomonas aeruginosa might effectively reduce the hemoptysis recurrence rate.

Polydopamine-coated thalidomide nanocrystals promote DSS-induced murine colitis recovery through Macrophage M2 polarization together with the synergistic anti-inflammatory and anti-angiogenic effects.

High levels of proinflammatory cytokines, macrophage polarization status and immune-mediated angiogenesis play pivotal roles in the pathogenesis of inflammatory bowel disease (IBD). Thalidomide, an anti-inflammatory, immunomodulatory and antiangiogenic agent, is used off-label for treatment of IBD. The therapeutic potential of thalidomide is limited by its poor solubility and side effects associated with its systemic exposure. To address these issues and promote its therapeutic effects on IBD, thalidomide nanocrystals (Thali NCs) were prepared and coated with polydopamine (PDA), a potential macrophage polarization modulator, to form PDA coated Thali NCs (Thali@PDA). Thali@PDA possessed a high drug loading and displayed average particle size of 764.7 ± 50.30 nm. It showed a better anti-colitis effect than bare thalidomide nanocrystals at the same dose of thalidomide. Synergistic effects of polydopamine on anti-inflammatory and anti-angiogenic activities of thalidomide were observed. Furthermore, PDA coating could direct polarization of macrophages towards M2 phenotype, which boosted therapeutic effects of Thali@PDA on IBD. Upon repeated dosing of Thali@PDA for one week, symptoms of IBD in mice were significantly relieved, and histomorphology of the colitis colons were normalized. Key proinflammatory cytokine levels in the inflamed intestines were significantly decreased. Toxicity study also revealed that Thali@PDA is a safe formulation.

Specimen mammography for intraoperative margin assessment in breast conserving surgery: a meta-analysis.

In breast conserving surgery (BCS), specimen mammography is one of the most widely used intraoperative methods of assessing margin status. We performed a meta-analysis to evaluate the diagnostic accuracy of specimen mammography. Literature databases including PubMed, Cochrane Library, Web of Science, and EMBASE were searched prior to Jun 2022. A total of 1967 patients were included from 20 studies. A pooled analysis, heterogeneity testing, threshold effect testing, publication bias analysis, and subgroup analyses were performed from extracted data. The pooled weighted values were a sensitivity of 0.55 (95% confidence interval [CI], 0.47-0.63), a specificity of 0.85 (95% CI, 0.78-0.90), a diagnostic odds ratio of 7 (95% CI, 4-12), and a pooled positive likelihood ratio of 3.7 (95% CI 2.6-5.5). The area under the receiver operator characteristic curve was 0.75 (95% CI 0.71-0.78). In the subgroup analysis, the pooled specificity in the positive margin defined as tumor at margin subgroup was lower than the other positive margin definition subgroup (0.82 [95% CI: 0.71, 0.92] vs. 0.87 [95% CI: 0.80, 0.94], p = 0.01). Our findings indicated that specimen mammography was an accurate intraoperative imaging technique for margin assessment in BCS.

Research on Risk Contagion among Financial Submarkets in China Based on Complex Networks.

As the COVID-19 outbreak has an impact on the global economy, there will be interest in how China's financial markets function during the outbreak. To investigate the path of risk contagion in China's financial sub-markets before and after the COVID-19 outbreak, we divided the 2016-2021 period into two phases. Based on the time of the COVID-19 outbreak, we divided the new stage of economic development into pre-epidemic and post-epidemic stages and employed the DCC-GARCH model to investigate the dynamic correlation coefficients among the financial sub-markets in China. Furthermore, we employed complex network theory and the minimum tree model to describe the risk contagion path between two-stage Chinese financial submarkets. Finally, we provided pertinent recommendations for investors and policymakers and conducted a brief discussion based on the findings of the research.

The association of healthy eating index with periodontitis in NHANES 2013-2014.

Background: Periodontal disease is very common worldwide and is one of the main causes of tooth loss in adults. Periodontal disease is characterized by chronic inflammation that can destroy adjacent alveolar bone and lead to a loss of periodontal ligaments. Although previous studies have found that a daily diet can influence the development of periodontal disease (e.g., a diet low in carbohydrates and rich in vitamins C and D and fiber can have a protective effect). Periodontal disease may present as gingivitis or periodontitis. However, studies on the role of healthy eating index in periodontitis are lacking. The purpose of this study was to assess the association between healthy eating index and periodontitis. Methods: We analyzed data collected from participants in the National Health and Nutrition Examination Survey (NHANES), a nationally representative survey conducted in 2-year cycles from 2013 to 2014. As part of our analysis, we developed multivariate logistic regression models to examine the independent association between the healthy eating index and periodontitis. We evaluated the significance of association using odds ratios (OR) with 95% confidence intervals (95%CI). Results: Individuals with a lower total healthy eating index had a higher prevalence of periodontitis. Adjusted multivariate regression models showed that a higher healthy diet index was associated with a lower prevalence of periodontitis (OR = 0.69, 95% CI: 0.55-0.86, P < 0.05). Conclusion: The results of the study showed that dietary structure was associated with the prevalence of periodontitis. Patients with a higher healthy eating index had a lower prevalence of periodontitis. These findings will need to be confirmed by longitudinal, prospective studies in the future.

Sevelamer arsenite nanoparticle as a Pi-responsive drug carrier and embolic agent for chemoembolization.

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

The E484K Substitution in a SARS-CoV-2 Spike Protein Subunit Vaccine Resulted in Limited Cross-Reactive Neutralizing Antibody Responses in Mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially emerging variants, poses an increased threat to global public health. The significant reduction in neutralization activity against the variants such as B.1.351 in the serum of convalescent patients and vaccinated people calls for the design of new potent vaccines targeting the emerging variant. However, since most vaccines approved and in clinical trials are based on the sequence of the original SARS-CoV-2 strain, the immunogenicity and protective efficacy of vaccines based on the B.1.351 variant remain largely unknown. In this study, we evaluated the immunogenicity, induced neutralization activity, and protective efficacy of wild-type spike protein nanoparticle (S-2P) and mutant spike protein nanoparticle (S-4M-2P) carrying characteristic mutations of B.1.351 variant in mice. Although there was no significant difference in the induction of spike-specific IgG responses in S-2P- and S-4M-2P-immunized mice, neutralizing antibodies elicited by S-4M-2P exhibited noteworthy, narrower breadth of reactivity with SARS-CoV-2 variants compared with neutralizing antibodies elicited by S-2P. Furthermore, the decrease of induced neutralizing antibody breadth at least partly resulted from the amino acid substitution at position 484. Moreover, S-4M-2P vaccination conferred insufficient protection against live SARS-CoV-2 virus infection, while S-2P vaccination gave definite protection against SARS-CoV-2 challenge in mice. Together, our study provides direct evidence that the E484K substitution in a SARS-CoV-2 subunit protein vaccine limited the cross-reactive neutralizing antibody breadth in mice and, more importantly, draws attention to the unfavorable impact of this mutation in spike protein of SARS-CoV-2 variants on the induction of potent neutralizing antibody responses.

Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin.

It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.

Co-deficiency of B7-H3 and B7-H4 identifies high CD8 + T cell infiltration and better prognosis in pancreatic cancer.

BACKGROUND: Immunotherapy is a novel hotspot for the treatment of pancreatic adenocarcinoma (PAAD). However, potential biomarkers which could identify the inflamed tumor microenvironment (TME) are urgently required. METHODS: In the present study, we measured the levels of B7-H3, B7-H4, and major tumor-infiltrating immune cells (TIICs) using bioinformatics analyses and immunohistochemistry (IHC) staining on PAAD samples represented in the tissue microarray (TMA) format. Statistical analysis and figures exhibition were performed using R 4.1.0, SPSS 26.0, and GraphPad Prism 6.0. RESULTS: B7-H3 and B7-H4 were up-regulated in PAAD compared with para-tumor tissues, and their expression exhibited no tight correlation in PAAD tissues. B7-H3 and B7-H4 were lowly expressed in well-differentiated PAAD tissues and correlated with poorly differentiated grades. Besides, single B7-H3 or B7-H4 expression exhibited limited prognostic value, but co-deficiency of B7-H3 and B7-H4 predicted a better prognosis in PAAD. Moreover, co-deficiency of B7-H3 and B7-H4 indicated immuno-hot tumors with high CD8 + T cell infiltration. CONCLUSIONS: Overall, combined B7-H3 and B7-H4 expression is a promising stratification strategy to assess prognosis and immunogenicity in PAAD, which could be used as a novel classifier in clinical practice.

MiR-195 promotes pancreatic ß-cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in type 2 diabetes.

OBJECTIVE: The aim of this study was to research the role and underlying mechanism of miR-195 involved in pancreatic ß-cell dedifferentiation induced by hyperlipemia in type 2 diabetes mellitus. METHODS: High-fat-diet-induced obese C57BL/6J mice and palmitate-stimulated Min6 cells were used as the models of ß-cell dedifferentiation in vivo and in vitro, respectively. The expression of miR-195 and insulin secretion during ß-cell dedifferentiation were measured. Also, the influence of regulated miR-195 expression on ß-cell dedifferentiation was examined. Meanwhile, the IRS-1/2/Pi3k/Akt pathway and mitofusin-2 (Mfn2) expression were investigated during ß-cell dedifferentiation. RESULTS: MiR-195 was upregulated during lipotoxicity-induced ß-cell dedifferentiation in both in vivo and in vitro experiments, and miR-195 functionally contributed to lipotoxicity-induced ß-cell dedifferentiation. Furthermore, miR-195 inhibited IRS-1/2/Pi3k/Akt pathway activation, which accompanied ß-cell dedifferentiation. Mfn2, a target of miR-195, was found to be downregulated and was associated with increased mitochondrial production of reactive oxygen species during ß-cell dedifferentiation. Instructively, inhibition of miR-195, at least partially, reversed the downregulation of Mfn2, restored IRS-1/2/Pi3k/Akt pathway activation, and prevented ß-cell dedifferentiation. CONCLUSIONS: MiR-195 promoted ß-cell dedifferentiation through negatively regulating Mfn2 expression and inhibiting the IRS-1/2/Pi3k/Akt pathway, providing a promising treatment for type 2 diabetes mellitus.